Substituted quinazoline compounds, methods of making, pharmaceutical compositions, and uses thereof

Abstract

The present application relates to substituted quinazoline compounds, preparation methods, pharmaceutical combinations and applications thereof, in particular, the present application provides a compound shown in formula O or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, a preparation method, a pharmaceutical combination and an application thereof,

Description

Substituted quinazoline compounds, preparation methods, drug combinations and applications thereof Technical Field

[0001] The present invention relates to the field of biomedicine, and specifically to substituted quinazoline compounds, their preparation methods, pharmaceutical compositions and uses. More specifically, the present invention provides a class of compounds having BRK kinase inhibitory activity or stereoisomers of the compounds, their prodrugs, their pharmaceutically acceptable salts or their pharmaceutically acceptable hydrates and solvates, pharmaceutical compositions containing the compounds, and uses of the compounds in preparing drugs for preventing or treating diseases mediated by BRK kinase in organisms, especially in preparing drugs for preventing or treating tumor growth and metastasis. Background Art

[0002] BRK kinase (Breast tumor kinase) is a non-receptor tyrosine kinase associated with a variety of tumors and plays an important role in tumorigenesis (Mitchell et al, Oncogene 1994, 9, 2383-2390). Studies have shown that BRK is highly expressed in breast cancer and many other types of tumors, including skin cancer, head and neck cancer, thyroid cancer, pancreatic cancer, cervical cancer, bladder cancer, etc., and can induce tumor cell proliferation, invasion and metastasis (Barker et al, Oncogene, 1997, 15, 799-805; Gilic et al, Biochim Biophys Acta Rev Cancer 2020, 1874, 188432; Zhao et al, Onco Targets Ther 2013, 6, 183-188). BRK has been shown to inhibit tumorigenesis by opposing EMT in a colon cancer cell line model (Mathur et al, Mol. Cancer Res. 2016, 14, 563-573). BRK has also been shown to have a tumor suppressor effect in esophageal cancer (Liu et al, J Transl Med 2013, 11, 59; Wu et al, Biochem Biophys Res Commun 2018, 503, 1378-1384). In HB4a, T47D, and Hela cells, overexpression of BRK can promote EGF- or serum-induced cell proliferation (Kamalati et al, J Biol Chem 1996, 271, 30956-30963). Knocking out or downregulating BRK expression can promote cell apoptosis, inhibit tumors, and reduce metastasis (Park et al, Breast Cancer Res 2015, 17, 86; Ito et al, Cancer Res 2016, 76, 4406-4417). Furthermore, small molecule inhibitors targeting BRK can effectively inhibit the growth of tumor cells with high BRK expression in both cells and animals (Jiang et al, Cancer Res 2017, 77, 175-186). Currently, no BRK inhibitors are used clinically or undergoing clinical research. Therefore, there is an urgent need to develop highly active and selective BRK inhibitors in this field to provide new treatment options for various tumors, including breast cancer.

[0003] Summary of the Invention

[0004] After extensive and in-depth research, the inventors of the present invention designed and synthesized a series of substituted quinazoline compounds with novel structures, high safety, and high inhibitory activity against BRK kinase.

[0005] The present invention provides compounds of the following general formula:

[0006] or a stereoisomer of the above-mentioned compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

[0007] More specifically, the present invention provides compounds of the following general formula (I, II, III):

[0008] The definitions of the substituents and symbols are detailed below.

[0009] One object of the present invention is to provide a class of compounds having the activity of inhibiting BRK kinase and their stereoisomers, prodrugs, pharmaceutically acceptable salts or pharmaceutically acceptable solvates.

[0010] Another object of the present invention is to provide a method for preparing the above compound.

[0011] Another object of the present invention is to provide a pharmaceutical composition comprising the above compound.

[0012] Another object of the present invention is to provide the use of the above-mentioned compound and a pharmaceutical composition comprising the above-mentioned compound in the preparation of a medicament for the prevention and / or treatment of BRK kinase-mediated cancer or other diseases.

[0013] Another object of the present invention is to provide a method for treating cancer, which comprises administering an effective amount of the compound or composition of the present invention to a subject.

[0014] Detailed Description of the Invention

[0015] Various specific embodiments, modes and examples are described herein, including exemplary embodiments and definitions for the purpose of understanding the claimed invention. Although the following detailed description sets forth specific preferred embodiments, it will be understood by those skilled in the art that these embodiments are exemplary only and that the invention may be practiced in other ways. For the purpose of determining infringement, the scope of the invention will be directed to any one or more of the appended claims, including their equivalents, and elements or limitations equivalent to those recited.

[0016] The present invention is achieved through the following technical solutions.

[0017] In the first aspect of the present invention, the present invention provides a compound represented by formula O or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof,

[0018] in:

[0019] R 1 Selected from R 1’ 、

[0020] Preferably, R 1 Selected from R 1’ 、

[0021] R 1’ Selected from

[0022] Preferably, R 1’ Selected from

[0023] R m 、R n Each independently selected from C1-C6 alkyl;

[0024] Preferably, R m 、R n Each independently selected from methyl, ethyl;

[0025] Preferably, R 1’ Selected from

[0026] Preferably, R 1’ Selected from

[0027] More preferably, R 1’ Selected from

[0028] Most preferably, R 1’ Selected from

[0029] R 4a 、R 4b Each is independently selected from hydrogen, C1-C6 alkyl;

[0030] Preferably, R 4a 、R 4b are each independently selected from hydrogen, methyl;

[0031] R 5a 、R 5b Each is independently selected from hydrogen, C1-C6 alkyl;

[0032] Preferably, R 5a 、R 5b are each independently selected from hydrogen, methyl;

[0033] R 6a 、R 6b Each is independently selected from hydrogen, C1-C6 alkyl;

[0034] Preferably, R 6a 、R 6b are each independently selected from hydrogen, methyl;

[0035] m is selected from 0 and 1;

[0036] W 1 、W 2 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl;

[0037] Preferably, W 1 、W 2 Among them, any one is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and the other is hydrogen;

[0038] More preferably, W 1 、W 2 Among them, any one is selected from hydrogen, chlorine, methyl, difluoromethyl, and the other is hydrogen;

[0039] Most preferably, As a whole, selected from:

[0040] W 31 、W 32 、W 33 、W 34 When both exist, W 31 、W 32 、W 33 、W 34 Each is independently selected from hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkyl substituted with hydroxy, C1-C6 alkoxy, -NR x R y ;

[0041] Preferably, W 31 、W 32 、W 33 、W 34 When both exist, W 31 、W 32 、W 33 、W 34Each is independently selected from hydrogen, halogen, C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy;

[0042] Preferably, W 31 、W 32 、W 33 、W 34 When both exist, W 31 、W 32 、W 33 、W 34 Any one of them is selected from hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl, -NR x R y , the rest are hydrogen; or, W 31 、W 32 、W 33 、W 34 Among them, any two are selected from hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, and the rest are hydrogen;

[0043] R x 、R y Each is independently selected from hydrogen, C1-C6 alkyl; preferably, R x 、R y wherein any one is selected from C1-C6 alkyl and the other is hydrogen; more preferably, R x 、R y Among them, any one is methyl and the other is hydrogen;

[0044] Preferably, W 31 、W 32 、W 33 、W 34 When both exist, W 31 、W 32 、W 33 、W 34 wherein any one of them is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkyl substituted with hydroxy, and the rest are hydrogen; or, W 31 、W 32 、W 33 、W 34 Among them, any two are selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, and the rest are hydrogen;

[0045] More preferably, W 31 、W 32 、W 33 、W 34 When both exist, W 31 、W 32 、W 33 、W34 Among them, any one is selected from hydrogen, fluorine, hydroxy, methyl, ethyl, methoxy, ethoxy, The remainder is hydrogen; or, W 31 、W 32 、W 33 、W 34 Among them, any two are selected from hydrogen, fluorine, chlorine, hydroxyl, methyl, methoxy, and the rest are hydrogen;

[0046] More preferably, W 31 、W 32 、W 33 、W 34 When both exist, W 31 、W 32 、W 33 、W 34 Among them, any one is selected from hydrogen, fluorine, methyl, ethyl, methoxy, The remainder is hydrogen; or, W 31 、W 32 、W 33 、W 34 Among them, any two are selected from hydrogen, fluorine, chlorine, methyl, methoxy, and the rest are hydrogen;

[0047] W 31 、W 32 、W 33 Both exist, but W does not exist 34 When W 31 、W 32 、W 33 Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and the rest are hydrogen;

[0048] Preferably, W 31 、W 32 、W 33 Both exist, but W does not exist 34 When W 31 、W 32 、W 33 Among them, any one is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and the rest are hydrogen;

[0049] More preferably, W 31 、W 32 、W 33 Both exist, but W does not exist 34 When W 31 、W 32 、W 33 Among them, any one is selected from hydrogen, methyl, methoxy, and the rest are hydrogen;

[0050] Preferably, R 1’ Selected from

[0051] Most preferably, R 1’ Selected from

[0052] W 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene-O-C1-C6 alkylene, R c R d N-C1-C6 alkylene, O=S(R e R f )=N-C1-C6 alkylene, R c R d NC(=O)-C1-C6 alkylene, C3-C6 cycloalkyl-SO2-, 3-7-membered saturated heterocyclyl, 3-7-membered saturated heterocyclyl-C1-C6 alkylene, 5-6-membered heteroaryl, 5-6-membered heteroaryl-C1-C6 alkylene, 8-10-membered saturated bridged heterocyclyl, and the 3-7-membered saturated heterocyclyl, 5-6-membered heteroaryl, and 8-10-membered saturated bridged heterocyclyl are each independently optionally substituted by 1-2 groups selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C(=O)-, hydroxy-C1-C6 alkylene-C(=O)-, and 3-6-membered saturated heterocyclyl, and the C1-C6 alkylene is optionally substituted by hydroxy;

[0053] Preferably, W 4 Selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene-O-C1-C6 alkylene, O=S(R e R f )=N-C1-C6 alkylene, R c R d N-C1-C6 alkylene, R c R dNC(=O)-C1-C6 alkylene, C3-C6 cycloalkyl-SO2-, 3-7-membered saturated heterocyclyl, 3-7-membered saturated heterocyclyl-C1-C6 alkylene, 5-6-membered heteroaryl, 5-6-membered heteroaryl-C1-C6 alkylene, 8-membered saturated bridged heterocyclyl, and the 3-7-membered saturated heterocyclyl and 8-membered saturated bridged heterocyclyl are each independently optionally substituted by 1-2 groups selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C(=O)-, hydroxy-C1-C6 alkylene-C(=O)-, and 4-membered saturated heterocyclyl, and the C1-C6 alkylene is optionally substituted by hydroxy;

[0054] More preferably, W 4 Selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene-O-C1-C6 alkylene, O=S(R e R f )=N-C1-C6 alkylene, R c R d N-C1-C6 alkylene, R c R d NC(=O)-C1-C6 alkylene, C3-C6 cycloalkyl-SO2-, 3-7 membered saturated heterocyclic group, 3-7 membered saturated heterocyclic group-C1-C6 alkylene, 5-6 membered heteroaryl, 5-6 membered heteroaryl-C1-C6 alkylene, 8 membered saturated bridged heterocyclic group, and the 3-7 membered saturated heterocyclic group and the 8 membered saturated bridged heterocyclic group are each independently optionally substituted by 1-2 (preferably 1) selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C(=O)-, hydroxy-C1-C6 alkylene-C(=O)-, 4 membered saturated heterocyclic group (preferably ) group, the C1-C6 alkylene group is optionally substituted by a hydroxyl group, the 3-7 membered saturated heterocyclic group is selected from The 5-6 membered heteroaryl group is selected from The 8-membered bridged heterocyclic group is

[0055] R c 、R dEach is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkylene, hydroxy-substituted C1-C6 alkyl, C1-C6 alkyl-C(=O)-, C2-C6 alkynyl-C1-C6 alkylene, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3-6 membered saturated heterocyclic group; or, R c 、R d Together with the nitrogen atom to which they are commonly attached, they form a 3-6 membered saturated heterocyclic ring, and the 3-6 membered saturated heterocyclic ring is optionally substituted by 1-2 groups selected from C1-C6 alkyl and halogen;

[0056] Preferably, R c 、R d Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkylene, hydroxy-substituted C1-C6 alkyl, C1-C6 alkyl-C(=O)-, C2-C6 alkynyl-C1-C6 alkylene, C1-C6 haloalkyl, C3-C6 cycloalkyl, 5-membered saturated heterocyclic group; or, R c 、R d Together with the nitrogen atom to which they are commonly attached, they form a 4-5 membered saturated heterocyclic ring, and the 4-5 membered saturated heterocyclic ring is optionally substituted by 1-2 groups selected from C1-C6 alkyl and halogen;

[0057] More preferably, R c 、R d Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkylene, hydroxy-substituted C1-C6 alkyl, C1-C6 alkyl-C(=O)-, C2-C6 alkynyl-C1-C6 alkylene, C1-C6 haloalkyl, C3-C6 cycloalkyl, Or, R c 、R d Together with the N atoms they are connected to, they form And the Each is independently optionally substituted by 1-2 groups selected from C1-C6 alkyl, halogen;

[0058] Most preferably, R c 、R d are each independently selected from hydrogen, methyl, ethyl, isopropyl, Acetyl, Cyclopropyl, cyclobutyl, Or, R c 、R d Together with the N atoms they are connected to, they form

[0059] Re 、R f Each is independently selected from hydrogen, C1-C6 alkyl;

[0060] Preferably, R e 、R f Each independently selected from C1-C6 alkyl;

[0061] More preferably, R e 、R f is methyl;

[0062] More preferably, W 4 Selected from hydrogen, methyl, ethyl, difluoromethyl, trideuterated methyl,

[0063] Most preferably, W 4 Selected from hydrogen, methyl, ethyl, difluoromethyl, trideuterated methyl,

[0064] W 5 、W 6 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, And W 5 、W 6 Not simultaneously hydrogen;

[0065] Preferably, W 5 、W 6 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and W 5 、W 6 Not simultaneously hydrogen;

[0066] Preferably, W 5 、W 6 Any one of them is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, the other is hydrogen;

[0067] R k 、R l Each independently selected from C1-C6 alkyl;

[0068] Preferably, R k 、R l is methyl;

[0069] Preferably, W 5 、W 6Among them, any one is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and the other is hydrogen;

[0070] More preferably, W 5 、W 6 Among them, any one is selected from hydrogen, chlorine, methyl, ethyl, methoxy, difluoromethyl, trifluoromethyl, the other is hydrogen;

[0071] More preferably, W 5 、W 6 Among them, any one is selected from chlorine, methyl, ethyl, methoxy, difluoromethyl, trifluoromethyl, and the other is hydrogen;

[0072] More preferably, As a whole, selected

[0073] Most preferably, As a whole, selected

[0074] Most preferably, As a whole,

[0075] R 2 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl;

[0076] Preferably, R 2 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl;

[0077] More preferably, R 2 Selected from methyl, ethyl, n-propyl,

[0078] R 3 Selected from:

[0079] 1) in:

[0080] Z 1 、Z 2 、Z 3 、Z 4 Each is independently selected from hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, -NR a Rb , R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl;

[0081] Preferably, Z 1 , Z 2 , Z 3 , Z 4 Each is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -NR a R b , R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl;

[0082] More preferably, Z 1 , Z 2 , Z 3 , Z 4 In, Z 1 is selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, and the rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 In, Z 1 , Z 4 Each is independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, amino, and the rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 All are hydrogen;

[0083] More preferably, Z 1 , Z 2 , Z 3 , Z 4 Each is independently selected from hydrogen, fluorine, cyano, methyl, trifluoromethyl, amino, methoxy;

[0084] More preferably, Z 1 , Z 2 , Z 3 , Z 4 In, Z 1 is selected from methyl, fluorine, methoxy, and the rest are hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 In, Z 1 , Z 4 Each is independently selected from fluorine, cyano, methyl, trifluoromethyl, amino, and the rest are hydrogen; or, Z 1 , Z 2 , Z3 , Z 4 All are hydrogen;

[0085] Most preferably, As a whole, selected

[0086] 2) in:

[0087] Z 1 , Z 3 , Z 4 , Z 5 Each is independently selected from hydrogen, nitro, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C3-C6 cycloalkyl, C2-C6 alkenyl, -NR a R b 、R a R b NC(=O)-、 R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl;

[0088] Preferably, Z 1 , Z 3 , Z 4 , Z 5 Each is independently selected from hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C3-C6 cycloalkyl, C2-C6 alkenyl, -NR a R b 、R a R b NC(=O)-、 R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl;

[0089] More preferably, Z 1 , Z 3 , Z 4 , Z 5 Any one of them is selected from cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C3-C6 cycloalkyl, C2-C6 alkenyl, -NR a R b 、R a R b NC(=O)-、 And Ra 、R b Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and the rest is hydrogen; or, Z 1 , Z 3 , Z 4 , Z 5 Among them, any two are selected from cyano, halogen, C1-C6 alkyl, amino, The rest is hydrogen; or, Z 1 , Z 3 , Z 4 , Z 5 All are hydrogen;

[0090] More preferably, Z 1 , Z 3 , Z 4 , Z 5 Each is independently selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, methoxy, isopropoxy, difluoromethyl, acetyl, cyclopropyl, amino,

[0091] More preferably, Z 1 , Z 3 , Z 4 , Z 5 Among them, any one is selected from cyano, fluorine, chlorine, bromine, methyl, ethyl, methoxy, isopropoxy, difluoromethyl, acetyl, cyclopropyl, amino, The rest is hydrogen; or, Z 1 , Z 3 , Z 4 , Z 5 Any two of them are selected from fluorine, chlorine, bromine, methyl, cyano, amino, The rest is hydrogen; or, Z 1 , Z 3 , Z 4 , Z 5 All are hydrogen;

[0092] Most preferably, As a whole, selected

[0093] 3) in:

[0094] Z 1 , Z 2 , Z 4 , Z 5Each is independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C(=O)-, -NR a R b , R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl;

[0095] Preferably, Z 1 , Z 2 , Z 4 , Z 5 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C(=O)-, -NR a R b , R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl;

[0096] More preferably, Z 1 , Z 2 , Z 4 , Z 5 wherein any one of them is selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, C1-C6 alkyl-C(=O)-, and the rest are hydrogen; or, Z 1 , Z 2 , Z 4 , Z 5 Among them, any two are selected from halogen, C1-C6 alkyl, and the rest are hydrogen; or, Z 1 , Z 2 , Z 4 , Z 5 All are hydrogen;

[0097] More preferably, Z 1 , Z 2 , Z 4 , Z 5 Each is independently selected from hydrogen, fluorine, methyl, methoxy, acetyl, amino;

[0098] More preferably, Z 1 , Z 2 , Z 4 , Z 5 Among them, any one is selected from methyl, fluoro, methoxy, amino, acetyl, and the rest are hydrogen; or, Z 1 , Z 2 , Z 4 , Z 5 Among them, any two are selected from fluorine and methyl, and the rest are hydrogen; or, Z 1 , Z 2 , Z 4 , Z5 All are hydrogen;

[0099] Most preferably, As a whole, selected

[0100] 4) in:

[0101] Z 1 , Z 3 , Z 4 Each is independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl, -NR a R b 、R a R b NC(=O)-,R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl;

[0102] Preferably, Z 1 , Z 3 , Z 4 Each is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl, -NR a R b 、R a R b NC(=O)-,R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl;

[0103] More preferably, Z 1 , Z 3 , Z 4 Any one of them is selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl, -NR a R b 、R a R b NC(=O)-, and R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl, and the rest is hydrogen; or, Z 1 , Z 3 , Z 4 Among them, any two are selected from C1-C6 alkyl, and the rest are hydrogen; or, Z 1 , Z 3 , Z 4 All are hydrogen;

[0104] More preferably, Z1 , Z 3 , Z 4 Each independently selected from hydrogen, fluorine, chlorine, cyano, methyl, methoxy, hydroxymethyl, amino,

[0105] More preferably, Z 1 , Z 3 , Z 4 Among them, any one is selected from fluorine, chlorine, cyano, methyl, methoxy, hydroxymethyl, amino, The rest is hydrogen; or, Z 1 , Z 3 , Z 4 In the formula (a), any two of them are methyl groups and the rest are hydrogen; or, Z 1 , Z 3 , Z 4 All are hydrogen;

[0106] Most preferably, As a whole, selected

[0107] 5) in:

[0108] Z 1 , Z 2 , Z 3 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0109] Preferably, Z 1 , Z 2 , Z 3 Each is independently selected from hydrogen, cyano, C1-C6 alkyl;

[0110] More preferably, Z 1 , Z 2 , Z 3 Among them, any one is selected from hydrogen, cyano, C1-C6 alkyl, and the rest are hydrogen;

[0111] More preferably, Z 1 , Z 2 , Z 3 are each independently selected from hydrogen, cyano, and methyl;

[0112] More preferably, Z 1 , Z 2 , Z 3 Among them, any one is selected from hydrogen, cyano, methyl, and the rest are hydrogen;

[0113] Most preferably, As a whole, selected

[0114] 6) in:

[0115] Z 1 , Z 2 , Z 5 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0116] Preferably, Z 1 , Z 2 , Z 5 All are hydrogen;

[0117] 7) in:

[0118] Z 1 , Z 3 , Z 5 Each is independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b , R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl;

[0119] Preferably, Z 1 , Z 3 , Z 5 Each is independently selected from hydrogen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b , R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl;

[0120] More preferably, Z 1 , Z 3 , Z 5 wherein any one is selected from C1-C6 alkyl, C1-C6 alkoxy, amino, and the rest are hydrogen; or, Z 1 , Z 3 , Z 5 wherein any two are selected from hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and the rest are hydrogen; or, Z 1 , Z 3 , Z 5 All are hydrogen;

[0121] More preferably, Z 1 , Z 3 , Z 5 Each is independently selected from hydrogen, hydroxy, fluorine, chlorine, methyl, methoxy, and amino;

[0122] More preferably, Z 1 , Z 3 , Z 5 Among them, any one is selected from methyl, methoxy, amino, and the rest are hydrogen; or, Z 1 , Z 3 , Z 5 Among them, any two are selected from hydroxy, fluorine, chlorine, methyl, methoxy, and amino, and the rest are hydrogen; or, Z 1 , Z 3 , Z 5 All are hydrogen;

[0123] Most preferably, As a whole, selected

[0124] 8) in:

[0125] Z 2 , Z 4 , Z 5 Each is independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl;

[0126] Preferably, Z 2 , Z 4 , Z 5 Each is independently selected from hydrogen, halogen, C1-C6 alkyl;

[0127] More preferably, Z 2 , Z 4 , Z 5 Among them, any one is selected from halogen, C1-C6 alkyl, and the rest are hydrogen; or, Z 2 , Z 4 , Z 5 Among them, any two are selected from halogen, C1-C6 alkyl, and the rest are hydrogen; or, Z 2 , Z 4 , Z 5 All are hydrogen;

[0128] More preferably, Z 2 , Z 4 , Z 5 Each independently selected from hydrogen, fluorine, chlorine, bromine, methyl;

[0129] More preferably, Z 2 , Z 4 , Z 5 Among them, any one is selected from fluorine, chlorine, bromine, methyl, and the rest are hydrogen; or, Z 2 , Z 4 , Z 5 Among them, any two are selected from fluorine, bromine, and methyl, and the rest are hydrogen; or, Z2 , Z 4 , Z 5 All are hydrogen;

[0130] Most preferably, As a whole, selected

[0131] 9) in:

[0132] Z 2 , Z 3 , Z 4 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0133] Preferably, Z 2 , Z 3 , Z 4 All are hydrogen;

[0134] 10) in:

[0135] Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently selected from hydrogen, hydroxy, cyano, nitro, halogen, C1-C6 alkyl; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In, Z 1 and Z 2 or Z 2 and Z 3 Together with the carbon atoms to which they are attached, they form a 5-membered heterocyclic ring or a 5-membered heteroaromatic ring, and the 5-membered heterocyclic ring or the 5-membered heteroaromatic ring are each independently optionally substituted by 1-2 halogens, and the rest are each independently selected from hydrogen, C1-C6 alkyl;

[0136] Preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently selected from hydrogen, hydroxy, cyano, halogen, C1-C6 alkyl; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In, Z 1 and Z 2 or Z 2 and Z 3Together with the carbon atoms to which they are attached, they form a 5-membered heterocyclic ring or a 5-membered heteroaromatic ring, and the 5-membered heterocyclic ring or the 5-membered heteroaromatic ring are each independently optionally substituted by 1-2 halogens, and the rest are each independently selected from hydrogen, C1-C6 alkyl;

[0137] More preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In, any two are selected from hydroxyl, cyano, halogen, C1-C6 alkyl, and the rest are hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In, Z 1 and Z 2 or Z 2 and Z 3 Together with the carbon atoms to which they are attached, And the Optionally substituted with 1-2 halogens, the rest are independently selected from hydrogen, C1-C6 alkyl;

[0138] More preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In, any two are selected from hydroxy, cyano, fluorine, methyl, and the rest are hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In, Z 1 and Z 2 or Z 2 and Z 3 Together with the carbon atoms to which they are attached, And the Optionally substituted with 1-2 fluorine atoms, the rest of which are independently selected from hydrogen and methyl;

[0139] Most preferably, As a whole, selected

[0140] 11) Among them, Z 1 Selected from hydrogen, C1-C6 alkyl, preferably selected from hydrogen, methyl; each Z 4 Independently selected from halogen, C1-C6 alkyl, preferably selected from chlorine, methyl;

[0141] 12) 5-9 membered heteroaryl, wherein the 5-9 membered heteroaryl is optionally substituted by 1-2 groups selected from C1-C6 alkyl, cyano; preferably selected from And the Each independently optionally substituted by 1-2 groups selected from C1-C6 alkyl, cyano; more preferably selected from

[0142] Preferably, R 3 Selected from

[0143] In some embodiments, the compound has the structural formula shown in Formula I,

[0144] in:

[0145] R 2 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl;

[0146] Preferably, R 2 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl;

[0147] More preferably, R 2 Selected from methyl, ethyl, n-propyl,

[0148] R 3 Selected from:

[0149] 1) in:

[0150] Z 1 、Z 2 、Z 3 、Z 4 Each is independently selected from hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, -NR a R b , R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl;

[0151] Preferably, Z 1 、Z 2 、Z 3 、Z 4 Each is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -NR a Rb , R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl;

[0152] More preferably, Z 1 , Z 2 , Z 3 , Z 4 In, Z 1 is selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, and the rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 In, Z 1 , Z 4 Each is independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, amino, and the rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 All are hydrogen;

[0153] More preferably, Z 1 , Z 2 , Z 3 , Z 4 Each is independently selected from hydrogen, fluorine, cyano, methyl, trifluoromethyl, amino, methoxy;

[0154] More preferably, Z 1 , Z 2 , Z 3 , Z 4 In, Z 1 is selected from methyl, fluorine, methoxy, and the rest are hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 In, Z 1 , Z 4 Each is independently selected from fluorine, cyano, methyl, trifluoromethyl, amino, and the rest are hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 All are hydrogen;

[0155] Most preferably, As a whole, selected

[0156] 2) in:

[0157] Z 1 , Z 3 , Z4 、Z 5 Each is independently selected from hydrogen, nitro, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C3-C6 cycloalkyl, C2-C6 alkenyl, -NR a R b 、R a R b NC(=O)-、 R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl;

[0158] Preferably, Z 1 、Z 3 、Z 4 、Z 5 Each is independently selected from hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C3-C6 cycloalkyl, C2-C6 alkenyl, -NR a R b 、R a R b NC(=O)-、 R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl;

[0159] More preferably, Z 1 、Z 3 、Z 4 、Z 5 Any one of them is selected from cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C3-C6 cycloalkyl, C2-C6 alkenyl, -NR a R b 、R a R b NC(=O)-、 And R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and the rest is hydrogen; or, Z 1 、Z 3 、Z 4 、Z 5 In, any two are selected from cyano, halogen, C1-C6 alkyl, amino, and the rest are hydrogen; or, Z 1 、Z 3 、Z 4 、Z 5All are hydrogen;

[0160] More preferably, Z 1 , Z 3 , Z 4 , Z 5 Each is independently selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, methoxy, isopropoxy, difluoromethyl, acetyl, cyclopropyl, amino,

[0161] More preferably, Z 1 , Z 3 , Z 4 , Z 5 Among them, any one is selected from cyano, fluorine, chlorine, bromine, methyl, ethyl, methoxy, isopropoxy, difluoromethyl, acetyl, cyclopropyl, amino, The rest is hydrogen; or, Z 1 , Z 3 , Z 4 , Z 5 Among them, any two are selected from fluorine, chlorine, bromine, methyl, cyano, amino, and the rest are hydrogen; or, Z 1 , Z 3 , Z 4 , Z 5 All are hydrogen;

[0162] Most preferably, As a whole, selected

[0163] 3) in:

[0164] Z 1 , Z 2 , Z 4 , Z 5 Each is independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C(=O)-, -NR a R b , R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl;

[0165] Preferably, Z 1 , Z 2 , Z 4 , Z 5 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C(=O)-, -NR a Rb , R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl;

[0166] More preferably, Z 1 、Z 2 、Z 4 、Z 5 wherein any one of them is selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, C1-C6 alkyl-C(=O)-, and the rest are hydrogen; or, Z 1 、Z 2 、Z 4 、Z 5 Among them, any two are selected from halogen, C1-C6 alkyl, and the rest are hydrogen; or, Z 1 、Z 2 、Z 4 、Z 5 All are hydrogen;

[0167] More preferably, Z 1 、Z 2 、Z 4 、Z 5 Each is independently selected from hydrogen, fluorine, methyl, methoxy, acetyl, amino;

[0168] More preferably, Z 1 、Z 2 、Z 4 、Z 5 Among them, any one is selected from methyl, fluoro, methoxy, amino, acetyl, and the rest are hydrogen; or, Z 1 、Z 2 、Z 4 、Z 5 Among them, any two are selected from fluorine and methyl, and the rest are hydrogen; or, Z 1 、Z 2 、Z 4 、Z 5 All are hydrogen;

[0169] Most preferably, As a whole, selected

[0170] 4) in:

[0171] Z 1 、Z 3 、Z 4 Each is independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl, -NR a Rb 、R a R b NC(=O)-,R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl;

[0172] Preferably, Z 1 、Z 3 、Z 4 Each is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl, -NR a R b 、R a R b NC(=O)-,R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl;

[0173] More preferably, Z 1 、Z 3 、Z 4 Any one of them is selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl, -NR a R b 、R a R b NC(=O)-, and R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl, and the rest is hydrogen; or, Z 1 、Z 3 、Z 4 Among them, any two are selected from C1-C6 alkyl, and the rest are hydrogen; or, Z 1 、Z 3 、Z 4 All are hydrogen;

[0174] More preferably, Z 1 、Z 3 、Z 4 Each independently selected from hydrogen, fluorine, chlorine, cyano, methyl, methoxy, hydroxymethyl, amino,

[0175] More preferably, Z 1 、Z 3 、Z 4 Among them, any one is selected from fluorine, chlorine, cyano, methyl, methoxy, hydroxymethyl, amino, The rest is hydrogen; or, Z 1 、Z 3 、Z 4 In the formula (a), any two of them are methyl groups and the rest are hydrogen; or, Z1 、Z 3 、Z 4 All are hydrogen;

[0176] Most preferably, As a whole, selected

[0177] 5) in:

[0178] Z 1 、Z 2 、Z 3 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0179] Preferably, Z 1 、Z 2 、Z 3 Each is independently selected from hydrogen, cyano, C1-C6 alkyl;

[0180] More preferably, Z 1 、Z 2 、Z 3 Among them, any one is selected from hydrogen, cyano, C1-C6 alkyl, and the rest are hydrogen;

[0181] More preferably, Z 1 、Z 2 、Z 3 are each independently selected from hydrogen, cyano, and methyl;

[0182] More preferably, Z 1 、Z 2 、Z 3 Among them, any one is selected from hydrogen, cyano, methyl, and the rest are hydrogen;

[0183] Most preferably, As a whole, selected

[0184] 6) in:

[0185] Z 1 、Z 2 、Z 5 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0186] Preferably, Z 1 、Z 2 、Z 5 All are hydrogen;

[0187] 7) in:

[0188] Z 1 、Z 3 、Z 5 Each is independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b , R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl;

[0189] Preferably, Z 1 、Z 3 、Z 5 Each is independently selected from hydrogen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b , R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl;

[0190] More preferably, Z 1 、Z 3 、Z 5 wherein any one is selected from C1-C6 alkyl, C1-C6 alkoxy, amino, and the rest are hydrogen; or, Z 1 、Z 3 、Z 5 wherein any two are selected from hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and the rest are hydrogen; or, Z 1 、Z 3 、Z 5 All are hydrogen;

[0191] More preferably, Z 1 、Z 3 、Z 5 Each is independently selected from hydrogen, hydroxy, fluorine, chlorine, methyl, methoxy, and amino;

[0192] More preferably, Z 1 、Z 3 、Z 5 Among them, any one is selected from methyl, methoxy, amino, and the rest are hydrogen; or, Z 1 、Z 3 、Z 5 Among them, any two are selected from hydroxy, fluorine, chlorine, methyl, methoxy, and amino, and the rest are hydrogen; or, Z 1 、Z 3 、Z 5 All are hydrogen;

[0193] Most preferably, As a whole, selected

[0194] 8) in:

[0195] Z 2 、Z 4 、Z 5 Each is independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl;

[0196] Preferably, Z 2 、Z 4 、Z 5 Each is independently selected from hydrogen, halogen, C1-C6 alkyl;

[0197] More preferably, Z 2 、Z 4 、Z 5 Among them, any one is selected from halogen, C1-C6 alkyl, and the rest are hydrogen; or, Z 2 、Z 4 、Z 5 Among them, any two are selected from halogen, C1-C6 alkyl, and the rest are hydrogen; or, Z 2 、Z 4 、Z 5 All are hydrogen;

[0198] More preferably, Z 2 、Z 4 、Z 5 Each independently selected from hydrogen, fluorine, chlorine, bromine, methyl;

[0199] More preferably, Z 2 、Z 4 、Z 5 Among them, any one is selected from fluorine, chlorine, bromine, methyl, and the rest are hydrogen; or, Z 2 、Z 4 、Z 5 Among them, any two are selected from fluorine, bromine, and methyl, and the rest are hydrogen; or, Z 2 、Z 4 、Z 5 All are hydrogen;

[0200] Most preferably, As a whole, selected

[0201] 9) in:

[0202] Z 2 、Z 3 、Z 4 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0203] Preferably, Z 2 , Z 3 , Z 4 All are hydrogen;

[0204] 10) in:

[0205] Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently selected from hydrogen, hydroxy, cyano, nitro, halogen, C1-C6 alkyl; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In, Z 1 and Z 2 or Z 2 and Z 3 Together with the carbon atoms to which they are attached, they form a 5-membered heterocyclic ring or a 5-membered heteroaromatic ring, and the 5-membered heterocyclic ring or the 5-membered heteroaromatic ring are each independently optionally substituted by 1-2 halogens, and the rest are each independently selected from hydrogen, C1-C6 alkyl;

[0206] Preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently selected from hydrogen, hydroxy, cyano, halogen, C1-C6 alkyl; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In, Z 1 and Z 2 or Z 2 and Z 3 Together with the carbon atoms to which they are attached, they form a 5-membered heterocyclic ring or a 5-membered heteroaromatic ring, and the 5-membered heterocyclic ring or the 5-membered heteroaromatic ring are each independently optionally substituted by 1-2 halogens, and the rest are each independently selected from hydrogen, C1-C6 alkyl;

[0207] More preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In, any two are selected from hydroxyl, cyano, halogen, C1-C6 alkyl, and the rest are hydrogen; or, Z 1 , Z 2 , Z 3 , Z4 、Z 5 In, Z 1 and Z 2 or Z 2 and Z 3 Together with the carbon atoms to which they are attached, And the Optionally substituted with 1-2 halogens, the rest are independently selected from hydrogen, C1-C6 alkyl;

[0208] More preferably, Z 1 、Z 2 、Z 3 、Z 4 、Z 5 In, any two are selected from hydroxy, cyano, fluorine, methyl, and the rest are hydrogen; or, Z 1 、Z 2 、Z 3 、Z 4 、Z 5 In, Z 1 and Z 2 or Z 2 and Z 3 Together with the carbon atoms to which they are attached, And the Optionally substituted with 1-2 fluorine atoms, the rest of which are independently selected from hydrogen and methyl;

[0209] Most preferably, As a whole, selected

[0210] 11) Among them, Z 1 Selected from C1-C6 alkyl, preferably methyl; each Z 4 Independently selected from halogen, C1-C6 alkyl, preferably selected from chlorine, methyl;

[0211] 12) 5-9 membered heteroaryl, wherein the 5-9 membered heteroaryl is optionally substituted with 1-2 C1-C6 alkyl groups; preferably selected from And the Each independently optionally substituted with 1-2 C1-C6 alkyl groups; more preferably selected from

[0212] Preferably, R 3 Selected from

[0213] R 4a 、R4b Each is independently selected from hydrogen, C1-C6 alkyl;

[0214] Preferably, R 4a 、R 4b are each independently selected from hydrogen, methyl;

[0215] R 5a 、R 5b Each is independently selected from hydrogen, C1-C6 alkyl;

[0216] Preferably, R 5a 、R 5b are each independently selected from hydrogen, methyl;

[0217] R 6a 、R 6b Each is independently selected from hydrogen, C1-C6 alkyl;

[0218] Preferably, R 6a 、R 6b are each independently selected from hydrogen, methyl;

[0219] m is selected from 0 and 1;

[0220] W 1 、W 2 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl;

[0221] Preferably, W 1 、W 2 Among them, any one is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and the other is hydrogen;

[0222] More preferably, W 1 、W 2 Among them, any one is selected from hydrogen, chlorine, methyl, difluoromethyl, and the other is hydrogen;

[0223] Most preferably, As a whole, selected from:

[0224] In some embodiments, the compound has the structural formula shown in Formula II,

[0225] in:

[0226] R 1’ Selected from

[0227] Preferably, R 1’ Selected from

[0228] R m 、R n Each independently selected from C1-C6 alkyl;

[0229] Preferably, R m 、R n Each independently selected from methyl, ethyl;

[0230] Preferably, R 1’ Selected from

[0231] Preferably, R 1’ Selected from

[0232] More preferably, R 1’ Selected from

[0233] Most preferably, R 1’ Selected from

[0234] W 31 、W 32 、W 33 、W 34 When both exist, W 31 、W 32 、W 33 、W 34 Each is independently selected from hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkyl substituted with hydroxy, C1-C6 alkoxy, -NR x R y ;

[0235] Preferably, W 31 、W 32 、W 33 、W 34 When both exist, W 31 、W 32 、W 33 、W 34 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy;

[0236] Preferably, W 31 、W 32 、W 33 、W 34 When both exist, W 31 、W 32 、W33 、W 34 Any one of them is selected from hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl, -NR x R y , the rest are hydrogen; or, W 31 、W 32 、W 33 、W 34 Among them, any two are selected from hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, and the rest are hydrogen;

[0237] R x 、R y Each is independently selected from hydrogen, C1-C6 alkyl; preferably, R x 、R y wherein any one is selected from C1-C6 alkyl and the other is hydrogen; more preferably, R x 、R y Among them, any one is methyl and the other is hydrogen;

[0238] Preferably, W 31 、W 32 、W 33 、W 34 When both exist, W 31 、W 32 、W 33 、W 34 wherein any one of them is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkyl substituted with hydroxy, and the rest are hydrogen; or, W 31 、W 32 、W 33 、W 34 Among them, any two are selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, and the rest are hydrogen;

[0239] More preferably, W 31 、W 32 、W 33 、W 34 When both exist, W 31 、W 32 、W 33 、W 34 Among them, any one is selected from hydrogen, fluorine, hydroxy, methyl, ethyl, methoxy, ethoxy, The remainder is hydrogen; or, W 31 、W 32 、W 33 、W 34 Among them, any two are selected from hydrogen, fluorine, chlorine, hydroxyl, methyl, methoxy, and the rest are hydrogen;

[0240] More preferably, W 31 、W 32 、W 33 、W 34 When both exist, W 31 、W 32 、W 33 、W 34 Among them, any one is selected from hydrogen, fluorine, methyl, ethyl, methoxy, The remainder is hydrogen; or, W 31 、W 32 、W 33 、W 34 Among them, any two are selected from hydrogen, fluorine, chlorine, methyl, methoxy, and the rest are hydrogen;

[0241] W 31 、W 32 、W 33 Both exist, but W does not exist 34 When W 31 、W 32 、W 33 Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and the rest are hydrogen;

[0242] Preferably, W 31 、W 32 、W 33 Both exist, but W does not exist 34 When W 31 、W 32 、W 33 Among them, any one is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and the rest are hydrogen;

[0243] More preferably, W 31 、W 32 、W 33 Both exist, but W does not exist 34 When W 31 、W 32 、W 33 Among them, any one is selected from hydrogen, methyl, methoxy, and the rest are hydrogen;

[0244] Preferably, R 1’ Selected from

[0245] Most preferably, R 1’ Selected from

[0246] R 2Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl;

[0247] Preferably, R 2 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl;

[0248] More preferably, R 2 Selected from methyl, ethyl, n-propyl,

[0249] R 3 Selected from:

[0250] 1) in:

[0251] Z 1 , Z 3 , Z 4 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0252] Preferably, Z 1 , Z 3 , Z 4 Each is independently selected from hydrogen, C1-C6 alkyl;

[0253] More preferably, Z 1 , Z 3 , Z 4 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen;

[0254] More preferably, Z 1 , Z 3 , Z 4 Among them, any one is methyl and the rest are hydrogen;

[0255] Most preferably, As a whole,

[0256] 2) in:

[0257] Z 1 , Z 3 , Z 5 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0258] Preferably, Z 1 , Z 3 , Z 5 Each is independently selected from hydrogen, C1-C6 alkyl;

[0259] More preferably, Z 1 , Z 3 , Z5 Among them, any two are selected from C1-C6 alkyl, and the rest are hydrogen;

[0260] More preferably, Z 1 、Z 3 、Z 5 are each independently selected from hydrogen, methyl;

[0261] More preferably, Z 1 、Z 3 、Z 5 Among them, any two are methyl groups and the rest are hydrogen;

[0262] Most preferably, As a whole,

[0263] 3) in:

[0264] Z 1 、Z 3 、Z 4 、Z 5 Each is independently selected from hydrogen, nitro, cyano, halogen, C1-C6 alkyl;

[0265] Preferably, Z 1 、Z 3 、Z 4 、Z 5 Each is independently selected from hydrogen, C1-C6 alkyl;

[0266] More preferably, Z 1 、Z 3 、Z 4 、Z 5 Among them, any one is selected from hydrogen, C1-C6 alkyl, and the rest are hydrogen;

[0267] More preferably, Z 1 、Z 3 、Z 4 、Z 5 are each independently selected from hydrogen, methyl;

[0268] More preferably, Z 1 、Z 3 、Z 4 、Z 5 Among them, any one is selected from hydrogen and methyl, and the rest are hydrogen;

[0269] Most preferably, As a whole, selected

[0270] 4) in:

[0271] Z1 、Z 2 、Z 3 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0272] Preferably, Z 1 、Z 2 、Z 3 Each is independently selected from hydrogen, C1-C6 alkyl;

[0273] More preferably, Z 1 、Z 2 、Z 3 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen;

[0274] More preferably, Z 1 、Z 2 、Z 3 Among them, any one is selected from methyl, and the rest are hydrogen;

[0275] Most preferably, As a whole,

[0276] Preferably, R 3 Selected from:

[0277] 1) in:

[0278] Z 1 、Z 3 、Z 4 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0279] Preferably, Z 1 、Z 3 、Z 4 Each is independently selected from hydrogen, C1-C6 alkyl;

[0280] More preferably, Z 1 、Z 3 、Z 4 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen;

[0281] More preferably, Z 1 、Z 3 、Z 4 Among them, any one is methyl and the rest are hydrogen;

[0282] Most preferably, As a whole,

[0283] 2) in:

[0284] Z 1 、Z 3 、Z 5 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0285] Preferably, Z 1 、Z 3 、Z 5 Each is independently selected from hydrogen, C1-C6 alkyl;

[0286] More preferably, Z 1 、Z 3 、Z 5 Among them, any two are selected from C1-C6 alkyl, and the rest are hydrogen;

[0287] More preferably, Z 1 、Z 3 、Z 5 are each independently selected from hydrogen, methyl;

[0288] More preferably, Z 1 、Z 3 、Z 5 Among them, any two are methyl groups and the rest are hydrogen;

[0289] Most preferably, As a whole,

[0290] Preferably, R 3 Selected from

[0291] Most preferably, R 3 Selected from

[0292] In some embodiments, the compound has the structural formula shown in Formula III,

[0293] in:

[0294] W 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene-O-C1-C6 alkylene, R c R d N-C1-C6 alkylene, O=S(R e R f )=N-C1-C6 alkylene, R c R dNC(=O)-C1-C6 alkylene, C3-C6 cycloalkyl-SO2-, 3-7-membered saturated heterocyclyl, 3-7-membered saturated heterocyclyl-C1-C6 alkylene, 5-6-membered heteroaryl, 5-6-membered heteroaryl-C1-C6 alkylene, 8-10-membered saturated bridged heterocyclyl, and the 3-7-membered saturated heterocyclyl, 5-6-membered heteroaryl, and 8-10-membered saturated bridged heterocyclyl are each independently optionally substituted by 1-2 groups selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C(=O)-, hydroxy-C1-C6 alkylene-C(=O)-, and 3-6-membered saturated heterocyclyl, and the C1-C6 alkylene is optionally substituted by hydroxy;

[0295] Preferably, W 4 Selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene-O-C1-C6 alkylene, O=S(R e R f )=N-C1-C6 alkylene, R c R d N-C1-C6 alkylene, R c R d NC(=O)-C1-C6 alkylene, C3-C6 cycloalkyl-SO2-, 3-7-membered saturated heterocyclyl, 3-7-membered saturated heterocyclyl-C1-C6 alkylene, 5-6-membered heteroaryl, 5-6-membered heteroaryl-C1-C6 alkylene, 8-membered saturated bridged heterocyclyl, and the 3-7-membered saturated heterocyclyl and 8-membered saturated bridged heterocyclyl are each independently optionally substituted by 1-2 groups selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C(=O)-, hydroxy-C1-C6 alkylene-C(=O)-, and 4-membered saturated heterocyclyl, and the C1-C6 alkylene is optionally substituted by hydroxy;

[0296] More preferably, W 4 Selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene-O-C1-C6 alkylene, O=S(R e R f )=N-C1-C6 alkylene, R c R d N-C1-C6 alkylene, R c R dNC(=O)-C1-C6 alkylene, C3-C6 cycloalkyl-SO2-, 3-7 membered saturated heterocyclic group, 3-7 membered saturated heterocyclic group-C1-C6 alkylene, 5-6 membered heteroaryl, 5-6 membered heteroaryl-C1-C6 alkylene, 8 membered saturated bridged heterocyclic group, and the 3-7 membered saturated heterocyclic group and the 8 membered saturated bridged heterocyclic group are each independently optionally substituted by 1-2 (preferably 1) selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C(=O)-, hydroxy-C1-C6 alkylene-C(=O)-, 4 membered saturated heterocyclic group (preferably ) group, the C1-C6 alkylene group is optionally substituted by a hydroxyl group, the 3-7 membered saturated heterocyclic group is selected from The 5-6 membered heteroaryl group is selected from The 8-membered bridged heterocyclic group is

[0297] R c 、R d Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkylene, hydroxy-substituted C1-C6 alkyl, C1-C6 alkyl-C(=O)-, C2-C6 alkynyl-C1-C6 alkylene, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3-6 membered saturated heterocyclic group; or, R c 、R d Together with the nitrogen atom to which they are commonly attached, they form a 3-6 membered saturated heterocyclic ring, and the 3-6 membered saturated heterocyclic ring is optionally substituted by 1-2 groups selected from C1-C6 alkyl and halogen;

[0298] Preferably, R c 、R d Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkylene, hydroxy-substituted C1-C6 alkyl, C1-C6 alkyl-C(=O)-, C2-C6 alkynyl-C1-C6 alkylene, C1-C6 haloalkyl, C3-C6 cycloalkyl, 5-membered saturated heterocyclic group; or, R c 、R d Together with the nitrogen atom to which they are commonly attached, they form a 4-5 membered saturated heterocyclic ring, and the 4-5 membered saturated heterocyclic ring is optionally substituted by 1-2 groups selected from C1-C6 alkyl and halogen;

[0299] More preferably, R c 、R dEach is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkylene, hydroxy-substituted C1-C6 alkyl, C1-C6 alkyl-C(=O)-, C2-C6 alkynyl-C1-C6 alkylene, C1-C6 haloalkyl, C3-C6 cycloalkyl, Or, R c 、R d Together with the N atoms they are connected to, they form And the Each is independently optionally substituted by 1-2 groups selected from C1-C6 alkyl, halogen;

[0300] Most preferably, R c 、R d are each independently selected from hydrogen, methyl, ethyl, isopropyl, Acetyl, Cyclopropyl, cyclobutyl, Or, R c 、R d Together with the N atoms they are connected to, they form

[0301] R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl;

[0302] Preferably, R e 、R f Each independently selected from C1-C6 alkyl;

[0303] More preferably, R e 、R f is methyl;

[0304] More preferably, W 4 Selected from hydrogen, methyl, ethyl, difluoromethyl, trideuterated methyl,

[0305] Most preferably, W 4 Selected from hydrogen, methyl, ethyl, difluoromethyl, trideuterated methyl,

[0306] W 5 、W 6 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and W 5 、W 6 Not simultaneously hydrogen;

[0307] Preferably, W 5 、W 6 Among them, any one is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and the other is hydrogen;

[0308] Preferably, W 5 、W 6 Among them, any one is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and the other is hydrogen;

[0309] More preferably, W 5 、W 6 Among them, any one is selected from hydrogen, chlorine, methyl, ethyl, methoxy, difluoromethyl, trifluoromethyl, and the other is hydrogen;

[0310] More preferably, W 5 、W 6 Among them, any one is selected from chlorine, methyl, ethyl, methoxy, difluoromethyl, trifluoromethyl, and the other is hydrogen;

[0311] More preferably, As a whole, selected

[0312] Most preferably, As a whole, selected

[0313] R 2 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl;

[0314] Preferably, R 2 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl;

[0315] More preferably, R 2 Selected from methyl, ethyl, n-propyl, trifluoromethyl;

[0316] R 3 Selected from:

[0317] 1) in:

[0318] R 7 Selected from hydrogen, C1-C6 alkyl;

[0319] Preferably, R7 is selected from hydrogen, methyl;

[0320] 2) in:

[0321] Z 1 、Z 2 、Z 3 、Z 4 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0322] Preferably, Z 1 、Z 2 、Z 3 、Z 4 Each is independently selected from hydrogen, C1-C6 alkyl;

[0323] More preferably, Z 1 、Z 2 、Z 3 、Z 4 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen;

[0324] More preferably, Z 1 、Z 2 、Z 3 、Z 4 Among them, any one is methyl and the rest are hydrogen;

[0325] Most preferably, As a whole,

[0326] 3) in:

[0327] Z 1 、Z 3 、Z 4 、Z 5 Each is independently selected from hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, R a R b NC(=O)-,R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl;

[0328] Preferably, Z 1 、Z 3 、Z 4 、Z 5 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, R a R b NC(=O)-,R a、R b Each is independently selected from hydrogen, C1-C6 alkyl;

[0329] More preferably, Z 1 , Z 3 , Z 4 , Z 5 Any one of them is selected from C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, R a R b NC(=O)-, and R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl, and the rest is hydrogen; or, Z 1 , Z 3 , Z 4 , Z 5 Among them, any two are selected from halogen, C1-C6 alkyl, R a R b NC(=O)-, and R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl, and the rest is hydrogen;

[0330] More preferably, Z 1 , Z 3 , Z 4 , Z 5 Each independently selected from hydrogen, fluorine, methyl, difluoromethyl, cyclopropyl,

[0331] More preferably, Z 1 , Z 3 , Z 4 , Z 5 Among them, any one is selected from methyl, Cyclopropyl, difluoromethyl, and the rest are hydrogen; or, Z 1 , Z 3 , Z 4 , Z 5 Any two of them are selected from fluorine, methyl, The rest is hydrogen;

[0332] Most preferably, As a whole, selected

[0333] 4) in:

[0334] Z 1 , Z 3 , Z 4Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0335] Preferably, Z 1 , Z 3 , Z 4 Each is independently selected from hydrogen, C1-C6 alkyl;

[0336] More preferably, Z 1 , Z 3 , Z 4 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen;

[0337] More preferably, Z 1 , Z 3 , Z 4 Among them, any one is methyl and the rest are hydrogen;

[0338] Most preferably, As a whole,

[0339] 5) in:

[0340] Z 1 , Z 2 , Z 3 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0341] Preferably, Z 1 , Z 2 , Z 3 Each is independently selected from hydrogen, C1-C6 alkyl;

[0342] More preferably, Z 1 , Z 2 , Z 3 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen;

[0343] More preferably, Z 1 , Z 2 , Z 3 Among them, any one is methyl and the rest are hydrogen;

[0344] Most preferably, As a whole,

[0345] 6) in:

[0346] Z 1 , Z 3 , Z 5 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0347] Preferably, Z 1 、Z 3 、Z 5 Each is independently selected from hydrogen, C1-C6 alkyl;

[0348] More preferably, Z 1 、Z 3 、Z 5 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen; or, Z 1 、Z 3 、Z 5 Among them, any two are selected from C1-C6 alkyl, and the rest are hydrogen;

[0349] More preferably, Z 1 、Z 3 、Z 5 are each independently selected from hydrogen, methyl;

[0350] More preferably, Z 1 、Z 3 、Z 5 In which any one is methyl and the rest are hydrogen; or, Z 1 、Z 3 、Z 5 Among them, any two are methyl groups and the rest are hydrogen;

[0351] Most preferably, As a whole, selected

[0352] 7) in:

[0353] Z 2 、Z 4 、Z 5 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0354] Preferably, Z 2 、Z 4 、Z 5 Each is independently selected from hydrogen, C1-C6 alkyl;

[0355] More preferably, Z 2 、Z 4 、Z 5 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen;

[0356] More preferably, Z 2 、Z 4 、Z 5 Among them, any one is methyl and the rest are hydrogen;

[0357] Most preferably, As a whole,

[0358] 8) in:

[0359] Z 1 、Z 2 、Z 3 、Z 4 、Z 5 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0360] Preferably, Z 1 、Z 2 、Z 3 、Z 4 、Z 5 Each is independently selected from hydrogen, cyano, C1-C6 alkyl;

[0361] More preferably, Z 1 、Z 2 、Z 3 、Z 4 、Z 5 Among them, any two are selected from cyano and C1-C6 alkyl, and the rest are hydrogen;

[0362] More preferably, Z 1 、Z 2 、Z 3 、Z 4 、Z 5 Among them, any two are selected from cyano and methyl, and the rest are hydrogen;

[0363] Most preferably, As a whole,

[0364] 9) 5-9 membered heteroaryl, wherein the 5-9 membered heteroaryl is optionally substituted by 1-2 groups selected from C1-C6 alkyl, cyano; preferably selected from And the Each independently optionally substituted by 1-2 groups selected from C1-C6 alkyl, cyano; more preferably selected from

[0365] Preferably, R 3 Selected from

[0366] In some embodiments, the compound has the structural formula shown in Formula III-1,

[0367] in:

[0368] W 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene-O-C1-C6 alkylene, R c R d N-C1-C6 alkylene, R c R d NC(=O)-C1-C6 alkylene, 3-7-membered saturated heterocyclyl, 3-7-membered saturated heterocyclyl-C1-C6 alkylene, 5-6-membered heteroaryl, 5-6-membered heteroaryl-C1-C6 alkylene, 8-10-membered saturated bridged heterocyclyl, and the 3-7-membered saturated heterocyclyl, 5-6-membered heteroaryl, and 8-10-membered saturated bridged heterocyclyl are each independently optionally substituted by 1-2 groups selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C(=O)-, hydroxy-C1-C6 alkylene-C(=O)-, and 3-6-membered saturated heterocyclyl, and the C1-C6 alkylene is optionally substituted by hydroxy;

[0369] Preferably, W 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene-O-C1-C6 alkylene, R c R d N-C1-C6 alkylene, R c R d NC(=O)-C1-C6 alkylene, 3-7-membered saturated heterocyclyl, 3-7-membered saturated heterocyclyl-C1-C6 alkylene, 5-6-membered heteroaryl, 5-6-membered heteroaryl-C1-C6 alkylene, 8-membered saturated bridged heterocyclyl, and the 3-7-membered saturated heterocyclyl and 8-membered saturated bridged heterocyclyl are each independently optionally substituted by 1-2 groups selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C(=O)-, hydroxy-C1-C6 alkylene-C(=O)-, and 4-membered saturated heterocyclyl, and the C1-C6 alkylene is optionally substituted by hydroxy;

[0370] More preferably, W 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene-O-C1-C6 alkylene, R c R dN-C1-C6 alkylene, R c R d NC(=O)-C1-C6 alkylene, 3-7 membered saturated heterocyclic group, 3-7 membered saturated heterocyclic group-C1-C6 alkylene, 5-6 membered heteroaryl, 5-6 membered heteroaryl-C1-C6 alkylene, 8 membered saturated bridged heterocyclic group, and the 3-7 membered saturated heterocyclic group and the 8 membered saturated bridged heterocyclic group are each independently optionally substituted by 1-2 (preferably 1) selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C(=O)-, hydroxy-C1-C6 alkylene-C(=O)-, 4 membered saturated heterocyclic group (preferably ) group, the C1-C6 alkylene group is optionally substituted by a hydroxyl group, the 3-7 membered saturated heterocyclic group is selected from The 5-6 membered heteroaryl group is selected from The 8-membered bridged heterocyclic group is

[0371] R c 、R d Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkylene, hydroxy-substituted C1-C6 alkyl, C1-C6 alkyl-C(=O)-, C2-C6 alkynyl-C1-C6 alkylene, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3-6 membered saturated heterocyclic group; or, R c 、R d Together with the nitrogen atom to which they are commonly attached, they form a 3-6 membered saturated heterocyclic ring, and the 3-6 membered saturated heterocyclic ring is optionally substituted by 1-2 groups selected from C1-C6 alkyl and halogen;

[0372] Preferably, R c 、R d Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkylene, hydroxy-substituted C1-C6 alkyl, C1-C6 alkyl-C(=O)-, C2-C6 alkynyl-C1-C6 alkylene, C1-C6 haloalkyl, C3-C6 cycloalkyl, 5-membered saturated heterocyclic group; or, R c 、R d Together with the nitrogen atom to which they are commonly attached, they form a 4-5 membered saturated heterocyclic ring, and the 4-5 membered saturated heterocyclic ring is optionally substituted by 1-2 groups selected from C1-C6 alkyl and halogen;

[0373] More preferably, R c 、R dEach is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkylene, hydroxy-substituted C1-C6 alkyl, C1-C6 alkyl-C(=O)-, C2-C6 alkynyl-C1-C6 alkylene, C1-C6 haloalkyl, C3-C6 cycloalkyl, Or, R c 、R d Together with the N atoms they are connected to, they form And the Each is independently optionally substituted by 1-2 groups selected from C1-C6 alkyl, halogen;

[0374] Most preferably, R c 、R d are each independently selected from hydrogen, methyl, ethyl, isopropyl, Acetyl, Cyclopropyl, cyclobutyl, Or, R c 、R d Together with the N atoms they are connected to, they form

[0375] Most preferably, W 4 Selected from hydrogen, methyl, ethyl, difluoromethyl, trideuterated methyl,

[0376] W 5 、W 6 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and W 5 、W 6 Not simultaneously hydrogen;

[0377] Preferably, W 5 、W 6 Among them, any one is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and the other is hydrogen;

[0378] More preferably, W 5 、W 6 Among them, any one is selected from chlorine, methyl, ethyl, methoxy, difluoromethyl, trifluoromethyl, and the other is hydrogen;

[0379] Most preferably, As a whole, selected

[0380] R 2Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl;

[0381] Preferably, R 2 Selected from C1-C6 alkyl, C3-C6 cycloalkyl;

[0382] More preferably, R 2 Selected from methyl, ethyl,

[0383] R 7 Selected from hydrogen, C1-C6 alkyl;

[0384] Preferably, R 7 Selected from hydrogen and methyl.

[0385] In some embodiments, the compound has the structural formula shown in Formula III-2,

[0386] in:

[0387] W 4 Selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, 3-6 membered saturated heterocyclic group, O=S(R e R f )=N-C1-C6 alkylene, R c R d N-C1-C6 alkylene, R c R d NC(=O)-C1-C6 alkylene, C3-C6 cycloalkyl-SO2-, wherein the 3-6 membered saturated heterocyclic group is optionally substituted by a C1-C6 alkyl group;

[0388] Preferably, W 4 Selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, 4-6 membered saturated heterocyclic group, O=S(R e R f )=N-C1-C6 alkylene, R c R d N-C1-C6 alkylene, R c R d NC(=O)-C1-C6 alkylene, C3-C6 cycloalkyl-SO2-, wherein the 4-6 membered saturated heterocyclic group is optionally substituted by a C1-C6 alkyl group;

[0389] More preferably, W 4 Selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, 4-6 membered saturated heterocyclic group, O=S(R e Rf )=N-C1-C6 alkylene, R c R d N-C1-C6 alkylene, R c R d NC(=O)-C1-C6 alkylene, C3-C6 cycloalkyl-SO2-, the 4-6 membered saturated heterocyclic group is optionally substituted by a C1-C6 alkyl group, the 4-6 membered saturated heterocyclic group is selected from

[0390] R c 、R d Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene;

[0391] Preferably, R c 、R d Each independently selected from hydrogen, methyl, ethyl,

[0392] R e 、R f Each is independently selected from hydrogen, C1-C6 alkyl;

[0393] Preferably, R e 、R f Each independently selected from C1-C6 alkyl;

[0394] More preferably, R e 、R f is methyl;

[0395] More preferably, W 4 Selected from methyl, trideuterated methyl,

[0396] Most preferably, W 4 Selected from methyl, trideuterated methyl,

[0397] W 5 、W 6 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and W 5 、W 6 Not simultaneously hydrogen;

[0398] Preferably, W 5 、W 6 Among them, any one is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and the other is hydrogen;

[0399] Preferably, W 5 、W6 Among them, any one is selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, and the other is hydrogen;

[0400] More preferably, W 5 、W 6 Among them, any one is selected from hydrogen, chlorine, methyl, difluoromethyl, and the other is hydrogen;

[0401] More preferably, W 5 、W 6 Among them, any one is selected from chlorine, methyl, difluoromethyl, and the other is hydrogen;

[0402] More preferably, As a whole, selected

[0403] Most preferably, As a whole, selected

[0404] R 2 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl;

[0405] Preferably, R 2 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl;

[0406] More preferably, R 2 Selected from methyl, ethyl, n-propyl, trifluoromethyl;

[0407] R 3 Selected from:

[0408] 1) in:

[0409] Z 1 、Z 2 、Z 3 、Z 4 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0410] Preferably, Z 1 、Z 2 、Z 3 、Z 4 Each is independently selected from hydrogen, C1-C6 alkyl;

[0411] More preferably, Z 1 、Z 2 、Z 3 、Z 4Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen;

[0412] More preferably, Z 1 , Z 2 , Z 3 , Z 4 Among them, any one is methyl and the rest are hydrogen;

[0413] Most preferably, As a whole,

[0414] 2) in:

[0415] Z 1 , Z 3 , Z 4 , Z 5 Each is independently selected from hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, R a R b NC(=O)-,R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl;

[0416] Preferably, Z 1 , Z 3 , Z 4 , Z 5 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, R a R b NC(=O)-,R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl;

[0417] More preferably, Z 1 , Z 3 , Z 4 , Z 5 Any one of them is selected from C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, R a R b NC(=O)-, and R a 、R b Each is independently selected from hydrogen, C1-C6 alkyl, and the rest is hydrogen; or, Z 1 , Z 3 , Z 4 , Z 5 Among them, any two are selected from halogen, C1-C6 alkyl, R a R b NC(=O)-, and Ra 、R b Each is independently selected from hydrogen, C1-C6 alkyl, and the rest is hydrogen;

[0418] More preferably, Z 1 , Z 3 , Z 4 , Z 5 Each independently selected from hydrogen, fluorine, methyl, difluoromethyl, cyclopropyl,

[0419] More preferably, Z 1 , Z 3 , Z 4 , Z 5 Among them, any one is selected from methyl, Cyclopropyl, difluoromethyl, and the rest are hydrogen; or, Z 1 , Z 3 , Z 4 , Z 5 Any two of them are selected from fluorine, methyl, The rest is hydrogen;

[0420] Most preferably, As a whole, selected

[0421] 3) in:

[0422] Z 1 , Z 3 , Z 4 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0423] Preferably, Z 1 , Z 3 , Z 4 Each is independently selected from hydrogen, C1-C6 alkyl;

[0424] More preferably, Z 1 , Z 3 , Z 4 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen;

[0425] More preferably, Z 1 , Z 3 , Z 4 Among them, any one is methyl and the rest are hydrogen;

[0426] Most preferably, As a whole,

[0427] 4) in:

[0428] Z 1 、Z 2 、Z 3 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0429] Preferably, Z 1 、Z 2 、Z 3 Each is independently selected from hydrogen, C1-C6 alkyl;

[0430] More preferably, Z 1 、Z 2 、Z 3 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen;

[0431] More preferably, Z 1 、Z 2 、Z 3 Among them, any one is methyl and the rest are hydrogen;

[0432] Most preferably, As a whole,

[0433] 5) in:

[0434] Z 1 、Z 3 、Z 5 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0435] Preferably, Z 1 、Z 3 、Z 5 Each is independently selected from hydrogen, C1-C6 alkyl;

[0436] More preferably, Z 1 、Z 3 、Z 5 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen; or, Z 1 、Z 3 、Z 5 Among them, any two are selected from C1-C6 alkyl, and the rest are hydrogen;

[0437] More preferably, Z 1 、Z 3 、Z 5 are each independently selected from hydrogen, methyl;

[0438] More preferably, Z 1、Z 3 、Z 5 In which any one is methyl and the rest are hydrogen; or, Z 1 、Z 3 、Z 5 Among them, any two are methyl groups and the rest are hydrogen;

[0439] Most preferably, As a whole, selected

[0440] 6) in:

[0441] Z 2 、Z 4 、Z 5 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0442] Preferably, Z 2 、Z 4 、Z 5 Each is independently selected from hydrogen, C1-C6 alkyl;

[0443] More preferably, Z 2 、Z 4 、Z 5 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen;

[0444] More preferably, Z 2 、Z 4 、Z 5 Among them, any one is methyl and the rest are hydrogen;

[0445] Most preferably, As a whole,

[0446] 7) in:

[0447] Z 1 、Z 2 、Z 3 、Z 4 、Z 5 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl;

[0448] Preferably, Z 1 、Z 2 、Z 3 、Z 4 、Z 5 Each is independently selected from hydrogen, cyano, C1-C6 alkyl;

[0449] More preferably, Z 1 、Z2 、Z 3 、Z 4 、Z 5 Among them, any two are selected from cyano and C1-C6 alkyl, and the rest are hydrogen;

[0450] More preferably, Z 1 、Z 2 、Z 3 、Z 4 、Z 5 Among them, any two are selected from cyano and methyl, and the rest are hydrogen;

[0451] Most preferably, As a whole,

[0452] 8) 5-9 membered heteroaryl, wherein the 5-9 membered heteroaryl is optionally substituted by 1-2 groups selected from C1-C6 alkyl, cyano; preferably selected from And the Each independently optionally substituted by 1-2 groups selected from C1-C6 alkyl, cyano; more preferably selected from

[0453] Preferably, R 3 Selected from

[0454] In the second aspect of the present invention, the present invention provides a method for preparing the compound described in any of the above technical solutions, comprising the following steps:

[0455] Wherein, X is halogen, R 1 、R 2 、R 3 The definition of is as described above.

[0456] Reaction conditions:

[0457] (a) Coupling reaction catalyzed by palladium metal;

[0458] (b) coupling reaction catalyzed by palladium metal;

[0459] (c) a coupling reaction catalyzed by metal palladium, or a nucleophilic substitution reaction under acidic conditions, or a nucleophilic substitution reaction under alkaline conditions;

[0460] (d) nucleophilic substitution reaction under acidic conditions or nucleophilic substitution reaction under alkaline conditions;

[0461] The metal palladium catalyst is selected from palladium acetate, tetrakis(triphenylphosphine)palladium, bistriphenylphosphine palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, and tris(dibenzylideneacetone)dipalladium;

[0462] The alkaline conditions refer to the conditions in which any of the following substances exist: triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride;

[0463] The acidic conditions refer to the conditions in which any of the following substances exist: acetic acid, trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid.

[0464] In the third aspect of the present invention, the present invention provides a pharmaceutical composition comprising the aforementioned compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate and optionally a pharmaceutically acceptable excipient.

[0465] In the fourth aspect of the present invention, the present invention provides the use of the aforementioned compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate or the aforementioned pharmaceutical composition in the preparation of a drug for preventing and / or treating BRK kinase-mediated diseases.

[0466] In the fifth aspect of the present invention, the present invention provides the aforementioned compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate or the aforementioned pharmaceutical composition, which is used for preventing and / or treating BRK kinase-mediated diseases.

[0467] In the sixth aspect of the present invention, the present invention provides a method for preventing and / or treating BRK kinase-mediated diseases, which comprises administering to a subject in need thereof an effective amount of the aforementioned compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate or the aforementioned pharmaceutical composition.

[0468] In some embodiments, the BRK kinase-mediated disease is selected from breast cancer, gastric cancer, leukemia, skin cancer, head and neck cancer, thyroid cancer, pancreatic cancer, cervical cancer, bladder cancer, ovarian cancer, nasopharyngeal cancer, non-small cell lung cancer, prostate cancer, colon cancer, and esophageal cancer.

[0469] In some embodiments, the BRK kinase-mediated disease is breast cancer or leukemia.

[0470] In some embodiments, the BRK kinase-mediated disease is breast cancer.

[0471] In some embodiments, the BRK kinase-mediated disease is gastric cancer.

[0472] Definition of terms

[0473] It should be understood that the terminology used herein is intended to describe specific embodiments and is not intended to be limiting. In addition, although any method, device, and material similar or equivalent to those described herein may be used for implementing or testing the present invention, preferred methods, devices, and materials are now described.

[0474] In the present invention, unless otherwise explicitly stated, the description method "... are independently selected from" used throughout this document can mean that in different groups, the specific options expressed by the same or different symbols do not affect each other, and can also mean that in the same group, the specific options expressed by the same or different symbols do not affect each other.

[0475] The substituents of the compounds of the present invention are disclosed by group class or range. It is specifically noted that the present invention includes each independent subcombination of the individual members of these group classes and ranges. For example, the term "C1-C6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0476] The term "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms, preferably a "C1-C4 alkyl group", more preferably a "C1-C3 alkyl group", and most preferably a "C1-C2 alkyl group". Examples of "C1-C6 alkyl" include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. Examples of "C1-C4 alkyl" include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and the like. Examples of "C1-C3 alkyl" include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl, isopropyl), and the like. Examples of "C1-C2 alkyl" include, but are not limited to, methyl and ethyl.

[0477] The term "C1-C6 haloalkyl" refers to a group in which one or more (such as 2, 3 or 4) hydrogen atoms in any of the above C1-C6 alkyl groups are replaced by halogen (preferably fluorine), examples of which include monofluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl, etc., preferably trifluoromethyl.

[0478] The term "deuterated C1-C6 alkyl group" refers to a group in which one or more (eg, 2, 3, or 4) hydrogen atoms in any of the above C1-C6 alkyl groups are replaced by deuterium, and examples include trideuterated methyl group.

[0479] The term "C1-C6 alkoxy" refers to any of the above C1-C6 alkyl groups linked to the rest of the molecule via an oxygen atom (-O-), and examples include methoxy, ethoxy, isopropoxy, and the like.

[0480] The term "C1-C6 alkylene" refers to a divalent group obtained by removing a hydrogen atom from any of the above C1-C6 alkyl groups (e.g., C1-C4 alkyl, C1-C3 alkyl, etc.), for example wait.

[0481] The term "C2-C6 alkenyl" refers to a straight or branched chain hydrocarbon group containing 2 to 6 carbon atoms and containing one or more (preferably one) carbon-carbon double bonds.

[0482] The term "C2-C6 alkynyl" refers to a straight or branched chain hydrocarbon group containing 2 to 6 carbon atoms and containing one or more (preferably one) carbon-carbon triple bonds.

[0483] The term "C3-C7 cycloalkyl" refers to a saturated monocyclic hydrocarbon containing 3 to 7 carbon atoms, for example, "C3-C6 cycloalkyl" refers to

[0484] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0485] The term "heteroatom" refers to N, O or S.

[0486] The term "heterocyclic radical" refers to a 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered (preferably 3-7 or 3-6 membered) saturated or partially unsaturated carbocyclic ring, wherein one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclic radicals include, for example, pyrans, pyrrolidines, pyrroline, imidazoline, imidazolidines, pyrazolidines, pyrazoline, thiazoline, thiazolidines, dihydrofuran, tetrahydrofuran, 1,3-dioxolanes, piperidines, piperazines, morpholine, morpholinyl, tetrahydropyrrolyl, thiomorpholinyl, etc. For example, a "6-membered heterocyclic radical" refers to a 6-membered saturated or partially unsaturated carbocyclic ring, wherein one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur. Non-limiting examples of 6-membered heterocyclic radicals include, for example, pyrans, piperidines, piperazines, morpholine, morpholinyl, thiomorpholinyl, etc. For another example, "5-membered heterocyclyl" refers to a 5-membered saturated or partially unsaturated carbocyclic ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, and sulfur. Non-limiting examples of 5-membered heterocyclyls include, for example, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, 1,3-dioxolane, and the like. The term "heterocycle" can be understood with reference to the aforementioned term "heterocyclyl".

[0487] The term "3-7 membered saturated heterocyclic group" refers to a group obtained by replacing at least one carbon atom in any of the above C3-C7 cycloalkyl groups with a heteroatom (N, O or S), such as tetrahydropyrrolyl, morpholinyl, etc.

[0488] The term "8-10 membered saturated bridged heterocyclic group" refers to a group formed by replacing at least one (preferably one) carbon atom in an 8-, 9- or 10-membered bridged carbocyclic group with a heteroatom such as nitrogen, oxygen and sulfur. Specific examples include but are not limited to

[0489] The term "heteroaryl" refers to an aromatic monocyclic group, bicyclic group, tricyclic group or more ring group having at least one heteroatom (N, O or S) in at least one ring of a 5-, 6-, 7-, 8-, 9- or 10-membered ring, wherein the heteroatom-containing ring optionally further comprises 1, 2 or 3 heteroatoms selected from N, O or S. The heteroaryl group of bicyclic or tricyclic or more rings requires that each ring in the bicyclic or tricyclic or polycyclic rings constitute an aromatic system. The non-limiting examples of the heteroaryl group are, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, thioxazolyl, pyrrolyl, phenyl-pyrrolyl, furyl, phenyl-furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzofuranyl, benzothienyl, benzimidazolyl, indazolyl, quinolyl, isoquinolyl etc. The term "heteroaromatic ring" can be understood accordingly with reference to the aforementioned term "heteroaryl".

[0490] From all the above descriptions, it is obvious to a person skilled in the art that any group whose name is a composite name, such as "C1-C6 alkoxy-C1-C6 alkylene", should refer to the group conventionally constructed from the part derived therefrom from left to right, such as "C1-C6 alkylene" substituted by "C1-C6 alkoxy", wherein "C1-C6 alkylene" is as defined above. Specifically, "C1-C6 alkoxy-C1-C6 alkylene" can be, for example, Other similar composite groups can be understood by referring to the above content.

[0491] The term "substituted" means that any one or more hydrogens on the designated atom or group are replaced with the selection of the designated group, provided that the normal valence of the designated atom is not exceeded.

[0492] The term "hydroxy-substituted C1-C6 alkyl" refers to a group formed by replacing one or more (preferably one) hydrogen atoms in any of the above C1-C6 alkyl groups with a hydroxy group, as exemplified by

[0493] In the present invention, “the Each independently optionally substituted by 1-2 groups selected from C1-C6 alkyl, halogen, may or may not be substituted, and if substituted, The respective substituents may be the same or different. Further, if When substituted with two substituents, the two substituents may be the same or different. For other similar definitions, please refer to the above content for understanding.

[0494] As used herein, "treat" generally refers to obtaining a desired pharmacological and / or physiological effect. This effect can be prophylactic, in terms of completely or partially preventing a disease or its symptoms; and / or therapeutic, in terms of partially or completely stabilizing or curing a disease and / or causing side effects due to the disease. As used herein, "treat" encompasses any treatment of a disease in a patient, including: (a) preventing the onset of a disease or symptom in a patient who is susceptible to the disease or symptom but has not yet been diagnosed with the disease; (b) suppressing the symptoms of a disease, i.e., arresting its development; or (c) alleviating the symptoms of a disease, i.e., causing the disease or symptom to regress.

[0495] In the present invention, "subject" refers to a vertebrate. In certain embodiments, the vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, the mammal refers to a human.

[0496] In the present invention, an "effective amount" refers to an amount that is effective at the necessary dosage and time to achieve the desired therapeutic or preventive effect. The "therapeutically effective amount" of the substance / molecule of the present invention may vary according to factors such as the disease state, age, sex and weight of the individual and the ability of the substance / molecule to elicit the desired response in the individual. A therapeutically effective amount also encompasses an amount in which the therapeutically beneficial effects of the substance / molecule outweigh any toxic or deleterious consequences. A "prophylactically effective amount" refers to an amount that is effective at the necessary dosage and time to achieve the desired preventive effect. Typically, but not necessarily, a prophylactic dose is used in subjects before the onset of disease or in the early stages of the disease, so the prophylactic effective amount will be lower than the therapeutically effective amount. In the case of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow down to a certain extent, preferably stop) cancer cell infiltration into surrounding organs; inhibit (i.e., slow down to a certain extent, preferably stop) tumor metastasis; inhibit tumor growth to a certain extent; and / or alleviate one or more symptoms associated with cancer to a certain extent.

[0497] The pharmaceutical compositions of the present invention may contain pharmaceutically acceptable excipients, including but not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable 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, lanolin, etc.

[0498] The pharmaceutical composition of the present invention can be prepared into various forms according to different routes of administration. For example, the pharmaceutical composition can be administered by any of the following methods: oral administration, spray inhalation, rectal administration, nasal administration, buccal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, and intracranial injection or infusion, or administration via an explanted reservoir. Oral and intravenous administration are preferred.

[0499] The compounds of the present invention may optionally be used in combination with one or more other active ingredients, and the dosage and ratio of each can be adjusted by those skilled in the art according to the specific disease and patient conditions and clinical needs.

[0500] As used herein, unless otherwise indicated, the term "prodrug" refers to a derivative that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the present invention. Prodrugs become active compounds only through this reaction under biological conditions, or they have no or only 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).

[0501] When the stereoisomers in the compounds described herein are specifically designated as (R)- or (S)-isomers in the chemical name, it should be understood that the predominant configuration is the (R)-isomer or the (S)-isomer, respectively. Any asymmetric carbon atom may be present in the (R)-, (S)-, or (R, S)-configuration, preferably in the (R)- or (S)-configuration.

[0502] "Solvate" or "solvate" are used interchangeably to refer to a compound that exists in combination with a solvent molecule. The combination may include a stoichiometric amount of a solvent, such as a monohydrate or dihydrate, or may include any amount of water; for example, methanol or ethanol may form an "alcoholate," which may also be stoichiometric or non-stoichiometric. As used herein, the term "solvate" refers to a solid form, i.e., a compound in solution in a solvent, which may be solvated but is not a solvate as the term is used herein.

[0503] As used herein, the term "pharmaceutically acceptable salt" refers to (i) a salt formed by an acidic functional group (e.g., -COOH) present in the compounds provided herein with a suitable inorganic or organic cation (base), and includes, but is not limited to, alkali metal salts, such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts, such as calcium salts, magnesium salts, etc.; other metal salts, such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, etc.; inorganic base salts, such as ammonium salts; organic base salts, such as tert-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucosamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzyl-phenethylamine salts, piperazine salts, tetramethylamine salts, tris(hydroxymethyl)aminomethane salts. and (ii) salts formed by basic functional groups (e.g., -NH2) present in the compounds provided by the present invention and appropriate inorganic or organic anions (acids), including but not limited to hydrohalides, such as hydrofluorides, hydrochlorides, hydrobromides, hydroiodides, etc.; inorganic acid salts, such as nitrates, perchlorates, sulfates, phosphates, etc.; lower alkanesulfonates, such as methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, etc.; arylsulfonates, such as benzenesulfonates, p-toluenesulfonates, etc.; organic acid salts, such as acetates, malates, fumarates, succinates, citrates, tartrates, oxalates, maleates, etc.; amino acid salts, such as glycine, trimethylglycine, arginine, ornithine, glutamate, aspartate, etc.

[0504] Experimental part

[0505] With respect to the examples referred to below, compounds of the invention were synthesized using the methods described herein or other methods well known in the art.

[0506] General purification and analytical methods:

[0507] Thin layer chromatography was performed on silica gel GF254 pre-coated plates (Qingdao Ocean Chemical Plant). Column chromatography separation was performed under medium pressure over silica gel (300-400 mesh, Huangwu Silica Gel Development Reagent Factory, Zhifu District, Yantai City) or by using an ISCO Combiflash Rf200 rapid purification system with pre-packed silica gel cartridges (ISCO or Welch). Thin layer chromatography (TLC) was visualized by UV light (wavelength 254 nm) and by iodine vapor. When necessary, compounds were purified by preparative HPLC using a Waters automated purification system (SunFire™ C18 column, 5 μM, 19 x 50 mm) including an autosampler and fraction collector (2767), a four-solvent binary high-pressure gradient pump (2545), a system flow path (SFO), a 515 compensation pump, a diode array detector (2998), and a QDA quadrupole mass spectrometer. The mobile phases were methanol (supplemented with 0.035% trifluoroacetic acid) and water (supplemented with 0.035% trifluoroacetic acid). Alternatively, an LC3000I high-performance liquid chromatograph (Beijing Innovation Tongheng Chromatography Technology Co., Ltd.) was used. The mobile phases were methanol (supplemented with 0.4% acetic acid) and water (supplemented with 0.4% acetic acid). Mass spectrometry was performed using a Waters liquid chromatography-mass spectrometry system with a mobile phase of methanol (supplemented with 0.035% trifluoroacetic acid) and water (supplemented with 0.035% trifluoroacetic acid).

[0508] 1 H-NMR spectra were recorded on a 600 MHz Bruker Avance 600 or Agilent 400 MHz nuclear magnetic resonance spectrometer. Chemical shifts (δ) are reported in parts per million (ppm) and coupling constants (J) are reported in Hz. The tetramethylsilane signal was used as a reference (δ = 0 ppm). The following abbreviations are used for peak splitting: s = singlet; br.s. = broad signal; d = doublet; t = triplet; m = multiplet; dd = doublet.

[0509] Unless otherwise stated, all final compounds were homogeneous (purity not less than 95%) as determined by high performance liquid chromatography (HPLC).

[0510] Reagents were purified according to Purification of Laboratory Chemicals (Perrin, DD, Armarego, WL F, and Perrins Eds, DR; Pergamon Press: Oxford, 1980). Petroleum ether (60-90°C fraction), ethyl acetate, methanol, and dichloromethane were all analytical grade. DETAILED DESCRIPTION

[0511] The embodiments of the present invention are described in detail below through specific examples, but they are not to be construed as limiting the present invention in any way.

[0512] Compounds can be divided into the following broad categories:

[0513] Among them, W 1 、W 2 、R 4a 、R 4b 、R 5a 、R 5b 、R 6a 、R 6b ,m,R 1’ 、W 4 、W 5 、W 6 、R 2 、R 3 As mentioned above.

[0514] Some of the raw materials and intermediates involved in the synthesis process are as follows:

[0515] 1.2-Chloro-6-bromo-8-methylquinazoline (CAS: 1388046-71-6) is obtained by cyclization of 5-bromo-2-fluoro-3-methylbenzaldehyde (CAS: 903875-64-9, Bidler, Shanghai) and guanidine carbonate (CAS: 593-85-1, Bidler, Shanghai) to give 2-amino-6-bromo-8-methylquinazoline, which is then reacted with antimony trichloride (CAS: 10025-91-9, Aladdin, Shanghai) and tert-butyl nitrite (CAS: 540-80-7, Aladdin, Shanghai);

[0516] 2.2-Chloro-6-bromo-8-ethylquinazoline (cas: 2568323-82-8) was converted from 4-bromo-2-ethyl-1-fluorobenzene (cas: 627463-25-6, Bidex, Shanghai) and lithium diisopropylamide (cas: 4111-54-0, Aladdin, Shanghai) and N,N-dimethylformamide (cas: 68-12-2, Titan Technology, Shanghai) into 2-fluoro-3-ethyl-5-bromobenzaldehyde, and then obtained by a similar method as in (1); 2-chloro-6-bromo-8-trifluoromethylquinazoline was obtained from 5-bromo-2-fluorotrifluorotoluene (cas: 393-37-3, Aladdin, Shanghai) by a similar method;

[0517] 3.2-Chloro-6-bromo-8-isopropylquinazoline, 1-(2-fluoro-5-bromo-phenyl)ethanone (cas: 198477-89-3, Bidler, Shanghai) was reacted with methylmagnesium bromide (cas: 75-16-1, Aladdin, Shanghai) to give 2-(2-fluoro-5-bromo-phenyl)propan-2-ol, and then the hydroxyl group was reduced to give 1-fluoro-2-isopropyl-4-bromobenzene (cas: 112611-93-5), which was subsequently obtained by a method similar to that in (2);

[0518] 4.2-Chloro-6-bromo-8-cyclopropylquinazoline was prepared by reacting 2-iodo-4-bromofluorobenzene (cas: 116272-41-4, Bidler, Shanghai) with cyclopropylboronic acid (cas: 411235-57-9, Aladdin, Shanghai) to give 2-cyclopropyl-4-bromofluorobenzene, which was subsequently obtained by a method similar to that described in (2).

[0519] 5.2-Chloro-6-bromo-8-cyclopropylquinazoline, 2-fluoro-5-bromobenzaldehyde (cas: 93777-26-5, Bidex, Shanghai) and ethyltriphenylphosphonium bromide (cas: 1530-32-1, Bidex, Shanghai) were reacted to give 2-(1-propenyl)-4-bromofluorobenzene, and the double bond was reduced to give 2-n-propyl-4-bromofluorobenzene, which was subsequently obtained by a method similar to that in (2);

[0520] 6. By reacting 4-nitropyrazole (cas: 2075-46-9, Bidler, Shanghai) with 2-bromoethanol (cas: 540-51-2, Bidler, Shanghai) Then reduce the nitro group to obtain;

[0521] 7. and By reacting 3-methyl-4-nitropyrazole (cas: 5334-39-4, Bidler, Shanghai) with 2-bromoethanol (cas: 540-51-2, Bidler, Shanghai), and The mixture is separated and purified to obtain two single isomers, and then the nitro group is reduced;

[0522] The following intermediates were obtained by similar methods:

[0523] The raw materials involved are: tert-butyl bromoacetate (cas: 5292-43-3, Anaiji, Shanghai), 3-bromo-1-propanol (cas: 627-18-9, Bidex, Shanghai), 3-iodooxetane (cas: 26272-85-5, Bidex, Shanghai), deuterated iodomethane (cas: 865-50-9, Aladdin, Shanghai), sodium difluorochloroacetate (cas: 1895-39-2, Bidex, Shanghai), 1,2-epoxy-2-methylpropane (cas: 558-30-5, Anaiji, Shanghai), 3-(difluoromethyl)-4-nitro-1H-pyrazole (cas: 1789048-54-9, Bidex, Shanghai), 3-chloro-4-nitro-1H-pyrazole (cas: 35852-75-6, Bidex, Shanghai);

[0524] 8. From (7) Reaction with methanesulfonyl chloride (cas: 124-63-0, West Asia, Shandong) to obtain Then react with methylethylamine (cas: 624-78-2, Myrel, Shanghai) to obtain Further reduction of the nitro group; from (7) The similar method can be used to obtain

[0525] The following intermediates were obtained by similar methods:

[0526] The raw materials involved are: N-(2-methoxyethyl)methylamine (cas: 38256-93-8, Bidex, Shanghai), 2-methyl-1-methylamino-propane-2-ol (cas: 67622-86-0, Bidex, Shanghai), (R)-3-methylmorpholine (cas: 74572-04-6, Bidex, Shanghai), (S)-3-methylmorpholine (cas: 350595-57-2, Bidex, Shanghai), 1-(2-methoxyethyl)piperazine (cas: 13484-40-7, Bidex, Shanghai), tetrahydropyrrole (cas: 123-75-1, Bidex, Shanghai), imidazole (cas: 288-32-4, McLean, Shanghai), (R)-3-aminotetrahydrofuran (cas: 111769-26-7, Bidex, Shanghai);

[0527] 9. From (8) Reaction with dimethylsulfenyl imide (cas: 1520-31-6, Aladdin, Shanghai) to obtain Then reduce the nitro group to obtain;

[0528] 10. From (7) Reaction with iodomethane (cas: 74-88-4, West Asia, Shandong) to obtain Then reduce the nitro group to obtain;

[0529] 11. and Obtained by the reaction of 1-methyl-4-piperidinol (cas: 106-52-5, Bidler, Shanghai) with methanesulfonyl chloride (cas: 124-63-0, West Asia, Shandong) Then react with 3-methyl-4-nitropyrazole (cas: 5334-39-4, Bidler, Shanghai) to obtain and The mixture was separated and purified to obtain two single isomers, and then the nitro group was reduced; the following intermediates were obtained by a similar method:

[0530] The raw materials involved are: 1-isopropyl-4-piperidinol (cas: 5570-78-5, Anaiji, Shanghai), tropine (cas: 120-29-6, Bidex, Shanghai), 4-nitro-5-trifluoromethylpyrazole (cas: 1046462-99-0, Bidex, Shanghai), 3-methoxy-4-nitropyrazole (cas: 400755-41-1, Bidex, Shanghai), 4-hydroxy- 1-Methylhexahydroazepine (cas: 19065-49-7, Bidex, Shanghai), 3-hydroxy-1-methyltetrahydropyrrole (cas: 13220-33-2, Bidex, Shanghai), 1-isopropyl-3-hydroxytetrahydropyrrole (cas: 42729-56-6, Bidex, Shanghai), (S)-1-methoxy-2-propanol (cas: 26550-55-0, Bidex, Shanghai);

[0531] 12. and A mixture of N-Boc-4-iodopiperidine (cas: 301673-14-3, Bidex, Shanghai) and 3-methyl-4-nitropyrazole (cas: 5334-39-4, Bidex, Shanghai) was obtained by reacting and The following mixtures of regioisomers were obtained by similar methods:

[0532] The raw materials involved are: 4-iodotetrahydropyran (cas: 25637-18-7, Bidex, Shanghai), 3-iodotetrahydrofuran (cas: 121138-01-0, Bidex, Shanghai), 2-bromoethyl methyl ether (cas: 6482-24-2, Bidex, Shanghai), 1-bromo-2-(2-methoxyethoxy)ethane (cas: 54149-17-6, Bidex, Shanghai);

[0533] 13. and A mixture of and After removing Boc from the mixture, and The mixture was then reacted with 3-oxetanone (cas: 6704-31-0, Bidler, Shanghai) to obtain and A mixture of further reducing nitro groups;

[0534] 14. and A mixture of (9) and The mixture was de-Boced and reacted with deuterated iodomethane (cas: 865-50-9, Aladdin, Shanghai) to obtain and A mixture of nitro groups and then reducing the nitro group;

[0535] 15. and A mixture of 3-methyl-4-nitropyrazole (cas: 5334-39-4, Bidler, Shanghai) and (R)-2-hydroxypropionic acid methyl ester (cas: 17392-83-5, Bidler, Shanghai) was obtained by Mitsunobu reaction. and The mixture was then reduced to obtain the nitro group; (R)-2-hydroxypropionic acid methyl ester was replaced by 3-hydroxyethyl oxetane (cas: 251922-46-0, Bidex, Shanghai), and a similar method was used to obtain and mixture;

[0536] 16. and A mixture of 3-methyl-4-nitropyrazole (cas: 5334-39-4, Bidex, Shanghai) and 5-pyrimidineboronic acid (cas: 109299-78-7, Bidex, Shanghai) was obtained. and A mixture of nitro groups and then reducing the nitro group;

[0537] 17. and A mixture of 3-methyl-4-nitropyrazole (cas: 5334-39-4, Bidler, Shanghai) and (R)-epoxypropyl methyl ether (cas: 64491-70-9, Aladdin, Shanghai) was obtained by reacting and A mixture of nitro groups and then reducing the nitro group;

[0538] 18. and A mixture of (7) and The mixture was reacted with methanesulfonyl chloride (cas: 124-63-0, West Asia, Shandong) to obtain and The mixture is further reacted with dimethylamine hydrochloride (cas: 506-59-2, Anaiji, Shanghai) to obtain and A mixture of nitro groups was obtained by reducing the nitro group; by a similar method, dimethylamine hydrochloride was replaced by diethylamine (cas: 109-89-7, Anaiji, Shanghai), and the obtained and mixture;

[0539] 19. and A mixture of 3-methyl-4-nitropyrazole (cas: 5334-39-4, Bidex, Shanghai) and cyclopropylsulfonyl chloride (cas: 139631-62-2, Anaiji, Shanghai) was obtained by reacting and A mixture of nitro groups and then reducing the nitro group;

[0540] 20.2-Methoxyethylamine (cas: 109-85-3, Bidex, Shanghai);

[0541] 21. 2-Fluoroethylamine hydrochloride (cas: 460-08-2, Bidex, Shanghai);

[0542] 22.2,2-Difluoroethylamine (cas: 430-67-1, Bidex, Shanghai);

[0543] 23. Cyclobutylamine (cas: 2516-34-9, Anaiji, Shanghai);

[0544] 24. Cyclopropylamine (cas: 765-30-0, Bidex, Shanghai);

[0545] 25. N-isopropylmethylamine (cas: 4747-21-1, Bidex, Shanghai);

[0546] 26. 2,2-Difluoro-N-methylethylamine hydrochloride (cas: 139364-36-6, Bidex, Shanghai);

[0547] 27. N-methylpropargylamine (cas: 35161-71-8, Bidex, Shanghai);

[0548] 28.3-Fluoroazetidine hydrochloride (cas: 617718-46-4, Bidex, Shanghai);

[0549] 29.3,3-Difluoroazetidine hydrochloride (cas: 288315-03-7, Bidex, Shanghai);

[0550] 30.1,3-Dimethyl-4-aminopyrazole (cas: 64517-88-0, Bidex, Shanghai);

[0551] 31.1,5-Dimethyl-4-aminopyrazole (cas: 121983-36-6, Bidex, Shanghai);

[0552] 32.3-Methyl-1H-pyrazol-4-amine (cas: 113140-10-6, Bidex, Shanghai);

[0553] 33.1-Ethyl-3-methyl-4-aminopyrazole (cas: 947763-34-0, Bidex, Shanghai);

[0554] 34. 1-Methyl-3-difluoromethyl-4-aminopyrazole, obtained by reacting 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid (CAS: 176969-34-9, Bidler, Shanghai) with diphenylphosphoryl azide (CAS: 26386-88-9, Anaiji, Shanghai) to obtain 1-methyl-3-difluoromethyl-4-(tert-butoxycarbonyl)aminopyrazole, followed by removal of the tert-butoxycarbonyl group;

[0555] 35.1-Methyl-3-chloro-4-aminopyrazole, obtained by reducing the nitro group of 1-methyl-3-chloro-4-nitropyrazole (cas: 299930-70-4, Jizhi Biochemical, Shanghai);

[0556] 36.1-Methyl-3-methoxy-4-aminopyrazole, obtained by reducing the nitro group of 1-methyl-3-methoxy-4-nitropyrazole (cas: 1201935-85-4, Jizhi Biochemical, Shanghai);

[0557] 37.2-Bromopyridine (cas: 109-04-6, Bidex, Shanghai);

[0558] 38.2-Bromo-3-fluoropyridine (cas: 40273-45-8, Bidex, Shanghai);

[0559] 39. 2-Bromo-3-methylpyridine (cas: 3430-17-9, Bidex, Shanghai);

[0560] 40.2-Bromo-3-methoxypyridine (cas: 24100-18-3, Bidex, Shanghai);

[0561] 41.5-Methyl-6-bromopyridine-2-carbonitrile (cas: 450844-27-6, Bidex, Shanghai);

[0562] 42.2-Bromo-3-methyl-6-fluoropyridine (cas: 1211536-01-4, Bidex, Shanghai);

[0563] 43.2-Bromo-3,6-difluoropyridine (cas: 1382786-22-2, Bidex, Shanghai);

[0564] 44.6-Chloro-5-(trifluoromethyl)pyridin-2-amine (cas: 79456-28-3, Bidex, Shanghai);

[0565] 45. Pyridine-4-boronic acid (cas: 1692-15-5, Bidex, Shanghai);

[0566] 46.3-Fluoropyridine-4-boronic acid (cas: 458532-97-3, Bidex, Shanghai);

[0567] 47.3-Methylpyridine-4-boronic acid (cas: 894808-72-1, Bidex, Shanghai);

[0568] 48.3-Methoxypyridine-4-boronic acid (cas: 1008506-24-8, Bidex, Shanghai);

[0569] 49.2-aminopyridine-4-boronic acid (cas: 903513-62-2, Bidex, Shanghai);

[0570] 50.2,3-Difluoropyridin-4-ylboronic acid (cas: 1263374-42-0, Bidex, Shanghai);

[0571] 51.2,5-Difluoropyridine-4-boronic acid (cas: 1263375-23-0, Bidex, Shanghai);

[0572] 52.2-Fluoro-5-methylpyridine-4-boronic acid (cas: 929194-41-2, Bidex, Shanghai);

[0573] 53.1-(4-bromopyridin-2-yl)ethanone (cas: 1060805-69-7, Bidex, Shanghai);

[0574] 54.2-Fluoro-4-iodo-5-methylpyridine (cas: 153034-94-7, Aikon, Jiangsu);

[0575] 55.3-Pyridineboronic acid (cas: 1692-25-7, Anaiji, Shanghai);

[0576] 56. 2-Methylpyridine-3-boronic acid pinacol ester (cas: 1012084-56-8, Bidex, Shanghai);

[0577] 57.2-Difluoromethyl-3-bromopyridine (cas: 1211520-77-2, Bidex, Shanghai);

[0578] 58.2-Ethyl-3-bromopyridine (cas: 38749-81-4, Bidex, Shanghai);

[0579] 59.2-Methoxypyridine-3-boronic acid (cas: 163105-90-6, Bidex, Shanghai);

[0580] 60.2-cyano-3-bromopyridine (cas: 55758-02-6, Bidex, Shanghai);

[0581] 61.2-Aminopyridine-3-boronic acid pinacol ester (cas: 1073354-97-8, Jizhi Biochemical, Shanghai)

[0582] 62.2-Cyclopropyl-3-bromopyridine (cas: 944718-27-8, Shaoyuan, Shanghai);

[0583] 63.3-Bromo-5-acetylpyridine (cas: 38940-62-4, Jizhi Biochemical, Shanghai)

[0584] 64.5-Fluoropyridine-3-boronic acid (cas: 872041-86-6, Bidex, Shanghai);

[0585] 65.4-Fluoropyridine-3-boronic acid pinacol ester (cas: 1220219-91-9, Bidex, Shanghai);

[0586] 66.4-Methylpyridine-3-boronic acid (cas: 148546-82-1, Bidex, Shanghai);

[0587] 67.4-Methoxypyridine-3-boronic acid pinacol ester (cas: 758699-74-0, Bidex, Shanghai);

[0588] 68.4-cyanopyridine-3-boronic acid pinacol ester (cas: 878194-91-3, Bidex, Shanghai);

[0589] 69. Prepared by the reaction of 3-bromo-4-aminopyridine (cas: 13534-98-0, Yao Shi, Jiangsu) and 4-chlorobutyryl chloride (cas: 4635-59-0, Bidex, Shanghai);

[0590] 70.3-Bromo-4-methyl-5-fluoropyridine (cas: 1211517-76-8, Jizhi Biochemical, Shanghai);

[0591] 71.3,5-Dibromo-4-chloropyridine (cas: 13626-17-0, Bidex, Shanghai);

[0592] 72.3-Bromo-4,5-dichloropyridine (cas: 1001056-83-2, Bidex, Shanghai);

[0593] 73.2-Fluoro-3-bromo-6-methylpyridine (cas: 375368-78-8, Bidex, Shanghai);

[0594] 74.3-Bromo-2,5-difluoropyridine (cas: 1211331-43-9, Aladdin, Shanghai)

[0595] 75.2-Methyl-3-bromo-5-fluoropyridine (cas: 1211542-29-8, Bidex, Shanghai);

[0596] 76. Obtained by the reaction of 5-bromo-6-methyl-nicotinic acid (cas: 1190862-72-6, Bidex, Shanghai) with ammonium chloride (cas: 12125-02-9, Aladdin, Shanghai) Then dehydrated;

[0597] 77.3-Bromo-2,4-difluoropyridine (cas: 1227502-60-4, Bidex, Shanghai);

[0598] 78.2,4-Dichloro-3-iodopyridine (cas: 343781-36-2, Bidex, Shanghai);

[0599] 79.2-Chloro-3-iodo-4-fluoropyridine (cas: 1271477-28-1, Leyan, Shanghai);

[0600] 80.2-Fluoro-4-methylpyridine-3-boronic acid (cas: 1029654-30-5, Leyan, Shanghai);

[0601] 81.3-Bromo-2,4-dimethylpyridine (cas: 27063-93-0, Leyan, Shanghai)

[0602] 82.2-Amino-3-bromo-4-fluoropyridine (cas: 1417407-29-4, Bidex, Shanghai);

[0603] 83.2-Amino-3-bromo-4-chloropyridine (cas: 221297-82-1, Bidex, Shanghai);

[0604] 84.2-Amino-3-bromo-4-methylpyridine (cas: 40073-38-9, Bidex, Shanghai);

[0605] 85.5-Bromo-N-methylnicotinamide (cas: 153435-68-8, Bidex, Shanghai);

[0606] 86.5-Bromo-N-cyclopropylnicotinamide (cas: 385382-48-9, Bidex, Shanghai);

[0607] 87.4-Chloropyridine-3-boronic acid pinacol ester (cas: 452972-15-5, Kaiwei, Shanghai)

[0608] 88.2-Fluoro-3-iodo-5-methylpyridine (cas: 153034-78-7, Bidex, Shanghai);

[0609] 89. Pyrazine-2-boronic acid (cas: 762263-64-9, Bidex, Shanghai);

[0610] 90.2-Bromo-3-fluoropyrazine (cas: 206278-27-5, Bidex, Shanghai);

[0611] 91.2-Bromo-3-chloropyrazine (cas: 1206250-01-2, Bidex, Shanghai);

[0612] 92.2-Bromo-3-methylpyrazine (cas: 120984-76-1, Bidex, Shanghai);

[0613] 93.2-Chloro-3-methoxypyrazine (cas: 40155-28-0, Bidex, Shanghai);

[0614] 94.2-(Hydroxymethyl)-3-chloropyrazine (cas: 89283-32-9, Bidex, Shanghai);

[0615] 95.2-Amino-3-chloropyrazine (cas: 6863-73-6, Bidex, Shanghai);

[0616] 96.2-Chloro-3-cyanopyrazine (cas: 55557-52-3, Bidex, Shanghai);

[0617] 97.3-Chloropyrazine-2-carboxamide (cas: 21279-62-9, Bidex, Shanghai);

[0618] 98.2,5-Dichloropyrazine (cas: 19745-07-4, Bidex, Shanghai);

[0619] 99.2-Chloro-5-methylpyrazine (cas: 59303-10-5, Bidex, Shanghai);

[0620] 100.2-Bromo-6-chloropyrazine (cas: 916791-07-6, Bidex, Shanghai);

[0621] 101.2-Chloro-6-methylpyrazine (cas: 38557-71-0, Anaiji, Shanghai);

[0622] 102.2-Chloro-6-methoxypyrazine (cas: 33332-30-8, Bidex, Shanghai);

[0623] 103.2-(Hydroxymethyl)-6-chloropyrazine (cas: 1240602-95-2, Bidex, Shanghai);

[0624] 104.2-Amino-6-chloropyrazine (cas: 33332-28-4, Bidex, Shanghai);

[0625] 105.6-Chloropyrazine-2-carbonitrile (cas: 6863-74-7, Bidex, Shanghai);

[0626] 106.6-Chloropyrazine-2-carboxamide (cas: 36070-79-8, Bidex, Shanghai);

[0627] 107.3-Chloro-2,5-dimethylpyrazine (cas: 95-89-6, Bidex, Shanghai);

[0628] 108.4-Chloropyridazine hydrochloride (cas: 1193386-63-8, Bidex, Shanghai);

[0629] 109.3-Bromopyridazine (cas: 88491-61-6, Bidex, Shanghai);

[0630] 110.3-Chloro-4-methylpyridazine (cas: 68206-04-2, Bidex, Shanghai);

[0631] 111.3-Chloropyridazine-4-carbonitrile (cas: 1445-56-3, Bidex, Shanghai);

[0632] 112. Pyrimidine-5-boronic acid pinacol ester (cas: 321724-19-0, Bidex, Shanghai);

[0633] 113.4-amino-5-bromopyrimidine (cas: 1439-10-7, Bidex, Shanghai);

[0634] 114.4-Methoxy-5-bromopyrimidine (cas: 4319-85-1, Bidex, Shanghai);

[0635] 115.4-Chloro-5-iodo-6-methylpyrimidine (cas: 83410-15-5, Jizhi Biochemical, Shanghai);

[0636] 116.5-Bromo-4,6-dimethylpyrimidine (cas: 157335-97-2, Bidex, Shanghai);

[0637] 117.4-Amino-5-bromo-6-methylpyrimidine (cas: 7752-48-9, Kaiwei, Shanghai);

[0638] 118.4-Methoxy-5-bromo-6-methylpyrimidine (cas: 4319-87-3, Bidex, Shanghai);

[0639] 119.2-Bromopyrimidine (cas: 4595-60-2, Bidex, Shanghai);

[0640] 120.2-chloro-4-bromopyrimidine (cas: 885702-34-1, Bidex, Shanghai);

[0641] 121.4-Iodopyrimidine hydroiodide (cas: 1965309-31-2, Bidex, Shanghai);

[0642] 122.4,5-dibromopyrimidine (cas: 1381946-49-1, Bidex, Shanghai);

[0643] 123.4-Bromo-5-chloropyrimidine (cas: 1261628-82-3, Bidex, Shanghai);

[0644] 124.4-Bromo-5-fluoropyrimidine (cas: 1003706-87-3, Bidex, Shanghai);

[0645] 125.4-Chloro-5-fluoro-6-methylpyrimidine (cas: 898044-55-8, Bidex, Shanghai);

[0646] 126.4-Methyl-5-bromopyrimidine (cas: 1439-09-4, Bidex, Shanghai);

[0647] 127.4-Methoxy-5-bromopyrimidine (cas: 4319-85-1, Bidex, Shanghai);

[0648] 128.4-chloro-5-methylpyrimidine (cas: 51957-32-5, Bidex, Shanghai);

[0649] 129.2-Fluoro-6-hydroxyphenylboronic acid (cas: 1256345-60-4, Bidex, Shanghai);

[0650] 130.2,3-Difluorophenylboronic acid (cas: 121219-16-7, Bidex, Shanghai);

[0651] 131.2-Fluoro-3-hydroxyphenylboronic acid (cas: 855230-60-3, Bidex, Shanghai);

[0652] 132.3,5-Difluorophenylboronic acid (cas: 156545-07-2, Bidex, Shanghai);

[0653] 133.2,5-Difluorophenylboronic acid (cas: 193353-34-3, Bidex, Shanghai);

[0654] 134.2-Fluoro-5-hydroxyphenylboronic acid (cas: 1150114-52-5, Bidex, Shanghai);

[0655] 135.2-Methyl-5-fluorophenylboronic acid (cas: 163517-62-2, Bidex, Shanghai);

[0656] 136.2-Methyl-5-cyanophenylboronic acid (cas: 867333-43-5, Bidler, Shanghai);

[0657] 137.4-Bromo-1,3-benzodioxazole (cas: 6698-13-1, Bidex, Shanghai);

[0658] 138.4-Bromo-2,2-difluoro-1,3-benzobisoxazole (cas: 144584-66-7, Bidex, Shanghai);

[0659] 139.1-Bromo-3,4-(methylenedioxy)benzene (cas: 2635-13-4, Bidex, Shanghai);

[0660] 140.3,5-Dichloro-2(1H)-pyrazinone (cas: 130879-62-8, Bidex, Shanghai);

[0661] 141.2-Hydroxy-3-bromo-5-methylpyrazine (cas: 1260810-61-4, Bidex, Shanghai);

[0662] 142.4-Bromo-3-hydroxy-6-pyrazinone (cas: 15456-86-7, Bidex, Shanghai);

[0663] 143.2-Hydroxy-3-chloro-5-bromopyrazine (cas: 21943-17-9, Bidex, Shanghai);

[0664] 144.4-iodo-5-methylpyridin-2(1H)-one (cas: 1227570-92-4, Bidex, Shanghai);

[0665] 145.4-Bromo-5-methyl-1H-indazole (cas: 926922-40-9, Bidex, Shanghai);

[0666] 146.4-Isoquinolineboronic acid (cas: 192182-56-2, Leyan, Shanghai);

[0667] 147.5-Methyl-6-bromoindazole (cas: 1000343-69-0, Bidex, Shanghai);

[0668] 148.3-Bromo-7-azaindole (cas: 74420-15-8, Bidex, Shanghai);

[0669] 149.3-Methylpyrazole-4-boronic acid pinacol ester (cas: 936250-20-3, Bidex, Shanghai);

[0670] 150.1,3-Dimethylpyrazole-4-boronic acid pinacol ester (cas: 1046832-21-6, Bidex, Shanghai);

[0671] 151.3,5-Dimethylpyrazole-4-boronic acid pinacol ester (cas: 857530-80-4, Bidex, Shanghai);

[0672] 152.3-Bromo-1,4-dimethyl-1H-pyrazole (cas: 13745-59-0, Bidex, Shanghai);

[0673] 153.1,4-dimethylpyrazole-5-boronic acid pinacol ester (cas: 1047644-76-7, Bidex, Shanghai);

[0674] 154.3-Bromo-4-methyl-4H-1,2,4-triazole (cas: 16681-73-5, Bidex, Shanghai);

[0675] 155.5-Methylisoxazole-4-boronic acid pinacol ester (cas: 1346808-41-0, Bidex, Shanghai);

[0676] 156.4-iodo-2-pyridone (cas: 858839-90-4, Bidex, Shanghai);

[0677] 157. Prepared by the reaction of 2-fluoro-4-iodo-5-methylpyridine (cas: 153034-94-7, Aikon, Jiangsu) and benzyl alcohol (cas: 100-51-6, Bidler, Shanghai);

[0678] 158. Prepared by the reaction of 3-bromoisonicotinic acid (cas: 13959-02-9, Bidex, Shanghai) and dimethylamine hydrochloride (cas: 506-59-2, Anaiji, Shanghai);

[0679] 159.3-Bromo-5-fluoroisonicotinamide (cas: 1353636-72-2, Bidex, Shanghai);

[0680] 160. Obtained by reacting 3-bromo-5-methylpyridine-2-carboxylic acid (cas: 1211515-68-2, Bidex, Shanghai) with ammonium chloride (cas: 12125-02-9, Aladdin, Shanghai);

[0681] 161. Prepared by the reaction of 2-bromo-5-amino-6-methylpyridine (CAS: 126325-47-1, Bidex, Shanghai) with dimethylphosphine oxide (CAS: 7211-39-4, Aikon, Jiangsu); the following intermediates were obtained by similar methods:

[0682] The raw materials involved are: 2-methoxy-3-amino-6-bromopyridine (cas: 89466-18-2, Bidex, Shanghai), 3-amino-6-bromopyridine (cas: 13534-97-9, Bidex, Shanghai), 2-bromo-4-methyl-5-aminopyridine (cas: 156118-16-0, Bidex, Shanghai), 6-chloro-4-methoxy-3-pyridinamine (cas: 1256805 -54-5, Bidex, Shanghai), 5-amino-2-bromo-3-methylpyridine (cas: 38186-83-3, Bidex, Shanghai), 3-amino-6-chloro-5-methoxypyridine (cas: 75711-01-2, Bidex, Shanghai), 2-amino-5-bromopyridine (cas: 1072-97-5, Bidex, Shanghai), 2-amino-5-bromo-4-methylpyridine (cas: 9819 8-48-2, Bidex, Shanghai), 2-amino-5-bromo-6-methylpyridine (cas: 42753-71-9, Bidex, Shanghai), 2-methyl-4-bromoaniline (cas: 583-75-5, Bidex, Shanghai), 2-methoxy-4-bromoaniline (cas: 59557-91-4, Bidex, Shanghai), 4-bromo-2-ethylaniline (cas: 45762-41-2, Bidex, Shanghai), 3-methoxy-4-bromoaniline (cas: 19056-40-7, Bidex, Shanghai), 4-bromo-3-chloro-2-fluoroaniline (cas: 115843-99-7, Bidex, Shanghai), 4-bromo-3-chloro-2-fluoroaniline (cas: 1540204-53-2, Jizhi Biochemical, Shanghai), 4-bromo-2-fluoro-3-methoxyaniline (cas: 1272719-19-3, Leyan, Shanghai), 4-bromo-2,5-Difluoroaniline (CAS: 112279-60-4, Aladdin, Shanghai), 4-Bromo-2-fluoro-5-methylaniline (CAS: 418762-26-2, Bidex, Shanghai), 4-Bromo-2-fluoro-5-methoxyaniline (CAS: 108310-38-9, Bidex, Shanghai), 4-Bromo-2-fluoro-6-methylaniline (CAS: 429683-46-5, Bidex, Shanghai), m-Bromoaniline (CAS: 591-19-5, Bidex, Shanghai), 5-Bromo-2-methylaniline (CAS: 39478-78-9, Bidex, Shanghai), 3-Bromo-5-methyloxyaniline (CAS: 16618-68-1, Bidex, Shanghai), 3-Bromo-4 1H-Anisidine (CAS: 19056-41-8, Aladdin, Shanghai), 2-amino-6-bromopyridine (CAS: 19798-81-3, Bidex, Shanghai), 5-bromo-6-methoxypyridin-2-amine (CAS: 1211533-83-3, Bidex, Shanghai), 2-bromo-5-nitrophenyl ether (CAS: 423165-33-7, Bidex, Shanghai), 2-bromo-5-nitrophenol (CAS: 52427-05-1, Bidex, Shanghai), 2-bromo-4-fluoro-5-nitrophenol (CAS: 84478-87-5, Bidex, Shanghai), 5-bromo-1H-pyrazol-3-amine (CAS: 950739-21-6, Bidex, Shanghai);

[0683] 162. (4-Aminophenyl) dimethylphosphine oxide (cas: 737751-54-1, Bidex, Shanghai);

[0684] 163. (4-Amino-3-fluorophenyl) dimethylphosphine oxide (cas: 1197956-35-6, Bidex, Shanghai);

[0685] 164. Obtained by the reaction of p-nitrophenylethanol (cas: 100-27-6, Bidler, Shanghai) with 1,3-dibromo-5,5-dimethylhydantoin (cas: 77-48-5, Bidler, Shanghai) Reduction of the nitro group yields Then it reacts with dimethylphosphine oxide (cas: 7211-39-4, Aikon, Jiangsu);

[0686] 165. Pinacol borate (cas: 73183-34-3, Bidex, Shanghai);

[0687] 166. Tris(dibenzylideneacetone)dipalladium (cas: 51364-51-3, Anaiji, Shanghai);

[0688] 167. [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (CAS: 95464-05-4, Bis(II) Ltd, Shanghai);

[0689] 168. Palladium acetate (cas: 3375-31-3, Bidex, Shanghai);

[0690] 169. Tricyclohexylphosphine (cas: 2622-14-2, Bidex, Shanghai);

[0691] 170. (S)-2-Hydroxypropionic acid (cas: 79-33-4, Bidex, Shanghai);

[0692] 171. (R)-2-Hydroxypropionic acid (cas: 10326-41-7, Bidex, Shanghai);

[0693] 172.5-Bromo-1-methyl-1H-pyrazole-4-carbonitrile (cas: 1269293-80-2, Bidler, Shanghai).

[0694] 173. 4-Bromo-3,5-dimethoxybenzoic acid (cas: 56518-42-4, Bidler, Shanghai) was converted to 4-Bromo-3,5-dimethoxybenzoyl azide, and then rearranged to obtain Deprotection was performed to obtain 4-bromo-3,5-dimethoxyaniline, which was then reacted with dimethylphosphine oxide (cas: 7211-39-4, Aikon, Jiangsu);

[0695] 174. Prepared by the reaction of 3-methoxy-4-bromoaniline (cas: 19056-40-7, Bidex, Shanghai) with diethylphosphine oxide (cas: 7215-33-0, Bidex, Shanghai);

[0696] 175. 2-Bromo-5-nitroaniline (cas: 10403-47-1, Bidex, Shanghai) was reacted with iodomethane (cas: 74-88-4, West Asia, Shandong) to obtain 2-bromo-5-nitro-N-methylaniline, which was then obtained by a similar method as described in 161;

[0697] 176. 4-nitropyrazole (cas: 2075-46-9, Bidler, Shanghai) and N, N-dimethyl-bromoacetamide (cas: 5468-77-9, Aladdin, Shanghai) were reacted to obtain Then reduce the nitro group to obtain;

[0698] Synthesis of compound I-1

[0699] 1) Preparation of compound 3:

[0700] Compound 1 (373 mg, 2.65 mmol), compound 2 (630 mg, 2.21 mmol), and methanesulfonic acid (318 mg, 3.32 mmol) were dissolved in 20 mL of acetonitrile and reacted at 125°C for 12 h. Completion of the reaction was determined by TLC and LC-MS. Aqueous ammonia was added to the reaction system under ice-cooling to precipitate a solid, which was filtered, washed with water, and dried to obtain compound 3 (575 mg), which was used directly in the next reaction.

[0701] 2) Preparation of compound 4:

[0702] Compound 3 (145 mg, 0.37 mmol), pinacol diboron (123 mg, 0.48 mmol), tricyclohexylphosphine (21 mg, 0.074 mmol), tris(dibenzylideneacetone)dipalladium (34 mg, 0.037 mmol), and potassium acetate (110 mg, 1.11 mmol) were dispersed in 1,4-dioxane (5 mL). After nitrogen displacement, the mixture was reacted at 100°C for 2 h. Completion of the reaction was confirmed by TLC and LC-MS. The reaction system was diluted with water and extracted with DCM. The organic phase was concentrated and purified by column chromatography to yield compound 4 (95 mg).

[0703] 3) Preparation of compound I-1:

[0704] Compound 4 (10 mg, 0.023 mmol), 2-bromopyridine (5.4 mg, 0.034 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (2 mg, 0.0022 mmol), and sodium carbonate (10 mg, 0.091 mmol) were dispersed in a mixture of 1,4-dioxane (0.6 mL) and water (0.3 mL). After nitrogen replacement, the mixture was reacted at 100°C overnight. Completion of the reaction was determined by TLC and LC-MS. The reaction system was diluted with water and extracted with DCM. The organic phase was concentrated, purified by silica gel column chromatography, and further purified by preparative HPLC to obtain compound I-1 (5.8 mg).

[0705] Synthesis of compound I-64

[0706] 1) Preparation of compound 5:

[0707] Compound 5 was obtained by a method similar to that of compound 4.

[0708] 2) Preparation of compound 6:

[0709] Compound 5 (30 mg, 0.077 mmol), 4-chloropyridine-3-boronic acid pinacol ester (27.6 mg, 0.11 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (6.2 mg, 0.0077 mmol), and sodium carbonate (32 mg, 0.31 mmol) were dispersed in a mixture of 1,4-dioxane (0.6 mL) and water (0.3 mL). After nitrogen replacement, the mixture was reacted at 100°C overnight. Completion of the reaction was determined by TLC and LC-MS. The reaction system was diluted with water and extracted with DCM. The organic phase was concentrated and purified by silica gel column chromatography to obtain compound 6 (20 mg).

[0710] 3) Preparation of compound I-64:

[0711] Compound 6 (20 mg, 0.047 mmol), 4-chloropyridine-3-boronic acid pinacol ester (9.5 mg, 0.057 mmol), palladium acetate (1.1 mg, 0.0047 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (4.5 mg, 0.0094 mmol), and potassium phosphate (30 mg, 0.14 mmol) were dispersed in a mixture of 1,4-dioxane (0.8 mL) and water (0.4 mL). After nitrogen replacement, the mixture was reacted at 100°C overnight. Completion of the reaction was determined by TLC and LC-MS. The reaction system was diluted with water and extracted with DCM. The organic phase was concentrated and purified by silica gel column chromatography. Further purification by preparative HPLC gave compound I-64 (10.2 mg).

[0712] The remaining compounds were obtained by similar methods.

[0713] The table below lists the specific compounds and their structural identification data.

[0714] Synthesis of compound II-1

[0715] 1) Preparation of compound 7:

[0716] Compound 2 (2.0 g, 7.0 mmol), bis(pinacol boronate) (3.57 g, 14.0 mmol), Pd2(dba)3 (514 mg, 0.56 mmol), PCy3 (393 mg, 1.4 mmol), and KOAc (2.06 g, 21.0 mmol) were dispersed in 1,4-dioxane (120 mL). The atmosphere was replaced with nitrogen and heated at 100°C for 1 h. The reaction was complete after LCMS analysis. The reaction mixture was filtered, and the filtrate was used directly in the next reaction.

[0717] 2) Preparation of compound 8:

[0718] To the filtrate from the previous step were added 2-bromo-3-methylpyrazine (1.34 g, 7.7 mmol), PdCl(dppf)·CHCl (575 mg, 0.7 mmol), and NaCO (2.23 g, 21.0 mmol), followed by HO (60 mL). The atmosphere was replaced with nitrogen and the mixture was heated at 100°C for 1 h. LCMS confirmed the reaction was complete. The reaction mixture was filtered, concentrated, diluted with water, and extracted with EtOAc. The organic phase was concentrated and purified on a silica gel column to afford compound 8 (1.9 g).

[0719] 3) Preparation of compound II-1:

[0720] Compound 8 (15 mg, 0.05 mmol), compound 9 (10 mg, 0.05 mmol), Pd2(dba)3 (3 mg, 0.003 mmol), X-phos (3 mg, 0.006 mmol), and Cs2CO3 (33 mg, 0.1 mmol) were dispersed in 1,4-dioxane (2 mL), replaced with nitrogen, and heated at 105°C for 16 h. The reaction was complete after LCMS. The reaction mixture was filtered, concentrated, diluted with water, and extracted with EtOAc. The organic phase was concentrated and purified on a silica gel column, and further purified by preparative HPLC to obtain compound II-1 (4.2 mg).

[0721] The remaining compounds were synthesized by similar methods.

[0722] The table below lists the specific compounds and their structural identification data.

[0723] Synthesis of Compound III-20A & III-20B (Regioisomer Mixture)

[0724] 1) Preparation of compound 7:

[0725] Compound 2 (1.0 g, 3.5 mmol), bis(pinacol boronate) (1.33 g, 5.2 mmol), Pd2(dba)3 (257 mg, 0.28 mmol), PCy3 (196 mg, 0.7 mmol), and KOAc (1.0 g, 10.2 mmol) were dispersed in 1,4-dioxane (20 mL). The atmosphere was replaced with nitrogen and heated at 100°C for 1 h. The reaction was complete after LCMS analysis. The reaction mixture was filtered, and the filtrate was used directly in the next reaction.

[0726] 2) Preparation of compound 10:

[0727] To the filtrate from the previous step were added 2-(benzyloxy)-4-iodo-5-methylpyridine (1.25 g, 3.8 mmol), XPhos-Pd-G2 (232 mg, 0.3 mmol), and K2CO3 (724 mg, 5.2 mmol), followed by H2O (10 mL). The atmosphere was replaced with nitrogen and the mixture was heated at 100°C for 1 h. LCMS confirmed the reaction was complete. The reaction mixture was filtered, concentrated, diluted with water, and extracted with EtOAc. The organic phase was concentrated and purified on a silica gel column to afford compound 10 (950 mg).

[0728] 3) Preparation of mixture 12A & 12B:

[0729] Compound 10 (18 mg, 0.046 mmol), compounds 11A & 11B (15 mg, 0.054 mmol), Xphos-Pd-G2 (2.0 mg, 0.002 mmol), and Cs2CO3 (44 mg, 0.136 mmol) were dispersed in 1,4-dioxane (3.0 mL), replaced with nitrogen, and heated at 100°C for 16 h. The reaction was complete by LCMS. The reaction mixture was filtered, concentrated, diluted with water, and extracted with EtOAc. The organic phase was concentrated and purified by preparative TLC to afford compound 12A & 12B (10 mg).

[0730] 4) Preparation of mixture III-20A & III-20B:

[0731] The mixture 12A & 12B (10 mg, 0.015 mmol) was dissolved in MeOH (10.0 mL), and 10% Pd / C (2 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The reaction was complete by LCMS. The reaction mixture was filtered, concentrated, and purified by preparative HPLC to afford a mixture of regioisomers III-20A & III-20B (1.2 mg).

[0732] Synthesis of compound III-74:

[0733] 1) Preparation of compound 14:

[0734] Compound 10 (200 mg, 0.5 mmol), compound 13 (158 mg, 0.75 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), X-phos (36 mg, 0.075 mmol), and K2CO3 (207 mg, 1.5 mmol) were dispersed in t-BuOH (10 mL), the atmosphere was replaced with nitrogen, and the mixture was heated at 105°C for 3.5 h. The reaction was complete after LCMS analysis. The reaction mixture was concentrated, diluted with water, and extracted with DCM. The organic phase was concentrated and purified on a silica gel column to obtain compound 14 (85 mg).

[0735] 2) Preparation of compound 15:

[0736] Compound 14 (21.3 mg, 0.036 mmol) was dissolved in DCM (2 mL), TFA (1.5 mL) was added, and the mixture was allowed to react overnight at 40°C. LCMS confirmed the completion of the reaction. The reaction mixture was concentrated to afford the trifluoroacetic acid salt of compound 15, which was directly used for the next step.

[0737] 3) Preparation of compound III-74:

[0738] Compound 15 (0.036 mmol), methylisopropylamine (4.2 mg, 0.057 mmol), HATU (20.6 mg, 0.057 mmol), and TEA (10.6 mg, 0.1 mmol) were dissolved in MeCN (2 mL) and reacted at 50°C overnight. LCMS confirmed the reaction was complete. The mixture was diluted with water and extracted with DCM. The organic phase was concentrated and purified on a silica gel column, followed by preparative HPLC to afford compound III-74 (2.1 mg).

[0739] The remaining compounds were synthesized by similar methods.

[0740] The table below lists the specific compounds and their structural identification data.

[0741] Activity test example 1: cell anti-proliferation activity detection

[0742] The activity of a compound against BRK kinase can be evaluated by its ability to inhibit the growth of BaF3 cells stably expressing BRK kinase (BRK-BaF3) and wild-type BaF3 cells (WT-BaF3). The growth of a cell line stably expressing kinase is dependent on its kinase activity, while the growth of wild-type BaF3 cells is not. Measuring the effect of a compound on the growth of WT-BaF3 can be used to evaluate its broad-spectrum toxicity. The half-maximal growth inhibitory concentration (IC50) of the compound on WT-BaF3 and BRK-BaF3 is the difference between the two. 50 ) indicates that the compound has better targeting ability.

[0743] Cell culture and cell viability assays

[0744] BRK-BaF3, WT-BaF3, WEHI cell lines, and the breast cancer cell line T47D were cultured in RPMI 1640 basal media or Dulbecco's modified eagle medium (Shanghai Peiyuan Biotechnology, L220KJ) with 10% FBS (Gibico, REF 10099-141C), and 1% P / S (Shanghai Peiyuan Biotechnology, S110JV) in a 37°C, 5% CO2 incubator (Thermo 3020). Cell viability was >95%. Cells were passaged at a 3:1 ratio every 3-4 days. For WT-BaF3 cells, WEHI cells were cultured first, and the culture supernatant was filtered through a 0.22 μM filter. 10% of this supernatant was added to regular culture medium to supplement IL3, which is required for WT-BaF3 cell proliferation. During the test, cells were first collected and counted, and then the cells were prepared into a cell suspension of 100,000 cells / ml and plated, with 100 μL of cell suspension per well. The drug concentration started from 10 μM and was diluted in a 3:1 gradient. After incubation for 3 days, 20 μL of CCK8 detection reagent (Targetmol C005) was added to each well. After incubation for 2-4 hours, the OD450 was read using a microplate reader (Varioskan LUX, Thermoscientific). After subtracting the blank background, the curve was fitted using XLfit software and the IC was calculated. 50 .

[0745] The following table lists the IC values ​​of some compounds of the present invention for BRK-BaF3 and WT-BaF3 cells. 50 .

[0746] Note: +++++ represents IC 50 ≤20nM; ++++ represents 20nM <IC 50 ≤100nM; +++ represents 100nM <IC 50 ≤500nM; ++ represents 500nM <IC 50 ≤2500nM; + represents IC 50 >2500nM; - represents not tested.

[0747] As shown in the table above, 1) the half-maximal growth inhibition concentration (IC 50) is small, indicating that the compounds of the present invention have excellent inhibitory activity against BRK kinase; 2) the ratio of the half-maximal growth inhibition concentration (IC50) of the compounds of the present invention on WT-BaF3 and BRK-BaF3 is large, indicating that the compounds of the present invention have excellent targeting; 3) the half-maximal growth inhibition concentration (IC50) of the compounds of the present invention on WT-BaF3 is 50 ) is large, indicating that the compounds of the present invention have low broad-spectrum toxicity.

[0748] In addition, the following table exemplifies the IC values ​​of some compounds of the present invention for T47D cells: 50 .

[0749] Note: ++++ represents IC 50 ≤500nM;+++ represents 500nM <IC 50 ≤1000nM.

[0750] As can be seen from the table above, the half-maximal growth inhibition concentration (IC 50 ) is small, indicating that the compounds of the present invention have excellent inhibitory activity against T47D.

[0751] Activity test example 2: in vitro activity test of gastric cancer PDX

[0752] Patient-derived xenograft (PDX) models involve transplanting tumor tissue from a patient into severely immunodeficient mice for culture and passage, allowing compound activity testing. The compounds of this invention were tested using three PDX samples (GA0119, GA6208, and GA6871, all gastric cancers with high BRK expression, cultured in DMEM).

[0753] Preparation of PDX model tumor cell suspension: PDX model animals are housed in an animal room, and tumor growth is monitored weekly. Once the PDX model tumor has grown to an appropriate size, it is removed and minced using sterile surgical instruments. Collagenase B digestion solution is added and digested at 37°C for approximately 2 hours. Undigested tissue is removed by passing through a cell sieve. The sieve is washed 3-5 times with PBS. The cell pellet is washed 4 times with PBS and the tumor cells are resuspended in culture medium. If necessary, red blood cells are removed using ACK lysis buffer.

[0754] Cell plating: Take the above cell suspension and count it, dilute it with culture medium and adjust the cell suspension concentration to 5.75×10 53.5 mL of cell suspension and 6.5 mL of 1% methylcellulose were mixed evenly, 100 μL of cell suspension was added to each well of a 96-well plate (including compound-treated cell plates and T0 control cell plates), and the plates were incubated overnight at 37°C, 5% CO2, and 95% humidity.

[0755] Day 0 cell viability reading: The reagent and T0 control cell culture plates were placed at room temperature for 30 minutes, and 100 μL of The cells were shaken on an orbital shaker for 20 minutes to fully lyse the cells, and the cell culture was placed at room temperature for 10 minutes to equilibrate. The chemiluminescence value was read using EnVision.

[0756] Day 0 Compound Treatment: Remove the test compound (stock concentration of 10 mM) and equilibrate at room temperature until ready for use. Remove the compound-treated cell plate and add the test compound solution to the corresponding wells. Each compound has a maximum concentration of 30 μM. Three-fold dilutions are performed over nine concentration points, with triplicate wells per concentration point (DMSO concentration will be normalized). The final DMSO concentration in each well is 0.3%. The cells in the treated 96-well plate are then incubated at 37°C, 5% CO2, and 95% humidity for 168 hours.

[0757] Cell viability readings on day 7: The reagents and cell culture plates were placed at room temperature for 30 minutes, and 100 μL of Reagent, shake on an orbital shaker for 20 minutes to lyse the cells, place the cell plate at room temperature for 10 minutes to stabilize the luminescent signal, and read the luminescent value using EnVision.

[0758] Data analysis: GraphPad Prism 9.0 software was used to analyze the data. Nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, from which the IC was calculated. 50 Cell viability (%) = (Lum test drug - Lum culture medium control) / (Lum cell control - Lum culture medium control) × 100%. Lum is the luminescence value.

[0759] Experimental results:

[0760] Note: nd stands for not tested.

[0761] As can be seen from the above table, the compounds of the present invention have excellent in vitro inhibitory activity against gastric cancer PDX with high BRK expression.

[0762] Activity Test Example 3: In Vivo Efficacy Evaluation of Gastric Cancer PDX (GA6208)

[0763] Tumor tissue was collected from GA6208 gastric cancer xenograft model mice, cut into 2-3 mm diameter tumor pieces and inoculated subcutaneously at the right anterior scapula of Balb / c nude mice. 3 (100-200mm 3 ), mice were randomly divided into four groups, each with eight mice, and administered vehicle control (0.5% CMC-Na solution, gavage, twice daily), compound I-21 (100 mg / kg, gavage, twice daily), compound I-81 (100 mg / kg for the first 8 days, 80 mg / kg for the next 27 days, gavage, twice daily), and cisplatin (3 mg / kg, tail vein injection, once weekly) for a total of 35 days. The results are as follows:

[0764] Note: - represents not applicable; TGI represents tumor growth inhibition, which is calculated as follows: TGI (%) = [1-(Ti-T0) / (Vi-V0)] × 100, where Ti is the average tumor volume on the i-th day after the start of administration in the treatment group, T0 is the average tumor volume at the first administration of the treatment group, V0 is the average tumor volume at the first administration of the vehicle control group, and Vi is the average tumor volume on the i-th day after the start of administration in the vehicle control group. Comparisons between the treatment groups and the vehicle control group were performed using one-way ANOVA followed by Dunnett's multiple comparisons.

[0765] As can be seen from the above table, the compounds of the present invention have excellent in vivo efficacy against gastric cancer PDX with high BRK expression, and are superior to the chemotherapy drug cisplatin.

Claims

1. A compound represented by formula O or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, in: R 1 Selected from R 1’ 、 Preferably, R 1 Selected from R 1’ 、 R 1’ Selected from Preferably, R 1’ Selected from R m , R n Each independently selected from C1-C6 alkyl; Preferably, R m , R n Each independently selected from methyl and ethyl; Preferably, R 1’ Selected from Preferably, R 1’ Selected from More preferably, R 1’ Selected from Most preferably, R 1’ Selected from R 4a , R 4b Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, R 4a , R 4b are each independently selected from hydrogen, methyl; R 5a , R 5b Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, R 5a , R 5b are each independently selected from hydrogen, methyl; R 6a , R 6b Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, R 6a , R 6b are each independently selected from hydrogen, methyl; m is selected from 0 and 1; W 1 , W 2 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl; Preferably, W 1 , W 2 Among them, any one is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and the other is hydrogen; More preferably, W 1 , W 2 Among them, any one is selected from hydrogen, chlorine, methyl, difluoromethyl, and the other is hydrogen; Most preferably, As a whole, selected from: W 31 , W 32 , W 33 , W 34 When both exist, W 31 , W 32 , W 33 , W 34 Each is independently selected from hydrogen, halogen, hydroxy, C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy, -NR x R y ; Preferably, W 31 , W 32 , W 33 , W 34 When both exist, W 31 , W 32 , W 33 , W 34 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy; Preferably, W 31 , W 32 , W 33 , W 34 When both exist, W 31 , W 32 , W 33 , W 34 Any one of them is selected from hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl, -NR x R y , the rest are hydrogen; or, W 31 , W 32 , W 33 , W 34 Among them, any two are selected from hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, and the rest are hydrogen; R x , R y Each is independently selected from hydrogen, C1-C6 alkyl; preferably, R x , R y In, any one is selected from C1-C6 alkyl, and the other is hydrogen; more preferably, R x , R y Among them, any one is methyl and the other is hydrogen; Preferably, W 31 , W 32 , W 33 , W 34 When both exist, W 31 , W 32 , W 33 , W 34 wherein any one of them is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkyl substituted with hydroxy, and the rest are hydrogen; or, W 31 , W 32 , W 33 , W 34 Among them, any two are selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, and the rest are hydrogen; More preferably, W 31 , W 32 , W 33 , W 34 When both exist, W 31 , W 32 , W 33 , W 34 Any one of them is selected from hydrogen, fluorine, hydroxy, methyl, ethyl, methoxy, ethoxy, The remainder is hydrogen; or, W 31 , W 32 , W 33 , W 34 Among them, any two are selected from hydrogen, fluorine, chlorine, hydroxyl, methyl, methoxy, and the rest are hydrogen; More preferably, W 31 , W 32 , W 33 , W 34 When both exist, W 31 , W 32 , W 33 , W 34 Any one of them is selected from hydrogen, fluorine, methyl, ethyl, methoxy, The remainder is hydrogen; or, W 31 , W 32 , W 33 , W 34 Among them, any two are selected from hydrogen, fluorine, chlorine, methyl, methoxy, and the rest are hydrogen; W 31 , W 32 , W 33 Both exist, but W does not exist 34 When W 31 , W 32 , W 33 Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and the rest is hydrogen; Preferably, W 31 , W 32 , W 33 Both exist, but W does not exist 34 When W 31 , W 32 , W 33 Among them, any one is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and the rest are hydrogen; More preferably, W 31 , W 32 , W 33 Both exist, but W does not exist 34 When W 31 , W 32 , W 33 Among them, any one is selected from hydrogen, methyl, methoxy, and the rest are hydrogen; Preferably, R 1’ Selected from Most preferably, R 1’ Selected from W 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene-O-C1-C6 alkylene, R c R d N-C1-C6 alkylene, O=S(R e R f )=N- C1-C6 alkylene, R c R d NC(=O)-C1-C6 alkylene, C3-C6 cycloalkyl-SO2-, 3-7-membered saturated heterocyclyl, 3-7-membered saturated heterocyclyl-C1-C6 alkylene, 5-6-membered heteroaryl, 5-6-membered heteroaryl-C1-C6 alkylene, 8-10-membered saturated bridged heterocyclyl, and the 3-7-membered saturated heterocyclyl, 5-6-membered heteroaryl, 8-10-membered saturated bridged heterocyclyl are each independently and optionally substituted by 1-2 groups selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C(=O)-, hydroxy-C1-C6 alkylene-C(=O)-, 3-6-membered saturated heterocyclyl, and the C1-C6 alkylene is optionally substituted by hydroxyl; Preferably, W 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene-O-C1-C6 alkylene, O=S(R e R f )=N-C1-C6 alkylene, R c R d N-C1-C6 alkylene, R c R d NC(=O)-C1-C6 alkylene, C3-C6 cycloalkyl-SO2-, 3-7-membered saturated heterocyclyl, 3-7-membered saturated heterocyclyl-C1-C6 alkylene, 5-6-membered heteroaryl, 5-6-membered heteroaryl-C1-C6 alkylene, 8-membered saturated bridged heterocyclyl, and the 3-7-membered saturated heterocyclyl and 8-membered saturated bridged heterocyclyl are each independently and optionally substituted by 1-2 groups selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C(=O)-, hydroxy-C1-C6 alkylene-C(=O)-, and 4-membered saturated heterocyclyl, and the C1-C6 alkylene is optionally substituted by hydroxyl; More preferably, W 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene-O-C1-C6 alkylene, O=S(R e R f )=N-C1-C6 alkylene, R c R d N-C1-C6 alkylene, R c R d NC(=O)-C1-C6 alkylene, C3-C6 cycloalkyl-SO2-, 3-7-membered saturated heterocyclic group, 3-7-membered saturated heterocyclic group-C1-C6 alkylene, 5-6-membered heteroaryl, 5-6-membered heteroaryl-C1-C6 alkylene, 8-membered saturated bridged heterocyclic group, and the 3-7-membered saturated heterocyclic group and the 8-membered saturated bridged heterocyclic group are each independently optionally substituted by 1-2 (preferably 1) selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C(=O)-, hydroxy-C1-C6 alkylene-C(=O)-, 4-membered saturated heterocyclic group (preferably ), the C1-C6 alkylene group is optionally substituted by a hydroxyl group, the 3-7 membered saturated heterocyclic group is selected from The 5-6 membered heteroaryl group is selected from The 8-membered bridged heterocyclic group is R c , R d Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkylene, hydroxy-substituted C1-C6 alkyl, C1-C6 alkyl-C(=O)-, C2-C6 alkynyl-C1-C6 alkylene, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3-6 membered saturated heterocyclic group; or, R c , R d Together with the N atom to which they are commonly attached, they form a 3-6 membered saturated heterocyclic ring, and the 3-6 membered saturated heterocyclic ring is optionally substituted by 1-2 groups selected from C1-C6 alkyl and halogen; Preferably, R c , R d Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkylene, hydroxy-substituted C1-C6 alkyl, C1-C6 alkyl-C(=O)-, C2-C6 alkynyl-C1-C6 alkylene, C1-C6 haloalkyl, C3-C6 cycloalkyl, 5-membered saturated heterocyclic group; or, R c , R d Together with the N atom to which they are commonly attached, they form a 4-5 membered saturated heterocyclic ring, and the 4-5 membered saturated heterocyclic ring is optionally substituted by 1-2 groups selected from C1-C6 alkyl and halogen; More preferably, R c , R d Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkylene, hydroxy-substituted C1-C6 alkyl, C1-C6 alkyl-C(=O)-, C2-C6 alkynyl-C1-C6 alkylene, C1-C6 haloalkyl, C3-C6 cycloalkyl, Or, R c , R d Together with the N atoms they are connected to, they form And the Each is independently optionally substituted by 1-2 groups selected from C1-C6 alkyl, halogen; Most preferably, R c , R d are each independently selected from hydrogen, methyl, ethyl, isopropyl, Acetyl, Cyclopropyl, cyclobutyl, Or, R c , R d Together with the N atoms they are connected to, they form R e , R f Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, R e , R f Each independently selected from C1-C6 alkyl; More preferably, R e , R f is methyl; More preferably, W 4 is selected from hydrogen, methyl, ethyl, difluoromethyl, trideuterated methyl, Most preferably, W 4 is selected from hydrogen, methyl, ethyl, difluoromethyl, trideuterated methyl, W 5 , W 6 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, And W 5 , W 6 Not at the same time hydrogen; Preferably, W 5 , W 6 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and W 5 , W 6 Not at the same time hydrogen; Preferably, W 5 , W 6 Any one of them is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, the other is hydrogen; R k , R l Each independently selected from C1-C6 alkyl; Preferably, R k , R l is methyl; Preferably, W 5 , W 6 Among them, any one is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and the other is hydrogen; More preferably, W 5 , W 6 Any one of them is selected from hydrogen, chlorine, methyl, ethyl, methoxy, difluoromethyl, trifluoromethyl, the other is hydrogen; More preferably, W 5 , W 6 Among them, any one is selected from chlorine, methyl, ethyl, methoxy, difluoromethyl, trifluoromethyl, and the other is hydrogen; More preferably, As a whole, selected Most preferably, As a whole, selected Most preferably, As a whole, R 2 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl; Preferably, R 2 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl; More preferably, R 2 Selected from methyl, ethyl, n-propyl, R 3 Selected from: 1) in: Z 1 , Z 2 , Z 3 , Z 4 Each is independently selected from hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, -NR a R b , R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, Z 1 , Z 2 , Z 3 , Z 4 Each is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -NR a R b , R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 2 , Z 3 , Z 4 In, Z 1 is selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, and the rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 In, Z 1 , Z 4 are each independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, amino, and the rest are hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 All are hydrogen; More preferably, Z 1 , Z 2 , Z 3 , Z 4 Each is independently selected from hydrogen, fluorine, cyano, methyl, trifluoromethyl, amino, methoxy; More preferably, Z 1 , Z 2 , Z 3 , Z 4 In, Z 1 is selected from methyl, fluorine, methoxy, and the rest are hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 In, Z 1 , Z 4 Each is independently selected from fluorine, cyano, methyl, trifluoromethyl, amino, and the rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 All are hydrogen; Most preferably, As a whole, selected 2) in: Z 1 , Z 3 , Z 4 , Z 5 Each is independently selected from hydrogen, nitro, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C3-C6 cycloalkyl, C2-C6 alkenyl, -NR a R b , R a R b NC(=O)-、 R a , R b Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; Preferably, Z 1 , Z 3 , Z 4 , Z 5 Each is independently selected from hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C3-C6 cycloalkyl, C2-C6 alkenyl, -NR a R b , R a R b NC(=O)-、 R a , R b Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; More preferably, Z 1 , Z 3 , Z 4 , Z 5 Any one of them is selected from cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C3-C6 cycloalkyl, C2-C6 alkenyl, -NR a R b , R a R b NC(=O)-、 And R a , R b Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and the rest is hydrogen; or, Z 1 , Z 3 , Z 4 , Z 5 Any two of them are selected from cyano, halogen, C1-C6 alkyl, amino, The rest is hydrogen; or, Z 1 , Z 3 , Z 4 , Z 5 All are hydrogen; More preferably, Z 1 , Z 3 , Z 4 , Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, methoxy, isopropoxy, difluoromethyl, acetyl, cyclopropyl, Amino, More preferably, Z 1 , Z 3 , Z 4 , Z 5 Any one of them is selected from cyano, fluorine, chlorine, bromine, methyl, ethyl, methoxy, isopropoxy, difluoromethyl, acetyl, cyclopropyl, Amino, The rest is hydrogen; or, Z 1 , Z 3 , Z 4 , Z 5 Any two of them are selected from fluorine, chlorine, bromine, methyl, cyano, amino, The rest is hydrogen; or, Z 1 , Z 3 , Z 4 , Z 5 All are hydrogen; Most preferably, As a whole, selected 3) in: Z 1 , Z 2 , Z 4 , Z 5 Each is independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C(=O)-, -NR a R b , R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, Z 1 , Z 2 , Z 4 , Z 5 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C(=O)-, -NR a R b , R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 2 , Z 4 , Z 5 wherein any one of them is selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, C1-C6 alkyl-C(=O)-, and the rest are hydrogen; or, Z 1 , Z 2 , Z 4 , Z 5 In, any two are selected from halogen, C1-C6 alkyl, and the rest are hydrogen; or, Z 1 , Z 2 , Z 4 , Z 5 All are hydrogen; More preferably, Z 1 , Z 2 , Z 4 , Z 5 Each is independently selected from hydrogen, fluorine, methyl, methoxy, acetyl, amino; More preferably, Z 1 , Z 2 , Z 4 , Z 5 wherein any one is selected from methyl, fluoro, methoxy, amino, acetyl, and the rest are hydrogen; or 1 , Z 2 , Z 4 , Z 5 Among them, any two are selected from fluorine and methyl, and the rest are hydrogen; or, Z 1 , Z 2 , Z 4 , Z 5 All are hydrogen; Most preferably, As a whole, selected 4) in: Z 1 , Z 3 , Z 4 Each is independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl, -NR a R b , R a R b NC(=O)-,R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, Z 1 , Z 3 , Z 4 Each is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl, -NR a R b , R a R b NC(=O)-,R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 3 , Z 4 Any one of them is selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl, -NR a R b , R a R b NC(=O)-, and R a , R b Each is independently selected from hydrogen, C1-C6 alkyl, and the rest is hydrogen; or, Z 1 , Z 3 , Z 4 In, any two are selected from C1-C6 alkyl, and the rest are hydrogen; or, Z 1 , Z 3 , Z 4 All are hydrogen; More preferably, Z 1 , Z 3 , Z 4 are independently selected from hydrogen, fluorine, chlorine, cyano, methyl, methoxy, hydroxymethyl, amino, More preferably, Z 1 , Z 3 , Z 4 Any one of them is selected from fluorine, chlorine, cyano, methyl, methoxy, hydroxymethyl, amino, The rest is hydrogen; or, Z 1 , Z 3 , Z 4 In the formula (A), any two of them are methyl groups and the rest are hydrogen; or, Z 1 , Z 3 , Z 4 All are hydrogen; Most preferably, As a whole, selected 5) in: Z 1 , Z 2 , Z 3 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 1 , Z 2 , Z 3 Each is independently selected from hydrogen, cyano, C1-C6 alkyl; More preferably, Z 1 , Z 2 , Z 3 Among them, any one is selected from hydrogen, cyano, C1-C6 alkyl, and the rest are hydrogen; More preferably, Z 1 , Z 2 , Z 3 Each is independently selected from hydrogen, cyano, methyl; More preferably, Z 1 , Z 2 , Z 3 Among them, any one is selected from hydrogen, cyano, methyl, and the rest are hydrogen; Most preferably, As a whole, selected 6) in: Z 1 , Z 2 , Z 5 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 1 , Z 2 , Z 5 All are hydrogen; 7) in: Z 1 , Z 3 , Z 5 Each is independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b , R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, Z 1 , Z 3 , Z 5 Each is independently selected from hydrogen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b , R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 3 , Z 5 wherein any one is selected from C1-C6 alkyl, C1-C6 alkoxy, amino, and the rest are hydrogen; or 1 , Z 3 , Z 5 In, any two are selected from hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and the rest are hydrogen; or, Z 1 , Z 3 , Z 5 All are hydrogen; More preferably, Z 1 , Z 3 , Z 5 Each is independently selected from hydrogen, hydroxy, fluorine, chlorine, methyl, methoxy, amino; More preferably, Z 1 , Z 3 , Z 5 Among them, any one is selected from methyl, methoxy, amino, and the rest are hydrogen; or, Z 1 , Z 3 , Z 5 In, any two are selected from hydroxyl, fluorine, chlorine, methyl, methoxy, amino, and the rest are hydrogen; or, Z 1 , Z 3 , Z 5 All are hydrogen; Most preferably, As a whole, selected 8) in: Z 2 , Z 4 , Z 5 Each is independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl; Preferably, Z 2 , Z 4 , Z 5 Each is independently selected from hydrogen, halogen, C1-C6 alkyl; More preferably, Z 2 , Z 4 , Z 5 wherein any one of them is selected from halogen, C1-C6 alkyl, and the rest are hydrogen; or, Z 2 , Z 4 , Z 5 In, any two are selected from halogen, C1-C6 alkyl, and the rest are hydrogen; or, Z 2 , Z 4 , Z 5 All are hydrogen; More preferably, Z 2 , Z 4 , Z 5 Each is independently selected from hydrogen, fluorine, chlorine, bromine, methyl; More preferably, Z 2 , Z 4 , Z 5 Among them, any one is selected from fluorine, chlorine, bromine, methyl, and the rest are hydrogen; or, Z 2 , Z 4 , Z 5 any two of them are selected from fluorine, bromine, and methyl, and the rest are hydrogen; or, Z 2 , Z 4 , Z 5 All are hydrogen; Most preferably, As a whole, selected 9) in: Z 2 , Z 3 , Z 4 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 2 , Z 3 , Z 4 All are hydrogen; 10) in: Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently selected from hydrogen, hydroxy, cyano, nitro, halogen, C1-C6 alkyl; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In, Z 1 and Z 2 or Z 2 and Z 3 Together with the carbon atoms to which they are attached, they form a 5-membered heterocyclic ring or a 5-membered heteroaromatic ring, and the 5-membered heterocyclic ring or the 5-membered heteroaromatic ring are each independently and optionally substituted by 1-2 halogens, and the rest are each independently selected from hydrogen and C1-C6 alkyl; Preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently selected from hydrogen, hydroxyl, cyano, halogen, C1-C6 alkyl; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In, Z 1 and Z 2 or Z 2 and Z 3 Together with the carbon atoms to which they are attached, they form a 5-membered heterocyclic ring or a 5-membered heteroaromatic ring, and the 5-membered heterocyclic ring or the 5-membered heteroaromatic ring are each independently and optionally substituted by 1-2 halogens, and the rest are each independently selected from hydrogen and C1-C6 alkyl; More preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In, any two are selected from hydroxyl, cyano, halogen, C1-C6 alkyl, and the rest are hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In, Z 1 and Z 2 or Z 2 and Z 3 Together with the carbon atoms to which they are attached, And the Optionally substituted with 1-2 halogens, the rest are independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In, any two are selected from hydroxyl, cyano, fluorine, methyl, and the rest are hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In, Z 1 and Z 2 or Z 2 and Z 3 Together with the carbon atoms to which they are attached, And the Optionally substituted with 1-2 fluorine, the rest are independently selected from hydrogen and methyl; Most preferably, As a whole, selected 11) Among them, Z 1 is selected from hydrogen, C1-C6 alkyl, preferably selected from hydrogen, methyl; each Z 4 Independently selected from halogen, C1-C6 alkyl, preferably selected from chlorine, methyl; 12) 5-9 membered heteroaryl, wherein the 5-9 membered heteroaryl is optionally substituted by 1-2 groups selected from C1-C6 alkyl, cyano; preferably selected from And the Each independently optionally substituted by 1-2 groups selected from C1-C6 alkyl, cyano; more preferably selected from Preferably, R 3 Selected from 2. The compound according to claim 1 or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein: The compound has the structural formula shown in Formula I, in: R 2 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl; Preferably, R 2 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl; More preferably, R 2 Selected from methyl, ethyl, n-propyl, R 3 Selected from: 1) in: Z 1 , Z 2 , Z 3 , Z 4 Each is independently selected from hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, -NR a R b , R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, Z 1 , Z 2 , Z 3 , Z 4 Each is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -NR a R b , R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 2 , Z 3 , Z 4 In, Z 1 is selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, and the rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 In, Z 1 , Z 4 are each independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, amino, and the rest are hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 All are hydrogen; More preferably, Z 1 , Z 2 , Z 3 , Z 4 Each is independently selected from hydrogen, fluorine, cyano, methyl, trifluoromethyl, amino, methoxy; More preferably, Z 1 , Z 2 , Z 3 , Z 4 In, Z 1 is selected from methyl, fluorine, methoxy, and the rest are hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 In, Z 1 , Z 4 Each is independently selected from fluorine, cyano, methyl, trifluoromethyl, amino, and the rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 All are hydrogen; Most preferably, As a whole, selected 2) in: Z 1 , Z 3 , Z 4 , Z 5 Each is independently selected from hydrogen, nitro, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C3-C6 cycloalkyl, C2-C6 alkenyl, -NR a R b , R a R b NC(=O)-、 R a , R b Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; Preferably, Z 1 , Z 3 , Z 4 , Z 5 Each is independently selected from hydrogen, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C3-C6 cycloalkyl, C2-C6 alkenyl, -NR a R b , R a R b NC(=O)-、 R a , R b Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; More preferably, Z 1 , Z 3 , Z 4 , Z 5 Any one of them is selected from cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C3-C6 cycloalkyl, C2-C6 alkenyl, -NR a R b , R a R b NC(=O)-、 And R a , R b Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and the rest is hydrogen; or, Z 1 , Z 3 , Z 4 , Z 5 In, any two are selected from cyano, halogen, C1-C6 alkyl, amino, and the rest are hydrogen; or, Z 1 , Z 3 , Z 4 , Z 5 All are hydrogen; More preferably, Z 1 , Z 3 , Z 4 , Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, methoxy, isopropoxy, difluoromethyl, acetyl, cyclopropyl, Amino, More preferably, Z 1 , Z 3 , Z 4 , Z 5 Any one of them is selected from cyano, fluorine, chlorine, bromine, methyl, ethyl, methoxy, isopropoxy, difluoromethyl, acetyl, cyclopropyl, Amino, The rest is hydrogen; or, Z 1 , Z 3 , Z 4 , Z 5 In, any two are selected from fluorine, chlorine, bromine, methyl, cyano, amino, and the rest are hydrogen; or, Z 1 , Z 3 , Z 4 , Z 5 All are hydrogen; Most preferably, As a whole, selected 3) in: Z 1 , Z 2 , Z 4 , Z 5 Each is independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C(=O)-, -NR a R b , R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, Z 1 , Z 2 , Z 4 , Z 5 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl-C(=O)-, -NR a R b , R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 2 , Z 4 , Z 5 wherein any one of them is selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, amino, C1-C6 alkyl-C(=O)-, and the rest are hydrogen; or, Z 1 , Z 2 , Z 4 , Z 5 In, any two are selected from halogen, C1-C6 alkyl, and the rest are hydrogen; or, Z 1 , Z 2 , Z 4 , Z 5 All are hydrogen; More preferably, Z 1 , Z 2 , Z 4 , Z 5 Each is independently selected from hydrogen, fluorine, methyl, methoxy, acetyl, amino; More preferably, Z 1 , Z 2 , Z 4 , Z 5 wherein any one is selected from methyl, fluoro, methoxy, amino, acetyl, and the rest are hydrogen; or 1 , Z 2 , Z 4 , Z 5 Among them, any two are selected from fluorine and methyl, and the rest are hydrogen; or, Z 1 , Z 2 , Z 4 , Z 5 All are hydrogen; Most preferably, As a whole, selected 4) in: Z 1 , Z 3 , Z 4 Each is independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl, -NR a R b , R a R b NC(=O)-,R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, Z 1 , Z 3 , Z 4 Each is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl, -NR a R b , R a R b NC(=O)-,R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 3 , Z 4 Any one of them is selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl, -NR a R b , R a R b NC(=O)-, and R a , R b Each is independently selected from hydrogen, C1-C6 alkyl, and the rest is hydrogen; or, Z 1 , Z 3 , Z 4 In, any two are selected from C1-C6 alkyl, and the rest are hydrogen; or, Z 1 , Z 3 , Z 4 All are hydrogen; More preferably, Z 1 , Z 3 , Z 4 are independently selected from hydrogen, fluorine, chlorine, cyano, methyl, methoxy, hydroxymethyl, amino, More preferably, Z 1 , Z 3 , Z 4 Any one of them is selected from fluorine, chlorine, cyano, methyl, methoxy, hydroxymethyl, amino, The rest is hydrogen; or, Z 1 , Z 3 , Z 4 In the formula (A), any two of them are methyl groups and the rest are hydrogen; or, Z 1 , Z 3 , Z 4 All are hydrogen; Most preferably, As a whole, selected 5) in: Z 1 , Z 2 , Z 3 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 1 , Z 2 , Z 3 Each is independently selected from hydrogen, cyano, C1-C6 alkyl; More preferably, Z 1 , Z 2 , Z 3 Among them, any one is selected from hydrogen, cyano, C1-C6 alkyl, and the rest are hydrogen; More preferably, Z 1 , Z 2 , Z 3 Each is independently selected from hydrogen, cyano, methyl; More preferably, Z 1 , Z 2 , Z 3 Among them, any one is selected from hydrogen, cyano, methyl, and the rest are hydrogen; Most preferably, As a whole, selected 6) in: Z 1 , Z 2 , Z 5 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 1 , Z 2 , Z 5 All are hydrogen; 7) in: Z 1 , Z 3 , Z 5 Each is independently selected from hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b , R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, Z 1 , Z 3 , Z 5 Each is independently selected from hydrogen, hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b , R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 3 , Z 5 wherein any one is selected from C1-C6 alkyl, C1-C6 alkoxy, amino, and the rest are hydrogen; or 1 , Z 3 , Z 5 In, any two are selected from hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, and the rest are hydrogen; or, Z 1 , Z 3 , Z 5 All are hydrogen; More preferably, Z 1 , Z 3 , Z 5 Each is independently selected from hydrogen, hydroxy, fluorine, chlorine, methyl, methoxy, amino; More preferably, Z 1 , Z 3 , Z 5 Among them, any one is selected from methyl, methoxy, amino, and the rest are hydrogen; or, Z 1 , Z 3 , Z 5 In, any two are selected from hydroxyl, fluorine, chlorine, methyl, methoxy, amino, and the rest are hydrogen; or, Z 1 , Z 3 , Z 5 All are hydrogen; Most preferably, As a whole, selected 8) in: Z 2 , Z 4 , Z 5 Each is independently selected from hydrogen, halogen, cyano, nitro, C1-C6 alkyl; Preferably, Z 2 , Z 4 , Z 5 Each is independently selected from hydrogen, halogen, C1-C6 alkyl; More preferably, Z 2 , Z 4 , Z 5 wherein any one of them is selected from halogen, C1-C6 alkyl, and the rest are hydrogen; or, Z 2 , Z 4 , Z 5 In, any two are selected from halogen, C1-C6 alkyl, and the rest are hydrogen; or, Z 2 , Z 4 , Z 5 All are hydrogen; More preferably, Z 2 , Z 4 , Z 5 Each is independently selected from hydrogen, fluorine, chlorine, bromine, methyl; More preferably, Z 2 , Z 4 , Z 5 Among them, any one is selected from fluorine, chlorine, bromine, methyl, and the rest are hydrogen; or, Z 2 , Z 4 , Z 5 any two of them are selected from fluorine, bromine, and methyl, and the rest are hydrogen; or, Z 2 , Z 4 , Z 5 All are hydrogen; Most preferably, As a whole, selected 9) in: Z 2 , Z 3 , Z 4 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 2 , Z 3 , Z 4 All are hydrogen; 10) in: Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently selected from hydrogen, hydroxy, cyano, nitro, halogen, C1-C6 alkyl; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In, Z 1 and Z 2 or Z 2 and Z 3 Together with the carbon atoms to which they are attached, they form a 5-membered heterocyclic ring or a 5-membered heteroaromatic ring, and the 5-membered heterocyclic ring or the 5-membered heteroaromatic ring are each independently and optionally substituted by 1-2 halogens, and the rest are each independently selected from hydrogen and C1-C6 alkyl; Preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently selected from hydrogen, hydroxyl, cyano, halogen, C1-C6 alkyl; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In, Z 1 and Z 2 or Z 2 and Z 3 Together with the carbon atoms to which they are attached, they form a 5-membered heterocyclic ring or a 5-membered heteroaromatic ring, and the 5-membered heterocyclic ring or the 5-membered heteroaromatic ring are each independently and optionally substituted by 1-2 halogens, and the rest are each independently selected from hydrogen and C1-C6 alkyl; More preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In, any two are selected from hydroxyl, cyano, halogen, C1-C6 alkyl, and the rest are hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In, Z 1 and Z 2 or Z 2 and Z 3 Together with the carbon atoms to which they are attached form And the Optionally substituted with 1-2 halogens, the rest are independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In, any two are selected from hydroxyl, cyano, fluorine, methyl, and the rest are hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In, Z 1 and Z 2 or Z 2 and Z 3 Together with the carbon atoms to which they are attached, And the Optionally substituted with 1-2 fluorine, the rest are independently selected from hydrogen and methyl; Most preferably, As a whole, selected 11) Among them, Z 1 is selected from C1-C6 alkyl, preferably methyl; each Z 4 Independently selected from halogen, C1-C6 alkyl, preferably selected from chlorine, methyl; 12) 5-9 membered heteroaryl, wherein the 5-9 membered heteroaryl is optionally substituted by 1-2 C1-C6 alkyl groups; preferably selected from And the Each independently optionally substituted by 1-2 C1-C6 alkyl groups; more preferably selected from Preferably, R 3 Selected from R 4a , R 4b Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, R 4a , R 4b are each independently selected from hydrogen, methyl; R 5a , R 5b Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, R 5a , R 5b are each independently selected from hydrogen, methyl; R 6a , R 6b Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, R 6a , R 6b are each independently selected from hydrogen, methyl; m is selected from 0 and 1; W 1 , W 2 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl; Preferably, W 1 , W 2 Among them, any one is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and the other is hydrogen; More preferably, W 1 , W 2 Among them, any one is selected from hydrogen, chlorine, methyl, difluoromethyl, and the other is hydrogen; Most preferably, As a whole, selected from:

3. The compound according to claim 1 or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein: The compound has the structural formula shown in Formula II, in: R 1’ Selected from Preferably, R 1’ Selected from R m , R n Each independently selected from C1-C6 alkyl; Preferably, R m , R n Each independently selected from methyl and ethyl; Preferably, R 1’ Selected from Preferably, R 1’ Selected from More preferably, R 1’ Selected from Most preferably, R 1’ Selected from W 31 , W 32 , W 33 , W 34 When both exist, W 31 , W 32 , W 33 , W 34 Each is independently selected from hydrogen, halogen, hydroxy, C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy, -NR x R y ; Preferably, W 31 , W 32 , W 33 , W 34 When both exist, W 31 , W 32 , W 33 , W 34 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy; Preferably, W 31 , W 32 , W 33 , W 34 When both exist, W 31 , W 32 , W 33 , W 34 Any one of them is selected from hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl, -NR x R y , the rest are hydrogen; or, W 31 , W 32 , W 33 , W 34 Among them, any two are selected from hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, and the rest are hydrogen; R x , R y Each is independently selected from hydrogen, C1-C6 alkyl; preferably, R x , R y In, any one is selected from C1-C6 alkyl, and the other is hydrogen; more preferably, R x , R y Among them, any one is methyl and the other is hydrogen; Preferably, W 31 , W 32 , W 33 , W 34 When both exist, W 31 , W 32 , W 33 , W 34 wherein any one of them is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkyl substituted with hydroxy, and the rest are hydrogen; or, W 31 , W 32 , W 33 , W 34 Among them, any two are selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, and the rest are hydrogen; More preferably, W 31 , W 32 , W 33 , W 34 When both exist, W 31 , W 32 , W 33 , W 34 Any one of them is selected from hydrogen, fluorine, hydroxy, methyl, ethyl, methoxy, ethoxy, The remainder is hydrogen; or, W 31 , W 32 , W 33 , W 34 Among them, any two are selected from hydrogen, fluorine, chlorine, hydroxyl, methyl, methoxy, and the rest are hydrogen; More preferably, W 31 , W 32 , W 33 , W 34 When both exist, W 31 , W 32 , W 33 , W 34 Any one of them is selected from hydrogen, fluorine, methyl, ethyl, methoxy, The remainder is hydrogen; or, W 31 , W 32 , W 33 , W 34 Among them, any two are selected from hydrogen, fluorine, chlorine, methyl, methoxy, and the rest are hydrogen; W 31 , W 32 , W 33 Both exist, but W does not exist 34 When W 31 , W 32 , W 33 Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and the rest is hydrogen; Preferably, W 31 , W 32 , W 33 Both exist, but W does not exist 34 When W 31 , W 32 , W 33 Among them, any one is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and the rest are hydrogen; More preferably, W 31 , W 32 , W 33 Both exist, but W does not exist 34 When W 31 , W 32 , W 33 Among them, any one is selected from hydrogen, methyl, methoxy, and the rest are hydrogen; Preferably, R 1’ Selected from Most preferably, R 1’ Selected from R 2 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl; Preferably, R 2 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl; More preferably, R 2 Selected from methyl, ethyl, n-propyl, R 3 Selected from: 1) in: Z 1 , Z 3 , Z 4 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 1 , Z 3 , Z 4 Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 3 , Z 4 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen; More preferably, Z 1 , Z 3 , Z 4 Among them, any one is methyl and the rest are hydrogen; Most preferably, As a whole, 2) in: Z 1 , Z 3 , Z 5 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 1 , Z 3 , Z 5 Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 3 , Z 5 Among them, any two are selected from C1-C6 alkyl, and the rest are hydrogen; More preferably, Z 1 , Z 3 , Z 5 are each independently selected from hydrogen, methyl; More preferably, Z 1 , Z 3 , Z 5 Among them, any two are methyl groups and the rest are hydrogen; Most preferably, As a whole, 3) in: Z 1 , Z 3 , Z 4 , Z 5 Each is independently selected from hydrogen, nitro, cyano, halogen, C1-C6 alkyl; Preferably, Z 1 , Z 3 , Z 4 , Z 5 Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 3 , Z 4 , Z 5 Among them, any one is selected from hydrogen, C1-C6 alkyl, and the rest are hydrogen; More preferably, Z 1 , Z 3 , Z 4 , Z 5 are each independently selected from hydrogen, methyl; More preferably, Z 1 , Z 3 , Z 4 , Z 5 Among them, any one is selected from hydrogen and methyl, and the rest are hydrogen; Most preferably, As a whole, selected 4) in: Z 1 , Z 2 , Z 3 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 1 , Z 2 , Z 3 Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 2 , Z 3 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen; More preferably, Z 1 , Z 2 , Z 3 Among them, any one is selected from methyl, and the rest are hydrogen; Most preferably, As a whole, Preferably, R 3 Selected from: 1) in: Z 1 , Z 3 , Z 4 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 1 , Z 3 , Z 4 Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 3 , Z 4 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen; More preferably, Z 1 , Z 3 , Z 4 Among them, any one is methyl and the rest are hydrogen; Most preferably, As a whole, 2) in: Z 1 , Z 3 , Z 5 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 1 , Z 3 , Z 5 Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 3 , Z 5 Among them, any two are selected from C1-C6 alkyl, and the rest are hydrogen; More preferably, Z 1 , Z 3 , Z 5 are each independently selected from hydrogen, methyl; More preferably, Z 1 , Z 3 , Z 5 Among them, any two are methyl groups and the rest are hydrogen; Most preferably, As a whole, Preferably, R 3 Selected from Most preferably, R 3 Selected from 4. The compound according to claim 1 or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein: The compound has a structural formula shown in Formula III, in: W 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene-O-C1-C6 alkylene, R c R d N-C1-C6 alkylene, O=S(R e R f )=N-C1-C6 alkylene, R c R d NC(=O)-C1-C6 alkylene, C3-C6 cycloalkyl-SO2-, 3-7-membered saturated heterocyclyl, 3-7-membered saturated heterocyclyl-C1-C6 alkylene, 5-6-membered heteroaryl, 5-6-membered heteroaryl-C1-C6 alkylene, 8-10-membered saturated bridged heterocyclyl, and the 3-7-membered saturated heterocyclyl, 5-6-membered heteroaryl, 8-10-membered saturated bridged heterocyclyl are each independently and optionally substituted by 1-2 groups selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C(=O)-, hydroxy-C1-C6 alkylene-C(=O)-, 3-6-membered saturated heterocyclyl, and the C1-C6 alkylene is optionally substituted by hydroxyl; Preferably, W 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene-O-C1-C6 alkylene, O=S(R e R f )=N-C1-C6 alkylene, R c R d N-C1-C6 alkylene, R c R d NC(=O)-C1-C6 alkylene, C3-C6 cycloalkyl-SO2-, 3-7-membered saturated heterocyclyl, 3-7-membered saturated heterocyclyl-C1-C6 alkylene, 5-6-membered heteroaryl, 5-6-membered heteroaryl-C1-C6 alkylene, 8-membered saturated bridged heterocyclyl, and the 3-7-membered saturated heterocyclyl and 8-membered saturated bridged heterocyclyl are each independently and optionally substituted by 1-2 groups selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C(=O)-, hydroxy-C1-C6 alkylene-C(=O)-, and 4-membered saturated heterocyclyl, and the C1-C6 alkylene is optionally substituted by hydroxyl; More preferably, W 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene-O-C1-C6 alkylene, O=S(R e R f )=N-C1-C6 alkylene, R c R d N-C1-C6 alkylene, R c R d NC(=O)-C1-C6 alkylene, C3-C6 cycloalkyl-SO2-, 3-7 membered saturated and heterocyclyl, 3-7 membered saturated heterocyclyl-C1-C6 alkylene, 5-6 membered heteroaryl, 5-6 membered heteroaryl-C1-C6 alkylene, 8 membered saturated bridged heterocyclyl, and the 3-7 membered saturated heterocyclyl and the 8 membered saturated bridged heterocyclyl are each independently optionally substituted by 1-2 (preferably 1) selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C(=O)-, hydroxy-C1-C6 alkylene-C(=O)-, 4 membered saturated heterocyclyl (preferably ), the C1-C6 alkylene group is optionally substituted by a hydroxyl group, the 3-7 membered saturated heterocyclic group is selected from The 5-6 membered heteroaryl group is selected from The 8-membered bridged heterocyclic group is R c , R d Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkylene, hydroxy-substituted C1-C6 alkyl, C1-C6 alkyl-C(=O)-, C2-C6 alkynyl-C1-C6 alkylene, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3-6 membered saturated heterocyclic group; or, R c , R d Together with the N atom to which they are commonly attached, they form a 3-6 membered saturated heterocyclic ring, and the 3-6 membered saturated heterocyclic ring is optionally substituted by 1-2 groups selected from C1-C6 alkyl and halogen; Preferably, R c , R d Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkylene, hydroxy-substituted C1-C6 alkyl, C1-C6 alkyl-C(=O)-, C2-C6 alkynyl-C1-C6 alkylene, C1-C6 haloalkyl, C3-C6 cycloalkyl, 5-membered saturated heterocyclic group; or, R c , R d Together with the N atom to which they are commonly attached, they form a 4-5 membered saturated heterocyclic ring, and the 4-5 membered saturated heterocyclic ring is optionally substituted by 1-2 groups selected from C1-C6 alkyl and halogen; More preferably, R c , R d Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkylene, hydroxy-substituted C1-C6 alkyl, C1-C6 alkyl-C(=O)-, C2-C6 alkynyl-C1-C6 alkylene, C1-C6 haloalkyl, C3-C6 cycloalkyl, Or, R c , R d Together with the N atoms they are connected to, they form And the Each is independently optionally substituted by 1-2 groups selected from C1-C6 alkyl, halogen; Most preferably, R c , R d are each independently selected from hydrogen, methyl, ethyl, isopropyl, Acetyl, Cyclopropyl, cyclobutyl, Or, R c , R d Together with the N atoms they are connected to, they form R e , R f Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, R e , R f Each independently selected from C1-C6 alkyl; More preferably, R e , R f is methyl; More preferably, W 4 is selected from hydrogen, methyl, ethyl, difluoromethyl, trideuterated methyl, Most preferably, W 4 is selected from hydrogen, methyl, ethyl, difluoromethyl, trideuterated methyl, W 5 , W 6 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and W 5 , W 6 Not at the same time hydrogen; Preferably, W 5 , W 6 Among them, any one is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and the other is hydrogen; Preferably, W 5 , W 6 Among them, any one is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and the other is hydrogen; More preferably, W 5 , W 6 Among them, any one is selected from hydrogen, chlorine, methyl, ethyl, methoxy, difluoromethyl, trifluoromethyl, and the other is hydrogen; More preferably, W 5 , W 6 Among them, any one is selected from chlorine, methyl, ethyl, methoxy, difluoromethyl, trifluoromethyl, and the other is hydrogen; More preferably, As a whole, selected Most preferably, As a whole, selected R 2 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl; Preferably, R 2 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl; More preferably, R 2 Selected from methyl, ethyl, n-propyl, trifluoromethyl; R 3 Selected from: 1) in: R 7 Selected from hydrogen, C1-C6 alkyl; Preferably, R 7 is selected from hydrogen, methyl; 2) in: Z 1 , Z 2 , Z 3 , Z 4 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 1 , Z 2 , Z 3 , Z 4 Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 2 , Z 3 , Z 4 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen; More preferably, Z 1 , Z 2 , Z 3 , Z 4 Among them, any one is methyl and the rest are hydrogen; Most preferably, As a whole, 3) in: Z 1 , Z 3 , Z 4 , Z 5 Each is independently selected from hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, R a R b NC(=O)-,R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, Z 1 , Z 3 , Z 4 , Z 5 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, R a R b NC(=O)-,R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 3 , Z 4 , Z 5 Any one of them is selected from C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, R a R b NC(=O)-, and R a , R b Each is independently selected from hydrogen, C1-C6 alkyl, and the rest is hydrogen; or, Z 1 , Z 3 , Z 4 , Z 5 Any two of them are selected from halogen, C1-C6 alkyl, R a R b NC(=O)-, and R a , R b Each is independently selected from hydrogen, C1-C6 alkyl, and the rest is hydrogen; More preferably, Z 1 , Z 3 , Z 4 , Z 5 are each independently selected from hydrogen, fluorine, methyl, difluoromethyl, cyclopropyl, More preferably, Z 1 , Z 3 , Z 4 , Z 5 Any one of them is selected from methyl, Cyclopropyl, difluoromethyl, and the rest are hydrogen; or, Z 1 , Z 3 , Z 4 , Z 5 Any two of them are selected from fluorine, methyl, The rest is hydrogen; Most preferably, As a whole, selected 4) in: Z 1 , Z 3 , Z 4 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 1 , Z 3 , Z 4 Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 3 , Z 4 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen; More preferably, Z 1 , Z 3 , Z 4 Among them, any one is methyl and the rest are hydrogen; Most preferably, As a whole, 5) in: Z 1 , Z 2 , Z 3 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 1 , Z 2 , Z 3 Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 2 , Z 3 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen; More preferably, Z 1 , Z 2 , Z 3 Among them, any one is methyl and the rest are hydrogen; Most preferably, As a whole, 6) in: Z 1 , Z 3 , Z 5 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 1 , Z 3 , Z 5 Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 3 , Z 5 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen; or, Z 1 , Z 3 , Z 5 Among them, any two are selected from C1-C6 alkyl, and the rest are hydrogen; More preferably, Z 1 , Z 3 , Z 5 are each independently selected from hydrogen, methyl; More preferably, Z 1 , Z 3 , Z 5 In which any one is methyl and the rest are hydrogen; or, Z 1 , Z 3 , Z 5 Among them, any two are methyl groups and the rest are hydrogen; Most preferably, As a whole, selected 7) in: Z 2 , Z 4 , Z 5 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 2 , Z 4 , Z 5 Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 2 , Z 4 , Z 5 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen; More preferably, Z 2 , Z 4 , Z 5 Among them, any one is methyl and the rest are hydrogen; Most preferably, As a whole, 8) in: Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Each is independently selected from hydrogen, cyano, C1-C6 alkyl; More preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any two are selected from cyano, C1-C6 alkyl, and the rest are hydrogen; More preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any two are selected from cyano and methyl, and the rest are hydrogen; Most preferably, As a whole, 9) 5-9 membered heteroaryl, wherein the 5-9 membered heteroaryl is optionally substituted by 1-2 groups selected from C1-C6 alkyl, cyano; preferably selected from And the Each independently optionally substituted by 1-2 groups selected from C1-C6 alkyl, cyano; more preferably selected from Preferably, R 3 Selected from 5. The compound according to claim 4, or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein: The compound has the structural formula shown in formula III-1, in: W 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene-O-C1-C6 alkylene, R c R d N-C1-C6 alkylene, R c R d NC(=O)-C1-C6 alkylene, 3-7-membered saturated heterocyclyl, 3-7-membered saturated heterocyclyl-C1-C6 alkylene, 5-6-membered heteroaryl, 5-6-membered heteroaryl-C1-C6 alkylene, 8-10-membered saturated bridged heterocyclyl, and the 3-7-membered saturated heterocyclyl, 5-6-membered heteroaryl, 8-10-membered saturated bridged heterocyclyl are each independently and optionally substituted by 1-2 groups selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C(=O)-, hydroxy-C1-C6 alkylene-C(=O)-, and 3-6-membered saturated heterocyclyl, and the C1-C6 alkylene is optionally substituted by hydroxy; Preferably, W 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene-O-C1-C6 alkylene, R c R d N-C1-C6 alkylene, R c R d NC(=O)-C1-C6 alkylene, 3-7-membered saturated heterocyclyl, 3-7-membered saturated heterocyclyl-C1-C6 alkylene, 5-6-membered heteroaryl, 5-6-membered heteroaryl-C1-C6 alkylene, 8-membered saturated bridged heterocyclyl, and the 3-7-membered saturated heterocyclyl and 8-membered saturated bridged heterocyclyl are each independently and optionally substituted by 1-2 groups selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C(=O)-, hydroxy-C1-C6 alkylene-C(=O)-, and 4-membered saturated heterocyclyl, and the C1-C6 alkylene is optionally substituted by hydroxyl; More preferably, W 4 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C1-C6 alkylene-O-C1-C6 alkylene, R c R d N-C1-C6 alkylene, R c R d NC(=O)-C1-C6 alkylene, 3-7-membered saturated heterocyclic group, 3-7-membered saturated heterocyclic group-C1-C6 alkylene, 5-6-membered heteroaryl, 5-6-membered heteroaryl-C1-C6 alkylene, 8-membered saturated bridged heterocyclic group, and the 3-7-membered saturated heterocyclic group and the 8-membered saturated bridged heterocyclic group are each independently optionally substituted by 1-2 (preferably 1) selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, C1-C6 alkoxy-C(=O)-, hydroxy-C1-C6 alkylene-C(=O)-, 4-membered saturated heterocyclic group (preferably ) group, the C1-C6 alkylene group is optionally substituted by a hydroxyl group, the 3- The 7-membered saturated heterocyclic group is selected from The 5-6 membered heteroaryl group is selected from The 8-membered bridged heterocyclic group is R c , R d Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkylene, hydroxy-substituted C1-C6 alkyl, C1-C6 alkyl-C(=O)-, C2-C6 alkynyl-C1-C6 alkylene, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3-6 membered saturated heterocyclic group; or, R c , R d Together with the N atom to which they are commonly attached, they form a 3-6 membered saturated heterocyclic ring, and the 3-6 membered saturated heterocyclic ring is optionally substituted by 1-2 groups selected from C1-C6 alkyl and halogen; Preferably, R c , R d Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkylene, hydroxy-substituted C1-C6 alkyl, C1-C6 alkyl-C(=O)-, C2-C6 alkynyl-C1-C6 alkylene, C1-C6 haloalkyl, C3-C6 cycloalkyl, 5-membered saturated heterocyclic group; or, R c , R d Together with the N atom to which they are commonly attached, they form a 4-5 membered saturated heterocyclic ring, and the 4-5 membered saturated heterocyclic ring is optionally substituted by 1-2 groups selected from C1-C6 alkyl and halogen; More preferably, R c , R d Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkylene, hydroxy-substituted C1-C6 alkyl, C1-C6 alkyl-C(=O)-, C2-C6 alkynyl-C1-C6 alkylene, C1-C6 haloalkyl, C3-C6 cycloalkyl, Or, R c , R d Together with the N atoms they are connected to, they form And the Each is independently optionally substituted by 1-2 groups selected from C1-C6 alkyl, halogen; Most preferably, R c , R d are each independently selected from hydrogen, methyl, ethyl, isopropyl, Acetyl, Cyclopropyl, cyclobutyl, Or, R c , R d Together with the N atoms they are connected to, they form Most preferably, W 4 is selected from hydrogen, methyl, ethyl, difluoromethyl, trideuterated methyl, W 5 , W 6 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and W 5 , W 6 Not at the same time hydrogen; Preferably, W 5 , W 6 Among them, any one is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and the other is hydrogen; More preferably, W 5 , W 6 Among them, any one is selected from chlorine, methyl, ethyl, methoxy, difluoromethyl, trifluoromethyl, and the other is hydrogen; Most preferably, As a whole, selected R 2 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl; Preferably, R 2 Selected from C1-C6 alkyl, C3-C6 cycloalkyl; More preferably, R 2 Selected from methyl, ethyl, R 7 Selected from hydrogen, C1-C6 alkyl; Preferably, R 7 Selected from hydrogen and methyl.

6. The compound according to claim 4, or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein: The compound has the structural formula shown in formula III-2, in: W 4 is selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, 3-6 membered saturated heterocyclic group, O=S(R e R f )=N-C1-C6 alkylene, R c R d N-C1-C6 alkylene, R c R d NC(=O)-C1-C6 alkylene, C3-C6 cycloalkyl-SO2-, the 3-6 membered saturated heterocyclic group is optionally substituted by a C1-C6 alkyl group; Preferably, W 4 is selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, 4-6 membered saturated heterocyclic group, O=S(R e R f )=N-C1-C6 alkylene, R c R d N-C1-C6 alkylene, R c R d NC(=O)-C1-C6 alkylene, C3-C6 cycloalkyl-SO2-, the 4-6 membered saturated heterocyclic group is optionally substituted by a C1-C6 alkyl group; More preferably, W 4 is selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene, 4-6 membered saturated heterocyclic group, O=S(R e R f )=N-C1-C6 alkylene, R c R d N-C1-C6 alkylene, R c R d NC(=O)-C1-C6 alkylene, C3-C6 cycloalkyl-SO2-, the 4-6 membered saturated heterocyclic group is optionally substituted by a C1-C6 alkyl group, the 4-6 membered saturated heterocyclic group is selected from R c , R d Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkylene; Preferably, R c , R d are independently selected from hydrogen, methyl, ethyl, R e , R f Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, R e , R f Each independently selected from C1-C6 alkyl; More preferably, R e , R f is methyl; More preferably, W 4 is selected from methyl, trideuterated methyl, Most preferably, W 4 is selected from methyl, trideuterated methyl, W 5 , W 6 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and W 5 , W 6 Not at the same time hydrogen; Preferably, W 5 , W 6 Among them, any one is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and the other is hydrogen; Preferably, W 5 , W 6 Among them, any one is selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, and the other is hydrogen; More preferably, W 5 , W 6 Among them, any one is selected from hydrogen, chlorine, methyl, difluoromethyl, and the other is hydrogen; More preferably, W 5 , W 6 Among them, any one is selected from chlorine, methyl, difluoromethyl, and the other is hydrogen; More preferably, As a whole, selected Most preferably, As a whole, selected R 2 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl; Preferably, R 2 Selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl; More preferably, R 2 Selected from methyl, ethyl, n-propyl, trifluoromethyl; R 3 Selected from: 1) in: Z 1 , Z 2 , Z 3 , Z 4 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 1 , Z 2 , Z 3 , Z 4 Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 2 , Z 3 , Z 4 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen; More preferably, Z 1 , Z 2 , Z 3 , Z 4 Among them, any one is methyl and the rest are hydrogen; Most preferably, As a whole, 2) in: Z 1 , Z 3 , Z 4 , Z 5 Each is independently selected from hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, R a R b NC(=O)-,R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, Z 1 , Z 3 , Z 4 , Z 5 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, R a R b NC(=O)-,R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 3 , Z 4 , Z 5 Any one of them is selected from C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, R a R b NC(=O)-, and R a , R b Each is independently selected from hydrogen, C1-C6 alkyl, and the rest is hydrogen; or, Z 1 , Z 3 , Z 4 , Z 5 Any two of them are selected from halogen, C1-C6 alkyl, R a R b NC(=O)-, and R a , R b Each is independently selected from hydrogen, C1-C6 alkyl, and the rest is hydrogen; More preferably, Z 1 , Z 3 , Z 4 , Z 5 are each independently selected from hydrogen, fluorine, methyl, difluoromethyl, cyclopropyl, More preferably, Z 1 , Z 3 , Z 4 , Z 5 Any one of them is selected from methyl, Cyclopropyl, difluoromethyl, and the rest are hydrogen; or, Z 1 , Z 3 , Z 4 , Z 5 Any two of them are selected from fluorine, methyl, The rest is hydrogen; Most preferably, As a whole, selected 3) in: Z 1 , Z 3 , Z 4 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 1 , Z 3 , Z 4 Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 3 , Z 4 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen; More preferably, Z 1 , Z 3 , Z 4 Among them, any one is methyl and the rest are hydrogen; Most preferably, As a whole, 4) in: Z 1 , Z 2 , Z 3 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 1 , Z 2 , Z 3 Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 2 , Z 3 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen; More preferably, Z 1 , Z 2 , Z 3 Among them, any one is methyl and the rest are hydrogen; Most preferably, As a whole, 5) in: Z 1 , Z 3 , Z 5 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 1 , Z 3 , Z 5 Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 1 , Z 3 , Z 5 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen; or, Z 1 , Z 3 , Z 5 Among them, any two are selected from C1-C6 alkyl, and the rest are hydrogen; More preferably, Z 1 , Z 3 , Z 5 are each independently selected from hydrogen, methyl; More preferably, Z 1 , Z 3 , Z 5 In which any one is methyl and the rest are hydrogen; or, Z 1 , Z 3 , Z 5 Among them, any two are methyl groups and the rest are hydrogen; Most preferably, As a whole, selected 6) in: Z 2 , Z 4 , Z 5 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 2 , Z 4 , Z 5 Each is independently selected from hydrogen, C1-C6 alkyl; More preferably, Z 2 , Z 4 , Z 5 Among them, any one is selected from C1-C6 alkyl, and the rest are hydrogen; More preferably, Z 2 , Z 4 , Z 5 Among them, any one is methyl and the rest are hydrogen; Most preferably, As a whole, 7) in: Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Each is independently selected from hydrogen, cyano, halogen, nitro, C1-C6 alkyl; Preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Each is independently selected from hydrogen, cyano, C1-C6 alkyl; More preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any two are selected from cyano, C1-C6 alkyl, and the rest are hydrogen; More preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any two are selected from cyano and methyl, and the rest are hydrogen; Most preferably, As a whole, 8) 5-9 membered heteroaryl, wherein the 5-9 membered heteroaryl is optionally substituted by 1-2 groups selected from C1-C6 alkyl, cyano; preferably selected from And the Each independently optionally substituted by 1-2 groups selected from C1-C6 alkyl, cyano; more preferably selected from Preferably, R 3 Selected from 7. The compound according to any one of claims 1 to 6, or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein: The compound is selected from the following:

8. A method for preparing a compound according to any one of claims 1 to 7, comprising: Where X is a halogen, R 1 , R 2 , R 3 Each independently as defined in any one of claims 1 to 7, Reaction conditions: (a) Coupling reaction catalyzed by palladium metal; (b) coupling reaction catalyzed by metal palladium; (c) a coupling reaction catalyzed by metal palladium, or a nucleophilic substitution reaction under acidic conditions, or a nucleophilic substitution reaction under alkaline conditions; (d) nucleophilic substitution reaction under acidic conditions or nucleophilic substitution reaction under alkaline conditions; The metal palladium catalyst is selected from palladium acetate, tetrakis(triphenylphosphine)palladium, bistriphenylphosphine palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tris(dibenzylideneacetone)dipalladium; The alkaline conditions refer to the conditions in which any of the following substances exist: triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride; The acidic conditions refer to the conditions in which any of the following substances exist: acetic acid, trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate and optionally a pharmaceutically acceptable excipient.

10. Use of the compound according to any one of claims 1 to 7 or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing and / or treating a BRK kinase-mediated disease; Preferably, the BRK kinase-mediated disease is selected from breast cancer, gastric cancer, leukemia, skin cancer, head and neck cancer, thyroid cancer, pancreatic cancer, cervical cancer, bladder cancer, ovarian cancer, nasopharyngeal carcinoma, non-small cell lung cancer, prostate cancer, colon cancer, and esophageal cancer.

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