TW202346293A - Nitrogen-containing heterocyclic derivative, and composition and pharmaceutical application thereof - Google Patents

Nitrogen-containing heterocyclic derivative, and composition and pharmaceutical application thereof Download PDF

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TW202346293A
TW202346293A TW112115902A TW112115902A TW202346293A TW 202346293 A TW202346293 A TW 202346293A TW 112115902 A TW112115902 A TW 112115902A TW 112115902 A TW112115902 A TW 112115902A TW 202346293 A TW202346293 A TW 202346293A
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張晨
廖雨亭
徐進雄
余彥
唐平明
鄒思佳
陳孝剛
高秋
程新帆
李宇鵬
李瑤
嚴龐科
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大陸商四川海思科製藥有限公司
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The present invention relates to a compound represented by general formula (I) or a stereoisomer, a deuterated product, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a co-crystal thereof, an intermediate thereof, and use thereof in AR-related diseases such as cancer. B-L-K (I).

Description

含氮雜環衍生物及其組合物和藥學上的應用Nitrogen-containing heterocyclic derivatives and their compositions and pharmaceutical applications

本發明涉及一種通式(I)的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，及其中間體和製備方法，以及在AR相關疾病如癌症疾病中的用途。The present invention relates to a compound of general formula (I) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, intermediates and preparation methods thereof, and Use in AR-related diseases such as cancer diseases.

雄激素受體 (Androgen receptor, AR) 是一種激素核受體，結構上可劃分為N-端活化區域 (NTD)、DNA結合區域 (DBD) 和配體結合區域 (LTD)，能夠調節誘發前列腺癌的基因表達，因此，抑制雄激素受體是治療前列腺癌的有效方法。目前上市的雄激素受體抑制劑如恩雜魯胺、比卡魯胺等主要是通過與雄激素受體的配體結合區域 (LTD) 作用發揮抑制效果，但部分患者在治療過程中會出現由於LTD片段缺失的雄激素受體剪切突變體 (Androgen receptor splice variants, AR-Vs) 導致的耐藥現象。臨床前研究表明，雄激素受體剪切突變體能加快恩雜魯胺耐藥的前列腺癌進展，如何解決其耐藥問題成為臨床醫學的關注點。Androgen receptor (AR) is a hormone nuclear receptor that can be structurally divided into N-terminal activation domain (NTD), DNA binding domain (DBD) and ligand binding domain (LTD), which can regulate the induction of prostate cancer. Cancer gene expression, therefore, inhibiting androgen receptors is an effective method to treat prostate cancer. The androgen receptor inhibitors currently on the market, such as enzalutamide and bicalutamide, mainly exert inhibitory effects by interacting with the ligand-binding domain (LTD) of the androgen receptor, but some patients may experience symptoms during treatment. Resistance occurs due to Androgen receptor splice variants (AR-Vs) lacking the LTD segment. Preclinical studies have shown that androgen receptor splice mutants can accelerate the progression of enzalutamide-resistant prostate cancer. How to solve the problem of resistance has become a focus of clinical medicine.

小分子降解劑是一種利用機體泛素-蛋白酶體系統 (UPS) 對靶蛋白進行定向降解的藥物。小分子降解劑憑藉獨特的催化機制，可以靶向難以成藥的靶點，解決藥物耐藥問題，目前在腫瘤、自身免疫性疾病等藥物研發領域是一大熱點。Small molecule degraders are drugs that utilize the body's ubiquitin-proteasome system (UPS) for targeted degradation of target proteins. With its unique catalytic mechanism, small molecule degraders can target difficult-to-drug targets and solve the problem of drug resistance. They are currently a hot topic in the field of drug research and development such as tumors and autoimmune diseases.

PROTAC (proteolysis targeting chimera) 分子是一類能夠同時結合靶向蛋白和E3泛素連接酶的雙功能化合物，此類化合物能夠被細胞的蛋白酶體識別，引起靶向蛋白的降解，能夠有效地降低靶向蛋白在細胞中的含量。通過在PROTAC分子引入能結合不同靶向蛋白的配體，使PROTAC技術應用於各種疾病的治療成為可能，該技術近年來同時得到了廣泛的關注。PROTAC (proteolysis targeting chimera) molecules are a type of bifunctional compounds that can simultaneously bind to targeting proteins and E3 ubiquitin ligases. Such compounds can be recognized by the proteasome of cells, causing the degradation of targeting proteins, and can effectively reduce targeting Protein content in cells. By introducing ligands that can bind to different target proteins into PROTAC molecules, it is possible to apply PROTAC technology to the treatment of various diseases. This technology has also received widespread attention in recent years.

分子膠 (molecular glue) 是一類促使靶蛋白和和E3泛素連接酶接觸，誘導兩者之間產生相互作用，從而導致靶蛋白降解的小分子。從功能性的角度說，分子膠主要是通過填補靶蛋白和E3泛素連接酶的空隙，增強二者的結合介面促進兩者之間發生強相互作用 ( Nat. Commun., 2022, 13, 815)。與傳統的小分子抑制劑相比，分子膠具有催化形式驅動靶蛋白降解和無需在靶蛋白上有結合口袋的優點，具有作用於不可成藥靶點的潛力。 Molecular glue is a type of small molecule that brings the target protein into contact with E3 ubiquitin ligase, inducing interaction between the two, thereby leading to the degradation of the target protein. From a functional perspective, molecular glue mainly fills the gap between the target protein and E3 ubiquitin ligase, enhancing the binding interface between the two and promoting a strong interaction between the two ( Nat. Commun. , 2022 , 13 , 815 ). Compared with traditional small molecule inhibitors, molecular glues have the advantages of driving the degradation of target proteins in a catalytic form and do not require a binding pocket on the target protein, and have the potential to act on undruggable targets.

因此，有必要開發新型的雄激素受體剪切突變體 (Androgen receptor splice variants, AR-Vs，特別是AR-V7突變體) 抑制劑和E3泛素連接酶的PROTAC或其它小分子降解劑藥物，用於治療與雄激素受體剪切突變體相關的腫瘤疾病。Therefore, it is necessary to develop new androgen receptor splice variants (AR-Vs, especially AR-V7 mutants) inhibitors and PROTACs of E3 ubiquitin ligase or other small molecule degrader drugs. , for the treatment of neoplastic diseases associated with androgen receptor splice mutants.

本發明的目的在於提供一種結構新穎的、藥效好、生物利用度高、更安全、能抑制並降解AR或/和AR-Vs (特別是AR-V7) 的化合物，用於治療與AR相關疾病如前列腺癌。The purpose of the present invention is to provide a compound with novel structure, good efficacy, high bioavailability, safer, capable of inhibiting and degrading AR or/and AR-Vs (especially AR-V7), for the treatment of AR-related Diseases such as prostate cancer.

本發明提供一種化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，其中，化合物選自通式（I）所示的化合物， B-L-K （I）； The present invention provides a compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the group consisting of compounds represented by general formula (I), B-L-K (I);

在某些實施方案中，L選自鍵或-C 1-50烴基-，所述烴基中有1至20個亞甲基單元任選被-Ak-、-Cy-替換； In certain embodiments, L is selected from a bond or -C 1-50 hydrocarbyl-, in which 1 to 20 methylene units are optionally replaced by -Ak-, -Cy-;

在某些實施方案中，L選自鍵或-C 1-20烴基-，所述烴基中有1至20個亞甲基單元任選被-Ak-、-Cy-替換； In certain embodiments, L is selected from a bond or -C 1-20 hydrocarbyl-, in which 1 to 20 methylene units are optionally replaced by -Ak-, -Cy-;

在某些實施方案中，L選自鍵或-C 1-10烴基-，所述烴基中有1至10個(例如1、2、3、4、5、6、7、8、9或10)亞甲基單元任選被-Ak-、-Cy-替換；在某些實施方案中，每個-Ak-各自獨立地選自Ak1、Ak2、Ak3、Ak4或Ak5； In certain embodiments, L is selected from a bond or -C 1-10 hydrocarbyl-, 1 to 10 of the hydrocarbyl groups (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 ) The methylene unit is optionally replaced by -Ak-, -Cy-; in certain embodiments, each -Ak- is independently selected from Ak1, Ak2, Ak3, Ak4 or Ak5;

在某些實施方案中，每個-Ak-各自獨立地選自-(CH 2) q-、-(CH 2) q-O-、-O-(CH 2) q-、-(CH 2) q-NR L-、-NR L-(CH 2) q-、-(CH 2) q-NR LC(=O)-、-NR L(CH 2) qC(=O)-、-(CH 2) q-C(=O)NR L-、-C(=O)-、-C(=O)-(CH 2) q-NR L-、-(C≡C) q-、-CH=CH-、-Si(R L) 2-、-Si(OH)(R L)-、-Si(OH) 2-、-P(=O)(OR L)-、-P(=O)(R L)-、-S-、-S(=O)-、-S(=O) 2-或者鍵，所述的-CH 2-、-CH=CH-任選被1至2個(例如1或2個)選自鹵素、OH、CN、NH 2、C 1-6烷基、C 1-6烷氧基、鹵素取代的C 1-6烷基、羥基取代的C 1-6烷基、氰基取代的C 1-6烷基的取代基所取代； In certain embodiments, each -Ak- is independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -NR L (CH 2 ) q C(=O)-, -( CH 2 ) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q -, -CH =CH-, -Si(R L ) 2 -, -Si(OH)(R L )-, -Si(OH) 2 -, -P(=O)(OR L )-, -P(=O) (R L )-, -S-, -S(=O)-, -S(=O) 2 - or bond, the -CH 2 -, -CH=CH- is optionally replaced by 1 to 2 ( For example, 1 or 2) selected from halogen, OH, CN, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl Substituted with substituents of C 1-6 alkyl groups substituted by cyano groups;

在某些實施方案中，每個-Cy-各自獨立地選自Cy1、Cy2、Cy3、Cy4或Cy5；In certain embodiments, each -Cy- is independently selected from Cy1, Cy2, Cy3, Cy4, or Cy5;

在某些實施方案中，每個-Cy-各自獨立地選自鍵或者任選取代的如下基團之一：4-8員雜單環、4-10員雜並環、5-12員雜螺環、7-10員雜橋環、3-7員單環烷基、4-10員並環烷基、5-12員螺環烷基、7-10員橋環烷基、苯並C 4-6碳環基、苯並4至6員雜環基、5-10員雜芳基或6-10員芳基，當被取代時，被被1至4個R L2取代，所述的雜環基、雜芳基、雜單環、雜並環、雜螺環或雜橋環含有1至4個選自O、S、N的雜原子，當雜原子選自S時，任選被1或2個=O取代； In certain embodiments, each -Cy- is independently selected from a bond or one of the optionally substituted groups: 4-8 membered heteromonocycle, 4-10 membered heterocycle, 5-12 membered heterocycle Spirocycle, 7-10 membered hetero-bridged ring, 3-7-membered monocyclic alkyl, 4-10-membered paracycloalkyl, 5-12-membered spirocycloalkyl, 7-10-membered bridged cycloalkyl, benzo C 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, is substituted by 1 to 4 R L2 , the Heterocyclyl, heteroaryl, heteromonocycle, heteroparacycle, heterospirocycle or heterobridged ring contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatoms are selected from S, optionally 1 or 2 =O substitution;

在某些實施方案中，Cy1、Cy2、Cy3、Cy4或Cy5各自獨立地選自鍵或者任選取代的如下基團之一：4-7員雜單環、4-10員雜並環、5-12員雜螺環、7-10員雜橋環、3-7員單環烷基、4-10員並環烷基、5-12員螺環烷基、7-10員橋環烷基、苯並C 4-6碳環基、苯並4至6員雜環基、5-10員雜芳基或6-10員芳基，當被取代時，被1至4個R L2取代，所述的雜環基、雜芳基、雜單環、雜並環、雜螺環或雜橋環含有1至4個選自O、S、N的雜原子，當雜原子選自S時，任選被1或2個=O取代； In certain embodiments, each of Cy1, Cy2, Cy3, Cy4 or Cy5 is independently selected from a bond or one of the optionally substituted groups: 4-7 membered heteromonocycle, 4-10 membered heterocycle, 5 -12-membered heterospirocyclic ring, 7-10-membered hetero-bridged ring, 3-7-membered monocyclic alkyl group, 4-10-membered paracycloalkyl group, 5-12-membered spirocycloalkyl group, 7-10-membered bridged cycloalkyl group , benzo C 4-6 carbocyclyl, benzo 4-6 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl, when substituted, is substituted by 1 to 4 R L2 , The heterocyclyl, heteroaryl, heteromonocyclic, heteroparacyclic, heterospirocyclic or heterobridged ring contains 1 to 4 heteroatoms selected from O, S, and N. When the heteroatoms are selected from S, optionally replaced by 1 or 2 =O;

在某些實施方案中，R L2各自獨立地選自氘、F、Cl、Br、I、OH、COOH、CN、NH 2、NHC 1-4烷基、N(C 1-4烷基) 2、=O、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、-O-C 1-4亞烷基-O-C 1-4烷基、-O-C 1-4亞烷基-O-C 3-10碳環基、-C 1-4亞烷基-O-C 1-4亞烷基-O-C 1-4烷基、-C 1-4亞烷基-O-C 1-4亞烷基-O-C 3-10碳環基、-O-C 0-4亞烷基-C 3-10碳環基、-C 0-4亞烷基-C 3-10碳環基、-C 0-4亞烷基-4至10員雜環基，所述的烷基、烯基、炔基、烷氧基、亞烷基、碳環基或雜環基任選被1至4個選自F、Cl、Br、I、OH、COOH、CN、NH 2、NHC 1-4烷基、N(C 1-4烷基) 2、=O、C 1-4烷基、鹵素取代的C 1-4烷基、羥基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, each R L2 is independently selected from deuterium, F, Cl, Br, I, OH, COOH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -OC 1-4 alkylene -OC 1-4 alkyl, - OC 1-4 alkylene-OC 3-10 carbocyclyl, -C 1-4 alkylene-OC 1-4 alkylene -OC 1-4 alkyl, -C 1-4 alkylene-OC 1-4 alkylene-OC 3-10 carbocyclyl, -OC 0-4 alkylene-C 3-10 carbocyclyl, -C 0-4 alkylene-C 3-10 carbocyclyl, - C 0-4 alkylene-4 to 10-membered heterocyclyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 Selected from F, Cl, Br, I, OH, COOH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl, halogen substituted Substituted with C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 heterocyclic groups selected from O, S, N atom;

在某些實施方案中，R L2各自獨立的選自氘、F、Cl、Br、I、OH、NH 2、NHCH 3、N(CH 3) 2、COOH、CN、=O、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、-O-C 1-2亞烷基-O-C 1-2烷基、-O-C 1-2亞烷基-O-C 3-6碳環基、-C 1-2亞烷基-O-C 1-2亞烷基-O-C 1-2烷基、-C 1-2亞烷基-O-C 1-2亞烷基-O-C 3-6碳環基、-O-C 0-2亞烷基-C 3-6碳環基、-C 0-2亞烷基-C 3-6碳環基、-C 0-2亞烷基-4至6員雜環基，所述的烷基、烯基、炔基、烷氧基、亞烷基、碳環基或雜環基任選被1至4個選自F、Cl、Br、I、OH、COOH、CN、NH 2、NHC 1-4烷基、N(C 1-4烷基) 2、=O、C 1-4烷基、鹵素取代的C 1-4烷基、鹵素取代的C 1-4烷氧基、羥基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, each R L2 is independently selected from deuterium, F, Cl, Br, I, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , COOH, CN, =O, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -OC 1-2 alkylene-OC 1-2 alkyl, -OC 1-2 alkylene- OC 3-6 carbocyclyl, -C 1-2 alkylene-OC 1-2 alkylene-OC 1-2 alkyl, -C 1-2 alkylene-OC 1-2 alkylene-OC 3-6 carbocyclyl, -OC 0-2 alkylene -C 3-6 carbocyclyl, -C 0-2 alkylene -C 3-6 carbocyclyl, -C 0-2 alkylene- 4 to 6 membered heterocyclyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, COOH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, halogen Substituted with substituted C 1-4 alkoxy, hydroxy-substituted C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 selected from O, S, N heteroatoms;

在某些實施方案中，R L2各自獨立地選自氘、F、Cl、Br、=O、COOH、CN、NHCH 3、N(CH 3) 2、OH、NH 2或任選取代的如下基團之一：甲基、乙基、異丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、丙氧基、異丙基氧基、環丙基、環丁基、環戊基、環己基、吡唑基、噻唑基、三氮唑基、四氮唑基、苯基、嗎啉、-CH 2-環丙基、-CH 2-嗎啉、-CH 2-吡唑、-OCH 2-環丙基、-O-環丙基、-OCH 2CH 2-O-甲基、-OCH 2CH 2-O-環丙基、-CH 2OCH 2CH 2-O-甲基、-CH 2OCH 2CH 2-O-環丙基，當被取代時，被1至4個選自F、CHF 2、CF 3、-OCHF 2、-OCF 3、甲基、甲氧基、=O、羥甲基、COOH、CN、NHCH 3、N(CH 3) 2、OH、NH 2的取代基所取代； In certain embodiments, each R L2 is independently selected from deuterium, F, Cl, Br, =O, COOH, CN, NHCH 3 , N(CH 3 ) 2 , OH, NH 2 or optionally substituted One of the groups: methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, morpholine, -CH 2 -cyclopropyl, -CH 2 -morpholine, - CH 2 -pyrazole, -OCH 2 -cyclopropyl, -O-cyclopropyl, -OCH 2 CH 2 -O-methyl, -OCH 2 CH 2 -O-cyclopropyl, -CH 2 OCH 2 CH 2 -O-Methyl, -CH 2 OCH 2 CH 2 -O-cyclopropyl, when substituted, is selected from 1 to 4 F, CHF 2 , CF 3 , -OCHF 2 , -OCF 3 , Methane Substituted with substituents of base, methoxy, =O, hydroxymethyl, COOH, CN, NHCH 3 , N(CH 3 ) 2 , OH, NH 2 ;

在某些實施方案中，R L2各自獨立的選自氘、F、Cl、Br、I、OH、COOH、CN、NH 2、NHC 1-4烷基、-N(C 1-4烷基) 2、=O、C 1-4烷基、鹵素取代的C 1-4烷基、羥基取代的C 1-4烷基或C 1-4烷氧基； In certain embodiments, each R L2 is independently selected from deuterium, F, Cl, Br, I, OH, COOH, CN, NH 2 , NHC 1-4 alkyl, -N(C 1-4 alkyl) 2. =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl or C 1-4 alkoxy;

在某些實施方案中，R L2各自獨立的選自氘、F、Cl、Br、I、OH、NH 2、NHCH 3、N(CH 3) 2、COOH、CN、=O、C 1-4烷基、鹵素取代的C 1-4烷基、羥基取代的C 1-4烷基或C 1-4烷氧基； In certain embodiments, each R L2 is independently selected from deuterium, F, Cl, Br, I, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , COOH, CN, =O, C 1-4 Alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl or C 1-4 alkoxy;

在某些實施方案中，R L2各自獨立的選自氘、F、CF 3、OH、甲基、甲氧基、=O、羥甲基、COOH、NHCH 3、N(CH 3) 2、CN或NH 2； In certain embodiments, each R L2 is independently selected from deuterium, F, CF 3 , OH, methyl, methoxy, =O, hydroxymethyl, COOH, NHCH 3 , N(CH 3 ) 2 , CN or NH 2 ;

在某些實施方案中，L選自-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-、-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-；In certain embodiments, L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5 -, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2 -Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4 -, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Ak1-Cy2-Cy3 -Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5 -, -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1 -Ak2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5 -, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2 -Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4 -, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1 -Cy2-Cy3-Cy4-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4 -, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3 -Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4 -, -Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1 -Cy2-Cy3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4 -, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-;

在某些實施方案中，L選自鍵、-Ak1-、-Cy1-、-Cy1-Ak1-、-Cy1-Ak1-Ak2-、-Cy1-Ak1-Ak2-Ak3-、-Cy1-Ak1-Ak2-Ak3-Ak4-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-Ak3-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Cy2-Ak2-Ak3-、-Cy1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Ak2-Cy3-、-Cy1-Ak1-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Cy1-Cy2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Cy3-Ak3-、-Cy1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Ak2-Cy3-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-Ak3-Ak4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak2-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-Ak4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Ak1-Ak2-Cy3-、-Ak1-Ak2-Cy3-Cy4-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Cy3-Ak3-Cy4-、-Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-、-Ak1-Cy2-Ak2-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-、-Ak1-Cy2-Ak2-Ak3-；In certain embodiments, L is selected from the group consisting of bonds, -Ak1-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2 -Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1 -Cy2-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2 -Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2 -Cy3-Ak3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3 -Cy4-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Ak1 -Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1 -Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2 -Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;

在某些實施方案中，L選自鍵、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Cy1-Ak1-、-Ak1-Cy2-Ak2-、-Cy1-Cy2-Cy3-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Ak1-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-、-Cy1-、-Ak1-Cy2-Ak2-Ak3-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Ak2-Ak3-Ak4-；In certain embodiments, L is selected from the group consisting of bonds, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Cy1-Ak1-, -Ak1-Cy2-Ak2-, -Cy1-Cy2-Cy3-, -Cy1 -Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Ak1-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-, -Cy1-, -Ak1-Cy2-Ak2-Ak3-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Ak2-Ak3-Ak4-;

在某些實施方案中，L選自-Cy1-Cy2-，較佳地，Cy1選自C 6-10芳基、苯並C 4-6碳環、苯並4至6員雜環、5至6員雜芳基或8至10員雜芳基，Cy2選自4至6員含氮雜環烷基、Cy2選自4-7員含氮雜單環、4-10員含氮雜並環、5-12員含氮雜螺環、7-10員含氮雜橋環，所述的雜環基、雜單環、雜並環、雜橋環、雜螺環或雜芳基含有1至4個選自O、S、N的雜原子，當雜原子選自S時，任選被1或2個=O取代； In certain embodiments, L is selected from -Cy1-Cy2-, preferably, Cy1 is selected from C 6-10 aryl, benzo C 4-6 carbocyclic ring, benzo 4 to 6 membered heterocycle, 5 to 6-membered heteroaryl or 8-10-membered heteroaryl, Cy2 is selected from 4-6-membered nitrogen-containing heterocycloalkyl, Cy2 is selected from 4-7-membered nitrogen-containing heteromonocyclic ring, 4-10-membered nitrogen-containing heterocyclic ring , 5-12 membered nitrogen-containing heterospirocycle, 7-10 membered nitrogen-containing heterobridged ring, the heterocyclic group, heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospirocyclic ring or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N. When the heteroatoms are selected from S, they are optionally substituted by 1 or 2 =O;

在某些實施方案中，L選自 、 、 、 、 、 、 ； In certain embodiments, L is selected from , , , , , , ;

在某些實施方案中，L選自鍵或表L-1所示的基團，基團左側與B連接；In certain embodiments, L is selected from a bond or a group shown in Table L-1, and the left side of the group is connected to B;

在某些實施方案中，L選自表L-2所示的基團，基團左側與B連接；In certain embodiments, L is selected from the groups shown in Table L-2, and the left side of the group is connected to B;

在某些實施方案中，Ak1、Ak2、Ak3、Ak4、Ak5各自獨立的選自-(CH 2) q-、-(CH 2) q-O-、-O-(CH 2) q-、-(CH 2) q-NR L-、-NR L-(CH 2) q-、-(CH 2) q-NR LC(=O)-、-(CH 2) q-C(=O)NR L-、-C(=O)-、-C(=O)-(CH 2) q-NR L-、-CH=CH-、-(C≡C) q-或者鍵，所述的-CH 2-、-CH=CH-任選被1至2個（例如1或2個）選自鹵素、OH、CN、NH 2、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、羥基取代的C 1-4烷基、氰基取代的C 1-4烷基的取代基所取代； In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, - (CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -(CH 2 ) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -CH=CH-, -(C≡C) q -or bond, the -CH 2 -, -CH=CH- optionally substituted by 1 to 2 (eg 1 or 2) selected from halogen, OH, CN, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, halogen Substituted with substituents of C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, and cyano-substituted C 1-4 alkyl;

在某些實施方案中，Ak1、Ak2、Ak3、Ak4、Ak5各自獨立的選自-O-、-OCH 2-、-CH 2O-、-OCH 2CH 2-、-CH 2CH 2O-、-CH=CH-、-CH=C(CN)-、-CH=C(F)-、-C(CN)=CH-、-C(F)=CH-、-C≡C-、-C(CH 3) 2-、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-N(CH 3)-、-NH-、-CH 2N(CH 3)-、-CH 2NH-、-NHCH 2-、-CH 2CH 2N(CH 3)-、-CH 2CH 2NH-、-NHCH 2CH 2-、-C(=O)-、-C(=O)CH 2NH-、-CH 2C(=O)NH-、-C(=O)NH-或-NHC(=O)-； In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -O-, -OCH 2 -, -CH 2 O-, -OCH 2 CH 2 -, -CH 2 CH 2 O- , -CH=CH-, -CH=C(CN)-, -CH=C(F)-, -C(CN)=CH-, -C(F)=CH-, -C≡C-, - C(CH 3 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -N(CH 3 )-, -NH-, -CH 2 N(CH 3 )- , -CH 2 NH-, -NHCH 2 -, -CH 2 CH 2 N(CH 3 )-, -CH 2 CH 2 NH-, -NHCH 2 CH 2 -, -C(=O)-, -C( =O)CH 2 NH-, -CH 2 C(=O)NH-, -C(=O)NH- or -NHC(=O)-;

在某些實施方案中，Ak1、Ak2、Ak3、Ak4各自獨立的選自-C(=O)-、-O-、NH、-CH=CH-、-CH=C(CN)-、-CH=C(F)-、-C(CN)=CH-、-C(F)=CH-、-C≡C-、-C(CH 3) 2-、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-NHCO-； In certain embodiments, Ak1, Ak2, Ak3, Ak4 are each independently selected from -C(=O)-, -O-, NH, -CH=CH-, -CH=C(CN)-, -CH =C(F)-, -C(CN)=CH-, -C(F)=CH-, -C≡C-, -C(CH 3 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -NHCO-;

在某些實施方案中，R L各自獨立的選自H、C 1-6烷基、3-7員雜環基、3-7員環烷基、苯基或5-6員雜芳基，所述的雜環基或雜芳基含有1至4個選自O、S、N的雜原子； In certain embodiments, each R L is independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, The heterocyclic group or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，R L各自獨立的選自H或C 1-6烷基； In certain embodiments, each R L is independently selected from H or C 1-6 alkyl;

在某些實施方案中，R L各自獨立的選自H或C 1-4烷基； In certain embodiments, each R L is independently selected from H or C 1-4 alkyl;

在某些實施方案中，R L各自獨立的自H、甲基或乙基； In certain embodiments, each R L is independently H, methyl, or ethyl;

在某些實施方案中，Cy1、Cy2、Cy3、Cy4或Cy5各自獨立的選自鍵或者任選取代的如下基團之一：4-7員含氮雜單環、4-10員含氮雜並環、5-12員含氮雜螺環、7-10員含氮雜橋環、3-7員單環烷基、4-10員並環烷基、5-12員螺環烷基、7-10員橋環烷基、苯並C 4-6碳環基、苯並4至6員雜環基、5-10員雜芳基或6-10員芳基，當被取代時，被1至4個R L2取代，所述的雜環基、雜單環、雜並環、雜橋環、雜螺環或雜芳基含有1至4個選自O、S、N的雜原子，當雜原子選自S時，任選被1或2個=O取代； In certain embodiments, Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the bond or optionally substituted following groups: 4-7 membered nitrogen-containing heteromonocycle, 4-10 membered nitrogen-containing heterocycle Parallel ring, 5-12-membered nitrogen-containing heterospirocycle, 7-10-membered nitrogen-containing heterobridged ring, 3-7-membered monocyclic alkyl group, 4-10-membered paracycloalkyl group, 5-12-membered spirocycloalkyl group, 7-10 membered bridged cycloalkyl, benzo C 4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl, when substituted, is 1 to 4 R L2 substitutions, the heterocyclic group, heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospirocyclic ring or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, N, When the heteroatom is selected from S, it is optionally substituted by 1 or 2 =O;

在某些實施方案中，Cy1、Cy2、Cy3、Cy4或Cy5各自獨立的選自鍵或取代的或者未取代的如下基團之一：環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、氮雜環己烯基、哌啶基、嗎啉基、哌嗪基、1,4-二氮雜庚烷基、苯基、、噻吩基、噻唑基、呋喃基、噁唑基、吡咯基、吡唑基、咪唑基、吡啶基、噠嗪基、吡嗪基、嘧啶基、吡啶酮、三嗪基、咪唑並吡啶基、咪唑並吡嗪基、咪唑並嘧啶、吡唑並吡啶基、吡唑並吡嗪基、吡唑並嘧啶基、苯並噻吩基、苯並呋喃基、苯並噁唑基、苯並噻唑基、苯並咪唑基、苯並吡唑基、苯並吡咯基、三氮唑並吡啶基、三氮唑並嘧啶基、三氮唑並噠嗪基、三氮唑並吡嗪基、三氮唑並噻唑基、三氮唑並噁唑基、三氮唑並吡唑基、三氮唑並吡咯基、三氮唑並咪唑基、環丙基並環丙基、環丙基並環丁基、環丙基並環戊基、環丙基並環己基、環丁基並環丁基、環丁基並環戊基、環丁基並環己基、環戊基並環戊基、環戊基並環己基、環己基並環己基、環丙基螺環丙基、環丙基螺環丁基、環丙基螺環戊基、環丙基螺環己基、環丁基螺環丁基、環丁基螺環戊基、環丁基螺環己基、環戊基螺環戊基、環戊基螺環己基、環己基螺環己基、環丙基並氮雜環丁基、環丙基並吡咯烷基、環丙基並哌啶基、環丁基並氮雜環丁基、環丁基並吡咯烷基、環丁基並哌啶基、環戊基並氮雜環丁基、環戊基並吡咯烷基、環戊基並哌啶基、環己基並氮雜環丁基、環己基並吡咯烷基、環己基並哌啶基、氮雜環丁基並氮雜環丁基、氮雜環丁基並吡咯烷基、氮雜環丁基並哌啶基、吡咯烷基並氮雜環丁基、吡咯烷基並吡咯烷基、吡咯烷基並哌啶基、哌啶基並氮雜環丁基、哌啶基並吡咯烷基、哌啶基並哌啶基、環丁基螺氮雜環丁基、環丁基螺吡咯烷基、環丁基螺哌啶基、環戊基螺氮雜環丁基、環戊基螺吡咯烷基、環戊基螺哌啶基、環己基螺氮雜環丁基、環己基螺吡咯烷基、環己基螺哌啶基、氮雜環丁基螺氮雜環丁基、氮雜環丁基螺吡咯烷基、氮雜環丁基螺哌啶基、吡咯烷基螺氮雜環丁基、吡咯烷基螺吡咯烷基、吡咯烷基螺哌啶基、哌啶基螺氮雜環丁基、哌啶基螺哌啶基、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ，當被取代時，被1至4個R L2取代； In certain embodiments, Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or one of the following groups, substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Azetidinyl, pyrrolidinyl, azepinenyl, piperidyl, morpholinyl, piperazinyl, 1,4-diazepanyl, phenyl, thienyl, thiazolyl, Furyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyridone, triazinyl, imidazopyridyl, imidazopyrazinyl, imidazole Pyrimidine, pyrazopyridyl, pyrazopyrazinyl, pyrazopyrimidinyl, benzothienyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzo Pyrazolyl, benzopyrrolyl, triazolopyridyl, triazolopyrimidinyl, triazolopyridazinyl, triazolopyrazinyl, triazolothiazyl, triazolo Oxazolyl, triazolopyrazolyl, triazolopyrrolyl, triazoloimidazolyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexyl , cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutyl Spirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidine base, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclopentyl Piperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl, azetidinylpyrrolidinyl, nitrogen Heterocyclobutylpiperidinyl, pyrrolidinaazetidinyl, pyrrolidinopyrrolidyl, pyrrolidinopiperidinyl, piperidinoazetidinyl, piperidinopyrrole Alkyl, piperidinopiperidinyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidyl, cyclobutylspiropyrolidinyl, cyclopentylspiroazetidinyl, cyclopentyl Spiropyrrolidinyl, cyclopentylspiropiperidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidyl, cyclohexylspiropyrolidinyl, azetidinylspiroazetidinyl, aza cyclobutylspiropyrrolidyl, azetidinylspiropiperidinyl, pyrrolidinylspiroazetidinyl, pyrrolidinylspiropyrrolidyl, pyrrolidinylspiropiperidinyl, piperidinylspiroazepine cyclobutyl, piperidylspiropiperidinyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , when substituted, by 1 to 4 R L2 ;

在某些實施方案中，Cy1、Cy2、Cy3、Cy4或Cy5各自獨立的選自鍵或取代的或者未取代的如下基團之一： 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ，當被取代時，被1至4個R L2取代； In certain embodiments, each Cy1, Cy2, Cy3, Cy4 or Cy5 is independently selected from a bond or one of the following groups, substituted or unsubstituted: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,, , , , , , , , , , , , , , , , , , , , , , , , when substituted, by 1 to 4 R L2 ;

在某些實施方案中，Cy1、Cy2、Cy3各自獨立的選自取代的或者未取代的如下基團之一： 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ，當被取代時，被1至4個R L2取代； In certain embodiments, Cy1, Cy2, and Cy3 are each independently selected from one of the following groups, substituted or unsubstituted: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , when substituted, by 1 to 4 R L2 ;

在某些實施方案中，L選自 ； In certain embodiments, L is selected from ;

在某些實施方案中，Cy1選自4-12員含氮雜環，較佳4-7員含氮雜單環、4-10員含氮雜並環、5-12員含氮雜螺環、7-10員含氮雜橋環，所述的含氮雜環含有1至4個(例如1、2、3或4個）選自O、S、N的雜原子，當雜原子選自S時，任選被0、1或2個=O取代；In certain embodiments, Cy1 is selected from 4-12 membered nitrogen-containing heterocycles, preferably 4-7-membered nitrogen-containing heteromonocycles, 4-10-membered nitrogen-containing heterocyclic rings, 5-12-membered nitrogen-containing heterospirocycles , 7-10 member nitrogen-containing heterobridged ring, the nitrogen-containing heterocycle contains 1 to 4 (such as 1, 2, 3 or 4) heteroatoms selected from O, S, N, when the heteroatoms are selected from S, optionally replaced by 0, 1 or 2 =O;

在某些實施方案中，Cy1選自4-6員含氮雜環；In certain embodiments, Cy1 is selected from 4-6 membered nitrogen-containing heterocycles;

在某些實施方案中，L選自 ； In certain embodiments, L is selected from ;

在某些實施方案中，L選自-Cy1-Cy2-，Cy1選自苯基、萘基、苯並C 4-6碳環基、苯並4至6員雜環基、5至6員雜芳基、8至10員並環雜芳基，Cy2選自4-6員含氮雜環，較佳氮雜環丁基、吡咯烷基或哌啶基，所述Cy1或Cy2任選被1至4個選自R L2的取代基所取代； In certain embodiments, L is selected from -Cy1-Cy2-, Cy1 is selected from phenyl, naphthyl, benzo C 4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, 5 to 6 membered heterocyclyl Aryl, 8- to 10-membered paracyclic heteroaryl, Cy2 is selected from 4-6 membered nitrogen-containing heterocycles, preferably azetidinyl, pyrrolidinyl or piperidinyl, the Cy1 or Cy2 is optionally replaced by 1 Substituted with 4 substituents selected from R L2 ;

在某些實施方案中，L選自 ，左側與B直接連接，Cy2選自4-6員含氮雜環，較佳氮雜環丁基、吡咯烷基或哌啶基； In certain embodiments, L is selected from , the left side is directly connected to B, Cy2 is selected from 4-6 membered nitrogen-containing heterocycles, preferably azetidinyl, pyrrolidinyl or piperidinyl;

在某些實施方案中，rr選自0、1、2、3或4；In certain embodiments, rr is selected from 0, 1, 2, 3, or 4;

在某些實施方案中，B選自 ； In certain embodiments, B is selected from ;

在某些實施方案中，V選自 ； In certain embodiments, V is selected from ;

在某些實施方案中，V選自 ； In certain embodiments, V is selected from ;

在某些實施方案中，V選自-N(R b5a)C(=W)-(CR b3R b4)-、-C(=W)-(CR b3R b4)-、-C(=W)-(CR b3R b4) v2-、-(CR b3R b4)C(=W)(CR b3R b4)-、-(CR b3R b4)C(=W)-、-N(R b5a)C(=W)N(R b5a)- 、-N(R b5a)C(=W)-、-N(R b5a)C(=W)-(CR b3R b4)-N(R b5a)- 、-N(R b5a)C(=W)-(CR b3R b4)-O-、-N(R b5a)C(=W)-(CR b3R b4) 2-N(R b5a)- 、-N(R b5a)C(=W)-(CR b3R b4) 2-O-、-N(R b5a)C(=W)-(CR b3R b4) 2-N(R b5a)C(=W)-、-N(R b5a)C(=W)-(CR b3R b4)-N(R b5a)C(=W)-、-NHC(=W)-(CR b6R b7)-、-C(=W)-、-C(=W)-C(=W)-、-(CR b3R b4) v1-N(R b5a)C(=W)-(CR b3R b4) v2-、-N(R b5a)C(=W)-(CR b3R b4)-C(=W)-、-N(R b5a)C(=W)-C(=W)-(CR b3R b4)-、-N(R b5a)C(=W)-C(=W)-、-C(=W)-C(=W)-、-C(=W)-(CR b3R b4)-C(=W)-、-C(=W)-N(R b5a)-(CR b3R b4)-、-C(=W)-(CR b6R b7)- C(=W)-、-N(R b5a)C(=W)-C(=W)-(CR b3R b4)-、-N(R b5a)C(=W)- 、-C(=W)N(R b5a)- 、-N(R b5a)C(=W)N(R b5a)-； In certain embodiments, V is selected from -N(R b5a )C(=W)-(CR b3 R b4 )-, -C(=W)-(CR b3 R b4 )-, -C(=W )-(CR b3 R b4 ) v2 -,-(CR b3 R b4 )C(=W)(CR b3 R b4 )-,-(CR b3 R b4 )C(=W)-,-N(R b5a )C(=W)N(R b5a )- , -N(R b5a )C(=W)-, -N(R b5a )C(=W)-(CR b3 R b4 )-N(R b5a ) - , -N(R b5a )C(=W)-(CR b3 R b4 )-O- , -N(R b5a )C(=W)-(CR b3 R b4 ) 2 -N(R b5a )- , -N(R b5a )C(=W)-(CR b3 R b4 ) 2 -O-, -N(R b5a )C(=W)-(CR b3 R b4 ) 2 -N(R b5a )C (=W)-, -N(R b5a )C(=W)-(CR b3 R b4 )-N(R b5a )C(=W)-, -NHC(=W)-(CR b6 R b7 ) -, -C(=W)-, -C(=W)-C(=W)-, -(CR b3 R b4 ) v1 -N(R b5a )C(=W)-(CR b3 R b4 ) v2 -, -N(R b5a )C(=W)-(CR b3 R b4 )-C(=W)-, -N(R b5a )C(=W)-C(=W)-(CR b3 R b4 )-, -N(R b5a )C(=W)-C(=W)-, -C(=W)-C(=W)-, -C(=W)-(CR b3 R b4 )-C(=W)-, -C(=W)-N(R b5a )-(CR b3 R b4 )-, -C(=W)-(CR b6 R b7 )- C(=W)- , -N(R b5a )C(=W)-C(=W)-(CR b3 R b4 )-, -N(R b5a )C(=W)- , -C(=W)N(R b5a )- , -N(R b5a )C(=W)N(R b5a )-;

在某些實施方案中，V選自-NH(C=O)(CR b3R b4)-、-NH(C=O) (CR b6R b7)-、-N(R b5)(C=O) (CR b3R b4)-、-N(R b5)(C=O)(CR b6R b7)-、-NH(C=O)(CR b3R b4)-NH-、-NH(C=O)(CR b3R b4)-O-、-NH(C=O)(CR b3R b4)- NH(C=O)-、-NH(C=O)(CR b3R b4)-(C=O)NH -、-NH(C=O)(CR b3R b4)-(C=O) -、-NH(C=O)-(C=O)-、-NH(C=O)-(C=O)-、-(C=O)-(C=O)、-(C=O)(CR b3R b4)-、-NH(C=O) -、-(C=O)NH -、-NH(C=O)NH-、-(C=O)(CR b3R b4)-、-NH(C=O)(CR b3R b4)-CH 2-、-NH(C=O)-CH 2-(CR b3R b4)-、-(C=O)-； In certain embodiments, V is selected from -NH(C=O)(CR b3 R b4 )-, -NH(C=O) (CR b6 R b7 )-, -N(R b5 )(C=O ) (CR b3 R b4 )-, -N(R b5 )(C=O)(CR b6 R b7 )-, -NH(C=O)(CR b3 R b4 )-NH-, -NH(C= O)(CR b3 R b4 )-O-, -NH(C=O)(CR b3 R b4 )- NH(C=O)-, -NH(C=O)(CR b3 R b4 )-(C =O)NH -, -NH(C=O)(CR b3 R b4 )-(C=O) -, -NH(C=O)-(C=O)-, -NH(C=O)- (C=O)-, -(C=O)-(C=O), -(C=O)(CR b3 R b4 )-, -NH(C=O) -, -(C=O)NH -, -NH(C=O)NH-, -(C=O)(CR b3 R b4 )-, -NH(C=O)(CR b3 R b4 )-CH 2 -, -NH(C=O )-CH 2 -(CR b3 R b4 )-, -(C=O)-;

在某些實施方案中，Y 1、Y 2、Y 3各自獨立地選自鍵、O、S、NR b5a、C(=S)、C(=O)、CONR b5a、NR b5aCO； In certain embodiments, Y 1 , Y 2 , Y 3 are each independently selected from bond, O, S, NR b5a , C(=S), C(=O), CONR b5a , NR b5a CO;

在某些實施方案中，P 1、P 2各自獨立地選自 或 ； In certain embodiments, P 1 and P 2 are each independently selected from or ;

在某些實施方案中，v 2各自獨立地選自0、1、2、3或4； In certain embodiments, each v 2 is independently selected from 0, 1, 2, 3, or 4;

在某些實施方案中，v 1各自獨立地選自0、1或2； In certain embodiments, each v 1 is independently selected from 0, 1, or 2;

在某些實施方案中，v 3選自0、1、2或3； In certain embodiments, v3 is selected from 0, 1, 2, or 3;

在某些實施方案中，v 4選自0、1、2或3； In certain embodiments, v 4 is selected from 0, 1, 2, or 3;

在某些實施方案中，z選自0、1、2或3；In certain embodiments, z is selected from 0, 1, 2, or 3;

在某些實施方案中，B選自 、 、 ； In certain embodiments, B is selected from , , ;

在某些實施方案中，B選自 ；在某些實施方案中，B選自 ； In certain embodiments, B is selected from ; In certain embodiments, B is selected from ;

在某些實施方案中，B選自 ，R b6選自-(CH 2) m1-C 3-6環烷基，R b7選自H、F、Cl、CN、C 1-4烷基、C 2-4炔基、C 3-6環烷基或-CH 2-C 3-6環烷基，所述的烷基、炔基或環烷基任選被1至4個選自F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基的取代基所取代； In certain embodiments, B is selected from , R b6 is selected from -(CH 2 ) m1 -C 3-6 cycloalkyl, R b7 is selected from H, F, Cl, CN, C 1-4 alkyl, C 2-4 alkynyl, C 3-6 Cycloalkyl or -CH 2 -C 3-6 cycloalkyl, the alkyl, alkynyl or cycloalkyl is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , Substituted by CN, C 1-4 alkyl substituents;

在某些實施方案中，B選自 或 ，R b7較佳H、F、Cl、甲基、乙基、環丙基、-CH 2-環丙基，B 4較佳苯基或5至6員雜芳基，B 2較佳吡唑，所述的B 4任選被1至4個R b1所取代，所述的B 2任選被1至4個R b2所取代； In certain embodiments, B is selected from or , R b7 is preferably H, F, Cl, methyl, ethyl, cyclopropyl, -CH 2 -cyclopropyl, B 4 is preferably phenyl or 5 to 6-membered heteroaryl, B 2 is preferably pyrazole , the B 4 is optionally replaced by 1 to 4 R b1 , the B 2 is optionally replaced by 1 to 4 R b2 ;

在某些實施方案中，B選自 ，V選自-NHC(=O)-、-NH(C=O)(CR b3R b4)-O-、-NH(C=O)(CR b3R b4)-，B 1較佳苯基或5至6員雜芳基，所述的B 1任選被1至4個R b1所取代； In certain embodiments, B is selected from , V is selected from -NHC(=O)-, -NH(C=O)(CR b3 R b4 )-O-, -NH(C=O)(CR b3 R b4 )-, B 1 is preferably phenyl Or 5 to 6 membered heteroaryl, the B 1 is optionally substituted by 1 to 4 R b1 ;

在某些實施方案中，B選自 ，B 1較佳苯基或5至6員雜芳基，所述的B 1任選被1至4個R b1所取代；在某些實施方案中，B選自 ，B 1較佳苯基或5至6員雜芳基，所述的B 1任選被1至4個R b1所取代； In certain embodiments, B is selected from , B 1 is preferably phenyl or 5 to 6-membered heteroaryl, and the B 1 is optionally substituted by 1 to 4 R b1 ; in certain embodiments, B is selected from , B 1 is preferably phenyl or 5 to 6-membered heteroaryl, and the B 1 is optionally substituted by 1 to 4 R b1 ;

在某些實施方案中，B選自 ，B 5選自 、 、 、6員雜芳基(如吡啶基、吡嗪基、嘧啶基、噠嗪基)、8至10員雜芳基(如喹啉基、異喹啉基、喹唑啉基)，B 1較佳苯基或5至6員雜芳基，所述的B 1任選被1至4個R b1所取代，所述的B 5任選被1至4個R b2所取代； In certain embodiments, B is selected from , B 5 is selected from , , , 6-membered heteroaryl (such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl), 8 to 10-membered heteroaryl (such as quinolyl, isoquinolinyl, quinazolinyl), B 1 is relatively Carbyl or 5 to 6-membered heteroaryl, the B 1 is optionally substituted by 1 to 4 R b1 , the B 5 is optionally substituted by 1 to 4 R b2 ;

在某些實施方案中， 選自 、 、 、 或 ，較佳 或 ； In certain embodiments, Selected from , , , or , better or ;

在某些實施方案中，B選自 ，B 1較佳苯基或5至6員雜芳基，所述的B 1任選被1至4個R b1所取代； In certain embodiments, B is selected from , B 1 is preferably phenyl or 5 to 6-membered heteroaryl, and the B 1 is optionally substituted by 1 to 4 R b1 ;

在某些實施方案中，B選自 ,y1選自0、1、2或3； In certain embodiments, B is selected from ,y1 is selected from 0, 1, 2 or 3;

在某些實施方案中，B選自 、 、 、 、 、 、 、 、 、 、 、 、 、 (較佳v1=0或1,v2=1)、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； In certain embodiments, B is selected from , , , , , , , , , , , , , (Better v1=0 or 1, v2=1), , , , , , , , , , , , , , , , , , , , ;

的定義與B 1相同； The definition of is the same as B 1 ;

在某些實施方案中，B選自 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ；在某些實施方案中， 選自 、 ； In certain embodiments, B is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; In certain embodiments, Selected from , ;

在某些實施方案中，B選自 、 ； In certain embodiments, B is selected from , ;

在某些實施方案中，B選自 ；在某些實施方案中，B選自 ；在某些實施方案中，B選自 ；在某些實施方案中，B選自 ；在某些實施方案中，B選自 ；在某些實施方案中，B選自 ；在某些實施方案中，B選自 ；在某些實施方案中，B選自 ； In certain embodiments, B is selected from ; In certain embodiments, B is selected from ; In certain embodiments, B is selected from ; In certain embodiments, B is selected from ; In certain embodiments, B is selected from ; In certain embodiments, B is selected from ; In certain embodiments, B is selected from ; In certain embodiments, B is selected from ;

在某些實施方案中，B選自 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； In certain embodiments, B is selected from , , , , , , , , , , , , , , , , , , , ;

在某些實施方案中，W選自O或S；In certain embodiments, W is selected from O or S;

在某些實施方案中，W選自O；In certain embodiments, W is selected from O;

在某些實施方案中，環S選自4至9員含氮雜環基，環S任選被1至4個R s取代； In certain embodiments, Ring S is selected from 4 to 9 membered nitrogen-containing heterocyclyl groups, and Ring S is optionally substituted by 1 to 4 Rs ;

在某些實施方案中，環S選自5員、6員或7員含有1或2個氮原子的環，環S任選被1至4個R s取代； In certain embodiments, Ring S is selected from a 5-, 6-, or 7-membered ring containing 1 or 2 nitrogen atoms, and Ring S is optionally substituted by 1 to 4 Rs ;

在某些實施方案中，環S選自氮雜環戊基、氮雜環己基，環S任選被1至4個R s取代； In certain embodiments, Ring S is selected from azacyclopentyl, azacyclohexyl, and Ring S is optionally substituted by 1 to 4 Rs ;

在某些實施方案中，B 1選自C 5-20碳環基或4-20員雜環基，所述B 1任選被1至4個R b1所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, B 1 is selected from C 5-20 carbocyclyl or 4-20 membered heterocyclyl, and said B 1 is optionally substituted by 1 to 4 R b 1 , and said heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，B 1、B 4各自獨立的選自C 6-14碳環基或4-14員雜環基，所述B 1、B 4任選被1至4個R b1所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, B 1 and B 4 are each independently selected from C 6-14 carbocyclyl or 4-14 membered heterocyclyl, and said B 1 and B 4 are optionally represented by 1 to 4 R b1 Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，B 1、B 4各自獨立的選自苯基、萘基、C 6-12碳環基、5-10員雜芳基、5-10員雜環基、C 10-14三環碳環基、12至14員三環雜環基，所述B 1、B 4任選被1至4個R b1所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, B 1 and B 4 are each independently selected from phenyl, naphthyl, C 6-12 carbocyclyl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, C 10- 14 tricyclic carbocyclyl, 12 to 14 membered tricyclic heterocyclyl, the B 1 and B 4 are optionally substituted by 1 to 4 R b1 , the heteroaryl or heterocyclyl contains 1 to 4 A heteroatom selected from O, S, N;

在某些實施方案中，B 1、B 4各自獨立的選自苯基、萘基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、吡嗪基、噠嗪基、喹啉基、異喹啉基、3-異喹啉酮基、喹唑啉基、3,4-二氫-1H-苯並吡喃基、1,2,3,4-四氫喹啉基、苯並呋喃基、苯並噻吩基、苯並吡咯基、苯並噁唑基、苯並噻唑基、苯並咪唑基、苯並吡唑基、 、 、 、 、 、 、 、 、 、 、 、 ，所述B 1、B 4任選被1至4個R b1所取代； In certain embodiments, B 1 and B 4 are each independently selected from phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, Isoquinolyl, 3-isoquinolinonyl, quinazolinyl, 3,4-dihydro-1H-benzopyranyl, 1,2,3,4-tetrahydroquinolyl, benzofuran base, benzothienyl, benzopyrrolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, , , , , , , , , , , , , the B 1 and B 4 are optionally replaced by 1 to 4 R b1 ;

在某些實施方案中，B 1選自取代或未取代的苯基或吡啶基，當被取代時，任選被1至4個R b1所取代； In certain embodiments, B1 is selected from substituted or unsubstituted phenyl or pyridyl, and when substituted, is optionally substituted by 1 to 4 Rb1 ;

在某些實施方案中，B 1選自 ,y1選自0、1、2或3； In certain embodiments, B1 is selected from ,y1 is selected from 0, 1, 2 or 3;

在某些實施方案中，B 1選自 ，Ba選自N、CR b1，Bb選自N、CR b1，Bc選自N、CR b1，Bd選自N、CR b1，且Ba、Bb、Bc、Bd中至多有2個為N，R b1A選自C 3-6環烷基、C 2-6炔基、苯基或5至6員雜芳基，較佳環丙基、環丁基、環戊基、環己基、乙炔基、丙炔基、苯基、吡唑基，所述的環烷基、炔基、環丙基、環丁基、環戊基、環己基、乙炔基、丙炔基、苯基、雜芳基、吡唑基任選被1至4個選自F、Cl、Br、I、OH、=O、- CN、COOH、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 2-4炔基、-C 1-4亞烷基-C 3-6環烷基、-C 1-4亞烷基-OH、-C 1-4亞烷基-O-C 1-4烷基、C 3-6環烷基的取代基所取代，較佳地，任選被1至4個選自F、Cl、Br、I、OH、CN、CHF 2、CF 3、NH 2、NHCH 3、N(CH 3) 2、甲基、乙基、異丙基、乙炔基、-CH 2-CN、-CH 2OH、-CH 2OMe、-CH 2-環丙基、甲氧基、環丙基、環丁基的取代基所取代； In certain embodiments, B1 is selected from , Ba is selected from N, CR b1 , Bb is selected from N, CR b1 , Bc is selected from N, CR b1 , Bd is selected from N, CR b1 , and at most 2 of Ba, Bb, Bc and Bd are N, R b1A is selected from C 3-6 cycloalkyl, C 2-6 alkynyl, phenyl or 5 to 6 membered heteroaryl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, propyl Alkynyl, phenyl, pyrazolyl, the cycloalkyl, alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, propynyl, phenyl, heteroaryl, pyridyl The azole group is optionally substituted with 1 to 4 C 1- selected from the group consisting of F, Cl, Br, I, OH, =O, - CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, and halogen. 4 alkyl, cyano substituted C 1-4 alkyl, C 2-4 alkynyl, -C 1-4 alkylene -C 3-6 cycloalkyl, -C 1-4 alkylene -OH, -C 1-4 alkylene-OC 1-4 alkyl, C 3-6 cycloalkyl substituent, preferably, optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, CN, CHF 2 , CF 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, isopropyl, ethynyl, -CH 2 -CN, -CH 2 OH, -CH 2 OMe, -CH 2 -substituted by cyclopropyl, methoxy, cyclopropyl, cyclobutyl substituents;

在某些實施方案中，B 2選自C 5-20碳環基或4-20員雜環基，所述B 2任選被1至4個R b2取代，所述的雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, B 2 is selected from C 5-20 carbocyclyl or 4-20 membered heterocyclyl, and the B 2 is optionally substituted by 1 to 4 R b 2 , and the heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，B 2選自C 5-10碳環基、5-10員雜環基或B 5，所述B 2任選被1至4個R b2取代，所述的雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, B 2 is selected from C 5-10 carbocyclyl, 5-10 membered heterocyclyl or B 5 , said B 2 is optionally substituted by 1 to 4 R b 2 , said heterocyclyl The base contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，B 2選自C 6-10芳基、5-7員雜環基、5-10員雜芳基或5-10員雜並環、5-10員雜橋環，所述B 2任選被1至4個R b2取代，所述的雜芳基、雜環基、雜並環、雜橋環含有1至4個選自O、S、N的雜原子； In certain embodiments, B 2 is selected from C 6-10 aryl, 5-7 membered heterocyclyl, 5-10 membered heteroaryl or 5-10 membered heteroacyclic ring, 5-10 membered heterobridged ring, The B 2 is optionally substituted by 1 to 4 R b2 , and the heteroaryl, heterocyclyl, heterocycle, and heterobridged ring contain 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，B 2選自5-7員雜環基、5-6員雜芳基或9-10員雜並環，所述B 2任選被1至4個R b2取代，所述的雜芳基、雜環基、雜並環含有1至4個選自O、S、N的雜原子； In certain embodiments, B2 is selected from 5-7 membered heterocyclyl, 5-6 membered heteroaryl, or 9-10 membered heterocyclic ring, and B2 is optionally substituted by 1 to 4 R b2 , The heteroaryl group, heterocyclic group, and heterocyclic ring contain 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，B 2選自B 5； In certain embodiments, B 2 is selected from B 5 ;

在某些實施方案中，B 2選自取代或未取代的如下基團之一：苯基、萘基、吡唑基、咪唑基、三氮唑基、噻唑基、噁唑基、異噁唑基、噻吩基、吡啶基、苯並吡咯基、苯並咪唑基、苯並吡唑基、苯並噻唑基、吡唑並四氫吡咯基、3-噠嗪酮基、2-吡啶酮基、1,2,3,4-四氫喹啉基、1,2,3,4-四氫異喹啉基、 、 、 、 、 、 、 、 、 、 、 、 、 或B 5，當被取代時，被1至4個R b2取代； In certain embodiments, B is selected from one of the following groups, substituted or unsubstituted: phenyl, naphthyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazole base, thienyl, pyridyl, benzopyrrolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, pyrazolotetrahydropyrrolyl, 3-pyridazinonyl, 2-pyridinonyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, , , , , , , , , , , , , or B5 , when substituted, by 1 to 4 R b2 ;

在某些實施方案中，B 2選自吡唑基，所述B 2任選被1至4個R b2取代； In certain embodiments, B2 is selected from pyrazolyl, and B2 is optionally substituted by 1 to 4 R b2 ;

在某些實施方案中，B 2選自吡唑基，所述B 2被1個R b2a取代、任選被1至3個R b2取代； In certain embodiments, B 2 is selected from pyrazolyl, and said B 2 is substituted by 1 R b2a , optionally substituted by 1 to 3 R b2 ;

在某些實施方案中，B 2選自 、 、 、 、 、 、 、 ，右側與L直接連接； In certain embodiments, B2 is selected from , , , , , , , , the right side is directly connected to L;

在某些實施方案中，B 2選自 、 、 、 、 、 ，右側與L直接連接； In certain embodiments, B2 is selected from , , , , , , the right side is directly connected to L;

在某些實施方案中，B 3選自C 6-14碳環基或5-14員雜環基，所述碳環基或雜環基任選被1至4個R b1所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, B 3 is selected from C 6-14 carbocyclyl or 5-14 membered heterocyclyl, said carbocyclyl or heterocyclyl optionally substituted by 1 to 4 R b1 , said The heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，B 3選自5-12員雜芳基、C 6-7碳環基、C 6-10並碳環基、C 6-12螺碳環基、C 7-12橋碳環基、4-7員單環雜環基、7-14員雜並環、7-14員雜螺環，所述B 3任選被1至4個R b1所取代，所述的雜芳基、雜環基、雜並環、雜螺環含有1至4個選自O、S、N的雜原子； In certain embodiments, B 3 is selected from 5-12 membered heteroaryl, C 6-7 carbocyclyl, C 6-10 carbonyl carbocyclyl, C 6-12 spiro carbocyclyl, C 7-12 bridge Carbocyclyl, 4-7-membered monocyclic heterocyclyl, 7-14-membered heterocyclic ring, 7-14-membered heterospirocyclic ring, the B 3 is optionally substituted by 1 to 4 R b1 , the hetero Aryl, heterocyclyl, heterocyclic, and heterospirocyclic contain 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，B 3選自取代或未取代的如下基團之一：苯基、萘基、吡啶基、嘧啶基、吡嗪基、噠嗪基、苯並吡咯基、苯並咪唑基、苯並吡唑基、苯並噻唑基、苯並三氮唑基、苯並吡咯烷基、苯並哌啶基、苯並四氫吡喃基、3-噠嗪酮基、2-吡啶酮基、1,2,3,4-四氫喹啉基、1,2,3,4-四氫異喹啉基、吡啶並咪唑基、吡啶並吡咯基、哢唑基、2,3-二氫吲哚基、苯並嗎啉基、 、 、 、 、 ，當被取代時，被1至4個R b1取代； In certain embodiments, B is selected from one of the following groups, substituted or unsubstituted: phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyrrolyl, benzimidazole base, benzopyrazolyl, benzothiazolyl, benzotriazolyl, benzopyrrolidinyl, benzopiperidinyl, chromanyl, 3-pyridazinonyl, 2-pyridine Keto group, 1,2,3,4-tetrahydroquinolyl group, 1,2,3,4-tetrahydroisoquinolyl group, pyrididoimidazolyl group, pyridopyrrolyl group, terazolyl group, 2,3- Indolyl, benzomorpholinyl, , , , , , when substituted, by 1 to 4 R b1 ;

在某些實施方案中，B 3選自取代或未取代的如下基團之一：苯基、萘基、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、苯並吡啶基、苯並噻吩基、苯並呋喃基、 、 、噻吩基、呋喃基、吡咯基，當被取代時，被1至4個R b1取代； In certain embodiments, B is selected from one of the following groups, substituted or unsubstituted: phenyl, naphthyl, , , , , , , , , , , , , , , , , , , , , , , benzopyridyl, benzothienyl, benzofuranyl, , , thienyl, furyl, pyrrolyl, when substituted, substituted by 1 to 4 R b1 ;

在某些實施方案中，B 4選自苯基、5-6員雜芳基，所述苯基或雜芳基任選被1至4個R b1所取代，所述的雜芳基含有1至4個選自O、S、N的雜原子； In certain embodiments, B 4 is selected from phenyl, 5-6 membered heteroaryl, the phenyl or heteroaryl is optionally substituted by 1 to 4 R b1 , the heteroaryl contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，B 4選自取代或未取代的如下基團之一：苯基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、吡嗪基、噠嗪基，當被取代時，被1至4個R b1所取代； In certain embodiments, B 4 is selected from one of the following groups: phenyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, substituted or unsubstituted. When replaced, it is replaced by 1 to 4 R b1 ;

在某些實施方案中，B 4選自苯基、萘基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、吡嗪基、噠嗪基，所述B 4被1個R b1a取代、任選被1至3個R b1取代； In certain embodiments, B 4 is selected from phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and said B 4 is substituted by 1 R b1a , optionally replaced by 1 to 3 R b1 ;

在某些實施方案中，B 4選自苯基、萘基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、吡嗪基、噠嗪基，所述B 4被1個R b1a取代、任選被1至3個選自F、Cl、Br、I、OH、CN、C 1-4烷基、C 1-4烷氧基、C 3-6環烷基的取代基所取代； In certain embodiments, B 4 is selected from phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and said B 4 is substituted by 1 R b1a , optionally substituted by 1 to 3 substituents selected from F, Cl, Br, I, OH, CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;

在某些實施方案中，B 4選自苯基、吡啶基，所述B 4被1個R b1a取代、任選被1至3個R b1取代； In certain embodiments, B 4 is selected from phenyl and pyridyl, and the B 4 is substituted by 1 R b1a , optionally substituted by 1 to 3 R b1 ;

在某些實施方案中，B 5選自C 12-18三並環、12至18員雜三並環、噻吩基、呋喃基、噻唑基、噁唑基、吡啶基、嘧啶基、噠嗪基、吡嗪基、三嗪基、苯基、苯並C 4-6碳環、苯並4至6員雜環、吡唑並C 4-6碳環、吡唑並4至6員雜環、三氮唑並C 4-6碳環、三氮唑並4至6員雜環、咪唑並C 4-6碳環、咪唑並4至6員雜環、噻吩並C 4-6碳環、噻吩並4至6員雜環、呋喃並C 4-6碳環、呋喃並4至6員雜環、4-7員含氮雜單環烷基(例如氮雜環丁基、吡咯烷基、哌嗪基、哌啶基)、4-10員含氮雜並環烷基、5-12員含氮雜螺環烷基、7-10員含氮雜橋環烷基、3-7員單環烷基、4-10員並環烷基、5-12員螺環烷基、7-10員橋環烷基，所述B 5任選被1至4個R b2取代，所述的雜環、雜單環烷基、雜並環烷基、雜螺環烷基、雜橋環烷基含有1至4個選自O、S、N的雜原子； In certain embodiments, B5 is selected from C 12-18 tricyclic, 12 to 18 membered heterotricyclic, thienyl, furyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl , pyrazinyl, triazinyl, phenyl, benzo C 4-6 carbocyclic ring, benzo 4 to 6 membered heterocyclic ring, pyrazolo C 4-6 carbocyclic ring, pyrazolo 4 to 6 membered heterocyclic ring, Triazolo C 4-6 carbocyclic ring, triazolo C 4-6 membered heterocyclic ring, imidazo C 4-6 carbocyclic ring, imidazo C 4-6 carbocyclic ring, thieno C 4-6 carbocyclic ring, thiophene And 4 to 6 membered heterocycle, furo C 4-6 carbocyclic ring, furo 4 to 6 membered heterocycle, 4-7 membered nitrogen-containing heteromonocyclic alkyl (such as azetidinyl, pyrrolidinyl, pipera Azinyl, piperidinyl), 4-10 membered nitrogen-containing heterocycloalkyl, 5-12-membered nitrogen-containing heterospirocycloalkyl, 7-10-membered nitrogen-containing heterobridged cycloalkyl, 3-7-membered monocyclic ring Alkyl, 4-10 membered paracycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, the B 5 is optionally substituted by 1 to 4 R b2 , the heterocycle , heteromonocycloalkyl, heterocycloalkyl, heterospirocycloalkyl, and heterobridged cycloalkyl contain 1 to 4 heteroatoms selected from O, S, and N;

B 5選自 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ，所述B 5任選被1至4個R b2取代； B 5 selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , the B 5 is optionally replaced by 1 to 4 R b2 ;

在某些實施方案中，R b1各自獨立的選自H、F、Cl、Br、I、=O、OH、CN、NO 2、COOH、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4烷硫基、-(CH 2) n-R b22、-OR b22、-N(R b21) 2、-C(=O)N(R b21) 2、-C(=O)OR b21、-C(=O)R b22、-S(=O) 2R b22、-P(=O)(R b22) 2、-S(=O) 2N(R b21) 2、-NR b21C(=O)R b22、-NR b21S(=O) 2R b22、C 3-12環烷基(較佳C 3-6環烷基)、C 6-10芳基、5-10員雜芳基(較佳5-6員雜芳基)或4-10員雜環基，所述的-CH 2-、烷基、烯基、炔基、烷氧基、烷硫基、環烷基、雜環基、芳基或雜芳基任選被1至4個選自F、Cl、Br、I、OH、=O、-N(R b21) 2、CN、COOH、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 2-4炔基、-C 1-4亞烷基-C 3-6環烷基、-C 1-4亞烷基-OH、-C 1-4亞烷基-O-C 1-4烷基、C 3-6環烷基、5-10員雜芳基或4-10員雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, R b1 is each independently selected from H, F, Cl, Br, I, =O, OH, CN, NO 2 , COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, -(CH 2 ) n -R b22 , -OR b22 , -N(R b21 ) 2 , -C(=O )N(R b21 ) 2 , -C(=O)OR b21 , -C(=O)R b22 , -S(=O) 2 R b22 , -P(=O)(R b22 ) 2 , -S (=O) 2 N(R b21 ) 2 , -NR b21 C(=O)R b22 , -NR b21 S(=O) 2 R b22 , C 3-12 cycloalkyl (preferably C 3-6 ring Alkyl), C 6-10 aryl, 5-10 membered heteroaryl (preferably 5-6 membered heteroaryl) or 4-10 membered heterocyclyl, the -CH 2 -, alkyl, alkenyl Alkyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally selected from 1 to 4 F, Cl, Br, I, OH, =O, - N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2- 4 alkynyl, -C 1-4 alkylene -C 3-6 cycloalkyl, -C 1-4 alkylene -OH, -C 1-4 alkylene -OC 1-4 alkyl, C 3 -6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl substituent, the heteroaryl or heterocyclyl contains 1 to 4 selected from O, S, N heteroatoms;

在某些實施方案中，R b1各自獨立的選自H、F、Cl、Br、I、=O、OH、NH 2、CN、NO 2、-C(=O)CH 3、-C(=O)NH 2、-C(=O)NH-CH 3、-C(=O)N(CH 3) 2、-S(=O) 2NH 2、-P(=O) 2(CH 3) 2、-S(=O) 2CH 3或者取代或未取代的如下基團之一：甲基、乙基、丙基、異丙基、乙烯基、乙炔基、甲氧基、乙氧基、環丙基、環丁基、環戊基、環己基、苯基、吡咯基、吡唑基、噁唑基、咪唑基、噻唑基、三氮唑基、氮雜環丁基、吡咯烷基、哌啶基、氧雜環丁基、氧雜環戊基、氧雜環己基、嗎啉、環戊基並環戊基、吡咯烷基並吡咯烷基、吡咯烷基並環戊基、氮雜環丁基螺環己基、環丁基螺環己基、環丁基螺哌啶基、環丙基螺環丁基、環丁基螺環丁基、環丁基螺環戊基、環丁基螺環己基、環戊基螺環己基、 ，當被取代時，任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、NHC 1-4烷基、N(C 1-4烷基) 2、CN、COOH、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 2-4炔基、-C 1-2亞烷基-C 3-6環烷基、-C 1-2亞烷基-OH、-C 1-2亞烷基-O-C 1-4烷基、C 3-6環烷基、5-6員雜芳基或4-6員雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, each R b1 is independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , CN, NO 2 , -C(=O)CH 3 , -C(= O)NH 2 , -C(=O)NH-CH 3 , -C(=O)N(CH 3 ) 2 , -S(=O) 2 NH 2 , -P(=O) 2 (CH 3 ) 2. -S(=O) 2 CH 3 or one of the following substituted or unsubstituted groups: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, azetidinyl, pyrrolidinyl, Piperidinyl, oxetanyl, oxolyl, oxanyl, morpholine, cyclopentacyclopentyl, pyrrolidinylpyrrolidinyl, pyrrolidinylcyclopentyl, aza Cyclobutylspirocyclohexyl, cyclobutylspirocyclohexyl, cyclobutylspiropiperidinyl, cyclopropylspirocyclobutyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspiro Cyclohexyl, cyclopentylspirocyclohexyl, , when substituted, optionally by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN , COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, -C 1- 2 alkylene-C 3-6 cycloalkyl, -C 1-2 alkylene-OH, -C 1-2 alkylene-OC 1-4 alkyl, C 3-6 cycloalkyl, 5- Substituted with a substituent of a 6-membered heteroaryl group or a 4-6 membered heterocyclyl group, the heteroaryl group or heterocyclic group containing 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，R b1各自獨立的選自H、F、Cl、Br、I、=O、OH、NH 2、N(CH 3) 2、CN、NO 2、-C(=O)CH 3、-C(=O)NH 2、-C(=O)NH-CH 3、-C(=O)N(CH 3) 2、-S(=O) 2NH 2、-P(=O) 2(CH 3) 2、-S(=O) 2CH 3或者任選取代的如下基團之一：甲基、乙基、丙基、異丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、環丙基、環丁基、環戊基、環己基、苯基、吡咯基、吡唑基、噁唑基、咪唑基、噻唑基、三氮唑基、氮雜環丁基、吡咯烷基、哌啶基、氧雜環丁基、氧雜環戊基、氧雜環己基、嗎啉、吡咯烷基並環戊基、氮雜環丁基螺環己基、環丙基螺環丁基、環丁基螺環丁基、環丁基螺環戊基、環丁基螺環己基、環戊基螺環己基、 ，當被取代時，被1至4個選自F、Cl、Br、I、OH、CN、CHF 2、CF 3、NH 2、NHCH 3、N(CH 3) 2、甲基、乙基、異丙基、乙炔基、-CH 2-CN、-CH 2OH、-CH 2OMe、-CH 2-環丙基、甲氧基、環丙基、環丁基、氮雜環丁基、吡咯烷基、哌啶基、嗎啉基、噻吩基、噻唑基、呋喃基、噁唑基、吡咯基、咪唑基、吡唑基、三氮唑基、四氮唑基的取代基所取代； In certain embodiments, each R b1 is independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , N(CH 3 ) 2 , CN, NO 2 , -C(=O) CH 3 , -C(=O)NH 2 , -C(=O)NH-CH 3 , -C(=O)N(CH 3 ) 2 , -S(=O) 2 NH 2 , -P(= O) 2 (CH 3 ) 2 , -S(=O) 2 CH 3 or one of the optionally substituted following groups: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propyne base, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, tris Azozolyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxanyl, oxanyl, morpholine, pyrrolidinylcyclopentyl, azetidinyl Spirocyclohexyl, cyclopropylspirocyclobutyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclohexyl, , when substituted, is selected from 1 to 4 F, Cl, Br, I, OH, CN, CHF 2 , CF 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, Isopropyl, ethynyl, -CH 2 -CN, -CH 2 OH, -CH 2 OMe, -CH 2 -cyclopropyl, methoxy, cyclopropyl, cyclobutyl, azetidinyl, pyrrole Substituted by alkyl, piperidyl, morpholinyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl substituents;

在某些實施方案中，R b1選自F、Cl、CN、CF 3、-OCF 3、甲基、乙基、甲氧基、乙氧基、乙炔基、丙炔基、環丙基、環丁基或R b1a； In certain embodiments, R b1 is selected from F, Cl, CN, CF 3 , -OCF 3 , methyl, ethyl, methoxy, ethoxy, ethynyl, propynyl, cyclopropyl, cyclo Butyl or R b1a ;

在某些實施方案中，R b1選自R b1a； In certain embodiments, R b1 is selected from R b1a ;

在某些實施方案中，R b2各自獨立的選自H、F、Cl、Br、I、=O、OH、NH 2、-N(R b21) 2、CN、NO 2、COOH、-C(=O)NH 2、-C(=O)NH-C 1-4烷基、-C(=O)N(C 1-4烷基) 2、-(CH 2) n-R b22、-(CH 2) nO(CH 2) n-R b22、-(CH 2) nO(CH 2) nO-R b22、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 3-8環烷基、C 6-10芳基、5至10員雜芳基、4至10員雜環基、-C 1-4亞烷基-4至10員雜環基，所述的亞烷基、CH 2、烷基、烯基、炔基、烷氧基、環烷基、雜環基、芳基或雜芳基任選被1至4個選自F、Cl、Br、I、OH、NH 2、-N(R b21) 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 3-6環烷基、C 3-6環烷基氧基、鹵素取代的C 3-6環烷基、鹵素取代的C 3-6環烷基氧基、5-6員雜芳基或4-8員雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, each R b2 is independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , -N(R b21 ) 2 , CN, NO 2 , COOH, -C( =O)NH 2 , -C(=O)NH-C 1-4 alkyl, -C(=O)N(C 1-4 alkyl) 2 , -(CH 2 ) n -R b22 , -( CH 2 ) n O(CH 2 ) n -R b22 , -(CH 2 ) n O(CH 2 ) n OR b22 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl, 4 to 10 membered heterocyclyl, -C 1-4 alkylene-4 to 10-membered heterocyclyl group, the alkylene group, CH 2 , alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group are optionally substituted by 1 to 4 Selected from F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 Alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, halogen-substituted C 3-6 cycloalkyl, halogen-substituted C 3-6 cycloalkyl Substituted with a substituent of an oxygen group, a 5-6 membered heteroaryl group or a 4-8 membered heterocyclyl group, the heteroaryl group or heterocyclyl group contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，R b2各自獨立的選自H、F、Cl、Br、I、=O、OH、NH 2、-N(R b21) 2、CN、NO 2、COOH、-C(=O)NH 2、-C(=O)NH-C 1-4烷基、-C(=O)N(C 1-4烷基) 2、-(CH 2) n-R b22、-(CH 2) nO(CH 2) n-R b22、-(CH 2) nO(CH 2) nO-R b22、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 3-8環烷基、C 6-10芳基、5至6員雜芳基、4至8員雜環基、-C 1-4亞烷基-4至8員雜環基，所述的亞烷基、CH 2、烷基、烯基、炔基、烷氧基、環烷基、雜環基、芳基或雜芳基任選被1至4個選自F、Cl、Br、I、OH、NH 2、-NHC 1-4烷基、-N(C 1-4烷基) 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 3-6環烷基、C 3-6環烷基氧基、鹵素取代的C 3-6環烷基、鹵素取代的C 3-6環烷基氧基、5-6員雜芳基或4-8員雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, each R b2 is independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , -N(R b21 ) 2 , CN, NO 2 , COOH, -C( =O)NH 2 , -C(=O)NH-C 1-4 alkyl, -C(=O)N(C 1-4 alkyl) 2 , -(CH 2 ) n -R b22 , -( CH 2 ) n O(CH 2 ) n -R b22 , -(CH 2 ) n O(CH 2 ) n OR b22 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, 5 to 6 membered heteroaryl, 4 to 8 membered heterocyclyl, -C 1-4 alkylene-4 to 8-membered heterocyclyl, the alkylene, CH 2 , alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are optionally substituted by 1 to 4 Selected from F, Cl, Br, I, OH, NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , CN, C 1-4 alkyl, halogen-substituted C 1- 4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, halogen substituted C 3-6 cycloalkyl substituted by a halogen-substituted C 3-6 cycloalkyloxy group, a 5-6-membered heteroaryl group or a 4-8-membered heterocyclyl substituent, and the heteroaryl group or heterocyclic group contains 1 to 4 A heteroatom selected from O, S, N;

在某些實施方案中，R b2各自獨立的選自H、F、Cl、Br、I、=O、OH、NH 2、NH(CH 3)、N(CH 3) 2、CN、NO 2、COOH、-C(=O)NH 2或者任選取代的如下基團之一：-CH 2OCH 2CH 3、甲基、乙基、異丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、丙氧基、異丙基氧基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、哌啶基、嗎啉基、吡唑基、噻唑基、三氮唑基、四氮唑基、苯基，當被取代時，被1至4個選自F、Cl、Br、I、OH、CN、CHF 2、CF 3、NH 2、NHCH 3、N(CH 3) 2、甲基、乙基、異丙基、甲氧基、乙氧基、吡唑基、嗎啉基、氧雜環己基、環丙基、 、環丁基、 、 、環丙基氧基、 、 、 、 的取代基所取代； In certain embodiments, each R b2 is independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CN, NO 2 , COOH, -C(=O)NH 2 or optionally substituted one of the following groups: -CH 2 OCH 2 CH 3 , methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, alkyne Propyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, Morpholinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, when substituted, are selected from 1 to 4 F, Cl, Br, I, OH, CN, CHF 2 , CF 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, isopropyl, methoxy, ethoxy, pyrazolyl, morpholinyl, oxanyl, cyclopropyl base, , cyclobutyl, , , cyclopropyloxy, , , , Substituted by substituents;

在某些實施方案中，R b2選自R b2a； In certain embodiments, R b2 is selected from R b2a ;

在某些實施方案中，R b21各自獨立的選自H或C 1-4烷基，所述的烷基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、CF 3、COOH、C 1-4烷基、C 3-6環烷基、C 1-4烷氧基的取代基所取代； In certain embodiments, R b21 is each independently selected from H or C 1-4 alkyl, and the alkyl group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, Substituted with substituents of NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkoxy;

在某些實施方案中，R b21各自獨立的選自H、甲基、乙基、異丙基； In certain embodiments, R b21 is each independently selected from H, methyl, ethyl, isopropyl;

在某些實施方案中，R b22各自獨立的選自H、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 3-6環烷基，所述的烷基、烷氧基、環烷基、烯基、炔基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、CF 3、COOH、C 1-4烷基、C 3-6環烷基、C 3-6環烷基氧基、C 1-4烷氧基的取代基所取代； In certain embodiments, R b22 is each independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 ring Alkyl group, the alkyl group, alkoxy group, cycloalkyl group, alkenyl group, and alkynyl group are optionally selected from 1 to 4 groups from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3. Substituted with substituents of COOH, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, and C 1-4 alkoxy;

在某些實施方案中，R b22各自獨立的選自H、甲基、乙基、丙基、異丙基、環丙基、環丁基； In certain embodiments, R b22 is each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl;

在某些實施方案中，n各自獨立的選自0、1、2、3或4；In certain embodiments, n is each independently selected from 0, 1, 2, 3, or 4;

在某些實施方案中，n各自獨立的選自0、1、2；In certain embodiments, n is each independently selected from 0, 1, and 2;

在某些實施方案中，n各自獨立的選自0、1；In certain embodiments, n is each independently selected from 0, 1;

在某些實施方案中，R b3、R b4、R b6、R b7各自獨立的選自H、F、Cl、Br、I、OH、NH 2、CN、NO 2、-(CH 2) m1-R b23、-(CH 2) m1-X-(CH 2) m2-R b24、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷硫基、C 3-12環烷基、C 6-10芳基、5-10員雜芳基或3-12員雜環基，所述的烷基、烯基、炔基、烷氧基、烷硫基、環烷基、芳基、雜芳基或雜環基任選被1至4個選自氘、F、Cl、Br、I、OH、NH 2、CN、C 1-6烷基、鹵素取代的C 1-6烷基、氰基取代的C 1-6烷基、C 1-6烷氧基、C 2-6炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, R b3 , R b4 , R b6 , R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 - R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkoxy group, C 1-6 alkylthio group, C 3-12 cycloalkyl group, C 6-10 aryl group, 5-10 membered heteroaryl group or 3-12 membered heterocyclyl group, the alkyl group, alkenyl group or alkynyl group , alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally selected from 1 to 4 deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkynyl, C 3-8 cycloalkyl or Substituted with 3 to 8 heterocyclyl substituents, the heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;

任選地，R b3、R b4不同時為H； Optionally, R b3 and R b4 are not H at the same time;

任選地，R b6、R b7不同時為H； Optionally, R b6 and R b7 are not H at the same time;

在某些實施方案中，R b3、R b4與其相連接的碳原子共同形成C 3-8環烷基或3至8員雜單環，所述的環烷基或雜單環任選被1至4個選自氘、F、Cl、Br、I、OH、NH 2、-N(R b21) 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-6環烷基、5-6員雜芳基或3至8雜環基的取代基所取代，所述的雜單環、雜芳基或雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, R b3 and R b4 and the carbon atoms to which they are connected together form a C 3-8 cycloalkyl group or a 3- to 8-membered heteromonocyclic ring, and the cycloalkyl group or heteromonocyclic ring is optionally replaced by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted Substituted with substituents of C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl , the heteromonocyclic, heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，R b3、R b4各自獨立的選自H、OH、NH 2、C 1-4烷基、C 2-4炔基、C 3-8環烷基(較佳C 3-6環烷基)或3至8雜單環，所述的烷基、炔基、環烷基或雜單環任選被1至4個選自氘、F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 3-6環烷基、C 1-4烷氧基、C 2-4炔基或3至8雜環基的取代基所取代，所述的雜單環、雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, R b3 and R b4 are each independently selected from H, OH, NH 2 , C 1-4 alkyl, C 2-4 alkynyl, C 3-8 cycloalkyl (preferably C 3 -6 cycloalkyl) or 3 to 8 heteromonocyclic rings, the alkyl, alkynyl, cycloalkyl or heteromonocyclic ring is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH , NH 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, Substituted with C 2-4 alkynyl or 3 to 8 heterocyclyl substituents, the heteromonocyclic and heterocyclic groups contain 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，R b3、R b4各自獨立的選自H、OH、NH 2或者任選取代的如下基團之一：甲基、乙基、乙炔基、丙炔基、炔丙基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、哌啶基、氧雜環丁基、氧雜環戊基、氧雜環己基、環丁基螺環丁基，當被取代時，被1至4個選自氘、F、Cl、Br、I、OH、NH 2、CN、CF 3、CHF 2、甲基、甲氧基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、吡唑基、哌啶基、氧雜環丁基、氧雜環戊基、氧雜環己基、環丁基螺環丁基的取代基所取代；； In certain embodiments, R b3 and R b4 are each independently selected from H, OH, NH 2 or optionally substituted one of the following groups: methyl, ethyl, ethynyl, propynyl, propargyl , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxanyl, oxanyl, cyclobutyl Spirocyclobutyl, when substituted, is substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, CF 3 , CHF 2 , methyl, methoxy, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, pyrazolyl, piperidinyl, oxetanyl, oxetanyl, oxetanyl, cyclobutyl Substituted by spirocyclobutyl substituent;;

在某些實施方案中，R b3、R b4與其相連接的碳原子共同形成C 3-8環烷基(較佳C 3-6環烷基)或3至8員雜單環，所述的環烷基或雜單環任選被1至4個選自氘、F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-8碳環基或3至8雜環基的取代基所取代，所述的雜單環含有1至4個選自O、S、N的雜原子； In certain embodiments, R b3 and R b4 and the carbon atoms to which they are connected together form a C 3-8 cycloalkyl group (preferably C 3-6 cycloalkyl group) or a 3 to 8-membered heteromonocyclic ring, as described The cycloalkyl or heteromonocyclic ring is optionally substituted with 1 to 4 C 1-4 alkyl groups selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen, Substituted with cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 carbocyclyl or 3 to 8 heterocyclyl substituents, the heterocyclic The single ring contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，R b3、R b4與其相連接的碳原子共同形成環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、哌啶基、氧雜環丁基、氧雜環戊基、氧雜環己基，所述的環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、哌啶基、氧雜環丁基、氧雜環戊基、氧雜環己基任選被1至4個(例如1、2、3或4個)選自氘、F、Cl、Br、I、OH、NH 2、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-6環烷基或4至6雜環基的取代基所取代，所述的雜單環或雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, R b3 and R b4 together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxy Heterocyclylbutyl, oxanyl, oxanyl, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxa Cyclobutyl, oxanyl, and oxanyl are optionally selected from 1 to 4 (for example, 1, 2, 3 or 4) from deuterium, F, Cl, Br, I, OH, NH 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl or Substituted with 4 to 6 heterocyclyl substituents, the heteromonocyclic or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，R b3、R b4與其相連接的碳原子共同形成環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、哌啶基、氧雜環丁基、氧雜環戊基、氧雜環己基、環丁基螺環丁基，所述的環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、哌啶基、氧雜環丁基、氧雜環戊基、氧雜環己基、環丁基螺環丁基任選被1至4個選自氘、F、Cl、Br、I、OH、NH 2、N(CH 3)、CN、CF 3、CHF 2、甲基、乙基、異丙基、甲氧基、乙氧基、丙氧基、異丙基氧基、環丙基、環丁基、氮雜環丁基、氧雜環丁基、吡唑基、噻唑基、三氮唑基、四氮唑基的取代基所取代； In certain embodiments, R b3 and R b4 together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxy Heterocyclylbutyl, oxolyl, oxanyl, cyclobutylspirocyclobutyl, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidine base, piperidinyl, oxetanyl, oxetanyl, oxetanyl, cyclobutylspirocyclobutyl optionally 1 to 4 selected from deuterium, F, Cl, Br, I, OH , NH 2 , N(CH 3 ), CN, CF 3 , CHF 2 , methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, Substituted by substituents of cyclobutyl, azetidinyl, oxetanyl, pyrazolyl, thiazolyl, triazolyl, and tetrazolyl;

在某些實施方案中，R b3與R b5a、R b1與R b5a直接連接形成環S，環S選自4至9員含氮雜環基，環S任選被1至4個選自R s的取代基所取代； In certain embodiments, R b3 and R b5a , R b1 and R b5a are directly connected to form ring S, ring S is selected from 4 to 9 membered nitrogen-containing heterocyclyl groups, and ring S is optionally surrounded by 1 to 4 members selected from R Substituted by s substituent;

在某些實施方案中，R s各自獨立的選自F、Cl、Br、I、OH、NH 2、-N(R b21) 2、CN、C 1-4烷基、C 1-4烷氧基、C 3-6環烷基、5-6員雜芳基或3至8雜環基，所述的烷基、烷氧基、環烷基、雜芳基或者雜環基任選被1至4個選自F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的雜環基或雜芳基含有1至4個選自O、S、N的雜原子； In certain embodiments, each R s is independently selected from F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, C 1-4 alkoxy base, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl, the alkyl, alkoxy, cycloalkyl, heteroaryl or heterocyclyl is optionally replaced by 1 Substituted with 4 substituents selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl or C 1-4 alkoxy, the heterocyclyl or heteroaryl Contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，R s各自獨立的選自F、Cl、Br、I、OH、NH 2、-NHC 1-4烷基、-N(C 1-4烷基) 2、CN、C 1-4烷基、C 1-4烷氧基、C 3-6環烷基，所述的烷基、烷氧基或者環烷基任選被1至4個選自F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基或C 1-4烷氧基的取代基所取代； In certain embodiments, each R s is independently selected from F, Cl, Br, I, OH, NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, the alkyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 selected from F, Cl, Br, Substituted by I, OH, NH 2 , CN, C 1-4 alkyl or C 1-4 alkoxy substituents;

在某些實施方案中，R s各自獨立的選自 \F、Cl、Br、I、OH、NH 2、CN、甲基、乙基、甲氧基、乙氧基或環丙基； In certain embodiments, each R s is independently selected from \ F, Cl, Br, I, OH, NH 2 , CN, methyl, ethyl, methoxy, ethoxy or cyclopropyl;

在某些實施方案中，R b5a選自H或R b5； In certain embodiments, R b5a is selected from H or R b5 ;

在某些實施方案中，R b5選自OH、NH 2、C 1-4烷基、-(CH 2) n-R b22、-C(=O)N(R b21) 2、-C(=O)R b22、C 3-6環烷基、C 6-10芳基、5-10員雜芳基或4-10員雜環基，所述的-CH 2-、烷基、環烷基、雜環基、芳基或雜芳基任選被1至4個選自F、Cl、Br、I、OH、=O、-N(R b21) 2、CN、COOH、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 3-6環烷基、5-10員雜芳基或4-10員雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, R b5 is selected from OH, NH 2 , C 1-4 alkyl, -(CH 2 ) n -R b22 , -C(=O)N(R b21 ) 2 , -C(= O)R b22 , C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, the -CH 2 -, alkyl, cycloalkyl , Heterocyclyl, aryl or heteroaryl are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkane group, C 1-4 alkoxy group, halogen-substituted C 1-4 alkyl group, cyano-substituted C 1-4 alkyl group, C 3-6 cycloalkyl group, 5-10 membered heteroaryl group or 4-10 Substituted with a substituent of a membered heterocyclyl group, the heteroaryl group or heterocyclyl group contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，R b5選自OH、NH 2、甲基、乙基、丙基、異丙基、-(CH 2) n-環丙基、-(CH 2) n-環丁基、-(CH 2) n-環戊基、-(CH 2) n-環己基、苯基、吡啶基，所述的-CH 2-、甲基、乙基、丙基、異丙基、環丙基、環丁基、環戊基、環己基、苯基、吡啶基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 3-6環烷基、5-10員雜芳基或4-10員雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, R b5 is selected from OH, NH 2 , methyl, ethyl, propyl, isopropyl, -(CH 2 ) n -cyclopropyl, -(CH 2 ) n -cyclobutyl , -(CH 2 ) n -cyclopentyl, -(CH 2 ) n -cyclohexyl, phenyl, pyridyl, the -CH 2 -, methyl, ethyl, propyl, isopropyl, cyclohexyl, Propyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and pyridyl are optionally selected from 1 to 4 from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1 -4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl or Substituted with a substituent of a 4-10 membered heterocyclic group, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，R b5選自甲基、乙基、丙基、異丙基、環丙基、環丁基、環戊基、環己基、-CH 2-環丙基、-CH 2-環丁基、-CH 2-環戊基、-CH 2-環己基、苯基、吡啶基，所述的-CH 2-、甲基、乙基、丙基、異丙基、環丙基、環丁基、環戊基、環己基、苯基、吡啶基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基的取代基所取代； In certain embodiments, R b5 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -Cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, phenyl, pyridyl, the -CH 2 -, methyl, ethyl, propyl, isopropyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and pyridyl are optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 Substituted with substituents of alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl;

在某些實施方案中，R b6選自F、Cl、Br、I、OH、NH 2、CN、NO 2、-(CH 2) m1-R b23、-(CH 2) m1-X-(CH 2) m2-R b24、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷硫基、C 3-12環烷基、C 6-10芳基、5-10員雜芳基或4-12員雜環基，所述的烷基、烯基、炔基、烷氧基、烷硫基、環烷基、芳基、雜芳基或雜環基任選被1至4個選自F、Cl、Br、I、OH、NH 2、CN、C 1-6烷基、鹵素取代的C 1-6烷基、氰基取代的C 1-6烷基、C 1-6烷氧基、C 2-4炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-12 cycloalkyl base, C 6-10 aryl group, 5-10 membered heteroaryl group or 4-12 membered heterocyclyl group, the alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, cycloalkyl group, aromatic group The base, heteroaryl or heterocyclic group is optionally substituted by 1 to 4 C 1-6 alkyl groups selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-6 alkyl, halogen, Substituted with cyano-substituted C 1-6 alkyl, C 1-6 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, the heterocyclic The aryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，R b6選自F、Cl、Br、I、OH、NH 2、CN、NO 2、-(CH 2) m1-R b23、-(CH 2) m1-X-(CH 2) m2-R b24、C 2-4炔基、C 3-12環烷基、C 6-10芳基、5-10員雜芳基或4-12員雜環基，所述的炔基、環烷基、芳基、雜芳基或雜環基任選被1至4個選自F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 2-4 alkynyl, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-12 membered heterocyclyl, the alkynyl group , cycloalkyl, aryl, heteroaryl or heterocyclyl optionally substituted by 1 to 4 C selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents Substituted, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，R b6選自F、Cl、Br、I、OH、NH 2、CN、NO 2、-(CH 2) m1-R b23、-(CH 2) m1-X-(CH 2) m2-R b24、C 2-4炔基、C 3-6環烷基、C 5-10橋環烷基、C 5-12螺環烷基、C 4-12並環烷基、C 6-10芳基、5-6員雜芳基、4-8員雜環基、5-10員雜橋環、5-12員雜螺環、5-12員雜並環，所述的炔基、環烷基、芳基、雜芳基、雜環基、雜橋環、雜螺環或雜並環任選被1至4個選自F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜芳基、雜環基、雜橋環、雜螺環或雜並環含有1至4個選自O、S、N的雜原子； In certain embodiments, R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 2-4 alkynyl, C 3-6 cycloalkyl, C 5-10 bridged cycloalkyl, C 5-12 spirocycloalkyl, C 4-12 cycloalkyl, C 6-10 aryl, 5-6-membered heteroaryl, 4-8-membered heterocyclyl, 5-10-membered heterobridged ring, 5-12-membered heterospirocyclic, 5-12-membered heterocyclic, the alkyne The base, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterobridged ring, heterospiro ring or heterocyclic ring is optionally 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 ring Substituted with alkyl or 3 to 8 heterocyclyl substituents, the heteroaryl, heterocyclyl, heterobridged ring, heterospiro ring or heterocyclic ring contains 1 to 4 selected from O, S, N heteroatoms;

在某些實施方案中，R b6選自F、Cl、Br、I、OH、NH 2、CN、NO 2、-CH 2-R b23、-CH 2-X-(CH 2) m2-R b24或者取代或未取代的如下基團之一：乙炔基、丙炔基、炔丙基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、氧雜環丁基、吡咯烷基、氮雜環己烯基、哌啶基、嗎啉基、哌嗪基、1,4-二氮雜庚烷基、苯基、吡啶基、環丙基並環丙基、環丙基並環丁基、環丙基並環戊基、環丙基並環己基、環丁基並環丁基、環丁基並環戊基、環丁基並環己基、環戊基並環戊基、環戊基並環己基、環己基並環己基、環丙基螺環丙基、環丙基螺環丁基、環丙基螺環戊基、環丙基螺環己基、環丁基螺環丁基、環丁基螺環戊基、環丁基螺環己基、環戊基螺環戊基、環戊基螺環己基、環己基螺環己基、環丙基並氮雜環丁基、環丙基並吡咯烷基、環丙基並哌啶基、環丁基並氮雜環丁基、環丁基並吡咯烷基、環丁基並哌啶基、環戊基並氮雜環丁基、環戊基並吡咯烷基、環戊基並哌啶基、環己基並氮雜環丁基、環己基並吡咯烷基、環己基並哌啶基、氮雜環丁基並氮雜環丁基、氮雜環丁基並吡咯烷基、氮雜環丁基並哌啶基、吡咯烷基並氮雜環丁基、吡咯烷基並吡咯烷基、吡咯烷基並哌啶基、哌啶基並氮雜環丁基、哌啶基並吡咯烷基、哌啶基並哌啶基、環丁基螺氮雜環丁基、環丁基螺吡咯烷基、環丁基螺哌啶基、環戊基螺氮雜環丁基、環戊基螺吡咯烷基、環戊基螺哌啶基、環己基螺氮雜環丁基、環己基螺吡咯烷基、環己基螺哌啶基、氮雜環丁基螺氮雜環丁基、氮雜環丁基螺吡咯烷基、氮雜環丁基螺哌啶基、吡咯烷基螺氮雜環丁基、吡咯烷基螺吡咯烷基、吡咯烷基螺哌啶基、哌啶基螺氮雜環丁基、哌啶基螺哌啶基、 、 、 、 、 、 、 、 、 、 ，當被取代時，被1至4個選自F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -CH 2 -R b23 , -CH 2 -X-(CH 2 ) m2 -R b24 Or one of the following groups, substituted or unsubstituted: ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, Pyrrolidinyl, azepinenyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, phenyl, pyridyl, cyclopropylcyclopropyl, cyclopropyl Cyclobutyl, cyclopropylcyclohexyl, cyclopropylcyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl base, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspiro Cyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, Cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl base, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinylazetidine Butyl, azetidinylpyrrolidinyl, azetidinylpiperidinyl, pyrrolidinylazetidinyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, pipera Aldynazetidinyl, piperidinopyrrolidinyl, piperidinopiperidinyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidyl, cyclobutylspiropiperidinyl , Cyclopentylspiroazetidinyl, cyclopentylspiropyrrolidyl, cyclopentylspiropiperidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidyl, cyclohexylspiropyrolidinyl, Azetidinylspiroazetidinyl, azetidinylspiropyrrolidyl, azetidinylspiropiperidinyl, pyrrolidinylspiroazetidinyl, pyrrolidinylspiropyrrolidinyl, Pyrrolidinylspiropiperidinyl, piperidinylspiroazetidinyl, piperidinylspiropiperidinyl, , , , , , , , , , , when substituted, C 1-4 alkyl substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen substituted, cyano substituted C Substituted with 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, the heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，R b3、R b4、R b7各自獨立的選自H、F、Cl、Br、I、OH、NH 2、CN、NO 2、-(CH 2) m1-R b23、-(CH 2) m1-X-(CH 2) m2-R b24、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 2-4炔基、C 3-12環烷基、C 6-10芳基、5-10員雜芳基或4-12員雜環基，所述的烷基、烷氧基、烷硫基、炔基、環烷基、芳基、雜芳基或雜環基任選被1至4個選自氘、F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, R b3 , R b4 , and R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkynyl, C 3 -12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-12 membered heterocyclyl, the alkyl, alkoxy, alkylthio, alkynyl, cycloalkyl, Aryl, heteroaryl or heterocyclyl are optionally substituted with 1 to 4 C 1-4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, and halogen. Alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, so The heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，R b3、R b4、R b7各自獨立的選自H、F、Cl、Br、I、OH、NH 2、CN、NO 2、-(CH 2) m1-R b23、-(CH 2) m1-X-(CH 2) m2-R b24、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 2-4炔基、C 3-6環烷基、C 5-10橋環烷基、C 5-12螺環烷基、C 4-12並環烷基、C 6-10芳基、5-6員雜芳基、4-8員雜環基、5-10員雜橋環、5-12員雜螺環、5-12員雜並環，所述的烷基、烷氧基、烷硫基、炔基、環烷基、芳基、雜芳基、雜環基、雜橋環、雜螺環或雜並環任選被1至4個選自氘、F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜芳基、雜環基、雜橋環、雜螺環或雜並環含有1至4個選自O、S、N的雜原子； In certain embodiments, R b3 , R b4 , and R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkynyl, C 3 -6 cycloalkyl, C 5-10 bridged cycloalkyl, C 5-12 spirocycloalkyl, C 4-12 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, 4- 8-membered heterocyclyl, 5-10-membered heterobridged ring, 5-12-membered heterospirocycle, 5-12-membered heterocyclic ring, the alkyl group, alkoxy group, alkylthio group, alkynyl group, cycloalkyl group , aryl, heteroaryl, heterocyclyl, heterobridged ring, heterospirocycle or heterocyclic ring optionally 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or Substituted with 3 to 8 heterocyclyl substituents, the heteroaryl, heterocyclyl, heterobridged ring, heterospirocyclic or heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，R b3、R b4、R b7各自獨立的選自H、F、Cl、Br、I、OH、NH 2、CN、NO 2、CHF 2、CF 3、-CH 2-R b23、-CH 2-X-(CH 2) m2-R b24或者取代或未取代的如下基團之一：乙炔基、丙炔基、炔丙基、甲基、乙基、甲氧基、乙氧基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、氮雜環己烯基、哌啶基、嗎啉基、哌嗪基、1,4-二氮雜庚烷基、苯基、環丙基並環丙基、環丙基並環丁基、環丙基並環戊基、環丙基並環己基、環丁基並環丁基、環丁基並環戊基、環丁基並環己基、環戊基並環戊基、環戊基並環己基、環己基並環己基、環丙基螺環丙基、環丙基螺環丁基、環丙基螺環戊基、環丙基螺環己基、環丁基螺環丁基、環丁基螺環戊基、環丁基螺環己基、環戊基螺環戊基、環戊基螺環己基、環己基螺環己基、環丙基並氮雜環丁基、環丙基並吡咯烷基、環丙基並哌啶基、環丁基並氮雜環丁基、環丁基並吡咯烷基、環丁基並哌啶基、環戊基並氮雜環丁基、環戊基並吡咯烷基、環戊基並哌啶基、環己基並氮雜環丁基、環己基並吡咯烷基、環己基並哌啶基、氮雜環丁基並氮雜環丁基、氮雜環丁基並吡咯烷基、氮雜環丁基並哌啶基、吡咯烷基並氮雜環丁基、吡咯烷基並吡咯烷基、吡咯烷基並哌啶基、哌啶基並氮雜環丁基、哌啶基並吡咯烷基、哌啶基並哌啶基、環丁基螺氮雜環丁基、環丁基螺吡咯烷基、環丁基螺哌啶基、環戊基螺氮雜環丁基、環戊基螺吡咯烷基、環戊基螺哌啶基、環己基螺氮雜環丁基、環己基螺吡咯烷基、環己基螺哌啶基、氮雜環丁基螺氮雜環丁基、氮雜環丁基螺吡咯烷基、氮雜環丁基螺哌啶基、吡咯烷基螺氮雜環丁基、吡咯烷基螺吡咯烷基、吡咯烷基螺哌啶基、哌啶基螺氮雜環丁基、哌啶基螺哌啶基、 、 、 、 、 、 、 、 、 、 ，當被取代時，被1至4個選自氘、F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-8環烷基或3至8雜環基的取代基所取代(較佳被1至4個選自氘、F、Cl、Br、I、OH、NH 2、CN、CF 3、CHF 2、甲基、乙基、甲氧基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、哌啶基、氧雜環丁基、氧雜環戊基、氧雜環己基、環丁基螺環丁基的取代基所取代)，所述的雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, R b3 , R b4 , R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , CHF 2 , CF 3 , -CH 2 - R b23 , -CH 2 -X-(CH 2 ) m2 -R b24 or one of the following substituted or unsubstituted groups: ethynyl, propynyl, propargyl, methyl, ethyl, methoxy, Ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, piperidinyl, morpholinyl, piperazinyl, 1, 4-Diazepanyl, phenyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclobutylcyclobutyl , cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocycle Butyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclobutyl Pentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutyl cyclopentapyrrolidinyl, cyclobutylazetidinyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclohexylazetidinyl, cyclohexylazetidinyl Hexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl, azetidinylpyrrolidinyl, azetidinylpiperidinyl, pyrrolidinyl azo Heterocyclylbutyl, pyrrolidinopyrrolidyl, pyrrolidinolopiperidinyl, piperidinoazetidinyl, piperidinopyrrolidinyl, piperidinopiperidinyl, cyclobutyl Spiroazetidinyl, cyclobutylspiropyrrolidyl, cyclobutylspiropiperidinyl, cyclopentylspiroazetidinyl, cyclopentylspiropyrrolidyl, cyclopentylspiropiperidinyl, cyclopentylspiropyrrolidyl Hexylspiroazetidinyl, cyclohexylspiropyrrolidyl, cyclohexylspiropiperidinyl, azetidinylspiroazetidinyl, azetidinylspiropyrrolidyl, azetidinylspiro Piperidinyl, pyrrolidinylspiroazetidinyl, pyrrolidinylspiropyrrolidyl, pyrrolidinylspiropiperidinyl, piperidinylspiroazetidinyl, piperidinylspiroazetidinyl, , , , , , , , , , , when substituted, is substituted by 1 to 4 C 1-4 alkyl substituted by deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen substituted, cyano Substituted with C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents (preferably by 1 to 4 Selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, CF 3 , CHF 2 , methyl, ethyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Substituted with azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxanyl, oxetanyl, cyclobutylspirocyclobutyl substituents), the heterocyclic ring The base contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中， 選自 、 、 、 ； In certain embodiments, Selected from , , , ;

在某些實施方案中，X各自獨立的選自NH、O或S；In certain embodiments, each X is independently selected from NH, O, or S;

在某些實施方案中，X各自獨立的選自NH、O；In certain embodiments, X is each independently selected from NH, O;

在某些實施方案中，R b23各自獨立的選自C 2-4烯基、C 2-4炔基、C 3-6環烷基或4-10員雜環基，所述的環烷基、烯基、炔基、雜環基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、CF 3、COOH、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or 4-10 membered heterocyclyl, and the cycloalkyl , alkenyl, alkynyl, heterocyclyl optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, halogen Substituted with substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 selected from O, S, N heteroatoms;

在某些實施方案中，R b23各自獨立的選自C 2-4烯基、C 2-4炔基、C 3-6環烷基或4-8員雜環基，所述的環烷基、烯基、炔基、雜環基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、CF 3、COOH、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or 4-8 membered heterocyclyl, and the cycloalkyl , alkenyl, alkynyl, heterocyclyl optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, halogen Substituted with substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 selected from O, S, N heteroatoms;

在某些實施方案中，R b23各自獨立的選自乙烯基、乙炔基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、氮雜環己烯基、氧雜環丁基、氧雜環戊基、氧雜環己基、哌啶或嗎啉，所述的乙烯基、乙炔基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、氮雜環己烯基、氧雜環丁基、氧雜環戊基、氧雜環己基、哌啶或嗎啉任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代； In certain embodiments, each R b23 is independently selected from vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azepine base, oxetanyl, oxanyl, oxanyl, piperidine or morpholine, the vinyl group, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, nitrogen Heterocyclylbutyl, pyrrolidinyl, azepinenyl, oxetanyl, oxanyl, oxanyl, piperidine or morpholine are optionally selected from 1 to 4 F, Cl , Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkyl Substituted by an oxygen substituent;

在某些實施方案中，R b24各自獨立的選自C 1-4烷氧基、C 3-6環烷基氧基、C 3-6環烷基或4-10員雜環基，所述的烷氧基、環烷基、環烷基氧基、雜環基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、CF 3、COOH、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, each R b24 is independently selected from C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl or 4-10 membered heterocyclyl, The alkoxy group, cycloalkyl group, cycloalkyloxy group and heterocyclic group are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, Substituted with C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，R b24各自獨立的選自C 1-4烷氧基、C 3-6環烷基氧基、C 3-6環烷基或4-8員雜環基，所述的烷氧基、環烷基、環烷基氧基、雜環基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、CF 3、COOH、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, each R b24 is independently selected from C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl or 4-8 membered heterocyclyl, The alkoxy group, cycloalkyl group, cycloalkyloxy group and heterocyclic group are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, Substituted with C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，R b24各自獨立的選自甲氧基、乙氧基、丙氧基、異丙基氧基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、氮雜環己烯基、氧雜環丁基、氧雜環戊基、氧雜環己基、哌啶或嗎啉，所述的甲氧基、乙氧基、丙氧基、異丙基氧基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、氮雜環己烯基、氧雜環丁基、氧雜環戊基、氧雜環己基、哌啶或嗎啉任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代； In certain embodiments, each R b24 is independently selected from methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetamine Butyl, pyrrolidinyl, azepinenyl, oxetanyl, oxanyl, oxanyl, piperidine or morpholine, the methoxy, ethoxy, propoxy base, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, oxetanyl, oxolane base, oxanyl, piperidine or morpholine optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl, halogen Substituted with C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy substituents;

在某些實施方案中，m1各自獨立的選自0、1、2或3；In certain embodiments, each m1 is independently selected from 0, 1, 2, or 3;

在某些實施方案中，m2各自獨立的選自0、1、2或3；In certain embodiments, each m2 is independently selected from 0, 1, 2, or 3;

在某些實施方案中，m2各自獨立的選自0、1、2；In certain embodiments, m2 is each independently selected from 0, 1, and 2;

在某些實施方案中，R b7選自H、F、Cl、Br、I、OH、NH 2、CN、NO 2、CHF 2、CF 3、甲基、乙基、乙炔基、丙炔基、炔丙基、-CH 2-環丙基、-CH 2-環丁基、-CH 2-環戊基、-CH 2-環己基、-CH 2-氧雜環丁基、-CH 2-氧雜環戊基、-CH 2-嗎啉基、-CH 2-氮雜環丁基、-CH 2-吡咯烷基、-CH 2-哌啶基、-CH 2O(CH 2) 2OCH 3、-CH 2O-環丁基、-CH 2O-環丙基、-CH 2OCH 2-環丁基、-CH 2OCH 2-環丙基、-CH 2NH-環丁基、-CH 2NH-環丙基、-CH 2OCH 2-氧雜環丁基、-CH 2OCH 2-氧雜環丙基，所述的甲基、乙基、乙炔基、丙炔基、炔丙基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、氧雜環丁基、氧雜環戊基、哌啶基或嗎啉任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基的、C 2-4炔基、C 3-8環烷基或3至8雜環基取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, R b7 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , CHF 2 , CF 3 , methyl, ethyl, ethynyl, propynyl, Propargyl , -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -oxetanyl, -CH 2 -oxo Heterocyclopentyl, -CH 2 -morpholinyl, -CH 2 -azetidinyl, -CH 2 -pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 O(CH 2 ) 2 OCH 3 , -CH 2 O-cyclobutyl, -CH 2 O-cyclopropyl, -CH 2 OCH 2 -cyclobutyl, -CH 2 OCH 2 -cyclopropyl, -CH 2 NH-cyclobutyl, -CH 2 NH-cyclopropyl, -CH 2 OCH 2 -oxetanyl, -CH 2 OCH 2 -oxetanyl, the methyl, ethyl, ethynyl, propynyl, and propargyl groups , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxetanyl, oxolyl, piperidyl or morpholine optionally substituted by 1 to 4 Each is selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl , C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents substituted, the heterocyclyl contains 1 to 4 selected from O , S, N heteroatoms;

在某些實施方案中，R b7選自取代或未取代的如下基團之一：乙炔基、丙炔基、炔丙基、甲基、乙基、甲氧基、乙氧基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、哌啶基、氧雜環丁基、氧雜環戊基、氧雜環己基、嗎啉、苯基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、吡嗪基、噠嗪基、環戊基並環戊基、環戊基並環己基、環丙基螺環丙基、環丙基螺環丁基、環丙基螺環戊基、環丙基螺環己基、環丁基螺環丁基、環丁基螺環戊基、環丁基螺環己基、環戊基螺環戊基、環戊基螺環己基、環己基螺環己基、 ，當被取代時，被1至4個選自F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, R b7 is selected from one of the following groups, substituted or unsubstituted: ethynyl, propynyl, propargyl, methyl, ethyl, methoxy, ethoxy, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolyl, oxetanyl, morpholine, phenyl, thiophene base, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocycle Butyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclobutyl Pentylspirocyclohexyl, cyclohexylspirocyclohexyl, , when substituted, C 1-4 alkyl substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen substituted, cyano substituted C Substituted with 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, the heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，R b6選自F、Cl、Br、I、OH、NH 2、CN、NO 2或者任選取代的如下基團之一：乙炔基、丙炔基、炔丙基、-CH 2-環丙基、-CH 2-環丁基、-CH 2-環戊基、-CH 2-環己基、-CH 2-氧雜環丁基、-CH 2-氧雜環戊基、-CH 2-嗎啉基、-CH 2-氮雜環丁基、-CH 2-吡咯烷基、-CH 2-哌啶基、-CH 2O(CH 2) 2OCH 3、-CH 2O-環丁基、-CH 2O-環丙基、-CH 2OCH 2-環丁基、-CH 2OCH 2-環丙基、-CH 2NH-環丁基、-CH 2NH-環丙基、-CH 2OCH 2-氧雜環丁基、-CH 2OCH 2-氧雜環丙基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、哌啶基、氧雜環丁基、氧雜環戊基、氧雜環己基、嗎啉、苯基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、吡嗪基、噠嗪基、環戊基並環戊基、環戊基並環己基、環丙基螺環丙基、環丙基螺環丁基、環丙基螺環戊基、環丙基螺環己基、環丁基螺環丁基、環丁基螺環戊基、環丁基螺環己基、環戊基螺環戊基、環戊基螺環己基、環己基螺環己基、 ，當被取代時，被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 or optionally substituted one of the following groups: ethynyl, propynyl, propargyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl , -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -oxetanyl, -CH 2 -oxanyl , -CH 2 -morpholinyl, -CH 2 -azetidinyl, -CH 2 -pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 O(CH 2 ) 2 OCH 3 , -CH 2 O-cyclobutyl, -CH 2 O-cyclopropyl, -CH 2 OCH 2 -cyclobutyl, -CH 2 OCH 2 -cyclopropyl, -CH 2 NH-cyclobutyl, -CH 2 NH-cyclo Propyl, -CH 2 OCH 2 -oxetanyl, -CH 2 OCH 2 -oxetanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidine base, piperidinyl, oxetanyl, oxanyl, oxetanyl, morpholine, phenyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazine base, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutyl Basespirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, , when substituted, C 1-4 alkyl substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl, halogen, Substituted with cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, the heterocyclic The ring group contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，R b6選自C 3-8環烷基、-CH 2-C 3-8環烷基或-CH 2CH 2-C 3-8環烷基，所述的環烷基較佳環丙基、環丁基、環戊基、環己基，所述R b6任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-8環烷基或3至8雜環基取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, R b6 is selected from C 3-8 cycloalkyl, -CH 2 -C 3-8 cycloalkyl, or -CH 2 CH 2 -C 3-8 cycloalkyl, said cycloalkyl The preferred base is cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and the R b6 is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl Substituted with a base or 3 to 8 heterocyclyl substituents, the heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中， 選自 或 ； In certain embodiments, Selected from or ;

在某些實施方案中， 選自 ，B 1選自C 6-14碳環基或5-14員雜環基，所述的B 1被1個R b1a取代、任選被1至3個R b1取代，B 2選自5-10員雜環基，所述B 2任選被1至3個R b2取代，所述的雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, Selected from , B 1 is selected from C 6-14 carbocyclyl or 5-14 membered heterocyclyl, the B 1 is substituted by 1 R b1a , optionally substituted by 1 to 3 R b1 , B 2 is selected from 5- A 10-membered heterocyclyl group, the B 2 is optionally substituted by 1 to 3 R b2 , and the heterocyclyl group contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中， 選自 ，B 1選自C 6-14碳環基或5-14員雜環基，所述的B 1任選被1至4個R b1取代，B 2選自5-10員雜環基，所述B 2被1個R b2a取代、任選被1至3個R b2取代，所述的雜環基含有1至4個選自O、S、N的雜原子； In certain embodiments, Selected from , B 1 is selected from C 6-14 carbocyclyl or 5-14 membered heterocyclyl, the B 1 is optionally substituted by 1 to 4 R b1 , B 2 is selected from 5-10 membered heterocyclyl, so The B 2 is substituted by 1 R b2a , optionally substituted by 1 to 3 R b2 , and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中， 選自 ， 選自 或C 5-10螺環，所述的 被1至3個選自R b3a取代，所述的螺環任選被1至3個選自鹵素或R b3a取代； In certain embodiments, Selected from , Selected from or C 5-10 spirocycle, as described Substituted by 1 to 3 selected from R b3a , the spiro ring is optionally substituted by 1 to 3 selected from halogen or R b3a ;

在某些實施方案中，B 1選自苯基，所述的苯基被3至5個R b1取代； In certain embodiments, B1 is selected from phenyl substituted with 3 to 5 R b1 ;

在某些實施方案中，R b3a各自獨立的選自OH、NH 2、CN、N(C 1-4烷基) 2、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基或C 1-4烷氧基的取代基所取代； In certain embodiments, R b3a is each independently selected from OH, NH 2 , CN, N(C 1-4 alkyl) 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano Substituted with C 1-4 alkyl or C 1-4 alkoxy substituents;

在某些實施方案中，R b3a各自獨立的選自OH、NH 2、CN、N(CH 3) 2、CF 3、-CH 2CN、甲基、乙基、甲氧基或乙氧基的取代基所取代； In certain embodiments, R b3a is each independently selected from OH, NH 2 , CN, N(CH 3 ) 2 , CF 3 , -CH 2 CN, methyl, ethyl, methoxy or ethoxy. Substituted by substituents;

在某些實施方案中，R b1a選自-C 1-4亞烷基-(C≡C)-H、-C 1-4亞烷基-NH 2、-C 1-4亞烷基-N(C 1-4烷基) 2、-C 1-4亞烷基-NHC 1-4烷基、N(C 1-4烷基) 2、C 5-6環烷基、C 5-9螺環、5至6員雜芳基、-(C≡C)-CH 3、環丙基、環丁基、 、苯基，所述的-(C≡C)-CH 3被1至3個選自F、Cl、Br、I、OH、NH 2、CN、COOH、N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 3-6環烷基的取代基所取代，所述的環丙基或環丁基被1至4個選自NH 2、CN、COOH、N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 2-4炔基、-C 1-4亞烷基-C 3-6環烷基、-C 1-4亞烷基-OH、-C 1-4亞烷基-O-C 1-4烷基、C 3-6環烷基的取代基所取代，所述的環烷基或雜芳基被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 3-6環烷基的取代基所取代，所述的螺環或苯基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 3-6環烷基的取代基所取代，所述的雜芳基含有1至4個選自O、S、N的雜原子； In certain embodiments, R b1a is selected from -C 1-4 alkylene-(C≡C)-H, -C 1-4 alkylene-NH 2 , -C 1-4 alkylene-N (C 1-4 alkyl) 2 , -C 1-4 alkylene-NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 5-6 cycloalkyl, C 5-9 spiro Ring, 5 to 6-membered heteroaryl, -(C≡C)-CH 3 , cyclopropyl, cyclobutyl, , phenyl, the -(C≡C)-CH 3 is 1 to 3 selected from F, Cl, Br, I, OH, NH 2 , CN, COOH, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl substituents, The cyclopropyl or cyclobutyl group is 1 to 4 selected from NH 2 , CN, COOH, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, Halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, -C 1-4 alkylene -C 3-6 cycloalkyl, -C 1-4 Alkylene-OH, -C 1-4 alkylene-OC 1-4 alkyl, C 3-6 cycloalkyl substituents are substituted, and the cycloalkyl or heteroaryl is substituted by 1 to 4 Selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl , C 3-6 cycloalkyl substituent, the spiro ring or phenyl group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH , C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl substituents, The heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，R b1a選自-CH 2NH 2、-CH 2N(CH 3) 2、-CH 2CH 2N(CH 3) 2、N(CH 3) 2、C(CH 3) 2NH 2、-(C≡C)-CH 3、環丙基、環丁基、環戊基、環己基、吡咯基、吡唑基、噁唑基、咪唑基、噻唑基、三氮唑基、環丙基螺環丁基、環丁基螺環丁基、環丁基螺環戊基、環丁基螺環己基、環戊基螺環己基、 、苯基，所述的-(C≡C)-CH 3被1至3個選自F、Cl、Br、I、OH、NH 2、CN、COOH、N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 3-6環烷基的取代基所取代，所述的環丙基或環丁基被1至4個選自NH 2、CN、COOH、N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 2-4炔基、-C 1-4亞烷基-C 3-6環烷基、-C 1-4亞烷基-OH、-C 1-4亞烷基-O-C 1-4烷基、C 3-6環烷基的取代基所取代，所述的環戊基、環己基、吡咯基、吡唑基、噁唑基、咪唑基、噻唑基、三氮唑基、被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 3-6環烷基的取代基所取代，所述的環丙基螺環丁基、環丁基螺環丁基、環丁基螺環戊基、環丁基螺環己基、環戊基螺環己基或苯基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 3-6環烷基的取代基所取代，所述的雜芳基含有1至4個選自O、S、N的雜原子； In certain embodiments, R b1a is selected from -CH 2 NH 2 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N (CH 3 ) 2 , N(CH 3 ) 2 , C(CH 3 ) 2 NH 2 , -(C≡C)-CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazole base, cyclopropylspirocyclobutyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclohexyl, , phenyl, the -(C≡C)-CH 3 is 1 to 3 selected from F, Cl, Br, I, OH, NH 2 , CN, COOH, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl substituents, The cyclopropyl or cyclobutyl group is 1 to 4 selected from NH 2 , CN, COOH, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, Halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, -C 1-4 alkylene -C 3-6 cycloalkyl, -C 1-4 Substituted with alkylene-OH, -C 1-4 alkylene-OC 1-4 alkyl, C 3-6 cycloalkyl substituents, the cyclopentyl, cyclohexyl, pyrrolyl, pyrazole Base, oxazolyl, imidazolyl, thiazolyl, triazolyl, 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkoxy Substituted with substituents such as halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, and C 3-6 cycloalkyl, the cyclopropylspirocyclobutyl, cyclobutyl Spirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclohexyl or phenyl are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O , NH 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl Substituted with a substituent of a base, the heteroaryl group contains 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，R b1a選自-CH 2NH 2、-CH 2N(CH 3) 2、-CH 2CH 2N(CH 3) 2、N(CH 3) 2、C(CH 3) 2NH 2、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； In certain embodiments, R b1a is selected from -CH 2 NH 2 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N (CH 3 ) 2 , N(CH 3 ) 2 , C(CH 3 ) 2 NH 2 , , , , , , , , , , , , , , , , , , , , , ;

在某些實施方案中，R b2a選自-COOH、-CONH 2、-(CH 2) n-NH 2、-(CH 2) n-N(C 1-4烷基) 2、-(CH 2) n-NHC 1-4烷基、N(C 1-4烷基) 2、-(CH 2) n-OH、-(CH 2) n-C 2-4炔基、-(CH 2) nOC 1-4烷基、-(CH 2) nO(CH 2) nOC 1-4烷基、-(CH 2) n-O(CH 2) nOC 3-6環烷基、-C 1-4亞烷基-4至6員雜環基、苯基、5至6員雜芳基，所述的亞烷基、烷基、環烷基、雜環基、苯基、雜芳基、炔基任選被被1至3個選自F、Cl、Br、I、OH、NH 2、CN、COOH、NHC 1-4烷基、N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 3-6環烷基的取代基所取代，所述的雜芳基含有1至4個選自O、S、N的雜原子； In certain embodiments, R b2a is selected from -COOH, -CONH 2 , -(CH 2 ) n -NH 2 , -(CH 2 ) n -N(C 1-4 alkyl) 2 , -(CH 2 ) n -NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -(CH 2 ) n -OH, -(CH 2 ) n -C 2-4 alkynyl, -(CH 2 ) n OC 1-4 alkyl, -(CH 2 ) n O(CH 2 ) n OC 1-4 alkyl, -(CH 2 ) n -O(CH 2 ) n OC 3-6 cycloalkyl, -C 1 -4 alkylene - 4 to 6 membered heterocyclyl, phenyl, 5 to 6 membered heteroaryl, the alkylene, alkyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, The alkynyl group is optionally 1 to 3 selected from F, Cl, Br, I, OH, NH 2 , CN, COOH, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1- 4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl substituents, the hetero Aryl groups contain 1 to 4 heteroatoms selected from O, S, and N;

在某些實施方案中，R b2a選自-COOH、-CONH 2、-CH 2NH 2、C(CH 3) 2OH、-CH 2OCH 3、-CH 2OCH 2CH 3、-CH 2OCH 2CH 2OCH 3、-CH 2OCH 2CH 2O-環丙基、 、-CH 2N(CH 3) 2、-CH 2CH 2N(CH 3) 2、苯基、 、 、 、 ； In certain embodiments, R b2a is selected from -COOH, -CONH 2 , -CH 2 NH 2 , C(CH 3 ) 2 OH, -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 OCH 2 CH 2 OCH 3 , -CH 2 OCH 2 CH 2 O-cyclopropyl, , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , phenyl, , , , ;

任選地，B不為 或 ； Optionally, B is not or ;

在某些實施方案中，B選自 表 B-1所示的結構片段之一： 表B-1  1    2    3    4    5    6    7    8    9   10   11   12   13   14   15   16   17   18   19   20   21   22   23   24   25   26   27   28   29   30   31   32   33   34   35   36   37   38   39   40   41   42   43   44   45   46   47   48   49   50   51   52   53   54   55   56   57   58   59   60   61   62   63   64   65   66   67   68   69   70   71   72   73   74   75   76   77   78   79   80   81   82   83   84   85   86   87   88   89   90   91   92   93   94   95   96   97   98   99   100   101   102   103   104   105   106   107   108   109   110   111   112   113   114   115   116   117   118   119   120   121   122   123   124   125   126   127   128   129   130   131   132   133   134   135   136   137   138   139   140   141   142   143   144   145   146   147   148   149   150   151   152   153   154   155   156   157   158   159   160   161   162   163   164   165   166   167   168   169   170   171      ； In certain embodiments, B is selected from one of the structural fragments shown in Table B-1 : Table B-1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 twenty one twenty two twenty three twenty four 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 ;

在某些實施方案中，B選自表B-2所示結構之一；In certain embodiments, B is selected from one of the structures shown in Table B-2;

表B-2          Table B-2

在某些實施方案中，q各自獨立的選自0、1、2、3、4、5或6；In certain embodiments, each q is independently selected from 0, 1, 2, 3, 4, 5, or 6;

在某些實施方案中，q各自獨立的選自0、1、2、3或4；In certain embodiments, each q is independently selected from 0, 1, 2, 3, or 4;

在某些實施方案中，q各自獨立的選自0、1或2；In certain embodiments, each q is independently selected from 0, 1, or 2;

在某些實施方案中，n1、n2、n3各自獨立的選自0、1、2或3；In certain embodiments, n1, n2, and n3 are each independently selected from 0, 1, 2, or 3;

在某些實施方案中，p1或p2各自獨立的選自0、1、2、3、4或5；In certain embodiments, p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5;

在某些實施方案中，p1或p2各自獨立的選自0、1、2或3；In certain embodiments, p1 or p2 are each independently selected from 0, 1, 2, or 3;

在某些實施方案中，p1或p2各自獨立的選自0、1或2；In certain embodiments, p1 or p2 are each independently selected from 0, 1 or 2;

在某些實施方案中，K選自K1、K2、K3、K4;In certain embodiments, K is selected from K1, K2, K3, K4;

在某些實施方案中，K1選自 、 ； In certain embodiments, K1 is selected from , ;

在某些實施方案中，K1選自 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； In certain embodiments, K1 is selected from , , , , , , , , , , , , , , ;

在某些實施方案中，K2選自 、 、 、 ； In certain embodiments, K2 is selected from , , , ;

在某些實施方案中，K2選自 、 、 、 、 、 、 、 、 、 ； In certain embodiments, K2 is selected from , , , , , , , , , ;

在某些實施方案中，K3選自 、 、 、 、 、 、 、 、 、 、 ； In certain embodiments, K3 is selected from , , , , , , , , , , ;

在某些實施方案中，K3選自 ； In certain embodiments, K3 is selected from ;

在某些實施方案中，K4選自 、 或 ；在某些實施方案中，K4選自 、 或 ； In certain embodiments, K4 is selected from , or ; In certain embodiments, K4 is selected from , or ;

在某些實施方案中，E各自獨立地選自C 3-10碳環、C 6-10芳環、3-12員雜環或5-12員雜芳環，所述雜環或雜芳環含有1至4個(例如1、2、3、4個)選自O、S、N的雜原子； In certain embodiments, each E is independently selected from a C 3-10 carbocyclic ring, a C 6-10 aromatic ring, a 3-12 membered heterocyclic ring, or a 5-12 membered heteroaromatic ring. Contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, and N;

在某些實施方案中，E各自獨立地選自C 3-10碳環、苯環、4-12員雜環、5-12員雜芳環，所述雜環或雜芳環含有1至4個(例如1、2、3、4個)選自O、S、N的雜原子； In certain embodiments, each E is independently selected from a C 3-10 carbocyclic ring, a benzene ring, a 4-12 membered heterocyclic ring, a 5-12 membered heteroaromatic ring, and the heterocyclic or heteroaromatic ring contains 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;

在某些實施方案中，E各自獨立地選自苯環、5-6員雜芳環，所述雜環或雜芳環含有1至3個(例如1、2、3個)選自O、S、N的雜原子；In certain embodiments, E is each independently selected from a benzene ring, a 5-6 membered heteroaromatic ring, and the heterocyclic or heteroaromatic ring contains 1 to 3 (e.g., 1, 2, 3) selected from O, Heteroatoms of S and N;

在某些實施方案中，E各自獨立地選自苯環、吡啶環、噠嗪環、吡嗪環、嘧啶環、吡咯環、吡唑環、咪唑環、噻唑環、呋喃環、噻吩環、噁唑環、吲哚啉環、異吲哚啉環、1,2,3,4-四氫喹啉環或1,2,3,4-四氫異喹啉環；In certain embodiments, E is each independently selected from benzene ring, pyridine ring, pyridazine ring, pyrazine ring, pyrimidine ring, pyrrole ring, pyrazole ring, imidazole ring, thiazole ring, furan ring, thiophene ring, oxane ring Azole ring, indoline ring, isoindoline ring, 1,2,3,4-tetrahydroquinoline ring or 1,2,3,4-tetrahydroisoquinoline ring;

在某些實施方案中，E各自獨立地選自苯環、吡啶環、噠嗪環、吡嗪環、嘧啶環、吡咯環、吡唑環、咪唑環、噻唑環、呋喃環、噻吩環或噁唑環；In certain embodiments, each E is independently selected from a benzene ring, a pyridine ring, a pyridazine ring, a pyrazine ring, a pyrimidine ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a thiazole ring, a furan ring, a thiophene ring, or an oxane ring. azole ring;

在某些實施方案中，E各自獨立地選自苯環、吡啶環、噠嗪環、吡嗪環、嘧啶環；In certain embodiments, E is each independently selected from benzene ring, pyridine ring, pyridazine ring, pyrazine ring, pyrimidine ring;

在某些實施方案中，E各自獨立的選自苯環或吡啶環；In certain embodiments, each E is independently selected from a benzene ring or a pyridine ring;

在某些實施方案中，A選自C 3-10碳環、C 6-10芳環、3-10員雜環或5-10員雜芳環，所述雜環或雜芳環含有1至4個(例如1、2、3或4個)選自O、S、N的雜原子； In certain embodiments, A is selected from a C 3-10 carbocyclic ring, a C 6-10 aromatic ring, a 3-10 membered heterocyclic ring, or a 5-10 membered heteroaromatic ring containing 1 to 4 (such as 1, 2, 3 or 4) heteroatoms selected from O, S, N;

在某些實施方案中，A選自C 3-8碳環、苯環、4-7員雜環或5-6員雜芳環，所述雜環或雜芳環含有1至4個(例如1、2、3或4個)選自O、S、N的雜原子； In certain embodiments, A is selected from a C 3-8 carbocyclic ring, a benzene ring, a 4-7 membered heterocyclic ring, or a 5-6 membered heteroaromatic ring containing 1 to 4 (e.g. 1, 2, 3 or 4) heteroatoms selected from O, S, N;

在某些實施方案中，A選自苯環、吡啶環、噠嗪環、吡嗪環、嘧啶環、吡咯環、吡唑環、咪唑環、噻唑環、呋喃環、噻吩環或噁唑環；In certain embodiments, A is selected from benzene ring, pyridine ring, pyridazine ring, pyrazine ring, pyrimidine ring, pyrrole ring, pyrazole ring, imidazole ring, thiazole ring, furan ring, thiophene ring or oxazole ring;

在某些實施方案中，A選自苯環或吡啶環；In certain embodiments, A is selected from a benzene ring or a pyridine ring;

在某些實施方案中，F各自獨立地選自C 3-20碳環、C 6-20芳環、3-20員雜環或5-20員雜芳環，所述雜環或雜芳環含有1至4個(例如1、2、3、4個)選自O、S、N的雜原子； In certain embodiments, each F is independently selected from a C 3-20 carbocyclic ring, a C 6-20 aromatic ring, a 3-20 membered heterocycle, or a 5-20 membered heteroaromatic ring. Contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, and N;

在某些實施方案中，F各自獨立地選自C 3-7單環碳環、C 4-10並環碳環、C 5-12螺環碳環、C 5-10橋環碳環、4-7員雜單環、4-10員雜並環、8-15員雜三並環、5-12員雜螺環、5-10員雜橋環、C 6-14芳基、5-10員雜芳基、 ，所述雜單環、雜並環、雜螺環、雜橋環或雜芳環含有1至4個(例如1、2、3、4個)選自O、S、N的雜原子； In certain embodiments, each F is independently selected from the group consisting of C 3-7 monocyclic carbocyclic ring, C 4-10 branched carbocyclic ring, C 5-12 spirocyclic carbocyclic ring, C 5-10 bridged carbocyclic ring, 4 -7-membered heteromonocyclic ring, 4-10-membered heterocyclic ring, 8-15-membered heterotricyclic ring, 5-12-membered heterospirocyclic ring, 5-10-membered heterobridged ring, C 6-14 aryl group, 5-10 Member heteroaryl, , the heteromonocyclic ring, heteroparacyclic ring, heterospirocyclic ring, heterobridged ring or heteroaromatic ring contains 1 to 4 (such as 1, 2, 3, 4) heteroatoms selected from O, S, N;

在某些實施方案中，F各自獨立地選自C 3-7單環碳環、C 4-10並環碳環、C 5-12螺環碳環、C 5-10橋環碳環、4-7員雜單環、4-10員雜並環、8-15員雜三並環、5-12員雜螺環、5-10員雜橋環、C 6-14芳基、5-10員雜芳基、 、 、 、 ，所述雜單環、雜並環、雜螺環、雜橋環或雜芳基含有1至4個選自O、S或N的雜原子； In certain embodiments, each F is independently selected from the group consisting of C 3-7 monocyclic carbocyclic ring, C 4-10 branched carbocyclic ring, C 5-12 spirocyclic carbocyclic ring, C 5-10 bridged carbocyclic ring, 4 -7-membered heteromonocyclic ring, 4-10-membered heterocyclic ring, 8-15-membered heterotricyclic ring, 5-12-membered heterospirocyclic ring, 5-10-membered heterobridged ring, C 6-14 aryl group, 5-10 Member heteroaryl, , , , , the heteromonocyclic ring, heterocyclic ring, heterospirocyclic ring, heterobridged ring or heteroaryl group contains 1 to 4 heteroatoms selected from O, S or N;

在某些實施方案中，F各自獨立地選自苯環、吡啶環、嘧啶環、吡嗪環、噠嗪環、 、 、 、 、 ； In certain embodiments, each F is independently selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, , , , , ;

在某些實施方案中，F各自獨立地選自苯環、吡啶環、嘧啶環、吡嗪環、噠嗪環、 、 、 、 、 、 、 、 、 、 ； In certain embodiments, each F is independently selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, , , , , , , , , , ;

在某些實施方案中，F各自獨立地選自環丁基、環戊基、環己基、雙環[1.1.1]戊烷基、6,7-二氫-5H-環戊[c]吡啶基、2,3-二氫-1H-茚基、苯基、萘基、蒽基、菲基、氮雜環丁基、吡咯烷基、哌啶基、嗎啉基、吡啶基、嘧啶基、噠嗪基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、三唑基、噁唑基、呋喃基、噻吩基、噻唑基、2-吡啶酮基、苯並噁唑基、吡啶並咪唑基、苯並咪唑基、苯並吡唑基、苯並噻唑基、苯並噻吩基、苯並呋喃基、苯並吡咯基、苯並吡啶基、苯並吡嗪基、苯並嘧啶基、苯並噠嗪基、苯並三嗪基、吡咯並吡咯基、吡咯並吡啶基、吡咯並嘧啶基、吡咯並噠嗪基、吡咯並吡嗪基、咪唑並嘧啶基、咪唑並吡啶基、咪唑並吡嗪基、咪唑並噠嗪基、吡唑並吡啶基、吡唑並嘧啶基、吡唑並噠嗪基、吡唑並吡嗪基、嘧啶並吡啶基、嘧啶並吡嗪基、嘧啶並噠嗪基、嘧啶並嘧啶基、吡啶並吡啶基、吡啶並吡嗪基、吡啶並噠嗪基、吡啶並吡唑基、噠嗪並噠嗪基、噠嗪並吡嗪基、吡嗪並吡嗪基、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ，其左側與L直接連接； In certain embodiments, each F is independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, 6,7-dihydro-5H-cyclopentyl[c]pyridyl , 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridyl Azinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, 2-pyridonyl, benzoxazolyl, Pyridinidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridyl, benzopyrazinyl, benzopyrimidine base, benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyridazinyl, imidazopyrimidinyl, imidazopyridinyl , imidazopyridazinyl, imidazopyridazinyl, pyrazopyridyl, pyrazopyrimidinyl, pyrazopyridazinyl, pyrazolopyrazinyl, pyrimidopyridyl, pyrimidopyrazinyl, Pyrimidopyridazinyl, pyrimidopyrimidinyl, pyridopyridyl, pyridopyrazinyl, pyridopyridazinyl, pyridopyrazolyl, pyridazinopyridazinyl, pyridopyrazinyl, pyrazine pyrazinyl, , , , , , , , , , , , , , , , , , , , , its left side is directly connected to L;

在某些實施方案中，Q各自獨立地選自鍵、-O-、-S-、-CH 2-、-NR q-、-CO-、-NR qCO-、-CONR q-或3-12員雜環，所述的雜環任選被1至4個(例如1、2、3、4個)選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述雜環含有1至4個(例如1、2、3、4個)選自O、S、N的雜原子； In certain embodiments, Q is each independently selected from bond, -O-, -S-, -CH2- , -NRq-, -CO- , -NRqCO- , -CONRq- , or 3- 12-membered heterocycle, the heterocycle is optionally composed of 1 to 4 (for example, 1, 2, 3, 4) selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, Substituted with CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocycle contains 1 to 4 (for example, 1, 2, 3, 4) selected from O, S, N of heteroatoms;

在某些實施方案中，Q各自獨立地選自-O-、-S-、-CH 2-、-NR q-、-CO-、-NR qCO-、-CONR q-或4-7員雜環，所述的雜環任選被1至4個(例如1、2、3、4個)選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述雜環含有1至4個(例如1、2、3、4個)選自O、S、N的雜原子； In certain embodiments, Q is each independently selected from -O-, -S-, -CH2- , -NRq-, -CO- , -NRqCO- , -CONRq- , or 4-7 Heterocycle, the heterocycle is optionally composed of 1 to 4 (for example, 1, 2, 3, 4) selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic ring contains 1 to 4 (for example, 1, 2, 3, 4) heterocycles selected from O, S, N atom;

在某些實施方案中，Q各自獨立地選自鍵、C(=O)、Q1或Q2；In certain embodiments, each Q is independently selected from bond, C(=O), Q1 or Q2;

在某些實施方案中，Q1選自鍵、CH 2、NH、N(CH 3)、O、S、C(=O)、NHC(=O)、C(=O)NH、N(CH 3)C(=O)、C(=O)N(CH 3)、 、 、 ； In certain embodiments, Q1 is selected from bond, CH2 , NH, N( CH3 ), O, S, C(=O), NHC(=O), C(=O)NH, N( CH3 )C(=O), C(=O)N(CH 3 ), , , ;

在某些實施方案中，Q2選自鍵、CH 2、O、S、C(=O)、NHC(=O)、N(CH 3)C(=O)； In certain embodiments, Q2 is selected from bond, CH 2 , O, S, C(=O), NHC(=O), N(CH 3 )C(=O);

在某些實施方案中，R q選自H或C 1-6烷基； In certain embodiments, R q is selected from H or C 1-6 alkyl;

在某些實施方案中，R q選自H或C 1-4烷基； In certain embodiments, R q is selected from H or C 1-4 alkyl;

在某些實施方案中，R q選自H、甲基、乙基； In certain embodiments, R q is selected from H, methyl, ethyl;

在某些實施方案中，R k2各自獨立地選自鍵、-CO-、-SO 2-、-SO-或-C(R k3) 2-； In certain embodiments, each R k2 is independently selected from bond, -CO-, -SO 2 -, -SO-, or -C(R k3 ) 2 -;

在某些實施方案中，R k2各自獨立地選自-CO-、-SO 2-或-C(R k3) 2-； In certain embodiments, each R k2 is independently selected from -CO-, -SO 2 -, or -C(R k3 ) 2 -;

在某些實施方案中，R k1各自獨立地選自H、F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-6烷基、C 1-6烷氧基、C 3-6環烷基、R k7a，所述的烷基、烷氧基、環烷基任選被1至4個(例如1、2、3、4個)選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基、C 1-4烷氧基、C 3-6環烷基的取代基所取代； In certain embodiments, each R k1 is independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 Alkoxy group, C 3-6 cycloalkyl group, R k7a , the alkyl group, alkoxy group, and cycloalkyl group are optionally 1 to 4 (for example, 1, 2, 3, 4) selected from F, Substituted with substituents of Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;

在某些實施方案中，R k1選自R k7a； In certain embodiments, Rk1 is selected from Rk7a ;

在某些實施方案中，R k3各自獨立地選自H、F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或3-8員雜環基，所述的烷基、烷氧基、環烷基或雜環基任選被1至4個(例如1、2、3、4個)選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述雜環基含有1至4個(例如1、2、3、4個)選自O、S、N的雜原子； In certain embodiments, each R k3 is independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally substituted by 1 to 4 (such as 1, 2, 3, 4) substituted by a substituent selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy, The heterocyclic group contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, and N;

在某些實施方案中，R k1、R k3各自獨立的選自H、F、Cl、Br、I、OH、=O、NH 2、CF 3、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基，所述烷基或烷氧基任選被1至4個(例如1、2、3或4個)選自F、Cl、Br、I、OH、NH 2的取代基所取代； In certain embodiments, R k1 and R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2 , C 1-4 alkane group or C 1-4 alkoxy group, the alkyl group or alkoxy group is optionally composed of 1 to 4 (for example, 1, 2, 3 or 4) selected from F, Cl, Br, I, OH, NH 2 Substituted by substituents;

在某些實施方案中，R k1、R k3各自獨立的選自H、F、Cl、Br、I、OH、=O、NH 2、CF 3、CN、COOH、CONH 2、甲基、乙基、異丙基、甲氧基、乙氧基或異丙氧基，所述甲基、乙基、異丙基、甲氧基、乙氧基或異丙氧基任選被1至4個(例如1、2、3或4個)選自F、Cl、Br、I、OH、NH 2的取代基所取代； In certain embodiments, R k1 and R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2 , methyl, ethyl , isopropyl, methoxy, ethoxy or isopropoxy, the methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy is optionally replaced by 1 to 4 ( For example, 1, 2, 3 or 4) substituted with substituents selected from F, Cl, Br, I, OH, NH 2 ;

在某些實施方案中，兩個R k3和與二者直接相連的碳原子或環骨架共同形成C 3-8碳環或3-8員雜環，兩個R k1和與二者直接相連的碳原子或環骨架共同形成C 3-8碳環或3-8員雜環，所述碳環或雜環任選被1至4個(例如1、2、3、4個)選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述雜環含有1至4個(例如1、2、3、4個)選自O、S、N的雜原子； In certain embodiments, two R k3 and the carbon atom or ring skeleton directly connected to the two together form a C 3-8 carbocyclic ring or 3-8 membered heterocycle, and two R k1 and the carbon atom or ring skeleton directly connected to the two The carbon atoms or ring skeleton together form a C 3-8 carbocyclic ring or a 3-8 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is optionally selected from 1 to 4 (for example, 1, 2, 3, 4) from F, Substituted with Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic ring contains 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;

在某些實施方案中，兩個R k3和與二者直接相連的碳原子或環骨架共同形成C 3-6碳環或3-7員雜環，兩個R k1和與二者直接相連的碳原子或環骨架共同形成C 3-6碳環或3-7員雜環，所述碳環或雜環任選被1至4個(例如1、2、3、4個)選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述雜環含有1至4個(例如1、2、3、4個)選自O、S、N的雜原子； In certain embodiments, two R k3 and the carbon atom or ring skeleton directly connected to the two together form a C 3-6 carbocyclic ring or 3-7 membered heterocycle, and two R k1 and the carbon atom or ring skeleton directly connected to the two The carbon atoms or ring skeleton together form a C 3-6 carbocyclic ring or a 3-7 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is optionally selected from 1 to 4 (for example, 1, 2, 3, 4) from F, Substituted with Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic ring contains 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;

在某些實施方案中，R k4各自獨立地選自H、OH、NH 2、CN、CONH 2、C 1-6烷基、C 3-8環烷基或3-8員雜環基，所述的烷基、環烷基或雜環基任選被1至4個(例如1、2、3、4個)選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述雜環基含有1至4個(例如1、2、3、4個)選自O、S、N的雜原子； In certain embodiments, each R k4 is independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-6 alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocyclyl, so The above-mentioned alkyl, cycloalkyl or heterocyclic group is optionally selected from 1 to 4 (for example, 1, 2, 3, 4) from F, Cl, Br, I, OH, =O, NH 2 , CN, Substituted with COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 (for example, 1, 2, 3, 4) selected from O, Heteroatoms of S and N;

在某些實施方案中，R k4各自獨立的選自H、OH、NH 2、CF 3、CN、C 1-4烷基； In certain embodiments, each R k4 is independently selected from H, OH, NH 2 , CF 3 , CN, C 1-4 alkyl;

在某些實施方案中，R k5各自獨立地選自 、C(CH 3) 2、CO、CH 2、SO 2、 、 、 ； In certain embodiments, each R k5 is independently selected from ,C(CH 3 ) 2 ,CO,CH 2 ,SO 2 , , , ;

在某些實施方案中，R k5各自獨立地選自CO、CH 2、SO 2或 ； In certain embodiments, each R k5 is independently selected from CO, CH 2 , SO 2 or ;

在某些實施方案中，R k6各自獨立地選自CO、CH、SO、SO 2、CH 2或N； In certain embodiments, each R k6 is independently selected from CO, CH, SO, SO 2 , CH 2 or N;

在某些實施方案中，R k7各自獨立地選自 、C(CH 3) 2、CO、CH、N、CH 2、O、S、NR k7a； In certain embodiments, each R k7 is independently selected from ,C(CH 3 ) 2 ,CO,CH,N,CH 2 ,O,S,NR k7a ;

在某些實施方案中，R k7各自獨立地選自 、C(CH 3) 2、CO、CH、N、CH 2、O、S、N(CH 3)、N(CH 2CH 3)、N(環丙基)或NH； In certain embodiments, each R k7 is independently selected from , C(CH 3 ) 2 , CO, CH, N, CH 2 , O, S, N(CH 3 ), N(CH 2 CH 3 ), N (cyclopropyl) or NH;

在某些實施方案中，R k7各自獨立地選自CO、CH、N、CH 2、O、S、N(CH 3)或NH； In certain embodiments, each Rk7 is independently selected from CO, CH, N, CH2 , O, S, N( CH3 ), or NH;

在某些實施方案中，R k7各自獨立地選自CH 2、O、N(CH 3)或NH； In certain embodiments, each Rk7 is independently selected from CH2 , O, N( CH3 ), or NH;

在某些實施方案中，R k7a選自H、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-6環烷基、3-6員雜環烷基，所述烷基、環烷基、雜環烷基任選被1至4個選自F、Cl、Br、I、OH、NH 2、CN、CF 3、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-6環烷基的取代基所取代； In certain embodiments, Rk7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl , the alkyl group, cycloalkyl group, and heterocycloalkyl group are optionally substituted by 1 to 4 members selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-6 alkyl, C 1 Substituted by -6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl substituents;

在某些實施方案中，R k7a選自H、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-6環烷基、3-6員雜環烷基，所述烷基、環烷基、雜環烷基任選被1至4個選自F、Cl、Br、I、OH、NH 2、CN、CF 3、C 1-4烷基、C 1-4烷氧基、C 2-4烯基、C 2-4炔基、C 3-6環烷基的取代基所取代； In certain embodiments, Rk7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl , the alkyl group, cycloalkyl group and heterocycloalkyl group are optionally substituted by 1 to 4 members selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-4 alkyl, C 1 Substituted by -4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl substituents;

在某些實施方案中，R k7a選自H、C 1-4烷基、C 3-6環烷基，所述的烷基或環烷基任選被1至4個選自鹵素、OH、CN、C 1-4烷基、C 1-4烷氧基、C 3-6環烷基的取代基所取代； In certain embodiments, R k7a is selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from halogen, OH, Substituted with substituents of CN, C 1-4 alkyl, C 1-4 alkoxy, and C 3-6 cycloalkyl;

在某些實施方案中，R k7a選自H、甲基、乙基、丙基、異丙基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、哌啶基、氧雜環丁基、四氫呋喃基、四氫吡喃基，所述甲基、乙基、丙基、異丙基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、哌啶基、氧雜環丁基、四氫呋喃基、四氫吡喃基任選被1至4個選自F、Cl、Br、I、OH、CN、CF 3、C 1-4烷基、C 1-4烷氧基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、C 3-6環烷基的取代基所取代； In certain embodiments, Rk7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, the methyl, ethyl, propyl base, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl 1 to 4 are selected from F, Cl, Br, I, OH, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, vinyl, propenyl, allyl, ethynyl , substituted by substituents of propynyl, propargyl, C 3-6 cycloalkyl;

在某些實施方案中，R k7a選自H、甲基、乙基、異丙基、環丙基、氧雜環丁基、四氫吡喃基、-CH 2CF 3、-CH(CH 3)CF 3、-CH(CH 3)-環丙基、-CH 2-環丙基、-CH 2-乙烯基、-CH 2-乙炔基、-CH 2CH 2-甲氧基； In certain embodiments, R k7a is selected from H, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, tetrahydropyranyl, -CH 2 CF 3 , -CH(CH 3 )CF 3 , -CH(CH 3 )-cyclopropyl, -CH 2 -cyclopropyl , -CH 2 -vinyl, -CH 2 -ethynyl, -CH 2 CH 2 -methoxy;

在某些實施方案中，R k7a選自H、CF 3、甲基、乙基、環丙基、-CH 2-環丙基； In certain embodiments, R k7a is selected from H, CF 3 , methyl, ethyl, cyclopropyl, -CH 2 -cyclopropyl;

在某些實施方案中，R k7a選自H、CH 3、CH 2CH 3、環丙基； In certain embodiments, R k7a is selected from H, CH 3 , CH 2 CH 3 , cyclopropyl;

在某些實施方案中，R k8各自獨立地選自C、N或CH； In certain embodiments, each Rk8 is independently selected from C, N, or CH;

在某些實施方案中，R k9各自獨立地選自鍵、 、C(CH 3) 2、CO、CH 2、CH 2CH 2或SO 2； In certain embodiments, each R k9 is independently selected from bond, , C(CH 3 ) 2 , CO, CH 2 , CH 2 CH 2 or SO 2 ;

在某些實施方案中，R k9各自獨立地選自CO、SO 2或CH 2； In certain embodiments, each R k9 is independently selected from CO, SO 2 or CH 2 ;

在某些實施方案中，M 1選自鍵、-CH 2-C(=O)NH-或-C(=O)CH 2NH-； In certain embodiments, M 1 is selected from bond, -CH 2 -C(=O)NH- or -C(=O)CH 2 NH-;

在某些實施方案中，M 2選自-NHC(=O)-C 1-6烷基、-NHC(=O)-C 3-6環烷基或4-10員雜環基，所述的烷基、環烷基或雜環基任選被1至4個(例如1、2、3、4個)選自F、Cl、Br、I、=O、OH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述雜環基含有1至4個(例如1、2、3、4個)選自O、S、N的雜原子； In certain embodiments, M is selected from -NHC(=O)-C 1-6 alkyl, -NHC(=O)-C 3-6 cycloalkyl, or 4-10 membered heterocyclyl, The alkyl, cycloalkyl or heterocyclic group is optionally 1 to 4 (for example, 1, 2, 3, 4) selected from F, Cl, Br, I, =O, OH, NH 2 , C 1- Substituted with a 4- alkyl or C 1-4 alkoxy substituent, the heterocyclic group contains 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from O, S, and N;

在某些實施方案中，M 3選自-NH-或-O-； In certain embodiments, M 3 is selected from -NH- or -O-;

在某些實施方案中，R k10選自C 1-6烷基，所述的烷基任選被1至4個(例如1、2、3、4個)選自F、Cl、Br、I、=O、OH、C 1-6烷基或C 3-6環烷基的取代基所取代； In certain embodiments, R k10 is selected from C 1-6 alkyl, and the alkyl group is optionally composed of 1 to 4 (eg, 1, 2, 3, 4) selected from F, Cl, Br, I , =O, OH, C 1-6 alkyl or C 3-6 cycloalkyl substituent substituted;

在某些實施方案中，G選自C 6-10芳環或5-10員雜芳環，所述的芳環或者雜芳環任選被1至4個(例如1、2、3、4個)選自F、Cl、Br、I、OH、=O、CF 3、CN、C 1-4烷基、鹵素取代的C 1-4烷基、羥基取代的C 1-4烷基、C 1-4烷氧基或C 3-6環烷基的取代基所取代，所述雜芳環含有1至4個(例如1、2、3、4個)選自N、O、S的雜原子； In certain embodiments, G is selected from a C 6-10 aromatic ring or a 5-10 membered heteroaromatic ring, and the aromatic ring or heteroaromatic ring is optionally substituted by 1 to 4 (e.g., 1, 2, 3, 4 ) selected from F, Cl, Br, I, OH, =O, CF 3 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, C Substituted with 1-4 alkoxy or C 3-6 cycloalkyl substituents, the heteroaromatic ring contains 1 to 4 (for example, 1, 2, 3, 4) heteroaromatic rings selected from N, O, S atom;

在某些實施方案中，R k11各自獨立的選自H、F、Cl、Br、I、=O、OH、SH、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基或-O-C(=O)-C 1-6烷基，所述的烷基、烷氧基或烷硫基任選被1至4個(例如1、2、3、4個)選自F、Cl、Br、I、OH、C 1-4烷基或C 1-4烷氧基的取代基所取代； In certain embodiments, R k11 is each independently selected from H, F, Cl, Br, I, =O, OH, SH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 Alkylthio group or -OC(=O)-C 1-6 alkyl group, the alkyl group, alkoxy group or alkylthio group is optionally selected from 1 to 4 (such as 1, 2, 3, 4) Substituted from a substituent of F, Cl, Br, I, OH, C 1-4 alkyl or C 1-4 alkoxy;

在某些實施方案中，R k12、R k13各自獨立的選自H、C 1-6烷基或C 3-6環烷基，所述的烷基或環烷基任選被1至4個(例如1、2、3、4個)選自F、Cl、Br、I、=O、OH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； In certain embodiments, R k12 and R k13 are each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 (For example, 1, 2, 3, 4) substituted with a substituent selected from F, Cl, Br, I, =O, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy;

在某些實施方案中，R k14選自5-6員雜芳基，所述的雜芳基任選被1至4個(例如1、2、3、4個)選自F、Cl、Br、I、OH、=O、CF 3、CN、C 1-4烷基、鹵素取代的C 1-4烷基、羥基取代的C 1-4烷基、C 1-4烷氧基或C 3-6環烷基的取代基所取代，所述雜芳基含有1至4個(例如1、2、3、4個)選自N、O、S的雜原子；在某些實施方案中，R k14選自噻唑，所述的噻唑任選被1至4個(例如1、2、3、4個)選自甲基的取代基取代；在某些實施方案中，R k14選自 ； In certain embodiments, Rk14 is selected from a 5-6 membered heteroaryl group, and the heteroaryl group is optionally composed of 1 to 4 members (such as 1, 2, 3, 4) selected from F, Cl, Br , I, OH, =O, CF 3 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3 -6 cycloalkyl substituents substituted, the heteroaryl group containing 1 to 4 (for example, 1, 2, 3, 4) heteroatoms selected from N, O, S; in certain embodiments, R k14 is selected from thiazole, and the thiazole is optionally substituted with 1 to 4 (eg, 1, 2, 3, 4) substituents selected from methyl; in certain embodiments, R k14 is selected from ;

在某些實施方案中，K選自 表 K-1所示的結構片段之一： 表K-1                   ； In certain embodiments, K is selected from one of the structural fragments shown in Table K-1 : Table K-1 ;

在某些實施方案中，K選自表K-2所示的結構片段之一； 表K-2             ； In certain embodiments, K is selected from one of the structural fragments shown in Table K-2; Table K-2 ;

在某些實施方案中，K選自表K-3所示的結構片段之一： K-3 In certain embodiments, K is selected from one of the structural fragments shown in Table K-3: K-3

在某些實施方案中，K選自 、 、 、 、 、 、 。 In certain embodiments, K is selected from , , , , , , .

作為本發明的第一種實施方案，上述通式(I)所示化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，As a first embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

L選自鍵或-C 1-50烴基-，所述烴基中有1至20個亞甲基單元任選被-Ak-、-Cy-替換； L is selected from a bond or -C 1-50 hydrocarbyl-, in which 1 to 20 methylene units are optionally replaced by -Ak-, -Cy-;

每個-Ak-各自獨立地選自-(CH 2) q-、-(CH 2) q-O-、-O-(CH 2) q-、-(CH 2) q-NR L-、-NR L-(CH 2) q-、-(CH 2) q-NR LC(=O)-、-NR L(CH 2) qC(=O)-、-(CH 2) q-C(=O)NR L-、-C(=O)-、-C(=O)-(CH 2) q-NR L-、-(C≡C) q-、-CH=CH-、-Si(R L) 2-、-Si(OH)(R L)-、-Si(OH) 2-、-P(=O)(OR L)-、-P(=O)(R L)-、-S-、-S(=O)-、-S(=O) 2-或者鍵，所述的-CH 2-、-CH=CH-任選被1至2個選自鹵素、OH、CN、NH 2、C 1-6烷基、C 1-6烷氧基、鹵素取代的C 1-6烷基、羥基取代的C 1-6烷基、氰基取代的C 1-6烷基的取代基所取代；q各自獨立的選自0、1、2、3、4、5或6； Each -Ak- is independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, - NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -NR L (CH 2 ) q C(=O)-, -(CH 2 ) q -C( =O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q -, -CH=CH-, -Si( R L ) 2 -, -Si(OH)(R L )-, -Si(OH) 2 -, -P(=O)(OR L )-, -P(=O)(R L )-, - S-, -S(=O)-, -S(=O) 2 - or bond, the -CH 2 -, -CH=CH- is optionally 1 to 2 selected from halogen, OH, CN, Substitution of NH 2 , C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl Substituted with a group; q is each independently selected from 0, 1, 2, 3, 4, 5 or 6;

R L各自獨立的選自H、C 1-6烷基、3-7員雜環基、3-7員環烷基、苯基或5-6員雜芳基，所述的雜環基或雜芳基含有1至4個選自O、S、N的雜原子； R L is each independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl, the heterocyclyl or Heteroaryl groups contain 1 to 4 heteroatoms selected from O, S, and N;

每個-Cy-各自獨立地選自鍵或者任選取代的如下基團之一：4-8員雜單環、4-10員雜並環、5-12員雜螺環、7-10員雜橋環、3-7員單環烷基、4-10員並環烷基、5-12員螺環烷基、7-10員橋環烷基、苯並C 4-6碳環基、苯並4至6員雜環基、5-10員雜芳基或6-10員芳基，當被取代時，被1至4個R L2取代，所述的雜環基、雜芳基、雜單環、雜並環、雜螺環或雜橋環含有1至4個選自O、S、N的雜原子，當雜原子選自S時，任選被1或2個=O取代； Each -Cy- is independently selected from one of the bonded or optionally substituted groups: 4-8 membered heteromonocycle, 4-10 membered heterocyclic ring, 5-12 membered heterospirocycle, 7-10 membered heterospirocycle Heterobridged ring, 3-7 membered monocyclic alkyl group, 4-10 membered cycloalkyl group, 5-12 membered spirocycloalkyl group, 7-10 membered bridged cycloalkyl group, benzo C 4-6 carbocyclyl group, Benzo 4- to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, is substituted by 1 to 4 R L2 , the heterocyclyl, heteroaryl, Heteromonocyclic, heteroparacyclic, heterospirocyclic or heterobridged rings contain 1 to 4 heteroatoms selected from O, S, and N. When the heteroatoms are selected from S, they are optionally substituted by 1 or 2 =O;

R L2各自獨立地選自氘、F、Cl、Br、I、OH、COOH、CN、NH 2、NHC 1-4烷基、N(C 1-4烷基) 2、=O、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、-O-C 1-4亞烷基-O-C 1-4烷基、-O-C 1-4亞烷基-O-C 3-10碳環基、-C 1-4亞烷基-O-C 1-4亞烷基-O-C 1-4烷基、-C 1-4亞烷基-O-C 1-4亞烷基-O-C 3-10碳環基、-O-C 0-4亞烷基-C 3-10碳環基、-C 0-4亞烷基-C 3-10碳環基、-C 0-4亞烷基-4至10員雜環基，所述的烷基、烯基、炔基、烷氧基、亞烷基、碳環基或雜環基任選被1至4個選自F、Cl、Br、I、OH、COOH、CN、NH 2、NHC 1-4烷基、N(C 1-4烷基) 2、=O、C 1-4烷基、鹵素取代的C 1-4烷基、羥基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； R L2 is each independently selected from deuterium, F, Cl, Br, I, OH, COOH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1- 4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -OC 1-4 alkylene -OC 1-4 alkyl, -OC 1-4 alkylene -OC 3-10 carbocyclyl, -C 1-4 alkylene-OC 1-4 alkylene-OC 1-4 alkyl, -C 1-4 alkylene -OC 1-4 alkylene- OC 3-10 carbocyclyl, -OC 0-4 alkylene -C 3-10 carbocyclyl, -C 0-4 alkylene -C 3-10 carbocyclyl, -C 0-4 alkylene -4 to 10-membered heterocyclyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 selected from F, Cl, Br , I, OH, COOH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, Substituted with hydroxyl-substituted C 1-4 alkyl and C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

B選自 ； B is selected from ;

B 1選自C 5-20碳環基或4-20員雜環基，所述B 1任選被1至4個R b1所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； B 1 is selected from C 5-20 carbocyclyl or 4-20 membered heterocyclyl. The B 1 is optionally substituted by 1 to 4 R b1 . The heterocyclyl contains 1 to 4 selected from O , S, N heteroatoms;

B 2選自C 5-20碳環基或4-20員雜環基，所述B 2任選被1至4個R b2取代，所述的雜環基含有1至4個選自O、S、N的雜原子； B 2 is selected from C 5-20 carbocyclyl or 4-20 membered heterocyclyl. The B 2 is optionally substituted by 1 to 4 R b2 . The heterocyclyl contains 1 to 4 selected from O, Heteroatoms of S and N;

V選自 ； V is selected from ;

W選自O或S；W is selected from O or S;

Y 1、Y 2、Y 3各自獨立地選自鍵、O、S、NR b5a、C(=S)、C(=O)、CONR b5a、NR b5aCO； Y 1 , Y 2 , Y 3 are each independently selected from bonds, O, S, NR b5a , C(=S), C(=O), CONR b5a , NR b5a CO;

P 1、P 2各自獨立地選自 或 ； P 1 and P 2 are each independently selected from or ;

v 2各自獨立地選自0、1、2、3或4； v 2 are each independently selected from 0, 1, 2, 3 or 4;

v 1各自獨立地選自0、1或2； v 1 are each independently selected from 0, 1 or 2;

R b1各自獨立的選自H、F、Cl、Br、I、=O、OH、CN、NO 2、COOH、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4烷硫基、-(CH 2) n-R b22、-OR b22、-N(R b21) 2、-C(=O)N(R b21) 2、-C(=O)OR b21、-C(=O)R b22、-S(=O) 2R b22、-P(=O)(R b22) 2、-S(=O) 2N(R b21) 2、-NR b21C(=O)R b22、-NR b21S(=O) 2R b22、C 3-12環烷基、C 6-10芳基、5-10員雜芳基或4-10員雜環基，所述的-CH 2-、烷基、烯基、炔基、烷氧基、烷硫基、環烷基、雜環基、芳基或雜芳基任選被1至4個選自F、Cl、Br、I、OH、=O、-N(R b21) 2、CN、COOH、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 2-4炔基、-C 1-4亞烷基-C 3-6環烷基、-C 1-4亞烷基-OH、-C 1-4亞烷基-O-C 1-4烷基、C 3-6環烷基、5-10員雜芳基或4-10員雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； R b1 is each independently selected from H, F, Cl, Br, I, =O, OH, CN, NO 2 , COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy group, C 1-4 alkylthio group, -(CH 2 ) n -R b22 , -OR b22 , -N(R b21 ) 2 , -C(=O)N(R b21 ) 2 , -C(=O)OR b21 , -C(=O)R b22 , -S(=O) 2 R b22 , -P(=O)(R b22 ) 2 , -S(=O) 2 N( R b21 ) 2 , -NR b21 C(=O)R b22 , -NR b21 S(=O) 2 R b22 , C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl Or 4-10 membered heterocyclyl, the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl is optional Substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, -C 1-4 alkylene -C 3-6 cycloalkyl, -C 1-4 alkylene Substituted with -OH, -C 1-4 alkylene -OC 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl substituents, the The heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

R b21各自獨立的選自H或C 1-4烷基，所述的烷基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、CF 3、COOH、C 1-4烷基、C 3-6環烷基、C 1-4烷氧基的取代基所取代； R b21 is each independently selected from H or C 1-4 alkyl, and the alkyl group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy substituents;

R b22各自獨立的選自H、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 3-6環烷基或4-8員雜環基，所述的烷基、烷氧基、環烷基、烯基、炔基或雜環基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、CF 3、COOH、C 1-4烷基、C 3-6環烷基、C 3-6環烷基氧基、C 1-4烷氧基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； R b22 is each independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl or 4-8 member Heterocyclyl, the alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl or heterocyclyl is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2. Substituted with substituents of CN, CF 3 , COOH, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, and C 1-4 alkoxy, as described The heterocyclyl group contains 1 to 4 heteroatoms selected from O, S, and N;

n各自獨立的選自0、1、2、3或4；n is independently selected from 0, 1, 2, 3 or 4;

R b2各自獨立的選自H、F、Cl、Br、I、=O、OH、NH 2、-N(R b21) 2、CN、NO 2、COOH、-C(=O)NH 2、-C(=O)NH-C 1-4烷基、-C(=O)N(C 1-4烷基) 2、-(CH 2) n-R b22、-(CH 2) nO(CH 2) n-R b22、-(CH 2) nO(CH 2) nO-R b22、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 3-8環烷基、C 6-10芳基、5-10員雜芳基、4-10員雜環基、-C 1-4亞烷基-4至10員雜環基，所述的亞烷基、CH 2、烷基、烯基、炔基、烷氧基、環烷基、雜環基、芳基或雜芳基任選被1至4個選自F、Cl、Br、I、OH、NH 2、-N(R b21) 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 3-6環烷基、C 3-6環烷基氧基、鹵素取代的C 3-6環烷基、鹵素取代的C 3-6環烷基氧基、5-6員雜芳基或4-8員雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； R b2 is each independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , -N(R b21 ) 2 , CN, NO 2 , COOH, -C(=O)NH 2 , - C(=O)NH-C 1-4 alkyl, -C(=O)N(C 1-4 alkyl) 2 , -(CH 2 ) n -R b22 , -(CH 2 ) n O(CH 2 ) n -R b22 , -(CH 2 ) n O(CH 2 ) n OR b22 , C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 alkoxy group , C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, -C 1-4 alkylene-4 to 10 membered heterocyclyl, so The above-mentioned alkylene, CH 2 , alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are optionally substituted by 1 to 4 selected from F, Cl, Br , I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, halogen-substituted C 3-6 cycloalkyl, halogen-substituted C 3-6 cycloalkyloxy, 5-6 members Substituted with a substituent of a heteroaryl group or a 4-8 membered heterocyclyl group, the heteroaryl group or heterocyclyl group contains 1 to 4 heteroatoms selected from O, S, and N;

R b3、R b4、R b6、R b7各自獨立的選自H、F、Cl、Br、I、OH、NH 2、CN、NO 2、-(CH 2) m1-R b23、-(CH 2) m1-X-(CH 2) m2-R b24、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷硫基、C 3-12環烷基、C 6-10芳基、5-10員雜芳基或3-12員雜環基，所述的烷基、烯基、炔基、烷氧基、烷硫基、環烷基、芳基、雜芳基或雜環基任選被1至4個選自氘、F、Cl、Br、I、OH、NH 2、CN、C 1-6烷基、鹵素取代的C 1-6烷基、氰基取代的C 1-6烷基、C 1-6烷氧基、C 2-6炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； R b3 , R b4 , R b6 , R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio , C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylthio The base, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-6 alkyl, halogen Substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl Substituted with substituents, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

或R b3、R b4與其相連接的碳原子共同形成C 3-8環烷基或3至8員雜單環，所述的環烷基或雜單環任選被1至4個選自氘、F、Cl、Br、I、OH、NH 2、-N(R b21) 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-6環烷基、5-6員雜芳基或3至8雜環基的取代基所取代，所述的雜單環、雜芳基或雜環基含有1至4個選自O、S、N的雜原子； Or R b3 , R b4 and the carbon atoms to which they are connected together form a C 3-8 cycloalkyl group or a 3 to 8-membered heteromonocyclic ring. The cycloalkyl group or heteromonocyclic ring is optionally substituted by 1 to 4 deuterium atoms. , F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl Substituted with substituents of base, C 1-4 alkoxy group, C 2-4 alkynyl group, C 3-6 cycloalkyl group, 5-6 membered heteroaryl group or 3 to 8 heterocyclic group, the heteromono The ring, heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;

作為選擇，R b3與R b5a、R b1與R b5a直接連接形成環S，環S選自4至9員含氮雜環基，環S任選被1至4個選自R s的取代基所取代； Alternatively, R b3 and R b5a , R b1 and R b5a are directly connected to form ring S. Ring S is selected from 4 to 9 membered nitrogen-containing heterocyclic groups. Ring S is optionally substituted by 1 to 4 substituents selected from R s replaced;

R s各自獨立的選自F、Cl、Br、I、OH、NH 2、-N(R b21) 2、CN、C 1-4烷基、C 1-4烷氧基、C 3-6環烷基、5-6員雜芳基或3至8雜環基，所述的烷基、烷氧基、環烷基、雜芳基或者雜環基任選被1至4個選自F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的雜環基或雜芳基含有1至4個選自O、S、N的雜原子； R s are each independently selected from F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 ring Alkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl, the alkyl, alkoxy, cycloalkyl, heteroaryl or heterocyclyl is optionally 1 to 4 selected from F, Substituted with Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic group or heteroaryl group contains 1 to 4 selected from Heteroatoms of O, S, and N;

R b5a選自H或R b5； R b5a is selected from H or R b5 ;

R b5選自OH、NH 2、C 1-4烷基、-(CH 2) n-R b22、-C(=O)N(R b21) 2、-C(=O)R b22、C 3-6環烷基、C 6-10芳基、5-10員雜芳基或4-10員雜環基，所述的-CH 2-、烷基、環烷基、雜環基、芳基或雜芳基任選被1至4個選自F、Cl、Br、I、OH、=O、-N(R b21) 2、CN、COOH、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 3-6環烷基、5-10員雜芳基或4-10員雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； R b5 is selected from OH, NH 2 , C 1-4 alkyl, -(CH 2 ) n -R b22 , -C(=O)N(R b21 ) 2 , -C(=O)R b22 , C 3 -6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, the -CH 2 -, alkyl, cycloalkyl, heterocyclyl, aryl Or the heteroaryl group is optionally selected from 1 to 4 F, Cl, Br, I, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkyl Substituents of oxygen group, halogen-substituted C 1-4 alkyl group, cyano-substituted C 1-4 alkyl group, C 3-6 cycloalkyl group, 5-10 membered heteroaryl group or 4-10 membered heterocyclyl group Substituted, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

X各自獨立的選自NH、O或S；X is each independently selected from NH, O or S;

m1各自獨立的選自0、1、2或3；m1 is each independently selected from 0, 1, 2 or 3;

m2各自獨立的選自0、1、2或3；m2 is independently selected from 0, 1, 2 or 3;

R b23各自獨立的選自C 2-4烯基、C 2-4炔基、C 3-6環烷基或4-10員雜環基，所述的環烷基、烯基、炔基、雜環基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、CF 3、COOH、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or 4-10 membered heterocyclyl, the cycloalkyl, alkenyl, alkynyl, The heterocyclyl group is optionally substituted with 1 to 4 C 1-4 alkyl groups selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, and halogen . Substituted with C 1-4 alkyl group, cyano group substituted C 1-4 alkoxy group substituent, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;

R b24各自獨立的選自C 1-4烷氧基、C 3-6環烷基氧基、C 3-6環烷基或4-10員雜環基，所述的烷氧基、環烷基、環烷基氧基、雜環基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、CF 3、COOH、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； R b24 is each independently selected from C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl or 4-10 membered heterocyclyl, the alkoxy, cycloalkyl The base, cycloalkyloxy group and heterocyclyl group are optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, Substituted with halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 selected from O, S , N heteroatoms;

K選自K1、K2、K3、K4;K is selected from K1, K2, K3, K4;

K1選自 、 ； K1 is selected from , ;

K2選自 、 、 、 ； K2 is selected from , , , ;

K3選自 、 、 、 、 、 、 、 、 、 、 ； K3 is selected from , , , , , , , , , , ;

K4選自 、 或 ； K4 is selected from , or ;

Q各自獨立地選自鍵、-O-、-S-、-CH 2-、-NR q-、-CO-、-NR qCO-、-CONR q-或3-12員雜環，所述的雜環任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述雜環含有1至4個選自O、S或N的雜原子； Q is each independently selected from a bond, -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q - or a 3-12 membered heterocycle, The heterocyclic ring is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy Substituted with substituents, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S or N;

R q選自H或C 1-6烷基； R q is selected from H or C 1-6 alkyl;

A選自C 3-10碳環、C 6-10芳環、3-10員雜環或5-10員雜芳環，所述雜環或雜芳環含有1至4個選自O、S或N的雜原子； A is selected from C 3-10 carbocyclic ring, C 6-10 aromatic ring, 3-10 membered heterocyclic ring or 5-10 membered heteroaromatic ring, the heterocyclic ring or heteroaromatic ring contains 1 to 4 selected from O, S or heteroatoms of N;

F各自獨立地選自C 3-20碳環、C 6-20芳環、3-20員雜環或5-20員雜芳環，所述雜環或雜芳環含有1至4個選自O、S或N的雜原子； Each F is independently selected from C 3-20 carbocyclic ring, C 6-20 aromatic ring, 3-20 membered heterocyclic ring or 5-20 membered heteroaromatic ring, the heterocyclic ring or heteroaromatic ring contains 1 to 4 selected from Heteroatom of O, S or N;

R k2各自獨立地選自鍵、-CO-、-SO 2-、-SO-或-C(R k3) 2-； R k2 is each independently selected from bond, -CO-, -SO 2 -, -SO- or -C(R k3 ) 2 -;

R k1各自獨立地選自H、F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-6烷基、C 1-6烷氧基、C 3-6環烷基、R k7a，所述的烷基、烷氧基或環烷基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基、C 1-4烷氧基或C 3-6環烷基的取代基所取代； R k1 is each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3- 6 cycloalkyl, Rk7a , the alkyl, alkoxy or cycloalkyl is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, Substituted by CONH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituents;

R k7a選自H、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-6環烷基、3-6員雜環烷基，所述烷基、環烷基、雜環烷基任選被1至4個選自F、Cl、Br、I、OH、NH 2、CN、CF 3、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-6環烷基的取代基所取代； Rk7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, the alkyl, cyclic Alkyl and heterocycloalkyl are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, C Substituted with substituents of 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl;

R k3各自獨立地選自H、F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或3-8員雜環基，所述的烷基、烷氧基、環烷基或雜環基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述雜環基含有1至4個選自O、S或N的雜原子； R k3 is each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3- 8 cycloalkyl or 3-8 membered heterocyclyl, the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, = Substituted with O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 selected from O, S or N heteroatoms;

或者兩個R k3和與二者直接相連的碳原子或環骨架共同形成C 3-8碳環或3-8員雜環，兩個R k1和與二者直接相連的碳原子或環骨架共同形成C 3-8碳環或3-8員雜環，所述碳環或雜環任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述雜環含有1至4個選自O、S或N的雜原子； Or two R k3 and the carbon atoms or ring skeleton directly connected to them together form a C 3-8 carbocyclic ring or 3-8 membered heterocyclic ring, and the two R k1 and the carbon atoms or ring skeleton directly connected to them together form Forming a C 3-8 carbocyclic ring or a 3-8 membered heterocyclic ring, the carbocyclic ring or heterocyclic ring is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH , CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S or N;

R k4各自獨立地選自H、OH、NH 2、CN、CONH 2、C 1-6烷基、C 3-8環烷基或3-8員雜環基，所述的烷基、環烷基或雜環基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述雜環基含有1至4個選自O、S或N的雜原子； R k4 is each independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, the alkyl, cycloalkyl The base or heterocyclic group is optionally selected from 1 to 4 F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy Substituted with a substituent of a base, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;

M 1選自鍵、-CH 2-C(=O)NH-或-C(=O)CH 2NH-； M 1 is selected from bond, -CH 2 -C(=O)NH- or -C(=O)CH 2 NH-;

M 2選自-NHC(=O)-C 1-6烷基、-NHC(=O)-C 3-6環烷基或4-10員雜環基，所述的烷基、環烷基或雜環基任選被1至4個選自F、Cl、Br、I、=O、OH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述雜環基含有1至4個選自O、S或N的雜原子； M 2 is selected from -NHC(=O)-C 1-6 alkyl, -NHC(=O)-C 3-6 cycloalkyl or 4-10 membered heterocyclyl, the alkyl, cycloalkyl Or the heterocyclic group is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, =O, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy, so The heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N;

M 3選自-NH-或-O-； M 3 is selected from -NH- or -O-;

R k10選自C 1-6烷基，所述的烷基任選被1至4個選自F、Cl、Br、I、=O、OH、C 1-6烷基或C 3-6環烷基的取代基所取代； R k10 is selected from C 1-6 alkyl, and the alkyl group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, =O, OH, C 1-6 alkyl or C 3-6 ring Substituted by alkyl substituents;

R k11各自獨立的選自H、F、Cl、Br、I、=O、OH、SH、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基或-O-C(=O)-C 1-6烷基，所述的烷基、烷氧基或烷硫基任選被1至4個選自F、Cl、Br、I、OH、C 1-4烷基或C 1-4烷氧基的取代基所取代； R k11 is each independently selected from H, F, Cl, Br, I, =O, OH, SH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or -OC( =O)-C 1-6 alkyl, the alkyl, alkoxy or alkylthio group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, C 1-4 alkyl or Substituted with C 1-4 alkoxy substituents;

R k12、R k13各自獨立的選自H、C 1-6烷基或C 3-6環烷基，所述的烷基或環烷基任選被1至4個選自F、Cl、Br、I、=O、OH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； R k12 and R k13 are each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from F, Cl, Br , I, =O, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent;

R k14選自5-6員雜芳基，所述的雜芳基任選被1至4個選自F、Cl、Br、I、OH、=O、CF 3、CN、C 1-4烷基、鹵素取代的C 1-4烷基、羥基取代的C 1-4烷基、C 1-4烷氧基或C 3-6環烷基的取代基所取代，所述雜芳基含有1至4個選自N、O或S的雜原子； R k14 is selected from 5-6 membered heteroaryl, and the heteroaryl is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, CF 3 , CN, C 1-4 alkane Substituted by a substituent of a halogen-substituted C 1-4 alkyl group, a hydroxyl-substituted C 1-4 alkyl group, a C 1-4 alkoxy group or a C 3-6 cycloalkyl group, the heteroaryl group contains 1 to 4 heteroatoms selected from N, O or S;

G選自C 6-10芳環或5-10員雜芳環，所述的芳環或者雜芳環任選被1至4個選自F、Cl、Br、I、OH、=O、CF 3、CN、C 1-4烷基、鹵素取代的C 1-4烷基、羥基取代的C 1-4烷基、C 1-4烷氧基或C 3-6環烷基的取代基所取代，所述雜芳環含有1至4個選自N、O或S的雜原子； G is selected from C 6-10 aromatic ring or 5-10 membered heteroaromatic ring, and the aromatic ring or heteroaromatic ring is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, CF 3. Substituents of CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl Substituted, the heteroaromatic ring contains 1 to 4 heteroatoms selected from N, O or S;

n1、n2、n3各自獨立的選自0、1、2或3；n1, n2 and n3 are each independently selected from 0, 1, 2 or 3;

p1或p2各自獨立的選自0、1、2、3、4或5。p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5.

作為本發明的第二種實施方案，上述通式(I)所示化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，As a second embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

B選自 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； B is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

v 2各自獨立地選自1、2、3或4； v 2 are each independently selected from 1, 2, 3 or 4;

v 1各自獨立地選自0、1或2； v 1 are each independently selected from 0, 1 or 2;

v 3選自0、1、2或3； v 3 is selected from 0, 1, 2 or 3;

v 4選自0、1、2或3； v 4 is selected from 0, 1, 2 or 3;

z選自0、1、2或3；z is selected from 0, 1, 2 or 3;

W選自O或S；W is selected from O or S;

的定義與B 1相同； The definition of is the same as B 1 ;

B 1、B 4各自獨立的選自C 6-14碳環基或5-14員雜環基，所述B 1、B 4任選被1至4個R b1所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； B 1 and B 4 are each independently selected from C 6-14 carbocyclyl or 5-14 membered heterocyclyl. The B 1 and B 4 are optionally substituted by 1 to 4 R b1 , and the heterocyclic The base contains 1 to 4 heteroatoms selected from O, S, and N;

B 2選自C 5-10碳環基、5-10員雜環基或B 5，所述B 2任選被1至4個R b2取代，所述的雜環基含有1至4個選自O、S、N的雜原子； B 2 is selected from C 5-10 carbocyclyl, 5-10 membered heterocyclyl or B 5 , the B 2 is optionally substituted by 1 to 4 R b2 , and the heterocyclyl contains 1 to 4 optional Heteroatoms from O, S, N;

B 3選自C 6-14碳環基或4-14員雜環基，所述B 3任選被1至4個R b1所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； B 3 is selected from C 6-14 carbocyclyl or 4-14 membered heterocyclyl. The B 3 is optionally substituted by 1 to 4 R b1 . The heterocyclyl contains 1 to 4 selected from O , S, N heteroatoms;

B 5選自C 12-18三並環、12至18員雜三並環、噻吩基、呋喃基、噻唑基、噁唑基、吡啶基、嘧啶基、噠嗪基、吡嗪基、三嗪基、苯基、苯並C 4-6碳環、苯並4至6員雜環、吡唑並C 4-6碳環、吡唑並4至6員雜環、三氮唑並C 4-6碳環、三氮唑並4至6員雜環、咪唑並C 4-6碳環、咪唑並4至6員雜環、噻吩並C 4-6碳環、噻吩並4至6員雜環、呋喃並C 4-6碳環、呋喃並4至6員雜環、4-7員含氮雜單環烷基、4-10員含氮雜並環烷基、5-12員含氮雜螺環烷基、7-10員含氮雜橋環烷基、3-7員單環烷基、4-10員並環烷基、5-12員螺環烷基、7-10員橋環烷基，所述B 5任選被1至4個R b2取代，所述的雜環、雜單環烷基、雜並環烷基、雜螺環烷基、雜橋環烷基含有1至4個選自O、S、N的雜原子； B 5 is selected from C 12-18 tricyclic ring, 12 to 18 membered heterotricyclic ring, thienyl, furyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazine Base, phenyl, benzo C 4-6 carbocyclic ring, benzo 4 to 6 membered heterocyclic ring, pyrazolo C 4-6 carbocyclic ring, pyrazolo 4 to 6 membered heterocyclic ring, triazolo C 4- 6 carbocyclic ring, triazolo C 4-6 membered heterocyclic ring, imidazo C 4-6 carbocyclic ring, imidazo C 4-6 membered heterocyclic ring, thieno C 4-6 membered heterocyclic ring, thieno C 4-6 membered heterocyclic ring , Furano C 4-6 carbocyclic ring, furano 4-6 membered heterocycle, 4-7 membered nitrogen-containing heteromonocycloalkyl, 4-10-membered nitrogen-containing heterocycloalkyl, 5-12-membered nitrogen-containing heterocyclic alkyl Spirocycloalkyl, 7-10-membered nitrogen-containing hetero-bridged cycloalkyl, 3-7-membered monocyclic alkyl, 4-10-membered cycloalkyl, 5-12-membered spirocycloalkyl, 7-10-membered bridged ring Alkyl, the B 5 is optionally substituted by 1 to 4 R b2 , the heterocycle, heteromonocycloalkyl, heterocycloalkyl, heterospirocycloalkyl, heterobridged cycloalkyl contains 1 to 4 4 heteroatoms selected from O, S, and N;

R b5選自OH、NH 2、C 1-4烷基、-(CH 2) n-R b22、-C(=O)N(R b21) 2、-C(=O)R b22、C 3-6環烷基、C 6-10芳基、5-10員雜芳基或4-10員雜環基，所述的-CH 2-、烷基、環烷基、雜環基、芳基或雜芳基任選被1至4個選自F、Cl、Br、I、OH、=O、-N(R b21) 2、CN、COOH、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 3-6環烷基、5-10員雜芳基或4-10員雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； R b5 is selected from OH, NH 2 , C 1-4 alkyl, -(CH 2 ) n -R b22 , -C(=O)N(R b21 ) 2 , -C(=O)R b22 , C 3 -6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, the -CH 2 -, alkyl, cycloalkyl, heterocyclyl, aryl Or the heteroaryl group is optionally selected from 1 to 4 F, Cl, Br, I, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkyl Substituents of oxygen group, halogen-substituted C 1-4 alkyl group, cyano-substituted C 1-4 alkyl group, C 3-6 cycloalkyl group, 5-10 membered heteroaryl group or 4-10 membered heterocyclyl group Substituted, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

R b6選自F、Cl、Br、I、OH、NH 2、CN、NO 2、-(CH 2) m1-R b23、-(CH 2) m1-X-(CH 2) m2-R b24、C 2-4炔基、C 3-12環烷基、C 6-10芳基、5-10員雜芳基或4-12員雜環基，所述的炔基、環烷基、芳基、雜芳基或雜環基任選被1至4個選自F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 2-4 alkynyl, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-12 membered heterocyclyl, the alkynyl, cycloalkyl, aryl , heteroaryl or heterocyclic group optionally substituted by 1 to 4 C 1-4 alkyl groups selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen, cyano The heteroaromatic _ _ The base or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

R b3、R b4、R b7各自獨立的選自H、F、Cl、Br、I、OH、NH 2、CN、NO 2、-(CH 2) m1-R b23、-(CH 2) m1-X-(CH 2) m2-R b24、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 2-4炔基、C 3-12環烷基、C 6-10芳基、5-10員雜芳基或4-12員雜環基，所述的烷基、烷氧基、烷硫基、炔基、環烷基、芳基、雜芳基或雜環基任選被1至4個選自氘、F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； R b3 , R b4 , and R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 - X-(CH 2 ) m2 -R b24 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkynyl, C 3-12 cycloalkyl, C 6-10 aryl group, 5-10 membered heteroaryl group or 4-12 membered heterocyclyl group, the alkyl group, alkoxy group, alkylthio group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group or The heterocyclic group is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, and cyano. Substituted with substituents of C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl, the heteroaryl or hetero The ring group contains 1 to 4 heteroatoms selected from O, S, and N;

或R b3、R b4與其相連接的碳原子共同形成C 3-8環烷基或3至8員雜單環，所述的環烷基或雜單環任選被1至4個選自氘、F、Cl、Br、I、OH、NH 2、-N(R b21) 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-6環烷基、5-6員雜芳基或3至8雜環基的取代基所取代，所述的雜單環、雜芳基或雜環基含有1至4個選自O、S、N的雜原子； Or R b3 , R b4 and the carbon atoms to which they are connected together form a C 3-8 cycloalkyl group or a 3- to 8-membered heteromonocyclic ring. The cycloalkyl group or heteromonocyclic ring is optionally substituted by 1 to 4 deuterium atoms. , F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl Substituted with substituents of base, C 1-4 alkoxy group, C 2-4 alkynyl group, C 3-6 cycloalkyl group, 5-6 membered heteroaryl group or 3 to 8 heterocyclic group, the heteromono The ring, heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;

其餘基團定義與本發明第一種實施方案相同。The definitions of the remaining groups are the same as in the first embodiment of the present invention.

作為本發明的第三種實施方案，上述通式(I)所示化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，As the third embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

B選自 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； B is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

環S選自5員、6員或7員含有1或2個氮原子的環，環S任選被1至4個R s取代； Ring S is selected from a 5-, 6- or 7-membered ring containing 1 or 2 nitrogen atoms, and Ring S is optionally substituted by 1 to 4 Rs ;

R s各自獨立的選自F、Cl、Br、I、OH、NH 2、-NHC 1-4烷基、-N(C 1-4烷基) 2、CN、C 1-4烷基、C 1-4烷氧基、C 3-6環烷基，所述的烷基、烷氧基或者環烷基任選被1至4個選自F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基或C 1-4烷氧基的取代基所取代； R s are each independently selected from F, Cl, Br, I, OH, NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , CN, C 1-4 alkyl, C 1-4 alkoxy group, C 3-6 cycloalkyl group, the alkyl group, alkoxy group or cycloalkyl group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , Substituted by CN, C 1-4 alkyl or C 1-4 alkoxy substituents;

B 1、B 4各自獨立的選自苯基、萘基、C 6-12碳環基、5-10員雜芳基、5-10員雜環基、C 10-14三環碳環基、12至14員三環雜環基，所述B 1、B 4任選被1至4個R b1所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； B 1 and B 4 are each independently selected from phenyl, naphthyl, C 6-12 carbocyclyl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, C 10-14 tricyclic carbocyclyl, 12 to 14-membered tricyclic heterocyclyl, the B 1 and B 4 are optionally substituted by 1 to 4 R b1 , the heteroaryl or heterocyclyl contains 1 to 4 selected from O, S, N heteroatoms;

B 2選自C 6-10芳基、5-7員雜環基、5-10員雜芳基或5-10員雜並環、5-10員雜橋環，所述B 2任選被1至4個R b2取代，所述的雜芳基、雜環基、雜並環、雜橋環含有1至4個選自O、S、N的雜原子； B 2 is selected from C 6-10 aryl, 5-7 membered heterocyclyl, 5-10 membered heteroaryl or 5-10 membered heterocyclic ring, 5-10 membered heterobridged ring, and the B 2 is optionally 1 to 4 R b2 substituted, and the heteroaryl, heterocyclyl, heterocyclic, and heterobridged rings contain 1 to 4 heteroatoms selected from O, S, and N;

B 3選自5-12員雜芳基、C 6-7碳環基、C 6-10並碳環基、C 6-12螺碳環基、C 7-12橋碳環基、4-7員單環雜環基、7-14員雜並環、7-14員雜螺環，所述B 3任選被1至4個R b1所取代，所述的雜芳基、雜環基、雜並環、雜螺環含有1至4個選自O、S、N的雜原子； B 3 is selected from 5-12 membered heteroaryl, C 6-7 carbocyclyl, C 6-10 carbonyl carbocyclyl, C 6-12 spiro carbocyclyl, C 7-12 bridged carbocyclyl, 4-7 7-14-membered heterocyclic ring, 7-14-membered heterocyclic ring, 7-14-membered heterospirocyclic ring, the B 3 is optionally substituted by 1 to 4 R b1 , the heteroaryl group, heterocyclyl group, Heterocyclic rings and heterospirocyclic rings contain 1 to 4 heteroatoms selected from O, S, and N;

R b2各自獨立的選自H、F、Cl、Br、I、=O、OH、NH 2、-N(R b21) 2、CN、NO 2、COOH、-C(=O)NH 2、-C(=O)NH-C 1-4烷基、-C(=O)N(C 1-4烷基) 2、-(CH 2) n-R b22、-(CH 2) nO(CH 2) n-R b22、-(CH 2) nO(CH 2) nO-R b22、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 3-8環烷基、C 6-10芳基、5至6員雜芳基、4至8員雜環基、-C 1-4亞烷基-4至8員雜環基，所述的亞烷基、CH 2、烷基、烯基、炔基、烷氧基、環烷基、雜環基、芳基或雜芳基任選被1至4個選自F、Cl、Br、I、OH、NH 2、-NHC 1-4烷基、-N(C 1-4烷基) 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 3-6環烷基、C 3-6環烷基氧基、鹵素取代的C 3-6環烷基、鹵素取代的C 3-6環烷基氧基、5-6員雜芳基或4-8員雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； R b2 is each independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , -N(R b21 ) 2 , CN, NO 2 , COOH, -C(=O)NH 2 , - C(=O)NH-C 1-4 alkyl, -C(=O)N(C 1-4 alkyl) 2 , -(CH 2 ) n -R b22 , -(CH 2 ) n O(CH 2 ) n -R b22 , -(CH 2 ) n O(CH 2 ) n OR b22 , C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 alkoxy group , C 3-8 cycloalkyl, C 6-10 aryl, 5 to 6 membered heteroaryl, 4 to 8 membered heterocyclyl, -C 1-4 alkylene-4 to 8 membered heterocyclyl, so The above-mentioned alkylene, CH 2 , alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are optionally substituted by 1 to 4 selected from F, Cl, Br , I, OH, NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, halogen-substituted C 3-6 cycloalkyl, halogen-substituted C 3 -6 cycloalkyloxy, 5-6-membered heteroaryl or 4-8-membered heterocyclyl substituent, the heteroaryl or heterocyclic group contains 1 to 4 selected from O, S, N heteroatoms;

R b6選自F、Cl、Br、I、OH、NH 2、CN、NO 2、-(CH 2) m1-R b23、-(CH 2) m1-X-(CH 2) m2-R b24、C 2-4炔基、C 3-6環烷基、C 5-10橋環烷基、C 5-12螺環烷基、C 4-12並環烷基、C 6-10芳基、5-6員雜芳基、4-8員雜環基、5-10員雜橋環、5-12員雜螺環、5-12員雜並環，所述的炔基、環烷基、芳基、雜芳基、雜環基、雜橋環、雜螺環或雜並環任選被1至4個選自F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 2-4 alkynyl, C 3-6 cycloalkyl, C 5-10 bridged cycloalkyl, C 5-12 spirocycloalkyl, C 4-12 cycloalkyl, C 6-10 aryl, 5 -6-membered heteroaryl, 4-8-membered heterocyclyl, 5-10-membered heterobridged ring, 5-12-membered heterospirocyclic, 5-12-membered heterocyclic, the alkynyl, cycloalkyl, aromatic The base, heteroaryl, heterocyclyl, heterobridged ring, heterospiro ring or heterocyclic ring is optionally selected from 1 to 4 F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkane base, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 hetero Substituted by the substituent of the ring group, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

R b3、R b4、R b7各自獨立的選自H、F、Cl、Br、I、OH、NH 2、CN、NO 2、-(CH 2) m1-R b23、-(CH 2) m1-X-(CH 2) m2-R b24、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 2-4炔基、C 3-6環烷基、C 5-10橋環烷基、C 5-12螺環烷基、C 4-12並環烷基、C 6-10芳基、5-6員雜芳基、4-8員雜環基、5-10員雜橋環、5-12員雜螺環、5-12員雜並環，所述的烷基、烷氧基、烷硫基、炔基、環烷基、芳基、雜芳基、雜環基、雜橋環、雜螺環或雜並環任選被1至4個選自氘、F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜芳基、雜環基、雜橋環、雜螺環或雜並環含有1至4個選自O、S、N的雜原子； R b3 , R b4 , and R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 - X-(CH 2 ) m2 -R b24 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkynyl, C 3-6 cycloalkyl, C 5-10 bridged cycloalkyl, C 5-12 spirocycloalkyl, C 4-12 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, 4-8 membered heterocyclyl, 5 -10-membered hetero-bridged ring, 5-12-membered heterospiro ring, 5-12-membered heterocyclic ring, the alkyl group, alkoxy group, alkylthio group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group , Heterocyclyl, heterobridged ring, heterospirocyclic or heterocyclic ring is optionally 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen Substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl Substituted with substituents, the heteroaryl, heterocyclyl, heterobridged ring, heterospirocycle or heterocyclic ring contains 1 to 4 heteroatoms selected from O, S, and N;

或R b3、R b4與其相連接的碳原子共同形成C 3-8環烷基或3至8員雜單環，所述的環烷基或雜單環任選被1至4個選自氘、F、Cl、Br、I、OH、NH 2、-N(R b21) 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-6環烷基、5-6員雜芳基或3至8雜環基的取代基所取代，所述的雜單環、雜芳基或雜環基含有1至4個選自O、S、N的雜原子； Or R b3 , R b4 and the carbon atoms to which they are connected together form a C 3-8 cycloalkyl group or a 3 to 8-membered heteromonocyclic ring. The cycloalkyl group or heteromonocyclic ring is optionally substituted by 1 to 4 deuterium atoms. , F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl Substituted with substituents of base, C 1-4 alkoxy group, C 2-4 alkynyl group, C 3-6 cycloalkyl group, 5-6 membered heteroaryl group or 3 to 8 heterocyclic group, the heteromono Ring, heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S, N;

R b23各自獨立的選自C 2-4烯基、C 2-4炔基、C 3-6環烷基或4-8員雜環基，所述的環烷基、烯基、炔基、雜環基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、CF 3、COOH、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or 4-8 membered heterocyclyl, the cycloalkyl, alkenyl, alkynyl, The heterocyclyl group is optionally substituted with 1 to 4 C 1-4 alkyl groups selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, and halogen . Substituted with C 1-4 alkyl group, cyano group substituted C 1-4 alkoxy group substituent, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N;

R b24各自獨立的選自C 1-4烷氧基、C 3-6環烷基氧基、C 3-6環烷基或4-8員雜環基，所述的烷氧基、環烷基、環烷基氧基、雜環基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、CF 3、COOH、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； R b24 is each independently selected from C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl or 4-8 membered heterocyclyl, the alkoxy, cycloalkyl The base, cycloalkyloxy group and heterocyclyl group are optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, Substituted with halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 selected from O, S , N heteroatoms;

任選地，B選自 時，R b3、R b4不能同時選自H； Optionally, B is selected from When , R b3 and R b4 cannot be selected from H at the same time;

其餘基團定義與本發明第一種或第二種實施方案相同。The definitions of the remaining groups are the same as in the first or second embodiment of the present invention.

作為本發明的第四種實施方案，上述通式(I)所示化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，As the fourth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

L選自-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-、-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-；L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1- Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3- Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2- Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3- Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1- Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3- Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2- Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3- Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1- Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4- Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1- Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2- Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2- Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4- Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-, -Ak1-Ak2- Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-;

Ak1、Ak2、Ak3、Ak4、Ak5各自獨立的選自-(CH 2) q-、-(CH 2) q-O-、-O-(CH 2) q-、-(CH 2) q-NR L-、-NR L-(CH 2) q-、-(CH 2)q-NR LC(=O)-、-(CH 2) q-C(=O)NR L-、-C(=O)-、-C(=O)-(CH 2) q-NR L-、-CH=CH-、-(C≡C) q-或者鍵，所述的-CH 2-、-CH=CH-任選被1至2個選自F、Cl、Br、I、OH、CN、NH 2、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、羥基取代的C 1-4烷基、氰基取代的C 1-4烷基的取代基所取代； Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 )q-NR L C(=O)-, -(CH 2 ) q -C(=O)NR L -, -C(= O)-, -C(=O)-(CH 2 ) q -NR L -, -CH=CH-, -(C≡C) q -or bond, the -CH 2 -, -CH=CH - C 1-4 alkyl optionally substituted by 1 to 2 selected from F, Cl, Br, I, OH, CN, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, halogen, Substituted with substituents of hydroxyl-substituted C 1-4 alkyl and cyano-substituted C 1-4 alkyl;

Cy1、Cy2、Cy3、Cy4或Cy5各自獨立地選自鍵或者任選取代的如下基團之一：4-7員雜單環、4-10員雜並環、5-12員雜螺環、7-10員雜橋環、3-7員單環烷基、4-10員並環烷基、5-12員螺環烷基、7-10員橋環烷基、苯並C 4-6碳環基、苯並4至6員雜環基、5-10員雜芳基或6-10員芳基，當被取代時，被1至4個R L2取代，所述的雜環基、雜芳基、雜單環、雜並環、雜螺環或雜橋環含有1至4個選自O、S、N的雜原子，當雜原子選自S時，任選被1或2個=O取代；q各自獨立的選自0、1、2、3或4； Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the bonded or optionally substituted following groups: 4-7 membered heteromonocyclic ring, 4-10 membered heterocyclic ring, 5-12 membered heterospirocyclic ring, 7-10 membered hetero-bridged ring, 3-7-membered monocyclic alkyl group, 4-10-membered cycloalkyl group, 5-12-membered spirocycloalkyl group, 7-10-membered bridged cycloalkyl group, benzo C 4-6 Carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, is substituted by 1 to 4 R L2 , the heterocyclyl, Heteroaryl, heteromonocycle, heteroparacycle, heterospirocycle or heterobridged ring contain 1 to 4 heteroatoms selected from O, S, N. When the heteroatoms are selected from S, they are optionally replaced by 1 or 2 =O substitution; q is independently selected from 0, 1, 2, 3 or 4;

R L各自獨立的選自H或C 1-6烷基； R L are each independently selected from H or C 1-6 alkyl;

K2選自 、 、 、 、 、 、 、 、 、 ； K2 is selected from , , , , , , , , , ;

K3選自 ； K3 is selected from ;

A選自C 3-8碳環、苯環、4-7員雜環或5-6員雜芳環，所述雜環或雜芳環含有1至4個選自O、S或N的雜原子； A is selected from C 3-8 carbocyclic ring, benzene ring, 4-7 membered heterocyclic ring or 5-6 membered heteroaromatic ring. The heterocyclic ring or heteroaromatic ring contains 1 to 4 heterocyclic rings selected from O, S or N. atom;

F各自獨立地選自C 3-7單環碳環、C 4-10並環碳環、C 5-12螺環碳環、C 5-10橋環碳環、4-7員雜單環、4-10員雜並環、8-15員雜三並環、5-12員雜螺環、5-10員雜橋環、C 6-14芳基、5-10員雜芳基、 、 、 、 ，所述雜單環、雜並環、雜螺環、雜橋環或雜芳基含有1至4個選自O、S或N的雜原子； F is each independently selected from C 3-7 monocyclic carbocyclic ring, C 4-10 paracyclic carbocyclic ring, C 5-12 spirocyclic carbocyclic ring, C 5-10 bridged carbocyclic ring, 4-7 membered heteromonocyclic ring, 4-10-membered heterocyclic ring, 8-15-membered heterotricyclic ring, 5-12-membered heterospirocyclic ring, 5-10-membered heterobridged ring, C 6-14- membered aryl group, 5-10-membered heteroaryl group, , , , , the heteromonocyclic ring, heterocyclic ring, heterospirocyclic ring, heterobridged ring or heteroaryl group contains 1 to 4 heteroatoms selected from O, S or N;

表示環選自芳香環或非芳香環； Indicates that the ring is selected from aromatic rings or non-aromatic rings;

E各自獨立地選自C 3-10碳環、苯環、4-12員雜環、5-12員雜芳環，所述雜環或雜芳環含有1至4個選自O、S或N的雜原子； Each E is independently selected from C 3-10 carbocyclic ring, benzene ring, 4-12 membered heterocyclic ring, 5-12 membered heteroaromatic ring, the heterocyclic ring or heteroaromatic ring contains 1 to 4 selected from O, S or N heteroatoms;

Q各自獨立地選自鍵、-O-、-S-、-CH 2-、-NR q-、-CO-、-NR qCO-、-CONR q-或4-7員雜環，所述的雜環任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述雜環含有1至4個選自O、S或N的雜原子； Q is each independently selected from a bond, -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q - or a 4-7 membered heterocycle, The heterocyclic ring is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy Substituted with substituents, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S or N;

R q選自H或C 1-4烷基； R q is selected from H or C 1-4 alkyl;

R k1、R k3各自獨立的選自H、F、Cl、Br、I、OH、=O、NH 2、CF 3、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基，所述烷基或烷氧基任選被1至4個選自F、Cl、Br、I、OH或NH 2的取代基所取代； R k1 and R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkyl Oxygen group, the alkyl or alkoxy group is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH or NH 2 ;

或者兩個R k3和與二者直接相連的碳原子或環骨架共同形成C 3-6碳環或3-7員雜環，兩個R k1和與二者直接相連的碳原子或環骨架共同形成C 3-6碳環或3-7員雜環，所述碳環或雜環任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述雜環含有1至4個選自O、S或N的雜原子； Or two R k3 and the carbon atoms or ring skeleton directly connected to them together form a C 3-6 carbocyclic ring or 3-7 membered heterocyclic ring, and the two R k1 and the carbon atoms or ring skeleton directly connected to them together form Forming a C 3-6 carbocyclic ring or a 3-7 membered heterocyclic ring, the carbocyclic ring or heterocyclic ring is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH , CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S or N;

R k4各自獨立的選自H、OH、NH 2、CF 3、CN或C 1-4烷基； R k4 is each independently selected from H, OH, NH 2 , CF 3 , CN or C 1-4 alkyl;

R k5各自獨立地選自 、C(CH 3) 2、CO、CH 2、SO 2、 、 、 ； R k5 are each independently selected from ,C(CH 3 ) 2 ,CO,CH 2 ,SO 2 , , , ;

R k6各自獨立地選自CO、CH、SO、SO 2、CH 2或N； R k6 is each independently selected from CO, CH, SO, SO 2 , CH 2 or N;

R k7各自獨立地選自 、C(CH 3) 2、CO、CH、N、CH 2、O、S、NR k7a； R k7 are each independently selected from ,C(CH 3 ) 2 ,CO,CH,N,CH 2 ,O,S,NR k7a ;

R k8各自獨立地選自C、N或CH； Rk8 is each independently selected from C, N or CH;

R k9各自獨立地選自鍵、 、C(CH 3) 2、CO、CH 2、CH 2CH 2或SO 2； R k9 are each independently selected from keys, , C(CH 3 ) 2 , CO, CH 2 , CH 2 CH 2 or SO 2 ;

R ka選自O、S或NH； R ka is selected from O, S or NH;

R k7a選自H、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6環烷基、3-6員雜環烷基，所述烷基、環烷基、雜環烷基任選被1至4個選自F、Cl、Br、I、OH、NH 2、CN、CF 3、C 1-4烷基、C 1-4烷氧基、C 2-4烯基、C 2-4炔基、C 3-6環烷基的取代基所取代; R k7a is selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, the alkyl, cycloalkyl Alkyl and heterocycloalkyl are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, C Substituted with substituents of 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl;

R k14選自 ； R k14 selected from ;

p1選自0、1、2或3；p1 is selected from 0, 1, 2 or 3;

p2選自0、1、2或3；p2 is selected from 0, 1, 2 or 3;

其餘基團定義與本發明第一種、第二種或第三種實施方案相同。The definitions of the remaining groups are the same as in the first, second or third embodiment of the present invention.

作為本發明的第五種實施方案，上述通式(I)所示化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，As the fifth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

Cy1、Cy2、Cy3、Cy4或Cy5各自獨立的選自鍵或者任選取代的如下基團之一： 4-7員含氮雜單環、4-10員含氮雜並環、5-12員含氮雜螺環、7-10員含氮雜橋環、3-7員單環烷基、4-10員並環烷基、5-12員螺環烷基、7-10員橋環烷基、苯並C 4-6碳環基、苯並4至6員雜環基、5-10員雜芳基或6-10員芳基，當被取代時，被1至4個R L2取代，所述的雜環基、雜單環、雜並環、雜橋環、雜螺環或雜芳基含有1至4個選自O、S、N的雜原子，當雜原子選自S時，任選被1或2個=O取代； Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the bonded or optionally substituted following groups: 4-7 membered nitrogen-containing heteromonocycle, 4-10-membered nitrogen-containing heterocyclic ring, 5-12 membered Nitrogen-containing heterospirocycle, 7-10 membered nitrogen-containing heterobridged ring, 3-7-membered monocyclic alkyl group, 4-10-membered cycloalkyl group, 5-12-membered spirocycloalkyl group, 7-10-membered bridged cycloalkyl group base, benzo C 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, substituted by 1 to 4 R L2 , the heterocyclic group, heteromonocyclic ring, heterocyclic ring, heterobridged ring, heterospirocyclic ring or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, N, when the heteroatoms are selected from S , optionally replaced by 1 or 2 =O;

R L各自獨立的選自H或C 1-4烷基； R L are each independently selected from H or C 1-4 alkyl;

K1選自 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； K1 is selected from , , , , , , , , , , , , , , ;

K4選自 、 、 ； K4 is selected from , , ;

Q選自鍵、C(=O)；Q is selected from key, C(=O);

Q1選自鍵、CH 2、NH、N(CH 3)、O、S、C(=O)、NHC(=O)、C(=O)NH、N(CH 3)C(=O)、C(=O)N(CH 3)、 、 、 ； Q1 is selected from bonds, CH 2 , NH, N(CH 3 ), O, S, C(=O), NHC(=O), C(=O)NH, N(CH 3 )C(=O), C(=O)N(CH 3 ), , , ;

Q2選自鍵、CH 2、O、S、C(=O)、NHC(=O)、N(CH 3)C(=O)； Q2 is selected from bonds, CH 2 , O, S, C(=O), NHC(=O), N(CH 3 )C(=O);

E、A各自獨立地選自苯環、吡啶環、噠嗪環、吡嗪環、嘧啶環、吡咯環、吡唑環、咪唑環、噻唑環、呋喃環、噻吩環或噁唑環；E and A are each independently selected from benzene ring, pyridine ring, pyridazine ring, pyrazine ring, pyrimidine ring, pyrrole ring, pyrazole ring, imidazole ring, thiazole ring, furan ring, thiophene ring or oxazole ring;

F各自獨立地選自環丁基、環戊基、環己基、雙環[1.1.1]戊烷基、6,7-二氫-5H-環戊[c]吡啶基、2,3-二氫-1H-茚基、苯基、萘基、蒽基、菲基、氮雜環丁基、吡咯烷基、哌啶基、嗎啉基、吡啶基、嘧啶基、噠嗪基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、三唑基、噁唑基、呋喃基、噻吩基、噻唑基、2-吡啶酮基、苯並噁唑基、吡啶並咪唑基、苯並咪唑基、苯並吡唑基、苯並噻唑基、苯並噻吩基、苯並呋喃基、苯並吡咯基、苯並吡啶基、苯並吡嗪基、苯並嘧啶基、苯並噠嗪基、苯並三嗪基、吡咯並吡咯基、吡咯並吡啶基、吡咯並嘧啶基、吡咯並噠嗪基、吡咯並吡嗪基、咪唑並嘧啶基、咪唑並吡啶基、咪唑並吡嗪基、咪唑並噠嗪基、吡唑並吡啶基、吡唑並嘧啶基、吡唑並噠嗪基、吡唑並吡嗪基、嘧啶並吡啶基、嘧啶並吡嗪基、嘧啶並噠嗪基、嘧啶並嘧啶基、吡啶並吡啶基、吡啶並吡嗪基、吡啶並噠嗪基、吡啶並吡唑基、噠嗪並噠嗪基、噠嗪並吡嗪基、吡嗪並吡嗪基、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ，其左側與L直接連接； F is each independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, 6,7-dihydro-5H-cyclopent[c]pyridyl, 2,3-dihydro -1H-Indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, Triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, 2-pyridonyl, benzoxazolyl, pyridimidazolyl, benzo Imidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl , benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridyl, imidazopyrazinyl, Imidazopyridazinyl, pyrazopyridinyl, pyrazopyrimidinyl, pyrazopyridazinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimidine Pyrimidinyl, pyridopyridyl, pyridopyrazinyl, pyridopyridazinyl, pyridopyrazolyl, pyridazinopyridazinyl, pyridazinopyridazinyl, pyrazinopyrazinyl, , , , , , , , , , , , , , , , , , , , , its left side is directly connected to L;

R ka選自O、S或NH； R ka is selected from O, S or NH;

R k7各自獨立地選自 、C(CH 3) 2、CH 2、O、N(CH 3)、N(CH 2CH 3)、N(環丙基)或NH； R k7 are each independently selected from , C(CH 3 ) 2 , CH 2 , O, N(CH 3 ), N(CH 2 CH 3 ), N (cyclopropyl) or NH;

R k1、R k3各自獨立的選自H、F、Cl、Br、I、OH、=O、NH 2、CF 3、CN、COOH、CONH 2、甲基、乙基、異丙基、甲氧基、乙氧基或異丙氧基，所述甲基、乙基、異丙基、甲氧基、乙氧基或異丙氧基任選被1至4個選自F、Cl、Br、I、OH、NH 2的取代基所取代； R k1 and R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2 , methyl, ethyl, isopropyl, methoxy methyl, ethoxy or isopropoxy, the methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy is optionally substituted by 1 to 4 selected from F, Cl, Br, Substituted by I, OH, NH 2 substituents;

R k7a選自H、甲基、乙基、丙基、異丙基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、哌啶基、氧雜環丁基、四氫呋喃基、四氫吡喃基，所述甲基、乙基、丙基、異丙基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、哌啶基、氧雜環丁基、四氫呋喃基、四氫吡喃基任選被1至4個選自F、Cl、Br、I、OH、CN、CF 3、C 1-4烷基、C 1-4烷氧基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、C 3-6環烷基的取代基所取代； Rk7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl base, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, the methyl, ethyl, propyl, isopropyl, cyclo Propyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl are optionally selected from 1 to 4 From F, Cl, Br, I, OH, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl Substituted with substituents of C 3-6 cycloalkyl group;

p1或p2各自獨立的選自0、1或2；p1 or p2 are each independently selected from 0, 1 or 2;

其餘基團定義與本發明第二、三、或四種實施方案中任意一種相同。The remaining group definitions are the same as in any one of the second, third, or fourth embodiments of the present invention.

作為本發明的第六種實施方案，上述通式(I)所示化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，As the sixth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

R L選自H、甲基或乙基； R L is selected from H, methyl or ethyl;

q各自獨立的選自0、1或2；q is independently selected from 0, 1 or 2;

Cy1、Cy2、Cy3、Cy4或Cy5各自獨立的選自鍵或取代的或者未取代的如下基團之一：環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、氮雜環己烯基、哌啶基、嗎啉基、哌嗪基、1,4-二氮雜庚烷基、苯基、噻吩基、噻唑基、呋喃基、噁唑基、吡咯基、吡唑基、咪唑基、吡啶基、噠嗪基、吡嗪基、嘧啶基、吡啶酮、三嗪基、咪唑並吡啶基、咪唑並吡嗪基、咪唑並嘧啶、吡唑並吡啶基、吡唑並吡嗪基、吡唑並嘧啶基、苯並噻吩基、苯並呋喃基、苯並噁唑基、苯並噻唑基、苯並咪唑基、苯並吡唑基、苯並吡咯基、三氮唑並吡啶基、三氮唑並嘧啶基、三氮唑並噠嗪基、三氮唑並吡嗪基、三氮唑並噻唑基、三氮唑並噁唑基、三氮唑並吡唑基、三氮唑並吡咯基、三氮唑並咪唑基、環丙基並環丙基、環丙基並環丁基、環丙基並環戊基、環丙基並環己基、環丁基並環丁基、環丁基並環戊基、環丁基並環己基、環戊基並環戊基、環戊基並環己基、環己基並環己基、環丙基螺環丙基、環丙基螺環丁基、環丙基螺環戊基、環丙基螺環己基、環丁基螺環丁基、環丁基螺環戊基、環丁基螺環己基、環戊基螺環戊基、環戊基螺環己基、環己基螺環己基、環丙基並氮雜環丁基、環丙基並吡咯烷基、環丙基並哌啶基、環丁基並氮雜環丁基、環丁基並吡咯烷基、環丁基並哌啶基、環戊基並氮雜環丁基、環戊基並吡咯烷基、環戊基並哌啶基、環己基並氮雜環丁基、環己基並吡咯烷基、環己基並哌啶基、氮雜環丁基並氮雜環丁基、氮雜環丁基並吡咯烷基、氮雜環丁基並哌啶基、吡咯烷基並氮雜環丁基、吡咯烷基並吡咯烷基、吡咯烷基並哌啶基、哌啶基並氮雜環丁基、哌啶基並吡咯烷基、哌啶基並哌啶基、環丁基螺氮雜環丁基、環丁基螺吡咯烷基、環丁基螺哌啶基、環戊基螺氮雜環丁基、環戊基螺吡咯烷基、環戊基螺哌啶基、環己基螺氮雜環丁基、環己基螺吡咯烷基、環己基螺哌啶基、氮雜環丁基螺氮雜環丁基、氮雜環丁基螺吡咯烷基、氮雜環丁基螺哌啶基、吡咯烷基螺氮雜環丁基、吡咯烷基螺吡咯烷基、吡咯烷基螺哌啶基、哌啶基螺氮雜環丁基、哌啶基螺哌啶基、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ，當被取代時，被1至4個R L2取代； Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the bonded or substituted or unsubstituted following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrole Alkyl, azepanyl, piperidyl, morpholinyl, piperazinyl, 1,4-diazepanyl, phenyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrole base, pyrazolyl, imidazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyridone, triazinyl, imidazopyridyl, imidazopyrazinyl, imidazopyrimidine, pyrazolopyridyl , pyrazolopyrazinyl, pyrazopyrimidinyl, benzothienyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, benzopyrrolyl , triazolopyridinyl, triazolopyrimidinyl, triazolopyridazinyl, triazolopyridinyl, triazolothiazolyl, triazoloxazolyl, triazolo Pyrazolyl, triazolopyrrolyl, triazoloimidazolyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclopropylcyclohexyl Butylcyclobutyl, cyclobutylcyclohexyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexyl, cyclopropylspirocyclopropyl , cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentyl Spirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidine cyclobutyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclohexylazetidinyl Heterocyclylbutyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl, azetidinylpyrrolidinyl, azetidinylpiperidinyl , pyrrolidinyl azetidinyl, pyrrolidinyl pyrrolidinyl, pyrrolidinyl piperidyl, piperidyl azetidinyl, piperidyl pyrrolidinyl, piperidyl piperidyl Aldyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidyl, cyclobutylspiropiperidinyl, cyclopentylspiroazetidinyl, cyclopentylspiropyrrolidyl, cyclopentyl Spiropiperidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidyl, cyclohexylspiropyrolidinyl, azetidinylspiroazetidinyl, azetidinylspiropyrrolidyl, Azetidinylspiroazetidinyl, pyrrolidinylspiroazetidinyl, pyrrolidinylspiropyrrolidyl, pyrrolidinylspiropiperidinyl, piperidinylspiroazetidinyl, piperidinylspiro Piperidinyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , when substituted, by 1 to 4 R L2 ;

R L2各自獨立的選自氘、F、Cl、Br、I、OH、NH 2、NHCH 3、N(CH 3) 2、COOH、CN、=O、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、-O-C 1-2亞烷基-O-C 1-2烷基、-O-C 1-2亞烷基-O-C 3-6碳環基、-C 1-2亞烷基-O-C 1-2亞烷基-O-C 1-2烷基、-C 1-2亞烷基-O-C 1-2亞烷基-O-C 3-6碳環基、-O-C 0-2亞烷基-C 3-6碳環基、-C 0-2亞烷基-C 3-6碳環基、-C 0-2亞烷基-4至6員雜環基，所述的烷基、烯基、炔基、烷氧基、亞烷基、碳環基或雜環基任選被1至4個選自F、Cl、Br、I、OH、COOH、CN、NH 2、NHC 1-4烷基、N(C 1-4烷基) 2、=O、C 1-4烷基、鹵素取代的C 1-4烷基、鹵素取代的C 1-4烷氧基、羥基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； R L2 is each independently selected from deuterium, F, Cl, Br, I, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , COOH, CN, =O, C 1-4 alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -OC 1-2 alkylene- OC 1-2 alkyl, -OC 1-2 alkylene-OC 3-6 carbocyclyl , -C 1-2 alkylene-OC 1-2 alkylene-OC 1-2 alkyl, -C 1-2 alkylene-OC 1-2 alkylene-OC 3-6 carbocyclyl, -OC 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 6-membered heterocyclyl , the alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylene group, carbocyclic group or heterocyclic group is optionally 1 to 4 selected from F, Cl, Br, I, OH, COOH, CN , NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, halogen-substituted C 1-4 alkyl Substituted with oxygen, hydroxyl-substituted C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

B 1、B 4各自獨立的選自苯基、萘基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、吡嗪基、噠嗪基、喹啉基、異喹啉基、3-異喹啉酮基、喹唑啉基、3,4-二氫-1H-苯並吡喃基、1,2,3,4-四氫喹啉基、苯並呋喃基、苯並噻吩基、苯並吡咯基、苯並噁唑基、苯並噻唑基、苯並咪唑基、苯並吡唑基、 、 、 、 、 、 、 、 、 、 、 、 ，所述的B 1、B 4任選被1至4個R b1所取代； B 1 and B 4 are each independently selected from phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, 3- Isoquinolinonyl, quinazolinyl, 3,4-dihydro-1H-benzopyranyl, 1,2,3,4-tetrahydroquinolyl, benzofuranyl, benzothienyl, benzopyrrolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, , , , , , , , , , , , , the B 1 and B 4 are optionally replaced by 1 to 4 R b1 ;

B 2選自取代或未取代的如下基團之一：苯基、萘基、吡唑基、咪唑基、三氮唑基、噻唑基、噁唑基、異噁唑基、噻吩基、吡啶基、苯並吡咯基、苯並咪唑基、苯並吡唑基、苯並噻唑基、吡唑並四氫吡咯基、3-噠嗪酮基、2-吡啶酮基、1,2,3,4-四氫喹啉基、1,2,3,4-四氫異喹啉基、 、 、 、 、 、 、 、 、 、 、 、 、 或B 5，當被取代時，被1至4個R b2取代； B 2 is selected from one of the following substituted or unsubstituted groups: phenyl, naphthyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, thienyl, pyridyl , benzopyrrolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, pyrazolotetrahydropyrrolyl, 3-pyridazinonyl, 2-pyridinonyl, 1,2,3,4 -Tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, , , , , , , , , , , , , or B5 , when substituted, by 1 to 4 R b2 ;

B 5選自 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ，所述B 5任選被1至4個R b2取代； B 5 selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , the B 5 is optionally replaced by 1 to 4 R b2 ;

B 3選自取代或未取代的如下基團之一：苯基、萘基、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、苯並吡啶基、苯並噻吩基、苯並呋喃基、噻吩基、呋喃基、吡咯基，當被取代時，被1至4個R b1取代； B 3 is selected from one of the following substituted or unsubstituted groups: phenyl, naphthyl, , , , , , , , , , , , , , , , , , , , , , , , , benzopyridyl, benzothienyl, benzofuryl, thienyl, furyl, pyrrolyl, when substituted, substituted by 1 to 4 R b1 ;

R b1各自獨立的選自H、F、Cl、Br、I、=O、OH、NH 2、N(CH 3) 2、CN、NO 2、-C(=O)CH 3、-C(=O)NH 2、-C(=O)NH-CH 3、-C(=O)N(CH 3) 2、-S(=O) 2NH 2、-P(=O)(CH 3) 2、-S(=O) 2CH 3或者任選取代的如下基團之一：甲基、乙基、丙基、異丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、環丙基、環丁基、環戊基、環己基、苯基、吡咯基、吡唑基、噁唑基、咪唑基、噻唑基、三氮唑基、氮雜環丁基、吡咯烷基、哌啶基、氧雜環丁基、氧雜環戊基、氧雜環己基、嗎啉、吡咯烷基並環戊基、氮雜環丁基螺環己基、環丙基螺環丁基、環丁基螺環丁基、環丁基螺環戊基、環丁基螺環己基、環戊基螺環己基、 ，當被取代時，被1至4個選自F、Cl、Br、I、OH、CN、CHF 2、CF 3、NH 2、NHCH 3、N(CH 3) 2、甲基、乙基、異丙基、乙炔基、-CH 2-CN、-CH 2OH、-CH 2OMe、-CH 2-環丙基、甲氧基、環丙基、環丁基、氮雜環丁基、吡咯烷基、哌啶基、嗎啉基、噻吩基、噻唑基、呋喃基、噁唑基、吡咯基、咪唑基、吡唑基、三氮唑基、四氮唑基的取代基所取代； R b1 is each independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , N(CH 3 ) 2 , CN, NO 2 , -C(=O)CH 3 , -C(= O)NH 2 , -C(=O)NH-CH 3 , -C(=O)N(CH 3 ) 2 , -S(=O) 2 NH 2 , -P(=O)(CH 3 ) 2 , -S(=O) 2 CH 3 or optionally substituted one of the following groups: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy base, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, azetidine base, pyrrolidinyl, piperidinyl, oxetanyl, oxanyl, oxanyl, morpholine, pyrrolidinyl, piperidinyl, azetidinylspirocyclohexyl, cyclopropyl Spirocyclobutyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclohexyl, , when substituted, is selected from 1 to 4 F, Cl, Br, I, OH, CN, CHF 2 , CF 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, Isopropyl, ethynyl, -CH 2 -CN, -CH 2 OH, -CH 2 OMe, -CH 2 -cyclopropyl, methoxy, cyclopropyl, cyclobutyl, azetidinyl, pyrrole Substituted by alkyl, piperidyl, morpholinyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl substituents;

R b2各自獨立的選自H、F、Cl、Br、I、=O、OH、NH 2、NH(CH 3)、N(CH 3) 2、CN、NO 2、COOH、-C(=O)NH 2或者任選取代的如下基團之一：-CH 2OCH 2CH 3、甲基、乙基、異丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、丙氧基、異丙基氧基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、哌啶基、嗎啉基、吡唑基、噻唑基、三氮唑基、四氮唑基、苯基，當被取代時，被1至4個選自F、Cl、Br、I、OH、CN、CHF 2、CF 3、NH 2、NHCH 3、N(CH 3) 2、甲基、乙基、異丙基、甲氧基、乙氧基、吡唑基、嗎啉基、氧雜環己基、環丙基、 、環丁基、 、 、環丙基氧基、 、 、 、 的取代基所取代； R b2 is each independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CN, NO 2 , COOH, -C(=O )NH 2 or optionally substituted one of the following groups: -CH 2 OCH 2 CH 3 , methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, Ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrazolyl , thiazolyl, triazolyl, tetrazolyl, phenyl, when substituted, 1 to 4 selected from F, Cl, Br, I, OH, CN, CHF 2 , CF 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, isopropyl, methoxy, ethoxy, pyrazolyl, morpholinyl, oxanyl, cyclopropyl, , cyclobutyl, , , cyclopropyloxy, , , , Substituted by substituents;

R b3、R b4各自獨立的選自H、OH、NH 2或者任選取代的如下基團之一：甲基、乙基、乙炔基、丙炔基、炔丙基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、哌啶基、氧雜環丁基、氧雜環戊基、氧雜環己基、環丁基螺環丁基，當被取代時，被1至4個選自氘、F、Cl、Br、I、OH、NH 2、CN、CF 3、CHF 2、甲基、甲氧基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、吡唑基、哌啶基、氧雜環丁基、氧雜環戊基、氧雜環己基、環丁基螺環丁基的取代基所取代； R b3 and R b4 are each independently selected from H, OH, NH 2 or one of the optionally substituted following groups: methyl, ethyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl base, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolyl, oxetanyl, cyclobutylspirocyclobutyl, when When substituted, it is replaced by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, CF 3 , CHF 2 , methyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl Substituents of base, cyclohexyl, azetidinyl, pyrrolidinyl, pyrazolyl, piperidinyl, oxetanyl, oxanyl, oxetanyl, cyclobutylspirocyclobutyl replaced;

或R b3、R b4與其相連接的碳原子共同形成任選取代的如下基團之一：環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、哌啶基、氧雜環丁基、氧雜環戊基、氧雜環己基、環丁基螺環丁基，當被取代時，被1至4個選自氘、F、Cl、Br、I、OH、NH 2、N(CH 3)、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-6環烷基、5-6員雜芳基或3至8雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； Or R b3 , R b4 and the carbon atoms to which they are connected together form one of the following optionally substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperazyl Aldyl, oxetanyl, oxetanyl, oxetanyl, cyclobutylspirocyclobutyl, when substituted, are selected from 1 to 4 deuterium, F, Cl, Br, I, OH, NH 2 , N(CH 3 ), CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C Substituted with 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl substituents, the heteroaryl or heterocyclyl contains 1 to 4 optional Heteroatoms from O, S, N;

R b5選自OH、NH 2、甲基、乙基、丙基、異丙基、-(CH 2) n-環丙基、-(CH 2) n-環丁基、-(CH 2) n-環戊基、-(CH 2) n-環己基、苯基、吡啶基，所述的-CH 2-、甲基、乙基、丙基、異丙基、環丙基、環丁基、環戊基、環己基、苯基、吡啶基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 3-6環烷基、5-10員雜芳基或4-10員雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； R b5 is selected from OH, NH 2 , methyl, ethyl, propyl, isopropyl, -(CH 2 ) n -cyclopropyl, -(CH 2 ) n -cyclobutyl, -(CH 2 ) n -Cyclopentyl, -(CH 2 ) n -cyclohexyl, phenyl, pyridyl, the -CH 2 -, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, phenyl, and pyridyl are optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl, C 1 -4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl Substituted with a substituent, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N;

n各自獨立的選自0、1；n is independently selected from 0 and 1;

R b6選自F、Cl、Br、I、OH、NH 2、CN、NO 2、-CH 2-R b23、-CH 2-X-(CH 2) m2-R b24或者取代或未取代的如下基團之一：乙炔基、丙炔基、炔丙基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、氧雜環丁基、吡咯烷基、氮雜環己烯基、哌啶基、嗎啉基、哌嗪基、1,4-二氮雜庚烷基、苯基、吡啶基、環丙基並環丙基、環丙基並環丁基、環丙基並環戊基、環丙基並環己基、環丁基並環丁基、環丁基並環戊基、環丁基並環己基、環戊基並環戊基、環戊基並環己基、環己基並環己基、環丙基螺環丙基、環丙基螺環丁基、環丙基螺環戊基、環丙基螺環己基、環丁基螺環丁基、環丁基螺環戊基、環丁基螺環己基、環戊基螺環戊基、環戊基螺環己基、環己基螺環己基、環丙基並氮雜環丁基、環丙基並吡咯烷基、環丙基並哌啶基、環丁基並氮雜環丁基、環丁基並吡咯烷基、環丁基並哌啶基、環戊基並氮雜環丁基、環戊基並吡咯烷基、環戊基並哌啶基、環己基並氮雜環丁基、環己基並吡咯烷基、環己基並哌啶基、氮雜環丁基並氮雜環丁基、氮雜環丁基並吡咯烷基、氮雜環丁基並哌啶基、吡咯烷基並氮雜環丁基、吡咯烷基並吡咯烷基、吡咯烷基並哌啶基、哌啶基並氮雜環丁基、哌啶基並吡咯烷基、哌啶基並哌啶基、環丁基螺氮雜環丁基、環丁基螺吡咯烷基、環丁基螺哌啶基、環戊基螺氮雜環丁基、環戊基螺吡咯烷基、環戊基螺哌啶基、環己基螺氮雜環丁基、環己基螺吡咯烷基、環己基螺哌啶基、氮雜環丁基螺氮雜環丁基、氮雜環丁基螺吡咯烷基、氮雜環丁基螺哌啶基、吡咯烷基螺氮雜環丁基、吡咯烷基螺吡咯烷基、吡咯烷基螺哌啶基、哌啶基螺氮雜環丁基、哌啶基螺哌啶基、 、 、 、 、 、 、 、 、 、 ，當被取代時，被1至4個選自F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -CH 2 -R b23 , -CH 2 -X-(CH 2 ) m2 -R b24 or substituted or unsubstituted as follows One of the groups: ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, azetamine Hexenyl, piperidyl, morpholinyl, piperazinyl, 1,4-diazepanyl, phenyl, pyridyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropyl Propylcyclopentyl, cyclopropylcyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl Hexyl, cyclohexyl-cyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutyl Spirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl , cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl Alkyl, cyclopentapiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl, azetidinyl pyrrolidinyl, azetidinyl piperidinyl, pyrrolidinyl azetidinyl, pyrrolidinyl pyrrolidinyl, pyrrolidinyl piperidinyl, piperidyl azetidinyl base, piperidinopyrrolidinyl, piperidinopiperidinyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidyl, cyclobutylspiropyrrolidyl, cyclopentylspiroazepine Cyclobutyl, cyclopentylspiropyrrolidyl, cyclopentylspiropiperidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidyl, cyclohexylspiropyrrolidyl, azetidinylspiroazetidine Heterocyclidyl, azetidinylspiropyrrolidyl, azetidinylspiropiperidinyl, pyrrolidinylspiroazetidinyl, pyrrolidinylspiropyrrolidyl, pyrrolidinylspiropiperidinyl , piperidinylspiroazetidinyl, piperidinylspiropiperidinyl, , , , , , , , , , , when substituted, C 1-4 alkyl substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen substituted, cyano substituted C Substituted with 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, the heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;

R b7選自H、F、Cl、Br、I、OH、NH 2、CN、NO 2、CHF 2、CF 3、-CH 2-R b23、-CH 2-X-(CH 2) m2-R b24或者取代或未取代的如下基團之一：乙炔基、丙炔基、炔丙基、甲基、乙基、甲氧基、乙氧基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、氮雜環己烯基、哌啶基、嗎啉基、哌嗪基、1,4-二氮雜庚烷基、苯基、環丙基並環丙基、環丙基並環丁基、環丙基並環戊基、環丙基並環己基、環丁基並環丁基、環丁基並環戊基、環丁基並環己基、環戊基並環戊基、環戊基並環己基、環己基並環己基、環丙基螺環丙基、環丙基螺環丁基、環丙基螺環戊基、環丙基螺環己基、環丁基螺環丁基、環丁基螺環戊基、環丁基螺環己基、環戊基螺環戊基、環戊基螺環己基、環己基螺環己基、環丙基並氮雜環丁基、環丙基並吡咯烷基、環丙基並哌啶基、環丁基並氮雜環丁基、環丁基並吡咯烷基、環丁基並哌啶基、環戊基並氮雜環丁基、環戊基並吡咯烷基、環戊基並哌啶基、環己基並氮雜環丁基、環己基並吡咯烷基、環己基並哌啶基、氮雜環丁基並氮雜環丁基、氮雜環丁基並吡咯烷基、氮雜環丁基並哌啶基、吡咯烷基並氮雜環丁基、吡咯烷基並吡咯烷基、吡咯烷基並哌啶基、哌啶基並氮雜環丁基、哌啶基並吡咯烷基、哌啶基並哌啶基、環丁基螺氮雜環丁基、環丁基螺吡咯烷基、環丁基螺哌啶基、環戊基螺氮雜環丁基、環戊基螺吡咯烷基、環戊基螺哌啶基、環己基螺氮雜環丁基、環己基螺吡咯烷基、環己基螺哌啶基、氮雜環丁基螺氮雜環丁基、氮雜環丁基螺吡咯烷基、氮雜環丁基螺哌啶基、吡咯烷基螺氮雜環丁基、吡咯烷基螺吡咯烷基、吡咯烷基螺哌啶基、哌啶基螺氮雜環丁基、哌啶基螺哌啶基、 、 、 、 、 、 、 、 、 、 ，當被取代時，被1至4個選自F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； R b7 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , CHF 2 , CF 3 , -CH 2 -R b23 , -CH 2 -X-(CH 2 ) m2 -R b24 or one of the following substituted or unsubstituted groups: ethynyl, propynyl, propargyl, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, azetidinyl, pyrrolidinyl, azepanyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, phenyl, cyclopropyl cyclopropyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl-cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, Cyclopent-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocycle Hexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropyl Azetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclopentyl Azetidinyl, cyclopentapyrrolidinyl, cyclopentapiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetamine Butyl azetidinyl, azetidinyl pyrrolidinyl, azetidinyl piperidinyl, pyrrolidinyl azetidinyl, pyrrolidinyl pyrrolidinyl, pyrrolidinyl piperidinyl, piperidinoazetidinyl, piperidinopyrrolidinyl, piperidinopiperidinyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidyl, ring Butylspiroazetidinyl, cyclopentylspiroazetidinyl, cyclopentylspiropyrrolidyl, cyclopentylspiropyridinyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidyl, cyclohexylspiropyrrolidyl Hexylspiropiperidinyl, azetidinylspiroazetidinyl, azetidinylspiropyrrolidyl, azetidinylspiropyrolidinyl, pyrrolidinylspiroazetidinyl, pyrrolidine Spiropyrrolidinyl, pyrrolidinylspiropiperidinyl, piperidinylspiroazetidinyl, piperidinylspiropiperidinyl, , , , , , , , , , , when substituted, C 1-4 alkyl substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen substituted, cyano substituted C Substituted with 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, the heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;

X各自獨立的選自NH、O或S；X is each independently selected from NH, O or S;

m2各自獨立的選自0、1或2；m2 is each independently selected from 0, 1 or 2;

R b23各自獨立的選自乙烯基、乙炔基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、氮雜環己烯基、氧雜環丁基、氧雜環戊基、氧雜環己基、哌啶或嗎啉，所述的乙烯基、乙炔基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、氮雜環己烯基、氧雜環丁基、氧雜環戊基、氧雜環己基、哌啶或嗎啉任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代； R b23 is each independently selected from vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, oxetanyl , oxolanyl, oxanyl, piperidine or morpholine, the vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidine base, azepanyl, oxetanyl, oxanyl, oxanyl, piperidine or morpholine optionally selected from 1 to 4 F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy substituents ;

R b24各自獨立的選自甲氧基、乙氧基、丙氧基、異丙基氧基、環丙基、環丙基氧基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、氮雜環己烯基、氧雜環丁基、氧雜環戊基、氧雜環己基、哌啶或嗎啉，所述的甲氧基、乙氧基、丙氧基、異丙基氧基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、氮雜環己烯基、氧雜環丁基、氧雜環戊基、氧雜環己基、哌啶或嗎啉任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代； R b24 is each independently selected from methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclopropyloxy, cyclobutyl, cyclopentyl, cyclohexyl, azetidine base, pyrrolidinyl, azepinenyl, oxetanyl, oxanyl, oxanyl, piperidine or morpholine, the methoxy, ethoxy, propoxy group , isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, oxetanyl, oxetanyl , oxanyl, piperidine or morpholine optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl, halogen Substituted with C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy substituents;

K選自 表 K-1所示的結構片段之一； K is selected from one of the structural fragments shown in Table K-1 ;

其餘基團定義與本發明第二、三、四或五種實施方案中任意一種相同。The remaining group definitions are the same as in any one of the second, third, fourth or fifth embodiments of the present invention.

作為本發明的第七種實施方案，上述通式(I)所示化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，As a seventh embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

Cy1、Cy2、Cy3、Cy4或Cy5各自獨立的選自鍵或取代的或者未取代的如下基團之一： 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ，當被取代時，被1至4個R L2取代； Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the following groups: bond or substituted or unsubstituted: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , when substituted, by 1 to 4 R L2 ;

R L2各自獨立地選自氘、F、Cl、Br、=O、COOH、CN、NHCH 3、N(CH 3) 2、OH、NH 2或任選取代的如下基團之一：甲基、乙基、異丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、丙氧基、異丙基氧基、環丙基、環丁基、環戊基、環己基、吡唑基、噻唑基、三氮唑基、四氮唑基、苯基、嗎啉、-CH 2-環丙基、-CH 2-嗎啉、-CH 2-吡唑、-OCH 2-環丙基、-O-環丙基、-OCH 2CH 2-O-甲基、-OCH 2CH 2-O-環丙基、-CH 2OCH 2CH 2-O-甲基、-CH 2OCH 2CH 2-O-環丙基，當被取代時，被1至4個選自F、CHF 2、CF 3、-OCHF 2、-OCF 3、甲基、甲氧基、=O、羥甲基、COOH、CN、NHCH 3、N(CH 3) 2、OH、NH 2的取代基所取代； RL2 is each independently selected from deuterium, F, Cl, Br, =O, COOH, CN, NHCH 3 , N(CH 3 ) 2 , OH, NH 2 or one of the optionally substituted following groups: methyl, Ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, morpholine, -CH 2 -cyclopropyl, -CH 2 -morpholine, -CH 2 -pyrazole, - OCH 2 -cyclopropyl, -O-cyclopropyl, -OCH 2 CH 2 -O-methyl, -OCH 2 CH 2 -O-cyclopropyl, -CH 2 OCH 2 CH 2 -O-methyl, -CH 2 OCH 2 CH 2 -O-cyclopropyl, when substituted, is selected from 1 to 4 F, CHF 2 , CF 3 , -OCHF 2 , -OCF 3 , methyl, methoxy, = Substituted by O, hydroxymethyl, COOH, CN, NHCH 3 , N(CH 3 ) 2 , OH, NH 2 substituents;

B選自 表 B-1 或表 B-2所示的結構片段之一； B is selected from one of the structural fragments shown in Table B-1 or Table B-2 ;

K選自 表 K-2所示的結構片段之一； K is selected from one of the structural fragments shown in Table K-2 ;

其餘基團定義與本發明第二、三、四、五或六種實施方案中任意一種相同。The remaining group definitions are the same as in any one of the second, third, fourth, fifth or sixth embodiments of the present invention.

作為本發明的第八種實施方案，上述通式(I)所示化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，As an eighth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

L選自鍵或 表 L-1 或表 L-2所示的結構片段之一，其中基團左側與B連接； L is selected from a bond or one of the structural fragments shown in Table L-1 or Table L-2 , in which the left side of the group is connected to B;

其餘基團定義與與本發明第二、三、四、五、六或七種實施方案中任意一種相同。The definitions of the remaining groups are the same as in any one of the second, third, fourth, fifth, sixth or seventh embodiments of the present invention.

作為本發明的第九種實施方案，上述通式(I)所示化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，As the ninth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

L的定義與本發明第三、四、五、六或七種實施方案中任意一項相同；The definition of L is the same as any one of the third, fourth, fifth, sixth or seventh embodiments of the present invention;

K的定義與本發明第三、四、五、六或七種實施方案中任意一項相同；The definition of K is the same as any one of the third, fourth, fifth, sixth or seventh embodiments of the present invention;

B的定義與本發明第七種實施方案相同。The definition of B is the same as in the seventh embodiment of the present invention.

作為本發明的第十種實施方案，上述通式(I)所示化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，As a tenth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,

L選自鍵、-Ak1-、-Cy1-、-Cy1-Ak1-、-Cy1-Ak1-Ak2-、-Cy1-Ak1-Ak2-Ak3-、-Cy1-Ak1-Ak2-Ak3-Ak4-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-Ak3-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Cy2-Ak2-Ak3-、-Cy1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Ak2-Cy3-、-Cy1-Ak1-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Cy1-Cy2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Cy3-Ak3-、-Cy1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Ak2-Cy3-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-Ak3-Ak4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak2-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-Ak4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Ak1-Ak2-Cy3-、-Ak1-Ak2-Cy3-Cy4-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Cy3-Ak3-Cy4-、-Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-、-Ak1-Cy2-Ak2-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-、-Ak1-Cy2-Ak2-Ak3-；L is selected from the group consisting of bonds, -Ak1-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, - Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2- Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2- Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3- Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3- Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, - Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4- , -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3-Cy4-, -Ak1- Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Ak1-Ak2-Ak3-Ak4- , -Ak1-Ak2-Ak3-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3- Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5- , -Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;

Ak1、Ak2、Ak3、Ak4、Ak5各自獨立的選自-O-、-OCH 2-、-CH 2O-、-OCH 2CH 2-、-CH 2CH 2O-、-CH=CH-、-CH=C(CN)-、-CH=C(F)-、-C(CN)=CH-、-C(F)=CH-、-C≡C-、-C(CH 3) 2-、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-N(CH 3)-、-NH-、-CH 2N(CH 3)-、-CH 2NH-、-NHCH 2-、-CH 2CH 2N(CH 3)-、-CH 2CH 2NH-、-NHCH 2CH 2-、-C(=O)-、-C(=O)CH 2NH-、-CH 2C(=O)NH-、-C(=O)NH-或-NHC(=O)-； Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from -O-, -OCH 2 -, -CH 2 O-, -OCH 2 CH 2 -, -CH 2 CH 2 O-, -CH=CH-, -CH=C(CN)-, -CH=C(F)-, -C(CN)=CH-, -C(F)=CH-, -C≡C-, -C(CH 3 ) 2 - , -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -N(CH 3 )-, -NH-, -CH 2 N(CH 3 )-, -CH 2 NH-, -NHCH 2 -, -CH 2 CH 2 N(CH 3 )-, -CH 2 CH 2 NH-, -NHCH 2 CH 2 -, -C(=O)-, -C(=O)CH 2 NH- , -CH 2 C(=O)NH-, -C(=O)NH- or -NHC(=O)-;

其餘基團定義與本發明第二、三、四、五、六、七、八或九種實施方案中任意一種相同。The remaining group definitions are the same as any one of the second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiments of the present invention.

作為本發明的第十一種實施方案，上述通式(I)所示化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，其中，As an eleventh embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein ,

L選自鍵、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Cy1-Ak1-、-Ak1-Cy2-Ak2-、-Cy1-Cy2-Cy3-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Ak1-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-、-Cy1-、-Ak1-Cy2-Ak2-Ak3-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Ak2-Ak3-Ak4-；L is selected from the group consisting of bonds, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Cy1-Ak1-, -Ak1-Cy2-Ak2-, -Cy1-Cy2-Cy3-, -Cy1-Cy2-, -Cy1- Ak1-Cy2-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Ak1-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-, -Cy1-, -Ak1- Cy2-Ak2-Ak3-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Ak2-Ak3-Ak4-;

Ak1、Ak2、Ak3、Ak4各自獨立的選自-C(=O)-、-O-、NH、-CH=CH-、-CH=C(CN)-、-CH=C(F)-、-C(CN)=CH-、-C(F)=CH-、-C≡C-、-C(CH 3) 2-、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-NHCO-； Ak1, Ak2, Ak3, and Ak4 are each independently selected from -C(=O)-, -O-, NH, -CH=CH-, -CH=C(CN)-, -CH=C(F)-, -C(CN)=CH-, -C(F)=CH-, -C≡C-, -C(CH 3 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -NHCO-;

Cy1、Cy2、Cy3各自獨立的選自取代的或者未取代的如下基團之一： 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ，當被取代時，被1至4個R L2取代； Cy1, Cy2, and Cy3 are each independently selected from one of the following substituted or unsubstituted groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , when substituted, by 1 to 4 R L2 ;

B、K的定義與本發明第二、三、四、五、六、七種實施方案中任意一種相同。The definitions of B and K are the same as any one of the second, third, fourth, fifth, sixth and seventh embodiments of the present invention.

作為本發明的第十二種實施方案，上述通式(I)所示化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，其中，As a twelfth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein ,

L選自-Cy1-Cy2-;L is selected from -Cy1-Cy2-;

Cy1選自任選取代的如下基團之一：苯基、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ，所述Cy1任選被1至3個R L2取代； Cy1 is selected from one of the following optionally substituted groups: phenyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , the Cy1 is optionally replaced by 1 to 3 R L2 ;

Cy2選自 、 、 ，所述Cy2任選被1至2個R L2取代； Cy2 is selected from , , , the Cy2 is optionally replaced by 1 to 2 R L2 ;

其餘基團定義與本發明第二、三、四、五、六、七種實施方案中任意一種相同。The definitions of the remaining groups are the same as any one of the second, third, fourth, fifth, sixth and seventh embodiments of the present invention.

本發明涉及一種下述化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，其中該化合物選自 表 E-1結構之一。 表E-1 1   2   3   4   5   6   7   8   9   10   11   12   13   14   15   16   17   18   19   20   21   22   23   24   25   26   27   28   29   30   31   32   33   34   35   36   37   38   39   40   41   42   43   44   45   46   47   48   49   50   51   52   53   54   55   56   57   58   59   60   61   62   63   64   65   66   67   68   69   70   71   72   73   74   75   76   77   78   79   80   81   82   83   84   85   86   87   88   89   90   91   92   93   94   95   96   97   98   99   100   101   102   103   104   105   106   107   108   109   110   111   112   113   114   115   116   117   118   119   120   121   122   123   124   125   126   127   128   129   130   131   132   133   134   135   136   137   138   139   140   141   142   143   144   145   146   147   148   149   150   151   152   153   154   155   156   157   158   159   160   161   162   163   164   165   166   167   168   169   170   171   172   173   174   175   176   177   178   179   180   181   182   183   184   185   186   187   188   189   190   191   192   193   194   195   196   197   198   199   200   201   202   203   204   205   206   207   208   209   210   211   212   213   214   215   216   217   218   219   220   221   222   223   224   225   226   227   228   229   230   231   232   233   234   235   236   237   238   239   240   241   242   243   244   245   246   247   248   249   250   251   252   253   254   255   256   257   258   259   260   261   262   263   264   265   266   267   268   269   270   271   272   273   274   275   276   277   278   279   280   281   282   283   284   285   286   287   288   289   290   291   292   293   294   295   296   297   298   299   300   301   302   303   304   305   306   307   308   309   310   311   312   313   314   315   316   317   318   319   320   321   322   323   324   325   326   327   328   329   330   331   332   333   334   335   336   337   338   339   340   341   342   343   344   345   346   347   348   349   350   351   352   353   354   355   356   357   358   359   360   361   362   363   364   365   366   367   368   369   370   371   372   373   374   375   376   377   378   379   380   381   382   383   384   385   386   387   388   389   390   391   392   393   394   395   396   397   398   399   400   401   402   403   404   405   406   407   408   409   410   411   412   413   414   415   416   417   418   419   420   421   422   423   424   425   426   427   428   429   430   431   432   433   434   435   436   437   438   439   440   441   442   443   444   445   446   447   448   449   450   451   452   453   454   455   456   457   458   459   460   461   462   463   464   465   466   467   468   469   470   471   472   473   474   475   476   477   478   479   480   481   482   483         。 表 L-1L基團                                                                -NH- -CH 2- 表L-2       The present invention relates to a following compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the group consisting of: surface E-1One of the structures. Table E-1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 twenty one twenty two twenty three twenty four 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483       . surface L-1L group -NH- -CH 2 - Table L-2      

本發明涉及一種藥物組合物，包括本發明上述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，以及藥學上可接受的載體。The present invention relates to a pharmaceutical composition, including the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and a pharmaceutically acceptable carrier. .

本發明涉及一種藥物組合物，包括治療有效量的本發明上述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，以及藥學上可接受的載體。The present invention relates to a pharmaceutical composition, including a therapeutically effective amount of the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and a pharmaceutical Acceptable carrier.

在一些實施方案中，本發明的藥物組合物可以為單位制劑形式(單位制劑中主藥的量也被稱為“製劑規格”)。In some embodiments, the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in a unit preparation is also referred to as "preparation strength").

本申請中所述“有效量”或“治療有效量”是指給予足夠量的本申請公開的化合物，其將在某種程度上緩解所治療的疾病或病症(例如抑制或降解AR或AR剪切突變體相關疾病如前列腺癌)的一種或多種症狀。在一些實施方案中，結果是減少和/或緩和疾病的體征、症狀或原因，或生物系統的任何其它希望改變。例如，針對治療用途的“有效量”是提供臨床上顯著的疾病症狀降低所需的包含本申請公開的化合物的組合物的量。治療有效量的實例包括但不限於1-1500mg、1-1200mg、1-1000mg、1-900mg、1-800mg、1-700mg、1-600mg、2-600mg、3-600mg、4-600mg、5-600mg、6-600mg、10-600mg、20-600mg、25-600mg、30-600mg、40-600mg、50-600mg、60-600mg、70-600mg、75-600mg、80-600mg、90-600mg、100-600mg、200-600mg、1-500mg、2-500mg、3-500mg、4-500mg、5-500mg、6-500mg、10-500mg、20-500mg、25-500mg、30-500mg、40-500mg、50-500mg、60-500mg、70-500mg、75-500mg、80-500mg、90-500mg、100-500mg、125-500mg、150-500mg、200-500mg、250-500mg、300-500mg、400-500mg、5-400mg、10-400mg、20-400mg、25-400mg、30-400mg、40-400mg、50-400mg、60-400mg、70-400mg、75-400mg、80-400mg、90-400mg、100-400mg、125-400mg、150-400mg、200-400mg、250-400mg、300-400mg、1-300mg、2-300mg、5-300mg、10-300mg、20-300mg、25-300mg、30-300mg、40-300mg、50-300mg、60-300mg、70-300mg、75-300mg、80-300mg、90-300mg、100-300mg、125-300mg、150-300mg、200-300mg、250-300mg、1-200mg、2-200mg、5-200mg、10-200mg、20-200mg、25-200mg、30-200mg、40-200mg、50-200mg、60-200mg、70-200mg、75-200mg、80-200mg、90-200mg、100-200mg、125-200mg、150-200mg、80-1000mg、80-800mg。"Effective amount" or "therapeutically effective amount" as used herein refers to administration of a sufficient amount of a compound disclosed herein that will alleviate the disease or condition being treated to some extent (e.g., inhibit or degrade AR or AR cleavage). One or more symptoms of mutant-related diseases such as prostate cancer. In some embodiments, the result is reduction and/or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein that is required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5 -600mg, 6-600mg, 10-600mg, 20-600mg, 25-600mg, 30-600mg, 40-600mg, 50-600mg, 60-600mg, 70-600mg, 75-600mg, 80-600mg, 90-600mg , 100-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40 -500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg , 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90 -400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg , 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250 -300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg , 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, 80-800mg.

在一些實施方案中，該藥物組合物包括但不限於1-1000mg、20-800mg、40-800mg、40-400mg、25-200mg、1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、110mg、120mg、125mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、300mg、320mg、400mg、480mg、500mg、600mg、640mg、840mg的本發明化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶。In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40mg, 45mg, 50mg, 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of the compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic.

一種用於治療哺乳動物的疾病的方法，所述方法包括給予受試者治療有效量的本發明化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，治療有效量較佳1-1500mg，所述的疾病較佳抑制或降解AR或AR剪切突變體相關疾病(如前列腺癌)。A method for treating diseases in mammals, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable Salt or co-crystal, the therapeutically effective dose is preferably 1-1500 mg, and the disease is preferably inhibited or degraded by AR or AR splicing mutant-related diseases (such as prostate cancer).

一種用於治療哺乳動物的疾病的方法所述方法包括，將藥物本發明化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶以1-1000mg/天的日劑量給予受試者，所述日劑量可以為單劑量或分劑量，在一些實施方案中，日劑量包括但不限於10-1500mg/天、10-1000mg/天、10-800mg/天、25-800mg/天、50-800mg/天、100-800mg/天、200-800mg/天、25-400mg/天、50-400mg/天、100-400mg/天、200-400mg/天，在一些實施方案中，日劑量包括但不限於10mg/天、20mg/天、25mg/天、50mg/天、80mg/天、100mg/天、125mg/天、150mg/天、160mg/天、200mg/天、300mg/天、320mg/天、400mg/天、480mg/天、600mg/天、640mg/天、800mg/天、1000mg/天。A method for treating diseases in mammals. The method includes: adding a pharmaceutical compound of the present invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal to 1 -A daily dose of 1000 mg/day is administered to the subject, which may be a single dose or divided dose. In some embodiments, the daily dose includes, but is not limited to, 10-1500 mg/day, 10-1000 mg/day, 10- 800mg/day, 25-800mg/day, 50-800mg/day, 100-800mg/day, 200-800mg/day, 25-400mg/day, 50-400mg/day, 100-400mg/day, 200-400mg/ Days, in some embodiments, daily dosages include, but are not limited to, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day, 200mg/day, 300mg/day, 320mg/day, 400mg/day, 480mg/day, 600mg/day, 640mg/day, 800mg/day, 1000mg/day.

本發明涉及一種試劑盒，該試劑盒可以包括單劑量或多劑量形式的組合物，該試劑盒包含本發明化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，本發明化合物的或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶的量與上述藥物組合物中其量相同。The present invention relates to a kit, which may include a composition in a single dose or multiple dose form. The kit contains a compound of the invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutical Acceptable salts or co-crystals, the amount of the compound of the present invention or its stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals is the same as the amount in the above-mentioned pharmaceutical composition same.

本發明涉及一種本發明上述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶或者上述藥物組合物在用於製備治療與AR或AR剪切突變體活性或表達量相關疾病的藥物中的應用。The present invention relates to the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal or the above-mentioned pharmaceutical composition used in the preparation of the treatment of AR or Application of AR splice mutants in drugs for diseases related to activity or expression level.

本發明涉及一種本發明上述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶、或者上述藥物組合物在用於製備治療與抑制或降解AR或AR剪切突變體相關疾病的藥物中的應用。The present invention relates to the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, or the above-mentioned pharmaceutical composition used in the preparation of treatment and inhibitory products Or application in drugs that degrade AR or AR splice mutant-related diseases.

本發明涉及的本發明上述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶、或者上述藥物組合物的應用，所述的疾病選自前列腺癌。The present invention relates to the application of the above-mentioned compounds of the present invention or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, or the above-mentioned pharmaceutical compositions. Selected from prostate cancer.

本發明化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶的量在每種情況下以游離鹼的形式換算。The amounts of the compounds of the invention or of their stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals are in each case converted to the free base form.

除非有相反的陳述，在說明書和請求項書中使用的術語具有下述含義。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

本發明所述基團和化合物中所涉及的碳、氫、氧、硫、氮或F、Cl、Br、I均包括它們的同位素情況，及本發明所述基團和化合物中所涉及的碳、氫、氧、硫或氮任選被一個或多個它們對應的同位素所替代，其中碳的同位素包括 12C、 13C和 14C，氫的同位素包括氕 (H)、氘(D，又叫重氫)、氚(T，又叫超重氫)，氧的同位素包括 16O、 17O和 18O，硫的同位素包括 32S、 33S、 34S和 36S，氮的同位素包括 14N和 15N，氟的同位素包括 17F和 19F，氯的同位素包括 35Cl和 37Cl，溴的同位素包括 79Br和 81Br。 The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotope conditions, and the carbon involved in the groups and compounds described in the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D), and (called deuterium), tritium (T, also called superheavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, and nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.

“鹵素”是指F、Cl、Br或I。"Halogen" refers to F, Cl, Br or I.

“鹵素取代的”是指F、Cl、Br或I取代，包括但不限於1至10個選自F、Cl、Br或I的取代基所取代， 1至6個選自F、Cl、Br或I的取代基所取代，1至4個選自F、Cl、Br或I的取代基所取代。“鹵素取代的” 簡稱為“鹵代”。"Halo-substituted" means substituted by F, Cl, Br or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br or I, 1 to 6 selected from F, Cl, Br Or substituted by I substituent, substituted by 1 to 4 substituents selected from F, Cl, Br or I. "Halogen-substituted" is simply referred to as "halogenated."

“烷基”是指取代的或者未取代的直鏈或支鏈飽和脂肪族烴基，包括但不限於1至20個碳原子的烷基、1至8個碳原子的烷基、1至6個碳原子的烷基、1至4個碳原子的烷基。非限制性實施例包括甲基、乙基、正丙基、異丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、異戊基、新戊基、正己基及其各種支鏈異構體；本文中出現的烷基，其定義與本定義一致。烷基可以是一價、二價、三價或四價。"Alkyl" refers to a substituted or unsubstituted linear or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, Alkyl group of carbon atoms, alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and its various branched chain isomers; the alkyl group appearing in this article has the same definition as this definition. Alkyl groups may be monovalent, divalent, trivalent or tetravalent.

“烴基”是指取代的或者未取代的、直鏈或支鏈的、飽和或不飽和的由碳、氫原子組成的基團。烴基可以是一價、二價、三價或四價。"Hydrocarbyl" refers to a substituted or unsubstituted, linear or branched, saturated or unsaturated group composed of carbon and hydrogen atoms. The hydrocarbyl group may be monovalent, divalent, trivalent or tetravalent.

“亞烷基”是指取代的或者未取代的直鏈和支鏈的二價飽和烴基，包括‒(CH 2) v‒(v為1至10的整數)，亞烷基實施例包括但不限於亞甲基、亞乙基、亞丙基和亞丁基等。 "Alkylene" refers to substituted or unsubstituted linear and branched divalent saturated hydrocarbon groups, including ‒(CH 2 ) v ‒ (v is an integer from 1 to 10). Examples of alkylene include but do not Limited to methylene, ethylene, propylene, butylene, etc.

“環烷基”是指取代的或者未取代的飽和的碳環烴基，通常有3至10個碳原子，非限制性實施例包括環丙基、環丁基、環戊基、環己基或環庚基等。本文中出現的環烷基，其定義如上所述。環烷基可以是一價、二價、三價或四價。"Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloalkyl. Gengji et al. Cycloalkyl groups appearing herein are as defined above. The cycloalkyl group may be monovalent, divalent, trivalent or tetravalent.

“雜環烷基”是指取代的或者未取代的飽和的含有雜原子的環烴基，包括但不限於3至10個原子、3至8個原子，包含1至3個選自N、O或S的雜原子，雜環烷基的環中選擇性取代的N、S可被氧化成各種氧化態。雜環烷基可以連接在雜原子或者碳原子上，雜環烷基可以連接在芳香環上或者非芳香環上，雜環烷基可以連接有橋環或者螺環，非限制性實施例包括環氧乙基、氮雜環丙基、氧雜環丁基、氮雜環丁基、四氫呋喃基、四氫-2 H-吡喃基、二氧戊環基、二氧六環基、吡咯烷基、哌啶基、咪唑烷基、噁唑烷基、噁嗪烷基、嗎啉基、六氫嘧啶基、哌嗪基。雜環烷基可以是一價、二價、三價或四價。 "Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 selected from N, O or The heteroatoms of S and the selectively substituted N and S in the heterocycloalkyl ring can be oxidized to various oxidation states. The heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, the heterocycloalkyl group can be connected to a bridged ring or a spiro ring, non-limiting examples include rings Oxyethyl, azetidinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro- 2H -pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl , piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocycloalkyl groups may be monovalent, divalent, trivalent or tetravalent.

“烯基”是指取代的或者未取代的直鏈和支鏈的不飽和烴基，其具有至少1個，通常有1、2或3個碳碳雙鍵，主鏈包括但不限於2至10個、2至6個或2至4個碳原子，烯基實施例包括但不限於乙烯基、烯丙基、1‒丙烯基、2‒丙烯基、1‒丁烯基、2‒丁烯基、3‒丁烯基、1‒戊烯基、2‒戊烯基、3‒戊烯基、4‒戊烯基、1‒甲基‒1‒丁烯基、2‒甲基‒1‒丁烯基、2‒甲基‒3‒丁烯基、1‒己烯基、2‒己烯基、3‒己烯基、4‒己烯基、5‒己烯基、1‒甲基‒1‒戊烯基、2‒甲基‒1‒戊烯基、1‒庚烯基、2‒庚烯基、3‒庚烯基、4‒庚烯基、1‒辛烯基、3‒辛烯基、1‒壬烯基、3‒壬烯基、1‒癸烯基、4‒癸烯基、1,3‒丁二烯、1,3‒戊二烯、1,4‒戊二烯和1,4‒己二烯等；本文中出現的烯基，其定義與本定義一致。烯基可以是一價、二價、三價或四價。"Alkenyl" refers to substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes but is not limited to 2 to 10 , 2 to 6 or 2 to 4 carbon atoms, examples of alkenyl include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl , 3‒butenyl, 1‒pentenyl, 2‒pentenyl, 3‒pentenyl, 4‒pentenyl, 1‒methyl‒1‒butenyl, 2‒methyl‒1‒butenyl Alkenyl, 2‒methyl‒3‒butenyl, 1‒hexenyl, 2‒hexenyl, 3‒hexenyl, 4‒hexenyl, 5‒hexenyl, 1‒methyl‒1 ‒Pentenyl, 2‒methyl‒1‒pentenyl, 1‒heptenyl, 2‒heptenyl, 3‒heptenyl, 4‒heptenyl, 1‒octenyl, 3‒octenyl base, 1‒nonenyl, 3‒nonenyl, 1‒decenyl, 4‒decenyl, 1,3‒butadiene, 1,3‒pentadiene, 1,4‒pentadiene and 1,4‒hexadiene, etc.; the alkenyl group appearing in this article has the same definition as this definition. Alkenyl groups may be monovalent, divalent, trivalent or tetravalent.

“炔基”是指取代的或者未取代的直鏈和支鏈的一價不飽和烴基，其具有至少1個，通常有1、2或3個碳碳三鍵，包括但不限於在主鏈包括2至10個碳原子、2至6個碳原子、2至4個碳原子，炔基實施例包括但不限於乙炔基、炔丙基、1‒丙炔基、2‒丙炔基、1‒丁炔基、2‒丁炔基、3‒丁炔基、1‒戊炔基、2‒戊炔基、3‒戊炔基、4‒戊炔基、1‒甲基‒1‒丁炔基、2‒甲基‒1‒丁炔基、2‒甲基‒3‒丁炔基、1‒己炔基、2‒己炔基、3‒己炔基、4‒己炔基、5‒己炔基、1‒甲基‒1‒戊炔基、2‒甲基‒1‒戊炔基、1‒庚炔基、2‒庚炔基、3‒庚炔基、4‒庚炔基、1‒辛炔基、3‒辛炔基、1‒壬炔基、3‒壬炔基、1‒癸炔基、4‒癸炔基等；炔基可以是一價、二價、三價或四價。"Alkynyl" refers to substituted or unsubstituted linear and branched monovalent unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, including but not limited to in the main chain Including 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, alkynyl examples include but are not limited to ethynyl, propargyl, 1‒propynyl, 2‒propynyl, 1 ‒Butynyl, 2‒butynyl, 3‒butynyl, 1‒pentynyl, 2‒pentynyl, 3‒pentynyl, 4‒pentynyl, 1‒methyl‒1‒butynyl base, 2‒methyl‒1‒butynyl, 2‒methyl‒3‒butynyl, 1‒hexynyl, 2‒hexynyl, 3‒hexynyl, 4‒hexynyl, 5‒ Hexynyl, 1‒methyl‒1‒pentynyl, 2‒methyl‒1‒pentynyl, 1‒heptynyl, 2‒heptynyl, 3‒heptynyl, 4‒heptynyl, 1‒octynyl, 3‒octynyl, 1‒nonynyl, 3‒nonynyl, 1‒decynyl, 4‒decynyl, etc.; the alkynyl group can be monovalent, divalent, trivalent or Four prices.

“烷氧基”是指取代的或者未取代的‒O‒烷基。非限制性實施例包括甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、環丙氧基和環丁氧基。"Alkoxy" refers to substituted or unsubstituted ‒O‒alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy Oxygen and cyclobutoxy.

“碳環基”或“碳環”是指取代的或未取代的飽和或不飽和的芳香環或者非芳香環，芳香環或者非芳香環可以是3至8員的單環、4至12員雙環或者10至15員三環體系，碳環基可以連接在芳香環上或者非芳香環上，芳香環或者非芳香環任選為單環、橋環或者螺環。非限制性實施例包括環丙烷、環丁烷、環戊烷、環己烷、環庚烷、1‒環戊基‒1‒烯基、1‒環戊基‒2‒烯基、1‒環戊基‒3‒烯基、環己基、1‒環己基‒2‒烯基、1‒環己基‒3‒烯基、環己烯基、苯環、萘環、 、 、 或 。“碳環基”或“碳環”可以是一價、二價、三價或四價。 "Carbocyclyl" or "carbocyclic ring" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring. The aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring. Bicyclic or 10 to 15-membered tricyclic system, the carbocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the aromatic ring or non-aromatic ring can be optionally a single ring, a bridged ring or a spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclo Pentyl‒3‒alkenyl, cyclohexyl, 1‒cyclohexyl‒2‒alkenyl, 1‒cyclohexyl‒3‒alkenyl, cyclohexenyl, benzene ring, naphthalene ring, , , or . "Carbocyclyl" or "carbocycle" may be monovalent, divalent, trivalent or tetravalent.

“雜環基”或“雜環”是指取代的或未取代的飽和或不飽和的芳香環或者非芳香環，芳香環或者非芳香環可以是3至8員的單環、4至12員雙環或者10至15員三環體系，且包含1個或多個（包括但不限於2、3、4或5個）個選自N、O或S的雜原子，雜環基的環中選擇性取代的C、N、S可被氧化成各種氧化態。雜環基可以連接在雜原子或者碳原子上，雜環基可以連接在芳香環上或者非芳香環上，雜環基可以連接有橋環或者螺環，非限制性實施例包括環氧乙基、氮雜環丙基、氧雜環丁基、氮雜環丁基、1,3‒二氧戊環基、1,4‒二氧戊環基、1,3‒二氧六環基、氮雜環庚基、吡啶基、呋喃基、噻吩基、吡喃基、N‒烷基吡咯基、嘧啶基、吡嗪基、噠嗪基、咪唑基、哌啶基、嗎啉基、硫代嗎啉基、1,3‒二噻基、二氫呋喃基、二氫吡喃基、二噻戊環基、四氫呋喃基、四氫吡咯基、四氫咪唑基、四氫噻唑基、四氫吡喃基、苯並咪唑基、苯並吡啶基、吡咯並吡啶基、苯並二氫呋喃基、吡咯基、吡唑基、噻唑基、噁唑基、吡嗪基、吲唑基、苯並噻吩基、苯並呋喃基、苯並吡咯基、苯並咪唑基、苯並噻唑基、苯並噁唑基、苯並吡啶基、苯並嘧啶基、苯並吡嗪基、哌嗪基、氮雜二環[3.2.1]辛烷基、氮雜二環[5.2.0]壬烷基、氧雜三環[5.3.1.1]十二烷基、氮雜金剛烷基、氧雜螺[3.3]庚烷基、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。“雜環基”或“雜環”可以是一價、二價、三價或四價。 "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring. The aromatic ring or non-aromatic ring can be a monocyclic ring with 3 to 8 members, or a monocyclic ring with 4 to 12 members. Bicyclic or 10 to 15-membered tricyclic ring system, and containing 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S, selected from the ring of the heterocyclyl group Sexually substituted C, N, and S can be oxidized into various oxidation states. The heterocyclyl group can be connected to a heteroatom or a carbon atom. The heterocyclyl group can be connected to an aromatic ring or a non-aromatic ring. The heterocyclyl group can be connected to a bridged ring or a spiro ring. Non-limiting examples include epoxyethyl. , aziridyl, oxetanyl, azetidinyl, 1,3‒dioxanyl, 1,4‒dioxanyl, 1,3‒dioxanyl, nitrogen Heterocycloheptyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorphyl Phenyl, 1,3-dithiyl, dihydrofuryl, dihydropyranyl, dithiopentanyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyran base, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl , benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabis Cycl[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl alkyl, , , , , , , , , , , , , , , , , , , , , , , , . "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

“螺環”或“螺環基”是指取代的或未取代的單環之間共用一個原子(稱螺原子)的多環基團，螺環體系中環原子的個數包括但不限於含有5至20個、6至14個、6至12個、6至10個，其中一個或多個環可以含有0個或多個(包括但不限於1、2、3或4)雙鍵，且任選可以含有0至5個選自N、O或S(=O)n(n為0、1或2)的雜原子。非限定性實例包括： 。“螺環”或“螺環基”可以是一價、二價、三價或四價。 "Spirocyclic" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom). The number of ring atoms in the spirocyclic system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and any Can contain 0 to 5 heteroatoms selected from N, O or S(=O)n (n is 0, 1 or 2). Non-limiting examples include: . "Spiro" or "spiryl" may be monovalent, divalent, trivalent or tetravalent.

“並環”或“並環基”是指系統中的每個環與體系中的其他環共用毗鄰的一對原子的多環基團，其中一個或多個環可以含有0個或多個(包括但不限於1、2、3或4)雙鍵，且可以是取代的或未取代，並環體系中的各個環可以含0至5個雜原子或含有雜原子的基團(包括但不限於選自Ｎ、S(=O) n或O，n為0、1或2)。並環體系中環原子的個數包括但不限於5至20個，5至14個，5至12個，5至10個。非限定性實例包括： 、 、 、 “並環”或“並環基”可以是一價、二價、三價或四價。 "Ring ring" or "ring ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, in which one or more rings may contain 0 or more ( Including but not limited to 1, 2, 3 or 4) double bonds, and may be substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not Limited to selected from N, S(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the parallel ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include: , , , "And ring" or "and ring group" can be monovalent, divalent, trivalent or tetravalent.

“橋環”或“橋環基”是指取代的或未取代的含有任意兩個不直接連接的原子的多環基團，可以含有0個或多個雙鍵，並環體系中的任意環可以含0至5個選自雜原子或含有雜原子的基團(包括但不限於N、S(=O)n或O，其中n為0、1、2)。環原子個數包括但不限於5至20個、5至14個、5至12個或5至10個。非限定性實例包括 、 、 、 、 、立方烷、金剛烷。“橋環”或“橋環基”可以是一價、二價、三價或四價。 "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected. It may contain 0 or more double bonds and any ring in the ring system. It may contain 0 to 5 selected from heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n or O, where n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include , , , , , cubane, adamantane. The "bridging ring" or "bridging ring base" may be monovalent, divalent, trivalent or tetravalent.

“碳螺環”、“螺環碳環基”、“螺碳環基”或者“碳螺環基”是指環體系僅有碳原子組成的“螺環”。"Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" in which the ring system consists only of carbon atoms.

“碳並環”、“並環碳環基”、“並碳環基”或者“碳並環基”是指環體系僅有碳原子組成的“並環”。"Carbocyclic ring", "carbocyclic ring radical", "carbocyclic ring radical" or "carbocyclic ring radical" refers to a "carbocyclic ring" in which the ring system only consists of carbon atoms.

“碳橋環”、“橋環碳環基”、“橋碳環基”或者“碳橋環基”是指環體系僅有碳原子組成的“橋環”。"Carbon bridged ring", "bridged carbocyclyl", "bridged carbocyclyl" or "carbon bridged ring" refers to a "bridged ring" in which the ring system consists only of carbon atoms.

“雜單環”、“單環雜環基”或“雜單環基”是指單環體系的“雜環基”或“雜環”。"Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a "heterocyclyl" or "heterocycle" of a monocyclic ring system.

“雜並環”、“雜並環基” 、“並環雜環基”或“並雜環基”是指含有雜原子的“並環”。"Heterocycle", "heterocyclyl", "cycloheterocyclyl" or "heterocyclyl" refers to a "paracycle" containing heteroatoms.

“雜螺環”、“雜螺環基”、“螺環雜環基”或“螺雜環基”是指含有雜原子的“螺環”。"Heterospirocycle", "heterospirocyclyl", "spirocycloheterocyclyl" or "spiroheterocyclyl" refers to a "spirocycle" containing heteroatoms.

“雜橋環”、“雜橋環基”、“橋環雜環基”或“橋雜環基”是指含有雜原子的“橋環”。"Heterobridged ring", "heterobridged cyclyl", "bridged heterocyclyl" or "bridged heterocyclyl" refers to a "bridged ring" containing heteroatoms.

“芳基”或“芳環”是指取代的或者未取代的具有單環或稠合環的芳香族烴基，芳香環中環原子個數包括但不限於6至18、6至12或6至10個碳原子。芳基環可以稠合於飽和或不飽和的碳環或雜環上，其中與母體結構連接在一起的環為芳基環，非限制性實施例包含苯環、萘環、 “芳基”或“芳環”可以是一價、二價、三價或四價。當為二價、三價或四價時，連接位點位於芳基環上。 "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group with a monocyclic or fused ring. The number of ring atoms in the aromatic ring includes but is not limited to 6 to 18, 6 to 12 or 6 to 10. carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, in which the ring connected to the parent structure is an aryl ring. Non-limiting examples include benzene ring, naphthalene ring, "Aryl" or "aryl ring" may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the aryl ring.

“雜芳基”或“雜芳環”是指取代或未取代的芳香族烴基，且含有1至5個選雜原子或含有雜原子的基團(包括但不限於N、O或S(=O)n，n為0、1、2)，雜芳香環中環原子個數包括但不限於5至15、5至10或5至6個。雜芳基的非限制性實施例包括但不限於吡啶基、呋喃基、噻吩基、吡啶基、吡喃基、N‒烷基吡咯基、嘧啶基、吡嗪基、噠嗪基、咪唑基、苯並吡唑、苯並咪唑、苯並吡啶、吡咯並吡啶等。所述雜芳基環可以稠合於飽和或不飽和的碳環或雜環上，其中與母體結構連接在一起的環為雜芳基環，非限制性實施例包含 和 。本文中出現的雜芳基，其定義與本定義一致。雜芳基可以是一價、二價、三價或四價。當為二價、三價或四價時，連接位點位於雜芳基環上。 "Heteroaryl" or "heteroaryl ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 optional heteroatoms or groups containing heteroatoms (including but not limited to N, O or S (= O)n, n is 0, 1, 2), the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is a heteroaryl ring. Non-limiting examples include and . Heteroaryl groups appearing herein have the same definition as this definition. Heteroaryl groups may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the heteroaryl ring.

“取代”或“取代的”是指被1個或多個(包括但不限於2、3、4或5個)取代基所取代，取代基包括但不限於H、F、Cl、Br、I、烷基、環烷基、烷氧基、鹵代烷基、硫醇、羥基、硝基、巰基、氨基、氰基、異氰基、芳基、雜芳基、雜環基、橋環基、螺環基、並環基、羥基烷基、=O、羰基、醛、羧酸、甲酸酯、‒(CH 2) m‒C(=O)‒R a、‒O‒(CH 2) m‒C(=O)‒R a、‒(CH 2) m‒C(=O)‒NR bR c、‒(CH 2) mS(=O) nR a、‒(CH 2) m‒烯基‒R a、OR d或‒(CH 2) m‒炔基‒R a(其中m、n為0、1或2)、芳基硫基、硫代羰基、矽烷基或‒NR bR c等基團，其中R b與R c獨立選自包括H、羥基、氨基、羰基、烷基、烷氧基、環烷基、雜環基、芳基、雜芳基、磺醯基、三氟甲磺醯基，作為選擇，R b與R c可形成五或六員環烷基或雜環基, R a與R d各自獨立選自芳基、雜芳基、烷基、烷氧基、環烷基、雜環基、羰基、酯基、橋環基、螺環基或並環基。 "Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I , alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyanyl, aryl, heteroaryl, heterocyclyl, bridged cyclic group, spiro Cyclic group, cyclic group, hydroxyalkyl group, =O, carbonyl group, aldehyde, carboxylic acid, formate, ‒(CH 2 ) m ‒C(=O)‒R a , ‒O‒(CH 2 ) m ‒ C(=O)‒R a , ‒(CH 2 ) m ‒C(=O)‒NR b R c , ‒(CH 2 ) m S(=O) n R a , ‒(CH 2 ) m ‒ene Base ‒R a , OR d or ‒(CH 2 ) m ‒Alkynyl ‒R a (where m and n are 0, 1 or 2), arylthio group, thiocarbonyl group, silyl group or ‒NR b R c and other groups, wherein R b and R c are independently selected from the group including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoro Methanesulfonyl group, as an option, R b and R c can form a five- or six-membered cycloalkyl or heterocyclic group, R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, Cycloalkyl, heterocyclyl, carbonyl, ester, bridged cyclyl, spirocyclyl or paracyclyl.

“含有1至5個選自O、S、N的雜原子”是指含有1、2、3、4或5個選自O、S、N的雜原子。"Containing 1 to 5 heteroatoms selected from O, S, and N" means containing 1, 2, 3, 4, or 5 heteroatoms selected from O, S, and N.

“0至X個選自…取代基所取代”是指被0、1、2、3….X個選自…取代基所取代，X選自1至10之間的任意整數。如“0至4個選自…取代基所取代”是指被0、1、2、3或4個選自…取代基所取代。如“0至5個選自…取代基所取代”是指被0、1、2、3、4或5個選自…取代基所取代。如“雜橋環任選被1至4個選自F的取代基所取代”是指雜橋環任選被0、1、2、3或4個選自F的取代基所取代。"Substituted by 0 to X substituents selected from..." means substituted by 0, 1, 2, 3... For example, "substituted with 0 to 4 substituents selected from..." means substituted with 0, 1, 2, 3 or 4 substituents selected from... For example, "substituted with 0 to 5 substituents selected from..." means substituted with 0, 1, 2, 3, 4 or 5 substituents selected from... For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from F" means that the heterobridged ring is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from F.

X‒Y員的環（X選自小於Y大於等於3的整數，Y選自4至12之間的任意整數）包括了X、X+1、X+2、X+3、X+4….Y員的環。環包括了雜環、碳環、芳環、芳基、雜芳基、環烷基、雜單環、雜並環、雜螺環或雜橋環。如“4‒7員雜單環”是指4員、5員、6員或7員的雜單環，“5‒10員雜並環” 是指5員、6員、7員、8員、9員或10員的雜並環。The ring of members .Y member’s ring. Rings include heterocycles, carbocycles, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocycles, heterocycles, heterospirocycles or heterobridged rings. For example, "4-7-member heteromonocyclic ring" refers to a heterocyclic monocyclic ring with 4, 5, 6, or 7 members, and "5-10-membered heterocyclic ring" refers to a heterocyclic ring with 5, 6, 7, or 8 members. , 9-membered or 10-membered heterocyclic rings.

“任選”或“任選地”是指隨後所描述的事件或環境可以但不必須發生，該說明包括該事件或環境發生或不發生的場合。如：“任選被F取代的烷基”指烷基可以但不必須被F取代，說明包括烷基被F取代的情形和烷基不被F取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that description includes instances where the event or circumstance does or does not occur. For example: "Alkyl optionally substituted by F" means that the alkyl group can but does not have to be substituted by F, including the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.

“藥學上可接受的鹽”或者“其藥學上可接受的鹽”是指本發明化合物保持游離酸或者游離鹼的生物有效性和特性，且所述的游離酸通過與無毒的無機鹼或者有機鹼，所述的游離鹼通過與無毒的無機酸或者有機酸反應獲得的鹽。"Pharmaceutically acceptable salts" or "pharmaceutically acceptable salts thereof" means that the compounds of the present invention retain the biological effectiveness and properties of free acids or free bases, and the free acids are combined with non-toxic inorganic bases or organic Base, the salt of the free base obtained by reacting with a non-toxic inorganic acid or organic acid.

“藥物組合物”是指一種或多種本發明所述化合物、或者其立體異構體、互變異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶和其它化學組分形成的混合物，其中，“其它化學組分”是指藥學上可接受的載體、賦形劑和/或一種或多種其它治療劑。"Pharmaceutical composition" refers to one or more compounds of the present invention, or their stereoisomers, tautomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and A mixture of other chemical components, where "other chemical components" refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.

“製劑規格”是指每一支、片或其他每一個單位制劑中含有主藥的重量。"Preparation specification" refers to the weight of the main drug contained in each tube, tablet or other unit preparation.

“載體”是指不會對生物體產生明顯刺激且不會消除所給予化合物的生物活性和特性的材料。"Carrier" refers to a material that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the compound to which it is administered.

“動物”是指包括哺乳動物，例如人、陪伴動物、動物園動物和家畜，較佳人、馬或者犬。"Animal" is meant to include mammals, such as humans, companion animals, zoo animals and domestic animals, preferably humans, horses or dogs.

“立體異構體”是指由分子中原子在空間上排列方式不同所產生的異構體，包括順反異構體、對映異構體和構象異構體。"Stereoisomers" refer to isomers produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

“互變異構體”是指分子中某一原子在兩個位置迅速移動而產生的官能團異構體，如酮式‒烯醇式異構和醯胺‒亞胺醇式異構等。"Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomers and amide-imino alcohol isomers.

“IC 50”是對指定的生物過程（或該過程中的某個組分比如酶、受體、細胞等）抑制一半時所需的藥物或者抑制劑的濃度。 “IC 50 ” is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component in the process such as an enzyme, receptor, cell, etc.) by half.

以下結合實施例詳細說明本發明的技術方案，但本發明的保護範圍包括但是不限於此。The technical solution of the present invention will be described in detail below with reference to the examples, but the protection scope of the present invention includes but is not limited thereto.

本文所述反應中使用的化合物是根據本領域技術人員已知的有機合成技術製備的，起始於市售化學品和（或）化學文獻中所述的化合物。“市售化學品”是從正規商業來源獲得的，供應商包括：泰坦科技、安耐吉化學、上海德默、成都科龍化工、韶遠化學科技、南京藥石、藥明康得和百靈威科技等公司。The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, and suppliers include: Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTech, and Bailingwei Technology, etc. company.

化合物的結構是通過核磁共振 (NMR) 或 (和) 質譜 (MS) 來確定的。NMR 位移 (δ) 以10 -6(ppm) 的單位給出。NMR的測定是用 (Bruker Avance III 400和Bruker Avance 300) 核磁儀，測定溶劑為氘代二甲基亞碸(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，內標為四甲基矽烷(TMS)； The structures of compounds are determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD ), the internal standard is tetramethylsilane (TMS);

MS的測定用(Agilent 6120B(ESI) 和Agilent 6120B(APCI))；For MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));

HPLC的測定使用Agilent 1260DAD高壓液相色譜儀 (Zorbax SB-C18 100 × 4.6 mm,3.5 μM)；HPLC was measured using Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

薄層層析矽膠板使用煙臺黃海HSGF254 或青島GF254 矽膠板，薄層色譜法 (TLC) 使用的矽膠板採用的規格是0.15 mm-0.20 mm，薄層層析分離純化產品採用的規格是0.4 mm - 0.5 mm；Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. Thin layer chromatography (TLC) uses silica gel plates with specifications of 0.15 mm-0.20 mm. Thin layer chromatography separation and purification products use specifications of 0.4 mm. - 0.5 mm;

柱層析一般使用煙臺黃海矽膠200-300目矽膠為載體。Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

SEM: ;THP: ;  Boc：叔丁氧基羰基；Ms： ; TBS: ;MTBE:甲基叔丁基醚; Bn: 苄基；DIPEA：N,N-二異丙基乙胺；DMAc：N,N-二甲基乙醯胺；DMSO：二甲基亞碸；DCM：二氯甲烷；Cbz: ；NMP：N-甲基吡咯烷酮；TCFH：四甲基氯代脲六氟磷酸酯； SEM: ;THP: ; Boc: tert-butoxycarbonyl; Ms: ; TBS: ;MTBE: methyl tert-butyl ether; Bn: benzyl; DIPEA: N,N-diisopropylethylamine; DMAc: N,N-dimethylacetamide; DMSO: dimethyltrisoxide; DCM : Dichloromethane; Cbz: ; NMP: N-methylpyrrolidone; TCFH: tetramethylchlorourea hexafluorophosphate;

中間體1的合成： Synthesis of intermediate 1:

第一步：1B鹽酸鹽的製備Step 1: Preparation of 1B hydrochloride

將1A (90 g, 0.50 mol) 溶解到500 mL 2 mol/L鹽酸乙酸乙酯溶液中，室溫反應5 h。將反應體系減壓濃縮，得粗品1B的鹽酸鹽 (59 g)。Dissolve 1A (90 g, 0.50 mol) into 500 mL of 2 mol/L hydrochloric acid ethyl acetate solution and react at room temperature for 5 h. The reaction system was concentrated under reduced pressure to obtain the hydrochloride salt of crude product 1B (59 g).

LCMS m/z = 82.3 [M+1] + LCMS m/z = 82.3 [M+1] +

第二步：中間體1的製備Step 2: Preparation of Intermediate 1

將上述粗品1B的鹽酸鹽 (59 g) 溶於500 mL DMSO中，加入碳酸氫鈉 (42 g，0.50 mol)，室溫攪拌10 min後，加入100 mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟異吲哚啉-1,3-二酮 (合成方法見WO2017197056) (165.6 g，0.60 mol)，85℃反應5 h。將反應液冷卻至室溫，加入5 L水，過濾，收集固體，用500 mL水洗滌，將固體鼓風乾燥，得粗中間體1 (40 g)。Dissolve the hydrochloride (59 g) of the above crude product 1B in 500 mL DMSO, add sodium bicarbonate (42 g, 0.50 mol), stir at room temperature for 10 min, then add 100 mL DIPEA and 2-(2,6- Dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (for synthesis method, see WO2017197056) (165.6 g, 0.60 mol), react at 85°C for 5 h. Cool the reaction solution to room temperature, add 5 L of water, filter, collect the solid, wash with 500 mL of water, and air-dry the solid to obtain crude intermediate 1 (40 g).

中間體2的合成： Synthesis of intermediate 2:

將上述粗品1B的鹽酸鹽 (0.72 g) 溶於20 mL DMSO中，加入2 mL DIPEA和2A (合成方法見WO2020239103) (1.80 g，6.12 mmol)，80℃反應3 h。將反應液冷卻至室溫，加入200 mL水，過濾，收集固體，用50 mL水洗滌，將固體鼓風乾燥，得粗品中間體2 (1.3 g)。 Dissolve the hydrochloride salt of the above crude product 1B (0.72 g) in 20 mL DMSO, add 2 mL DIPEA and 2A (see WO2020239103 for the synthesis method) (1.80 g, 6.12 mmol), and react at 80°C for 3 h. The reaction solution was cooled to room temperature, 200 mL of water was added, filtered, the solid was collected, washed with 50 mL of water, and the solid was air-dried to obtain crude intermediate 2 (1.3 g).

實施例 1：製備化合物1 Example 1 : Preparation of Compound 1

第一步： 1b的製備Step 1: Preparation of 1b

將1a (4.1 g, 19.80 mmol) 和4-碘-1H-吡唑 (4.22 g, 21.75 mmol) 溶於40 mL乙腈中，加入碳酸銫 (9.68 g, 29.70 mmol)，80℃反應3 h。將反應液冷卻至室溫，加入30 mL水和100 mL乙酸乙酯，分液，有機相用30 mL飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮後粗品用矽膠色譜柱分離純化 (乙酸乙酯/石油醚 (v/v) = 1:9)，得到1b(2.40 g，收率：38%)。Dissolve 1a (4.1 g, 19.80 mmol) and 4-iodo-1H-pyrazole (4.22 g, 21.75 mmol) in 40 mL acetonitrile, add cesium carbonate (9.68 g, 29.70 mmol), and react at 80°C for 3 h. Cool the reaction solution to room temperature, add 30 mL water and 100 mL ethyl acetate, separate the layers, wash the organic phase with 30 mL saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column. (Ethyl acetate/petroleum ether (v/v) = 1:9), obtained 1b (2.40 g, yield: 38%).

第二步： 1c的製備Step 2: Preparation of 1c

將1b(2.30 g, 7.18 mmol) 溶解在20 mL四氫呋喃中，加入4 mL水，再加入一水合氫氧化鋰 (0.6 g, 14.3 mmol)，室溫反應30 min。向反應液中滴加1 mol/L稀鹽酸調pH至6，加入50 mL乙酸乙酯，分液，有機相用20 mL飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，得粗品 (2.0 g)。將上述粗品 (0.5 g) 溶於10 mL DCM中，加入1-氯-N,N,2-三甲基丙烯胺 (0.34 g，2.54 mmol)，室溫反應2 h後，依次加入三乙胺 (0.52 g，5.14 mmol) 和5-三氟甲基吲哚啉 (0.38 g，2.03 mmol)，室溫反應18 h。向反應液中加入30 mL二氯甲烷，加入40 mL飽和碳酸氫鈉水溶液，分離出有機相，有機相用100 mL飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 5:1)，得 1c (0.51 g，收率：54%)。Dissolve 1b (2.30 g, 7.18 mmol) in 20 mL tetrahydrofuran, add 4 mL water, then add lithium hydroxide monohydrate (0.6 g, 14.3 mmol), and react at room temperature for 30 min. Add 1 mol/L dilute hydrochloric acid dropwise to the reaction solution to adjust the pH to 6, add 50 mL ethyl acetate, separate the liquids, wash the organic phase with 20 mL saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product (2.0 g). Dissolve the above crude product (0.5 g) in 10 mL DCM, add 1-chloro-N,N,2-trimethylpropenylamine (0.34 g, 2.54 mmol), react at room temperature for 2 h, then add triethylamine in sequence (0.52 g, 5.14 mmol) and 5-trifluoromethylindoline (0.38 g, 2.03 mmol), reacted at room temperature for 18 h. Add 30 mL dichloromethane and 40 mL saturated sodium bicarbonate aqueous solution to the reaction solution, separate the organic phase, wash the organic phase with 100 mL saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is subjected to silica gel chromatography. Column separation and purification (petroleum ether/ethyl acetate (v/v) = 5:1) gave 1c (0.51 g, yield: 54%).

LCMS m/z = 462.1 [M+1] + LCMS m/z = 462.1 [M+1] +

第三步：化合物1的製備 Step 3: Preparation of Compound 1

將1c (0.22 g，0.48 mmol) 溶於5 mL DMF中，依次加入上述粗品中間體1 (0.19 g)、TEA (0.15 g，1.48 mmol)、CuI(18 mg，0.095 mmol) 和PdCl 2(PPh 3) 2(67 mg，0.095 mmol)，置換氮氣三次，80℃反應18 h。將反應液冷卻至室溫，加入50 mL水，析出固體，過濾，濾餅用20 mL水洗滌，濾餅用100 mL DCM溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 1:1)，得化合物1 (0.1 g，收率：31%)。 Dissolve 1c (0.22 g, 0.48 mmol) in 5 mL DMF, and add the above crude intermediate 1 (0.19 g), TEA (0.15 g, 1.48 mmol), CuI (18 mg, 0.095 mmol) and PdCl 2 (PPh) in sequence. 3 ) 2 (67 mg, 0.095 mmol), replaced with nitrogen three times, and reacted at 80°C for 18 hours. Cool the reaction solution to room temperature, add 50 mL of water, precipitate the solid, filter, wash the filter cake with 20 mL of water, dissolve the filter cake with 100 mL of DCM, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column. (Petroleum ether/ethyl acetate (v/v) = 1:1), compound 1 (0.1 g, yield: 31%) was obtained.

1H NMR (400 MHz, CDCl 3) δ 8.26 (d, 1H), 8.08 (s, 1H), 7.72 – 7.56 (m, 3H), 7.51 – 7.34 (m, 2H), 6.84 – 6.75 (m, 1H), 6.54 (dd, 1H), 5.20 – 5.06 (m, 1H), 4.99 – 4.86 (m, 1H), 4.44 – 4.26 (m, 2H), 4.13 – 3.67 (m, 6H), 3.26 – 3.11 (m, 2H), 2.97 – 2.63 (m, 4H), 2.53 – 2.23 (m, 2H), 2.20 – 2.00 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.26 (d, 1H), 8.08 (s, 1H), 7.72 – 7.56 (m, 3H), 7.51 – 7.34 (m, 2H), 6.84 – 6.75 (m, 1H ), 6.54 (dd, 1H), 5.20 – 5.06 (m, 1H), 4.99 – 4.86 (m, 1H), 4.44 – 4.26 (m, 2H), 4.13 – 3.67 (m, 6H), 3.26 – 3.11 (m , 2H), 2.97 – 2.63 (m, 4H), 2.53 – 2.23 (m, 2H), 2.20 – 2.00 (m, 2H).

LCMS m/z = 671.1 [M+1] + LCMS m/z = 671.1 [M+1] +

實施例 2：製備化合物2 Example 2 : Preparation of Compound 2

第一步： 2b的製備Step 1: Preparation of 2b

將2a (4.1 g, 19.80 mmol) 和4-碘-1H-吡唑 (4.22 g, 21.75 mmol) 溶於40 mL乙腈中，加入碳酸銫 (9.68 g, 29.70 mmol)，80℃反應3 h。將反應液冷卻至室溫，加入30 mL水和100 mL乙酸乙酯，分液，有機相用30 mL飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮後粗品用矽膠色譜柱分離純化 (乙酸乙酯/石油醚 (v/v) = 1:9)，得到2b (2.40 g，收率：38%)。Dissolve 2a (4.1 g, 19.80 mmol) and 4-iodo-1H-pyrazole (4.22 g, 21.75 mmol) in 40 mL acetonitrile, add cesium carbonate (9.68 g, 29.70 mmol), and react at 80°C for 3 h. Cool the reaction solution to room temperature, add 30 mL water and 100 mL ethyl acetate, separate the layers, wash the organic phase with 30 mL saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column. (Ethyl acetate/petroleum ether (v/v) = 1:9), obtaining 2b (2.40 g, yield: 38%).

第二步： 2c的製備Step 2: Preparation of 2c

將2b (2.30 g, 7.18 mmol) 溶解在20 mL四氫呋喃中，加入4 mL水，再加入一水合氫氧化鋰 (0.6 g, 14.3 mmol)，室溫反應30 min，滴加1 mol/L稀鹽酸調pH至6，加入50 mL乙酸乙酯，分液，有機相用20 mL飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，得粗品 (2.0 g)。將上述粗品 (0.51 g) 溶解在10 mL二氯甲烷中，緩慢滴加1-氯-N,N,2-三甲基丙烯胺 (0.35 g, 2.62 mmol)，室溫反應2 h。向反應液中加入三乙胺 (0.53 g, 5.24 mmol) 和2-氯-4-(三氟甲基)苯胺 (0.34 g, 1.74 mmol)，室溫反應3 h。向反應液中加入20 mL飽和碳酸氫鈉水溶液，用100 mL乙酸乙酯萃取，有機相用50 mL水洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (乙酸乙酯/石油醚 (v/v) = 1:3)，得到2c(0.45 g, 收率：52%)。Dissolve 2b (2.30 g, 7.18 mmol) in 20 mL tetrahydrofuran, add 4 mL water, then add lithium hydroxide monohydrate (0.6 g, 14.3 mmol), react at room temperature for 30 min, and add 1 mol/L dilute hydrochloric acid dropwise Adjust the pH to 6, add 50 mL of ethyl acetate, separate the layers, wash the organic phase with 20 mL of saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product (2.0 g). Dissolve the above crude product (0.51 g) in 10 mL of methylene chloride, slowly add 1-chloro-N,N,2-trimethylpropenylamine (0.35 g, 2.62 mmol) dropwise, and react at room temperature for 2 h. Triethylamine (0.53 g, 5.24 mmol) and 2-chloro-4-(trifluoromethyl)aniline (0.34 g, 1.74 mmol) were added to the reaction solution, and the reaction was carried out at room temperature for 3 h. Add 20 mL saturated aqueous sodium bicarbonate solution to the reaction solution, extract with 100 mL ethyl acetate, wash the organic phase with 50 mL water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (ethyl acetate/ Petroleum ether (v/v) = 1:3) to obtain 2c (0.45 g, yield: 52%).

第三步： 2d的製備Step 3: Preparation of 2d

將 2c (0.5 g，1.06 mmol) 溶於5 mL DMF中，冰浴冷卻至0℃，加入0.08 g 60%氫化鈉，0℃反應30 min後，加入碘甲烷 (0.3 g，2.11 mmol)，0℃反應1 h。向反應液中加入50 mL水，用50 mL乙酸乙酯萃取兩次，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 20:1)，得到2d (0.4 g，收率：78%)。Dissolve 2c (0.5 g, 1.06 mmol) in 5 mL DMF, cool to 0°C in an ice bath, add 0.08 g 60% sodium hydride, react at 0°C for 30 min, add methyl iodide (0.3 g, 2.11 mmol), 0 ℃ reaction for 1 h. Add 50 mL of water to the reaction solution, extract twice with 50 mL of ethyl acetate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified by a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 20: 1), obtained 2d (0.4 g, yield: 78%).

LCMS m/z = 484.0 [M+1] + LCMS m/z = 484.0 [M+1] +

第四步：化合物2的製備Step 4: Preparation of Compound 2

將 2d (0.2 g，0.41 mmol)、上述粗品中間體1 (0.14 g)、TEA (0.25 g，2.47 mmol)、CuI (16 mg，0.084 mmol) 和PdCl 2(PPh 3) 2(29 mg，0.041 mmol)，置換氮氣三次，在氮氣保護下加入5 mL DMF， 60℃反應3 h。將反應液冷卻至室溫，加入50 mL水，抽濾，濾餅用10 mL水洗滌，將濾餅用100 mL DCM溶解，無水硫酸鈉乾燥，減壓濃縮後粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 100:1-1:5)，所得粗品再進行手性拆分 (儀器及製備柱：採用Waters 150 SFC製備液相，製備柱型號是Chiralpak Column)。製備方法：粗品用甲醇和二甲亞碸溶解，並用0.45 μm濾膜過濾，製備成樣品液。流動相體系：超臨界二氧化碳/甲醇和乙腈的混合溶劑。梯度沖提方法：甲醇和乙腈的混合溶劑由65%等梯度沖提)，凍乾得到化合物2)的手性異構體1 (13.1 mg，收率：5%) 和手性異構體2 (11.1 mg，收率：4%)。 2d (0.2 g, 0.41 mmol), the above crude intermediate 1 (0.14 g), TEA (0.25 g, 2.47 mmol), CuI (16 mg, 0.084 mmol) and PdCl 2 (PPh 3 ) 2 (29 mg, 0.041 mmol), replace nitrogen three times, add 5 mL DMF under nitrogen protection, and react at 60°C for 3 h. Cool the reaction solution to room temperature, add 50 mL of water, and filter with suction. The filter cake is washed with 10 mL of water. The filter cake is dissolved in 100 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated and purified using a silica gel chromatography column ( Petroleum ether/ethyl acetate (v/v) = 100:1-1:5), the obtained crude product is then subjected to chiral separation (instrument and preparative column: Waters 150 SFC is used to prepare the liquid phase, and the preparative column model is Chiralpak Column) . Preparation method: Dissolve the crude product with methanol and dimethyl sulfoxide, filter it with a 0.45 μm filter membrane, and prepare a sample solution. Mobile phase system: supercritical carbon dioxide/mixed solvent of methanol and acetonitrile. Gradient elution method: a mixed solvent of methanol and acetonitrile (isogradient elution of 65%) was followed by freeze-drying to obtain chiral isomer 1 (13.1 mg, yield: 5%) and chiral isomer 2 of compound 2). (11.1 mg, yield: 4%).

化合物2的手性分析方法Chiral analysis method of compound 2

儀器：SHIMADZU LC-30AD sf，色譜柱：Chiralcel AD-3,規格：50 mm × 4.6 mm, 3 μmInstrument: SHIMADZU LC-30AD sf, column: Chiralcel AD-3, specifications: 50 mm × 4.6 mm, 3 μm

流動相A：超臨界CO 2，流動相B：含0.05%二乙胺的甲醇和乙腈混合溶液，柱溫：35℃ Mobile phase A: supercritical CO 2 , mobile phase B: mixed solution of methanol and acetonitrile containing 0.05% diethylamine, column temperature: 35°C

流速：3 mL/min，波長：220 nm，沖提程式：流動相A:B = 50:50。Flow rate: 3 mL/min, wavelength: 220 nm, extraction program: mobile phase A:B = 50:50.

化合物2的手性異構體1的保留時間：0.871 minRetention time of chiral isomer 1 of compound 2: 0.871 min

化合物2的手性異構體2的保留時間：1.863 min Retention time of chiral isomer 2 of compound 2: 1.863 min

化合物2的手性異構體1的核磁譜圖NMR spectrum of chiral isomer 1 of compound 2

1H NMR (400 MHz, CDCl 3) δ 7.95 (s, 1H), 7.83 –6.50 (m, 8H), 5.00 – 4.85 (m, 1H), 4.42 – 4.31 (m, 2H), 4.14 – 3.99 (m, 2H), 3.90 – 3.73 (m, 1H), 3.30 – 2.64 (m, 9H), 2.39 – 1.80 (m, 4H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.95 (s, 1H), 7.83 –6.50 (m, 8H), 5.00 – 4.85 (m, 1H), 4.42 – 4.31 (m, 2H), 4.14 – 3.99 (m , 2H), 3.90 – 3.73 (m, 1H), 3.30 – 2.64 (m, 9H), 2.39 – 1.80 (m, 4H).

LCMS m/z = 693.1 [M+1] + LCMS m/z = 693.1 [M+1] +

化合物2的手性異構體2的核磁譜圖NMR spectrum of chiral isomer 2 of compound 2

1H NMR (400 MHz, CDCl 3) δ 8.02 (s, 1H), 7.83 – 6.50 (m, 8H), 4.99 – 4.85 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 3.99 (m, 2H), 3.90 – 3.73 (m, 1H), 3.30 – 2.64 (m, 9H), 2.37 – 1.80 (m, 4H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.02 (s, 1H), 7.83 – 6.50 (m, 8H), 4.99 – 4.85 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 3.99 (m , 2H), 3.90 – 3.73 (m, 1H), 3.30 – 2.64 (m, 9H), 2.37 – 1.80 (m, 4H).

LCMS m/z = 693.2 [M+1] + LCMS m/z = 693.2 [M+1] +

實施例 3：製備化合物3 Example 3 : Preparation of compound 3

化合物3以化合物2c為原料，參考實施例2方法的合成方法得到化合物3 的手性異構體1  和手性異構體2。Compound 3 uses compound 2c as raw material, and the chiral isomer 1 and chiral isomer 2 of compound 3 are obtained by referring to the synthesis method of the method in Example 2.

化合物3的手性分析方法Chiral analysis method of compound 3

儀器：SHIMADZU LC-30AD sf，色譜柱：Chiralcel AD-3,規格：50 mm × 4.6 mm, 3 μmInstrument: SHIMADZU LC-30AD sf, column: Chiralcel AD-3, specifications: 50 mm × 4.6 mm, 3 μm

流動相A：超臨界CO 2，流動相B：含0.05%二乙胺的甲醇和乙腈混合溶液，柱溫：35℃ Mobile phase A: supercritical CO 2 , mobile phase B: mixed solution of methanol and acetonitrile containing 0.05% diethylamine, column temperature: 35°C

流速：3 mL/min，波長：220 nm，沖提程式：流動相A:B = 50:50。Flow rate: 3 mL/min, wavelength: 220 nm, extraction program: mobile phase A:B = 50:50.

化合物3的手性異構體1的保留時間：0.839 minRetention time of chiral isomer 1 of compound 3: 0.839 min

化合物3的手性異構體2的保留時間：2.053 min Retention time of chiral isomer 2 of compound 3: 2.053 min

化合物3的手性異構體1的核磁譜圖NMR spectrum of chiral isomer 1 of compound 3

1H NMR (400 MHz, CDCl 3) δ 7.92 (s, 1H), 7.81 – 6.43 (m, 8H), 5.00 – 4.88 (m, 1H), 4.42 – 3.29 (m, 6H), 3.20 – 2.63 (m, 7H), 2.40 – 0.90 (m, 7H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.92 (s, 1H), 7.81 – 6.43 (m, 8H), 5.00 – 4.88 (m, 1H), 4.42 – 3.29 (m, 6H), 3.20 – 2.63 (m , 7H), 2.40 – 0.90 (m, 7H).

LCMS m/z = 707.2 [M+1] + LCMS m/z = 707.2 [M+1] +

化合物3的手性異構體2的核磁譜圖NMR spectrum of chiral isomer 2 of compound 3

1H NMR (400 MHz, CDCl 3) δ 7.93 (s, 1H), 7.81 – 6.43 (m, 8H), 5.00 – 4.88 (m, 1H), 4.44 – 3.29 (m, 6H), 3.20 – 2.63 (m, 7H), 2.40 – 0.90 (m, 7H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.93 (s, 1H), 7.81 – 6.43 (m, 8H), 5.00 – 4.88 (m, 1H), 4.44 – 3.29 (m, 6H), 3.20 – 2.63 (m , 7H), 2.40 – 0.90 (m, 7H).

LCMS m/z = 707.2 [M+1] + LCMS m/z = 707.2 [M+1] +

實施例 4：製備化合物4 Example 4 : Preparation of compound 4

第一步： 4b的製備Step 1: Preparation of 4b

將4a (2 g，9.66 mmol) 和4-碘吡唑 (1.8 g，9.28 mmol) 溶於30 mL 乙腈中，加入碳酸銫 (9.44 g，28.97 mmol)，80 oC反應4 h。將反應液冷卻至室溫，用40 mL飽和氯化鈉溶液洗滌，水相用50 mL乙酸乙酯萃取，合併有機相，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 5:1)，得4b (2.8 g，收率：94%)。 Dissolve 4a (2 g, 9.66 mmol) and 4-iodopyrazole (1.8 g, 9.28 mmol) in 30 mL acetonitrile, add cesium carbonate (9.44 g, 28.97 mmol), and react at 80 ° C for 4 h. The reaction solution was cooled to room temperature, washed with 40 mL saturated sodium chloride solution, the aqueous phase was extracted with 50 mL ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum) Ether/ethyl acetate (v/v) = 5:1), yield 4b (2.8 g, yield: 94%).

LCMS m/z = 321.1 [M+1] + LCMS m/z = 321.1 [M+1] +

第二步： 4c的製備Step 2: Preparation of 4c

將4b (1.4 g，4.37 mmol) 溶於5 mL 乙醇中，加入一水合氫氧化鋰 (0.70 g，16.68 mmol) 和3 mL水，40 oC反應2 h。將反應液冷卻至室溫，用1 mol/L稀鹽酸調pH至3，用30 mL乙酸乙酯萃取，合併有機相，無水硫酸鈉乾燥，減壓濃縮，將濃縮物溶於10 mL DCM中，加入1-氯-N,N,2-三甲基丙烯胺 (0.88 g，6.60 mmol)，室溫反應2 h後，依次加入三乙胺 (1.33 g，13.14 mmol) 和3-氯-4-氨基三氟甲苯 (1.11 g，5.68 mmol)，室溫反應18 h。向反應液中加入50 mL二氯甲烷，加入40 mL飽和碳酸氫鈉水溶液，分離出有機相，有機相用100 mL飽和氯化鈉水溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 5:1)，得4c (0.62 g，收率：23%)。 Dissolve 4b (1.4 g, 4.37 mmol) in 5 mL ethanol, add lithium hydroxide monohydrate (0.70 g, 16.68 mmol) and 3 mL water, and react at 40 ° C for 2 h. Cool the reaction solution to room temperature, adjust the pH to 3 with 1 mol/L dilute hydrochloric acid, extract with 30 mL ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and dissolve the concentrate in 10 mL DCM , add 1-chloro-N,N,2-trimethylpropenylamine (0.88 g, 6.60 mmol), react at room temperature for 2 h, then add triethylamine (1.33 g, 13.14 mmol) and 3-chloro-4 -Aminotrifluorotoluene (1.11 g, 5.68 mmol), react at room temperature for 18 h. Add 50 mL dichloromethane and 40 mL saturated aqueous sodium bicarbonate solution to the reaction solution, separate the organic phase, wash the organic phase with 100 mL saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is subjected to silica gel chromatography. Column separation and purification (petroleum ether/ethyl acetate (v/v) = 5:1) gave 4c (0.62 g, yield: 23%).

LCMS m/z = 470.0 [M+1] + LCMS m/z = 470.0 [M+1] +

第三步：化合物4的製備Step 3: Preparation of Compound 4

將 4c (0.30 g，0.64 mmol) 溶於5 mL DMF中，依次加入上述粗品中間體1 (0.26 g)、TEA (0.19 g，1.88 mmol)、CuI (24 mg，0.13 mmol) 和PdCl 2(PPh 3) 2(90 mg，0.13 mmol)，置換氮氣三次，80℃反應18 h。將反應液冷卻至室溫，加入50 mL水，析出固體，過濾，收集濾餅，濾餅用20 mL水洗滌，將濾餅用100 mL DCM溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 1:1)，得化合物4 (0.12 g，收率：28%)。 Dissolve 4c (0.30 g, 0.64 mmol) in 5 mL DMF, and add the above crude intermediate 1 (0.26 g), TEA (0.19 g, 1.88 mmol), CuI (24 mg, 0.13 mmol) and PdCl 2 (PPh) in sequence. 3 ) 2 (90 mg, 0.13 mmol), replace nitrogen three times, and react at 80°C for 18 hours. Cool the reaction solution to room temperature, add 50 mL of water, precipitate the solid, filter, collect the filter cake, wash the filter cake with 20 mL of water, dissolve the filter cake with 100 mL of DCM, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use crude product Silica gel column separation and purification (petroleum ether/ethyl acetate (v/v) = 1:1) gave compound 4 (0.12 g, yield: 28%).

1H NMR (400 MHz, CDCl 3) δ 9.49 (s, 1H), 8.55 (d, 1H), 8.11 (s, 1H), 7.82 – 7.59 (m, 4H), 7.55 – 7.48 (m, 1H), 6.84 – 6.78 (m, 1H), 6.56 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.42 – 4.30 (m, 2H), 4.17 (d, 1H), 4.12 – 4.03 (m, 2H), 3.88 – 3.74 (m, 1H), 2.96 – 2.64 (m, 3H), 2.20 – 2.07 (m, 1H), 1.83 – 1.67 (m, 1H), 1.00 – 0.88 (m, 1H), 0.81 – 0.65 (m, 2H), 0.55 – 0.40 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.49 (s, 1H), 8.55 (d, 1H), 8.11 (s, 1H), 7.82 – 7.59 (m, 4H), 7.55 – 7.48 (m, 1H), 6.84 – 6.78 (m, 1H), 6.56 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.42 – 4.30 (m, 2H), 4.17 (d, 1H), 4.12 – 4.03 (m, 2H), 3.88 – 3.74 (m, 1H), 2.96 – 2.64 (m, 3H), 2.20 – 2.07 (m, 1H), 1.83 – 1.67 (m, 1H), 1.00 – 0.88 (m, 1H), 0.81 – 0.65 (m , 2H), 0.55 – 0.40 (m, 1H).

LCMS m/z = 679.1 [M+1] + LCMS m/z = 679.1 [M+1] +

實施例 5：製備化合物5 Example 5 : Preparation of Compound 5

第一步： 5a的製備Step 1: Preparation of 5a

將4b(1.25 g，3.90 mmol) 溶於20 mL 四氫呋喃，將反應體系冷卻至-78℃，緩慢滴加LDA溶液 (2.0 mol/L 四氫呋喃/正庚烷 (v/v) = 12/25的溶液) (2.34 mL，4.68 mmol)，繼續在-78℃下攪拌30 min後，加入碘甲烷 (0.92 g，6.48 mmol)，升至室溫反應3 h。向反應液中加入40 mL飽和氯化鈉水溶液，用50 mL乙酸乙酯萃取，合併有機相，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 5:1)，得5a (0.88 g，收率：67%)。Dissolve 4b (1.25 g, 3.90 mmol) in 20 mL tetrahydrofuran, cool the reaction system to -78°C, and slowly add LDA solution (2.0 mol/L tetrahydrofuran/n-heptane (v/v) = 12/25 solution ) (2.34 mL, 4.68 mmol), continue stirring at -78°C for 30 min, add methyl iodide (0.92 g, 6.48 mmol), and raise to room temperature for 3 h. Add 40 mL of saturated aqueous sodium chloride solution to the reaction solution, extract with 50 mL of ethyl acetate, combine the organic phases, dry the organic phases over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate). Ester (v/v) = 5:1), giving 5a (0.88 g, yield: 67%).

第二步： 5b的製備Step 2: Preparation of 5b

將5a (0.87 g，2.60 mmol) 溶於8 mL 乙醇中，加入一水合氫氧化鋰 (0.42 g，10.00 mmol) 和4 mL水，40 oC反應2 h。將反應液冷卻至室溫，用1 mol/L稀鹽酸調pH至3，用40 mL乙酸乙酯萃取，合併有機相，有機相用無水硫酸鈉乾燥，減壓濃縮，將濃縮物溶於8 mL DCM中，加入1-氯-N,N,2-三甲基丙烯胺 (0.53 g，3.97 mmol)，室溫反應2 h後，依次加入三乙胺 (0.80 g，7.91 mmol) 和3-氯-4-氨基三氟甲苯 (0.67 g，3.43 mmol)，室溫反應19 h。向反應液中加入40 mL二氯甲烷，加入40 mL飽和碳酸氫鈉水溶液，分離出有機相，有機相用80 mL飽和氯化鈉水溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 5:1)，得5b (0.32 g，收率：19%)。 Dissolve 5a (0.87 g, 2.60 mmol) in 8 mL ethanol, add lithium hydroxide monohydrate (0.42 g, 10.00 mmol) and 4 mL water, and react at 40 ° C for 2 h. Cool the reaction solution to room temperature, adjust the pH to 3 with 1 mol/L dilute hydrochloric acid, extract with 40 mL ethyl acetate, combine the organic phases, dry the organic phases over anhydrous sodium sulfate, concentrate under reduced pressure, and dissolve the concentrate in 8 1-Chloro-N,N,2-trimethylpropenylamine (0.53 g, 3.97 mmol) was added to mL DCM. After reacting at room temperature for 2 h, triethylamine (0.80 g, 7.91 mmol) and 3- Chloro-4-aminotrifluorotoluene (0.67 g, 3.43 mmol), reacted at room temperature for 19 h. Add 40 mL of methylene chloride and 40 mL of saturated aqueous sodium bicarbonate solution to the reaction solution to separate the organic phase. Wash the organic phase with 80 mL of saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is subjected to silica gel chromatography. Column separation and purification (petroleum ether/ethyl acetate (v/v) = 5:1) gave 5b (0.32 g, yield: 19%).

LCMS m/z = 484.0 [M+1] + LCMS m/z = 484.0 [M+1] +

第三步： 化合物 5的製備 Step 3: Preparation of Compound 5

將 5b(0.32 g，0.66 mmol) 溶於9 mL DMF中，依次加入上述粗品中間體1 (0.27 g)、TEA (0.20 g，1.98 mmol)、CuI (24 mg，0.13 mmol) 和PdCl 2(PPh 3) 2(90 mg，0.13 mmol)，置換氮氣三次，80℃反應18 h。將反應液冷卻至室溫，加入50 mL水，析出固體，過濾，收集濾餅，濾餅用20 mL水洗滌，將濾餅用100 mL DCM溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 1:1)，得 化合物 5(0.21 g，收率：46%)。 Dissolve 5b (0.32 g, 0.66 mmol) in 9 mL DMF, and add the above crude intermediate 1 (0.27 g), TEA (0.20 g, 1.98 mmol), CuI (24 mg, 0.13 mmol) and PdCl 2 (PPh) in sequence 3 ) 2 (90 mg, 0.13 mmol), replace nitrogen three times, and react at 80°C for 18 hours. Cool the reaction solution to room temperature, add 50 mL of water, precipitate the solid, filter, collect the filter cake, wash the filter cake with 20 mL of water, dissolve the filter cake with 100 mL of DCM, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use crude product Silica gel column separation and purification (petroleum ether/ethyl acetate (v/v) = 1:1) gave compound 5 (0.21 g, yield: 46%).

1H NMR (400 MHz, CDCl 3) δ 9.24 (s, 1H), 8.53 (d, 1H), 8.03 – 7.90 (m, 2H), 7.77 (s, 1H), 7.67 (d, 1H), 7.63 – 7.58 (m, 1H), 7.54 – 7.47 (m, 1H), 6.85 – 6.78 (m, 1H), 6.56 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.43 – 4.30 (m, 2H), 4.15 – 4.03 (m, 2H), 3.90 – 3.75 (m, 1H), 2.96 – 2.64 (m, 3H), 2.20 – 2.06 (m, 1H), 1.80 – 1.68 (m, 4H), 0.86 – 0.79 (m, 2H), 0.74 – 0.58 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.24 (s, 1H), 8.53 (d, 1H), 8.03 – 7.90 (m, 2H), 7.77 (s, 1H), 7.67 (d, 1H), 7.63 – 7.58 (m, 1H), 7.54 – 7.47 (m, 1H), 6.85 – 6.78 (m, 1H), 6.56 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.43 – 4.30 (m, 2H), 4.15 – 4.03 (m, 2H), 3.90 – 3.75 (m, 1H), 2.96 – 2.64 (m, 3H), 2.20 – 2.06 (m, 1H), 1.80 – 1.68 (m, 4H), 0.86 – 0.79 (m , 2H), 0.74 – 0.58 (m, 2H).

LCMS m/z = 693.2 [M+1] + LCMS m/z = 693.2 [M+1] +

實施例 6：製備化合物6 Example 6 : Preparation of Compound 6

第一步： 6b的製備Step 1: Preparation of 6b

將6a (4.06 g，20.00 mmol) 與4-碘吡唑 (4.27 g， 22.00 mmol) 溶於50 mL乙腈中，加入碳酸銫 (9.77 g，30.00 mmol)，80℃反應3 h。將反應體系冷卻至室溫，過濾，將濾液減壓濃縮，向殘留物中加入80 mL THF與20 mL水溶解，加入一水合氫氧化鋰 (0.98 g，23.36 mmol)，室溫反應0.5 h。將反應體系用濃鹽酸調pH至4，減壓濃縮，將殘留物凍乾，將凍乾的殘留物用80 mL DCM/MeOH (v/v) = 10:1溶解，過濾，將濾液減壓濃縮，得粗品 (2.7 g)。將上述粗品 (0.80 g) 溶於10 mL DCM中，加入1-氯-N,N,2-三甲基丙烯胺 (0.51 g，3.82 mmol)，室溫反應2 h。向反應液中加入2-氯-4-三氟甲基苯胺 (0.5 g，2.56 mmol) 和三乙胺 (0.77 g，7.61 mmol)，室溫反應16 h。向反應液中加入80 mL乙酸乙酯，加入30 mL飽和碳酸氫鈉水溶液，分離出有機相，有機相用30 mL飽和氯化鈉水溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 5:1)，得6b (0.22 g，收率：18%)。Dissolve 6a (4.06 g, 20.00 mmol) and 4-iodopyrazole (4.27 g, 22.00 mmol) in 50 mL acetonitrile, add cesium carbonate (9.77 g, 30.00 mmol), and react at 80°C for 3 h. Cool the reaction system to room temperature, filter, and concentrate the filtrate under reduced pressure. Add 80 mL THF and 20 mL water to the residue to dissolve, add lithium hydroxide monohydrate (0.98 g, 23.36 mmol), and react at room temperature for 0.5 h. Adjust the pH of the reaction system to 4 with concentrated hydrochloric acid, concentrate under reduced pressure, and lyophilize the residue. Dissolve the lyophilized residue with 80 mL DCM/MeOH (v/v) = 10:1, filter, and decompress the filtrate. Concentrate to obtain crude product (2.7 g). Dissolve the above crude product (0.80 g) in 10 mL DCM, add 1-chloro-N,N,2-trimethylpropenylamine (0.51 g, 3.82 mmol), and react at room temperature for 2 h. 2-Chloro-4-trifluoromethylaniline (0.5 g, 2.56 mmol) and triethylamine (0.77 g, 7.61 mmol) were added to the reaction solution, and the reaction was carried out at room temperature for 16 h. Add 80 mL of ethyl acetate to the reaction solution, add 30 mL of saturated aqueous sodium bicarbonate solution, and separate the organic phase. The organic phase is washed with 30 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is subjected to silica gel chromatography. Column separation and purification (petroleum ether/ethyl acetate (v/v) = 5:1) gave 6b (0.22 g, yield: 18%).

第二步：化合物6的製備Step 2: Preparation of compound 6

將 6b (0.20 g，0.43 mmol) 溶於5 mL DMF中，依次加入上述粗品中間體1 (0.16 g)、TEA (0.13 g，1.28 mmol)、CuI (0.008 g，0.042 mmol) 和PdCl 2(PPh 3) 2(0.030 g，0.043 mmol)，置換氮氣三次，55℃反應1 h。將反應液冷卻至室溫，加入50 mL水，析出固體，過濾，濾餅用10 mL水洗滌，收集濾餅，將濾餅用30 mL DCM溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 1:1)，得化合物6(0.10 g，收率：35%)。 Dissolve 6b (0.20 g, 0.43 mmol) in 5 mL DMF, and add the above crude intermediate 1 (0.16 g), TEA (0.13 g, 1.28 mmol), CuI (0.008 g, 0.042 mmol) and PdCl 2 (PPh) in sequence. 3 ) 2 (0.030 g, 0.043 mmol), replace nitrogen three times, and react at 55°C for 1 hour. Cool the reaction solution to room temperature, add 50 mL of water, precipitate the solid, filter, wash the filter cake with 10 mL of water, collect the filter cake, dissolve the filter cake with 30 mL of DCM, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use the crude product Silica gel column separation and purification (petroleum ether/ethyl acetate (v/v) = 1:1) gave compound 6 (0.10 g, yield: 35%).

1H NMR (400 MHz, CDCl 3) δ 9.42 (s, 1H), 8.54 (d, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.82 – 7.55 (m, 4H), 6.86 – 6.78 (m, 1H), 6.56 (dd, 1H), 5.00 – 4.88 (m, 1H), 4.45 – 4.30 (m, 2H), 4.15 – 4.02 (m, 2H), 3.90 – 3.75 (m, 1H), 3.00 – 2.62 (m, 3H), 2.21 – 2.08 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.42 (s, 1H), 8.54 (d, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.82 – 7.55 (m, 4H), 6.86 – 6.78 (m, 1H), 6.56 (dd, 1H), 5.00 – 4.88 (m, 1H), 4.45 – 4.30 (m, 2H), 4.15 – 4.02 (m, 2H), 3.90 – 3.75 (m, 1H), 3.00 – 2.62 (m, 3H), 2.21 – 2.08 (m, 1H).

LCMS m/z = 673.0 [M-1] - LCMS m/z = 673.0 [M-1] -

實施例 7：製備化合物7 Example 7 : Preparation of Compound 7

第一步： 7b的製備Step One: Preparation of 7b

將2-(4-碘代-1H-吡唑-1-基)-2-甲基丙酸 (0.5 g，1.78 mmol) (合成方法見WO2019074962) 溶於10 mL DCM中，加入1-氯-N,N,2-三甲基丙烯胺 (0.36 g，2.69 mmol)，室溫反應2 h後，依次加入三乙胺 (1.09 g，10.77 mmol) 和7a (0.34 g，1.82 mmol)，室溫反應12 h。向反應液中加入50 mL二氯甲烷，加入50 mL水，分離出有機相，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 1:0-3:1)，得7b (0.5 g，收率：63%)。Dissolve 2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropionic acid (0.5 g, 1.78 mmol) (see WO2019074962 for synthesis method) in 10 mL DCM, add 1-chloro- N,N,2-trimethylpropenylamine (0.36 g, 2.69 mmol) was reacted at room temperature for 2 h, then triethylamine (1.09 g, 10.77 mmol) and 7a (0.34 g, 1.82 mmol) were added successively at room temperature. Reaction 12 hours. Add 50 mL of methylene chloride to the reaction solution, add 50 mL of water, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 1:0-3:1), 7b (0.5 g, yield: 63%) was obtained.

第二步：化合物7的製備Step 2: Preparation of Compound 7

將7b (0.42 g，0.93 mmol)、上述粗品中間體1 (0.32 g)、TEA (0.57 g，5.63 mmol)、CuI (36 mg，0.18 mmol) 和PdCl 2(PPh 3) 2(66 mg，0.094 mmol) 加入5 mL DMF中，氮氣氛圍55℃反應1.5 h。將反應液冷卻至室溫，加入50 mL水，抽濾，濾餅用10 mL水洗滌，將濾餅用100 mL DCM溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/二氯甲烷/乙酸乙酯 (v/v) = 1:1:2)，得化合物7 (0.1 g，收率：16%)。 7b (0.42 g, 0.93 mmol), the above crude intermediate 1 (0.32 g), TEA (0.57 g, 5.63 mmol), CuI (36 mg, 0.18 mmol) and PdCl 2 (PPh 3 ) 2 (66 mg, 0.094 mmol) was added to 5 mL DMF, and the reaction was carried out at 55°C in a nitrogen atmosphere for 1.5 h. Cool the reaction solution to room temperature, add 50 mL of water, and filter with suction. The filter cake is washed with 10 mL of water. The filter cake is dissolved in 100 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated and purified using a silica gel chromatography column ( Petroleum ether/dichloromethane/ethyl acetate (v/v) = 1:1:2) to obtain compound 7 (0.1 g, yield: 16%).

1H NMR (400 MHz, CDCl 3) δ 8.36 (d, 1H), 7.95 (s, 1H), 7.72 – 7.60 (m, 3H), 7.52 – 7.44 (m, 1H), 7.42 – 7.34 (m, 1H), 6.85 – 6.75 (m, 1H), 6.55 (dd, 1H), 5.00 – 4.87 (m, 1H), 4.44 – 4.30 (m, 2H), 4.15 – 4.00 (m, 2H), 3.89 – 3.73 (m, 1H), 3.25 – 3.12 (m, 2H), 3.06 – 2.62 (m, 5H), 2.20 – 2.04 (m, 1H), 1.89 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.36 (d, 1H), 7.95 (s, 1H), 7.72 – 7.60 (m, 3H), 7.52 – 7.44 (m, 1H), 7.42 – 7.34 (m, 1H ), 6.85 – 6.75 (m, 1H), 6.55 (dd, 1H), 5.00 – 4.87 (m, 1H), 4.44 – 4.30 (m, 2H), 4.15 – 4.00 (m, 2H), 3.89 – 3.73 (m , 1H), 3.25 – 3.12 (m, 2H), 3.06 – 2.62 (m, 5H), 2.20 – 2.04 (m, 1H), 1.89 (s, 6H).

LCMS m/z = 659.2 [M+1] + LCMS m/z = 659.2 [M+1] +

實施例 8：製備化合物8 Example 8 : Preparation of compound 8

化合物8以化合物8a為原料，參考實施例1得到。 Compound 8 was obtained by referring to Example 1 using compound 8a as a raw material.

1H NMR (400 MHz, CDCl 3) δ 7.99 (s, 1H), 7.73 – 7.17 (m, 6H), 6.82 – 6.75 (m, 1H), 6.53 (dd, 1H), 4.99 – 4.85 (m, 3H), 4.40 – 4.28 (m, 2H), 4.27 – 4.16 (m, 2H), 4.10 – 4.00 (m, 2H), 3.86 – 3.72 (m, 1H), 3.08 – 2.63 (m, 7H), 2.19 – 1.88 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (s, 1H), 7.73 – 7.17 (m, 6H), 6.82 – 6.75 (m, 1H), 6.53 (dd, 1H), 4.99 – 4.85 (m, 3H ), 4.40 – 4.28 (m, 2H), 4.27 – 4.16 (m, 2H), 4.10 – 4.00 (m, 2H), 3.86 – 3.72 (m, 1H), 3.08 – 2.63 (m, 7H), 2.19 – 1.88 (m, 3H).

LCMS m/z = 671.8 [M+1] + LCMS m/z = 671.8 [M+1] +

實施例 9：製備化合物9 Example 9 : Preparation of Compound 9

化合物9以化合物9a為原料，參考實施例7得到。Compound 9 was obtained by referring to Example 7 using compound 9a as a raw material.

1H NMR (400 MHz, CDCl 3) δ 8.35 (d, 1H), 8.08 – 7.99 (m, 1H), 7.74 – 7.60 (m, 3H), 7.56 – 7.48 (m, 1H), 7.39 (s, 1H), 6.84 – 6.76 (m, 1H), 6.55 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.12 – 4.00 (m, 2H), 3.86 – 3.74 (m, 1H), 3.24 – 3.12 (m, 2H), 3.04 – 2.65 (m, 5H), 2.19 – 2.08 (m, 1H), 1.89 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.35 (d, 1H), 8.08 – 7.99 (m, 1H), 7.74 – 7.60 (m, 3H), 7.56 – 7.48 (m, 1H), 7.39 (s, 1H ), 6.84 – 6.76 (m, 1H), 6.55 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.12 – 4.00 (m, 2H), 3.86 – 3.74 (m , 1H), 3.24 – 3.12 (m, 2H), 3.04 – 2.65 (m, 5H), 2.19 – 2.08 (m, 1H), 1.89 (s, 6H).

LCMS m/z = 616.2 [M+1] + LCMS m/z = 616.2 [M+1] +

實施例10：製備化合物10 Example 10: Preparation of Compound 10

化合物10以化合物10a為原料，參考實施例1得到。Compound 10 was obtained by referring to Example 1 using compound 10a as a raw material.

1H NMR (400 MHz, CDCl 3) δ 8.40 – 8.25 (m, 1H), 7.98 (s, 1H), 7.71 – 7.60 (m, 3H), 7.58 – 7.49 (m, 1H), 7.40 (s, 1H), 6.83 – 6.76 (m, 1H), 6.54 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.40 – 4.26 (m, 2H), 4.10 – 3.98 (m, 2H), 3.85 – 3.72 (m, 1H), 3.57 – 3.43 (m, 2H), 3.12 – 2.65 (m, 9H), 2.19 – 1.90 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.40 – 8.25 (m, 1H), 7.98 (s, 1H), 7.71 – 7.60 (m, 3H), 7.58 – 7.49 (m, 1H), 7.40 (s, 1H) ), 6.83 – 6.76 (m, 1H), 6.54 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.40 – 4.26 (m, 2H), 4.10 – 3.98 (m, 2H), 3.85 – 3.72 (m , 1H), 3.57 – 3.43 (m, 2H), 3.12 – 2.65 (m, 9H), 2.19 – 1.90 (m, 3H).

LCMS m/z = 628.7 [M+1] + LCMS m/z = 628.7 [M+1] +

實施例 11：製備化合物11 Example 11 : Preparation of Compound 11

以化合物11a和2b為原料，參照實施例1的合成方法得到化合物11 (0.38 g)Using compounds 11a and 2b as raw materials, compound 11 (0.38 g) was obtained by referring to the synthesis method of Example 1.

1H NMR (400 MHz, CDCl 3) δ 8.12 (s, 1H), 7.74 – 7.45 (m, 5H), 7.25 – 7.17 (m, 2H), 6.85 – 6.77 (m, 1H), 6.56 (dd, 1H), 5.01 – 4.66 (m, 2H), 4.42 – 4.28 (m, 2H), 4.16 – 3.98 (m, 2H), 3.89 – 3.65 (m, 2H), 3.15 – 2.55 (m, 10H), 2.20 – 1.80 (m, 4H), 1.70 – 1.50 (m, 2H), 1.11 – 0.92 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.12 (s, 1H), 7.74 – 7.45 (m, 5H), 7.25 – 7.17 (m, 2H), 6.85 – 6.77 (m, 1H), 6.56 (dd, 1H ), 5.01 – 4.66 (m, 2H), 4.42 – 4.28 (m, 2H), 4.16 – 3.98 (m, 2H), 3.89 – 3.65 (m, 2H), 3.15 – 2.55 (m, 10H), 2.20 – 1.80 (m, 4H), 1.70 – 1.50 (m, 2H), 1.11 – 0.92 (m, 1H).

LCMS m/z = 713.8 [M+1] + LCMS m/z = 713.8 [M+1] +

實施例 12：製備化合物12 Example 12 : Preparation of compound 12

以化合物12a為原料，參考實施例11得到化合物12(0.10g)得到。Using compound 12a as a raw material, compound 12 (0.10 g) was obtained with reference to Example 11.

1H NMR (400 MHz, CDCl 3) δ 8.06 (s, 1H), 7.73 – 7.48 (m, 5H), 7.31 – 7.22 (m, 1H), 7.16 – 7.08 (m, 1H), 6.84 – 6.77 (m, 1H), 6.55 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.43 – 4.30 (m, 2H), 4.13 – 3.69 (m, 4H), 3.68 – 3.07 (m, 3H), 3.05 – 2.57 (m, 8H), 2.34 – 1.77 (m, 5H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (s, 1H), 7.73 – 7.48 (m, 5H), 7.31 – 7.22 (m, 1H), 7.16 – 7.08 (m, 1H), 6.84 – 6.77 (m , 1H), 6.55 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.43 – 4.30 (m, 2H), 4.13 – 3.69 (m, 4H), 3.68 – 3.07 (m, 3H), 3.05 – 2.57 (m, 8H), 2.34 – 1.77 (m, 5H).

LCMS m/z = 699.2 [M+1] + LCMS m/z = 699.2 [M+1] +

實施例 13：製備化合物13 Example 13 : Preparation of compound 13

以化合物13a為原料，參考實施例11得到化合物13(0.16g)得到。Using compound 13a as a raw material, compound 13 (0.16g) was obtained with reference to Example 11.

1H NMR (400 MHz, CDCl 3) δ 8.12 (s, 1H), 7.72 – 7.64 (m, 2H), 7.60 – 7.42 (m, 3H), 7.22 – 6.96 (m, 2H), 6.86 – 6.78 (m, 1H), 6.62 – 6.51 (m, 1H), 5.22 – 5.11 (m, 1H), 5.00 – 4.86 (m, 1H), 4.45 – 4.27 (m, 2H), 4.15 – 3.96 (m, 2H), 3.92 – 3.68 (m, 1H), 3.30 – 2.53 (m, 9H), 2.34 – 1.64 (m, 7H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.12 (s, 1H), 7.72 – 7.64 (m, 2H), 7.60 – 7.42 (m, 3H), 7.22 – 6.96 (m, 2H), 6.86 – 6.78 (m , 1H), 6.62 – 6.51 (m, 1H), 5.22 – 5.11 (m, 1H), 5.00 – 4.86 (m, 1H), 4.45 – 4.27 (m, 2H), 4.15 – 3.96 (m, 2H), 3.92 – 3.68 (m, 1H), 3.30 – 2.53 (m, 9H), 2.34 – 1.64 (m, 7H).

LCMS m/z = 699.2 [M+1] +LCMS m/z = 699.2 [M+1] +

實施例 14：製備化合物14 Example 14 : Preparation of Compound 14

以化合物14a為原料，參考實施例1得到化合物14(0.17g)。Using compound 14a as a raw material, compound 14 (0.17g) was obtained with reference to Example 1.

1H NMR (400 MHz, CDCl 3) δ 8.00 (s, 1H), 7.72 – 6.90 (m, 6H), 6.84 – 6.74 (m, 1H), 6.59 – 6.49 (m, 1H), 4.99 – 4.87 (m, 1H), 4.84 – 4.20 (m, 4H), 4.10 – 3.95 (m, 2H), 3.92 – 3.68 (m, 2H), 3.52 – 3.36 (m, 1H), 3.10 – 2.63 (m, 8H), 2.54 – 2.40 (m, 1H), 2.18 – 1.81 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.00 (s, 1H), 7.72 – 6.90 (m, 6H), 6.84 – 6.74 (m, 1H), 6.59 – 6.49 (m, 1H), 4.99 – 4.87 (m , 1H), 4.84 – 4.20 (m, 4H), 4.10 – 3.95 (m, 2H), 3.92 – 3.68 (m, 2H), 3.52 – 3.36 (m, 1H), 3.10 – 2.63 (m, 8H), 2.54 – 2.40 (m, 1H), 2.18 – 1.81 (m, 3H).

LCMS m/z = 685.2 [M+1] + LCMS m/z = 685.2 [M+1] +

實施例 15：製備化合物15 Example 15 : Preparation of Compound 15

以15a和2b為原料，參考實施例1得到化合物15 (0.15 g)Using 15a and 2b as raw materials, compound 15 (0.15 g) was obtained with reference to Example 1.

第二步：化合物15的製備Step 2: Preparation of Compound 15

1H NMR (400 MHz, DMSO- d 6 ) δ 11.07 (s, 1H), 8.69 (s, 1H), 8.63 (s, 1H), 8.37 – 8.30 (m, 1H), 8.08 – 8.00 (m, 1H), 7.83 – 7.72 (m, 1H), 7.72 – 7.59 (m, 2H), 7.53 – 7.36 (m, 3H), 6.89 – 6.78 (m, 1H), 6.69 (dd, 1H), 5.12 – 5.02 (m, 1H), 4.42 – 4.28 (m, 2H), 4.04 – 3.93 (m, 2H), 3.92 – 3.77 (m, 1H), 3.28 – 2.98 (m, 4H), 2.97 – 2.80 (m, 1H), 2.68 – 2.44 (m, 2H), 2.14 – 1.84 (m, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.07 (s, 1H), 8.69 (s, 1H), 8.63 (s, 1H), 8.37 – 8.30 (m, 1H), 8.08 – 8.00 (m, 1H) ), 7.83 – 7.72 (m, 1H), 7.72 – 7.59 (m, 2H), 7.53 – 7.36 (m, 3H), 6.89 – 6.78 (m, 1H), 6.69 (dd, 1H), 5.12 – 5.02 (m , 1H), 4.42 – 4.28 (m, 2H), 4.04 – 3.93 (m, 2H), 3.92 – 3.77 (m, 1H), 3.28 – 2.98 (m, 4H), 2.97 – 2.80 (m, 1H), 2.68 – 2.44 (m, 2H), 2.14 – 1.84 (m, 3H).

實施例16：製備化合物16 Example 16: Preparation of Compound 16

第一步： 16B的製備Step One: Preparation of 16B

向反應瓶中依次加入16A (2.00 g, 10.15 mmol)、環丙基硼酸 (1.31 g, 15.25 mmol)、無水磷酸鉀 (8.62 g, 40.61 mmol)、三環己基膦 (1.14 g, 4.07 mmol) 和醋酸鈀 (0.46 g, 2.05 mmol)，氮氣氛圍加入1,4-二氧六環 (25 mL) 和水 (2.5 mL)，90℃反應16 h。將反應液冷卻至室溫，加入乙酸乙酯萃取 (40 mL × 3)，有機相用20 mL飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (乙酸乙酯/石油醚 (v/v) = 1:5)，得16B (1.32 g，收率：82%)。To the reaction flask, add 16A (2.00 g, 10.15 mmol), cyclopropylboronic acid (1.31 g, 15.25 mmol), anhydrous potassium phosphate (8.62 g, 40.61 mmol), tricyclohexylphosphine (1.14 g, 4.07 mmol) and Palladium acetate (0.46 g, 2.05 mmol), 1,4-dioxane (25 mL) and water (2.5 mL) were added in a nitrogen atmosphere, and the reaction was carried out at 90°C for 16 h. The reaction solution was cooled to room temperature, and extracted with ethyl acetate (40 mL × 3). The organic phase was washed with 20 mL saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (acetic acid). Ethyl ester/petroleum ether (v/v) = 1:5) to obtain 16B (1.32 g, yield: 82%).

LCMS m/z = 159.1 [M+1] + LCMS m/z = 159.1 [M+1] +

第二步： 16b的製備Step 2: Preparation of 16b

將16a (1.5 g，13.87 mmol) 加入到100 mL三口瓶中，加入50%濃硫酸 (40 mL)，冷卻至0℃，緩慢加入N-碘代丁二醯亞胺 (4.6 g，20.45 mmol)，室溫反應16 h。將反應體系緩慢加入到40 mL飽和碳酸鈉水溶液中，用乙酸乙酯萃取 (80 mL×2)，有機相用飽和硫代硫酸鈉水溶液洗滌 (80 mL×2) 和飽和氯化鈉水溶液洗滌 (50 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 81:19)，得16b (2.3 g，收率：71%)。Add 16a (1.5 g, 13.87 mmol) to a 100 mL three-necked flask, add 50% concentrated sulfuric acid (40 mL), cool to 0°C, and slowly add N-iodosuccinimide (4.6 g, 20.45 mmol) , react at room temperature for 16 h. The reaction system was slowly added to 40 mL of saturated aqueous sodium carbonate solution, extracted with ethyl acetate (80 mL×2), and the organic phase was washed with saturated aqueous sodium thiosulfate solution (80 mL×2) and saturated aqueous sodium chloride solution ( 50 ml %).

LCMS m/z = 235.1 [M+1] + LCMS m/z = 235.1 [M+1] +

第三步： 16c的製備Step 3: Preparation of 16c

將16b (0.8 g，3.42 mmol) 加入到100 mL單口瓶中，加入20 mL乙腈，依次加入1-溴環丁烷-1-甲酸乙酯 (698 mg，3.37 mmol) 和碳酸銫 (2.2 g，6.75 mmol)，90℃反應3 h。將反應液冷卻至室溫，過濾，將濾液減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 89:11)，得16c (0.9 g，收率：73%)。Add 16b (0.8 g, 3.42 mmol) into a 100 mL single-neck bottle, add 20 mL acetonitrile, and then add 1-bromocyclobutane-1-carboxylic acid ethyl ester (698 mg, 3.37 mmol) and cesium carbonate (2.2 g, 6.75 mmol), react at 90°C for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 89:11) to obtain 16c (0.9 g, yield: 73%).

LCMS m/z = 361.1 [M+1] + LCMS m/z = 361.1 [M+1] +

第四步：16d的製備Step 4: Preparation of 16d

將16c (0.9 g，2.5 mmol) 溶於15 mL四氫呋喃中，加入5 mL水，冷卻至0℃，加入一水合氫氧化鋰 (315 mg，7.51 mmol)，室溫反應2 h。將反應液用0.5 mol/L鹽酸調pH至4，用乙酸乙酯萃取 (60 mL×3)，有機相用飽和氯化鈉水溶液洗滌 (60 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (二氯甲烷:甲醇 (v/v) = 95:5)，得粗品 (0.6 g)。將上述粗品 (200 mg) 加入到50 mL單口瓶中，加入15 mL二氯甲烷，加入1-氯-N，N，2-三甲基丙烯胺 (120 mg，0.9 mmol)，室溫反應1 h後，依次加入三乙胺 (182 mg，1.8 mmol) 和16B (95mg，0.6 mmol)，室溫反應1 h。將反應體系減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 85:15)，得16d (120 mg，收率：42%)。 Dissolve 16c (0.9 g, 2.5 mmol) in 15 mL tetrahydrofuran, add 5 mL water, cool to 0°C, add lithium hydroxide monohydrate (315 mg, 7.51 mmol), and react at room temperature for 2 h. Adjust the pH of the reaction solution to 4 with 0.5 mol/L hydrochloric acid, extract with ethyl acetate (60 mL×3), wash the organic phase with saturated sodium chloride aqueous solution (60 mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure , the crude product was separated and purified using a silica gel chromatography column (methylene chloride: methanol (v/v) = 95:5) to obtain the crude product (0.6 g). Add the above crude product (200 mg) into a 50 mL single-neck bottle, add 15 mL dichloromethane, add 1-chloro-N, N, 2-trimethylpropenylamine (120 mg, 0.9 mmol), and react at room temperature 1 After h, triethylamine (182 mg, 1.8 mmol) and 16B (95 mg, 0.6 mmol) were added successively, and the reaction was carried out at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 85:15) to obtain 16d (120 mg, yield: 42%).

LCMS m/z = 473.1 [M+1] + LCMS m/z = 473.1 [M+1] +

第五步；化合物16的製備Step 5; Preparation of compound 16

將16d (120 mg，0.25 mmol) 加入到50 mL單口瓶中，加入DMF (10 mL)，加入粗品中間體1 (126 mg) 、TEA (76 mg，0.75 mmol)、PdCl 2(PPh 3) 2(17 mg，0.024 mmol) 和CuI (10 mg，0.053 mmol)，置換氮氣三次，50℃反應2 h，將反應體系冷卻至室溫，加入飽和氯化銨水溶液 (120 mL)，用乙酸乙酯萃取 (50 mL×3)，有機相用飽和氯化鈉水溶液洗滌 (60 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 37:63)，得化合物16 (90 mg，收率：53%)。 Add 16d (120 mg, 0.25 mmol) into a 50 mL single-neck bottle, add DMF (10 mL), add crude intermediate 1 (126 mg), TEA (76 mg, 0.75 mmol), PdCl 2 (PPh 3 ) 2 (17 mg, 0.024 mmol) and CuI (10 mg, 0.053 mmol), replace nitrogen three times, react at 50°C for 2 h, cool the reaction system to room temperature, add saturated aqueous ammonium chloride solution (120 mL), and use ethyl acetate to Extract (50 ml v) = 37:63), compound 16 (90 mg, yield: 53%) was obtained.

1H NMR (400 MHz, CDCl 3) δ 8.53 (s, 1H), 8.40 (d, 1H), 7.94 (s, 1H), 7.67 (d, 1H), 7.59 (s, 1H), 7.49 (dd, 1H), 7.37 – 7.32 (m, 1H), 6.84 – 6.78 (m, 1H), 6.56 (dd, 1H), 4.99 – 4.88 (m, 1H), 4.44 – 4.30 (m, 2H), 4.10 – 4.00 (m, 2H), 3.88 – 3.76 (m, 1H), 3.10 – 2.60 (m, 7H), 2.30 – 1.90 (m, 4H), 1.53 – 1.40 (m, 1H), 1.06 – 0.81 (m, 6H), 0.59 – 0.50 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.53 (s, 1H), 8.40 (d, 1H), 7.94 (s, 1H), 7.67 (d, 1H), 7.59 (s, 1H), 7.49 (dd, 1H), 7.37 – 7.32 (m, 1H), 6.84 – 6.78 (m, 1H), 6.56 (dd, 1H), 4.99 – 4.88 (m, 1H), 4.44 – 4.30 (m, 2H), 4.10 – 4.00 ( m, 2H), 3.88 – 3.76 (m, 1H), 3.10 – 2.60 (m, 7H), 2.30 – 1.90 (m, 4H), 1.53 – 1.40 (m, 1H), 1.06 – 0.81 (m, 6H), 0.59 – 0.50 (m, 2H).

LCMS m/z = 680.1 [M-1] - LCMS m/z = 680.1 [M-1] -

實施例17：化合物17的製備 Example 17: Preparation of Compound 17

以化合物17B和16c為原料，參照實施例16的合成方法得到化合物17(60 mg)Using compounds 17B and 16c as raw materials, compound 17 (60 mg) was obtained by referring to the synthesis method of Example 16.

1H NMR (400 MHz, CDCl 3) δ 8.44 (d, 1H), 8.31 (s, 1H), 7.93 (s, 1H), 7.73 – 7.45 (m, 4H), 6.84 – 6.77 (m, 1H), 6.56 (dd, 1H), 4.98 – 4.87 (m, 1H), 4.44 – 4.30 (m, 2H), 4.10 – 3.97 (m, 2H), 3.90 – 3.76 (m, 1H), 3.07 – 2.61 (m, 7H), 2.26 – 1.94 (m, 7H), 1.11 – 1.03 (m, 2H), 1.01 – 0.93 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.44 (d, 1H), 8.31 (s, 1H), 7.93 (s, 1H), 7.73 – 7.45 (m, 4H), 6.84 – 6.77 (m, 1H), 6.56 (dd, 1H), 4.98 – 4.87 (m, 1H), 4.44 – 4.30 (m, 2H), 4.10 – 3.97 (m, 2H), 3.90 – 3.76 (m, 1H), 3.07 – 2.61 (m, 7H ), 2.26 – 1.94 (m, 7H), 1.11 – 1.03 (m, 2H), 1.01 – 0.93 (m, 2H).

LCMS m/z = 723.8 [M+1] + LCMS m/z = 723.8 [M+1] +

實施例18：化合物18的製備 Example 18: Preparation of Compound 18

第一步：18b的製備Step 1: Preparation of 18b

將18a (5.0 g，30.1 mmol)、4-氟-1H-吡唑 (4.11 g，47.75 mmol) 和碳酸鉀 (6.60 g，47.76 mmol) 加入80 mL DMF中，80℃反應16 h。將反應液冷卻到室溫，加入100 mL水，用100 mL乙酸乙酯萃取，有機相用50 mL水洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 3:1)，得到18b (4.0 g，收率：57%)。18a (5.0 g, 30.1 mmol), 4-fluoro-1H-pyrazole (4.11 g, 47.75 mmol) and potassium carbonate (6.60 g, 47.76 mmol) were added to 80 mL DMF and reacted at 80°C for 16 h. Cool the reaction solution to room temperature, add 100 mL of water, and extract with 100 mL of ethyl acetate. The organic phase is washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/acetic acid). Ethyl ester (v/v) = 3:1), giving 18b (4.0 g, yield: 57%).

第二步： 18c的製備Step 2: Preparation of 18c

將18b (1.5 g，6.46 mmol) 溶於30 mL甲醇中，加入0.2 g 10% Pd/C，置換氫氣三次，置於氫氣球氛圍下室溫反應2 h。將反應體系過濾，將濾液減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 3:1)，得粗品18c (0.8 g)。Dissolve 18b (1.5 g, 6.46 mmol) in 30 mL methanol, add 0.2 g 10% Pd/C, replace the hydrogen gas three times, and react at room temperature for 2 h under a hydrogen balloon atmosphere. The reaction system was filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 3:1) to obtain crude product 18c (0.8 g).

LCMS m/z = 203.1 [M+1] + LCMS m/z = 203.1 [M+1] +

第三步： 18d的製備Step 3: Preparation of 18d

將上述粗品18c (0.4 g) 與2-(4-碘代-1H-吡唑-1-基)-2-甲基丙酸 (0.67 g，2.39 mmol)溶於15 mL DCM中，加入TCFH (0.83 g，2.96 mmol)，緩慢滴加N-甲基咪唑 (0.65 g，7.92 mmol)，室溫反應16 h。將反應體系減壓濃縮，粗品用50 mL二氯甲烷溶解，有機相用20 mL水洗滌，無水硫酸乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 5:1)，得到18d (0.78 g，收率：70%)。The above crude product 18c (0.4 g) and 2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropionic acid (0.67 g, 2.39 mmol) were dissolved in 15 mL DCM, and TCFH ( 0.83 g, 2.96 mmol), slowly add N-methylimidazole (0.65 g, 7.92 mmol) dropwise, and react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the crude product was dissolved in 50 mL of methylene chloride. The organic phase was washed with 20 mL of water, dried with anhydrous sulfuric acid, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) ) = 5:1), obtaining 18d (0.78 g, yield: 70%).

LCMS m/z = 465.4 [M+1] + LCMS m/z = 465.4 [M+1] +

第四步：化合物18的製備Step 4: Preparation of Compound 18

將18d (0.23 g，0.50 mmol)、中間體1 (0.25 g)、TEA (0.15 g，1.48 mmol)、CuI (10 mg，0.0525 mmol) 和PdCl 2(PPh 3) 2(35 mg，0.0499 mmol)加入5 mL DMF，氮氣氛圍50℃反應1 h。將反應液冷卻至室溫，加入50 mL水，抽濾，濾餅用10 mL水洗滌，將濾餅用100 mL DCM溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠柱色譜分離純化 (石油醚/乙酸乙酯 (v/v) = 1:1)，得到化合物18 (0.05 g，收率：15%)。 Combine 18d (0.23 g, 0.50 mmol), Intermediate 1 (0.25 g), TEA (0.15 g, 1.48 mmol), CuI (10 mg, 0.0525 mmol) and PdCl 2 (PPh 3 ) 2 (35 mg, 0.0499 mmol). Add 5 mL DMF and react at 50°C for 1 h in a nitrogen atmosphere. Cool the reaction solution to room temperature, add 50 mL of water, and filter with suction. The filter cake is washed with 10 mL of water. The filter cake is dissolved in 100 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated and purified by silica gel column chromatography ( Petroleum ether/ethyl acetate (v/v) = 1:1) to obtain compound 18 (0.05 g, yield: 15%).

1H NMR (400 MHz, CDCl 3) δ 10.29 (s, 1H), 8.72 (d, 1H), 8.02 (s, 1H), 7.74 (s, 1H), 7.72 – 7.65 (m, 1H), 7.65 – 7.58 (m, 3H), 7.56 – 7.52 (m, 1H), 7.50 – 7.46 (m, 1H), 6.86 – 6.80 (m, 1H), 6.57 (dd, 1H), 4.98 – 4.90 (m, 1H), 4.45 – 4.34 (m, 2H), 4.17 – 4.04 (m, 2H), 3.92 – 3.78 (m, 1H), 2.96 – 2.65 (m, 3H), 2.19 – 2.07 (m, 1H), 1.88 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 10.29 (s, 1H), 8.72 (d, 1H), 8.02 (s, 1H), 7.74 (s, 1H), 7.72 – 7.65 (m, 1H), 7.65 – 7.58 (m, 3H), 7.56 – 7.52 (m, 1H), 7.50 – 7.46 (m, 1H), 6.86 – 6.80 (m, 1H), 6.57 (dd, 1H), 4.98 – 4.90 (m, 1H), 4.45 – 4.34 (m, 2H), 4.17 – 4.04 (m, 2H), 3.92 – 3.78 (m, 1H), 2.96 – 2.65 (m, 3H), 2.19 – 2.07 (m, 1H), 1.88 (s, 6H ).

LCMS m/z = 674.3 [M+1] + LCMS m/z = 674.3 [M+1] +

實施例19：化合物19的製備 Example 19: Preparation of Compound 19

以化合物19b和2-(4-碘代-1H-吡唑-1-基)-2-甲基丙酸為原料，參照實施例18的合成方法得到化合物19 (0.33 g)Using compound 19b and 2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropionic acid as raw materials, compound 19 (0.33 g) was obtained by referring to the synthesis method of Example 18.

1H NMR (400 MHz, CDCl 3) δ 8.98 (s, 1H), 8.49 (d, 1H), 8.05 (s, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.67 (d, 1H), 7.59 – 7.54 (m, 1H), 7.54 – 7.47 (m, 1H), 6.84 – 6.77 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.40 – 4.30 (m, 2H), 4.10 – 3.97 (m, 2H), 3.88 – 3.72 (m, 1H), 2.95 – 2.65 (m, 3H), 2.22 – 2.06 (m, 4H), 1.93 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.98 (s, 1H), 8.49 (d, 1H), 8.05 (s, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.67 (d, 1H), 7.59 – 7.54 (m, 1H), 7.54 – 7.47 (m, 1H), 6.84 – 6.77 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.40 – 4.30 ( m, 2H), 4.10 – 3.97 (m, 2H), 3.88 – 3.72 (m, 1H), 2.95 – 2.65 (m, 3H), 2.22 – 2.06 (m, 4H), 1.93 (s, 6H).

LCMS m/z = 628.6 [M+1] + LCMS m/z = 628.6 [M+1] +

實施例20：化合物20的製備 Example 20: Preparation of Compound 20

以化合物20b為原料，參考實施例18得到化合物20(0.02g)。Using compound 20b as a raw material, compound 20 (0.02g) was obtained with reference to Example 18.

1H NMR (400 MHz, CDCl 3) δ 7.91 (s, 1H), 7.77 (s, 1H), 7.74 – 7.64 (m, 3H), 7.61 (s, 1H), 7.50 – 7.44 (m, 1H), 6.84 – 6.77 (m, 1H), 6.56 (dd, 1H), 5.48 (q, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.15 – 4.03 (m, 2H), 3.89 – 3.76 (m, 1H), 2.96 – 2.65 (m, 3H), 2.18 – 2.08 (m, 1H), 1.98 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.91 (s, 1H), 7.77 (s, 1H), 7.74 – 7.64 (m, 3H), 7.61 (s, 1H), 7.50 – 7.44 (m, 1H), 6.84 – 6.77 (m, 1H), 6.56 (dd, 1H), 5.48 (q, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.15 – 4.03 (m, 2H), 3.89 – 3.76 (m, 1H), 2.96 – 2.65 (m, 3H), 2.18 – 2.08 (m, 1H), 1.98 (s, 6H).

LCMS m/z = 725.2 [M+1] + LCMS m/z = 725.2 [M+1] +

實施例21：化合物21的製備 Example 21: Preparation of Compound 21

以化合物21a為原料，參考實施例19得到化合物21(0.20g)。Using compound 21a as a raw material, compound 21 (0.20 g) was obtained with reference to Example 19.

1H NMR (400 MHz, CDCl 3) δ 8.95 (s, 1H), 8.43 (d, 1H), 8.08 (s, 1H), 7.78 (s, 1H), 7.71 (s, 1H), 7.67 (d, 1H), 7.62 – 7.56 (m, 1H), 7.47 (dd, 1H), 6.83 – 6.78 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.40 – 4.30 (m, 2H), 4.10 – 3.97 (m, 2H), 3.88 – 3.72 (m, 1H), 2.96 – 2.64 (m, 4H), 2.17 – 2.07 (m, 1H), 1.94 (s, 6H), 1.33 (d, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.95 (s, 1H), 8.43 (d, 1H), 8.08 (s, 1H), 7.78 (s, 1H), 7.71 (s, 1H), 7.67 (d, 1H), 7.62 – 7.56 (m, 1H), 7.47 (dd, 1H), 6.83 – 6.78 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.40 – 4.30 (m, 2H), 4.10 – 3.97 (m, 2H), 3.88 – 3.72 (m, 1H), 2.96 – 2.64 (m, 4H), 2.17 – 2.07 (m, 1H), 1.94 (s, 6H), 1.33 (d, 6H).

LCMS m/z = 699.2 [M+1] + LCMS m/z = 699.2 [M+1] +

實施例22：化合物22的製備 Example 22: Preparation of Compound 22

參考化合物17的製備方法，得到化合物22 (85 mg)Referring to the preparation method of compound 17, compound 22 (85 mg) was obtained

1H NMR (400 MHz, CDCl 3) δ 8.37 – 8.22 (m, 2H), 8.03 (br.s, 1H), 7.81 – 7.61 (m, 3H), 7.36 – 7.28 (m, 1H), 7.22 – 7.12 (m, 1H), 6.85 – 6.74 (m, 1H), 6.55 (dd, 1H), 4.99 – 4.87 (m, 1H), 4.42 – 4.28 (m, 2H), 4.12 – 4.00 (m, 2H), 3.88 – 3.72 (m, 1H), 3.45 – 3.30 (m, 2H), 3.15 – 3.00 (m, 2H), 2.97 – 2.65 (m, 5H), 2.28 – 1.95 (m, 9H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.37 – 8.22 (m, 2H), 8.03 (br.s, 1H), 7.81 – 7.61 (m, 3H), 7.36 – 7.28 (m, 1H), 7.22 – 7.12 (m, 1H), 6.85 – 6.74 (m, 1H), 6.55 (dd, 1H), 4.99 – 4.87 (m, 1H), 4.42 – 4.28 (m, 2H), 4.12 – 4.00 (m, 2H), 3.88 – 3.72 (m, 1H), 3.45 – 3.30 (m, 2H), 3.15 – 3.00 (m, 2H), 2.97 – 2.65 (m, 5H), 2.28 – 1.95 (m, 9H).

LCMS m/z = 668.3 [M+1] + LCMS m/z = 668.3 [M+1] +

實施例23：化合物23的三氟乙酸鹽的製備 Example 23: Preparation of trifluoroacetate salt of compound 23

第一步： 23B的製備Step One: Preparation of 23B

將23A (2.8 g，10.02 mmol) (合成方法見WO2019074962)、3-乙炔基氮雜環丁烷-1-甲酸叔丁酯 (2.17 g，11.97 mmol)、TEA (3.04 g，30.04 mmol)、CuI (190 mg，1.00 mmol) 和PdCl 2(PPh 3) 2(700 mg，1.00 mmol)加入60 mL二氯甲烷，氮氣氛圍室溫反應18 h。向反應體系中加入150 mL水，用1 mol/L鹽酸調體系pH至2，用100 mL二氯甲烷萃取，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠柱色譜分離純化 (二氯甲烷/甲醇 (v/v) = 20:1)，得到23B (3.3 g，收率：99%)。 23A (2.8 g, 10.02 mmol) (see WO2019074962 for the synthesis method), tert-butyl 3-ethynylazetidine-1-carboxylate (2.17 g, 11.97 mmol), TEA (3.04 g, 30.04 mmol), CuI (190 mg, 1.00 mmol) and PdCl 2 (PPh 3 ) 2 (700 mg, 1.00 mmol) were added to 60 mL dichloromethane, and the reaction was carried out at room temperature in a nitrogen atmosphere for 18 h. Add 150 mL of water to the reaction system, adjust the pH of the system to 2 with 1 mol/L hydrochloric acid, extract with 100 mL of dichloromethane, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified by silica gel column chromatography (dichloromethane/ Methanol (v/v) = 20:1), obtaining 23B (3.3 g, yield: 99%).

LCMS m/z = 334.5 [M+1] +。 LCMS m/z = 334.5 [M+1] + .

第二步：23d的製備Step 2: Preparation of 23d

將23c (0.15 g，1.00 mmol) 與23B (0.40 g，1.20 mmol) 溶於15 mL DCM中，加入TCFH (0.42 g，1.50 mmol)，緩慢滴加N-甲基咪唑 (0.33 g，4.02 mmol)，室溫反應16 h。將反應體系減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 4:1)，得到23d (0.2 g，收率：43%)。Dissolve 23c (0.15 g, 1.00 mmol) and 23B (0.40 g, 1.20 mmol) in 15 mL DCM, add TCFH (0.42 g, 1.50 mmol), and slowly add N-methylimidazole (0.33 g, 4.02 mmol) dropwise. , react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 4:1) to obtain 23d (0.2 g, yield: 43%).

第三步： 23e的對甲苯磺酸鹽的製備Step 3: Preparation of p-toluenesulfonate salt of 23e

將23d (200 mg, 0.43 mmol) 溶於4 mL乙腈中，加入一水合對甲苯磺酸 (0.22 g，1.05 mmol)，室溫反應2 h。將反應液減壓濃縮，得粗品23e的對甲苯磺酸鹽 (0.44 g)。Dissolve 23d (200 mg, 0.43 mmol) in 4 mL acetonitrile, add p-toluenesulfonic acid monohydrate (0.22 g, 1.05 mmol), and react at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain crude product 23e p-toluenesulfonate (0.44 g).

LCMS m/z = 367.4 [M+1] + LCMS m/z = 367.4 [M+1] +

第四步：化合物23的三氟乙酸鹽的製備Step 4: Preparation of trifluoroacetate salt of compound 23

將上述粗品23e的對甲苯磺酸鹽 (0.44 g) 溶於5 mL DMSO中，加入DIPEA (0.34 g，2.63 mmol) 和2-(2,6-二氧代哌啶-3-基)-5-氟異吲哚啉-1,3-二酮 (0.12 g，0.43 mmol)，80℃反應3 h。將反應液冷卻至室溫，加入40 mL水，過濾，濾餅用10 mL水洗滌，將濾餅用50 mL DCM溶解，無水硫酸鈉乾燥，減壓濃縮後粗品過Pre-HPLC (儀器及製備柱：採用Glison GX-281製備液相，製備柱型號是Sunfire C18，5 μm，內徑×長度 = 30 mm×150 mm)。製備方法：粗品用甲醇和二甲亞碸溶解，並用0.45 μm濾膜過濾，製備成樣品液。流動相體系：乙腈/水 (含0.1% TFA)。梯度沖提方法：乙腈由5%梯度沖提60% (沖提時間15 min)，凍乾得到化合物23的三氟乙酸鹽 (0.05 g)。Dissolve the p-toluenesulfonate salt of the above crude product 23e (0.44 g) in 5 mL DMSO, add DIPEA (0.34 g, 2.63 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5 -Fluoroisoindoline-1,3-dione (0.12 g, 0.43 mmol), react at 80°C for 3 h. Cool the reaction solution to room temperature, add 40 mL of water, filter, wash the filter cake with 10 mL of water, dissolve the filter cake with 50 mL of DCM, dry over anhydrous sodium sulfate, concentrate under reduced pressure and pass the crude product through Pre-HPLC (Instrument and Preparation Column: Glison GX-281 was used to prepare the liquid phase. The column model was Sunfire C18, 5 μm, inner diameter × length = 30 mm × 150 mm). Preparation method: Dissolve the crude product with methanol and dimethyl sulfoxide, filter it with a 0.45 μm filter membrane, and prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA). Gradient elution method: Gradient elution from 5% acetonitrile to 60% (elution time 15 min), and freeze-drying to obtain the trifluoroacetate salt of compound 23 (0.05 g).

1H NMR (400 MHz, DMSO- d 6 ) δ 11.06 (s, 1H), 9.01 (s, 1H), 8.30 (s, 1H), 7.87 – 7.77 (m, 2H), 7.68 (d, 1H), 7.63 – 7.58 (m, 1H), 7.44 (dd, 1H), 6.90 – 6.84 (m, 1H), 6.71 (dd, 1H), 5.11 – 5.02 (m, 1H), 4.45 – 4.32 (m, 2H), 4.28 (s, 1H), 4.06 – 3.96 (m, 2H), 3.95 – 3.83 (m, 1H), 2.95 – 2.80 (m, 1H), 2.71 – 2.51 (m, 2H), 2.08 – 1.95 (m, 1H), 1.84 (s, 6H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.06 (s, 1H), 9.01 (s, 1H), 8.30 (s, 1H), 7.87 – 7.77 (m, 2H), 7.68 (d, 1H), 7.63 – 7.58 (m, 1H), 7.44 (dd, 1H), 6.90 – 6.84 (m, 1H), 6.71 (dd, 1H), 5.11 – 5.02 (m, 1H), 4.45 – 4.32 (m, 2H), 4.28 (s, 1H), 4.06 – 3.96 (m, 2H), 3.95 – 3.83 (m, 1H), 2.95 – 2.80 (m, 1H), 2.71 – 2.51 (m, 2H), 2.08 – 1.95 (m, 1H ), 1.84 (s, 6H).

LCMS m/z = 623.1 [M+1] + LCMS m/z = 623.1 [M+1] +

實施例24：化合物24的製備 Example 24: Preparation of Compound 24

以24b和2-(4-碘代-1H-吡唑-1-基)-2-甲基丙酸為原料，參考化合物18的製備方法，得到化合物24 (0.05 g).Using 24b and 2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropionic acid as raw materials and referring to the preparation method of compound 18, compound 24 (0.05 g) was obtained.

1H NMR (400 MHz, CDCl 3) δ 9.12 (s, 1H), 8.33 (d, 1H), 8.00 (s, 1H), 7.86 – 7.76 (m, 2H), 7.67 (d, 1H), 7.62 – 7.56 (m, 1H), 7.56 – 7.45 (m, 1H), 6.83 – 6.76 (m, 1H), 6.54 (dd, 1H), 4.98 – 4.87 (m, 1H), 4.40 – 4.30 (m, 2H), 4.10 – 4.00 (m, 2H), 3.86 – 3.72 (m, 1H), 2.95 – 2.64 (m, 3H), 2.18 – 2.08 (m, 1H), 1.97 (s, 6H), 1.69 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.12 (s, 1H), 8.33 (d, 1H), 8.00 (s, 1H), 7.86 – 7.76 (m, 2H), 7.67 (d, 1H), 7.62 – 7.56 (m, 1H), 7.56 – 7.45 (m, 1H), 6.83 – 6.76 (m, 1H), 6.54 (dd, 1H), 4.98 – 4.87 (m, 1H), 4.40 – 4.30 (m, 2H), 4.10 – 4.00 (m, 2H), 3.86 – 3.72 (m, 1H), 2.95 – 2.64 (m, 3H), 2.18 – 2.08 (m, 1H), 1.97 (s, 6H), 1.69 (s, 6H).

實施例25：化合物25的製備 Example 25: Preparation of Compound 25

第一步：25c的製備Step One: Preparation of 25c

將25b (1.5 g，5.10 mmol) 溶於20 mL四氫呋喃中，冷卻至-78℃，緩慢滴加LDA的四氫呋喃/正己烷 (v/v) = 12:25溶液 (2.0 mol/L) (3.05 mL，6.10 mmol)，-78℃反應30 min後，加入溴甲基環丙烷 (1.38 g，10.2 mmol)，升至室溫反應3 h。向反應液中加入40 mL飽和氯化鈉溶液洗滌，用60 mL乙酸乙酯萃取，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 5:1)，得到25c (288 mg，收率：16%)。Dissolve 25b (1.5 g, 5.10 mmol) in 20 mL tetrahydrofuran, cool to -78°C, slowly add LDA solution of tetrahydrofuran/n-hexane (v/v) = 12:25 (2.0 mol/L) (3.05 mL) dropwise , 6.10 mmol), reacted at -78°C for 30 min, then added bromomethylcyclopropane (1.38 g, 10.2 mmol), and raised to room temperature for 3 h. Add 40 mL saturated sodium chloride solution to the reaction solution for washing, extract with 60 mL ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v /v) = 5:1), obtaining 25c (288 mg, yield: 16%).

以25c和2-氯-4-(三氟甲基)苯胺為原料，參考實施例5得到化合物25(81mg)。Using 25c and 2-chloro-4-(trifluoromethyl)aniline as raw materials, compound 25 (81 mg) was obtained with reference to Example 5.

1H NMR (400 MHz, CDCl 3) δ 9.64 (s, 1H), 8.55 – 8.47 (m, 1H), 7.99 (s, 1H), 7.86 – 7.76 (m, 2H), 7.71 – 7.63 (m, 1H), 7.62 – 7.57 (m, 1H), 7.53 – 7.45 (m, 1H), 6.84 – 6.78 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.44 – 4.30 (m, 2H), 4.15 – 4.00 (m, 2H), 3.88 – 3.75 (m, 1H), 2.96 – 2.64 (m, 3H), 2.50 – 2.35 (m, 1H), 2.20 – 2.05 (m, 2H), 2.00 (s, 3H), 0.60 – 0.30 (m, 3H), 0.20 – 0.07 (m, 1H), 0.02 – -0.10 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.64 (s, 1H), 8.55 – 8.47 (m, 1H), 7.99 (s, 1H), 7.86 – 7.76 (m, 2H), 7.71 – 7.63 (m, 1H) ), 7.62 – 7.57 (m, 1H), 7.53 – 7.45 (m, 1H), 6.84 – 6.78 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.44 – 4.30 (m , 2H), 4.15 – 4.00 (m, 2H), 3.88 – 3.75 (m, 1H), 2.96 – 2.64 (m, 3H), 2.50 – 2.35 (m, 1H), 2.20 – 2.05 (m, 2H), 2.00 (s, 3H), 0.60 – 0.30 (m, 3H), 0.20 – 0.07 (m, 1H), 0.02 – -0.10 (m, 1H).

LCMS m/z = 707.6 [M+1] + LCMS m/z = 707.6 [M+1] +

實施例26：製備化合物26的三氟乙酸鹽 Example 26: Preparation of trifluoroacetate salt of compound 26

第一步：26c的製備Step One: Preparation of 26c

將60%氫化鈉 (2.45 g) 加入到300 mL DMSO中，冷卻至0℃，將40 mL叔丁基((1,3-二溴丙-2-基)氧基)二苯基矽烷 (20.4 g，44.7 mmol) (合成方法見WO2013173720) 和26b (10.5 g，34.08 mmol) 的DMSO溶液滴加到上述溶液中，室溫反應12 h。向反應體系中加入1 L純化水，用300 mL乙酸乙酯萃取，分離出有機相，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚:乙酸乙酯 (v/v) =4:1)，得26c (3.5 g，收率：17%)。Add 60% sodium hydride (2.45 g) to 300 mL DMSO, cool to 0°C, and add 40 mL tert-butyl ((1,3-dibromoprop-2-yl)oxy)diphenylsilane (20.4 g, 44.7 mmol) (see WO2013173720 for the synthesis method) and DMSO solution of 26b (10.5 g, 34.08 mmol) were added dropwise to the above solution and reacted at room temperature for 12 h. Add 1 L of purified water to the reaction system, extract with 300 mL of ethyl acetate, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) ) =4:1), 26c (3.5 g, yield: 17%) was obtained.

LCMS m/z = 603.2 [M+1] +。 LCMS m/z = 603.2 [M+1] + .

第二步：26d的製備Step 2: Preparation of 26d

將26c (3.5 g, 5.81 mmol) 加入60 mL二氯甲烷中，加入20 mL三氟乙酸，室溫反應3 h。將反應液減壓濃縮，加入100 mL二氯甲烷，用飽和碳酸鈉水溶液調pH至9，再用2 mol/L鹽酸調pH至5，分離出有機相，無水硫酸鈉乾燥，減壓濃縮，得粗品 (2.5 g)。將上述粗品 (2.5 g) 與2-氯-4-(三氟甲基)苯胺 (0.88 g，4.5 mmol) 溶於100 mL DCM中，加入TCFH (1.96 g，7.0 mmol)，緩慢滴加N-甲基咪唑 (1.5 g，18.27 mmol)，室溫反應16 h。將反應體系減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 4:1)，得到26d (2.3 g，收率：71%)。Add 26c (3.5 g, 5.81 mmol) to 60 mL dichloromethane, add 20 mL trifluoroacetic acid, and react at room temperature for 3 h. Concentrate the reaction solution under reduced pressure, add 100 mL of dichloromethane, adjust the pH to 9 with saturated aqueous sodium carbonate solution, and then adjust the pH to 5 with 2 mol/L hydrochloric acid. Separate the organic phase, dry it over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain crude product (2.5 g). Dissolve the above crude product (2.5 g) and 2-chloro-4-(trifluoromethyl)aniline (0.88 g, 4.5 mmol) in 100 mL DCM, add TCFH (1.96 g, 7.0 mmol), and slowly add N- Methylimidazole (1.5 g, 18.27 mmol), react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 4:1) to obtain 26d (2.3 g, yield: 71%).

第三步：26e的製備Step 3: Preparation of 26e

將26d (2.3 g，3.2 mmol) 溶於60 mL THF中，加入TBAF (2.6 g，9.94 mmol)，回流反應5 h。將反應體系冷卻至室溫，減壓濃縮，向殘留物中加入50 mL乙酸乙酯，有機相用100 mL純化水洗滌，無水硫酸鈉乾燥，減壓濃縮，得26e (0.6 g，收率：39.0%)。Dissolve 26d (2.3 g, 3.2 mmol) in 60 mL THF, add TBAF (2.6 g, 9.94 mmol), and reflux for 5 h. The reaction system was cooled to room temperature, concentrated under reduced pressure, 50 mL of ethyl acetate was added to the residue, the organic phase was washed with 100 mL of purified water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 26e (0.6 g, yield: 39.0%).

LCMS m/z = 485.9 [M+1] +。 LCMS m/z = 485.9 [M+1] + .

第四步：化合物26的三氟乙酸鹽的製備Step 4: Preparation of trifluoroacetate salt of compound 26

將26e (0.1 g，0.21 mmol)、中間體1 (0.1 g，0.3 mmol)、TEA (0.1 g，1.0 mmol)、CuI (3.6 mg，0.019 mmol) 和PdCl 2(PPh 3) 2(14 mg，0.02 mmol)加入5 mL DMF，氮氣氛圍60℃反應3 h。將反應液冷卻至室溫，過濾，將反應液過Pre-HPLC (儀器及製備柱：採用Glison GX-281製備液相，製備柱型號是Sunfire C18，5 μm，內徑×長度 = 30 mm×150 mm)。製備方法：粗品用甲醇和二甲亞碸溶解，並用0.45 μm濾膜過濾，製備成樣品液。流動相體系：乙腈/水 (含0.1% TFA)。梯度沖提方法：乙腈由5%梯度沖提60% (沖提時間15 min)，凍乾得化合物26的三氟乙酸鹽 (0.08 g)。 26e (0.1 g, 0.21 mmol), Intermediate 1 (0.1 g, 0.3 mmol), TEA (0.1 g, 1.0 mmol), CuI (3.6 mg, 0.019 mmol) and PdCl 2 (PPh 3 ) 2 (14 mg, 0.02 mmol), 5 mL DMF was added, and the reaction was carried out at 60°C for 3 h in a nitrogen atmosphere. Cool the reaction solution to room temperature, filter, and pass the reaction solution through Pre-HPLC (instrument and preparation column: Glison GX-281 is used to prepare the liquid phase, and the preparation column model is Sunfire C18, 5 μm, inner diameter × length = 30 mm × 150 mm). Preparation method: Dissolve the crude product with methanol and dimethyl sulfoxide, filter it with a 0.45 μm filter membrane, and prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA). Gradient elution method: Gradient elute from 5% to 60% acetonitrile (elution time: 15 min), and freeze-dry to obtain the trifluoroacetate salt of compound 26 (0.08 g).

1H NMR (400 MHz, DMSO- d 6 ) δ 11.06 (s, 1H), 9.05 – 8.91 (m, 1H), 8.48 – 8.27 (m, 1H), 8.23 – 8.12 (m, 1H), 7.94 – 7.84 (m, 2H), 7.78 – 7.64 (m, 2H), 6.90 – 6.83 (m, 1H), 6.76 – 6.67 (m, 1H), 5.11 – 5.01 (m, 1H), 4.45 – 4.32 (m, 2H), 4.28 – 4.07 (m, 1H), 4.05 – 3.95 (m, 2H), 3.95 – 3.83 (m, 1H), 3.28 – 3.05 (m, 2H), 2.97 – 2.70 (m, 2H), 2.65 – 2.51 (m, 3H), 2.08 – 1.95 (m, 1H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.06 (s, 1H), 9.05 – 8.91 (m, 1H), 8.48 – 8.27 (m, 1H), 8.23 – 8.12 (m, 1H), 7.94 – 7.84 (m, 2H), 7.78 – 7.64 (m, 2H), 6.90 – 6.83 (m, 1H), 6.76 – 6.67 (m, 1H), 5.11 – 5.01 (m, 1H), 4.45 – 4.32 (m, 2H) , 4.28 – 4.07 (m, 1H), 4.05 – 3.95 (m, 2H), 3.95 – 3.83 (m, 1H), 3.28 – 3.05 (m, 2H), 2.97 – 2.70 (m, 2H), 2.65 – 2.51 ( m, 3H), 2.08 – 1.95 (m, 1H).

LCMS m/z = 695.2 [M+1] + LCMS m/z = 695.2 [M+1] +

實施例27：化合物27的三氟乙酸鹽的製備 Example 27: Preparation of trifluoroacetate salt of compound 27

第一步：27b的製備Step One: Preparation of 27b

將27a (2.7 g，10 mmol)、(E)-2-(2-乙氧基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷 (3.0 g，15.15 mmol)、Pd(dppf)Cl 2(725.7 mg，1.0 mmol) 和CsF (4.6 g，30.28 mmol)加入80 mL 1,4-二氧六環和20 mL水中，85℃反應12 h。將反應體系冷卻至室溫，減壓濃縮，加入100 mL乙酸乙酯，用100 mL純化水洗滌，分離出有機相，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚:乙酸乙酯 (v/v) = 10:1)，得27b (2.3 g，收率：88%)。 27a (2.7 g, 10 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxolabor Alkane (3.0 g, 15.15 mmol), Pd(dppf)Cl 2 (725.7 mg, 1.0 mmol) and CsF (4.6 g, 30.28 mmol) were added to 80 mL 1,4-dioxane and 20 mL water, and the reaction was carried out at 85°C. 12h. Cool the reaction system to room temperature, concentrate under reduced pressure, add 100 mL of ethyl acetate, wash with 100 mL of purified water, separate the organic phase, dry the organic phase over anhydrous sodium sulfate, concentrate under reduced pressure, and use a silica gel chromatography column to separate and purify the crude product. (Petroleum ether: ethyl acetate (v/v) = 10:1), 27b (2.3 g, yield: 88%) was obtained.

第二步：27c的製備Step 2: Preparation of 27c

將27b (2.3 g，8.81 mmol) 加入50 mL四氫呋喃中，加入4 mL濃鹽酸，室溫反應16 h。將反應液減壓濃縮，加入100 mL二氯甲烷，用飽和碳酸鈉水溶液調pH至10，分離出有機相，無水硫酸鈉乾燥，減壓濃縮，得粗品27c (1.5 g)。Add 27b (2.3 g, 8.81 mmol) to 50 mL tetrahydrofuran, add 4 mL concentrated hydrochloric acid, and react at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, 100 mL of dichloromethane was added, and the pH was adjusted to 10 with saturated aqueous sodium carbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 27c (1.5 g).

第三步：27d的製備Step 3: Preparation of 27d

將上述粗品27c (1.5 g) 溶於30 mL甲醇中，加入碳酸鉀 (2.0 g，14.47 mmol)，冷卻至0℃，滴入(1-重氮基-2-氧代丙基)膦酸二甲酯 (1.93 g，10 mmol)，置換氮氣三次，室溫反應16 h。將反應體系減壓濃縮，加入100 mL乙酸乙酯，用100 mL水洗滌，分離出有機相，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚:乙酸乙酯 (v/v) = 4:1)，得27d (0.47 g，從化合物27b算兩步收率：23%)。The above crude product 27c (1.5 g) was dissolved in 30 mL methanol, potassium carbonate (2.0 g, 14.47 mmol) was added, cooled to 0°C, and (1-diazo-2-oxopropyl)phosphonic acid diphosphate was added dropwise. Methyl ester (1.93 g, 10 mmol), replaced with nitrogen three times, and reacted at room temperature for 16 h. The reaction system was concentrated under reduced pressure, 100 mL of ethyl acetate was added, washed with 100 mL of water, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v /v) = 4:1), to obtain 27d (0.47 g, two-step yield calculated from compound 27b: 23%).

第四步：27e的製備Step 4: Preparation of 27e

將27d (0.47 g，2.05 mmol) 加入到8 mL乙醇中，加入還原鐵粉 (0.56 g，10 mmol) 和2 mL飽和氯化銨水溶液，回流反應2 h。將反應體系冷卻至室溫，減壓濃縮，加入40 mL乙酸乙酯，用40 mL水洗滌，分離出有機相，無水硫酸鈉乾燥，減壓濃縮，得粗品27e (0.36 g)。Add 27d (0.47 g, 2.05 mmol) to 8 mL of ethanol, add reduced iron powder (0.56 g, 10 mmol) and 2 mL of saturated aqueous ammonium chloride solution, and reflux for 2 h. The reaction system was cooled to room temperature, concentrated under reduced pressure, 40 mL of ethyl acetate was added, washed with 40 mL of water, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 27e (0.36 g).

LCMS m/z = 200.1 [M+1] + LCMS m/z = 200.1 [M+1] +

化合物27的三氟乙酸鹽以化合物27e+23B為原料，參考實施例23製備方法，經酸性製備[流動相體系：乙腈/水 (含0.1% TFA)]，凍乾得到化合物27的三氟乙酸鹽(50mg)。The trifluoroacetic acid salt of compound 27 was prepared using compound 27e+23B as raw materials. Referring to the preparation method of Example 23, it was prepared through acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and then lyophilized to obtain the trifluoroacetic acid salt of compound 27. Salt (50mg).

1H NMR (400 MHz, CDCl 3) δ 8.83 (s, 1H), 8.47 (d, 1H), 8.09 (s, 1H), 7.81 (s, 1H), 7.75 (s, 1H), 7.67 (d, 1H), 7.59 – 7.43 (m, 2H), 6.83 – 6.78 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.90 (m, 1H), 4.42 – 4.30 (m, 2H), 4.11 – 4.00 (m, 2H), 3.88 – 3.75 (m, 1H), 2.98 – 2.65 (m, 3H), 2.18 – 2.08 (m, 4H), 1.94 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.83 (s, 1H), 8.47 (d, 1H), 8.09 (s, 1H), 7.81 (s, 1H), 7.75 (s, 1H), 7.67 (d, 1H), 7.59 – 7.43 (m, 2H), 6.83 – 6.78 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.90 (m, 1H), 4.42 – 4.30 (m, 2H), 4.11 – 4.00 ( m, 2H), 3.88 – 3.75 (m, 1H), 2.98 – 2.65 (m, 3H), 2.18 – 2.08 (m, 4H), 1.94 (s, 6H).

實施例28：化合物28的製備 Example 28: Preparation of Compound 28

第一步：28B的製備Step One: Preparation of 28B

向反應瓶中分別加入28A (5.00 g, 24.15 mmol)、2 mol/L氫氧化鈉水溶液 (25 mL) 和25 mL乙醇，室溫攪拌2 h。將反應液冷卻至0℃，加入1 mol/L鹽酸調pH值至2，用乙酸乙酯萃取 (50 mL×3)，有機相用20 mL飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，得到粗品 (4.6 g)。向上述粗品 (4.6 g) 加入1-氯-N,N,2-三甲基丙烯胺 (5.14 g, 38.55 mmol) 和DCM (100 mL)，室溫攪拌1 h後，加入TEA (10.67 mL, 76.55 mmol) 和2-氯-4-三氟甲基苯胺 (5.02 g, 25.67 mmol)，室溫反應16 h。將反應液減壓濃縮，粗品用矽膠色譜柱分離純化 (乙酸乙酯/石油醚 (v/v) = 1:5)，得到28B (6.05 g，收率：70%)。Add 28A (5.00 g, 24.15 mmol), 2 mol/L sodium hydroxide aqueous solution (25 mL) and 25 mL ethanol to the reaction flask respectively, and stir at room temperature for 2 h. Cool the reaction solution to 0°C, add 1 mol/L hydrochloric acid to adjust the pH to 2, extract with ethyl acetate (50 mL×3), wash the organic phase with 20 mL saturated sodium chloride solution, dry over anhydrous sodium sulfate, and reduce Concentrate under pressure to obtain crude product (4.6 g). To the above crude product (4.6 g), 1-chloro-N,N,2-trimethylpropenylamine (5.14 g, 38.55 mmol) and DCM (100 mL) were added. After stirring at room temperature for 1 h, TEA (10.67 mL, 76.55 mmol) and 2-chloro-4-trifluoromethylaniline (5.02 g, 25.67 mmol) at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v) = 1:5) to obtain 28B (6.05 g, yield: 70%).

第二步：28b的製備Step 2: Preparation of 28b

將28a (5.0 g，39.64 mmol) 溶於25 mL三氟乙酸中，加入N-碘代丁二醯亞胺 (9.82 g，43.65 mmol)，室溫反應16 h。將反應體系減壓濃縮，將殘留物緩慢滴加到100 mL飽和碳酸氫鈉水溶液中，析出產物，過濾，收集濾餅，濾餅用20 mL水洗滌，減壓乾燥，得粗品28b (4.0 g，收率：40%)。Dissolve 28a (5.0 g, 39.64 mmol) in 25 mL trifluoroacetic acid, add N-iodosuccinimide (9.82 g, 43.65 mmol), and react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the residue was slowly added dropwise to 100 mL of saturated aqueous sodium bicarbonate solution to precipitate the product, filtered, and the filter cake was collected. The filter cake was washed with 20 mL of water and dried under reduced pressure to obtain crude product 28b (4.0 g , Yield: 40%).

LCMS m/z = 252.9 [M+1] + LCMS m/z = 252.9 [M+1] +

第三步：28c的製備Step 3: Preparation of 28c

將上述粗品28b (1.0 g) 與28B (1.7 g，4.77 mmol) 溶於25 mL 乙腈中，加入碳酸銫 (2.59 g，7.95 mmol)，50℃反應6 h。將反應體系冷卻至室溫，過濾，將濾液減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚/乙酸乙酯 (v/v) = 5:1)，得28c (350 mg，收率：14%)。Dissolve the above crude products 28b (1.0 g) and 28B (1.7 g, 4.77 mmol) in 25 mL acetonitrile, add cesium carbonate (2.59 g, 7.95 mmol), and react at 50°C for 6 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 5:1) to obtain 28c (350 mg, yield: 14%).

LCMS m/z = 528.4 [M+1] + LCMS m/z = 528.4 [M+1] +

第四步：28d的製備Step 4: Preparation of 28d

將28c (110 mg，0.21 mmol) 溶於3 mL DMF中，加入3-乙炔基氮雜環丁烷-1-甲酸叔丁酯 (57 mg, 0.31 mmol) 和TEA (64 mg, 0.63 mmol)、CuI (5 mg, 0.026 mmol) 和PdCl 2(PPh 3) 2(15 mg，0.021 mmol)，置換氮氣三次，50℃反應2 h。將反應液冷卻至室溫，加入10 mL水，用30 mL乙酸乙酯萃取，有機相用20 mL水洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚/乙酸乙酯 (v/v) = 3:1)，得粗品28d (0.12 g)。 Dissolve 28c (110 mg, 0.21 mmol) in 3 mL DMF, add 3-ethynylazetidine-1-carboxylic acid tert-butyl ester (57 mg, 0.31 mmol) and TEA (64 mg, 0.63 mmol), CuI (5 mg, 0.026 mmol) and PdCl 2 (PPh 3 ) 2 (15 mg, 0.021 mmol) were replaced with nitrogen three times and reacted at 50°C for 2 h. Cool the reaction solution to room temperature, add 10 mL of water, and extract with 30 mL of ethyl acetate. The organic phase is washed with 20 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether/acetic acid). Ethyl ester (v/v) = 3:1) to obtain crude product 28d (0.12 g).

第五步：28e的製備Step 5: Preparation of 28e

將粗品28d (120 mg) 溶於5 mL四氫呋喃與1 mL水中，加入一水合氫氧化鋰 (27 mg，0.64 mmol)，室溫反應3 h。將反應體系用2 mol/L鹽酸調pH至3，用50 mL DCM萃取，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (二氯甲烷/甲醇 (v/v) = 15:1)，得粗品28e (0.12 g)。Dissolve crude product 28d (120 mg) in 5 mL tetrahydrofuran and 1 mL water, add lithium hydroxide monohydrate (27 mg, 0.64 mmol), and react at room temperature for 3 h. Adjust the pH of the reaction system to 3 with 2 mol/L hydrochloric acid, extract with 50 mL DCM, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (dichloromethane/methanol (v/v) = 15:1), and the crude product 28e (0.12 g) was obtained.

第六步：28f的對甲苯磺酸鹽的製備Step 6: Preparation of 28f p-toluenesulfonate

將粗品28e (120 mg) 溶於4 mL 乙腈中，加入一水合對甲苯磺酸 (0.16 g，0.84 mmol)，室溫反應2 h。將反應液減壓濃縮，得粗品28f的對甲苯磺酸鹽 (300 mg)。Dissolve crude product 28e (120 mg) in 4 mL acetonitrile, add p-toluenesulfonic acid monohydrate (0.16 g, 0.84 mmol), and react at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain crude product 28f p-toluenesulfonate (300 mg).

LCMS m/z = 467.1 [M+1] + LCMS m/z = 467.1 [M+1] +

第七步：化合物28的製備Step 7: Preparation of compound 28

將粗品28f的對甲苯磺酸鹽 (300 mg) 溶於5 mL DMSO中，加入0.25 mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟異吲哚啉-1,3-二酮(100 mg，0.36 mmol)，80℃反應3 h。將反應液冷卻至室溫，加入50 mL水，過濾，收集濾餅，濾餅用10 mL水洗滌，將濾餅用30 mL DCM溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (二氯甲烷/甲醇 (v/v) = 15:1)，得化合物28 (15 mg，收率：6%)。Dissolve crude 28f p-toluenesulfonate (300 mg) in 5 mL DMSO, add 0.25 mL DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline -1,3-dione (100 mg, 0.36 mmol), react at 80°C for 3 hours. Cool the reaction solution to room temperature, add 50 mL of water, filter, collect the filter cake, wash the filter cake with 10 mL of water, dissolve the filter cake with 30 mL of DCM, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use the crude product with a silica gel chromatography column After separation and purification (dichloromethane/methanol (v/v) = 15:1), compound 28 (15 mg, yield: 6%) was obtained.

1H NMR (400 MHz, DMSO- d 6 ) δ 11.06 (s, 1H), 9.57 (s, 1H), 8.45 (s, 1H), 7.98 – 7.87 (m, 2H), 7.78 – 7.65 (m, 2H), 6.92 – 6.87 (m, 1H), 6.80 – 6.71 (m, 2H), 5.11 – 5.02 (m, 1H), 4.43 – 4.30 (m, 2H), 4.24 – 4.12 (m, 2H), 4.08 – 3.96 (m, 1H), 3.12 – 2.97 (m, 2H), 2.97 – 2.80 (m, 3H), 2.72 – 2.50 (m, 2H), 2.10 – 1.95 (m, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.06 (s, 1H), 9.57 (s, 1H), 8.45 (s, 1H), 7.98 – 7.87 (m, 2H), 7.78 – 7.65 (m, 2H ), 6.92 – 6.87 (m, 1H), 6.80 – 6.71 (m, 2H), 5.11 – 5.02 (m, 1H), 4.43 – 4.30 (m, 2H), 4.24 – 4.12 (m, 2H), 4.08 – 3.96 (m, 1H), 3.12 – 2.97 (m, 2H), 2.97 – 2.80 (m, 3H), 2.72 – 2.50 (m, 2H), 2.10 – 1.95 (m, 3H).

實施例29：化合物29的製備 Example 29: Preparation of Compound 29

第一步：29b的製備Step 1: Preparation of 29b

將29a (2 g，7.63 mmol)加入40 mL乙腈，依次加入2-溴-2-甲基丙酸甲酯 (1.5 g，8.29 mmol) 和碳酸銫 (4.9 g，15.04 mmol)，90℃反應16 h。將反應體系冷卻至室溫，過濾，將濾液減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 17:3)，得29b (2.7 g，收率：98%)。Add 29a (2 g, 7.63 mmol) to 40 mL acetonitrile, then add methyl 2-bromo-2-methylpropionate (1.5 g, 8.29 mmol) and cesium carbonate (4.9 g, 15.04 mmol), and react at 90°C for 16 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 17:3) to obtain 29b (2.7 g, yield: 98%).

1H NMR (400 MHz, CDCl 3) δ 7.70 – 7.66 (m, 1H), 3.73 (s, 3H), 1.86 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.70 – 7.66 (m, 1H), 3.73 (s, 3H), 1.86 (s, 6H).

第二步：29c的製備Step 2: Preparation of 29c

將29b (2.7 g，7.46 mmol) 溶於40 mL四氫呋喃中，加入10 mL水，冷卻至0℃，加入一水合氫氧化鋰 (1.5 g，35.75 mmol)，室溫反應2 h。將反應體系用0.5 mol/L鹽酸調pH至4，用乙酸乙酯萃取 (80 mL×3)，有機相用飽和氯化鈉水溶液洗滌 (80 mL×2)，無水硫酸鈉乾燥，減壓濃縮，得粗品 (2.1 g)。將上述粗品 (200 mg) 加入到50 mL單口瓶中，加入15 mL二氯甲烷，加入1-氯-N,N,2-三甲基丙烯胺 (115 mg，0.86 mmol)，室溫反應1 h後，依次加入三乙胺 (172 mg，1.70 mmol) 和16B (90 mg，0.57 mmol)，室溫反應1 h。將反應體系減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 91:9)，得29c (190 mg，收率：68%)。Dissolve 29b (2.7 g, 7.46 mmol) in 40 mL tetrahydrofuran, add 10 mL water, cool to 0°C, add lithium hydroxide monohydrate (1.5 g, 35.75 mmol), and react at room temperature for 2 h. Adjust the pH of the reaction system to 4 with 0.5 mol/L hydrochloric acid, extract with ethyl acetate (80 mL×3), wash the organic phase with saturated aqueous sodium chloride solution (80 mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure , to obtain crude product (2.1 g). Add the above crude product (200 mg) to a 50 mL single-neck bottle, add 15 mL dichloromethane, add 1-chloro-N,N,2-trimethylpropenylamine (115 mg, 0.86 mmol), and react at room temperature 1 After h, triethylamine (172 mg, 1.70 mmol) and 16B (90 mg, 0.57 mmol) were added successively, and the reaction was carried out at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 91:9) to obtain 29c (190 mg, yield: 68%).

LCMS m/z = 489.1 [M+1] + LCMS m/z = 489.1 [M+1] +

第三步；化合物29的製備Step 3: Preparation of compound 29

將29c (90 mg，0.18 mmol)加入10 mL DMF，加入粗品中間體1 (93 mg) 和三乙胺 (55 mg，0.54 mmol)、PdCl 2(PPh 3) 2(13 mg，0.019 mmol) 和CuI (7 mg，0.037 mmol)，置換氮氣三次，50℃反應2 h。將反應體系冷卻至室溫，緩慢加入10 mL飽和氯化銨水溶液，用乙酸乙酯萃取 (50 mL×3)，有機相用飽和氯化鈉水溶液洗滌 (50 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 22:78)，得化合物29 (52 mg，收率：41%)。 Add 29c (90 mg, 0.18 mmol) to 10 mL DMF, add crude intermediate 1 (93 mg) and triethylamine (55 mg, 0.54 mmol), PdCl 2 (PPh 3 ) 2 (13 mg, 0.019 mmol) and CuI (7 mg, 0.037 mmol), replaced with nitrogen three times, and reacted at 50°C for 2 h. Cool the reaction system to room temperature, slowly add 10 mL of saturated aqueous ammonium chloride solution, extract with ethyl acetate (50 mL×3), wash the organic phase with saturated aqueous sodium chloride solution (50 mL×2), and dry over anhydrous sodium sulfate. , concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 22:78) to obtain compound 29 (52 mg, yield: 41%).

1H NMR (400 MHz, CDCl 3) δ 8.89 (s, 1H), 8.36 (d, 1H), 7.96 – 7.82 (m, 2H), 7.74 – 7.63 (m, 1H), 7.54 – 7.46 (m, 1H), 7.42 – 7.35 (m, 1H), 6.83 – 6.78 (m, 1H), 6.56 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.43 – 4.30 (m, 2H), 4.13 – 3.97 (m, 2H), 3.90 – 3.75 (m, 1H), 2.98 – 2.64 (m, 3H), 2.18 – 2.07 (m, 1H), 1.99 (s, 6H), 1.59 – 1.46 (m, 1H), 1.06 – 0.98 (m, 2H), 0.62 – 0.55 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.89 (s, 1H), 8.36 (d, 1H), 7.96 – 7.82 (m, 2H), 7.74 – 7.63 (m, 1H), 7.54 – 7.46 (m, 1H ), 7.42 – 7.35 (m, 1H), 6.83 – 6.78 (m, 1H), 6.56 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.43 – 4.30 (m, 2H), 4.13 – 3.97 (m , 2H), 3.90 – 3.75 (m, 1H), 2.98 – 2.64 (m, 3H), 2.18 – 2.07 (m, 1H), 1.99 (s, 6H), 1.59 – 1.46 (m, 1H), 1.06 – 0.98 (m, 2H), 0.62 – 0.55 (m, 2H).

實施例30：化合物30的製備 Example 30: Preparation of Compound 30

化合物30以29b與17B為原料，參考實施例29得到化合物30(60mg)。Compound 30 was prepared by using 29b and 17B as raw materials and referring to Example 29 to obtain compound 30 (60 mg).

1H NMR (400 MHz, CDCl 3) δ 8.49 (s, 1H), 8.40 (d, 1H), 7.96 (s, 1H), 7.88 – 7.82 (m, 1H), 7.68 (d, 1H), 7.61 – 7.56 (m, 1H), 7.53 – 7.46 (m, 1H), 6.84 – 6.78 (m, 1H), 6.56 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.10 – 4.00 (m, 2H), 3.88 – 3.75 (m, 1H), 2.97 – 2.65 (m, 3H), 2.18 – 2.07 (m, 4H), 1.97 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.49 (s, 1H), 8.40 (d, 1H), 7.96 (s, 1H), 7.88 – 7.82 (m, 1H), 7.68 (d, 1H), 7.61 – 7.56 (m, 1H), 7.53 – 7.46 (m, 1H), 6.84 – 6.78 (m, 1H), 6.56 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.10 – 4.00 (m, 2H), 3.88 – 3.75 (m, 1H), 2.97 – 2.65 (m, 3H), 2.18 – 2.07 (m, 4H), 1.97 (s, 6H).

實施例31：化合物31的製備 Example 31: Preparation of Compound 31

第一步：31b的製備Step One: Preparation of 31b

將 (甲氧基甲基)三苯基氯化膦 (1.65g，4.81 mmol) 加入到反應瓶中，在氮氣保護下加入30 mL無水四氫呋喃，冷卻至0℃，加入叔丁醇鉀 (0.57 g，5.08 mmol)，0℃攪拌0.5 h後，加入31a (0.5 g，3.21 mmol)，室溫反應19 h。向反應液中加入70 mL水，用乙酸乙酯萃取 (80 mL×3)，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 10:1-5:1)，得31b (0.12 g，收率：20%)。Add (methoxymethyl)triphenylphosphine chloride (1.65g, 4.81 mmol) into the reaction flask, add 30 mL anhydrous tetrahydrofuran under nitrogen protection, cool to 0°C, and add potassium tert-butoxide (0.57 g , 5.08 mmol), stirred at 0°C for 0.5 h, then added 31a (0.5 g, 3.21 mmol), and reacted at room temperature for 19 h. Add 70 mL of water to the reaction solution, extract with ethyl acetate (80 mL v) = 10:1-5:1), get 31b (0.12 g, yield: 20%).

LCMS m/z = 184.1 [M+1] + LCMS m/z = 184.1 [M+1] +

第二步：31c的製備Step 2: Preparation of 31c

將31b (0.11 g，0.60 mmol) 溶於3 mL THF中，加入3 mL 6 mol/L鹽酸，室溫反應2 h。向反應液中加入10 mL水，用飽和碳酸氫鈉水溶液調pH至7，用20 mL乙酸乙酯萃取，分離出有機相，無水硫酸鈉乾燥，減壓濃縮，得到粗品31c (0.11 g)。Dissolve 31b (0.11 g, 0.60 mmol) in 3 mL THF, add 3 mL 6 mol/L hydrochloric acid, and react at room temperature for 2 h. Add 10 mL of water to the reaction solution, adjust the pH to 7 with saturated sodium bicarbonate aqueous solution, extract with 20 mL of ethyl acetate, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product 31c (0.11 g).

化合物31以化合物31c為原料，參考實施例22得到化合物31(5mg)。Compound 31 Compound 31 (5 mg) was obtained by referring to Example 22 using compound 31c as a raw material.

1H NMR (400 MHz, CDCl 3) δ 8.37 – 8.22 (m, 2H), 7.80 – 7.42 (m, 4H), 7.22 – 7.17 (m, 1H), 7.13 – 7.05 (m, 1H), 6.85 – 6.77 (m, 1H), 6.64 – 6.52 (m, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.00 (m, 2H), 3.88 – 3.75 (m, 1H), 3.13 – 2.67 (m, 9H), 2.59 (s, 6H), 2.30 – 1.96 (m, 5H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.37 – 8.22 (m, 2H), 7.80 – 7.42 (m, 4H), 7.22 – 7.17 (m, 1H), 7.13 – 7.05 (m, 1H), 6.85 – 6.77 (m, 1H), 6.64 – 6.52 (m, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.00 (m, 2H), 3.88 – 3.75 (m, 1H) , 3.13 – 2.67 (m, 9H), 2.59 (s, 6H), 2.30 – 1.96 (m, 5H).

LCMS m/z = 682.2 [M+1] + LCMS m/z = 682.2 [M+1] +

實施例32：化合物32的製備 Example 32: Preparation of Compound 32

以化合物32b為原料，參考實施例19得到化合物32(60mg)。 Using compound 32b as a raw material, compound 32 (60 mg) was obtained with reference to Example 19.

1H NMR (400 MHz, CDCl 3) δ 8.89 (s, 1H), 8.46 (d, 1H), 8.05 (s, 1H), 7.80 (s, 1H), 7.72 (s, 1H), 7.67 (d, 1H), 7.60 – 7.56 (m, 1H), 7.51 – 7.45 (m, 1H), 6.83 – 6.79 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.44 – 4.30 (m, 2H), 4.10 – 3.97 (m, 2H), 3.88 – 3.75 (m, 1H), 2.96 – 2.64 (m, 3H), 2.52 (q, 2H), 2.18 – 2.08 (m, 1H), 1.94 (s, 6H), 1.29 (t, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.89 (s, 1H), 8.46 (d, 1H), 8.05 (s, 1H), 7.80 (s, 1H), 7.72 (s, 1H), 7.67 (d, 1H), 7.60 – 7.56 (m, 1H), 7.51 – 7.45 (m, 1H), 6.83 – 6.79 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.44 – 4.30 ( m, 2H), 4.10 – 3.97 (m, 2H), 3.88 – 3.75 (m, 1H), 2.96 – 2.64 (m, 3H), 2.52 (q, 2H), 2.18 – 2.08 (m, 1H), 1.94 ( s, 6H), 1.29 (t, 3H).

實施例33：化合物33的製備 Example 33: Preparation of Compound 33

以33b為原料，參考實施例19得到化合物33(11mg)。Using 33b as a raw material, compound 33 (11 mg) was obtained with reference to Example 19.

1H NMR (400 MHz, CDCl 3) δ 8.87 (s, 1H), 8.49 (d, 1H), 8.03 – 7.95 (m, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.70 – 7.59 (m, 2H), 7.56 – 7.48 (m, 1H), 6.83 – 6.76 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.42 – 4.28 (m, 2H), 4.12 – 3.99 (m, 2H), 3.88 – 3.75 (m, 1H), 3.59 (s, 2H), 2.95 – 2.65 (m, 3H), 2.39 (s, 6H), 2.18 – 2.08 (m, 1H), 1.94 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.87 (s, 1H), 8.49 (d, 1H), 8.03 – 7.95 (m, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.70 – 7.59 (m, 2H), 7.56 – 7.48 (m, 1H), 6.83 – 6.76 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.42 – 4.28 (m, 2H), 4.12 – 3.99 (m, 2H), 3.88 – 3.75 (m, 1H), 3.59 (s, 2H), 2.95 – 2.65 (m, 3H), 2.39 (s, 6H), 2.18 – 2.08 (m, 1H), 1.94 (s, 6H).

LCMS m/z = 714.2 [M+1] + LCMS m/z = 714.2 [M+1] +

實施例34：化合物34的製備 Example 34: Preparation of Compound 34

以化合物34a+2-溴-2-甲基丙酸甲酯為原料，參考實施例29得到化合物34(70mg)。 Using compound 34a + methyl 2-bromo-2-methylpropionate as raw materials, compound 34 (70 mg) was obtained with reference to Example 29.

1H NMR (400 MHz, CDCl 3) δ 8.55 – 8.37 (m, 2H), 7.92 (s, 1H), 7.72 – 7.65 (m, 2H), 7.60 – 7.45 (m, 2H), 6.84 – 6.78 (m, 1H), 6.60 – 6.52 (m, 1H), 4.98 – 4.88 (m, 1H), 4.44 – 4.32 (m, 2H), 4.10 – 4.00 (m, 2H), 3.90 – 3.77 (m, 1H), 2.96 – 2.64 (m, 3H), 2.20 – 1.95 (m, 5H), 1.86 (s, 6H), 1.09 – 1.02 (m, 2H), 1.00 – 0.92 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.55 – 8.37 (m, 2H), 7.92 (s, 1H), 7.72 – 7.65 (m, 2H), 7.60 – 7.45 (m, 2H), 6.84 – 6.78 (m , 1H), 6.60 – 6.52 (m, 1H), 4.98 – 4.88 (m, 1H), 4.44 – 4.32 (m, 2H), 4.10 – 4.00 (m, 2H), 3.90 – 3.77 (m, 1H), 2.96 – 2.64 (m, 3H), 2.20 – 1.95 (m, 5H), 1.86 (s, 6H), 1.09 – 1.02 (m, 2H), 1.00 – 0.92 (m, 2H).

LCMS m/z = 711.2 [M+1] + LCMS m/z = 711.2 [M+1] +

實施例35：化合物35的製備 Example 35: Preparation of Compound 35

以化合物34b+16B為原料，參考實施例29得到化合物35(50mg)。Using compound 34b+16B as raw materials, compound 35 (50 mg) was obtained with reference to Example 29.

1H NMR (400 MHz, CDCl 3) δ 8.86 (s, 1H), 8.36 (d, 1H), 7.97 (s, 1H), 7.72 – 7.64 (m, 2H), 7.49 (dd, 1H), 7.38 – 7.32 (m, 1H), 6.84 – 6.77 (m, 1H), 6.56 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.10 – 4.00 (m, 2H), 3.90 – 3.75 (m, 1H), 2.97 – 2.62 (m, 3H), 2.22 – 1.82 (m, 8H), 1.66 – 1.46 (m, 1H), 1.06 – 0.78 (m, 6H), 0.60 – 0.50 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.86 (s, 1H), 8.36 (d, 1H), 7.97 (s, 1H), 7.72 – 7.64 (m, 2H), 7.49 (dd, 1H), 7.38 – 7.32 (m, 1H), 6.84 – 6.77 (m, 1H), 6.56 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.10 – 4.00 (m, 2H), 3.90 – 3.75 (m, 1H), 2.97 – 2.62 (m, 3H), 2.22 – 1.82 (m, 8H), 1.66 – 1.46 (m, 1H), 1.06 – 0.78 (m, 6H), 0.60 – 0.50 (m , 2H).

LCMS m/z = 670.3 [M+1] + LCMS m/z = 670.3 [M+1] +

實施例36：化合物36的製備 Example 36: Preparation of Compound 36

以化合物36b為原料，參考實施例19得到化合物36(34mg)。 Using compound 36b as a raw material, compound 36 (34 mg) was obtained with reference to Example 19.

1H NMR (400 MHz, CDCl 3) δ 8.55 (s, 1H), 8.32 (d, 1H), 8.03 (s, 1H), 7.80 (s, 1H), 7.73 (s, 1H), 7.67 (d, 1H), 7.34 – 7.20 (m, 2H), 7.02 – 6.95 (m, 1H), 6.83 – 6.78 (m, 1H), 6.55 (dd, 1H), 4.99 – 4.88 (m, 1H), 4.42 – 4.30 (m, 2H), 4.10 – 4.00 (m, 2H), 3.88 – 3.73 (m, 1H), 2.95 – 2.64 (m, 3H), 2.18 – 2.08 (m, 4H), 1.94 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.55 (s, 1H), 8.32 (d, 1H), 8.03 (s, 1H), 7.80 (s, 1H), 7.73 (s, 1H), 7.67 (d, 1H), 7.34 – 7.20 (m, 2H), 7.02 – 6.95 (m, 1H), 6.83 – 6.78 (m, 1H), 6.55 (dd, 1H), 4.99 – 4.88 (m, 1H), 4.42 – 4.30 ( m, 2H), 4.10 – 4.00 (m, 2H), 3.88 – 3.73 (m, 1H), 2.95 – 2.64 (m, 3H), 2.18 – 2.08 (m, 4H), 1.94 (s, 6H).

實施例37：化合物37的製備 Example 37: Preparation of Compound 37

第一步：37b的製備Step 1: Preparation of 37b

將37a (1.00 g，6.32 mmol) (合成方法見 Bioorganic & Medicinal Chemistry, 2012, 20, 1188-1200) 溶於15 mL二氯甲烷中，加入三乙胺 (1.92 g，18.97 mmol)，冷卻至0℃，滴加MsCl (0.87 g，7.59 mmol)，室溫反應3 h。向反應液中加入20 mL水，用二氯甲烷萃取 (30 mL×3)，合併有機相，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 10:1-5:1)，得37b (1.1 g，收率：74%)。 Dissolve 37a (1.00 g, 6.32 mmol) (for synthesis methods, see Bioorganic & Medicinal Chemistry , 2012 , 20 , 1188-1200) in 15 mL dichloromethane, add triethylamine (1.92 g, 18.97 mmol), and cool to 0 ℃, MsCl (0.87 g, 7.59 mmol) was added dropwise, and the reaction was carried out at room temperature for 3 h. Add 20 mL of water to the reaction solution, extract with dichloromethane (30 mL Esters (v/v) = 10:1-5:1), yielding 37b (1.1 g, yield: 74%).

第二步：37c的製備Step 2: Preparation of 37c

將37b (0.7 g，2.96 mmol) 溶於15 mL DMF中，加入碳酸銫 (2.89 g，8.87 mmol) 和4-碘吡唑 (0.86 g，4.43 mmol)，80℃反應12 h。將反應體系冷卻至室溫，加入30 mL水，用乙酸乙酯萃取 (20 mL×3)，合併有機相，有機相用無水硫酸鈉乾燥，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 10:1-5:1)，得37c (0.3 g，收率：30%)。Dissolve 37b (0.7 g, 2.96 mmol) in 15 mL DMF, add cesium carbonate (2.89 g, 8.87 mmol) and 4-iodopyrazole (0.86 g, 4.43 mmol), and react at 80°C for 12 h. Cool the reaction system to room temperature, add 30 mL of water, extract with ethyl acetate (20 mL Esters (v/v) = 10:1-5:1), 37c (0.3 g, yield: 30%) was obtained.

第三步：37d的製備Step 3: Preparation of 37d

將37c (0.38 g，1.14 mmol) 溶於3 mL THF/H 2O (v/v) = 4:1的混合溶劑中，加入一水合氫氧化鋰 (72 mg，1.72 mmol)，40℃反應3 h。將反應體系冷卻至室溫，加入10 mL水，用1 mol/L鹽酸調pH至3，用乙酸乙酯萃取 (25 mL×3)，合併有機相，有機相用無水硫酸鈉乾燥，減壓濃縮，得粗品 (0.34 g)。將上述粗品 (0.34 g) 溶於10 mL DCM中，加入1-氯-N,N,2-三甲基丙烯胺 (0.22 g，1.65 mmol)，室溫反應2 h後，依次加入三乙胺 (0.34 g，3.36 mmol) 和2-氯-4-(三氟甲基)苯胺 (0.22 g，1.12 mmol)，室溫反應19 h。向反應液中加入15 mL二氯甲烷，加入20 mL水，分離出有機相，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 10:1-1:1)，得到37d (0.305 g，收率：56%)。 Dissolve 37c (0.38 g, 1.14 mmol) in 3 mL THF/H 2 O (v/v) = 4:1 mixed solvent, add lithium hydroxide monohydrate (72 mg, 1.72 mmol), and react at 40°C 3 h. Cool the reaction system to room temperature, add 10 mL of water, adjust the pH to 3 with 1 mol/L hydrochloric acid, extract with ethyl acetate (25 mL×3), combine the organic phases, dry the organic phases over anhydrous sodium sulfate, and reduce the pressure Concentrate to obtain crude product (0.34 g). Dissolve the above crude product (0.34 g) in 10 mL DCM, add 1-chloro-N,N,2-trimethylpropenylamine (0.22 g, 1.65 mmol), react at room temperature for 2 h, then add triethylamine in sequence (0.34 g, 3.36 mmol) and 2-chloro-4-(trifluoromethyl)aniline (0.22 g, 1.12 mmol), reacted at room temperature for 19 h. Add 15 mL of methylene chloride to the reaction solution, add 20 mL of water, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10:1-1:1), obtaining 37d (0.305 g, yield: 56%).

第四步：化合物37的製備Step 4: Preparation of Compound 37

將37d (305 mg，0.63 mmol)、粗品中間體1 (320 mg)、TEA (190 mg，1.88 mmol)、CuI (24 mg，0.126 mmol) 和PdCl 2(PPh 3) 2(88 mg，0.125 mmol)加入10 mL DMF，氮氣氛圍55℃反應4 h。將反應液冷卻至室溫，加入25 mL水，抽濾，濾餅用5 mL水洗滌，將濾餅用100 mL DCM/MeOH (v/v) = 5:1的混合溶劑溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (二氯甲烷/甲醇 (v/v) = 10:1-5:1)，得化合物37 (51 mg，收率：12%)。 Combine 37d (305 mg, 0.63 mmol), crude intermediate 1 (320 mg), TEA (190 mg, 1.88 mmol), CuI (24 mg, 0.126 mmol) and PdCl 2 (PPh 3 ) 2 (88 mg, 0.125 mmol). ), add 10 mL DMF, and react at 55°C for 4 h in a nitrogen atmosphere. Cool the reaction solution to room temperature, add 25 mL water, filter with suction, wash the filter cake with 5 mL water, dissolve the filter cake with 100 mL DCM/MeOH (v/v) = 5:1 mixed solvent, and anhydrous sodium sulfate Dry and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (dichloromethane/methanol (v/v) = 10:1-5:1) to obtain compound 37 (51 mg, yield: 12%).

1H NMR (400 MHz, CDCl 3) δ 8.46 (d, 1H), 8.27 (s, 1H), 8.04 (s, 1H), 7.77 – 7.40 (m, 5H), 6.83 – 6.77 (m, 1H), 6.54 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.40 – 4.26 (m, 2H), 4.07 – 3.96 (m, 2H), 3.84 – 3.70 (m, 1H), 3.28 (s, 2H), 2.98 – 2.49 (m, 7H), 2.18 – 1.96 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.46 (d, 1H), 8.27 (s, 1H), 8.04 (s, 1H), 7.77 – 7.40 (m, 5H), 6.83 – 6.77 (m, 1H), 6.54 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.40 – 4.26 (m, 2H), 4.07 – 3.96 (m, 2H), 3.84 – 3.70 (m, 1H), 3.28 (s, 2H), 2.98 – 2.49 (m, 7H), 2.18 – 1.96 (m, 3H).

實施例38：化合物38的製備 Example 38: Preparation of Compound 38

第一步：38b的製備Step 1: Preparation of 38b

將38a (1.5 g，9.15 mmol) 加入到100 mL單口瓶中，加入30 mL DMF，加入3-乙炔基氮雜環丁烷-1-甲酸叔丁酯 (2.5 g，13.8 mmol) 和三乙胺 (2.7 g，26.7 mmol)，置換氮氣三次，加入PdCl 2(PPh 3) 2(645 mg，0.92 mmol) 和CuI (350 mg，1.84 mmol)，置換氮氣三次，50℃反應2 h。將反應體系冷卻至室溫，緩慢加入200 mL飽和氯化銨水溶液，用乙酸乙酯萃取 (100 mL×3)，有機相用飽和氯化鈉水溶液洗滌 (150 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 87:13)，得38b (2 g，收率：83%)。 Add 38a (1.5 g, 9.15 mmol) into a 100 mL single-neck bottle, add 30 mL DMF, add 3-ethynylazetidine-1-carboxylic acid tert-butyl ester (2.5 g, 13.8 mmol) and triethylamine (2.7 g, 26.7 mmol), replace nitrogen three times, add PdCl 2 (PPh 3 ) 2 (645 mg, 0.92 mmol) and CuI (350 mg, 1.84 mmol), replace nitrogen three times, and react at 50°C for 2 h. Cool the reaction system to room temperature, slowly add 200 mL of saturated aqueous ammonium chloride solution, extract with ethyl acetate (100 mL×3), wash the organic phase with saturated aqueous sodium chloride solution (150 mL×2), and dry over anhydrous sodium sulfate. , concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 87:13) to obtain 38b (2 g, yield: 83%).

LCMS m/z = 265.1 [M+1] + LCMS m/z = 265.1 [M+1] +

第二步：38c的製備Step 2: Preparation of 38c

將38b (1.0 g，3.79 mmol) 加入到100 mL三口瓶中，加入20 mL四氫呋喃，置換氮氣三次，冷卻至-78℃，緩慢加入2 mol/L二異丙基氨基鋰的四氫呋喃溶液 (3.8 mL，7.6 mmol)，在-78℃下反應20 min後，升溫至0℃反應1 h。將反應體系冷卻至-78℃，加入38A (986 mg，5.69 mmol) (合成方法見WO2014045031)，室溫反應16 h。向反應體系中加入50 mL飽和氯化銨水溶液，用乙酸乙酯萃取 (70 mL×3)，有機相用飽和氯化鈉水溶液洗滌 (80 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 78:22)，得38c (0.35 g，收率：21%)。Add 38b (1.0 g, 3.79 mmol) into a 100 mL three-necked flask, add 20 mL tetrahydrofuran, replace nitrogen three times, cool to -78°C, and slowly add 2 mol/L lithium diisopropylamide in tetrahydrofuran (3.8 mL , 7.6 mmol), reacted at -78°C for 20 min, then raised the temperature to 0°C and reacted for 1 h. The reaction system was cooled to -78°C, 38A (986 mg, 5.69 mmol) was added (see WO2014045031 for the synthesis method), and the reaction was carried out at room temperature for 16 h. Add 50 mL of saturated aqueous ammonium chloride solution to the reaction system, extract with ethyl acetate (70 mL×3), wash the organic phase with saturated aqueous sodium chloride solution (80 mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 78:22) to obtain 38c (0.35 g, yield: 21%).

LCMS m/z = 438.1 [M+1] + LCMS m/z = 438.1 [M+1] +

第三步：38d的鹽酸鹽的製備Step 3: Preparation of 38d hydrochloride

將38c (0.335 g，0.77 mmol) 溶於15 mL甲醇中，冷卻至0℃，加入0.5 mol/L氯化氫的乙酸乙酯溶液 (10 mL，5 mmol)，在0℃下反應1 h。將反應體系減壓濃縮，得到粗品38d的鹽酸鹽 (210 mg)。Dissolve 38c (0.335 g, 0.77 mmol) in 15 mL methanol, cool to 0°C, add 0.5 mol/L hydrogen chloride in ethyl acetate solution (10 mL, 5 mmol), and react at 0°C for 1 h. The reaction system was concentrated under reduced pressure to obtain the hydrochloride salt of crude product 38d (210 mg).

第四步：38e的製備Step 4: Preparation of 38e

將2-氯-4-(三氟甲基)苯甲酸 (67 mg，0.3 mmol) 加入到50 mL單口瓶中，加入10 mL二氯甲烷，加入1-氯-N,N,2-三甲基丙烯胺 (58 mg，0.43 mmol)，室溫反應1 h後，依次加入三乙胺 (88 mg，0.87 mmol) 和上述粗品38d的鹽酸鹽 (110 mg)，室溫反應1 h。將反應體系減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 72:28)，得38e (80 mg，收率：49%)。Add 2-chloro-4-(trifluoromethyl)benzoic acid (67 mg, 0.3 mmol) into a 50 mL single-neck bottle, add 10 mL dichloromethane, and add 1-chloro-N,N,2-trimethyl Allylylamine (58 mg, 0.43 mmol) was reacted at room temperature for 1 h, then triethylamine (88 mg, 0.87 mmol) and the hydrochloride of the crude product 38d (110 mg) were added in sequence, and the reaction was carried out at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 72:28) to obtain 38e (80 mg, yield: 49%).

LCMS m/z = 540.1 [M+1] + LCMS m/z = 540.1 [M+1] +

第五步；38f的對甲苯磺酸鹽的製備Step 5: Preparation of p-toluenesulfonate of 38f

將38e (80 mg，0.15 mmol) 加入到50 mL單口瓶中，加入20 mL乙腈，加入對甲苯磺酸 (103 mg，0.6 mmol)，30℃反應2 h。將反應體系減壓濃縮，得到粗品38f的對甲苯磺酸鹽 (70 mg)。Add 38e (80 mg, 0.15 mmol) into a 50 mL single-neck bottle, add 20 mL acetonitrile, add p-toluenesulfonic acid (103 mg, 0.6 mmol), and react at 30°C for 2 h. The reaction system was concentrated under reduced pressure to obtain crude product 38f p-toluenesulfonate (70 mg).

LCMS m/z = 440.1 [M+1] + LCMS m/z = 440.1 [M+1] +

第六步；化合物38的製備 Step 6; Preparation of compound 38

將粗品38f的對甲苯磺酸鹽 (70 mg) 加入到50 mL單口瓶中，加入6 mL DMSO和DIPEA (103 mg，0.80 mmol)，攪拌20 min後，加入2-(2,6-二氧代哌啶-3-基)-5-氟異吲哚啉-1,3-二酮 (66 mg，0.24 mmol)，80℃反應2 h。將反應體系冷卻至室溫，緩慢加入80 mL水，用乙酸乙酯萃取 (50 mL×3)，有機相用飽和氯化鈉水溶液洗滌 (60 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 28:72)，得化合物38 (25 mg，收率：15%)。Add crude 38f p-toluenesulfonate (70 mg) into a 50 mL single-neck bottle, add 6 mL DMSO and DIPEA (103 mg, 0.80 mmol), stir for 20 min, and add 2-(2,6-dioxo Piperidin-3-yl)-5-fluoroisoindoline-1,3-dione (66 mg, 0.24 mmol), react at 80°C for 2 h. Cool the reaction system to room temperature, slowly add 80 mL of water, extract with ethyl acetate (50 mL×3), wash the organic phase with saturated aqueous sodium chloride solution (60 mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. , the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 28:72) to obtain compound 38 (25 mg, yield: 15%).

1H NMR (400 MHz, CDCl 3) δ 8.15 – 8.00 (m, 1H), 7.84 – 7.54 (m, 5H), 7.14 – 7.02 (m, 1H), 6.88 – 6.75 (m, 1H), 6.65 – 6.50 (m, 1H), 4.99 – 4.87 (m, 1H), 4.45 – 4.30 (m, 2H), 4.17 – 4.03 (m, 2H), 3.95 – 3.80 (m, 1H), 2.97 – 2.65 (m, 7H), 2.31 – 2.05 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.15 – 8.00 (m, 1H), 7.84 – 7.54 (m, 5H), 7.14 – 7.02 (m, 1H), 6.88 – 6.75 (m, 1H), 6.65 – 6.50 (m, 1H), 4.99 – 4.87 (m, 1H), 4.45 – 4.30 (m, 2H), 4.17 – 4.03 (m, 2H), 3.95 – 3.80 (m, 1H), 2.97 – 2.65 (m, 7H) , 2.31 – 2.05 (m, 3H).

實施例39：製備化合物39 Example 39: Preparation of Compound 39

第一步：39b的製備Step 1: Preparation of 39b

將2-氯-4-三氟甲基苯甲酸 (0.1 g，0.45 mmol) 溶於2 mL DCM中，加入1-氯-N,N,2-三甲基丙烯胺 (0.09 g，0.67 mmol)，室溫反應2 h後，依次加入三乙胺 (0.27 g，2.67 mmol) 和39a (合成方法見WO2016116061) (0.1 g，0.40 mmol)，室溫反應12 h。向反應液中加入50 mL二氯甲烷，加入50 mL水，分離出有機相，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 20:1-5:1)，得到39b (0.06 g，收率：33%)。Dissolve 2-chloro-4-trifluoromethylbenzoic acid (0.1 g, 0.45 mmol) in 2 mL DCM, and add 1-chloro-N,N,2-trimethylpropenylamine (0.09 g, 0.67 mmol) , after reacting at room temperature for 2 h, add triethylamine (0.27 g, 2.67 mmol) and 39a (see WO2016116061 for the synthesis method) (0.1 g, 0.40 mmol) in sequence, and react at room temperature for 12 h. Add 50 mL of methylene chloride to the reaction solution, add 50 mL of water, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 20:1-5:1), obtaining 39b (0.06 g, yield: 33%).

LCMS m/z = 455.0 [M+1] + LCMS m/z = 455.0 [M+1] +

第二步：化合物39的製備Step 2: Preparation of Compound 39

將39b (0.06 g，0.13 mmol)、粗品中間體1 (0.044 g)、TEA (0.079 g，0.78 mmol)、CuI (5 mg，0.026 mmol) 和雙三苯基膦二氯化鈀 (9 mg，0.013 mmol)加入5 mL DMF，氮氣氛圍50℃反應0.5 h。將反應液冷卻至室溫，加入50 mL水，抽濾，濾餅用10 mL水洗滌，將濾餅用20 mL DCM溶解，無水硫酸鈉乾燥，粗品用矽膠色譜柱分離純化 (石油醚/二氯甲烷/乙酸乙酯 (v/v) = 1:1:2)，得化合物39 (0.015 g，收率：17%)。39b (0.06 g, 0.13 mmol), crude intermediate 1 (0.044 g), TEA (0.079 g, 0.78 mmol), CuI (5 mg, 0.026 mmol) and bistriphenylphosphine palladium dichloride (9 mg, 0.013 mmol), add 5 mL DMF, and react at 50°C for 0.5 h in a nitrogen atmosphere. Cool the reaction solution to room temperature, add 50 mL of water, and filter with suction. The filter cake is washed with 10 mL of water. The filter cake is dissolved in 20 mL of DCM and dried over anhydrous sodium sulfate. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/dihydrogen). Methyl chloride/ethyl acetate (v/v) = 1:1:2) to obtain compound 39 (0.015 g, yield: 17%).

1H NMR (400 MHz, CDCl 3) δ 7.94 (s, 1H), 7.77 – 7.56 (m, 3H), 7.52 – 7.40 (m, 1H), 6.84 – 6.70 (m, 2H), 6.58 – 6.48 (m, 1H), 6.17 – 5.82 (m, 1H), 5.04 – 4.80 (m, 2H), 4.54 – 3.45 (m, 10H), 2.99 – 2.62 (m, 3H), 2.20 – 2.06 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (s, 1H), 7.77 – 7.56 (m, 3H), 7.52 – 7.40 (m, 1H), 6.84 – 6.70 (m, 2H), 6.58 – 6.48 (m , 1H), 6.17 – 5.82 (m, 1H), 5.04 – 4.80 (m, 2H), 4.54 – 3.45 (m, 10H), 2.99 – 2.62 (m, 3H), 2.20 – 2.06 (m, 1H).

LCMS m/z = 664.2 [M+1] + LCMS m/z = 664.2 [M+1] +

實施例40：化合物40的三氟乙酸鹽的製備 Example 40: Preparation of trifluoroacetate salt of compound 40

第一步：40b的製備Step One: Preparation of 40b

將40a (2.2 g，9.9 mmol) 加入到50 mL DMF中，加入28B (4.3 g，12 mmol)和碳酸銫 (6.5 g，19.95 mmol)，85℃反應3 h。將反應液冷卻至室溫，加入100 mL乙酸乙酯和200 mL純化水，分離出有機相，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 4:1)，得40b (1.5 g，收率：30%)。Add 40a (2.2 g, 9.9 mmol) to 50 mL DMF, add 28B (4.3 g, 12 mmol) and cesium carbonate (6.5 g, 19.95 mmol), and react at 85°C for 3 h. The reaction solution was cooled to room temperature, 100 mL of ethyl acetate and 200 mL of purified water were added, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate). Esters (v/v) = 4:1), yielding 40b (1.5 g, yield: 30%).

第二步：40c的製備Step 2: Preparation of 40c

將40b (0.5 g，1.0 mmol) 加入到30 mL 1,2-二氯乙烷中，加入嗎啉 (0.2 g，2.3 mmol)，加入三乙醯氧基硼氫化鈉 (0.42 g，1.98 mmol)，室溫反應12 h。向反應液中加入20 mL二氯甲烷，加入50 mL純化水，分離出有機相，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚:乙酸乙酯 (v/v) = 3:1)，得40c (0.38 g，收率：67%)。Add 40b (0.5 g, 1.0 mmol) to 30 mL 1,2-dichloroethane, add morpholine (0.2 g, 2.3 mmol), and add sodium triacetyloxyborohydride (0.42 g, 1.98 mmol) , react at room temperature for 12 h. Add 20 mL of methylene chloride to the reaction solution, add 50 mL of purified water, and separate the organic phase. The organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product is separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v /v) = 3:1), 40c (0.38 g, yield: 67%) was obtained.

LCMS m/z = 569.1 [M+1] + LCMS m/z = 569.1 [M+1] +

第三步：40d的製備Step 3: Preparation of 40d

將40c (0.38 g，0.67 mmol)、3-乙炔基氮雜環丁-1-甲酸叔丁酯 (0.18 g，0.99 mmol)、TEA (0.3 g，2.96 mmol)、CuI (11 mg，0.058 mmol) 和PdCl 2(PPh 3) 2(42 mg，0.06 mmol)加入5 mL DMF，氮氣保護下90℃反應3 h。將反應液冷卻至室溫，加入30 mL純化水，過濾，濾餅用30 mL二氯甲烷溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 3:1)，得40d (0.32 g，收率：77%)。 40c (0.38 g, 0.67 mmol), tert-butyl 3-ethynylazetidine-1-carboxylate (0.18 g, 0.99 mmol), TEA (0.3 g, 2.96 mmol), CuI (11 mg, 0.058 mmol) Add 5 mL DMF to PdCl 2 (PPh 3 ) 2 (42 mg, 0.06 mmol), and react at 90°C for 3 h under nitrogen protection. Cool the reaction solution to room temperature, add 30 mL of purified water, filter, dissolve the filter cake with 30 mL of methylene chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate ( v/v) = 3:1), 40d (0.32 g, yield: 77%) was obtained.

LCMS m/z = 622.3 [M+1] +LCMS m/z = 622.3 [M+1] +

以化合物40d為原料，參考實施例23製備方法，經酸性製備[流動相體系：乙腈/水 (含0.1% TFA)]，凍乾得到化合物40的三氟乙酸鹽 (10 mg)。Using compound 40d as raw material, refer to the preparation method of Example 23, undergo acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and freeze-dry to obtain the trifluoroacetate salt of compound 40 (10 mg).

1H NMR (400 MHz, DMSO- d 6 ) δ 11.06 (s, 1H), 9.21 (s, 1H), 8.52 (s, 1H), 7.98 – 7.87 (m, 2H), 7.80 – 7.65 (m, 2H), 6.92 – 6.86 (m, 1H), 6.73 (dd, 1H), 5.12 – 5.01 (m, 1H), 4.48 – 4.28 (m, 4H), 4.15 – 3.02 (m, 11H), 3.02 – 2.70 (m, 5H), 2.67 – 2.46 (m, 2H), 2.08 – 1.92 (m, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.06 (s, 1H), 9.21 (s, 1H), 8.52 (s, 1H), 7.98 – 7.87 (m, 2H), 7.80 – 7.65 (m, 2H ), 6.92 – 6.86 (m, 1H), 6.73 (dd, 1H), 5.12 – 5.01 (m, 1H), 4.48 – 4.28 (m, 4H), 4.15 – 3.02 (m, 11H), 3.02 – 2.70 (m , 5H), 2.67 – 2.46 (m, 2H), 2.08 – 1.92 (m, 3H).

LCMS m/z = 778.2 [M+1] + LCMS m/z = 778.2 [M+1] +

實施例41：化合物41的三氟乙酸鹽的製備 Example 41: Preparation of trifluoroacetate salt of compound 41

第一步：41a的製備Step One: Preparation of 41a

將40b (0.5 g，1.0 mmol) 加入到30 mL二氯甲烷中，加入DAST (0.48 g，2.98 mmol)，室溫反應3 h。向反應體系中加入2 mL甲醇，減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚:乙酸乙酯 (v/v) = 4:1)，得41a (0.31 g，收率：60%)。Add 40b (0.5 g, 1.0 mmol) to 30 mL dichloromethane, add DAST (0.48 g, 2.98 mmol), and react at room temperature for 3 h. 2 mL of methanol was added to the reaction system, concentrated under reduced pressure, and the crude product was separated and purified with a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 4:1) to obtain 41a (0.31 g, yield: 60%) .

第二步：41b的製備Step 2: Preparation of 41b

將41a (0.38 g，0.73 mmol)、3-乙炔基氮雜環丁烷-1-甲酸叔丁酯 (0.18 g，0.99 mmol)、TEA (0.3 g，2.96 mmol)、CuI (11 mg，0.058 mmol) 和PdCl 2(PPh 3) 2(42 mg，0.06 mmol) 5 mL DMF，氮氣氛圍下95℃反應3 h。將反應液冷卻至室溫，加入30 mL純化水，過濾，濾餅用30 mL二氯甲烷溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚:乙酸乙酯 (v/v) = 4:1)，得41b (0.32 g，收率：77%)。 41a (0.38 g, 0.73 mmol), tert-butyl 3-ethynylazetidine-1-carboxylate (0.18 g, 0.99 mmol), TEA (0.3 g, 2.96 mmol), CuI (11 mg, 0.058 mmol) ) and PdCl 2 (PPh 3 ) 2 (42 mg, 0.06 mmol) 5 mL DMF, react at 95°C for 3 h under nitrogen atmosphere. Cool the reaction solution to room temperature, add 30 mL of purified water, filter, dissolve the filter cake with 30 mL of methylene chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether: ethyl acetate ( v/v) = 4:1), 41b (0.32 g, yield: 77%) was obtained.

化合物41的三氟乙酸鹽以化合物41b為原料，參考實施例23製備方法，經酸性製備[流動相體系：乙腈/水 (含0.1% TFA)]，凍乾得到化合物41的三氟乙酸鹽(50mg)。The trifluoroacetate salt of compound 41 was prepared using compound 41b as a raw material, with reference to the preparation method of Example 23, through acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and then lyophilized to obtain the trifluoroacetate salt of compound 41 ( 50mg).

1H NMR (400 MHz, CDCl 3) δ 8.60 – 8.50 (m, 2H), 8.07 – 7.98 (m, 1H), 7.73 (s, 1H), 7.67 (d, 1H), 7.62 – 7.56 (m, 1H), 7.55 – 7.48 (m, 1H), 6.92 – 6.60 (m, 2H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.43 – 4.30 (m, 2H), 4.13 – 4.00 (m, 2H), 3.90 – 3.76 (m, 1H), 3.15 – 3.02 (m 2H), 2.95 – 2.66 (m, 5H), 2.30 – 2.02 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.60 – 8.50 (m, 2H), 8.07 – 7.98 (m, 1H), 7.73 (s, 1H), 7.67 (d, 1H), 7.62 – 7.56 (m, 1H) ), 7.55 – 7.48 (m, 1H), 6.92 – 6.60 (m, 2H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.43 – 4.30 (m, 2H), 4.13 – 4.00 (m , 2H), 3.90 – 3.76 (m, 1H), 3.15 – 3.02 (m 2H), 2.95 – 2.66 (m, 5H), 2.30 – 2.02 (m, 3H).

LCMS m/z = 727.1 [M-1] - LCMS m/z = 727.1 [M-1] -

實施例42：化合物42的三氟乙酸鹽的製備 Example 42: Preparation of trifluoroacetate salt of compound 42

第一步：42a的製備Step 1: Preparation of 42a

將40b (0.5 g，1.0 mmol) 加入到30 mL 1,2-二氯乙烷中，加入二甲胺 (0.2 g，4.44 mmol)，加入三乙醯氧基硼氫化鈉 (0.42 g，1.98 mmol)，室溫反應12 h。向反應液中加入20 mL二氯甲烷，加入50 mL純化水，分離出有機相，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 1:1)，得42a (0.27 g，收率：51%)。Add 40b (0.5 g, 1.0 mmol) to 30 mL 1,2-dichloroethane, add dimethylamine (0.2 g, 4.44 mmol), and add sodium triacetyloxyborohydride (0.42 g, 1.98 mmol ), react at room temperature for 12 h. Add 20 mL of methylene chloride to the reaction solution, add 50 mL of purified water, and separate the organic phase. The organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product is separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v /v) = 1:1), 42a (0.27 g, yield: 51%) was obtained.

LCMS m/z = 527.1 [M+1] + LCMS m/z = 527.1 [M+1] +

第二步：42b的製備Step 2: Preparation of 42b

將42a (0.27 g，0.51 mmol)、3-乙炔基氮雜環丁烷-1-甲酸叔丁酯 (0.18 g，0.99 mmol)、TEA (0.3 g，2.96 mmol)、CuI (11 mg，0.058 mmol) 和PdCl 2(PPh 3) 2(42 mg，0.06 mmol)加入5 mL DMF，氮氣氛圍下95℃反應3 h。將反應液冷卻至室溫，加入30 mL純化水，過濾，濾餅用30 mL二氯甲烷溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚:乙酸乙酯 (v/v) = 1:1)，得42b (0.25 g，收率：85%)。 42a (0.27 g, 0.51 mmol), tert-butyl 3-ethynylazetidine-1-carboxylate (0.18 g, 0.99 mmol), TEA (0.3 g, 2.96 mmol), CuI (11 mg, 0.058 mmol) ) and PdCl 2 (PPh 3 ) 2 (42 mg, 0.06 mmol) were added with 5 mL DMF, and the reaction was carried out at 95°C for 3 h under nitrogen atmosphere. Cool the reaction solution to room temperature, add 30 mL of purified water, filter, dissolve the filter cake with 30 mL of methylene chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether: ethyl acetate ( v/v) = 1:1), 42b (0.25 g, yield: 85%) was obtained.

化合物42的三氟乙酸鹽以化合物42b為原料，參考實施例23製備方法，經酸性製備[流動相體系：乙腈/水 (含0.1% TFA)]，凍乾得到化合物42的三氟乙酸鹽(6mg)。The trifluoroacetate salt of compound 42 was prepared using compound 42b as a raw material, with reference to the preparation method of Example 23, through acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and then lyophilized to obtain the trifluoroacetate salt of compound 42 ( 6mg).

1H NMR (400 MHz, DMSO- d 6 ) δ 11.06 (br.s, 1H), 9.29 (s, 1H), 8.59 (s, 1H), 7.98 – 7.90 (m, 1H), 7.89 – 7.81 (m, 1H), 7.78 – 7.65 (m, 2H), 6.92 – 6.84 (m, 1H), 6.73 (dd, 1H), 5.14 – 5.00 (m, 1H), 4.57 (s, 2H), 4.47 – 4.35 (m, 2H), 4.13 – 4.02 (m, 2H), 4.01 – 3.89 (m, 1H), 3.10 (s, 6H), 3.01 – 2.72 (m, 5H), 2.71 – 2.50 (m, 2H), 2.08 – 1.93 (m, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.06 (br.s, 1H), 9.29 (s, 1H), 8.59 (s, 1H), 7.98 – 7.90 (m, 1H), 7.89 – 7.81 (m , 1H), 7.78 – 7.65 (m, 2H), 6.92 – 6.84 (m, 1H), 6.73 (dd, 1H), 5.14 – 5.00 (m, 1H), 4.57 (s, 2H), 4.47 – 4.35 (m , 2H), 4.13 – 4.02 (m, 2H), 4.01 – 3.89 (m, 1H), 3.10 (s, 6H), 3.01 – 2.72 (m, 5H), 2.71 – 2.50 (m, 2H), 2.08 – 1.93 (m, 3H).

實施例43：化合物43的製備 Example 43: Preparation of Compound 43

第一步：化合物43b的製備 Step One: Preparation of Compound 43b

將43a (0.19 g，0.73 mmol) (合成方法見 Bioorganic & Medicinal Chemistry Letters, 2021, 33, 127749) 溶於2 mL DCM中，加入1-氯-N,N,2-三甲基丙烯胺 (0.19 g，1.42 mmol)，室溫反應2 h後，依次加入三乙胺 (0.58 g，5.73 mmol) 和16B (0.25 g，1.58 mmol)，室溫反應12 h。向反應液中加入50 mL二氯甲烷，加入50 mL水，分離出有機相，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚/乙酸乙酯 (v/v) = 20:1-5:1)，得到43b (0.2 g，收率：69%)。 Dissolve 43a (0.19 g, 0.73 mmol) (for synthesis methods, see Bioorganic & Medicinal Chemistry Letters , 2021 , 33 , 127749) in 2 mL DCM, add 1-chloro-N,N,2-trimethylpropenylamine (0.19 g, 1.42 mmol), react at room temperature for 2 h, then add triethylamine (0.58 g, 5.73 mmol) and 16B (0.25 g, 1.58 mmol) in sequence, and react at room temperature for 12 h. Add 50 mL of methylene chloride to the reaction solution, add 50 mL of water, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 20:1-5:1), obtaining 43b (0.2 g, yield: 69%).

第二步：化合物43的製備Step 2: Preparation of compound 43

將43b (0.092 g，0.23 mmol)、粗品中間體1 (0.078 g)、TEA (0.14 g，1.38 mmol)、CuI (8.8 mg，0.046 mmol) 和PdCl 2(PPh 3) 2(16 mg，0.023 mmol) 加入2 mL DMF，氮氣氛圍55℃反應1 h。將反應液冷卻至室溫，加入50 mL水，抽濾，濾餅用10 mL水洗滌，將濾餅用20 mL DCM溶解，無水硫酸鈉乾燥，粗品用矽膠色譜柱分離純化 (石油醚/二氯甲烷/乙酸乙酯 (v/v) = 1:1:2)，得化合物43 (0.005 g，收率：3%)。 43b (0.092 g, 0.23 mmol), crude intermediate 1 (0.078 g), TEA (0.14 g, 1.38 mmol), CuI (8.8 mg, 0.046 mmol) and PdCl 2 (PPh 3 ) 2 (16 mg, 0.023 mmol) were added. ) Add 2 mL DMF and react at 55°C for 1 h in a nitrogen atmosphere. Cool the reaction solution to room temperature, add 50 mL of water, and filter with suction. The filter cake is washed with 10 mL of water. The filter cake is dissolved in 20 mL of DCM and dried over anhydrous sodium sulfate. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/dihydrogen). Methyl chloride/ethyl acetate (v/v) = 1:1:2) to obtain compound 43 (0.005 g, yield: 3%).

1H NMR (400 MHz, CDCl 3) δ 9.44 (s, 1H), 8.52 (d, 1H), 7.97 (s, 1H), 7.72 – 7.62 (m, 1H), 7.60 – 7.51 (m, 1H), 7.51 – 7.42 (m, 1H), 7.39 – 7.32 (m, 2H), 6.94 – 6.87 (m, 2H), 6.84 – 6.77 (m, 1H), 6.56 (dd, 1H), 4.99 – 4.88 (m, 1H), 4.43 – 4.32 (m, 2H), 4.13 – 4.02 (m, 2H), 3.89 – 3.77 (m, 1H), 2.96 – 2.64 (m, 3H), 2.19 – 2.08 (m, 1H), 1.70 – 1.48 (m, 7H), 0.92 – 0.78 (m, 2H), 0.58 – 0.47 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.44 (s, 1H), 8.52 (d, 1H), 7.97 (s, 1H), 7.72 – 7.62 (m, 1H), 7.60 – 7.51 (m, 1H), 7.51 – 7.42 (m, 1H), 7.39 – 7.32 (m, 2H), 6.94 – 6.87 (m, 2H), 6.84 – 6.77 (m, 1H), 6.56 (dd, 1H), 4.99 – 4.88 (m, 1H ), 4.43 – 4.32 (m, 2H), 4.13 – 4.02 (m, 2H), 3.89 – 3.77 (m, 1H), 2.96 – 2.64 (m, 3H), 2.19 – 2.08 (m, 1H), 1.70 – 1.48 (m, 7H), 0.92 – 0.78 (m, 2H), 0.58 – 0.47 (m, 2H).

LCMS m/z = 656.3 [M+1] + LCMS m/z = 656.3 [M+1] +

實施例44：化合物44的製備 Example 44: Preparation of Compound 44

第一步：44b的製備Step One: Preparation of 44b

將44a (0.90 g, 3.63 mmol) 和1-氯-N,N,2-三甲基丙烯胺 (0.73 g, 5.46 mmol)加入二氯甲烷 (10 mL)，室溫攪拌1 h後，加入三乙胺 (1.51 mL) 與2-氯-4-(三氟甲基)苯胺 (0.85 g, 4.35 mmol)，室溫反應16 h。將反應液減壓濃縮，粗品用矽膠色譜柱分離純化 (乙酸乙酯/石油醚 (v/v) = 1:20)，得到44b (0.50 g, 產率：32%)。44a (0.90 g, 3.63 mmol) and 1-chloro-N,N,2-trimethylpropenylamine (0.73 g, 5.46 mmol) were added to dichloromethane (10 mL). After stirring at room temperature for 1 h, trimethylpropyleneamine was added. Ethylamine (1.51 mL) and 2-chloro-4-(trifluoromethyl)aniline (0.85 g, 4.35 mmol) were reacted at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v) = 1:20) to obtain 44b (0.50 g, yield: 32%).

LCMS m/z = 426.0 [M+1] + LCMS m/z = 426.0 [M+1] +

第二步：化合物44的製備Step 2: Preparation of Compound 44

將44b (0.17 g, 0.4 mmol)、粗品中間體1 (0.20 g)、PdCl 2(PPh 3) 2(27 mg, 0.038 mmol)、CuI (15 mg, 0.079 mmol) 和DIPEA (0.15 g, 1.16 mmol)加入DMF (5 mL)，氮氣氛圍60℃反應5 h。將反應體系冷卻至室溫，加入到水 (20 mL) 中，用乙酸乙酯/甲醇 (v/v) = 5:1的混合溶劑萃取 (20 mL×3)，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 1:2)，得到的粗品再用矽膠柱色譜分離提純 (石油醚/乙酸乙酯 (v/v) = 1:1)，得到化合物44 (13 mg, 收率：5%)。 Combine 44b (0.17 g, 0.4 mmol), crude intermediate 1 (0.20 g), PdCl 2 (PPh 3 ) 2 (27 mg, 0.038 mmol), CuI (15 mg, 0.079 mmol) and DIPEA (0.15 g, 1.16 mmol). ), add DMF (5 mL), and react at 60°C for 5 h in a nitrogen atmosphere. Cool the reaction system to room temperature, add it to water (20 mL), extract with a mixed solvent of ethyl acetate/methanol (v/v) = 5:1 (20 mL×3), and dry the organic phase with anhydrous sodium sulfate. , concentrated under reduced pressure, the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 1:2), and the obtained crude product was separated and purified using a silica gel column chromatography (petroleum ether/ethyl acetate (v/v) v) = 1:1), compound 44 (13 mg, yield: 5%) was obtained.

1H NMR (400 MHz, DMSO- d 6) δ 11.05 (s, 1H), 10.36 (s, 1H), 8.09 (s, 1H), 8.02 – 7.93 (m, 2H), 7.92 – 7.85 (m, 1H), 7.82 – 7.74 (m, 1H), 7.74 – 7.65 (m, 2H), 7.62 – 7.53 (m, 1H), 6.93 – 6.85 (m, 1H), 6.74 (dd, 1H), 5.12 – 5.01 (m, 1H), 4.50 – 4.36 (m, 2H), 4.17 – 3.90 (m, 3H), 3.00 – 2.80 (m, 1H), 2.67 – 2.50 (m, 2H), 2.10 – 1.92 (m, 1H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.05 (s, 1H), 10.36 (s, 1H), 8.09 (s, 1H), 8.02 – 7.93 (m, 2H), 7.92 – 7.85 (m, 1H ), 7.82 – 7.74 (m, 1H), 7.74 – 7.65 (m, 2H), 7.62 – 7.53 (m, 1H), 6.93 – 6.85 (m, 1H), 6.74 (dd, 1H), 5.12 – 5.01 (m , 1H), 4.50 – 4.36 (m, 2H), 4.17 – 3.90 (m, 3H), 3.00 – 2.80 (m, 1H), 2.67 – 2.50 (m, 2H), 2.10 – 1.92 (m, 1H).

LCMS m/z = 635.0 [M+1] + LCMS m/z = 635.0 [M+1] +

實施例45：化合物45的製備 Example 45: Preparation of Compound 45

以化合物45a為原料，參考實施例43得到化合物45(15mg)。 Using compound 45a as a raw material, compound 45 (15 mg) was obtained with reference to Example 43.

1H NMR (400 MHz, CDCl 3) δ 8.45 (d, 1H), 7.94 (s, 1H), 7.74 (s, 1H), 7.68 (d, 1H), 7.53 – 7.40 (m, 5H), 7.36 – 7.32 (m, 1H), 6.86 – 6.80 (m, 1H), 6.57 (dd, 1H), 4.98 – 4.90 (m, 1H), 4.45 – 4.32 (m, 2H), 4.17 – 4.07 (m, 2H), 3.94 – 3.80 (m, 1H), 2.96 – 2.66 (m, 3H), 2.18 – 2.08 (m, 1H), 1.69 (s, 6H), 1.20 – 1.10 (m, 1H), 0.56 – 0.47 (m, 2H), 0.36 – 0.28 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.45 (d, 1H), 7.94 (s, 1H), 7.74 (s, 1H), 7.68 (d, 1H), 7.53 – 7.40 (m, 5H), 7.36 – 7.32 (m, 1H), 6.86 – 6.80 (m, 1H), 6.57 (dd, 1H), 4.98 – 4.90 (m, 1H), 4.45 – 4.32 (m, 2H), 4.17 – 4.07 (m, 2H), 3.94 – 3.80 (m, 1H), 2.96 – 2.66 (m, 3H), 2.18 – 2.08 (m, 1H), 1.69 (s, 6H), 1.20 – 1.10 (m, 1H), 0.56 – 0.47 (m, 2H ), 0.36 – 0.28 (m, 2H).

LCMS m/z = 640.3 [M+1] + LCMS m/z = 640.3 [M+1] +

實施例46：化合物46的製備 Example 46: Preparation of Compound 46

以化合物46a+2-氯-4-(三氟甲基)苯胺為原料，參考實施例43得到化合物46(12mg)。Using compound 46a + 2-chloro-4-(trifluoromethyl)aniline as raw materials, compound 46 (12 mg) was obtained with reference to Example 43.

1H NMR (400 MHz, CDCl 3) δ 8.56 (d, 1H), 7.93 (s, 1H), 7.72 – 7.64 (m, 1H), 7.57 (s, 1H), 7.54 – 7.46 (m, 4H), 7.38 – 7.30 (m, 2H), 6.84 – 6.80 (m, 1H), 6.57 (dd, 1H), 4.98 – 4.90 (m, 1H), 4.44 – 4.32 (m, 2H), 4.18 – 4.07 (m, 2H), 3.93 – 3.80 (m, 1H), 3.00 – 2.66 (m, 5H), 2.64 – 2.51 (m, 2H), 2.30 – 2.07 (m, 2H), 2.03 – 1.90 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.56 (d, 1H), 7.93 (s, 1H), 7.72 – 7.64 (m, 1H), 7.57 (s, 1H), 7.54 – 7.46 (m, 4H), 7.38 – 7.30 (m, 2H), 6.84 – 6.80 (m, 1H), 6.57 (dd, 1H), 4.98 – 4.90 (m, 1H), 4.44 – 4.32 (m, 2H), 4.18 – 4.07 (m, 2H ), 3.93 – 3.80 (m, 1H), 3.00 – 2.66 (m, 5H), 2.64 – 2.51 (m, 2H), 2.30 – 2.07 (m, 2H), 2.03 – 1.90 (m, 1H).

實施例47：化合物47的三氟乙酸鹽的製備 Example 47: Preparation of trifluoroacetate salt of compound 47

第一步：47b的製備Step One: Preparation of 47b

將47a (0.7 g，2.27 mmol) (合成方法見WO2012074951) 溶於10 mL甲醇中，加入一水合氫氧化鋰 (0.29 g，6.91 mmol) 的水溶液 (5 mL)，室溫反應2 h。向反應體系中加入50 mL水，用1 mol/L鹽酸調pH至2，用乙酸乙酯萃取 (50 mL×3)，有機相用無水硫酸鈉乾燥，減壓濃縮，得到粗品 (0.7 g)。將上述粗品 (0.2 g) 溶於2 mL DCM中，加入16B (0.11 g，0.70 mmol)、TCFH (0.38 g，1.36 mmol) 和N-甲基咪唑 (0.28 g，3.41 mmol)，室溫反應12 h。向反應液中加入50 mL二氯甲烷，加入50 mL水，分離出有機相，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 20:1-5:1)，得到47b (0.2 g，收率：66%)。Dissolve 47a (0.7 g, 2.27 mmol) (see WO2012074951 for synthesis method) in 10 mL methanol, add an aqueous solution of lithium hydroxide monohydrate (0.29 g, 6.91 mmol) (5 mL), and react at room temperature for 2 h. Add 50 mL of water to the reaction system, adjust the pH to 2 with 1 mol/L hydrochloric acid, extract with ethyl acetate (50 mL×3), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product (0.7 g) . Dissolve the above crude product (0.2 g) in 2 mL DCM, add 16B (0.11 g, 0.70 mmol), TCFH (0.38 g, 1.36 mmol) and N-methylimidazole (0.28 g, 3.41 mmol), and react at room temperature for 12 h. Add 50 mL of methylene chloride to the reaction solution, add 50 mL of water, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 20:1-5:1), obtaining 47b (0.2 g, yield: 66%).

第二步：化合物47的三氟乙酸鹽的製備Step 2: Preparation of the trifluoroacetate salt of compound 47

將47b (0.1 g，0.23 mmol)、粗品中間體1 (0.12 g)、TEA (0.14 g，1.38 mmol)、CuI (8.8 mg，0.046 mmol) 和PdCl 2(PPh 3) 2(16 mg，0.023 mmol)加入2 mL DMF，氮氣氛圍下55℃反應1 h。將反應液冷卻至室溫，加入50 mL水，抽濾，濾餅用10 mL水洗滌，將濾餅用20 mL DCM溶解，無水硫酸鈉乾燥，減壓濃縮後粗品過Pre-HPLC (儀器及製備柱：採用Glison GX-281製備液相，製備柱型號是Sunfire C18，5 μm，內徑×長度 = 30 mm×150 mm)。製備方法：粗品用甲醇和二甲亞碸溶解，並用0.45 μm濾膜過濾，製備成樣品液。流動相體系：乙腈/水 (含0.1% TFA)。梯度沖提方法：乙腈由5%梯度沖提60% (沖提時間15 min)，凍乾得到化合物47的三氟乙酸鹽 (0.05 g)。 47b (0.1 g, 0.23 mmol), crude intermediate 1 (0.12 g), TEA (0.14 g, 1.38 mmol), CuI (8.8 mg, 0.046 mmol) and PdCl 2 (PPh 3 ) 2 (16 mg, 0.023 mmol) were added. ), add 2 mL DMF, and react at 55°C for 1 h under nitrogen atmosphere. Cool the reaction solution to room temperature, add 50 mL of water, suction filter, wash the filter cake with 10 mL of water, dissolve the filter cake with 20 mL of DCM, dry over anhydrous sodium sulfate, concentrate under reduced pressure and pass the crude product through Pre-HPLC (instrument and Preparative column: Glison GX-281 was used to prepare the liquid phase. The preparative column model was Sunfire C18, 5 μm, inner diameter × length = 30 mm × 150 mm). Preparation method: Dissolve the crude product with methanol and dimethyl sulfoxide, filter it with a 0.45 μm filter membrane, and prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA). Gradient elution method: acetonitrile gradient elution from 5% to 60% (elution time 15 min), and freeze-drying to obtain the trifluoroacetate salt of compound 47 (0.05 g).

1H NMR (400 MHz, CDCl 3) δ 8.44 – 8.32 (m, 2H), 8.12 (s, 1H), 7.67 (d, 1H), 7.58 – 7.50 (m, 3H), 7.48 – 7.43 (m, 1H), 6.83 – 6.75 (m, 1H), 6.54 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.41 – 4.27 (m, 4H), 4.08 – 3.98 (m, 2H), 3.83 – 3.71 (m, 1H), 2.97 – 2.64 (m, 3H), 2.19 – 2.08 (m, 1H), 1.69 – 1.52 (m, 1H), 1.40 (s, 6H), 1.06 – 0.96 (m, 2H), 0.67 – 0.58 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.44 – 8.32 (m, 2H), 8.12 (s, 1H), 7.67 (d, 1H), 7.58 – 7.50 (m, 3H), 7.48 – 7.43 (m, 1H ), 6.83 – 6.75 (m, 1H), 6.54 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.41 – 4.27 (m, 4H), 4.08 – 3.98 (m, 2H), 3.83 – 3.71 (m , 1H), 2.97 – 2.64 (m, 3H), 2.19 – 2.08 (m, 1H), 1.69 – 1.52 (m, 1H), 1.40 (s, 6H), 1.06 – 0.96 (m, 2H), 0.67 – 0.58 (m, 2H).

LCMS m/z = 644.8 [M+1] + LCMS m/z = 644.8 [M+1] +

實施例48：化合物48的製備 Example 48: Preparation of Compound 48

第一步：48b-A和48b-B的製備Step One: Preparation of 48b-A and 48b-B

將28B (0.4 g, 1.12 mmol)、28a (0.22 g, 1.13 mmol)、碳酸銫 (0.73 g, 2.24 mmol) 加入乙腈 (10 mL)，50℃反應4 h。將反應體系冷卻至室溫，過濾，將濾液減壓除去溶劑，粗品用矽膠色譜柱分離提純 (乙酸乙酯/石油醚 (v/v) = 1:20)，分別得到48b-A (0.14 g, 產率：26%) 和48b-B (65 mg, 產率：12%)。28B (0.4 g, 1.12 mmol), 28a (0.22 g, 1.13 mmol), and cesium carbonate (0.73 g, 2.24 mmol) were added to acetonitrile (10 mL) and reacted at 50°C for 4 h. The reaction system was cooled to room temperature, filtered, and the solvent was removed from the filtrate under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v) = 1:20) to obtain 48b-A (0.14 g). , yield: 26%) and 48b-B (65 mg, yield: 12%).

48b-A的核磁數據：NMR data of 48b-A:

1H NMR (400 MHz, CDCl 3) δ 8.87 (s, 1H), 8.57 (d, 1H), 7.64 – 7.56 (m, 1H), 7.55 – 7.46 (m, 1H), 7.46 – 7.40 (m, 1H), 6.62 – 6.56 (m, 1H), 3.15 – 3.00 (m, 2H), 2.84 – 2.72 (m, 2H), 2.32 – 2.01 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.87 (s, 1H), 8.57 (d, 1H), 7.64 – 7.56 (m, 1H), 7.55 – 7.46 (m, 1H), 7.46 – 7.40 (m, 1H) ), 6.62 – 6.56 (m, 1H), 3.15 – 3.00 (m, 2H), 2.84 – 2.72 (m, 2H), 2.32 – 2.01 (m, 2H).

48b-B的核磁數據：NMR data of 48b-B:

1H NMR (400 MHz, CDCl 3) δ 8.64 – 8.55 (m, 1H), 7.72 – 7.64 (m, 1H), 7.60 – 7.56 (m, 3H), 6.64 – 6.58 (m, 1H), 3.20 – 2.99 (m, 4H), 2.33 – 2.16 (m, 1H), 2.09 – 1.93 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.64 – 8.55 (m, 1H), 7.72 – 7.64 (m, 1H), 7.60 – 7.56 (m, 3H), 6.64 – 6.58 (m, 1H), 3.20 – 2.99 (m, 4H), 2.33 – 2.16 (m, 1H), 2.09 – 1.93 (m, 1H).

第二步：化合物48的製備Step 2: Preparation of Compound 48

將48b-A (0.14 g, 0.30 mmol)、中間體1 (0.15 g)、PdCl 2(PPh 3) 2(21 mg, 0.030 mmol)、CuI (11 mg, 0.060 mmol) 和DIPEA (0.12 g, 0.93 mmol)加入DMF (5 mL)，氮氣氛圍60℃反應3 h。將反應體系冷卻至室溫，加入到水 (20 mL) 中，用乙酸乙酯/甲醇的混合溶劑 (v/v) = 5:1萃取 (20 mL×3)，合併有機相，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚/乙酸乙酯 (v/v) = 1:2)，得到的粗品再用矽膠柱色譜分離提純 (石油醚/乙酸乙酯 (v/v) = 1:1)，得到化合物48 (101 mg, 收率：50%)。 Combine 48b-A (0.14 g, 0.30 mmol), Intermediate 1 (0.15 g), PdCl 2 (PPh 3 ) 2 (21 mg, 0.030 mmol), CuI (11 mg, 0.060 mmol) and DIPEA (0.12 g, 0.93 mmol), DMF (5 mL) was added, and the reaction was carried out at 60°C for 3 h in a nitrogen atmosphere. Cool the reaction system to room temperature, add it to water (20 mL), extract with a mixed solvent of ethyl acetate/methanol (v/v) = 5:1 (20 mL×3), combine the organic phases, and add anhydrous sodium sulfate Dry and concentrate under reduced pressure. The crude product is separated and purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) = 1:2). The obtained crude product is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v) /v) = 1:1), compound 48 (101 mg, yield: 50%) was obtained.

1H NMR (400 MHz, CDCl 3) δ 8.77 (s, 1H), 8.55 (dd, 1H), 7.95 (s, 1H), 7.68 (d, 1H), 7.61 – 7.54 (m, 2H), 7.54 – 7.47 (m, 1H), 6.86 – 6.80 (m, 1H), 6.57 (dd, 1H), 6.54 – 6.50 (m, 1H), 4.99 – 4.89 (m, 1H), 4.45 – 4.34 (m, 2H), 4.19 – 4.10 (m, 2H), 3.94 – 3.81 (m, 1H), 3.15 – 3.01 (m, 2H), 2.95 – 2.65 (m, 5H), 2.34 – 2.02 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.77 (s, 1H), 8.55 (dd, 1H), 7.95 (s, 1H), 7.68 (d, 1H), 7.61 – 7.54 (m, 2H), 7.54 – 7.47 (m, 1H), 6.86 – 6.80 (m, 1H), 6.57 (dd, 1H), 6.54 – 6.50 (m, 1H), 4.99 – 4.89 (m, 1H), 4.45 – 4.34 (m, 2H), 4.19 – 4.10 (m, 2H), 3.94 – 3.81 (m, 1H), 3.15 – 3.01 (m, 2H), 2.95 – 2.65 (m, 5H), 2.34 – 2.02 (m, 3H).

LCMS m/z = 679.2 [M+1] + LCMS m/z = 679.2 [M+1] +

實施例49：化合物49的製備 Example 49: Preparation of Compound 49

以化合物48b-B為原料，參考實施例48得到化合物49(12mg)。Using compound 48b-B as a raw material, compound 49 (12 mg) was obtained with reference to Example 48.

1H NMR (400 MHz, CDCl 3) δ 8.54 (d, 1H), 7.91 (s, 1H), 7.73 (s, 1H), 7.71 – 7.64 (m, 2H), 7.57 – 7.53 (m, 1H), 7.48 – 7.42 (m, 1H), 6.82 – 6.76 (m, 1H), 6.58 – 6.51 (m, 2H), 4.99 – 4.89 (m, 1H), 4.37 – 4.26 (m, 2H), 4.08 – 3.97 (m, 2H), 3.84 – 3.72 (m, 1H), 3.12 – 2.96 (m, 4H), 2.95 – 2.66 (m, 3H), 2.32 – 1.99 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.54 (d, 1H), 7.91 (s, 1H), 7.73 (s, 1H), 7.71 – 7.64 (m, 2H), 7.57 – 7.53 (m, 1H), 7.48 – 7.42 (m, 1H), 6.82 – 6.76 (m, 1H), 6.58 – 6.51 (m, 2H), 4.99 – 4.89 (m, 1H), 4.37 – 4.26 (m, 2H), 4.08 – 3.97 (m , 2H), 3.84 – 3.72 (m, 1H), 3.12 – 2.96 (m, 4H), 2.95 – 2.66 (m, 3H), 2.32 – 1.99 (m, 3H).

LCMS m/z = 679.1 [M+1] + LCMS m/z = 679.1 [M+1] +

實施例50：化合物50的製備 Example 50: Preparation of Compound 50

第一步：50b的製備Step One: Preparation of 50b

將50a (合成方法見WO2014086316)(45 mg, 0.13 mmol)、2c (61 mg, 0.13 mmol)、Pd(dppf)Cl 2·CH 2Cl 2(CAS: 95464-05-4) (11 mg, 0.0136 mmol)、碳酸鉀 (54 mg, 0.39 mmol) 加入1,4-二氧六環與水的混合溶液 (6 mL, v/v = 5:1)中，氮氣氛圍90℃反應16 h，將反應液冷卻至室溫，過濾，將濾液減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚/乙酸乙酯 (v/v) = 4:1)，得到50b (42 mg, 產率：56%)。 50a (see WO2014086316 for the synthesis method) (45 mg, 0.13 mmol), 2c (61 mg, 0.13 mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (CAS: 95464-05-4) (11 mg, 0.0136 mmol), potassium carbonate (54 mg, 0.39 mmol) were added to a mixed solution of 1,4-dioxane and water (6 mL, v/v = 5:1), and the reaction was carried out at 90°C for 16 h in a nitrogen atmosphere. The liquid was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 4:1) to obtain 50b (42 mg, yield: 56% ).

LCMS m/z = 575.1 [M+1] + LCMS m/z = 575.1 [M+1] +

以化合物50b為原料，參考實施例23得到化合物50(22mg)。Using compound 50b as a raw material, compound 50 (22 mg) was obtained with reference to Example 23.

1H NMR (400 MHz, CDCl 3) δ 8.77 (s, 1H), 8.58 (d, 1H), 8.01 (s, 2H), 7.83 (s, 1H), 7.69 (d, 1H), 7.59 – 7.47 (m, 4H), 7.40 – 7.34 (m, 2H), 6.89 – 6.83 (m, 1H), 6.61 (dd, 1H), 4.98 – 4.90 (m, 1H), 4.54 – 4.42 (m, 2H), 4.14 – 3.98 (m, 3H), 3.19 – 3.05 (m, 2H), 2.96 – 2.65 (m, 5H), 2.43 – 1.95 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.77 (s, 1H), 8.58 (d, 1H), 8.01 (s, 2H), 7.83 (s, 1H), 7.69 (d, 1H), 7.59 – 7.47 ( m, 4H), 7.40 – 7.34 (m, 2H), 6.89 – 6.83 (m, 1H), 6.61 (dd, 1H), 4.98 – 4.90 (m, 1H), 4.54 – 4.42 (m, 2H), 4.14 – 3.98 (m, 3H), 3.19 – 3.05 (m, 2H), 2.96 – 2.65 (m, 5H), 2.43 – 1.95 (m, 3H).

實施例51：化合物51的製備 Example 51: Preparation of Compound 51

第一步：51b的製備Step One: Preparation of 51b

將51a (2.0 g，8.51 mmol) 溶於25 mL二氯甲烷中，加入1-氯-N,N,2-三甲基丙烯胺 (1.71 g，12.80 mmol)，室溫反應2 h。將反應體系緩慢滴加到10 mL濃氨水中，室溫反應30 min。向反應體系中加入50 mL飽和碳酸氫鈉水溶液，用50 mL二氯甲烷萃取，有機相用30 mL水洗滌，無水硫酸鈉乾燥，減壓濃縮，得粗品51b (1.5 g)。Dissolve 51a (2.0 g, 8.51 mmol) in 25 mL dichloromethane, add 1-chloro-N,N,2-trimethylpropenylamine (1.71 g, 12.80 mmol), and react at room temperature for 2 h. Slowly add the reaction system dropwise to 10 mL of concentrated ammonia water, and react at room temperature for 30 min. Add 50 mL of saturated aqueous sodium bicarbonate solution to the reaction system, extract with 50 mL of dichloromethane, wash the organic phase with 30 mL of water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product 51b (1.5 g).

第二步：51c的製備Step 2: Preparation of 51c

將上述粗品51b (1.5 g) 溶解在20 mL四氫呋喃中，加入勞森試劑 (CAS: 19172-47-5) (2.59 g，6.40 mmol)，室溫反應16 h。將反應體系減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚/乙酸乙酯 (v/v) = 4:1)，得51c (1.5 g，收率：94%)。Dissolve the above crude product 51b (1.5 g) in 20 mL tetrahydrofuran, add Lawson's reagent (CAS: 19172-47-5) (2.59 g, 6.40 mmol), and react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 4:1) to obtain 51c (1.5 g, yield: 94%).

第三步：51d的製備Step 3: Preparation of 51d

將51c (250 mg，1.00 mmol) 溶於5 mL 1,4-二氧六環中，加入1-溴-3-甲基丁-2-酮 (200 mg, 1.21 mmol)，置於封管中100℃反應16 h。將反應體系冷卻至室溫，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 5:1)，得51d (0.18 g，收率：57%)。Dissolve 51c (250 mg, 1.00 mmol) in 5 mL of 1,4-dioxane, add 1-bromo-3-methylbutan-2-one (200 mg, 1.21 mmol), and place in a sealed tube React at 100°C for 16 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 5:1) to obtain 51d (0.18 g, yield: 57%).

LCMS m/z = 317.0 [M+1] +. LCMS m/z = 317.0 [M+1] + .

第四步：51e的製備Step 4: Preparation of 51e

將化合物51d (180 mg，0.57 mmol) 溶於10 mL甲醇中，加入0.1 g 10%鈀碳，置換氫氣三次，置於氫氣球氛圍下室溫反應16 h。將反應體系過濾，將濾液減壓濃縮，得粗品51e (0.14 g)。Compound 51d (180 mg, 0.57 mmol) was dissolved in 10 mL of methanol, 0.1 g of 10% palladium on carbon was added, hydrogen was replaced three times, and the reaction was carried out at room temperature under a hydrogen balloon atmosphere for 16 h. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 51e (0.14 g).

LCMS m/z = 287.3 [M+1] + LCMS m/z = 287.3 [M+1] +

以化合物51e為原料，參考實施例18得到化合物51(0.08g)。Using compound 51e as a raw material, compound 51 (0.08g) was obtained with reference to Example 18.

1H NMR (400 MHz, CDCl 3) δ 8.87 (s, 1H), 8.28 – 8.22 (m, 1H), 8.20 – 8.15 (m, 1H), 8.07 – 8.00 (m, 1H), 7.97 (s, 1H), 7.81 – 7.75 (m, 2H), 7.67 (d, 1H), 6.92 – 6.87 (m, 1H), 6.84 – 6.79 (m, 1H), 6.56 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.41 – 4.31 (m, 2H), 4.14 – 4.02 (m, 2H), 3.88 – 3.76 (m, 1H), 3.22 – 3.08 (m, 1H), 2.95 – 2.65 (m, 3H), 2.18 – 2.08 (m, 1H), 1.95 (s, 6H), 1.35 (d, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.87 (s, 1H), 8.28 – 8.22 (m, 1H), 8.20 – 8.15 (m, 1H), 8.07 – 8.00 (m, 1H), 7.97 (s, 1H ), 7.81 – 7.75 (m, 2H), 7.67 (d, 1H), 6.92 – 6.87 (m, 1H), 6.84 – 6.79 (m, 1H), 6.56 (dd, 1H), 4.98 – 4.88 (m, 1H ), 4.41 – 4.31 (m, 2H), 4.14 – 4.02 (m, 2H), 3.88 – 3.76 (m, 1H), 3.22 – 3.08 (m, 1H), 2.95 – 2.65 (m, 3H), 2.18 – 2.08 (m, 1H), 1.95 (s, 6H), 1.35 (d, 6H).

實施例52：化合物52的製備 Example 52: Preparation of Compound 52

第一步：52d的製備Step One: Preparation of 52d

將叔丁醇鉀 (2.0 g，17.82 mmol) 與CuI (1.13 g，5.93 mmol) 溶於30 mL超乾DMF中，氮氣保護下冷卻至0℃，加入(二氟甲基)三甲基矽烷 (1.48 g，11.92 mmol)，置換氮氣三次，0℃攪拌15 min後，加入菲-9,10-二酮 (1.48 g，7.11 mmol)，緩慢滴加52c (1.098 g, 5.93 mmol) 的DMF溶液 (10 mL)，0℃反應1 h，室溫反應16 h。向反應體系裡加入80 mL飽和氯化銨水溶液，墊矽藻土過濾，將濾液用100 mL乙酸乙酯萃取，有機相用50 mL水洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚/乙酸乙酯 (v/v) = 8:1), 得52d (0.35 g，收率：25%)。Dissolve potassium tert-butoxide (2.0 g, 17.82 mmol) and CuI (1.13 g, 5.93 mmol) in 30 mL of ultra-dry DMF, cool to 0°C under nitrogen protection, and add (difluoromethyl)trimethylsilane ( 1.48 g, 11.92 mmol), replaced with nitrogen three times, stirred at 0°C for 15 min, then added phenanthrene-9,10-dione (1.48 g, 7.11 mmol), and slowly added dropwise the DMF solution of 52c (1.098 g, 5.93 mmol) ( 10 mL), react at 0°C for 1 h, and at room temperature for 16 h. Add 80 mL of saturated ammonium chloride aqueous solution to the reaction system, filter through diatomaceous earth, extract the filtrate with 100 mL of ethyl acetate, wash the organic phase with 50 mL of water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is subjected to silica gel chromatography. Column separation and purification (petroleum ether/ethyl acetate (v/v) = 8:1) gave 52d (0.35 g, yield: 25%).

以化合物52d為原料，參考實施例23得到化合物52(30mg)。Using compound 52d as a raw material, compound 52 (30 mg) was obtained with reference to Example 23.

1H NMR (400 MHz, CDCl 3) δ 9.31 (s, 1H), 8.53 (d, 1H), 8.03 (s, 1H), 7.82 – 7.76 (m, 2H), 7.74 – 7.59 (m, 3H), 6.85 – 6.77 (m, 1H), 6.70 – 6.35 (m, 2H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.00 (m, 2H), 3.88 – 3.74 (m, 1H), 2.97 – 2.64 (m, 3H), 2.19 – 2.05 (m, 1H), 1.94 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.31 (s, 1H), 8.53 (d, 1H), 8.03 (s, 1H), 7.82 – 7.76 (m, 2H), 7.74 – 7.59 (m, 3H), 6.85 – 6.77 (m, 1H), 6.70 – 6.35 (m, 2H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.00 (m, 2H), 3.88 – 3.74 (m , 1H), 2.97 – 2.64 (m, 3H), 2.19 – 2.05 (m, 1H), 1.94 (s, 6H).

LCMS m/z = 707.2 [M+1] +. LCMS m/z = 707.2 [M+1] + .

實施例53：化合物53的製備 Example 53: Preparation of Compound 53

第一步：53B的製備Step One: Preparation of 53B

將53A (1.0 g，5.99 mmol) 加入到100 mL單口瓶中，依次加入乾燥二氯甲烷 (20 mL)、16B (952 mg，6.02 mmol) 和TCFH (2.5 g，8.91 mmol)，緩慢滴加N-甲基咪唑 (2.46 g，29.96 mmol)，室溫反應3 h。將反應體系過濾，將濾液減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 93:7)，得53B (1.5 g，收率：82%)。Add 53A (1.0 g, 5.99 mmol) into a 100 mL single-neck bottle, add dry dichloromethane (20 mL), 16B (952 mg, 6.02 mmol) and TCFH (2.5 g, 8.91 mmol) in sequence, and slowly add N dropwise -Methylimidazole (2.46 g, 29.96 mmol), react at room temperature for 3 h. The reaction system was filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 93:7) to obtain 53B (1.5 g, yield: 82%).

LCMS m/z = 307.1 [M+1] + LCMS m/z = 307.1 [M+1] +

第二步：53b的製備Step 2: Preparation of 53b

將3-乙炔基氮雜環丁烷鹽酸鹽 (540 mg，4.59 mmol) 和碳酸鉀 (1.3 g，9.41 mmol) 加入到100 mL單口瓶中，加入20 mL乾燥二甲基亞碸，室溫攪拌20 min後，加入53a (1.0 g，3.08 mmol)，加入CuI (88 mg，0.462 mmol) 和L-脯氨酸(106 mg，0.92 mmol)，置換氮氣三次，100℃反應16 h。將反應體系冷卻至室溫，緩慢傾倒入飽和氯化銨水溶液中 (220 mL)，用乙酸乙酯萃取 (50 mL×2)，有機相用飽和氯化鈉水溶液洗滌 (50 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 58:42)，得53b (0.27g，收率：32%)。Add 3-ethynyl azetidine hydrochloride (540 mg, 4.59 mmol) and potassium carbonate (1.3 g, 9.41 mmol) into a 100 mL single-mouth bottle, add 20 mL dry dimethyl sulfoxide, and keep at room temperature After stirring for 20 min, add 53a (1.0 g, 3.08 mmol), add CuI (88 mg, 0.462 mmol) and L-proline (106 mg, 0.92 mmol), replace nitrogen three times, and react at 100°C for 16 h. Cool the reaction system to room temperature, slowly pour it into saturated aqueous ammonium chloride solution (220 mL), extract with ethyl acetate (50 mL×2), and wash the organic phase with saturated aqueous sodium chloride solution (50 mL×2). Dry over anhydrous sodium sulfate and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 58:42) to obtain 53b (0.27g, yield: 32%).

LCMS m/z = 278.1 [M+1] + LCMS m/z = 278.1 [M+1] +

第三步：53c的製備Step 3: Preparation of 53c

將53b (0.27 g，0.97 mmol) 溶於10 mL二氯甲烷中，加入三氟乙酸 (3 mL)，室溫反應16 h。將反應體系減壓濃縮，加入飽和碳酸鈉水溶液 (30 ml)，用乙酸乙酯萃取 (30 mL×3)，有機相用飽和氯化鈉水溶液洗滌 (30 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 42:58)，得53c (100 mg，收率：70%)。Dissolve 53b (0.27 g, 0.97 mmol) in 10 mL dichloromethane, add trifluoroacetic acid (3 mL), and react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, saturated aqueous sodium carbonate solution (30 ml) was added, extracted with ethyl acetate (30 mL×3), the organic phase was washed with saturated aqueous sodium chloride solution (30 mL×2), and dried over anhydrous sodium sulfate. Concentrate under reduced pressure, and the crude product is separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 42:58) to obtain 53c (100 mg, yield: 70%).

LCMS m/z = 148.1 [M+1] + LCMS m/z = 148.1 [M+1] +

第四步：53d的製備Step 4: Preparation of 53d

將53c (100 mg，0.68 mmol) 加入乾燥乙腈 (10 mL)中、加入碳酸銫 (442 mg，1.36 mmol) 和53B (250 mg，0.82 mmol)，90℃反應16 h。將反應體系冷卻至室溫，過濾，將濾液減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 1:99)，得53d (90 mg，收率：35%)。Add 53c (100 mg, 0.68 mmol) to dry acetonitrile (10 mL), add cesium carbonate (442 mg, 1.36 mmol) and 53B (250 mg, 0.82 mmol), and react at 90°C for 16 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 1:99) to obtain 53d (90 mg, yield: 35%).

LCMS m/z = 374.1 [M+1] + LCMS m/z = 374.1 [M+1] +

第五步：化合物53的製備Step 5: Preparation of Compound 53

將53d (90 mg，0.24 mmol) 加入乾燥DMF (10.0 mL)中，加入53C (67 mg，0.2 mmol) 和三乙胺 (61 mg，0.6 mmol)，置換氮氣三次，加入PdCl 2(PPh 3) 2(14 mg，0.02 mmol) 和CuI (6 mg，0.031 mmol)，置換氮氣三次，60℃反應3 h。將反應體系冷卻至室溫，緩慢加入飽和氯化銨水溶液 (80.0 mL)，用乙酸乙酯萃取 (50 mL×3)，有機相用飽和氯化鈉水溶液洗滌 (50 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 22:78)，得化合物53 (50 mg，收率：40%)。 Add 53d (90 mg, 0.24 mmol) to dry DMF (10.0 mL), add 53C (67 mg, 0.2 mmol) and triethylamine (61 mg, 0.6 mmol), replace nitrogen three times, and add PdCl 2 (PPh 3 ) 2 (14 mg, 0.02 mmol) and CuI (6 mg, 0.031 mmol), replaced with nitrogen three times, and reacted at 60°C for 3 h. Cool the reaction system to room temperature, slowly add saturated aqueous ammonium chloride solution (80.0 mL), extract with ethyl acetate (50 mL×3), wash the organic phase with saturated aqueous sodium chloride solution (50 mL×2), and add anhydrous sulfuric acid. It was dried over sodium and concentrated under reduced pressure. The crude product was separated and purified by silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 22:78) to obtain compound 53 (50 mg, yield: 40%).

1H NMR (400 MHz, CDCl 3) δ 9.04 (s, 1H), 8.43 – 8.34 (m, 1H), 7.98 (s, 1H), 7.89 – 7.78 (m, 2H), 7.76 – 7.71 (m, 1H), 7.51 – 7.45 (m, 1H), 7.38 – 7.33 (m, 1H), 7.24 – 7.21 (m, 1H), 7.15 – 7.11 (m, 1H), 5.01 – 4.93 (m, 1H), 4.19 – 4.06 (m, 2H), 3.84 – 3.70 (m, 3H), 2.98 – 2.67 (m, 3H), 2.21 – 2.11 (m, 1H), 1.98 – 1.90 (m, 6H), 1.54 – 1.45 (m, 1H), 1.05 – 0.96 (m, 2H), 0.63 – 0.52 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.04 (s, 1H), 8.43 – 8.34 (m, 1H), 7.98 (s, 1H), 7.89 – 7.78 (m, 2H), 7.76 – 7.71 (m, 1H) ), 7.51 – 7.45 (m, 1H), 7.38 – 7.33 (m, 1H), 7.24 – 7.21 (m, 1H), 7.15 – 7.11 (m, 1H), 5.01 – 4.93 (m, 1H), 4.19 – 4.06 (m, 2H), 3.84 – 3.70 (m, 3H), 2.98 – 2.67 (m, 3H), 2.21 – 2.11 (m, 1H), 1.98 – 1.90 (m, 6H), 1.54 – 1.45 (m, 1H) , 1.05 – 0.96 (m, 2H), 0.63 – 0.52 (m, 2H).

LCMS m/z = 630.2 [M+1] + LCMS m/z = 630.2 [M+1] +

實施例54：化合物54的製備 Example 54: Preparation of Compound 54

以化合物54a為原料，參考實施例19得到化合物54(45mg)。 Using compound 54a as a raw material, compound 54 (45 mg) was obtained with reference to Example 19.

1H NMR (400 MHz, CDCl 3) δ 8.56 (s, 1H), 8.11 (dd, 1H), 8.08 – 7.97 (m, 1H), 7.81 (s, 1H), 7.75 – 7.62 (m, 2H), 7.24 – 7.15 (m, 1H), 7.11 – 7.06 (m, 1H), 7.04 – 6.97 (m, 1H), 6.84 – 6.77 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.43 – 4.30 (m, 2H), 4.13 – 4.00 (m, 2H), 3.88 – 3.73 (m, 1H), 2.95 – 2.63 (m, 3H), 2.18 – 2.07 (m, 1H), 2.02 – 1.90 (m, 6H), 1.56 – 1.45 (m, 1H), 0.92 – 0.80 (m, 2H), 0.60 – 0.45 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.56 (s, 1H), 8.11 (dd, 1H), 8.08 – 7.97 (m, 1H), 7.81 (s, 1H), 7.75 – 7.62 (m, 2H), 7.24 – 7.15 (m, 1H), 7.11 – 7.06 (m, 1H), 7.04 – 6.97 (m, 1H), 6.84 – 6.77 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H) ), 4.43 – 4.30 (m, 2H), 4.13 – 4.00 (m, 2H), 3.88 – 3.73 (m, 1H), 2.95 – 2.63 (m, 3H), 2.18 – 2.07 (m, 1H), 2.02 – 1.90 (m, 6H), 1.56 – 1.45 (m, 1H), 0.92 – 0.80 (m, 2H), 0.60 – 0.45 (m, 2H).

LCMS m/z = 605.3 [M+1] + LCMS m/z = 605.3 [M+1] +

實施例 55：化合物55的製備 Example 55 : Preparation of Compound 55

第一步：55b的製備Step One: Preparation of 55b

將2-碘苯甲酸 (0.45 g, 1.81 mmol) 、1-氯-N, N, 2-三甲基丙烯胺 (0.36 g, 2.69 mmol)加入二氯甲烷 (10 mL)中，室溫攪拌1 h後，加入三乙胺 (0.75 mL) 與2-氯-4-(三氟甲基)苯胺 (0.42 g, 2.15 mmol)，室溫反應16 h。將反應體系減壓濃縮，粗品用矽膠色譜柱分離提純 (乙酸乙酯/石油醚 (v/v) = 1:20)，得到55b (0.33 g，產率：43%)。Add 2-iodobenzoic acid (0.45 g, 1.81 mmol) and 1-chloro-N, N, 2-trimethylpropenylamine (0.36 g, 2.69 mmol) to dichloromethane (10 mL), and stir at room temperature for 1 After h, add triethylamine (0.75 mL) and 2-chloro-4-(trifluoromethyl)aniline (0.42 g, 2.15 mmol), and react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v) = 1:20) to obtain 55b (0.33 g, yield: 43%).

LCMS m/z = 425.9 [M+1] + LCMS m/z = 425.9 [M+1] +

第二步：55c的製備 Step 2: Preparation of 55c

將55b (0.20 g, 0.47 mmol)、3-乙炔基氮雜環丁-1-甲酸叔丁酯 (0.13 g, 0.72 mmol)、PdCl 2(PPh 3) 2(33 mg, 0.047 mmol)、CuI (18 mg, 0.095 mmol) 和DIPEA (0.18 g, 1.39 mmol)加入DMF (5 mL)，氮氣氛圍60℃反應5 h。將反應體系冷卻至室溫，加入水 (20 mL) 中，用乙酸乙酯/甲醇 (v/v) = 5:1 的混合溶劑萃取 (20 mL×3)，合併有機相，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠柱色譜分離提純 (石油醚/乙酸乙酯 (v/v) = 1:1)，得到55c (0.22 g，收率：98%)。 55b (0.20 g, 0.47 mmol), tert-butyl 3-ethynylazetidine-1-carboxylate (0.13 g, 0.72 mmol), PdCl 2 (PPh 3 ) 2 (33 mg, 0.047 mmol), CuI ( 18 mg, 0.095 mmol) and DIPEA (0.18 g, 1.39 mmol) were added to DMF (5 mL), and the reaction was carried out at 60°C for 5 h in a nitrogen atmosphere. Cool the reaction system to room temperature, add water (20 mL), extract with a mixed solvent of ethyl acetate/methanol (v/v) = 5:1 (20 mL×3), combine the organic phases, and use anhydrous It was dried over sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:1) to obtain 55c (0.22 g, yield: 98%).

以化合物55c為原料，參考實施例23得到化合物55(18mg)。Using compound 55c as a raw material, compound 55 (18 mg) was obtained with reference to Example 23.

1H NMR (400 MHz, CDCl 3) δ 8.07 – 7.97 (m, 2H), 7.93 – 7.80 (m, 2H), 7.79 – 7.69 (m, 2H), 7.68 – 7.61 (m, 2H), 7.58 – 7.50 (m, 1H), 6.79 (d, 1H), 6.54 (dd, 1H), 4.98 – 4.87 (m, 1H), 4.55 – 4.32 (m, 3H), 3.92 – 3.80 (m, 2H), 2.95 – 2.63 (m, 3H), 2.19 – 2.07 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.07 – 7.97 (m, 2H), 7.93 – 7.80 (m, 2H), 7.79 – 7.69 (m, 2H), 7.68 – 7.61 (m, 2H), 7.58 – 7.50 (m, 1H), 6.79 (d, 1H), 6.54 (dd, 1H), 4.98 – 4.87 (m, 1H), 4.55 – 4.32 (m, 3H), 3.92 – 3.80 (m, 2H), 2.95 – 2.63 (m, 3H), 2.19 – 2.07 (m, 1H).

實施例 56 ：化合物56的製備 Example 56 : Preparation of Compound 56

以化合物56a為原料，參考實施例22得到化合物56(50mg)。Using compound 56a as a raw material, compound 56 (50 mg) was obtained with reference to Example 22.

1H NMR (400 MHz, CDCl 3) δ 8.62 (s, 1H), 8.44 (d, 1H), 7.96 (s, 1H), 7.85 – 7.73 (m, 3H), 7.72 – 7.63 (m, 2H), 6.81 (d, 1H), 6.55 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.43 – 4.30 (m, 2H), 4.13 – 4.00 (m, 2H), 3.88 – 3.73 (m, 1H), 3.12 – 2.98 (m, 2H), 2.96 – 2.64 (m, 5H), 2.30 – 2.20 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.62 (s, 1H), 8.44 (d, 1H), 7.96 (s, 1H), 7.85 – 7.73 (m, 3H), 7.72 – 7.63 (m, 2H), 6.81 (d, 1H), 6.55 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.43 – 4.30 (m, 2H), 4.13 – 4.00 (m, 2H), 3.88 – 3.73 (m, 1H), 3.12 – 2.98 (m, 2H), 2.96 – 2.64 (m, 5H), 2.30 – 2.20 (m, 3H).

實施例 57 ：化合物57的製備 Example 57 : Preparation of Compound 57

第一步：57b的製備Step One: Preparation of 57b

將57a (1.95 g，10.05 mmol) 加入到30 mL超乾DMF中，冷卻至5℃，加入60%氫化鈉 (0.29 g)，在5℃下反應1 h後，加入2-(2,6-二氧代哌啶-3-基)-5-氟異吲哚啉-1,3-二酮 (3.0 g，10.87 mmol)，60℃反應3 h。將反應體系冷卻至室溫，加入100 mL水，析出固體，過濾，將濾餅減壓乾燥，得粗品57b (2.1 g)。Add 57a (1.95 g, 10.05 mmol) to 30 mL of ultra-dry DMF, cool to 5°C, add 60% sodium hydride (0.29 g), react at 5°C for 1 h, then add 2-(2,6- Dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (3.0 g, 10.87 mmol), react at 60°C for 3 h. The reaction system was cooled to room temperature, 100 mL of water was added, the solid was precipitated, filtered, and the filter cake was dried under reduced pressure to obtain crude product 57b (2.1 g).

LCMS m/z = 451.3 [M+1] + LCMS m/z = 451.3 [M+1] +

第二步：57d的製備Step 2: Preparation of 57d

將2c (4.7 g，10 mmol) 溶於100 mL 二氯甲烷中，依次加入乙炔基三甲基矽烷 (1.96 g，20 mmol)、TEA (2.0 g，19.8 mmol)、CuI (0.19 g，1 mmol) 和PdCl 2(PPh 3) 2(0.7 g，1 mmol)，置換氮氣三次，室溫反應4 h。將反應體系減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) =4:1)，得57d (4.3 g，收率：98%)。 Dissolve 2c (4.7 g, 10 mmol) in 100 mL dichloromethane, and add ethynyltrimethylsilane (1.96 g, 20 mmol), TEA (2.0 g, 19.8 mmol), and CuI (0.19 g, 1 mmol) in sequence ) and PdCl 2 (PPh 3 ) 2 (0.7 g, 1 mmol), replaced with nitrogen three times, and reacted at room temperature for 4 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) =4:1) to obtain 57d (4.3 g, yield: 98%).

第三步：57e的製備Step 3: Preparation of 57e

將57d (4.3 g，9.77 mmol) 加入到60 mL四氫呋喃中，加入20 mL 1 mol/L四丁基氟化銨的四氫呋喃溶液，室溫反應2 h。向反應液中加入100 mL乙酸乙酯，用100 mL水洗滌三次，無水硫酸鈉乾燥，減壓濃縮，得粗品57e (3.5 g)。Add 57d (4.3 g, 9.77 mmol) to 60 mL of tetrahydrofuran, add 20 mL of 1 mol/L tetrabutylammonium fluoride in tetrahydrofuran, and react at room temperature for 2 h. 100 mL of ethyl acetate was added to the reaction solution, washed three times with 100 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 57e (3.5 g).

第四步：化合物57的製備Step 4: Preparation of Compound 57

將上述粗品57e (0.22 g) 溶於5 mL DMF中，依次加入上述粗品57b (0.27 g)、TEA (0.2 g，1.98 mmol)、CuI (0.019 g，0.1 mmol) 和PdCl 2(PPh 3) 2(0.07 g，0.1 mmol)，置換氮氣三次，65℃反應4 h。將反應液冷卻至室溫，加入20 mL飽和氯化銨水溶液，過濾，將濾餅用10 mL水洗滌，將濾餅用50 mL DCM溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) =1:1)，得化合物57 (150 mg，從化合物57d算兩步收率：35%)。 Dissolve the above crude product 57e (0.22 g) in 5 mL DMF, and add the above crude product 57b (0.27 g), TEA (0.2 g, 1.98 mmol), CuI (0.019 g, 0.1 mmol) and PdCl 2 (PPh 3 ) 2 in sequence. (0.07 g, 0.1 mmol), replaced with nitrogen three times, and reacted at 65°C for 4 h. Cool the reaction solution to room temperature, add 20 mL saturated aqueous ammonium chloride solution, filter, wash the filter cake with 10 mL water, dissolve the filter cake with 50 mL DCM, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel chromatography for the crude product Column separation and purification (petroleum ether/ethyl acetate (v/v) =1:1) gave compound 57 (150 mg, two-step yield calculated from compound 57d: 35%).

1H NMR (400 MHz, DMSO- d 6 ) δ 11.13 (s, 1H), 9.20 – 9.08 (m, 2H), 8.50 (s, 1H), 8.45 – 8.32 (m, 2H), 8.23 – 8.04 (m, 3H), 8.04 – 7.87 (m, 2H), 7.80 – 7.71 (m, 1H), 5.26 – 5.12 (m, 1H), 3.05 – 2.73 (m, 5H), 2.70 – 2.50 (m, 2H), 2.18 – 1.92 (m, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.13 (s, 1H), 9.20 – 9.08 (m, 2H), 8.50 (s, 1H), 8.45 – 8.32 (m, 2H), 8.23 – 8.04 (m , 3H), 8.04 – 7.87 (m, 2H), 7.80 – 7.71 (m, 1H), 5.26 – 5.12 (m, 1H), 3.05 – 2.73 (m, 5H), 2.70 – 2.50 (m, 2H), 2.18 – 1.92 (m, 3H).

實施例58：化合物58的製備 Example 58: Preparation of Compound 58

第一步：58a的製備Step One: Preparation of 58a

將上述粗品57e (0.74 g) 加入到12 mL四氫呋喃中，加入1-Boc-3-疊氮基氮雜環丁烷 (CAS: 429672-02-6) (0.4 g，2.02 mmol)，加入五水硫酸銅 (1.0 g，4.0 mmol) 和L-抗壞血酸鈉 (CAS: 134-03-2) (0.4 g，2.02 mmol)，室溫反應16 h。向反應體系中加入50 mL水，析出固體，用50 mL乙酸乙酯萃取，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚/乙酸乙酯 (v/v) = 1:1)，得58a (0.9 g，收率：79%)。 Add the above crude product 57e (0.74 g) to 12 mL tetrahydrofuran, add 1-Boc-3-azidoazetidine (CAS: 429672-02-6) (0.4 g, 2.02 mmol), and add pentahydrate Copper sulfate (1.0 g, 4.0 mmol) and L-sodium ascorbate (CAS: 134-03-2) (0.4 g, 2.02 mmol) were reacted at room temperature for 16 h. Add 50 mL of water to the reaction system, precipitate the solid, extract with 50 mL of ethyl acetate, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 1 :1), obtained 58a (0.9 g, yield: 79%).

LCMS m/z = 566.2 [M+1] + LCMS m/z = 566.2 [M+1] +

第二步：58b的對甲苯磺酸鹽的製備Step 2: Preparation of p-toluenesulfonate of 58b

將58a (0.28 g，0.495 mmol) 加入到5 mL乙腈中，加入對甲苯磺酸一水合物 (0.38 g，2.0 mmol)，室溫反應3 h。將反應體系減壓濃縮，得粗品58b的對甲苯磺酸鹽 (0.23 g)。Add 58a (0.28 g, 0.495 mmol) to 5 mL acetonitrile, add p-toluenesulfonic acid monohydrate (0.38 g, 2.0 mmol), and react at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the p-toluenesulfonate salt of crude product 58b (0.23 g).

第三步：化合物58的製備Step 3: Preparation of Compound 58

將上述粗品58b的對甲苯磺酸鹽 (0.23 g) 溶於5 mL DMSO中，加入1.0 mL DIPEA和2-(2,6-二氧代哌啶-3-基)-5-氟異吲哚啉-1,3-二酮 (280 mg，1.01 mmol)，95℃反應3 h。將反應液冷卻至室溫，加入20 mL水，析出固體，抽濾，將濾餅用50 mL二氯甲烷溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (二氯甲烷/甲醇 (v/v) = 15:1)，得化合物58 (110 mg，收率：15%)。Dissolve the p-toluenesulfonate salt of the above crude product 58b (0.23 g) in 5 mL DMSO, add 1.0 mL DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole Phenoline-1,3-dione (280 mg, 1.01 mmol), react at 95°C for 3 h. Cool the reaction solution to room temperature, add 20 mL of water, precipitate the solid, filter with suction, dissolve the filter cake with 50 mL of methylene chloride, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify the crude product with a silica gel chromatography column (methylene chloride) /methanol (v/v) = 15:1), compound 58 (110 mg, yield: 15%) was obtained.

1H NMR (400 MHz, DMSO- d 6 ) δ 11.07 (s, 1H), 9.12 (s, 1H), 8.63 (s, 1H), 8.47 (s, 1H), 8.23 (d, 1H), 8.10 (s, 1H), 7.94 – 7.88 (m, 1H), 7.78 – 7.68 (m, 2H), 6.98 (d, 1H), 6.82 (dd, 1H), 5.82 – 5.70 (m, 1H), 5.14 – 5.02 (m, 1H), 4.73 – 4.60 (m, 2H), 4.48 – 4.37 (m, 2H), 3.05 – 2.73 (m, 5H), 2.71 – 2.50 (m, 2H), 2.10 – 1.95 (m, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.07 (s, 1H), 9.12 (s, 1H), 8.63 (s, 1H), 8.47 (s, 1H), 8.23 (d, 1H), 8.10 ( s, 1H), 7.94 – 7.88 (m, 1H), 7.78 – 7.68 (m, 2H), 6.98 (d, 1H), 6.82 (dd, 1H), 5.82 – 5.70 (m, 1H), 5.14 – 5.02 ( m, 1H), 4.73 – 4.60 (m, 2H), 4.48 – 4.37 (m, 2H), 3.05 – 2.73 (m, 5H), 2.71 – 2.50 (m, 2H), 2.10 – 1.95 (m, 3H).

LCMS m/z = 722.6 [M+1] + LCMS m/z = 722.6 [M+1] +

實施例59：化合物59的合成 Example 59: Synthesis of Compound 59

第一步：59b的製備Step One: Preparation of 59b

將59a (2.26 g，9.96 mmol) 加入到40 mL 1,4-二氧六環中，加入乙烯基硼酸頻哪醇酯 (3.1 g，20.1 mmol) 和氟化銫 (3.0 g，19.75 mmol)，加入Pd(dppf)Cl 2(0.7 g，0.96 mmol) 和10 mL水，85℃反應16 h。將反應體系冷卻至室溫，減壓濃縮，加入100 ml乙酸乙酯和50 mL水，分離出有機相，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚:乙酸乙酯 (v/v) = 10:1)，得59b (1.0 g，收率：58%)。 Add 59a (2.26 g, 9.96 mmol) to 40 mL of 1,4-dioxane, add vinylboronic acid pinacol ester (3.1 g, 20.1 mmol) and cesium fluoride (3.0 g, 19.75 mmol), Add Pd(dppf)Cl 2 (0.7 g, 0.96 mmol) and 10 mL water, and react at 85°C for 16 h. The reaction system was cooled to room temperature, concentrated under reduced pressure, 100 ml of ethyl acetate and 50 mL of water were added, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate). Ester (v/v) = 10:1), giving 59b (1.0 g, yield: 58%).

第二步：59c的製備Step 2: Preparation of 59c

將59b (1.0 g，5.74 mmol) 加入到20 mL四氫呋喃中，加入碘化鈉 (0.15 g，1.0 mmol) 和三氟甲基三甲基矽烷 (3.3 g，23.2 mmol)，65℃反應5 h。將反應體系冷卻至室溫，減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚:乙酸乙酯 (v/v) = 1:1)，得59c (0.5 g，收率：39%)。Add 59b (1.0 g, 5.74 mmol) to 20 mL tetrahydrofuran, add sodium iodide (0.15 g, 1.0 mmol) and trifluoromethyltrimethylsilane (3.3 g, 23.2 mmol), and react at 65°C for 5 h. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 1:1) to obtain 59c (0.5 g, yield: 39%).

第三步：59d的製備Step 3: Preparation of 59d

將59c (0.22 g，0.98 mmol) 加入到10 mL乙醇中，加入鐵粉 (0.34 g，6.07 mmol) 和2 mL飽和氯化銨水溶液，回流反應2 h。將反應液冷卻至室溫，加入50 mL乙酸乙酯和50 mL水，分離出有機相，無水硫酸鈉乾燥，減壓濃縮，得粗品59d (0.16 g)。Add 59c (0.22 g, 0.98 mmol) to 10 mL of ethanol, add iron powder (0.34 g, 6.07 mmol) and 2 mL of saturated aqueous ammonium chloride solution, and reflux for 2 h. The reaction solution was cooled to room temperature, 50 mL of ethyl acetate and 50 mL of water were added, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 59d (0.16 g).

LCMS m/z = 195.1 [M+1] + LCMS m/z = 195.1 [M+1] +

以化合物59d為原料，參考實施例19得到化合物59(0.19g)。Using compound 59d as a raw material, compound 59 (0.19g) was obtained with reference to Example 19.

1H NMR (400 MHz, CDCl 3) δ 9.30 (s, 1H), 8.29 (d, 1H), 8.09 (s, 1H), 7.80 (s, 1H), 7.75 (s, 1H), 7.67 (d, 1H), 7.58 (dd, 1H), 7.49 (s, 1H), 6.80 (d, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.12 – 4.00 (m, 2H), 3.88 – 3.72 (m, 1H), 2.95 – 2.62 (m, 3H), 2.54 – 2.41 (m, 1H), 2.04 – 1.88 (m, 7H), 1.70 – 1.50 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.30 (s, 1H), 8.29 (d, 1H), 8.09 (s, 1H), 7.80 (s, 1H), 7.75 (s, 1H), 7.67 (d, 1H), 7.58 (dd, 1H), 7.49 (s, 1H), 6.80 (d, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.12 – 4.00 (m, 2H), 3.88 – 3.72 (m, 1H), 2.95 – 2.62 (m, 3H), 2.54 – 2.41 (m, 1H), 2.04 – 1.88 (m, 7H), 1.70 – 1.50 (m, 2H).

實施例60：化合物60的製備 Example 60: Preparation of Compound 60

以化合物60a為原料，參考實施例59得到化合物60（55mg）。Using compound 60a as a raw material, compound 60 (55 mg) was obtained with reference to Example 59.

1H NMR (400 MHz, CDCl 3) δ 9.06 (s, 1H), 8.28 – 8.14 (m, 2H), 7.81 (s, 1H), 7.75 (s, 1H), 7.67 (d, 1H), 7.54 (d, 1H), 7.45 (s, 1H), 6.84 – 6.78 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.01 (m, 2H), 3.86 – 3.74 (m, 1H), 2.94 – 2.62 (m, 3H), 2.60 – 2.46 (m, 1H), 2.18 – 2.06 (m, 1H), 2.00 – 1.86 (m, 7H), 1.62 – 1.49 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.06 (s, 1H), 8.28 – 8.14 (m, 2H), 7.81 (s, 1H), 7.75 (s, 1H), 7.67 (d, 1H), 7.54 ( d, 1H), 7.45 (s, 1H), 6.84 – 6.78 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.01 ( m, 2H), 3.86 – 3.74 (m, 1H), 2.94 – 2.62 (m, 3H), 2.60 – 2.46 (m, 1H), 2.18 – 2.06 (m, 1H), 2.00 – 1.86 (m, 7H), 1.62 – 1.49 (m, 1H).

實施例61：化合物61的三氟乙酸鹽的製備 Example 61: Preparation of trifluoroacetate salt of compound 61

第一步：61b的製備Step One: Preparation of 61b

將61a (2.41 g，9.88 mmol) 和1-溴環丁烷-1-甲酸乙酯 (1.5 g，7.24 mmol) 溶於40 mL乙腈中，加入碳酸銫 (4.39 g，13.47 mmol)，80 oC反應18 h。將反應液冷卻至室溫，抽濾，將濾液減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 5:1)，得61b (1.1 g，收率：41%)。 Dissolve 61a (2.41 g, 9.88 mmol) and 1-bromocyclobutane-1-carboxylic acid ethyl ester (1.5 g, 7.24 mmol) in 40 mL acetonitrile, add cesium carbonate (4.39 g, 13.47 mmol), 80 o C React for 18 hours. The reaction solution was cooled to room temperature, filtered with suction, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 5:1) to obtain 61b (1.1 g, yield :41%).

LCMS m/z = 371.4 [M+1] + LCMS m/z = 371.4 [M+1] +

第二步：61c的製備Step 2: Preparation of 61c

將61b (1.1 g，2.97 mmol) 溶於10 mL四氫呋喃/水 (v/v) = 4:1中，加入一水合氫氧化鋰 (0.62 g，14.78 mmol)，40 oC反應5 h。將反應液冷卻至室溫，加入5 mL水，用1 mol/L鹽酸溶液調pH至3，用20 mL乙酸乙酯萃取三次，分離出有機相，無水硫酸鈉乾燥，減壓濃縮，得粗品 (0.99 g)。將上述粗品 (0.99 g) 溶於10 mL DCM中，加入TCFH (1.22 g，4.35 mmol) 和2-氯-4-(三氟甲基)苯胺 (0.73 g，3.73 mmol)，加入N-甲基咪唑 (0.95 g，11.57 mmol)，室溫反應19 h。向反應液中加入30 mL二氯甲烷，加入30 mL水，分離出有機相，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 5:1-1:1)，得到61c (650 mg，收率：42%)。 Dissolve 61b (1.1 g, 2.97 mmol) in 10 mL tetrahydrofuran/water (v/v) = 4:1, add lithium hydroxide monohydrate (0.62 g, 14.78 mmol), and react at 40 ° C for 5 h. Cool the reaction solution to room temperature, add 5 mL of water, adjust the pH to 3 with 1 mol/L hydrochloric acid solution, extract three times with 20 mL of ethyl acetate, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product (0.99 g). Dissolve the above crude product (0.99 g) in 10 mL DCM, add TCFH (1.22 g, 4.35 mmol) and 2-chloro-4-(trifluoromethyl)aniline (0.73 g, 3.73 mmol), add N-methyl Imidazole (0.95 g, 11.57 mmol), reacted at room temperature for 19 h. Add 30 mL of methylene chloride to the reaction solution, add 30 mL of water, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 5:1-1:1), obtaining 61c (650 mg, yield: 42%).

第三步：化合物61的三氟乙酸鹽的製備Step 3: Preparation of trifluoroacetate salt of compound 61

將61c (0.40 g，0.77 mmol)、上述粗品中間體1 (0.39 g)、TEA (0.23 g，2.27 mmol)、CuI (29 mg，0.15 mmol) 和PdCl 2(PPh 3) 2(110 mg，0.157 mmol) 加入5 mL DMF，氮氣氛圍55℃反應5 h。將反應液冷卻至室溫，加入50 mL水，抽濾，濾餅用10 mL水洗滌，將濾餅用50 mL 二氯甲烷/甲醇 (v/v) = 5:1的混合溶劑溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚/乙酸乙酯 (v/v) = 1:1.5)，所得粗品過Pre-HPLC (儀器及製備柱：採用Glison GX-281製備液相，製備柱型號是Sunfire C18，5 μm，內徑×長度 = 30 mm×150 mm)。製備方法：粗品用甲醇和二甲亞碸溶解，並用0.45 μm濾膜過濾，製備成樣品液。流動相體系：乙腈/水 (含0.1% TFA)。梯度沖提方法：乙腈由5%梯度沖提60% (沖提時間15 min)，凍乾得到化合物61的三氟乙酸鹽 (210 mg)。 61c (0.40 g, 0.77 mmol), the above crude intermediate 1 (0.39 g), TEA (0.23 g, 2.27 mmol), CuI (29 mg, 0.15 mmol) and PdCl 2 (PPh 3 ) 2 (110 mg, 0.157 mmol), add 5 mL DMF, and react at 55°C for 5 h in a nitrogen atmosphere. Cool the reaction solution to room temperature, add 50 mL of water, filter with suction, wash the filter cake with 10 mL of water, dissolve the filter cake with 50 mL of a mixed solvent of methylene chloride/methanol (v/v) = 5:1, anhydrous Dry over sodium sulfate and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 1:1.5). The crude product obtained is subjected to Pre-HPLC (instrument and preparation column: use Glison GX-281 Preparation liquid phase, the preparation column model is Sunfire C18, 5 μm, inner diameter × length = 30 mm × 150 mm). Preparation method: Dissolve the crude product with methanol and dimethyl sulfoxide, filter it with a 0.45 μm filter membrane, and prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA). Gradient elution method: Gradient elution from 5% acetonitrile to 60% (elution time 15 min), and freeze-drying to obtain the trifluoroacetate salt of compound 61 (210 mg).

1H NMR (400 MHz, CDCl 3) δ 9.16 (s, 1H), 8.63 (d, 1H), 7.96 (s, 1H), 7.83 – 7.75 (m, 1H), 7.70 (d, 1H), 7.55 – 7.38 (m, 4H), 7.30 – 7.20 (m, 1H), 6.86 (d, 1H), 6.61 (dd, 1H), 5.24 – 5.10 (m, 1H), 5.01 – 4.87 (m, 1H), 4.53 – 4.41 (m, 2H), 4.30 – 4.17 (m, 2H), 4.17 – 3.93 (m, 2H), 2.97 – 2.36 (m, 6H), 2.36 – 2.21 (m, 1H), 2.21 – 2.07 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.16 (s, 1H), 8.63 (d, 1H), 7.96 (s, 1H), 7.83 – 7.75 (m, 1H), 7.70 (d, 1H), 7.55 – 7.38 (m, 4H), 7.30 – 7.20 (m, 1H), 6.86 (d, 1H), 6.61 (dd, 1H), 5.24 – 5.10 (m, 1H), 5.01 – 4.87 (m, 1H), 4.53 – 4.41 (m, 2H), 4.30 – 4.17 (m, 2H), 4.17 – 3.93 (m, 2H), 2.97 – 2.36 (m, 6H), 2.36 – 2.21 (m, 1H), 2.21 – 2.07 (m, 1H ).

實施例62：化合物62的三氟乙酸鹽的製備 Example 62: Preparation of trifluoroacetate salt of compound 62

第一步：62b的製備Step One: Preparation of 62b

將62a (0.65 g，2.90 mmol) 溶於10 mL DCM中，加入DMAP (71 mg，0.58 mmol) 和 (Boc) 2O (0.69 g，3.16 mmol)，室溫反應4 h。向反應液中加入20 mL二氯甲烷和30 mL水，分離出有機相，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 5:1-1:1)，得到62b (0.8 g，收率：85%)。 Dissolve 62a (0.65 g, 2.90 mmol) in 10 mL DCM, add DMAP (71 mg, 0.58 mmol) and (Boc) 2 O (0.69 g, 3.16 mmol), and react at room temperature for 4 h. Add 20 mL dichloromethane and 30 mL water to the reaction solution, separate the organic phase, dry it over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 5 :1-1:1), obtaining 62b (0.8 g, yield: 85%).

第二步：62c的製備Step 2: Preparation of 62c

將62b (0.4 g，1.23 mmol)、氰化鋅 (0.14 g，1.19 mmol)、4,5-雙二苯基膦-9,9-二甲基氧雜蒽 (CAS: 161265-03-8) (71 mg，0.12 mmol) 和雙(二亞芐基丙酮)鈀 (CAS: 32005-36-0) (71 mg，0.125 mmol) 溶於5 mL DMF中，加入N,N,N',N'-四甲基乙二胺 (0.57 g，4.91 mmol)，100 oC反應18 h。將反應液冷卻至室溫，加入50 mL飽和氯化鈉水溶液，用60 mL乙酸乙酯萃取，合併有機相，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 5:1)，得62c (0.22 g，收率：68%)。 Combine 62b (0.4 g, 1.23 mmol), zinc cyanide (0.14 g, 1.19 mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (CAS: 161265-03-8) (71 mg, 0.12 mmol) and bis(dibenzylideneacetone)palladium (CAS: 32005-36-0) (71 mg, 0.125 mmol) were dissolved in 5 mL DMF, and N,N,N',N' were added -Tetramethylethylenediamine (0.57 g, 4.91 mmol), react at 100 ° C for 18 h. The reaction solution was cooled to room temperature, 50 mL of saturated aqueous sodium chloride solution was added, extracted with 60 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum) Ether/ethyl acetate (v/v) = 5:1), 62c (0.22 g, yield: 68%) was obtained.

LCMS m/z = 271.4 [M+1] + LCMS m/z = 271.4 [M+1] +

第三步：62d的製備Step 3: Preparation of 62d

將62c (0.22 g，0.81 mmol) 溶於2 mL DCM中，加入2 mL三氟乙酸，室溫反應3.5 h。向反應液中加入5 mL水，用飽和碳酸氫鈉水溶液調pH至8，用20 mL二氯甲烷萃取三次，分離出有機相，無水硫酸鈉乾燥，減壓濃縮，得粗品62d (0.11 g)。Dissolve 62c (0.22 g, 0.81 mmol) in 2 mL DCM, add 2 mL trifluoroacetic acid, and react at room temperature for 3.5 h. Add 5 mL of water to the reaction solution, adjust the pH to 8 with saturated sodium bicarbonate aqueous solution, extract three times with 20 mL of dichloromethane, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product 62d (0.11 g) .

以62d+2-(4-碘代-1H-吡唑-1-基)-2-甲基丙酸為原料，參考實施例7的合成方法得到化合物62的三氟乙酸鹽 (19 mg)。Using 62d+2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropionic acid as raw material, the trifluoroacetate salt of compound 62 (19 mg) was obtained with reference to the synthesis method of Example 7.

1H NMR (400 MHz, CDCl 3) δ 8.35 (d, 1H), 8.00 (s, 1H), 7.72 – 7.59 (m, 3H), 7.48 (dd, 1H), 6.82 (dd, 2H), 6.55 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.43 – 4.27 (m, 2H), 4.13 – 4.01 (m, 2H), 3.88 – 3.72 (m, 1H), 3.10 (s, 2H), 2.95 – 2.69 (m, 3H), 2.18 – 2.07 (m, 1H), 1.87 (s, 6H), 1.04 – 0.84 (m, 4H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.35 (d, 1H), 8.00 (s, 1H), 7.72 – 7.59 (m, 3H), 7.48 (dd, 1H), 6.82 (dd, 2H), 6.55 ( dd, 1H), 4.98 – 4.88 (m, 1H), 4.43 – 4.27 (m, 2H), 4.13 – 4.01 (m, 2H), 3.88 – 3.72 (m, 1H), 3.10 (s, 2H), 2.95 – 2.69 (m, 3H), 2.18 – 2.07 (m, 1H), 1.87 (s, 6H), 1.04 – 0.84 (m, 4H).

LCMS m/z = 642.3 [M+1] + LCMS m/z = 642.3 [M+1] +

實施例63：化合物63的三氟乙酸鹽的製備 Example 63: Preparation of trifluoroacetate salt of compound 63

以化合物63a+2-(4-碘代-1H-吡唑-1-基)-2-甲基丙酸為原料，參考實施例19得到化合物63的三氟乙酸鹽(110mg) Using compound 63a+2-(4-iodo-1H-pyrazol-1-yl)-2-methylpropionic acid as raw materials, the trifluoroacetate salt of compound 63 (110 mg) was obtained with reference to Example 19.

1H NMR (400 MHz, CDCl 3) δ 9.12 (s, 1H), 8.10 – 8.02 (m, 1H), 7.91 (s, 1H), 7.76 (s, 1H), 7.71 (s, 1H), 7.60 (d, 1H), 7.21 – 7.13 (m, 2H), 6.77 – 6.70 (m, 1H), 6.48 (dd, 1H), 4.91 – 4.81 (m, 1H), 4.33 – 4.22 (m, 2H), 4.05 – 3.95 (m, 2H), 3.80 – 3.67 (m, 1H), 2.90 – 2.57 (m, 3H), 2.12 – 2.00 (m, 1H), 1.87 (s, 6H), 1.83 – 1.73 (m, 1H), 0.97 – 0.88 (m, 2H), 0.61 – 0.54 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.12 (s, 1H), 8.10 – 8.02 (m, 1H), 7.91 (s, 1H), 7.76 (s, 1H), 7.71 (s, 1H), 7.60 ( d, 1H), 7.21 – 7.13 (m, 2H), 6.77 – 6.70 (m, 1H), 6.48 (dd, 1H), 4.91 – 4.81 (m, 1H), 4.33 – 4.22 (m, 2H), 4.05 – 3.95 (m, 2H), 3.80 – 3.67 (m, 1H), 2.90 – 2.57 (m, 3H), 2.12 – 2.00 (m, 1H), 1.87 (s, 6H), 1.83 – 1.73 (m, 1H), 0.97 – 0.88 (m, 2H), 0.61 – 0.54 (m, 2H).

LCMS m/z = 630.2 [M+1] + LCMS m/z = 630.2 [M+1] +

實施例64：化合物64的製備 Example 64: Preparation of Compound 64

第一步：64b的製備Step 1: Preparation of 64b

將64a (3.52 g，20.0 mmol)、三苯基膦 (15.73 g，59.97 mmol)、碘化鉀 (6.64 g，40.0 mmol) 加入60 mL乙腈中，氮氣氛圍70℃反應30 min,冷卻至室溫，緩慢滴加2,2-二氟-2-(氟磺醯基)乙酸甲酯 (6.72 g，34.98 mmol) 的20 mL乙腈溶液，氮氣氛圍70℃反應3 h。將反應體系冷卻到室溫，加入80 mL水，用100 mL乙酸乙酯萃取，有機相用50 mL水洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化(純石油醚)，得到64b (0.34 g，收率：7%)。Add 64a (3.52 g, 20.0 mmol), triphenylphosphine (15.73 g, 59.97 mmol), and potassium iodide (6.64 g, 40.0 mmol) into 60 mL acetonitrile, react at 70°C for 30 min in a nitrogen atmosphere, cool to room temperature, and slowly A 20 mL acetonitrile solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid methyl ester (6.72 g, 34.98 mmol) was added dropwise, and the reaction was carried out at 70°C in a nitrogen atmosphere for 3 hours. Cool the reaction system to room temperature, add 80 mL of water, and extract with 100 mL of ethyl acetate. The organic phase is washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (pure petroleum ether). , obtained 64b (0.34 g, yield: 7%).

第二步：64c的製備Step 2: Preparation of 64c

將64b (0.2 g，0.87 mmol) 溶於5 mL乙醇中，加入2 mL飽和氯化銨水溶液和還原鐵粉 (0.49 g，8.75 mmol)，回流反應2 h。將反應體系冷卻至室溫，過濾，將濾液用100 mL乙酸乙酯萃取，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 5:1)，得64c (0.16 g，收率：92%)。Dissolve 64b (0.2 g, 0.87 mmol) in 5 mL of ethanol, add 2 mL of saturated aqueous ammonium chloride solution and reduced iron powder (0.49 g, 8.75 mmol), and react under reflux for 2 h. The reaction system was cooled to room temperature and filtered. The filtrate was extracted with 100 mL of ethyl acetate. The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) ) = 5:1), 64c (0.16 g, yield: 92%) was obtained.

LCMS m/z = 201.1 [M+1] + LCMS m/z = 201.1 [M+1] +

以化合物64c為原料，參考實施例19得到化合物64(0.110g)。 Using compound 64c as a raw material, compound 64 (0.110 g) was obtained with reference to Example 19.

1H NMR (400 MHz, CDCl 3) δ 9.25 (s, 1H), 8.15 (d, 1H), 7.98 (s, 1H), 7.83 – 7.75 (m, 2H), 7.71 – 7.60 (m, 2H), 7.58 – 7.52 (m, 1H), 6.81 (d, 1H), 6.56 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.12 – 4.01 (m, 2H), 3.88 – 3.75 (m, 1H), 3.30 (q, 2H), 2.95 – 2.65 (m, 3H), 2.17 – 2.06 (m, 1H), 1.93 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.25 (s, 1H), 8.15 (d, 1H), 7.98 (s, 1H), 7.83 – 7.75 (m, 2H), 7.71 – 7.60 (m, 2H), 7.58 – 7.52 (m, 1H), 6.81 (d, 1H), 6.56 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.12 – 4.01 (m, 2H), 3.88 – 3.75 (m, 1H), 3.30 (q, 2H), 2.95 – 2.65 (m, 3H), 2.17 – 2.06 (m, 1H), 1.93 (s, 6H).

實施例65：化合物65三氟乙酸鹽的製備 Example 65: Preparation of compound 65 trifluoroacetate salt

以65b為原料，參考實施例19製備方法，經酸性製備[流動相體系：乙腈/水 (含0.1% TFA)]，凍乾得到化合物65的三氟乙酸鹽(20mg)。Using 65b as raw material, refer to the preparation method of Example 19, undergo acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and freeze-dry to obtain the trifluoroacetate salt of compound 65 (20 mg).

化合物65的游離鹼以化合物65b為原料，參考實施例19的製備方法，經中性製備[流動相體系：乙腈/水 (含10 mmol/L碳酸氫銨)] 凍乾得到。The free base of compound 65 was prepared by using compound 65b as raw material, referring to the preparation method of Example 19, and was prepared by neutral preparation [mobile phase system: acetonitrile/water (containing 10 mmol/L ammonium bicarbonate)] and freeze-drying.

化合物65游離鹼核磁數據：Compound 65 free base NMR data:

1H NMR (400 MHz, CDCl 3) δ 8.43 (s, 1H), 8.02 (s, 1H), 7.96 (d, 1H), 7.80 (s, 1H), 7.70 (s, 1H), 7.67 (d, 1H), 6.88 (dd, 1H), 6.84 – 6.77 (m, 2H), 6.55 (dd, 1H), 4.99 – 4.88 (m, 1H), 4.40 – 4.30 (m, 2H), 4.13 – 4.00 (m, 2H), 3.88 – 3.73 (m, 1H), 2.94 – 2.64 (m, 3H), 2.20 – 2.05 (m, 1H), 1.94 (s, 6H), 1.85 – 1.73 (m, 1H), 1.53 – 1.41 (m, 1H), 0.95 – 0.77 (m, 4H), 0.65 – 0.55 (m, 2H), 0.55 – 0.47 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.43 (s, 1H), 8.02 (s, 1H), 7.96 (d, 1H), 7.80 (s, 1H), 7.70 (s, 1H), 7.67 (d, 1H), 6.88 (dd, 1H), 6.84 – 6.77 (m, 2H), 6.55 (dd, 1H), 4.99 – 4.88 (m, 1H), 4.40 – 4.30 (m, 2H), 4.13 – 4.00 (m, 2H), 3.88 – 3.73 (m, 1H), 2.94 – 2.64 (m, 3H), 2.20 – 2.05 (m, 1H), 1.94 (s, 6H), 1.85 – 1.73 (m, 1H), 1.53 – 1.41 ( m, 1H), 0.95 – 0.77 (m, 4H), 0.65 – 0.55 (m, 2H), 0.55 – 0.47 (m, 2H).

LCMS m/z = 645.3 [M+1] + LCMS m/z = 645.3 [M+1] +

實施例66：化合物66的製備 Example 66: Preparation of Compound 66

第一步：66c的製備Step One: Preparation of 66c

向反應瓶中分別加入1-氯-N,N,2-三甲基丙烯胺 (0.72 g, 5.39 mmol)、2-(4-碘代-1H-吡唑-1-基)-2-甲基丙酸 (1.00 g, 3.57 mmol) 和DCM (20 mL)，室溫攪拌1 h後，依次加入TEA (1.48 mL, 10.65 mmol) 和66b (0.56 g, 3.54 mmol)，室溫反應1 h。將反應液減壓濃縮，粗品用矽膠色譜柱分離純化 (乙酸乙酯/石油醚 (v/v) = 1:5)，得66c (1.05 g，收率：71%)。Add 1-chloro-N,N,2-trimethylpropenylamine (0.72 g, 5.39 mmol) and 2-(4-iodo-1H-pyrazol-1-yl)-2-methyl to the reaction bottle respectively. Propionic acid (1.00 g, 3.57 mmol) and DCM (20 mL) were stirred at room temperature for 1 h, then TEA (1.48 mL, 10.65 mmol) and 66b (0.56 g, 3.54 mmol) were added in sequence, and the reaction was carried out at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v) = 1:5) to obtain 66c (1.05 g, yield: 71%).

LCMS m/z = 421.0 [M+1] + LCMS m/z = 421.0 [M+1] +

第二步：66e的製備Step 2: Preparation of 66e

將66d (7.6 g，49.96 mmol) 溶於100 mL DMSO中，加入DIPEA (16.15 g，125.00 mmol) 和3-乙炔基氮雜環丁烷鹽酸鹽 (8.82 g，75.01 mmol)，120℃反應3 h。將反應液冷卻至室溫，將反應體系緩慢倒入800 mL水中，過濾，收集濾餅，將濾餅用20 mL水洗滌，將濾餅鼓風乾燥，得粗品66e (6.9 g)。Dissolve 66d (7.6 g, 49.96 mmol) in 100 mL DMSO, add DIPEA (16.15 g, 125.00 mmol) and 3-ethynyl azetidine hydrochloride (8.82 g, 75.01 mmol), and react at 120°C 3 h. Cool the reaction solution to room temperature, slowly pour the reaction system into 800 mL of water, filter, collect the filter cake, wash the filter cake with 20 mL of water, and air-dry the filter cake to obtain crude product 66e (6.9 g).

第三步：66f的製備Step 3: Preparation of 66f

將上述粗品66e (6.5 g) 懸浮於100 mL THF、50 mL甲醇與50 mL水的混合溶劑中，加入一水合氫氧化鋰 (3.84 g, 91.52 mmol)，室溫反應16 h。將反應體系減壓濃縮，向殘留物中加入100 mL水，用濃鹽酸調體系pH至3，析出固體，過濾，收集濾餅，將濾餅用20 mL水洗滌，將濾餅鼓風乾燥，得粗品66f (5.8 g)。The above crude product 66e (6.5 g) was suspended in a mixed solvent of 100 mL THF, 50 mL methanol and 50 mL water, lithium hydroxide monohydrate (3.84 g, 91.52 mmol) was added, and the reaction was carried out at room temperature for 16 h. Concentrate the reaction system under reduced pressure, add 100 mL of water to the residue, adjust the pH of the system to 3 with concentrated hydrochloric acid, precipitate the solid, filter, collect the filter cake, wash the filter cake with 20 mL of water, and blast dry the filter cake. The crude product 66f (5.8 g) was obtained.

LCMS m/z = 232.2 [M+1] + LCMS m/z = 232.2 [M+1] +

第四步：66g的製備Step 4: Preparation of 66g

將上述粗品66f (5.8 g) 溶解於200 mL DCM中，加入咪唑 (5.13 g，75.35 mmol)，冷卻至0℃，緩慢分批加入TBSCl (5.67 g，37.62 mmol)，室溫反應16 h。向反應體系裡加入200 mL水，用濃鹽酸調體系pH至3，用100 mL DCM萃取，有機相用50 mL水洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (二氯甲烷/甲醇 (v/v) = 15:1)，得到66g (8.5 g，從化合物66d算三步收率：52%)。Dissolve the above crude product 66f (5.8 g) in 200 mL DCM, add imidazole (5.13 g, 75.35 mmol), cool to 0°C, slowly add TBSCl (5.67 g, 37.62 mmol) in batches, and react at room temperature for 16 h. Add 200 mL of water to the reaction system, adjust the pH of the system to 3 with concentrated hydrochloric acid, extract with 100 mL of DCM, wash the organic phase with 50 mL of water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (II Methyl chloride/methanol (v/v) = 15:1), obtained 66g (8.5 g, three-step yield calculated from compound 66d: 52%).

LCMS m/z = 346.2 [M+1] + LCMS m/z = 346.2 [M+1] +

第五步：66h的製備Step 5: Preparation for 66h

將66g (7.5 g，21.73 mmol) 溶於80 mL DMF中，加入HATU (0.51 g，1.34 mmol) 和DIPEA (11.22 g，86.81 mmol)，室溫反應30 min後，加入3-氨基哌啶-2,6-二酮鹽酸鹽 (4.29 g，26.06 mmol)，室溫反應16 h。向反應體系裡加入250 mL水，用200 mL DCM萃取，有機相用50 mL水洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (二氯甲烷/甲醇 (v/v) = 15:1)，得到66h (6.2 g，收率：63%)。Dissolve 66g (7.5 g, 21.73 mmol) in 80 mL DMF, add HATU (0.51 g, 1.34 mmol) and DIPEA (11.22 g, 86.81 mmol), react at room temperature for 30 min, then add 3-aminopiperidine-2 , 6-diketone hydrochloride (4.29 g, 26.06 mmol), reacted at room temperature for 16 h. Add 250 mL water to the reaction system, extract with 200 mL DCM, wash the organic phase with 50 mL water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (dichloromethane/methanol (v/v) = 15:1), obtaining 66h (6.2 g, yield: 63%).

LCMS m/z = 456.3 [M+1] + LCMS m/z = 456.3 [M+1] +

第六步：66i的製備Step 6: Preparation of 66i

將66h (6.2 g, 13.62 mmol) 溶解在100 mL THF中，加入四丁基氟化銨三水合物 (6.44 g，20.41 mmol)，室溫反應0.5 h。將反應液減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚/乙酸乙酯 (v/v) = 1:2)，得66i (4.0 g，收率：86%)。Dissolve 66h (6.2 g, 13.62 mmol) in 100 mL THF, add tetrabutylammonium fluoride trihydrate (6.44 g, 20.41 mmol), and react at room temperature for 0.5 h. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 1:2) to obtain 66i (4.0 g, yield: 86%).

第七步：66j的製備Step 7: Preparation of 66j

將66i (4.0 g, 11.72 mmol) 溶解在200 mL DCM中，加入三乙胺 (4.74 g，46.84 mmol)，加入對甲苯磺醯氯 (2.9 g，15.21 mmol)，40℃反應16 h。將反應液冷卻至室溫，減壓濃縮，粗品用矽膠色譜柱分離提純 (二氯甲烷/甲醇 (v/v) = 15:1)，得66j (3.3 g，收率：87%)。Dissolve 66i (4.0 g, 11.72 mmol) in 200 mL DCM, add triethylamine (4.74 g, 46.84 mmol), add p-toluenesulfonyl chloride (2.9 g, 15.21 mmol), and react at 40°C for 16 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (dichloromethane/methanol (v/v) = 15:1) to obtain 66j (3.3 g, yield: 87%).

LCMS m/z = 324.1 [M+1] + LCMS m/z = 324.1 [M+1] +

第八步：化合物66的製備Step 8: Preparation of compound 66

將66j (0.2 g，0.62 mmol) 與66c (0.39 g，0.93 mmol) 溶於8 mL DMF中，加入TEA (0.19 g，1.88 mmol)，置換氮氣三次，加入CuI (12 mg，0.063 mmol) 和PdCl 2(PPh 3) 2(44 mg，0.063 mmol)，置換氮氣三次，50℃反應1.5 h。將反應液冷卻至室溫，加入60 mL水，用100 mL乙酸乙酯萃取，有機相用50 mL水洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠柱色譜分離純化 (石油醚/乙酸乙酯 (v/v) = 1:2)，得到化合物66 (0.065 g，收率：17%)。 Dissolve 66j (0.2 g, 0.62 mmol) and 66c (0.39 g, 0.93 mmol) in 8 mL DMF, add TEA (0.19 g, 1.88 mmol), replace nitrogen three times, add CuI (12 mg, 0.063 mmol) and PdCl 2 (PPh 3 ) 2 (44 mg, 0.063 mmol), replace nitrogen three times, and react at 50°C for 1.5 h. Cool the reaction solution to room temperature, add 60 mL of water, and extract with 100 mL of ethyl acetate. The organic phase is washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether/acetic acid). Ethyl ester (v/v) = 1:2) to obtain compound 66 (0.065 g, yield: 17%).

1H NMR (400 MHz, CDCl 3) δ 9.09 (s, 1H), 8.37 (d, 1H), 7.87 – 7.76 (m, 2H), 7.71 (s, 1H), 7.49 (dd, 1H), 7.40 – 7.35 (m, 1H), 6.47 (dd, 1H), 6.32 – 6.26 (m, 1H), 5.41 – 5.24 (m, 2H), 4.77 – 4.69 (m, 1H), 4.37 – 4.24 (m, 2H), 4.07 – 3.94 (m, 2H), 3.84 – 3.70 (m, 1H), 3.02 – 2.87 (m, 1H), 2.73 – 2.15 (m, 3H), 1.95 (s, 6H), 1.57 – 1.44 (m, 1H), 1.03 – 0.92 (m, 2H), 0.61 – 0.54 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.09 (s, 1H), 8.37 (d, 1H), 7.87 – 7.76 (m, 2H), 7.71 (s, 1H), 7.49 (dd, 1H), 7.40 – 7.35 (m, 1H), 6.47 (dd, 1H), 6.32 – 6.26 (m, 1H), 5.41 – 5.24 (m, 2H), 4.77 – 4.69 (m, 1H), 4.37 – 4.24 (m, 2H), 4.07 – 3.94 (m, 2H), 3.84 – 3.70 (m, 1H), 3.02 – 2.87 (m, 1H), 2.73 – 2.15 (m, 3H), 1.95 (s, 6H), 1.57 – 1.44 (m, 1H ), 1.03 – 0.92 (m, 2H), 0.61 – 0.54 (m, 2H).

LCMS m/z = 616.8 [M+1] + LCMS m/z = 616.8 [M+1] +

實施例67：化合物67的製備 Example 67: Preparation of Compound 67

第一步：67c的製備Step One: Preparation of 67c

將67A (2.95 g，10.68 mmol) 溶於50 mL DMSO中，加入上述粗品67b的鹽酸鹽 (1.7 g)，加入DIPEA (4.14 g，32.03 mmol)，80℃反應3 h。將反應體系冷卻至室溫，緩慢倒入400 mL水中，過濾，濾餅用20 mL水洗滌，將濾餅減壓乾燥，得粗品67c (1.7 g)。Dissolve 67A (2.95 g, 10.68 mmol) in 50 mL DMSO, add the hydrochloride of the crude product 67b (1.7 g), add DIPEA (4.14 g, 32.03 mmol), and react at 80°C for 3 h. The reaction system was cooled to room temperature, slowly poured into 400 mL of water, filtered, the filter cake was washed with 20 mL of water, and the filter cake was dried under reduced pressure to obtain crude product 67c (1.7 g).

第二步：化合物67的製備Step 2: Preparation of Compound 67

將上述粗品67c (0.2 g)、2c (0.32 g，0.68 mmol) 和TEA (0.17 g，1.68 mmol)加入到5 mL DMF中，置換氮氣三次，加入CuI (11 mg，0.058 mmol) 和PdCl 2(PPh 3) 2(40 mg，0.057 mmol)，氮氣氛圍下50℃反應1.5 h。將反應液冷卻至室溫，加入60 mL水，抽濾，濾餅用10 mL水洗滌，將濾餅用100 mL DCM溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠柱色譜分離純化 (石油醚/乙酸乙酯 (v/v) = 1:2)，得到化合物67 (110 mg，收率：23%)。 Add the above crude products 67c (0.2 g), 2c (0.32 g, 0.68 mmol) and TEA (0.17 g, 1.68 mmol) to 5 mL DMF, replace nitrogen three times, add CuI (11 mg, 0.058 mmol) and PdCl 2 ( PPh 3 ) 2 (40 mg, 0.057 mmol), reacted at 50°C for 1.5 h under nitrogen atmosphere. Cool the reaction solution to room temperature, add 60 mL of water, and filter with suction. The filter cake is washed with 10 mL of water. The filter cake is dissolved in 100 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated and purified by silica gel column chromatography ( Petroleum ether/ethyl acetate (v/v) = 1:2) to obtain compound 67 (110 mg, yield: 23%).

1H NMR (400 MHz, CDCl 3) δ 8.68 (s, 1H), 8.54 (d, 1H), 8.02 (s, 1H), 7.71 (s, 1H), 7.64 (d, 1H), 7.61 – 7.55 (m, 2H), 7.50 (dd, 1H), 6.79 (d, 1H), 6.52 (dd, 1H), 4.97 – 4.89 (m, 1H), 4.24 – 4.12 (m, 2H), 3.89 – 3.80 (m, 2H), 3.12 – 2.98 (m, 3H), 2.94 – 2.65 (m, 7H), 2.28 – 1.98 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.68 (s, 1H), 8.54 (d, 1H), 8.02 (s, 1H), 7.71 (s, 1H), 7.64 (d, 1H), 7.61 – 7.55 ( m, 2H), 7.50 (dd, 1H), 6.79 (d, 1H), 6.52 (dd, 1H), 4.97 – 4.89 (m, 1H), 4.24 – 4.12 (m, 2H), 3.89 – 3.80 (m, 2H), 3.12 – 2.98 (m, 3H), 2.94 – 2.65 (m, 7H), 2.28 – 1.98 (m, 3H).

實施例68：化合物68的製備 Example 68: Preparation of Compound 68

第一步： 68c的製備Step One: Preparation of 68c

向反應瓶中分別加入1-氯-N,N,2-三甲基丙烯胺 (0.72 g, 5.38 mmol)、2-(4-碘代-1H-吡唑-1-基)-2-甲基丙酸 (1.00 g，3.58 mmol) 和DCM (20 mL)，室溫攪拌1 h後，依次加入TEA (1.48 mL, 10.65 mmol) 和68b (0.56 g, 3.54 mmol)，室溫反應1 h。將反應液減壓濃縮，粗品用矽膠色譜柱分離純化 (乙酸乙酯/石油醚 (v/v) = 1:5)，得68c (1.05 g，收率：71%)。Add 1-chloro-N,N,2-trimethylpropenylamine (0.72 g, 5.38 mmol) and 2-(4-iodo-1H-pyrazol-1-yl)-2-methyl to the reaction flask respectively. After stirring at room temperature for 1 h, TEA (1.48 mL, 10.65 mmol) and 68b (0.56 g, 3.54 mmol) were added in sequence, and the reaction was carried out at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v) = 1:5) to obtain 68c (1.05 g, yield: 71%).

LCMS m/z = 421.0 [M+1] +。 LCMS m/z = 421.0 [M+1] + .

以化合物68c+67c為原料，參考實施例67得到化合物68(130mg)。Using compounds 68c+67c as raw materials, compound 68 (130 mg) was obtained with reference to Example 67.

1H NMR (400 MHz, CDCl 3) δ 9.05 (s, 1H), 8.36 (d, 1H), 8.02 (s, 1H), 7.71 – 7.60 (m, 3H), 7.48 (dd, 1H), 7.40 – 7.33 (m, 1H), 6.82 – 6.76 (m, 1H), 6.56 – 6.48 (m, 1H), 4.98 – 4.88 (m, 1H), 4.24 – 4.12 (m, 2H), 3.90 – 3.79 (m, 2H), 3.14 – 3.00 (m, 1H), 2.95 – 2.65 (m, 5H), 2.17 – 2.07 (m, 1H), 1.93 (s, 6H), 1.53 – 1.42 (m, 1H), 1.00 – 0.90 (m, 2H), 0.61 – 0.51 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.05 (s, 1H), 8.36 (d, 1H), 8.02 (s, 1H), 7.71 – 7.60 (m, 3H), 7.48 (dd, 1H), 7.40 – 7.33 (m, 1H), 6.82 – 6.76 (m, 1H), 6.56 – 6.48 (m, 1H), 4.98 – 4.88 (m, 1H), 4.24 – 4.12 (m, 2H), 3.90 – 3.79 (m, 2H ), 3.14 – 3.00 (m, 1H), 2.95 – 2.65 (m, 5H), 2.17 – 2.07 (m, 1H), 1.93 (s, 6H), 1.53 – 1.42 (m, 1H), 1.00 – 0.90 (m , 2H), 0.61 – 0.51 (m, 2H).

實施例69：化合物69的製備 Example 69: Preparation of Compound 69

以化合物69a為原料，參考實施例22得到化合物69(0.20g)。Using compound 69a as a raw material, compound 69 (0.20 g) was obtained with reference to Example 22.

1H NMR (400 MHz, CDCl 3) δ 8.12 (s, 1H), 7.94 (s, 1H), 7.76 (s, 1H), 7.72 – 7.62 (m, 2H), 7.44 – 7.37 (m, 2H), 7.32 – 7.23 (m, 2H), 7.08 (t, 1H), 6.80 (s, 1H), 6.58 – 6.52 (m, 1H), 4.93 (dd, 1H), 4.40 – 4.30 (m, 2H), 4.12 – 4.01 (m, 2H), 3.87 – 3.74 (m, 1H), 3.14 – 2.97 (m, 2H), 2.95 – 2.64 (m, 5H), 2.27 – 1.96 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.12 (s, 1H), 7.94 (s, 1H), 7.76 (s, 1H), 7.72 – 7.62 (m, 2H), 7.44 – 7.37 (m, 2H), 7.32 – 7.23 (m, 2H), 7.08 (t, 1H), 6.80 (s, 1H), 6.58 – 6.52 (m, 1H), 4.93 (dd, 1H), 4.40 – 4.30 (m, 2H), 4.12 – 4.01 (m, 2H), 3.87 – 3.74 (m, 1H), 3.14 – 2.97 (m, 2H), 2.95 – 2.64 (m, 5H), 2.27 – 1.96 (m, 3H).

LCMS m/z = 577.2 [M+1] + ­ LCMS m/z = 577.2 [M+1] + ­

實施例70：化合物70的製備 Example 70: Preparation of Compound 70

第一步：70b的製備Step One: Preparation of 70b

將2c (1.0 g，2.13 mmol)、70a (1.30 g，10.63 mmol) (合成方法見WO2018052949) 和三乙胺 (1.05 g，10.38 mmol) 溶於20 mL DCM中，置換氮氣三次，加入CuI (40.6 mg，0.213 mmol) 和PdCl 2(PPh 3) 2(150 mg，0.214 mmol)，氮氣氛圍下室溫反應16 h。將反應液減壓濃縮，粗品用矽膠柱色譜分離純化 (石油醚/乙酸乙酯 (v/v) = 10:1)，得到70b (0.3 g，收率：30%)。 Dissolve 2c (1.0 g, 2.13 mmol), 70a (1.30 g, 10.63 mmol) (see WO2018052949 for synthesis method) and triethylamine (1.05 g, 10.38 mmol) in 20 mL DCM, replace nitrogen three times, and add CuI (40.6 mg, 0.213 mmol) and PdCl 2 (PPh 3 ) 2 (150 mg, 0.214 mmol), reacted at room temperature for 16 h under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 10:1) to obtain 70b (0.3 g, yield: 30%).

第二步：70c的製備Step 2: Preparation of 70c

將70b (0.15 g，0.32 mmol) 溶於5 mL THF中，加入四丁基氟化銨三水合物(0.20 g，0.63 mmol)，室溫反應0.5 h。將反應體系減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 5:1)，得70c (0.12 g，收率：96%)。Dissolve 70b (0.15 g, 0.32 mmol) in 5 mL THF, add tetrabutylammonium fluoride trihydrate (0.20 g, 0.63 mmol), and react at room temperature for 0.5 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 5:1) to obtain 70c (0.12 g, yield: 96%).

第三步：化合物70的製備Step 3: Preparation of Compound 70

將70c (0.12 g，0.31 mmol)、70A (0.16 g，0.47 mmol) 和TEA (0.10 g，0.99 mmol)加入到5 mL DMF中，置換氮氣三次，加入CuI (6 mg，0.032 mmol) 和PdCl 2(PPh 3) 2(22 mg，0.031 mmol)，置換氮氣三次，50℃反應1.5 h。將反應液冷卻至室溫，加入60 mL水，抽濾，濾餅用10 mL水洗滌，將濾餅用100 mL DCM溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠柱色譜分離純化 (石油醚/乙酸乙酯 (v/v) = 1:2)，得到化合物70 (30 mg，收率：15%)。 Add 70c (0.12 g, 0.31 mmol), 70A (0.16 g, 0.47 mmol) and TEA (0.10 g, 0.99 mmol) to 5 mL DMF, replace nitrogen three times, and add CuI (6 mg, 0.032 mmol) and PdCl 2 (PPh 3 ) 2 (22 mg, 0.031 mmol), replaced with nitrogen three times, and reacted at 50°C for 1.5 h. Cool the reaction solution to room temperature, add 60 mL of water, and filter with suction. The filter cake is washed with 10 mL of water. The filter cake is dissolved in 100 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated and purified by silica gel column chromatography ( Petroleum ether/ethyl acetate (v/v) = 1:2) to obtain compound 70 (30 mg, yield: 15%).

1H NMR (400 MHz, CDCl 3) δ 8.71 (s, 1H), 8.55 (d, 1H), 8.02 – 7.80 (m, 6H), 7.64 – 7.57 (m, 1H), 7.56 – 7.48 (m, 1H), 5.04 – 4.92 (m, 1H), 3.18 – 3.03 (m, 2H), 2.99 – 2.67 (m, 5H), 2.34 – 1.99 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.71 (s, 1H), 8.55 (d, 1H), 8.02 – 7.80 (m, 6H), 7.64 – 7.57 (m, 1H), 7.56 – 7.48 (m, 1H ), 5.04 – 4.92 (m, 1H), 3.18 – 3.03 (m, 2H), 2.99 – 2.67 (m, 5H), 2.34 – 1.99 (m, 3H).

實施例71：化合物71的製備 Example 71: Preparation of Compound 71

第一步：71b的製備Step One: Preparation of 71b

將71a (5.0 g，20.49 mmol) 溶於80 mL THF中，氮氣氛圍下冷卻至0℃，緩慢分批加入60%氫化鈉 (1.23 g)，室溫攪拌1 h後，加入SEMCl (5.12 g，30.71 mmol)，室溫反應16 h。加入200 mL飽和氯化銨水溶液，用200 mL DCM萃取，有機相用50 mL水洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚)，得到71b (7.0 g，收率：91%)。Dissolve 71a (5.0 g, 20.49 mmol) in 80 mL THF, cool to 0°C under nitrogen atmosphere, slowly add 60% sodium hydride (1.23 g) in batches, stir at room temperature for 1 h, then add SEMCl (5.12 g, 30.71 mmol), reacted at room temperature for 16 h. Add 200 mL saturated aqueous ammonium chloride solution, extract with 200 mL DCM, wash the organic phase with 50 mL water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether) to obtain 71b (7.0 g, Yield: 91%).

LCMS m/z = 375.3 [M+1] + LCMS m/z = 375.3 [M+1] +

第二步：71c的製備Step 2: Preparation of 71c

將71b (7.0 g，18.7 mmol) 溶於80 mL DMSO中，加入3-乙炔基氮雜環丁烷鹽酸鹽 (5.02 g，42.69 mmol) 和碳酸鉀 (8.86 g，64.11 mmol)，置換氮氣三次，加入CuI (0.81 g，4.25 mmol) 和L-脯氨酸 (0.98 g，8.51 mmol)，置換氮氣三次，100℃反應16 h。將反應體系冷卻至室溫，加入到60 mL水中，用100 mL乙酸乙酯萃取，有機相用50 mL水洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚/乙酸乙酯 (v/v) =10:1)，得71c (3.7 g，收率：60%)。Dissolve 71b (7.0 g, 18.7 mmol) in 80 mL DMSO, add 3-ethynyl azetidine hydrochloride (5.02 g, 42.69 mmol) and potassium carbonate (8.86 g, 64.11 mmol), and replace nitrogen three times , add CuI (0.81 g, 4.25 mmol) and L-proline (0.98 g, 8.51 mmol), replace nitrogen three times, and react at 100°C for 16 h. The reaction system was cooled to room temperature, added to 60 mL of water, extracted with 100 mL of ethyl acetate, the organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified with a silica gel chromatography column (petroleum ether/ Ethyl acetate (v/v) =10:1), to obtain 71c (3.7 g, yield: 60%).

LCMS m/z = 328.2 [M+1] + LCMS m/z = 328.2 [M+1] +

第三步：71d的製備Step 3: Preparation of 71d

將71c (1.5 g，4.58 mmol) 溶於20 mL THF中，加入四丁基氟化銨三水合物 (14.45 g，45.81 mmol)，70℃反應16 h。將反應液冷卻至室溫，加入50 mL水，用100 mL乙酸乙酯萃取，有機相用50 mL水洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠柱色譜分離純化 (二氯甲烷/甲醇 (v/v) = 15:1)，得到71d (800 mg，收率：89%)。Dissolve 71c (1.5 g, 4.58 mmol) in 20 mL THF, add tetrabutylammonium fluoride trihydrate (14.45 g, 45.81 mmol), and react at 70°C for 16 h. The reaction solution was cooled to room temperature, 50 mL of water was added, and extracted with 100 mL of ethyl acetate. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane/dichloromethane/ Methanol (v/v) = 15:1), obtained 71d (800 mg, yield: 89%).

LCMS m/z = 198.3 [M+1] + LCMS m/z = 198.3 [M+1] +

第四步：71e-1和71e-2的製備Step 4: Preparation of 71e-1 and 71e-2

將71d (0.8 g，4.05 mmol) 溶於20 mL DMF中，氮氣氛圍下冷卻至0℃，緩慢分批加入60%氫化鈉 (0.32 g)，室溫攪拌1 h後，加入3-溴哌啶-2,6-二酮 (1.00 g，5.21 mmol)，室溫反應16 h。向反應體系中加入200 mL飽和氯化銨水溶液，用200 mL乙酸乙酯萃取，有機相用50 mL水洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (二氯甲烷/甲醇 (v/v) = 15:1)，所得粗品過Pre-HPLC (儀器及製備柱：採用Glison GX-281製備液相，製備柱型號是Sunfire C18，5 μm，內徑×長度 = 30 mm×150 mm)。製備方法：粗品用甲醇和二甲亞碸溶解，並用0.45 μm濾膜過濾，製備成樣品液。流動相體系：乙腈/水 (含0.05 mol/L乙酸銨)。梯度沖提方法：乙腈由10%梯度沖提60% (沖提時間15 min)，凍乾得到分別得到71e-1 (0.14 g，收率：11%) 和71e-2 (0.18 g，收率：14%)。Dissolve 71d (0.8 g, 4.05 mmol) in 20 mL DMF, cool to 0°C under nitrogen atmosphere, slowly add 60% sodium hydride (0.32 g) in batches, stir at room temperature for 1 h, then add 3-bromopiperidine -2,6-dione (1.00 g, 5.21 mmol), reacted at room temperature for 16 h. Add 200 mL saturated aqueous ammonium chloride solution to the reaction system, extract with 200 mL ethyl acetate, wash the organic phase with 50 mL water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (dichloromethane/ Methanol (v/v) = 15:1), and the crude product obtained was subjected to Pre-HPLC (instrument and preparation column: Glison GX-281 was used to prepare the liquid phase, and the preparation column model was Sunfire C18, 5 μm, inner diameter × length = 30 mm ×150 mm). Preparation method: Dissolve the crude product with methanol and dimethyl sulfoxide, filter it with a 0.45 μm filter membrane, and prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05 mol/L ammonium acetate). Gradient elution method: acetonitrile was gradient eluted from 10% to 60% (elution time 15 min), and then freeze-dried to obtain 71e-1 (0.14 g, yield: 11%) and 71e-2 (0.18 g, yield: 11%). :14%).

71e-1的沖提時間：13 min；71e-1 withdrawal time: 13 minutes;

71e-2的沖提時間：14 min。The withdrawal time of 71e-2: 14 minutes.

第五步：化合物71的製備Step 5: Preparation of Compound 71

將71e-1 (0.07 g，0.23 mmol)、2c (0.13 g，0.28 mmol) 和TEA (0.07 g，0.69 mmol) 加入到5 mL DMF中，置換氮氣三次，加入CuI (5 mg，0.026 mmol) 和PdCl 2(PPh 3) 2(16 mg，0.023 mmol)，氮氣氛圍下50℃反應1.5 h。將反應液冷卻至室溫，加入60 mL水，抽濾，濾餅用10 mL水洗滌，將濾餅用50 mL DCM溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠柱色譜分離純化 (石油醚/乙酸乙酯 (v/v) = 1:2)，得到化合物71 (35 mg，收率：23.41%)。 Add 71e-1 (0.07 g, 0.23 mmol), 2c (0.13 g, 0.28 mmol) and TEA (0.07 g, 0.69 mmol) to 5 mL DMF, replace nitrogen three times, add CuI (5 mg, 0.026 mmol) and PdCl 2 (PPh 3 ) 2 (16 mg, 0.023 mmol), reacted at 50°C for 1.5 h under nitrogen atmosphere. Cool the reaction solution to room temperature, add 60 mL of water, and filter with suction. The filter cake is washed with 10 mL of water. The filter cake is dissolved in 50 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated and purified by silica gel column chromatography ( Petroleum ether/ethyl acetate (v/v) = 1:2) to obtain compound 71 (35 mg, yield: 23.41%).

1H NMR (400 MHz, CDCl 3) δ 8.69 (s, 1H), 8.54 (d, 1H), 8.00 (s, 1H), 7.83 (s, 1H), 7.77 (s, 1H), 7.68 (s, 1H), 7.63 – 7.55 (m, 2H), 7.53 – 7.47 (m, 1H), 6.83 – 6.70 (m, 1H), 6.51 (s, 1H), 5.29 – 5.18 (m, 1H), 4.29 – 4.17 (m, 2H), 3.94 – 3.83 (m, 2H), 3.79 – 3.65 (m, 1H), 3.14 – 3.00 (m, 3H), 2.94 – 2.70 (m, 4H), 2.60 – 2.47 (m, 1H), 2.30 – 2.15 (m, 1H), 2.15 – 2.02 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.69 (s, 1H), 8.54 (d, 1H), 8.00 (s, 1H), 7.83 (s, 1H), 7.77 (s, 1H), 7.68 (s, 1H), 7.63 – 7.55 (m, 2H), 7.53 – 7.47 (m, 1H), 6.83 – 6.70 (m, 1H), 6.51 (s, 1H), 5.29 – 5.18 (m, 1H), 4.29 – 4.17 ( m, 2H), 3.94 – 3.83 (m, 2H), 3.79 – 3.65 (m, 1H), 3.14 – 3.00 (m, 3H), 2.94 – 2.70 (m, 4H), 2.60 – 2.47 (m, 1H), 2.30 – 2.15 (m, 1H), 2.15 – 2.02 (m, 1H).

實施例72：化合物72的製備 Example 72: Preparation of Compound 72

以化合物71e-2為原料，參考實施例71得到化合物72(85mg)。Using compound 71e-2 as a raw material, compound 72 (85 mg) was obtained with reference to Example 71.

1H NMR (400 MHz, CDCl 3) δ 8.69 (s, 1H), 8.54 (d, 1H), 8.10 (s, 1H), 7.91 (s, 1H), 7.77 (s, 1H), 7.68 (s, 1H), 7.60 – 7.55 (m, 1H), 7.53 – 7.46 (m, 1H), 7.29 – 7.23 (m, 1H), 6.79 – 6.67 (m, 2H), 5.32 – 5.22 (m, 1H), 4.30 – 4.18 (m, 2H), 3.93 – 3.82 (m, 2H), 3.80 – 3.67 (m, 1H), 3.14 – 2.98 (m, 3H), 2.91 – 2.67 (m, 4H), 2.52 – 2.38 (m, 1H), 2.30 – 2.01 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.69 (s, 1H), 8.54 (d, 1H), 8.10 (s, 1H), 7.91 (s, 1H), 7.77 (s, 1H), 7.68 (s, 1H), 7.60 – 7.55 (m, 1H), 7.53 – 7.46 (m, 1H), 7.29 – 7.23 (m, 1H), 6.79 – 6.67 (m, 2H), 5.32 – 5.22 (m, 1H), 4.30 – 4.18 (m, 2H), 3.93 – 3.82 (m, 2H), 3.80 – 3.67 (m, 1H), 3.14 – 2.98 (m, 3H), 2.91 – 2.67 (m, 4H), 2.52 – 2.38 (m, 1H ), 2.30 – 2.01 (m, 2H).

實施例73：化合物73的製備 Example 73: Preparation of Compound 73

第一步：73b的合成Step One: Synthesis of 73b

將73a (375 mg, 2.00 mmol) 溶於10 mL二氯甲烷中，加入73A (0.59 g，2.43 mmol) 和TCFH (0.85 g, 3.03 mmol)，加入NMI (0.66 g, 8.04 mmol)，室溫反應16 h。將反應體系減壓濃縮，加入50 mL飽和碳酸氫鈉水溶液，用100 mL二氯甲烷萃取，有機相用25 mL水洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚:乙酸乙酯 (v/v) = 5:1)，得到73b (800 mg，收率：97%)。Dissolve 73a (375 mg, 2.00 mmol) in 10 mL dichloromethane, add 73A (0.59 g, 2.43 mmol) and TCFH (0.85 g, 3.03 mmol), add NMI (0.66 g, 8.04 mmol), and react at room temperature 16h. The reaction system was concentrated under reduced pressure, 50 mL of saturated sodium bicarbonate aqueous solution was added, extracted with 100 mL of methylene chloride, the organic phase was washed with 25 mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified with a silica gel chromatography column (petroleum) Ether:ethyl acetate (v/v) = 5:1) gave 73b (800 mg, yield: 97%).

LCMS m/z = 412.0 [M+1] + LCMS m/z = 412.0 [M+1] +

以化合物73b為原料，參考實施例45得到化合物73(50mg)。Using compound 73b as a raw material, compound 73 (50 mg) was obtained with reference to Example 45.

1H NMR (400 MHz, CDCl 3) δ 8.39 (d, 1H), 8.09 (s, 1H), 7.67 (d, 1H), 7.52 – 7.38 (m, 3H), 7.34 (s, 1H), 7.30 – 7.21 (m, 2H), 6.85 – 6.78 (m, 1H), 6.56 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.44 – 4.32 (m, 2H), 4.17 – 4.05 (m, 2H), 3.92 – 3.77 (m, 1H), 3.48 – 3.36 (m, 2H), 2.95 – 2.65 (m, 5H), 2.18 – 2.05 (m, 1H), 1.63 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.39 (d, 1H), 8.09 (s, 1H), 7.67 (d, 1H), 7.52 – 7.38 (m, 3H), 7.34 (s, 1H), 7.30 – 7.21 (m, 2H), 6.85 – 6.78 (m, 1H), 6.56 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.44 – 4.32 (m, 2H), 4.17 – 4.05 (m, 2H), 3.92 – 3.77 (m, 1H), 3.48 – 3.36 (m, 2H), 2.95 – 2.65 (m, 5H), 2.18 – 2.05 (m, 1H), 1.63 (s, 6H).

實施例74：化合物74的製備 Example 74: Preparation of Compound 74

以化合物74a為原料，參考實施例44得到化合物74(0.065g)。 1H NMR (400 MHz, DMSO- d 6 ) δ 11.06 (s, 1H), 10.50 (s, 1H), 8.07 – 7.97 (m, 3H), 7.89 – 7.75 (m, 3H), 7.69 (d, 1H), 6.89 (d, 1H), 6.74 (dd, 1H), 5.12 – 5.02 (m, 1H), 4.49 – 4.37 (m, 2H), 4.17 – 4.06 (m, 2H), 4.04 – 3.92 (m, 1H), 2.98 – 2.81 (m, 1H), 2.65 – 2.45 (m, 2H), 2.08 – 1.96 (m, 1H). Using compound 74a as a raw material, compound 74 (0.065g) was obtained with reference to Example 44. 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.06 (s, 1H), 10.50 (s, 1H), 8.07 – 7.97 (m, 3H), 7.89 – 7.75 (m, 3H), 7.69 (d, 1H ), 6.89 (d, 1H), 6.74 (dd, 1H), 5.12 – 5.02 (m, 1H), 4.49 – 4.37 (m, 2H), 4.17 – 4.06 (m, 2H), 4.04 – 3.92 (m, 1H ), 2.98 – 2.81 (m, 1H), 2.65 – 2.45 (m, 2H), 2.08 – 1.96 (m, 1H).

實施例75：化合物75的製備 Example 75: Preparation of Compound 75

以化合物75a為原料，參考實施例44得到化合物75(0.06g)。Using compound 75a as a raw material, compound 75 (0.06g) was obtained with reference to Example 44.

1H NMR (400 MHz, CDCl 3) δ 8.70 (d, 1H), 8.45 (s, 1H), 7.95 – 7.86 (m, 1H), 7.77 – 7.55 (m, 4H), 7.52 – 7.31 (m, 2H), 6.88 – 6.80 (m, 1H), 6.64 – 6.53 (m, 1H), 4.99 – 4.89 (m, 1H), 4.48 – 4.33 (m, 2H), 4.20 – 4.06 (m, 2H), 3.95 – 3.81 (m, 1H), 2.97 – 2.65 (m, 3H), 2.18 – 2.07 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.70 (d, 1H), 8.45 (s, 1H), 7.95 – 7.86 (m, 1H), 7.77 – 7.55 (m, 4H), 7.52 – 7.31 (m, 2H ), 6.88 – 6.80 (m, 1H), 6.64 – 6.53 (m, 1H), 4.99 – 4.89 (m, 1H), 4.48 – 4.33 (m, 2H), 4.20 – 4.06 (m, 2H), 3.95 – 3.81 (m, 1H), 2.97 – 2.65 (m, 3H), 2.18 – 2.07 (m, 1H).

實施例76：化合物76的製備 Example 76: Preparation of Compound 76

以化合物76c為原料，參考實施例19得到化合物76(10mg)。Using compound 76c as a raw material, compound 76 (10 mg) was obtained with reference to Example 19.

1H NMR (400 MHz, CDCl 3) δ 8.87 (s, 1H), 8.32 (d, 1H), 7.99 (s, 1H), 7.82 – 7.76 (m, 2H), 7.67 (d, 1H), 7.29 – 7.23 (m, 1H), 7.21 – 7.13 (m, 1H), 6.84 – 6.78 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.40 – 4.30 (m, 2H), 4.13 – 4.00 (m, 2H), 3.88 – 3.75 (m, 1H), 3.28 (q, 2H), 2.95 – 2.65 (m, 3H), 2.18 – 2.07 (m, 1H), 1.94 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.87 (s, 1H), 8.32 (d, 1H), 7.99 (s, 1H), 7.82 – 7.76 (m, 2H), 7.67 (d, 1H), 7.29 – 7.23 (m, 1H), 7.21 – 7.13 (m, 1H), 6.84 – 6.78 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.40 – 4.30 (m, 2H), 4.13 – 4.00 (m, 2H), 3.88 – 3.75 (m, 1H), 3.28 (q, 2H), 2.95 – 2.65 (m, 3H), 2.18 – 2.07 (m, 1H), 1.94 (s, 6H).

實施例77：化合物77的製備 Example 77: Preparation of Compound 77

以化合物71e-2為原料，參考實施例71得到化合物77(80mg)。Using compound 71e-2 as a raw material, compound 77 (80 mg) was obtained with reference to Example 71.

1H NMR (400 MHz, CDCl 3) δ 9.07 (s, 1H), 8.37 (d, 1H), 8.02 (s, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.70 (s, 1H), 7.48 (dd, 1H), 7.39 – 7.34 (m, 1H), 7.31 – 7.24 (m, 1H), 6.81 – 6.67 (m, 2H), 5.33 – 5.22 (m, 1H), 4.30 – 4.18 (m, 2H), 3.94 – 3.83 (m, 2H), 2.99 – 3.67 (m, 1H), 3.13 – 3.00 (m, 1H), 2.92 – 2.72 (m, 2H), 2.53 – 2.40 (m, 1H), 1.95 (s, 6H), 1.55 – 1.42 (m, 1H), 1.04 – 0.92 (m, 2H), 0.60 – 0.52 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.07 (s, 1H), 8.37 (d, 1H), 8.02 (s, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.70 (s, 1H), 7.48 (dd, 1H), 7.39 – 7.34 (m, 1H), 7.31 – 7.24 (m, 1H), 6.81 – 6.67 (m, 2H), 5.33 – 5.22 (m, 1H), 4.30 – 4.18 ( m, 2H), 3.94 – 3.83 (m, 2H), 2.99 – 3.67 (m, 1H), 3.13 – 3.00 (m, 1H), 2.92 – 2.72 (m, 2H), 2.53 – 2.40 (m, 1H), 1.95 (s, 6H), 1.55 – 1.42 (m, 1H), 1.04 – 0.92 (m, 2H), 0.60 – 0.52 (m, 2H).

實施例78：化合物78的製備 Example 78: Preparation of Compound 78

以化合物71e-1為原料，參考實施例71得到化合物78(40mg)。Using compound 71e-1 as a starting material, compound 78 (40 mg) was obtained with reference to Example 71.

1H NMR (400 MHz, CDCl 3) δ 9.06 (s, 1H), 8.37 (d, 1H), 8.16 (s, 1H), 7.82 (s, 1H), 7.78 (s, 1H), 7.70 (s, 1H), 7.60 (d, 1H), 7.48 (dd, 1H), 7.40 – 7.33 (m, 1H), 6.75 (dd, 1H), 6.47 (s, 1H), 5.28 – 5.19 (m, 1H), 4.28 – 4.17 (m, 2H), 3.93 – 3.81 (m, 2H), 3.77 – 3.64 (m, 1H), 3.14 – 3.01 (m, 1H), 2.94 – 2.70 (m, 2H), 2.59 – 2.47 (m, 1H), 1.95 (s, 6H), 1.55 – 1.43 (m, 1H), 1.02 – 0.92 (m, 2H), 0.60 – 0.52 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.06 (s, 1H), 8.37 (d, 1H), 8.16 (s, 1H), 7.82 (s, 1H), 7.78 (s, 1H), 7.70 (s, 1H), 7.60 (d, 1H), 7.48 (dd, 1H), 7.40 – 7.33 (m, 1H), 6.75 (dd, 1H), 6.47 (s, 1H), 5.28 – 5.19 (m, 1H), 4.28 – 4.17 (m, 2H), 3.93 – 3.81 (m, 2H), 3.77 – 3.64 (m, 1H), 3.14 – 3.01 (m, 1H), 2.94 – 2.70 (m, 2H), 2.59 – 2.47 (m, 1H), 1.95 (s, 6H), 1.55 – 1.43 (m, 1H), 1.02 – 0.92 (m, 2H), 0.60 – 0.52 (m, 2H).

實施例79：化合物79的製備 Example 79: Preparation of Compound 79

以化合物79b為原料，參考實施例19得到化合物79(380mg)。Using compound 79b as a raw material, compound 79 (380 mg) was obtained with reference to Example 19.

1H NMR (400 MHz, CDCl 3) δ 8.49 (s, 1H), 8.15 (s, 1H), 7.87 (d, 1H), 7.78 (s, 1H), 7.74 (s, 1H), 7.67 (d, 1H), 7.30 – 7.23 (m, 1H), 7.19 (dd, 1H), 6.83 – 6.77 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.14 – 4.02 (m, 2H), 3.89 – 3.74 (m, 1H), 2.94 – 2.65 (m, 3H), 2.19 – 2.06 (m, 1H), 1.98 – 1.82 (m, 7H), 1.04 – 0.92 (m, 2H), 0.72 – 0.62 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.49 (s, 1H), 8.15 (s, 1H), 7.87 (d, 1H), 7.78 (s, 1H), 7.74 (s, 1H), 7.67 (d, 1H), 7.30 – 7.23 (m, 1H), 7.19 (dd, 1H), 6.83 – 6.77 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.14 – 4.02 (m, 2H), 3.89 – 3.74 (m, 1H), 2.94 – 2.65 (m, 3H), 2.19 – 2.06 (m, 1H), 1.98 – 1.82 (m, 7H), 1.04 – 0.92 (m, 2H), 0.72 – 0.62 (m, 2H).

LCMS m/z = 673.2 [M+1] + LCMS m/z = 673.2 [M+1] +

實施例80：化合物80的製備 Example 80: Preparation of Compound 80

以化合物80b為原料，參考實施例19得到化合物80(150mg)。Using compound 80b as a raw material, compound 80 (150 mg) was obtained with reference to Example 19.

1H NMR (400 MHz, CDCl 3) δ 8.63 (s, 1H), 8.13 (d, 1H), 8.04 (s, 1H), 7.82 – 7.74 (m, 2H), 7.67 (d, 1H), 7.04 – 6.99 (m, 1H), 6.94 (dd, 1H), 6.81 (d, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.95 – 2.64 (m, 3H), 2.20 – 2.06 (m, 1H), 1.94 (s, 6H), 1.87 – 1.75 (m, 1H), 0.98 – 0.87 (m, 2H), 0.67 – 0.57 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.63 (s, 1H), 8.13 (d, 1H), 8.04 (s, 1H), 7.82 – 7.74 (m, 2H), 7.67 (d, 1H), 7.04 – 6.99 (m, 1H), 6.94 (dd, 1H), 6.81 (d, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.02 ( m, 2H), 3.88 – 3.75 (m, 1H), 2.95 – 2.64 (m, 3H), 2.20 – 2.06 (m, 1H), 1.94 (s, 6H), 1.87 – 1.75 (m, 1H), 0.98 – 0.87 (m, 2H), 0.67 – 0.57 (m, 2H).

LCMS m/z = 639.2 [M+1] + LCMS m/z = 639.2 [M+1] +

實施例81：化合物81的製備 Example 81: Preparation of Compound 81

第一步：81b的製備Step One: Preparation of 81b

在氮氣保護下將60%氫化鈉 (3.4 g) 加入到60 mL DMF中，冷卻至0℃，緩慢滴加丙二酸二乙酯 (6.8 g，42.45 mmol)，0℃反應30 min後，室溫反應30 min。0℃下緩慢滴加81a (6.0 g，28.7 mmol)，室溫反應3 h。0℃下向反應體系中加入10 mL水，用乙酸乙酯萃取 (80 mL×3)，有機相用飽和氯化鈉水溶液洗滌 (60 mL×3)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 10:1)，得粗品81b (10.5 g)。Under nitrogen protection, add 60% sodium hydride (3.4 g) to 60 mL DMF, cool to 0°C, slowly add diethyl malonate (6.8 g, 42.45 mmol) dropwise, and react at 0°C for 30 minutes. Warm reaction for 30 minutes. 81a (6.0 g, 28.7 mmol) was slowly added dropwise at 0°C, and the reaction was carried out at room temperature for 3 h. Add 10 mL water to the reaction system at 0°C, extract with ethyl acetate (80 mL×3), wash the organic phase with saturated sodium chloride aqueous solution (60 mL×3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product Separate and purify using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 10:1) to obtain crude product 81b (10.5 g).

第二步：81c的製備Step 2: Preparation of 81c

將上述粗品81b (10.5 g) 溶於60 mL冰乙酸和30 mL濃鹽酸的混合溶劑中，100℃反應16 h。將反應體系冷卻至室溫，加入水 (400 mL)，用乙酸乙酯萃取 (90 mL×2)，有機相用飽和氯化鈉水溶液洗滌 (20 ml×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 4:1)，得粗品 (5.2 g)。將上述粗品 (5.2 g) 溶於80 mL甲醇中，0℃下緩慢滴加二氯亞碸 (3 ml)，室溫反應16 h。將反應體系減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 10:1)，得81c (3.3 g，從化合物81a算兩步收率：44%)。The above crude product 81b (10.5 g) was dissolved in a mixed solvent of 60 mL glacial acetic acid and 30 mL concentrated hydrochloric acid, and reacted at 100°C for 16 h. Cool the reaction system to room temperature, add water (400 mL), extract with ethyl acetate (90 mL×2), wash the organic phase with saturated aqueous sodium chloride solution (20 ml×2), dry over anhydrous sodium sulfate, and reduce pressure Concentrate, and the crude product is separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 4:1) to obtain the crude product (5.2 g). Dissolve the above crude product (5.2 g) in 80 mL methanol, slowly add trisene chloride (3 ml) dropwise at 0°C, and react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 10:1) to obtain 81c (3.3 g, two-step yield calculated from compound 81a: 44%) .

LCMS m/z = 264.1 [M+1] + LCMS m/z = 264.1 [M+1] +

第三步：81d的製備Step 3: Preparation of 81d

在氮氣保護下將81c (3.3 g，12.5 mmol) 溶於40 mL DMF中，0℃下緩慢分批加入60%氫化鈉 (2.0 g)，0℃反應30 min後，室溫反應1 h，0℃下緩慢加入碘甲烷 (6.1 g，42.98 mmol)，室溫反應3 h。向反應體系中加入水 (150 mL)，用乙酸乙酯萃取 (60 mL×2)，有機相用飽和氯化鈉水溶液洗滌 (80 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 10:1)，得81d (2.6 g，收率：71%)。Dissolve 81c (3.3 g, 12.5 mmol) in 40 mL DMF under nitrogen protection, slowly add 60% sodium hydride (2.0 g) in batches at 0°C, react at 0°C for 30 min, then react at room temperature for 1 h, 0 Methyl iodide (6.1 g, 42.98 mmol) was slowly added at ℃, and the reaction was carried out at room temperature for 3 h. Add water (150 mL) to the reaction system, extract with ethyl acetate (60 mL×2), wash the organic phase with saturated aqueous sodium chloride solution (80 mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is Silica gel column separation and purification (petroleum ether: ethyl acetate (v/v) = 10:1) gave 81d (2.6 g, yield: 71%).

LCMS m/z = 292.1 [M+1] + LCMS m/z = 292.1 [M+1] +

第四步：81e的製備Step 4: Preparation of 81e

將81d (2.6 g，8.93 mmol) 加入到250 mL單口瓶中，依次加入乙醇 (50 mL)、水 (10 mL)、氯化銨 (2.4 g，44.9 mmol) 和還原鐵粉 (2.5 g，44.64 mmol)，70℃反應4 h。將反應體系冷卻至室溫，墊矽藻土過濾，向濾液中加入水 (200 mL)，用乙酸乙酯萃取 (80 mL×2)，有機相用飽和氯化鈉水溶液洗滌 (60 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 73:27)，得81e (2.2 g，收率：94%)。Add 81d (2.6 g, 8.93 mmol) into a 250 mL single-neck bottle, then add ethanol (50 mL), water (10 mL), ammonium chloride (2.4 g, 44.9 mmol) and reduced iron powder (2.5 g, 44.64 mmol), react at 70°C for 4 h. Cool the reaction system to room temperature, filter through diatomaceous earth, add water (200 mL) to the filtrate, extract with ethyl acetate (80 mL×2), and wash the organic phase with saturated sodium chloride aqueous solution (60 mL×2 ), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 73:27) to obtain 81e (2.2 g, yield: 94%).

LCMS m/z = 262.1 [M+1] + LCMS m/z = 262.1 [M+1] +

第五步：81f的製備Step 5: Preparation of 81f

將81e (1.2 g，4.59 mmol) 溶於甲苯 (10 mL) 和水 (10 mL)中，0℃加入濃鹽酸 (3 mL)，攪拌10 min後緩慢加入亞硝酸鈉 (380 mg，5.51 mmol)，0-5℃反應30 min，加入10 mL碘化鉀 (1.5 g，9.04 mmol) 的水溶液，室溫反應2 h。向反應體系中加入水 (50 mL)，用乙酸乙酯萃取 (40 mL×2)，有機相用飽和硫代硫酸鈉溶液洗滌 (40 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 92:8)，得81f (1.5 g，收率：88%)。Dissolve 81e (1.2 g, 4.59 mmol) in toluene (10 mL) and water (10 mL), add concentrated hydrochloric acid (3 mL) at 0°C, stir for 10 min, and then slowly add sodium nitrite (380 mg, 5.51 mmol) , react at 0-5°C for 30 minutes, add 10 mL of potassium iodide (1.5 g, 9.04 mmol) aqueous solution, and react at room temperature for 2 hours. Add water (50 mL) to the reaction system, extract with ethyl acetate (40 mL×2), wash the organic phase with saturated sodium thiosulfate solution (40 mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product Separate and purify using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 92:8) to obtain 81f (1.5 g, yield: 88%).

LCMS m/z = 373.1 [M+1] + LCMS m/z = 373.1 [M+1] +

第六步：81g的製備Step 6: Preparation of 81g

將81f (1.5 g，4.03 mmol) 加入到100 mL單口瓶中，依次加入四氫呋喃 (60 mL)、水 (6 mL) 和一水合氫氧化鋰 (850 mg，20.26 mmol)，室溫反應16 h。將反應體系用0.5 mol/L鹽酸調pH至5，用乙酸乙酯萃取 (30 mL×2)，有機相用飽和氯化鈉水溶液洗滌 (40 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 72:28)，得粗品 (1.1 g)。將上述粗品 (0.1 g) 溶於10 mL 二氯甲烷中，加入66b (45 mg，0.28 mmol)、TCFH (118 mg，0.42 mmol)、N-甲基咪唑 (92 mg，1.12 mmol)，室溫反應16 h。將反應體系減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 84:16)，得81g (90 mg，收率：65%)。Add 81f (1.5 g, 4.03 mmol) into a 100 mL single-neck bottle, add tetrahydrofuran (60 mL), water (6 mL) and lithium hydroxide monohydrate (850 mg, 20.26 mmol) in sequence, and react at room temperature for 16 h. Adjust the pH of the reaction system to 5 with 0.5 mol/L hydrochloric acid, extract with ethyl acetate (30 mL×2), wash the organic phase with saturated aqueous sodium chloride solution (40 mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure , the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 72:28) to obtain the crude product (1.1 g). Dissolve the above crude product (0.1 g) in 10 mL dichloromethane, add 66b (45 mg, 0.28 mmol), TCFH (118 mg, 0.42 mmol), N-methylimidazole (92 mg, 1.12 mmol), and keep at room temperature React for 16 hours. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 84:16) to obtain 81g (90 mg, yield: 65%).

LCMS m/z = 499.1 [M+1] + LCMS m/z = 499.1 [M+1] +

第七步：化合物81的製備Step 7: Preparation of Compound 81

將81g (90 mg，0.18 mmol) 加入到50 mL單口瓶中，依次加入乾燥DMF (12 mL)、上述粗品中間體1 (91 mg) 和TEA (54 mg，0.53 mmol)，置換氮氣三次，加入PdCl 2(PPh 3) 2(13 mg，0.019 mmol) 和CuI (6 mg，0.032 mmol)，置換氮氣三次，60℃反應2 h。將反應體系冷卻至室溫，緩慢加入飽和氯化銨水溶液 (150 mL)，用乙酸乙酯萃取 (30 mL×2)，有機相用飽和氯化鈉水溶液洗滌 (30 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 23:77)，得化合物81 (60 mg，收率：47%)。 Add 81g (90 mg, 0.18 mmol) into a 50 mL single-neck bottle, add dry DMF (12 mL), the above crude intermediate 1 (91 mg) and TEA (54 mg, 0.53 mmol) in sequence, replace nitrogen three times, and add PdCl 2 (PPh 3 ) 2 (13 mg, 0.019 mmol) and CuI (6 mg, 0.032 mmol) were replaced with nitrogen three times and reacted at 60°C for 2 h. Cool the reaction system to room temperature, slowly add saturated aqueous ammonium chloride solution (150 mL), extract with ethyl acetate (30 mL×2), wash the organic phase with saturated aqueous sodium chloride solution (30 mL×2), and add anhydrous sulfuric acid. It was dried over sodium and concentrated under reduced pressure. The crude product was separated and purified by silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 23:77) to obtain compound 81 (60 mg, yield: 47%).

1H NMR (400 MHz, CDCl 3) δ 8.43 (d, 1H), 7.93 (s, 1H), 7.78 – 7.66 (m, 3H), 7.63 – 7.56 (m, 2H), 7.56 – 7.48 (m, 1H), 7.41 – 7.35 (m, 1H), 6.86 – 6.80 (m, 1H), 6.58 (dd, 1H), 4.98 – 4.89 (m, 1H), 4,47 – 4.35 (m, 2H), 4.18 – 4.06 (m, 2H), 3.97 – 3.84 (m, 1H), 2.95 – 2.65 (m, 3H), 2.18 – 2.08 (m, 1H), 1.73 (s, 6H), 1.28 – 1.17 (m, 1H), 0.62 – 0.53 (m, 2H), 0.40 – 0.32 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.43 (d, 1H), 7.93 (s, 1H), 7.78 – 7.66 (m, 3H), 7.63 – 7.56 (m, 2H), 7.56 – 7.48 (m, 1H ), 7.41 – 7.35 (m, 1H), 6.86 – 6.80 (m, 1H), 6.58 (dd, 1H), 4.98 – 4.89 (m, 1H), 4,47 – 4.35 (m, 2H), 4.18 – 4.06 (m, 2H), 3.97 – 3.84 (m, 1H), 2.95 – 2.65 (m, 3H), 2.18 – 2.08 (m, 1H), 1.73 (s, 6H), 1.28 – 1.17 (m, 1H), 0.62 – 0.53 (m, 2H), 0.40 – 0.32 (m, 2H).

LCMS m/z =706.8 [M-1] - LCMS m/z =706.8 [M-1] -

實施例82：化合物82的製備 Example 82: Preparation of Compound 82

LCMS m/z = 271.1 [M+1] + LCMS m/z = 271.1 [M+1] +

第一步：82c的製備Step One: Preparation of 82c

將82b (0.3 g，1.11 mmol) 溶於15 mL乙腈中，依次加入28B (390 mg，1.094 mmol) 和碳酸銫 (715 mg，2.19 mmol)，90℃反應16 h。將反應體系冷卻至室溫，加入150 mL水，用乙酸乙酯萃取 (50 mL×2)，有機相用飽和氯化鈉水溶液洗滌 (20 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 80:20)，得82c (50 mg，收率：8%)。Dissolve 82b (0.3 g, 1.11 mmol) in 15 mL acetonitrile, add 28B (390 mg, 1.094 mmol) and cesium carbonate (715 mg, 2.19 mmol) in sequence, and react at 90°C for 16 h. Cool the reaction system to room temperature, add 150 mL of water, extract with ethyl acetate (50 mL×2), wash the organic phase with saturated aqueous sodium chloride solution (20 mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 80:20) to obtain 82c (50 mg, yield: 8%).

LCMS m/z = 546.1 [M+1] + LCMS m/z = 546.1 [M+1] +

以82c和中間體1為原料，參考化合物81第七步的製備方法得化合物82 (35 mg)。Using 82c and intermediate 1 as raw materials, compound 82 (35 mg) was obtained by referring to the preparation method of the seventh step of compound 81.

1H NMR (400 MHz, CDCl 3) δ 9.02 (s, 1H), 8.59 – 8.52 (m, 1H), 8.17 – 8.09 (m, 2H), 7.93 (s, 1H), 7.79 (s, 1H), 7.73 – 7.65 (m, 1H), 7.54 – 7.34 (m, 5H), 6.84 – 6.79 (m, 1H), 6.56 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.43 – 4.32 (m, 2H), 4.14 – 4.04 (m, 2H), 3.94 – 3.81 (m, 1H), 3.17 – 3.03 (m, 2H), 2.95 – 2.63 (m, 5H), 2.32 – 2.05 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.02 (s, 1H), 8.59 – 8.52 (m, 1H), 8.17 – 8.09 (m, 2H), 7.93 (s, 1H), 7.79 (s, 1H), 7.73 – 7.65 (m, 1H), 7.54 – 7.34 (m, 5H), 6.84 – 6.79 (m, 1H), 6.56 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.43 – 4.32 (m, 2H ), 4.14 – 4.04 (m, 2H), 3.94 – 3.81 (m, 1H), 3.17 – 3.03 (m, 2H), 2.95 – 2.63 (m, 5H), 2.32 – 2.05 (m, 3H).

實施例83和84：化合物83與化合物84的製備 Examples 83 and 84: Preparation of Compound 83 and Compound 84

第一步：83a的製備Step 1: Preparation of 83a

向反應瓶中分別加入2-溴-2-甲基丙酸 (1.5 g, 8.98 mmol) 與10 mL二氯甲烷，加入1-氯-N,N,2-三甲基丙烯胺 (1.80 g, 13.47 mmol)，室溫攪拌1 h後，加入TEA (2.72 g, 26.88 mmol) 與16B (1.70 g, 10.75 mmol)，室溫反應16 h。將反應體系減壓濃縮，粗品用矽膠色譜柱分離提純 (乙酸乙酯/石油醚 (v/v) = 1:20)，得到83a (1.46 g, 產率：53%)。Add 2-bromo-2-methylpropionic acid (1.5 g, 8.98 mmol) and 10 mL dichloromethane to the reaction flask respectively, and add 1-chloro-N,N,2-trimethylpropenylamine (1.80 g, 13.47 mmol), stirred at room temperature for 1 h, then added TEA (2.72 g, 26.88 mmol) and 16B (1.70 g, 10.75 mmol), and reacted at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v) = 1:20) to obtain 83a (1.46 g, yield: 53%).

第二步：83b-1與83b-2的製備Step 2: Preparation of 83b-1 and 83b-2

向反應瓶中分別加入3-碘-1H-吡唑 (1.0 g, 5.16 mmol)、83a (1.91 g, 6.22 mmol)、碳酸銫 (3.37 g, 10.34 mmol) 和15 mL乙腈，50℃反應4 h。將反應體系冷卻至室溫，過濾，減壓濃縮，粗品用矽膠色譜柱分離純化 (乙酸乙酯/石油醚 (v/v) = 1:20)，得到粗品83b-1與83b-2的混合物 (1.0 g)。Add 3-iodo-1H-pyrazole (1.0 g, 5.16 mmol), 83a (1.91 g, 6.22 mmol), cesium carbonate (3.37 g, 10.34 mmol) and 15 mL acetonitrile to the reaction flask, and react at 50°C for 4 h. . The reaction system was cooled to room temperature, filtered, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v) = 1:20) to obtain a mixture of crude products 83b-1 and 83b-2. (1.0 g).

第三步：化合物83與化合物84的製備Step 3: Preparation of Compound 83 and Compound 84

在氮氣氛圍下，向反應瓶中分別加入上述粗品83b-1與83b-2的混合物 (0.50 g)、上述粗品中間體1 (0.60 g)、PdCl 2(PPh 3) 2(83 mg, 0.12 mmol)、CuI (45 mg, 0.24 mmol) 和DIPEA (0.46 g, 3.56 mmol)，加入10 mL DMF，60℃反應5 h。將反應體系冷卻至室溫，加入到40 mL水中，過濾，將濾餅過SFC (儀器及製備柱：採用SFC Prep 150 AP製備液相，製備柱型號是Torus DEA，內徑×長度 = 19 mm×250 mm)。製備方法：粗品的DMF溶液用0.45 μm濾膜過濾，製備成樣品液。流動相體系：二氧化碳/甲醇。沖提方法：等度沖提，流動相甲醇含量35%，流量30 mL/min。即可得到化合物83 (沖提時間8.12 min) (25 mg，從化合物83a算兩步收率：13%) 與化合物84 (沖提時間9.87 min) (60 mg，從化合物83a算兩步收率：31%)。 Under a nitrogen atmosphere, the mixture of the above crude products 83b-1 and 83b-2 (0.50 g), the above crude intermediate 1 (0.60 g), and PdCl 2 (PPh 3 ) 2 (83 mg, 0.12 mmol) were added to the reaction flask. ), CuI (45 mg, 0.24 mmol) and DIPEA (0.46 g, 3.56 mmol), add 10 mL DMF, and react at 60°C for 5 h. Cool the reaction system to room temperature, add it to 40 mL of water, filter, and pass the filter cake through SFC (instrument and preparation column: use SFC Prep 150 AP to prepare the liquid phase, the preparation column model is Torus DEA, inner diameter × length = 19 mm ×250 mm). Preparation method: Filter the crude DMF solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: carbon dioxide/methanol. Elution method: isocratic extraction, mobile phase methanol content 35%, flow rate 30 mL/min. Compound 83 (elution time 8.12 min) (25 mg, two-step yield calculated from compound 83a: 13%) and compound 84 (elution time 9.87 min) (60 mg, two-step yield calculated from compound 83a) can be obtained :31%).

化合物83的核磁數據：NMR data of compound 83:

1H NMR (400 MHz, CDCl 3) δ 8.32 (d, 1H), 7.96 (d, 2H), 7.71 (d, 1H), 7.59 (d, 1H), 7.36 – 7.30 (m, 1H), 7.22 (dd, 1H), 6.67 (d, 1H), 6.57 (d, 1H), 6.46 (dd, 1H), 4.96 (dd, 1H), 4.23 – 4.16 (m, 2H), 3.86 – 3.77 (m, 2H), 3.73 – 3.64 (m, 1H), 2.97 – 2.65 (m, 3H), 2.25 – 2.15 (m, 1H), 1.97 (s, 6H), 1.36 – 1.26 (m, 1H), 0.70 – 0.60 (m, 2H), 0.45 – 0.34 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.32 (d, 1H), 7.96 (d, 2H), 7.71 (d, 1H), 7.59 (d, 1H), 7.36 – 7.30 (m, 1H), 7.22 ( dd, 1H), 6.67 (d, 1H), 6.57 (d, 1H), 6.46 (dd, 1H), 4.96 (dd, 1H), 4.23 – 4.16 (m, 2H), 3.86 – 3.77 (m, 2H) , 3.73 – 3.64 (m, 1H), 2.97 – 2.65 (m, 3H), 2.25 – 2.15 (m, 1H), 1.97 (s, 6H), 1.36 – 1.26 (m, 1H), 0.70 – 0.60 (m, 2H), 0.45 – 0.34 (m, 2H).

LCMS m/z = 630.5 [M+1] + LCMS m/z = 630.5 [M+1] +

化合物84的核磁數據：NMR data of compound 84:

1H NMR (400 MHz, CDCl 3) δ 9.22 (s, 1H), 8.39 (d, 1H), 7.98 (s, 1H), 7.69 (d, 1H), 7.66 (d, 1H), 7.48 (dd, 1H), 7.38 – 7.34 (m, 1H), 6.83 (d, 1H), 6.58 (dd, 1H), 6.49 (d, 1H), 4.95 (dd, 1H), 4.43 – 4.35 (m, 2H), 4.14 – 4.07 (m, 2H), 3.89 – 3.78 (m, 1H), 2.98 – 2.65 (m, 3H), 2.19 – 2.10 (m, 1H), 1.97 (s, 6H), 1.58 – 1.46 (m, 1H), 1.08 – 1.02 (m, 2H), 0.60 – 0.54 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.22 (s, 1H), 8.39 (d, 1H), 7.98 (s, 1H), 7.69 (d, 1H), 7.66 (d, 1H), 7.48 (dd, 1H), 7.38 – 7.34 (m, 1H), 6.83 (d, 1H), 6.58 (dd, 1H), 6.49 (d, 1H), 4.95 (dd, 1H), 4.43 – 4.35 (m, 2H), 4.14 – 4.07 (m, 2H), 3.89 – 3.78 (m, 1H), 2.98 – 2.65 (m, 3H), 2.19 – 2.10 (m, 1H), 1.97 (s, 6H), 1.58 – 1.46 (m, 1H) , 1.08 – 1.02 (m, 2H), 0.60 – 0.54 (m, 2H).

LCMS m/z = 630.5 [M+1] + LCMS m/z = 630.5 [M+1] +

實施例85：化合物85的製備 Example 85: Preparation of Compound 85

以化合物85d為原料，參考實施例81得到化合物85(13mg)。Using compound 85d as a raw material, compound 85 (13 mg) was obtained with reference to Example 81.

1H NMR (400 MHz, CDCl 3) δ 8.48 (d, 1H), 7.97 (s, 1H), 7.90 (s, 1H), 7.69 (d, 1H), 7.56 – 7.28 (m, 4H), 7.15 (dd, 1H), 6.85 – 6.80 (m, 1H), 6.58 (dd, 1H), 5.00 – 4.90 (m, 1H), 4.44 – 4.34 (m, 2H), 4.17 – 4.05 (m, 2H), 3.92 – 3.80 (m, 1H), 2.97 – 2.65 (m, 3H), 2.21 – 2.07 (m, 1H), 1.69 (s, 6H), 1.34 – 1.22 (m, 1H), 0.57 – 0.48 (m, 2H), 0.41 – 0.33 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.48 (d, 1H), 7.97 (s, 1H), 7.90 (s, 1H), 7.69 (d, 1H), 7.56 – 7.28 (m, 4H), 7.15 ( dd, 1H), 6.85 – 6.80 (m, 1H), 6.58 (dd, 1H), 5.00 – 4.90 (m, 1H), 4.44 – 4.34 (m, 2H), 4.17 – 4.05 (m, 2H), 3.92 – 3.80 (m, 1H), 2.97 – 2.65 (m, 3H), 2.21 – 2.07 (m, 1H), 1.69 (s, 6H), 1.34 – 1.22 (m, 1H), 0.57 – 0.48 (m, 2H), 0.41 – 0.33 (m, 2H).

實施例86：化合物86的製備 Example 86: Preparation of Compound 86

以化合物88b為原料，參考實施例50得到化合物86(0.07g)。Using compound 88b as a raw material, compound 86 (0.07g) was obtained with reference to Example 50.

1H NMR (400 MHz, CDCl 3) δ 9.21 (s, 1H), 8.41 (d, 1H), 8.02 (s, 1H), 7.96 – 7.90 (m, 2H), 7.69 (d, 1H), 7.54 – 7.42 (m, 3H), 7.39 – 7.34 (m, 1H), 7.32 – 7.26 (m, 2H), 7.03 – 6.96 (m, 1H), 6.73 (dd, 1H), 4.99 – 4.89 (m, 1H), 3.94 – 3.82 (m, 1H), 3.74 – 3.43 (m, 4H), 2.95 – 2.66 (m, 3H), 2.60 – 2.44 (m, 1H), 2.31 – 2.08 (m, 2H), 2.02 (s, 6H), 1.59 – 1.46 (m, 1H), 1.02 – 0.90 (m, 2H), 0.60 – 0.52 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.21 (s, 1H), 8.41 (d, 1H), 8.02 (s, 1H), 7.96 – 7.90 (m, 2H), 7.69 (d, 1H), 7.54 – 7.42 (m, 3H), 7.39 – 7.34 (m, 1H), 7.32 – 7.26 (m, 2H), 7.03 – 6.96 (m, 1H), 6.73 (dd, 1H), 4.99 – 4.89 (m, 1H), 3.94 – 3.82 (m, 1H), 3.74 – 3.43 (m, 4H), 2.95 – 2.66 (m, 3H), 2.60 – 2.44 (m, 1H), 2.31 – 2.08 (m, 2H), 2.02 (s, 6H ), 1.59 – 1.46 (m, 1H), 1.02 – 0.90 (m, 2H), 0.60 – 0.52 (m, 2H).

實施例87：化合物87的製備 Example 87: Preparation of Compound 87

以化合物90b為原料，參考實施例50得到化合物87(0.06g)。Using compound 90b as a raw material, compound 87 (0.06g) was obtained with reference to Example 50.

1H NMR (400 MHz, CDCl 3) δ 8.76 (s, 1H), 8.58 (d, 1H), 8.10 – 7.96 (m, 2H), 7.81 (s, 1H), 7.71 (d, 1H), 7.60 – 7.41 (m, 4H), 7.36 (s, 1H), 7.27 – 7.21 (m, 2H), 7.16 (d, 1H), 5.00 – 4.91 (m, 1H), 4.18 – 4.02 (m, 2H), 3.20 – 3.00 (m, 4H), 2.98 – 2.65 (m, 6H), 2.35 – 1.77 (m, 7H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.76 (s, 1H), 8.58 (d, 1H), 8.10 – 7.96 (m, 2H), 7.81 (s, 1H), 7.71 (d, 1H), 7.60 – 7.41 (m, 4H), 7.36 (s, 1H), 7.27 – 7.21 (m, 2H), 7.16 (d, 1H), 5.00 – 4.91 (m, 1H), 4.18 – 4.02 (m, 2H), 3.20 – 3.00 (m, 4H), 2.98 – 2.65 (m, 6H), 2.35 – 1.77 (m, 7H).

實施例88：化合物88的製備 Example 88: Preparation of Compound 88

以化合物88b為原料，參考實施例50得到化合物88(0.07g)。 Using compound 88b as a raw material, compound 88 (0.07g) was obtained with reference to Example 50.

1H NMR (400 MHz, CDCl 3) δ 8.77 (s, 1H), 8.58 (d, 1H), 8.01 (s, 2H), 7.83 (s, 1H), 7.69 (d, 1H), 7.62 – 7.42 (m, 4H), 7.32 – 7.26 (m, 2H), 7.03 – 6.95 (m, 1H), 6.73 (dd, 1H), 5.00 – 4.88 (m, 1H), 3.93 – 3.80 (m, 1H), 3.73 – 3.42 (m, 4H), 3.19 – 3.05 (m, 2H), 2.96 – 2.64 (m, 5H), 2.58 – 2.44 (m, 1H), 2.38 – 2.02 (m, 4H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.77 (s, 1H), 8.58 (d, 1H), 8.01 (s, 2H), 7.83 (s, 1H), 7.69 (d, 1H), 7.62 – 7.42 ( m, 4H), 7.32 – 7.26 (m, 2H), 7.03 – 6.95 (m, 1H), 6.73 (dd, 1H), 5.00 – 4.88 (m, 1H), 3.93 – 3.80 (m, 1H), 3.73 – 3.42 (m, 4H), 3.19 – 3.05 (m, 2H), 2.96 – 2.64 (m, 5H), 2.58 – 2.44 (m, 1H), 2.38 – 2.02 (m, 4H).

實施例89：化合物89的製備 Example 89: Preparation of Compound 89

以化合物89c為原料，參考實施例81得到化合物89(75mg)。Using compound 89c as a raw material, compound 89 (75 mg) was obtained with reference to Example 81.

1H NMR (400 MHz, CDCl 3) δ 9.89 (s, 1H), 8.64 – 8.58 (m, 1H), 8.42 (d, 1H), 7.95 (s, 1H), 7.80 – 7.63 (m, 2H), 7.52 – 7.35 (m, 3H), 6.87 – 6.80 (m, 1H), 6.58 (dd, 1H), 4.98 – 4.90 (m, 1H), 4.45 – 4.35 (m, 2H), 4.18 – 4.07 (m, 2H), 3.94 – 3.82 (m, 1H), 2.96 – 2.66 (m, 3H), 2.19 – 2.08 (m, 1H), 1.77 (s, 6H), 1.73 – 1.63 (m, 1H), 1.13 – 1.02 (m, 2H), 0.70 – 0.62 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.89 (s, 1H), 8.64 – 8.58 (m, 1H), 8.42 (d, 1H), 7.95 (s, 1H), 7.80 – 7.63 (m, 2H), 7.52 – 7.35 (m, 3H), 6.87 – 6.80 (m, 1H), 6.58 (dd, 1H), 4.98 – 4.90 (m, 1H), 4.45 – 4.35 (m, 2H), 4.18 – 4.07 (m, 2H ), 3.94 – 3.82 (m, 1H), 2.96 – 2.66 (m, 3H), 2.19 – 2.08 (m, 1H), 1.77 (s, 6H), 1.73 – 1.63 (m, 1H), 1.13 – 1.02 (m , 2H), 0.70 – 0.62 (m, 2H).

LCMS m/z = 641.2 [M+1] + LCMS m/z = 641.2 [M+1] +

實施例90：化合物90的製備 Example 90: Preparation of Compound 90

以化合物90b為原料，參考實施例50得到化合物90(0.085g)。 Using compound 90b as a raw material, compound 90 (0.085g) was obtained with reference to Example 50.

1H NMR (400 MHz, CDCl 3) δ 9.19 (s, 1H), 8.41 (d, 1H), 8.11 (s, 1H), 7.91 (d, 2H), 7.70 (d, 1H), 7.53 – 7.40 (m, 3H), 7.39 – 7.30 (m, 2H), 7.27 – 7.20 (m, 2H), 7.11 (dd, 1H), 5.00 – 4.90 (m, 1H), 4.18 – 4.02 (m, 2H), 3.20 – 3.02 (m, 2H), 2.97 – 2.65 (m, 4H), 2.20 – 2.08 (m, 1H), 2.08 – 1.93 (m, 8H), 1.92 – 1.75 (m, 2H), 1.57 – 1.45 (m, 1H), 1.02 – 0.90 (m, 2H), 0.60 – 0.51 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.19 (s, 1H), 8.41 (d, 1H), 8.11 (s, 1H), 7.91 (d, 2H), 7.70 (d, 1H), 7.53 – 7.40 ( m, 3H), 7.39 – 7.30 (m, 2H), 7.27 – 7.20 (m, 2H), 7.11 (dd, 1H), 5.00 – 4.90 (m, 1H), 4.18 – 4.02 (m, 2H), 3.20 – 3.02 (m, 2H), 2.97 – 2.65 (m, 4H), 2.20 – 2.08 (m, 1H), 2.08 – 1.93 (m, 8H), 1.92 – 1.75 (m, 2H), 1.57 – 1.45 (m, 1H ), 1.02 – 0.90 (m, 2H), 0.60 – 0.51 (m, 2H).

實施例91：化合物91的製備 Example 91: Preparation of Compound 91

第一步：91b的製備Step One: Preparation of 91b

向反應瓶中依次加入91a (0.20 g，1.14 mmol)、 91A的鹽酸鹽 (0.16 g)、碳酸銫 (1.08 g，3.31 mmol) 和DMF (5 mL)，室溫反應15 h。向反應液中加入30 mL乙酸乙酯和20 mL水，有機相用飽和氯化鈉水溶液洗滌 (10 mL×3)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (乙酸乙酯/石油醚 (v/v) = 1:20-1:10)，得到91b (0.22 g，產率：84%)。91a (0.20 g, 1.14 mmol), 91A hydrochloride (0.16 g), cesium carbonate (1.08 g, 3.31 mmol) and DMF (5 mL) were added in sequence to the reaction flask, and the reaction was carried out at room temperature for 15 h. Add 30 mL ethyl acetate and 20 mL water to the reaction solution, wash the organic phase with saturated sodium chloride aqueous solution (10 mL Ester/petroleum ether (v/v) = 1:20-1:10), afforded 91b (0.22 g, yield: 84%).

第二步：91c的製備Step 2: Preparation of 91c

向反應瓶中加入91b (0.22 g，0.95 mmol)、鋅粉 (0.62 g，9.54 mmol)、氯化銨 (0.51 g，9.53 mmol)、四氫呋喃 (9 mL) 和水 (3 mL)，室溫反應1 h。將反應體系墊矽藻土過濾，將濾餅用50 mL乙酸乙酯洗滌，向濾液中加入50 mL水和50 mL乙酸乙酯，有機相用無水硫酸鈉乾燥，減壓濃縮，得粗品91c (0.19 g)。Add 91b (0.22 g, 0.95 mmol), zinc powder (0.62 g, 9.54 mmol), ammonium chloride (0.51 g, 9.53 mmol), tetrahydrofuran (9 mL) and water (3 mL) to the reaction flask, and react at room temperature 1 hour. The reaction system was filtered through diatomaceous earth, and the filter cake was washed with 50 mL of ethyl acetate. 50 mL of water and 50 mL of ethyl acetate were added to the filtrate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 91c ( 0.19 g).

以化合物91c為原料，參考實施例19得到化合物91(0.12g)。Using compound 91c as a raw material, compound 91 (0.12g) was obtained with reference to Example 19.

1H NMR (400 MHz, CDCl 3) δ 8.40 (s, 1H), 8.15 (s, 1H), 8.00 (d, 1H), 7.82 – 7.74 (m, 2H), 7.67 (d, 1H), 6.83 – 6.78 (m, 1H), 6.55 (dd, 1H), 6.44 – 6.38 (m, 1H), 6.33 (dd, 1H), 5.52 – 5.25 (m, 1H), 4.98 – 4.87 (m, 1H), 4.42 – 4.30 (m, 2H), 4.22 – 4.02 (m, 4H), 3.98 – 3.73 (m, 3H), 2.95 – 2.66 (m, 3H), 2.18 – 2.07 (m, 1H), 1.93 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.40 (s, 1H), 8.15 (s, 1H), 8.00 (d, 1H), 7.82 – 7.74 (m, 2H), 7.67 (d, 1H), 6.83 – 6.78 (m, 1H), 6.55 (dd, 1H), 6.44 – 6.38 (m, 1H), 6.33 (dd, 1H), 5.52 – 5.25 (m, 1H), 4.98 – 4.87 (m, 1H), 4.42 – 4.30 (m, 2H), 4.22 – 4.02 (m, 4H), 3.98 – 3.73 (m, 3H), 2.95 – 2.66 (m, 3H), 2.18 – 2.07 (m, 1H), 1.93 (s, 6H).

實施例92：化合物92三氟乙酸鹽的製備 Example 92: Preparation of compound 92 trifluoroacetate salt

以化合物92b為原料，參考實施例19製備方法，經酸性製備[流動相體系：乙腈/水 (含0.1% TFA)]，凍乾得到化合物92的三氟乙酸鹽(255mg)。Using compound 92b as raw material, refer to the preparation method of Example 19, undergo acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and freeze-dry to obtain the trifluoroacetate salt of compound 92 (255 mg).

1H NMR (400 MHz, CDCl 3) δ 8.63 (s, 1H), 8.16 (d, 1H), 7.98 (s, 1H), 7.83 – 7.74 (m, 2H), 7.67 (d, 1H), 7.20 – 7.14 (m, 1H), 7.13 – 7.05 (m, 1H), 6.84 – 6.76 (m, 1H), 6.60 – 6.50 (m, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.14 – 4.00 (m, 2H), 3.88 – 3.75 (m, 1H), 2.97 – 2.65 (m, 4H), 2.20 – 2.07 (m, 1H), 1.94 (s, 6H), 1.19 (d, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.63 (s, 1H), 8.16 (d, 1H), 7.98 (s, 1H), 7.83 – 7.74 (m, 2H), 7.67 (d, 1H), 7.20 – 7.14 (m, 1H), 7.13 – 7.05 (m, 1H), 6.84 – 6.76 (m, 1H), 6.60 – 6.50 (m, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H ), 4.14 – 4.00 (m, 2H), 3.88 – 3.75 (m, 1H), 2.97 – 2.65 (m, 4H), 2.20 – 2.07 (m, 1H), 1.94 (s, 6H), 1.19 (d, 6H ).

LCMS m/z = 641.1 [M+1] + LCMS m/z = 641.1 [M+1] +

實施例93：化合物93三氟乙酸鹽的製備 Example 93: Preparation of compound 93 trifluoroacetate salt

以化合物93a為原料，參考實施例19製備方法，經酸性製備[流動相體系：乙腈/水 (含0.1% TFA)]，凍乾得到化合物93的三氟乙酸鹽(220mg)。Using compound 93a as raw material, refer to the preparation method of Example 19, undergo acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and freeze-dry to obtain the trifluoroacetate salt of compound 93 (220 mg).

1H NMR (400 MHz, CDCl 3) δ 8.65 (s, 1H), 8.16 (d, 1H), 8.05 – 7.95 (m, 1H), 7.83 – 7.75 (m, 2H), 7.67 (d, 1H), 7.13 – 7.07 (m, 1H), 7.01 (dd, 1H), 6.83 – 6.77 (m, 1H), 6.55 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.95 – 2.66 (m, 3H), 2.39 (d, 2H), 2.18 – 2.07 (m, 1H), 1.94 (s, 6H), 1.87 – 1.73 (m, 1H), 0.86 (d, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.65 (s, 1H), 8.16 (d, 1H), 8.05 – 7.95 (m, 1H), 7.83 – 7.75 (m, 2H), 7.67 (d, 1H), 7.13 – 7.07 (m, 1H), 7.01 (dd, 1H), 6.83 – 6.77 (m, 1H), 6.55 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.95 – 2.66 (m, 3H), 2.39 (d, 2H), 2.18 – 2.07 (m, 1H), 1.94 (s, 6H), 1.87 – 1.73 (m, 1H), 0.86 (d, 6H).

LCMS m/z = 655.1 [M+1] + LCMS m/z = 655.1 [M+1] +

實施例94：化合物94的製備 Example 94: Preparation of Compound 94

第一步：94b的製備Step 1: Preparation of 94b

將94a (0.2 g，0.9 mmol) 溶於5 mL甲苯中，加入94A (0.2 g，0.91 mmol) 和TEA (0.14 g，1.38 mmol)，55 oC反應2 h。將反應體系冷卻至室溫，抽濾，收集濾餅，得粗品94b (0.21 g)。 Dissolve 94a (0.2 g, 0.9 mmol) in 5 mL toluene, add 94A (0.2 g, 0.91 mmol) and TEA (0.14 g, 1.38 mmol), and react at 55 ° C for 2 h. The reaction system was cooled to room temperature, filtered with suction, and the filter cake was collected to obtain crude product 94b (0.21 g).

LCMS m/z = 441.2 [M+1] + LCMS m/z = 441.2 [M+1] +

第二步：化合物94的製備Step 2: Preparation of Compound 94

將上述粗品94b (0.289 g)、上述粗品中間體1 (0.33 g)、TEA (0.20 g，1.98 mmol)、CuI (25 mg，0.13 mmol) 和PdCl 2(PPh 3) 2(93 mg，0.13 mmol) 加入到反應瓶中，加入8 mL DMF，氮氣氛圍下55℃反應3 h。將反應液冷卻至室溫，加入50 mL水，抽濾，濾餅用10 mL水洗滌，將濾餅用100 mL DCM/MeOH (v/v) = 5:1的混合溶劑溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 5:1-1:1)，得化合物94 (120 mg，從化合物94a算兩步收率：15%)。 The above crude product 94b (0.289 g), the above crude intermediate 1 (0.33 g), TEA (0.20 g, 1.98 mmol), CuI (25 mg, 0.13 mmol) and PdCl 2 (PPh 3 ) 2 (93 mg, 0.13 mmol) were added. ) into the reaction bottle, add 8 mL DMF, and react at 55°C for 3 hours under nitrogen atmosphere. Cool the reaction solution to room temperature, add 50 mL water, filter with suction, wash the filter cake with 10 mL water, dissolve the filter cake with 100 mL DCM/MeOH (v/v) = 5:1 mixed solvent, and anhydrous sodium sulfate Dry, concentrate under reduced pressure, and the crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 5:1-1:1) to obtain compound 94 (120 mg, the two-step yield is calculated from compound 94a :15%).

1H NMR (400 MHz, CDCl 3) δ 8.47 – 8.40 (m, 1H), 8.15 (s, 1H), 7.68 – 7.57 (m, 2H), 7.54 – 7.47 (m, 1H), 7.44 – 7.27 (m, 6H), 6.68 – 6.64 (m, 1H), 6.51 (dd, 1H), 5.01 – 4.92 (m, 1H), 4.38 – 4.27 (m, 2H), 4.14 – 4.01 (m, 2H), 3.91 – 3.77 (m, 1H), 2.99 – 2.67 (m, 3H), 2.19 – 2.10 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.47 – 8.40 (m, 1H), 8.15 (s, 1H), 7.68 – 7.57 (m, 2H), 7.54 – 7.47 (m, 1H), 7.44 – 7.27 (m , 6H), 6.68 – 6.64 (m, 1H), 6.51 (dd, 1H), 5.01 – 4.92 (m, 1H), 4.38 – 4.27 (m, 2H), 4.14 – 4.01 (m, 2H), 3.91 – 3.77 (m, 1H), 2.99 – 2.67 (m, 3H), 2.19 – 2.10 (m, 1H).

LCMS m/z = 650.2 [M+1] + LCMS m/z = 650.2 [M+1] +

實施例95：化合物95三氟乙酸鹽的製備 Example 95: Preparation of compound 95 trifluoroacetate salt

以95b為原料，參考實施例19製備方法，經酸性製備[流動相體系：乙腈/水 (含0.1% TFA)]，凍乾得到化合物95的三氟乙酸鹽(215mg)。Use 95b as raw material, refer to the preparation method of Example 19, undergo acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and freeze-dry to obtain the trifluoroacetate salt of compound 95 (215 mg).

1H NMR (400 MHz, CDCl 3) δ 8.84 (s, 1H), 8.37 (d, 1H), 7.98 (s, 1H), 7.85 – 7.77 (m, 2H), 7.67 (d, 1H), 7.60 – 7.30 (m, 7H), 6.84 – 6.77 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.14 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.97 – 2.63 (m, 3H), 2.18 – 2.08 (m, 1H), 1.97 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.84 (s, 1H), 8.37 (d, 1H), 7.98 (s, 1H), 7.85 – 7.77 (m, 2H), 7.67 (d, 1H), 7.60 – 7.30 (m, 7H), 6.84 – 6.77 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.14 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.97 – 2.63 (m, 3H), 2.18 – 2.08 (m, 1H), 1.97 (s, 6H).

LCMS m/z = 675.3 [M+1] + LCMS m/z = 675.3 [M+1] +

實施例96：化合物96的製備 Example 96: Preparation of Compound 96

以96a為原料，參考實施例19得到化合物96(0.20g)。Using 96a as a raw material, compound 96 (0.20 g) was obtained with reference to Example 19.

1H NMR (400 MHz, CDCl 3) δ 9.00 (s, 1H), 8.43 (d, 1H), 8.13 (d, 1H), 7.95 (s, 1H), 7.84 (s, 2H), 7.80 (d, 1H), 7.75 (d, 1H), 7.67 (d, 1H), 7.59 – 7.53 (m, 1H), 7.49 – 7.43 (m, 1H), 6.84 – 6.78 (m, 1H), 6.55 (dd, 1H), 4.97 – 4.89 (m, 1H), 4.40 – 4.32 (m, 2H), 4.12 – 4.04 (m, 2H), 3.88 – 3.77 (m, 1H), 2.95 – 2.62 (m, 3H), 2.18 – 2.08 (m, 1H), 1.99 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.00 (s, 1H), 8.43 (d, 1H), 8.13 (d, 1H), 7.95 (s, 1H), 7.84 (s, 2H), 7.80 (d, 1H), 7.75 (d, 1H), 7.67 (d, 1H), 7.59 – 7.53 (m, 1H), 7.49 – 7.43 (m, 1H), 6.84 – 6.78 (m, 1H), 6.55 (dd, 1H) , 4.97 – 4.89 (m, 1H), 4.40 – 4.32 (m, 2H), 4.12 – 4.04 (m, 2H), 3.88 – 3.77 (m, 1H), 2.95 – 2.62 (m, 3H), 2.18 – 2.08 ( m, 1H), 1.99 (s, 6H).

實施例97：化合物97的製備 Example 97: Preparation of Compound 97

以化合物97b為原料，參考實施例19得到化合物97(220mg)。Using compound 97b as a raw material, compound 97 (220 mg) was obtained with reference to Example 19.

1H NMR (400 MHz, CDCl 3) δ 8.91 (s, 1H), 8.42 (d, 1H), 7.94 (s, 1H), 7.86 (d, 1H), 7.83 – 7.74 (m, 3H), 7.73 – 7.62 (m, 2H), 7.52 (dd, 1H), 6.84 – 6.77 (m, 1H), 6.55 (dd, 1H), 6.50 – 6.43 (m, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.02 (m, 2H), 3.87 – 3.76 (m, 1H), 2.96 – 2.62 (m, 3H), 2.18 – 2.08 (m, 1H), 1.96 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.91 (s, 1H), 8.42 (d, 1H), 7.94 (s, 1H), 7.86 (d, 1H), 7.83 – 7.74 (m, 3H), 7.73 – 7.62 (m, 2H), 7.52 (dd, 1H), 6.84 – 6.77 (m, 1H), 6.55 (dd, 1H), 6.50 – 6.43 (m, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.02 (m, 2H), 3.87 – 3.76 (m, 1H), 2.96 – 2.62 (m, 3H), 2.18 – 2.08 (m, 1H), 1.96 (s, 6H).

實施例98：化合物98三氟乙酸鹽的製備 Example 98: Preparation of compound 98 trifluoroacetate salt

第一步：98b的製備Step 1: Preparation of 98b

將98a (1.1 g，5 mmol) 加入到20 mL DMF中，加入28B (2.2 g，6.17 mmol)和碳酸銫 (3.3 g，10.1 mmol)，85℃反應3 h。將反應液冷卻至室溫，加入100 mL乙酸乙酯和200 mL純化水，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚:乙酸乙酯 (v/v) = 3:1)，得98b (0.6 g，收率：24%)。Add 98a (1.1 g, 5 mmol) to 20 mL DMF, add 28B (2.2 g, 6.17 mmol) and cesium carbonate (3.3 g, 10.1 mmol), and react at 85°C for 3 h. The reaction solution was cooled to room temperature, 100 mL of ethyl acetate and 200 mL of purified water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified with a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) ) = 3:1), obtaining 98b (0.6 g, yield: 24%).

第二步：化合物98三氟乙酸鹽的製備Step 2: Preparation of compound 98 trifluoroacetate salt

將98b (0.2 g，0.4 mmol) 溶於5 mL DMF中，依次加入上述粗品中間體1 (0.17 g)、TEA (0.1 g，0.99 mmol)、CuI (0.019 g，0.1 mmol) 和PdCl 2(PPh 3) 2(0.07 g，0.1 mmol)，氮氣氛圍下95℃反應1 h。將反應液冷卻至室溫，加入20 mL水，過濾，將濾餅用10 mL水洗滌，將濾餅用30 mL DCM溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 1:3)，所得粗品過Pre-HPLC (儀器及製備柱：採用Glison GX-281製備液相，製備柱型號是Sunfire C18，5 μm，內徑×長度 = 30 mm×150 mm)。製備方法：粗品用甲醇和二甲亞碸溶解，並用0.45 μm濾膜過濾，製備成樣品液。流動相體系：乙腈/水 (含0.1% TFA)。梯度沖提方法：乙腈由5%梯度沖提60% (沖提時間15 min)，凍乾得化合物98的三氟乙酸鹽 (0.02 g)。 Dissolve 98b (0.2 g, 0.4 mmol) in 5 mL DMF, and add the above crude intermediate 1 (0.17 g), TEA (0.1 g, 0.99 mmol), CuI (0.019 g, 0.1 mmol) and PdCl 2 (PPh) in sequence. 3 ) 2 (0.07 g, 0.1 mmol), reacted at 95°C for 1 h under nitrogen atmosphere. Cool the reaction solution to room temperature, add 20 mL of water, filter, wash the filter cake with 10 mL of water, dissolve the filter cake with 30 mL of DCM, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column ( Petroleum ether/ethyl acetate (v/v) = 1:3), and the crude product was subjected to Pre-HPLC (instrument and preparation column: Glison GX-281 was used to prepare the liquid phase, and the preparation column model was Sunfire C18, 5 μm, inner diameter × length = 30 mm × 150 mm). Preparation method: Dissolve the crude product with methanol and dimethyl sulfoxide, filter it with a 0.45 μm filter membrane, and prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% TFA). Gradient elution method: acetonitrile gradient elution from 5% to 60% (elution time 15 min), and freeze-dried to obtain the trifluoroacetate salt of compound 98 (0.02 g).

1H NMR (400 MHz, CDCl 3) δ 8.74 (s, 1H), 8.51 (d, 1H), 8.09 (s, 1H), 7.98 (s, 1H), 7.70 (d, 1H), 7.65 – 7.58 (m, 1H), 7.57 – 7.49 (m, 1H), 6.88 – 6.80 (m, 1H), 6.59 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.48 – 4.37 (m, 2H), 4.23 – 4.11 (m, 2H), 3.98 – 3.87 (m, 1H), 3.20 – 2.66 (m, 7H), 2.33 – 2.04 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.74 (s, 1H), 8.51 (d, 1H), 8.09 (s, 1H), 7.98 (s, 1H), 7.70 (d, 1H), 7.65 – 7.58 ( m, 1H), 7.57 – 7.49 (m, 1H), 6.88 – 6.80 (m, 1H), 6.59 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.48 – 4.37 (m, 2H), 4.23 – 4.11 (m, 2H), 3.98 – 3.87 (m, 1H), 3.20 – 2.66 (m, 7H), 2.33 – 2.04 (m, 3H).

實施例99：化合物99三氟乙酸鹽的製備 Example 99: Preparation of compound 99 trifluoroacetate salt

以99b為原料，參考實施例92製備方法，經酸性製備[流動相體系：乙腈/水 (含0.1% TFA)]，凍乾得到化合物99的三氟乙酸鹽(185mg)。Use 99b as raw material, refer to the preparation method of Example 92, undergo acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and freeze-dry to obtain the trifluoroacetate salt of compound 99 (185 mg).

1H NMR (400 MHz, CDCl 3) δ 8.63 (s, 1H), 8.19 – 8.08 (m, 2H), 7.84 – 7.75 (m, 2H), 7.67 (d, 1H), 7.17 – 7.12 (m, 1H), 7.09 – 7.03 (m, 1H), 6.83 – 6.78 (m, 1H), 6.55 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.40 – 4.30 (m, 2H), 4.13 – 4.02 (m, 2H), 3.87 – 3.75 (m, 1H), 2.95 – 2.65 (m, 3H), 2.57 (q, 2H), 2.20 – 2.05 (m, 1H), 1.94 (s, 6H), 1.18 (t, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.63 (s, 1H), 8.19 – 8.08 (m, 2H), 7.84 – 7.75 (m, 2H), 7.67 (d, 1H), 7.17 – 7.12 (m, 1H ), 7.09 – 7.03 (m, 1H), 6.83 – 6.78 (m, 1H), 6.55 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.40 – 4.30 (m, 2H), 4.13 – 4.02 (m , 2H), 3.87 – 3.75 (m, 1H), 2.95 – 2.65 (m, 3H), 2.57 (q, 2H), 2.20 – 2.05 (m, 1H), 1.94 (s, 6H), 1.18 (t, 3H ).

LCMS m/z = 627.0 [M+1] + LCMS m/z = 627.0 [M+1] +

實施例100與101：化合物100與101的製備 Examples 100 and 101: Preparation of Compounds 100 and 101

以化合物100a為原料，參考實施例83與84得到化合物100與化合物101Using compound 100a as raw material, compound 100 and compound 101 were obtained with reference to Examples 83 and 84.

終產物提純方法：SFC (儀器及製備柱：採用SFC Prep 150 AP製備液相，製備柱型號是大賽璐Torus 2-pic，內徑×長度 = 19 mm×250 mm)。製備方法：粗品的甲醇溶液用0.45 μm濾膜過濾，製備成樣品液。流動相體系：二氧化碳/甲醇。沖提方法：等度沖提，流動相甲醇含量20%，流量40 mL/min，分別得到化合物100 (沖提時間7.57 min) (50 mg) 與化合物101 (沖提時間11.53 min) (190 mg)。Purification method of the final product: SFC (instrument and preparation column: SFC Prep 150 AP is used to prepare the liquid phase, the preparation column model is Daicel Torus 2-pic, inner diameter × length = 19 mm × 250 mm). Preparation method: Filter the methanol solution of the crude product with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: carbon dioxide/methanol. Elution method: isocratic extraction, mobile phase methanol content 20%, flow rate 40 mL/min, compound 100 (elution time 7.57 min) (50 mg) and compound 101 (elution time 11.53 min) (190 mg) were obtained respectively. ).

化合物100的核磁氫譜：Proton NMR spectrum of compound 100:

1H NMR (400 MHz, CDCl 3) δ 8.34 (d, 1H), 8.05 – 7.95 (m, 2H), 7.71 (d, 1H), 7.47 – 7.41 (m, 1H), 7.35 – 7.30 (m, 1H), 7.22 (dd, 1H), 6.71 – 6.65 (m, 1H), 6.47 (dd, 1H), 5.00 – 4.91 (m, 1H), 4.26 – 4.18 (m, 2H), 3.85 – 3.67 (m, 3H), 2.96 – 2.66 (m, 3H), 2.25 – 2.14 (m, 1H), 2.10 (s, 3H), 1.94 (s, 6H), 1.36 – 1.23 (m, 1H), 0.69 – 0.61 (m, 2H), 0.44 – 0.35 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, 1H), 8.05 – 7.95 (m, 2H), 7.71 (d, 1H), 7.47 – 7.41 (m, 1H), 7.35 – 7.30 (m, 1H) ), 7.22 (dd, 1H), 6.71 – 6.65 (m, 1H), 6.47 (dd, 1H), 5.00 – 4.91 (m, 1H), 4.26 – 4.18 (m, 2H), 3.85 – 3.67 (m, 3H ), 2.96 – 2.66 (m, 3H), 2.25 – 2.14 (m, 1H), 2.10 (s, 3H), 1.94 (s, 6H), 1.36 – 1.23 (m, 1H), 0.69 – 0.61 (m, 2H ), 0.44 – 0.35 (m, 2H).

LCMS m/z = 644.1 [M+1] + LCMS m/z = 644.1 [M+1] +

化合物101的核磁氫譜：Proton NMR spectrum of compound 101:

1H NMR (400 MHz, CDCl 3) δ 9.24 (s, 1H), 8.39 (d, 1H), 7.96 (s, 1H), 7.70 (d, 1H), 7.54 – 7.43 (m, 2H), 7.38 – 7.33 (m, 1H), 6.86 – 6.81 (m, 1H), 6.58 (dd, 1H), 5.00 – 4.90 (m, 1H), 4.47 – 4.36 (m, 2H), 4.17 – 4.05 (m, 2H), 3.94 – 3.80 (m, 1H), 2.97 – 2.65 (m, 3H), 2.21 – 2.07 (m, 4H), 1.94 (s, 6H), 1.59 – 1.46 (m, 1H), 1.10 – 0.99 (m, 2H), 0.62 – 0.54 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.24 (s, 1H), 8.39 (d, 1H), 7.96 (s, 1H), 7.70 (d, 1H), 7.54 – 7.43 (m, 2H), 7.38 – 7.33 (m, 1H), 6.86 – 6.81 (m, 1H), 6.58 (dd, 1H), 5.00 – 4.90 (m, 1H), 4.47 – 4.36 (m, 2H), 4.17 – 4.05 (m, 2H), 3.94 – 3.80 (m, 1H), 2.97 – 2.65 (m, 3H), 2.21 – 2.07 (m, 4H), 1.94 (s, 6H), 1.59 – 1.46 (m, 1H), 1.10 – 0.99 (m, 2H ), 0.62 – 0.54 (m, 2H).

LCMS m/z = 644.0 [M+1] + LCMS m/z = 644.0 [M+1] +

實施例102：化合物102的製備 Example 102: Preparation of Compound 102

第一步：102b的製備Step One: Preparation of 102b

將102a (4.7 g，22.6 mmol) 溶解於80 mL DCM中，加入TEA (4.58 g，45.26 mmol) 與DMAP (0.28 g，2.29 mmol)，0℃緩慢滴加三氟乙酸酐 (5.70 g，27.14 mmol)，室溫反應3 h。向反應體系中加入100 mL飽和碳酸氫鈉水溶液，用200 mL DCM萃取，有機相用50 mL水洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠柱色譜分離純化 (石油醚/乙酸乙酯 (v/v) = 3:1)，得到102b (6.5 g，收率：95%)。Dissolve 102a (4.7 g, 22.6 mmol) in 80 mL DCM, add TEA (4.58 g, 45.26 mmol) and DMAP (0.28 g, 2.29 mmol), and slowly add trifluoroacetic anhydride (5.70 g, 27.14 mmol) at 0°C. ), react at room temperature for 3 h. Add 100 mL saturated aqueous sodium bicarbonate solution to the reaction system, extract with 200 mL DCM, wash the organic phase with 50 mL water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate). (v/v) = 3:1), obtaining 102b (6.5 g, yield: 95%).

第二步：102c的製備Step 2: Preparation of 102c

將102b (6.08 g，20.00 mmol) 與3-碘氮雜環丁-1-甲酸叔丁酯 (6.79 g，23.98 mmol) 溶解於80 mL DMA中，加入鋅粉 (7.85 g，120.8 mmol)，氮氣氛圍下加入2-脒基吡啶鹽酸鹽 (CAS: 51285-26-8) (0.63 g，4.0 mmol) 與氯化鎳乙二醇二甲醚錯合物 (CAS: 29046-78-4) (0.88 g，4.00 mmol)，氮氣氛圍下100℃反應16 h。將反應體系冷卻至室溫，加入200 mL水和100 mL乙酸乙酯，過濾，將濾液分液，水相用200 mL乙酸乙酯萃取，有機相用100 mL水洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠柱色譜分離純化 (石油醚/乙酸乙酯 (v/v) = 4:1)，得到102c (4.3 g，收率：57%)。Dissolve 102b (6.08 g, 20.00 mmol) and 3-iodoazetidine-1-carboxylic acid tert-butyl ester (6.79 g, 23.98 mmol) in 80 mL DMA, add zinc powder (7.85 g, 120.8 mmol), and add nitrogen 2-amidinopyridine hydrochloride (CAS: 51285-26-8) (0.63 g, 4.0 mmol) and nickel chloride ethylene glycol dimethyl ether complex (CAS: 29046-78-4) ( 0.88 g, 4.00 mmol), reacted at 100°C for 16 h under nitrogen atmosphere. Cool the reaction system to room temperature, add 200 mL water and 100 mL ethyl acetate, filter, separate the filtrate, extract the aqueous phase with 200 mL ethyl acetate, wash the organic phase with 100 mL water, dry over anhydrous sodium sulfate, and reduce The mixture was concentrated under pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4:1) to obtain 102c (4.3 g, yield: 57%).

第三步：102d的製備Step 3: Preparation of 102d

將102c (4.3 g，11.31 mmol) 溶解於80 mL甲醇中，加入碳酸鉀 (9.38 g，67.87 mmol) 與碳酸銫 (7.37 g，22.62 mmol)，60℃反應16 h。將反應體系冷卻至室溫，加入150 mL DCM，過濾，將濾液減壓濃縮，粗品用矽膠柱色譜分離純化 (石油醚/乙酸乙酯 (v/v) = 2:1)，得到102d (2.4 g，收率：75%)。Dissolve 102c (4.3 g, 11.31 mmol) in 80 mL methanol, add potassium carbonate (9.38 g, 67.87 mmol) and cesium carbonate (7.37 g, 22.62 mmol), and react at 60°C for 16 h. The reaction system was cooled to room temperature, 150 mL DCM was added, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2:1) to obtain 102d (2.4 g, yield: 75%).

第四步：102e的製備Step 4: Preparation of 102e

將102d (1.8 g，6.33 mmol) 溶解於60 mL乙腈中，加入KI (1.58 g，9.52 mmol) 與CuI (1.81 g，9.50 mmol) 和I 2(2.41 g，9.50 mmol)，氮氣氛圍下0℃緩慢滴加亞硝酸異戊酯 (1.11 g，9.48 mmol)，室溫反應16 h。向反應體系中加入100 mL飽和硫代硫酸鈉水溶液，過濾，將濾液用100 mL乙酸乙酯萃取，有機相用50 mL水洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠柱色譜分離純化 (石油醚/乙酸乙酯 (v/v) = 3:1)，得到102e (1.2 g，收率：48%)。 Dissolve 102d (1.8 g, 6.33 mmol) in 60 mL acetonitrile, add KI (1.58 g, 9.52 mmol), CuI (1.81 g, 9.50 mmol) and I 2 (2.41 g, 9.50 mmol) at 0°C under nitrogen atmosphere Isoamyl nitrite (1.11 g, 9.48 mmol) was slowly added dropwise, and the reaction was carried out at room temperature for 16 h. Add 100 mL of saturated sodium thiosulfate aqueous solution to the reaction system, filter, extract the filtrate with 100 mL of ethyl acetate, wash the organic phase with 50 mL of water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified by silica gel column chromatography. (Petroleum ether/ethyl acetate (v/v) = 3:1), 102e (1.2 g, yield: 48%) was obtained.

第五步：102f的製備Step 5: Preparation of 102f

將102e (1.2 g，3.04 mmol)、4-吡唑硼酸頻哪醇酯 (CAS: 269410-08-4) (0.88 g，4.54 mmol)、碳酸鉀 (0.84 g，6.08 mmol)，氮氣氛圍下加入 [1,1′-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷錯合物 (250 mg，0.31 mmol)，氮氣氛圍下100℃反應4 h。將反應液冷卻至室溫，加入80 mL水，用100 mL乙酸乙酯萃取，有機相用50 mL水洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠柱色譜分離純化 (石油醚/乙酸乙酯 (v/v) = 3:1)，得到102f (520 mg，收率：51%)。102e (1.2 g, 3.04 mmol), 4-pyrazole boronic acid pinacol ester (CAS: 269410-08-4) (0.88 g, 4.54 mmol), and potassium carbonate (0.84 g, 6.08 mmol) were added under nitrogen atmosphere. [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (250 mg, 0.31 mmol), reacted at 100°C for 4 h under nitrogen atmosphere. The reaction solution was cooled to room temperature, 80 mL of water was added, and extracted with 100 mL of ethyl acetate. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether/acetic acid). Ethyl ester (v/v) = 3:1), giving 102f (520 mg, yield: 51%).

LCMS m/z = 336.1 [M+1] + LCMS m/z = 336.1 [M+1] +

第六步：102g的製備Step 6: Preparation of 102g

將102f (0.072 g，0.21 mmol) 溶解於8 mL乙腈中，加入碳酸銫 (0.14 g，0.43 mmol) 與53B (0.32 g，1.04 mmol)，80℃反應8 h。將反應體系冷卻至室溫，過濾，將濾液減壓濃縮，粗品用矽膠柱色譜分離純化 (石油醚/乙酸乙酯 (v/v) = 4:1)，得到102g (90 mg，收率：76%)。Dissolve 102f (0.072 g, 0.21 mmol) in 8 mL acetonitrile, add cesium carbonate (0.14 g, 0.43 mmol) and 53B (0.32 g, 1.04 mmol), and react at 80°C for 8 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4:1) to obtain 102g (90 mg, yield: 76%).

LCMS m/z = 562.2 [M+1] + LCMS m/z = 562.2 [M+1] +

以化合物102g為原料，參考實施例23得到化合物102(40mg)。Using compound 102g as a raw material, compound 102 (40 mg) was obtained with reference to Example 23.

1H NMR (400 MHz, CDCl 3) δ 9.19 (s, 1H), 8.40 (d, 1H), 8.09 – 8.05 (m, 1H), 8.00 (s, 1H), 7.92 (s, 1H), 7.70 (d, 1H), 7.49 (dd, 1H), 7.40 – 7.32 (m, 1H), 7.27 – 7.14 (m, 2H), 6.90 – 6.84 (m, 1H), 6.62 (dd, 1H), 5.00 – 4.86 (m, 1H), 4.56 – 4.44 (m, 2H), 4.33 – 4.20 (m, 1H), 4.16 – 4.05 (m, 2H), 2.96 – 2.65 (m, 3H), 2.20 – 2.08 (m, 1H), 2.03 (s, 6H), 1.58 – 1.46 (m, 1H), 1.00 – 0.91 (m, 2H), 0.62 – 0.52 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.19 (s, 1H), 8.40 (d, 1H), 8.09 – 8.05 (m, 1H), 8.00 (s, 1H), 7.92 (s, 1H), 7.70 ( d, 1H), 7.49 (dd, 1H), 7.40 – 7.32 (m, 1H), 7.27 – 7.14 (m, 2H), 6.90 – 6.84 (m, 1H), 6.62 (dd, 1H), 5.00 – 4.86 ( m, 1H), 4.56 – 4.44 (m, 2H), 4.33 – 4.20 (m, 1H), 4.16 – 4.05 (m, 2H), 2.96 – 2.65 (m, 3H), 2.20 – 2.08 (m, 1H), 2.03 (s, 6H), 1.58 – 1.46 (m, 1H), 1.00 – 0.91 (m, 2H), 0.62 – 0.52 (m, 2H).

實施例103：化合物103的製備 第一步：103b的製備 Example 103: Preparation of Compound 103 Step One: Preparation of 103b

將103a (450 mg, 2.0 mmol) 溶解於10 mL二氯甲烷中，加入103A (0.53 g，2.42 mmol) 和TCFH (0.85 g, 3.03 mmol)，加入NMI (0.66 g, 8.04 mmol)，室溫反應16 h。向反應體系中加入50 mL飽和碳酸氫鈉水溶液，用100 mL二氯甲烷萃取，有機相用50 mL水洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚:乙酸乙酯 (v/v) = 5:1)，得到103b (800 mg，收率：94%)。Dissolve 103a (450 mg, 2.0 mmol) in 10 mL dichloromethane, add 103A (0.53 g, 2.42 mmol) and TCFH (0.85 g, 3.03 mmol), add NMI (0.66 g, 8.04 mmol), and react at room temperature 16h. Add 50 mL of saturated sodium bicarbonate aqueous solution to the reaction system, extract with 100 mL of dichloromethane, wash the organic phase with 50 mL of water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether: acetic acid Ethyl ester (v/v) = 5:1), giving 103b (800 mg, yield: 94%).

LCMS m/z = 426.1 [M+1] + LCMS m/z = 426.1 [M+1] +

第二步：化合物103的製備Step 2: Preparation of Compound 103

將103b (0.21 g，0.49 mmol)、上述粗品中間體1 (0.25 g)、TEA (0.15 g，1.48 mmol)、CuI (10 mg，0.053 mmol) 和PdCl 2(PPh 3) 2(35 mg，0.05 mmol) 加入到反應瓶中，加入4 mL DMF，氮氣氛圍下50℃反應2 h。將反應液冷卻至室溫，加入50 mL水，抽濾，將濾餅用10 mL水洗滌，將濾餅用100 mL DCM溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠柱色譜分離純化 (石油醚/乙酸乙酯 (v/v) = 1:2)，得到化合物103 (0.21 g，收率：68%)。 103b (0.21 g, 0.49 mmol), the above crude intermediate 1 (0.25 g), TEA (0.15 g, 1.48 mmol), CuI (10 mg, 0.053 mmol) and PdCl 2 (PPh 3 ) 2 (35 mg, 0.05 mmol) into the reaction bottle, add 4 mL DMF, and react at 50°C for 2 h under nitrogen atmosphere. Cool the reaction solution to room temperature, add 50 mL of water, filter with suction, wash the filter cake with 10 mL of water, dissolve the filter cake with 100 mL of DCM, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified by silica gel column chromatography. (Petroleum ether/ethyl acetate (v/v) = 1:2), compound 103 (0.21 g, yield: 68%) was obtained.

1H NMR (400 MHz, CDCl 3) δ 8.05 (s, 1H), 7.94 (s, 1H), 7.88 – 7.78 (m, 2H), 7.72 (s, 1H), 7.70 – 7.60 (m, 2H), 7.58 – 7.50 (m, 1H), 7.37 – 7.29 (m, 1H), 7.27 – 7.21 (m, 1H), 6.84 – 6.78 (m, 1H), 6.56 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.43 – 4.32 (m, 2H), 4.17 – 4.06 (m, 2H), 3.93 – 3.78 (m, 1H), 2.95 – 2.64 (m, 3H), 2.19 – 2.07 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.05 (s, 1H), 7.94 (s, 1H), 7.88 – 7.78 (m, 2H), 7.72 (s, 1H), 7.70 – 7.60 (m, 2H), 7.58 – 7.50 (m, 1H), 7.37 – 7.29 (m, 1H), 7.27 – 7.21 (m, 1H), 6.84 – 6.78 (m, 1H), 6.56 (dd, 1H), 4.98 – 4.88 (m, 1H) ), 4.43 – 4.32 (m, 2H), 4.17 – 4.06 (m, 2H), 3.93 – 3.78 (m, 1H), 2.95 – 2.64 (m, 3H), 2.19 – 2.07 (m, 1H).

實施例104：化合物104的製備 Example 104: Preparation of Compound 104

第一步：104b的製備Step One: Preparation of 104b

將104a (1.00 g，7.57 mmol) 溶於15 mL二氯甲烷中，氮氣氛圍下-15℃緩慢滴加溴素 (1.21 g，7.57 mmol) 的5 mL二氯甲烷溶液，-15℃反應0.5 h。-15℃向反應液加入30 mL飽和碳酸氫鈉水溶液，水相用二氯甲烷萃取 (10 mL×2)，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 5:1)，得104b (1.30 g，收率：81%)。Dissolve 104a (1.00 g, 7.57 mmol) in 15 mL dichloromethane, slowly add bromine (1.21 g, 7.57 mmol) in 5 mL dichloromethane solution at -15°C under nitrogen atmosphere, and react at -15°C for 0.5 h. . Add 30 mL saturated aqueous sodium bicarbonate solution to the reaction solution at -15°C, extract the aqueous phase with dichloromethane (10 mL Ether:ethyl acetate (v/v) = 5:1) to obtain 104b (1.30 g, yield: 81%).

LCMS m/z = 211.1 [M+1] + LCMS m/z = 211.1 [M+1] +

第二步：參考由16A製備16B的製備方法，以104a為起始原料得到104c(0.74g)Step 2: Refer to the preparation method of preparing 16B from 16A, and use 104a as the starting material to obtain 104c (0.74g)

LCMS m/z = 173.2 [M+1] + LCMS m/z = 173.2 [M+1] +

以化合物104c為原料，參考實施例19得到化合物104（0.11g）。Using compound 104c as a raw material, compound 104 (0.11g) was obtained with reference to Example 19.

1H NMR (400 MHz, CDCl 3) δ 8.19 (s, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 7.68 (d, 1H), 7.37 – 7.30 (m, 1H), 7.18 – 7.10 (m, 1H), 6.85 – 6.77 (m, 1H), 6.56 (dd, 1H), 4.99 – 4.87 (m, 1H), 4.42 – 4.32 (m, 2H), 4.12 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.98 – 2.65 (m, 3H), 2.18 – 2.07 (m, 4H), 1.97 (s, 6H), 1.70 – 1.58 (m, 1H), 0.92 – 0.80 (m, 2H), 0.57 – 0.47 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.19 (s, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 7.68 (d, 1H), 7.37 – 7.30 ( m, 1H), 7.18 – 7.10 (m, 1H), 6.85 – 6.77 (m, 1H), 6.56 (dd, 1H), 4.99 – 4.87 (m, 1H), 4.42 – 4.32 (m, 2H), 4.12 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.98 – 2.65 (m, 3H), 2.18 – 2.07 (m, 4H), 1.97 (s, 6H), 1.70 – 1.58 (m, 1H), 0.92 – 0.80 (m, 2H), 0.57 – 0.47 (m, 2H).

LCMS m/z = 644.3 [M+1] + LCMS m/z = 644.3 [M+1] +

實施例105：化合物105的製備 Example 105: Preparation of Compound 105

以化合物105a為原料，參考實施例104得到化合物105（0.24g）。Using compound 105a as a raw material, compound 105 (0.24g) was obtained with reference to Example 104.

1H NMR (400 MHz, CDCl 3) δ 8.90 (s, 1H), 8.44 (dd, 1H), 7.97 (s, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 7.67 (d, 1H), 7.37 – 7.25 (m, 2H), 6.84 – 6.78 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.00 (m, 2H), 3.88 – 3.74 (m, 1H), 2.94 – 2.65 (m, 3H), 2.18 – 2.07 (m, 1H), 1.95 (s, 6H), 1.68 – 1.55 (m, 1H), 1.18 – 1.08 (m, 2H), 0.74 – 0.65 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.90 (s, 1H), 8.44 (dd, 1H), 7.97 (s, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 7.67 (d, 1H), 7.37 – 7.25 (m, 2H), 6.84 – 6.78 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.00 ( m, 2H), 3.88 – 3.74 (m, 1H), 2.94 – 2.65 (m, 3H), 2.18 – 2.07 (m, 1H), 1.95 (s, 6H), 1.68 – 1.55 (m, 1H), 1.18 – 1.08 (m, 2H), 0.74 – 0.65 (m, 2H).

LCMS m/z = 630.2 [M+1] + LCMS m/z = 630.2 [M+1] +

實施例106：化合物106的製備 Example 106: Preparation of Compound 106

以化合物106b為原料，參考實施例104得到化合物106（150mg）。 Using compound 106b as a raw material, compound 106 (150 mg) was obtained with reference to Example 104.

1H NMR (400 MHz, CDCl 3) δ 8.96 (s, 1H), 8.56 – 8.50 (m, 1H), 8.24 (s, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.67 (d, 1H), 7.38 – 7.24 (m, 1H), 7.18 – 7.10 (m, 1H), 6.85 – 6.75 (m, 1H), 6.55 (dd, 1H), 4.99 – 4.90 (m, 1H), 4.43 – 4.30 (m, 2H), 4.12 – 4.00 (m, 2H), 3.88 – 3.75 (m, 1H), 2.95 – 2.65 (m, 3H), 2.18 – 2.08 (m, 1H), 1.96 (s, 6H), 1.61 – 1.49 (m, 1H), 1.04 – 0.94 (m, 2H), 0.64 – 0.56 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.96 (s, 1H), 8.56 – 8.50 (m, 1H), 8.24 (s, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.67 ( d, 1H), 7.38 – 7.24 (m, 1H), 7.18 – 7.10 (m, 1H), 6.85 – 6.75 (m, 1H), 6.55 (dd, 1H), 4.99 – 4.90 (m, 1H), 4.43 – 4.30 (m, 2H), 4.12 – 4.00 (m, 2H), 3.88 – 3.75 (m, 1H), 2.95 – 2.65 (m, 3H), 2.18 – 2.08 (m, 1H), 1.96 (s, 6H), 1.61 – 1.49 (m, 1H), 1.04 – 0.94 (m, 2H), 0.64 – 0.56 (m, 2H).

實施例107：化合物107的製備 Example 107: Preparation of Compound 107

以化合物107a為原料，參考實施例104得到化合物107（20mg）。 1H NMR (400 MHz, DMSO- d 6 ) δ 11.07 (s, 1H), 9.06 (s, 1H), 8.35 (s, 1H), 7.94 – 7.86 (m, 1H), 7.84 (s, 1H), 7.79 – 7.71 (m, 1H), 7.68 (d, 1H), 6.90 – 6.83 (m, 1H), 6.72 (dd, 1H), 5.12 – 5.02 (m, 1H), 4.47 – 4.32 (m, 2H), 4.07 – 3.96 (m, 2H), 3.96 – 3.82 (m, 1H), 2.97 – 2.80 (m, 1H), 2.67 – 2.51 (m, 2H), 2.10 – 1.96 (m, 1H), 1.86 (s, 6H), 1.56 – 1.44 (m, 1H), 0.98 – 0.85 (m, 2H), 0.56 – 0.45 (m, 2H). Using compound 107a as a raw material, compound 107 (20 mg) was obtained with reference to Example 104. 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.07 (s, 1H), 9.06 (s, 1H), 8.35 (s, 1H), 7.94 – 7.86 (m, 1H), 7.84 (s, 1H), 7.79 – 7.71 (m, 1H), 7.68 (d, 1H), 6.90 – 6.83 (m, 1H), 6.72 (dd, 1H), 5.12 – 5.02 (m, 1H), 4.47 – 4.32 (m, 2H), 4.07 – 3.96 (m, 2H), 3.96 – 3.82 (m, 1H), 2.97 – 2.80 (m, 1H), 2.67 – 2.51 (m, 2H), 2.10 – 1.96 (m, 1H), 1.86 (s, 6H ), 1.56 – 1.44 (m, 1H), 0.98 – 0.85 (m, 2H), 0.56 – 0.45 (m, 2H).

LCMS m/z = 646.5 [M-1] - LCMS m/z = 646.5 [M-1] -

實施例108：化合物108的製備 Example 108: Preparation of Compound 108

以化合物108a為原料，參考實施例104得到化合物108(300mg)。 Using compound 108a as a raw material, compound 108 (300 mg) was obtained with reference to Example 104.

1H NMR (400 MHz, CDCl 3) δ 8.50 – 8.30 (m, 2H), 7.84 (s, 1H), 7.76 (s, 1H), 7.67 (d, 1H), 7.23 (dd, 1H), 7.09 (s, 1H), 6.85 – 6.75 (m, 1H), 6.56 (dd, 1H), 4.99 – 4.88 (m, 1H), 4.43 – 4.30 (m, 2H), 4.14 – 4.00 (m, 2H), 3.88 – 3.75 (m, 1H), 2.94 – 2.65 (m, 3H), 2.18 – 2.07 (m, 1H), 1.96 (s, 6H), 1.77 – 1.64 (m, 1H), 1.02 – 0.91 (m, 2H), 0.65 – 0.55 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.50 – 8.30 (m, 2H), 7.84 (s, 1H), 7.76 (s, 1H), 7.67 (d, 1H), 7.23 (dd, 1H), 7.09 ( s, 1H), 6.85 – 6.75 (m, 1H), 6.56 (dd, 1H), 4.99 – 4.88 (m, 1H), 4.43 – 4.30 (m, 2H), 4.14 – 4.00 (m, 2H), 3.88 – 3.75 (m, 1H), 2.94 – 2.65 (m, 3H), 2.18 – 2.07 (m, 1H), 1.96 (s, 6H), 1.77 – 1.64 (m, 1H), 1.02 – 0.91 (m, 2H), 0.65 – 0.55 (m, 2H).

實施例109：化合物109的製備 Example 109: Preparation of Compound 109

以化合物109d為原料，參考實施例59得到化合物109(0.15g)。Using compound 109d as a raw material, compound 109 (0.15g) was obtained with reference to Example 59.

1H NMR (400 MHz, CDCl 3) δ 9.94 (s, 1H), 8.28 (d, 1H), 7.95 (s, 1H), 7.74 – 7.65 (m, 3H), 7.62 (d, 1H), 7.59 (s, 1H), 7.03 (dd, 1H), 6.99 – 6.95 (m, 1H), 6.85 – 6.80 (m, 1H), 6.57 (dd, 1H), 6.14 (t, 1H), 4.99 – 4.87 (m, 1H), 4.43 – 4.32 (m, 2H), 4.15 – 4.05 (m, 2H), 3.92 – 3.78 (m, 1H), 2.98 – 2.66 (m, 3H), 2.19 – 2.08 (m, 1H), 1.95 – 1.79 (m, 7H), 1.02 – 0.92 (m, 2H), 0.71 – 0.62 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.94 (s, 1H), 8.28 (d, 1H), 7.95 (s, 1H), 7.74 – 7.65 (m, 3H), 7.62 (d, 1H), 7.59 ( s, 1H), 7.03 (dd, 1H), 6.99 – 6.95 (m, 1H), 6.85 – 6.80 (m, 1H), 6.57 (dd, 1H), 6.14 (t, 1H), 4.99 – 4.87 (m, 1H), 4.43 – 4.32 (m, 2H), 4.15 – 4.05 (m, 2H), 3.92 – 3.78 (m, 1H), 2.98 – 2.66 (m, 3H), 2.19 – 2.08 (m, 1H), 1.95 – 1.79 (m, 7H), 1.02 – 0.92 (m, 2H), 0.71 – 0.62 (m, 2H).

實施例110：化合物110的製備 Example 110: Preparation of Compound 110

以化合物110a為原料，參考實施例102得到化合物110（50mg）。 Using compound 110a as a raw material, compound 110 (50 mg) was obtained with reference to Example 102.

1H NMR (400 MHz, CDCl 3) δ 9.18 (s, 1H), 8.41 (d, 1H), 8.10 – 7.94 (m, 3H), 7.70 (d, 1H), 7.58 – 7.46 (m, 2H), 7.39 – 7.32 (m, 1H), 7.21 – 7.12 (m, 2H), 6.90 – 6.84 (m, 1H), 6.62 (m, 1H), 5.00 – 4.86 (m, 1H), 4.55 – 4.40 (m, 2H), 4.14 – 3.95 (m, 3H), 2.96 – 2.65 (m, 3H), 2.23 – 2.07 (m, 1H), 2.03 (s, 6H), 1.58 – 1.46 (m, 1H), 1.00 – 0.90 (m, 2H), 0.60 – 0.51 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.18 (s, 1H), 8.41 (d, 1H), 8.10 – 7.94 (m, 3H), 7.70 (d, 1H), 7.58 – 7.46 (m, 2H), 7.39 – 7.32 (m, 1H), 7.21 – 7.12 (m, 2H), 6.90 – 6.84 (m, 1H), 6.62 (m, 1H), 5.00 – 4.86 (m, 1H), 4.55 – 4.40 (m, 2H ), 4.14 – 3.95 (m, 3H), 2.96 – 2.65 (m, 3H), 2.23 – 2.07 (m, 1H), 2.03 (s, 6H), 1.58 – 1.46 (m, 1H), 1.00 – 0.90 (m , 2H), 0.60 – 0.51 (m, 2H).

實施例111：化合物111的製備 Example 111: Preparation of Compound 111

以化合物111a為原料，參考實施例102得到化合物111（100mg）。 Using compound 111a as a raw material, compound 111 (100 mg) was obtained with reference to Example 102.

1H NMR (400 MHz, CDCl 3) δ 9.21 (s, 1H), 8.41 (d, 1H), 8.03 – 7.88 (m, 3H), 7.68 (d, 1H), 7.49 (dd, 1H), 7.42 – 7.28 (m, 4H), 6.90 – 6.85 (m, 1H), 6.62 (dd, 1H), 4.98 – 4.87 (m, 1H), 4.55 – 4.44 (m, 2H), 4.34 – 4.21 (m, 1H), 4.15 – 4.05 (m, 2H), 2.95 – 2.66 (m, 3H), 2.33 (s, 3H), 2.18 – 2.08 (m, 1H), 2.02 (s, 6H), 1.58 – 1.45 (m, 1H), 1.00 – 0.92 (m, 2H), 0.58 – 0.51 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.21 (s, 1H), 8.41 (d, 1H), 8.03 – 7.88 (m, 3H), 7.68 (d, 1H), 7.49 (dd, 1H), 7.42 – 7.28 (m, 4H), 6.90 – 6.85 (m, 1H), 6.62 (dd, 1H), 4.98 – 4.87 (m, 1H), 4.55 – 4.44 (m, 2H), 4.34 – 4.21 (m, 1H), 4.15 – 4.05 (m, 2H), 2.95 – 2.66 (m, 3H), 2.33 (s, 3H), 2.18 – 2.08 (m, 1H), 2.02 (s, 6H), 1.58 – 1.45 (m, 1H), 1.00 – 0.92 (m, 2H), 0.58 – 0.51 (m, 2H).

LCMS m/z = 696.2 [M+1] + LCMS m/z = 696.2 [M+1] +

實施例112：化合物112三氟乙酸鹽的製備 Example 112: Preparation of compound 112 trifluoroacetate salt

以化合物80b為原料，參考實施例22製備方法，經酸性製備[流動相體系：乙腈/水 (含0.1% TFA)]，凍乾得到化合物112的三氟乙酸鹽（90mg）。Using compound 80b as raw material, refer to the preparation method of Example 22, undergo acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and freeze-dry to obtain the trifluoroacetate salt of compound 112 (90 mg).

1H NMR (400 MHz, CDCl 3) δ 8.20 (s, 1H), 8.14 (d, 1H), 8.04 (s, 1H), 7.77 (s, 1H), 7.72 – 7.64 (m, 2H), 7.03 – 6.98 (m, 1H), 6.94 (dd, 1H), 6.84 – 6.76 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.02 (m, 2H), 3.86 – 3.76 (m, 1H), 3.13 – 2.99 (m, 2H), 2.96 – 2.65 (m, 5H), 2.31 – 1.97 (m, 3H), 1.87 – 1.75 (m, 1H), 0.97 – 0.90 (m, 2H), 0.68 – 0.58 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.20 (s, 1H), 8.14 (d, 1H), 8.04 (s, 1H), 7.77 (s, 1H), 7.72 – 7.64 (m, 2H), 7.03 – 6.98 (m, 1H), 6.94 (dd, 1H), 6.84 – 6.76 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.02 (m, 2H), 3.86 – 3.76 (m, 1H), 3.13 – 2.99 (m, 2H), 2.96 – 2.65 (m, 5H), 2.31 – 1.97 (m, 3H), 1.87 – 1.75 (m, 1H ), 0.97 – 0.90 (m, 2H), 0.68 – 0.58 (m, 2H).

實施例113：化合物113三氟乙酸鹽的製備 Example 113: Preparation of compound 113 trifluoroacetate salt

以化合物80c和中間體2為原料，參考實施例19製備方法，經酸性製備[流動相體系：乙腈/水 (含0.1% TFA)]，凍乾得到化合物113的三氟乙酸鹽。Using compound 80c and intermediate 2 as raw materials, refer to the preparation method of Example 19, undergo acidic preparation [mobile phase system: acetonitrile/water (containing 0.1% TFA)], and freeze-dry to obtain the trifluoroacetate salt of compound 113.

1H NMR (400 MHz, CDCl 3) δ 8.61 (s, 1H), 8.11 (d, 1H), 8.04 (s, 1H), 7.82 – 7.75 (m, 2H), 7.39 (d, 1H), 7.05 – 6.99 (m, 1H), 6.94 (dd, 1H), 6.88 – 6.81 (m, 1H), 4.97 – 4.87 (m, 1H), 4.55 – 4.42 (m, 2H), 4.27 – 4.15 (m, 2H), 3.85 – 3.74 (m, 1H), 2.97 – 2.64 (m, 3H), 2.18 – 2.07 (m, 1H), 1.94 (s, 6H), 1.86 – 1.76 (m, 1H), 0.98 – 0.90 (m, 2H), 0.67 – 0.58 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.61 (s, 1H), 8.11 (d, 1H), 8.04 (s, 1H), 7.82 – 7.75 (m, 2H), 7.39 (d, 1H), 7.05 – 6.99 (m, 1H), 6.94 (dd, 1H), 6.88 – 6.81 (m, 1H), 4.97 – 4.87 (m, 1H), 4.55 – 4.42 (m, 2H), 4.27 – 4.15 (m, 2H), 3.85 – 3.74 (m, 1H), 2.97 – 2.64 (m, 3H), 2.18 – 2.07 (m, 1H), 1.94 (s, 6H), 1.86 – 1.76 (m, 1H), 0.98 – 0.90 (m, 2H ), 0.67 – 0.58 (m, 2H).

實施例114：化合物114的製備 Example 114: Preparation of Compound 114

以化合物28B為原料，參考實施例101得到化合物114（0.17g）。 Using compound 28B as a raw material, compound 114 (0.17g) was obtained with reference to Example 101.

1H NMR (400 MHz, CDCl 3) δ 8.78 (s, 1H), 8.59 – 8.52 (m, 1H), 8.01 (s, 1H), 7.69 (d, 1H), 7.60 – 7.54 (m, 1H), 7.53 – 7.46 (m, 1H), 7.40 – 7.34 (m, 1H), 6.86 – 6.80 (m, 1H), 6.57 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.48 – 4.35 (m, 2H), 4.19 – 4.08 (m, 2H), 3.98 – 3.85 (m, 1H), 3.10 – 2.96 (m, 2H), 2.96 – 2.65 (m, 5H), 2.31 – 2.03 (m, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.78 (s, 1H), 8.59 – 8.52 (m, 1H), 8.01 (s, 1H), 7.69 (d, 1H), 7.60 – 7.54 (m, 1H), 7.53 – 7.46 (m, 1H), 7.40 – 7.34 (m, 1H), 6.86 – 6.80 (m, 1H), 6.57 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.48 – 4.35 (m, 2H ), 4.19 – 4.08 (m, 2H), 3.98 – 3.85 (m, 1H), 3.10 – 2.96 (m, 2H), 2.96 – 2.65 (m, 5H), 2.31 – 2.03 (m, 6H).

LCMS m/z = 693.1 [M+1] + LCMS m/z = 693.1 [M+1] +

實施例115：化合物115的製備 Example 115: Preparation of Compound 115

第一步：115a的製備Step One: Preparation of 115a

氮氣保護下將60%氫化鈉 (1.06 g) 加入到20 mL DMSO中，緩慢加入85a (2.0 g，8.80 mmol) 和1,3-二溴丙烷 (2.66 g，13.2 mmol) 的5 mL二氯甲烷溶液，30℃反應19 h。向反應體系中加入水 (80 mL)，用二氯甲烷萃取 (80 mL×2)，有機相用飽和氯化鈉水溶液洗滌 (60 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 10:1)，得115a (0.65 g，收率：28%)。Add 60% sodium hydride (1.06 g) to 20 mL DMSO under nitrogen protection, and slowly add 85a (2.0 g, 8.80 mmol) and 1,3-dibromopropane (2.66 g, 13.2 mmol) in 5 mL dichloromethane. solution, react at 30°C for 19 hours. Add water (80 mL) to the reaction system, extract with dichloromethane (80 mL×2), wash the organic phase with saturated aqueous sodium chloride solution (60 mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is Silica gel column separation and purification (petroleum ether: ethyl acetate (v/v) = 10:1) gave 115a (0.65 g, yield: 28%).

LCMS m/z = 268.4 [M+1] + LCMS m/z = 268.4 [M+1] +

第二步：115b的製備Step 2: Preparation of 115b

將115a (0.65 g，2.43 mmol) 溶解於10 mL甲醇，加入10% Pd/C (300 mg)，置於氫氣球氛圍下室溫反應5 h。將反應體系墊矽藻土過濾，將濾液減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 3:1)，得115b (0.38 g，收率：66%)。Dissolve 115a (0.65 g, 2.43 mmol) in 10 mL methanol, add 10% Pd/C (300 mg), and react at room temperature for 5 h under a hydrogen balloon atmosphere. The reaction system was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 3:1) to obtain 115b (0.38 g, yield: 66 %).

LCMS m/z = 238.2 [M+1] + LCMS m/z = 238.2 [M+1] +

第三步：115c的製備Step 3: Preparation of 115c

將115b (0.38 g，1.60 mmol) 溶於甲苯 (4 mL) 和水 (0.4 mL) 的混合溶劑中，0℃下加入濃鹽酸 (1 mL)，攪拌30 min後緩慢加入亞硝酸鈉 (150 mg，2.17 mmol)，0-5℃反應30 min，加入2 mL碘化鉀 (0.53 g，3.2 mmol) 的水溶液，室溫反應4 h。向反應體系中加入水 (20 mL)，用乙酸乙酯萃取 (30 mL×2)，有機相用飽和硫代硫酸鈉溶液洗滌 (20 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 91:9)，得115c (0.35 g，收率：63%)。Dissolve 115b (0.38 g, 1.60 mmol) in a mixed solvent of toluene (4 mL) and water (0.4 mL), add concentrated hydrochloric acid (1 mL) at 0°C, stir for 30 min, and slowly add sodium nitrite (150 mg , 2.17 mmol), react at 0-5°C for 30 min, add 2 mL of potassium iodide (0.53 g, 3.2 mmol) aqueous solution, and react at room temperature for 4 h. Add water (20 mL) to the reaction system, extract with ethyl acetate (30 mL×2), wash the organic phase with saturated sodium thiosulfate solution (20 mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product Separate and purify using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 91:9) to obtain 115c (0.35 g, yield: 63%).

LCMS m/z = 349.0 [M+1] + LCMS m/z = 349.0 [M+1] +

第四步：115d的製備Step 4: Preparation of 115d

將115c (0.35 g，1.01 mmol) 加入到100 mL單口瓶中，依次加入甲醇 (4 mL)、水 (0.4 mL) 和氫氧化鉀 (0.21 g，3.74 mmol)，60℃反應5 h。將反應體系冷卻至室溫，用1 mol/L鹽酸調pH至3，用乙酸乙酯萃取 (30 mL×2)，有機相用飽和氯化鈉水溶液洗滌 (30 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 1:1)，得粗品 (0.15 g)。將上述粗品 (0.1 g) 溶於1 mL 乙腈中，加入二氯亞碸 (55 mg，0.46 mmol)，60℃反應1 h後，冷卻至室溫，加入TEA (0.2 mL)，加入2-氯-4-(三氟甲基)苯胺 (61 mg，0.31 mmol)，室溫反應16 h。將反應體系減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 5:1)，得115d (86 mg，收率：56%)。Add 115c (0.35 g, 1.01 mmol) into a 100 mL single-neck bottle, add methanol (4 mL), water (0.4 mL) and potassium hydroxide (0.21 g, 3.74 mmol) in sequence, and react at 60°C for 5 h. Cool the reaction system to room temperature, adjust the pH to 3 with 1 mol/L hydrochloric acid, extract with ethyl acetate (30 mL×2), wash the organic phase with saturated sodium chloride aqueous solution (30 mL×2), and anhydrous sodium sulfate. Dry and concentrate under reduced pressure. The crude product is separated and purified by silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 1:1) to obtain the crude product (0.15 g). Dissolve the above crude product (0.1 g) in 1 mL acetonitrile, add trisyanide (55 mg, 0.46 mmol), react at 60°C for 1 h, cool to room temperature, add TEA (0.2 mL), and add 2-chloro -4-(Trifluoromethyl)aniline (61 mg, 0.31 mmol), react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 5:1) to obtain 115d (86 mg, yield: 56%).

第五步：化合物115的製備Step 5: Preparation of Compound 115

將115d (130 mg，0.26 mmol) 加入到反應瓶中，依次加入乾燥DMF (3 mL)、上述粗品中間體1 (130 mg) 和TEA (79 mg，0.78 mmol)，置換氮氣三次，加入PdCl 2(PPh 3) 2(36 mg，0.051 mmol) 和CuI (9 mg，0.047 mmol)，氮氣氛圍下55℃反應3 h。將反應體系冷卻至室溫，緩慢加入飽和氯化銨水溶液 (150 mL)，用乙酸乙酯萃取 (30 mL×2)，有機相用飽和氯化鈉水溶液洗滌 (30 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 1:2)，得化合物115 (21 mg，收率：11%)。 Add 115d (130 mg, 0.26 mmol) into the reaction flask, add dry DMF (3 mL), the above crude intermediate 1 (130 mg) and TEA (79 mg, 0.78 mmol) in sequence, replace nitrogen three times, and add PdCl 2 (PPh 3 ) 2 (36 mg, 0.051 mmol) and CuI (9 mg, 0.047 mmol) were reacted at 55°C for 3 h under nitrogen atmosphere. Cool the reaction system to room temperature, slowly add saturated aqueous ammonium chloride solution (150 mL), extract with ethyl acetate (30 mL×2), wash the organic phase with saturated aqueous sodium chloride solution (30 mL×2), and add anhydrous sulfuric acid. It was dried over sodium and concentrated under reduced pressure. The crude product was separated and purified by silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 1:2) to obtain compound 115 (21 mg, yield: 11%).

1H NMR (400 MHz, CDCl 3) δ 8.59 (d, 1H), 8.04 – 7.82 (m, 2H), 7.68 (d, 1H), 7.60 – 7.44 (m, 2H), 7.37 – 7.25 (m, 2H), 7.21 – 7.11 (m, 1H), 6.87 – 6.77 (m, 1H), 6.57 (dd, 1H), 4.98 – 4.87 (m, 1H), 4.44 – 4.32 (m, 2H), 4.17 – 4.04 (m, 2H), 3.93 – 3.76 (m, 1H), 3.04 – 2.54 (m, 7H), 2.36 – 2.19 (m, 1H), 2.19 – 2.08 (m, 1H), 2.06 – 1.90 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.59 (d, 1H), 8.04 – 7.82 (m, 2H), 7.68 (d, 1H), 7.60 – 7.44 (m, 2H), 7.37 – 7.25 (m, 2H) ), 7.21 – 7.11 (m, 1H), 6.87 – 6.77 (m, 1H), 6.57 (dd, 1H), 4.98 – 4.87 (m, 1H), 4.44 – 4.32 (m, 2H), 4.17 – 4.04 (m , 2H), 3.93 – 3.76 (m, 1H), 3.04 – 2.54 (m, 7H), 2.36 – 2.19 (m, 1H), 2.19 – 2.08 (m, 1H), 2.06 – 1.90 (m, 1H).

實施例116：化合物116的製備 Example 116: Preparation of Compound 116

以化合物116a為原料，參考實施例102的合成方法得到化合物116。Using compound 116a as a raw material, compound 116 was obtained by referring to the synthesis method of Example 102.

1H NMR (400 MHz, CDCl 3) δ 9.43 (s, 1H), 8.45 (d, 1H), 8.22 – 8.08 (m, 2H), 7.96 – 7.82 (m, 3H), 7.73 – 7.35 (m, 7H), 6.93 – 6.87 (m, 1H), 6.64 (dd, 1H), 4.98 – 4.87 (m, 1H), 4.87 – 4.62 (m, 3H), 4.35 – 4.21 (m, 2H), 2.94 – 2.62 (m, 3H), 2.18 – 2.02 (m, 7H), 1.68 – 1.52 (m, 1H), 1.07 – 0.96 (m, 2H), 0.66 – 0.56 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.43 (s, 1H), 8.45 (d, 1H), 8.22 – 8.08 (m, 2H), 7.96 – 7.82 (m, 3H), 7.73 – 7.35 (m, 7H ), 6.93 – 6.87 (m, 1H), 6.64 (dd, 1H), 4.98 – 4.87 (m, 1H), 4.87 – 4.62 (m, 3H), 4.35 – 4.21 (m, 2H), 2.94 – 2.62 (m , 3H), 2.18 – 2.02 (m, 7H), 1.68 – 1.52 (m, 1H), 1.07 – 0.96 (m, 2H), 0.66 – 0.56 (m, 2H).

實施例117：化合物117的製備 Example 117: Preparation of Compound 117

第一步：117b的製備Step One: Preparation of 117b

將117a (5.3 g，39.79 mmol) 溶解於100 mL DCM中，加入TEA (6.1 g，60.3 mmol)，0℃緩慢滴加三氟乙酸酐 (10.5 g，50 mmol)，室溫反應2 h。將反應體系減壓濃縮，粗品用矽膠柱色譜分離純化 (石油醚/乙酸乙酯 (v/v) = 4:1)，得到117b (9.0 g，收率：99%)。Dissolve 117a (5.3 g, 39.79 mmol) in 100 mL DCM, add TEA (6.1 g, 60.3 mmol), slowly add trifluoroacetic anhydride (10.5 g, 50 mmol) at 0°C, and react at room temperature for 2 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4:1) to obtain 117b (9.0 g, yield: 99%).

第二步：117c的製備Step 2: Preparation of 117c

將117b (9.0 g，39.27 mmol) 溶解於100 mL 乙腈中，0℃加入NBS (7.7 g，43.26 mmol)，室溫反應12 h。將反應體系減壓濃縮，加入200 mL乙酸乙酯和200 mL純化水，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠柱色譜分離純化 (石油醚/乙酸乙酯 (v/v) = 4:1)，得到117c (12.0 g，收率：99%)。Dissolve 117b (9.0 g, 39.27 mmol) in 100 mL acetonitrile, add NBS (7.7 g, 43.26 mmol) at 0°C, and react at room temperature for 12 h. The reaction system was concentrated under reduced pressure, and 200 mL of ethyl acetate and 200 mL of purified water were added. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4:1), obtaining 117c (12.0 g, yield: 99%).

以化合物117c為原料，參考實施例102得到化合物117(120mg)。 Using compound 117c as a raw material, compound 117 (120 mg) was obtained with reference to Example 102.

1H NMR (400 MHz, CDCl 3) δ 9.22 (s, 1H), 8.48 – 8.34 (m, 2H), 7.94 – 7.84 (m, 2H), 7.67 (d, 1H), 7.48 (dd, 1H), 7.39 – 7.20 (m, 3H), 6.91 – 6.83 (m, 1H), 6.60 (dd, 1H), 5.00 – 4.87 (m, 1H), 4.55 – 4.40 (m, 2H), 4.24 – 4.05 (m, 3H), 3.10 – 2.98 (m, 2H), 2.98 – 2.65 (m, 5H), 2.23 – 2.07 (m, 3H), 2.03 (s, 6H), 1.58 – 1.46 (m, 1H), 1.00 – 0.90 (m, 2H), 0.60 – 0.52 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.22 (s, 1H), 8.48 – 8.34 (m, 2H), 7.94 – 7.84 (m, 2H), 7.67 (d, 1H), 7.48 (dd, 1H), 7.39 – 7.20 (m, 3H), 6.91 – 6.83 (m, 1H), 6.60 (dd, 1H), 5.00 – 4.87 (m, 1H), 4.55 – 4.40 (m, 2H), 4.24 – 4.05 (m, 3H ), 3.10 – 2.98 (m, 2H), 2.98 – 2.65 (m, 5H), 2.23 – 2.07 (m, 3H), 2.03 (s, 6H), 1.58 – 1.46 (m, 1H), 1.00 – 0.90 (m , 2H), 0.60 – 0.52 (m, 2H).

實施例118：化合物118的製備 Example 118: Preparation of Compound 118

第一步：118b的製備Step One: Preparation of 118b

將118a (0.4 g，1.51 mmol) (合成方法見WO2022187588) 溶解於20 mL DCM中，加入戴斯-馬丁氧化劑 (0.77 g，1.82 mmol)，室溫反應10 min。向反應體系中加入10 mL水和20 mL二氯甲烷，攪拌2 min後，分液，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠柱色譜分離純化 (石油醚/乙酸乙酯 (v/v) = 3:1)，得到118b (0.3 g，收率：76%)。Dissolve 118a (0.4 g, 1.51 mmol) (see WO2022187588 for synthesis method) in 20 mL DCM, add Dess-Martin oxidant (0.77 g, 1.82 mmol), and react at room temperature for 10 min. Add 10 mL water and 20 mL methylene chloride to the reaction system, stir for 2 minutes, separate the liquids, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate ( v/v) = 3:1), 118b (0.3 g, yield: 76%) was obtained.

第二步：118c的製備Step 2: Preparation of 118c

將118b (0.15 g，0.57 mmol)、(1-重氮基-2-氧代丙基)膦酸二甲酯 (0.17 g，0.88 mmol) 和碳酸鉀 (0.16 g，1.16 mmol) 加入到5 mL甲醇中，30℃反應12 h。將反應體系減壓濃縮，粗品用矽膠柱色譜分離純化 (石油醚/乙酸乙酯 (v/v) =10:1)，得到118c (0.05 g，收率：34%)。Add 118b (0.15 g, 0.57 mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (0.17 g, 0.88 mmol) and potassium carbonate (0.16 g, 1.16 mmol) to 5 mL React in methanol at 30°C for 12 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =10:1) to obtain 118c (0.05 g, yield: 34%).

第三步：118d的製備Step 3: Preparation of 118d

將118c (0.05 g，0.19 mmol) 溶於5 mL乙醇中，加入5 mL氫氧化鈉 (0.023 g，0.58 mmol) 的水溶液，80℃反應2 h。將反應體系冷卻至室溫，減壓濃縮，加入5 mL水，用1 mol/L鹽酸調pH至2，用乙酸乙酯萃取 (20 mL×3)，有機相用無水硫酸鈉乾燥，減壓濃縮，得到粗品 (0.02 g)。將上述粗品 (0.02 g) 溶於5 mL乙腈中，加入3-氨基-2,6-哌啶二酮鹽酸鹽 (0.014 g，0.085 mmol) 和N,N'-羰基二咪唑 (0.028 g，0.17 mmol)，90℃反應3 h。將反應體系冷卻至室溫，減壓濃縮，粗品用矽膠柱色譜分離純化 (二氯甲烷/甲醇 (v/v) = 50:1)，得到118d (0.01 g，收率：37%)。Dissolve 118c (0.05 g, 0.19 mmol) in 5 mL ethanol, add 5 mL aqueous sodium hydroxide (0.023 g, 0.58 mmol), and react at 80°C for 2 h. Cool the reaction system to room temperature, concentrate under reduced pressure, add 5 mL of water, adjust the pH to 2 with 1 mol/L hydrochloric acid, extract with ethyl acetate (20 mL×3), dry the organic phase over anhydrous sodium sulfate, and dry under reduced pressure. Concentrate to obtain crude product (0.02 g). Dissolve the above crude product (0.02 g) in 5 mL acetonitrile, add 3-amino-2,6-piperidinedione hydrochloride (0.014 g, 0.085 mmol) and N,N'-carbonyldiimidazole (0.028 g, 0.17 mmol), react at 90°C for 3 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 50:1) to obtain 118d (0.01 g, yield: 37%).

LCMS m/z = 323.4 [M+1] + LCMS m/z = 323.4 [M+1] +

第四步：化合物118的製備Step 4: Preparation of Compound 118

將118d (0.01 g，0.031 mmol)、2c (0.15 g，0.032 mmol)、PdCl 2(PPh 3) 2(2.2 mg，0.003 mmol)、CuI (1.2 mg，0.0063mmol) 和TEA (0.019 g，0.19 mmol) 加入到反應瓶中，氮氣氛圍下55℃反應2 h。將反應體系冷卻至室溫，加入到20 mL乙酸乙酯中，有機相用飽和氯化鈉水溶液洗滌 (10 mL×3)，無水硫酸鈉乾燥，減壓濃縮，粗品用prep-TLC製備純化 (二氯甲烷:石油醚:乙酸乙酯 (v/v) = 2:2:1)，得到化合物118 (6 mg，收率：29%)。 Combine 118d (0.01 g, 0.031 mmol), 2c (0.15 g, 0.032 mmol), PdCl 2 (PPh 3 ) 2 (2.2 mg, 0.003 mmol), CuI (1.2 mg, 0.0063mmol) and TEA (0.019 g, 0.19 mmol). ) was added to the reaction bottle and reacted at 55°C for 2 h under nitrogen atmosphere. The reaction system was cooled to room temperature and added to 20 mL of ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by prep-TLC ( Dichloromethane:petroleum ether:ethyl acetate (v/v) = 2:2:1), compound 118 (6 mg, yield: 29%) was obtained.

1H NMR (400 MHz, CDCl 3) δ 8.71 (s, 1H), 8.54 (d, 1H), 8.05 (s, 1H), 7.80 – 7.62 (m, 4H), 7.61 – 7.55 (m, 1H), 7.54 – 7.45 (m, 1H), 5.00 – 4.92 (m, 1H), 3.60 – 3.47 (m, 1H), 3.46 – 3.32 (m, 2H), 3.25 – 3.13 (m, 2H), 3.12 – 2.97 (m, 2H), 2.97 – 2.65 (m, 5H), 2.30 – 1.95 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.71 (s, 1H), 8.54 (d, 1H), 8.05 (s, 1H), 7.80 – 7.62 (m, 4H), 7.61 – 7.55 (m, 1H), 7.54 – 7.45 (m, 1H), 5.00 – 4.92 (m, 1H), 3.60 – 3.47 (m, 1H), 3.46 – 3.32 (m, 2H), 3.25 – 3.13 (m, 2H), 3.12 – 2.97 (m , 2H), 2.97 – 2.65 (m, 5H), 2.30 – 1.95 (m, 3H).

實施例119：化合物119的製備 Example 119: Preparation of Compound 119

以化合物118d和68c為原料，參考實施例118的合成方法得到化合物119。Using compounds 118d and 68c as raw materials, compound 119 was obtained by referring to the synthesis method of Example 118.

1H NMR (400 MHz, CDCl 3) δ 9.09 (s, 1H), 8.37 (d, 1H), 7.99 (s, 1H), 7.77 (s, 1H), 7.74 – 7.65 (m, 3H), 7.49 (dd, 1H), 7.41 – 7.34 (m, 1H), 5.02 – 4.90 (m, 1H), 3.60 – 3.47 (m, 1H), 3.47 – 3.33 (m, 2H), 3.26 – 3.12 (m, 2H), 2.97 – 2.65 (m, 3H), 2.20 – 2.09 (m, 1H), 1.94 (s, 6H), 1.54 – 1.44 (m, 1H), 1.03 – 0.92 (m, 2H), 0.63 – 0.52 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.09 (s, 1H), 8.37 (d, 1H), 7.99 (s, 1H), 7.77 (s, 1H), 7.74 – 7.65 (m, 3H), 7.49 ( dd, 1H), 7.41 – 7.34 (m, 1H), 5.02 – 4.90 (m, 1H), 3.60 – 3.47 (m, 1H), 3.47 – 3.33 (m, 2H), 3.26 – 3.12 (m, 2H), 2.97 – 2.65 (m, 3H), 2.20 – 2.09 (m, 1H), 1.94 (s, 6H), 1.54 – 1.44 (m, 1H), 1.03 – 0.92 (m, 2H), 0.63 – 0.52 (m, 2H ).

實施例120與121：化合物120與121三氟乙酸鹽的製備 Examples 120 and 121: Preparation of trifluoroacetate salts of compounds 120 and 121

第一步：120b-1與120b-2的製備Step One: Preparation of 120b-1 and 120b-2

向反應瓶中分別加入120a (0.32 g, 1.51 mmol) (合成方法參考WO2022199503)、28B (0.52 g, 1.46 mmol)、碳酸銫 (0.98 g, 3.01 mmol) 和6 mL乙腈，60℃反應4 h。將反應體系冷卻至室溫，過濾，將濾液減壓濃縮，粗品用矽膠色譜柱分離純化 (乙酸乙酯/石油醚 (v/v) = 1:20)，得到粗品120b-1與120b-2的混合物 (0.50 g)。Add 120a (0.32 g, 1.51 mmol) (refer to WO2022199503 for the synthesis method), 28B (0.52 g, 1.46 mmol), cesium carbonate (0.98 g, 3.01 mmol) and 6 mL acetonitrile respectively into the reaction flask, and react at 60°C for 4 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v) = 1:20) to obtain crude products 120b-1 and 120b-2. mixture (0.50 g).

第二步：化合物120與121三氟乙酸鹽的製備Step 2: Preparation of trifluoroacetate salts of compounds 120 and 121

在氮氣氛圍下，向反應瓶中分別加入上述粗品120b-1與120b-2的混合物 (0.50 g)、粗品中間體1 (0.52 g, 1.53 mmol)、PdCl 2(PPh 3) 2(72 mg, 0.10 mmol)、CuI (39 mg, 0.20 mmol) 和DIPEA (0.40 g, 3.09 mmol)，加入10 mL DMF，60℃反應5 h。將反應體系冷卻至室溫，加入到水 (40 mL) 中，過濾，將濾餅過Pre-HPLC (儀器及製備柱：採用Waters 2767製備液相，製備柱型號是SunFire@Prep C18，5 μm，內徑×長度 = 19 mm×250 mm)。製備方法：粗品的DMSO溶液用0.45 μm濾膜過濾，製備成樣品液。流動相體系：水 (含0.1%三氟乙酸)/乙腈。梯度沖提方法：乙腈由50%梯度沖提90%，凍乾分別得到化合物120的三氟乙酸鹽 (沖提時間16.90 min) (5 mg) 與化合物121的三氟乙酸鹽 (沖提時間16.02 min) (10 mg)。 Under a nitrogen atmosphere, the mixture of the above crude products 120b-1 and 120b-2 (0.50 g), crude intermediate 1 (0.52 g, 1.53 mmol), and PdCl 2 (PPh 3 ) 2 (72 mg, 0.10 mmol), CuI (39 mg, 0.20 mmol) and DIPEA (0.40 g, 3.09 mmol), add 10 mL DMF, and react at 60°C for 5 h. Cool the reaction system to room temperature, add it to water (40 mL), filter, and pass the filter cake through Pre-HPLC (instrument and preparation column: Waters 2767 is used to prepare the liquid phase, and the preparation column model is SunFire@Prep C18, 5 μm , inner diameter × length = 19 mm × 250 mm). Preparation method: Filter the crude DMSO solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% trifluoroacetic acid)/acetonitrile. Gradient elution method: Gradient elute from 50% to 90% acetonitrile, and freeze-dry to obtain the trifluoroacetate salt of compound 120 (elution time 16.90 min) (5 mg) and the trifluoroacetate salt of compound 121 (elution time 16.02 min). min) (10 mg).

化合物120三氟乙酸鹽的表徵數據：Characterization data of compound 120 trifluoroacetate:

LCMS m/z = 697.1 [M+1] + LCMS m/z = 697.1 [M+1] +

化合物121三氟乙酸鹽的表徵數據：Characterization data of compound 121 trifluoroacetate:

LCMS m/z = 697.1 [M+1] + LCMS m/z = 697.1 [M+1] +

將化合物121三氟乙酸鹽用氨水游離得化合物121的游離鹼。The free base of compound 121 is obtained by dissociating the trifluoroacetate salt of compound 121 with ammonia water.

化合物121游離鹼核磁：Compound 121 free base NMR:

1H NMR (400 MHz, CDCl 3) δ 8.62 (s, 1H), 8.53 (d, 1H), 8.03 (s, 1H), 7.69 (d, 1H), 7.62 – 7.57 (m, 1H), 7.55 – 7.44 (m, 2H), 6.83 (d, 1H), 6.58 (dd, 1H), 4.99 – 4.90 (m, 1H), 4.47 – 4.34 (m, 2H), 4.22 – 4.10 (m, 2H), 3.97 – 3.85 (m, 1H), 3.12 – 2.97 (m, 2H), 2.96 – 2.66 (m, 5H), 2.30 – 2.02 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.62 (s, 1H), 8.53 (d, 1H), 8.03 (s, 1H), 7.69 (d, 1H), 7.62 – 7.57 (m, 1H), 7.55 – 7.44 (m, 2H), 6.83 (d, 1H), 6.58 (dd, 1H), 4.99 – 4.90 (m, 1H), 4.47 – 4.34 (m, 2H), 4.22 – 4.10 (m, 2H), 3.97 – 3.85 (m, 1H), 3.12 – 2.97 (m, 2H), 2.96 – 2.66 (m, 5H), 2.30 – 2.02 (m, 3H).

實施例122與123：化合物122與123三氟乙酸鹽的製備 Examples 122 and 123: Preparation of trifluoroacetate salts of compounds 122 and 123

第一步：122a-1與122a-2的製備Step 1: Preparation of 122a-1 and 122a-2

向反應瓶中分別加入120a (0.31 g, 1.46 mmol) (合成方法參考WO2022199503)、53B (0.46 g, 1.50 mmol)、碳酸銫 (0.94 g, 2.89 mmol) 和6 mL乙腈，60℃反應4 h。將反應體系冷卻至室溫，過濾，將濾液減壓濃縮，粗品用矽膠色譜柱分離純化 (乙酸乙酯/石油醚 (v/v) = 1:20)，得到粗品122a-1與122a-2的混合物 (0.52 g)。Add 120a (0.31 g, 1.46 mmol) (refer to WO2022199503 for the synthesis method), 53B (0.46 g, 1.50 mmol), cesium carbonate (0.94 g, 2.89 mmol) and 6 mL acetonitrile respectively into the reaction flask, and react at 60°C for 4 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (ethyl acetate/petroleum ether (v/v) = 1:20) to obtain crude products 122a-1 and 122a-2. mixture (0.52 g).

第二步：化合物122與123三氟乙酸鹽的製備Step 2: Preparation of trifluoroacetate salts of compounds 122 and 123

在氮氣氛圍下，向反應瓶中分別加入上述粗品122a-1與122a-2的混合物 (0.52 g)、粗品中間體1 (0.61 g)、PdCl 2(PPh 3) 2(84 mg, 0.12 mmol)、CuI (46 mg, 0.24 mmol) 和DIPEA (0.47 g, 3.64 mmol)，加入10 mL DMF，60℃反應5 h。將反應體系冷卻至室溫，加入到水 (40 mL) 中，過濾，將濾餅過Pre-HPLC (儀器及製備柱：採用Waters 2767製備液相，製備柱型號是SunFire@Prep C18，5 μm，內徑×長度 = 19 mm×250 mm)。製備方法：粗品的DMSO溶液用0.45 μm濾膜過濾，製備成樣品液。流動相體系：水 (含0.1%三氟乙酸)/乙腈。梯度沖提方法：乙腈由50%梯度沖提70%，凍乾分別得到化合物122的三氟乙酸鹽 (沖提時間15.88 min) (6 mg) 與化合物123的三氟乙酸鹽 (沖提時間14.58 min) (20 mg)。 Under a nitrogen atmosphere, the mixture of the above crude products 122a-1 and 122a-2 (0.52 g), crude intermediate 1 (0.61 g), and PdCl 2 (PPh 3 ) 2 (84 mg, 0.12 mmol) were added to the reaction flask. , CuI (46 mg, 0.24 mmol) and DIPEA (0.47 g, 3.64 mmol), add 10 mL DMF, and react at 60°C for 5 h. Cool the reaction system to room temperature, add it to water (40 mL), filter, and pass the filter cake through Pre-HPLC (instrument and preparation column: Waters 2767 is used to prepare the liquid phase, and the preparation column model is SunFire@Prep C18, 5 μm , inner diameter × length = 19 mm × 250 mm). Preparation method: Filter the crude DMSO solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% trifluoroacetic acid)/acetonitrile. Gradient elution method: Gradient elute from 50% to 70% acetonitrile, and freeze-dry to obtain the trifluoroacetate salt of compound 122 (elution time 15.88 min) (6 mg) and the trifluoroacetate salt of compound 123 (elution time 14.58 min). min) (20 mg).

化合物122三氟乙酸鹽的表徵數據：Characterization data of compound 122 trifluoroacetate:

LCMS m/z = 648.2 [M+1] + 、 LCMS m/z = 648.2 [M+1] + ,

化合物123的三氟乙酸鹽表徵數據：Characterization data of the trifluoroacetate salt of compound 123:

LCMS m/z = 648.2 [M+1] + LCMS m/z = 648.2 [M+1] +

將化合物123三氟乙酸鹽用氨水游離得化合物123的游離鹼。The free base of compound 123 is obtained by dissociating the trifluoroacetate salt of compound 123 with ammonia water.

化合物123游離鹼核磁：Compound 123 free base NMR:

1H NMR (400 MHz, CDCl 3) δ 9.06 (s, 1H), 8.37 (d, 1H), 8.12 (s, 1H), 7.69 (d, 1H), 7.58 (d, 1H), 7.49 (dd, 1H), 7.40 – 7.36 (m, 1H), 6.88 – 6.80 (m, 1H), 6.58 (dd, 1H), 5.00 – 4.91 (m, 1H), 4.46 – 4.35 (m, 2H), 4.17 – 4.06 (m, 2H), 3.95 – 3.81 (m, 1H), 2.96 – 2.66 (m, 3H), 2.20 – 2.07 (m, 1H), 1.94 (s, 6H), 1.58 – 1.45 (m, 1H), 1.14 – 1.02 (m, 2H), 0.65 – 0.56 (m, 2H) 1 H NMR (400 MHz, CDCl 3 ) δ 9.06 (s, 1H), 8.37 (d, 1H), 8.12 (s, 1H), 7.69 (d, 1H), 7.58 (d, 1H), 7.49 (dd, 1H), 7.40 – 7.36 (m, 1H), 6.88 – 6.80 (m, 1H), 6.58 (dd, 1H), 5.00 – 4.91 (m, 1H), 4.46 – 4.35 (m, 2H), 4.17 – 4.06 ( m, 2H), 3.95 – 3.81 (m, 1H), 2.96 – 2.66 (m, 3H), 2.20 – 2.07 (m, 1H), 1.94 (s, 6H), 1.58 – 1.45 (m, 1H), 1.14 – 1.02 (m, 2H), 0.65 – 0.56 (m, 2H)

實施例124：化合物124的製備 Example 124: Preparation of Compound 124

第一步：124b的製備Step One: Preparation of 124b

將124a (1.0 g，4.11 mmol) 與124A (0.88 g，4.50 mmol) 溶於40 mL DCM中，加入TCFH (1.72 g，6.14 mmol) 與NMI (1.34 g，16.32 mmol)，室溫反應16 h。向反應體系中加入50 mL水，用200 mL DCM萃取，有機相用50 mL水洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠柱色譜分離純化 (石油醚/乙酸乙酯 (v/v) = 10:1)，得到124b (1.3 g，收率：75%)。Dissolve 124a (1.0 g, 4.11 mmol) and 124A (0.88 g, 4.50 mmol) in 40 mL DCM, add TCFH (1.72 g, 6.14 mmol) and NMI (1.34 g, 16.32 mmol), and react at room temperature for 16 h. Add 50 mL of water to the reaction system, extract with 200 mL of DCM, wash the organic phase with 50 mL of water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ) = 10:1), obtaining 124b (1.3 g, yield: 75%).

第二步：124c的製備Step 2: Preparation of 124c

將124b (0.1 g，0.24 mmol)、50a (102 mg，0.28 mmol)、碳酸鈉 (76 mg，0.72 mmol) 加入到5 mL 1,4-二氧六環與1 mL水中，氮氣氛圍下加入四三苯基膦鈀 (28 mg，0.024 mmol)，氮氣氛圍下100℃反應4 h。將反應液冷卻至室溫，加入20 mL水，用50 mL乙酸乙酯萃取，有機相用50 mL水洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠柱色譜分離純化 (石油醚/乙酸乙酯 (v/v) = 5:1)，得到124c (50 mg，收率：36%)。Add 124b (0.1 g, 0.24 mmol), 50a (102 mg, 0.28 mmol), and sodium carbonate (76 mg, 0.72 mmol) to 5 mL of 1,4-dioxane and 1 mL of water, and add tetrahydrofuran under nitrogen atmosphere. Triphenylphosphine palladium (28 mg, 0.024 mmol), reacted at 100°C for 4 h under nitrogen atmosphere. The reaction solution was cooled to room temperature, 20 mL of water was added, and extracted with 50 mL of ethyl acetate. The organic phase was washed with 50 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether/acetic acid). Ethyl ester (v/v) = 5:1), giving 124c (50 mg, yield: 36%).

以化合物124c為原料，參考實施例23得到化合物124(25mg)。Using compound 124c as a raw material, compound 124 (25 mg) was obtained with reference to Example 23.

1H NMR (400 MHz, CDCl 3) δ 8.56 (d, 1H), 7.91 (s, 1H), 7.75 – 7.58 (m, 6H), 7.58 – 7.48 (m, 4H), 7.48 – 7.40 (m, 2H), 6.90 – 6.85 (m, 1H), 6.62 (dd, 1H), 4.99 – 4.90 (m, 1H), 4.57 – 4.45 (m, 2H), 4.17 – 4.02 (m, 3H), 2.96 – 2.66 (m, 3H), 2.19 – 2.08 (m, 1H), 1.75 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.56 (d, 1H), 7.91 (s, 1H), 7.75 – 7.58 (m, 6H), 7.58 – 7.48 (m, 4H), 7.48 – 7.40 (m, 2H ), 6.90 – 6.85 (m, 1H), 6.62 (dd, 1H), 4.99 – 4.90 (m, 1H), 4.57 – 4.45 (m, 2H), 4.17 – 4.02 (m, 3H), 2.96 – 2.66 (m , 3H), 2.19 – 2.08 (m, 1H), 1.75 (s, 6H).

實施例125：化合物125的製備 Example 125: Preparation of Compound 125

以65c和中間體2為原料，參考實施例19得到化合物125(10mg)。 1H NMR (400 MHz, CDCl 3) δ 8.43 (s, 1H), 8.00 – 7.90 (m, 2H), 7.80 (s, 1H), 7.70 (s, 1H), 7.39 (d, 1H), 6.91 – 6.79 (m, 3H), 4.95 – 4.87 (m, 1H), 4.53 – 4.42 (m, 2H), 4.24 – 4.15 (m, 2H), 3.85 – 3.73 (m, 1H), 2.94 – 2.64 (m, 3H), 2.18 – 2.08 (m, 1H), 1.95 (s, 6H), 1.86 – 1.74 (m, 1H), 1.53 – 1.42 (m, 1H), 0.94 – 0.80 (m, 4H), 0.63 – 0.57 (m, 2H), 0.55 – 0.48 (m, 2H). Using 65c and intermediate 2 as raw materials, compound 125 (10 mg) was obtained with reference to Example 19. 1 H NMR (400 MHz, CDCl 3 ) δ 8.43 (s, 1H), 8.00 – 7.90 (m, 2H), 7.80 (s, 1H), 7.70 (s, 1H), 7.39 (d, 1H), 6.91 – 6.79 (m, 3H), 4.95 – 4.87 (m, 1H), 4.53 – 4.42 (m, 2H), 4.24 – 4.15 (m, 2H), 3.85 – 3.73 (m, 1H), 2.94 – 2.64 (m, 3H ), 2.18 – 2.08 (m, 1H), 1.95 (s, 6H), 1.86 – 1.74 (m, 1H), 1.53 – 1.42 (m, 1H), 0.94 – 0.80 (m, 4H), 0.63 – 0.57 (m , 2H), 0.55 – 0.48 (m, 2H).

LCMS m/z = 663.1 [M+1] + LCMS m/z = 663.1 [M+1] +

實施例126：化合物126的製備 Example 126: Preparation of Compound 126

以65b為原料，參考實施例22得到化合物126(8mg)。Using 65b as a raw material, compound 126 (8 mg) was obtained with reference to Example 22.

1H NMR (400 MHz, CDCl 3) δ 8.12 (s, 1H), 8.00 (d, 1H), 7.96 (s, 1H), 7.71 – 7.64 (m, 3H), 6.92 – 6.85 (m, 1H), 6.83 – 6.77 (m, 2H), 6.55 (dd, 1H), 4.97 – 4.89 (m, 1H), 4.39 – 4.30 (m, 2H), 4.10 – 4.02 (m, 2H), 3.87 – 3.74 (m, 1H), 3.13 – 3.02 (m, 2H), 2.96 – 2.65 (m, 5H), 2.30 – 1.96 (m, 3H), 1.84 – 1.74 (m, 1H), 1.48 – 1.37 (m, 1H), 0.93 – 0.79 (m, 4H), 0.63 – 0.57 (m, 2H), 0.53 – 0.46 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.12 (s, 1H), 8.00 (d, 1H), 7.96 (s, 1H), 7.71 – 7.64 (m, 3H), 6.92 – 6.85 (m, 1H), 6.83 – 6.77 (m, 2H), 6.55 (dd, 1H), 4.97 – 4.89 (m, 1H), 4.39 – 4.30 (m, 2H), 4.10 – 4.02 (m, 2H), 3.87 – 3.74 (m, 1H ), 3.13 – 3.02 (m, 2H), 2.96 – 2.65 (m, 5H), 2.30 – 1.96 (m, 3H), 1.84 – 1.74 (m, 1H), 1.48 – 1.37 (m, 1H), 0.93 – 0.79 (m, 4H), 0.63 – 0.57 (m, 2H), 0.53 – 0.46 (m, 2H).

LCMS m/z = 657.1 [M+1] + LCMS m/z = 657.1 [M+1] +

實施例127：化合物127的製備 Example 127: Preparation of Compound 127

第一步：127b的製備Step One: Preparation of 127b

向反應瓶中分別加入127a的鹽酸鹽 (0.30 g) (合成方法見WO2022187588)、溴丙炔 (0.12 g, 1.01 mmol)、DIPEA (0.46 g, 3.56 mmol) 和5 mL DMF，40℃反應4 h。將反應體系冷卻至室溫，倒入50 mL水中，用乙酸乙酯萃取 (50 mL×2)，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用10 mL二氯甲烷/甲醇 (v/v) = 5:1的混合溶劑打漿，過濾，將濾餅減壓乾燥，得粗品127b (70 mg)。Add 127a hydrochloride (0.30 g) (for synthesis method, see WO2022187588), bromopropyne (0.12 g, 1.01 mmol), DIPEA (0.46 g, 3.56 mmol) and 5 mL DMF respectively into the reaction flask, and react at 40°C 4 h. Cool the reaction system to room temperature, pour into 50 mL of water, extract with ethyl acetate (50 mL×2), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is added with 10 mL of dichloromethane/methanol (v/ v) = 5:1 mixed solvent was beaten, filtered, and the filter cake was dried under reduced pressure to obtain crude product 127b (70 mg).

LCMS m/z = 338.1 [M+1] + LCMS m/z = 338.1 [M+1] +

第二步：化合物127的製備Step 2: Preparation of Compound 127

在氮氣氛圍下，向反應瓶中分別加入上述粗品127b (70 mg)、68c (88 mg, 0.21 mmol)、PdCl 2(PPh 3) 2(15 mg, 0.021 mmol)、CuI (8 mg, 0.042 mmol) 和DIPEA (81 mg, 0.63 mmol)，加入5 mL DMF，60℃反應5 h。將反應體系冷卻至室溫，加入到50 mL水中，過濾，將濾餅用二氯甲烷/甲醇 (v/v) = 2:1的混合溶劑溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚/乙酸乙酯 (v/v) = 1:2)，所得粗品再用矽膠柱色譜分離提純 (石油醚/乙酸乙酯 (v/v) = 1:1)，得到化合物127 (2 mg，收率：2%)。 Under a nitrogen atmosphere, the above crude products 127b (70 mg), 68c (88 mg, 0.21 mmol), PdCl 2 (PPh 3 ) 2 (15 mg, 0.021 mmol), and CuI (8 mg, 0.042 mmol) were added to the reaction flask. ) and DIPEA (81 mg, 0.63 mmol), add 5 mL DMF, and react at 60°C for 5 h. Cool the reaction system to room temperature, add it to 50 mL of water, filter, dissolve the filter cake with a mixed solvent of dichloromethane/methanol (v/v) = 2:1, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use crude product Separate and purify with silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:2), and then separate and purify the crude product with silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 1:1). Compound 127 was obtained (2 mg, yield: 2%).

1H NMR (400 MHz, CDCl 3) δ 9.09 (s, 1H), 8.36 (d, 1H), 8.10 (s, 1H), 7.83 – 7.77 (m, 1H), 7.73 – 7.67 (m, 3H), 7.53 – 7.45 (m, 1H), 7.40 – 7.34 (m, 1H), 5.00 – 4.92 (m, 1H), 4.22 (s, 4H), 3.85 (s, 2H), 2.97 – 2.67 (m, 3H), 2.20 – 2.10 (m, 1H), 1.95 (s, 6H), 1.54 – 1.44 (m, 1H), 1.00 – 0.92 (m, 2H), 0.60 – 0.52 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.09 (s, 1H), 8.36 (d, 1H), 8.10 (s, 1H), 7.83 – 7.77 (m, 1H), 7.73 – 7.67 (m, 3H), 7.53 – 7.45 (m, 1H), 7.40 – 7.34 (m, 1H), 5.00 – 4.92 (m, 1H), 4.22 (s, 4H), 3.85 (s, 2H), 2.97 – 2.67 (m, 3H), 2.20 – 2.10 (m, 1H), 1.95 (s, 6H), 1.54 – 1.44 (m, 1H), 1.00 – 0.92 (m, 2H), 0.60 – 0.52 (m, 2H).

LCMS m/z = 630.2 [M+1] + LCMS m/z = 630.2 [M+1] +

實施例128：化合物128的製備 Example 128: Preparation of Compound 128

以128b為原料，參考實施例19得到化合物128(110mg)。Using 128b as a raw material, compound 128 (110 mg) was obtained with reference to Example 19.

1H NMR (400 MHz, CDCl 3) δ 8.64 (s, 1H), 8.17 (d, 1H), 7.95 (s, 1H), 7.82 – 7.74 (m, 2H), 7.67 (d, 1H), 7.24 – 7.19 (m, 1H), 7.11 (dd, 1H), 6.84 – 6.78 (m, 1H), 6.55 (dd, 1H), 4.97 – 4.88 (m, 1H), 4.40 – 4.30 (m, 2H), 4.13 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.94 – 2.57 (m, 3H), 2.46 (d, 2H), 2.18 – 2.07 (m, 1H), 1.94 (s, 6H), 0.97 – 0.84 (m, 1H), 0.54 – 0.45 (m, 2H), 0.20 – 0.12 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.64 (s, 1H), 8.17 (d, 1H), 7.95 (s, 1H), 7.82 – 7.74 (m, 2H), 7.67 (d, 1H), 7.24 – 7.19 (m, 1H), 7.11 (dd, 1H), 6.84 – 6.78 (m, 1H), 6.55 (dd, 1H), 4.97 – 4.88 (m, 1H), 4.40 – 4.30 (m, 2H), 4.13 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.94 – 2.57 (m, 3H), 2.46 (d, 2H), 2.18 – 2.07 (m, 1H), 1.94 (s, 6H), 0.97 – 0.84 (m, 1H), 0.54 – 0.45 (m, 2H), 0.20 – 0.12 (m, 2H).

LCMS m/z = 653.1 [M+1] + LCMS m/z = 653.1 [M+1] +

實施例129：化合物129的製備 Example 129: Preparation of Compound 129

以化合物89g和50a為原料，參考實施例124得到化合物129（36mg）。Using compounds 89g and 50a as raw materials, compound 129 (36 mg) was obtained with reference to Example 124.

1H NMR (400 MHz, CDCl 3) δ 9.95 (s, 1H), 8.81 (s, 1H), 8.44 (d, 1H), 8.02 – 7.86 (m, 2H), 7.74 – 7.67 (m, 1H), 7.66 – 7.54 (m, 3H), 7.54 – 7.44 (m, 3H), 7.42 – 7.37 (m, 1H), 6.92 – 6.84 (m, 1H), 6.62 (dd, 1H), 5.00 – 4.90 (m, 1H), 4.58 – 4.45 (m, 2H), 4.18 – 4.02 (m, 3H), 2.98 – 2.65 (m, 3H), 2.20 – 2.07 (m, 1H), 1.85 (s, 6H), 1.80 – 1.70 (m, 1H), 1.13 – 1.04 (m, 2H), 0.70 – 0.63 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.95 (s, 1H), 8.81 (s, 1H), 8.44 (d, 1H), 8.02 – 7.86 (m, 2H), 7.74 – 7.67 (m, 1H), 7.66 – 7.54 (m, 3H), 7.54 – 7.44 (m, 3H), 7.42 – 7.37 (m, 1H), 6.92 – 6.84 (m, 1H), 6.62 (dd, 1H), 5.00 – 4.90 (m, 1H) ), 4.58 – 4.45 (m, 2H), 4.18 – 4.02 (m, 3H), 2.98 – 2.65 (m, 3H), 2.20 – 2.07 (m, 1H), 1.85 (s, 6H), 1.80 – 1.70 (m , 1H), 1.13 – 1.04 (m, 2H), 0.70 – 0.63 (m, 2H).

LCMS m/z = 693.1 [M+1] + LCMS m/z = 693.1 [M+1] +

實施例130：化合物130的製備 Example 130: Preparation of Compound 130

以化合物68c為原料，參考實施例124得到化合物130(48mg)。Using compound 68c as a raw material, compound 130 (48 mg) was obtained with reference to Example 124.

1H NMR (400 MHz, CDCl 3) δ 9.22 (s, 1H), 8.41 (d, 1H), 7.98 – 7.88 (m, 3H), 7.69 (d, 1H), 7.53 – 7.45 (m, 3H), 7.41 – 7.33 (m, 3H), 6.90 – 6.84 (m, 1H), 6.62 (dd, 1H), 5.00 – 4.87 (m, 1H), 4.55 – 4.42 (m, 2H), 4.17 – 3.99 (m, 3H), 2.98 – 2.65 (m, 3H), 2.22 – 2.08 (m, 1H), 2.03 (s, 6H), 1.58 – 1.47 (m, 1H), 1.00 – 0.90 (m, 2H), 0.60 – 0.52 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.22 (s, 1H), 8.41 (d, 1H), 7.98 – 7.88 (m, 3H), 7.69 (d, 1H), 7.53 – 7.45 (m, 3H), 7.41 – 7.33 (m, 3H), 6.90 – 6.84 (m, 1H), 6.62 (dd, 1H), 5.00 – 4.87 (m, 1H), 4.55 – 4.42 (m, 2H), 4.17 – 3.99 (m, 3H ), 2.98 – 2.65 (m, 3H), 2.22 – 2.08 (m, 1H), 2.03 (s, 6H), 1.58 – 1.47 (m, 1H), 1.00 – 0.90 (m, 2H), 0.60 – 0.52 (m , 2H).

實施例131：化合物131的製備 Example 131: Preparation of Compound 131

以化合物131a為原料，參考實施例110的合成方法得到化合物131。Using compound 131a as a raw material, compound 131 was obtained by referring to the synthesis method of Example 110.

化合物131的核磁數據：NMR data of compound 131:

1H NMR (400 MHz, CDCl 3) δ 9.20 (s, 1H), 8.41 (d, 1H), 8.18 – 8.11 (m, 2H), 7.98 (s, 1H), 7.70 (d, 1H), 7.49 (dd, 1H), 7.38 – 7.34 (m, 1H), 7.06 – 6.96 (m, 2H), 6.87 (d, 1H), 6.62 (dd, 1H), 4.99 – 4.91 (m, 1H), 4.52 – 4.43 (m, 2H), 4.10 – 3.93 (m, 3H), 2.96 – 2.67 (m, 3H), 2.19 – 2.09 (m, 1H), 2.04 (s, 6H), 1.57 – 1.47 (m, 1H), 1.01 – 0.92 (m, 2H), 0.60 – 0.52 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.20 (s, 1H), 8.41 (d, 1H), 8.18 – 8.11 (m, 2H), 7.98 (s, 1H), 7.70 (d, 1H), 7.49 ( dd, 1H), 7.38 – 7.34 (m, 1H), 7.06 – 6.96 (m, 2H), 6.87 (d, 1H), 6.62 (dd, 1H), 4.99 – 4.91 (m, 1H), 4.52 – 4.43 ( m, 2H), 4.10 – 3.93 (m, 3H), 2.96 – 2.67 (m, 3H), 2.19 – 2.09 (m, 1H), 2.04 (s, 6H), 1.57 – 1.47 (m, 1H), 1.01 – 0.92 (m, 2H), 0.60 – 0.52 (m, 2H).

實施例132：化合物132的製備 Example 132: Preparation of Compound 132

以化合物132a為原料，參考實施例110的合成方法得到化合物132。Using compound 132a as a raw material, compound 132 was obtained by referring to the synthesis method of Example 110.

化合物132的核磁數據：NMR data of compound 132:

1H NMR (400 MHz, CDCl 3) δ 9.20 (s, 1H), 8.41 (d, 1H), 8.07 (s, 1H), 8.02 (s, 1H), 7.97 (s, 1H), 7.69 (d, 1H), 7.50 (dd, 1H), 7.40 – 7.35 (m, 1H), 7.35 – 7.27 (m, 1H), 7.21 – 7.13 (m, 1H), 6.87 (d, 1H), 6.62 (dd, 1H), 4.99 – 4.90 (m, 1H), 4.56 – 4.46 (m, 2H), 4.38 – 4.25 (m, 1H), 4.18 – 4.08 (m, 2H), 2.96 – 2.66 (m, 3H), 2.18 – 2.09 (m, 1H), 2.03 (s, 6H), 1.59 – 1.48 (m, 1H), 1.00 – 0.92 (m, 2H), 0.60 – 0.53 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.20 (s, 1H), 8.41 (d, 1H), 8.07 (s, 1H), 8.02 (s, 1H), 7.97 (s, 1H), 7.69 (d, 1H), 7.50 (dd, 1H), 7.40 – 7.35 (m, 1H), 7.35 – 7.27 (m, 1H), 7.21 – 7.13 (m, 1H), 6.87 (d, 1H), 6.62 (dd, 1H) , 4.99 – 4.90 (m, 1H), 4.56 – 4.46 (m, 2H), 4.38 – 4.25 (m, 1H), 4.18 – 4.08 (m, 2H), 2.96 – 2.66 (m, 3H), 2.18 – 2.09 ( m, 1H), 2.03 (s, 6H), 1.59 – 1.48 (m, 1H), 1.00 – 0.92 (m, 2H), 0.60 – 0.53 (m, 2H).

實施例133：化合物133的製備 Example 133: Preparation of Compound 133

化合物133以化合物127b和2c為原料，參照實施例127的合成方法得到。Compound 133 was obtained by referring to the synthesis method of Example 127 using compounds 127b and 2c as raw materials.

1H NMR (400 MHz, CDCl 3) δ 8.71 (s, 1H), 8.53 (d, 1H), 7.97 (s, 1H), 7.77 (s, 1H), 7.73 – 7.67 (m, 3H), 7.59 – 7.56 (m, 1H), 7.53 – 7.46 (m, 1H), 5.01 – 4.91 (m, 1H), 4.24 (s, 4H), 3.86 (s, 2H), 3.13 – 2.99 (m, 2H), 2.96 – 2.65 (m, 5H), 2.30 – 1.98 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.71 (s, 1H), 8.53 (d, 1H), 7.97 (s, 1H), 7.77 (s, 1H), 7.73 – 7.67 (m, 3H), 7.59 – 7.56 (m, 1H), 7.53 – 7.46 (m, 1H), 5.01 – 4.91 (m, 1H), 4.24 (s, 4H), 3.86 (s, 2H), 3.13 – 2.99 (m, 2H), 2.96 – 2.65 (m, 5H), 2.30 – 1.98 (m, 3H).

實施例 134：化合物134的製備 Example 134 : Preparation of Compound 134

化合物134以80c和66j為原料，參照實施例66的合成方法得到。Compound 134 was obtained by referring to the synthesis method of Example 66 using 80c and 66j as raw materials.

1H NMR (400 MHz, CDCl 3) δ 8.62 (s, 1H), 8.12 (d, 1H), 7.82 – 7.65 (m, 4H), 7.04 – 6.99 (m, 1H), 6.94 (dd, 1H), 6.46 (dd, 1H), 6.34 – 6.26 (m, 1H), 5.34 – 5.17 (m, 2H), 4.73 (t, 1H), 4.33 – 4.22 (m, 2H), 4.03 – 3.93 (m, 2H), 3.83 – 3.70 (m, 1H), 3.00 – 2.86 (m, 1H), 2.71 – 2.56 (m, 1H), 2.30 – 2.12 (m, 2H), 1.93 (s, 6H), 1.87 – 1.75 (m, 1H), 0.99 – 0.89 (m, 2H), 0.67 – 0.56 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.62 (s, 1H), 8.12 (d, 1H), 7.82 – 7.65 (m, 4H), 7.04 – 6.99 (m, 1H), 6.94 (dd, 1H), 6.46 (dd, 1H), 6.34 – 6.26 (m, 1H), 5.34 – 5.17 (m, 2H), 4.73 (t, 1H), 4.33 – 4.22 (m, 2H), 4.03 – 3.93 (m, 2H), 3.83 – 3.70 (m, 1H), 3.00 – 2.86 (m, 1H), 2.71 – 2.56 (m, 1H), 2.30 – 2.12 (m, 2H), 1.93 (s, 6H), 1.87 – 1.75 (m, 1H) ), 0.99 – 0.89 (m, 2H), 0.67 – 0.56 (m, 2H).

實施例135：化合物135三氟乙酸鹽的製備 Example 135: Preparation of compound 135 trifluoroacetate salt

化合物135以化合物23e的對甲苯磺酸鹽和2A為原料，參照實施例23的合成方法得到。Compound 135 was obtained using the p-toluenesulfonate salt of compound 23e and 2A as raw materials, and was obtained by referring to the synthesis method of Example 23.

1H NMR (400 MHz, CDCl 3) δ 8.96 (s, 1H), 8.32 (d, 1H), 8.08 (s, 1H), 7.79 (s, 2H), 7.45 (s, 1H), 7.42 – 7.31 (m, 2H), 6.84 (d, 1H), 4.98 – 4.85 (m, 1H), 4.55 – 4.40 (m, 2H), 4.27 – 4.13 (m, 2H), 3.85 – 3.72 (m, 1H), 3.06 (s, 1H), 2.97 – 2.65 (m, 3H), 2.20 – 2.06 (m, 1H), 1.94 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.96 (s, 1H), 8.32 (d, 1H), 8.08 (s, 1H), 7.79 (s, 2H), 7.45 (s, 1H), 7.42 – 7.31 ( m, 2H), 6.84 (d, 1H), 4.98 – 4.85 (m, 1H), 4.55 – 4.40 (m, 2H), 4.27 – 4.13 (m, 2H), 3.85 – 3.72 (m, 1H), 3.06 ( s, 1H), 2.97 – 2.65 (m, 3H), 2.20 – 2.06 (m, 1H), 1.94 (s, 6H).

實施例136：化合物136的製備 Example 136: Preparation of Compound 136

第一步：136b的製備Step 1: Preparation of 136b

將136a (2.0 g，5.01 mmol) (合成方法見WO2022187588) 溶於5 mL DCM中，加入4 mol/L鹽酸乙酸乙酯溶液 (50 mL)，室溫反應3 h。將反應體系減壓濃縮，殘留物用30 mL二氯甲烷和5 mL甲醇溶解，加入碳酸氫鉀調pH至7，過濾，將濾液減壓濃縮，得到粗品136b (1.4 g)。Dissolve 136a (2.0 g, 5.01 mmol) (see WO2022187588 for synthesis method) in 5 mL DCM, add 4 mol/L hydrochloric acid ethyl acetate solution (50 mL), and react at room temperature for 3 h. The reaction system was concentrated under reduced pressure, and the residue was dissolved in 30 mL of methylene chloride and 5 mL of methanol. Potassium bicarbonate was added to adjust the pH to 7, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 136b (1.4 g).

LCMS m/z = 300.3 [M+1] + LCMS m/z = 300.3 [M+1] +

第二步：136c的製備Step 2: Preparation of 136c

將2c (2.0 g，4.26 mmol) 溶於30 mL DMSO中，依次加入氮雜環丁-3-基甲醇的鹽酸鹽 (790 mg，6.39 mmol)、CuI (160 mg，0.84 mmol)、L-脯氨酸 (200 mg，1.74 mmol) 和碳酸鉀 (1.77 g，12.81 mmol)，氮氣氛圍下90℃反應16 h。將反應液冷卻至室溫，加入150 mL水和50 mL乙酸乙酯，水相用50 mL乙酸乙酯萃取，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 1:1-0:1)，得136c (300 mg，收率：16%)。Dissolve 2c (2.0 g, 4.26 mmol) in 30 mL DMSO, and add azetidin-3-ylmethanol hydrochloride (790 mg, 6.39 mmol), CuI (160 mg, 0.84 mmol), and L- Proline (200 mg, 1.74 mmol) and potassium carbonate (1.77 g, 12.81 mmol) were reacted at 90°C for 16 h under nitrogen atmosphere. Cool the reaction solution to room temperature, add 150 mL water and 50 mL ethyl acetate, extract the aqueous phase with 50 mL ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify the crude product with a silica gel chromatography column (petroleum) Ether/ethyl acetate (v/v) = 1:1-0:1), 136c (300 mg, yield: 16%) was obtained.

LCMS m/z = 429.1 [M+1] + LCMS m/z = 429.1 [M+1] +

第三步：136d的製備Step 3: Preparation of 136d

將136c (60 mg，0.14 mmol) 溶於15 mL DMSO中，加入IBX (180 mg，0.64 mmol)，50℃反應4 h。將反應體系冷卻至室溫，加入15 mL飽和碳酸氫鈉水溶液，室溫攪拌10 min後，加入40 mL水和40 mL乙酸乙酯，有機相用20 mL飽和氯化鈉水溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，得到粗品136d (70 mg)。Dissolve 136c (60 mg, 0.14 mmol) in 15 mL DMSO, add IBX (180 mg, 0.64 mmol), and react at 50°C for 4 h. Cool the reaction system to room temperature, add 15 mL of saturated aqueous sodium bicarbonate solution, stir for 10 min at room temperature, add 40 mL of water and 40 mL of ethyl acetate, and wash the organic phase with 20 mL of saturated aqueous sodium chloride solution and anhydrous sodium sulfate. Dry and concentrate under reduced pressure to obtain crude product 136d (70 mg).

第四步：化合物136的製備Step 4: Preparation of Compound 136

將上述粗品136b (63 mg) 和上述粗品136d (70 mg) 溶於10 mL DCM和2 mL DMF中，加入1 mL醋酸，40℃反應16 h後，分批加入三乙醯氧基硼氫化鈉 (89 mg，0.42 mmol)，室溫反應2 h。向反應液中加入30 mL二氯甲烷和30 mL飽和碳酸氫鈉水溶液，有機相用30 mL飽和氯化鈉水溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 1:1-0:1)，得化合物136 (10 mg，從化合物136c算兩步收率：10%)。Dissolve the above crude product 136b (63 mg) and the above crude product 136d (70 mg) in 10 mL DCM and 2 mL DMF, add 1 mL acetic acid, react at 40°C for 16 h, then add sodium triacetyloxyborohydride in batches (89 mg, 0.42 mmol), react at room temperature for 2 h. Add 30 mL dichloromethane and 30 mL saturated aqueous sodium bicarbonate solution to the reaction solution, wash the organic phase with 30 mL saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether). /ethyl acetate (v/v) = 1:1-0:1) to obtain compound 136 (10 mg, two-step yield calculated from compound 136c: 10%).

1H NMR (400 MHz, CDCl 3) δ 8.57 (d, 1H), 8.52 (s, 1H), 8.10 (s, 2H), 7.99 (s, 1H), 7.61 – 7.54 (m, 1H), 7.54 – 7.46 (m, 1H), 7.41 (s, 2H), 5.07 – 4.98 (m, 1H), 4.70 – 4.50 (m, 2H), 4.00 – 3.80 (m, 2H), 3.75 – 3.50 (m, 2H), 3.34 – 3.15 (m, 1H), 3.08 – 2.68 (m, 10H), 2.30 – 1.95 (m, 4H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.57 (d, 1H), 8.52 (s, 1H), 8.10 (s, 2H), 7.99 (s, 1H), 7.61 – 7.54 (m, 1H), 7.54 – 7.46 (m, 1H), 7.41 (s, 2H), 5.07 – 4.98 (m, 1H), 4.70 – 4.50 (m, 2H), 4.00 – 3.80 (m, 2H), 3.75 – 3.50 (m, 2H), 3.34 – 3.15 (m, 1H), 3.08 – 2.68 (m, 10H), 2.30 – 1.95 (m, 4H).

實施例 137 ：化合物137的製備 Example 137 : Preparation of Compound 137

化合物137以化合物137a為原料，參照實施例44的合成方法得到。Compound 137 was obtained by referring to the synthesis method of Example 44 using compound 137a as a raw material.

1H NMR (400 MHz, CDCl 3) δ 8.72 (d, 1H), 8.49 (s, 1H), 7.95 (s, 1H), 7.74 – 7.53 (m, 6H), 6.89 – 6.80 (m, 1H), 6.59 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.48 – 4.36 (m, 2H), 4.23 – 4.10 (m, 2H), 4.00 – 3.86 (m, 1H), 3.00 – 2.62 (m, 3H), 2.20 – 2.08 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.72 (d, 1H), 8.49 (s, 1H), 7.95 (s, 1H), 7.74 – 7.53 (m, 6H), 6.89 – 6.80 (m, 1H), 6.59 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.48 – 4.36 (m, 2H), 4.23 – 4.10 (m, 2H), 4.00 – 3.86 (m, 1H), 3.00 – 2.62 (m, 3H ), 2.20 – 2.08 (m, 1H).

LCMS m/z = 653.0 [M+1] + LCMS m/z = 653.0 [M+1] +

實施例 138 ：化合物138的製備 Example 138 : Preparation of Compound 138

化合物138以化合物138a為原料，參照實施例44的合成方法得到。Compound 138 was obtained by referring to the synthesis method of Example 44 using compound 138a as a raw material.

1H NMR (400 MHz, CDCl 3) δ 10.81 (s, 1H), 8.82 (d, 1H), 8.63 (s, 1H), 8.28 (s, 1H), 7.92 (s, 1H), 7.74 – 7.66 (m, 2H), 7.64 – 7.56 (m, 1H), 7.56 – 7.46 (m, 1H), 6.86 – 6.82 (m, 1H), 6.60 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.48 – 4.37 (m, 2H), 4.22 – 4.10 (m, 2H), 3.98 – 3.85 (m, 1H), 3.00 – 2.63 (m, 3H), 2.22 – 2.08 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 10.81 (s, 1H), 8.82 (d, 1H), 8.63 (s, 1H), 8.28 (s, 1H), 7.92 (s, 1H), 7.74 – 7.66 ( m, 2H), 7.64 – 7.56 (m, 1H), 7.56 – 7.46 (m, 1H), 6.86 – 6.82 (m, 1H), 6.60 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.48 – 4.37 (m, 2H), 4.22 – 4.10 (m, 2H), 3.98 – 3.85 (m, 1H), 3.00 – 2.63 (m, 3H), 2.22 – 2.08 (m, 1H).

LCMS m/z = 636.1 [M+1] + LCMS m/z = 636.1 [M+1] +

實施例 139：化合物139的製備 Example 139 : Preparation of Compound 139

化合物139以化合物139a和139A為原料，參考實施例44的合成方法得到。Compound 139 was obtained by referring to the synthesis method of Example 44 using compounds 139a and 139A as raw materials.

1H NMR (400 MHz, CDCl 3) δ 8.73 (s, 1H), 8.59 (d, 1H), 7.97 (s, 2H), 7.82 (d, 1H), 7.72 – 7.56 (m, 3H), 7.55 – 7.44 (m, 2H), 6.87 – 6.80 (m, 1H), 6.58 (dd, 1H), 4.99 – 4.88 (m, 1H), 4.47 – 4.35 (m, 2H), 4.18 – 4.07 (m, 2H), 3.95 – 3.81 (m, 1H), 2.96 – 2.65 (m, 3H), 2.18 – 2.08 (m, 1H), 1.90 – 1.78 (m, 1H), 1.18 – 1.10 (m, 2H), 0.83 – 0.72 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.73 (s, 1H), 8.59 (d, 1H), 7.97 (s, 2H), 7.82 (d, 1H), 7.72 – 7.56 (m, 3H), 7.55 – 7.44 (m, 2H), 6.87 – 6.80 (m, 1H), 6.58 (dd, 1H), 4.99 – 4.88 (m, 1H), 4.47 – 4.35 (m, 2H), 4.18 – 4.07 (m, 2H), 3.95 – 3.81 (m, 1H), 2.96 – 2.65 (m, 3H), 2.18 – 2.08 (m, 1H), 1.90 – 1.78 (m, 1H), 1.18 – 1.10 (m, 2H), 0.83 – 0.72 (m , 2H).

實施例 140 ：化合物140的製備 Example 140 : Preparation of Compound 140

第一步： 140c的製備Step One: Preparation of 140c

向140b (2.0 g，6.02 mmol) 和氫氧化鋰 (0.69 g，28.81 mmol) 加入10 mL水和10 mL甲醇，室溫反應16 h。將反應液加入到50 mL水中，用1 mol/L鹽酸調pH至2，用乙酸乙酯萃取 (50 mL×3)，有機相用無水硫酸鈉乾燥，減壓濃縮，得到粗品 (1.5 g)。將上述粗品 (410 mg) 與5-(三氟甲基)吲哚啉 (0.2 g，1.07 mmol) 溶解於20 mL二氯甲烷中，加入TCFH (0.45 g, 1.60 mmol) 和NMI (0.35 g, 4.26 mmol)，室溫反應16 h。將反應體系減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 3:1)，得到140c (450 mg，收率：86%)。Add 10 mL water and 10 mL methanol to 140b (2.0 g, 6.02 mmol) and lithium hydroxide (0.69 g, 28.81 mmol), and react at room temperature for 16 h. Add the reaction solution to 50 mL of water, adjust the pH to 2 with 1 mol/L hydrochloric acid, extract with ethyl acetate (50 mL×3), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product (1.5 g) . Dissolve the above crude product (410 mg) and 5-(trifluoromethyl)indoline (0.2 g, 1.07 mmol) in 20 mL dichloromethane, add TCFH (0.45 g, 1.60 mmol) and NMI (0.35 g, 4.26 mmol), react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 3:1) to obtain 140c (450 mg, yield: 86%).

LCMS m/z = 488.0 [M+1] + LCMS m/z = 488.0 [M+1] +

第二步：化合物140的製備Step 2: Preparation of Compound 140

將140c (0.20 g，0.41 mmol)、上述粗品中間體1 (0.21 g)、TEA (0.12 g，1.19 mmol)、CuI (8 mg，0.042 mmol) 和PdCl 2(PPh 3) 2(29 mg，0.041 mmol) 加入到反應瓶中，氮氣保護下加入4 mL DMF，50℃反應2 h。將反應液冷卻至室溫，加入50 mL水，抽濾，濾餅用10 mL水洗滌，將濾餅用100 mL DCM溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠柱色譜分離純化 (石油醚/乙酸乙酯 (v/v) = 1:2)，得到化合物140 (0.18 g，收率：63%)。 140c (0.20 g, 0.41 mmol), the above crude intermediate 1 (0.21 g), TEA (0.12 g, 1.19 mmol), CuI (8 mg, 0.042 mmol) and PdCl 2 (PPh 3 ) 2 (29 mg, 0.041 mmol) into the reaction bottle, add 4 mL DMF under nitrogen protection, and react at 50°C for 2 h. Cool the reaction solution to room temperature, add 50 mL of water, and filter with suction. The filter cake is washed with 10 mL of water. The filter cake is dissolved in 100 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated and purified by silica gel column chromatography ( Petroleum ether/ethyl acetate (v/v) = 1:2) to obtain compound 140 (0.18 g, yield: 63%).

1H NMR (400 MHz, CDCl 3) δ 8.31 (d, 1H), 8.01 (s, 1H), 7.66 (d, 1H), 7.50 – 7.38 (m, 2H), 7.36 – 7.29 (m, 2H), 6.90 – 6.83 (m, 2H), 6.81 – 6.77 (m, 1H), 6.54 (dd, 1H), 4.97 – 4.88 (m, 1H), 4.48 – 4.16 (m, 5H), 4.10 – 4.02 (m, 2H), 3.86 – 3.75 (m, 1H), 3.32 – 3.07 (m, 2H), 2.95 – 2.63 (m, 3H), 2.18 – 2.08 (m, 1H), 1.51 – 1.39 (m, 1H), 0.83 – 0.66 (m, 3H), 0.66 – 0.56 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.31 (d, 1H), 8.01 (s, 1H), 7.66 (d, 1H), 7.50 – 7.38 (m, 2H), 7.36 – 7.29 (m, 2H), 6.90 – 6.83 (m, 2H), 6.81 – 6.77 (m, 1H), 6.54 (dd, 1H), 4.97 – 4.88 (m, 1H), 4.48 – 4.16 (m, 5H), 4.10 – 4.02 (m, 2H ), 3.86 – 3.75 (m, 1H), 3.32 – 3.07 (m, 2H), 2.95 – 2.63 (m, 3H), 2.18 – 2.08 (m, 1H), 1.51 – 1.39 (m, 1H), 0.83 – 0.66 (m, 3H), 0.66 – 0.56 (m, 1H).

LCMS m/z = 697.1 [M+1] + LCMS m/z = 697.1 [M+1] +

實施例 141：化合物141的製備 Example 141 : Preparation of Compound 141

第一步：141b的製備Step One: Preparation of 141b

將CuI (1.72 g，9.03 mmol) 和KI (1.5 g，9.04 mmol) 加入到60 mL乙腈中，75℃加入亞硝酸異戊酯 (1.26 g，10.76 mmol)，加入141a (1.5 g，6.05 mmol)，75℃反應2 h。將反應體系冷卻至室溫，加入200 mL水和150 mL乙酸乙酯，墊矽藻土過濾，分液，水相用乙酸乙酯萃取 (60 mL×3)，有機相用飽和氯化鈉水溶液洗滌 (80 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 35:65)，得141b (0.8 g，收率：37%)。Add CuI (1.72 g, 9.03 mmol) and KI (1.5 g, 9.04 mmol) to 60 mL acetonitrile, add isoamyl nitrite (1.26 g, 10.76 mmol) at 75°C, and add 141a (1.5 g, 6.05 mmol). , react at 75°C for 2 h. Cool the reaction system to room temperature, add 200 mL water and 150 mL ethyl acetate, filter through diatomaceous earth, separate the liquids, extract the aqueous phase with ethyl acetate (60 mL×3), and use saturated sodium chloride aqueous solution for the organic phase. Wash (80 ml :37%).

LCMS m/z = 360.1 [M+1] + LCMS m/z = 360.1 [M+1] +

第二步：141c的製備Step 2: Preparation of 141c

將141b (200 mg，0.56 mmol) 溶於10 mL二氯甲烷，加入2 mL三氟乙酸，室溫反應2 h。將反應體系減壓濃縮，加入10 mL甲苯和TEA (56 mg，0.55 mmol)，加入141A (124 mg，0.56 mmol)，55℃反應16 h。將反應體系冷卻至室溫，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 91:8)，得141c (100 mg，收率：38%)。Dissolve 141b (200 mg, 0.56 mmol) in 10 mL dichloromethane, add 2 mL trifluoroacetic acid, and react at room temperature for 2 h. The reaction system was concentrated under reduced pressure, 10 mL of toluene and TEA (56 mg, 0.55 mmol) were added, 141A (124 mg, 0.56 mmol) was added, and the reaction was carried out at 55°C for 16 h. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 91:8) to obtain 141c (100 mg, yield: 38%).

第三步：化合物141的製備Step 3: Preparation of Compound 141

化合物141以化合物141c為原料，參照實施例18的合成方法得到。Compound 141 was obtained by referring to the synthesis method of Example 18 using compound 141c as raw material.

1H NMR (400 MHz, CDCl 3) δ 8.44 (d, 1H), 7.96 (s, 1H), 7.72 – 7.65 (m, 1H), 7.64 – 7.60 (m, 1H), 7.51 (dd, 1H), 7.33 – 7.26 (m, 2H), 7.23 (s, 1H), 7.19 – 7.12 (m, 1H), 6.82 (d, 1H), 6.61 (dd, 1H), 4.98 – 4.90 (m, 1H), 4.68 (s, 2H), 4.43 – 4.34 (m, 2H), 4.17 – 4.06 (m, 2H), 3.92 – 3.80 (m, 1H), 3.80 – 3.73 (m, 2H), 3.03 – 2.94 (m, 2H), 2.94 – 2.65 (m, 3H), 2.18 – 2.08 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.44 (d, 1H), 7.96 (s, 1H), 7.72 – 7.65 (m, 1H), 7.64 – 7.60 (m, 1H), 7.51 (dd, 1H), 7.33 – 7.26 (m, 2H), 7.23 (s, 1H), 7.19 – 7.12 (m, 1H), 6.82 (d, 1H), 6.61 (dd, 1H), 4.98 – 4.90 (m, 1H), 4.68 ( s, 2H), 4.43 – 4.34 (m, 2H), 4.17 – 4.06 (m, 2H), 3.92 – 3.80 (m, 1H), 3.80 – 3.73 (m, 2H), 3.03 – 2.94 (m, 2H), 2.94 – 2.65 (m, 3H), 2.18 – 2.08 (m, 1H).

LCMS m/z = 690.2 [M+1] +­ LCMS m/z = 690.2 [M+1] +

實施例 142：化合物142的製備 Example 142 : Preparation of Compound 142

化合物142以化合物142c為原料，參照實施例80的合成方法得到。Compound 142 was obtained by referring to the synthesis method of Example 80 using compound 142c as raw material.

1H NMR (400 MHz, CDCl 3) δ 8.54 (s, 1H), 8.13 (s, 1H), 8.01 (d, 1H), 7.82 – 7.74 (m, 2H), 7.67 (d, 1H), 7.07 (d, 1H), 6.82 – 6.79 (m, 1H), 6.55 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.99 – 2.60 (m, 7H), 2.18 – 2.00 (m, 3H), 1.94 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.54 (s, 1H), 8.13 (s, 1H), 8.01 (d, 1H), 7.82 – 7.74 (m, 2H), 7.67 (d, 1H), 7.07 ( d, 1H), 6.82 – 6.79 (m, 1H), 6.55 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.99 – 2.60 (m, 7H), 2.18 – 2.00 (m, 3H), 1.94 (s, 6H).

LCMS m/z = 639.3 [M+1] + LCMS m/z = 639.3 [M+1] +

實施例 143：化合物143的製備 Example 143 : Preparation of Compound 143

第一步：143b的製備Step One: Preparation of 143b

將143a (0.45 g，2.0 mmol) 與143A (530 mg, 2.24 mmol) 溶解於20 mL二氯甲烷中，加入TCFH (0.85 g, 3.03 mmol)，加入NMI (0.67 g, 8.16 mmol)，室溫反應16 h。將反應體系減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚:乙酸乙酯 (v/v) = 5:1)，得到143b (820 mg，收率：93%)。Dissolve 143a (0.45 g, 2.0 mmol) and 143A (530 mg, 2.24 mmol) in 20 mL dichloromethane, add TCFH (0.85 g, 3.03 mmol), add NMI (0.67 g, 8.16 mmol), and react at room temperature 16h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 5:1) to obtain 143b (820 mg, yield: 93%).

LCMS m/z = 444.2 [M+1] + LCMS m/z = 444.2 [M+1] +

第二步：化合物143的製備Step 2: Preparation of Compound 143

將143b (0.22 g，0.50 mmol)、上述粗品中間體1 (0.25 g)、TEA (0.15 g，1.48 mmol)、CuI (10 mg，0.053 mmol) 和PdCl 2(PPh 3) 2(35 mg，0.050 mmol) 加入到反應瓶中，氮氣保護下加入4 mL DMF，50℃反應2 h。將反應液冷卻至室溫，加入50 mL水，抽濾，濾餅用10 mL水洗滌，將濾餅用100 mL DCM溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠柱色譜分離純化 (石油醚/乙酸乙酯 (v/v) = 1:2)，得到化合物143 (0.18 g，收率：55%)。 143b (0.22 g, 0.50 mmol), the above crude intermediate 1 (0.25 g), TEA (0.15 g, 1.48 mmol), CuI (10 mg, 0.053 mmol) and PdCl 2 (PPh 3 ) 2 (35 mg, 0.050 mmol) into the reaction bottle, add 4 mL DMF under nitrogen protection, and react at 50°C for 2 h. Cool the reaction solution to room temperature, add 50 mL of water, and filter with suction. The filter cake is washed with 10 mL of water. The filter cake is dissolved in 100 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product is separated and purified by silica gel column chromatography ( Petroleum ether/ethyl acetate (v/v) = 1:2) to obtain compound 143 (0.18 g, yield: 55%).

1H NMR (400 MHz, CDCl 3) δ 8.04 (s, 1H), 7.98 (s, 1H), 7.85 (d, 1H), 7.73 (s, 1H), 7.70 – 7.60 (m, 2H), 7.58 – 7.48 (m, 1H), 7.43 (s, 1H), 6.99 – 6.90 (m, 1H), 6.86 – 6.77 (m, 1H), 6.56 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.44 – 4.32 (m, 2H), 4.17 – 4.05 (m, 2H), 3.92 – 3.77 (m, 1H), 2.95 – 2.63 (m, 3H), 2.19 – 2.07 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.04 (s, 1H), 7.98 (s, 1H), 7.85 (d, 1H), 7.73 (s, 1H), 7.70 – 7.60 (m, 2H), 7.58 – 7.48 (m, 1H), 7.43 (s, 1H), 6.99 – 6.90 (m, 1H), 6.86 – 6.77 (m, 1H), 6.56 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.44 – 4.32 (m, 2H), 4.17 – 4.05 (m, 2H), 3.92 – 3.77 (m, 1H), 2.95 – 2.63 (m, 3H), 2.19 – 2.07 (m, 1H).

LCMS m/z = 653.0 [M+1] + LCMS m/z = 653.0 [M+1] +

實施例 144：化合物144的製備 Example 144 : Preparation of Compound 144

化合物144以化合物144a為原料，參考實施例18的合成方法得到。Compound 144 was obtained by using compound 144a as a raw material and referring to the synthesis method of Example 18.

1H NMR (400 MHz, CDCl 3) δ 8.05 (s, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.67 (d, 1H), 7.58 (s, 1H), 6.84 – 6.78 (m, 1H), 6.77 – 6.69 (m, 2H), 6.59 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.42 – 4.30 (m, 2H), 4.17 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.94 – 2.64 (m, 3H), 2.18 – 2.08 (m, 1H), 2.05 (s, 6H), 1.95 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.05 (s, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.67 (d, 1H), 7.58 (s, 1H), 6.84 – 6.78 ( m, 1H), 6.77 – 6.69 (m, 2H), 6.59 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.42 – 4.30 (m, 2H), 4.17 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.94 – 2.64 (m, 3H), 2.18 – 2.08 (m, 1H), 2.05 (s, 6H), 1.95 (s, 6H).

LCMS m/z = 611.2 [M+1] + LCMS m/z = 611.2 [M+1] +

實施例 145：化合物145的製備 Example 145 : Preparation of Compound 145

化合物145以化合物145a為原料，參考實施例18的合成方法得到。Compound 145 was obtained by using compound 145a as a raw material and referring to the synthesis method of Example 18.

1H NMR (400 MHz, CDCl 3) δ 8.14 (s, 1H), 8.09 (s, 1H), 7.80 (s, 1H), 7.76 (s, 1H), 7.70 (d, 1H), 7.67 (d, 1H), 7.00 – 6.95 (m, 1H), 6.95 – 6.91 (m, 1H), 6.83 – 6.78 (m, 1H), 6.55 (dd, 1H), 4.97 – 4.89 (m, 1H), 4.40 – 4.31 (m, 2H), 4.13 – 4.02 (m, 2H), 3.87 – 3.75 (m, 1H), 2.95 – 2.65 (m, 3H), 2.26 (s, 3H), 2.17 – 2.07 (m, 1H), 2.06 – 2.02 (m, 3H), 1.94 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.14 (s, 1H), 8.09 (s, 1H), 7.80 (s, 1H), 7.76 (s, 1H), 7.70 (d, 1H), 7.67 (d, 1H), 7.00 – 6.95 (m, 1H), 6.95 – 6.91 (m, 1H), 6.83 – 6.78 (m, 1H), 6.55 (dd, 1H), 4.97 – 4.89 (m, 1H), 4.40 – 4.31 ( m, 2H), 4.13 – 4.02 (m, 2H), 3.87 – 3.75 (m, 1H), 2.95 – 2.65 (m, 3H), 2.26 (s, 3H), 2.17 – 2.07 (m, 1H), 2.06 – 2.02 (m, 3H), 1.94 (s, 6H).

LCMS m/z = 593.2 [M+1] + LCMS m/z = 593.2 [M+1] +

實施例146：化合物146的製備 Example 146: Preparation of Compound 146

化合物146以化合物146d為原料，參考實施例110的合成方法得到。Compound 146 was obtained by using compound 146d as raw material and referring to the synthesis method of Example 110.

化合物146的核磁數據：NMR data of compound 146:

1H NMR (400 MHz, DMSO- d 6 ) δ 9.00 (s, 1H), 8.65 (s, 1H), 8.22 (s, 1H), 8.05 (d, 1H), 7.73 – 7.62 (m, 2H), 7.62 – 7.46 (m, 5H), 6.91 – 6.86 (m, 1H), 6.75 (dd, 1H), 5.11 – 5.02 (m, 1H), 4.55 – 4.44 (m, 2H), 4.32 – 4.20 (m, 1H), 4.18 – 4.08 (m, 2H), 2.95 – 2.80 (m, 1H), 2.70 – 2.45 (m, 2H), 2.07 – 1.97 (m, 1H), 1.92 (s, 6H), 1.68 – 1.58 (m, 1H), 0.88 – 0.76 (m, 2H), 0.62 – 0.53 (m, 2H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.00 (s, 1H), 8.65 (s, 1H), 8.22 (s, 1H), 8.05 (d, 1H), 7.73 – 7.62 (m, 2H), 7.62 – 7.46 (m, 5H), 6.91 – 6.86 (m, 1H), 6.75 (dd, 1H), 5.11 – 5.02 (m, 1H), 4.55 – 4.44 (m, 2H), 4.32 – 4.20 (m, 1H ), 4.18 – 4.08 (m, 2H), 2.95 – 2.80 (m, 1H), 2.70 – 2.45 (m, 2H), 2.07 – 1.97 (m, 1H), 1.92 (s, 6H), 1.68 – 1.58 (m , 1H), 0.88 – 0.76 (m, 2H), 0.62 – 0.53 (m, 2H).

實施例147：化合物147的製備 Example 147: Preparation of Compound 147

第一步：147b的製備Step One: Preparation of 147b

將147a (1.42 g，4.98 mmol) 溶於50 mL 1,4-二氧六環和10 mL純化水中，氮氣氛圍下依次加入環丙基硼酸 (0.81 g，9.43 mmol)、磷酸鉀 (2.2 g，10.36 mmol)、醋酸鈀 (0.23 g，1.02 mmol) 和三環己基膦 (0.56 g，2.0 mmol)，95℃反應16 h。將反應體系冷卻至室溫，加入80 mL乙酸乙酯和50 mL純化水，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 4:1)，得147b (0.8 g，收率：78%)。 Dissolve 147a (1.42 g, 4.98 mmol) in 50 mL of 1,4-dioxane and 10 mL of purified water, and add cyclopropylboronic acid (0.81 g, 9.43 mmol) and potassium phosphate (2.2 g, respectively) under a nitrogen atmosphere. 10.36 mmol), palladium acetate (0.23 g, 1.02 mmol) and tricyclohexylphosphine (0.56 g, 2.0 mmol), reacted at 95°C for 16 h. The reaction system was cooled to room temperature, 80 mL of ethyl acetate and 50 mL of purified water were added, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) ) = 4:1), get 147b (0.8 g, yield: 78%).

LCMS m/z = 208.1 [M+1] + LCMS m/z = 208.1 [M+1] +

化合物147以化合物147b為原料，參考實施例18的合成方法得到。Compound 147 was obtained by using compound 147b as a raw material and referring to the synthesis method of Example 18.

1H NMR (400 MHz, CDCl 3) δ 8.18 (s, 1H), 7.83 (s, 1H), 7.79 – 7.71 (m, 2H), 7.67 (d, 1H), 6.92 – 6.85 (m, 1H), 6.83 – 6.77 (m, 1H), 6.66 – 6.60 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.40 – 4.31 (m, 2H), 4.13 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.94 – 2.63 (m, 3H), 2.17 – 2.04 (m, 1H), 1.96 (s, 6H), 1.84 – 1.64 (m, 2H), 0.97 – 0.88 (m, 2H), 0.84 – 0.75 (m, 2H), 0.66 – 0.58 (m, 2H), 0.55 – 0.47 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.18 (s, 1H), 7.83 (s, 1H), 7.79 – 7.71 (m, 2H), 7.67 (d, 1H), 6.92 – 6.85 (m, 1H), 6.83 – 6.77 (m, 1H), 6.66 – 6.60 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.40 – 4.31 (m, 2H), 4.13 – 4.02 (m, 2H ), 3.88 – 3.75 (m, 1H), 2.94 – 2.63 (m, 3H), 2.17 – 2.04 (m, 1H), 1.96 (s, 6H), 1.84 – 1.64 (m, 2H), 0.97 – 0.88 (m , 2H), 0.84 – 0.75 (m, 2H), 0.66 – 0.58 (m, 2H), 0.55 – 0.47 (m, 2H).

LCMS m/z = 679.1 [M+1] + LCMS m/z = 679.1 [M+1] +

實施例 148：化合物148的製備 Example 148 : Preparation of Compound 148

化合物148以化合物148a為原料，參考實施例147的合成方法得到。Compound 148 was obtained by using compound 148a as a raw material and referring to the synthesis method of Example 147.

1H NMR (400 MHz, CDCl 3) δ 8.25 (s, 1H), 7.93 (s, 1H), 7.84 (s, 1H), 7.74 (s, 1H), 7.68 (d, 1H), 7.15 (s, 2H), 6.85 – 6.77 (m, 1H), 6.56 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.44 – 4.30 (m, 2H), 4.12 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.96 – 2.66 (m, 3H), 2.19 – 2.07 (m, 1H), 1.97 (s, 6H), 1.77 – 1.65 (m, 2H), 0.94 – 0.78 (m, 4H), 0.58 – 0.49 (m, 4H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.25 (s, 1H), 7.93 (s, 1H), 7.84 (s, 1H), 7.74 (s, 1H), 7.68 (d, 1H), 7.15 (s, 2H), 6.85 – 6.77 (m, 1H), 6.56 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.44 – 4.30 (m, 2H), 4.12 – 4.02 (m, 2H), 3.88 – 3.75 ( m, 1H), 2.96 – 2.66 (m, 3H), 2.19 – 2.07 (m, 1H), 1.97 (s, 6H), 1.77 – 1.65 (m, 2H), 0.94 – 0.78 (m, 4H), 0.58 – 0.49 (m, 4H).

LCMS m/z = 670.7 [M+1] + LCMS m/z = 670.7 [M+1] +

實施例 149：化合物149的製備 Example 149 : Preparation of Compound 149

第一步：149b的製備Step One: Preparation of 149b

將149a (2 g，6.06 mmol) 溶於100 mL 1,4-二氧六環和20 mL水的混合溶劑中，加入環丙基硼酸 (4.7 g，54.7 mmol)、磷酸鉀 (19 g，89.51 mmol)、Pd(OAc) 2(410 mg，1.83 mmol) 和三環己基膦 (512 mg，1.83 mmol)，氮氣氛圍下100℃反應16 h。將反應體系冷卻至室溫，加入水 (120 mL) 和乙酸乙酯 (160 mL)，墊矽藻土過濾，將濾液分液，水相用乙酸乙酯萃取 (100 mL×2)，有機相用飽和氯化鈉水溶液洗滌 (100 mL×3)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 87:13)，得149b (700 mg，收率：54%)。 Dissolve 149a (2 g, 6.06 mmol) in a mixed solvent of 100 mL 1,4-dioxane and 20 mL water, add cyclopropylboronic acid (4.7 g, 54.7 mmol) and potassium phosphate (19 g, 89.51 mmol), Pd(OAc) 2 (410 mg, 1.83 mmol) and tricyclohexylphosphine (512 mg, 1.83 mmol), reacted at 100°C for 16 h under nitrogen atmosphere. Cool the reaction system to room temperature, add water (120 mL) and ethyl acetate (160 mL), filter through diatomaceous earth, separate the filtrate, extract the aqueous phase with ethyl acetate (100 mL×2), and extract the organic phase Wash with saturated sodium chloride aqueous solution (100 mL×3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 87:13) to obtain 149b (700 mg, yield: 54%).

LCMS m/z = 214.3 [M+1] + LCMS m/z = 214.3 [M+1] +

化合物149以化合物149b為原料，參照實施例18的合成方法得到。Compound 149 was obtained by referring to the synthesis method of Example 18 using compound 149b as raw material.

1H NMR (400 MHz, CDCl 3) δ 7.91 (s, 1H), 7.83 (s, 1H), 7.75 – 7.70 (m, 2H), 7.67 (d, 1H), 6.84 – 6.78 (m, 1H), 6.60 – 6.50 (m, 3H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.95 – 2.65 (m, 3H), 2.18 – 2.08 (m, 1H), 1.97 (s, 6H), 1.83 – 1.72 (m, 1H), 1.72 – 1.60 (m, 2H), 0.93 – 0.83 (m, 2H), 0.80 – 0.70 (m, 4H), 0.62 – 0.55 (m, 2H), 0.54 – 0.45 (m, 4H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.91 (s, 1H), 7.83 (s, 1H), 7.75 – 7.70 (m, 2H), 7.67 (d, 1H), 6.84 – 6.78 (m, 1H), 6.60 – 6.50 (m, 3H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.95 – 2.65 (m , 3H), 2.18 – 2.08 (m, 1H), 1.97 (s, 6H), 1.83 – 1.72 (m, 1H), 1.72 – 1.60 (m, 2H), 0.93 – 0.83 (m, 2H), 0.80 – 0.70 (m, 4H), 0.62 – 0.55 (m, 2H), 0.54 – 0.45 (m, 4H).

LCMS m/z = 685.3 [M+1] + LCMS m/z = 685.3 [M+1] +

實施例 150：化合物150的製備 Example 150 : Preparation of Compound 150

化合物150以化合物150a為原料，參照實施例18的合成方法得到。Compound 150 was obtained by using compound 150a as a raw material and referring to the synthesis method of Example 18.

1H NMR (400 MHz, CDCl 3) δ 8.58 (s, 1H), 8.08 – 7.99 (m, 2H), 7.77 (s, 2H), 7.67 (d, 1H), 6.86 – 6.78 (m, 2H), 6.72 (dd, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.12 – 4.00 (m, 2H), 3.88 – 3.72 (m, 1H), 2.95 – 2.63 (m, 3H), 2.18 – 2.05 (m, 1H), 1.92 (s, 6H), 1.88 – 1.75 (m, 1H), 0.96 – 0.88 (m, 2H), 0.66 – 0.58 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.58 (s, 1H), 8.08 – 7.99 (m, 2H), 7.77 (s, 2H), 7.67 (d, 1H), 6.86 – 6.78 (m, 2H), 6.72 (dd, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.12 – 4.00 (m, 2H), 3.88 – 3.72 (m, 1H), 2.95 – 2.63 (m, 3H), 2.18 – 2.05 (m, 1H), 1.92 (s, 6H), 1.88 – 1.75 (m, 1H), 0.96 – 0.88 (m, 2H), 0.66 – 0.58 (m, 2H ).

LCMS m/z = 623.3 [M+1] + LCMS m/z = 623.3 [M+1] +

實施例 151 ：化合物151的製備 Example 151 : Preparation of Compound 151

第一步：151b的製備Step One: Preparation of 151b

將151a (1.0 g，5.11 mmol) 溶於20 mL DMF中，加入3-氟-5-碘苯胺 (1.2 g，5.06 mmol) 和N,N'-羰基二咪唑 (0.91 g，5.61 mmol)，80℃反應12 h。將反應體系冷卻到室溫，加入到100 mL乙酸乙酯中，有機相用飽和氯化鈉水溶液洗滌 (50 mL×3)，無水硫酸鈉乾燥，減壓濃縮，粗品用20 mL乙醚打漿，過濾，將濾餅真空乾燥，得到粗品151b (1.0 g)。Dissolve 151a (1.0 g, 5.11 mmol) in 20 mL DMF, add 3-fluoro-5-iodoaniline (1.2 g, 5.06 mmol) and N,N'-carbonyldiimidazole (0.91 g, 5.61 mmol), 80 ℃ reaction for 12 h. Cool the reaction system to room temperature, add it to 100 mL of ethyl acetate, wash the organic phase with saturated aqueous sodium chloride solution (50 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is slurried with 20 mL of diethyl ether and filtered. , the filter cake was vacuum dried to obtain crude product 151b (1.0 g).

第二步：化合物151的製備Step 2: Preparation of Compound 151

將上述粗品151b (0.11 g) 和上述粗品中間體1 (0.12 g)、TEA (0.14 g，1.38 mmol)、CuI (8.8 mg，0.046 mmol) 和PdCl 2(PPh 3) 2(16 mg，0.023 mmol) 加入到反應瓶中，氮氣保護下加入2 mL DMF，55℃反應3 h。將反應液冷卻至室溫，加入到50 mL乙酸乙酯中，有機相用飽和氯化鈉水溶液洗滌 (20 mL×3)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 1:0-10:7)，得到化合物151 (0.05 g，從化合物151a算兩步收率：13%)。 The above crude product 151b (0.11 g) and the above crude intermediate 1 (0.12 g), TEA (0.14 g, 1.38 mmol), CuI (8.8 mg, 0.046 mmol) and PdCl 2 (PPh 3 ) 2 (16 mg, 0.023 mmol) were added. ) into the reaction bottle, add 2 mL DMF under nitrogen protection, and react at 55°C for 3 hours. The reaction solution was cooled to room temperature and added to 50 mL of ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution (20 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column ( Petroleum ether/ethyl acetate (v/v) = 1:0-10:7) to obtain compound 151 (0.05 g, two-step yield calculated from compound 151a: 13%).

1H NMR (400 MHz, CDCl 3) δ 8.38 (d, 1H), 8.14 (s, 1H), 7.67 – 7.56 (m, 2H), 7.50 (d, 1H), 7.44 – 7.27 (m, 2H), 7.23 – 7.12 (m, 2H), 6.88 – 6.80 (m, 1H), 6.76 – 6.68 (m, 1H), 6.54 – 6.46 (m, 1H), 5.02 – 4.90 (m, 1H), 4.40 – 4.27 (m, 2H), 4.10 – 3.97 (m, 2H), 3.88 – 3.72 (m, 1H), 2.97 – 2.65 (m, 3H), 2.21 – 2.08 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.38 (d, 1H), 8.14 (s, 1H), 7.67 – 7.56 (m, 2H), 7.50 (d, 1H), 7.44 – 7.27 (m, 2H), 7.23 – 7.12 (m, 2H), 6.88 – 6.80 (m, 1H), 6.76 – 6.68 (m, 1H), 6.54 – 6.46 (m, 1H), 5.02 – 4.90 (m, 1H), 4.40 – 4.27 (m , 2H), 4.10 – 3.97 (m, 2H), 3.88 – 3.72 (m, 1H), 2.97 – 2.65 (m, 3H), 2.21 – 2.08 (m, 1H).

實施例 152 ：化合物152的製備 Example 152 : Preparation of Compound 152

化合物152以化合物152b+152A為原料，參照實施例18的合成方法得到。Compound 152 was obtained by using compound 152b+152A as raw materials and referring to the synthesis method of Example 18.

1H NMR (400 MHz, CDCl 3) δ 8.51 (s, 1H), 7.95 (s, 1H), 7.90 (d, 1H), 7.80 (s, 1H), 7.72 – 7.64 (m, 2H), 6.98 – 6.92 (m, 1H), 6.81 (d, 1H), 6.74 (dd, 1H), 6.55 (dd, 1H), 4.98 – 4.87 (m, 1H), 4.40 – 4.30 (m, 2H), 4.12 – 4.02 (m, 2H), 3.88 – 3.73 (m, 1H), 2.95 – 2.62 (m, 3H), 2.18 – 2.07 (m, 1H), 1.95 (s, 6H), 1.91 – 1.80 (m, 1H), 1.49 – 1.39 (m, 1H), 0.95 – 0.77 (m, 4H), 0.73 – 0.62 (m, 2H), 0.55 – 0.44 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.51 (s, 1H), 7.95 (s, 1H), 7.90 (d, 1H), 7.80 (s, 1H), 7.72 – 7.64 (m, 2H), 6.98 – 6.92 (m, 1H), 6.81 (d, 1H), 6.74 (dd, 1H), 6.55 (dd, 1H), 4.98 – 4.87 (m, 1H), 4.40 – 4.30 (m, 2H), 4.12 – 4.02 ( m, 2H), 3.88 – 3.73 (m, 1H), 2.95 – 2.62 (m, 3H), 2.18 – 2.07 (m, 1H), 1.95 (s, 6H), 1.91 – 1.80 (m, 1H), 1.49 – 1.39 (m, 1H), 0.95 – 0.77 (m, 4H), 0.73 – 0.62 (m, 2H), 0.55 – 0.44 (m, 2H).

LCMS m/z = 645.3 [M+1] + LCMS m/z = 645.3 [M+1] +

實施例 153：化合物153的製備 Example 153 : Preparation of Compound 153

化合物153以化合物74b和中間體2為原料，參照實施例44的合成方法得到。Compound 153 was obtained by referring to the synthesis method of Example 44 using compound 74b and intermediate 2 as raw materials.

1H NMR (400 MHz, CDCl 3) δ 8.69 (d, 1H), 8.43 (s, 1H), 7.93 (s, 1H), 7.84 (s, 1H), 7.80 (s, 1H), 7.71 (s, 1H), 7.67 – 7.57 (m, 2H), 7.41 (d, 1H), 6.87 (d, 1H), 4.98 – 4.85 (m, 1H), 4.58 – 4.46 (m, 2H), 4.34 – 4.20 (m, 2H), 3.94 – 3.77 (m, 1H), 2.97 – 2.65 (m, 3H), 2.21 – 2.07 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.69 (d, 1H), 8.43 (s, 1H), 7.93 (s, 1H), 7.84 (s, 1H), 7.80 (s, 1H), 7.71 (s, 1H), 7.67 – 7.57 (m, 2H), 7.41 (d, 1H), 6.87 (d, 1H), 4.98 – 4.85 (m, 1H), 4.58 – 4.46 (m, 2H), 4.34 – 4.20 (m, 2H), 3.94 – 3.77 (m, 1H), 2.97 – 2.65 (m, 3H), 2.21 – 2.07 (m, 1H).

實施例154：化合物154的製備 Example 154: Preparation of Compound 154

化合物154以化合物154a為原料，參照實施例147的合成方法得到。Compound 154 was obtained by using compound 154a as a raw material and referring to the synthesis method of Example 147.

1H NMR (400 MHz, CDCl 3) δ 8.38 (s, 1H), 7.98 (s, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.67 (d, 1H), 7.55 – 7.49 (m, 1H), 7.23 – 7.18 (m, 1H), 6.84 – 6.78 (m, 1H), 6.56 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.43 – 4.30 (m, 2H), 4.13 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.95 – 2.65 (m, 3H), 2.18 – 2.06 (m, 1H), 1.97 (s, 6H), 1.83 – 1.70 (m, 1H), 0.96 – 0.84 (m, 2H), 0.62 – 0.52 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.38 (s, 1H), 7.98 (s, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.67 (d, 1H), 7.55 – 7.49 ( m, 1H), 7.23 – 7.18 (m, 1H), 6.84 – 6.78 (m, 1H), 6.56 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.43 – 4.30 (m, 2H), 4.13 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.95 – 2.65 (m, 3H), 2.18 – 2.06 (m, 1H), 1.97 (s, 6H), 1.83 – 1.70 (m, 1H), 0.96 – 0.84 (m, 2H), 0.62 – 0.52 (m, 2H).

實施例 156：化合物156的製備 Example 156 : Preparation of Compound 156

第一步：156b的製備Step 1: Preparation of 156b

將156A (140 mg，0.53 mmol) 溶於15 mL乾燥二氯甲烷，加入1-氯-N,N,2-三甲基丙烯胺 (100 mg，0.75 mmol)，室溫反應1.5 h後，加入TEA (151 mg，1.49 mmol) 和156a (94 mg，0.5 mmol)，室溫反應16 h。將反應體系減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 9:1)，得156b (100 mg，收率：46%)。Dissolve 156A (140 mg, 0.53 mmol) in 15 mL dry dichloromethane, add 1-chloro-N,N,2-trimethylpropenylamine (100 mg, 0.75 mmol), react at room temperature for 1.5 h, then add TEA (151 mg, 1.49 mmol) and 156a (94 mg, 0.5 mmol), reacted at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 9:1) to obtain 156b (100 mg, yield: 46%).

LCMS m/z = 436.1 [M+1] + LCMS m/z = 436.1 [M+1] +

化合物156以化合物156b為原料，參照實施例44的合成方法得到。Compound 156 was obtained by referring to the synthesis method of Example 44 using compound 156b as a raw material.

1H NMR (400 MHz, DMSO- d 6 ) δ 11.05 (s, 1H), 8.40 – 7.40 (m, 7H), 6.92 – 6.84 (m, 1H), 6.73 (dd, 1H), 5.11 – 4.98 (m, 1H), 4.47 – 4.35 (m, 2H), 4.15 – 3.90 (m, 5H), 3.23 – 3.09 (m, 2H), 2.96 – 2.79 (m, 1H), 2.70 – 2.45 (m, 2H), 2.07 – 1.96 (m, 1H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.05 (s, 1H), 8.40 – 7.40 (m, 7H), 6.92 – 6.84 (m, 1H), 6.73 (dd, 1H), 5.11 – 4.98 (m , 1H), 4.47 – 4.35 (m, 2H), 4.15 – 3.90 (m, 5H), 3.23 – 3.09 (m, 2H), 2.96 – 2.79 (m, 1H), 2.70 – 2.45 (m, 2H), 2.07 – 1.96 (m, 1H).

LCMS m/z = 645.6 [M+1] + LCMS m/z = 645.6 [M+1] +

實施例 157 ：化合物157的製備 Example 157 : Preparation of Compound 157

化合物157以化合物157a和65b為原料，參照實施例44的合成方法得到。Compound 157 was obtained by referring to the synthesis method of Example 44 using compounds 157a and 65b as raw materials.

1H NMR (400 MHz, CDCl 3) δ 8.40 (s, 1H), 8.15 (d, 1H), 7.90 (s, 1H), 7.72 – 7.57 (m, 3H), 7.57 – 7.50 (m, 1H), 7.02 – 6.92 (m, 2H), 6.87 – 6.81 (m, 1H), 6.58 (dd, 1H), 4.98 – 4.90 (m, 1H), 4.48 – 4.36 (m, 2H), 4.20 – 4.12 (m, 2H), 3.97 – 3.86 (m, 1H), 2.96 – 2.64 (m, 3H), 2.18 – 2.08 (m, 1H), 1.93 – 1.77 (m, 2H), 1.07 – 0.98 (m, 2H), 0.98 – 0.90 (m, 2H), 0.76 – 0.70 (m, 2H), 0.70 – 0.63 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.40 (s, 1H), 8.15 (d, 1H), 7.90 (s, 1H), 7.72 – 7.57 (m, 3H), 7.57 – 7.50 (m, 1H), 7.02 – 6.92 (m, 2H), 6.87 – 6.81 (m, 1H), 6.58 (dd, 1H), 4.98 – 4.90 (m, 1H), 4.48 – 4.36 (m, 2H), 4.20 – 4.12 (m, 2H ), 3.97 – 3.86 (m, 1H), 2.96 – 2.64 (m, 3H), 2.18 – 2.08 (m, 1H), 1.93 – 1.77 (m, 2H), 1.07 – 0.98 (m, 2H), 0.98 – 0.90 (m, 2H), 0.76 – 0.70 (m, 2H), 0.70 – 0.63 (m, 2H).

實施例 158 ：化合物158的製備 Example 158 : Preparation of Compound 158

化合物158以化合物158a和65b為原料，參照實施例44的合成方法得到。Compound 158 was obtained by referring to the synthesis method of Example 44 using compounds 158a and 65b as raw materials.

1H NMR (400 MHz, CDCl 3) δ 10.62 (s, 1H), 8.57 (d, 1H), 8.35 – 8.26 (m, 2H), 7.94 (s, 1H), 7.69 (d, 1H), 7.47 – 7.41 (m, 1H), 7.02 – 6.89 (m, 2H), 6.88 – 6.81 (m, 1H), 6.59 (dd, 1H), 4.98 – 4.90 (m, 1H), 4.47 – 4.36 (m, 2H), 4.20 – 4.10 (m, 2H), 3.97 – 3.83 (m, 1H), 2.96 – 2.66 (m, 3H), 2.18 – 2.08 (m, 1H), 1.95 – 1.81 (m, 2H), 1.12 – 1.03 (m, 2H), 0.98 – 0.82 (m, 2H), 0.75 – 0.63 (m, 4H). 1 H NMR (400 MHz, CDCl 3 ) δ 10.62 (s, 1H), 8.57 (d, 1H), 8.35 – 8.26 (m, 2H), 7.94 (s, 1H), 7.69 (d, 1H), 7.47 – 7.41 (m, 1H), 7.02 – 6.89 (m, 2H), 6.88 – 6.81 (m, 1H), 6.59 (dd, 1H), 4.98 – 4.90 (m, 1H), 4.47 – 4.36 (m, 2H), 4.20 – 4.10 (m, 2H), 3.97 – 3.83 (m, 1H), 2.96 – 2.66 (m, 3H), 2.18 – 2.08 (m, 1H), 1.95 – 1.81 (m, 2H), 1.12 – 1.03 (m , 2H), 0.98 – 0.82 (m, 2H), 0.75 – 0.63 (m, 4H).

實施例 159：化合物159的製備 Example 159 : Preparation of Compound 159

第一步：159b的製備Step One: Preparation of 159b

將159a (1.00 g，7.51 mmol) 溶於10 mL乙腈中，冷卻至0℃，加入NCS (2.01 g，15.05 mmol)，40℃反應5 h。將反應液冷卻至室溫，加入90 mL乙酸乙酯、100 mL水和20 mL 10%硫代硫酸鈉水溶液，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 10:1-2:1)，得到159b (0.22 g，收率：15%)。Dissolve 159a (1.00 g, 7.51 mmol) in 10 mL acetonitrile, cool to 0°C, add NCS (2.01 g, 15.05 mmol), and react at 40°C for 5 h. The reaction solution was cooled to room temperature, 90 mL of ethyl acetate, 100 mL of water and 20 mL of 10% sodium thiosulfate aqueous solution were added. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum). Ether/ethyl acetate (v/v) = 10:1-2:1), afforded 159b (0.22 g, yield: 15%).

LCMS m/z = 202.1 [M+1] + LCMS m/z = 202.1 [M+1] +

化合物159以化合物159b為原料，參照實施例18的合成方法得到。Compound 159 was obtained by referring to the synthesis method of Example 18 using compound 159b as raw material.

1H NMR (400 MHz, CDCl 3) δ 7.94 (s, 2H), 7.83 (s, 1H), 7.74 (s, 1H), 7.67 (d, 1H), 7.23 (d, 1H), 6.87 (d, 1H), 6.81 (d, 1H), 6.56 (dd, 1H), 4.99 – 4.88 (m, 1H), 4.44 – 4.28 (m, 2H), 4.15 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.98 – 2.65 (m, 3H), 2.18 – 2.07 (m, 1H), 1.96 (s, 6H), 1.77 – 1.66 (m, 1H), 0.92 – 0.80 (m, 2H), 0.60 – 0.50 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (s, 2H), 7.83 (s, 1H), 7.74 (s, 1H), 7.67 (d, 1H), 7.23 (d, 1H), 6.87 (d, 1H), 6.81 (d, 1H), 6.56 (dd, 1H), 4.99 – 4.88 (m, 1H), 4.44 – 4.28 (m, 2H), 4.15 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.98 – 2.65 (m, 3H), 2.18 – 2.07 (m, 1H), 1.96 (s, 6H), 1.77 – 1.66 (m, 1H), 0.92 – 0.80 (m, 2H), 0.60 – 0.50 ( m, 2H).

LCMS m/z = 673.2 [M+1] + LCMS m/z = 673.2 [M+1] +

實施例 160：化合物160的製備 Example 160 : Preparation of Compound 160

化合物160以化合物160a為原料，參照實施例147的合成方法得到。Compound 160 was obtained by using compound 160a as a raw material and referring to the synthesis method of Example 147.

1H NMR (400 MHz, CDCl 3) δ 8.29 (s, 1H), 7.97 (s, 1H), 7.77 (d, 2H), 7.67 (d, 1H), 6.94 – 6.86 (m, 2H), 6.84 – 6.78 (m, 1H), 6.60 – 6.48 (m, 2H), 4.98 – 4.88 (m, 1H), 4.43 – 4.30 (m, 2H), 4.13 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.95 – 2.65 (m, 3H), 2.18 – 2.06 (m, 1H), 1.90 (s, 6H), 1.85 – 1.74 (m, 2H), 0.96 – 0.82 (m, 4H), 0.70 – 0.60 (m, 4H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.29 (s, 1H), 7.97 (s, 1H), 7.77 (d, 2H), 7.67 (d, 1H), 6.94 – 6.86 (m, 2H), 6.84 – 6.78 (m, 1H), 6.60 – 6.48 (m, 2H), 4.98 – 4.88 (m, 1H), 4.43 – 4.30 (m, 2H), 4.13 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H ), 2.95 – 2.65 (m, 3H), 2.18 – 2.06 (m, 1H), 1.90 (s, 6H), 1.85 – 1.74 (m, 2H), 0.96 – 0.82 (m, 4H), 0.70 – 0.60 (m , 4H).

LCMS m/z = 645.3 [M+1] + LCMS m/z = 645.3 [M+1] +

實施例 161：化合物161的製備 Example 161 : Preparation of Compound 161

化合物161以化合物161a為原料，參考實施例160的合成方法得到。Compound 161 was obtained by using compound 161a as a raw material and referring to the synthesis method of Example 160.

1H NMR (400 MHz, CDCl 3) δ 8.26 (s, 1H), 7.96 (s, 1H), 7.80 – 7.74 (m, 2H), 7.67 (d, 1H), 7.12 – 7.06 (m, 1H), 7.04 – 7.00 (m, 1H), 6.87 (d, 1H), 6.83 – 6.77 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.32 (m, 2H), 4.12 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.96 – 2.64 (m, 3H), 2.24 – 2.05 (m, 3H), 1.90 (s, 6H), 1.00 – 0.82 (m, 4H), 0.70 – 0.55 (m, 4H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.26 (s, 1H), 7.96 (s, 1H), 7.80 – 7.74 (m, 2H), 7.67 (d, 1H), 7.12 – 7.06 (m, 1H), 7.04 – 7.00 (m, 1H), 6.87 (d, 1H), 6.83 – 6.77 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.32 (m, 2H), 4.12 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.96 – 2.64 (m, 3H), 2.24 – 2.05 (m, 3H), 1.90 (s, 6H), 1.00 – 0.82 (m, 4H ), 0.70 – 0.55 (m, 4H).

LCMS m/z = 645.2 [M+1] + LCMS m/z = 645.2 [M+1] +

實施例 162：化合物162的製備 Example 162 : Preparation of Compound 162

化合物162以化合物74b和66j為原料，參考實施例74的合成方法得到。Compound 162 was obtained by referring to the synthesis method of Example 74 using compounds 74b and 66j as raw materials.

1H NMR (400 MHz, CDCl 3) δ 8.68 (d, 1H), 8.43 (s, 1H), 7.94 – 7.77 (m, 3H), 7.74 – 7.68 (m, 1H), 7.66 – 7.56 (m, 2H), 6.58 – 6.48 (m, 1H), 6.33 (s, 1H), 5.66 – 5.35 (m, 2H), 4.84 – 4.66 (m, 1H), 4.50 – 4.33 (m, 2H), 4.24 – 4.06 (m, 2H), 3.97 – 3.77 (m, 1H), 3.04 – 2.87 (m, 1H), 2.85 – 2.50 (m, 2H), 2.48 – 2.27 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.68 (d, 1H), 8.43 (s, 1H), 7.94 – 7.77 (m, 3H), 7.74 – 7.68 (m, 1H), 7.66 – 7.56 (m, 2H ), 6.58 – 6.48 (m, 1H), 6.33 (s, 1H), 5.66 – 5.35 (m, 2H), 4.84 – 4.66 (m, 1H), 4.50 – 4.33 (m, 2H), 4.24 – 4.06 (m , 2H), 3.97 – 3.77 (m, 1H), 3.04 – 2.87 (m, 1H), 2.85 – 2.50 (m, 2H), 2.48 – 2.27 (m, 1H).

LCMS m/z = 655.0 [M+1] + LCMS m/z = 655.0 [M+1] +

實施例 163 ：化合物163的製備 Example 163 : Preparation of Compound 163

第一步：163b的製備Step 1: Preparation of 163b

將163A (1.0 g，4.84 mmol) 溶於30 mL 1,4-二氧六環和10 mL水中，氮氣保護下加入163a (1.01 g，7.22 mmol)、碳酸鉀 (1.07 g，7.74 mmol) 和 [1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷錯合物 (0.39 g，0.48 mmol)，86℃反應12 h。將反應體系冷卻到室溫，加入到50 mL水中，用50 mL乙酸乙酯萃取三次，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 1:0-10:7)，得到163b (1.0g，收率：93%)。Dissolve 163A (1.0 g, 4.84 mmol) in 30 mL 1,4-dioxane and 10 mL water, add 163a (1.01 g, 7.22 mmol), potassium carbonate (1.07 g, 7.74 mmol) and [ 1,1'-Bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.39 g, 0.48 mmol), reacted at 86°C for 12 h. The reaction system was cooled to room temperature, added to 50 mL of water, and extracted three times with 50 mL of ethyl acetate. The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate ( v/v) = 1:0-10:7), 163b (1.0g, yield: 93%) was obtained.

LCMS m/z = 222.1 [M+1] + LCMS m/z = 222.1 [M+1] +

化合物163以化合物163b為原料，參照實施例104的合成方法得到。Compound 163 was obtained by referring to the synthesis method of Example 104 using compound 163b as a raw material.

1H NMR (400 MHz, CDCl 3) δ 8.66 (s, 1H), 8.20 (d, 1H), 7.92 (s, 1H), 7.82 (s, 1H), 7.73 (s, 1H), 7.67 (d, 1H), 7.51 – 7.42 (m, 2H), 7.37 (dd, 1H), 7.27 – 7.23 (m, 1H), 7.13 – 7.04 (m, 2H), 6.84 – 6.77 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.96 – 2.64 (m, 3H), 2.18 – 2.07 (m, 1H), 1.97 (s, 6H), 1.62 – 1.50 (m, 1H), 1.00 – 0.78 (m, 2H), 0.64 – 0.54 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.66 (s, 1H), 8.20 (d, 1H), 7.92 (s, 1H), 7.82 (s, 1H), 7.73 (s, 1H), 7.67 (d, 1H), 7.51 – 7.42 (m, 2H), 7.37 (dd, 1H), 7.27 – 7.23 (m, 1H), 7.13 – 7.04 (m, 2H), 6.84 – 6.77 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.96 – 2.64 (m, 3H), 2.18 – 2.07 (m, 1H), 1.97 (s, 6H), 1.62 – 1.50 (m, 1H), 1.00 – 0.78 (m, 2H), 0.64 – 0.54 (m, 2H).

實施例 164 ：化合物164的製備 Example 164 : Preparation of Compound 164

化合物164以化合物164a (合成方法見WO2022143489) 為原料，參照實施例165的合成方法得到。Compound 164 was obtained by using compound 164a (see WO2022143489 for the synthesis method) as a raw material and referring to the synthesis method of Example 165.

1H NMR (400 MHz, DMSO- d 6 ) δ 8.85 (s, 1H), 8.38 – 8.32 (m, 1H), 8.29 – 8.24 (m, 1H), 8.23 – 8.18 (m, 1H), 8.07 – 7.97 (m, 1H), 7.83 (s, 2H), 7.70 – 7.57 (m, 2H), 7.49 – 7.40 (m, 1H), 7.39 – 7.30 (m, 1H), 6.88 – 6.82 (m, 1H), 6.74 – 6.64 (m, 1H), 5.12 – 5.02 (m, 1H), 4.47 – 4.35 (m, 2H), 4.10 – 3.97 (m, 2H), 3.95 – 3.80 (m, 1H), 2.99 – 2.80 (m, 1H), 2.68 – 2.52 (m, 2H), 2.10 – 2.00 (m, 1H), 1.92 (s, 6H), 1.77 – 1.65 (m, 1H), 0.96 – 0.84 (m, 2H), 0.68 – 0.58 (m, 2H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.85 (s, 1H), 8.38 – 8.32 (m, 1H), 8.29 – 8.24 (m, 1H), 8.23 – 8.18 (m, 1H), 8.07 – 7.97 (m, 1H), 7.83 (s, 2H), 7.70 – 7.57 (m, 2H), 7.49 – 7.40 (m, 1H), 7.39 – 7.30 (m, 1H), 6.88 – 6.82 (m, 1H), 6.74 – 6.64 (m, 1H), 5.12 – 5.02 (m, 1H), 4.47 – 4.35 (m, 2H), 4.10 – 3.97 (m, 2H), 3.95 – 3.80 (m, 1H), 2.99 – 2.80 (m, 1H), 2.68 – 2.52 (m, 2H), 2.10 – 2.00 (m, 1H), 1.92 (s, 6H), 1.77 – 1.65 (m, 1H), 0.96 – 0.84 (m, 2H), 0.68 – 0.58 ( m, 2H).

實施例 165：化合物165的製備 Example 165 : Preparation of Compound 165

化合物165以化合物165a為原料，參照實施例147的合成方法得到。Compound 165 was obtained by referring to the synthesis method of Example 147 using compound 165a as a raw material.

1H NMR (400 MHz, CDCl 3) δ 7.94 (s, 1H), 7.82 (s, 1H), 7.73 (s, 1H), 7.67 (d, 1H), 7.49 (s, 1H), 6.83 – 6.79 (m, 1H), 6.72 (s, 2H), 6.56 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.42 – 4.31 (m, 2H), 4.13 – 4.02 (m, 2H), 3.87 – 3.76 (m, 1H), 2.96 – 2.66 (m, 3H), 2.18 – 2.07 (m, 1H), 2.02 (s, 6H), 1.95 (s, 6H), 1.83 – 1.72 (m, 1H), 0.92 – 0.84 (m, 2H), 0.66 – 0.57 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (s, 1H), 7.82 (s, 1H), 7.73 (s, 1H), 7.67 (d, 1H), 7.49 (s, 1H), 6.83 – 6.79 ( m, 1H), 6.72 (s, 2H), 6.56 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.42 – 4.31 (m, 2H), 4.13 – 4.02 (m, 2H), 3.87 – 3.76 ( m, 1H), 2.96 – 2.66 (m, 3H), 2.18 – 2.07 (m, 1H), 2.02 (s, 6H), 1.95 (s, 6H), 1.83 – 1.72 (m, 1H), 0.92 – 0.84 ( m, 2H), 0.66 – 0.57 (m, 2H).

LCMS m/z = 633.2 [M+1] + LCMS m/z = 633.2 [M+1] +

實施例 166 ：化合物166的製備 Example 166 : Preparation of Compound 166

化合物166以化合物166a和65b為原料，參考實施例44的合成方法得到。Compound 166 was obtained by referring to the synthesis method of Example 44 using compounds 166a and 65b as raw materials.

1H NMR (400 MHz, CDCl 3) δ 8.35 (s, 1H), 8.11 (d, 1H), 7.92 (s, 1H), 7.74 – 7.65 (m, 2H), 7.60 – 7.51 (m, 1H), 7.34 – 7.26 (m, 1H), 7.02 – 6.92 (m, 2H), 6.86 – 6.79 (m, 1H), 6.58 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.45 – 4.35 (m, 2H), 4.18 – 4.07 (m, 2H), 3.94 – 3.80 (m, 1H), 2.96 – 2.66 (m, 3H), 2.20 – 2.08 (m, 1H), 1.94 – 1.76 (m, 2H), 1.08 – 0.98 (m, 2H), 0.98 – 0.90 (m, 2H), 0.77 – 0.69 (m, 2H), 0.69 – 0.63 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.35 (s, 1H), 8.11 (d, 1H), 7.92 (s, 1H), 7.74 – 7.65 (m, 2H), 7.60 – 7.51 (m, 1H), 7.34 – 7.26 (m, 1H), 7.02 – 6.92 (m, 2H), 6.86 – 6.79 (m, 1H), 6.58 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.45 – 4.35 (m, 2H ), 4.18 – 4.07 (m, 2H), 3.94 – 3.80 (m, 1H), 2.96 – 2.66 (m, 3H), 2.20 – 2.08 (m, 1H), 1.94 – 1.76 (m, 2H), 1.08 – 0.98 (m, 2H), 0.98 – 0.90 (m, 2H), 0.77 – 0.69 (m, 2H), 0.69 – 0.63 (m, 2H).

實施例 167 ：化合物167的製備 Example 167 : Preparation of Compound 167

化合物167以化合物167a和65b為原料，參照實施例44的合成方法得到。Compound 167 was obtained by referring to the synthesis method of Example 44 using compounds 167a and 65b as raw materials.

1H NMR (400 MHz, CDCl 3) δ 8.33 (s, 1H), 8.09 (d, 1H), 7.95 (s, 1H), 7.83 – 7.77 (m, 2H), 7.69 (d, 1H), 7.61 – 7.55 (m, 1H), 7.02 – 6.90 (m, 2H), 6.86 – 6.80 (m, 1H), 6.58 (dd, 1H), 4.98 – 4.90 (m, 1H), 4.45 – 4.35 (m, 2H), 4.18 – 4.07 (m, 2H), 3.93 – 3.80 (m, 1H), 2.96 – 2.65 (m, 3H), 2.20 – 2.08 (m, 1H), 1.92 – 1.76 (m, 2H), 1.08 – 0.98 (m, 2H), 0.98 – 0.90 (m, 2H), 0.78 – 0.69 (m, 2H), 0.69 – 0.62 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.33 (s, 1H), 8.09 (d, 1H), 7.95 (s, 1H), 7.83 – 7.77 (m, 2H), 7.69 (d, 1H), 7.61 – 7.55 (m, 1H), 7.02 – 6.90 (m, 2H), 6.86 – 6.80 (m, 1H), 6.58 (dd, 1H), 4.98 – 4.90 (m, 1H), 4.45 – 4.35 (m, 2H), 4.18 – 4.07 (m, 2H), 3.93 – 3.80 (m, 1H), 2.96 – 2.65 (m, 3H), 2.20 – 2.08 (m, 1H), 1.92 – 1.76 (m, 2H), 1.08 – 0.98 (m , 2H), 0.98 – 0.90 (m, 2H), 0.78 – 0.69 (m, 2H), 0.69 – 0.62 (m, 2H).

實施例 168：化合物168的製備 Example 168 : Preparation of Compound 168

化合物168以化合物168a為原料，參照實施例166的合成方法得到。Compound 168 was obtained by referring to the synthesis method of Example 166 using compound 168a as raw material.

1H NMR (400 MHz, CDCl 3) δ 8.41 (s, 1H), 8.35 – 8.27 (m, 2H), 8.02 – 7.90 (m, 3H), 7.84 – 7.62 (m, 5H), 7.41 – 7.34 (m, 1H), 6.84 – 6.76 (m, 1H), 6.57 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.48 – 4.35 (m, 2H), 4.20 – 4.07 (m, 2H), 3.95 – 3.82 (m, 1H), 2.95 – 2.63 (m, 3H), 2.18 – 2.07 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.41 (s, 1H), 8.35 – 8.27 (m, 2H), 8.02 – 7.90 (m, 3H), 7.84 – 7.62 (m, 5H), 7.41 – 7.34 (m , 1H), 6.84 – 6.76 (m, 1H), 6.57 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.48 – 4.35 (m, 2H), 4.20 – 4.07 (m, 2H), 3.95 – 3.82 (m, 1H), 2.95 – 2.63 (m, 3H), 2.18 – 2.07 (m, 1H).

LCMS m/z = 624.2 [M-1] - LCMS m/z = 624.2 [M-1] -

實施例 169 ：化合物169的製備 Example 169 : Preparation of Compound 169

化合物169以化合物65b為原料，參考實施例151的合成方法得到。Compound 169 was obtained by using compound 65b as raw material and referring to the synthesis method of Example 151.

1H NMR (400 MHz, CDCl 3) δ 8.02 (s, 1H), 7.59 (d, 1H), 7.29 (d, 1H), 7.25 – 7.19 (m, 1H), 7.07 – 7.02 (m, 1H), 6.86 – 6.77 (m, 1H), 6.77 – 6.63 (m, 4H), 6.57 – 6.40 (m, 2H), 4.92 – 4.80 (m, 1H), 4.34 – 4.22 (m, 2H), 4.04 – 3.92 (m, 2H), 3.79 – 3.62 (m, 1H), 2.88 – 2.55 (m, 3H), 2.12 – 2.00 (m, 1H), 1.87 – 1.72 (m, 2H), 0.94 – 0.80 (m, 4H), 0.64 – 0.52 (m, 4H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.02 (s, 1H), 7.59 (d, 1H), 7.29 (d, 1H), 7.25 – 7.19 (m, 1H), 7.07 – 7.02 (m, 1H), 6.86 – 6.77 (m, 1H), 6.77 – 6.63 (m, 4H), 6.57 – 6.40 (m, 2H), 4.92 – 4.80 (m, 1H), 4.34 – 4.22 (m, 2H), 4.04 – 3.92 (m , 2H), 3.79 – 3.62 (m, 1H), 2.88 – 2.55 (m, 3H), 2.12 – 2.00 (m, 1H), 1.87 – 1.72 (m, 2H), 0.94 – 0.80 (m, 4H), 0.64 – 0.52 (m, 4H).

實施例 170：化合物170的製備 Example 170 : Preparation of Compound 170

化合物170以化合物75b和中間體2為原料，參照實施例153的合成方法得到。Compound 170 was obtained by referring to the synthesis method of Example 153 using compound 75b and intermediate 2 as raw materials.

1H NMR (400 MHz, CDCl 3) δ 11.07 (s, 1H), 10.47 (s, 1H), 8.02 – 7.97 (m, 1H), 7.97 – 7.93 (m, 1H), 7.91 – 7.83 (m, 1H), 7.83 – 7.74 (m, 2H), 7.69 – 7.59 (m, 2H), 7.03 (d, 1H), 5.12 – 5.02 (m, 1H), 4.60 – 4.47 (m, 2H), 4.28 – 4.17 (m, 2H), 4.03 – 3.88 (m, 1H), 2.96 – 2.79 (m, 1H), 2.67 – 2.44 (m, 2H), 2.10 – 1.95 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 11.07 (s, 1H), 10.47 (s, 1H), 8.02 – 7.97 (m, 1H), 7.97 – 7.93 (m, 1H), 7.91 – 7.83 (m, 1H) ), 7.83 – 7.74 (m, 2H), 7.69 – 7.59 (m, 2H), 7.03 (d, 1H), 5.12 – 5.02 (m, 1H), 4.60 – 4.47 (m, 2H), 4.28 – 4.17 (m , 2H), 4.03 – 3.88 (m, 1H), 2.96 – 2.79 (m, 1H), 2.67 – 2.44 (m, 2H), 2.10 – 1.95 (m, 1H).

LCMS m/z = 669.0 [M-1] - LCMS m/z = 669.0 [M-1] -

實施例 171：化合物171的製備 Example 171 : Preparation of Compound 171

化合物171以化合物75b和66j為原料，參照實施例66的合成方法得到。Compound 171 was obtained by referring to the synthesis method of Example 66 using compounds 75b and 66j as raw materials.

1H NMR (400 MHz, CDCl 3) δ 8.70 (d, 1H), 8.44 (s, 1H), 7.80 – 7.66 (m, 4H), 7.66 – 7.52 (m, 2H), 7.38 – 7.28 (m, 1H), 6.53 – 6.45 (m, 1H), 6.33 (s, 1H), 5.34 – 5.20 (m, 2H), 4.78 – 4.69 (m, 1H), 4.38 – 4.27 (m, 2H), 4.10 – 3.98 (m, 2H), 3.90 – 3.75 (m, 1H), 3.02 – 2.85 (m, 1H), 2.72 – 2.55 (m, 1H), 2.28 – 2.10 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.70 (d, 1H), 8.44 (s, 1H), 7.80 – 7.66 (m, 4H), 7.66 – 7.52 (m, 2H), 7.38 – 7.28 (m, 1H ), 6.53 – 6.45 (m, 1H), 6.33 (s, 1H), 5.34 – 5.20 (m, 2H), 4.78 – 4.69 (m, 1H), 4.38 – 4.27 (m, 2H), 4.10 – 3.98 (m , 2H), 3.90 – 3.75 (m, 1H), 3.02 – 2.85 (m, 1H), 2.72 – 2.55 (m, 1H), 2.28 – 2.10 (m, 2H).

LCMS m/z = 639.1 [M+1] + LCMS m/z = 639.1 [M+1] +

實施例 172 ：化合物172的製備 Example 172 : Preparation of Compound 172

化合物172以化合物172a為原料，參照實施例154的合成方法得到。Compound 172 was obtained by using compound 172a as a raw material and referring to the synthesis method of Example 154.

1H NMR (400 MHz, CDCl 3) δ 8.50 (s, 1H), 8.38 (s, 1H), 8.03 – 7.95 (m, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.66 (d, 1H), 6.94 – 6.83 (m, 1H), 6.83 – 6.78 (m, 1H), 6.78 – 6.72 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.00 (m, 2H), 3.87 – 3.72 (m, 1H), 2.93 – 2.65 (m, 3H), 2.17 – 2.07 (m, 1H), 1.95 (s, 6H), 1.56 – 1.46 (m, 1H), 0.94 – 0.84 (m, 2H), 0.58 – 0.49 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.50 (s, 1H), 8.38 (s, 1H), 8.03 – 7.95 (m, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.66 ( d, 1H), 6.94 – 6.83 (m, 1H), 6.83 – 6.78 (m, 1H), 6.78 – 6.72 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.00 (m, 2H), 3.87 – 3.72 (m, 1H), 2.93 – 2.65 (m, 3H), 2.17 – 2.07 (m, 1H), 1.95 (s, 6H), 1.56 – 1.46 (m, 1H), 0.94 – 0.84 (m, 2H), 0.58 – 0.49 (m, 2H).

LCMS m/z = 623.2 [M+1] + LCMS m/z = 623.2 [M+1] +

實施例 173 ：化合物173的製備 Example 173 : Preparation of Compound 173

化合物173以化合物173a (合成方法見WO2021173917) 和65b為原料，參考實施例44的合成方法得到。Compound 173 was obtained by using compound 173a (see WO2021173917 for the synthesis method) and 65b as raw materials, and referring to the synthesis method of Example 44.

1H NMR (400 MHz, CDCl 3) δ 8.31 (s, 1H), 8.12 (d, 1H), 7.96 (s, 1H), 7.68 (d, 1H), 7.58 (d, 1H), 7.53 (d, 1H), 6.99 – 6.92 (m, 2H), 6.82 (d, 1H), 6.57 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.44 – 4.32 (m, 2H), 4.17 – 4.05 (m, 2H), 3.91 – 3.77 (m, 1H), 2.98 – 2.64 (m, 3H), 2.18 – 2.08 (m, 1H), 1.92 – 1.76 (m, 2H), 1.10 – 1.00 (m, 2H), 0.99 – 0.82 (m, 2H), 0.76 – 0.69 (m, 2H), 0.69 – 0.62 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.31 (s, 1H), 8.12 (d, 1H), 7.96 (s, 1H), 7.68 (d, 1H), 7.58 (d, 1H), 7.53 (d, 1H), 6.99 – 6.92 (m, 2H), 6.82 (d, 1H), 6.57 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.44 – 4.32 (m, 2H), 4.17 – 4.05 (m, 2H), 3.91 – 3.77 (m, 1H), 2.98 – 2.64 (m, 3H), 2.18 – 2.08 (m, 1H), 1.92 – 1.76 (m, 2H), 1.10 – 1.00 (m, 2H), 0.99 – 0.82 (m, 2H), 0.76 – 0.69 (m, 2H), 0.69 – 0.62 (m, 2H).

實施例 174 ：化合物174的製備 Example 174 : Preparation of Compound 174

化合物174以化合物174b為原料，參照實施例154的合成方法得到。Compound 174 was obtained by referring to the synthesis method of Example 154 using compound 174b as a raw material.

1H NMR (400 MHz, CDCl 3) δ 8.43 (s, 1H), 8.06 (s, 1H), 7.95 (d, 1H), 7.80 (s, 1H), 7.74 – 7.63 (m, 2H), 7.03 – 6.95 (m, 1H), 6.92 – 6.84 (m, 1H), 6.80 (d, 1H), 6.55 (dd, 1H), 4.99 – 4.88 (m, 1H), 4.42 – 4.30 (m, 2H), 4.12 – 4.01 (m, 2H), 3.87 – 3.75 (m, 1H), 2.95 – 2.66 (m, 3H), 2.25 (s, 3H), 2.18 – 2.06 (m, 1H), 1.95 (s, 6H), 1.55 – 1.40 (m, 1H), 0.89 – 0.79 (m, 2H), 0.56 – 0.46 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.43 (s, 1H), 8.06 (s, 1H), 7.95 (d, 1H), 7.80 (s, 1H), 7.74 – 7.63 (m, 2H), 7.03 – 6.95 (m, 1H), 6.92 – 6.84 (m, 1H), 6.80 (d, 1H), 6.55 (dd, 1H), 4.99 – 4.88 (m, 1H), 4.42 – 4.30 (m, 2H), 4.12 – 4.01 (m, 2H), 3.87 – 3.75 (m, 1H), 2.95 – 2.66 (m, 3H), 2.25 (s, 3H), 2.18 – 2.06 (m, 1H), 1.95 (s, 6H), 1.55 – 1.40 (m, 1H), 0.89 – 0.79 (m, 2H), 0.56 – 0.46 (m, 2H).

LCMS m/z = 619.2 [M+1] + LCMS m/z = 619.2 [M+1] +

實施例 175：化合物175的製備 Example 175 : Preparation of Compound 175

化合物175以化合物65b和81f為原料，參照實施例81的合成方法得到。Compound 175 was obtained by referring to the synthesis method of Example 81 using compounds 65b and 81f as raw materials.

1H NMR (400 MHz, CDCl 3) δ 7.99 (d, 1H), 7.93 (s, 1H), 7.76 – 7.73 (m, 1H), 7.68 (d, 1H), 7.64 – 7.55 (m, 2H), 7.52 (s, 1H), 6.96 (d, 1H), 6.83 (d, 1H), 6.72 (dd, 1H), 6.58 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.44 – 4.35 (m, 2H), 4.17 – 4.06 (m, 2H), 3.95 – 3.82 (m, 1H), 2.96 – 2.64 (m, 3H), 2.18 – 2.07 (m, 1H), 1.93 – 1.80 (m, 1H), 1.72 (s, 6H), 1.30 – 1.15 (m, 1H), 0.97 – 0.80 (m, 2H), 0.73 – 0.65 (m, 2H), 0.53 – 0.43 (m, 2H), 0.37 – 0.28 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (d, 1H), 7.93 (s, 1H), 7.76 – 7.73 (m, 1H), 7.68 (d, 1H), 7.64 – 7.55 (m, 2H), 7.52 (s, 1H), 6.96 (d, 1H), 6.83 (d, 1H), 6.72 (dd, 1H), 6.58 (dd, 1H), 4.99 – 4.89 (m, 1H), 4.44 – 4.35 (m, 2H), 4.17 – 4.06 (m, 2H), 3.95 – 3.82 (m, 1H), 2.96 – 2.64 (m, 3H), 2.18 – 2.07 (m, 1H), 1.93 – 1.80 (m, 1H), 1.72 ( s, 6H), 1.30 – 1.15 (m, 1H), 0.97 – 0.80 (m, 2H), 0.73 – 0.65 (m, 2H), 0.53 – 0.43 (m, 2H), 0.37 – 0.28 (m, 2H).

LCMS m/z = 723.3 [M+1] + LCMS m/z = 723.3 [M+1] +

實施例 176：化合物176的製備 Example 176 : Preparation of Compound 176

化合物176以化合物65c和66j為原料，參照實施例66的合成方法得到。Compound 176 was obtained by referring to the synthesis method of Example 66 using compounds 65c and 66j as raw materials.

1H NMR (400 MHz, CDCl 3) δ 8.43 (s, 1H), 7.99 – 7.88 (m, 2H), 7.79 (s, 1H), 7.73 – 7.67 (m, 2H), 6.87 (dd, 1H), 6.83 – 6.77 (m, 1H), 6.45 (dd, 1H), 6.33 – 6.27 (m, 1H), 5.32 – 5.18 (m, 2H), 4.76 – 4.69 (m, 1H), 4.33 – 4.22 (m, 2H), 4.02 – 3.92 (m, 2H), 3.83 – 3.70 (m, 1H), 2.99 – 2.85 (m, 1H), 2.70 – 2.55 (m, 1H), 2.24 – 2.12 (m, 2H), 1.94 (s, 6H), 1.86 – 1.74 (m, 1H), 1.53 – 1.41 (m, 1H), 0.92 – 0.80 (m, 4H), 0.64 – 0.56 (m, 2H), 0.54 – 0.46 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.43 (s, 1H), 7.99 – 7.88 (m, 2H), 7.79 (s, 1H), 7.73 – 7.67 (m, 2H), 6.87 (dd, 1H), 6.83 – 6.77 (m, 1H), 6.45 (dd, 1H), 6.33 – 6.27 (m, 1H), 5.32 – 5.18 (m, 2H), 4.76 – 4.69 (m, 1H), 4.33 – 4.22 (m, 2H ), 4.02 – 3.92 (m, 2H), 3.83 – 3.70 (m, 1H), 2.99 – 2.85 (m, 1H), 2.70 – 2.55 (m, 1H), 2.24 – 2.12 (m, 2H), 1.94 (s , 6H), 1.86 – 1.74 (m, 1H), 1.53 – 1.41 (m, 1H), 0.92 – 0.80 (m, 4H), 0.64 – 0.56 (m, 2H), 0.54 – 0.46 (m, 2H).

LCMS m/z = 631.7 [M+1] + LCMS m/z = 631.7 [M+1] +

實施例 177：化合物177的製備 Example 177 : Preparation of Compound 177

化合物177以化合物177a為原料，參照實施例174的合成方法得到。Compound 177 was obtained by referring to the synthesis method of Example 174 using compound 177a as a raw material.

1H NMR (400 MHz, CDCl 3) δ 8.67 (s, 1H), 8.05 (d, 1H), 7.99 (s, 1H), 7.82 – 7.73 (m, 2H), 7.67 (d, 1H), 7.16 (d, 1H), 6.80 (d, 1H), 6.74 (dd, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.40 – 4.32 (m, 2H), 4.12 – 4.02 (m, 2H), 3.87 – 3.75 (m, 1H), 2.94 – 2.64 (m, 3H), 2.18 – 2.08 (m, 1H), 1.94 (s, 6H), 1.90 – 1.80 (m, 1H), 0.98 – 0.90 (m, 2H), 0.72 – 0.62 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.67 (s, 1H), 8.05 (d, 1H), 7.99 (s, 1H), 7.82 – 7.73 (m, 2H), 7.67 (d, 1H), 7.16 ( d, 1H), 6.80 (d, 1H), 6.74 (dd, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.40 – 4.32 (m, 2H), 4.12 – 4.02 (m, 2H), 3.87 – 3.75 (m, 1H), 2.94 – 2.64 (m, 3H), 2.18 – 2.08 (m, 1H), 1.94 (s, 6H), 1.90 – 1.80 (m, 1H), 0.98 – 0.90 ( m, 2H), 0.72 – 0.62 (m, 2H).

實施例 178：化合物178的製備 Example 178 : Preparation of Compound 178

化合物178以化合物178a為原料，參照實施例177的合成方法得到。Compound 178 was obtained by using compound 178a as a raw material and referring to the synthesis method of Example 177.

1H NMR (400 MHz, CDCl 3) δ 8.08 – 8.00 (m, 1H), 7.90 (s, 1H), 7.84 (s, 1H), 7.74 (s, 1H), 7.67 (d, 1H), 7.22 (dd, 1H), 7.10 (t, 1H), 6.94 – 6.86 (m, 1H), 6.81 (d, 1H), 6.56 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.31 (m, 2H), 4.12 – 4.03 (m, 2H), 3.88 – 3.74 (m, 1H), 2.98 – 2.64 (m, 3H), 2.18 – 2.07 (m, 1H), 1.98 (s, 6H), 1.80 – 1.68 (m, 1H), 0.88 – 0.78 (m, 2H), 0.58 – 0.49 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.08 – 8.00 (m, 1H), 7.90 (s, 1H), 7.84 (s, 1H), 7.74 (s, 1H), 7.67 (d, 1H), 7.22 ( dd, 1H), 7.10 (t, 1H), 6.94 – 6.86 (m, 1H), 6.81 (d, 1H), 6.56 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.31 (m, 2H), 4.12 – 4.03 (m, 2H), 3.88 – 3.74 (m, 1H), 2.98 – 2.64 (m, 3H), 2.18 – 2.07 (m, 1H), 1.98 (s, 6H), 1.80 – 1.68 ( m, 1H), 0.88 – 0.78 (m, 2H), 0.58 – 0.49 (m, 2H).

LCMS m/z = 639.2 [M+1] + LCMS m/z = 639.2 [M+1] +

實施例 179：化合物179的製備 Example 179 : Preparation of Compound 179

第一步：179b的製備Step One: Preparation of 179b

將179a (2.00 g，9.69 mmol) 溶於20 mL 甲苯和2 mL 水的混合溶劑中，加入環丙基硼酸 (4.15 g，48.3 mmol)，2-二環己基膦-2’,6’-二甲氧基-聯苯 (0.79 g，1.92 mmol)、Pd(OAc) 2(0.22 g，0.98 mmol) 和磷酸鉀 (8.20 g，38.63 mmol)，氮氣氛圍下75℃反應19 h後，加入環丙基硼酸 (1.66 g，19.32 mmol)、2-二環己基膦-2’,6’-二甲氧基-聯苯 (0.79 g，1.92 mmol) 和醋酸鈀 (0.22 g，0.98 mmol)，氮氣氛圍下75℃反應5 h。將反應體系冷卻至室溫，加入100 mL乙酸乙酯和100 mL水，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 10:1-1:1)，得到179b (0.62 g，收率：37%)。 Dissolve 179a (2.00 g, 9.69 mmol) in a mixed solvent of 20 mL toluene and 2 mL water, add cyclopropylboronic acid (4.15 g, 48.3 mmol), 2-dicyclohexylphosphine-2',6'-di Methoxy-biphenyl (0.79 g, 1.92 mmol), Pd(OAc) 2 (0.22 g, 0.98 mmol) and potassium phosphate (8.20 g, 38.63 mmol) were reacted at 75°C for 19 hours under a nitrogen atmosphere, then cyclopropane was added boronic acid (1.66 g, 19.32 mmol), 2-dicyclohexylphosphine-2',6'-dimethoxy-biphenyl (0.79 g, 1.92 mmol) and palladium acetate (0.22 g, 0.98 mmol), nitrogen atmosphere React at 75°C for 5 hours. Cool the reaction system to room temperature, add 100 mL ethyl acetate and 100 mL water, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10:1-1:1), obtaining 179b (0.62 g, yield: 37%).

LCMS m/z = 174.1 [M+1] + LCMS m/z = 174.1 [M+1] +

化合物179以化合物179b為原料，參照實施例80的合成方法得到。Compound 179 was obtained by referring to the synthesis method of Example 80 using compound 179b as raw material.

1H NMR (400 MHz, CDCl 3) δ 8.18 (s, 1H), 7.88 – 7.80 (m, 2H), 7.73 (s, 1H), 7.67 (d, 1H), 7.08 (t, 1H), 6.88 – 6.77 (m, 3H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.03 (m, 2H), 3.88 – 3.75 (m, 1H), 2.94 – 2.64 (m, 3H), 2.18 – 2.05 (m, 1H), 1.98 (s, 6H), 1.77 – 1.63 (m, 2H), 0.84 – 0.74 (m, 4H), 0.56 – 0.47 (m, 4H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.18 (s, 1H), 7.88 – 7.80 (m, 2H), 7.73 (s, 1H), 7.67 (d, 1H), 7.08 (t, 1H), 6.88 – 6.77 (m, 3H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.03 (m, 2H), 3.88 – 3.75 (m, 1H), 2.94 – 2.64 (m, 3H), 2.18 – 2.05 (m, 1H), 1.98 (s, 6H), 1.77 – 1.63 (m, 2H), 0.84 – 0.74 (m, 4H), 0.56 – 0.47 (m, 4H ).

LCMS m/z = 645.3 [M+1] + LCMS m/z = 645.3 [M+1] +

實施例 180：化合物180的製備 Example 180 : Preparation of Compound 180

化合物180以化合物65b和180A為原料，參照實施例44的合成方法得到。Compound 180 was obtained by referring to the synthesis method of Example 44 using compounds 65b and 180A as raw materials.

1H NMR (400 MHz, CDCl 3) δ 8.60 – 8.45 (m, 2H), 8.24 – 8.10 (m, 2H), 8.02 – 7.92 (m, 2H), 7.70 (d, 1H), 7.04 – 6.92 (m, 2H), 6.88 – 6.80 (m, 1H), 6.60 (dd, 1H), 5.00 – 4.89 (m, 1H), 4.48 – 4.38 (m, 2H), 4.28 – 4.18 (m, 2H), 4.03 – 3.92 (m, 1H), 2.96 – 2.64 (m, 3H), 2.18 – 2.07 (m, 1H), 1.93 – 1.80 (m, 2H), 1.09 – 1.00 (m, 2H), 0.98 – 0.91 (m, 2H), 0.78 – 0.63 (m, 4H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.60 – 8.45 (m, 2H), 8.24 – 8.10 (m, 2H), 8.02 – 7.92 (m, 2H), 7.70 (d, 1H), 7.04 – 6.92 (m , 2H), 6.88 – 6.80 (m, 1H), 6.60 (dd, 1H), 5.00 – 4.89 (m, 1H), 4.48 – 4.38 (m, 2H), 4.28 – 4.18 (m, 2H), 4.03 – 3.92 (m, 1H), 2.96 – 2.64 (m, 3H), 2.18 – 2.07 (m, 1H), 1.93 – 1.80 (m, 2H), 1.09 – 1.00 (m, 2H), 0.98 – 0.91 (m, 2H) , 0.78 – 0.63 (m, 4H).

實施例 181：化合物181的製備 Example 181 : Preparation of Compound 181

第一步：181b的製備Step One: Preparation of 181b

將181a (1.35 g，10.00 mmol) 溶解於20 mL乙腈中，0℃緩慢加入NBS (2.14 g, 12.02 mmol)，0℃攪拌1 h後，室溫反應2 h。將反應體系減壓濃縮，粗品用矽膠色譜柱分離提純 (石油醚:乙酸乙酯 (v/v) = 3:1)，得到181b (1.2 g，收率：56%)。Dissolve 181a (1.35 g, 10.00 mmol) in 20 mL acetonitrile, slowly add NBS (2.14 g, 12.02 mmol) at 0°C, stir for 1 h at 0°C, and react at room temperature for 2 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 3:1) to obtain 181b (1.2 g, yield: 56%).

LCMS m/z = 213.9 [M+1] + LCMS m/z = 213.9 [M+1] +

化合物181以化合物181b為原料，參照實施例104的合成方法得到。Compound 181 was obtained by referring to the synthesis method of Example 104 using compound 181b as raw material.

1H NMR (400 MHz, CDCl 3) δ 8.28 (s, 1H), 8.04 (s, 1H), 7.82 – 7.72 (m, 2H), 7.67 (d, 1H), 7.28 (s, 1H), 6.81 (d, 1H), 6.67 (d, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.63 – 4.53 (m, 2H), 4.43 – 4.31 (m, 2H), 4.12 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 3.01 – 2.65 (m, 5H), 2.18 – 2.07 (m, 1H), 1.96 – 1.82 (m, 7H), 0.90 – 0.82 (m, 2H), 0.70 – 0.62 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.28 (s, 1H), 8.04 (s, 1H), 7.82 – 7.72 (m, 2H), 7.67 (d, 1H), 7.28 (s, 1H), 6.81 ( d, 1H), 6.67 (d, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.63 – 4.53 (m, 2H), 4.43 – 4.31 (m, 2H), 4.12 – 4.02 ( m, 2H), 3.88 – 3.75 (m, 1H), 3.01 – 2.65 (m, 5H), 2.18 – 2.07 (m, 1H), 1.96 – 1.82 (m, 7H), 0.90 – 0.82 (m, 2H), 0.70 – 0.62 (m, 2H).

實施例 182：化合物182的製備 Example 182 : Preparation of Compound 182

第一步：182b的製備Step 1: Preparation of 182b

將182a (0.3 g，5.45 mmol) 溶於5 mL DMSO溶劑中，加入TEA (2.21 g，21.84 mmol) 和182A (1.96 g，7.10 mmol)，80℃反應3 h。將反應體系冷卻至室溫，加入50 mL乙酸乙酯和50 mL水，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 10:1-1:1)，得到182b (0.11 g，收率：6%)。Dissolve 182a (0.3 g, 5.45 mmol) in 5 mL DMSO solvent, add TEA (2.21 g, 21.84 mmol) and 182A (1.96 g, 7.10 mmol), and react at 80°C for 3 h. Cool the reaction system to room temperature, add 50 mL of ethyl acetate and 50 mL of water, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10:1-1:1), obtaining 182b (0.11 g, yield: 6%).

LCMS m/z = 312.1 [M+1] + LCMS m/z = 312.1 [M+1] +

第二步：化合物182的製備Step 2: Preparation of Compound 182

將182b (0.11 g，0.35 mmol)、2c (0.16 g，0.34 mmol)、TEA (0.10 g，0.99 mmol)、CuI (13 mg，0.068 mmol) 和PdCl 2(PPh 3) 2(48 mg，0.068 mmol) 加入到反應瓶中，氮氣氛圍下加入5 mL DMF，55℃反應2 h。將反應液冷卻至室溫，加入50 mL水，抽濾，濾餅用10 mL水洗滌，將濾餅用60 mL DCM/MeOH (v/v) = 5:1溶解，無水硫酸鈉乾燥，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 1:1.5)，得化合物182 (32 mg，收率：14%)。 Combine 182b (0.11 g, 0.35 mmol), 2c (0.16 g, 0.34 mmol), TEA (0.10 g, 0.99 mmol), CuI (13 mg, 0.068 mmol) and PdCl 2 (PPh 3 ) 2 (48 mg, 0.068 mmol). ) into the reaction bottle, add 5 mL DMF under nitrogen atmosphere, and react at 55°C for 2 h. Cool the reaction solution to room temperature, add 50 mL of water, filter with suction, wash the filter cake with 10 mL of water, dissolve the filter cake with 60 mL of DCM/MeOH (v/v) = 5:1, dry over anhydrous sodium sulfate, and obtain the crude product Separate and purify using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 1:1.5) to obtain compound 182 (32 mg, yield: 14%).

1H NMR (400 MHz, CDCl 3) δ 8.69 (s, 1H), 8.53 (d, 1H), 8.16 (s, 1H), 7.77 (s, 1H), 7.70 (s, 1H), 7.66 (d, 1H), 7.60 – 7.55 (m, 1H), 7.53 – 7.46 (m, 1H), 7.09 (d, 1H), 6.86 (dd, 1H), 4.99 – 4.74 (m, 2H), 4.22 (s, 2H), 3.13 – 2.98 (m, 2H), 2.94 – 2.64 (m, 5H), 2.30 – 1.98 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.69 (s, 1H), 8.53 (d, 1H), 8.16 (s, 1H), 7.77 (s, 1H), 7.70 (s, 1H), 7.66 (d, 1H), 7.60 – 7.55 (m, 1H), 7.53 – 7.46 (m, 1H), 7.09 (d, 1H), 6.86 (dd, 1H), 4.99 – 4.74 (m, 2H), 4.22 (s, 2H) , 3.13 – 2.98 (m, 2H), 2.94 – 2.64 (m, 5H), 2.30 – 1.98 (m, 3H).

LCMS m/z = 653.2 [M+1] + LCMS m/z = 653.2 [M+1] +

實施例 183 ：化合物183的製備 Example 183 : Preparation of Compound 183

化合物183以化合物183a (合成方法見 Australian Journal of Chemistry, 1965, 18, 1351-1364) 和65b 為原料，參考實施例44的合成方法得到。 Compound 183 was obtained by using compound 183a (for the synthesis method, see Australian Journal of Chemistry , 1965 , 18 , 1351-1364) and 65b as raw materials, and referring to the synthesis method of Example 44.

1H NMR (400 MHz, CDCl 3) δ 8.45 – 8.33 (m, 1H), 8.30 – 8.18 (m, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 7.93 (s, 1H), 7.88 – 7.81 (m, 1H), 7.77 (s, 1H), 7.69 (d, 1H), 7.63 – 7.53 (m, 2H), 7.07 – 6.97 (m, 1H), 6.94 (s, 1H), 6.84 (d, 1H), 6.59 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.47 – 4.35 (m, 2H), 4.22 – 4.11 (m, 2H), 3.98 – 3.85 (m, 1H), 2.96 – 2.64 (m, 3H), 2.20 – 2.08 (m, 1H), 1.94 – 1.70 (m, 2H), 1.00 – 0.80 (m, 4H), 0.72 – 0.62 (m, 4H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.45 – 8.33 (m, 1H), 8.30 – 8.18 (m, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 7.93 (s, 1H), 7.88 – 7.81 (m, 1H), 7.77 (s, 1H), 7.69 (d, 1H), 7.63 – 7.53 (m, 2H), 7.07 – 6.97 (m, 1H), 6.94 (s, 1H), 6.84 ( d, 1H), 6.59 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.47 – 4.35 (m, 2H), 4.22 – 4.11 (m, 2H), 3.98 – 3.85 (m, 1H), 2.96 – 2.64 (m, 3H), 2.20 – 2.08 (m, 1H), 1.94 – 1.70 (m, 2H), 1.00 – 0.80 (m, 4H), 0.72 – 0.62 (m, 4H).

實施例 184 ：化合物184的製備 Example 184 : Preparation of Compound 184

化合物184以化合物184a (合成方法見 Australian Journal of Chemistry, 1965, 18, 1351-1364) 為原料，參考實施例183的合成方法得到。 Compound 184 was obtained by using compound 184a (for the synthesis method, see Australian Journal of Chemistry , 1965 , 18 , 1351-1364) as a raw material, and referring to the synthesis method of Example 183.

1H NMR (400 MHz, CDCl 3) δ 8.75 (d, 1H), 8.34 – 8.17 (m, 2H), 8.04 (s, 1H), 7.98 – 7.85 (m, 1H), 7.85 – 7.76 (m, 1H), 7.76 – 7.70 (m, 1H), 7.68 – 7.48 (m, 5H), 6.80 – 6.74 (m, 1H), 6.52 (dd, 1H), 4.92 – 4.81 (m, 1H), 4.42 – 4.30 (m, 2H), 4.15 – 4.05 (m, 2H), 3.90 – 3.76 (m, 1H), 2.90 – 2.55 (m, 3H), 2.12 – 2.00 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.75 (d, 1H), 8.34 – 8.17 (m, 2H), 8.04 (s, 1H), 7.98 – 7.85 (m, 1H), 7.85 – 7.76 (m, 1H) ), 7.76 – 7.70 (m, 1H), 7.68 – 7.48 (m, 5H), 6.80 – 6.74 (m, 1H), 6.52 (dd, 1H), 4.92 – 4.81 (m, 1H), 4.42 – 4.30 (m , 2H), 4.15 – 4.05 (m, 2H), 3.90 – 3.76 (m, 1H), 2.90 – 2.55 (m, 3H), 2.12 – 2.00 (m, 1H).

實施例 185：化合物185的製備 Example 185 : Preparation of Compound 185

第一步：185b的製備Step One: Preparation of 185b

將185a (2 g，7.52 mmol) 溶於30 mL甲醇中，緩慢滴加二氯亞碸 (2 mL)，室溫反應16 h。將反應體系減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 92:8)，得到185b (1.9 g，收率：90%)。Dissolve 185a (2 g, 7.52 mmol) in 30 mL methanol, slowly add trisene chloride (2 mL) dropwise, and react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 92:8) to obtain 185b (1.9 g, yield: 90%).

第二步：185c的製備Step 2: Preparation of 185c

將185b (1.9 g，6.79 mmol) 加入到100 mL單口瓶中，加入DMF (30.0 mL)，加入3-乙炔基氮雜環丁烷-1-甲酸叔丁酯 (1.8 g，9.93 mmol) 和TEA (2.1 g，20.75 mmol)，氮氣氛圍下加入PdCl 2(PPh 3) 2(497 mg，0.71 mmol) 和CuI (194 mg，1.02 mmol)，50℃反應2 h。將反應體系冷卻至室溫，緩慢加入飽和氯化銨水溶液 (200 mL)，用乙酸乙酯萃取 (150 mL×3)，有機相用飽和氯化鈉水溶液洗滌 (200 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 67:33)，得185c (1.3 g，收率：57%)。 Add 185b (1.9 g, 6.79 mmol) to a 100 mL single-neck bottle, add DMF (30.0 mL), add 3-ethynylazetidine-1-carboxylic acid tert-butyl ester (1.8 g, 9.93 mmol) and TEA (2.1 g, 20.75 mmol), add PdCl 2 (PPh 3 ) 2 (497 mg, 0.71 mmol) and CuI (194 mg, 1.02 mmol) under nitrogen atmosphere, and react at 50°C for 2 h. Cool the reaction system to room temperature, slowly add saturated aqueous ammonium chloride solution (200 mL), extract with ethyl acetate (150 mL×3), wash the organic phase with saturated aqueous sodium chloride solution (200 mL×2), and add anhydrous sulfuric acid. It was dried over sodium and concentrated under reduced pressure. The crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 67:33) to obtain 185c (1.3 g, yield: 57%).

LCMS m/z = 334.1 [M+1] + LCMS m/z = 334.1 [M+1] +

第三步：185d的製備Step 3: Preparation of 185d

將185c (1.3 g，3.90 mmol) 加入到四氫呋喃 (30 mL) 和水 (10 mL) 的混合溶劑中，加入一水合氫氧化鋰 (819 mg，19.5 mmol)，室溫反應16 h。將反應體系用0.5 mol/L鹽酸調pH至7，用乙酸乙酯萃取 (70 mL×3)，有機相用飽和氯化鈉水溶液洗滌 (70 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 72:28)，得粗品185d (700 mg)。將上述粗品185d (130 mg) 加入到500 mL單口瓶中，加入乾燥DCM (10 mL)，加入23c (62 mg，0.41 mmol) 和TCFH (173 mg，0.62 mmol)，緩慢滴加N-甲基咪唑 (174 mg，2.12 mmol)，室溫反應16 h。將反應體系減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 67:33)，得185d (45 mg，收率：24%)。185c (1.3 g, 3.90 mmol) was added to a mixed solvent of tetrahydrofuran (30 mL) and water (10 mL), lithium hydroxide monohydrate (819 mg, 19.5 mmol) was added, and the reaction was carried out at room temperature for 16 h. Adjust the pH of the reaction system to 7 with 0.5 mol/L hydrochloric acid, extract with ethyl acetate (70 mL×3), wash the organic phase with saturated aqueous sodium chloride solution (70 mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure , the crude product was separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 72:28) to obtain crude product 185d (700 mg). Add the above crude product 185d (130 mg) into a 500 mL single-neck bottle, add dry DCM (10 mL), add 23c (62 mg, 0.41 mmol) and TCFH (173 mg, 0.62 mmol), and slowly add N-methyl Imidazole (174 mg, 2.12 mmol), react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 67:33) to obtain 185d (45 mg, yield: 24%).

LCMS m/z = 453.1 [M+1] + LCMS m/z = 453.1 [M+1] +

第四步：185e的對甲苯磺酸鹽的製備Step 4: Preparation of 185e p-toluenesulfonate

將185d (45 mg，0.1 mmol) 加入到500 mL單口瓶中，加入乙腈 (5 mL)，加入對甲苯磺酸 (69 mg，0.4 mmol)，35℃反應4 h。減壓濃縮，得到粗品185f的對甲苯磺酸鹽 (40 mg)。Add 185d (45 mg, 0.1 mmol) into a 500 mL single-neck bottle, add acetonitrile (5 mL), add p-toluenesulfonic acid (69 mg, 0.4 mmol), and react at 35°C for 4 h. Concentrate under reduced pressure to obtain crude product 185f p-toluenesulfonate (40 mg).

LCMS m/z = 353.1 [M+1] + LCMS m/z = 353.1 [M+1] +

第五步：化合物185的製備Step 5: Preparation of Compound 185

將上述粗品185f的對甲苯磺酸鹽 (40 mg) 加入到25 mL單口瓶中，加入乾燥DMSO (5 mL)，加入DIPEA (64 mg，0.49 mmol) 和2-(2,6-二氧代哌啶-3-基)-5-氟異吲哚啉-1,3-二酮 (41 mg，0.15 mmol)，80℃反應2 h。將反應體系冷卻至室溫，緩慢加入水 (60 mL)，用乙酸乙酯萃取 (30 mL×3)，有機相用飽和氯化鈉水溶液洗滌 (20 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 23:77)，所得粗品經Prep-HPLC製備 (儀器：WATERS AUTOP 製備液相；色譜柱: SunFire@PrepC18(19x250nm)；流動相A：乙腈；流動相B：水 (含5 mmol/L乙酸銨)；梯度沖提：流動相A含量從25-80%；流速：17mL /min；柱溫：室溫；檢測波長：210 nm；樣品用DMF溶解，用0.45 μm濾頭過濾，製成樣品液；沖提時間：15 min，凍乾得到化合物185 (3 mg，收率：3%)。Add the p-toluenesulfonate salt of the above crude product 185f (40 mg) into a 25 mL single-neck bottle, add dry DMSO (5 mL), add DIPEA (64 mg, 0.49 mmol) and 2-(2,6-dioxo Piperidin-3-yl)-5-fluoroisoindoline-1,3-dione (41 mg, 0.15 mmol), react at 80°C for 2 h. The reaction system was cooled to room temperature, water (60 mL) was slowly added, extracted with ethyl acetate (30 mL×3), the organic phase was washed with saturated aqueous sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, and reduced to Concentrate under pressure, and the crude product is separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 23:77). The crude product is prepared by Prep-HPLC (instrument: WATERS AUTOP preparative liquid phase; chromatographic column: SunFire@PrepC18 (19x250nm); mobile phase A: acetonitrile; mobile phase B: water (containing 5 mmol/L ammonium acetate); gradient elution: mobile phase A content from 25-80%; flow rate: 17mL/min; column temperature: room temperature ; Detection wavelength: 210 nm; Dissolve the sample with DMF and filter it with a 0.45 μm filter to prepare a sample solution; Elution time: 15 min, freeze-dry to obtain compound 185 (3 mg, yield: 3%).

1H NMR (400 MHz, CDCl 3) δ 8.50 (d, 1H), 8.37 (s, 1H), 7.98 (s, 1H), 7.73 – 7.65 (m, 2H), 7.62 – 7.53 (m, 2H), 7.46 (dd, 1H), 7.36 – 7.30 (m, 1H), 6.84 (d, 1H), 6.59 (dd, 1H), 4.98 – 4.90 (m, 1H), 4.48 – 4.35 (m, 2H), 4.20 – 4.07 (m, 2H), 3.95 – 3.82 (m, 1H), 3.11 (s, 1H), 2.96 – 2.65 (m, 3H), 2.18 – 2.08 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.50 (d, 1H), 8.37 (s, 1H), 7.98 (s, 1H), 7.73 – 7.65 (m, 2H), 7.62 – 7.53 (m, 2H), 7.46 (dd, 1H), 7.36 – 7.30 (m, 1H), 6.84 (d, 1H), 6.59 (dd, 1H), 4.98 – 4.90 (m, 1H), 4.48 – 4.35 (m, 2H), 4.20 – 4.07 (m, 2H), 3.95 – 3.82 (m, 1H), 3.11 (s, 1H), 2.96 – 2.65 (m, 3H), 2.18 – 2.08 (m, 1H).

LCMS m/z = 609.7 [M+1] + LCMS m/z = 609.7 [M+1] +

實施例 186：化合物186的製備 Example 186 : Preparation of Compound 186

第一步：186b的製備Step 1: Preparation of 186b

在0℃下將70%硝酸 (1.1 mL) 滴加到186a (5.4 g，33.29 mmol) 的TFA (60 mL) 溶液中 (滴加時間為30 min)，0℃下反應2 h。將反應體系倒入到400 mL冰水中，攪拌20 min，用二氯甲烷萃取 (200 mL×3)，有機相用飽和氯化鈉水溶液洗滌 (50 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 7:3)，得到186b (4.2 g，收率：61%)。70% nitric acid (1.1 mL) was added dropwise to a solution of 186a (5.4 g, 33.29 mmol) in TFA (60 mL) at 0°C (the dropping time was 30 min), and the reaction was carried out at 0°C for 2 h. Pour the reaction system into 400 mL ice water, stir for 20 min, extract with dichloromethane (200 mL×3), wash the organic phase with saturated sodium chloride aqueous solution (50 mL×2), dry over anhydrous sodium sulfate, and reduce pressure After concentration, the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 7:3) to obtain 186b (4.2 g, yield: 61%).

LCMS m/z = 206.1 [M-1] - LCMS m/z = 206.1 [M-1] -

第二步：186c的製備Step 2: Preparation of 186c

將186b (1 g，4.83 mmol) 溶於20 mL甲醇中，加入10%鈀碳 (200 mg)，置於氫氣球氛圍下室溫反應16 h。將反應體系墊矽藻土過濾，將濾液減壓濃縮，得到粗品186c (800 mg)。Dissolve 186b (1 g, 4.83 mmol) in 20 mL methanol, add 10% palladium on carbon (200 mg), and react at room temperature for 16 h under a hydrogen balloon atmosphere. The reaction system was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain crude product 186c (800 mg).

LCMS m/z = 178.2 [M+1] + LCMS m/z = 178.2 [M+1] +

第三步：186d的製備Step 3: Preparation of 186d

將上述粗品186c (800 mg) 加入到甲苯 (10 mL) 和水 (10 mL) 的混合溶劑中，加入濃鹽酸 (1.2 mL)，0℃下加入亞硝酸鈉 (372 mg，5.39 mmol)，0℃下反應30 min後，緩慢加入KI (1.6 g，9.64 mmol) 的水 (10 mL) 溶液，室溫反應2 h。向反應體系中加入水 (100 mL)，用乙酸乙酯萃取 (60 mL×3)，有機相用飽和氯化鈉水溶液洗滌 (60 mL×2)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 67:33)，得186d (500 mg，收率：32%)。The above crude product 186c (800 mg) was added to a mixed solvent of toluene (10 mL) and water (10 mL), concentrated hydrochloric acid (1.2 mL) was added, and sodium nitrite (372 mg, 5.39 mmol) was added at 0°C. After reacting at ℃ for 30 min, a solution of KI (1.6 g, 9.64 mmol) in water (10 mL) was slowly added, and the reaction was carried out at room temperature for 2 h. Add water (100 mL) to the reaction system, extract with ethyl acetate (60 mL×3), wash the organic phase with saturated aqueous sodium chloride solution (60 mL×2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is Silica gel column separation and purification (petroleum ether:ethyl acetate (v/v) = 67:33) gave 186d (500 mg, yield: 32%).

化合物186以化合物186d為原料，參照實施例44的合成方法得到。Compound 186 was obtained by referring to the synthesis method of Example 44 using compound 186d as raw material.

1H NMR (400 MHz, CDCl 3) δ 8.65 – 8.54 (m, 1H), 7.95 (s, 1H), 7.88 – 7.78 (m, 1H), 7.76 – 7.60 (m, 2H), 7.58 – 7.50 (m, 1H), 7.50 – 7.12 (m, 3H), 6.82 (d, 1H), 6.56 (dd, 1H), 4.99 – 4.88 (m, 1H), 4.45 – 4.32 (m, 2H), 4.18 – 4.03 (m, 2H), 3.95 – 3.77 (m, 1H), 3.50 – 3.20 (m, 5H), 2.97 – 2.64 (m, 3H), 2.19 – 2.07 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.65 – 8.54 (m, 1H), 7.95 (s, 1H), 7.88 – 7.78 (m, 1H), 7.76 – 7.60 (m, 2H), 7.58 – 7.50 (m , 1H), 7.50 – 7.12 (m, 3H), 6.82 (d, 1H), 6.56 (dd, 1H), 4.99 – 4.88 (m, 1H), 4.45 – 4.32 (m, 2H), 4.18 – 4.03 (m , 2H), 3.95 – 3.77 (m, 1H), 3.50 – 3.20 (m, 5H), 2.97 – 2.64 (m, 3H), 2.19 – 2.07 (m, 1H).

實施例 187 ：化合物187的製備 Example 187 : Preparation of Compound 187

化合物187以化合物187a為原料，參照實施例147的合成方法得到。Compound 187 was obtained by referring to the synthesis method of Example 147 using compound 187a as a raw material.

1H NMR (400 MHz, CDCl 3) δ 7.96 (s, 1H), 7.83 (s, 1H), 7.75 – 7.61 (m, 3H), 6.83 – 6.78 (m, 1H), 6.73 – 6.67 (m, 1H), 6.59 – 6.52 (m, 2H), 4.98 – 4.88 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.02 (m, 2H) 3.88 – 3.76 (m, 1H), 2.95 – 2.65 (m, 3H), 2.18 – 2.08 (m, 1H), 2.05 (s, 3H), 1.96 (s, 6H), 1.83 – 1.73 (m, 1H), 1.65 – 1.55 (m, 1H), 0.93 – 0.84 (m, 2H), 0.81 – 0.71 (m, 2H), 0.63 – 0.57 (m, 2H), 0.54 – 0.45 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.96 (s, 1H), 7.83 (s, 1H), 7.75 – 7.61 (m, 3H), 6.83 – 6.78 (m, 1H), 6.73 – 6.67 (m, 1H ), 6.59 – 6.52 (m, 2H), 4.98 – 4.88 (m, 1H), 4.42 – 4.30 (m, 2H), 4.13 – 4.02 (m, 2H) 3.88 – 3.76 (m, 1H), 2.95 – 2.65 ( m, 3H), 2.18 – 2.08 (m, 1H), 2.05 (s, 3H), 1.96 (s, 6H), 1.83 – 1.73 (m, 1H), 1.65 – 1.55 (m, 1H), 0.93 – 0.84 ( m, 2H), 0.81 – 0.71 (m, 2H), 0.63 – 0.57 (m, 2H), 0.54 – 0.45 (m, 2H).

LCMS m/z = 659.3 [M+1] + LCMS m/z = 659.3 [M+1] +

實施例 188 ：化合物188的製備 Example 188 : Preparation of Compound 188

第一步：188b的製備Step 1: Preparation of 188b

將2b (2.30 g, 7.18 mmol) 溶解在20 mL四氫呋喃中，加入4 mL水，再加入一水合氫氧化鋰 (0.6 g, 14.3 mmol)，室溫反應30 min。向反應液中滴加1 mol/L稀鹽酸調pH至6，加入50 mL乙酸乙酯，分液，有機相用20 mL飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，減壓濃縮，得粗品 (2.0 g)。將上述粗品 (0.56 g) 溶於20 mL二氯甲烷中，滴加1-氯-N,N,2-三甲基丙烯胺 (0.34 g，2.54 mmol)，室溫反應2 h後，依次加入188a (0.25 g，1.18 mmol) 和TEA (0.71 g，7.02 mmol)，室溫反應16 h。將反應體系減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 4:1)，得188b (0.45 g，收率：79%)。Dissolve 2b (2.30 g, 7.18 mmol) in 20 mL tetrahydrofuran, add 4 mL water, then add lithium hydroxide monohydrate (0.6 g, 14.3 mmol), and react at room temperature for 30 min. Add 1 mol/L dilute hydrochloric acid dropwise to the reaction solution to adjust the pH to 6, add 50 mL ethyl acetate, separate the liquids, wash the organic phase with 20 mL saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product (2.0 g). Dissolve the above crude product (0.56 g) in 20 mL dichloromethane, add 1-chloro-N,N,2-trimethylpropenylamine (0.34 g, 2.54 mmol) dropwise, react at room temperature for 2 h, and then add in sequence 188a (0.25 g, 1.18 mmol) and TEA (0.71 g, 7.02 mmol) were reacted at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 4:1) to obtain 188b (0.45 g, yield: 79%).

第二步：化合物188的製備Step 2: Preparation of Compound 188

將188b (0.45 g，0.93 mmol) 溶於10 mL DMF中，依次加入上述粗品中間體1 (0.5 g)、TEA (0.25 g，2.47 mmol)、CuI (0.032 g，0.17 mmol) 和PdCl 2(PPh 3) 2(0.058 g，0.083 mmol)，60℃反應2 h。將反應體系冷卻至室溫，加入40 mL飽和氯化銨溶液，過濾，濾餅用20 mL二氯甲烷溶解，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 1:2)，得化合物188 (0.33 g，收率：51%)。 Dissolve 188b (0.45 g, 0.93 mmol) in 10 mL DMF, and add the above crude intermediate 1 (0.5 g), TEA (0.25 g, 2.47 mmol), CuI (0.032 g, 0.17 mmol) and PdCl 2 (PPh) in sequence. 3 ) 2 (0.058 g, 0.083 mmol), react at 60°C for 2 h. Cool the reaction system to room temperature, add 40 mL of saturated ammonium chloride solution, filter, dissolve the filter cake with 20 mL of methylene chloride, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether: acetic acid). Ethyl ester (v/v) = 1:2) to obtain compound 188 (0.33 g, yield: 51%).

1H NMR (400 MHz, CDCl 3) δ 8.48 (s, 1H), 8.40 (d, 1H), 8.06 (s, 1H), 7.82 – 7.63 (m, 3H), 7.24 – 7.19 (m, 1H), 7.17 – 7.09 (m, 1H), 6.80 (d, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.43 – 4.30 (m, 2H), 4.14 – 4.00 (m, 2H), 3.88 – 3.74 (m, 1H), 3.14 – 2.99 (m, 2H), 2.96 – 2.65 (m, 5H), 2.30 – 2.00 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.48 (s, 1H), 8.40 (d, 1H), 8.06 (s, 1H), 7.82 – 7.63 (m, 3H), 7.24 – 7.19 (m, 1H), 7.17 – 7.09 (m, 1H), 6.80 (d, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.43 – 4.30 (m, 2H), 4.14 – 4.00 (m, 2H), 3.88 – 3.74 (m, 1H), 3.14 – 2.99 (m, 2H), 2.96 – 2.65 (m, 5H), 2.30 – 2.00 (m, 3H).

LCMS m/z = 693.1 [M-1] - LCMS m/z = 693.1 [M-1] -

實施例 189：化合物189的製備 Example 189 : Preparation of Compound 189

第一步：189b的製備Step One: Preparation of 189b

將189a (3.00 g，12.69 mmol) 溶於30 mL乙醇和10 mL水的混合溶劑中，加入還原鐵粉 (2.12 g，37.86 mmol) 和10 mL乙酸，室溫反應19 h。將反應液用5 mol/L氫氧化鈉水溶液調pH至7，加入100 mL水和100 mL乙酸乙酯，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 10:1-1:1)，得到189b (2.3 g，收率：88%)。Dissolve 189a (3.00 g, 12.69 mmol) in a mixed solvent of 30 mL ethanol and 10 mL water, add reduced iron powder (2.12 g, 37.86 mmol) and 10 mL acetic acid, and react at room temperature for 19 h. Adjust the pH of the reaction solution to 7 with 5 mol/L sodium hydroxide aqueous solution, add 100 mL water and 100 mL ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify the crude product with a silica gel chromatography column (petroleum ether) /ethyl acetate (v/v) = 10:1-1:1) to obtain 189b (2.3 g, yield: 88%).

LCMS m/z = 206.0 [M+1] + LCMS m/z = 206.0 [M+1] +

化合物189以化合物189b為原料，參照實施例174的合成方法得到。Compound 189 was obtained by using compound 189b as a raw material and referring to the synthesis method of Example 174.

1H NMR (400 MHz, CDCl 3) δ 8.71 (s, 1H), 8.15 – 8.07 (m, 2H), 7.83 – 7.75 (m, 2H), 7.65 (d, 1H), 7.12 (t, 1H), 6.79 (d, 1H), 6.74 – 6.67 (m, 1H), 6.54 (dd, 1H), 4.97 – 4.87 (m, 1H), 4.40 – 4.29 (m, 2H), 4.12 – 4.01 (m, 2H), 3.88 – 3.73 (m, 1H), 2.97 – 2.63 (m, 3H), 2.18 – 2.02 (m, 2H), 1.94 (s, 6H), 1.00 – 0.90 (m, 2H), 0.67 – 0.57 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.71 (s, 1H), 8.15 – 8.07 (m, 2H), 7.83 – 7.75 (m, 2H), 7.65 (d, 1H), 7.12 (t, 1H), 6.79 (d, 1H), 6.74 – 6.67 (m, 1H), 6.54 (dd, 1H), 4.97 – 4.87 (m, 1H), 4.40 – 4.29 (m, 2H), 4.12 – 4.01 (m, 2H), 3.88 – 3.73 (m, 1H), 2.97 – 2.63 (m, 3H), 2.18 – 2.02 (m, 2H), 1.94 (s, 6H), 1.00 – 0.90 (m, 2H), 0.67 – 0.57 (m, 2H ).

LCMS m/z = 639.8 [M+1] + LCMS m/z = 639.8 [M+1] +

實施例 190：化合物190的製備 Example 190 : Preparation of Compound 190

第一步：190b的製備Step 1: Preparation of 190b

將190a (1.0 g，6.80 mmol) 溶於20 mL DMF中，0℃下加入NBS (1.21 g，6.80 mmol)，0℃反應0.5 h。向反應液中加入50 mL乙酸乙酯和50 mL水，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 10:1-1:1)，得到190b (700 mg，收率：46%)。Dissolve 190a (1.0 g, 6.80 mmol) in 20 mL DMF, add NBS (1.21 g, 6.80 mmol) at 0°C, and react at 0°C for 0.5 h. Add 50 mL ethyl acetate and 50 mL water to the reaction solution, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10:1 -1:1) to obtain 190b (700 mg, yield: 46%).

第二步：190c的製備Step 2: Preparation of 190c

將190b (600 mg，2.65 mmol) 溶於5 mL三氟乙酸中，加入三乙基矽烷 (3.08 g，26.49 mmol)，60℃反應16 h。將反應體系冷卻至室溫，減壓濃縮，殘留物用飽和碳酸氫鈉水溶液調pH至9，加入50 mL乙酸乙酯和50 mL水，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 10:1-1:1)，得到190c (510 mg，收率：91%)。Dissolve 190b (600 mg, 2.65 mmol) in 5 mL trifluoroacetic acid, add triethylsilane (3.08 g, 26.49 mmol), and react at 60°C for 16 h. The reaction system was cooled to room temperature and concentrated under reduced pressure. The pH of the residue was adjusted to 9 with saturated aqueous sodium bicarbonate solution. 50 mL of ethyl acetate and 50 mL of water were added. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was Silica gel column separation and purification (petroleum ether/ethyl acetate (v/v) = 10:1-1:1) gave 190c (510 mg, yield: 91%).

化合物190以化合物190c為原料，參考實施例165的合成方法得到。Compound 190 was obtained by using compound 190c as raw material and referring to the synthesis method of Example 165.

1H NMR (400 MHz, CDCl 3) δ 8.42 (s, 1H), 8.00 (s, 1H), 7.88 (d, 1H), 7.80 (s, 1H), 7.72 – 7.64 (m, 2H), 7.07 (d, 1H), 6.81 (d, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.40 – 4.32 (m, 2H), 4.12 – 4.02 (m, 2H), 3.87 – 3.75 (m, 1H), 2.97 – 2.64 (m, 7H), 2.18 – 2.07 (m, 1H), 2.06 – 1.90 (m, 8H), 1.51 – 1.40 (m, 1H), 0.92 – 0.80 (m, 2H), 0.45 – 0.37 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.42 (s, 1H), 8.00 (s, 1H), 7.88 (d, 1H), 7.80 (s, 1H), 7.72 – 7.64 (m, 2H), 7.07 ( d, 1H), 6.81 (d, 1H), 6.55 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.40 – 4.32 (m, 2H), 4.12 – 4.02 (m, 2H), 3.87 – 3.75 ( m, 1H), 2.97 – 2.64 (m, 7H), 2.18 – 2.07 (m, 1H), 2.06 – 1.90 (m, 8H), 1.51 – 1.40 (m, 1H), 0.92 – 0.80 (m, 2H), 0.45 – 0.37 (m, 2H).

LCMS m/z = 645.4 [M+1] + LCMS m/z = 645.4 [M+1] +

實施例 191 ：化合物191的製備 Example 191 : Preparation of Compound 191

化合物191以化合物191a和191A為原料，參照實施例180的合成方法得到。Compound 191 was obtained by referring to the synthesis method of Example 180 using compounds 191a and 191A as raw materials.

1H NMR (400 MHz, CDCl 3) δ 8.76 (d, 1H), 8.62 (s, 1H), 8.51 (d, 1H), 8.18 (d, 1H), 8.06 – 7.96 (m, 2H), 7.75 – 7.67 (m, 2H), 7.65 – 7.59 (m, 1H), 6.84 (d, 1H), 6.60 (dd, 1H), 4.99 – 4.90 (m, 1H), 4.49 – 4.40 (m, 2H), 4.28 – 4.17 (m, 2H), 4.05 – 3.92 (m, 1H), 2.98 – 2.65 (m, 3H), 2.20 – 2.03 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.76 (d, 1H), 8.62 (s, 1H), 8.51 (d, 1H), 8.18 (d, 1H), 8.06 – 7.96 (m, 2H), 7.75 – 7.67 (m, 2H), 7.65 – 7.59 (m, 1H), 6.84 (d, 1H), 6.60 (dd, 1H), 4.99 – 4.90 (m, 1H), 4.49 – 4.40 (m, 2H), 4.28 – 4.17 (m, 2H), 4.05 – 3.92 (m, 1H), 2.98 – 2.65 (m, 3H), 2.20 – 2.03 (m, 1H).

實施例 192：化合物192的製備 Example 192 : Preparation of Compound 192

第一步：192b的製備Step 1: Preparation of 192b

將192a (3.00 g，13.04 mmol) 溶於30 mL甲苯和3 mL水的混合溶劑中，加入環丙基硼酸 (1.76 g，20.49 mmol)、三環己基膦 (0.89 g，3.17 mmol)、醋酸鈀 (0.35 g，1.56 mmol) 和磷酸鉀 (11.73 g，55.26 mmol)，氮氣保護下100℃反應19 h。將反應體系冷卻至室溫，加入100 mL乙酸乙酯和100 mL水，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 10:1-1:1)，得到192b (2.05 g，收率：82%)。Dissolve 192a (3.00 g, 13.04 mmol) in a mixed solvent of 30 mL toluene and 3 mL water, add cyclopropylboronic acid (1.76 g, 20.49 mmol), tricyclohexylphosphine (0.89 g, 3.17 mmol), and palladium acetate (0.35 g, 1.56 mmol) and potassium phosphate (11.73 g, 55.26 mmol), reacted at 100°C for 19 h under nitrogen protection. Cool the reaction system to room temperature, add 100 mL ethyl acetate and 100 mL water, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10:1-1:1), obtaining 192b (2.05 g, yield: 82%).

第二步：192c的製備Step 2: Preparation of 192c

將192b (1.00 g，5.23 mmol) 溶於10 mL乙腈中，加入KI (1.30 g，7.83 mmol)和CuI (1.49 g，7.82 mmol)，75℃下加入亞硝基異戊酯 (1.10 g，9.39 mmol)，75℃反應2 h。將反應體系冷卻至室溫，加入80 mL乙酸乙酯和100 mL水，抽濾，將濾液分液，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 10:1-1:1)，得到192c (0.65 g，收率：41%)。Dissolve 192b (1.00 g, 5.23 mmol) in 10 mL acetonitrile, add KI (1.30 g, 7.83 mmol) and CuI (1.49 g, 7.82 mmol), and add nitrosisoamyl ester (1.10 g, 9.39 mmol), react at 75°C for 2 h. Cool the reaction system to room temperature, add 80 mL ethyl acetate and 100 mL water, filter with suction, separate the filtrate, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify the crude product with a silica gel chromatography column (petroleum ether/petroleum ether/ Ethyl acetate (v/v) = 10:1-1:1) to obtain 192c (0.65 g, yield: 41%).

第三步：192d的製備Step 3: Preparation of 192d

將192c (0.65 g，2.15 mmol) 溶於5 mL甲醇和1 mL水中，加入一水合氫氧化鋰 (0.45 g，10.72 mmol)，室溫反應2 h。將反應液用1 mol/L鹽酸調pH至3，加入20 mL乙酸乙酯，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 5:1-1:1)，得到192d (0.45 g，收率：73%)。Dissolve 192c (0.65 g, 2.15 mmol) in 5 mL methanol and 1 mL water, add lithium hydroxide monohydrate (0.45 g, 10.72 mmol), and react at room temperature for 2 h. Adjust the pH of the reaction solution to 3 with 1 mol/L hydrochloric acid, add 20 mL of ethyl acetate, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified with a silica gel chromatography column (petroleum ether/ethyl acetate (v/ v) = 5:1-1:1), obtaining 192d (0.45 g, yield: 73%).

化合物192以化合物192d為原料，參照實施例44的合成方法得到。Compound 192 was obtained by using compound 192d as a raw material and referring to the synthesis method of Example 44.

1H NMR (400 MHz, CDCl 3) δ 7.94 (s, 1H), 7.81 (s, 1H), 7.76 (s, 1H), 7.68 (d, 1H), 7.58 – 7.43 (m, 3H), 7.29 (s, 1H), 7.17 (s, 1H), 6.82 (d, 1H), 6.57 (dd, 1H), 4.99 – 4.87 (m, 1H), 4.44 – 4.32 (m, 2H), 4.17 – 4.03 (m, 2H), 3.90 – 3.78 (m, 1H), 2.96 – 2.66 (m, 3H), 2.19 – 2.06 (m, 1H), 1.89 – 1.72 (m, 1H), 1.04 – 0.91 (m, 2H), 0.72 – 0.52 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (s, 1H), 7.81 (s, 1H), 7.76 (s, 1H), 7.68 (d, 1H), 7.58 – 7.43 (m, 3H), 7.29 ( s, 1H), 7.17 (s, 1H), 6.82 (d, 1H), 6.57 (dd, 1H), 4.99 – 4.87 (m, 1H), 4.44 – 4.32 (m, 2H), 4.17 – 4.03 (m, 2H), 3.90 – 3.78 (m, 1H), 2.96 – 2.66 (m, 3H), 2.19 – 2.06 (m, 1H), 1.89 – 1.72 (m, 1H), 1.04 – 0.91 (m, 2H), 0.72 – 0.52 (m, 2H).

實施例 193：化合物193的製備 Example 193 : Preparation of Compound 193

化合物193以化合物80b為原料，參照實施例81的合成方法得到。Compound 193 was obtained by referring to the synthesis method of Example 81 using compound 80b as raw material.

1H NMR (400 MHz, CDCl 3) δ 8.12 (d, 1H), 7.93 (s, 1H), 7.78 – 7.64 (m, 2H), 7.62 – 7.54 (m, 2H), 7.34 (s, 1H), 7.01 – 6.93 (m, 2H), 6.83 (d, 1H), 6.57 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.45 – 4.32 (m, 2H), 4.17 – 4.06 (m, 2H), 3.93 – 3.82 (m, 1H), 2.95 – 2.65 (m, 3H), 2.18 – 2.05 (m, 1H), 1.90 – 1.77 (m, 1H), 1.70 (s, 6H), 0.98 – 0.80 (m, 2H), 0.67 – 0.57 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.12 (d, 1H), 7.93 (s, 1H), 7.78 – 7.64 (m, 2H), 7.62 – 7.54 (m, 2H), 7.34 (s, 1H), 7.01 – 6.93 (m, 2H), 6.83 (d, 1H), 6.57 (dd, 1H), 4.98 – 4.89 (m, 1H), 4.45 – 4.32 (m, 2H), 4.17 – 4.06 (m, 2H), 3.93 – 3.82 (m, 1H), 2.95 – 2.65 (m, 3H), 2.18 – 2.05 (m, 1H), 1.90 – 1.77 (m, 1H), 1.70 (s, 6H), 0.98 – 0.80 (m, 2H ), 0.67 – 0.57 (m, 2H).

實施例 194：化合物194的製備 Example 194 : Preparation of Compound 194

化合物194以化合物80b為原料，參照實施例168的合成方法得到。Compound 194 was obtained by using compound 80b as a raw material and referring to the synthesis method of Example 168.

1H NMR (400 MHz, DMSO- d 6 ) δ 11.06 (s, 1H), 10.17 (s, 1H), 7.93 (s, 1H), 7.80 – 7.72 (m, 1H), 7.69 (d, 1H), 7.63 – 7.55 (m, 1H), 7.38 (d, 1H), 7.26 (d, 1H), 7.08 (dd, 1H), 6.89 (d, 1H), 6.74 (dd, 1H), 5.11 – 5.02 (m, 1H), 4.48 – 4.37 (m, 2H), 4.17 – 4.05 (m, 2H), 4.05 – 3.92 (m, 1H), 2.98 – 2.80 (m, 1H), 2.68 – 2.46 (m, 2H), 2.10 – 1.90 (m, 2H), 1.03 – 0.94 (m, 2H), 0.77 – 0.69 (m, 2H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.06 (s, 1H), 10.17 (s, 1H), 7.93 (s, 1H), 7.80 – 7.72 (m, 1H), 7.69 (d, 1H), 7.63 – 7.55 (m, 1H), 7.38 (d, 1H), 7.26 (d, 1H), 7.08 (dd, 1H), 6.89 (d, 1H), 6.74 (dd, 1H), 5.11 – 5.02 (m, 1H), 4.48 – 4.37 (m, 2H), 4.17 – 4.05 (m, 2H), 4.05 – 3.92 (m, 1H), 2.98 – 2.80 (m, 1H), 2.68 – 2.46 (m, 2H), 2.10 – 1.90 (m, 2H), 1.03 – 0.94 (m, 2H), 0.77 – 0.69 (m, 2H).

實施例 195 ：化合物195的製備 Example 195 : Preparation of Compound 195

第一步：195b的製備Step One: Preparation of 195b

將吡唑 (0.75 g，11.02 mmol) 溶於30 mL四氫呋喃中，0℃下加入60%氫化鈉 (0.29 g)，室溫反應30 min後，加入195a (2.2 g，10 mmol)，60℃反應16 h。將反應體系冷卻至室溫，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 3:1)，得195b (2.1 g，收率：79%)。Dissolve pyrazole (0.75 g, 11.02 mmol) in 30 mL tetrahydrofuran, add 60% sodium hydride (0.29 g) at 0°C, react at room temperature for 30 min, add 195a (2.2 g, 10 mmol), and react at 60°C 16h. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column (petroleum ether:ethyl acetate (v/v) = 3:1) to obtain 195b (2.1 g, yield: 79%).

LCMS m/z = 268.1 [M+1] + LCMS m/z = 268.1 [M+1] +

第二步：195c的製備Step 2: Preparation of 195c

將195b (2.1 g，7.86 mmol) 溶於50 mL乙醇中，加入還原鐵粉 (2.24 g，40 mmol) 和10 mL飽和氯化銨水溶液，回流反應1 h。將反應體系冷卻至室溫，過濾，將濾液減壓濃縮，加入80 mL乙酸乙酯和50 mL純化水，有機相用無水硫酸鈉乾燥，減壓濃縮，得粗品195c (1.64 g)。Dissolve 195b (2.1 g, 7.86 mmol) in 50 mL ethanol, add reduced iron powder (2.24 g, 40 mmol) and 10 mL saturated aqueous ammonium chloride solution, and reflux for 1 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. 80 mL of ethyl acetate and 50 mL of purified water were added. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product 195c (1.64 g).

化合物195以化合物195c為原料，參考實施例165的合成方法得到。Compound 195 was obtained by using compound 195c as raw material and referring to the synthesis method of Example 165.

1H NMR (400 MHz, CDCl 3) δ 8.69 (s, 1H), 8.38 (s, 1H), 8.22 (d, 1H), 7.90 – 7.80 (m, 2H), 7.77 – 7.60 (m, 3H), 7.53 – 7.37 (m, 2H), 6.80 (s, 1H), 6.54 (d, 1H), 6.43 (s, 1H), 5.01 – 4.86 (m, 1H), 4.44 – 4.27 (m, 2H), 4.15 – 3.96 (m, 2H), 3.90 – 3.70 (m, 1H), 2.96 – 2.62 (m, 3H), 2.20 – 2.04 (m, 1H), 1.97 (s, 6H), 1.64 – 1.47 (m, 1H), 1.02 – 0.82 (m, 2H), 0.70 – 0.54 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.69 (s, 1H), 8.38 (s, 1H), 8.22 (d, 1H), 7.90 – 7.80 (m, 2H), 7.77 – 7.60 (m, 3H), 7.53 – 7.37 (m, 2H), 6.80 (s, 1H), 6.54 (d, 1H), 6.43 (s, 1H), 5.01 – 4.86 (m, 1H), 4.44 – 4.27 (m, 2H), 4.15 – 3.96 (m, 2H), 3.90 – 3.70 (m, 1H), 2.96 – 2.62 (m, 3H), 2.20 – 2.04 (m, 1H), 1.97 (s, 6H), 1.64 – 1.47 (m, 1H), 1.02 – 0.82 (m, 2H), 0.70 – 0.54 (m, 2H).

實施例 196 ：化合物196的製備 Example 196 : Preparation of Compound 196

化合物196以化合物196a (CN111138307) 為原料，參照實施例164的合成方法得到。Compound 196 was obtained by using compound 196a (CN111138307) as a raw material and referring to the synthesis method of Example 164.

1H NMR (400 MHz, DMSO- d 6 ) δ 8.70 (s, 1H), 8.30 (s, 1H), 8.27 (s, 2H), 7.91 (s, 1H), 7.86 – 7.74 (m, 2H), 7.66 (d, 1H), 7.57 – 7.48 (m, 1H), 7.36 – 7.29 (m, 1H), 7.29 – 7.21 (m, 1H), 6.88 – 6.83 (m, 1H), 6.70 (dd, 1H), 5.12 – 5.01 (m, 1H), 4.45 – 4.33 (m, 2H), 4.10 – 3.97 (m, 2H), 3.95 – 3.80 (m, 3H), 2.98 – 2.80 (m, 1H), 2.65 – 2.52 (m, 2H), 2.10 – 1.98 (m, 1H), 1.88 (s, 6H), 1.75 – 1.65 (m, 1H), 0.90 – 0.75 (m, 2H), 0.65 – 0.57 (m, 2H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.70 (s, 1H), 8.30 (s, 1H), 8.27 (s, 2H), 7.91 (s, 1H), 7.86 – 7.74 (m, 2H), 7.66 (d, 1H), 7.57 – 7.48 (m, 1H), 7.36 – 7.29 (m, 1H), 7.29 – 7.21 (m, 1H), 6.88 – 6.83 (m, 1H), 6.70 (dd, 1H), 5.12 – 5.01 (m, 1H), 4.45 – 4.33 (m, 2H), 4.10 – 3.97 (m, 2H), 3.95 – 3.80 (m, 3H), 2.98 – 2.80 (m, 1H), 2.65 – 2.52 (m , 2H), 2.10 – 1.98 (m, 1H), 1.88 (s, 6H), 1.75 – 1.65 (m, 1H), 0.90 – 0.75 (m, 2H), 0.65 – 0.57 (m, 2H).

實施例 197 ：化合物197的製備 Example 197 : Preparation of Compound 197

化合物197以化合物197a為原料，參照實施例163的合成方法得到。Compound 197 was obtained by referring to the synthesis method of Example 163 using compound 197a as a raw material.

1H NMR (400 MHz, CDCl 3) δ 8.89 (s, 1H), 8.39 (d, 1H), 8.12 (s, 1H), 7.85 – 7.77 (m, 2H), 7.68 (d, 1H), 7.58 – 7.51 (m, 1H), 7.48 – 7.26 (m, 3H), 7.24 – 7.07 (m, 2H), 6.84 – 6.77 (m, 1H), 6.55 (dd, 1H), 4.99 – 4.88 (m, 1H), 4.43 – 4.28 (m, 2H), 4.14 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.98 – 2.65 (m, 3H), 2.20 – 2.05 (m, 1H), 1.97 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.89 (s, 1H), 8.39 (d, 1H), 8.12 (s, 1H), 7.85 – 7.77 (m, 2H), 7.68 (d, 1H), 7.58 – 7.51 (m, 1H), 7.48 – 7.26 (m, 3H), 7.24 – 7.07 (m, 2H), 6.84 – 6.77 (m, 1H), 6.55 (dd, 1H), 4.99 – 4.88 (m, 1H), 4.43 – 4.28 (m, 2H), 4.14 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.98 – 2.65 (m, 3H), 2.20 – 2.05 (m, 1H), 1.97 (s, 6H ).

實施例 198：化合物198的製備 Example 198 : Preparation of Compound 198

第一步：198b的製備Step 1: Preparation of 198b

將198a (3.16 g，12.68 mmol) 溶於30 mL乙醇和10 mL水的混合溶劑中，加入還原鐵粉 (2.13 g，38.04 mmol) 和氯化銨 (3.39 g，63.38 mmol)，80℃反應3 h。將反應體系冷卻至室溫，加入100 mL乙酸乙酯和100 mL水，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚/乙酸乙酯 (v/v) = 10:1-1:1)，得到198b (1.4 g，收率：50%)。Dissolve 198a (3.16 g, 12.68 mmol) in a mixed solvent of 30 mL ethanol and 10 mL water, add reduced iron powder (2.13 g, 38.04 mmol) and ammonium chloride (3.39 g, 63.38 mmol), and react at 80°C 3 h. Cool the reaction system to room temperature, add 100 mL ethyl acetate and 100 mL water, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether/ethyl acetate (v/v) = 10:1-1:1), obtaining 198b (1.4 g, yield: 50%).

化合物198以化合物198b為原料，參照實施例192的合成方法得到。Compound 198 was obtained by referring to the synthesis method of Example 192 using compound 198b as raw material.

1H NMR (400 MHz, CDCl 3) δ 8.00 (br.s, 1H), 7.86 – 7.78 (m, 2H), 7.74 – 7.60 (m, 2H), 7.57 – 7.51 (m, 1H), 7.39 – 7.32 (m, 1H), 7.28 – 7.23 (m, 1H), 7.01 (d, 1H), 6.86 – 6.80 (m, 1H), 6.58 (dd, 1H), 5.00 – 4.87 (m, 1H), 4.47 – 4.35 (m, 2H), 4.18 – 4.07 (m, 2H), 3.95 – 3.80 (m, 1H), 2.97 – 2.68 (m, 3H), 2.20 – 2.05 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.00 (br.s, 1H), 7.86 – 7.78 (m, 2H), 7.74 – 7.60 (m, 2H), 7.57 – 7.51 (m, 1H), 7.39 – 7.32 (m, 1H), 7.28 – 7.23 (m, 1H), 7.01 (d, 1H), 6.86 – 6.80 (m, 1H), 6.58 (dd, 1H), 5.00 – 4.87 (m, 1H), 4.47 – 4.35 (m, 2H), 4.18 – 4.07 (m, 2H), 3.95 – 3.80 (m, 1H), 2.97 – 2.68 (m, 3H), 2.20 – 2.05 (m, 1H).

實施例 199：化合物199的製備 Example 199 : Preparation of Compound 199

化合物199以化合物199a為原料，參照實施例198的合成方法得到。Compound 199 was obtained by using compound 199a as a raw material and referring to the synthesis method of Example 198.

1H NMR (400 MHz, CDCl 3) δ 8.78 – 8.72 (m, 1H), 8.29 – 8.21 (m, 1H), 8.05 – 7.46 (m, 8H), 7.43 – 7.32 (m, 1H), 6.88 – 6.80 (m, 2H), 6.64 – 6.55 (m, 1H), 4.99 – 4.87 (m, 1H), 4.49 – 4.36 (m, 2H), 4.23 – 4.10 (m, 2H), 3.99 – 3.85 (m, 1H), 2.98 – 2.65 (m, 3H), 2.20 – 2.07 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.78 – 8.72 (m, 1H), 8.29 – 8.21 (m, 1H), 8.05 – 7.46 (m, 8H), 7.43 – 7.32 (m, 1H), 6.88 – 6.80 (m, 2H), 6.64 – 6.55 (m, 1H), 4.99 – 4.87 (m, 1H), 4.49 – 4.36 (m, 2H), 4.23 – 4.10 (m, 2H), 3.99 – 3.85 (m, 1H) , 2.98 – 2.65 (m, 3H), 2.20 – 2.07 (m, 1H).

實施例 200：化合物200的製備 Example 200 : Preparation of Compound 200

化合物200以化合物80b為原料，參照實施例159的合成方法得到。Compound 200 was obtained by referring to the synthesis method of Example 159 using compound 80b as raw material.

1H NMR (400 MHz, CDCl 3) δ 8.08 (s, 1H), 7.96 (s, 1H), 7.82 (s, 1H), 7.75 (s, 1H), 7.67 (d, 1H), 7.01 (s, 2H), 6.84 – 6.77 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.43 – 4.30 (m, 2H), 4.14 – 4.02 (m, 2H), 3.88 – 3.75 (m, 1H), 2.96 – 2.62 (m, 3H), 2.20 – 2.06 (m, 1H), 1.95 (s, 6H), 1.88 – 1.74 (m, 1H), 1.06 – 0.94 (m, 2H), 0.72 – 0.60 (m, 2H) 1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (s, 1H), 7.96 (s, 1H), 7.82 (s, 1H), 7.75 (s, 1H), 7.67 (d, 1H), 7.01 (s, 2H), 6.84 – 6.77 (m, 1H), 6.55 (dd, 1H), 4.98 – 4.88 (m, 1H), 4.43 – 4.30 (m, 2H), 4.14 – 4.02 (m, 2H), 3.88 – 3.75 ( m, 1H), 2.96 – 2.62 (m, 3H), 2.20 – 2.06 (m, 1H), 1.95 (s, 6H), 1.88 – 1.74 (m, 1H), 1.06 – 0.94 (m, 2H), 0.72 – 0.60 (m, 2H)

實施例201：化合物201的製備 Example 201: Preparation of Compound 201

第一步：201b的製備Step One: Preparation of 201b

氮氣氛圍下將201a (0.5 g，1.39 mmol) (合成方法見WO2017036968)、3-哌啶甲酸甲酯 (0.24 g，1.68 mmol)、CuI (0.082 g，0.43 mmol)、L-脯氨酸 (0.19 g，1.65 mmol) 和碳酸鉀 (0.39 g，2.82 mmol) 加入到10 mL DMSO中，70℃反應18 h。將反應體系冷卻到室溫，加入到50 mL水中，用乙酸乙酯萃取 (50 mL×3)，有機相用飽和氯化鈉水溶液洗滌 (50 mL×3)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠柱色譜分離純化 (石油醚/乙酸乙酯 (v/v) =3:1)，得到201b (0.1 g，收率：19%)。Under nitrogen atmosphere, 201a (0.5 g, 1.39 mmol) (see WO2017036968 for synthesis method), 3-piperidinecarboxylic acid methyl ester (0.24 g, 1.68 mmol), CuI (0.082 g, 0.43 mmol), L-proline (0.19 g, 1.65 mmol) and potassium carbonate (0.39 g, 2.82 mmol) were added to 10 mL DMSO and reacted at 70°C for 18 h. Cool the reaction system to room temperature, add it to 50 mL of water, extract with ethyl acetate (50 mL×3), wash the organic phase with saturated aqueous sodium chloride solution (50 mL×3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. , the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =3:1) to obtain 201b (0.1 g, yield: 19%).

LCMS m/z = 375.4 [M+1] + LCMS m/z = 375.4 [M+1] +

第二步：201c的製備Step Two: Preparation of 201c

將201b (0.1 g，0.27 mmol) 溶於2 mL甲醇中，用2 mol/L氫氧化鈉水溶液調pH至10，室溫反應2 h。向反應液中加入20 mL水，用2 mol/L鹽酸調pH至3，用乙酸乙酯萃取 (30 mL×3)，有機相用無水硫酸鈉乾燥，減壓濃縮，得到粗品 (0.05 g)。將上述粗品 (0.05 g) 溶於2 mL DCM中，加入16B (0.022 g，0.14 mmol)、TCFH (0.059 g，0.21 mmol) 和N-甲基咪唑 (0.046 g，0.56 mmol)，室溫反應12 h。向反應液中加入50 mL二氯甲烷和50 mL水，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 1:0-3:1)，得到201c (0.04 g，收率：57%)。Dissolve 201b (0.1 g, 0.27 mmol) in 2 mL methanol, adjust the pH to 10 with 2 mol/L sodium hydroxide aqueous solution, and react at room temperature for 2 h. Add 20 mL of water to the reaction solution, adjust the pH to 3 with 2 mol/L hydrochloric acid, extract with ethyl acetate (30 mL×3), dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product (0.05 g) . Dissolve the above crude product (0.05 g) in 2 mL DCM, add 16B (0.022 g, 0.14 mmol), TCFH (0.059 g, 0.21 mmol) and N-methylimidazole (0.046 g, 0.56 mmol), and react at room temperature for 12 h. Add 50 mL dichloromethane and 50 mL water to the reaction solution, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 1:0 -3:1) to obtain 201c (0.04 g, yield: 57%).

LCMS m/z = 501.2 [M+1] + LCMS m/z = 501.2 [M+1] +

第三步：201d三氟乙酸鹽的製備Step 3: Preparation of 201d trifluoroacetate

將201c (0.04 g，0.08 mmol) 溶解於6 mL二氯甲烷中，加入2 mL三氟乙酸，室溫攪拌1 h。將反應體系減壓濃縮，得到粗品201d的三氟乙酸鹽 (0.032 g)。Dissolve 201c (0.04 g, 0.08 mmol) in 6 mL dichloromethane, add 2 mL trifluoroacetic acid, and stir at room temperature for 1 h. The reaction system was concentrated under reduced pressure to obtain crude product 201d trifluoroacetate (0.032 g).

LCMS m/z = 401.5 [M+1] + LCMS m/z = 401.5 [M+1] +

第四步：化合物201的製備Step 4: Preparation of Compound 201

將上述粗品201d的三氟乙酸鹽 (0.032 g) 溶解於5 mL DMSO中，加入DIPEA (0.062 g，0.48 mmol) 和2-(2,6-二氧代哌啶-3-基)-5-氟異吲哚啉-1,3-二酮 (0.044 g，0.16 mmol)，90℃反應1.5 h。將反應體系冷卻至室溫，加入到40 mL乙酸乙酯中，有機相用飽和氯化鈉水溶液洗滌 (40 mL×3)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:二氯甲烷:乙酸乙酯 (v/v) = 1:1:0-1:1:1)，得到化合物201 (0.005 g，收率：5%)。Dissolve the trifluoroacetate salt of the above crude product 201d (0.032 g) in 5 mL DMSO, add DIPEA (0.062 g, 0.48 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5- Fluoroisoindoline-1,3-dione (0.044 g, 0.16 mmol), react at 90°C for 1.5 h. The reaction system was cooled to room temperature, added to 40 mL of ethyl acetate, the organic phase was washed with saturated sodium chloride aqueous solution (40 mL×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column ( Petroleum ether: dichloromethane: ethyl acetate (v/v) = 1:1:0-1:1:1) to obtain compound 201 (0.005 g, yield: 5%).

1H NMR (400 MHz, CDCl 3) δ 9.67 (s, 1H), 8.51 (d, 1H), 7.99 (s, 1H), 7.68 (d, 1H), 7.51 (dd, 1H), 7.38 – 7.26 (m, 3H), 7.10 – 6.95 (m, 2H), 6.90 – 6.80 (m, 1H), 6.59 (dd, 1H), 5.00 – 4.86 (m, 1H), 4.54 – 4.37 (m, 2H), 4.10 – 3.90 (m, 3H), 3.77 – 3.65 (m, 1H), 3.54 – 3.37 (m, 1H), 3.28 – 3.15 (m, 1H), 3.10 – 2.65 (m, 5H), 2.22 – 1.76 (m, 5H), 1.62 – 1.47 (m, 1H), 0.82 – 0.44 (m, 4H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.67 (s, 1H), 8.51 (d, 1H), 7.99 (s, 1H), 7.68 (d, 1H), 7.51 (dd, 1H), 7.38 – 7.26 ( m, 3H), 7.10 – 6.95 (m, 2H), 6.90 – 6.80 (m, 1H), 6.59 (dd, 1H), 5.00 – 4.86 (m, 1H), 4.54 – 4.37 (m, 2H), 4.10 – 3.90 (m, 3H), 3.77 – 3.65 (m, 1H), 3.54 – 3.37 (m, 1H), 3.28 – 3.15 (m, 1H), 3.10 – 2.65 (m, 5H), 2.22 – 1.76 (m, 5H ), 1.62 – 1.47 (m, 1H), 0.82 – 0.44 (m, 4H).

LCMS m/z = 657.2 [M+1] + LCMS m/z = 657.2 [M+1] +

實施例202：化合物202的製備 Example 202: Preparation of Compound 202

第一步：202a的製備Step One: Preparation of 202a

將146f (0.3 g，0.95 mmol)、1-溴代環丁烷甲酸乙酯 (0.2 g，0.97 mmol) 和碳酸銫 (0.62 g，1.9 mmol) 溶於10 mL乙腈中，50℃反應16 h。將反應體系冷卻到室溫，過濾，將濾液加入到50 mL水中，用乙酸乙酯萃取 (50 mL×3)，無水硫酸鈉乾燥，減壓濃縮，粗品用prep-TLC製備分離純化 (石油醚:乙酸乙酯 (v/v) =5:1)，得到202a (70 mg，收率：17%)。Dissolve 146f (0.3 g, 0.95 mmol), ethyl 1-bromocyclobutanecarboxylate (0.2 g, 0.97 mmol) and cesium carbonate (0.62 g, 1.9 mmol) in 10 mL acetonitrile and react at 50°C for 16 h. Cool the reaction system to room temperature, filter, add the filtrate to 50 mL of water, extract with ethyl acetate (50 mL×3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified by prep-TLC (petroleum ether). : ethyl acetate (v/v) =5:1) to obtain 202a (70 mg, yield: 17%).

LCMS m/z = 444.2 [M+1] + LCMS m/z = 444.2 [M+1] +

第二步：202b的製備Step 2: Preparation of 202b

將202a (0.07 g，0.158 mmol) 溶於2 mL甲醇中，用2 mol/L氫氧化鈉水溶液調pH至10，室溫反應2 h。將反應體系加入到50 mL水中，用2 mol/L鹽酸調pH至2，用乙酸乙酯萃取 (50 mL×3)，無水硫酸鈉乾燥，減壓濃縮，得到粗品 (50 mg)。將上述粗品 (50 mg) 溶於2 mL DCM中，加入3-氯-4-氨基三氟甲苯 (0.023 g，0.12 mmol)、TCFH (0.051 g，0.182 mmol) 和N-甲基咪唑 (0.039 g，0.475 mmol)，室溫反應12 h。向反應液中加入50 mL二氯甲烷和50 mL水，有機相用無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:乙酸乙酯 (v/v) = 1:0-3:1)，得到202b (0.04 g，收率：56%)。Dissolve 202a (0.07 g, 0.158 mmol) in 2 mL methanol, adjust the pH to 10 with 2 mol/L sodium hydroxide aqueous solution, and react at room temperature for 2 h. Add the reaction system to 50 mL of water, adjust the pH to 2 with 2 mol/L hydrochloric acid, extract with ethyl acetate (50 mL×3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product (50 mg). Dissolve the above crude product (50 mg) in 2 mL DCM, add 3-chloro-4-aminotrifluorotoluene (0.023 g, 0.12 mmol), TCFH (0.051 g, 0.182 mmol) and N-methylimidazole (0.039 g , 0.475 mmol), react at room temperature for 12 h. Add 50 mL dichloromethane and 50 mL water to the reaction solution, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is separated and purified using a silica gel chromatography column (petroleum ether: ethyl acetate (v/v) = 1:0 -3:1) to obtain 202b (0.04 g, yield: 56%).

第三步：202c三氟乙酸鹽的製備Step 3: Preparation of 202c trifluoroacetate

將202b (0.04 g，0.067 mmol) 溶於6 mL二氯甲烷中，加入2 mL三氟乙酸，室溫反應1 h。將反應體系減壓濃縮，得到粗品202c三氟乙酸鹽 (0.033 g)。Dissolve 202b (0.04 g, 0.067 mmol) in 6 mL dichloromethane, add 2 mL trifluoroacetic acid, and react at room temperature for 1 h. The reaction system was concentrated under reduced pressure to obtain crude product 202c trifluoroacetate (0.033 g).

第四步：化合物202的製備Step 4: Preparation of Compound 202

將上述粗品202c三氟乙酸鹽 (0.033 g) 溶於5 mL DMSO中，加入DIPEA (0.053 g，0.41 mmol) 和2-(2,6-二氧代哌啶-3-基)-5-氟異吲哚啉-1,3-二酮 (0.044 g，0.16 mmol)，90℃反應1.5 h。將反應體系冷卻至室溫，加入到40 mL乙酸乙酯中，有機相用飽和氯化鈉水溶液洗滌 (40 mL×3)，無水硫酸鈉乾燥，減壓濃縮，粗品用矽膠色譜柱分離純化 (石油醚:二氯甲烷:乙酸乙酯 (v/v) = 1:1:0-1:1:1)，得到化合物202 (5 mg，收率：4%)。Dissolve the above crude product 202c trifluoroacetate (0.033 g) in 5 mL DMSO, add DIPEA (0.053 g, 0.41 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoro Isoindoline-1,3-dione (0.044 g, 0.16 mmol), react at 90°C for 1.5 h. The reaction system was cooled to room temperature, added to 40 mL of ethyl acetate, the organic phase was washed with saturated sodium chloride aqueous solution (40 mL×3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified using a silica gel chromatography column ( Petroleum ether: dichloromethane: ethyl acetate (v/v) = 1:1:0-1:1:1) to obtain compound 202 (5 mg, yield: 4%).

生物測試例Biological test examples

1. 抑制22RV1細胞增殖實驗1. Inhibition of 22RV1 cell proliferation experiment

前列腺癌細胞22RV1購置於ATCC，細胞培養基為RPMI 1640+10%FBS，培養於37 ºC, 5% CO 2孵箱中。第一天收集處於指數生長期的細胞，用1% css-FBS無酚紅培養基將細胞懸液調整為相應濃度鋪板，使細胞為2000個/孔，孵育過夜。第二天加入不同濃度的化合物，置於孵箱中培養繼續孵育7天。培養結束後，按照CellTiter-Glo試劑盒（Promega，G7573）操作說明，每孔加入50 µL預先融化並平衡到室溫的CellTiter-Glo試劑，用微孔板震盪器混勻2分鐘，於室溫放置10分鐘後用酶標儀（PHERAstar FSX）測定螢光信號值。結果按照式（1）處理，計算出化合物各個濃度的抑制率，並使用origin9.2軟體，採用DoseResp函數計算化合物抑制率為50%的IC 50值。其中RLU compound為藥物處理組的讀數，RLU control為DMSO溶劑對照組的平均值。 Inhibition % = [1-RLU compound/RLU control]×100%     式（1） Prostate cancer cell 22RV1 was purchased from ATCC. The cell culture medium was RPMI 1640+10% FBS and cultured in a 37 ºC, 5% CO 2 incubator. Collect the cells in the exponential growth phase on the first day, use 1% css-FBS phenol red-free medium, adjust the cell suspension to the corresponding concentration and plate it to 2000 cells/well, and incubate overnight. The next day, compounds of different concentrations were added, placed in an incubator, and incubated for another 7 days. After the incubation, according to the instructions of CellTiter-Glo kit (Promega, G7573), add 50 µL of CellTiter-Glo reagent that has been melted and equilibrated to room temperature in each well, mix with a microplate shaker for 2 minutes, and allow to cool to room temperature. After leaving for 10 minutes, the fluorescence signal value was measured using a microplate reader (PHERAstar FSX). The results are processed according to formula (1), the inhibition rate of each concentration of the compound is calculated, and the IC 50 value of the compound's inhibition rate of 50% is calculated using the origin9.2 software and the DoseResp function. Among them, RLU compound is the reading of the drug treatment group, and RLU control is the average value of the DMSO solvent control group. Inhibition % = [1-RLU compound /RLU control ]×100% Formula (1)

抑制22RV1細胞增殖的IC 50值結果見 表 1。 表1 本發明化合物抑制22RV1細胞的IC50值 化合物編號 IC 50 化合物編號 IC 50 化合物1 11nM 化合物99的三氟乙酸鹽 ＜50nM 化合物4 17nM 化合物101 1.1nM 化合物5 15nM 化合物102 3.1nM 化合物7 4.8nM 化合物103 ＜100nM 化合物8 ＜100nM 化合物105 2nM 化合物9 3.5nM 化合物107 3.1nM 化合物10 2nM 化合物109 4.8nM 化合物12 ＜500nM 化合物110 3.6nM 化合物13 44nM 化合物112的三氟乙酸鹽 18.2nM 化合物14 5.7nM 化合物114 ＜1nM 化合物17 6.9nM 化合物115 3.9nM 化合物18 ＜50nM 化合物118 ＜100nM 化合物19 2.7nM 化合物121的三氟乙酸鹽 1.4nM 化合物20 ＜50nM 化合物123的三氟乙酸鹽 10.1nM 化合物23的三氟乙酸鹽 21nM 化合物126 22.3nM 化合物25 18nM 化合物128 25.3nM 化合物27的三氟乙酸鹽 11nM 化合物130 5.2nM 化合物29 2.9nM 化合物131 4.6nM 化合物30 7.4nM 化合物132 3.8nM 化合物32 14nM 化合物138 20.5nM 化合物34 7nM 化合物140 22.3nM 化合物35 1.9nM 化合物141 3.4nM 化合物36 11.1nM 化合物142 6.2nM 化合物41的三氟乙酸鹽 2.3nM 化合物143 17nM 化合物43 15nM 化合物146 12.3nM 化合物44 17nM 化合物151 ＜200nM 化合物45 6nM 化合物152 23nM 化合物46 21nM 化合物153 ＜50nM 化合物48 9nM 化合物155 7.2nM 化合物49 20nM 化合物156 3.6nM 化合物50 ＜50nM 化合物157 19.6nM 化合物51 16nM 化合物158 ＜50nM 化合物61的三氟乙酸鹽 3.7nM 化合物163 26.4nM 化合物62的三氟乙酸鹽 ＜1nM 化合物164 2.9nM 化合物65的三氟乙酸鹽 3.8nM 化合物166 ＜100nM 化合物74 3.1nM 化合物167 ＜100nM 化合物75 3.2nM 化合物168 ＜100nM 化合物76 12.2nM 化合物169 ＜50nM 化合物80 13nM 化合物170 ＜100nM 化合物81 2.4nM 化合物182 22nM 化合物82 ＜50nM 化合物183 5.5nM 化合物84 ＜50nM 化合物184 14.6nM 化合物85 3.2nM 化合物184 ＜50nM 化合物88 ＜500nM 化合物189 11.2nM 化合物89 ＜500nM 化合物190 3.7nM 化合物91 ＜50nM 化合物193 10.5nM 化合物93的三氟乙酸鹽 ＜50nM 化合物194 5.3nM 化合物94 ＜100nM 化合物195 5.2nM 化合物95的三氟乙酸鹽 3.9nM 化合物196 2.7nM 化合物96 6.8nM 化合物197 10.2nM 化合物97 1.4nM       The IC 50 value results for inhibiting 22RV1 cell proliferation are shown in Table 1 . Table 1 IC50 value of compounds of the present invention inhibiting 22RV1 cells Compound number IC 50 Compound number IC 50 Compound 1 11nM Trifluoroacetate salt of compound 99 <50nM Compound 4 17nM Compound 101 1.1nM Compound 5 15nM Compound 102 3.1nM Compound 7 4.8nM Compound 103 <100nM Compound 8 <100nM Compound 105 2nM Compound 9 3.5nM Compound 107 3.1nM Compound 10 2nM Compound 109 4.8nM Compound 12 <500nM Compound 110 3.6nM Compound 13 44nM Trifluoroacetate salt of compound 112 18.2nM Compound 14 5.7nM Compound 114 <1nM Compound 17 6.9nM Compound 115 3.9nM Compound 18 <50nM Compound 118 <100nM Compound 19 2.7nM Trifluoroacetate salt of compound 121 1.4nM Compound 20 <50nM Trifluoroacetate salt of compound 123 10.1nM Trifluoroacetate salt of compound 23 21nM Compound 126 22.3nM Compound 25 18nM Compound 128 25.3nM Trifluoroacetate salt of compound 27 11nM Compound 130 5.2nM Compound 29 2.9nM Compound 131 4.6nM Compound 30 7.4nM Compound 132 3.8nM Compound 32 14nM Compound 138 20.5nM Compound 34 7nM Compound 140 22.3nM Compound 35 1.9nM Compound 141 3.4nM Compound 36 11.1nM Compound 142 6.2nM Trifluoroacetate salt of compound 41 2.3nM Compound 143 17nM Compound 43 15nM Compound 146 12.3nM Compound 44 17nM Compound 151 <200nM Compound 45 6nM Compound 152 23nM Compound 46 21nM Compound 153 <50nM Compound 48 9nM Compound 155 7.2nM Compound 49 20nM Compound 156 3.6nM Compound 50 <50nM Compound 157 19.6nM Compound 51 16nM Compound 158 <50nM Trifluoroacetate salt of compound 61 3.7nM Compound 163 26.4nM Trifluoroacetate salt of compound 62 <1nM Compound 164 2.9nM Trifluoroacetate salt of compound 65 3.8nM Compound 166 <100nM Compound 74 3.1nM Compound 167 <100nM Compound 75 3.2nM Compound 168 <100nM Compound 76 12.2nM Compound 169 <50nM Compound 80 13nM Compound 170 <100nM Compound 81 2.4nM Compound 182 22nM Compound 82 <50nM Compound 183 5.5nM Compound 84 <50nM Compound 184 14.6nM Compound 85 3.2nM Compound 184 <50nM Compound 88 <500nM Compound 189 11.2nM Compound 89 <500nM Compound 190 3.7nM Compound 91 <50nM Compound 193 10.5nM Trifluoroacetate salt of compound 93 <50nM Compound 194 5.3nM Compound 94 <100nM Compound 195 5.2nM Trifluoroacetate salt of compound 95 3.9nM Compound 196 2.7nM Compound 96 6.8nM Compound 197 10.2nM Compound 97 1.4nM

結論：本發明化合物，例如實施例化合物對前列腺細胞22RV1具有良好的抑制作用，具體的如表1所示。Conclusion: The compounds of the present invention, such as the example compounds, have good inhibitory effects on prostate cells 22RV1, as shown in Table 1.

2. 22RV1細胞中AR剪切突變體7 (AR-V7) 的降解實驗2. Degradation experiment of AR splicing mutant 7 (AR-V7) in 22RV1 cells

前列腺癌細胞22RV1購置於ATCC，細胞培養基為1640+10%FBS，培養於37 ℃，5% CO 2孵箱中。第一天收集處於指數生長期的細胞，用1% css-FBS無酚紅培養基將細胞懸液調整為相應濃度鋪板，6孔板每孔1 mL，細胞數量為300000個/孔。次日加入含待測化合物的1% css-FBS無酚紅培養基，其中一個孔加入0.2% DMSO的1% css-FBS無酚紅培養基作為DMSO溶媒對照，6孔板培養於37 ℃， 5% CO 2孵箱中。24或48小時後，胰酶消化，收集細胞於1.5 mL 離心管，向每孔加入15 μL RIPA裂解液（含1X蛋白酶抑制劑混合物(Protease Inhibitor cocktail)），於冰上裂解15分鐘後，12000g，4℃，離心10分鐘。收集上清蛋白樣品，用BCA法進行蛋白定量。使用全自動蛋白質表達定量分析檢測AR-V7，實驗過程如下，將待測蛋白濃度稀釋至2 mg/mL。取4 μL稀釋後的蛋白樣品加入1 μL 5x Master Mix（試劑盒提供），將配製好的樣品放在95 ℃變性5分鐘，放在冰上待用。使用Antibody Diluent II（試劑盒提供）稀釋一抗，一抗為AR V7（CST, 19672S）與β-actin（CST,3700），稀釋比例分別為1:10和1:500。二抗為1:1混合羊抗小鼠和羊抗兔二抗，顯色液為1:1混合的Lumino-S和Peroxide。按照試劑盒說明書將配製好的試劑依次加入檢測板內，上機檢測。Western條帶處理使用全自動蛋白質表達定量分析軟體“Compass for SW”根據信號值自動類比western條帶。根據式（2）計算不同藥物濃度下，AR-V7（2）相對於溶媒對照的降解率。其中AR-V7 compound為給藥組AR-V7相對峰面積，AR-V7 solvent為溶媒對照組AR-V7相對峰面積。 AR-V7% =(1-AR-V7 compound/AR-V7 solvent)× 100%  式（2） Prostate cancer cell 22RV1 was purchased from ATCC, the cell culture medium was 1640+10% FBS, and cultured in a 37°C, 5% CO 2 incubator. On the first day, cells in the exponential growth phase were collected, and the cell suspension was adjusted to the corresponding concentration using 1% css-FBS phenol red-free medium and plated, with 1 mL per well of a 6-well plate, and the number of cells was 300,000 cells/well. The next day, 1% css-FBS phenol red-free medium containing the compound to be tested was added, and 1% css-FBS phenol red-free medium containing 0.2% DMSO was added to one well as a DMSO solvent control. The 6-well plate was cultured at 37°C, 5% CO 2 incubator. After 24 or 48 hours, trypsinize, collect cells in a 1.5 mL centrifuge tube, add 15 μL RIPA lysis solution (containing 1X protease inhibitor cocktail) to each well, lyse on ice for 15 minutes, 12000g , 4°C, centrifuge for 10 minutes. Supernatant protein samples were collected and protein quantified using BCA method. Use fully automated protein expression quantitative analysis to detect AR-V7. The experimental process is as follows: dilute the protein concentration to be tested to 2 mg/mL. Add 4 μL of the diluted protein sample to 1 μL of 5x Master Mix (provided by the kit), denature the prepared sample at 95°C for 5 minutes, and put it on ice until use. Use Antibody Diluent II (provided in the kit) to dilute the primary antibodies. The primary antibodies are AR V7 (CST, 19672S) and β-actin (CST, 3700). The dilution ratios are 1:10 and 1:500 respectively. The secondary antibody was a 1:1 mixture of goat anti-mouse and goat anti-rabbit secondary antibodies, and the chromogenic solution was a 1:1 mixture of Lumino-S and Peroxide. According to the instructions of the kit, add the prepared reagents to the detection plate in sequence, and run the test on the machine. Western band processing uses the fully automatic protein expression quantitative analysis software "Compass for SW" to automatically compare western bands based on signal values. Calculate the degradation rate of AR-V7(2) relative to the vehicle control under different drug concentrations according to formula (2). Among them, AR-V7 compound is the relative peak area of AR-V7 in the administration group, and AR-V7 solvent is the relative peak area of AR-V7 in the vehicle control group. AR-V7% =(1-AR-V7 compound /AR-V7 solvent )× 100% Formula (2)

DC 50計算：按照式（2）處理，使用Graphpad軟體計算並採用log(inhibitor) vs. response – Variable slope (four parameters)函數分析AR-V7降解率為50 %時的化合物濃度DC 50值。 表2 48小時降解AR-V7的DC 50 序號 化合物 AR-V7 DC50 (μM) 1 化合物4 ＜0.2 2 化合物18 ＜0.2 3 化合物20 ＜0.5 4 化合物23的三氟乙酸鹽 ＜0.2 5 化合物45 ＜0.2 6 化合物48 ＜0.2 7 化合物65的三氟乙酸鹽 ＜0.2 8 化合物80 ＜0.2 9 化合物114 ＜0.2 DC 50 calculation: According to formula (2), use Graphpad software to calculate and use the log(inhibitor) vs. response – Variable slope (four parameters) function to analyze the DC 50 value of the compound concentration when the AR-V7 degradation rate is 50%. Table 2 DC 50 for degradation of AR-V7 in 48 hours serial number compound AR-V7 DC50 (μM) 1 Compound 4 <0.2 2 Compound 18 <0.2 3 Compound 20 <0.5 4 Trifluoroacetate salt of compound 23 <0.2 5 Compound 45 <0.2 6 Compound 48 <0.2 7 Trifluoroacetate salt of compound 65 <0.2 8 Compound 80 <0.2 9 Compound 114 <0.2

結論：本發明化合物，例如實施例化合物對前列腺細胞22RV1中AR-V7具有良好的降解作用。Conclusion: The compounds of the present invention, such as the example compounds, have a good degradation effect on AR-V7 in prostate cells 22RV1.

3. 大鼠藥代動力學測試3. Rat pharmacokinetic test

實驗目的：本試驗通過單劑量靜脈和灌胃給予受試物於SD大鼠，測定大鼠血漿中受試物的濃度，評價受試物在大鼠體內藥代特徵。 Purpose of the experiment: In this experiment, the test substance was administered to SD rats through a single dose intravenously and intragastrically, to measure the concentration of the test substance in rat plasma, and to evaluate the pharmacokinetic characteristics of the test substance in rats.

試驗動物：雄性SD大鼠，200~250g，6~8周齡，6隻/化合物。購於成都達碩實驗動物有限公司。 Test animals: male SD rats, 200~250g, 6~8 weeks old, 6 rats/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

試驗方法：試驗當天，6只SD大鼠按體重隨機分組。給藥前1天禁食不禁水12~14 h，給藥後4 h給食。 表3 組別 數量 給藥信息 雄性 受試物 給藥劑量* (mg/kg) 給藥濃度 (mg/mL) 給藥體積 (mL/kg) 採集樣本 給藥 方式 溶媒 G1 3 本發明 化合物 5 0.5 10 血漿 口服 (灌胃) 5% DMSO+ 5%Solutol+ 30%PEG-400+60% (20%SBE-β-CD) G2 3 2 0.4 5 血漿 靜脈注射 5%DMA+5%Solutol+90% Saline Test method: On the day of the test, 6 SD rats were randomly divided into groups according to body weight. The subjects were fasted for 12 to 14 hours on the day before administration and fed 4 hours after administration. table 3 Group quantity Dosing information male test substance Dosage* (mg/kg) Dosing concentration (mg/mL) Dosing volume (mL/kg) Collect samples Dosing method solvent G1 3 Compounds of the present invention 5 0.5 10 plasma Oral administration (gavage) 5% DMSO+ 5%Solutol+ 30%PEG-400+60% (20%SBE-β-CD) G2 3 2 0.4 5 plasma intravenous injection 5%DMA+5%Solutol+90% Saline

*劑量以游離鹼計。*Dosage is based on free base.

取樣：於給藥前及給藥後異氟烷麻醉經眼眶取血0.1 mL，置於EDTAK2離心管中。5000 rpm，4 ℃離心10 min，收集血漿。Sampling: Before and after administration, 0.1 mL of blood was taken from the orbit under isoflurane anesthesia and placed in an EDTAK2 centrifuge tube. Centrifuge at 5000 rpm and 4°C for 10 min to collect plasma.

IV&PO組採集血漿時間點：0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 24 h。The plasma collection time points in the IV&PO group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, and 24 h.

分析檢測前，所有樣品存於-60℃。用LC-MS/MS對樣品進行定量分析。 表4 本發明化合物在大鼠血漿中藥代動力學參數 受試化合物 給藥方式* AUC 0-t(ng/mL·h) 口服T 1/2 F% 化合物1 i.g. (5 mg/kg) 31180±1470 N/A 76.9±3.6 化合物4 i.g. (5 mg/kg) 30632±2685 34.0±9.6 91.3±8.0 化合物5 i.g. (5 mg/kg) 58405±4378 N/A 63.1±4.7 化合物7 i.g. (5 mg/kg) 14560±3924 N/A 34.0±9.2 化合物9 i.g. (5 mg/kg) 6771±760 N/A 60.6±6.8 化合物18 i.g. (5 mg/kg) 12339±2759 N/A 52.2±12 化合物20 i.g. (5 mg/kg) 6686±1199 N/A N/A 化合物23的三氟乙酸鹽 i.g. (5 mg/kg) 18824±1746 N/A 47.4±4.4 化合物50 i.g. (5 mg/kg) 6284±990 N/A N/A 化合物65的三氟乙酸鹽 i.g. (5 mg/kg) 12994±2091 N/A 113±18 化合物80 i.g. (5 mg/kg) 21176±3784 N/A 69.2±12 化合物91 i.g. (5 mg/kg) 8134±1990 N/A N/A 化合物95的三氟乙酸鹽 i.g. (5 mg/kg) 7236±763 N/A N/A 化合物97 i.g. (5 mg/kg) 19933±1456 N/A N/A 化合物102 i.g. (5 mg/kg) 18578±2095 N/A N/A 化合物103 i.g. (5 mg/kg) 20628±13377 N/A N/A 化合物107 i.g. (5 mg/kg) 28248±8329 N/A N/A 化合物109 i.g. (5 mg/kg) 8298±2003 N/A N/A 化合物110 i.g. (5 mg/kg) 22684±1630 N/A N/A 化合物130 i.g. (5 mg/kg) 19203±4547 N/A N/A 化合物131 i.g. (5 mg/kg) 8885±2743 28.0±4.5 N/A 化合物132 i.g. (5 mg/kg) 7771±1478 20.8±3.0 N/A 化合物146 i.g. (5 mg/kg) 17375±2986 24.4±7.4 N/A Before analysis and detection, all samples were stored at -60°C. Samples were analyzed quantitatively using LC-MS/MS. Table 4 Pharmacokinetic parameters of the compounds of the present invention in rat plasma test compound Mode of administration* AUC 0-t (ng/mL·h) Oral T 1/2 F% Compound 1 ig (5 mg/kg) 31180±1470 N/A 76.9±3.6 Compound 4 ig (5 mg/kg) 30632±2685 34.0±9.6 91.3±8.0 Compound 5 ig (5 mg/kg) 58405±4378 N/A 63.1±4.7 Compound 7 ig (5 mg/kg) 14560±3924 N/A 34.0±9.2 Compound 9 ig (5 mg/kg) 6771±760 N/A 60.6±6.8 Compound 18 ig (5 mg/kg) 12339±2759 N/A 52.2±12 Compound 20 ig (5 mg/kg) 6686±1199 N/A N/A Trifluoroacetate salt of compound 23 ig (5 mg/kg) 18824±1746 N/A 47.4±4.4 Compound 50 ig (5 mg/kg) 6284±990 N/A N/A Trifluoroacetate salt of compound 65 ig (5 mg/kg) 12994±2091 N/A 113±18 Compound 80 ig (5 mg/kg) 21176±3784 N/A 69.2±12 Compound 91 ig (5 mg/kg) 8134±1990 N/A N/A Trifluoroacetate salt of compound 95 ig (5 mg/kg) 7236±763 N/A N/A Compound 97 ig (5 mg/kg) 19933±1456 N/A N/A Compound 102 ig (5 mg/kg) 18578±2095 N/A N/A Compound 103 ig (5 mg/kg) 20628±13377 N/A N/A Compound 107 ig (5 mg/kg) 28248±8329 N/A N/A Compound 109 ig (5 mg/kg) 8298±2003 N/A N/A Compound 110 ig (5 mg/kg) 22684±1630 N/A N/A Compound 130 ig (5 mg/kg) 19203±4547 N/A N/A Compound 131 ig (5 mg/kg) 8885±2743 28.0±4.5 N/A Compound 132 ig (5 mg/kg) 7771±1478 20.8±3.0 N/A Compound 146 ig (5 mg/kg) 17375±2986 24.4±7.4 N/A

*註：i.g.（灌胃）給予化合物；N/A：未測*Note: Compounds administered i.g. (gavage); N/A: Not tested

結論：運用本發明化合物，例如實施例化合物在大鼠體內具有較好的的口服吸收。Conclusion: Using the compounds of the present invention, for example, the example compounds have better oral absorption in rats.

4. 小鼠藥代動力學測試4. Mouse pharmacokinetic testing

4.1 試驗動物：雄性ICR小鼠，25~30 g，6隻/化合物。購於成都達碩實驗動物有限公司。 4.1 Test animals: male ICR mice, 25~30 g, 6/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

4.2 試驗設計：試驗當天，6隻ICR小鼠按體重隨機分組。給藥前1天禁食不禁水12~14 h，給藥後4 h給食。 表5. 給藥信息 組別 數量 給藥信息                                           雄性 測試化合物 給藥劑量 (mg/kg) 給藥濃度 (mg/mL) 給藥體積 (mL/kg) 採集樣本 給藥 方式 G1 3 本發明化合物 2 0.4 5 血漿 靜脈 G2 3 5 0.5 10 血漿 口服(灌胃) 4.2 Experimental design: On the day of the experiment, 6 ICR mice were randomly divided into groups according to body weight. The subjects were fasted for 12 to 14 hours on the day before administration and fed 4 hours after administration. Table 5. Dosing information Group quantity Dosing information male test compound Dosage (mg/kg) Dosing concentration (mg/mL) Dosing volume (mL/kg) Collect samples Dosing method G1 3 Compounds of the present invention 2 0.4 5 plasma veins G2 3 5 0.5 10 plasma Oral administration (gavage)

註：靜脈給藥溶媒: 5%DMA+5%Solutol+90%Saline；Note: Intravenous administration vehicle: 5%DMA+5%Solutol+90%Saline;

口服 (灌胃) 給藥溶媒：5%DMSO+5%Solutol+30%PEG400+60%(20%SBE-CD)；Oral (gavage) administration vehicle: 5% DMSO+5% Solutol+30%PEG400+60%(20%SBE-CD);

*劑量以游離鹼計。*Dosage is based on free base.

於給藥前及給藥後異氟烷麻醉經眼眶取血0.1 mL，置於EDTAK2離心管中，5000 rpm，4℃離心10 min，收集血漿。靜脈組和灌胃組採血時間點均為: 0, 5, 15, 30min, 1, 2, 4, 7, 24 h。分析檢測前，所有樣品存於-60℃，用LC-MS/MS對樣品進行定量分析。Before and after administration, 0.1 mL of blood was taken from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for both the intravenous group and the intragastric group were: 0, 5, 15, 30min, 1, 2, 4, 7, and 24 h. Before analysis and detection, all samples were stored at -60°C and quantitatively analyzed using LC-MS/MS.

結論：運用本發明化合物，例如實施例化合物在小鼠體內具有較好的口服吸收。Conclusion: Using the compounds of the present invention, for example, the example compounds have better oral absorption in mice.

5. 比格犬藥代動力學測試5. Pharmacokinetic test in beagle dogs

試驗動物：雄性比格犬，8~10 kg左右，6隻/化合物，購於北京瑪斯生物技術有限公司。 Experimental animals: male beagles, about 8-10 kg, 6/compound, purchased from Beijing Mas Biotechnology Co., Ltd.

試驗方法：試驗當天，6隻比格犬按體重隨機分組。給藥前1天禁食不禁水14~18 h，給藥後4 h給食。 Test method: On the day of the test, 6 beagle dogs were randomly divided into groups according to body weight. The subjects were fasted for 14 to 18 hours one day before administration and fed 4 hours after administration.

表6. 給藥信息 組別 數量 給藥信息                                           雄性 測試化合物 給藥劑量 (mg/kg) 給藥濃度 (mg/mL) 給藥體積 (mL/kg) 採集樣本 給藥 方式 G1 3 本發明化合物 1 1 1 血漿 靜脈 G2 3 5 1 5 血漿 口服(灌胃) Table 6. Dosing information Group quantity Dosing information male test compound Dosage (mg/kg) Dosing concentration (mg/mL) Dosing volume (mL/kg) Collect samples Dosing method G1 3 Compounds of the present invention 1 1 1 plasma veins G2 3 5 1 5 plasma Oral administration (gavage)

註：靜脈給藥溶媒：5%DMA+5%Solutol+90%Saline；Note: Intravenous administration vehicle: 5% DMA+5% Solutol+90% Saline;

口服 (灌胃) 給藥溶媒：5%DMSO+5%Solutol+30%PEG400+60%(20%SBE-CD)；Oral (gavage) administration vehicle: 5% DMSO+5% Solutol+30%PEG400+60%(20%SBE-CD);

*劑量以游離鹼計。*Dosage is based on free base.

於給藥前及給藥後通過頸靜脈或四肢靜脈取血1 mL，置於EDTAK2離心管中。5000 rpm，4 ℃離心10 min，收集血漿。靜脈組和灌胃組採血時間點均為:0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48 h。分析檢測前，所有樣品存於-80℃，用LC-MS/MS對樣品進行定量分析。Before and after administration, 1 mL of blood was taken from the jugular vein or limb veins and placed in EDTAK2 centrifuge tubes. Centrifuge at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for both the intravenous group and the intragastric group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, and 48 h. Before analysis and detection, all samples were stored at -80°C and quantitatively analyzed using LC-MS/MS.

結論：運用本發明化合物，例如實施例化合物在犬體內具有較好的口服吸收。Conclusion: Using the compounds of the present invention, for example, the example compounds have better oral absorption in dogs.

6. 猴藥代動力學測試6. Monkey pharmacokinetic testing

試驗動物：雄性食蟹猴，3~5 kg，3~6年齡，4隻/化合物。購于蘇州西山生物技術有限公司。 Experimental animals: male cynomolgus monkeys, 3~5 kg, 3~6 years old, 4/compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

試驗方法：試驗當天，4隻猴按體重隨機分組。給藥前1天禁食不禁水14~18 h，給藥後4 h給食。 表7. 給藥信息 組別 數量 給藥信息 雄性 測試化合物 給藥劑量 (mg/kg) 給藥濃度 (mg/mL) 給藥體積 (mL/kg) 採集樣本 給藥 方式 G1 2 本發明化合物 1 1 1 血漿 靜脈 G2 2 5 1 5 血漿 口服(灌胃) Test method: On the day of the test, 4 monkeys were randomly divided into groups according to body weight. The subjects were fasted for 14 to 18 hours one day before administration and fed 4 hours after administration. Table 7. Dosing information Group quantity Dosing Information male test compound Dosage (mg/kg) Dosing concentration (mg/mL) Dosing volume (mL/kg) Collect samples Dosing method G1 2 Compounds of the present invention 1 1 1 plasma veins G2 2 5 1 5 plasma Oral administration (gavage)

註：靜脈給藥溶媒：5%DMA+5%Solutol+90%Saline；Note: Intravenous administration vehicle: 5% DMA+5% Solutol+90% Saline;

口服 (灌胃) 給藥溶媒：5%DMSO+5%Solutol+30%PEG400+60%(20%SBE-CD)；Oral (gavage) administration vehicle: 5% DMSO+5% Solutol+30%PEG400+60%(20%SBE-CD);

*劑量以游離鹼計。*Dosage is based on free base.

於給藥前及給藥後通過四肢靜脈取血1.0 mL，置於EDTAK2離心管中。5000 rpm，4 ℃離心10 min，收集血漿。靜脈組和灌胃組採血時間點均為:0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h。分析檢測前，所有樣品存於-80℃，用LC-MS/MS對樣品進行定量分析。 Before and after administration, 1.0 mL of blood was taken from the veins of the limbs and placed in EDTAK2 centrifuge tubes. 5000 rpm, 4 Centrifuge at 10°C for 10 min to collect plasma. The blood collection time points for both the intravenous group and the intragastric group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, and 24 h. Before analysis and detection, all samples were stored at -80°C and quantitatively analyzed using LC-MS/MS.

結論：運用本發明化合物，例如實施例化合物在猴體內具有較好的口服吸收。 Conclusion: The compounds of the present invention, such as the compounds in the examples, have better oral absorption in monkeys.

7. hERG鉀離子通道作用測試7. hERG potassium channel function test

實驗平臺：電生理手動膜片鉗系統 Experimental platform: electrophysiology manual patch clamp system

細胞系：穩定表達hERG 鉀離子通道的中國倉鼠卵巢 (CHO) 細胞系 Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

實驗方法：穩定表達hERG 鉀通道的CHO (Chinese Hamster Ovary) 細胞，在室溫下用全細胞膜片鉗技術記錄hERG 鉀通道電流。玻璃微電極由玻璃電極毛胚 (BF150-86-10，Sutter) 經拉製儀拉製而成，灌注電極內液後的尖端電阻為2-5 MΩ左右，將玻璃微電極插入放大器探頭即可連接至膜片鉗放大器。鉗制電壓和資料記錄由pClamp 10 軟體通過電腦控制和記錄，採樣頻率為10 kHz，濾波頻率為2kHz。在得到全細胞記錄後，細胞鉗制在-80 mV，誘發hERG 鉀電流( I hERG) 的步階電壓從-80 mV 給予一個2 s 的去極化電壓到+20 mV，再複極化到-50 mV，持續1 s 後回到-80 mV。每10 s 給予此電壓刺激，確定hERG 鉀電流穩定後 (至少1 分鐘) 開始給藥過程。化合物每個測試濃度至少給予 1 分鐘，每個濃度至少測試2個細胞 (n≥2)。 Experimental method: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents at room temperature using whole-cell patch clamp technology. The glass microelectrode is made from a glass electrode blank (BF150-86-10, Sutter) by a drawing instrument. The tip resistance after filling the electrode internal liquid is about 2-5 MΩ. Just insert the glass microelectrode into the amplifier probe. Connect to patch clamp amplifier. The clamping voltage and data recording are controlled and recorded by the pClamp 10 software through the computer. The sampling frequency is 10 kHz and the filtering frequency is 2 kHz. After obtaining whole-cell recordings, the cells were clamped at -80 mV, and the step voltage of the induced hERG potassium current ( I hERG ) was given by a 2 s depolarization voltage from -80 mV to +20 mV, and then repolarization to - 50 mV, lasts for 1 s and then returns to -80 mV. This voltage stimulation was given every 10 s, and the administration process was started after confirming that the hERG potassium current was stable (at least 1 minute). Compounds were administered for at least 1 min at each concentration tested, and at least 2 cells were tested at each concentration (n ≥ 2).

資料處理：資料分析處理採用pClamp 10，GraphPad Prism 5 和Excel 軟體。不同化合物濃度對hERG 鉀電流 (-50 mV 時誘發的hERG 尾電流峰值) 的抑制程度用以下公式計算： Inhibition % = [1 – ( I/ Io)]×100% Data processing: pClamp 10, GraphPad Prism 5 and Excel software were used for data analysis and processing. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) at different compound concentrations was calculated using the following formula: Inhibition % = [1 – ( I / I o)] × 100%

其中，Inhibition %代表化合物對hERG鉀電流的抑制百分率， I和 Io分別表示在加藥後和加藥前hERG 鉀電流的幅度。 Among them, Inhibition % represents the inhibition percentage of the hERG potassium current by the compound, and I and I o represent the amplitude of the hERG potassium current after and before the addition of the drug, respectively.

化合物IC 50使用GraphPad Prism 5 軟體通過以下方程擬合計算得出： Y=Bottom + (Top-Bottom)/(1+10^((LogIC 50-X)*HillSlope)) Compound IC 50 was calculated by fitting the following equation using GraphPad Prism 5 software: Y=Bottom + (Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope))

其中， X為供試品檢測濃度的Log 值，Y為對應濃度下抑制百分率，Bottom和Top分別為最小和最大抑制百分率。 Among them, X is the Log value of the detected concentration of the test product, Y is the inhibition percentage at the corresponding concentration, Bottom and Top are the minimum and maximum inhibition percentages respectively.

結論：本發明化合物，例如實施例化合物對hERG鉀通道電流沒有明顯的抑制作用。 Conclusion: The compounds of the present invention, such as the examples, have no obvious inhibitory effect on hERG potassium channel current.

8. 肝微粒體穩定性測試8. Liver Microsome Stability Test

本實驗採用人、犬、大鼠和小鼠五種屬肝微粒體作為體外模型來評價受試物的代謝穩定性。This experiment uses five types of hepatic microsomes from humans, dogs, rats and mice as in vitro models to evaluate the metabolic stability of the test substance.

在37°C條件下，1 µM的受試物與微粒體蛋白、輔酶NADPH共同孵育，反應至一定時間（5, 10, 20, 30, 60 min）加入冰冷含內標的乙腈終止反應，採用LC-MS/MS方法檢測樣品中受試物濃度，以孵育體系中藥物剩餘率的ln值和孵育時間求得T 1/2，並進一步計算肝微粒體固有清除率CL int(mic)和肝固有清除率CL int(Liver)。 At 37°C, 1 µM of the test substance was incubated with microsomal protein and coenzyme NADPH. After the reaction reached a certain time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing an internal standard was added to terminate the reaction. LC was used. -MS/MS method detects the concentration of the test substance in the sample, calculates T 1/2 based on the ln value of the remaining rate of the drug in the incubation system and the incubation time, and further calculates the liver microsome intrinsic clearance rate CL int (mic) and liver intrinsic clearance rate Clearance CL int(Liver) .

結論：本發明化合物，例如實施例化合物具有良好的肝微粒體穩定性。 Conclusion: The compounds of the present invention, such as the example compounds, have good liver microsome stability.

9. CYP450酶抑制測試9. CYP450 Enzyme Inhibition Test

本項研究的目的是應用體外測試體系評價受試物對人肝微粒體細胞色素P450（CYP）的5種同工酶（CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4）活性的影響。CYP450同工酶的特異性探針底物分別與人肝微粒體以及不同濃度的受試物共同孵育，加入還原型煙醯胺腺嘌呤二核苷酸磷酸（NADPH）啟動反應，在反應結束後，通過處理樣品並採用液相色譜-串聯質譜聯用（LC-MS/MS）法定量檢測特異性底物產生的代謝產物，測定CYP酶活性的變化，計算IC 50值，評價受試物對各CYP酶亞型的抑制潛能。 The purpose of this study is to apply an in vitro test system to evaluate the effect of test substances on the activity of five isoenzymes of human liver microsomal cytochrome P450 (CYP) (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). The specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and test substances of different concentrations. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to start the reaction. After the reaction, , by processing the sample and using liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantitatively detect the metabolites produced by the specific substrate, determine the changes in CYP enzyme activity, calculate the IC 50 value, and evaluate the effect of the test substance on Inhibitory potential of each CYP enzyme isoform.

結論：本發明化合物，例如實施例化合物對人肝微粒體細胞色素P450的5種同工酶沒有明顯的抑制作用。 Conclusion: The compounds of the present invention, such as the examples, have no obvious inhibitory effect on the five isoenzymes of human liver microsomal cytochrome P450.

10. Caco2滲透性測試10. Caco2 Penetration Test

試驗使用單層Caco-2細胞，在96孔Transwell板中採用三平行孵育。將含有本發明化合物（2 μM）或對照化合物地高辛（10 μM）、納多洛爾（2 μM）和美托洛爾（2 μM）的轉運緩衝溶液（HBSS，10 mM HEPES，pH 7.4±0.05）加入頂端側或基底側的給藥端孔中。對應接收端孔中加入含DMSO的轉運緩衝溶液。在37±1°C條件下孵育2小時後，取出細胞板並從頂端和底端各取出適量樣品至新的96孔板中。隨後加入含內標的乙腈沉澱蛋白。使用LC MS/MS分析樣品並測定本發明化合物和對照化合物的濃度。濃度資料用於計算從單層細胞頂端側向基底側、以及基底側向頂端轉運的表觀滲透係數，從而計算外排率。用螢光黃的滲漏評價孵育2小時後單層細胞的完整性。The assay uses a monolayer of Caco-2 cells incubated in triplicate in a 96-well Transwell plate. Transport buffer solution (HBSS, 10 mM HEPES, pH 7.4± 0.05) into the administration port hole on the apical or basal side. Add DMSO-containing transport buffer solution to the corresponding receiving port hole. After incubation for 2 hours at 37±1°C, remove the cell plate and transfer appropriate amounts of samples from the top and bottom ends to a new 96-well plate. Acetonitrile containing internal standard was then added to precipitate the protein. Samples were analyzed using LC MS/MS and the concentrations of compounds of the invention and control compounds were determined. Concentration data are used to calculate apparent permeability coefficients for transport from the apical side to the basal side and from the basal side to the apical side of a monolayer of cells, thereby calculating the efflux rate. The integrity of the monolayer after 2 hours of incubation was assessed by the leakage of Lucifer Yellow.

結論：本發明化合物，例如實施例化合物具有一定的Caco2滲透性。Conclusion: The compounds of the present invention, such as the example compounds, have certain Caco2 permeability.

11. 本發明化合物對小鼠22RV1皮下移植瘤模型生長的抑制實驗11. Experiment on the inhibition of the growth of the 22RV1 subcutaneous transplanted tumor model in mice by the compounds of the present invention

細胞培養：22RV1細胞（來源於ATCC）體外培養，培養條件為添加10％胎牛血清以及含10 μg/mL重組胰島素的培養基，37 ºC，5% CO 2。一周常規傳代2次。當細胞維持在指數增長期時，收取細胞，計數，接種。 Cell culture: 22RV1 cells (derived from ATCC) were cultured in vitro. The culture conditions were medium supplemented with 10% fetal calf serum and 10 μg/mL recombinant insulin at 37 ºC and 5% CO 2 . Passaging was performed twice a week. When the cells are maintained in the exponential growth phase, cells are harvested, counted, and seeded.

動物：BALB/c nude小鼠，雄性，4-6周齡，體重14-20克。由北京維通利華實驗動物技術有限公司提供。Animals: BALB/c nude mice, male, 4-6 weeks old, weighing 14-20 grams. Provided by Beijing Weitonglihua Experimental Animal Technology Co., Ltd.

腫瘤接種：實驗小鼠於右側背部皮下接種5×10 622RV1細胞，細胞重懸在PBS與基質膠（1:1）中，定期觀察腫瘤生長情況，待腫瘤生長至平均體積為80 mm 3時進行去勢：用異氟烷麻醉小鼠，手術閹割通過陰囊中線切口進行，允許雙側進入，暴露每個睾丸後，用5-0 vicryl縫線結紮精索，然後切除睾丸，然後分別用5-0 Vicyryl縫合陰囊和皮膚，術後需繼續觀察動物至完全蘇醒。去勢後，腫瘤可能縮小（腫瘤退化），當平均腫瘤體積重新生長到100 mm 3左右時開始分組和治療，分組當天為Day 0。 Tumor inoculation: Experimental mice were subcutaneously inoculated with 5×10 6 22RV1 cells on the right back. The cells were resuspended in PBS and Matrigel (1:1). Tumor growth was observed regularly until the tumor grew to an average volume of 80 mm 3 Perform castration: Anesthetize the mouse with isoflurane. Surgical castration is performed through a midline incision in the scrotum, allowing bilateral access. After exposing each testicle, the spermatic cord is ligated with 5-0 vicryl sutures, and then the testicles are removed, followed by 5-0 vicryl sutures. -0 Vicyryl sutures the scrotum and skin. After surgery, the animal needs to be observed until it fully wakes up. After castration, the tumors may shrink (tumor regression). Grouping and treatment will begin when the average tumor volume re-grows to about 100 mm. The day of grouping is Day 0.

給藥：本發明化合物按照一定給藥劑量，口服給藥（PO），每天一次給藥（QD），每組10隻小鼠，所有組持續給藥28天。Administration: The compound of the present invention was administered orally (PO) and once a day (QD) according to a certain dosage. There were 10 mice in each group, and all groups were administered continuously for 28 days.

實驗觀察和結束：每週3次測量小鼠體重以及腫瘤測量。給藥28天後結束實驗，安樂死所有小鼠。腫瘤體積計算公式：腫瘤體積（mm 3）= 1/2 ×（a × b 2）（其中a表示長徑，b表示短徑），原始資料由天平和遊標卡尺測量。 Experimental observation and conclusion: The mouse body weight and tumor measurement were measured three times a week. The experiment was terminated 28 days after administration, and all mice were euthanized. Tumor volume calculation formula: tumor volume (mm 3 ) = 1/2 × (a × b 2 ) (where a represents the long diameter and b represents the short diameter), and the original data were measured by a balance and a vernier caliper.

結論：本發明化合物，例如實施例化合物對小鼠22RV1皮下移植瘤模型生長有一定的抑制作用。Conclusion: The compounds of the present invention, such as the example compounds, have a certain inhibitory effect on the growth of the mouse 22RV1 subcutaneous transplanted tumor model.

12. 1.HEK293細胞增殖實驗12. 1.HEK293 cell proliferation experiment

人胚腎293細胞HEK293購置於ATCC，完全培養基為EMEM+10%FBS，培養於37 ºC, 5% CO 2孵箱中。收集處於指數生長期的細胞，用完全培養基將細胞懸液調整為相應濃度並鋪板，使細胞為1000個/孔，體積為每孔180 μL。次日加入20 μL不同濃度的化合物，置於孵箱中繼續孵育培養7天。培養結束後，按照CellTiter-Glo試劑盒（Promega，G7573）操作說明，每孔加入50 µL預先融化並平衡到室溫的CTG溶液，用微孔板震盪器混勻2分鐘，於室溫放置10分鐘後用酶標儀（PHERAstar FSX）測定螢光信號值。化學發光讀數使用Graphpad Prim 8.0軟體，採用使用四參數非線性回歸模型繪製S型濃度曲線並計算IC 50值。結果按照式（3）處理，計算出化合物各個濃度的增殖率Growth %，並使用Graphpad Prim 8.0軟體，計算增殖率為50%時化合物的濃度IC 50值。其中RLU compound為藥物處理組的讀數，RLU control為溶劑對照組的平均值。 Growth % =RLU compound/ RLU control×100%     式（3） Human embryonic kidney 293 cells HEK293 were purchased from ATCC. The complete culture medium was EMEM+10% FBS and cultured in a 37 ºC, 5% CO 2 incubator. Collect cells in the exponential growth phase, adjust the cell suspension to the corresponding concentration with complete culture medium and plate it so that the number of cells is 1000/well and the volume is 180 μL per well. The next day, 20 μL of compounds of different concentrations were added and placed in an incubator to continue incubation for 7 days. After the culture, according to the instructions of CellTiter-Glo kit (Promega, G7573), add 50 µL of CTG solution that has been melted and equilibrated to room temperature in each well, mix with a microplate shaker for 2 minutes, and leave it at room temperature for 10 Minutes later, the fluorescence signal value was measured using a microplate reader (PHERAstar FSX). Chemiluminescence readings were performed using Graphpad Prim 8.0 software, and a four-parameter nonlinear regression model was used to draw a S-shaped concentration curve and calculate the IC 50 value. The results were processed according to formula (3) to calculate the Growth % of the compound's growth rate at each concentration, and using Graphpad Prim 8.0 software, the IC 50 value of the compound's concentration when the growth rate was 50% was calculated. Among them, RLU compound is the reading of the drug treatment group, and RLU control is the average value of the solvent control group. Growth % =RLU compound / RLU control ×100% Formula (3)

抑制HEK293細胞增殖的IC 50值結果見 表 8。 表8 本發明化合物抑制HEK293細胞的IC50值 序號 化合物 IC50 (μM) 1 化合物107 ＞1 2 化合物182 ＞1 The IC 50 value results for inhibiting HEK293 cell proliferation are shown in Table 8 . Table 8 IC50 value of compounds of the present invention inhibiting HEK293 cells serial number compound IC50 (μM) 1 Compound 107 >1 2 Compound 182 >1

結論：本發明化合物，例如實施例化合物對人胚腎293細胞HEK293具有較弱的抑制作用，具體的如表8所示。Conclusion: The compounds of the present invention, such as the example compounds, have weak inhibitory effects on human embryonic kidney 293 cells HEK293, as shown in Table 8.

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Claims (14)

一種化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，其中，化合物選自通式（I）所示的化合物， B-L-K （I）； L選自鍵或-C 1-50烴基-，所述烴基中有1至20個亞甲基單元任選被-Ak-、-Cy-替換； 每個-Ak-各自獨立地選自-(CH 2) q-、-(CH 2) q-O-、-O-(CH 2) q-、-(CH 2) q-NR L-、-NR L-(CH 2) q-、-(CH 2) q-NR LC(=O)-、-NR L(CH 2) qC(=O)-、-(CH 2) q-C(=O)NR L-、-C(=O)-、-C(=O)-(CH 2) q-NR L-、-(C≡C) q-、-CH=CH-、-Si(R L) 2-、-Si(OH)(R L)-、-Si(OH) 2-、-P(=O)(OR L)-、-P(=O)(R L)-、-S-、-S(=O)-、-S(=O) 2-或者鍵，所述的-CH 2-、-CH=CH-任選被1至2個選自鹵素、OH、CN、NH 2、C 1-6烷基、C 1-6烷氧基、鹵素取代的C 1-6烷基、羥基取代的C 1-6烷基、氰基取代的C 1-6烷基的取代基所取代； q各自獨立的選自0、1、2、3、4、5或6； R L各自獨立的選自H、C 1-6烷基、3-7員雜環基、3-7員環烷基、苯基或5-6員雜芳基，所述的雜環基或雜芳基含有1至4個選自O、S、N的雜原子； 每個-Cy-各自獨立地選自鍵或者任選取代的如下基團之一：4-8員雜單環、4-10員雜並環、5-12員雜螺環、7-10員雜橋環、3-7員單環烷基、4-10員並環烷基、5-12員螺環烷基、7-10員橋環烷基、苯並C 4-6碳環基、苯並4至6員雜環基、5-10員雜芳基或6-10員芳基，當被取代時，被1至4個R L2取代，所述的雜環基、雜芳基、雜單環、雜並環、雜螺環或雜橋環含有1至4個選自O、S、N的雜原子，當雜原子選自S時，任選被1或2個=O取代； R L2各自獨立地選自氘、F、Cl、Br、I、OH、COOH、CN、NH 2、NHC 1-4烷基、N(C 1-4烷基) 2、=O、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、-O-C 1-4亞烷基-O-C 1-4烷基、-O-C 1-4亞烷基-O-C 3-10碳環基、-C 1-4亞烷基-O-C 1-4亞烷基-O-C 1-4烷基、-C 1-4亞烷基-O-C 1-4亞烷基-O-C 3-10碳環基、-O-C 0-4亞烷基-C 3-10碳環基、-C 0-4亞烷基-C 3-10碳環基、-C 0-4亞烷基-4至10員雜環基，所述的烷基、烯基、炔基、烷氧基、亞烷基、碳環基或雜環基任選被1至4個選自F、Cl、Br、I、OH、COOH、CN、NH 2、NHC 1-4烷基、N(C 1-4烷基) 2、=O、C 1-4烷基、鹵素取代的C 1-4烷基、羥基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； B選自 ； B 1選自C 5-20碳環基或4-20員雜環基，所述B 1任選被1至4個R b1所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； B 2選自C 5-20碳環基或4-20員雜環基，所述B 2任選被1至4個R b2取代，所述的雜環基含有1至4個選自O、S、N的雜原子； V選自 ； W選自O或S； Y 1、Y 2、Y 3各自獨立地選自鍵、O、S、NR b5a、C(=S)、C(=O)、CONR b5a、NR b5aCO； P 1、P 2各自獨立地選自 或 ； v 2各自獨立地選自0、1、2、3或4； v 1各自獨立地選自0、1或2； R b1各自獨立的選自H、F、Cl、Br、I、=O、OH、CN、NO 2、COOH、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4烷硫基、-(CH 2) n-R b22、-OR b22、-N(R b21) 2、-C(=O)N(R b21) 2、-C(=O)OR b21、-C(=O)R b22、-S(=O) 2R b22、-P(=O)(R b22) 2、-S(=O) 2N(R b21) 2、-NR b21C(=O)R b22、-NR b21S(=O) 2R b22、C 3-12環烷基、C 6-10芳基、5-10員雜芳基或4-10員雜環基，所述的-CH 2-、烷基、烯基、炔基、烷氧基、烷硫基、環烷基、雜環基、芳基或雜芳基任選被1至4個選自F、Cl、Br、I、OH、=O、-N(R b21) 2、CN、COOH、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 2-4炔基、-C 1-4亞烷基-C 3-6環烷基、-C 1-4亞烷基-OH、-C 1-4亞烷基-O-C 1-4烷基、C 3-6環烷基、5-10員雜芳基或4-10員雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； R b21各自獨立的選自H或C 1-4烷基，所述的烷基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、CF 3、COOH、C 1-4烷基、C 3-6環烷基、C 1-4烷氧基的取代基所取代； R b22各自獨立的選自H、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 3-6環烷基或4-8員雜環基，所述的烷基、烷氧基、環烷基、烯基、炔基或雜環基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、CF 3、COOH、C 1-4烷基、C 3-6環烷基、C 3-6環烷基氧基、C 1-4烷氧基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； n各自獨立的選自0、1、2、3或4； R b2各自獨立的選自H、F、Cl、Br、I、=O、OH、NH 2、-N(R b21) 2、CN、NO 2、COOH、-C(=O)NH 2、-C(=O)NH-C 1-4烷基、-C(=O)N(C 1-4烷基) 2、-(CH 2) n-R b22、-(CH 2) nO(CH 2) n-R b22、-(CH 2) nO(CH 2) nO-R b22、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 3-8環烷基、C 6-10芳基、5-10員雜芳基、4-10員雜環基、-C 1-4亞烷基-4至10員雜環基，所述的亞烷基、CH 2、烷基、烯基、炔基、烷氧基、環烷基、雜環基、芳基或雜芳基任選被1至4個選自F、Cl、Br、I、OH、NH 2、-N(R b21) 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 3-6環烷基、C 3-6環烷基氧基、鹵素取代的C 3-6環烷基、鹵素取代的C 3-6環烷基氧基、5-6員雜芳基或4-8員雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； R b3、R b4、R b6、R b7各自獨立的選自H、F、Cl、Br、I、OH、NH 2、CN、NO 2、-(CH 2) m1-R b23、-(CH 2) m1-X-(CH 2) m2-R b24、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷硫基、C 3-12環烷基、C 6-10芳基、5-10員雜芳基或3-12員雜環基，所述的烷基、烯基、炔基、烷氧基、烷硫基、環烷基、芳基、雜芳基或雜環基任選被1至4個選自氘、F、Cl、Br、I、OH、NH 2、CN、C 1-6烷基、鹵素取代的C 1-6烷基、氰基取代的C 1-6烷基、C 1-6烷氧基、C 2-6炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； 或R b3、R b4與其相連接的碳原子共同形成C 3-8環烷基或3至8員雜單環，所述的環烷基或雜單環任選被1至4個選自氘、F、Cl、Br、I、OH、NH 2、-N(R b21) 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-6環烷基、5-6員雜芳基或3至8雜環基的取代基所取代，所述的雜單環、雜芳基或雜環基含有1至4個選自O、S、N的雜原子； 作為選擇，R b3與R b5a、R b1與R b5a直接連接形成環S，環S選自4至9員含氮雜環基，環S任選被1至4個選自R s的取代基所取代； R s各自獨立的選自F、Cl、Br、I、OH、NH 2、-N(R b21) 2、CN、C 1-4烷基、C 1-4烷氧基、C 3-6環烷基、5-6員雜芳基或3至8雜環基，所述的烷基、烷氧基、環烷基、雜芳基或者雜環基任選被1至4個選自F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述的雜環基或雜芳基含有1至4個選自O、S、N的雜原子； R b5a選自H或R b5； R b5選自OH、NH 2、C 1-4烷基、-(CH 2) n-R b22、-C(=O)N(R b21) 2、-C(=O)R b22、C 3-6環烷基、C 6-10芳基、5-10員雜芳基或4-10員雜環基，所述的-CH 2-、烷基、環烷基、雜環基、芳基或雜芳基任選被1至4個選自F、Cl、Br、I、OH、=O、-N(R b21) 2、CN、COOH、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 3-6環烷基、5-10員雜芳基或4-10員雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； X各自獨立的選自NH、O或S； m1各自獨立的選自0、1、2或3； m2各自獨立的選自0、1、2或3； R b23各自獨立的選自C 2-4烯基、C 2-4炔基、C 3-6環烷基或4-10員雜環基，所述的環烷基、烯基、炔基、雜環基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、CF 3、COOH、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； R b24各自獨立的選自C 1-4烷氧基、C 3-6環烷基氧基、C 3-6環烷基或4-10員雜環基，所述的烷氧基、環烷基、環烷基氧基、雜環基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、CF 3、COOH、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； K選自K1、K2、K3、K4; K1選自 、 ； K2選自 、 、 、 ； K3選自 、 、 、 、 、 、 、 、 、 、 ； K4選自 、 或 ； Q各自獨立地選自鍵、-O-、-S-、-CH 2-、-NR q-、-CO-、-NR qCO-、-CONR q-或3-12員雜環，所述的雜環任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述雜環含有1至4個選自O、S或N的雜原子； R q選自H或C 1-6烷基； A選自C 3-10碳環、C 6-10芳環、3-10員雜環或5-10員雜芳環，所述雜環或雜芳環含有1至4個選自O、S或N的雜原子； F各自獨立地選自C 3-20碳環、C 6-20芳環、3-20員雜環或5-20員雜芳環，所述雜環或雜芳環含有1至4個選自O、S或N的雜原子； R k2各自獨立地選自鍵、-CO-、-SO 2-、-SO-或-C(R k3) 2-； R k1各自獨立地選自H、F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-6烷基、C 1-6烷氧基、C 3-6環烷基、R k7a，所述的烷基、烷氧基或環烷基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基、C 1-4烷氧基或C 3-6環烷基的取代基所取代； R k7a選自H、C 1-4烷基、C 2-6烯基、C 2-6炔基、C 3-6環烷基、3-6員雜環烷基，所述烷基、環烷基、雜環烷基任選被1至4個選自F、Cl、Br、I、OH、NH 2、CN、CF 3、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-6環烷基的取代基所取代； R k3各自獨立地選自H、F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-6烷基、C 1-6烷氧基、C 3-8環烷基或3-8員雜環基，所述的烷基、烷氧基、環烷基或雜環基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述雜環基含有1至4個選自O、S或N的雜原子； 或者兩個R k3和與二者直接相連的碳原子或環骨架共同形成C 3-8碳環或3-8員雜環，兩個R k1和與二者直接相連的碳原子或環骨架共同形成C 3-8碳環或3-8員雜環，所述碳環或雜環任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述雜環含有1至4個選自O、S或N的雜原子； R k4各自獨立地選自H、OH、NH 2、CN、CONH 2、C 1-6烷基、C 3-8環烷基或3-8員雜環基，所述的烷基、環烷基或雜環基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述雜環基含有1至4個選自O、S或N的雜原子； M 1選自鍵、-CH 2-C(=O)NH-或-C(=O)CH 2NH-； M 2選自-NHC(=O)-C 1-6烷基、-NHC(=O)-C 3-6環烷基或4-10員雜環基，所述的烷基、環烷基或雜環基任選被1至4個選自F、Cl、Br、I、=O、OH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述雜環基含有1至4個選自O、S或N的雜原子； M 3選自-NH-或-O-； R k10選自C 1-6烷基，所述的烷基任選被1至4個選自F、Cl、Br、I、=O、OH、C 1-6烷基或C 3-6環烷基的取代基所取代； R k11各自獨立的選自H、F、Cl、Br、I、=O、OH、SH、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基或-O-C(=O)-C 1-6烷基，所述的烷基、烷氧基或烷硫基任選被1至4個選自F、Cl、Br、I、OH、C 1-4烷基或C 1-4烷氧基的取代基所取代； R k12、R k13各自獨立的選自H、C 1-6烷基或C 3-6環烷基，所述的烷基或環烷基任選被1至4個選自F、Cl、Br、I、=O、OH、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； R k14選自5-6員雜芳基，所述的雜芳基任選被1至4個選自F、Cl、Br、I、OH、=O、CF 3、CN、C 1-4烷基、鹵素取代的C 1-4烷基、羥基取代的C 1-4烷基、C 1-4烷氧基或C 3-6環烷基的取代基所取代，所述雜芳基含有1至4個選自N、O或S的雜原子； G選自C 6-10芳環或5-10員雜芳環，所述的芳環或者雜芳環任選被1至4個選自F、Cl、Br、I、OH、=O、CF 3、CN、C 1-4烷基、鹵素取代的C 1-4烷基、羥基取代的C 1-4烷基、C 1-4烷氧基或C 3-6環烷基的取代基所取代，所述雜芳環含有1至4個選自N、O或S的雜原子； n1、n2、n3各自獨立的選自0、1、2或3； p1或p2各自獨立的選自0、1、2、3、4或5。 A compound or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from compounds represented by general formula (I), BLK (I) ; L is selected from bond or -C 1-50 hydrocarbyl-, in which 1 to 20 methylene units are optionally replaced by -Ak-, -Cy-; Each -Ak- is independently selected from - (CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, - (CH 2 ) q -NR L C(=O)-, -NR L (CH 2 ) q C(=O)-, -(CH 2 ) q -C(=O)NR L -, -C(= O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q -, -CH=CH-, -Si(R L ) 2 -, -Si(OH) (R L )-, -Si(OH) 2 -, -P(=O)(OR L )-, -P(=O)(R L )-, -S-, -S(=O)-, -S(=O) 2 - or bond, the -CH 2 -, -CH=CH- is optionally 1 to 2 selected from halogen, OH, CN, NH 2 , C 1-6 alkyl, C Substituted with substituents of 1-6 alkoxy, halogen-substituted C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, and cyano-substituted C 1-6 alkyl; q is independently selected from 0 , 1, 2, 3, 4, 5 or 6; R L is each independently selected from H, C 1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5- 6-membered heteroaryl, the heterocyclyl or heteroaryl contains 1 to 4 heteroatoms selected from O, S, N; each -Cy- is independently selected from the following groups: bonds or optional substitutions Group one: 4-8 membered heteromonocyclic ring, 4-10 membered heterocyclic ring, 5-12 membered heterospirocyclic ring, 7-10 membered heterobridged ring, 3-7 membered monocyclic alkyl group, 4-10 membered heterocyclic ring Cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, benzo C 4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl, when substituted, is substituted by 1 to 4 R L2 , and the heterocyclyl, heteroaryl, heteromonocyclic, heteroparacyclic, heterospirocyclic or heterobridged ring contains 1 to 4 4 heteroatoms selected from O, S, N, when the heteroatoms are selected from S, optionally substituted by 1 or 2 =O; R L2 are each independently selected from deuterium, F, Cl, Br, I, OH , COOH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -OC 1-4 alkylene-OC 1-4 alkyl, -OC 1-4 alkylene-OC 3-10 carbocyclyl, -C 1-4 alkylene- OC 1-4 alkylene-OC 1-4 alkyl, -C 1-4 alkylene-OC 1-4 alkylene-OC 3-10 carbocyclyl, -OC 0-4 alkylene-C 3-10 carbocyclyl, -C 0-4 alkylene -C 3-10 carbocyclyl, -C 0-4 alkylene -4 to 10 membered heterocyclyl, the alkyl, alkenyl, Alkynyl, alkoxy, alkylene, carbocyclic or heterocyclic groups are optionally substituted by 1 to 4 alkyl groups selected from F, Cl, Br, I, OH, COOH, CN, NH 2 , NHC 1-4 , N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, C 1-4 alkoxy Substituted with substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; B is selected from ; B 1 is selected from C 5-20 carbocyclyl or 4-20 membered heterocyclyl, the B 1 is optionally substituted by 1 to 4 R b1 , and the heterocyclyl contains 1 to 4 selected from Heteroatoms of O, S, and N; B 2 is selected from C 5-20 carbocyclyl or 4-20 membered heterocyclyl, and the B 2 is optionally substituted by 1 to 4 R b2 , and the heterocyclyl Contains 1 to 4 heteroatoms selected from O, S, N; V is selected from ; W is selected from O or S; Y 1 , Y 2 , Y 3 are each independently selected from bonds, O, S, NR b5a , C(=S), C(=O), CONR b5a , NR b5a CO; P 1 and P 2 are each independently selected from or ; v 2 is each independently selected from 0, 1, 2, 3 or 4; v 1 is each independently selected from 0, 1 or 2; R b1 is each independently selected from H, F, Cl, Br, I, =O , OH, CN, NO 2 , COOH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, -(CH 2 ) n -R b22 , -OR b22 , -N(R b21 ) 2 , -C(=O)N(R b21 ) 2 , -C(=O)OR b21 , -C(=O)R b22 , -S(=O) 2 R b22 , -P(=O)(R b22 ) 2 , -S(=O) 2 N(R b21 ) 2 , -NR b21 C(=O)R b22 , -NR b21 S(=O) 2 R b22 , C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, the -CH 2 -, alkyl , alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally selected from 1 to 4 F, Cl, Br, I, OH, =O , -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 2-4 alkynyl, -C 1-4 alkylene -C 3-6 cycloalkyl, -C 1-4 alkylene -OH, -C 1-4 alkylene -OC 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl substituent, the heteroaryl or heterocyclyl contains 1 to 4 selected from O, S, N heteroatoms; R b21 are each independently selected from H or C 1-4 alkyl, and the alkyl group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy substituents; R b22 is each independently selected from H, C 1-4 alkyl base, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl or 4-8 membered heterocyclyl, the alkyl, alkoxy, Cycloalkyl, alkenyl, alkynyl or heterocyclyl is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkane Substituted with substituents of base, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 1-4 alkoxy, the heterocyclic group contains 1 to 4 selected from O, S, N heteroatoms; n is each independently selected from 0, 1, 2, 3 or 4; R b2 is each independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , -N(R b21 ) 2 , CN, NO 2 , COOH, -C(=O)NH 2 , -C(=O)NH-C 1-4 alkyl, -C(=O)N(C 1-4 alkyl) 2 , -(CH 2 ) n -R b22 , -(CH 2 ) n O(CH 2 ) n -R b22 , -(CH 2 ) n O(CH 2 ) n OR b22 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-10 membered hetero Ring group, -C 1-4 alkylene group - 4 to 10 membered heterocyclyl group, the alkylene group, CH 2 , alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group , aryl or heteroaryl optionally substituted by 1 to 4 C selected from F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, halogen substituted C 3-6 Substituted with cycloalkyl, halogen-substituted C 3-6 cycloalkyloxy, 5-6-membered heteroaryl or 4-8-membered heterocyclyl substituents, the heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N; R b3 , R b4 , R b6 , and R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl, the alkyl Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally selected from 1 to 4 deuterium, F, Cl, Br, I, OH , NH 2 , CN, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, cyano-substituted C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkynyl, C Substituted with 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, the heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S, N; or R b3 , R b4 and the carbon atoms to which it is connected together form a C 3-8 cycloalkyl group or a 3 to 8 membered heteromonocyclic ring. The cycloalkyl group or heteromonocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1- 4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl substituents, the heteromonocyclic, heteroaryl Or the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; As an option, R b3 and R b5a , R b1 and R b5a are directly connected to form ring S, and ring S is selected from 4 to 9 members containing nitrogen. Heterocyclyl, ring S is optionally substituted by 1 to 4 substituents selected from R s ; R s are each independently selected from F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl, the alkyl, alkoxy , cycloalkyl, heteroaryl or heterocyclyl is optionally selected from 1 to 4 F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl or C 1-4 alkoxy Substituted with a substituent, the heterocyclyl or heteroaryl group contains 1 to 4 heteroatoms selected from O, S, N; R b5a is selected from H or R b5 ; R b5 is selected from OH, NH 2 , C 1-4 alkyl, -(CH 2 ) n -R b22 , -C(=O)N(R b21 ) 2 , -C(=O)R b22 , C 3-6 cycloalkyl, C 6- 10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, the -CH 2 -, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally replaced by 1 to 4 selected from F, Cl, Br, I, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1- 4 alkyl, cyano substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl substituent, the heteroaryl Or the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N; X is each independently selected from NH, O or S; m1 is each independently selected from 0, 1, 2 or 3; m2 is each independently selected Selected from 0, 1, 2 or 3; R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or 4-10 membered heterocyclyl, the Cycloalkyl, alkenyl, alkynyl and heterocyclyl are optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkane Substituted with a substituent of a base, a halogen-substituted C 1-4 alkyl group, a cyano-substituted C 1-4 alkyl group, or a C 1-4 alkoxy group, the heterocyclic group contains 1 to 4 selected from O , heteroatoms of S and N; R b24 are each independently selected from C 1-4 alkoxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl or 4-10 membered heterocyclyl, so The above-mentioned alkoxy group, cycloalkyl group, cycloalkyloxy group and heterocyclic group are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N; K is selected from K1, K2, K3, K4; K1 is selected from , ; K2 is selected from , , , ; K3 is selected from , , , , , , , , , , ; K4 is selected from , or ; Q is each independently selected from bond, -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q - or 3-12 membered heterocycle, so The above-mentioned heterocyclic ring is optionally composed of 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy Substituted with substituents, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S or N; R q is selected from H or C 1-6 alkyl; A is selected from C 3-10 carbocyclic ring, C 6-10 aromatic ring, 3-10 membered heterocyclic ring or 5-10 membered heteroaromatic ring, the heterocyclic ring or heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S or N; F is each independently selected From C 3-20 carbocyclic ring, C 6-20 aromatic ring, 3-20 membered heterocyclic ring or 5-20 membered heteroaromatic ring, the heterocyclic ring or heteroaromatic ring contains 1 to 4 selected from O, S or N heteroatoms; R k2 is each independently selected from bond, -CO-, -SO 2 -, -SO- or -C(R k3 ) 2 -; R k1 is each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, R k7a , the alkyl, alkyl The oxygen group or cycloalkyl group is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl, C 1-4 alkyl Substituted with oxygen or C 3-6 cycloalkyl substituents; Rk7a is selected from H, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl , 3-6 membered heterocycloalkyl, the alkyl, cycloalkyl, heterocycloalkyl is optionally selected from 1 to 4 from F, Cl, Br, I, OH, NH 2 , CN, CF 3 , Substituted with substituents of C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl; R k3 is each independently selected from H , F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or 3-8 Member heterocyclic group, the alkyl group, alkoxy group, cycloalkyl group or heterocyclic group is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH , CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S or N; or two R k3 Together with the carbon atoms or ring skeleton directly connected to them, they form a C 3-8 carbocyclic ring or 3-8 membered heterocyclic ring. The two R k1 and the carbon atoms or ring skeleton directly connected to them together form C 3-8 Carbocyclic ring or 3-8 membered heterocyclic ring, the carbocyclic ring or heterocyclic ring is optionally composed of 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C Substituted with 1-4 alkyl or C 1-4 alkoxy substituents, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S or N; Rk4 is each independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, the alkyl, cycloalkyl or heterocyclyl is optionally replaced by 1 to 4 Substituted with a substituent selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy, the heterocyclic ring The group contains 1 to 4 heteroatoms selected from O, S or N; M 1 is selected from bond, -CH 2 -C(=O)NH- or -C(=O)CH 2 NH-; M 2 is selected from -NHC(=O)-C 1-6 alkyl, -NHC(=O)-C 3-6 cycloalkyl or 4-10 membered heterocyclyl, the alkyl, cycloalkyl or heterocyclyl Optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, =O, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy, the heterocyclic group Contains 1 to 4 heteroatoms selected from O, S or N; M 3 is selected from -NH- or -O-; R k10 is selected from C 1-6 alkyl, and the alkyl is optionally replaced by 1 to 4 Substituted by a substituent selected from F, Cl, Br, I, =O, OH, C 1-6 alkyl or C 3-6 cycloalkyl; R k11 is each independently selected from H, F, Cl, Br , I, =O, OH, SH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or -OC(=O)-C 1-6 alkyl, the described Alkyl, alkoxy or alkylthio is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH, C 1-4 alkyl or C 1-4 alkoxy; R k12 and R k13 are each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from F, Cl, Br, I, =O, OH, NH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent; R k14 is selected from 5-6 membered heteroaryl, and the heteroaryl is optional C 1-4 alkyl substituted by 1 to 4 selected from F, Cl, Br, I, OH, =O, CF 3 , CN, C 1-4 alkyl, halogen, C 1-4 alkyl substituted by hydroxyl Substituted with a substituent of a C 1-4 alkoxy group or a C 3-6 cycloalkyl group, the heteroaryl group contains 1 to 4 heteroatoms selected from N, O or S; G is selected from C 6- 10 aromatic rings or 5-10 membered heteroaromatic rings, the aromatic ring or heteroaromatic ring is optionally composed of 1 to 4 selected from F, Cl, Br, I, OH, =O, CF 3 , CN, C 1 -4 alkyl, halogen-substituted C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituents, the heteroaryl The ring contains 1 to 4 heteroatoms selected from N, O or S; n1, n2, n3 are each independently selected from 0, 1, 2 or 3; p1 or p2 are each independently selected from 0, 1, 2, 3 , 4 or 5. 根據請求項1所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，其中， B選自 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； v 2各自獨立地選自1、2、3或4； v 1各自獨立地選自0、1或2； v 3選自0、1、2或3； v 4選自0、1、2或3； z選自0、1、2或3； W選自O或S； 的定義與B 1相同； B 1、B 4各自獨立的選自C 6-14碳環基或5-14員雜環基，所述B 1、B 4任選被1至4個R b1所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； B 2選自C 5-10碳環基、5-10員雜環基或B 5，所述B 2任選被1至4個R b2取代，所述的雜環基含有1至4個選自O、S、N的雜原子； B 3選自C 6-14碳環基或4-14員雜環基，所述B 3任選被1至4個R b1所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； B 5選自C 12-18三並環、12至18員雜三並環、噻吩基、呋喃基、噻唑基、噁唑基、吡啶基、嘧啶基、噠嗪基、吡嗪基、三嗪基、苯基、苯並C 4-6碳環、苯並4至6員雜環、吡唑並C 4-6碳環、吡唑並4至6員雜環、三氮唑並C 4-6碳環、三氮唑並4至6員雜環、咪唑並C 4-6碳環、咪唑並4至6員雜環、噻吩並C 4-6碳環、噻吩並4至6員雜環、呋喃並C 4-6碳環、呋喃並4至6員雜環、4-7員含氮雜單環烷基、4-10員含氮雜並環烷基、5-12員含氮雜螺環烷基、7-10員含氮雜橋環烷基、3-7員單環烷基、4-10員並環烷基、5-12員螺環烷基、7-10員橋環烷基，所述B 5任選被1至4個R b2取代，所述的雜環、雜單環烷基、雜並環烷基、雜螺環烷基、雜橋環烷基含有1至4個選自O、S、N的雜原子； R b5選自OH、NH 2、C 1-4烷基、-(CH 2) n-R b22、-C(=O)N(R b21) 2、-C(=O)R b22、C 3-6環烷基、C 6-10芳基、5-10員雜芳基或4-10員雜環基，所述的-CH 2-、烷基、環烷基、雜環基、芳基或雜芳基任選被1至4個選自F、Cl、Br、I、OH、=O、-N(R b21) 2、CN、COOH、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 3-6環烷基、5-10員雜芳基或4-10員雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； R b6選自F、Cl、Br、I、OH、NH 2、CN、NO 2、-(CH 2) m1-R b23、-(CH 2) m1-X-(CH 2) m2-R b24、C 2-4炔基、C 3-12環烷基、C 6-10芳基、5-10員雜芳基或4-12員雜環基，所述的炔基、環烷基、芳基、雜芳基或雜環基任選被1至4個選自F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； R b3、R b4、R b7各自獨立的選自H、F、Cl、Br、I、OH、NH 2、CN、NO 2、-(CH 2) m1-R b23、-(CH 2) m1-X-(CH 2) m2-R b24、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 2-4炔基、C 3-12環烷基、C 6-10芳基、5-10員雜芳基或4-12員雜環基，所述的烷基、烷氧基、烷硫基、炔基、環烷基、芳基、雜芳基或雜環基任選被1至4個選自氘、F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； 或R b3、R b4與其相連接的碳原子共同形成C 3-8環烷基或3至8員雜單環，所述的環烷基或雜單環任選被1至4個選自氘、F、Cl、Br、I、OH、NH 2、-N(R b21) 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-6環烷基、5-6員雜芳基或3至8雜環基的取代基所取代，所述的雜單環、雜芳基或雜環基含有1至4個選自O、S、N的雜原子。 The compound according to claim 1 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein B is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; v 2 is each independently selected from 1, 2, 3 or 4; v 1 is each independently selected from 0, 1 or 2; v 3 is selected from 0, 1, 2 or 3; v 4 is selected from 0, 1, 2 or 3; z is selected from 0, 1, 2 or 3; W is selected from O or S; The definition of B 1 is the same as B 1; B 1 and B 4 are each independently selected from C 6-14 carbocyclyl or 5-14 membered heterocyclyl, and the B 1 and B 4 are optionally represented by 1 to 4 R b1 Substituted, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N; B 2 is selected from C 5-10 carbocyclyl, 5-10 membered heterocyclyl or B 5 , the B 2 is optionally substituted by 1 to 4 R b2 , and the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; B 3 is selected from C 6-14 carbocyclyl or 4-14 member Heterocyclyl, the B 3 is optionally substituted by 1 to 4 R b1 , the heterocyclyl contains 1 to 4 heteroatoms selected from O, S, N; B 5 is selected from C 12-18 Tricyclic, 12 to 18-membered heterotricyclic, thienyl, furyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, phenyl, benzoC 4-6 carbocyclic ring, benzo 4 to 6 membered heterocyclic ring, pyrazolo C 4-6 carbocyclic ring, pyrazolo 4 to 6 membered heterocyclic ring, triazolo C 4-6 carbocyclic ring, triazolo 4 to 6 membered heterocycle, imidazo C 4-6 carbocycle, imidazo 4 to 6 membered heterocycle, thieno C 4-6 carbocycle, thieno 4 to 6 membered heterocycle, furano C 4-6 carbon Ring, furano 4- to 6-membered heterocycle, 4-7-membered nitrogen-containing heteromonocycloalkyl, 4-10-membered nitrogen-containing heterocycloalkyl, 5-12-membered nitrogen-containing heterospirocycloalkyl, 7-10 A nitrogen-containing heterobridged cycloalkyl group, a 3-7 membered monocyclic alkyl group, a 4-10 membered paracycloalkyl group, a 5-12 membered spirocycloalkyl group, a 7-10 membered bridged cycloalkyl group, and the B 5 is any is selected from 1 to 4 R b2 substituted, and the heterocycle, heteromonocycloalkyl, heterocycloalkyl, heterospirocycloalkyl, and heterobridged cycloalkyl contain 1 to 4 selected from O, S, Heteroatom of N; R b5 is selected from OH, NH 2 , C 1-4 alkyl, -(CH 2 ) n -R b22 , -C(=O)N(R b21 ) 2 , -C(=O) R b22 , C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, the -CH 2 -, alkyl, cycloalkyl, hetero The ring group, aryl group or heteroaryl group is optionally substituted by 1 to 4 members selected from F, Cl, Br, I, OH, =O, -N(R b21 ) 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered hetero Substituted by the substituent of the ring group, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N; R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 2-4 alkynyl, C 3-12 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-12 membered heterocyclyl, the alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally selected from 1 to 4 From F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy Substituted with substituents of base, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl groups, the heteroaryl group or heterocyclyl group contains 1 to 4 selected from O, S, Heteroatoms of N; R b3 , R b4 , and R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -( CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkynyl, C 3-12 Cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl or 4-12 membered heterocyclyl, the alkyl, alkoxy, alkylthio, alkynyl, cycloalkyl, aryl , heteroaryl or heterocyclyl optionally substituted by 1 to 4 C 1-4 alkyl selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, and halogen , substituted by cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, the The heteroaryl or heterocyclyl group contains 1 to 4 heteroatoms selected from O, S, and N; or R b3 and R b4 and the carbon atoms to which they are connected together form a C 3-8 cycloalkyl group or a 3 to 8-membered heterocyclic group. Monocyclic ring, the cycloalkyl or heteromonocyclic ring is optionally 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , -N(R b21 ) 2 , CN, C 1- 4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5- Substituted with 6-membered heteroaryl or 3 to 8 heterocyclyl substituents, the heteromonocyclic, heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N. 根據請求項2所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，其中， B選自 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； 環S選自5員、6員或7員含有1或2個氮原子的環，環S任選被1至4個R s取代； R s各自獨立的選自F、Cl、Br、I、OH、NH 2、-NHC 1-4烷基、-N(C 1-4烷基) 2、CN、C 1-4烷基、C 1-4烷氧基、C 3-6環烷基，所述的烷基、烷氧基或者環烷基任選被1至4個選自F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基或C 1-4烷氧基的取代基所取代； B 1、B 4各自獨立的選自苯基、萘基、C 6-12碳環基、5-10員雜芳基、5-10員雜環基、C 10-14三環碳環基、12至14員三環雜環基，所述B 1、B 4任選被1至4個R b1所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； B 2選自C 6-10芳基、5-7員雜環基、5-10員雜芳基或5-10員雜並環、5-10員雜橋環，所述B 2任選被1至4個R b2取代，所述的雜芳基、雜環基、雜並環、雜橋環含有1至4個選自O、S、N的雜原子； B 3選自5-12員雜芳基、C 6-7碳環基、C 6-10並碳環基、C 6-12螺碳環基、C 7-12橋碳環基、4-7員單環雜環基、7-14員雜並環、7-14員雜螺環，所述B 3任選被1至4個R b1所取代，所述的雜芳基、雜環基、雜並環、雜螺環含有1至4個選自O、S、N的雜原子； R b2各自獨立的選自H、F、Cl、Br、I、=O、OH、NH 2、-N(R b21) 2、CN、NO 2、COOH、-C(=O)NH 2、-C(=O)NH-C 1-4烷基、-C(=O)N(C 1-4烷基) 2、-(CH 2) n-R b22、-(CH 2) nO(CH 2) n-R b22、-(CH 2) nO(CH 2) nO-R b22、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 3-8環烷基、C 6-10芳基、5至6員雜芳基、4至8員雜環基、-C 1-4亞烷基-4至8員雜環基，所述的亞烷基、CH 2、烷基、烯基、炔基、烷氧基、環烷基、雜環基、芳基或雜芳基任選被1至4個選自F、Cl、Br、I、OH、NH 2、-NHC 1-4烷基、-N(C 1-4烷基) 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 3-6環烷基、C 3-6環烷基氧基、鹵素取代的C 3-6環烷基、鹵素取代的C 3-6環烷基氧基、5-6員雜芳基或4-8員雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； R b6選自F、Cl、Br、I、OH、NH 2、CN、NO 2、-(CH 2) m1-R b23、-(CH 2) m1-X-(CH 2) m2-R b24、C 2-4炔基、C 3-6環烷基、C 5-10橋環烷基、C 5-12螺環烷基、C 4-12並環烷基、C 6-10芳基、5-6員雜芳基、4-8員雜環基、5-10員雜橋環、5-12員雜螺環、5-12員雜並環，所述的炔基、環烷基、芳基、雜芳基、雜環基、雜橋環、雜螺環或雜並環任選被1至4個選自F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； R b3、R b4、R b7各自獨立的選自H、F、Cl、Br、I、OH、NH 2、CN、NO 2、-(CH 2) m1-R b23、-(CH 2) m1-X-(CH 2) m2-R b24、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 2-4炔基、C 3-6環烷基、C 5-10橋環烷基、C 5-12螺環烷基、C 4-12並環烷基、C 6-10芳基、5-6員雜芳基、4-8員雜環基、5-10員雜橋環、5-12員雜螺環、5-12員雜並環，所述的烷基、烷氧基、烷硫基、炔基、環烷基、芳基、雜芳基、雜環基、雜橋環、雜螺環或雜並環任選被1至4個選自氘、F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜芳基、雜環基、雜橋環、雜螺環或雜並環含有1至4個選自O、S、N的雜原子； 或R b3、R b4與其相連接的碳原子共同形成C 3-8環烷基或3至8員雜單環，所述的環烷基或雜單環任選被1至4個選自氘、F、Cl、Br、I、OH、NH 2、-N(R b21) 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-6環烷基、5-6員雜芳基或3至8雜環基的取代基所取代，所述的雜單環、雜芳基或雜環基含有1至4個選自O、S、N的雜原子； R b23各自獨立的選自C 2-4烯基、C 2-4炔基、C 3-6環烷基或4-8員雜環基，所述的環烷基、烯基、炔基、雜環基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、CF 3、COOH、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； R b24各自獨立的選自C 1-4烷氧基、C 3-6環烷基氧基、C 3-6環烷基或4-8員雜環基，所述的烷氧基、環烷基、環烷基氧基、雜環基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、CF 3、COOH、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； 任選地，B選自 時，R b3、R b4不能同時選自H。 The compound according to claim 2 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein B is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; Ring S is selected from a 5-, 6- or 7-membered ring containing 1 or 2 nitrogen atoms, and Ring S is optionally substituted by 1 to 4 R s ; R s are each independently selected from F, Cl, Br, I , OH, NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl , the alkyl group, alkoxy group or cycloalkyl group is optionally substituted by 1 to 4 members selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl or C 1-4 alkyl Substituted with an oxygen substituent; B 1 and B 4 are each independently selected from phenyl, naphthyl, C 6-12 carbocyclyl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, C 10 -14 tricyclic carbocyclyl, 12 to 14 membered tricyclic heterocyclyl, the B 1 and B 4 are optionally substituted by 1 to 4 R b1 , the heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S, N; B 2 is selected from C 6-10 aryl, 5-7 membered heterocyclyl, 5-10 membered heteroaryl or 5-10 membered heterocyclic ring, 5- 10-membered hetero-bridged ring, the B 2 is optionally substituted by 1 to 4 R b2 , the heteroaryl, heterocyclic group, heterocyclic ring and hetero-bridged ring contain 1 to 4 selected from O, S, Heteroatom of N; B 3 is selected from 5-12 membered heteroaryl, C 6-7 carbocyclyl, C 6-10 carbonyl carbocyclyl, C 6-12 spiro carbocyclyl, C 7-12 bridged carbocyclyl base, 4-7 membered monocyclic heterocyclic group, 7-14 membered heterocyclic ring, 7-14 membered heterospirocyclic group, the B 3 is optionally substituted by 1 to 4 R b1 , the heteroaryl group , Heterocyclyl, heteroparacycle, heterospirocycle contains 1 to 4 heteroatoms selected from O, S, N; R b2 is each independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , -N(R b21 ) 2 , CN, NO 2 , COOH, -C(=O)NH 2 , -C(=O)NH-C 1-4 alkyl, -C(=O)N( C 1-4 alkyl) 2 , -(CH 2 ) n -R b22 , -(CH 2 ) n O(CH 2 ) n -R b22 , -(CH 2 ) n O(CH 2 ) n OR b22 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, 5 to 6-membered heteroaryl base, 4 to 8 membered heterocyclyl group, -C 1-4 alkylene group-4 to 8 membered heterocyclyl group, the alkylene group, CH 2 , alkyl group, alkenyl group, alkynyl group, alkoxy group, Cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , -NHC 1-4 alkyl, -N(C 1- 4 alkyl) 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl base, C 3-6 cycloalkyloxy group, halogen-substituted C 3-6 cycloalkyl group, halogen-substituted C 3-6 cycloalkyloxy group, 5-6 membered heteroaryl group or 4-8 membered heterocycle Substituted with a substituent of a base, the heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 2-4 alkynyl group, C 3-6 cycloalkyl group, C 5 -10 bridged cycloalkyl, C 5-12 spirocycloalkyl, C 4-12 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, 4-8 membered heterocyclyl, 5- 10-membered hetero-bridged ring, 5-12-membered heterospirocyclic ring, 5-12-membered heterospirocyclic ring, the alkynyl group, cycloalkyl group, aryl group, heteroaryl group, heterocyclyl group, hetero-bridged ring, heterospirocyclic ring Or the heterocyclic ring is optionally substituted with 1 to 4 C atoms selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, and cyano. Substituted with 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, the heteroaryl or heterocyclic The group contains 1 to 4 heteroatoms selected from O, S, and N; R b3 , R b4 , and R b7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -(CH 2 ) m1 -R b23 , -(CH 2 ) m1 -X-(CH 2 ) m2 -R b24 , C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 alkylthio group , C 2-4 alkynyl, C 3-6 cycloalkyl, C 5-10 bridged cycloalkyl, C 5-12 spirocycloalkyl, C 4-12 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, 4-8 membered heterocyclic group, 5-10 membered heterobridged ring, 5-12 membered heterospirocyclic ring, 5-12 membered heterocyclic ring, the alkyl group, alkoxy group, Alkylthio group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group, heterocyclyl group, heterobridged ring, heterospiro ring or heterocyclic ring are optionally 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkyne Substituted with substituents of C 3-8 cycloalkyl or 3 to 8 heterocyclyl groups, the heteroaryl group, heterocyclyl group, heterobridged ring, heterospiro ring or heterocyclic ring contains 1 to 4 options Heteroatoms from O, S, N; or R b3 , R b4 and the carbon atoms to which they are connected together form a C 3-8 cycloalkyl group or a 3 to 8 membered heteromonocyclic ring, the cycloalkyl group or heteromonocyclic ring C 1-4 alkyl optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH , NH 2 , -N(R b21 ) 2 , CN, C 1-4 alkyl, and halogen , cyano-substituted C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl Substituted with substituents, the heteromonocyclic, heteroaryl or heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N; R b23 is each independently selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl or 4-8 membered heterocyclyl, the cycloalkyl, alkenyl, alkynyl, heterocyclyl is optionally 1 to 4 selected from F, Cl , Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1 -4 alkoxy substituent, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N; R b24 is each independently selected from C 1-4 alkoxy, C 3 -6 cycloalkyloxy group, C 3-6 cycloalkyl group or 4-8 membered heterocyclyl group, the alkoxy group, cycloalkyl group, cycloalkyloxy group and heterocyclyl group are optionally substituted by 1 to 4 Each is selected from F, Cl, Br, I, OH, =O, NH 2 , CN, CF 3 , COOH, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1- 4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N; Optionally, B is selected from When , R b3 and R b4 cannot be selected from H at the same time. 根據請求項3所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，其中， L選自-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-、-Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-、-Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-、-Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-； Ak1、Ak2、Ak3、Ak4、Ak5各自獨立的選自-(CH 2) q-、-(CH 2) q-O-、-O-(CH 2) q-、-(CH 2) q-NR L-、-NR L-(CH 2) q-、-(CH 2)q-NR LC(=O)-、-(CH 2) q-C(=O)NR L-、-C(=O)-、-C(=O)-(CH 2) q-NR L-、-CH=CH-、-(C≡C) q-或者鍵，所述的-CH 2-、-CH=CH-任選被1至2個選自F、Cl、Br、I、OH、CN、NH 2、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、羥基取代的C 1-4烷基、氰基取代的C 1-4烷基的取代基所取代； Cy1、Cy2、Cy3、Cy4或Cy5各自獨立地選自鍵或者任選取代的如下基團之一：4-7員雜單環、4-10員雜並環、5-12員雜螺環、7-10員雜橋環、3-7員單環烷基、4-10員並環烷基、5-12員螺環烷基、7-10員橋環烷基、苯並C 4-6碳環基、苯並4至6員雜環基、5-10員雜芳基或6-10員芳基，當被取代時，被1至4個R L2取代，所述的雜環基、雜芳基、雜單環、雜並環、雜螺環或雜橋環含有1至4個選自O、S、N的雜原子，當雜原子選自S時，任選被1或2個=O取代；q各自獨立的選自0、1、2、3或4； R L各自獨立的選自H或C 1-6烷基； K2選自 、 、 、 、 、 、 、 、 、 ； K3選自 ； A選自C 3-8碳環、苯環、4-7員雜環或5-6員雜芳環，所述雜環或雜芳環含有1至4個選自O、S或N的雜原子； F各自獨立地選自C 3-7單環碳環、C 4-10並環碳環、C 5-12螺環碳環、C 5-10橋環碳環、4-7員雜單環、4-10員雜並環、8-15員雜三並環、5-12員雜螺環、5-10員雜橋環、C 6-14芳基、5-10員雜芳基、 、 、 、 ，所述雜單環、雜並環、雜螺環、雜橋環或雜芳基含有1至4個選自O、S或N的雜原子； 表示環選自芳香環或非芳香環； E各自獨立地選自C 3-10碳環、苯環、4-12員雜環、5-12員雜芳環，所述雜環或雜芳環含有1至4個選自O、S或N的雜原子； Q各自獨立地選自鍵、-O-、-S-、-CH 2-、-NR q-、-CO-、-NR qCO-、-CONR q-或4-7員雜環，所述的雜環任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述雜環含有1至4個選自O、S或N的雜原子； R q選自H或C 1-4烷基； R k1、R k3各自獨立的選自H、F、Cl、Br、I、OH、=O、NH 2、CF 3、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基，所述烷基或烷氧基任選被1至4個選自F、Cl、Br、I、OH或NH 2的取代基所取代； 或者兩個R k3和與二者直接相連的碳原子或環骨架共同形成C 3-6碳環或3-7員雜環，兩個R k1和與二者直接相連的碳原子或環骨架共同形成C 3-6碳環或3-7員雜環，所述碳環或雜環任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、CONH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代，所述雜環含有1至4個選自O、S或N的雜原子； R k4各自獨立的選自H、OH、NH 2、CF 3、CN或C 1-4烷基； R k5各自獨立地選自 、C(CH 3) 2、CO、CH 2、SO 2、 、 、 ； R k6各自獨立地選自CO、CH、SO、SO 2、CH 2或N； R k7各自獨立地選自 、C(CH 3) 2、CO、CH、N、CH 2、O、S、NR k7a； R k8各自獨立地選自C、N或CH； R k9各自獨立地選自鍵、 、C(CH 3) 2、CO、CH 2、CH 2CH 2或SO 2； R ka選自O、S或NH； R k7a選自H、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6環烷基、3-6員雜環烷基，所述烷基、環烷基、雜環烷基任選被1至4個選自F、Cl、Br、I、OH、NH 2、CN、CF 3、C 1-4烷基、C 1-4烷氧基、C 2-4烯基、C 2-4炔基、C 3-6環烷基的取代基所取代; R k14選自 ； p1選自0、1、2或3； p2選自0、1、2或3。 The compound according to claim 3 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein L is selected from -Cy1-Ak1-Cy2-Ak2 -Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4 -Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2 -Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3 -Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1 -Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4 -Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2 -Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4 -Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3 -Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4 -Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Ak1-Ak2-Ak3 -Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3 -Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy1 -Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3 -Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3 -Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5 -Cy4-; Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 )q-NR L C(=O)-, -(CH 2 ) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -CH=CH-, -(C≡C) q -or bond, the -CH 2 -, -CH=CH-C 1- optionally substituted by 1 to 2 selected from F, Cl, Br, I, OH, CN, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, halogen 4 alkyl, hydroxy-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl substituents; Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from the bond or optionally substituted One of the following groups: 4-7-membered heteromonocyclic ring, 4-10-membered heterocyclic ring, 5-12-membered heterospirocyclic ring, 7-10-membered hetero-bridged ring, 3-7-membered monocyclic alkyl group, 4-10 Membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, benzo C 4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, 5-10 membered heteroaryl base or 6-10 membered aryl group, when substituted, is substituted by 1 to 4 R L2 , the heterocyclyl group, heteroaryl group, heteromonocyclic group, heterocyclic ring, heterospirocyclic ring or heterobridged ring contains 1 to 4 heteroatoms selected from O, S, and N. When the heteroatoms are selected from S, they are optionally substituted by 1 or 2 =O; q is each independently selected from 0, 1, 2, 3, or 4; R L is each independently selected from H or C 1-6 alkyl; K2 is selected from , , , , , , , , , ; K3 is selected from ; A is selected from C 3-8 carbocyclic ring, benzene ring, 4-7 membered heterocyclic ring or 5-6 membered heteroaromatic ring, the heterocyclic ring or heteroaromatic ring contains 1 to 4 selected from O, S or N Heteroatom; F is each independently selected from C 3-7 monocyclic carbocyclic ring, C 4-10 paracyclic carbocyclic ring, C 5-12 spirocyclic carbocyclic ring, C 5-10 bridged carbocyclic ring, 4-7 membered heterocyclic carbocyclic ring Monocyclic ring, 4-10 membered heteroacyclic ring, 8-15 membered heterotriacyclic ring, 5-12 membered heterospiro ring, 5-10 membered heterobridged ring, C 6-14 aryl group, 5-10 membered heteroaryl group , , , , , the heteromonocyclic ring, heterocyclic ring, heterospirocyclic ring, heterobridged ring or heteroaryl group contains 1 to 4 heteroatoms selected from O, S or N; Indicates that the ring is selected from an aromatic ring or a non-aromatic ring; E is each independently selected from a C 3-10 carbocyclic ring, a benzene ring, a 4-12 membered heterocyclic ring, and a 5-12 membered heteroaromatic ring. The heterocyclic ring or heteroaromatic ring Contains 1 to 4 heteroatoms selected from O, S or N; Q is each independently selected from bond, -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO -, -CONR q - or 4-7 membered heterocycle, the heterocycle is optionally composed of 1 to 4 members selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy substituent, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S or N; R q is selected from H or C 1- 4 alkyl; R k1 and R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2 , C 1-4 alkyl or C 1-4 alkoxy, the alkyl or alkoxy is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH or NH ; or two R k3 and two The carbon atoms or ring skeletons directly connected to them together form a C 3-6 carbocyclic ring or a 3-7 membered heterocycle, and the two R k1 and the carbon atoms or ring skeletons directly connected to them together form a C 3-6 carbocyclic ring or 3-7 membered heterocyclic ring, the carbocyclic ring or heterocyclic ring is optionally composed of 1 to 4 members selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 Substituted with alkyl or C 1-4 alkoxy substituents, the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S or N; Rk4 is each independently selected from H, OH, NH 2 , CF 3 , CN or C 1-4 alkyl; R k5 is each independently selected from ,C(CH 3 ) 2 ,CO,CH 2 ,SO 2 , , , ; R k6 is each independently selected from CO, CH, SO, SO 2 , CH 2 or N; R k7 is each independently selected from , C(CH 3 ) 2 , CO, CH, N, CH 2 , O, S, NR k7a ; R k8 is each independently selected from C, N or CH; R k9 is each independently selected from bond, , C(CH 3 ) 2 , CO, CH 2 , CH 2 CH 2 or SO 2 ; R ka is selected from O, S or NH; R k7a is selected from H, C 1-4 alkyl, C 2-4 alkenyl , C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, the alkyl, cycloalkyl, heterocycloalkyl is optionally 1 to 4 selected from F, Cl , Br, I, OH, NH 2 , CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl Substituted by the substituent of the base; R k14 is selected from ; p1 is selected from 0, 1, 2 or 3; p2 is selected from 0, 1, 2 or 3. 根據請求項4所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，其中， Cy1、Cy2、Cy3、Cy4或Cy5各自獨立的選自鍵或者任選取代的如下基團之一： 4-7員含氮雜單環、4-10員含氮雜並環、5-12員含氮雜螺環、7-10員含氮雜橋環、3-7員單環烷基、4-10員並環烷基、5-12員螺環烷基、7-10員橋環烷基、苯並C 4-6碳環基、苯並4至6員雜環基、5-10員雜芳基或6-10員芳基，當被取代時，被1至4個R L2取代，所述的雜環基、雜單環、雜並環、雜橋環、雜螺環或雜芳基含有1至4個選自O、S、N的雜原子，當雜原子選自S時，任選被1或2個=O取代； R L各自獨立的選自H或C 1-4烷基； K1選自 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； K4選自 、 、 ； Q選自鍵、C(=O)； Q1選自鍵、CH 2、NH、N(CH 3)、O、S、C(=O)、NHC(=O)、C(=O)NH、N(CH 3)C(=O)、C(=O)N(CH 3)、 、 、 ； Q2選自鍵、CH 2、O、S、C(=O)、NHC(=O)、N(CH 3)C(=O)； E、A各自獨立地選自苯環、吡啶環、噠嗪環、吡嗪環、嘧啶環、吡咯環、吡唑環、咪唑環、噻唑環、呋喃環、噻吩環或噁唑環； F各自獨立地選自環丁基、環戊基、環己基、雙環[1.1.1]戊烷基、6,7-二氫-5H-環戊[c]吡啶基、2,3-二氫-1H-茚基、苯基、萘基、蒽基、菲基、氮雜環丁基、吡咯烷基、哌啶基、嗎啉基、吡啶基、嘧啶基、噠嗪基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、三唑基、噁唑基、呋喃基、噻吩基、噻唑基、2-吡啶酮基、苯並噁唑基、吡啶並咪唑基、苯並咪唑基、苯並吡唑基、苯並噻唑基、苯並噻吩基、苯並呋喃基、苯並吡咯基、苯並吡啶基、苯並吡嗪基、苯並嘧啶基、苯並噠嗪基、苯並三嗪基、吡咯並吡咯基、吡咯並吡啶基、吡咯並嘧啶基、吡咯並噠嗪基、吡咯並吡嗪基、咪唑並嘧啶基、咪唑並吡啶基、咪唑並吡嗪基、咪唑並噠嗪基、吡唑並吡啶基、吡唑並嘧啶基、吡唑並噠嗪基、吡唑並吡嗪基、嘧啶並吡啶基、嘧啶並吡嗪基、嘧啶並噠嗪基、嘧啶並嘧啶基、吡啶並吡啶基、吡啶並吡嗪基、吡啶並噠嗪基、吡啶並吡唑基、噠嗪並噠嗪基、噠嗪並吡嗪基、吡嗪並吡嗪基、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ，其左側與L直接連接； R ka選自O、S或NH； R k7各自獨立地選自 、C(CH 3) 2、CH 2、O、N(CH 3)、N(CH 2CH 3)、N(環丙基)或NH； R k1、R k3各自獨立的選自H、F、Cl、Br、I、OH、=O、NH 2、CF 3、CN、COOH、CONH 2、甲基、乙基、異丙基、甲氧基、乙氧基或異丙氧基，所述甲基、乙基、異丙基、甲氧基、乙氧基或異丙氧基任選被1至4個選自F、Cl、Br、I、OH、NH 2的取代基所取代； R k7a選自H、甲基、乙基、丙基、異丙基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、哌啶基、氧雜環丁基、四氫呋喃基、四氫吡喃基，所述甲基、乙基、丙基、異丙基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、哌啶基、氧雜環丁基、四氫呋喃基、四氫吡喃基任選被1至4個選自F、Cl、Br、I、OH、CN、CF 3、C 1-4烷基、C 1-4烷氧基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、C 3-6環烷基的取代基所取代； p1或p2各自獨立的選自0、1或2。 The compound according to claim 4 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently is selected from one of the bonded or optionally substituted following groups: 4-7 membered nitrogen-containing heteromonocyclic ring, 4-10-membered nitrogen-containing heterocyclic ring, 5-12-membered nitrogen-containing heterospirocyclic ring, 7-10-membered nitrogen-containing heterocyclic ring Aza bridged ring, 3-7 membered monocyclic alkyl group, 4-10 membered cycloalkyl group, 5-12 membered spirocycloalkyl group, 7-10 membered bridged cycloalkyl group, benzo C 4-6 carbocyclyl group , benzo 4- to 6-membered heterocyclyl, 5-10-membered heteroaryl or 6-10-membered aryl, when substituted, is substituted by 1 to 4 R L2 , the heterocyclyl, heteromonocyclic , heterocyclic ring, heterobridged ring, heterospirocyclic ring or heteroaryl group containing 1 to 4 heteroatoms selected from O, S, N. When the heteroatoms are selected from S, they are optionally substituted by 1 or 2 =O ; R L is each independently selected from H or C 1-4 alkyl; K1 is selected from , , , , , , , , , , , , , , ; K4 is selected from , , ; Q is selected from bond, C(=O); Q1 is selected from bond, CH 2 , NH, N(CH 3 ), O, S, C(=O), NHC(=O), C(=O)NH ,N(CH 3 )C(=O),C(=O)N(CH 3 ), , , ; Q2 is selected from bonds, CH 2 , O, S, C(=O), NHC(=O), N(CH 3 )C(=O); E and A are each independently selected from benzene ring, pyridine ring, Pyridazine ring, pyrazine ring, pyrimidine ring, pyrrole ring, pyrazole ring, imidazole ring, thiazole ring, furan ring, thiophene ring or oxazole ring; F is each independently selected from cyclobutyl, cyclopentyl, cyclohexyl , Bicyclo[1.1.1]pentyl, 6,7-dihydro-5H-cyclopentyl[c]pyridyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrene base, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazole base, oxazolyl, furyl, thienyl, thiazolyl, 2-pyridinone, benzoxazolyl, pyridimidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzo Thienyl, benzofuranyl, benzopyrrolyl, benzopyridyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridyl ,pyrrolopyrimidyl,pyrrolopyridazinyl,pyrrolopyrazinyl,imidazopyrimidinyl,imidazopyridinyl,imidazopyrazinyl,imidazopyridazinyl,pyrazopyridyl,pyrazopyrimidine base, pyrazopyridazinyl, pyrazopyridazinyl, pyrimidopyridyl, pyrimidopyridazinyl, pyrimidopyridazinyl, pyrimidopyrimidinyl, pyridopyridyl, pyridopyrazinyl, pyridine Pyridazinyl, pyridopyrazolyl, pyridazinopyridazinyl, pyridazinopyrazinyl, pyrazinopyrazinyl, , , , , , , , , , , , , , , , , , , , , its left side is directly connected to L; R ka is selected from O, S or NH; R k7 is each independently selected from , C(CH 3 ) 2 , CH 2 , O, N(CH 3 ), N(CH 2 CH 3 ), N (cyclopropyl) or NH; R k1 and R k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2 , methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, the methyl The base, ethyl, isopropyl, methoxy, ethoxy or isopropoxy group is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH, NH 2 ; R k7a Selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, the methyl, ethyl, propyl, isopropyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, optionally 1 to 4 selected from F , Cl, Br, I, OH, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, Substituted with C 3-6 cycloalkyl substituent; p1 or p2 are each independently selected from 0, 1 or 2. 根據請求項5所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，其中， R L選自H、甲基或乙基； q各自獨立的選自0、1或2； Cy1、Cy2、Cy3、Cy4或Cy5各自獨立的選自鍵或取代的或者未取代的如下基團之一：環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、氮雜環己烯基、哌啶基、嗎啉基、哌嗪基、1,4-二氮雜庚烷基、苯基、噻吩基、噻唑基、呋喃基、噁唑基、吡咯基、吡唑基、咪唑基、吡啶基、噠嗪基、吡嗪基、嘧啶基、吡啶酮、三嗪基、咪唑並吡啶基、咪唑並吡嗪基、咪唑並嘧啶、吡唑並吡啶基、吡唑並吡嗪基、吡唑並嘧啶基、苯並噻吩基、苯並呋喃基、苯並噁唑基、苯並噻唑基、苯並咪唑基、苯並吡唑基、苯並吡咯基、三氮唑並吡啶基、三氮唑並嘧啶基、三氮唑並噠嗪基、三氮唑並吡嗪基、三氮唑並噻唑基、三氮唑並噁唑基、三氮唑並吡唑基、三氮唑並吡咯基、三氮唑並咪唑基、環丙基並環丙基、環丙基並環丁基、環丙基並環戊基、環丙基並環己基、環丁基並環丁基、環丁基並環戊基、環丁基並環己基、環戊基並環戊基、環戊基並環己基、環己基並環己基、環丙基螺環丙基、環丙基螺環丁基、環丙基螺環戊基、環丙基螺環己基、環丁基螺環丁基、環丁基螺環戊基、環丁基螺環己基、環戊基螺環戊基、環戊基螺環己基、環己基螺環己基、環丙基並氮雜環丁基、環丙基並吡咯烷基、環丙基並哌啶基、環丁基並氮雜環丁基、環丁基並吡咯烷基、環丁基並哌啶基、環戊基並氮雜環丁基、環戊基並吡咯烷基、環戊基並哌啶基、環己基並氮雜環丁基、環己基並吡咯烷基、環己基並哌啶基、氮雜環丁基並氮雜環丁基、氮雜環丁基並吡咯烷基、氮雜環丁基並哌啶基、吡咯烷基並氮雜環丁基、吡咯烷基並吡咯烷基、吡咯烷基並哌啶基、哌啶基並氮雜環丁基、哌啶基並吡咯烷基、哌啶基並哌啶基、環丁基螺氮雜環丁基、環丁基螺吡咯烷基、環丁基螺哌啶基、環戊基螺氮雜環丁基、環戊基螺吡咯烷基、環戊基螺哌啶基、環己基螺氮雜環丁基、環己基螺吡咯烷基、環己基螺哌啶基、氮雜環丁基螺氮雜環丁基、氮雜環丁基螺吡咯烷基、氮雜環丁基螺哌啶基、吡咯烷基螺氮雜環丁基、吡咯烷基螺吡咯烷基、吡咯烷基螺哌啶基、哌啶基螺氮雜環丁基、哌啶基螺哌啶基、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ，當被取代時，被1至4個R L2取代； R L2各自獨立的選自氘、F、Cl、Br、I、OH、NH 2、NHCH 3、N(CH 3) 2、COOH、CN、=O、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、-O-C 1-2亞烷基-O-C 1-2烷基、-O-C 1-2亞烷基-O-C 3-6碳環基、-C 1-2亞烷基-O-C 1-2亞烷基-O-C 1-2烷基、-C 1-2亞烷基-O-C 1-2亞烷基-O-C 3-6碳環基、-O-C 0-2亞烷基-C 3-6碳環基、-C 0-2亞烷基-C 3-6碳環基、-C 0-2亞烷基-4至6員雜環基，所述的烷基、烯基、炔基、烷氧基、亞烷基、碳環基或雜環基任選被1至4個選自F、Cl、Br、I、OH、COOH、CN、NH 2、NHC 1-4烷基、N(C 1-4烷基) 2、=O、C 1-4烷基、鹵素取代的C 1-4烷基、鹵素取代的C 1-4烷氧基、羥基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； B 1、B 4各自獨立的選自苯基、萘基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、吡嗪基、噠嗪基、喹啉基、異喹啉基、3-異喹啉酮基、喹唑啉基、3,4-二氫-1H-苯並吡喃基、1,2,3,4-四氫喹啉基、苯並呋喃基、苯並噻吩基、苯並吡咯基、苯並噁唑基、苯並噻唑基、苯並咪唑基、苯並吡唑基、 、 、 、 、 、 、 、 、 、 、 、 ，所述的B 1、B 4任選被1至4個R b1所取代； B 2選自取代或未取代的如下基團之一：苯基、萘基、吡唑基、咪唑基、三氮唑基、噻唑基、噁唑基、異噁唑基、噻吩基、吡啶基、苯並吡咯基、苯並咪唑基、苯並吡唑基、苯並噻唑基、吡唑並四氫吡咯基、3-噠嗪酮基、2-吡啶酮基、1,2,3,4-四氫喹啉基、1,2,3,4-四氫異喹啉基、 、 、 、 、 、 、 、 、 、 、 、 、 或B 5，當被取代時，被1至4個R b2取代； B 5選自 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ，所述B 5任選被1至4個R b2取代； B 3選自取代或未取代的如下基團之一：苯基、萘基、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、苯並吡啶基、苯並噻吩基、苯並呋喃基、噻吩基、呋喃基、吡咯基，當被取代時，被1至4個R b1取代； R b1各自獨立的選自H、F、Cl、Br、I、=O、OH、NH 2、N(CH 3) 2、CN、NO 2、-C(=O)CH 3、-C(=O)NH 2、-C(=O)NH-CH 3、-C(=O)N(CH 3) 2、-S(=O) 2NH 2、-P(=O)(CH 3) 2、-S(=O) 2CH 3或者任選取代的如下基團之一：甲基、乙基、丙基、異丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、環丙基、環丁基、環戊基、環己基、苯基、吡咯基、吡唑基、噁唑基、咪唑基、噻唑基、三氮唑基、氮雜環丁基、吡咯烷基、哌啶基、氧雜環丁基、氧雜環戊基、氧雜環己基、嗎啉、吡咯烷基並環戊基、氮雜環丁基螺環己基、環丙基螺環丁基、環丁基螺環丁基、環丁基螺環戊基、環丁基螺環己基、環戊基螺環己基、 ，當被取代時，被1至4個選自F、Cl、Br、I、OH、CN、CHF 2、CF 3、NH 2、NHCH 3、N(CH 3) 2、甲基、乙基、異丙基、乙炔基、-CH 2-CN、-CH 2OH、-CH 2OMe、-CH 2-環丙基、甲氧基、環丙基、環丁基、氮雜環丁基、吡咯烷基、哌啶基、嗎啉基、噻吩基、噻唑基、呋喃基、噁唑基、吡咯基、咪唑基、吡唑基、三氮唑基、四氮唑基的取代基所取代； R b2各自獨立的選自H、F、Cl、Br、I、=O、OH、NH 2、NH(CH 3)、N(CH 3) 2、CN、NO 2、COOH、-C(=O)NH 2或者任選取代的如下基團之一：-CH 2OCH 2CH 3、甲基、乙基、異丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、丙氧基、異丙基氧基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、哌啶基、嗎啉基、吡唑基、噻唑基、三氮唑基、四氮唑基、苯基，當被取代時，被1至4個選自F、Cl、Br、I、OH、CN、CHF 2、CF 3、NH 2、NHCH 3、N(CH 3) 2、甲基、乙基、異丙基、甲氧基、乙氧基、吡唑基、嗎啉基、氧雜環己基、環丙基、 、環丁基、 、 、環丙基氧基、 、 、 、 的取代基所取代； R b3、R b4各自獨立的選自H、OH、NH 2或者任選取代的如下基團之一：甲基、乙基、乙炔基、丙炔基、炔丙基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、哌啶基、氧雜環丁基、氧雜環戊基、氧雜環己基、環丁基螺環丁基，當被取代時，被1至4個選自氘、F、Cl、Br、I、OH、NH 2、CN、CF 3、CHF 2、甲基、甲氧基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、吡唑基、哌啶基、氧雜環丁基、氧雜環戊基、氧雜環己基、環丁基螺環丁基的取代基所取代； 或R b3、R b4與其相連接的碳原子共同形成任選取代的如下基團之一：環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、哌啶基、氧雜環丁基、氧雜環戊基、氧雜環己基、環丁基螺環丁基，當被取代時，被1至4個選自氘、F、Cl、Br、I、OH、NH 2、N(CH 3)、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-6環烷基、5-6員雜芳基或3至8雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； R b5選自OH、NH 2、甲基、乙基、丙基、異丙基、-(CH 2) n-環丙基、-(CH 2) n-環丁基、-(CH 2) n-環戊基、-(CH 2) n-環己基、苯基、吡啶基，所述的-CH 2-、甲基、乙基、丙基、異丙基、環丙基、環丁基、環戊基、環己基、苯基、吡啶基任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、C 1-4烷基、C 1-4烷氧基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 3-6環烷基、5-10員雜芳基或4-10員雜環基的取代基所取代，所述的雜芳基或雜環基含有1至4個選自O、S、N的雜原子； n各自獨立的選自0、1； R b6選自F、Cl、Br、I、OH、NH 2、CN、NO 2、-CH 2-R b23、-CH 2-X-(CH 2) m2-R b24或者取代或未取代的如下基團之一：乙炔基、丙炔基、炔丙基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、氧雜環丁基、吡咯烷基、氮雜環己烯基、哌啶基、嗎啉基、哌嗪基、1,4-二氮雜庚烷基、苯基、吡啶基、環丙基並環丙基、環丙基並環丁基、環丙基並環戊基、環丙基並環己基、環丁基並環丁基、環丁基並環戊基、環丁基並環己基、環戊基並環戊基、環戊基並環己基、環己基並環己基、環丙基螺環丙基、環丙基螺環丁基、環丙基螺環戊基、環丙基螺環己基、環丁基螺環丁基、環丁基螺環戊基、環丁基螺環己基、環戊基螺環戊基、環戊基螺環己基、環己基螺環己基、環丙基並氮雜環丁基、環丙基並吡咯烷基、環丙基並哌啶基、環丁基並氮雜環丁基、環丁基並吡咯烷基、環丁基並哌啶基、環戊基並氮雜環丁基、環戊基並吡咯烷基、環戊基並哌啶基、環己基並氮雜環丁基、環己基並吡咯烷基、環己基並哌啶基、氮雜環丁基並氮雜環丁基、氮雜環丁基並吡咯烷基、氮雜環丁基並哌啶基、吡咯烷基並氮雜環丁基、吡咯烷基並吡咯烷基、吡咯烷基並哌啶基、哌啶基並氮雜環丁基、哌啶基並吡咯烷基、哌啶基並哌啶基、環丁基螺氮雜環丁基、環丁基螺吡咯烷基、環丁基螺哌啶基、環戊基螺氮雜環丁基、環戊基螺吡咯烷基、環戊基螺哌啶基、環己基螺氮雜環丁基、環己基螺吡咯烷基、環己基螺哌啶基、氮雜環丁基螺氮雜環丁基、氮雜環丁基螺吡咯烷基、氮雜環丁基螺哌啶基、吡咯烷基螺氮雜環丁基、吡咯烷基螺吡咯烷基、吡咯烷基螺哌啶基、哌啶基螺氮雜環丁基、哌啶基螺哌啶基、 、 、 、 、 、 、 、 、 、 ，當被取代時，被1至4個選自F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； R b7選自H、F、Cl、Br、I、OH、NH 2、CN、NO 2、CHF 2、CF 3、-CH 2-R b23、-CH 2-X-(CH 2) m2-R b24或者取代或未取代的如下基團之一：乙炔基、丙炔基、炔丙基、甲基、乙基、甲氧基、乙氧基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、氮雜環己烯基、哌啶基、嗎啉基、哌嗪基、1,4-二氮雜庚烷基、苯基、環丙基並環丙基、環丙基並環丁基、環丙基並環戊基、環丙基並環己基、環丁基並環丁基、環丁基並環戊基、環丁基並環己基、環戊基並環戊基、環戊基並環己基、環己基並環己基、環丙基螺環丙基、環丙基螺環丁基、環丙基螺環戊基、環丙基螺環己基、環丁基螺環丁基、環丁基螺環戊基、環丁基螺環己基、環戊基螺環戊基、環戊基螺環己基、環己基螺環己基、環丙基並氮雜環丁基、環丙基並吡咯烷基、環丙基並哌啶基、環丁基並氮雜環丁基、環丁基並吡咯烷基、環丁基並哌啶基、環戊基並氮雜環丁基、環戊基並吡咯烷基、環戊基並哌啶基、環己基並氮雜環丁基、環己基並吡咯烷基、環己基並哌啶基、氮雜環丁基並氮雜環丁基、氮雜環丁基並吡咯烷基、氮雜環丁基並哌啶基、吡咯烷基並氮雜環丁基、吡咯烷基並吡咯烷基、吡咯烷基並哌啶基、哌啶基並氮雜環丁基、哌啶基並吡咯烷基、哌啶基並哌啶基、環丁基螺氮雜環丁基、環丁基螺吡咯烷基、環丁基螺哌啶基、環戊基螺氮雜環丁基、環戊基螺吡咯烷基、環戊基螺哌啶基、環己基螺氮雜環丁基、環己基螺吡咯烷基、環己基螺哌啶基、氮雜環丁基螺氮雜環丁基、氮雜環丁基螺吡咯烷基、氮雜環丁基螺哌啶基、吡咯烷基螺氮雜環丁基、吡咯烷基螺吡咯烷基、吡咯烷基螺哌啶基、哌啶基螺氮雜環丁基、哌啶基螺哌啶基、 、 、 、 、 、 、 、 、 、 ，當被取代時，被1至4個選自F、Cl、Br、I、OH、NH 2、CN、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 2-4炔基、C 3-8環烷基或3至8雜環基的取代基所取代，所述的雜環基含有1至4個選自O、S、N的雜原子； X各自獨立的選自NH、O或S； m2各自獨立的選自0、1或2； R b23各自獨立的選自乙烯基、乙炔基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、氮雜環己烯基、氧雜環丁基、氧雜環戊基、氧雜環己基、哌啶或嗎啉，所述的乙烯基、乙炔基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、氮雜環己烯基、氧雜環丁基、氧雜環戊基、氧雜環己基、哌啶或嗎啉任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代； R b24各自獨立的選自甲氧基、乙氧基、丙氧基、異丙基氧基、環丙基、環丙基氧基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、氮雜環己烯基、氧雜環丁基、氧雜環戊基、氧雜環己基、哌啶或嗎啉，所述的甲氧基、乙氧基、丙氧基、異丙基氧基、環丙基、環丁基、環戊基、環己基、氮雜環丁基、吡咯烷基、氮雜環己烯基、氧雜環丁基、氧雜環戊基、氧雜環己基、哌啶或嗎啉任選被1至4個選自F、Cl、Br、I、OH、=O、NH 2、CN、COOH、C 1-4烷基、鹵素取代的C 1-4烷基、氰基取代的C 1-4烷基、C 1-4烷氧基的取代基所取代； K選自 表 K-1所示的結構片段之一。 The compound according to claim 5 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein R L is selected from H, methyl or ethyl ; q is each independently selected from 0, 1 or 2; Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from one of the following groups: bond or substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclo Pentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, piperidinyl, morpholinyl, piperazinyl, 1,4-diazepanyl, phenyl, thiophene base, thiazolyl, furyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyridone, triazinyl, imidazopyridyl, imidazolyl Pyrazinyl, imidazopyrimidine, pyrazolopyridyl, pyrazolopyrazinyl, pyrazolopyrimidinyl, benzothienyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzo Imidazolyl, benzopyrazolyl, benzopyrrolyl, triazolopyridinyl, triazolopyrimidinyl, triazolopyridazinyl, triazolopyrazinyl, triazolothiazolyl , triazoloxazolyl, triazolopyrazolyl, triazolopyrrolyl, triazoloimidazolyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropyl and cyclopentyl, cyclopropyl and cyclohexyl, cyclobutyl and cyclobutyl, cyclobutyl and cyclopentyl, cyclobutyl and cyclohexyl, cyclopentyl and cyclohexyl, cyclopentyl and cyclohexyl, Cyclohexylcyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocycle Pentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpyrrolidinyl Propylpiperidinyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl , cyclopentapiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinylazetidinyl, azetidinyl Pyrrolidinyl, azetidinylpiperidinyl, pyrrolidinylazetidinyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, piperidinylazetidinyl, Piperidinopyrrolidinyl, piperidinopiperidinyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidyl, cyclobutylspiropyrrolidyl, cyclopentylspiroazetidine base, cyclopentylspiropyrrolidyl, cyclopentylspiropiperidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidyl, cyclohexylspiropyrrolidyl, azetidinylspiroazetidine Butyl, azetidinylspiropyrrolidyl, azetidinylspiropiperidinyl, pyrrolidinylspiroazetidinyl, pyrrolidinylspiropyrrolidyl, pyrrolidinylspiropiperidinyl, piperidyl Aldylspiroazetidinyl, piperidinylspiropiperidinyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , when substituted, by 1 to 4 R L2 ; R L2 is each independently selected from deuterium, F, Cl, Br, I, OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , COOH, CN , =O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -OC 1-2 alkylene -OC 1-2 alkyl, - OC 1-2 alkylene-OC 3-6 carbocyclyl, -C 1-2 alkylene-OC 1-2 alkylene -OC 1-2 alkyl, -C 1-2 alkylene-OC 1-2 alkylene-OC 3-6 carbocyclyl, -OC 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-C 3-6 carbocyclyl, - C 0-2 alkylene-4 to 6-membered heterocyclyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 Selected from F, Cl, Br, I, OH, COOH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , =O, C 1-4 alkyl, halogen substituted Substituted with C 1-4 alkyl, halogen-substituted C 1-4 alkoxy, hydroxyl-substituted C 1-4 alkyl, C 1-4 alkoxy substituents, the heterocyclic group contains 1 to 4 heteroatoms selected from O, S, N; B 1 and B 4 are each independently selected from phenyl, naphthyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazine base, quinolyl, isoquinolyl, 3-isoquinolinonyl, quinazolinyl, 3,4-dihydro-1H-benzopyranyl, 1,2,3,4-tetrahydroquinyl Phenyl, benzofuryl, benzothienyl, benzopyrrolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, , , , , , , , , , , , , the B 1 and B 4 are optionally substituted by 1 to 4 R b1 ; B 2 is selected from one of the following substituted or unsubstituted groups: phenyl, naphthyl, pyrazolyl, imidazolyl, tris Azolyl, thiazolyl, oxazolyl, isoxazolyl, thienyl, pyridyl, benzopyrrolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, pyrazolotetrahydropyrrolyl , 3-pyridinonyl, 2-pyridinonyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, , , , , , , , , , , , , or B5 , when substituted, is substituted by 1 to 4 R b2 ; B5 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , the B 5 is optionally substituted by 1 to 4 R b2 ; B 3 is selected from one of the following substituted or unsubstituted groups: phenyl, naphthyl, , , , , , , , , , , , , , , , , , , , , , , , , benzopyridyl, benzothienyl, benzofuryl, thienyl, furyl, pyrrolyl, when substituted, are substituted by 1 to 4 R b1 ; R b1 are each independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , N(CH 3 ) 2 , CN, NO 2 , -C(=O)CH 3 , -C(=O)NH 2 , -C(=O) NH-CH 3 , -C(=O)N(CH 3 ) 2 , -S(=O) 2 NH 2 , -P(=O)(CH 3 ) 2 , -S(=O) 2 CH 3 or One of the following optionally substituted groups: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclopropyl Butyl, cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, triazolyl, azetidinyl, pyrrolidinyl, piperidinyl, oxygen Heterobutyl, oxanyl, oxanyl, morpholine, pyrrolidinylcyclopentyl, azetidinylspirocyclohexyl, cyclopropylspirocyclobutyl, cyclobutylspirocyclobutyl base, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclohexyl, , when substituted, is selected from 1 to 4 F, Cl, Br, I, OH, CN, CHF 2 , CF 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, Isopropyl, ethynyl, -CH 2 -CN, -CH 2 OH, -CH 2 OMe, -CH 2 -cyclopropyl, methoxy, cyclopropyl, cyclobutyl, azetidinyl, pyrrole Substituted by alkyl, piperidyl, morpholinyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl substituents; R b2 is each independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CN, NO 2 , COOH, -C(=O) NH 2 or optionally substituted one of the following groups: -CH 2 OCH 2 CH 3 , methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethyl Oxygen, propoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrazolyl, Thiazolyl, triazolyl, tetrazolyl, phenyl, when substituted, are selected from 1 to 4 from F, Cl, Br, I, OH, CN, CHF 2 , CF 3 , NH 2 , NHCH 3. N(CH 3 ) 2 , methyl, ethyl, isopropyl, methoxy, ethoxy, pyrazolyl, morpholinyl, oxanyl, cyclopropyl, , cyclobutyl, , , cyclopropyloxy, , , , Substituted with substituents; R b3 and R b4 are each independently selected from H, OH, NH 2 or one of the optionally substituted following groups: methyl, ethyl, ethynyl, propynyl, propargyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxanyl, oxanyl, cyclobutylspiro Cyclobutyl, when substituted, is substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH 2 , CN, CF 3 , CHF 2 , methyl, methoxy, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, pyrazolyl, piperidinyl, oxetanyl, oxanyl, oxanyl, cyclobutylspiro Substituted by the substituent of cyclobutyl; or R b3 , R b4 and the carbon atom to which they are connected together form one of the following optionally substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aza Cyclobutyl, pyrrolidinyl, piperidinyl, oxetanyl, oxanyl, oxanyl, cyclobutylspirocyclobutyl, when substituted, by 1 to 4 selected from deuterium , F, Cl, Br, I, OH, NH 2 , N(CH 3 ), CN, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, Substituted with substituents of C 1-4 alkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl or 3 to 8 heterocyclyl, the heteroaryl or The heterocyclic group contains 1 to 4 heteroatoms selected from O, S, and N; R b5 is selected from OH, NH 2 , methyl, ethyl, propyl, isopropyl, -(CH 2 ) n -cyclopropyl base, -(CH 2 ) n -cyclobutyl, -(CH 2 ) n -cyclopentyl, -(CH 2 ) n -cyclohexyl, phenyl, pyridyl, the -CH 2 -, methyl , ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 3-6 Substituted with cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl substituents, the heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from O, S, N ; n is independently selected from 0, 1; R b6 is selected from F, Cl, Br, I, OH, NH 2 , CN, NO 2 , -CH 2 -R b23 , -CH 2 -X-(CH 2 ) m2 -R b24 or one of the following substituted or unsubstituted groups: ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxa Cyclobutyl, pyrrolidinyl, azepinenyl, piperidyl, morpholinyl, piperazinyl, 1,4-diazepanyl, phenyl, pyridyl, cyclopropyl and cyclopropyl base, cyclopropyl and cyclobutyl, cyclopropyl and cyclopentyl, cyclopropyl and cyclohexyl, cyclobutyl and cyclobutyl, cyclobutyl and cyclopentyl, cyclobutyl and cyclohexyl, cyclopentyl Cyclopentyl, cyclopentacyclohexyl, cyclohexylcyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, Cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylaza cyclobutyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl, cyclobutylpiperidinyl, cyclopentyl Azetidinyl, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl, cyclohexylpiperidinyl, azetidinyl Azetidinyl, azetidinylpyrrolidinyl, azetidinylpiperidinyl, pyrrolidinylazetidinyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl Aldyl, piperidinoazetidinyl, piperidinopyrrolidinyl, piperidinopiperidinyl, cyclobutylspiroazetidinyl, cyclobutylspiropyrrolidyl, cyclobutyl Spiropiperidinyl, cyclopentylspiroazetidinyl, cyclopentylspiropyrrolidyl, cyclopentylspiroazetidinyl, cyclohexylspiroazetidinyl, cyclohexylspiropyrrolidyl, cyclohexylspiro Piperidinyl, azetidinylspiroazetidinyl, azetidinylspiropyrrolidinyl, azetidinylspiropiperidinyl, pyrrolidinylspiroazetidinyl, pyrrolidinylspiro Pyrrolidinyl, pyrrolidinylspiropiperidinyl, piperidinylspiroazetidinyl, piperidinylspiropiperidinyl, , , , , , , , , , , when substituted, C 1-4 alkyl substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen substituted, cyano substituted C Substituted with 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, the heterocyclyl contains 1 to 4 heteroatoms selected from O, S, N; R b7 selected from H, F, Cl, Br, I, OH, NH 2 , CN, NO 2 , CHF 2 , CF 3 , -CH 2 -R b23 , -CH 2 -X-(CH 2 ) m2 -R b24 or one of the following substituted or unsubstituted groups: ethynyl, propynyl, propargyl, methyl, ethyl, methoxy, ethoxy , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, piperidinyl, morpholinyl, piperazinyl, 1,4-di Azepanyl, phenyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclobutylcyclobutyl, cyclobutyl Cyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspiro Cyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylpyrrolidinyl, cyclopropylpiperidinyl, cyclobutylazetidinyl, cyclobutylpyrrolidinyl Alkyl, cyclobutylazetidinyl, cyclopentylazetidinyl, cyclopentylpyrrolidinyl, cyclopentylpiperidinyl, cyclohexylazetidinyl, cyclohexylpyrrolidinyl Alkyl, cyclohexylpiperidinyl, azetidinylazetidinyl, azetidinylpyrrolidinyl, azetidinylpiperidinyl, pyrrolidinylazetidinyl base, pyrrolidinopyrrolidinyl, pyrrolidinolopiperidinyl, piperidinoazetidinyl, piperidinopyrrolidinyl, piperidinopiperidinyl, cyclobutylspiroazepine Cyclobutyl, cyclobutylspiropyrrolidyl, cyclobutylspiropiperidinyl, cyclopentylspiroazetidinyl, cyclopentylspiropyrrolidyl, cyclopentylspiropyrolidinyl, cyclohexylspiroazetidine Heterocyclylbutyl, cyclohexylspiropyrrolidyl, cyclohexylspiropiperidinyl, azetidinylspiroazetidinyl, azetidinylspiropyrrolidyl, azetidinylspiropiperidinyl ,pyrrolidinylspiroazetidinyl,pyrrolidinylspiropyrrolidyl,pyrrolidinylspiropiperidinyl,piperidinylspiroazetidinyl,piperidinylspiropiperidinyl, , , , , , , , , , , when substituted, C 1-4 alkyl substituted by 1 to 4 selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-4 alkyl, halogen substituted, cyano substituted C Substituted with 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkynyl, C 3-8 cycloalkyl or 3 to 8 heterocyclyl substituents, the heterocyclyl contains 1 to 4 heteroatoms selected from O, S, N; X is each independently selected from NH, O or S; m2 is each independently selected from 0, 1 or 2; R b23 is each independently selected from vinyl, ethynyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, oxetanyl, oxanyl, oxanyl, pipera Dydine or morpholine, the vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, oxetanyl The base, oxanyl, oxanyl, piperidine or morpholine is optionally 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1- 4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 alkoxy substituents; R b24 are each independently selected from methoxy, ethyl Oxygen, propoxy, isopropyloxy, cyclopropyl, cyclopropyloxy, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl , oxetanyl, oxanyl, oxanyl, piperidine or morpholine, the methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyl, cyclopropyl Butyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, azetidinyl, oxetanyl, oxetanyl, oxetanyl, piperidine or morpholine Selected from 1 to 4 selected from F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, cyano-substituted C Substituted with 1-4 alkyl and C 1-4 alkoxy substituents; K is selected from one of the structural fragments shown in Table K-1 . 根據請求項6所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，其中， Cy1、Cy2、Cy3、Cy4或Cy5各自獨立的選自鍵或取代的或者未取代的如下基團之一： 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ，當被取代時，被1至4個R L2取代； R L2各自獨立地選自氘、F、Cl、Br、=O、COOH、CN、NHCH 3、N(CH 3) 2、OH、NH 2或任選取代的如下基團之一：甲基、乙基、異丙基、乙烯基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基、丙氧基、異丙基氧基、環丙基、環丁基、環戊基、環己基、吡唑基、噻唑基、三氮唑基、四氮唑基、苯基、嗎啉、-CH 2-環丙基、-CH 2-嗎啉、-CH 2-吡唑、-OCH 2-環丙基、-O-環丙基、-OCH 2CH 2-O-甲基、-OCH 2CH 2-O-環丙基、-CH 2OCH 2CH 2-O-甲基、-CH 2OCH 2CH 2-O-環丙基，當被取代時，被1至4個選自F、CHF 2、CF 3、-OCHF 2、-OCF 3、甲基、甲氧基、=O、羥甲基、COOH、CN、NHCH 3、N(CH 3) 2、OH、NH 2的取代基所取代； B選自 表 B-1 或表 B-2所示的結構片段之一； K選自 表 K-2所示的結構片段之一。 The compound according to claim 6 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently is selected from one of the following groups: bond or substituted or unsubstituted: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , when substituted, by 1 to 4 R L2 ; each R L2 is independently selected from deuterium, F, Cl, Br, =O, COOH, CN, NHCH 3 , N(CH 3 ) 2 , OH, NH 2 or one of the optionally substituted following groups: methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, propoxy, isopropyl Oxygen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, phenyl, morpholine, -CH 2 -cyclopropyl, -CH 2 -morpholine, -CH 2 -pyrazole, -OCH 2 -cyclopropyl, -O - cyclopropyl, -OCH 2 CH 2 -O-methyl, -OCH 2 CH 2 -O-cyclopropyl base, -CH 2 OCH 2 CH 2 -O-methyl, -CH 2 OCH 2 CH 2 -O-cyclopropyl, when substituted, by 1 to 4 selected from F, CHF 2 , CF 3 , - Substituted by OCHF 2 , -OCF 3 , methyl, methoxy, =O, hydroxymethyl, COOH, CN, NHCH 3 , N(CH 3 ) 2 , OH, NH 2 substituents; B is selected from Table B -1 or one of the structural fragments shown in Table B-2 ; K is selected from one of the structural fragments shown in Table K-2 . 根據請求項7所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，其中， L選自鍵或 表 L-1 或表 L-2所示的結構片段之一，其中基團左側與B連接。 The compound according to claim 7 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein L is selected from the group consisting of bonds or Table L-1 or Table One of the structural fragments shown in L-2 , in which the left side of the group is connected to B. 根據請求項1所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，其中該化合物選自 表 E-1所示結構之一。 The compound according to claim 1 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the structures shown in Table E-1 one. 一種藥物組合物，包括請求項1-9任意一項所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，以及藥學上可接受的載體，較佳地，藥物組合物中包含1-1500mg請求項1-9任意一項所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶。A pharmaceutical composition, including the compound described in any one of claims 1-9 or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and a pharmaceutical Acceptable carrier, preferably, the pharmaceutical composition contains 1-1500 mg of the compound described in any one of claims 1-9 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutical Acceptable salts or eutectics. 一種根據請求項1-9任意一項所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶在用於製備治療與AR或AR剪切突變體活性或表達量相關疾病的藥物中的應用。A compound according to any one of claims 1-9 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal for use in the preparation of treatments for AR or Application of AR splice mutants in drugs for diseases related to activity or expression level. 一種根據請求項1-9任意一項所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶在用於製備治療與抑制或降解AR或AR剪切突變體相關疾病的藥物中的應用。A compound according to any one of claims 1-9 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal for use in the preparation of treatments and inhibitors or Application in drugs that degrade AR or AR splice mutant-related diseases. 根據請求項11或12所述的應用，其中，所述的疾病選自前列腺癌。The application according to claim 11 or 12, wherein the disease is selected from prostate cancer. 一種用於治療哺乳動物的疾病的方法，所述方法包括給予受試者治療有效量的請求項1-9任意一項所述的化合物或者其立體異構體、氘代物、溶劑化物、前藥、代謝產物、藥學上可接受的鹽或共晶，治療有效量較佳1-1500mg，所述的疾病較佳AR或AR剪切突變體活性或表達量相關疾病。A method for treating diseases in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound described in any one of claims 1-9 or its stereoisomers, deuterated products, solvates, and prodrugs , metabolites, pharmaceutically acceptable salts or co-crystals, the therapeutically effective dose is preferably 1-1500 mg, and the disease is preferably related to the activity or expression of AR or AR splicing mutants.
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