AMPK agonist and use thereof

Abstract

The present invention belongs to the field of drugs and cosmetics, and particularly relates to an AMPK agonist, and a preparation method therefor and the use thereof. In particular, the AMPK agonist is used in the preparation of a drug for treating and / or preventing alopecia, etc.

Description

AMPK agonists and their uses

[0001] Citation of Related Applications

[0002] This application claims priority to Chinese patent application CN202310904807.7 filed on July 21, 2023 and Chinese patent application CN202311128823.8 filed on August 30, 2023, the contents of which are incorporated by reference into this application in their entirety and for all purposes. Technical Field

[0003] The present invention belongs to the field of medicine and cosmetics, and particularly relates to an AMPK agonist and a preparation method and use thereof. Background Art

[0004] AMPK (adenosine monophosphate (AMP)-activated protein kinase) is a serine / threonine protein kinase. It is a heterotrimeric complex composed of an α subunit containing the kinase domain and two regulatory subunits (β- and γ-). AMPK is regulated by the upstream kinases LKB1 (liver kinase B1) and CAMKK2 (calcium / calmodulin-dependent protein kinase kinase 2). Phosphorylation of Thr174 in the activation loop (T-loop) of the α subunit (Thr172 in α2) leads to a 500- to 1000-fold increase in activity. AMPK acts as a metabolic switch, and its activation affects lipid, cholesterol, carbohydrate, and amino acid metabolism, as well as mitochondrial function, autophagy, and cell growth.

[0005] Hair has its own growth and metabolic cycle. Its growth is driven by the hair follicle stem cells inside the hair follicles. As these stem cells switch back and forth between activation and resting states, they show a process of growth, rest, shedding and regrowth. Therefore, the hair growth cycle includes the growth phase, regression phase and resting phase.

[0006] Alopecia is the loss of hair from the head or body, typically the scalp. It's generally classified as androgenic alopecia, focal alopecia (alopecia areata), traction alopecia, telogen effluvium, and anagen effluvium. Each type of hair loss has different causes. Currently, androgenic alopecia and alopecia areata are the most common and most studied.

[0007] Currently, products that truly prevent hair loss and promote hair growth are very limited. Minoxidil and finasteride are the only two approved medications for treating hair loss. Minoxidil is the only OTC medication. Its main side effects are irritant dermatitis and hirsutism, and its long onset of effect. Furthermore, minoxidil is only effective in 40% of the population, limiting its use. More hair loss prevention and hair growth products are needed to meet this demand.

[0008] A recent Cell Report (Cell Reports 27, 3413–3421) reported that the AMPK agonist AICAR can activate hair follicle stem cells in quiescent mice, initiating a new round of hair growth. Therefore, it is necessary to design and synthesize novel AMPK agonists that can activate hair follicle stem cells by activating AMPK, thereby promoting hair growth and providing more anti-hair loss and hair growth products to meet demand.

[0009] Type 2 diabetes, also known as non-insulin-dependent diabetes mellitus, is a chronic metabolic disease characterized by hyperglycemia, insulin deficiency, and insulin resistance. In addition to genetic factors, lifestyle habits and dietary patterns greatly influence the incidence of type 2 diabetes. Currently, the main drugs used to treat type 2 diabetes include biguanides, sulfonylureas, thiazolidinediones, DPP-4 inhibitors, SGLT-2 inhibitors, and GLP-1 analogs. However, all currently used therapeutic drugs have certain side effects, so there is a need to develop hypoglycemic drugs with novel mechanisms of action to meet the needs of diabetic patients.

[0010] AMPK reduces lipid storage by phosphorylating multiple substrates. These pathways work together to promote fatty acid oxidation while inhibiting fatty acid and cholesterol synthesis. AMPK may also indirectly control the rate of fatty acid oxidation by regulating mitochondrial function. In addition to regulating fatty acid metabolism and indirectly influencing carbohydrate metabolism, AMPK also directly regulates carbohydrate metabolism pathways through various mechanisms. Activation of AMPK promotes cellular glucose uptake by enhancing the translocation and expression of GLUT proteins.

[0011] Related literature (Cell Metabolism 25, 1147–1159, ACS Med. Chem. Lett. 2018, 9, 1, 39–44) has reported that AMPK agonists can significantly lower blood glucose levels in mice, returning their blood glucose levels to normal. Therefore, AMPK agonists have the potential to lower blood glucose. Therefore, it is necessary to design and synthesize new AMPK agonists to regulate blood glucose levels in the body by activating AMPK.

[0012] Summary of the Invention

[0013] The first aspect of the present invention provides a compound represented by formula (I), or its enantiomers, diastereomers, racemates, stereoisomers, geometric isomers, tautomers, polymorphs, solvates, hydrates, N-oxides, isotope-labeled compounds, metabolites, esters, prodrugs, or pharmaceutically acceptable salts,

[0014] in,

[0015] is selected from single bonds and double bonds;

[0016] when When it is a single bond, X1 is selected from CH and N, and X2 is selected from CR X2a R X2b and C(=O); or

[0017] X1 selected from CR X1 and N, X2 selected from CR X2a R X2b and C(=O); or

[0018] X1 is C, L1 is -CR L1b -, and X1 and L1 are connected by a double bond;

[0019] when When it is a double bond, X1 is C, and X2 is selected from CR X2a and N;

[0020] X3 selected from NR X3 , O and S;

[0021] Y1 is selected from CR Y1 , N and N-oxides;

[0022] Y2 is selected from CR Y2 and N;

[0023] Y3 is selected from CR Y3 and N;

[0024] L1 is selected from -C(=O)- and -CR L1a R L1b -;

[0025] L2 is selected from a bond and -C(=O)-;

[0026] L3 is selected from a bond, -O-, -NR L3 -、-S-、-C 1-6 Alkylene-O-, -C 1-6 Alkylene-NR L3 -、-C 1-6 Alkylene-S-, -C 1-6 Alkylene-, -C2-6 Alkenylene- and -C 2-6 Alkynylidene-;

[0027] R1 is selected from -OR 1a 、-NR 1b R 1c , tetrazolyl and oxodihydrooxadiazolyl

[0028] R2 is selected from C 6-10 Aryl, C 3-10 Cycyl, 4-10 membered heterocyclic and 5-10 membered heteroaryl, the C 6-10 Aryl, C 3-10 Cycyl, 4-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted by 1, 2, 3, 4 or 5 members independently selected from R 2a 、R 2b 、R 2c 、R 2d and R 2e The group substitution;

[0029] R x1 Selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0030] R X2a and R X2b are independently selected from H, halogen, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -SC 1-6 Alkyl and -SC 1-6 haloalkyl; or

[0031] R X2a and R X2b are independently selected from H, halogen, hydroxyl, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -SC 1-6 Alkyl and -SC 1-6 alkyl halide;

[0032] R X3 Selected from H, C1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl and C 3-6 Halogenated cycloalkyl;

[0033] R Y1 Selected from H, D, halogen, hydroxyl, carboxyl, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl and 4-10 membered heterocycloalkyl;

[0034] R Y2 and R Y3 are independently selected from H, D, halogen, -CN, hydroxyl, carboxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl and 4-10 membered heterocycloalkyl; or

[0035] R Y2 and R Y3 Together with the atoms to which they are attached, they form a phenyl group and a 5-6 membered heteroaryl group;

[0036] R L1a and R L1b are independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy; or

[0037] R L1a and R L1b Together with the atoms they are connected to form C 3-6 Cycloalkyl;

[0038] R L3 Selected from H, D and C 1-4 alkyl;

[0039] R 1a 、R 1b and R 1c are independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10Aryl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -C 1-6 Alkylene-4-10 membered heterocyclic group, -C 1-6 Alkylene-C 6-10 Aryl, -C 1-6 Alkylene-5-10 membered heteroaryl, -C 1-6 Halogenated alkylene-C 3-10 Cycloalkyl, -C 1-6 Halogenated alkylene-4-10 membered heterocyclic group, -C 1-6 Halogenated alkylene-C 6-10 Aryl and -C 1-6 haloalkylene-5-10 membered heteroaryl; or

[0040] R 1a 、R 1b and R 1c are independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 Aryl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -C 1-6 Alkylene-4-10 membered heterocyclic group, -C 1-6 Alkylene-C 6-10 Aryl, -C 1-6 Alkylene-5-10 membered heteroaryl, -C 1-6 Halogenated alkylene-C 3-10 Cycloalkyl, -C 1-6 Halogenated alkylene-4-10 membered heterocyclic group, -C 1-6 Halogenated alkylene-C 6-10 Aryl and -C 1-6 Haloalkylene-5-10 membered heteroaryl; wherein, C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 Aryl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -C 1-6 Alkylene-4-10 membered heterocyclic group, -C 1-6 Alkylene-C 6-10 Aryl, -C 1-6 Alkylene-5-10 membered heteroaryl, -C 1-6 Halogenated alkylene-C 3-10 Cycloalkyl, -C 1-6 Halogenated alkylene-4-10 membered heterocyclic group, -C 1-6 Halogenated alkylene-C 6-10 Aryl and -C1-6 The haloalkylene-5-10 membered heteroaryl group is optionally substituted by one or more groups selected from oxo, hydroxy, cyano, carboxyl, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl substituted by a substituent;

[0041] R 2a 、R 2b 、R 2c 、R 2d and R 2e are independently selected from H, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 Cyclic group, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 6-10 Arylene-4-10 membered heterocyclic group, -C 6-10 Arylene-5-10 membered heteroaryl, -C 6-10 Arylene-C 6-10 Aryl and -5-10 membered heteroarylene-5-10 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 Cyclic group, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 6-10 Arylene-4-10 membered heterocyclic group, -C 6-10 Arylene-5-10 membered heteroaryl, -C 6-10 Arylene-C 6-10 Aryl or -5-10 membered heteroarylene-5-10 membered heteroaryl is optionally substituted with one or more R;

[0042] R is independently selected from halogen, -OH, -CN, -COOH, C 1-6 Alkyl, -C 1-6 Alkylene-OH, C1-6 Alkoxy, -C 1-6 Alkyleneoxy-C 1-6 Alkoxy, -C(=O)NH-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -N=S(=O)(C 1-6 alkyl)-C 1-6 Alkyl, -NH-S(=O)2C 1-6 Alkyl, -S(=O)2-C 1-6 alkyl, -S(=O)2-4-10 membered heterocyclyl, -C(=O)-4-10 membered heterocyclyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, and

[0043] The condition is that when L2 is a bond,

[0044] 1) L1 is -CR L1a R L1b -,or

[0045] 2) R1 is selected from -NR 1b R 1c , tetrazolyl and oxodihydrooxadiazolyl or

[0046] 3) For a single bond.

[0047] In certain embodiments, each R is independently selected from halogen, -OH, -CN, -COOH, oxo, C 1-6 Alkyl, -C 1-6 Alkylene-OH, C 1-6 Alkoxy, -C 1-6 Alkyleneoxy-C 1-6 Alkoxy, -C(=O)NH-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -N=S(=O)(C 1-6 alkyl)-C 1-6 Alkyl, -NH-S(=O)2C 1-6 Alkyl, -S(=O)2-C 1-6 alkyl, -S(=O)2-4-10 membered heterocyclyl, -C(=O)-4-10 membered heterocyclyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, and

[0048] In certain embodiments, with the proviso that, when L2 is a bond,

[0049] 1) L1 is -CR L1a R L1b -,or

[0050] 2) R1 is selected from -NR 1b R 1c , tetrazolyl and oxodihydrooxadiazolyl or

[0051] 3) is a single key, or

[0052] 4) R1 is selected from -OR 1a , where R 1a Selected from 5-10 membered heteroaryl, -C 1-6 Alkylene-5-10 membered heteroaryl, -C 1-6 Alkylene-4-10 membered heterocyclic group.

[0053] In certain embodiments, For double bonds.

[0054] In certain embodiments, L2 is -C(=O)-.

[0055] In certain embodiments,

[0056] when When it is a single bond, X1 is selected from CR X1 and N, X2 selected from CR X2a R X2b and C(=O), or

[0057] X1 is C, L1 is -CR L1b -, and X1 and L1 are connected by a double bond;

[0058] when When it is a double bond, X1 is C, and X2 is selected from CR X2a and N; R x1 Selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl.

[0059] In certain embodiments, R x1 Selected from H or C 1-3 alkyl.

[0060] In certain embodiments, R x1 C 1-3 alkyl.

[0061] In certain embodiments, the R x1 For H.

[0062] In certain embodiments, is a single bond, X1 is C, and L1 is -CR L1b -, and X1 and L1 are connected by a double bond.

[0063] In certain embodiments, is a single bond, X1 is selected from CR X1 and N, X2 selected from CR X2a R X2b and C(=O).

[0064] In certain embodiments, is a single bond, X1 is selected from N, X2 is selected from C(=O); or X1 is selected from CR X1 , X2 selected from CR X2a R X2b .

[0065] In certain embodiments, is a single bond, X1 is selected from CR X1 , X2 is selected from C(=O).

[0066] In certain embodiments, is a double bond, X1 is C, and X2 is selected from CR X2a and N.

[0067] In certain embodiments, is a double bond, X1 is C, and X2 is selected from CR X2a .

[0068] In certain embodiments, is a double bond, X1 is C, and X2 is selected from CH or C(OH).

[0069] In certain embodiments, R X2a and R X2b are independently selected from H, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Haloalkyl, -NH-C 1-4 Alkyl, -N(C 1-4 alkyl)-C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -SC 1-4 Alkyl and -SC 1-4 Halogenated alkyl.

[0070] In certain embodiments, the R X2a and R X2b are independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -NH-C 1-4 Alkyl, -N(C1-4 alkyl)-C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -SC 1- 4-alkyl and -SC 1-4 Halogenated alkyl.

[0071] In certain embodiments, R X2a and R X2b are independently selected from H, halogen, hydroxyl, C 1-4 Alkoxy, C 1- 4-halogenated alkoxy, -SC 1-4 alkyl.

[0072] In certain embodiments, R X2a and R X2b and each is independently selected from H, halogen, hydroxy, methyl, ethyl, propyl, butyl, halomethyl, haloethyl, halopropyl, halobutyl, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(methyl)-methyl, -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl)-ethyl, -N(ethyl)-propyl, methoxy, ethoxy, propoxy, butoxy, halomethoxy, haloethoxy, halopropoxy, halobutoxy, -S-methyl, -S-ethyl, -S-propyl, -S-butyl, -S-halomethyl, -S-haloethyl, -S-halopropyl, and -S-halobutyl.

[0073] In certain embodiments, the R X2a and R X2b and each is independently selected from H, halogen, methyl, ethyl, propyl, butyl, halomethyl, haloethyl, halopropyl, halobutyl, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(methyl)-methyl, -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl)-ethyl, -N(ethyl)-propyl, methoxy, ethoxy, propoxy, butoxy, halomethoxy, haloethoxy, halopropoxy, halobutoxy, -S-methyl, -S-ethyl, -S-propyl, -S-butyl, -S-halomethyl, -S-haloethyl, -S-halopropyl, and -S-halobutyl.

[0074] In certain embodiments, R X2a and R X2bThey are independently selected from H, F, Cl, Br, hydroxyl, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CF3, -NHCH3, -N(CH3)2, -N(CH2CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, -OCF2CF3, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3 and -S-CH(CH3)2.

[0075] In certain embodiments, the R X2a and R X2b Each is independently selected from H, F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CF3, -NHCH3, -N(CH3)2, -N(CH2CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, -OCF2CF3, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3 and -S-CH(CH3)2.

[0076] In certain embodiments, R X2a Selected from H, F, Cl, hydroxy, -OCH3, -OCF3 and -SCH3.

[0077] In certain embodiments, the R X2a Selected from H, F, Cl, -OCH3, -OCF3 and -SCH3.

[0078] In certain embodiments, the R X2a Selected from H, hydroxyl.

[0079] In certain embodiments, the R X2b For H.

[0080] In certain embodiments, the R X3 Selected from H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-5 Cycloalkyl and C 3- 5-halogenated cycloalkyl.

[0081] In certain embodiments, the R X3 Selected from H, C 1-4 Alkyl, C 1-4 Halogenated alkyl.

[0082] In certain embodiments, X3 is selected from NR X3 , O and S; said R X3 Selected from H, C1-4 Alkyl, C 1- 4 haloalkyl, C 3-5 Cycloalkyl and C 3-5 Halogenated cycloalkyl.

[0083] In certain embodiments, the R X3 is selected from H, methyl, ethyl, propyl, halomethyl, haloethyl, halopropyl, cyclopropyl, cyclobutyl, cyclopentyl, halocyclopropyl, halocyclobutyl and halocyclopentyl.

[0084] In certain embodiments, the R X3 For H.

[0085] In certain embodiments, X3 is selected from NR X3 .

[0086] In certain embodiments, X3 is selected from O and S.

[0087] In certain embodiments, the Y1 is selected from CR Y1 and N; Y2 is selected from CR Y2 and N; Y3 is selected from CR Y3 and N; R Y1 、R Y2 and R Y3 are independently selected from H, D, halogen, -CN, hydroxyl, carboxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl, or R Y2 and R Y3 Together with the atoms to which they are attached, they form a phenyl group or a 5-6 membered heteroaryl group.

[0088] In certain embodiments, the R Y1 、R Y2 and R Y3 are independently selected from H, D, halogen, -CN, hydroxyl, carboxyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl.

[0089] In certain embodiments, Y1 is selected from CR Y1 and N.

[0090] In certain embodiments, Y1 is selected from CR Y1 .

[0091] In certain embodiments, Y2 is selected from CR Y2 and N.

[0092] In certain embodiments, Y2 is selected from CR Y2 .

[0093] In certain embodiments, Y3 is selected from CR Y3 and N.

[0094] In certain embodiments, Y3 is selected from CR Y3 .

[0095] In certain embodiments, the R Y1 、R Y2 and R Y3 Each of the following groups is independently selected from H, D, halogen, -CN, methyl, ethyl, propyl, butyl, halomethyl, haloethyl, halopropyl, halobutyl, methoxy, ethoxy, propoxy, butoxy, halomethoxy, haloethoxy, halopropoxy, halobutoxy, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl and morpholinyl.

[0096] In certain embodiments, the R Y1 、R Y2 and R Y3 Each is independently selected from H, D, F, Cl, Br, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CF2CF3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl.

[0097] In certain embodiments, R Y1 Selected from H, D, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy.

[0098] In certain embodiments, R Y1 Selected from H, D, halogen.

[0099] In certain embodiments, R Y2Selected from H, D, halogen, -CN, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-4 Alkynyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl.

[0100] In certain embodiments, R Y2 Selected from halogen.

[0101] In certain embodiments, R Y3 Selected from H, D, halogen, C 1-4 alkyl.

[0102] In certain embodiments, the R Y1 Selected from H and F.

[0103] In certain embodiments, the R Y1 Selected from H.

[0104] In certain embodiments, the R Y2 Selected from F, Cl, -CN, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCF3, ethynyl, cyclopropyl and

[0105] In certain embodiments, the R Y2 Selected from Cl.

[0106] In certain embodiments, the R Y3 For H.

[0107] In certain embodiments, the R Y2 and R Y3 Together with the atoms to which they are attached, they form a phenyl group or a 5-6 membered heteroaryl group.

[0108] In certain embodiments, the R Y2 and R Y3 Together with the atoms to which they are attached, they form a phenyl group or a 5-membered heteroaryl group.

[0109] In certain embodiments, the R Y2 and R Y3 Together with the atoms to which they are attached they form thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and phenyl.

[0110] In certain embodiments, the R Y2 and R Y3 Together with the atoms to which they are attached they form a thienyl group and a phenyl group.

[0111] In certain embodiments, the R Y1 For H.

[0112] In certain embodiments, the structural unit Selected from

[0113] In certain embodiments, the structural unit Selected from Among them, R X2a 、R X2b 、R Y1 、R Y2 and R Y3 The definition of is as described in the present invention.

[0114] In certain embodiments, the structural unit Selected from Among them, R X2a 、R X2b 、R Y1 、R Y2 and R Y3 The definition of is as described in the present invention.

[0115] In certain embodiments, the structural unit Selected from Among them, R X2a 、R X2b 、R Y1 、R Y2 and R Y3 The definition of is as described in the present invention.

[0116] In certain embodiments, the structural unit Selected from Among them, R X2a 、R X2b 、R Y1 、R Y2 and R Y3 The definition of is as described in the present invention.

[0117] In certain embodiments, the structural unit Selected from Among them, R X2a 、R X2b and R Y1The definition of is as described in the present invention.

[0118] In certain embodiments, the structural unit Selected from

[0119] In certain embodiments, the structural unit Selected from Among them, R X2a 、R Y1 、R Y2 and R Y3 The definition of is as described in the present invention.

[0120] In certain embodiments, the structural unit Selected from

[0121] In certain embodiments, the structural unit Selected from Among them, R X2a 、R Y1 、R Y2 and R Y3 The definition of is as described in the present invention.

[0122] In certain embodiments, the structural unit Selected from

[0123] In certain embodiments, the structural unit for Among them, R X2a and R Y2 The definition of is as described in the present invention.

[0124] In certain embodiments, the L1 is selected from -C(=O)- and -CR L1a R L1b -; the R L1a and R L1b are independently selected from H, D, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy, or R L1a and R L1b Together with the atoms they are connected to form C 3-6 Cycloalkyl.

[0125] In certain embodiments, the R L1a and R L1b are independently selected from H, D, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy.

[0126] In certain embodiments, R L1a and R L1b are independently selected from H, D, and halogen.

[0127] In certain embodiments, L1 is selected from -C(=O)-.

[0128] In certain embodiments, L1 is selected from -CR L1a R L1b -.

[0129] In certain embodiments, the L1 is selected from -CR L1a R L1b -; the R L1a and R L1b are independently selected from H, D, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy.

[0130] In certain embodiments, the R L1a and R L1b Each of the following is independently selected from H, D, F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CF3, -OCH3, -OCH2CH3, -OCH2CH2CH3 and -OCF3.

[0131] In certain embodiments, the R L1a and R L1b are independently selected from H and F.

[0132] In certain embodiments, the R L1a and R L1b are independently selected from H.

[0133] In certain embodiments, the R L1a and R L1b Together with the atoms to which they are attached they form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

[0134] In certain embodiments, the R L1a and R L1b Together with the atoms to which they are attached they form a cyclopropyl or cyclobutyl group.

[0135] In certain embodiments, L1 is selected from -C(=O)-, -CH2-, -CHF-, =CH-, and -CF2-.

[0136] In certain embodiments, said L1 is selected from -C(=O)-, -CH2-, -CHF-, and -CF2-.

[0137] In certain embodiments, L1 is selected from -C(=O)-, -CH2-, =CH-.

[0138] In certain embodiments, L1 is -C(=O)-.

[0139] In certain embodiments, said L2 is a bond.

[0140] In certain embodiments, L2 is -C(=O)-.

[0141] In certain embodiments, the R1 is selected from -OR 1a 、-NR 1b R 1c , tetrazolyl and oxodihydrooxadiazolyl R 1a 、R 1b and R 1c are independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, phenyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4-6 membered heterocyclic group, -C 1-4 Alkylene-phenyl, -C 1-4 Alkylene-5-6 membered heteroaryl, -C 1-4 Halogenated alkylene-C 3-6 Cycloalkyl, -C 1-4 Halogenated alkylene-4-6 membered heterocyclic group, -C 1-4 Halogenated alkylene-phenyl and -C 1-4 Haloalkylene-5-6 membered heteroaryl; wherein, C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, phenyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4-6 membered heterocyclic group, -C 1-4 Alkylene-phenyl, -C 1-4 Alkylene-5-6 membered heteroaryl, -C 1-4 Halogenated alkylene-C 3-6Cycloalkyl, -C 1-4 Halogenated alkylene-4-6 membered heterocyclic group, -C 1-4 Halogenated alkylene-phenyl and -C 1-4 The haloalkylene-5-6 membered heteroaryl is optionally substituted with one or more substituents selected from oxo, hydroxy, cyano, carboxyl, and halogen.

[0142] In certain embodiments, the R 1a 、R 1b and R 1c are independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, phenyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4-6 membered heterocyclic group, -C 1-4 Alkylene-phenyl, -C 1-4 Alkylene-5-6 membered heteroaryl, -C 1-4 Halogenated alkylene-C 3-6 Cycloalkyl, -C 1-4 Halogenated alkylene-4-6 membered heterocyclic group, -C 1-4 Halogenated alkylene-phenyl and -C 1-4 Haloalkylene-5-6 membered heteroaryl; wherein, C 1-4 The alkyl group is optionally substituted with one or more substituents selected from oxo, hydroxy, and carboxyl.

[0143] In certain embodiments, R 1a Selected from H, C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, phenyl, -C 1-3 Alkylene-4-6 membered heterocyclic group, -C 1-3 Alkylene-5-6 membered heteroaryl.

[0144] In certain embodiments, the R 1a Selected from H, C 1-6 Alkyl (e.g. C 1-3 alkyl).

[0145] In certain embodiments, the R 1a Selected from H, methyl, cyclopropyl, cyclobutyl, oxetanyl (e.g. ), oxacyclohexyl (e.g. ), pyrazolyl (e.g. ), oxazolyl (e.g. ), phenyl, -C 1-3 Alkylene-4-6 membered heterocyclic group (e.g. ),-C1-3 Alkylene-5-membered heteroaryl (e.g. ).

[0146] In certain embodiments, the R 1a is H or methyl.

[0147] In certain embodiments, the R 1a It is a methyl group.

[0148] In certain embodiments, the R 1b Selected from H, C 1-3 Alkyl; the R 1c Selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, phenyl, -C 1-3 Alkylene-4-6 membered heterocyclic group, -C 1-3 Alkylene-phenyl, -C 1-3 Alkylene-5-6 membered heteroaryl, wherein C 1-3 The alkyl group is optionally substituted with 1 or 2 substituents selected from oxo, hydroxy, and carboxyl.

[0149] In certain embodiments ， The R 1c selected from methyl, -CH2C(=O)OH, cyclopropyl, pyrrolyl (e.g. ), furyl (e.g. ), thienyl (e.g. ), imidazolyl (e.g. ), pyrazolyl (e.g. ), oxazolyl (e.g. ), tetrazolyl (e.g. ), phenyl, -CH2-phenyl, -C 1-3 Alkylene-4-6 membered heterocyclic group (e.g. ),-C 1-3 Alkylene-5-6 membered heteroaryl (e.g. ).

[0150] In certain embodiments, the R 1c selected from methyl, -CH2C(=O)OH, cyclopropyl, pyrrolyl (e.g. ), furyl (e.g. ), thienyl (e.g. ), imidazolyl (e.g. ), pyrazolyl (e.g. ), oxazolyl (e.g. ), tetrazolyl (e.g. ), phenyl, -CH2-phenyl, -C 1-3 Alkylene-4-6 membered heterocyclic group (e.g. ),-C 1-3 Alkylene-5-6 membered heteroaryl (e.g. ).

[0151] In certain embodiments, the R 1b Selected from H, C 1-3 Alkyl; R 1c Selected from C 1-3 Alkyl, 5-membered heteroaryl, -C 1-3 Alkylene-4-6 membered heterocyclic group, -C 1-3 Alkylene-5-6 membered heteroaryl, wherein C 1-3 The alkyl group is optionally substituted with a carboxyl group.

[0152] In certain embodiments, R 1b Selected from H, C 1-3 Alkyl; R 1c Selected from C 1-3 Alkyl, 5-membered heteroaryl, -C 1-3 Alkylene-5-membered heteroaryl, wherein C 1-3 The alkyl group is substituted with one carboxyl group.

[0153] In certain embodiments, the R 1b Selected from H, C 1-3 Alkyl; the R 1c Selected from C 1-3 Alkyl, 5-membered heteroaryl, -C 1-3 Alkylene-5-membered heteroaryl, wherein C 1-3 The alkyl group is optionally substituted with a carboxyl group.

[0154] In certain embodiments ， The R 1b Selected from H; R 1c Selected from -CH2C(=O)OH, pyrazolyl (e.g. ),-C 1-3 Alkylene-5-membered heteroaryl (e.g. ).

[0155] In certain embodiments, the R 1b Selected from H; R 1c Selected from methyl, imidazolyl (e.g. ),-C 1- 3-alkylene-5-membered heteroaryl (e.g. ).

[0156] In certain embodiments, the R 1a 、R 1b and R1c are independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, phenyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4-6 membered heterocyclic group, -C 1-4 Alkylene-phenyl, -C 1-4 Alkylene-5-6 membered heteroaryl, -C 1-4 Halogenated alkylene-C 3-6 Cycloalkyl, -C 1-4 Halogenated alkylene-4-6 membered heterocyclic group, -C 1-4 Halogenated alkylene-phenyl and -C 1-4 Haloalkylene-5-6 membered heteroaryl.

[0157] In certain embodiments, the R 1a 、R 1b and R 1c are independently selected from H, C 1-4 Alkyl, -(CR 1aa R 1bb ) m -C 3-6 Cycloalkyl, -(CR 1aa R 1bb ) m -4-6 membered heterocyclic group, -(CR 1aa R 1bb ) m -5-6 membered heteroaryl and -(CR 1aa R 1bb ) m -phenyl, wherein R 1aa and R 1bb are independently selected from H, F and -CH3, and m is selected from 0, 1 and 2.

[0158] In certain embodiments, the R 1a 、R 1b and R 1c are independently selected from H, methyl, ethyl, propyl, butyl, -(CR 1aa R 1bb ) m -cyclopropyl, -(CR 1aa R 1bb ) m -cyclobutyl, -(CR 1aa R 1bb ) m -cyclopentyl, -(CR 1aa R 1bb ) m -cyclohexyl, -(CR1aa R 1bb ) m -oxetanyl, -(CR 1aa R 1bb ) m -azetidinyl, -(CR 1aa R 1bb ) m -tetrahydrofuranyl, -(CR 1aa R 1bb ) m -pyrrolidinyl, -(CR 1aa R 1bb ) m -tetrahydropyranyl, -(CR 1aa R 1bb ) m -piperidinyl, -(CR 1aa R 1bb ) m -morpholinyl, -(CR 1aa R 1bb ) m -phenyl, -(CR 1aa R 1bb ) m -thienyl, -(CR 1aa R 1bb ) m -pyrazolyl, -(CR 1aa R 1bb ) m -imidazolyl, -(CR 1aa R 1bb ) m -tetrazolyl, -(CR 1aa R 1bb ) m -furyl, -(CR 1aa R 1bb ) m -pyrrolyl, -(CR 1aa R 1bb ) m -thiazolyl, -(CR 1aa R 1bb ) m -oxazolyl, -(CR 1aa R 1bb ) m -isoxazolyl, -(CR 1aa R 1bb ) m -oxadiazolyl, -(CR 1aa R 1bb ) m -pyridyl, -(CR 1aa R 1bb ) m-pyrimidinyl and -(CR 1aa R 1bb ) m -pyrazinyl, wherein R 1aa and R 1bb are independently selected from H, F and -CH3, and m is selected from 0, 1 and 2.

[0159] In certain embodiments, the R 1a 、R 1b and R 1c are independently selected from H, methyl, ethyl, propyl, butyl, -(CR 1aa R 1bb ) m -cyclopropyl, -(CR 1aa R 1bb ) m -cyclobutyl, -(CR 1aa R 1bb ) m -cyclopentyl, -(CR 1aa R 1bb ) m -cyclohexyl, -(CR 1aa R 1bb ) m -oxetanyl, -(CR 1aa R 1bb ) m -azetidinyl, -(CR 1aa R 1bb ) m -tetrahydrofuranyl, -(CR 1aa R 1bb ) m -pyrrolidinyl, -(CR 1aa R 1bb ) m -tetrahydropyranyl, -(CR 1aa R 1bb ) m -piperidinyl, -(CR 1aa R 1bb ) m -morpholinyl, -(CR 1aa R 1bb ) m -phenyl, -(CR 1aa R 1bb ) m -thienyl, -(CR 1aa R 1bb ) m -furyl, -(CR 1aa R 1bb ) m -pyrrolyl, -(CR 1aa R1bb ) m -thiazolyl, -(CR 1aa R 1bb ) m -oxazolyl, -(CR 1aa R 1bb ) m -oxadiazolyl, -(CR 1aa R 1bb ) m -pyridyl, -(CR 1aa R 1bb ) m -pyrimidinyl and -(CR 1aa R 1bb ) m -pyrazinyl, wherein R 1aa and R 1bb are independently selected from H, F and -CH3, and m is selected from 0, 1 and 2.

[0160] In certain embodiments, the R 1a and R 1c Each of the following groups is independently selected from H, -CH3, cyclopropyl, cyclobutyl, oxetanyl, tetrahydropyranyl, phenyl, pyrazolyl, imidazolyl, oxazolyl, tetrazolyl, pyrrolyl, thienyl, furyl, -CH2-oxetanyl, -CH2-tetrahydropyranyl, -CH2-phenyl, -CH2-oxadiazolyl, -CH2-oxazolyl, -CH2-furyl, -CH2-thienyl, -CH2-pyridyl, -CH2-isoxazolyl, and -CH2-tetrazolyl.

[0161] In certain embodiments, the R 1a and R 1c Each is independently selected from H, -CH3, cyclopropyl, cyclobutyl, oxetanyl, tetrahydropyranyl, phenyl, -CH2-oxetanyl, -CH2-tetrahydropyranyl, -CH2-phenyl and -CH2-oxadiazolyl.

[0162] In certain embodiments, R 1a R is selected from H, -CH3, cyclopropyl, cyclobutyl, oxetanyl, tetrahydropyranyl, pyrazolyl, phenyl, -CH2-oxetanyl, -CH2-oxadiazolyl, -CH2-oxazolyl; 1c Selected from methyl, cyclopropyl, phenyl, -CH2-phenyl, -CH2-tetrahydropyranyl, pyrazolyl, imidazolyl, oxazolyl, tetrazolyl, pyrrolyl, thienyl, furyl, -CH2-oxazolyl, -CH2-furyl, -CH2-thienyl, -CH2-pyridyl, -CH2-oxetanyl, -CH2-isoxazolyl, -CH2-tetrazolyl.

[0163] In certain embodiments, the R 1a and R 1c Each is independently selected from H, methyl, pyrazolyl, -CH2-thienyl, -CH2-oxazolyl, -CH2-furyl, and -CH2-tetrazolyl.

[0164] In certain embodiments, the R 1a is selected from H, methyl; R 1c Selected from pyrazolyl, -CH2-thienyl, -CH2-oxazolyl, -CH2-furyl, -CH2-tetrazolyl.

[0165] In certain embodiments, the R 1b For H.

[0166] In certain embodiments, the R1 is selected from -OR 1a 、-NR 1b R 1c .

[0167] In certain embodiments, the R1 is selected from -OH, -OCH3, -O-cyclopropyl, -O-cyclobutyl, -NHCH3,

[0168] In certain embodiments, the R1 is selected from -OH, -OCH3, -O-cyclopropyl, -O-cyclobutyl, -O-oxetanyl (e.g. ), -NHCH3,

[0169] In certain embodiments, the R1 is selected from -OH, -OCH3, -O-cyclopropyl, -O-cyclobutyl, -O-oxetanyl (e.g. ), -NHCH3,

[0170] In certain embodiments, the R1 is selected from -OH, -OCH3, -O-cyclopropyl, -O-cyclobutyl, -NHCH3,

[0171] In certain embodiments, the R1 is selected from -OH, -OCH3, -NHCH3,

[0172] In certain embodiments, the R1 is selected from -OH, -OCH3,

[0173] In certain embodiments, said R1 is selected from -OH.

[0174] In certain embodiments, the -L1-L2- is selected from -C(=O)C(=O)-, #X1-CR L1a R L1b -C(=O)-$R1、-C(=O)-、-CR L1a R L1b -、#X1=CR L1b -$R1.

[0175] In certain embodiments, the -L1-L2- is selected from -C(=O)C(=O)-, #X1-CH2-C(=O)-$R1, #X1-CF2-C(=O)-$R1, -C(=O)-, -CHF-, -CH2-, #X1=CH-$R1; wherein #X1 is the point of connection with X1, and $R1 is the point of connection with R1.

[0176] In certain embodiments, the -L1-L2- is selected from -C(=O)C(=O)-, #X1-CH2-C(=O)-$R1, #X1-CF2-C(=O)-$R1, -C(=O)-, -CHF-, and -CH2-; wherein #X1 is the point of connection with X1, and $R1 is the point of connection with R1.

[0177] In certain embodiments, the -L1-L2- is selected from -C(=O)C(=O)-, #X1-CH2-C(=O)-$R1, -C(=O)-, #X1=CH-$R1.

[0178] In certain embodiments, the -L1-L2- is selected from -C(=O)-, -C(=O)C(=O)-.

[0179] In certain embodiments, said -L1-L2- is -C(=O)-.

[0180] In certain embodiments, the -L1-L2-R1 is selected from -C(=O)-OR 1a 、-CR L1a R L1b -C(=O)-OR 1a 、-C(=O)-C(=O)-OR 1a 、-C(=O)-C(=O)-NR 1b R 1c 、 -C(=O)-NR 1b R 1c 、=CR L1b -NR 1b R 1c .

[0181] In certain embodiments, the -L1-L2-R1 is selected from -CR L1a R L1b -C(=O)-OR 1a 、-C(=O)-C(=O)-OR 1a 、-C(=O)-C(=O)-NR 1b R 1c 、-C(=O)-NR 1b R 1c 、=CR L1b -NR 1b R 1c .

[0182] In certain embodiments, the -L1-L2-R1 is selected from -C(=O)-C(=O)-OR 1a 、-C(=O)-NR 1b R 1c .

[0183] In certain embodiments, the -L1-L2-R1 is selected from -C(=O)-NR 1b R 1c .

[0184] In certain embodiments, the -L1-L2-R1 is selected from -COOH, -C(=O)-C(=O)-OH, -CH2-C(=O)-OH, -CF2-C(=O)-OH, -C(=O)-C(=O)-OCH3, -C(=O)-C(=O)-NHCH3,

[0185] In certain embodiments, the -L1-L2-R1 is selected from -C(=O)-C(=O)-OH, -CH2-C(=O)-OH, -CF2-C(=O)-OH, -C(=O)-C(=O)-OCH3, -C(=O)-C(=O)-NHCH3,

[0186] In certain embodiments, the -L1-L2-R1 is selected from -COOH, -C(=O)-C(=O)-OH, -CH2-C(=O)-OH, -CF2-C(=O)-OH, -C(=O)-C(=O)-OCH3, -C(=O)-C(=O)-NHCH3,

[0187] In certain embodiments, the -L1-L2-R1 is selected from -CH2-C(=O)-OH, -C(=O)-C(=O)-OH, -C(=O)-C(=O)-OCH3, -C(=O)-C(=O)-NHCH3,

[0188] In certain embodiments, the -L1-L2-R1 is selected from -CH2-C(=O)-OH, -C(=O)-C(=O)-OH, -C(=O)-C(=O)-OCH3, -C(=O)-C(=O)-NHCH3,

[0189] In certain embodiments, the -L1-L2-R1 is selected from -C(=O)-C(=O)-OH, -C(=O)-C(=O)-OCH3,

[0190] In certain embodiments, L1 is -C(=O)-, L2 is a bond or -C(=O)-, and R1 is selected from -OR 1a 、-NR 1b R 1c , R 1a C 1-3 Alkyl, R 1b Selected from H, R 1c Selected from C 1-3 Alkyl, 5-membered heteroaryl (e.g., pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, tetrazolyl), -C 1-3 Alkylene-5-membered heteroaryl (e.g., -CH2-pyrazolyl, -CH2-oxazolyl, -CH2-furyl, -CH2-thienyl, -CH2-tetrazolyl), wherein C 1-3 The alkyl group is optionally substituted with a carboxyl group.

[0191] In certain embodiments, L1 is -C(=O)-, L2 is a bond or -C(=O)-, and R1 is selected from -OR 1a 、-NR 1b R 1c , R1a C 1-3 Alkyl, R 1b Selected from H, R 1c Selected from C 1-3 Alkyl, 5-membered heteroaryl (e.g., pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl), -C 1-3 Alkylene-5-membered heteroaryl (e.g., -CH2-pyrazolyl, -CH2-oxazolyl, -CH2-furyl), wherein C 1-3 The alkyl group is optionally substituted with a carboxyl group.

[0192] In certain embodiments, said L2 is a bond.

[0193] In certain embodiments, said -L1-L2-R1 is selected from -C(=O)-C(=O)-OH.

[0194] In certain embodiments, the -L1-L2-R1 is selected from -C(=O)-C(=O)-OCH3, -C(=O)-C(=O)-NHCH3,

[0195] In certain embodiments, the R L3 is selected from H, D, -CH3, -CH2CH3 and -CH(CH3)2.

[0196] In certain embodiments, the R L3 Selected from H.

[0197] In certain embodiments, said L3 is selected from a bond, -O-, -NR L3 -、-S-、#-C 1-6 Alkylene-O-*, #-C 1- 6-alkylene-NR L3 -*,#-C 1-6 Alkylene-S-*, -C 1-6 Alkylene-, -C 2-6 Alkenylene- and -C 2-6 Alkyne-, wherein the end indicated by "#" is connected to R2 and the end indicated by "*" is connected to are connected.

[0198] In certain embodiments, said L3 is selected from a bond, -O-, -NR L3 -、-S-、#-C 1-4 Alkylene-O-*, #-C 1- 4-alkylene-NR L3 -*,#-C 1-4 Alkylene-S-*, -C 1-4 Alkylene-, -C 2-4 Alkenylene- and -C2-4 Alkyne-, wherein the end indicated by "#" is connected to R2, and the end indicated by "*" is connected to Connected, R L3 The definition of is as described in the present invention.

[0199] In certain embodiments, said L3 is selected from a bond, -O-, -NR L3 -、-S-、#-(CH2) n -O-*、#-(CH2) n -NR L3 -*、#-(CH2) n -S-*, vinylene, propenylene, ethynylene and propynylene, wherein the end indicated by "#" is connected to R2, and the end indicated by "*" is connected to connected, n is selected from 1 and 2, R L3 As defined in the present invention,

[0200] In certain embodiments, the L3 is selected from a bond, -O-, -NH-, #-CH2-NH-*, #-CH2-S-* and -C≡C-, wherein the end indicated by "#" is connected to R2 and the end indicated by "*" is connected to are connected.

[0201] In certain embodiments, said L3 is selected from a bond.

[0202] In certain embodiments, each of the R groups is independently selected from halogen, -OH, -CN, -COOH, oxo, C 1-4 Alkyl, -C 1-4 Alkylene-OH, C 1-4 Alkoxy, -C 1-4 Alkyleneoxy-C 1-4 Alkoxy, -C(=O)NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -NHC(=O)-C 1-4 Alkyl, -N=S(=O)(C 1-4 alkyl)-C 1-4 Alkyl, -NH-S(=O)2C 1-4 Alkyl, -S(=O)2-C 1-4 alkyl, -S(=O)2-4-6 membered heterocyclic group, -C(=O)-4-6 membered heterocyclic group, 4-6 membered heterocyclic group, 5-6 membered heteroaryl and

[0203] In certain embodiments, each of the R groups is independently selected from halogen, -OH, -CN, -COOH, C 1-4 Alkyl, -C 1-4 Alkylene-OH, C 1-4Alkoxy, -C 1-4 Alkyleneoxy-C 1-4 Alkoxy, -C(=O)NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -NHC(=O)-C 1-4 Alkyl, -N=S(=O)(C 1-4 alkyl)-C 1-4 Alkyl, -NH-S(=O)2C 1-4 Alkyl, -S(=O)2-C 1-4 alkyl, -S(=O)2-4-6 membered heterocyclic group, -C(=O)-4-6 membered heterocyclic group, 4-6 membered heterocyclic group, 5-6 membered heteroaryl and

[0204] In certain embodiments, the R is selected from -OH, -C 1-4 Alkylene-OH.

[0205] In certain embodiments, R is selected from halogen, -OH, -CN, -COOH, -CH2OH, methyl, ethyl, propyl, butyl, -ethylene-OH, -propylene-OH, -butylene-OH, methoxy, ethoxy, propoxy, butoxy, -methyleneoxy-methoxy, -methyleneoxy-ethoxy, -methyleneoxy-propoxy, -ethyleneoxy-methoxy, -ethyleneoxy-ethoxy, -ethyleneoxy-propoxy, -C(=O)-NH-methyl, -C(=O)-NH-ethyl, -C(=O)-NH-propyl, -C(=O)-NH-butyl, -N=S(=O)(methyl)-methyl, -N=S(=O)(methyl)-ethyl, -N=S(=O)(methyl)-propyl, -N=S(=O)(methyl)-butyl, -N=S(=O)(ethyl)-ethyl, -N=S(=O)(ethyl)-propyl, -(NH) p -W-methyl, -(NH) p -W-ethyl, -(NH) p -W-propyl, -(NH) p -W-butyl, -(W) q -oxetanyl, -(W) q -azetidinyl, -(W) q -tetrahydrofuranyl, -(W) q -pyrrolidinyl, -(W) q -tetrahydropyranyl, -(W) q -piperidinyl, -(W) q -morpholinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and wherein W is C(=O) or S(=O)2, and p or q is independently 0 or 1.

[0206] In certain embodiments, R is selected from F, -OH, -CN, -COOH, -CH3, -CH2OH, -C(CH3)2OH, -CH2C(CH3)2OH, -OCH3, -OCH2CH2OCH3, -C(=O)CH3, -C(=O)NHCH3, -NHC(=O)CH3, -N=S(=O)(CH3)2, -NH-S(=O)2CH3, -S(=O)2CH3, -S(=O)2-piperidinyl (e.g. ), -C(=O)-pyrrolidinyl (e.g. ), -C(=O)-morpholinyl (e.g. ), morpholinyl (e.g. ), pyrazolyl (e.g. )and

[0207] In certain embodiments, R is selected from -OH.

[0208] In certain embodiments, R is selected from -OH, -CH2OH.

[0209] In certain embodiments, the R 2a 、R 2b 、R 2c 、R 2d and R 2e are independently selected from H, halogen, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, -NHC 1-4 Alkyl, -N(C 1-4 alkyl)-C 1-4 Alkyl, C 1-4 Alkoxy, C 1- 4-halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -phenylene-4-6 membered heterocyclyl, -phenylene-5-6 membered heteroaryl, -phenylene-phenyl and -5-6 membered heteroaryl-5-6 membered heteroaryl, the C 1-4 Alkyl, C 1-4 Haloalkyl, -NHC 1-4 Alkyl, -N(C 1-4 alkyl)-C 1-4 Alkyl, C 1-4 Alkoxy, C 1- 4-halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6Cycloalkenyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -phenylene-4-6 membered heterocyclyl, -phenylene-5-6 membered heteroaryl, -phenylene-phenyl or -5-6 membered heteroarylene-5-6 membered heteroaryl is optionally substituted with 1, 2 or 3 R, wherein R is as defined herein.

[0210] In certain embodiments, the R 2a 、R 2b 、R 2c 、R 2d and R 2e are independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl; the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl are optionally substituted with 1, 2 or 3 R groups.

[0211] In certain embodiments, the R 2a 、R 2b 、R 2c 、R 2d and R 2e are independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, phenyl; the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and phenyl groups are optionally substituted with 1, 2 or 3 R groups.

[0212] In certain embodiments, the R 2a 、R 2b 、R 2c 、R 2d and R 2e are independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl; the C 1-4 Alkyl, C 3-6 Cycloalkyl and phenyl groups are optionally substituted with 1, 2 or 3 R groups.

[0213] In certain embodiments, the R 2a 、R 2b 、R 2c 、R 2d and R 2eEach of the following groups is independently selected from H, F, Cl, Br, -OH, methyl, ethyl, propyl, butyl, halomethyl, haloethyl, halopropyl, halobutyl, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(CH3)2, -N(CH3)(CH2CH3), -N(CH2CH3)2, methoxy, ethoxy, propoxy, butoxy, halomethoxy, haloethoxy, halopropoxy, halobutoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, -(phenylene) r -oxetanyl, -(phenylene) r -azetidinyl, -(phenylene) r -tetrahydrofuranyl, -(phenylene) r -pyrrolidinyl, -(phenylene) r -tetrahydropyranyl, -(phenylene) r -piperidinyl, -(phenylene) r -morpholinyl, -(phenylene) r -Oxopyrrolidinyl, -(phenylene) r -Oximidazole, -(phenylene) r -oxopyrazolyl, -(phenylene) r -Oxodihydrotriazolyl, -(phenylene) r -phenyl-, -(V) r -thienyl, -(V) r -furyl, -(V) r -pyrrolyl, -(V) r -imidazolyl, -(V) r -pyrazolyl, -(V) r -thiazolyl, -(V) r -oxazolyl, -(V) r -oxadiazolyl, -(V) r -triazole, -(V) r -tetrazolyl, -(V) r -pyridyl, -(V) r -pyrimidinyl and -(V) r -pyrazinyl, the methyl, ethyl, propyl, butyl, halomethyl, haloethyl, halopropyl, halobutyl, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(CH3)2, -N(CH3)(CH2CH3), -N(CH2CH3)2, methoxy, ethoxy, propoxy, butoxy, halomethoxy, haloethoxy, halopropoxy, halobutoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, -(phenylene) r -oxetanyl, -(phenylene) r-azetidinyl, -(phenylene) r -tetrahydrofuranyl, -(phenylene) r -pyrrolidinyl, -(phenylene) r -tetrahydropyranyl, -(phenylene) r -piperidinyl, -(phenylene) r -morpholinyl, -(phenylene) r -Oxopyrrolidinyl, -(phenylene) r -Oximidazole, -(phenylene) r -oxopyrazolyl, -(phenylene) r -Oxodihydrotriazolyl, -(phenylene) r -phenyl-, -(V) r -thienyl, -(V) r -furyl, -(V) r -pyrrolyl, -(V) r -imidazolyl, -(V) r -pyrazolyl, -(V) r -thiazolyl, -(V) r -oxazolyl, -(V) r -oxadiazolyl, -(V) r -triazole, -(V) r -tetrazolyl, -(V) r -pyridyl, -(V) r -pyrimidinyl or -(V) r -pyrazinyl is optionally substituted by 1, 2 or 3 R, wherein V is selected from phenylene and pyridinylene, r is 0 or 1, and R is as defined herein.

[0214] In certain embodiments, the R 2a 、R 2b 、R 2c 、R 2d and R 2eEach independently selected from H, F, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, cyclopropyl, cyclobutyl, cyclohexenyl, azetidinyl, oxetanyl, morpholinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperyl, pyridyl, phenyl, pyridyl, -phenylene-oxetanyl, -phenylene-morpholinyl, -phenylene-oxopyrrolidinyl, -phenylene-oxoimidazolyl, -phenylene-oxopyrazolyl, -phenylene-oxodihydrotriazolyl, -phenylene-phenyl, -phenylene-imidazolyl, -phenylene-pyrazolyl, -phenylene-oxadiazolyl, -phenylene-triazolyl, -phenylene-tetrazolyl, -phenylene-pyrimidinyl and -pyridyl-pyrazolyl, the -CH3 , -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, cyclopropyl, cyclobutyl, cyclohexenyl, azetidinyl, oxetanyl, morpholinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, phenyl, pyridyl, -phenylene-oxetane The phenylene-oxadiazolyl, -phenylene-triazolyl, -phenylene-tetrazolyl, -phenylene-pyrimidinyl or -pyridinyl-pyrazolyl groups are optionally substituted with 1, 2 or 3 R groups, wherein R is as defined herein.

[0215] In certain embodiments, the R 2a 、R 2b 、R 2c 、R 2d and R 2e Each is independently selected from H, methyl, methoxy, cyclopropyl, cyclobutyl, and phenyl, and the methyl, methoxy, cyclopropyl, cyclobutyl, and phenyl are optionally substituted by 1, 2, or 3 Rs.

[0216] In certain embodiments, the R 2a 、R 2b 、R 2c 、R 2d and R 2e Each is independently selected from H, methyl, cyclopropyl, cyclobutyl, and phenyl, and the methyl, cyclopropyl, cyclobutyl, and phenyl are optionally substituted by 1, 2, or 3 Rs.

[0217] In certain embodiments, the R2 is selected from C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 9 membered heteroaryl, 9-10 membered heterocyclic group and C 9-10 Cyclic group, the C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 9 membered heteroaryl, 9-10 membered heterocyclic group or C 9-10 The cyclic group is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2a 、R 2b 、R 2c 、R 2d and R 2e substituted by a group, wherein R 2a 、R 2b 、R 2c 、R 2d and R 2e The definition of is as described in the present invention.

[0218] In certain embodiments, the R2 is selected from phenyl or 9-membered heteroaryl, wherein the phenyl or 9-membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2a 、R 2b 、R 2c 、R 2d and R 2e substituted by a group.

[0219] In certain embodiments, the R2 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, dihydroindole, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzodioxanyl and 2,3-dihydroindenyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, dihydroindole, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzodioxanyl or 2,3-dihydroindenyl is optionally replaced by 1, 2, 3, 4, or 5 independently selected R 2a 、R 2b 、R 2c 、R 2d and R 2e substituted by a group, wherein R 2a 、R 2b 、R 2c 、R 2d and R 2e The definition of is as described in the present invention.

[0220] In certain embodiments, R2 is selected from phenyl or indolyl, wherein the phenyl or indolyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2a 、R2b 、R 2c 、R 2d and R 2e substituted by a group.

[0221] In certain embodiments, the R2 is selected from cyclopropyl, cyclobutyl, phenyl, thienyl, thiazolyl, oxazolyl, pyridinyl, indolyl, dihydroindole, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzodioxanyl and 2,3-dihydroindenyl, and the cyclopropyl, cyclobutyl, phenyl, thienyl, thiazolyl, oxazolyl, pyridinyl, indolyl, dihydroindole, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzodioxanyl or 2,3-dihydroindenyl is optionally replaced by 1, 2, 3, 4, or 5 independently selected R 2a 、R 2b 、R 2c 、R 2d and R 2e substituted by a group, wherein R 2a 、R 2b 、R 2c 、R 2d and R 2e The definition of is as described in the present invention.

[0222] In certain embodiments, the R2 is selected from where R 2a 、R 2b 、R 2c 、R 2d and R 2e The definition of is as described in the present invention.

[0223] In certain embodiments, the R2 is selected from

[0224] In certain embodiments, the R2 is selected from

[0225] In certain embodiments, the R2 is selected from

[0226] In certain embodiments, the R2 is selected from

[0227] In certain embodiments, the R2 is selected from

[0228] In certain embodiments, the compound is selected from formula (I-1) and (I-2),

[0229] in,

[0230] Y1, Y2, Y3, L1, L2, L3, R1, R2, R X2a and R X3 The definition of is as described in the present invention.

[0231] In certain embodiments, the compound is selected from the group consisting of formula (I-3), (I-4) and (I-5)

[0232] in,

[0233] L1, L2, L3, R1, R2, R X2a 、R X3 、R Y1 、R Y2 and R Y3 The definition of is as described in the present invention.

[0234] In certain embodiments, the compound is selected from the group consisting of Formula (I-6), (I-7), (I-8), (I-9), (I-10), (I-11), and (I-12),

[0235] in,

[0236] L1, L2, L3, R1, R X2a 、R X3 、R Y1 、R Y2 、R Y3 、R 2a 、R 2b 、R 2c 、R 2d and R 2e The definition of is as described in the present invention.

[0237] In certain embodiments, the compound is selected from the group consisting of Formula (I-13), (I-14), (I-15), (I-16), (I-17), (I-18), (I-19), (I-20), and (I-21),

[0238] In certain embodiments, the compound is selected from Formula (IA), (IB), and (IC),

[0239] In certain embodiments, L2 is -C(=O)-.

[0240] In certain embodiments, the compound has the structure shown in formula (II-1),

[0241] Among them, Y1, Y2, Y3, L1, L2, R1, R2, R X2a and R X3 The definition of is as described in the present invention.

[0242] In certain embodiments, the compound is selected from formula (II-2) and (II-3),

[0243] Among them, Y1, L1, L2, R1, R2, R X2a and R Y2 The definition of is as described in the present invention.

[0244] In certain embodiments, the compound is selected from formula (II-2') and (II-3),

[0245] In certain embodiments, the compound is selected from the group consisting of Formula (II-4), (II-5), (II-6) and (II-7),

[0246] Among them, R2, R X2a 、R Y2 、R 1a 、R 1b and R 1c The definition of is as described in the present invention.

[0247] In certain embodiments, the compound is selected from formula (II-8) and (II-9),

[0248] In certain embodiments, the compound has the structure shown in formula (II-6),

[0249] Among them, R X2a Selected from H, -OH, -C 1-3 alkoxy;

[0250] R Y2 selected from halogen;

[0251] R 1b Selected from H, C 1-3 alkyl;

[0252] R 1c Selected from C 1-3 Alkyl, 5-6 membered heteroaryl, -C 1-3 Alkylene-5-6 membered heteroaryl, -C 1-3 Alkylene-4-7 membered heterocyclic group, and the C1-3 The alkyl group is optionally substituted with a carboxyl group;

[0253] R2 is selected from phenyl, 5-10 membered heteroaryl, wherein the phenyl, 5-10 membered heteroaryl are optionally selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The substituents of cycloalkyl and phenyl are substituted, and the C 3-6 Cycloalkyl, phenyl are optionally selected from -OH, -C 1-3 The substituent of the alkylene group -OH is substituted.

[0254] In certain embodiments, R X2a Selected from H or -OH.

[0255] In certain embodiments, R X2a For H.

[0256] In certain embodiments, R Y2 For Cl.

[0257] In certain embodiments, R 1b Selected from H, methyl.

[0258] In certain embodiments, R 1b For H.

[0259] In certain embodiments, R 1c Selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocyclic group, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -C 1-3 Alkylene-phenyl, -C 1-3 Alkylene-5-6 membered heteroaryl, -C 1-3 Alkylene-4-7 membered heterocyclic group, and the C 1-3 The alkyl group is optionally substituted with a carboxyl group.

[0260] In certain embodiments, R 1c Selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, -C 1-3 Alkylene-phenyl, -C 1-3 Alkylene-5-6 membered heteroaryl, -C 1-3 Alkylene-4-7 membered heterocyclic group, and the C 1-3 The alkyl group is optionally substituted with a carboxyl group.

[0261] In certain embodiments, R 1c Selected from C1-3 Alkyl, 5-6 membered heteroaryl, -C 1-3 Alkylene-5-6 membered heteroaryl, -C 1-3 Alkylene-4-7 membered heterocyclic group, and the C 1-3 The alkyl group is optionally substituted with a carboxyl group.

[0262] In certain embodiments, R 1c Selected from CH2C(=O)OH, pyrazolyl (e.g. ), imidazolyl (e.g. ), oxazolyl (e.g. ),-C 1-3 Alkylene-pyridyl (e.g. ),-C 1- 3-alkylene-furyl (e.g. ),-C 1-3 Alkylene-thienyl (e.g. ),-C 1-3 Alkylene-oxazolyl (e.g. ),-C 1-3 Alkylene-isoxazolyl (e.g. ),-C 1- 3-alkylene-tetrazolyl (e.g. ),-C 1-3 Alkylene-oxetane (e.g. ).

[0263] In certain embodiments, R 1c Selected from pyrazolyl (e.g. ), imidazolyl (e.g. ), oxazolyl (e.g. ),-C 1-3 Alkylene-pyridyl (e.g. ),-C 1-3 Alkylene-furyl (e.g. ),-C 1-3 Alkylene-thienyl (e.g. ),-C 1-3 Alkylene-oxazolyl (e.g. ),-C 1-3 Alkylene-isoxazolyl (e.g. ).

[0264] In certain embodiments, R2 is selected from phenyl, 9-membered heteroaryl (eg, indolyl), wherein the phenyl, 9-membered heteroaryl is optionally selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6The substituents of cycloalkyl and phenyl are substituted, and the C 3-6 Cycloalkyl, phenyl are optionally selected from -OH, -C 1-3 The substituent of the alkylene group -OH is substituted.

[0265] In certain embodiments, R2 is phenyl, wherein the phenyl group is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 substituted by a cycloalkyl group or a phenyl group, and the C 3-6 Cycloalkyl, phenyl are optionally selected from -OH, -C 1-3 The substituent of the alkylene group -OH is substituted.

[0266] In certain embodiments, R2 is selected from

[0267] In certain embodiments, R2 is indolyl, wherein the indolyl is replaced by C 1-3 Alkyl substitution.

[0268] In certain embodiments, R2 is

[0269] In certain embodiments, R X2a H; R Y2 is Cl; R 1b For H.

[0270] In certain embodiments, the compound is selected from (V-1),

[0271] in,

[0272] L4 is selected from -O- or -NR 1b -;

[0273] u is selected from 0, 1 or 2;

[0274] Q is selected from C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 Aryl, the C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 The aryl group is optionally substituted by one or more groups selected from oxo, hydroxy, cyano, carboxyl, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, C 6-10 Substitution of aryl and 5-10 membered heteroaryl

[0275] In certain embodiments, L4 is selected from -NR 1b -.

[0276] In certain embodiments, u is selected from 0 or 1.

[0277] In certain embodiments, Q is selected from C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, phenyl.

[0278] In certain embodiments, Q is selected from 4-6 membered heterocyclyl, 5-6 membered heteroaryl.

[0279] In certain embodiments, the compound is selected from Formula (V-2) or (V-3),

[0280] In certain embodiments, the compound is selected from Formula (V-4),

[0281] In certain embodiments, the compound is selected from Formula (VI-1),

[0282] In certain embodiments, the compound is selected from formula (III-1), (III-2),

[0283] In certain embodiments, the compound is selected from formula (III-3) and (III-4),

[0284] In certain embodiments, the compound is selected from formula (III-5) and (III-6),

[0285] In certain embodiments, the conditions are:

[0286] 1) When the structural unit for When -L1-L2-R1 is not -C(=O)-C(=O)-OH; or

[0287] 2) When the structural unit for When R X2a is not H; or

[0288] 3) When the structural unit for When R Y2 Not H, halogen, C 1-3 Alkyl, -CF3;

[0289] 4) when -L1-L2-R1 is -C(=O)-C(=O)-OH, L3 is not a bond; or

[0290] 5) When -L1-L2-R1 is -C(=O)-C(=O)-OH, R2 is not phenyl or 5-membered heteroaryl, and the phenyl or 5-membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2a 、R 2b 、R 2c 、R 2d and R 2e The group substitution;

[0291] Among them, L1, L2, L3, R1, R2, R Y1 、R Y2 、R Y3 、R X2a 、R 2a 、R 2b 、R 2c 、R 2d and R 2e The definition of the present invention.

[0292] In certain embodiments, the conditions are:

[0293] 1) When the structural unit for When -L1-L2-R1 is not -C(=O)-C(=O)-OH; or

[0294] 2) When the structural unit for X2 is CR X2a When R X2a Not for H;

[0295] 3) When the structural unit for When R Y2 Not H, halogen, C 1-3 Alkyl, -CF3;

[0296] 4) when -L1-L2-R1 is -C(=O)-C(=O)-OH, L3 is not a bond; or

[0297] 5) When -L1-L2-R1 is -C(=O)-C(=O)-OH, R2 is not phenyl or 5-membered heteroaryl, and the phenyl or 5-membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2a 、R 2b 、R 2c 、R 2d and R 2e The group substitution;

[0298] Among them, X2, Y1, L1, L2, L3, R1, R2, R X3 、R 2a 、R 2b 、R 2c 、R 2d and R 2e The definition of is as described in any one of claims 1-20.

[0299] In certain embodiments, there is the proviso that -L1-L2-R1 is not -COOR 1a ;.

[0300] In certain embodiments, with the proviso that -L1-L2-R1 is not -CR L1a R L1b -COOR 1a .

[0301] In certain embodiments, there is the proviso that -L1-L2-R1 is not -CO-CO-OR 1a .

[0302] In certain embodiments, with the proviso that -L1-L2-R1 is not -CO-CO-NR 1b R 1c .

[0303] In certain embodiments, provided that: the compound is not

[0304] In certain embodiments, the compound is selected from

[0305] In certain embodiments, the compound is selected from

[0306] In certain embodiments, the compound is selected from

[0307] In certain embodiments, the compound is selected from

[0308] The present invention encompasses compounds resulting from any combination of the various embodiments.

[0309] A second aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the compound of the present invention, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, is present in an effective amount.

[0310] A third aspect of the present invention provides the use of the compound of the present invention, or its enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt, or the composition of the present invention in the preparation of a medicament as an AMPK agonist.

[0311] A fourth aspect of the present invention provides the use of the compound of the present invention, or its enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt, or the composition of the present invention in the preparation of a medicament for treating and / or preventing type II diabetes, dyslipidemia, obesity, chronic kidney disease, diabetic nephropathy, acute kidney injury, polycystic kidney disease or alopecia.

[0312] A fifth aspect of the present invention provides a compound of the present invention, or its enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt, or a composition of the present invention, for use in treating and / or preventing type II diabetes, dyslipidemia, obesity, chronic kidney disease, diabetic nephropathy, acute kidney injury, polycystic kidney disease, or alopecia.

[0313] A sixth aspect of the present invention provides a compound of the present invention, or its enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt or composition of the present invention, which is used as an AMPK agonist.

[0314] A seventh aspect of the present invention provides a method for treating and / or preventing a disease, comprising administering to an individual in need thereof a therapeutically or prophylactically effective amount of a compound of the present invention, or its enantiomers, diastereomers, racemates, stereoisomers, geometric isomers, tautomers, polymorphs, solvates, hydrates, N-oxides, isotope-labeled compounds, metabolites, esters, prodrugs, or pharmaceutically acceptable salts or the composition of the present invention, wherein the disease is type II diabetes, dyslipidemia, obesity, chronic kidney disease, diabetic nephropathy, acute kidney injury, polycystic kidney disease or alopecia.

[0315] In terms of drug absorption, replacing carboxylic acid groups with groups such as amides can help improve the absorption of the molecule in vivo, increase bioavailability, and enhance the efficacy of the drug. The compounds described herein can be synthesized using conventional chemical synthesis techniques familiar to those skilled in the art or various similar methods known in the art. Isolation and purification of the products can be achieved using standard procedures known to those skilled in the art.

[0316] Definition of terms

[0317] The various terms and phrases used in the present invention have general meanings known to those skilled in the art. Even so, the present invention still hopes to provide a more detailed description and explanation of these terms and phrases herein. If the mentioned terms and phrases are inconsistent with the known meanings, the meanings expressed in the present invention shall prevail.

[0318] When the name of the compound used in the present invention is inconsistent with the chemical structural formula, the chemical structural formula shall prevail.

[0319] In the structural formula of the present invention, the nitrogen-containing heteroaryl fragment substituted by a hydroxyl group may undergo tautomerism, for example: wait.

[0320] Unless otherwise defined, a divalent group has no directional restrictions, for example, ALB, when L is -C(=O)-NH-, ALB is AC(=O)-NH-B or A-NH-C(=O)-B.

[0321] As used herein, "selected from a bond" means that the groups on both sides of the variable are directly connected, for example, ALB, when L is a bond, ALB is AB.

[0322] As used herein, "pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic or organic acids, or coordination compounds formed by the substitution of acidic protons present in the parent compound with metal ions or organic bases.

[0323] As used herein, the term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0324] Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof, such as racemic mixtures and diastereomeric pairs.

[0325] In the present invention, solid lines can be used Solid wedge virtual wedge Wavy lines The chemical bonds of the compounds of the present invention are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate the presence of the stereoisomers shown. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. The use of wavy lines to depict bonds to one carbon atom in a carbon-carbon double bond is intended to indicate the presence of cis- and trans-isomers in the compound. Unless otherwise indicated, the compounds of the present invention may exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0326] As used herein, the term "isotopically labeled compound" refers to a compound in which one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of suitable isotopes for inclusion in the compounds of the present invention include, but are not limited to, hydrogen isotopes such as 2 H, 3 H; carbon isotopes such as 11 C, 13 C and 14 C; chlorine isotopes such as 36 Cl; fluorine isotopes such as 18 F; iodine isotopes such as 123 I and 125 I; Nitrogen isotopes such as 13 N and 15 N; oxygen isotopes such as 15 O, 17 O and 18 O; and sulfur isotopes such as 35 S.

[0327] As used in the present invention, the term "prodrug" refers to a derivative of a compound that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound disclosed herein. Prodrugs are active compounds that react only under biological conditions, or they do not have or only have relatively low activity in their unreactive form. Prodrugs can generally be prepared using known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, 5th edition).

[0328] As used herein, the term "ester" refers to esters that are hydrolyzed in vivo and includes those that readily decompose in the human body, thereby separating from the parent compound. The hydroxyl-containing compounds of the present invention can form esters with organic or inorganic acids, or the carboxyl-containing compounds of the present invention can form esters with alcohols such as methanol, ethanol, or propanol.

[0329] The compounds of the present invention may exist in the form of solvates (e.g., hydrates), wherein the compounds of the present application contain a solvent, such as water, methanol, or ethanol, as a structural element of the crystal lattice of the compound. The amount of the solvent may be present in a stoichiometric or non-stoichiometric ratio.

[0330] The present invention encompasses all possible crystalline forms or polymorphs of the compounds, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0331] As used herein, the term "N-oxide" refers to a compound containing an amine oxide moiety (i.e., an oxide of a tertiary amine group) formed by oxidation of at least one nitrogen atom in the compound. Those skilled in the art will understand that not all nitrogen-containing heterocycles are capable of forming N-oxides because nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of nitrogen-containing heterocycles and tertiary amines are well known to those skilled in the art, for example, nitrogen atoms (e.g., trivalent nitrogen) can be converted to the corresponding N-oxide form by known methods such as treatment with an oxidizing agent. Specific examples include, but are not limited to, wait.

[0332] As used in the present invention, the term "optionally substituted with..." when used to modify a substituent means that the substituent may be substituted or unsubstituted.

[0333] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine, preferably fluorine, chlorine, and bromine.

[0334] As used in the present invention, the term "C 1-6 "Alkyl" refers to a linear or branched monovalent saturated hydrocarbon group having 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5 or 6 carbon atoms. 1-6 Alkyl groups include C 1-5 Alkyl, C 1-4 Alkyl, C 1-3Alkyl, etc., specific examples include but are not limited to methyl, ethyl, propyl, butyl, pentyl or hexyl; the propyl, butyl, pentyl or hexyl, etc. include straight-chain or branched saturated hydrocarbon groups, for example, specific examples of propyl include n-propyl or isopropyl, specific examples of butyl include but are not limited to -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)CH3 or -CH(CH3)3, etc.

[0335] As used in the present invention, the term "C 2-6 "Alkenyl" refers to a straight or branched unsaturated hydrocarbon group having 2 to 6 (eg, 2, 3, 4, 5 or 6) carbon atoms containing at least one double bond. 2-6 Alkenyl groups include C 2-5 Alkenyl, C 2-4 Alkenyl, C 2-3 Alkenyl, etc., specific examples include but are not limited to -CH=CH2, -CH=CH-CH=CH2 or -CH=C(CH)3-CH3, etc.

[0336] As used in the present invention, the term "C 2-6 "Alkynyl" refers to a straight or branched chain unsaturated hydrocarbon group having 2 to 6 (eg, 2, 3, 4, 5 or 6) carbon atoms containing at least one triple bond. 2-6 Alkynyl groups include C 2-5 Alkynyl, C 2-4 Alkynyl, C 2-3 Alkynyl, etc., specific examples include but are not limited to ethynyl (-C≡CH) or propynyl (-C≡C-CH3) and the like.

[0337] As used in the present invention, the term "C 1-6 "Alkylene" refers to a straight or branched divalent saturated hydrocarbon group having 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5 or 6 carbon atoms. 1-6 Alkylene includes C 1-5 Alkylene, C 1-4 Alkylene, C 1-3 Specific examples include, but are not limited to, methylene, ethylene, propylene, or isopropylene.

[0338] As used in the present invention, the term "C 2-6 "Alkenylene" refers to a straight or branched divalent unsaturated hydrocarbon group having 2 to 6 (eg, 2, 3, 4, 5 or 6) carbon atoms containing at least one double bond. 2-6 Alkenylene includes C 2-5 Alkenylene, C 2-4 Alkenylene, C 2-3 Specific examples include, but are not limited to, -CH=CH-, -CH=CH-CH=CH- or -CH=CH-CH2-.

[0339] As used in the present invention, the term "C 2-6 "Alkyne" refers to a straight or branched divalent unsaturated hydrocarbon group having 2 to 6 (e.g., 2, 3, 4, 5 or 6) carbon atoms containing at least one triple bond. 2-6 Alkynylidene groups include C 2-5 Alkynylidene, C 2-4 Alkynylidene, C 2-3 Specific examples include, but are not limited to, -C≡C- or -C≡CC≡C-, etc.

[0340] As used in the present invention, the term "C 1-6 "Alkoxy" refers to -OC 1-6 Alkoxy, that is, C 1-6 The group obtained by connecting the carbon atom on the alkyl group with the oxygen atom, C 1-6 Alkoxy groups include C 1-5 Alkoxy, C 1-4 Alkoxy, C 1- 3 alkoxy, etc., specific examples include but are not limited to methoxy, ethoxy, propoxy or butoxy, etc.

[0341] As used in the present invention, the term "C 1-6 "Alkyleneoxy" refers to -OC 1-6 Alkyleneoxy, i.e. C 1- 6 The group obtained by connecting the carbon atom on the alkylene group with the oxygen atom, C 1-6 Alkyleneoxy includes C 1-5 Alkyleneoxy, C 1- 4 alkyleneoxy, C 1-3 Specific examples include, but are not limited to, methyleneoxy (-OCH2-) or ethyleneoxy (-OCH2CH2-).

[0342] As used herein, the term "halo" means that the group it modifies is substituted by one or more halogens, for example, 1, 2, 3, 4, 5 or 6 halogens. For example, "C 1-6 "Haloalkyl" refers to a C 1-6 The alkyl group is substituted with one or more halogens, specific examples of which include but are not limited to -CF3, -CHF2, -CH2F or -CF2CF3; "C 1-6 "Haloalkoxy" refers to a C 1-6 The alkoxy group is substituted by one or more halogens, specific examples of which include but are not limited to -OCF3 or -OCF2CF3.

[0343] As used in the present invention, the term "C 6-10"Aryl" refers to an unsaturated aromatic carbocyclic group having a conjugated π electron system and consisting of 6 to 10 (e.g., 6, 7, 8, 9 or 10) carbon atoms and having a single ring or two or more condensed rings. Specific examples include, but are not limited to, phenyl or naphthyl.

[0344] As used herein, the term "5-10 membered heteroaryl" refers to a group having a conjugated π electron system consisting of 5 to 10 (e.g., 5, 6, 7, 8, 9, or 10) ring atoms, including monocyclic heteroaromatic rings and polycyclic aromatic rings, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms and the rest are carbon atoms; preferably, the heteroatoms are selected from N, O, or S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized. 5-10 membered heteroaryl includes 5-9 membered, 6-9 membered, 5-6 membered heteroaryl, and the like, and specific examples include, but are not limited to, imidazolyl, thiazolyl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, or pyrazinyl.

[0345] As used in the present invention, the term "C 3-10 Cyclic group" or "C 3-10 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group or a partially unsaturated cyclic hydrocarbon group consisting of 3 to 10 (such as 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms. 3-10 The ring group includes C 4-8 Cyclic group, C 4-6 Cyclic group, C 4-7 Cyclic group, C 5-6 Cyclic group, C 5-7 Cyclic or C 6-7 Cyclic group, etc. 3-10 The cyclic group includes monocyclic, bicyclic or polycyclic rings, including spirocyclic, fused or bridged rings. Specific examples include but are not limited to cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl or 1,4-cyclohexadienyl.

[0346] As used in the present invention, the term "C 3-10 "Cycloalkyl" refers to a saturated hydrocarbon group consisting of 3 to 10 (such as 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms. 3-10 Cycloalkyl groups include C 3-6 Cycloalkyl, C 4-8 Cycloalkyl, C 4-6 Cycloalkyl or C 5-9 Cycloalkyl, etc. 3-10 Cycloalkyl includes monocyclic, bicyclic or polycyclic rings, including spirocyclic, fused or bridged rings. Specific examples include but are not limited to cyclobutyl, cyclopentyl or cyclohexyl.

[0347] As used in the present invention, the term "C 3-6"Cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group consisting of 3 to 6 (such as 3, 4, 5 or 6) carbon atoms and containing at least one carbon-carbon double bond. 3-6 Cycloalkenyl groups include C 4-6 Cycloalkenyl, C5 cycloalkenyl or C6 cycloalkenyl, etc. 3-6 Specific examples of the cycloalkenyl group include, but are not limited to, cyclopentenyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, and the like.

[0348] As used herein, the term "4-10 membered heterocyclyl" refers to a saturated or partially unsaturated cyclic group consisting of 4 to 10 (e.g., 4, 5, 6, 7, 8, 9, or 10) ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms and the remainder are carbon atoms; preferably, the heteroatoms are selected from N, O, or S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized; preferably, the carbon atoms are optionally substituted with =O. The 4-10 membered heterocyclyl includes 4-8, 4-6, 4-5, 5-6, and 9-10 membered heterocyclyls. The 4-10 membered heterocyclyl includes monocyclic, bicyclic, or polycyclic rings, including spirocyclic, fused, or bridged rings. Specific examples of 4-10 membered heterocyclyls include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, 2,3-dihydrofuranyl, 3,4-dihydro-2H-pyranyl, or 2-oxopyrrolidinyl.

[0349] As used in the present invention, the term "C 6-10 "Arylene" refers to a divalent unsaturated aromatic carbocyclic group consisting of 6 to 10 (such as 6, 7, 8, 9 or 10) carbon atoms with a conjugated π electron system. Specific examples include, but are not limited to, phenylene and the like.

[0350] As used herein, the term "5-10 membered heteroarylene" refers to a divalent group having a conjugated π electron system consisting of 5 to 10 (e.g., 5, 6, 7, 8, 9, or 10) ring atoms, including monocyclic heteroaromatic rings and polycyclic aromatic rings, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms and the remainder are carbon atoms; preferably, the heteroatoms are selected from N, O, or S, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized. 5-10 membered heteroarylene groups include 5-9 membered, 6-9 membered, and 5-6 membered heteroarylene groups, and specific examples include, but are not limited to, imidazolylene or pyridylene groups.

[0351] In the present invention, the purpose of the pharmaceutical composition is to promote administration to an organism, facilitate the absorption of the active ingredient, and thus exert its biological activity. The carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated plant fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, beeswax, and lanolin. The excipients refer to additives other than the main drug in a pharmaceutical preparation. They are stable in nature, have no incompatibility with the main drug, do not produce side effects, do not affect the efficacy, are not easily deformed, cracked, molded, or damaged by insects at room temperature, are harmless to the human body, have no physiological effects, do not chemically or physically interact with the main drug, and do not affect the content determination of the main drug. For example, adhesives, fillers, disintegrants, and lubricants in tablets; wine, vinegar, and medicinal juice in Chinese medicine pills; the matrix part in semi-solid preparations such as ointments and creams; preservatives, antioxidants, flavoring agents, fragrances, cosolvents, emulsifiers, solubilizers, osmotic pressure regulators, colorants, etc. in liquid preparations can all be called excipients.

[0352] In the present invention, the pharmaceutical composition can be prepared into various suitable dosage forms according to the route of administration, such as tablets, capsules, granules, oral solutions, oral suspensions, oral emulsions, powders, tinctures, syrups, injections, suppositories, ointments, creams, pastes, ophthalmic preparations, pills, implants, aerosols, powder sprays, sprays, etc. The pharmaceutical composition or suitable dosage form can contain 0.01 mg to 1000 mg of the compound of the present invention or its enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt, preferably 0.1 mg to 800 mg, preferably 0.5-500 mg, more preferably 0.5 to 350 mg, and particularly preferably 1-250 mg.

[0353] As used herein, the term "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from a disease (e.g., a disease described herein) (referred to as a patient) or normal individuals. The term "non-human animal" in the present disclosure includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0354] As used herein, the term "treatment" is intended to alleviate, alleviate, improve, or eliminate the disease state or condition being treated. If a subject receives a therapeutic amount of the compound or its enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt according to the methods described herein, and the subject exhibits an observable and / or detectable reduction or improvement in one or more signs and symptoms, the subject is successfully "treated." It should also be understood that the treatment of the disease state or condition includes not only complete treatment, but also includes not achieving complete treatment but achieving some biologically or medically relevant results.

[0355] As used herein, the term "prevention" is intended to avoid, reduce, prevent, or delay the onset of a disease or disease-related symptoms, provided that the disease or disease-related symptoms have not yet appeared before the administration of the relevant drug. "Prevention" does not necessarily require the complete prevention of the onset of a disease or disease-related symptoms. For example, if the administration of the relevant drug can reduce the risk of a subject developing a particular disease or disease-related symptom, or reduce the severity of related symptoms that later appear, it can be considered to have "prevented" the onset or development of the disease.

[0356] As used herein, the term "effective amount" refers to an amount sufficient to achieve a desired therapeutic or preventive effect, for example, an amount that alleviates the symptoms associated with the disease to be treated, or an amount that is effective in preventing, arresting, or delaying the onset of the disease. Determining such an effective amount is within the capabilities of those skilled in the art.

[0357] It should also be noted that the dosage and method of use of the compounds of this invention depend on many factors, including the patient's age, weight, sex, natural health, nutritional status, the potency of the compound, time of administration, metabolic rate, severity of the condition, and the subjective judgment of the treating physician. The preferred dosage is between 0.01 and 100 mg / kg body weight / day.

[0358] Unless otherwise stated, substituents or group combinations contemplated herein for Markush structures are those that are stable or chemically feasible. Beneficial effects

[0359] The compounds of the present invention have AMPK agonist activity, and in particular, some of the compounds exhibit even better AMPK agonist activity. DETAILED DESCRIPTION

[0360] The embodiments of the present invention will be described in detail below with reference to the examples, but it will be understood by those skilled in the art that the following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be obtained commercially.

[0361] Example 1: Synthesis of Compound 1

[0362] Step 1: To a single-necked flask at room temperature, add Intermediate 1a (50 mg, 0.16 mmol), Intermediate 1b (50.83 mg, 0.20 mmol), tri-tert-butylphosphine tetrafluoroborate (90.0 mg, 0.3 mmol), triethylenediamine (1.01 g, 9.0 mmol), tris(dibenzylideneacetone)dipalladium (0.14 g, 0.15 mmol), and N,N-dimethylaniline (10 mL). The mixture was reacted at 120°C for 16 hours under nitrogen. After completion of the reaction, the reaction solution was poured into 20 mL of water and extracted with 3 × 10 mL of ethyl acetate. The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography to obtain Intermediate 1c. LC-MS: m / z: 303.0 (M+H). + .

[0363] Step 2: At room temperature, intermediate 1c (105 mg, 0.35 mmol), 1d (Bis(diphenylphosphino)ferrocene, 113.8 mg, 0.42 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (28.25 mg, 0.03 mmol), cesium carbonate (338.12 mg, 1.04 mmol), 1,4-dioxane (3.0 mL) and water (1.0 mL) were added to a single-necked bottle. The mixture was reacted at 100 degrees Celsius for 16 hours under nitrogen protection. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (mobile phase: A: 0.05% TFA / H2O B: ACN, column: Waters-SunFire-C 18 -10μm-19*250mm) to separate and purify to obtain compound 1. LC-MS: m / z: 357.2 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ11.29(s,1H),7.95(s,1H),7.60(m,6H),5.54(s,1H), 3.69(s,2H),2.44–2.42(m,1H),2.37–2.24(m,3H),1.94(m,1H),1.70(m,1H).

[0364] Example 2: Synthesis of Compound 2

[0365] Step 1: Under nitrogen, magnesium turnings (0.24 g, 9.96 mmol) and THF (10 mL) were added to a three-necked flask. Intermediate 2a (2.35 g, 9.96 mmol), 1,2-dibromoethane (0.02 g, 0.10 mmol), and THF (10 mL) were then added sequentially with stirring. The mixture was allowed to react at room temperature for 1 hour to obtain a reaction solution containing Intermediate 2b, which was used directly in the next step.

[0366] Step 2: Under nitrogen at -40°C, add intermediate 2c (700 mg, 9.99 mmol) and THF (5 mL) to a three-necked flask. Add the reaction solution containing intermediate 2b (20 mL, 7.69 mmol) with stirring. Reaction at zero degrees for two hours. The reaction solution is quenched with water, extracted with ethyl acetate, and the organic phase is concentrated under reduced pressure to obtain a crude product. The crude product is separated and purified by silica gel column chromatography to obtain intermediate 2d. LC-MS: m / z: 209.0 (M+H-18) + .

[0367] Step 3: Under nitrogen protection, intermediate 2d (500 mg, 2.20 mmol) and THF (5 mL) were added to a three-necked flask, and n-butyl lithium (1.76 mL, 4.40 mmol) was added under stirring. After stirring at -78 ° C for half an hour, triisopropyl borate (496.88 mg, 2.64 mmol) and THF (2 mL) were added. The reaction was completed after two hours. Water was added to the reaction solution to quench the reaction, and the solution was extracted with ethyl acetate. The organic phase was dried over anhydrous NaSO4 and concentrated under reduced pressure to obtain a crude product. The crude product was slurried with petroleum ether to obtain intermediate 2e. LC-MS: m / z: 175.0 (M+H-18) + .

[0368] Step 4: Under nitrogen protection, intermediate 2f (1.0 g, 4.34 mmol) and dichloromethane (10 mL) were added to a three-necked flask. Aluminum chloride (2.31 g, 17.36 mmol) was added under stirring, and a dichloromethane solution (4 mL) of monomethyl oxalyl chloride (1.85 mg, 15.12 mmol) was added dropwise. The reaction was allowed to react at room temperature for 24 hours. The reaction solution was poured into water and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was slurried with petroleum ether / ethyl acetate (V / V = 5 / 1) to obtain intermediate 2g. LC-MS: m / z: 316.0 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ12.78(s,1H),8.57(s,1H),8.45(s,1H),7.85(s,1H),3.90(s,3H).

[0369] Step 5: Add intermediate 2g (100 mg, 0.32 mmol), intermediate 2e (72.79 mg, 0.38 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (25.80 mg, 0.03 mmol), potassium carbonate (130.98 mg, 0.95 mmol), 1,4-dioxane (3 mL) and water (0.75 mL) to a microwave tube and microwave for 2 hours at 100 degrees Celsius until the reaction is complete. The reaction solution is filtered and the filtrate is purified by high performance liquid chromatography (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) to separate and purify to obtain compound 2. LC-MS: m / z: 370.0 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ12.41(s,1H),8.51(s,1H),8.12(s,1H),7.73(s,1H),7.59(d,2H),7.43( d,2H),5.53(s,1H),2.47-2.32(m,2H),2.30-2.27(m,2H),2.01-1.97(m,1H),1.94-1.64(m,1H).

[0370] Example 3: Synthesis of Compound 3

[0371] Step 1: At room temperature, intermediate 3a (500 mg, 2.16 mmol), dichloromethane (15 mL) and aluminum chloride (1.01 g, 7.56 mmol) were added to a three-necked flask in sequence. After nitrogen replacement, the reaction was stirred at room temperature for 1 hour. Subsequently, methyl oxalyl chloride (926 mg, 7.56 mmol) dissolved in dichloromethane (2 mL) was slowly added dropwise to the three-necked flask, and then the reaction was allowed to proceed at room temperature overnight until the reaction was complete. After the reaction was completed, ice water was poured into the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate three times. The organic phase was collected and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was slurried with petroleum ether / ethyl acetate (V / V = 5 / 1) to obtain intermediate 3b. LC-MS: m / z: 317.0 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ12.89(s,1H),8.71(s,1H),8.26(s,1H),3.92(s,3H).

[0372] Step 2: At room temperature, intermediate 3b (50 mg, 0.16 mmol), 2e (45 mg, 0.24 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (12.86 mg, 0.02 mmol), potassium carbonate (65 mg, 0.47 mmol), 1,4-dioxane (2 mL) and water (0.50 mL) were added to a microwave tube and reacted at 100 degrees Celsius for two hours under nitrogen protection. After the reaction was completed, the reaction solution was filtered and the filtrate was purified by high performance liquid chromatography (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) was separated and purified to obtain compound 3. LC-MS: m / z: 371.0 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ8.41(s,1H),8.07(s,1H),7.63–7.57(m,4H),7.25(d,J=8.6Hz,1H) ,5.58(s,1H),2.48–2.41(m,2H),2.35–2.28(m,2H),1.99–1.89(m,1H),1.76–1.65(m,1H).

[0373] Example 4: Synthesis of Compound 4

[0374] Step 1: Add intermediate 2g (100 mg, 0.32 mmol), intermediate 4a (102.92 mg, 0.35 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (25.80 mg, 0.03 mmol), potassium carbonate (130.98 mg, 0.95 mmol), 1,4-dioxane (4 mL) and water (1 mL) to a microwave tube and react at 100°C for 2 hours. The reaction solution was filtered and the filtrate was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) to separate and purify to obtain compound 4. LC-MS: m / z: 392.1 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.15(m,2H),7.65-7.63(m,3H),7.47-7.44(m ,2H),7.36-7.33(m,1H),7.20-7.16(m,2H),6.99-6.97(m,1H),6.93-6.89(m,1H).

[0375] Example 5: Synthesis of Compound 5

[0376] Step 1: Add intermediate 2g (50 mg, 0.16 mmol), intermediate 5a (50.83 mg, 0.20 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (13.07 mg, 0.02 mmol), potassium carbonate (66.34 mg, 0.48 mmol), 1,4-dioxane (2 mL) and water (0.5 mL) to a microwave tube and react at 100 degrees Celsius for two hours. The reaction solution was filtered and the filtrate was purified by high performance liquid chromatography (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) to separate and purify to obtain compound 5. LC-MS: m / z: 353.0 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ8.31(s,1H),8.16(s,1H),7.66(s,1H),7.57(s,1H),7.56- 7.49(m,1H),7.39-7.38(m,1H),7.22-7.17(m,2H),6.49-6.48(m,1H),3.84(s,3H).

[0377] Example 6: Synthesis of Compound 6

[0378] Step 1: Dissolve sodium hydroxide (24g, 1.02mol) in a three-necked flask containing DMF (300ml), cool to zero degrees Celsius, and replace nitrogen. Then dissolve intermediate 6a (20g, 0.102mol) and intermediate 6b (134g, 0.714mol) in DMF (200ml), add dropwise to the three-necked flask at zero degrees Celsius, warm to room temperature, and react at room temperature for two hours. Pour the reaction solution into ice water (500ml), add ethyl acetate (500ml), extract, wash the organic phase with sodium chloride aqueous solution, dry over anhydrous sodium sulfate overnight, and filter to obtain the filtrate. Concentrate the filtrate to obtain the crude product, which is chromatographed on a silica gel column to obtain intermediate 6c. LC-MS: m / z: 222.0 (M+H) + . 1 H NMR (400MHz, CDCl3) δ7.48 (d, J = 8.6 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 1.77-1.72 (m, 2H), 1.41-1.36 (m, 2H).

[0379] Step 2: Dissolve intermediate 6c (20 g, 90.05 mmol) and barium hydroxide (62 g, 360.21 mmol) in isopropanol (200 ml) and water (600 ml) and react at 100°C for 16 hours. Adjust the pH of the reaction solution to 3-4 with 1 mol / L dilute hydrochloric acid and extract with ethyl acetate. The organic phase is washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate overnight, filtered, and concentrated to obtain intermediate 6d. LC-MS: m / z: 241.0 (M+H) + . 1 H NMR (400MHz, CDCl3) δ7.41 (d, J = 7.9 Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H), 1.58 (d, J = 5.2 Hz, 2H), 1.16 (s, 2H).

[0380] Step 3: Dissolve intermediate 6d (23 g, 95.40 mmol) in methanol (300 ml) and cool to 0°C. Then, add thionyl chloride (34 g, 286.21 mmol) dropwise. The reaction is continued at 80°C for 16 hours. Concentrate under reduced pressure to obtain the crude product, which is then purified by silica gel column chromatography to obtain intermediate 6e. LC-MS: m / z: 255.0 (M+H). + . 1H NMR (400MHz, DMSO-d6) δ7.53-7.47(m,2H),7.33–7.27(m,2H),3.55(s,3H),1.49(q,m,2H),1.21-1.17(m,2H).

[0381] Step 4: Dissolve intermediate 6e (13.8 g, 54.09 mmol) in tetrahydrofuran (150 ml), replace nitrogen and cool to zero degrees Celsius. Then, add 1 mol / L lithium aluminum hydride tetrahydrofuran solution (64.91 ml, 64.91 mmol) dropwise at zero degrees Celsius, then warm to room temperature for two hours to complete the reaction. Then, cool to zero degrees Celsius and add water (2.5 mL), 15% sodium hydroxide aqueous solution (2.5 mL), and water (7.5 mL) dropwise to the reaction solution in sequence. Warm to room temperature and stir for 30 minutes. Then add an appropriate amount of anhydrous sodium sulfate and stir at room temperature for 30 minutes. Finally, filter and concentrate the filtrate to obtain intermediate 6f. LC-MS: m / z: 210 (M+H-OH) + . 1 H NMR (400MHz, DMSO-d6) δ7.49-7.42(m,2H),7.28-7.22(m,2H),4.72(t,J=5.6Hz,1H),3.50(d,J=5.5Hz,2H),0.86-0.80(m,2H),0.75-0.69(m,2H).

[0382] Step 5: Dissolve intermediate 6f (9.8 g, 43.16 mmol), pinacol diboronate (13.14 g, 51.78 mmol), potassium acetate (12.7 g, 129.46 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (3.52 g, 4.32 mmol) in 1,4-dioxane (100 mL). Replace the atmosphere with nitrogen and react at 80°C for 16 hours. Filter the reaction mixture, wash the filter cake three times with appropriate amounts of ethyl acetate, extract the filtrate with water and ethyl acetate, and wash the organic phase with sodium chloride solution, dry over anhydrous sodium sulfate overnight, filter, and concentrate to obtain the crude product, which is then purified by silica gel column chromatography (mobile phase: PE / EA = 10 / 1) to obtain intermediate 6g. LC-MS: m / z: 297.2 (M+Na) + . 1 H NMR (400MHz, DMSO-d6) δ7.58(d,J=7.9Hz,2H),7.29(d,J=8.1Hz,2H),4.68(t,J=5.6H z, 1H), 3.54 (d, J = 5.7Hz, 2H), 1.28 (s, 12H), 0.89-0.83 (m, 2H), 0.74 (t, J = 2.9Hz, 2H).

[0383] Step 6: Add intermediate 2g (80 mg, 0.25 mmol), intermediate 6g (75.40 mg, 0.28 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (20.42 mg, 0.03 mmol), potassium carbonate (86.37 mg, 0.63 mmol), 1,4-dioxane (3 mL) and water (0.75 mL) to a microwave tube and microwave at 100 degrees Celsius for two hours. The reaction solution was filtered and the filtrate was purified by high performance liquid chromatography (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) to separate and purify to obtain compound 6. LC-MS: m / z: 370.0 (M+H) + . 1 HNMR(400MHz,DMSO-d6)δ8.27(s,1H),8.09(s,1H),7.65(s,1H),7.41-7.3 2(m,5H),4.75(s,1H),3.59(s,2H),0.89-0.85(m,2H),0.83-0.79(m,2H).

[0384] Example 7: Synthesis of Compound 7

[0385] Step 1: Add intermediate 2g (50 mg, 0.16 mmol), intermediate 7a (26.74 mg, 0.18 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (13.07 mg, 0.02 mmol), potassium carbonate (55.28 mg, 0.40 mmol), 1,4-dioxane (2 mL) and water (0.5 mL) to a microwave tube and react at 100 degrees Celsius for two hours. The reaction solution was filtered and the filtrate was purified by high performance liquid chromatography (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) to separate and purify to obtain compound 7. LC-MS: m / z: 330.0 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ8.25(s,1H),8.10(s,1H),7.64(s,1H),7.37-7.34(m,2H),7.21(s,1H),7.04-7.00(m,2H),3.81(s,3H).

[0386] Example 8: Synthesis of Compound 8

[0387] Step 1: Add intermediate 2g (50 mg, 0.16 mmol), intermediate 8a (34.85 mg, 0.18 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (13.07 mg, 0.02 mmol), potassium carbonate (55.28 mg, 0.40 mmol), 1,4-dioxane (2 mL) and water (0.5 mL) to a microwave tube and react at 100°C for 2 hours. The reaction solution was filtered and the filtrate was purified by high performance liquid chromatography (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) to separate and purify to obtain compound 8. LC-MS: m / z: 376.0 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ12.25(s,1H),8.37(s,1H),8.17(s,1H),7.78-7.74(m,4H),7.71(s,1H),7.55-7.50(m,4H)7.42-7.38(m,1H).

[0388] Example 9: Synthesis of Compound 9

[0389] Step 1: At room temperature, intermediate 2f (5.0 g, 21.7 mmol), 4-dimethylaminopyridine (270 mg, 2.17 mmol), pyridine (4.46 g, 56.4 mmol), and tetrahydrofuran (60 mL) were added to a 250 mL single-necked flask. Trichloroacetyl chloride 9a (9.47 g, 52.1 mmol) was slowly added dropwise under ice-cooling. The reaction mixture was stirred at 60°C for 8 hours. After the reaction, the reaction mixture was quenched with water (100 mL), extracted with ethyl acetate (50 mL x 3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography to obtain intermediate 9b. LC-MS: m / z: 375.8 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ12.75(s,1H),8.71–8.65(m,1H),8.50–8.45(m,1H),7.86–7.82(m,1H).

[0390] Step 2: At room temperature, intermediate 9b (6.3 g, 16.1 mmol) was added to a 100 mL single-necked bottle and dissolved in a mixed solvent of methanol (25 mL) and water (30 mL). Then, sodium hydroxide (1.68 g, 41.9 mmol) was added, and the reaction solution was reacted at 60 ° C for 18 hours. After the reaction was completed, the methanol was removed by concentration under reduced pressure, and then the aqueous phase was extracted with ethyl acetate (30 mL x 3). Dilute hydrochloric acid was added to the aqueous phase to adjust the pH to acidic. After extraction with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was pulped to obtain intermediate 9c. LC-MS: m / z: 275.9 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ12.31 (s, 1H), 12.08 (s, 1H), 8.30 (s, 1H), 8.12 (d, J = 2.6Hz, 1H), 7.75 (s, 1H).

[0391] Step 3: At room temperature, intermediate 9c (600 mg, 2.19 mmol), 1d (719.13 mg, 2.62 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (159.94 mg, 0.22 mmol), potassium carbonate (604.15 mg, 4.37 mmol), N,N-dimethylformamide (5 mL) and water (1 mL) were added to a 25 mL single-necked flask in sequence. After nitrogen substitution three times, the reaction solution was reacted at 80°C for 18 hours. After completion of the reaction, the reaction solution was concentrated, and the crude product was separated and purified by silica gel column chromatography to obtain intermediate 9d. LC-MS: m / z: 324.1 (M+H-18) + .

[0392] Step 4: At room temperature, intermediate 9d (50 mg, 0.15 mmol), HATU (65 mg, 0.18 mmol) and N,N-diisopropylethylamine (38 mg, 0.30 mmol) were dissolved in N,N-dimethylformamide (2.0 mL) in a 25 mL single-necked bottle. 2-Aminomethylpyridine (intermediate 9e) (15.8 mg, 0.15 mmol) was then added dropwise. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated and the crude product was purified by high performance liquid chromatography (mobile phase: A: 0.05% TFA / H2O B: ACN, column: Waters-SunFire-C 18 -10μm-19*250mm) separation and purification were finally carried out to obtain compound 9. LC-MS: m / z: 432.2 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ11.77(d,J=2.9Hz,1H),8.73(t,J=5.9Hz,1H),8.63(d,J=5.0 Hz,1H),8.19(d,J=2.9Hz,1H),8.12(s,1H),8.08–8.00(m,1H),7.64(s,1H),7.58(d, J=8.0Hz,1H),7.57–7.53(m,2H),7.53–7.48(m,1H),7.41–7.37(m,2H),4.64(d,J=5. 7Hz,2H),2.47–2.39(m,2H),2.34–2.25(m,2H),2.00–1.88(m,1H),1.74–1.63(m,1H).

[0393] Example 10: Synthesis of Compound 10

[0394] Step 1: At room temperature, intermediate 9d (100 mg, 0.29 mmol) was added to a 25 mL single-necked bottle and dissolved in ultra-dry N,N-dimethylformamide (3.0 mL). HATU (111.25 mg, 0.29 mmol), N,N-diisopropylethylamine (0.1 mL, 0.59 mmol) and intermediate 10a (28.04 mg, 0.32 mmol) were then added in sequence. The reaction was completed after 2 hours. After the reaction was completed, the reaction solution was concentrated and the crude product was separated by silica gel column chromatography to obtain the crude compound 10, which was then purified by high performance liquid chromatography (mobile phase: A: 0.05% TFA / H2O B: ACN, chromatographic column: Waters-SunFire-C 18 -10μm-19*250mm) separation and purification were finally carried out to obtain compound 10. LC-MS: m / z: 411.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.68 (s, 1H), 8.11 (d, J = 2.0Hz, 2H), 8.07 (s, 1H), 7. 61(s,1H),7.59–7.53(m,2H),7.43–7.35(m,2H),5.53(s,1H),4.62(dd,J=7.8 ,6.0Hz,2H),4.35(t,J=6.0Hz,2H),3.51(t,J=6.3Hz,2H),3.19–3.11(m,1H) ,2.48–2.39(m,2H),2.34–2.27(m,2H),2.00–1.91(m,1H),1.76–1.62(m,1H).

[0395] Example 11: Synthesis of Compound 11

[0396] Step 1: At room temperature, intermediate 9d (100 mg, 0.29 mmol) was added to a 25 mL single-necked bottle and dissolved in ultra-dry N,N-dimethylformamide (3.0 mL). Intermediate 11a (39.02 mg, 0.29 mmol), HATU (111.25 mg, 0.29 mmol), and N,N-diisopropylethylamine (0.15 mL, 0.88 mmol) were then added. The reaction was allowed to proceed for 2 hours at room temperature until the reaction was complete. After the reaction was completed, the reaction solution was concentrated and the crude product was separated by silica gel column chromatography to obtain crude compound 11, which was then purified by high performance liquid chromatography (mobile phase: A: 0.05% TFA / H2O B: ACN, column: Waters-SunFire-C 18 -10μm-19*250mm) separation and purification were finally carried out to obtain compound 11. LC-MS: m / z: 422.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.78–11.72(m,1H),8.66(t,J=5.8Hz,1H),8.47( d,J=2.0Hz,1H),8.14(d,J=3.2Hz,1H),8.12(s,1H),7.62(s,1H),7.58–7.5 3(m,2H),7.42–7.37(m,2H),6.34(d,J=1.6Hz,1H),4.60(d,J=5.8Hz,2H),2 .48–2.38(m,2H),2.36–2.24(m,2H),2.02–1.87(m,1H),1.75–1.63(m,1H).

[0397] Example 12: Synthesis of Compound 12

[0398] Step 1: At room temperature, intermediate 9d (100 mg, 0.29 mmol) was added to a 25 mL single-necked bottle and dissolved in ultra-dry N,N-dimethylformamide (3.0 mL). Intermediate 12a (39.02 mg, 0.29 mmol), HATU (111.25 mg, 0.29 mmol), and N,N-diisopropylethylamine (0.15 mL, 0.88 mmol) were then added. The reaction was allowed to proceed for 2 hours at room temperature until the reaction was complete. After the reaction was completed, the reaction solution was concentrated and the crude product was separated by silica gel column chromatography and then purified by high performance liquid chromatography (mobile phase: A: 0.05% TFA / H2O B: ACN, column: Waters-SunFire-C 18-10μm-19*250mm) separation and purification were finally carried out to obtain compound 12. LC-MS: m / z: 422.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.71(d,J=2.4Hz,1H),8.84(s,1H),8.55(s,1H),8.43(t,J=5.6Hz,1H),8.13(s,1H),8.09(d,J=2.8Hz,1H),7.61(s, 1H),7.59–7.53(m,2H),7.43–7.37(m,2H),4.32(d,J=5.6Hz,2H),2.47 –2.40(m,2H),2.36–2.24(m,2H),2.01–1.89(m,1H),1.76–1.64(m,1H).

[0399] Example 13: Synthesis of Compound 13

[0400] Step 1: At room temperature, to a 25 mL single-necked bottle, intermediate 9c (280 mg, 1.02 mmol), intermediate 8a (242.4 mg, 1.22 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (74.64 mg, 0.1 mmol), potassium carbonate (281.94 mg, 2.04 mmol), N,N-dimethylformamide (5 mL) and water (1 mL) were added in sequence. After nitrogen substitution three times, the reaction solution was reacted at 90 ° C for 3 hours. After the reaction was completed, the reaction solution was concentrated and the crude product was separated by silica gel column chromatography to obtain intermediate 13a. LC-MS: m / z: 348.1 (M+H) + .

[0401] Step 2: To a 50 mL single-necked vial at room temperature, add intermediate 13a (120 mg, 0.35 mmol) and N,N-dimethylformamide (0.01 mL, 0.13 mmol). Dissolve the mixture in ultra-dry dichloromethane (5 mL). Slowly add oxalyl chloride (0.09 mL, 1.04 mmol) under an ice bath. Allow to warm to room temperature and react for 2 hours. After the reaction, concentrate the reaction mixture to obtain a residue, which is used directly in the next step. To a 25 mL single-necked vial at room temperature, add the above residue (50 mg, 0.14 mmol) and dissolve it in ultra-dry tetrahydrofuran (3.0 mL). Add intermediate 13b (22.69 mg, 0.27 mmol) and triethylamine (0.06 mL, 0.41 mmol) sequentially under an ice bath. The final reaction mixture is reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated and the crude product was purified by high performance liquid chromatography (mobile phase: A: 0.05% TFA / H2O B: ACN, column: Waters-SunFire-C 18 -10μm-19*250mm) separation and purification were finally carried out to obtain compound 13. LC-MS: m / z: 413.2 (M+H) + . 1 HNMR (400MHz, DMSO-d6) δ12.74(d,J=3.3Hz,1H),8.42(s,2H),8.40(d,J=3.3Hz,1H),8.07(s,1H),7. 85–7.72(m,5H),7.60(d,J=2.7Hz,1H),7.58–7.47(m,4H),7.45–7.37(m,1H),7.10(d,J=2.7Hz,1H).

[0402] Example 14: Synthesis of Compound 14

[0403] Step 1: To a 100 mL single-necked flask at room temperature, add intermediate 9c (600 mg, 2.19 mmol) and dissolve in ultra-dry dichloromethane (40.0 mL). After cooling to 0°C in an ice bath, add oxalyl chloride (0.37 mL, 4.38 mmol) and N,N-dimethylformamide (0.033 mL, 0.44 mmol) sequentially. Allow to warm to room temperature naturally. The reaction is complete after 2 hours. After completion of the reaction, the reaction solution is concentrated to yield intermediate 14a, which is used directly in the next reaction.

[0404] Step 2: At room temperature, intermediate 14a (100 mg, 0.34 mmol) was added to a 50 mL single-necked flask and dissolved in ultra-dry dichloromethane (20.0 mL). After cooling to 0°C in an ice bath, 14b (49.53 mg, 0.51 mmol) and N,N-diisopropylethylamine (0.22 mL, 1.36 mmol) were added in sequence. The mixture was allowed to warm to room temperature naturally. The reaction was complete after 2 hours. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain intermediate 14c. LC-MS: m / z: 353.0 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.82(s,1H),8.53(t,J=5.6Hz,1H),8.49(s,1H),8.16(d,J=2.6Hz,1H),7.71( s, 1H), 7.58 (d, J = 1.0Hz, 1H), 6.40 (dd, J = 3.2, 2.0Hz, 1H), 6.28 (d, J = 3.0Hz, 1H), 4.45 (d, J = 6.0Hz, 1H).

[0405] Step 3: At room temperature, intermediate 14c (77 mg, 0.22 mmol), 14d (62.72 mg, 0.33 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (31.87 mg, 0.04 mmol), potassium carbonate (60.19 mg, 0.44 mmol), dioxane (8.0 mL), and water (1.6 mL) were added to a 50 mL single-necked bottle. The reaction was carried out at 90°C under nitrogen protection for 2 hours until the reaction was complete. After the reaction was completed, the reaction solution was concentrated and the crude product was purified by silica gel column chromatography to obtain the crude compound 14, which was then purified by high performance liquid chromatography (mobile phase: A: H2O B: ACN, column: Waters-SunFire-C 18 -10μm-19*250mm) separation and purification were finally carried out to obtain compound 14. LC-MS: m / z: 421.2 (M+H) + . 1H NMR(400MHz,DMSO-d6)δ11.67(d,J=1.6Hz,1H),8.43(t,J=5.6Hz,1H),8.16–8.09 (m,2H),7.59(s,1H),7.56(dd,J=1.6,0.6Hz,1H),7.40–7.35(m,2H),7.35–7.30(m ,2H),6.39(dd,J=3.2,2.0Hz,1H),6.26(d,J=2.8Hz,1H),4.70(t,J=5.6Hz,1H),4 .44(d,J=5.6Hz,2H),3.59(d,J=5.6Hz,2H),0.89–0.87(m,2H),0.81–0.78(m,2H).

[0406] Example 15: Synthesis of Compound 15

[0407] Step 1: To a 50 mL single-necked flask at room temperature, intermediate 14a (100 mg, 0.34 mmol) was added and dissolved in ultra-dry dichloromethane (20.0 mL). After cooling to 0°C in an ice bath, 15a (57.95 mg, 0.51 mmol) and N,N-diisopropylethylamine (0.22 mL, 1.36 mmol) were added sequentially. The mixture was allowed to warm to room temperature naturally. The reaction was complete after 2 hours. After completion of the reaction, the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain intermediate 15b. 1 H NMR (400MHz, DMSO-d6) δ11.82(d,J=2.4Hz,1H),8.70(t,J=6.0Hz,1H),8.49(s,1H),8.14(d,J=3.2Hz,1H),7. 72(s,1H),7.38(dd,J=5.0,1.2Hz,1H),7.04–7.00(m,1H),6.96(dd,J=5.2,3.6Hz,1H),4.62(d,J=6.0Hz,2H).

[0408] Step 2: At room temperature, intermediate 15b (52 mg, 0.14 mmol), 14d (40.52 mg, 0.21 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (20.59 mg, 0.03 mmol), potassium carbonate (38.88 mg, 0.28 mmol), dioxane (7.0 mL), and water (1.4 mL) were added to a 50 mL single-necked bottle. The mixture was purged and nitrogen was protected at 90°C for 2 hours until the reaction was complete. After the reaction was completed, the reaction solution was concentrated and the crude product was separated and purified by silica gel column chromatography to obtain crude compound 15, which was then purified by high performance liquid chromatography (mobile phase: A: H2O B: ACN, column: Waters-SunFire-C 18 -10μm-19*250mm) separation and purification were finally carried out to obtain compound 15. LC-MS: m / z: 437.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.69(d,J=2.0Hz,1H),8.60(t,J=6.0Hz,1H),8.12(s,1H),8.10(d,J=2.8Hz,1H),7.60(s,1H),7.40–7.32(m,5H),7.01(d,J =2.4Hz,1H),6.95(dd,J=5.0,3.4Hz,1H),4.70(t,J=5.6Hz,1H),4.61(d,J =5.8Hz,2H),3.59(d,J=5.7Hz,2H),0.91–0.85(m,2H),0.82–0.75(m,2H).

[0409] Example 16: Synthesis of Compound 16

[0410] Step 1: To a 50 mL single-necked flask at room temperature, intermediate 14a (100 mg, 0.34 mmol) was added and dissolved in ultra-dry dichloromethane (20.0 mL). After cooling to 0°C in an ice bath, 16a (68.90 mg, 0.51 mmol) and N,N-diisopropylethylamine (0.22 mL, 1.36 mmol) were added sequentially. The mixture was allowed to warm to room temperature and allowed to react for 2 hours to complete. After completion of the reaction, the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain intermediate 16b. 1 H NMR (400MHz, DMSO-d6) δ11.85 (s, 1H), 8.73 (t, J = 5.8Hz, 1H), 8.46 (s, 1H), 8.17 (d,J=2.4Hz,1H),8.05(s,1H),7.73(s,1H),7.16(s,1H),4.57(d,J=5.8Hz,2H).

[0411] Step 2: At room temperature, intermediate 16b (68 mg, 0.19 mmol), intermediate 14d (55.24 mg, 0.29 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (28.06 mg, 0.04 mmol), potassium carbonate (53.01 mg, 0.38 mmol), dioxane (7.0 mL), and water (1.4 mL) were added to a 50 mL single-necked bottle. The mixture was purged and nitrogen was protected at 90°C for 2 hours until the reaction was complete. After the reaction was completed, the reaction solution was concentrated and the crude product was separated and purified by silica gel column chromatography to obtain crude compound 16, which was then purified by high performance liquid chromatography (mobile phase: A: H2O B: ACN, chromatographic column: Waters-SunFire-C 18 -10μm-19*250mm) separation and purification were finally carried out to obtain compound 16. LC-MS: m / z: 422.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.72(br,1H),8.63(t,J=5.8Hz,1H),8.14(d,J=2.8Hz,1H),8.10(s,1H),8.03(s,1H),7.61(s,1H),7.39–7 .30(m,4H),7.14(s,1H),4.70(t,J=5.6Hz,1H),4.56(d,J=5.8Hz,2H),3.58(d,J=6.0Hz,2H),0.91–0.84(m,2H),0.82–0.75(m,2H).

[0412] Example 17: Synthesis of Compound 17

[0413] Step 1: Under nitrogen, an 8 mL microwave tube was charged with Intermediate 2g (200 mg, 0.63 mmol), Intermediate 14d (133.46 mg, 0.70 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (77.39 mg, 0.15 mmol), potassium carbonate (218.3 mg, 1.58 mmol), and N,N-dimethylformamide (4 mL). The reaction was microwaved at 110°C for three hours, and the reaction was complete. The reaction solution was concentrated to obtain the crude product, which was separated and purified by HPLC (mobile phase: A: 0.1% FA / H2OB:ACN, column: Waters-CORTECS-C18-2.7μm-4.6*30mm) to obtain Compound 17. LC-MS: m / z: 384.0 (M+H) + , 1H NMR (400MHz, DMSO-d6) δ12.57(s,1H),8.53(s,1H),8.08(s,1H),7.72(s,1H),7.37(q,J=8.2 Hz,4H),4.72(s,1H),3.89(s,3H),3.59(s,2H),0.88(q,J=4.1Hz,2H),0.80(q,J=4.0Hz,2H).

[0414] Example 18: Synthesis of Compound 18

[0415] Step 1: Compound 6 (50 mg, 0.14 mmol), methylamine hydrochloride (13.69 mg, 0.20 mmol), HATU (77.12 mg, 0.2 mmol), N,N-diisopropylethylamine (52.43 mg, 0.41 mmol), and N,N-dimethylformamide (2 mL) were added to a 10 mL round-bottom flask. The reaction was complete after five hours at room temperature. The reaction solution was concentrated to obtain a crude product, which was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) to separate and purify to obtain compound 18. LC-MS: m / z: 383.1 (M+H) + , 1 H NMR (400MHz, DMSO-d6) δ12.31(s,1H),8.84(s,1H),8.67(d,J=4.8Hz,1H),8.15(s,1H),7.71(s,1H),7. 40-7.33(m,4H),4.73(t,J=6.0Hz,1H),3.58(d,J=5.6Hz,2H),2.74(d,J=4.8Hz,3H),0.90-0.79(m,4H).

[0416] Example 19: Synthesis of Compound 19

[0417] Step 1: Under nitrogen, add Intermediate 14b (2 g, 20.59 mmol) and dichloromethane (40 mL) to a 250 mL three-necked flask. The temperature is lowered to 0°C. A solution of triphosgene (6.11 g, 20.59 mmol) and dichloromethane (40 mL) is slowly added dropwise at approximately 0°C. Then, a solution of triethylamine (4.38 g, 43.25 mmol) and dichloromethane (20 mL) is slowly added dropwise at approximately 0°C. The temperature is slowly raised to 25°C, and the reaction is complete after 15 hours. The reaction solution is filtered and concentrated under reduced pressure to obtain the crude product, which is then purified by silica gel column chromatography to obtain Intermediate 19a. 1 H NMR (400MHz, CDCl3) δ7.37 (dd, J = 5.7, 0.9 Hz, 1H), 6.32 (dd, J = 3.2, 1.9 Hz, 1H), 6.26 (d, J = 3.2 Hz, 1H), 5.22 (s, 2H).

[0418] Step 2: Under nitrogen, to a 250 mL single-necked flask were added Intermediate 19b (9 g, 36.5 mmol), Intermediate 5a (9.86 g, 38.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (2.98 g, 3.65 mmol), potassium carbonate (12.62 g, 91.28 mmol), dioxane (135 mL), and water (27 mL). The reaction was heated to 100°C for 15 hours until completion. After completion, the reaction mixture was cooled and poured into water (1000 mL). Extraction was performed with dichloromethane (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered to obtain a filtrate. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then slurried with dichloromethane and methanol to obtain Intermediate 19d. 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),7.51(d,J=1.9Hz,1H),7.46(d,J=8.5Hz,1H),7.36(d,J=3.1Hz,1H) ,7.24(s,1H),7.14(dd,J=8.4,1.7Hz,1H),6.92(s,1H),6.45(d,J=3.1Hz,1H),3.81(s,3H),3.52(s,2H).

[0419] Step 3: Under nitrogen protection, add intermediate 19d (7 g, 23.59 mmol), di-tert-butyl dicarbonate (7.72 g, 35.38 mmol), sodium carbonate (6.25 g, 58.97 mmol), and tetrahydrofuran (140 mL) to a 250 mL single-necked flask. Heat to 70°C for 8 hours until the reaction is complete. After the reaction is completed, cool the reaction mixture and pour it into water (800 mL). Extract with dichloromethane (80 mL x 3). The organic phase is dried over anhydrous sodium sulfate and filtered to obtain a filtrate. The filtrate is concentrated under reduced pressure to obtain a crude product, which is then purified by silica gel column chromatography to obtain intermediate 19e. LC-MS: m / z: 397.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.84(s,1H),7.55(d,J=1.7Hz,1H),7.50(d,J=8.4Hz,1H ),7.41-7.32(m,2H),7.17(m,1H),6.47(m,1H),3.87-3.71(m,5H),1.58(s,9H).

[0420] Step 4: Under nitrogen, add intermediate 19e (1 g, 2.52 mmol) and N,N-dimethylformamide (15 mL) to a 50 mL three-necked flask. After cooling to 0°C, sodium hydride (0.3 g, 7.56 mmol) was added in batches. The reaction solution was heated to 25°C and stirred for 0.5 h. After cooling to 0°C, a solution of intermediate 19a (0.62 g, 5.04 mmol) in tetrahydrofuran (5 mL) was slowly added dropwise. The reaction solution was heated to 25°C and stirred for 15 h until the reaction was complete. The reaction solution was poured into an ice-cold saturated ammonium chloride solution (100 mL) and extracted with dichloromethane (80 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and then concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography to obtain intermediate 19f. LC-MS: m / z: 420.2 (M-100+H) + .

[0421] Step 5: To an 8 mL flat-bottomed reaction flask, intermediate 19f (40 mg, 0.08 mmol), tetrahydrofuran (0.5 mL), and methanol (0.1 mL) were added, followed by the slow addition of a solution of lithium hydroxide monohydrate (12.91 mg, 0.31 mmol) and water (0.2 mL). The reaction mixture was heated to 50°C for 5 hours until complete. After the reaction, the temperature was lowered and the pH was adjusted to approximately 7 with 0.5 M hydrochloric acid. The crude product was purified by HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm) to yield compound 19. LC-MS: m / z: 420.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.70 (s, 1H), 8.82 (t, J = 5.7Hz, 1H), 7.55 (d, J = 1.9 Hz,1H),7.49(dd,J=5.1,3.3Hz,2H),7.37(d,J=3.1Hz,1H),7.20(s,1H),7.1 3(dd,J=8.5,1.6Hz,1H),6.96(s,1H),6.47(d,J=3.1Hz,1H),6.39(t,J=2.6 Hz,1H),6.27(d,J=3.2Hz,1H),4.49(s,1H),4.42-4.25(m,2H),3.82(s,3H).

[0422] Example 20: Synthesis of Compound 20

[0423] Step 1: Under nitrogen, to a 50 mL three-necked flask, add Intermediate 19e (500 mg, 1.26 mmol) and N,N-dimethylformamide (15 mL). After cooling to 0°C, sodium hydride (75.59 mg, 1.89 mmol) was added portionwise. The reaction solution was warmed to 25°C and stirred for 0.5 h. After cooling to 0°C, a solution of 20a (244.01 mg, 1.89 mmol) and tetrahydrofuran (0.5 mL) was slowly added dropwise. The reaction solution was warmed to 25°C and stirred for 15 h, after which the reaction was complete. The reaction solution was poured into ice-cold saturated ammonium chloride solution (50 mL) and extracted with dichloromethane (15 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography to afford Intermediate 20b. 1H NMR (400MHz, DMSO-d6) δ8.58(s,1H),7.77(s,1H),7.67(d,J=6.4Hz,1H),7.52(s,1H),7.45(t,J=6.9Hz,1H),7.38-7.30(m,1 H),7.18(d,J=8.5Hz,1H),6.45(s,1H),4.21-3.88(m,4H),3.82(s,3H),1.59(d,J=9.9Hz,9H),1.19(dt,J=14.1,7.3Hz,3H).

[0424] Step 2: To an 8 mL flat-bottomed reaction flask, intermediate 20b (50 mg, 0.1 mmol), tetrahydrofuran (0.5 mL), and methanol (0.1 mL) were added, followed by the slow addition of a solution of lithium hydroxide monohydrate (16.78 mg, 0.4 mmol) and water (0.2 mL). The reaction mixture was heated to 50°C for 15 hours, leading to completion. After completion, the reaction mixture was cooled and adjusted to pH 7 with 0.5 M hydrochloric acid. The crude product was purified by HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm) to yield compound 20. LC-MS: m / z: 398.2 (M+H)+. 1 H NMR (400MHz, DMSO-d6) δ13.19(s,1H),9.47(s,1H),8.65(s,1H),7.50(s,2H),7.42(d,J=8.6Hz,1H),7.3 2(d,J=3.0Hz,1H),7.18(d,J=8.5Hz,1H),6.75(s,1H),6.43(d,J=3.0Hz,1H),3.88(s,2H),3.81(s,3H).

[0425] Example 21: Synthesis of Compound 21

[0426] Step 1: To a 500 mL single-necked flask were added Intermediate 19b (5 g, 20.28 mmol), di-tert-butyl dicarbonate (11.07 g, 50.70 mmol), sodium bicarbonate (5.96 g, 70.98 mmol), and tetrahydrofuran (200 mL) at room temperature. The reaction was complete after 5 hours at 100°C. Water (500 mL) was then added and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was concentrated under reduced pressure to obtain the crude product, which was then slurried with petroleum ether / dichloromethane (V:V = 10:1) to afford Intermediate 21a. LC-MS: m / z: 368.0 (M+Na). + . 1H NMR (400MHz, DMSO-d6) δ7.87 (s, 1H), 7.72 (d, J = 1.2 Hz, 1H), 3.74 (d, J = 1.2 Hz, 2H), 1.56 (s, 9H).

[0427] Step 2: To a 50 mL reaction flask at room temperature, intermediate 21a (1000 mg, 2.89 mmol), chloroform (10 mL), and N,N-dimethylformamide dimethyl acetal (413 mg, 3.46 mmol) were added sequentially. The atmosphere was purged with nitrogen three times and stirred at 70°C for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain intermediate 21b. LC-MS: m / z: 345.0 (M+H-56). + . 1 H NMR (400MHz, DMSO-d6) δ7.91(s,1H),7.77(s,1H),7.76(s,1H),3.54(s,3H),3.32(s,3H),1.55(s,9H).

[0428] Step 3: To a 25 mL reaction flask at room temperature, intermediate 21b (630 mg, 1.57 mmol), ethanol (10 mL), and 14b (183 mg, 1.88 mmol) were added sequentially. The atmosphere was replaced with nitrogen three times and stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered, and the resulting filter cake was purified by petroleum ether / ethyl acetate slurry to obtain intermediate 21c. LC-MS: m / z: 397.0 (M+H-56). + . 1 H NMR (400MHz, DMSO-d6) δ9.53-9.31(m,1H),8.33(d,J=13.9Hz,1H),7.92-7.77(m ,2H),7.75-7.60(m,1H),6.50-6.33(m,2H),4.58(d,J=6.0Hz,2H),1.56(s,9H).

[0429] Step 4: To a 10 mL microwave tube at room temperature, intermediate 21c (150 mg, 0.33 mmol), 14d (109 mg, 0.40 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (27 mg, 0.03 mmol), potassium carbonate (137 mg, 0.99 mmol), dioxane (3 mL), and water (0.60 mL) were added. The mixture was microwaved at 100°C for two hours under nitrogen protection. After the reaction, the reaction mixture was filtered and the filtrate was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2OB:ACN, column: Waters-Xbridge-C18 -10μm-19*250mm) to separate and purify the intermediate 21d. LC-MS: m / z: 465.1 (M+H-56) + . 1 H NMR(400MHz,DMSO-d6)δ9.40-8.55(m,1H),8.30-7.77(m,2H),7.66-7.47(m,2H),7.42-7.27(m,4H),6.47-6.41(m,1H),6.41- 6.36(m,1H),4.75-4.67(m,1H),4.62-4.50(m,2H),3.58(d,J=5.2Hz,2H),1.58(s,9H),0.91-0.81(m,2H),0.81-0.73(m,2H).

[0430] Step 5: To a 10 mL reaction flask, intermediate 21d (150 mg, 0.29 mmol), methanol (3 mL), and methanolic hydrogen chloride (1 mL, 4 M) were added at room temperature and stirred for 16 hours. After completion of the reaction, the reaction solution was filtered and the filtrate was purified by HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm) to obtain compound 21. LC-MS: m / z: 421.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.36(s,1H),9.02-8.93(m,1H),8.06(d,J=13.3Hz,1H),7.65(d,J=12.8Hz,1H),7.38-7.28(m,4H),6. 86(d,J=14.7Hz,1H),6.47-6.34(m,2H),4.69(q,J=5.4Hz,1H),4.52(t,J=5.4Hz,2H),3.57(t,J=5.0Hz,2H),0.92-0.70(m,4H).

[0431] Example 22: Synthesis of Compound 22

[0432] Step 1: Under nitrogen, to an 8 mL flat-bottom flask were added intermediate 19f (80 mg, 0.15 mmol), potassium carbonate (63.79 mg, 0.46 mmol), iodomethane (43.68 mg, 0.31 mmol), and N,N-dimethylformamide (2 mL). The reaction was heated to 50°C and completed after 4 hours. After the reaction, water (20 mL) was added and the mixture was extracted with dichloromethane (2 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield intermediate 22a. LC-MS: m / z: 434.2 (M-100+H). + .

[0433] Step 2: To an 8 mL flat-bottomed reaction flask, intermediate 22a (70 mg, 0.13 mmol), trifluoroacetic acid (0.5 mL), and dichloromethane (5 mL) were added. The reaction was complete after 4 hours at 25°C. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 mL) and dichloromethane (3 mL x 3) were added, and the liquids were extracted. The organic phase was dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and then concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7μm-4.6*30mm) to obtain compound 22. LC-MS: m / z: 434.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.75(s,1H),8.46(s,1H),8.16(t,J=5.8Hz,1H),7.51( d,J=9.9Hz,1H),7.49(d,J=7.8Hz,1H),7.37(d,J=3.1Hz,1H),7.33(s,1H),7.15 (dd,J=8.3,1.8Hz,1H),6.99(s,1H),6.47(d,J=3.0Hz,1H),6.37(dd,J=3.2,1.9 Hz,1H),6.12(d,J=3.2Hz,1H),4.25(d,J=5.8Hz,2H),3.82(s,3H),1.56(s,3H).

[0434] Example 23: Synthesis of Compound 23

[0435] Step 1: At room temperature, intermediate 14a (160 mg, 0.55 mmol) was added to a 50 mL single-necked flask and dissolved in dry dichloromethane (20.0 mL). After cooling to 0°C in an ice bath, intermediate 23a (45.41 mg, 0.55 mmol) and N,N-diisopropylethylamine (0.36 mL, 2.19 mmol) were added in sequence. The mixture was allowed to warm to room temperature naturally. The reaction was completed after 2 hours. After the reaction was completed, the reaction solution was concentrated and the crude product was purified by silica gel column chromatography to obtain intermediate 23b. LC-MS: m / z: 339.0 (M+H) + .

[0436] Step 2: At room temperature, intermediate 23b (60 mg, 0.18 mmol), intermediate 14d (50.89 mg, 0.27 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (25.86 mg, 0.04 mmol), potassium carbonate (48.84 mg, 0.35 mmol), dioxane (7.0 mL) and water (1.2 mL) were added to a 50 mL single-necked bottle. The mixture was purged and nitrogen atmosphere was protected at 90°C for 2 hours until the reaction was complete. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain a crude compound 23, which was then purified by high performance liquid chromatography (mobile phase: A: H2O B: ACN, column: Waters-SunFire-C 18 -10μm-19*250mm) to separate and purify to obtain compound 23. LC-MS: m / z: 407.20 (M+H) + , 1 H NMR(400MHz,DMSO-d6)δ12.30(s,1H),11.79(s,1H),10.39(s,1H),8.44(s,1H),8.19(s,1H),7.67–7.54(m,2H),7 .41–7.32(m,4H),6.62(s,1H),4.71(t,J=5.6Hz,1H),3.59(d,J=5.6Hz,2H),0.91–0.85(m,2H),0.83–0.76(m,2H).

[0437] Example 24: Synthesis of Compound 24

[0438] Step 1: To a 50 mL single-necked vial at room temperature, intermediate 13a (100 mg, 0.35 mmol) and N,N-dimethylformamide (0.02 mL, 0.29 mmol) were added and dissolved in ultra-dry dichloromethane (5 mL). Oxalyl chloride (0.07 mL, 0.86 mmol) was slowly added under an ice bath, and the mixture was allowed to warm to room temperature and allowed to react for 2 hours. After the reaction, the reaction solution was concentrated, and the residue was used directly in the next reaction. The residue was dissolved in ultra-dry dichloromethane (4.0 mL) at room temperature, and intermediate 24a (24.17 mg, 0.29 mmol) and triethylamine (0.08 mL, 0.58 mmol) were added sequentially under an ice bath. The reaction mixture was allowed to react at room temperature for 2 hours. After the reaction, the reaction solution was concentrated, and the crude product was purified by HPLC (mobile phase: A: 0.05% TFA / H2O B: ACN, column: Waters-SunFire-C 18 -10μm-19*250mm) separation and purification were finally carried out to obtain compound 24. LC-MS: m / z: 414.2 (M+H) + , 1 H NMR (400MHz, DMSO-d6) δ12.04(s,1H),11.13(s,1H),8.43(d,J=3.0Hz,1H),8.19(s,1H) ,7.92(s,1H),7.81–7.69(m,5H),7.60–7.46(m,4H),7.39(t,J=7.4Hz,1H),7.15(s,1H).

[0439] Example 25: Synthesis of Compound 25

[0440] Step 1: At room temperature, intermediate 14a (160 mg, 0.55 mmol) was added to a 50 mL single-necked flask and dissolved in ultra-dry tetrahydrofuran (20.0 mL). After cooling to 0°C in an ice bath, intermediate 25a (139.02 mg, 1.09 mmol) and N,N-diisopropylethylamine (0.36 mL, 2.19 mmol) were added sequentially. The mixture was allowed to warm to room temperature naturally. The reaction was complete after 2 hours. After the reaction was completed, the reaction solution was concentrated and the crude product was purified by silica gel column separation to obtain intermediate 25b. LC-MS: m / z: 383.00 (M+H) + .

[0441] Step 2: At room temperature, intermediate 25b (100 mg, 0.26 mmol), intermediate 14d (75.07 mg, 0.39 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (38.14 mg, 0.05 mmol), potassium carbonate (72.04 mg, 0.52 mmol), dioxane (7.0 mL), and water (1.2 mL) were added to a 50 mL single-necked bottle. The mixture was purged and nitrogen was protected at 90°C for 2 hours to complete the reaction. After the reaction was completed, the reaction solution was concentrated and the crude product was separated and purified by silica gel column chromatography to obtain a crude compound 25, which was then purified by high performance liquid chromatography (mobile phase: A: H2O B: ACN, column: Waters-SunFire-C 18 -10μm-19*250mm) separation and purification were finally carried out to obtain compound 25. LC-MS: m / z: 451.20 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.75(d,J=2.0Hz,1H),7.85(d,J=2.4Hz,1H),7.80( s,1H),7.60(s,1H),7.43(dd,J=5.1,1.1Hz,1H),7.39–7.35(m,2H),7.35–7. 30(m,2H),7.07(d,J=2.9Hz,1H),6.98(dd,J=4.8,1.2Hz,1H),4.83(s,2H),4 .60(s,1H),3.59(s,2H),3.10(s,3H),0.91–0.84(m,2H),0.84–0.76(m,2H).

[0442] Example 26: Synthesis of Compound 26

[0443] Step 1: At room temperature, intermediate 14a (160 mg, 0.55 mmol) was added to a 50 mL single-necked flask and dissolved in ultra-dry tetrahydrofuran (20.0 mL). After cooling to 0°C in an ice bath, intermediate 26a (59.95 mg, 0.61 mmol), N,N-diisopropylethylamine (0.46 mL, 2.75 mmol), and 4-dimethylaminopyridine (13.44 mg, 0.11 mmol) were added in sequence. The mixture was allowed to warm to room temperature naturally. The reaction was completed after 2 hours. After the reaction was completed, the reaction solution was concentrated, and the crude product was separated and purified by silica gel column chromatography to obtain intermediate 26b. LC-MS: m / z: 355.00 (M+H) + .

[0444] Step 2: At room temperature, intermediate 26b (67 mg, 0.19 mmol), intermediate 14d (54.27 mg, 0.28 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (27.58 mg, 0.04 mmol), potassium carbonate (52.08 mg, 0.38 mmol), dioxane (8.0 mL), water (1.6 mL) were added to a 50 mL single-necked bottle. The mixture was purged and nitrogen was protected at 90°C for 2 hours until the reaction was complete. After the reaction was completed, the reaction solution was concentrated and the crude product was separated and purified by silica gel column chromatography to obtain crude compound 26, which was then purified by high performance liquid chromatography (mobile phase: A: H2O B: ACN, chromatographic column: Waters-SunFire-C 18 -10μm-19*250mm) separation and purification were finally carried out to obtain compound 26. LC-MS: m / z: 423.20 (M+H) + , 1 H NMR (400MHz, DMSO-d6) δ12.18(d,J=2.7Hz,1H),8.23(d,J=3.0Hz,1H),8.13(s,1H),7.92(s,1H),7.66(s,1H),7. 41–7.36(m,2H),7.35–7.31(m,2H),7.24(s,1H),5.40(s,2H),3.59(s,2H),0.90–0.85(m,2H),0.83–0.77(m,2H).

[0445] Example 27: Synthesis of Compound 27

[0446] Step 1: At room temperature, intermediate 23a (5 g, 60.18 mmol) was added to a 250 mL single-necked flask and dissolved in ultra-dry tetrahydrofuran (100.0 mL). After cooling to 0°C in an ice bath, di-tert-butyl dicarbonate (28.33 mL, 132.40 mmol) and 4-dimethylaminopyridine (2.21 g, 18.05 mmol) were added sequentially. The mixture was naturally warmed to room temperature and allowed to react for 3 hours until the reaction was complete. After the reaction was completed, the reaction solution was poured into water (500 mL), extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography to obtain intermediate 27a. LC-MS: m / z: 306.2 (M+Na) + .

[0447] Step 2: To a 50 mL single-necked flask at 0°C, add ultra-dry N,N-dimethylformamide (10.0 mL), intermediate 27a (1 g, 3.53 mmol), and sodium hydride (0.14 g, 3.53 mmol, 60%). Iodomethane (0.22 mL, 3.53 mmol) was then added and the mixture was allowed to warm to room temperature. The reaction was complete after 1 hour. After the reaction, the reaction solution was poured into 100 mL of water and extracted with ethyl acetate (5 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was then purified by silica gel column chromatography to obtain intermediate 27b. LC-MS: m / z: 320.2 (M+Na) + . 1 H NMR (400MHz, DMSO-d6) δ8.14(d,J=2.9Hz,1H),6.69(s,1H),3.27(s,3H),1.56(s,9H),1.49(s,9H).

[0448] Step 3: To a 50 mL single-necked flask at room temperature, add Intermediate 27b (800 mg, 2.69 mmol), dissolve in ultra-dry dichloromethane (7.0 mL), and then add trifluoroacetic acid (2 mL). The reaction is allowed to proceed for 1 hour until complete. After completion of the reaction, the reaction solution is concentrated to obtain the crude product, which is then purified by silica gel column chromatography to obtain Intermediate 27c. 1 H NMR (400MHz, DMSO-d6) δ7.82(d,J=2.7Hz,1H),5.77(d,J=2.7Hz,1H),2.77(s,3H).

[0449] Step 4: At room temperature, intermediate 14a (340 mg, 1.16 mmol) was added to a 25 mL single-necked flask and dissolved in tetrahydrofuran (20.0 mL). After cooling to 0°C in an ice bath, 27c (169.08 mg, 1.74 mmol), N,N-diisopropylethylamine (0.96 mL, 5.80 mmol), and 4-dimethylaminopyridine (14.18 mg, 0.12 mmol) were added in sequence. The mixture was allowed to warm to room temperature naturally. The reaction was completed after 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain intermediate 27d. LC-MS: m / z: 353.0 (M+H) + .

[0450] Step 5: At room temperature, intermediate 27d (100 mg, 0.28 mmol), intermediate 14d (80.65 mg, 0.42 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (40.98 mg, 0.06 mmol), potassium carbonate (78.17 mg, 0.57 mmol), dioxane (8.0 mL), and water (1.6 mL) were added to a 25 mL single-necked bottle. The mixture was purged and nitrogen atmosphere was protected at 90°C for 2 hours to complete the reaction. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was purified by high performance liquid chromatography (mobile phase: A: 0.05% TFA / H2O B: ACN, column: Waters-SunFire-C 18 -10μm-19*250mm) separation and purification were finally carried out to obtain compound 27. LC-MS: m / z: 421.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.50(s,1H),7.90(s,1H),7.72(d,J=1.9Hz,1H),7.52(s,1H),7.39–7.28(m,4H) ,6.72(s,1H),6.13(d,J=2.2Hz,1H),3.59(s,2H),3.30(s,3H),0.87(d,J=4.1Hz,2H),0.82–0.78(m,2H).

[0451] Example 28: Synthesis of Compound 28

[0452] Step 1: To a 100 mL single-necked flask at 0°C, add intermediate 28a (1 g, 6.89 mmol), p-toluenesulfonyl chloride (1.445 g, 7.58 mmol), and dichloromethane (25 mL). Triethylamine (1.39 g, 13.78 mmol) was added under stirring. The reaction was complete after 16 hours at room temperature. The reaction solution was poured into ice water (200 mL) and extracted with dichloromethane (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 28b. LC-MS: m / z: 300.0 (M+H). + . 1H NMR (400MHz, DMSO-d6) δ7.51-7.44(m,2H),7.11(d,J=7.9Hz,2H),4.28-4.23(m,2H),3.77(d,J=4.7Hz,2H),3.67(t,J=6.5 Hz,1H),3.58(s,1H),3.51(d,J=5.0Hz,2H),3.09(q,J=7.8Hz,2H),2.47-2.37(m,2H),2.29(s,3H),1.18(d,J=7.3Hz,2H).

[0453] Step 2: At room temperature, intermediate 28b (161.67 mg, 0.54 mmol), intermediate 28c (100 mg, 0.45 mmol), potassium carbonate (186.57 mg, 1.35 mmol) and N,N-dimethylformamide (3 mL) were added to a 50 mL single-necked bottle. The reaction was heated to 70°C for five hours until the reaction was complete. The reaction solution was poured into water (30 mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with saturated sodium chloride aqueous solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography to obtain intermediate 28d. LC-MS: m / z: 348.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.63-7.55(m,2H),6.95-6.88(m,2H),4.03(t,J=6.4H z,2H),3.58-3.55(m,4H),2.41-2.32(m,6H),1.90-1.85(m,2H),1.27(s,12H).

[0454] Step 3: Under nitrogen protection, intermediate 28d (111 mg, 0.32 mmol), intermediate 2g (100 mg, 0.32 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (26.10 mg, 0.03 mmol), potassium carbonate (110.44 mg, 0.80 mmol), dioxane (3 mL) and water (0.75 mL) were added to an 8 mL microwave tube. The reaction was completed after two hours of microwave reaction at 100°C. The reaction solution was then filtered and the filtrate was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) to separate and purify to obtain compound 28. LC-MS: m / z: 442.9 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ12.29(s,1H),8.42(d,J=2.9Hz,1H),8.09(s,1H),7.68(s,1H),7.35(d,J=8.6Hz,2H), 7.05-6.98(m,2H),4.08(t,J=6.2Hz,2H),3.64(t,J=4.6Hz,4H),2.61(d,J=20.9Hz,6H),1.98(q,J=6.8Hz,2H).

[0455] Example 29: Synthesis of Compound 29

[0456] Step 1: To a 100 mL three-necked flask at 25°C was added intermediate 29a (1 g, 3.62 mmol), paraformaldehyde (1.47 g, 18.08 mmol), tetrahydrofuran (10 mL), and methanol (10 mL). Sodium triacetoxyborohydride (1.53 g, 7.23 mmol) was then added in three batches. The reaction was complete after 15 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to yield intermediate 29b. LC-MS: m / z: 254.0 (M+H). + .

[0457] Step 2: Under nitrogen, to a 15 mL single-necked vial was added Intermediate 29b (400 mg, 1.57 mmol), pinacol diboron (479.6 mg, 1.89 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (115.15 mg, 0.16 mmol), potassium acetate (308.9 mg, 3.15 mmol), and dioxane (4 mL). The reaction was heated to 90°C for 15 hours, after which the reaction was complete. After completion of the reaction, the temperature was cooled, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography to afford Intermediate 29c. 1 H NMR (400MHz, CDCl3) δ7.75(d,J=8.1Hz,2H),7.24(d,J=8.0Hz,2H),3.04(d,J=11.2Hz,2H),2.51(t d,J=10.9,5.0Hz,1H),2.37(s,3H),2.13(td,J=11.2,3.8Hz,2H),1.93–1.76(m,4H),1.33(s,12H).

[0458] Step 3: Under nitrogen, an 8 mL microwave tube was charged with intermediate 29c (95.17 mg, 0.32 mmol), intermediate 2g (100 mg, 0.32 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (23.12 mg, 0.03 mmol), potassium carbonate (109.15 mg, 0.79 mmol), N,N-dimethylformamide (4 mL), and water (0.4 mL). The reaction was heated to 100°C for 4 hours until completion. After completion, the reaction was cooled, filtered, and the filtrate was directly purified by HPLC (mobile phase: A: 0.1% FA / H2OB:ACN, column: Waters-CORTECS-C18-2.7μm-4.6*30mm) to obtain compound 29. LC-MS: m / z: 397.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.89(s,1H),8.22(s,2H),8.11(s,1H),7.62(s,1H),7.34(d,J=4 .2Hz,4H),2.94(d,J=11.0Hz,2H),2.26(s,3H),2.08(t,J=11.4Hz,2H),1.86-1.69(m,4H).

[0459] Example 30: Synthesis of Compound 30

[0460] Step 1: Under nitrogen protection, intermediate 14a (533.59 mg, 1.82 mmol), 5 mL of tetrahydrofuran, triethylamine (1.01 mL, 7.29 mmol), and intermediate 30a (309.91 mg, 3.64 mmol) were added to a 100 mL three-necked flask. After reacting at room temperature for 15 hours, the reaction solution was poured into water (100 mL). Extraction was performed with 100 mL x 3 of dichloromethane:methanol (V:V = 10:1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was purified by high-performance liquid chromatography (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) to separate and purify to obtain compound 30b. LC-MS: m / z: 340.8 (M+H) + .

[0461] Step 2: Under nitrogen, to a 100 mL three-necked flask were added Intermediate 30b (117 mg, 0.34 mmol), potassium carbonate (118.35 mg, 0.86 mmol), dioxane (2 mL), water (0.4 mL), N,N-dimethylformamide (1 mL), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (25 mg, 0.03 mmol), and Intermediate 6g (122.09 mg, 0.45 mmol). The reaction was carried out at 100°C for 5 hours. The reaction solution was added to water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was spin-dried to dryness to obtain a crude product, which was then separated and purified by HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm) to obtain compound 30. LC-MS: m / z: 409.0 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ15.81(s,1H),12.08(s,1H),11.88(s,1H),8.58(s,1H),8.20(s,1H),7 .69(s,1H),7.40-7.35(m,4H),4.72(t,J=4.0Hz,1H),3.55(d,J=8.0Hz,2H),0.90-0.79(m,4H).

[0462] Example 31: Synthesis of Compound 31

[0463] Step 1: Under nitrogen protection, add intermediate 21a (1.6 g, 4.62 mmol) and N,N-dimethylformamide (25 mL) to a 250 mL three-necked flask, cool to 0°C, add sodium hydroxide (0.28 g, 6.92 mmol) with stirring, stir for 30 minutes, and then add intermediate 19a (1.14 g, 9.23 mmol). Then warm to room temperature and react for 16 hours until the reaction is complete. Pour the reaction solution into ice water (30 ml) and extract three times with ethyl acetate (300 ml). The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The solid is then filtered, and the filtrate is concentrated under reduced pressure to obtain a crude product. The crude product is separated and purified by silica gel column chromatography (dichloromethane / methanol system) to obtain intermediate 31a. LC-MS: m / z: 413.0 (M-55) + .

[0464] Step 2: To a 50 mL single-necked flask at room temperature, add intermediate 31a (620 mg, 1.32 mmol) and dichloromethane (4 mL). Add trifluoroacetic acid (2 mL) under stirring. After stirring at room temperature for 2 hours, the reaction is complete. The reaction solution is concentrated under reduced pressure to obtain crude intermediate 31b, which is used directly in the next step. LC-MS: m / z: 369.0 (M+1) + .

[0465] Step 3: Under nitrogen, to a 5 mL microwave tube were added intermediate 31b (100 mg, 0.27 mmol), 6 g (74.18 mg, 0.27 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (22.1 mg, 0.03 mmol), potassium carbonate (93.48 mg, 0.68 mmol), dioxane (3 mL), and water (0.75 mL). The reaction was complete after 2 hours at 100°C. The solid was then filtered, and the filtrate was purified by HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm) to obtain compound 31. LC-MS: m / z: 437.2 (M+1). + . 1 H-NMR (400MHz, DMSO-d6) δ10.72(s,1H),8.81(t,J=5.6Hz,1H),7.56(d,J=1.8 Hz,1H),7.36(d,J=8.3Hz,2H),7.26(d,J=8.2Hz,2H),7.16(s,1H),6.96(s,1H) ,6.40(dd,J=3.2,1.9Hz,1H),6.27(d,J=3.2Hz,1H),4.48(d,J=7.3Hz,1H),4. 32(d,J=5.6Hz,2H),3.57(s,2H),0.86(t,J=2.8Hz,2H),0.78(q,J=4.0Hz,2H).

[0466] Example 32: Synthesis of Compound 32

[0467] Step 1: Under nitrogen, to a 100 mL three-necked flask at 0°C was added intermediate 16a (100 mg, 1.02 mmol), toluene (5 mL), triethylamine (0.30 mL, 2.14 mmol), and triphosgene (151 mg, 0.51 mmol). After 1 hour of reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford crude product 32a, which was used directly in the next reaction.

[0468] Step 2: To a 100 mL three-necked flask at 0°C, add Intermediate 32a (200 mg, 0.50 mmol), N,N-dimethylformamide (4 mL), and sodium bicarbonate (200.00 mg, 5.00 mmol, 60%). Stir at 0°C for 0.5 hours, then slowly add Intermediate 19e (125.08 mg, 1.01 mmol) to the reaction mixture. After 1 hour of reaction, pour the reaction mixture into water (100 mL). Extract with dichloromethane (100 mL x 3), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography to obtain Intermediate 32b. LC-MS: m / z: 421.2 (M-100). + .

[0469] Step 3: Under nitrogen, methanol (0.5 mL), tetrahydrofuran (0.5 mL), intermediate 32b (50 mg, 0.10 mmol), and lithium hydroxide (17 mg, 0.38 mmol) were added to a 100 mL three-necked flask. After reacting at 40°C for 1 hour, the reaction mixture was adjusted to pH 6 with dilute hydrochloric acid and purified by HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7μm-4.6*30mm) to obtain compound 32. LC-MS: m / z: 421.2 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ10.71(s,1H),9.02(s,1H),8.02-8.00(m,1H),7.51-7.49(m,2H),7.43-7.37(m,1 H),7.32-7.29(m,1H),7.19-7.11(m,2H),6.96(s,1H),6.47-6.43(m,1H),4.54-4.43(m,3H),3.82(s,3H).

[0470] Example 33: Synthesis of Compound 33

[0471] Step 1: Under nitrogen, a 100 mL three-necked flask was charged with dioxane (4 mL), water (0.8 mL), intermediate 23b (70 mg, 0.21 mmol), potassium carbonate (71 mg, 0.52 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (15 mg, 0.02 mmol), and intermediate 1d (67.82 mg, 0.25 mmol). After reacting at 100°C for 2 hours, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7μm-4.6*30mm) to obtain compound 33. LC-MS: m / z: 407.0 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ12.30(s,1H),11.82(s,1H),10.41(s,1H),8.45(s,1H),8.21(s,1H),7.62-7.55(m,4H),7.43 -7.40(m,2H),6.61(s,1H),5.53(s,1H),2.46-2.42(m,2H),2.34-2.31(m,2H),2.29-1.93(m,1H),1.71-1.68(m,1H).

[0472] Example 34: Synthesis of Compound 34

[0473] Step 1: Under nitrogen, a 100 mL three-necked flask was charged with dioxane (4 mL), water (0.8 mL), intermediate 23b (70 mg, 0.21 mmol), potassium carbonate (71 mg, 0.52 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (15 mg, 0.02 mmol), and intermediate 4a (73.26 mg, 0.25 mmol). After reacting at 100°C for 2 hours, the reaction solution was added to water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was separated and purified by HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7μm-4.6*30mm) to obtain compound 34. LC-MS: m / z: 429.0 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ12.30(s,1H),11.82(d,J=4.0Hz,1H),9.59(s,1H),8.47(d,J =4.0Hz,1H),8.26(s,1H),7.66-7.60(m,4H),7.49-7.46(m,2H),7.35-7.33(m,1H),7. 20-7.16(m,1H),6.99-6.91(m,1H),6.90-6.89(m,1H),6.61(s,1H),1.71-1.68(m,1H).

[0474] Example 35: Synthesis of Compound 35

[0475] Step 1: To a 100 mL three-necked flask were added Intermediate 9c (100 mg, 0.36 mmol), Intermediate 35a (53.51 mg, 0.54 mmol), N,N-dimethylformamide (3 mL), triethylamine (147 mg, 1.46 mmol), and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (173 mg, 0.46 mmol). After reacting at 25°C for 4 hours, the reaction solution was purified by HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7μm-4.6*30mm) to obtain Intermediate 35b. LC-MS: m / z: 355.0 (M+H). + .

[0476] Step 2: Under nitrogen, dioxane (2 mL), water (0.4 mL), intermediate 35b (50 mg, 0.14 mmol), potassium carbonate (49 mg, 0.35 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (11 mg, 0.01 mmol), and intermediate 6g (50.12 mg, 0.18 mmol) were added to a 100 mL three-necked flask. After reacting at 100°C for 2 hours, the reaction solution was added to water (100 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC (mobile phase: A: 10 mM NH4HCO3 / H2O B: ACN, column: Waters-Xbridge-C 18 -10μm-19*250mm) to separate and purify to obtain compound 35. LC-MS: m / z: 421.0 (MH) - . 1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),8.48(s,1H),8.15(s,1H),8.12(s,1H),7.60(s ,1H),7.38-7.32(m,4H),4.73-4.65(m,3H),3.58(d,J=5.2Hz,2H),0.87-0.79(m,4H).

[0477] Example 36: Synthesis of Compound 36

[0478] Step 1: To a 100 mL three-necked flask were added dioxane (2 mL), water (0.4 mL), intermediate 14c (66 mg, 0.19 mmol), potassium carbonate (64.49 mg, 0.47 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (27.31 mg, 0.04 mmol), and intermediate 4a (66 mg, 0.22 mmol). The mixture was reacted at 100°C for 2 hours. The reaction solution was added to water (100 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7μm-4.6*30mm) to obtain compound 36. LC-MS: m / z: 443.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.72(s,1H),9.59(s,1H),8.47(t,J=4.0Hz,1H),8.19-8.14(m,2H),7.64-7.63(m,3H),7.62-7.57(m,1H),7. 47-7.45(m,2H),7.35-7.32(m,1H),7.20-7.16(m,1H),6.98-6.88(m,2H),6.40-6.38(m,1H),6.27-6.26(m,1H),4.45(d,J=4.0Hz,2H).

[0479] Example 37: Synthesis of Compound 37

[0480] Step 1: Under nitrogen at room temperature, a 5 mL microwave tube was charged with dioxane (6 mL), water (1.2 mL), intermediate 31b (250 mg, 0.68 mmol), intermediate 4a (220.36 mg, 0.74 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (55.37 mg, 0.07 mmol), and potassium carbonate (233.70 mg, 1.69 mmol). The reaction was complete after 16 hours at 100°C. The reaction solution was then filtered, and the filtrate was purified by HPLC (mobile phase: A: 0.1% FA / H2O B: ACN, column: Waters-CORTECS-C18-2.7μm-4.6*30mm) to obtain compound 37. LC-MS: m / z: 459.2 (M+1). + 1H NMR (400MHz, DMSO-d6) δ10.75(s,1H),9.58(d,J=9.1Hz,1H),8.83(t,J=5.7Hz,1H ),7.63(d,J=8.2Hz,2H),7.56(d,J=1.8Hz,1H),7.47-7.36(m,2H),7.32(dd,J=7. 7,1.7Hz,1H),7.25-7.14(m,2H),7.01-6.94(m,2H),6.90(t,J=7.4Hz,1H),6.41- 6.39(m,1H), 6.28(d,J=3.1Hz,1H), 4.50(d,J=11.5Hz,1H), 4.33(d,J=5.6Hz,1H).

[0481] Biological testing:

[0482] Test Example 1: In vitro test of AMPK (α1β1γ1) enzyme activating activity

[0483] The test compound was dissolved in DMSO to prepare a 10 mM stock solution. The stock solution was diluted to the desired assay concentration using kinase buffer (50 mM HEPES, 1 mM EDTA, 10 mM MgCl2, 0.01% Brij-35, pH = 7.5). 5 μL of AMPKα1β1γ1 (CARNA, 02-113), 2.5 μL of the diluted test compound solution, and 2.5 μL of a mixture of Ulight-CRBN and ATP were added to a 384-well plate to achieve the following final concentrations: AMPKα1β1γ1 at 1.6 mg / L, Ulight-CRBN at 5 nM, and ATP at 0.1 mM. Mix the components and incubate at room temperature for 1 hour. Then, add 5 μL of LANCE Detection Buffer (CR97-100, PerkinElmer) containing 40 mM EDTA. After incubation for 5 minutes, add 5 μL of 4× Eu-anti-phospho-CREB Antibody (TRF0200-M, PerkinElmer) and incubate at room temperature for 1 hour. Read the values ​​of each well using a microplate reader in TR-FRET mode (excitation wavelength: 320 nm, emission wavelengths: 665 nm and 615 nm). The relative activity of AMPKα1β1γ1 at each test compound concentration (4.57 nM, 13.72 nM, 41.15 nM, 123.46 nM, 370.37 nM, 1111.11 nM, 3333.33 nM, and 10000 nM) was calculated by comparing the values ​​with those of the blank control group (1% DMSO) and the positive control group (1 μM A769662). The activity of AMPKα1β1γ1 at each test compound concentration (4.57 nM, 13.72 nM, 41.15 nM, 123.46 nM, 370.37 nM, 1111.11 nM, 3333.33 nM, and 10000 nM) was calculated (the activity of 1 μM A769662 was set as 100%). The data were subjected to a dose-response-stimulation four-parameter regression analysis in GraphPad Prism 9 to obtain the Top value and EC value of the test compound. 50 The test results of some compounds are shown in Table 1.

[0484] Among them, the structure of A769662 is

[0485] Table 1

[0486] In Table 1: A indicates EC50 < 200 nM; B indicates 200 nM ≤ EC50 < 800 nM; C indicates 800 nM ≤ EC50; taking the AMPK (α1β1γ1) enzyme agonist activity value of 1 μM A769662 as 100%, ++++ indicates that the Top value of the AMPK (α1β1γ1) enzyme agonist activity of the test compound is ≥ 100%; +++ indicates that the Top value of the AMPK (α1β1γ1) enzyme agonist activity of the test compound is 70% ≤ < 100%; ++ indicates that the Top value of the AMPK (α1β1γ1) enzyme agonist activity of the test compound is 50% ≤ < 70%; + indicates that the Top value of the AMPK (α1β1γ1) enzyme agonist activity of the test compound is < 50%.

[0487] The test results show that the compounds of the present invention have good AMPK agonist activity, and some compounds show even better AMPK agonist activity.

[0488] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to preferred embodiments, ordinary technicians in the field should understand that the specific implementation methods of the present invention can still be modified or some technical features can be replaced by equivalents without departing from the spirit of the technical solutions of the present invention. They should all be included in the scope of the technical solutions claimed for protection by the present invention.

Claims

1. A compound represented by formula (I), or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, in, Selected from single bonds and double bonds, preferably, is a double bond; when When it is a single bond, X1 is selected from CH and N, and X2 is selected from CR X2a R X2b and C(=O); or X1 from CR X1 and N, X2 is selected from CR X2a R X2b and C(=O); or X1 is C, L1 is -CR L1b -, and X1 and L1 are connected by a double bond; when When it is a double bond, X1 is C and X2 is selected from CR X2a and N; X3 Selected from NR X3 , O and S; Y1 is selected from CR Y1 , N and N-oxides; Y2 is selected from CR Y2 and N; Y3 is selected from CR Y3 and N; L1 is selected from -C(=O)- and -CR L1a R L1b -; L2 is selected from a bond and -C(=O)-; L3 is selected from a bond, -O-, -NR L3 -、-S-、-C 1-6 Alkylene-O-, -C 1-6 Alkylene-NR L3 -、-C 1-6 Alkylene-S-, -C 1-6 Alkylene-, -C 2-6 Alkenylene- and -C 2-6 Alkynylidene-; R1 is selected from -OR 1a 、-NR 1b R 1c , tetrazolyl and oxadiazolyl R2 is selected from C 6-10 Aryl, C 3-10 Cycyl, 4-10 membered heterocyclyl and 5-10 membered heteroaryl, the C 6-10 Aryl, C 3-10 Cycyl, 4-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted by 1, 2, 3, 4, 5 independently selected from R 2a , R 2b , R 2c , R 2d and R 2e The group substitution; R x1 Selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl; R X2a and R X2b are independently selected from H, halogen, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -SC 1-6 Alkyl and -SC 1-6 haloalkyl; or R X2a and R X2b are independently selected from H, halogen, hydroxyl, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, -SC 1-6 Alkyl and -SC 1-6 Haloalkyl; R X3 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and C 3-6 Halogenated cycloalkyl; R Y1 Selected from H, D, halogen, hydroxyl, carboxyl, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl and 4-10 membered heterocycloalkyl; R Y2 and R Y3 are independently selected from H, D, halogen, -CN, hydroxyl, carboxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl and 4-10 membered heterocycloalkyl; or, R Y2 and R Y3 Together with the atoms to which they are attached, they form a phenyl group or a 5-6 membered heteroaryl group; R L1a and R L1b are independently selected from H, D, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy; or R L1a and R L1b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl; R L3 Selected from H, D and C 1-4 alkyl; R 1a , R 1b and R 1c are independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 Aryl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -C 1-6 Alkylene-4-10 membered heterocyclic group, -C 1-6 Alkylene-C 6-10 Aryl, -C 1-6 Alkylene-5-10 membered heteroaryl, -C 1-6 Halogenated alkylene-C 3-10 Cycloalkyl, -C 1-6 Haloalkylene-4-10 membered heterocyclic group, -C 1-6 Halogenated alkylene-C 6-10 Aryl and -C 1-6 haloalkylene-5-10 membered heteroaryl; or R 1a , R 1b and R 1c are independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 Aryl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -C 1-6 Alkylene-4-10 membered heterocyclic group, -C 1-6 Alkylene-C 6-10 Aryl, -C 1-6 Alkylene-5-10 membered heteroaryl, -C 1-6 Halogenated alkylene-C 3-10 Cycloalkyl, -C 1-6 Haloalkylene-4-10 membered heterocyclic group, -C 1-6 Halogenated alkylene-C 6-10 Aryl and -C 1-6 haloalkylene-5-10 membered heteroaryl; wherein C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 Aryl, -C 1-6 Alkylene-C 3-10 Cycloalkyl, -C 1-6 Alkylene-4-10 membered heterocyclic group, -C 1-6 Alkylene-C 6-10 Aryl, -C 1-6 Alkylene-5-10 membered heteroaryl, -C 1-6 Halogenated alkylene-C 3-10 Cycloalkyl, -C 1-6 Haloalkylene-4-10 membered heterocyclic group, -C 1-6 Halogenated alkylene-C 6-10 Aryl and -C 1-6 The haloalkylene-5-10 membered heteroaryl is optionally substituted with one or more selected from oxo, hydroxy, cyano, carboxyl, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl substituent substitution; R 2a , R 2b , R 2c , R 2d and R 2e are independently selected from H, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 Cyclic group, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 6-10 Arylene-4-10 membered heterocyclic group, -C 6-10 Arylene-5-10 membered heteroaryl, -C 6-10 Arylene-C 6-10 Aryl and -5-10 membered heteroarylene-5-10 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Haloalkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)-C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 Cyclic group, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 6-10 Arylene-4-10 membered heterocyclic group, -C 6-10 Arylene-5-10 membered heteroaryl, -C 6-10 Arylene-C 6-10 Aryl or -5-10 membered heteroarylene-5-10 membered heteroaryl is optionally substituted with one or more R; R is independently selected from halogen, -OH, -CN, -COOH, oxo, C 1-6 Alkyl, -C 1-6 Alkylene-OH, C 1-6 Alkoxy, -C 1-6 Alkyleneoxy-C 1-6 Alkoxy, -C(=O)NH-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -NHC(=O)-C 1-6 Alkyl, -N=S(=O)(C 1-6 Alkyl)-C 1-6 Alkyl, -NH-S(=O)2C 1-6 Alkyl, -S(=O)2-C 1-6 alkyl, -S(=O)2-4-10 membered heterocyclyl, -C(=O)-4-10 membered heterocyclyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, and The condition is that when L2 is a bond, 1) L1 is -CR L1a R L1b -,or 2) R1 is selected from -NR 1b R 1c , tetrazolyl and oxadiazolyl or 3) is a single key, or 4) R1 is selected from -OR 1a , where R 1a is selected from 5-10 membered heteroaryl, -C 1-6 Alkylene-5-10 membered heteroaryl, -C 1-6 Alkylene-4-10 membered heterocyclic group.

2. The compound according to claim 1, or its enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt, wherein: when When it is a single bond, X1 is selected from CR X1 and N, X2 is selected from CR X2a R X2b and C(=O), or X1 is C, L1 is -CR L1b -, and X1 and L1 are connected by a double bond; when When it is a double bond, X1 is C and X2 is selected from CR X2a and N; R x1 Selected from H, C 1-3 Alkyl, C 1-3 Haloalkyl; Preferably, R x1 Select from H or C 1-3 alkyl; Preferably, R x1 C 1-3 alkyl; Preferably, is a single bond, X1 is C, L1 is -CR L1b -, and X1 and L1 are connected by a double bond; Preferably, is a single bond, X1 is selected from CR X1 and N, X2 is selected from CR X2a R X2b and C(=O); Preferably, is a single bond, X1 is selected from N, X2 is selected from C(=O); or X1 is selected from CR X1 , X2 is selected from CR X2a R X2b ; or X1 is selected from CR X1 , X2 is selected from C(=O); Preferably, is a double bond, X1 is C, and X2 is selected from CR X2a and N; More preferably, is a double bond, X1 is C, and X2 is selected from CR X2a ; More preferably, is a double bond, X1 is C, and X2 is selected from CH or C(OH).

3. The compound according to claim 1 or 2, or its enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt, wherein: R X2a and R X2b are independently selected from H, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Haloalkyl, -NH-C 1-4 Alkyl, -N(C 1-4 Alkyl)-C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -SC 1-4 Alkyl and -SC 1-4 Haloalkyl; Preferably, R X2a and R X2b are independently selected from H, halogen, hydroxyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, -SC 1-4 alkyl; Preferably, R X2a and R X2b Each of the following groups is independently selected from H, halogen, hydroxy, methyl, ethyl, propyl, butyl, halomethyl, haloethyl, halopropyl, halobutyl, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(methyl)-methyl, -N(methyl)-ethyl, -N(methyl)-propyl, -N(ethyl)-ethyl, -N(ethyl)-propyl, methoxy, ethoxy, propoxy, butoxy, halomethoxy, haloethoxy, halopropoxy, halobutoxy, -S-methyl, -S-ethyl, -S-propyl, -S-butyl, -S-halomethyl, -S-haloethyl, -S-halopropyl and -S-halobutyl; More preferably, R X2a and R X2b Each of the following is independently selected from H, F, Cl, Br, hydroxyl, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CF3, -NHCH3, -N(CH3)2, -N(CH2CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, -OCF2CF3, -S-CH3, -S-CH2CH3, -S-CH2CH2CH3 and -S-CH(CH3)2; More preferably, R X2a Selected from H, F, Cl, hydroxyl, -OCH3, -OCF3 and -SCH3; More preferably, R X2b is H; More preferably, R X2a Selected from H, hydroxyl.

4. A compound according to any one of claims 1 to 3, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, wherein: R X3 Selected from H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-5 Cycloalkyl and C 3-5 Halogenated cycloalkyl; Preferably, R X3 Selected from H, C 1-4 Alkyl, C 1-4 Haloalkyl; Preferably, R X3 is selected from the group consisting of H, methyl, ethyl, propyl, halomethyl, haloethyl, halopropyl, cyclopropyl, cyclobutyl, cyclopentyl, halocyclopropyl, halocyclobutyl and halocyclopentyl; More preferably, R X3 is H; Preferably, X3 is selected from NR X3 ; Preferably, X3 is selected from O and S.

5. A compound according to any one of claims 1 to 4, or its enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt, wherein: R Y1 , R Y2 and R Y3 are independently selected from H, D, halogen, -CN, hydroxyl, carboxyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1- 4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl; or, R Y2 and R Y3 Together with the atoms to which they are attached, they form a phenyl group or a 5-6 membered heteroaryl group; Preferably, Y1 is selected from CR Y1 and N; more preferably, Y1 is selected from CR Y1 ; Preferably, Y2 is selected from CR Y2 and N; more preferably, Y2 is selected from CR Y2 ; Preferably, Y3 is selected from CR Y3 and N; more preferably, Y3 is selected from CR Y3 ; Preferably, R Y1 , R Y2 and R Y3 are independently selected from H, D, halogen, -CN, hydroxyl, carboxyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl; Preferably, R Y1 , R Y2 and R Y3 Each of the following is independently selected from H, D, halogen, -CN, methyl, ethyl, propyl, butyl, halomethyl, haloethyl, halopropyl, halobutyl, methoxy, ethoxy, propoxy, butoxy, halomethoxy, haloethoxy, halopropoxy, halobutoxy, vinyl, propenyl, butenyl, ethynyl, propynyl, butynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl and morpholinyl; More preferably, R Y1 , R Y2 and R Y3 Each of the following is independently selected from H, D, F, Cl, Br, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CF2CF3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl; Preferably, R Y1 Selected from H, D, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 More preferably, R Y1 is selected from H, D, halogen; Preferably, R Y2 Selected from H, D, halogen, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-4 Alkynyl, C 3-6 Cycloalkyl and 4-6 membered heterocycloalkyl; more preferably, R Y2 is selected from halogen; Preferably, R Y3 Selected from H, D, halogen, C 1-4 alkyl; More preferably, R Y1 is selected from H and F; more preferably, R Y1 Selected from H; More preferably, R Y2 Selected from F, Cl, -CN, -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCF3, ethynyl, cyclopropyl and More preferably, R Y2 Selected from Cl; More preferably, R Y3 For H.

6. A compound according to any one of claims 1 to 5, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, wherein: R Y2 and R Y3 Together with the atoms to which they are attached, they form a phenyl group or a 5-6 membered heteroaryl group; Preferably, R Y2 and R Y3 Together with the atoms to which they are attached, they form a phenyl group or a 5-membered heteroaryl group; More preferably, R Y2 and R Y3 Together with the atoms to which they are attached, they form thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and phenyl; More preferably, R Y2 and R Y3 Together with the atoms to which they are attached they form thienyl and phenyl; More preferably, R Y1 For H.

7. A compound according to any one of claims 1 to 6, or its enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt, wherein: Structural unit Selected from Preferably, the structural unit Selected from Preferably, the structural unit Selected from More preferably, the structural unit Selected from More preferably, the structural unit for 8. A compound according to any one of claims 1 to 7, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, wherein: R L1a and R L1b are independently selected from H, D, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy; or R L1a and R L1b Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl; Preferably, R L1a and R L1b are independently selected from H, D, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy; Preferably, R L1a and R L1b are independently selected from H, D, and halogen; Preferably, L1 is selected from -C(=O)-; Preferably, L1 is selected from -CR L1a R L1b -; More preferably, R L1a and R L1b Each of the following is independently selected from H, D, F, Cl, Br, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CF2CF3, -OCH3, -OCH2CH3, -OCH2CH2CH3 and -OCF3; More preferably, R L1a and R L1b are independently selected from H and F; More preferably, R L1a and R L1b Each is independently selected from H; More preferably, R L1a and R L1b together with the atoms to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group; More preferably, the R L1a and R L1b Together with the atoms to which they are attached they form a cyclopropyl or cyclobutyl group.

9. The compound according to any one of claims 1 to 8, or its enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt, wherein: L1 is selected from -C(=O)-, -CH2-, -CHF-, =CH- and -CF2-; Preferably, L1 is selected from -C(=O)-, -CH2-, =CH-; Preferably, L1 is -C(=O)-.

10. The compound according to any one of claims 1 to 9, or its enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt, wherein: L2 is a bond or L2 is -C(=O)-.

11. A compound according to any one of claims 1 to 10, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, wherein: R 1a , R 1b and R 1c are independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4-6 membered heterocyclic group, -C 1-4 Alkylene-phenyl, -C 1-4 Alkylene-5-6 membered heteroaryl, -C 1-4 Halogenated alkylene-C 3-6 Cycloalkyl, -C 1-4 Haloalkylene-4-6 membered heterocyclic group, -C 1-4 Halogenated alkylene-phenyl and -C 1-4 haloalkylene-5-6 membered heteroaryl; wherein C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4-6 membered heterocyclic group, -C 1-4 Alkylene-phenyl, -C 1-4 Alkylene-5-6 membered heteroaryl, -C 1-4 Halogenated alkylene-C 3-6 Cycloalkyl, -C 1-4 Haloalkylene-4-6 membered heterocyclic group, -C 1-4 Halogenated alkylene-phenyl and -C 1-4 The haloalkylene-5-6 membered heteroaryl is optionally substituted with one or more substituents selected from oxo, hydroxy, cyano, carboxyl, halogen; Preferably, R 1a Selected from H, C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, -C 1-3 Alkylene-4-6 membered heterocyclic group, -C 1-3 Alkylene-5-6 membered heteroaryl; Preferably, R 1a Selected from H, C 1-6 Alkyl (e.g. C 1-3 alkyl); More preferably, R 1a is selected from H, methyl, cyclopropyl, cyclobutyl, oxetanyl (e.g. ), oxacyclohexyl (e.g. ), pyrazolyl (e.g. ), oxazolyl (e.g. ), phenyl, -C 1-3 Alkylene-4-6 membered heterocyclic group (e.g. ),-C 1-3 Alkylene-5-membered heteroaryl (e.g. )； More preferably, R 1a is H or methyl; Preferably, R 1b Selected from H, C 1-3 Alkyl; R 1c Selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heteroaryl, phenyl, -C 1-3 Alkylene-4-6 membered heterocyclic group, -C 1-3 Alkylene-phenyl, -C 1-3 Alkylene-5-6 membered heteroaryl, wherein C 1-3 The alkyl group is optionally substituted with 1 or 2 substituents selected from oxo, hydroxyl, and carboxyl; More preferably, R 1c is selected from methyl, -CH2C(=O)OH, cyclopropyl, pyrrolyl (e.g. ), furanyl (e.g. ), thienyl (e.g. ), imidazole (e.g. ), pyrazolyl (e.g. ), oxazolyl (e.g. ), tetrazolyl (e.g. ), phenyl, -CH2-phenyl, -C 1-3 Alkylene-4-6 membered heterocyclic group (e.g. ),-C 1-3 Alkylene-5-6 membered heteroaryl (e.g. )； Preferably, R 1b Selected from H, C 1-3 Alkyl; R 1c Selected from C 1-3 Alkyl, 5-membered heteroaryl, -C 1-3 Alkylene-4-6 membered heterocyclic group, -C 1-3 Alkylene-5-6 membered heteroaryl, wherein C 1-3 The alkyl group is optionally substituted with a carboxyl group; Preferably, R 1b Selected from H, C 1-3 Alkyl; R 1c Selected from C 1-3 Alkyl, 5-membered heteroaryl, -C 1-3 Alkylene-5 1-membered heteroaryl, wherein C 1-3 The alkyl group is substituted with 1 carboxyl group; More preferably, R 1b Selected from H; R 1c Selected from -CH2C(=O)OH, pyrazolyl (e.g. ),-C 1-3 Alkylene-5-membered heteroaryl (e.g. )； Preferably, R 1a , R 1b and R 1c are independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, -C 1-4 Alkylene-4-6 membered heterocyclic group, -C 1-4 Alkylene-phenyl, -C 1-4 Alkylene-5-6 membered heteroaryl, -C 1-4 Halogenated alkylene-C 3-6 Cycloalkyl, -C 1-4 Haloalkylene-4-6 membered heterocyclic group, -C 1-4 Halogenated alkylene-phenyl and -C 1-4 haloalkylene-5-6 membered heteroaryl; or R 1a , R 1b and R 1c are independently selected from H, C 1-4 Alkyl, -(CR 1aa R 1bb ) m -C 3-6 Cycloalkyl, -(CR 1aa R 1bb ) m -4-6 membered heterocyclic group, -(CR 1aa R 1bb ) m -5-6 membered heteroaryl and -(CR 1aa R 1bb ) m -phenyl, wherein R 1aa and R 1bb are independently selected from H, F and -CH3, m is selected from 0, 1 and 2; Preferably, R 1a , R 1b and R 1c are independently selected from H, methyl, ethyl, propyl, butyl, -(CR 1aa R 1bb ) m -cyclopropyl, -(CR 1aa R 1bb ) m -cyclobutyl, -(CR 1aa R 1bb ) m -cyclopentyl, -(CR 1aa R 1bb ) m -cyclohexyl, -(CR 1aa R 1bb ) m -oxetane, -(CR 1aa R 1bb ) m -azetidinyl, -(CR 1aa R 1bb ) m -tetrahydrofuranyl, -(CR 1aa R 1bb ) m -pyrrolidinyl, -(CR 1aa R 1bb ) m -tetrahydropyranyl, -(CR 1aa R 1bb ) m -piperidinyl, -(CR 1aa R 1bb ) m -morpholinyl, -(CR 1aa R 1bb ) m -phenyl, -(CR 1aa R 1bb ) m -thienyl, -(CR 1aa R 1bb ) m -pyrazolyl, -(CR 1aa R 1bb ) m -imidazolyl, -(CR 1aa R 1bb ) m -tetrazolyl, -(CR 1aa R 1bb ) m -furanyl, -(CR 1aa R 1bb ) m -pyrrolyl, -(CR 1aa R 1bb ) m -thiazolyl, -(CR 1aa R 1bb ) m -oxazolyl, -(CR 1aa R 1bb ) m -isoxazolyl, -(CR 1aa R 1bb ) m -oxadiazole, -(CR 1aa R 1bb ) m -pyridyl, -(CR 1aa R 1bb ) m -pyrimidinyl and -(CR 1aa R 1bb ) m -pyrazinyl, wherein R 1aa and R 1bb are independently selected from H, F and -CH3, m is selected from 0, 1 and 2; More preferably, R 1a and R 1c Each of the following is independently selected from H, -CH3, cyclopropyl, cyclobutyl, oxetanyl, tetrahydropyranyl, phenyl, pyrazolyl, imidazolyl, oxazolyl, tetrazolyl, pyrrolyl, thienyl, furyl, -CH2-oxetanyl, -CH2-tetrahydropyranyl, -CH2-phenyl, -CH2-oxadiazolyl, -CH2-oxazolyl, -CH2-furanyl, -CH2-thienyl, -CH2-pyridyl, -CH2-isoxazolyl, -CH2-tetrazolyl; Preferably, R 1a R is selected from H, -CH3, cyclopropyl, cyclobutyl, oxetanyl, tetrahydropyranyl, pyrazolyl, phenyl, -CH2-oxetanyl, -CH2-oxadiazolyl, -CH2-oxazolyl; 1c is selected from methyl, cyclopropyl, phenyl, -CH2-phenyl, -CH2-tetrahydropyranyl, pyrazolyl, imidazolyl, oxazolyl, tetrazolyl, pyrrolyl, thienyl, furanyl, -CH2-oxazolyl, -CH2-furanyl, -CH2-thienyl, -CH2-pyridyl, -CH2-oxetanyl, -CH2-isoxazolyl, -CH2-tetrazolyl; Preferably, R 1a and R 1c Each is independently selected from H, methyl, pyrazolyl, -CH2-thienyl, -CH2-oxazolyl, -CH2-furanyl, -CH2-tetrazolyl; Preferably, R 1a is selected from H, methyl; R 1c is selected from pyrazolyl, -CH2-thienyl, -CH2-oxazolyl, -CH2-furanyl, -CH2-tetrazolyl; More preferably, R 1b For H.

12. A compound according to any one of claims 1 to 11, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, wherein: R1 is selected from -OH, -OCH3, -O-cyclopropyl, -O-cyclobutyl, -NHCH3, Preferably, R1 is selected from -OR 1a 、-NR 1b R 1c ; Further preferably, R1 is selected from -OH, -OCH3, -O-cyclopropyl, -O-cyclobutyl, <h2 style=";text-align:left;direction:ltr">-NHCH3、<h2 style=";text-align:left;direction:ltr"> Preferably, R1 is selected from -OH, -OCH3, -NHCH3, More preferably, R1 is selected from -OH, -OCH3, 13. A compound according to any one of claims 1 to 12, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, wherein: -L1-L2- is selected from -C(=O)C(=O)-, #X1-CR L1a R L1b -C(=O)-$R1、-C(=O)-、-CR L1a R L1b -、#X1=CR L1b -$R1; Preferably, -L1-L2- is selected from -C(=O)C(=O)-, #X1-CH2-C(=O)-$R1, #X1-CF2-C(=O)-$R1, -C(=O)-, -CHF-, -CH2-, #X1=CH-$R1; wherein #X1 is the connection point with X1, and $R1 is the connection point with R1; Preferably, -L1-L2- is selected from -C(=O)C(=O)-, #X1-CH2-C(=O)-$R1, -C(=O)-, #X1=CH-$R1; Further preferably, -L1-L2- is selected from -C(=O)-, -C(=O)C(=O)-; More preferably, -L1-L2- is -C(=O)-.

14. A compound according to any one of claims 1 to 13, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, wherein: -L1-L2-R1 is selected from -C(=O)-OR 1a 、-CR L1a R L1b -C(=O)-OR 1a 、-C(=O)-C(=O)-OR 1a 、-C(=O)-C(=O)-NR 1b R 1c 、 -C(=O)-NR 1b R 1c 、=CR L1b -NR 1b R 1c ; Preferably, -L1-L2-R1 is selected from -CR L1a R L1b -C(=O)-OR 1a , -C(=O)-C(=O)-OR 1a 、-C(=O)-C(=O)-NR 1b R 1c 、-C(=O)-NR 1b R 1c , =CR L1b -NR 1b R 1c ; Preferably, -L1-L2-R1 is selected from -C(=O)-C(=O)-OR 1a 、-C(=O)-NR 1b R 1c ; Preferably, -L1-L2-R1 is selected from -C(=O)-NR 1b R 1c ; Preferably, -L1-L2-R1 is selected from -COOH、-C(=O)-C(=O)-OH、-CH2-C(=O)-OH、-CF2-C(=O)-OH、-C(=O)-C(=O)-OCH3、-C(=O)-C(=O)-NHCH3、 Preferably, -L1-L2-R1 is selected from -CH2-C(=O)-OH, -C(=O)-C(=O)-OH, -C(=O)-C(=O)-OCH3, -C(=O)-C(=O)-NHCH3, Preferably, -L1-L2-R1 is selected from -CH2-C(=O)-OH, -C(=O)-C(=O)-OH, -C(=O)-C(=O)-OCH3, -C(=O)-C(=O)-NHCH3, Preferably, -L1-L2-R1 is selected from -C(=O)-C(=O)-OH, -C(=O)-C(=O)-OCH3, Preferably, -L1-L2-R1 is selected from -C(=O)-C(=O)-OH; Preferably, L1 is -C(=O)-, L2 is a bond or -C(=O)-, and R1 is selected from -OR 1a 、-NR 1b R 1c , R 1a C 1-3 Alkyl, R 1b Selected from H, R 1c Selected from C 1-3 Alkyl, 5-membered heteroaryl (e.g. pyrrolyl, furanyl, thienyl, imidazole yl, pyrazolyl, oxazolyl, tetrazolyl), -C 1-3 Alkylene-5-membered heteroaryl (e.g., -CH2-pyrazolyl, -CH2-oxazolyl, -CH2-furyl, -CH2-thienyl, -CH2-tetrazolyl), wherein C 1-3 The alkyl group is optionally substituted with a carboxyl group; More preferably, L2 is a bond.

15. A compound according to any one of claims 1 to 14, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, wherein: L3 is selected from a bond, -O-, -NR L3 -、-S-、#-C 1-6 Alkylene-O-*, #-C 1-6 Alkylene-NR L3 -*,#-C 1-6 Alkylene-S-*, -C 1-6 Alkylene-, -C 2-6 Alkenylene- and -C 2-6 Alkyne-, wherein the end indicated by "#" is connected to R2, and the end indicated by "*" is connected to Connected, R L3 As defined in any one of claims 1 to 14, preferably, R L3 is selected from H, D, -CH3, -CH2CH3 and -CH(CH3)2, further preferably, R L3 Selected from H; Preferably, L3 is selected from a bond, -O-, -NR L3 -、-S-、#-C 1-4 Alkylene-O-*, #-C 1-4 Alkylene-NR L3 -*,#-C 1-4 Alkylene-S-*, -C 1-4 Alkylene-, -C 2-4 Alkenylene- and -C 2-4 Alkyne-, wherein the end indicated by "#" is connected to R2, and the end indicated by "*" is connected to Connected, R L3 As defined in any one of claims 1 to 14, preferably, R L3 is selected from H, D, -CH3, -CH2CH3 and -CH(CH3)2, further preferably, R L3 Selected from H; Preferably, L3 is selected from a bond, -O-, -NR L3 -、-S-、#-(CH2) n -O-*, #-(CH2) n -NR L3 -*、#-(CH2) n -S-*, vinylene, propenylene, ethynylene and propynylene, wherein the end indicated by "#" is connected to R2, and the end indicated by "*" is connected to connected, n is selected from 1 and 2, R L3 As defined in any one of claims 1 to 14, preferably, R L3 is selected from H, D, -CH3, -CH2CH3 and -CH(CH3)2, further preferably, R L3 Selected from H; More preferably, L3 is selected from a bond, -O-, -NH-, #-CH2-NH-*, #-CH2-S-* and -C≡C-, wherein the end indicated by "#" is connected to R2, and the end indicated by "*" is connected to Connected; Further preferably, L3 is selected from a bond.

16. A compound according to any one of claims 1 to 15, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, wherein: R is independently selected from halogen, -OH, -CN, -COOH, oxo, C 1-4 Alkyl, -C 1-4 Alkylene-OH, C 1-4 Alkoxy, -C 1-4 Alkyleneoxy-C 1-4 Alkoxy, -C(=O)NH-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -NHC(=O)-C 1-4 Alkyl, -N=S(=O)(C 1-4 Alkyl)-C 1-4 Alkyl, -NH-S(=O)2C 1-4 Alkyl, -S(=O)2-C 1-4 alkyl, -S(=O)2-4-6 membered heterocyclic group, -C(=O)-4-6 membered heterocyclic group, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, and Preferably, R is selected from -OH, -C 1-4 Alkylene-OH; Preferably, R is selected from halogen, -OH, -CN, -COOH, =O, -CH2OH, methyl, ethyl, propyl, butyl, -ethylene-OH, -propylene-OH, -butylene-OH, methoxy, ethoxy, propoxy, butoxy, -methyleneoxy-methoxy, -methyleneoxy-ethoxy, -methyleneoxy-propoxy, -ethyleneoxy-methoxy, -ethyleneoxy-ethoxy, -ethyleneoxy-propoxy, -C(=O)-NH-methyl, -C(=O)-NH-ethyl, -C(=O)-NH-propyl, -C(=O)-NH-butyl, -N=S(=O)(methyl)-methyl, -N=S(=O)(methyl)-ethyl, -N=S(=O)(methyl)-propyl, -N=S(=O)(methyl)-butyl, -N=S(=O)(ethyl)-ethyl, -N=S(=O)(ethyl)-propyl, -(NH) p -W-methyl, -(NH) p -W-ethyl, -(NH) p -W-propyl, -(NH) p -W-butyl, -(W) q -oxetane, -(W) q -azetidinyl, -(W) q -tetrahydrofuranyl, -(W) q -pyrrolidinyl, -(W) q -tetrahydropyranyl, -(W) q -piperidinyl, -(W) q -morpholinyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl and Wherein, W is C(=O) or S(=O)2, and p or q is independently 0 or 1; Further preferably, R is selected from F, -OH, -CN, -COOH, =O, -CH3, -CH2OH, -C(CH3)2OH, -CH2C(CH3)2OH, -OCH3, -OCH2CH2OCH3, -C(=O)CH3, -C(=O)NHCH3, -NHC(=O)CH3, -N=S(=O)(CH3)2, -NH-S(=O)2CH3, -S(=O)2CH3, -S(=O)2-piperidinyl (e.g. ), -C(=O)-pyrrolidinyl (e.g. ), -C(=O)-morpholinyl (e.g. ), morpholinyl (e.g. ), pyrazolyl (e.g. )and More preferably, R is selected from -OH, -CH2OH.

17. A compound according to any one of claims 1 to 16, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, wherein: R 2a , R 2b , R 2c , R 2d and R 2e are independently selected from H, halogen, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, -NHC 1- 4-alkyl, -N(C 1-4 Alkyl)-C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -phenylene-4-6 membered heterocyclyl, -phenylene-5-6 membered heteroaryl, -phenylene-phenyl and -5-6 membered heteroarylene-5-6 membered heteroaryl, the C 1-4 Alkyl, C 1-4 Haloalkyl, -NHC 1- 4-alkyl, -N(C 1-4 Alkyl)-C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -phenylene-4-6 membered heterocyclyl, -phenylene-5-6 membered heteroaryl, -phenylene-phenyl or -5-6 membered heteroarylene-5-6 membered heteroaryl is optionally substituted with 1, 2 or 3 R; Preferably, R 2a , R 2b , R 2c , R 2d and R 2e are independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 3- 6-membered cycloalkyl, 4-6-membered heterocyclic group, phenyl, 5-6-membered heteroaryl; the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 R; Preferably, R 2a , R 2b , R 2c , R 2d and R 2e are independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 3- 6 cycloalkyl, phenyl; said C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, phenyl are optionally substituted by 1, 2 or 3 R; Preferably, R 2a , R 2b , R 2c , R 2d and R 2e are independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl; the C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl are optionally substituted by 1, 2 or 3 R; Preferably, R 2a , R 2b , R 2c , R 2d and R 2e Each of the following is independently selected from H, F, Cl, Br, -OH, methyl, ethyl, propyl, butyl, halomethyl, haloethyl, halopropyl, halobutyl, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(CH3)2, -N(CH3)(CH2CH3), -N(CH2CH3)2, methoxy, ethoxy, propoxy, butoxy, halomethoxy, haloethoxy, halopropoxy, halobutoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, -(phenylene) r -Oxetane, -(phenylene) r - Azetidinyl, -(phenylene) r -tetrahydrofuranyl, -(phenylene) r -pyrrolidinyl, -(phenylene) r -tetrahydropyranyl, -(phenylene) r -piperidinyl, -(phenylene) r -morpholinyl, -(phenylene) r -Oxopyrrolidinyl, -(phenylene) r -Oximidazole, -(phenylene) r -Oxopyrazolyl, -(phenylene) r -Oxodihydrotriazolyl, -(phenylene) r -phenyl-, -(V) r -thienyl, -(V) r -furanyl, -(V) r -pyrrolyl, -(V) r -imidazolyl, -(V) r -pyrazolyl, -(V) r -thiazolyl, -(V) r -oxazolyl, -(V) r -oxadiazolyl, -(V) r -triazole, -(V) r -tetrazolyl, -(V) r -pyridyl, -(V) r -pyrimidinyl and -(V) r -pyrazinyl, the methyl, ethyl, propyl, butyl, halomethyl, haloethyl, halopropyl, halobutyl, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-butyl, -N(CH3)2, -N(CH3)(CH2CH3), -N(CH2CH3)2, methoxy, ethoxy, propoxy, butoxy, halomethoxy, haloethoxy, halopropoxy, halobutoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, -(phenylene) r -Oxetane, -(phenylene) r -azetidinyl, -(phenylene) r -tetrahydrofuranyl, -(phenylene) r -pyrrolidinyl, -(phenylene) r -tetrahydropyranyl, -(phenylene) r -piperidinyl, -(phenylene) r -morpholinyl, -(phenylene) r -Oxopyrrolidinyl, -(phenylene) r -Oximidazole, -(phenylene) r -Oxopyrazolyl, -(phenylene) r -Oxodihydrotriazolyl, -(phenylene) r -phenyl-, -(V) r -thienyl, -(V) r -furanyl, -(V) r -pyrrolyl, -(V) r -imidazolyl, -(V) r -pyrazolyl, -(V) r -thiazolyl, -(V) r -oxazolyl, -(V) r -oxadiazolyl, -(V) r -triazole, -(V) r -tetrazolyl, -(V) r -pyridyl, -(V) r -pyrimidinyl or -(V) r -pyrazinyl is optionally substituted by 1, 2 or 3 R, wherein V is selected from phenylene and pyridinylene, and r is 0 or 1; More preferably, R 2a , R 2b , R 2c , R 2d and R 2e Each of the following is independently selected from H, F, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, cyclopropyl, cyclobutyl, cyclohexenyl, azetidinyl, oxetanyl, morpholinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl phenyl, piperidinyl, phenyl, pyridinyl, -phenylene-oxetanyl, -phenylene-morpholinyl, -phenylene-oxopyrrolidinyl, -phenylene-oxoimidazolyl, -phenylene-oxopyrazolyl, -phenylene-oxodihydrotriazolyl, -phenylene-phenyl, -phenylene-imidazolyl, -phenylene-pyrazolyl, -phenylene-oxadiazolyl, -phenylene-triazolyl, -phenylene-tetrazolyl, -phenylene-pyrimidinyl and -pyridinyl-pyrazolyl , the -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, cyclopropyl, cyclobutyl, cyclohexenyl, azetidinyl, oxetanyl, morpholinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, phenyl, pyridyl , -phenylene-oxetanyl, -phenylene-morpholinyl, -phenylene-oxopyrrolidinyl, -phenylene-oxoimidazolyl, -phenylene-oxopyrazolyl, -phenylene-oxodihydrotriazolyl, -phenylene-phenyl, -phenylene-imidazolyl, -phenylene-pyrazolyl, -phenylene-oxadiazolyl, -phenylene-triazolyl, -phenylene-tetrazolyl, -phenylene-pyrimidinyl or -pyridinyl-pyrazolyl are optionally substituted with 1, 2 or 3 R; Preferably, R 2a , R 2b , R 2c , R 2d and R 2e Each is independently selected from H, methyl, methoxy, cyclopropyl, cyclobutyl, and phenyl, wherein the methyl, methoxy, cyclopropyl, cyclobutyl, and phenyl are optionally substituted by 1, 2, or 3 R; Preferably, R 2a , R 2b , R 2c , R 2d and R 2e They are independently selected from H, methyl, cyclopropyl, cyclobutyl and phenyl, and the methyl, cyclopropyl, cyclobutyl and phenyl are optionally substituted by 1, 2 or 3 R.

18. A compound according to any one of claims 1 to 17, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, wherein: R2 is selected from C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 9 membered heteroaryl, 9-10 membered heterocyclic group and C 9-10 Cyclic group, the C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 9 membered heteroaryl, 9-10 membered heterocyclic group or C 9-10 The ring group is optionally 1, 2, 3, 4, or 5 independently selected from R 2a , R 2b , R 2c , R 2d and R 2e The group substitution; Preferably, R2 is selected from phenyl or 9-membered heteroaryl, wherein the phenyl or 9-membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2a , R 2b , R 2c , R 2d and R 2e substituted by a group; preferably, R2 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, dihydroindole, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzodioxane and 2,3-dihydroindenyl, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furyl, Pyrrolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, dihydroindolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzodioxanyl or 2,3-dihydroindanyl are optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from R 2a , R 2b , R 2c , R 2d and R 2e The group substitution; Preferably, R2 is selected from phenyl or indolyl, and the phenyl or indolyl is optionally substituted by 1, 2, 3, 4, 5 independently selected from R 2a , R 2b , R 2c , R 2d and R 2e The group substitution; Further preferably, R2 is selected from cyclopropyl, cyclobutyl, phenyl, thienyl, thiazolyl, oxazolyl, pyridyl, indolyl, dihydroindolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzodioxolyl and 2,3-dihydroindenyl, wherein the cyclopropyl, cyclobutyl, phenyl, thienyl, thiazolyl, oxazolyl, pyridyl, indolyl, dihydroindolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzodioxolyl or 2,3-dihydroindenyl is optionally replaced by 1, 2, 3, 4, 5 independently selected from R 2a , R 2b , R 2c , R 2d and R 2e The group substitution; Further preferably, R2 is selected from Preferably, R2 is selected from Further preferably, the R2 is selected from Further preferably, the R2 is selected from More preferably, said R2 is selected from 19. A compound according to any one of claims 1 to 18, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, wherein: The compound is selected from formula (I-1) and (I-2), Preferably, the compound is selected from formula (I-3), (I-4) and (I-5), Step by step selection, the compounds listed below are selected as formula (I-6), (I-7), (I-8), (I-9), (I-10), (I-11), (I-12), (I-13), (I-14), (I-15), (I-16), (I-17), (I-18), (I-19), (I-20) and (I-21). More preferably, the compound is selected from the group consisting of formula (IA), (IB) and (IC), 20. A compound according to any one of claims 1 to 19, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, wherein: The compound has a structure shown in formula (II-1), Preferably, the compound is selected from formula (II-2') and (II-3), Further preferably, the compound is selected from formula (II-4), (II-5), (II-6), (II-7), (II-8) and (II-9), 21. A compound according to any one of claims 1 to 20, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, wherein: The compound has a structure shown in formula (II-6), Among them, R X2a Selected from H, -OH, -C 1-3 Alkoxy; R Y2 is selected from halogen; R 1b Selected from H, C 1-3 alkyl; R 1c Selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocyclic group, -C 1-3 Alkylene-C 3-6 Cycloalkyl, -C 1-3 Alkylene-phenyl, -C 1-3 Alkylene-5-6 membered heteroaryl, -C 1-3 Alkylene-4-7 membered heterocyclic group, and the C 1-3 The alkyl group is optionally substituted with a carboxyl group; R2 is selected from phenyl, 5-10 membered heteroaryl, wherein the phenyl, 5-10 membered heteroaryl is optionally selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The phenyl group or the 5-10 heteroaryl group is substituted with a cycloalkyl group or a phenyl group. 3-6 Cycloalkyl, phenyl is optionally selected from -OH, -C 1-3 Substitution of the alkylene -OH group; Preferably, R X2a is selected from H or -OH; more preferably, R X2a is H; Preferably, R Y2 is Cl; Preferably, R 1b is selected from H, methyl; more preferably, R 1b is H; Preferably, R 1c Selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, -C 1-3 Alkylene-phenyl, -C 1-3 Alkylene-5-6 membered heteroaryl, -C 1-3 Alkylene-4-7 membered heterocyclic group, and the C 1-3 The alkyl group is optionally substituted with a carboxyl group; Preferably, R 1c Selected from C 1-3 Alkyl, 5-6 membered heteroaryl, -C 1-3 Alkylene-5-6 membered heteroaryl, -C 1-3 Alkylene-4-7 membered heterocyclic group, and the C 1-3 The alkyl group is optionally substituted with a carboxyl group; Preferably, R 1c Selected from CH2C(=O)OH, pyrazolyl (e.g. ), imidazole (e.g. )、 Oxazolyl (e.g. ),-C 1-3 Alkylene-pyridyl (e.g. ),-C 1-3 Alkylene-furanyl (e.g. ),-C 1-3 Alkylene-thienyl (e.g. ),-C 1-3 Alkylene-oxazolyl (e.g. ),-C 1-3 Alkylene-isoxazolyl (e.g. ),-C 1-3 Alkylene-tetrazolyl (e.g. ),-C 1-3 Alkylene-oxetane (e.g. )； Preferably, R2 is selected from phenyl, 9-membered heteroaryl (eg, indolyl), wherein the phenyl, 9-membered heteroaryl is optionally selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl group or the phenyl group is substituted with a substituent, and the C 3-6 Cycloalkyl, phenyl are optionally selected from -OH, -C 1-3 Substitution of the alkylene -OH group; More preferably, R2 is a phenyl group, wherein the phenyl group is selected from C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl, phenyl substituent, and the C 3-6 Cycloalkyl, phenyl are optionally selected from -OH, -C 1-3 Substitution of the alkylene -OH group; More preferably, R2 is selected from More preferably, R2 is indolyl, wherein the indolyl is C 1-3 Alkyl substitution; More preferably, R2 is 22. A compound according to any one of claims 1 to 21, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, wherein: The compound has a structure shown in formula (V-1), Wherein, L4 is selected from -O- or -NR 1b -, preferably L4 is selected from -NR 1b -; u is selected from 0, 1 or 2, preferably u is selected from 0 or 1; Q is selected from C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 Aryl, the C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 The aryl group is optionally substituted with one or more selected from oxo, hydroxy, cyano, carboxyl, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl substituent substitution; Preferably, Q is selected from C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, phenyl; More preferably, Q is selected from 4-6 membered heterocyclyl, 5-6 membered heteroaryl; Preferably, the compound has a structure shown in formula (V-2) or (V-3), More preferably, the compound has a structure shown in formula (V-4), 23. A compound according to any one of claims 1 to 22, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, wherein: The compound is selected from formula (VI-1), 24. A compound according to any one of claims 1 to 23, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, wherein: The compound is selected from formula (III-1) and (III-2), Preferably, the compound is selected from formula (III-3) and (III-4), Further preferably, the compound is selected from formula (III-5) and (III-6), 25. A compound according to any one of claims 1 to 24, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, provided that: 1) When the structural unit for When -L1-L2-R1 is not -C(=O)-C(=O)-OH; or 2) When the structural unit for When R X2a is not H; or 3) When the structural unit for When R Y2 Not H, halogen, C 1-3 Alkyl, -CF3; 4) when -L1-L2-R1 is -C(=O)-C(=O)-OH, L3 is not a bond; or 5) When -L1-L2-R1 is -C(=O)-C(=O)-OH, R2 is not phenyl or 5-membered heteroaryl, and the phenyl or 5-membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2a , R 2b , R 2c , R 2d and R 2e The group substitution; in, L1, L2, L3, R1, R2, R Y1 , R Y2 , R Y3 , R X2a , R 2a , R 2b , R 2c , R 2d and R 2e The definition is as described in any one of claims 1-21; Preferably, the conditions are: 1) When the structural unit for When -L1-L2-R1 is not -C(=O)-C(=O)-OH; or 2) When the structural unit for X2 for CR X2a When R X2a Not for H; 3) When the structural unit for When R Y2 Not H, halogen, C 1-3 Alkyl, -CF3; 4) when -L1-L2-R1 is -C(=O)-C(=O)-OH, L3 is not a bond; or 5) When -L1-L2-R1 is -C(=O)-C(=O)-OH, R2 is not phenyl or 5-membered heteroaryl, and the phenyl or 5-membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 independently selected from R 2a , R 2b , R 2c , R 2d and R 2e The group substitution; Among them, X2, Y1, L1, L2, L3, R1, R2, R X3 , R 2a , R 2b , R 2c , R 2d and R 2e The definition is as described in any one of claims 1-21; Preferably, the conditions are: 1) -L1-L2-R1 is not -COOR 1a ;or 2) -L1-L2-R1 is not -CR L1a R L1b -COOR 1a ;or 3) -L1-L2-R1 is not -CO-CO-OR 1a ;or 4) -L1-L2-R1 is not -CO-CO-NR 1b R 1c ; Preferably, the conditions are: The compound is not 26. A compound according to any one of claims 1 to 25, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, wherein: The compound is selected from:

27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients or carriers.

28. Use of a compound according to any one of claims 1 to 26, or its enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, prodrug, or pharmaceutically acceptable salt, or the composition of claim 27 in the preparation of a medicament as an AMPK agonist; or, in the preparation of a medicament for treating and / or preventing type II diabetes, dyslipidemia, obesity, chronic kidney disease, diabetic nephropathy, acute kidney injury, polycystic kidney disease or alopecia.

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