2-Piperidyl or 2-Pyrazolyl Substituted Pyrimidine Compounds as EGFR Inhibitors

Abstract

2-piperidyl or 2-pyrazolyl substituted pyrimidine compounds represented by formula (I) or pharma- ceutically acceptable salts, isotopic substitutes, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof, pharmaceutical compositions comprising said compounds, and uses of said pharmaceutical compositions in the treatment of diseases mediated by EGFR protein and its mutants. TIFF2025502559000208.tif5256(I)

Description

[Technical field]

[0001] The present disclosure is in the pharmaceutical field, specifically, it relates to 2-piperidinyl or 2-pyrazolyl substituted pyrimidine compounds as EGFR inhibitors. [Background technology]

[0002] Lung cancer is one of the most common malignant tumors, with approximately 1.6 million new cases worldwide each year. There are two types of lung cancer: small cell lung cancer and non-small cell lung cancer (NSCLC), of which NSCLC accounts for approximately 85% of all lung cancer patients (Nature Reviews Disease Primers, 2015, 1,15009). Epidermal growth factor receptor (EGFR) is the most common driver gene for NSCLC, with a positive rate of 17% in all NSCLC cases, 30-40% in Chinese patients, and up to 60% in lung adenocarcinoma.

[0003] EGFR is a transmembrane glycoprotein that belongs to the ErbB family of tyrosine kinase receptors. EGFR is aberrantly activated by various mechanisms, including receptor overexpression, mutations, ligand-dependent receptor dimerization, and ligand-independent activation. Continuous activation of its kinase activity leads to downstream signaling of cell proliferation, differentiation, and survival. Small molecule inhibitors of EGFR kinase can block tyrosine kinase activation, inhibit tumor cell proliferation, and promote tumor cell apoptosis and other biological effects, which is a hot topic area in lung cancer development.

[0004] Osimertinib is a drug developed for EGFR mutants (del19 or L858R) with T790M mutations that are resistant to first- and second-generation drugs. Although this drug has shown very high efficacy in clinical trials, patients also show drug resistance as treatment continues. In 2015 (Nature Medicine, 2015, 21, 560-562), drug resistance data for 15 patients who took osimertinib was first reported, and the data showed that the EGFR C797S mutation was one of the main mechanisms inducing drug resistance to osimertinib, accounting for approximately 40%. In addition, according to the latest report, 22-25% of patients who gained resistance after second-line treatment with osimertinib had the C797S mutation (Nature Cancer, 2021, 377-391). Thus, there is an urgent clinical need to develop novel small molecule inhibitors that target the C797S mutation and provide patients with safer and more effective fourth-generation EGFR inhibitors.

[0005] On the other hand, both the first-generation EGFR inhibitor gefitinib and the third-generation EGFR inhibitor osimertinib showed good therapeutic effects in the first-line treatment group with EGFR activating mutations, but in subgroup analysis, the benefit in the L858R group was much lower than that in the del19 group, with PFS of 14.4 months and 21.4 months, respectively (The New England Journal of Medicine, 2018, 378, pp. 113-125). Summary of the Invention

[0006] In the present disclosure, we performed enzymatic evaluations using major mutations that appear in clinical practice, such as L858R / C797S, L858R / T790M / C797S, and L858R, confirmed them at the constructed Ba / F3 cell level, and ultimately discovered a series of novel chemical compounds with strong biological activity.

[0007] In one aspect, the present disclosure provides a compound of formula (I): [ka] (I) or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof. [In the formula, structure: [ka] The structure: [ka] where: [ka] But the structure: [ka] When X is selected from CH and N, Y is CH 2 , C=O and C=S; and the structure: [ka] But the structure: [ka] when X is C and Y is CH; Z is selected from CH and N; Ring A is a 4-8 membered heterocyclyl; Ring B has the structure: [ka] Selected from; L is a chemical bond, -S(=O)(=M)-, -N(R N )-S(=O)(=M)-, -S(=O)(=M)-N(R N )-, -N(R N )-C(=O)-, -C(=O)-N(R N )-, -CH(R N )-C(=O)-, -C(=O)-CH(R N )-, -CH(R N)-S(=O)(=M)- and -S(=O)(=M)-CH(R N )-selected from; R 1 and R 2 are independently H, halogen, or C 1~6 Alkyl and C 1~6 haloalkyl; R 3 and R 4 are independently H, OR a , C 1~6 Alkyl and C 1~6 haloalkyl; R 5 H, halogen, C 1~6 Alkyl and C 1~6 haloalkyl; R 6 OR a , N.R. b R c , C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 6~10 aryl and 5-6 membered heteroaryl; R 7 , H, C 1~6 Alkyl, C 1~6 Haloalkyl and -S(=O)(=M)-R 8 Selected from; where M is O or NH; R N is H, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R N and R 6 is concatenated to form C 1~6 Alkylene, C 2~6 Alkenylene or C 2~6 Forming an alkynylene; R 8 OR a , N.R. b R c , C 1~6 Alkyl, -C 1~6 Alkylene-C 3~6Cycloalkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 6~10 aryl and 5- to 6-membered heteroaryl, which are selected from one or more of R a with appropriate substitutions; R a , R b and R c are independent of each other, H, C 1~6 Alkyl and C 1~6 haloalkyl; or R b and R c together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl; However, L is -CH(R N )-S(=O)(=M)-, and the ring in which X, Y and Z are located is a benzene ring, then B has the structure: [ka] [is].

[0008] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and, optionally, a pharma- ceutically acceptable excipient.

[0009] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of the disclosure and a pharma- ceutically acceptable excipient, and also including another therapeutic agent.

[0010] In another aspect, the disclosure provides the use of a compound of the disclosure in the manufacture of a medicament for treating and / or preventing a disease mediated by the EGFR protein and its mutants.

[0011] In another aspect, the present disclosure provides a method for treating and / or preventing a disease mediated by EGFR protein and its mutants in a subject, comprising administering to said subject a compound or composition of the present disclosure.

[0012] In another aspect, the present disclosure provides a compound or composition of the present disclosure for use in the treatment and / or prevention of diseases mediated by the EGFR protein and its mutants.

[0013] In certain embodiments, the EGFR mutation is one or more of the L858R mutation, the del19 mutation, the T790M mutation, and the C797S mutation; or the disease is selected from lung cancer, colon cancer, urothelial cancer, breast cancer, prostate cancer, brain cancer, ovarian cancer, gastric cancer, pancreatic cancer, head and neck cancer, bladder cancer, and mesothelioma, or non-small cell lung cancer.

[0014] Other objects and advantages of the present disclosure will be apparent to those skilled in the art from the following detailed description, examples, and claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] (definition) (Definition of the Chemical Field) Definitions of specific functional groups and chemical terms are detailed below.

[0016] When a range of values ​​is listed, it is intended to include each value and each subrange within that range. For example, "C 1~6 Alkyl" is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 and C 5~6 It is intended to include alkyl.

[0017] "C 1~6"Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. 1~4 Alkyl and C 1~2 C is selected from alkyl. 1~6 An example of an alkyl group is methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-Butyl (C 4 ), tert-Butyl (C 4 ), sec-Butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butyl (C 5 ), tert-pentyl (C 5 ) and n-hexyl (C 6 ) are included. 1~6 "Alkyl" also includes heteroalkyl, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkyl groups can be optionally substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional abbreviations for alkyl include Me(-CH 3 ), Et(-CH 2 CH 3 ), iPr(-CH(CH 3 ) 2 ), nPr(-CH 2 CH 2 CH 3 ), n-Bu(-CH 2 CH 2 CH 2 CH 3 ) or i-Bu(-CH 2 CH(CH 3 ) 2 ) are mentioned.

[0018] "C 2~6"Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2~4 Alkenyl is selected. 2~6 An example of an alkenyl is vinyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ) and others. 2~6 "Alkenyl" also includes heteroalkenyl in which one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced with a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkenyl groups can be optionally substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0019] "C 2~6 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally, one or more carbon-carbon double bonds. In some embodiments, C 2~4 Alkynyl is selected. 2~6 Examples of alkynyl include, but are not limited to, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), pentynyl (C 5 ), Hexynyl (C 6 ) and others. 2~6Alkynyl" also includes heteroalkynyl in which one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced with a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups can be substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0020] "C 1~6 "Alkylene" means C 1~6 It refers to a divalent group formed by removing one more hydrogen from an alkyl, and may be substituted or unsubstituted. 1~4 Alkylene, C 2~4 Alkylene, and C 1~3 Unsubstituted alkylene includes, but is not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), butylene (-CH 2 CH 2 CH 2 CH 2 -), pentylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -), hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 Examples of substituted alkylenes include, but are not limited to, substituted methylene (-CH(CH)) such as those substituted with one or more alkyl (methyl) groups. 3 )-, -C(CH 3 ) 2 -), substituted ethylene (-CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 -, -CH2 C(CH 3 ) 2 -), substituted propylene (-CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 C(CH 3 ) 2 -) etc.

[0021] "C 0~6 "Alkylene" refers to a chemical bond and the above C 1~6 It refers to alkylene.

[0022] "C 2~6 "Alkenylene" means C 2~6 It refers to an alkenylene divalent group provided by further removing hydrogen from an alkenyl group, and may be substituted or unsubstituted. 2~4 Alkenylene is selected. Examples of unsubstituted alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH 2 -, -CH 2 Examples of substituted alkenylene groups include, but are not limited to, substituted ethylene (-C(CH)) substituted with one or more alkyl (methyl) groups. 3 )=CH-, -CH=C(CH 3 )-), substituted propylene (e.g., -C(CH 3 )=CHCH 2 -, -CH=C(CH 3 )CH 2 -, -CH=CHCH(CH 3)-, -CH=CHC(CH 3 ) 2 -, -CH(CH 3 )-CH=CH-, -C(CH 3 ) 2 -CH=CH-, -CH 2 -C(CH 3 )=CH-, -CH 2 -CH=C(CH 3 )-) etc.

[0023] "C 2~6 "Alkynylene" means C 2~6 It refers to a divalent alkynylene group provided by removing additional hydrogen from an alkynyl group, and may be substituted or unsubstituted. 2~4 Alkynylene is selected. Examples of alkynylene groups include, but are not limited to, ethynylene (-C≡C-) substituted or unsubstituted propynylene (-C≡CCH 2 -) etc.

[0024] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0025] Therefore, "C 1~6 Haloalkyl means any of the above "C" substituted with one or more halogens. 1~6 In some embodiments, C 1~4 Haloalkyl is selected, or C 1~2 Examples of haloalkyl groups include, but are not limited to, -CF 3 , -CH 2 F, -CHF 2 , -CHFCH 2 F, -CH 2 CHF 2 , -CF 2 CF 3 , -CCl 3 , -CH 2 Cl, -CHCl 2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. The haloalkyl can be substituted with, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent at any available point of attachment.

[0026] "C 3~10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and no heteroatoms. 5~7 Cycloalkyl, C 3~6 Cycloalkyl and C 3~5 Cycloalkyl is selected, or C 5~6 Cycloalkyl. Said cycloalkyl also includes ring systems in which a cycloalkyl as described herein is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring, and further in this case the number of carbon atoms still indicates the number of carbon atoms of said cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 The cycloalkyl may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0027] "3- to 12-membered heterocyclyl" refers to a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1-5 ring heteroatoms, where the heteroatoms are each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyls containing one or more nitrogen atoms, the point of attachment can be carbon or nitrogen, where valence permits. In some embodiments, a 4- to 8-membered heterocyclyl is selected that is a 4- to 8-membered non-aromatic ring system radical having ring carbon atoms and 1-5 ring heteroatoms. In some embodiments, a 5- to 8-membered heterocyclyl is selected that is a 5- to 8-membered non-aromatic ring system radical having ring carbon atoms and 1-5 ring heteroatoms. In some embodiments, a 3- to 8-membered heterocyclyl is selected that is a 3- to 8-membered non-aromatic ring system radical having ring carbon atoms and 1-4 ring heteroatoms. A 3- to 6-membered heterocyclyl is selected which is a 3- to 6-membered non-aromatic ring system radical having a ring carbon atom and 1 to 3 heteroatoms. A 4- to 7-membered heterocyclyl is selected which is a 4- to 7-membered non-aromatic ring system radical having a ring carbon atom and 1 to 3 heteroatoms. A 4- to 6-membered heterocyclyl is selected which is a 4- to 6-membered non-aromatic ring system radical having a ring carbon atom and 1 to 3 heteroatoms. A 5- to 6-membered heterocyclyl is selected which is a 5- to 6-membered non-aromatic ring system radical having a ring carbon atom and 1 to 3 heteroatoms. The heterocyclyl also includes ring systems in which the above-mentioned heterocyclyl is fused with one or more cycloalkyl groups, where the attachment point is on the cycloalkyl ring, or the above-mentioned heterocyclyl is fused with one or more aryl or heteroaryl groups, where the attachment point is on the heterocyclyl ring, in which case the number of ring atoms still indicates the number of ring atoms of the heterocyclyl ring system. Examples of 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Examples of 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.Examples of 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Examples of 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Examples of 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Examples of 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Examples of 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. C. 6 Examples of 5-membered heterocyclyl groups fused to aryl (also referred to herein as 5,6-bicycloheterocyclyl) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinonyl, and the like. 6 Examples of 6-membered heterocyclyl groups (also referred to herein as 6,6-bicycloheterocyclyl) fused to an aryl include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. The heterocyclyl can be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0028] "C 6~10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared pi electrons in the ring structure) having 6 to 10 ring carbon atoms and no heteroatoms. In some embodiments, the aryl group has 6 ring carbon atoms ("C 6 aryl"; e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C 10"aryl"; for example naphthyl, e.g. 1-naphthyl and 2-naphthyl). The aryl group also includes ring systems in which the aryl ring as described above is fused with one or more cycloalkyl or heterocyclyl groups, where the point of attachment is on the aryl ring, in which case the number of carbon atoms still indicates the number of carbon atoms in the aryl ring system. The aryl may be substituted with one or more substituents, e.g. 1-5 substituents, 1-3 substituents or 1 substituent.

[0029] "5-14 membered heteroaryl" refers to a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10 or 14 shared π electrons in the ring structure) having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be carbon or nitrogen, where valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the heteroaryl ring as described above is fused to one or more cycloalkyl or heterocyclyl groups, the attachment point being on the heteroaryl ring. In such cases, the number of carbon atoms still refers to the number of carbon atoms in the heteroaryl ring system. In some embodiments, a 5-10 membered heteroaryl group is selected that is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5- to 9-membered heteroaryl groups are selected that are 5- to 9-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5- to 6-membered heteroaryl groups are selected that are 5- to 6-membered monocyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Examples of 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. Examples of 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Examples of 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl. Examples of 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl.Examples of 6-membered heteroaryl groups containing three or four heteroatoms, respectively, include, but are not limited to, triazinyl and tetrazinyl. Examples of 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicycloheteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Examples of 6,6-bicycloheteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl can be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0030] "Cycloalkylene", "heterocyclylene", "arylene" or "heteroarylene" is a divalent group formed by removing one more hydrogen from the "cycloalkyl", "heterocyclyl", "aryl" or "heteroaryl" defined above, and may be substituted or unsubstituted. For example, "C 5~7 "Cycloalkylene" means 5~7 "5-8 membered heterocyclylene" refers to a divalent group formed by removing one more hydrogen from a 5-8 membered heterocyclyl, and "C 6~10 "Arylene" means C 6~10 It refers to a divalent group formed by removing one more hydrogen from an aryl, and "5- to 6-membered heteroarylene" refers to a divalent group formed by removing one more hydrogen from a 5- to 6-membered heteroaryl.

[0031] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, as defined herein, are optionally substituted groups.

[0032] Examples of substituents attached to carbon atoms include, but are not limited to, halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR aa , -ON(R bb ) 2 , -N(R bb ) 2 , -N(R bb ) 3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO 2 H, -CHO, -C(OR cc ) 2 , -CO 2 R aa , -OC(=O)R aa , -OCO 2 R aa , -C(=O)N(R bb ) 2 , -OC(=O)N(R bb ) 2 , -NR bb C(=O)R aa , -NR bb CO 2 R aa , -NR bb C(=O)N(R bb ) 2 , -C(=NR bb )R aa , -C(=NR bb ) OR aa , -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -C(=NR bb )N(R bb ) 2、-OC(=NR bb )N(R bb ) 2 、-NR bb C(=NR bb )N(R bb ) 2 、-C(=O)NR bb SO 2 R aa 、-NR bb SO 2 R aa 、-SO 2 N(R bb ) 2 、-SO 2 R aa 、-SO 2 OR aa 、-OSO 2 R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa ) 3 、-OSi(R aa ) 3 、-C(=S)N(R bb ) 2 、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O) 2 R aa 、-OP(=O) 2 R aa 、-P(=O)(R aa ) 2 、-OP(=O)(R aa ) 2 、-OP(=O)(OR cc ) 2 、-P(=O) 2 N(R bb ) 2 、-OP(=O) 2 N(R bb ) 2 、-P(=O)(NR bb ) 2 、-OP(=O)(NRbb ) 2 , -NR bb P(=O)(OR cc ) 2 , -NR bb P(=O)(NR bb ) 2 , -P(R cc ) 2 , -P(R cc ) 3 , -OP(R cc ) 2 , -OP(R cc ) 3 , -B(R aa ) 2 , -B(OR cc ) 2 , -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R dd substituted with a group; Or the two geminal hydrogens on a carbon atom are =O, =S, =NN(R bb ) 2 , =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O) 2 R aa , =NR bb OR =NOR cc is substituted with a group; R aa are each independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; or two R aa The groups combine to form a heterocyclyl or heteroaryl ring, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R ddis substituted with a group; R bb are each independently hydrogen, -OH, or -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(R cc ) 2 , -P(=O)(NR cc ) 2 , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb The groups combine to form a heterocyclyl or heteroaryl ring, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R dd is substituted with a group; R cc are each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; or two Rcc The groups combine to form a heterocyclyl or heteroaryl ring, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R dd is substituted with a group; R dd are each independently halogen, -CN, or -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR ee , -ON(R ff ) 2 , -N(R ff ) 2 , -N(R ff ) 3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO 2 H, -CO 2 R ee , -OC(=O)R ee , -OCO 2 R ee , -C(=O)N(R ff ) 2 , -OC(=O)N(R ff ) 2 , -NR ff C(=O)R ee , -NR ff CO 2 R ee , -NR ff C(=O)N(R ff ) 2 , -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff ) 2 , -OC(=NR ff )N(Rff ) 2 , -NR ff C(=NR ff )N(R ff ) 2 , -NR ff SO 2 R ee , -SO 2 N(R ff ) 2 , -SO 2 R ee , -SO 2 OR ee , -OSO 2 R ee , -S(=O)R ee , -Si(R ee ) 3 , -OSi(R ee ) 3 , -C(=S)N(R ff ) 2 , -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O) 2 R ee , -P(=O)(R ee ) 2 , -OP(=O)(R ee ) 2 ,-OP(=O)(OR ee ) 2 , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently selected from 0, 1, 2, 3, 4, or 5 R gg or two geminal R dd The substituents may combine to form =O or =S; R eeare each independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently selected from 0, 1, 2, 3, 4, or 5 R gg is substituted with a group; R ff are each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; or two R ff The groups combine to form a heterocyclyl or heteroaryl ring, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R gg is substituted with a group; R gg are each independently halogen, -CN, or -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 Alkyl) 2 , -N(C 1~6 Alkyl) 2 , -N(C 1~6 Alkyl) 3 + X - , -NH(C 1~6 Alkyl) 2 + X - , -NH 2 (C 1~6 Alkyl) + X - , -NH 3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6alkyl), -C(=O)(C 1~6 Alkyl), -CO 2 H, -CO 2 (C 1~6 alkyl), -OC(=O)(C 1~6 Alkyl), -OCO 2 (C 1~6 alkyl), -C(=O)NH 2 , -C(=O)N(C 1~6 Alkyl) 2 , -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 Alkyl)C(=O)(C 1~6 alkyl), -NHCO 2 (C 1~6 alkyl), -NHC(=O)N(C 1~6 Alkyl) 2 , -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH 2 , -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 Alkyl) 2 , -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH 2 , -OC(=NH)N(C 1~6 Alkyl) 2 , -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH 2 , -NHC(NH)N(C 1~6 Alkyl) 2 , -NHC(=NH)NH 2 , -NHSO 2 (C 1~6 Alkyl), -SO 2 N(C 1~6 Alkyl) 2 , -SO 2 NH(C 1~6 Alkyl), -SO 2 NH 2 , -SO 2 C 1~6Alkyl, -SO 2 O.C. 1~6 Alkyl, -OSO 2 C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 Alkyl) 3 , -OSi(C 1~6 Alkyl) 3 , -C(=S)N(C 1~6 Alkyl) 2 , C(=S)NH(C 1~6 alkyl), C(=S)NH 2 , -C(=O)S(C 1~6 Alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O) 2 (C 1~6 alkyl), -P(=O)(C 1~6 Alkyl) 2 , -OP(=O)(C 1~6 Alkyl) 2 , -OP(=O)(OC 1~6 Alkyl) 2 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 7 Cycloalkyl, C 6 ~C 10 Aryl, C 3 ~C 7 Heterocyclyl, and C 5 ~C 10 heteroaryl; or two geminal R gg The substituents may combine to form =O or =S; where X - is the counter ion.

[0033] Examples of substituents attached to a nitrogen atom include, but are not limited to, hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa, -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(R cc ) 2 , -P(=O)(NR cc ) 2 , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; or two R cc The groups combine to form a heterocyclyl or heteroaryl ring, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl each independently represent 0, 1, 2, 3, 4, or 5 R dd group, wherein R aa , R bb , R cc and R dd is as described herein.

[0034] (Other definitions)

[0035] The term "pharmaceutically acceptable salts" as used herein refers to carboxylate and amino acid addition salts of the compounds of the present disclosure which, within the scope of sound medical judgment, are suitable for contact with the tissues of a patient and do not produce undue toxicity, irritation, allergy, and the like, with a reasonable benefit / risk ratio and which are effective for their intended use. The term includes zwitterionic forms of the compounds of the present disclosure, where possible.

[0036] A "subject" contemplated for dosing includes, but is not limited to, humans (e.g., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or old adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, mice, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" may be used interchangeably herein.

[0037] "Disease," "disorder," and "condition" may be used interchangeably herein.

[0038] Generally, an "effective amount" of a compound refers to an amount sufficient to induce a desired biological effect. As will be appreciated by those skilled in the art, the effective amount of a compound of the present disclosure will vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health and condition of the patient. An effective amount includes a therapeutically effective amount and a prophylactically effective amount.

[0039] "Combination" and related terms refer to the administration of a compound of the present disclosure and another therapeutic agent, either simultaneously or sequentially. For example, the compound of the present disclosure may be administered simultaneously or sequentially with the other therapeutic agent in separate unit doses, or may be administered simultaneously in a single unit dose with the other therapeutic agent.

[0040] As used herein, "compound(s) of the present disclosure" refers to compounds of the following formula (I) (including subformulas, such as formula (II), formula (V-1), etc.), pharma- ceutically acceptable salts, enantiomers, diastereomers, solvates, hydrates, or isotopic substitutes thereof, and mixtures thereof.

[0041] In one embodiment, the present disclosure provides a compound of formula (I): [ka] (I) or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof. [In the formula, structure: [ka] The structure: [ka] where: [ka] But the structure: [ka] When X is selected from CH and N, Y is CH 2 , C=O and C=S; and the structure: [ka] But the structure: [ka] when X is C and Y is CH; Z is selected from CH and N; Ring A is a 4-8 membered heterocyclyl; Ring B has the structure: [ka] Selected from; L is a chemical bond, -S(=O)(=M)-, -N(R N )-S(=O)(=M)-, -S(=O)(=M)-N(R N )-, -N(R N )-C(=O)-, -C(=O)-N(R N )-, -CH(R N )-C(=O)-, -C(=O)-CH(R N )-, -CH(R N )-S(=O)(=M)- and -S(=O)(=M)-CH(R N )-selected from; R 1 and R 2 are independently H, halogen, or C 1~6 Alkyl and C 1~6 haloalkyl; R 3 and R 4 are independently H, OR a , C 1~6 Alkyl and C 1~6 haloalkyl; R 5 H, halogen, C 1~6 Alkyl and C 1~6 haloalkyl; R 6 -C 0~6 Alkylene-OR a , -C 0~6 Alkylene-NR b R c , C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 6~10 selected from aryl and 5-6 membered heteroaryl; R7 -H, -C 1~6 Alkylene -CN, -C 1~6 Alkylene-OR a , -C 1~6 Alkylene-NR b R c , C 1~6 Alkyl, C 1~6 Haloalkyl and -S(=O)(=M)-R 8 Selected from; where M is O or NH; R N is H, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R N and R 6 is concatenated to form C 1~6 Alkylene, C 2~6 Alkenylene or C 2~6 Forming an alkynylene; R 8 -C 0~6 Alkylene-OR a , -C 0~6 Alkylene-NR b R c , C 1~6 Alkyl, -C 1~6 Alkylene-C 3~6 Cycloalkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 6~10 aryl and 5- to 6-membered heteroaryl, which are selected from one or more of R a with appropriate substitutions; R a , R b and R c are independent of each other, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 cycloalkyl and 4- to 6-membered heterocyclyl; or R b and R c together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl; X, Y, Z, Ring A, Ring B, L, R 1 ~R8 , R N , R a , R b and R c each group in may be substituted with one or more deuterium atoms until fully deuterized; However, L is -CH(R N )-S(=O)(=M)-, and the ring in which X, Y and Z are located is a benzene ring, then B has the structure: [ka] [is].

[0042] (About X, Y, and Z) In one embodiment, the structure: [ka] The structure: [ka] where X is selected from CH and N, and Y is CH 2 , C=O and C=S, or C=O, and in other embodiments the structure: [ka] The structure: [ka] where X is C and Y is CH.

[0043] In one embodiment Z is CH; in another embodiment Z is N.

[0044] In yet certain embodiments, the ring in which X, Y and Z are located has the structure: [ka] is selected from.

[0045] (About Ring A) In one embodiment, ring A is a 4-8 membered heterocyclyl, and in another embodiment, ring A has the structure: [ka] is selected from.

[0046] (About Ring B) In one embodiment, Ring B has the structure: [ka] and in another embodiment, ring B has the structure: [ka] and in another embodiment, ring B has the structure: [ka] It is.

[0047] (About L) In one embodiment, L is a chemical bond; in another embodiment, L is -S(=O)(=M)-; in another embodiment, L is -N(R N )-S(=O)(=M)-; in other embodiments, L is -S(=O)(=M)-N(R N )-; in other embodiments, L is -N(R N )-C(=O)-; in other embodiments, L is -C(=O)-N(R N )-; in other embodiments, L is -CH(R N )-C(=O)-; in other embodiments, L is -C(=O)-CH(R N )-; in other embodiments, L is -CH(R N )-S(=O)(=M)-; in other embodiments, L is -S(=O)(=M)-CH(R N )-.

[0048] (R 1 , R 2 , R 3 and R 4 About In one embodiment, R 1 and R 2 are independently H, halogen, or C 1~6 Alkyl and C 1~6 haloalkyl; in other embodiments, R 1 and R 2 One of them is a halogen, and the other is H, halogen and C 1~6 alkyl; in other embodiments, R 1 and R 2 is F and the other is selected from H, F, and Me; in other embodiments, R 1 and R 2 One is F and the other is H.

[0049] In one embodiment, R 3 and R 4 One of the two is OR a and the other is H and C 1~6 alkyl; in other embodiments, R 3 and R 4 One of is OH or OMe and the other is selected from H and Me.

[0050] (R 5 About In one embodiment, R 5 is H; in other embodiments, R 5 is halogen; in other embodiments, R 5 is C 1~6 alkyl; in other embodiments, R 5 is C 1~6 haloalkyl; in other embodiments, R 5 is selected from H and Me.

[0051] (R 6 About In one embodiment, R 6 -C 0~6 Alkylene-OR a In other embodiments, R 6 OR a In other embodiments, R 6 -C 0~6Alkylene-NR b R c In other embodiments, R 6 is NR b R c In other embodiments, R 6 is C 1~6 alkyl; in other embodiments, R 6 is C 1~6 haloalkyl; in other embodiments, R 6 is C 3~6 cycloalkyl; in other embodiments, R 6 is 4-6 membered heterocyclyl; in other embodiments, R 6 is C 6~10 aryl; in other embodiments, R 6 is a 5-6 membered heteroaryl.

[0052] (R 7 About In one embodiment, R 7 is H; in other embodiments, R 7 -C 1~6 alkylene-CN; in other embodiments, R 7 -C 1~6 Alkylene-OR a In other embodiments, R 7 -C 1~6 Alkylene-NR b R c In other embodiments, R 7 is C 1~6 alkyl; in other embodiments, R 7 is C 1~6 haloalkyl; in other embodiments, R 7 -S(=O)(=M)-R 8 It is.

[0053] (About M) In one embodiment, M is O; in another embodiment, M is NH.

[0054] (R N About In one embodiment, R Nis H; in other embodiments, R N is C 1~6 alkyl; in other embodiments, R N is C 1~6 haloalkyl; in other embodiments, R N and R 6 is concatenated to C 1~6 In another embodiment, R N and R 6 is concatenated to form C 2~6 In another embodiment, R N and R 6 is concatenated to form C 2~6 Forms an alkynylene.

[0055] (R 8 About In one embodiment, R 8 -C 0~6 Alkylene-OR a In other embodiments, R 8 OR a In other embodiments, R 8 -C 0~6 Alkylene-NR b R c In other embodiments, R 8 is NR b R c In other embodiments, R 8 is C 1~6 alkyl; in other embodiments, R 8 -C 1~6 Alkylene-C 3~6 cycloalkyl; in other embodiments, R 8 is C 1~6 haloalkyl; in other embodiments, R 8 is C 3~6 cycloalkyl; in other embodiments, R 8 is 4-6 membered heterocyclyl; in other embodiments, R 8 is C 6~10 aryl; in other embodiments, R 8 is a 5-6 membered heteroaryl.

[0056] Any technical solution or any combination thereof in any one of the above specific embodiments may be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution or any combination thereof of X may be combined with Y, Z, ring A, ring B, L, R 5 , R 6 , or any combination thereof. The present disclosure is intended to include all combinations of such technical solutions, although not exhaustively listed for brevity's sake.

[0057] Further, in certain embodiments, the present disclosure provides a compound of formula (I): [ka] (I) or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof. [In the formula, structure: [ka] The structure: [ka] where: [ka] But the structure: [ka] When X is selected from CH and N, Y is CH 2 , C=O and C=S; and the structure: [ka] But the structure: [ka] when X is C and Y is CH; Z is selected from CH and N; Ring A is a 4-8 membered heterocyclyl; Ring B has the structure: [ka] Selected from; L is a chemical bond, -S(=O)(=M)-, -N(R N )-S(=O)(=M)-, -S(=O)(=M)-N(R N )-, -N(R N )-C(=O)-, -C(=O)-N(R N )-, -CH(R N )-C(=O)-, -C(=O)-CH(R N )-, -CH(R N )-S(=O)(=M)- and -S(=O)(=M)-CH(R N )-selected from; R 1 and R 2 are independently H, halogen, or C 1~6 Alkyl and C 1~6 haloalkyl; R 3 and R 4 are independently H, OR a , C 1~6 Alkyl and C 1~6 haloalkyl; R 5 H, halogen, C 1~6 Alkyl and C 1~6 haloalkyl; R 6 -C 0~6 Alkylene-OR a , -C 0~6 Alkylene-NR b R c , C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 6~10 selected from aryl and 5-6 membered heteroaryl; R 7 -H, -C 1~6Alkylene -CN, -C 1~6 Alkylene-OR a , -C 1~6 Alkylene-NR b R c , C 1~6 Alkyl, C 1~6 Haloalkyl and -S(=O)(=M)-R 8 Selected from; where M is O or NH; R N , H, C 1~6 alkyl and C1-6 haloalkyl; Or, R N and R 6 is concatenated to form C 1~6 Alkylene, C 2~6 Alkenylene or C 2~6 Forming an alkynylene; R 8 -C 0~6 Alkylene-OR a , -C 0~6 Alkylene-NR b R c , C 1~6 Alkyl, -C 1~6 Alkylene-C 3~6 Cycloalkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 6~10 aryl and 5- to 6-membered heteroaryl, which are selected from one or more of R a with appropriate substitutions; R a , R b and R c are independent of each other, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 cycloalkyl and 4- to 6-membered heterocyclyl; or R b and R c together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl; X, Y, Z, Ring A, Ring B, L, R 1 ~R 8 , R N , R a , Rb and R c each group in may be substituted with one or more deuterium atoms until fully deuterized; However, L is -CH(R N )-S(=O)(=M)-, and the ring in which X, Y and Z are located is a benzene ring, then B has the structure: [ka] [is].

[0058] In further certain embodiments, the present disclosure provides a compound of formula (I) above, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein the ring in which X, Y and Z are located has the structure: [ka] is selected from.

[0059] In further certain embodiments, the present disclosure provides a compound of formula (I) above, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein ring A has the structure: [ka] is selected from.

[0060] In further certain embodiments, the present disclosure provides a compound of formula (I) above, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein ring B has the structure: [ka] It is.

[0061] In further certain embodiments, the present disclosure provides a compound of formula (I) above, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein ring B has the structure: [ka] It is.

[0062] In further certain embodiments, the present disclosure provides a compound of formula (I) above, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein L is -S(=O)(=M)-, -N(R N )-S(=O)(=M)-, -N(R N )-C(=O)-, -CH(R N )-C(=O)- and -CH(R N )-S(=O)(=M)-; or L is selected from -N(R N )-S(=O)(=M)- or -CH(R N )-S(=O)(=M)-.

[0063] In further certain embodiments, the present disclosure provides a compound of formula (I) above, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein R 1 and R 2 One of them is halogen and the other is H, halogen and C 1~6 alkyl; or R 1 and R 2 is F and the other is selected from H, F and Me; or R 1 and R 2 One of them is F and the other is H.

[0064] In further certain embodiments, the present disclosure provides a compound of formula (I) above, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein R 3and R 4 One of the two is OR a and the other is H and C 1~6 alkyl; or R 3 and R 4 One of is OH or OMe and the other is selected from H and Me.

[0065] In further certain embodiments, the present disclosure provides a compound of formula (I) above, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein R 5 is selected from H and Me.

[0066] In further certain embodiments, the present disclosure provides a compound of formula (I) above, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, which has the following structure: [ka] [ka] where each group is as defined above.

[0067] In further certain embodiments, the present disclosure provides a compound of formula (II): [ka] (II) or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof. [In the formula, structure: [ka] The structure: [ka] where: [ka] But the structure: [ka] When X is selected from CH and N, Y is CH 2 , C=O and C=S; and the structure: [ka] But the structure: [ka] when X is C and Y is CH; Z is selected from CH and N; Ring A is a 4-8 membered heterocyclyl; L is -S(=O)(=M)-, -N(R N )-S(=O)(=M)-, -S(=O)(=M)-N(R N )-, -N(R N )-C(=O)-, -C(=O)-N(R N )-, -CH(R N )-C(=O)-, -C(=O)-CH(R N )-, -CH(R N )-S(=O)(=M)- and -S(=O)(=M)-CH(R N )-selected from; R 5 H, halogen, C 1~6 Alkyl and C 1~6 haloalkyl; R 6 OR a , N.R. b R c , C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 6~10 selected from aryl and 5-6 membered heteroaryl; R 7 , H, C 1~6 Alkyl, C 1~6Haloalkyl and -S(=O)(=M)-R 8 Selected from; where M is O or NH; R N , H, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R N and R 6 is concatenated to form C 1~6 Alkylene, C 2~6 Alkenylene or C 2~6 Forming an alkynylene; R 8 OR a , N.R. b R c , C 1~6 Alkyl, -CH 2 -C 3~6 Cycloalkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 6~10 aryl and 5- to 6-membered heteroaryl, which are selected from one or more of R a with appropriate substitutions; R a , R b and R c are independent of each other, H, C 1~6 Alkyl and C 1~6 haloalkyl; or R b and R c together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl.

[0068] In further certain embodiments, the present disclosure provides a compound of formula (III): [ka] (III) or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof. [In the formula, Ring A is a 4-8 membered heterocyclyl; L is -S(=O)(=M)-, -N(R N )-S(=O)(=M)-, -S(=O)(=M)-N(R N )-, -N(R N )-C(=O)-, -C(=O)-N(R N )-, -CH(R N )-C(=O)-, -C(=O)-CH(R N )-, -CH(R N )-S(=O)(=M)- and -S(=O)(=M)-CH(R N )-selected from; R 5 H, halogen, C 1~6 Alkyl and C 1~6 haloalkyl; R 6 OR a , N.R. b R c , C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 6~10 selected from aryl and 5-6 membered heteroaryl; R 7 , H, C 1~6 Alkyl, C 1~6 Haloalkyl and -S(=O)(=M)-R 8 Selected from; where M is O or NH; R N , H, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R N and R 6 are connected, C 1~6 Alkylene, C 2~6 Alkenylene or C 2~6 Forming an alkynylene; R 8 OR a , N.R. b R c , C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6Cycloalkyl, 4-6 membered heterocyclyl, C 6~10 aryl and 5- to 6-membered heteroaryl, which are selected from one or more of R a with appropriate substitutions; R a , R b and R c are independent of each other, H, C 1~6 Alkyl and C 1~6 haloalkyl; or R b and R c together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl.

[0069] In further certain embodiments, the disclosure provides the above-mentioned compound, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein ring A is of the formula: [ka] Selected from; L is -S(=O)(=M)-, -N(R N )-S(=O)(=M)-, -S(=O)(=M)-N(R N )-, -N(R N )-C(=O)-, -C(=O)-N(R N )-, -CH(R N )-C(=O)-, -C(=O)-CH(R N )-, -CH(R N )-S(=O)(=M)- and -S(=O)(=M)-CH(R N )-selected from; R 5 is selected from H and Me; R 6 Me, Et, Pr, CH 2 CF 3 , cyclopropyl, OH, NH 2 , NHMe, NMe 2 , furan-2-yl and pyridin-4-yl; R 7 is H, trifluoroethyl and -S(=O)(=M)-R8 Selected from; where M is O or NH; R N , H, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R N and R 6 is concatenated to form C 1~6 Alkylene, C 2~6 Alkenylene or C 2~6 Forming an alkynylene; R 8 Me, Et, Pr, CH 2 CF 3 , cyclopropyl, OH, NH 2 , NHMe, NMe 2 , pyran-4-yl, furan-2-yl and pyridin-4-yl; R a , R b and R c are independent of each other, H, C 1~6 Alkyl and C 1~6 haloalkyl; or R b and R c together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl.

[0070] Moreover, in certain embodiments, the present disclosure provides a compound as described above, or a pharma- ceutically acceptable salt, isotopic substitute, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein: Ring A is a 4-8 membered heterocyclyl; L is -S(=O)(=M)-, -CH(R N )-C(=O)- and -CH(R N )-S(=O)(=M)-; R 5 , H, C 1~6 Alkyl or C 1~6 is haloalkyl; R 6 OR a , N.R. b R c , C1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 selected from cycloalkyl and 4- to 6-membered heterocyclyl; R 7 is H, trifluoroethyl and -S(=O)(=M)-R 8 Selected from; where M is O or NH; R N , H, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R N and R 6 is concatenated to form C 1~6 Alkylene, C 2~6 Alkenylene or C 2~6 Forming an alkynylene; R 8 OR a , N.R. b R c , C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 selected from cycloalkyl and 4- to 6-membered heterocyclyl; R a , R b and R c are independent of each other, H, C 1~6 Alkyl and C 1~6 haloalkyl; or R b and R c together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl.

[0071] Moreover, in certain embodiments, the present disclosure provides a compound as described above, or a pharma- ceutically acceptable salt, isotopic substitute, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein: Ring A is a 4-8 membered heterocyclyl; L is -S(=O)(=M)-, -CH(R N )-C(=O)- and -CH(R N )-S(=O)(=M)-; R5 H and C 1~6 alkyl; R 6 is NR b R c , C 1~6 Alkyl and C 1~6 haloalkyl; R 7 is H, trifluoroethyl and -S(=O)(=M)-R 8 Selected from; where M is O or NH; R N , H, C 1~6 Alkyl and C 1~6 haloalkyl; R 8 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 cycloalkyl and pyran-4-yl; R b and R c are independent of each other, H, C 1~6 Alkyl and C 1~6 haloalkyl.

[0072] Moreover, in certain embodiments, the present disclosure provides a compound as described above, or a pharma- ceutically acceptable salt, isotopic substitute, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein: Ring A has the structure: [ka] Selected from; L is -S(=O)(=M)-, -CH(R N )-C(=O)- and -CH(R N )-S(=O)(=M)-; R 5 is H; R 6 Me and NH 2 Selected from; R 7 is H and -S(=O)(=M)-R 8Selected from; where M is O; R N , H, C 1~6 Alkyl and C 1~6 haloalkyl; R 8 is selected from Me, Et, Pr, cyclopropyl and pyran-4-yl.

[0073] In further certain embodiments, the present disclosure provides a compound of formula (IV): [ka] (IV) or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof. [In the formula, Ring A is a 4-8 membered heterocyclyl; L is -S(=O)(=M)-, -N(R N )-S(=O)(=M)-, -S(=O)(=M)-N(R N )-, -N(R N )-C(=O)-, -C(=O)-N(R N )-, -CH(R N )-C(=O)- and -C(=O)-CH(R N )-selected from; R 1 and R 2 are independently H, halogen, or C 1~6 Alkyl and C 1~6 haloalkyl; R 3 and R 4 are independently H, OR a , C 1~6 Alkyl and C 1~6 haloalkyl; R 5 H, halogen, C 1~6 Alkyl and C 1~6 haloalkyl; R 6 OR a , N.R. b Rc , C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 6~10 selected from aryl and 5-6 membered heteroaryl; where M is O or NH; R N , H, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R N and R 6 is concatenated to form C 1~6 Alkylene, C 2~6 Alkenylene or C 2~6 Forming an alkynylene; R a , R b and R c are independent of each other, H, C 1~6 Alkyl and C 1~6 haloalkyl; or R b and R c together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl.

[0074] Moreover, in certain embodiments, the present disclosure provides the above-mentioned compound, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein Ring A has the structure: [ka] Selected from; L is -S(=O)(=M)-, -N(R N )-S(=O)(=M)-, -S(=O)(=M)-N(R N )-, -N(R N )-C(=O)-, -C(=O)-N(R N )-, -CH(R N )-C(=O)- and -C(=O)-CH(R N )-selected from; R 1 and R2 are independently H, halogen, or C 1~6 Alkyl and C 1~6 haloalkyl; R 3 and R 4 are independently H, OR a , C 1~6 Alkyl and C 1~6 haloalkyl; R 5 , H, C 1~6 Alkyl and C 1~6 haloalkyl; R 6 OR a , N.R. b R c , C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 6~10 selected from aryl and 5-6 membered heteroaryl; where M is O or NH; R N , H, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R N and R 6 is concatenated to form C 1~6 Alkylene, C 2~6 Alkenylene or C 2~6 Forming an alkynylene; R a , R b and R c are independent of each other, H, C 1~6 Alkyl and C 1~6 haloalkyl; or R b and R c together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl.

[0075] In further certain embodiments, the present disclosure provides compounds of formula (V), (V-1) or (V-2): [ka] or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof. [In the formula, L is -S(=O)(=M)-, -N(R N )-S(=O)(=M)-, -S(=O)(=M)-N(R N )-, -N(R N )-C(=O)-, -C(=O)-N(R N )-, -CH(R N )-C(=O)- and -C(=O)-CH(R N )-selected from; R 1 and R 2 are independently H, halogen, or C 1~6 Alkyl and C 1~6 haloalkyl; R 3 and R 4 are independently H, OR a , C 1~6 Alkyl and C 1~6 haloalkyl; R 5 H, halogen, C 1~6 Alkyl and C 1~6 haloalkyl; R 6 OR a , N.R. b R c , C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 6~10 selected from aryl and 5-6 membered heteroaryl; where M is O or NH; R N , H, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R N and R 6 is concatenated to form C 1~6 Alkylene, C 2~6 Alkenylene or C 2~6Forming an alkynylene; R a , R b and R c are independent of each other, H, C 1~6 Alkyl and C 1~6 haloalkyl; or R b and R c together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl.

[0076] In further certain embodiments, the present disclosure provides a compound as described above, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein: L is -S(=O)(=M)-, -N(R N )-S(=O)(=M)-, -N(R N )-C(=O)- and -CH(R N )-C(=O)-; R 1 and R 2 One of them is a halogen, and the other is H, halogen and C 1~6 alkyl; R 3 and R 4 One of the two is OR a and the other is H and C 1~6 alkyl; R 5 , H, C 1~6 Alkyl and C 1~6 haloalkyl; R 6 OR a , N.R. b R c , C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 selected from cycloalkyl and 5-6 membered heteroaryl; where M is O or NH; R N , H, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R N and R 6 is concatenated to form C 1~6 Alkylene, C 2~6 Alkenylene or C 2~6 Forming an alkylene; R a , R b and R c are independent of each other, H, C 1~6 Alkyl and C 1~6 haloalkyl; or R b and R c together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl.

[0077] Further in certain embodiments, the present disclosure provides a compound represented by formula (VI), (VI-1) or (VI-2): [ka] or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein: M is O or NH; R 1 and R 2 are independently H, halogen, or C 1~6 Alkyl and C 1~6 haloalkyl; R 3 and R 4 are independently H, OR a , C 1~6 Alkyl and C 1~6 haloalkyl; R 5 H, halogen, C 1~6 Alkyl and C 1~6 haloalkyl; R 6 OR a , N.R. b R c , C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 6~10selected from aryl and 5-6 membered heteroaryl; R N , H, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R N and R 6 is concatenated to form C 1~6 Alkylene, C 2~6 Alkenylene or C 2~6 Forming an alkynylene; Here, R a , R b and R c are independent of each other, H, C 1~6 Alkyl and C 1~6 haloalkyl; or R b and R c together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl.

[0078] In further certain embodiments, the disclosure provides a compound as described above, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein: M is O or NH; R 1 and R 2 One of them is a halogen, and the other is H, halogen and C 1~6 alkyl; R 3 and R 4 One of the two is OR a and the other is H and C 1~6 alkyl; R 5 H and C 1~6 alkyl; R 6 OR a , N.R. b R c , C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 selected from cycloalkyl and 5-6 membered heteroaryl; RN H and C 1~6 alkyl; Or, R N and R 6 is concatenated to form C 1~6 Forming an alkylene; Here, R a , R b and R c are independent of each other, H, C 1~6 Alkyl and C 1~6 haloalkyl.

[0079] In further certain embodiments, the disclosure provides a compound as described above, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein: M is O; R 1 and R 2 is F and the other is selected from H, F and Me; R 3 and R 4 one of is OH or OMe and the other is selected from H and Me; R 5 is selected from H and Me; R 6 Me, Et, Pr, CH 2 CF 3 , Cyclopropyl, NMe 2 , furan-2-yl and pyridin-4-yl; R N is selected from H and Me; Or, R N and R 6 is concatenated to form C 1~4 Form an alkylene.

[0080] In further certain embodiments, the disclosure provides a compound as described above, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein: M is O or NH; R 1and R 2 One of them is halogen, C 1~6 Alkyl and C 1~6 haloalkyl, and the other is H; R 3 and R 4 One of the two is OR a , C 1~6 Alkyl and C 1~6 haloalkyl, and the other is H; R 5 H, halogen, C 1~6 Alkyl and C 1~6 haloalkyl; R 6 OR a , N.R. b R c , C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 6~10 selected from aryl and 5-6 membered heteroaryl; R N , H, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R N and R 6 is concatenated to form C 1~6 Alkylene, C 2~6 Alkenylene or C 2~6 Forming an alkynylene; Here, R a , R b and R c are independent of each other, H, C 1~6 Alkyl and C 1~6 haloalkyl; or R b and R c together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl.

[0081] In further certain embodiments, the disclosure provides a compound as described above, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein: M is O or NH; R 1 and R 2 One of the two is halogen and C 1~6 alkyl, and the other is H; R 3 and R 4 One of the two is OR a and the other is H; R 5 , H, C 1~6 Alkyl and C 1~6 haloalkyl; R 6 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 selected from cycloalkyl and 4- to 6-membered heterocyclyl; R N , H, C 1~6 Alkyl and C 1~6 haloalkyl; Here, R a , H, C 1~6 Alkyl and C 1~6 haloalkyl.

[0082] In further certain embodiments, the present disclosure provides a compound as described above, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein: M is O; R 1 and R 2 one of which is a halogen (or F) and the other is H; R 3 and R 4 One of the two is OR a and the other is H; R 5 H and C 1~4 alkyl; R 6 is C 1~4 Alkyl and C 1~4 haloalkyl; R N, H, C 1~4 Alkyl and C 1~4 haloalkyl; or C 1~4 is alkyl; Here, R a H and C 1~4 is selected from alkyl.

[0083] Further in certain embodiments, the present disclosure provides compounds of formula (VII), (VII-1) or (VII-2): [ka] or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof. [In the formula, L is -S(=O)(=M)-, -N(R N )-S(=O)(=M)-, -S(=O)(=M)-N(R N )-, -N(R N )-C(=O)-, -C(=O)-N(R N )-, -CH(R N )-C(=O)-, -C(=O)-CH(R N )-, -CH(R N )-S(=O)(=M)- and -S(=O)(=M)-CH(R N )-selected from; R 5 H, halogen, C 1~6 Alkyl and C 1~6 haloalkyl; R 6 OR a , N.R. b R c , C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 6~10 selected from aryl and 5-6 membered heteroaryl; R 7 , H, C 1~6 Alkyl, C 1~6 Haloalkyl and -S(=O)(=M)-R 8Selected from; where M is O or NH; R N , H, C 1~6 Alkyl and C 1~6 haloalkyl; Or, R N and R 6 is concatenated to form C 1~6 Alkylene, C 2~6 Alkenylene or C 2~6 Forming an alkynylene; R 8 OR a , N.R. b R c , C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocyclyl, C 6~10 aryl and 5- to 6-membered heteroaryl, which are selected from one or more of R a with appropriate substitutions; R a , R b and R c are independent of each other, H, C 1~6 Alkyl and C 1~6 haloalkyl; or R b and R c together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl.

[0084] In further certain embodiments, the disclosure provides a compound as described above, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein: L is -N(R N )-S(=O)(=M)- and -CH(R N )-S(=O)(=M)-; R 5 is C 1~6 Alkyl and C 1~6 haloalkyl; R 6 is C 1~6 Alkyl, C 1~6Haloalkyl, C 3~6 selected from cycloalkyl and 4- to 6-membered heterocyclyl; R 7 is -S(=O)(=M)-R 8 and; where M is O or NH; R N , H, C 1~6 Alkyl and C 1~6 haloalkyl; R 8 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 cycloalkyl and 4- to 6-membered heterocyclyl, which may be one or more of R a with appropriate substitutions; R a , H, C 1~6 Alkyl and C 1~6 haloalkyl.

[0085] In further certain embodiments, the present disclosure provides a compound as described above, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein: L is -N(R N )-S(=O)(=M)- and -CH 2 - selected from S(=O)(=M)-; R 5 is C 1~6 Alkyl and C 1~6 haloalkyl; R 6 is C 1~6 Alkyl and C 1~6 haloalkyl; R 7 is -S(=O)(=M)-R 8 and; where M is O or NH; R N is C 1~6 Alkyl and C 1~6 haloalkyl; R 8 is C1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 It is selected from cycloalkyl and 4- to 6-membered heterocyclyl.

[0086] In further certain embodiments, the disclosure provides a compound as described above, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein: L is -N(R N )-S(=O) 2 - and -CH 2 -S(=O) 2 - Selected from; R 5 is C 1~6 Alkyl and C 1~6 haloalkyl; R 6 is C 1~6 Alkyl and C 1~6 haloalkyl; R 7 is -S(=O) 2 -R 8 and; Here, R N is C 1~6 Alkyl and C 1~6 haloalkyl; R 8 is C 1~6 Alkyl, C 1~6 Haloalkyl and C 3~6 cycloalkyl.

[0087] In further certain embodiments, the disclosure provides a compound as described above, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof, wherein: L is -N(R N )-S(=O) 2 - and -CH 2 -S(=O) 2 - Selected from; R 5 is C 1~4 is alkyl; R6 is C 1~4 is alkyl; R 7 is -S(=O) 2 -R 8 and; Here, R N is C 1~4 is alkyl; R 8 is C 1~4 Alkyl and C 3~6 cycloalkyl.

[0088] In further certain embodiments, the present disclosure provides a compound having the structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0089] The compounds of the present disclosure may have one or more asymmetric centers and therefore may exist in various stereochemical forms, such as enantiomers and / or diastereomers. For example, the compounds of the present disclosure may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; alternatively, another isomer can be prepared by asymmetric synthesis.

[0090] The compounds of the present disclosure may exist as tautomers. For compounds that exist in different tautomeric forms, the compounds are not limited to any particular tautomer but are intended to include all tautomeric forms.

[0091] It is understood by those skilled in the art that organic compounds may form complexes with solvents in which they react or precipitate or crystallize. These complexes are known as "solvates." When the solvent is water, the complexes are known as "hydrates." The present disclosure encompasses all solvates of the compounds of the present disclosure.

[0092] The term "solvate" refers to a form of a compound or its salt that is associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form and may be solvated. Suitable solvates include pharma- ceutically acceptable solvates, further including both solvates of stoichiometric composition and solvates of non-stoichiometric composition. In some cases, the solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes both solution phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0093] The term "hydrate" refers to a compound that is associated with water. Generally, the number of water molecules in a hydrate of a compound is in a fixed ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound may be, for example, a compound of the general formula R xH 2 O, where R is the compound and x is a number greater than 0. A compound may be, for example, a monohydrate (x is 1), a hypohydrate (x is a number greater than 0 and less than 1, e.g., a hemihydrate (R 0.5H 2 O)) and polyhydrates (where x is greater than 1, e.g., dihydrates (R 2H 2 O) and hexahydrate (R 6H 2 It may form more than one hydrate form, including hydrates of the formula I and II.

[0094] The compounds of the present disclosure may be in amorphous or crystalline form (polymorphs). Furthermore, the compounds of the present disclosure may exist in one or more crystalline forms. Thus, the present disclosure includes within its scope all amorphous or crystalline forms of the compounds of the present disclosure. The term "polymorph" refers to a crystalline form of a compound (or salt, hydrate or solvate) that is a particular crystal packing arrangement. All polymorphs have the same elemental composition. In general, different crystalline forms have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystalline form to predominate. Various polymorphs of a compound may be prepared by crystallization under various conditions.

[0095] The present disclosure also includes isotopically labeled compounds (isotopically substituted compounds), which are equivalent to those described in formula (I), but in which one or more atoms are replaced by atoms whose atomic masses or mass numbers are different from those of the atoms common in nature. Examples of isotopes that may be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, e.g., 2 H, 3 H, 13 C. 11 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 The compound of the present disclosure, its prodrugs, and pharma- ceutically acceptable salts of said compounds or said prodrugs, which contain the aforementioned isotopes and / or other isotopes of other atoms, are all within the scope of the present disclosure. Certain isotopically labeled compounds of the present disclosure, e.g., compounds containing radioactive isotopes (e.g., 3 H and 14 C) can be used to measure the distribution of drugs and / or substrates within cells. 3 H) and carbon-14 ( 14C isotope) is selected. Additionally, heavier isotopes such as deuterium ( 2 H) may provide therapeutic benefits, such as increased half-life or reduced dosage requirements in vivo, due to its high metabolic stability and therefore may be selected in some cases. Isotopically labeled compounds of formula (I) and prodrugs thereof in the present disclosure can generally be prepared by substituting readily available isotopically labeled reagents for nonisotopically labeled reagents in the schemes and / or procedures disclosed in the Examples and Preparative Examples below.

[0096] In addition, prodrugs are also included in the context of this disclosure. The term "prodrug" as used herein refers to a compound that is converted in vivo into an active form that has a therapeutic effect, for example, by hydrolysis in blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACS Symposium Series, Vol. 14, Ed. Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) pp. 115-130, each of which is incorporated herein by reference.

[0097] Pharmaceutical Compositions and Kits In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (also referred to as an "active ingredient") and a pharma- ceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present disclosure. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present disclosure.

[0098] The pharma- ceutically acceptable excipient for use in the present disclosure refers to a non-toxic carrier, auxiliary, or vehicle that does not impair the pharmaceutical activity of the compound with which it is formulated.The pharma-ceutically acceptable carrier, auxiliary, or vehicle that may be used in the compositions of the present disclosure includes, but is not limited to, ion exchange agents, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substrates (e.g., phosphates), glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate), disodium hydrogen phosphate, potassium monohydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0099] The disclosure also includes kits (e.g., pharmaceutical packs). The kits provided may include a compound disclosed herein, another pharmaceutical agent, and a first or second container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a disposable package or other material) that includes the compound disclosed herein or another pharmaceutical agent. In some embodiments, the kits provided may also optionally include a third container that includes a pharma- ceutically acceptable excipient for diluting or suspending the compound disclosed herein and / or another pharmaceutical agent. In some embodiments, the compound disclosed herein, provided in the first container, and the other pharmaceutical agent, provided in the second container, are combined to form a unit dosage form.

[0100] (Administration) The pharmaceutical compositions provided in the present disclosure may be provided by a variety of routes, including, but not limited to, oral, parenteral, inhalation, topical, rectal, nasal, oral, vaginal, implanted or other means of administration. For example, as used herein, parenteral administration includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intraventricular, intralesional, and intracranial injection or infusion techniques.

[0101] Generally, the compounds provided herein are administered in effective amounts. The amount of the compound actually administered is typically determined by a physician, taking into account the relevant circumstances, including the condition to be treated in the individual patient, the selected route of administration, the compound actually administered, the age, weight, and response, the severity of the patient's condition, and the like.

[0102] When used to prevent the disorders disclosed herein, the compounds provided herein are typically administered at the dosage levels described above under the guidance and supervision of a physician to patients at risk of developing said condition. Subjects at risk of developing a particular condition generally include those who have a family history of the condition or who have been identified by genetic or screening tests as being particularly susceptible to developing the condition.

[0103] The pharmaceutical compositions provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof for an extended period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue indefinitely, such as for the remaining lifespan of a subject. In certain embodiments, the chronic administration aims to maintain a certain level of the compound in the blood, such as within a therapeutic window, for an extended period of time.

[0104] The pharmaceutical compositions of the present disclosure may also be delivered using various dosing methods. For example, in some embodiments, the pharmaceutical composition may be given as a bolus, e.g., to raise the concentration of the compound in the blood to an effective level. The bolus administration is arranged according to the systemic level of the active ingredient desired throughout the body, e.g., an intramuscular or subcutaneous bolus administration allows for a sustained release of the active ingredient, while a bolus delivered directly into a vein (e.g., by intravenous drip) allows for a fast delivery, quickly raising the active ingredient concentration in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered by continuous infusion, e.g., intravenous drip, to maintain a steady state concentration of the active ingredient in the subject's body. In yet other embodiments, the pharmaceutical composition may be administered first as a bolus administration, and then by continuous infusion.

[0105] Compositions for oral administration may take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as single dosages for human subjects and other mammals, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect, together with suitable pharmaceutical excipients. Typical unit dosage forms include prefilled, premeasured ampoules or syringes containing liquid compositions, or pills, tablets, capsules, and the like, in the case of solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, or about 1 to about 40% by weight), with the remainder including various vehicles or excipients and processing aids that help form the desired dosage form.

[0106] For oral administration, 1 to 5 times daily, particularly 2 to 4 times daily, typically 3 times daily, is a typical regimen. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg / kg of a compound provided herein, and each separate dose provides from about 0.1 to about 10 mg / kg, particularly from about 1 to about 5 mg / kg.

[0107] Transdermal administration is generally selected to provide similar or lower blood levels than are achieved using injection administration, generally amounts in the range of about 0.01 to about 20% by weight, or about 0.1 to about 20% by weight, or about 0.1 to about 10% by weight, or about 0.5 to 15% by weight.

[0108] Injection dosage levels range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour for a total of about 1 to about 120 hours, particularly 24 to 96 hours. A preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may be administered to achieve adequate steady state. Maximum total doses are not expected to exceed about 2 g / day for a 40-80 kg human patient.

[0109] Liquid dosage forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispersing agents, colorants, flavors, etc. Solid dosage forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavor.

[0110] Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As before, the active compound in such compositions is typically a minor component, often about 0.05-10% by weight, with the remainder being injectable excipients etc.

[0111] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient(s). When formulated as an ointment, the active ingredient is typically combined with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated into a cream, for example with an oil-in-water cream base. Such transdermal formulations are known in the art and generally further comprise ingredients to improve the stability of the active ingredient or formulation for skin penetration. All such transdermal formulations and ingredients are included within the scope provided herein.

[0112] The compounds provided herein can also be administered by a transdermal device, that is, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0113] The above ingredients for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Chapter 8 of Remington's Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, and are incorporated herein by reference.

[0114] The compounds of the present disclosure can also be administered in sustained release dosage forms or through sustained release drug delivery systems. Representative sustained release materials are described in Remington's Pharmaceutical Sciences.

[0115] The present disclosure also relates to pharma- ceutically acceptable formulations of the compounds of the present disclosure. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, consisting of 6, 7, and 8 α-1,4 linked glucose units, respectively, optionally containing one or more substituents (including but not limited to methyl, hydroxyalkyl, acryl, and sulfoalkyl ether substitutions) on the attached sugar moiety. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as Captisol (see, e.g., U.S. Patent No. 5,376,645). In certain embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0116] (Example) The reagents used in this disclosure are either directly purchased commercially available reagents or are synthesized by methods known in the art.

[0117] The specific reaction pathways or steps exemplified below are used in this disclosure. EXAMPLES

[0118] (Preparation of key intermediate) Synthesis of intermediate a1 [ka] Step 1: 3-Chloroisoquinoline a1-1 (3.5 g, 21.4 mmol) was dissolved in 50 mL of trifluoromethanesulfonic acid at -10° C. under nitrogen protection. N-iodosuccinimide NIS (7.21 g, 32.1 mmol) was added in batches and the mixture was stirred for 4 hours. The completion of the reaction was confirmed by TLC. The reaction solution was quenched by slowly adding 100 mL of aqueous ammonia, extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was separated by column chromatography (PE / EA=100 / 1) to give a white solid a1-2 (4.1 g). Yield: 60%, LCMS: ESI-MS (m / z): 289.8 [M+H] + .

[0119] 1 H NMR (400 MHz, CDCl 3 ) δ 8.95 (s, 1H), 8.26 (dd, J = 7.4, 1.1 Hz, 1H), 7.98 - 7.94 (m, 1H), 7.93 (d, J = 0.7 Hz, 1H), 7.33 (dd, J = 8.2, 7.4 Hz, 1H).

[0120] Step 2: Under nitrogen protection, the intermediate a1-2 (4.1 g, 14.2 mmol) obtained in the previous step and K 2 CO 3 (5.87 g, 42.3 mmol) was mixed with 110 mL of a mixture of 1,4-dioxane and water (v / v=10 / 1) and Pd(dppf)Cl 2 (1.04g, 1.42mmol) was added. The mixture was heated to 90°C. Isopropenylboronic acid pinacol ester a1-3 (3.6g, 21.2mmol) was added to the reaction solution, and the reaction solution was reacted at 60°C for another 3 hours. The reaction was stopped. The reaction solution was filtered, and the residue was concentrated. 50mL of water was added to the system, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by flash column chromatography to obtain a yellow solid a1-4 (1.9g). Yield: 53%, LC-MS: M+H+ =204.0.

[0121] 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.21 (s, 1H), 8.09 (dd, J = 6.2, 3.1 Hz, 1H), 7.85 (s, 1H), 7.68 - 7.65 (m, 2H), 5.49 (t, J = 1.6 Hz, 1H), 5.03 (s, 1H), 2.14 (s, 3H).

[0122] Step 3: 3-chloro-5-(prop-1-en-2-yl)isoquinoline a1-4 (3.5 g, 17.2 mmol) obtained in the previous step was dissolved in 50 mL of ethyl acetate, and platinum dioxide (0.78 g, 3.4 mmol) was added. The mixture was reacted at room temperature for 6 hours under a hydrogen atmosphere. The reaction solution was filtered. The filtrate was concentrated and separated by column chromatography to obtain oily intermediate a1-5 (2.1 g). Yield: 54%, LC-MS: ESI-MS (m / z): 206.1 [M+H] + .

[0123] 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.21 (s, 1H), 8.12 (s, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 6.7 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 3.76 - 3.65 (m, 1H), 1.32 (d, J = 6.8 Hz, 6H).

[0124] Step 4: The intermediate a1-5 (1.8 g, 8.75 mmol) obtained in the previous step was dissolved in 24 mL of concentrated sulfuric acid at -10° C. under nitrogen protection. N-bromosuccinimide NBS (2.02 g, 11.4 mmol) was added in batches, and the mixture was stirred for 8 hours. The completion of the reaction was confirmed by LC-MS. 200 mL of ice water was slowly added to the reaction solution to quench the reaction, and the pH of the mixture was adjusted to about 8 with aqueous ammonia. The mixture was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was separated by column chromatography (PE / EA=50 / 1) to obtain a white solid a1 (1.0 g). Yield: 36%, LCMS: ESI-MS (m / z): 283.9 [M+H] + .

[0125] 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.34 (s, 1H), 8.22 (s, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 3.72 (dt, J = 13.7, 6.8 Hz, 1H), 1.31 (d, J = 6.8 Hz, 6H).

[0126] Synthesis of intermediate a2 [ka] Step 1: tert-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate A2-1 (4.8 g, 22 mmol) and triethylamine (4.53 g, 44 mmol) were dissolved in 50 mL of dichloromethane under nitrogen protection in an ice bath, and methylsulfonyl chloride (3.08 g, 26 mmol) was added dropwise. After the addition was complete, the mixture was stirred for another 2 hours. 10 mL of saturated aqueous sodium dicarbonate was added to the reaction solution to quench the reaction, and the mixture was extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and concentrated to give crude product A2-2 (6.24 g). Yield: 86%.

[0127] Step 2: Under nitrogen protection, the intermediate a2-2 (6.24 g, 21 mmol) obtained in the previous step and sodium thiomethoxide (20% aqueous solution) (15.0 g, 42 mmol) were dissolved in 50 mL of DMF, and the solution was heated to 60° C. and stirred for 12 hours. The completion of the reaction was confirmed by LC-MS. 200 mL of water was added to the system, and the mixture was extracted with ethyl acetate and washed with saturated saline. The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain a colorless oily substance a2-3 (3.98 g). Yield: 69%.

[0128] Step 3: The intermediate a2-3 (3.98 g, 16 mmol) obtained in the previous step was dissolved in 200 mL of dichloromethane, and the oxidizing agent oxone (50.1 g, 81 mmol) was added. The mixture was reacted at room temperature for 48 hours. The reaction was stopped, and the mixture was filtered. The filtrate was concentrated to obtain compound a2-4 (4.18 g). Yield: 83%.

[0129] 1 H NMR (400 MHz, CDCl 3 ) δ 3.95 (d, J = 5.7 Hz, 4H), 3.72 - 3.52 (m, 1H), 2.80 (s, 3H), 2.76 - 2.65 (m, 2H), 2.59 - 2.49 (m, 2H), 1.43 (s, 9H).

[0130] Step 4: Compound a2-4 (3.72 g, 13 mmol) was dissolved in 40 mL of dichloromethane, and trifluoroacetic acid (4.62 g, 41 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours. The solvent was removed by evaporation under reduced pressure to give crude product a2-5 (1.95 g). LCMS: ESI-MS (m / z): 176.0 [M+H] + .

[0131] Step 5: Under nitrogen protection, the intermediate a2-5 (1.6 g, 5.5 mmol) obtained in the previous step and Cs 2 CO 3(5.38 g, 16.5 mmol) were mixed in 25 mL of 1,4-dioxane and Xantphos Pd G3 (520 mg, 0.5 mmol) was added. The mixture was heated to 100° C. Intermediate a1 (1.57 g, 5.5 mmol) was added to the reaction solution and the reaction solution was reacted at 100° C. for another 3 hours. The reaction was stopped and the mixture was filtered. The filtrate was concentrated and separated by flash column chromatography to give a yellow solid a2 (820 mg). Yield: 35%, LCMS: ESI-MS (m / z): 379.1 [M+H] + .

[0132] Synthesis of intermediates a3, a5, and a9 [ka] Step 1: Under nitrogen protection, tert-butyl [3-(iodomethyl)azetidin-1-yl]carboxylate a3-1 (6.0 g, 16 mmol) and sodium thiomethoxide (20% aqueous solution) (6.0 g, 16 mmol) were dissolved in a mixture of 50 mL of acetonitrile and water (v / v=3 / 1). The mixture was heated to 60° C. and stirred for 12 hours. The completion of the reaction was confirmed by LC-MS. 100 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give a yellow oil a3-2 (2.43 g). Yield: 81%, LC-MS: [M+H] + =162.0.

[0133] Step 2: Under nitrogen protection, the oily substance a3-2 (2.43 g, 10 mmol) obtained in the previous step was dissolved in 50 mL of dichloromethane, and the oxidizing agent oxone (34.4 g, 56 mmol) was added. The mixture was reacted at room temperature for 48 hours. The completion of the reaction was confirmed by LC-MS. The reaction solution was filtered, and the filtrate was concentrated to obtain a white solid a3-3 (2.99 g). Yield: 95%, LC-MS: [M+H] + =250.0.

[0134] Step 3: The intermediate a3-3 (2.99 g, 12 mmol) obtained in the previous step was dissolved in 20 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product a3-4. LC-MS: [M+H] + =150.0.

[0135] Step 4: Under nitrogen protection, the crude product a3-4 (1.39 g, 5.27 mmol) obtained in the previous step, intermediate a1 (500 mg, 1.76 mmol) and Cs 2 CO 3 (2.86 g, 8.79 mmol) was mixed in 10 mL of 1,4-dioxane and Xantphos Pd G3 (167 mg, 0.18 mmol) was added. The mixture was heated to 100° C. and reacted for 3 hours. The reaction was stopped and filtered. The filtrate was concentrated and separated by flash column chromatography to give a green solid a3 (410 mg). Yield: 60%, LC-MS: M+H + =353.0.

[0136] 1 H NMR (400 MHz, CDCl 3 ) δ 9.11 (d, J = 0.5 Hz, 1H), 7.84 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 4.45 (t, J = 7.5 Hz, 2H), 4.02 (dd, J = 7.6, 5.3 Hz, 2H), 3.50 - 3.40 (m, 4H), 2.98 (s, 3H), 1.33 (d, J = 6.8 Hz, 6H).

[0137] Referring to the synthetic route of intermediate a3, the following intermediates were synthesized using similar framework structures. [Table 1]

[0138] Synthesis of intermediate a4 [ka] Step 1: Intermediate a3 (200 mg, 0.57 mmol) was dissolved in 20 mL of DMF, and N-iodosuccinimide NIS (380 mg, 1.7 mmol) was added. The mixture was reacted at room temperature for 2 hours. The completion of the reaction was confirmed by LC-MS. 100 mL of water was added to the reaction solution. The mixture was extracted with ethyl acetate, washed with saturated sodium thiosulfate solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give a yellow solid a4-1 (200 mg). Yield: 59%, LC-MS: M+H + =478.9.

[0139] Step 2: Under nitrogen protection, intermediate a4-1 (20 mg, 0.042 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate a4-2 (40 mg, 0.21 mmol) and CuI (24 mg, 0.12 mmol) were mixed in 5 mL of DMF. The mixture was heated to 90° C. and reacted for 1 hour. The completion of the reaction was confirmed by LC-MS. 50 mL of water was added to the reaction solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (DCM / MeOH=25 / 1) to obtain a yellow solid a4 (15 mg). Yield: 77%, LC-MS: M+H + =421.0.

[0140] Synthesis of intermediate a6 [ka] Step 1: Methyl 2-(1-(3-chloro-5-isopropylisoquinolin-8-yl)azetidin-3-yl)acetate a5 (120 mg, 0.36 mmol) was dissolved in 6 mL of a mixture of tetrahydrofuran and water (v / v=5 / 1), and lithium hydroxide monohydrate (23 mg, 0.54 mmol) was added. The mixture was stirred at room temperature for 12 hours. The reaction was stopped, and acetic acid was slowly added to the reaction solution to adjust the pH to about 6. The mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give crude intermediate a6-1 (100 mg). Yield: 18%, LC-MS: ESI-MS (m / z): 319.1 [M+H] + .

[0141] Step 2: The crude product a6-1 (50 mg, 0.16 mmol) obtained in the previous step was dissolved in 3 mL of dichloromethane. HOBT (6 mg, 0.047 mmol), EDCI (36 mg, 0.19 mmol) and DIPEA (40 mg, 0.31 mmol) were added. The mixture was stirred at room temperature for 1 hour. 0.2 mL of aqueous ammonia was added to the reaction solution, and the mixture was reacted at room temperature for another 2 hours. The reaction was stopped, and 20 mL of water was added to the reaction solution. The mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and separated by thin layer chromatography to obtain intermediate a6 (20 mg). Yield: 36%, LC-MS: ESI-MS (m / z): 318.1 [M+H] + .

[0142] Synthesis of intermediate a7 [ka] Step 1: In an ice bath, the raw material 1-(diphenylmethyl)-2,2-dimethylazetidin-3-one a7-1 (3.2 g, 12.1 mmol) was dissolved in 50 mL of methanol, and sodium borohydride (912 mg, 24.1 mmol) was added. The mixture was heated to 70° C. and reacted for 16 hours. The reaction was stopped and evaporated under reduced pressure to remove the solvent. 100 mL of water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by flash column chromatography (PE / EA=3 / 1) to give a white solid a7-2 (2.0 g). Yield: 59%, LC-MS: ESI-MS (m / z): 268.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.46 (dd, J = 18.3, 7.4 Hz, 4H), 7.24 - 7.08 (m, 6H), 4.58 (s, 1H), 4.05 - 3.95 (m, 1H), 3.40 - 3.28 (m, 1H), 2.72 (dd, J = 7.7, 5.9 Hz, 1H), 1.69 (d, J = 7.5 Hz, 1H), 1.08 (s, 3H), 1.01 (s, 3H).

[0143] Step 2: In an ice bath, the intermediate a7-2 (1.0 g, 3.74 mmol) obtained in the previous step and triethylamine (605 mg, 5.98 mmol) were dissolved in 20 mL of dichloromethane, and methylsulfonyl chloride (554 mg, 4.86 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was stopped. 50 mL of water was added to the system. The mixture was extracted with dichloromethane and concentrated to give the crude product a7-3 (1.1 g), which was used directly in the next step.

[0144] Step 3: In an ice bath, methyl 2-methanesulfonyl acetate a7-4 (745 mg, 4.89 mmol) was dissolved in 20 mL of DMF, and NaH (181 mg, 4.52 mmol, 60%) was added. The reaction solution was stirred at 0° C. for 15 minutes, and the crude product a7-3 (1.1 g) obtained in the previous step was added to the system. The mixture was heated to 80° C. and reacted for 16 hours. 50 mL of saturated aqueous ammonium chloride solution was added to the system to quench the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by flash column chromatography (DCM / MeOH=20 / 1) to obtain a white solid a7-5 (900 mg). Yield: 54%, LC-MS: ESI-MS (m / z): 402.0 [M+H] + .

[0145] Step 4: The intermediate a7-5 (900 mg, 2.24 mmol) obtained in the previous step was dissolved in 20 mL of DMA, and LiCl (950 mg, 22.42 mmol) was added. The mixture was heated to 150° C. and reacted for 1 hour. The reaction was stopped, and 80 mL of water was added to the system. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by flash column chromatography (DCM / MeOH=20 / 1) to obtain a white solid a7-6 (200 mg). Yield: 27%, LC-MS: ESI-MS (m / z): 344.0 [M+H] + .

[0146] Step 5: Under a hydrogen balloon atmosphere, the intermediate a7-6 (2200 mg, 0.64 mmol) obtained in the previous step was dissolved in 12 mL of methanol. 0.5 mL of trifluoroacetic acid and Pd(OH) 2 A 20 mg / C mixture was added. The mixture was reacted at room temperature for 16 hours. The reaction was stopped and filtered. The filtrate was concentrated under reduced pressure to give yellow trifluoroacetate a7-7 (150 mg). Yield: 92%, LC-MS: ESI-MS (m / z): 178.2 [M+H] + .

[0147] Step 6: Under nitrogen protection, the trifluoroacetate a7-7 (92 mg, 0.31 mmol) obtained in the previous step, intermediate a1 (60 mg, 0.21 mmol) and Cs 2 CO 3 (171 mg, 0.52 mmol) was mixed in 3 mL of 1,4-dioxane. Xantphos Pd G3 (65 mg, 0.063 mmol) was added. The mixture was heated to 100° C. and reacted for 6 h. The reaction was stopped and filtered. The filtrate was concentrated and separated by flash column chromatography to give a yellow solid a7 (35 mg). Yield: 39%, LC-MS: ESI-MS (m / z): 381.1 [M+H] + .

[0148] Synthesis of intermediate a8 [ka] Step 1: Dimethylphosphine oxide a8-1 (1.0 g, 12.8 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran under nitrogen protection at -20°C, and LDA (1 M, 38.4 mL) was added dropwise. After stirring for 20 minutes, a solution of intermediate a3-1 (5.72 g, 19.2 mmol) in tetrahydrofuran (10 mL) was added dropwise. After the addition was completed, the mixture was slowly warmed to room temperature, and the mixture was reacted at room temperature for 5 hours. The reaction was stopped. 50 mL of saturated aqueous ammonium chloride solution was added to the system to quench the reaction. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by flash column chromatography to obtain a brown solid a8-2 (0.8 g). Yield: 24%, LC-MS: ESI-MS (m / z): 248.1 [M+H] + .

[0149] Step 2: Intermediate a8-2 (800 mg, 3.23 mmol) was dissolved in 6 mL of dichloromethane and 3 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to give crude product a8-3, which was used directly in the next step. LC-MS: ESI-MS (m / z): 148.1 [M+H]+ .

[0150] Step 3: Under nitrogen protection, trifluoroacetate a8-3, intermediate a1 (774 mg, 2.7 mmol) and Cs 2 CO 3 (2.66 g, 8.2 mmol) was mixed in 15 mL of 1,4-dioxane. Xantphos Pd G3 (258 mg, 0.27 mmol) was added. The mixture was heated to 100° C. and reacted for 16 h. The reaction was stopped and filtered. The filtrate was concentrated and separated by flash column chromatography to give a yellow solid a8 (200 mg). LC-MS: ESI-MS (m / z): 351.0 [M+H] + .

[0151] Synthesis of intermediates a10 and a17 [ka] Step 1: Activated zinc powder (0.6 g, 9.16 mmol) was dissolved in 4 mL of DMA and the mixture was heated to 65° C. Trimethylsilyl chloride (0.13 g, 0.13 mL) and 1,2-dibromoethane (0.1 mL, 1.3 mmol) were added dropwise to the system. After the addition was complete, the mixture was stirred for an additional 40 min. A solution of a10-2 (2.0 g, 7.06 mmol) in DMF (4 mL) was added to the reaction solution and the mixture was allowed to react for an additional 30 min. The mixture was allowed to cool to room temperature for use.

[0152] Under nitrogen protection, 3-iodopyridine a10-1 (1.45 g, 7.1 mmol), Pd 2 (dba) 3(647 mg, 0.71 mmol) and Xphos (673 mg, 1.41 mmol) were dissolved in 4 mL of DMA in another reaction bottle. The solution prepared in the previous step was added dropwise. The mixture was heated to 85° C. and reacted for 16 hours. The reaction was stopped and the mixture was cooled to room temperature. The reaction solution was poured into 30 mL of ice water, and the mixture was suction filtered. The filter cake was dissolved in ethyl acetate, concentrated, and separated by flash column chromatography (PE / EA=1 / 1) to obtain compound a10-3 (200 mg). Yield 11%, LC-MS: ESI-MS (m / z): 235.2 [M+H] + .

[0153] Step 2: Intermediate a10-3 (200 mg, 0.85 mmol) was dissolved in 4 mL of dichloromethane and 1.5 mL of trifluoroacetic acid was added dropwise. The mixture was reacted at room temperature for 3 hours. The reaction was stopped. The solvent was removed by evaporation under reduced pressure to give trifluoroacetate a10-4 (160 mg). Yield: 69%, LC-MS: ESI-MS (m / z): 135.1 [M+H] + .

[0154] Step 3: Under nitrogen protection, the trifluoroacetate salt a10-4 (31 mg, 0.23 mmol) obtained in the previous step, intermediate a1 (65 mg, 0.23 mmol) and Cs 2 CO 3 (223 mg, 0.69 mmol) was mixed in 3 mL of 1,4-dioxane. Xantphos Pd G3 (22 mg, 0.023 mmol) was added. The mixture was heated to 100° C. and reacted for 16 h. The reaction was stopped and filtered. The filtrate was concentrated and separated by flash column chromatography to give a yellow solid a10 (50 mg). LC-MS: ESI-MS (m / z): 338.0 [M+H] + .

[0155] Referring to the synthetic route of compound a10, the following intermediates were synthesized using similar framework structures. [Table 2]

[0156] Synthesis of intermediate a11 [ka] Step 1: Ethyl 4,6-dichloronicotinate a11-1 (3.0 g, 0.013 mol) was dissolved in 50 mL of ethanol, and isopropylamine (2.41 g, 0.040 mol) was added. The reaction solution was stirred at 80° C. for 12 hours. The completion of the reaction was confirmed by LC-MS. The solvent was removed by evaporation under reduced pressure, and the residue was separated by column chromatography (PE / EA=10 / 1) to obtain a white solid a11-2 (3.31 g). Yield: 91%, LCMS: ESI-MS (m / z): 243.1 [M+H] + .

[0157] Step 2: Intermediate a11-2 (3.3 g, 13 mmol) was dissolved in 40 mL of ethanol, and 20 mL of aqueous NaOH solution (1N) was added. The mixture was heated to 80° C. and reacted for 2 hours. The reaction was stopped. The solvent ethanol was removed by vacuum distillation, and the residue was adjusted to pH 3-4 using 1 M hydrochloric acid to obtain a large amount of white solid precipitate. The mixture was suction filtered. The filter cake was washed with water and dried to obtain a white solid a11-3 (1.6 g). Yield: 50%, LC-MS: ESI-MS (m / z): 215.0 [M+H] + .

[0158] Step 3: The intermediate a11-3 (1.6 g, 7.48 mmol) obtained in the previous step was dissolved in 30 mL of dichloromethane. Benzotriazole (1.07 g, 8.99 mmol), EDCI (1.73 g, 8.99 mmol) and HOBT (0.3 g, 2.2 mmol) were added. The mixture was reacted at room temperature for 2 hours. The reaction was stopped. 50 mL of water was added to the reaction solution. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (PE / EA=10 / 1) to obtain an oily substance a11-4 (1.65 g). Yield: 63%, LC-MS: ESI-MS (m / z): 315.9 [M+H]+ .

[0159] Step 4: In an ice bath under nitrogen protection, NaH (420 mg, 10.gmmol, 60%) was dissolved in 10 mL of anhydrous tetrahydrofuran, and tert-butyl ethyl malonate a11-5 (1.96 g, 10.5 mmol) was added slowly. The mixture was stirred for 30 minutes, and a solution of intermediate a11-4 (1.65 g, 5.24 mmol) in tetrahydrofuran (10 mL) was added. The mixture was stirred in an ice bath for another 2 hours. 30 mL of saturated aqueous ammonium chloride was added to the reaction solution to quench the reaction. Tetrahydrofuran was removed by distillation under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a crude product. The crude product was dissolved in dichloromethane, and 10 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, 20 mL of toluene was added, and the mixture was separated by column chromatography (PE / EA=10 / 1) to obtain a colorless oily substance a11-6 (780 mg). Yield: 48%, LCMS: ESI-MS (m / z): 285.1 [M+H] + .

[0160] Step 5: The intermediate a11-6 (780 mg, 2.75 mmol) obtained in the previous step was dissolved in 10 mL of ethanol, and DBU (1.23 g, 8.22 mmol) was added. The mixture was heated to 80° C. and reacted for 2 hours. The reaction was stopped. Ethanol was removed by vacuum concentration. 1 M hydrochloric acid was added to the reaction solution to adjust the pH to about 3, and a white solid precipitate was obtained. The mixture was suction filtered. The filter cake was washed with water and dried to obtain intermediate a11-7 (440 mg). Yield: 61%, LC-MS: ESI-MS (m / z): 239.0 [M+H] + .

[0161] Step 6: The intermediate a11-7 (440 mg, 1.67 mmol) obtained in the previous step was dissolved in 10 mL of DMF. Triethylamine (507 mg, 5.02 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (718 mg, 2.0 mmol) were added, and the mixture was reacted at room temperature for 2 hours. The reaction was stopped. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by thin layer chromatography (PE / EA=3 / 1) to obtain a white solid a11-8 (620 mg). Yield: 90%, LCMS: ESI-MS (m / z): 371.0 [M+H] + .

[0162] Step 7: Under nitrogen protection, the intermediate a11-8 (210 mg, 0.57 mmol) obtained in the previous step, the intermediate a3-4 (140 mg, 0.53 mmol) and Cs 2 CO 3 (556 mg, 1.71 mmol) were mixed in 10 mL of 1,4-dioxane. 2 (dba) 3 (52 mg, 0.057 mmol) and Xantphos (65 mg, 0.113 mmol) were added. The mixture was heated to 60° C. and reacted for 2 h. The reaction was stopped and filtered. The filtrate was concentrated and separated by flash column chromatography to give a white solid a11 (30 mg). Yield: 15%, LC-MS: ESI-MS (m / z): 370.0 [M+H] + .

[0163] Synthesis of intermediate a12 [ka] Step 1: Under nitrogen protection, intermediate a1 (700 mg, 2.46 mmol), Pd 2 (dba) 3(225 mg, 0.25 mmol), Xphos (234 mg, 0.49 mmol) and freshly prepared raw material a12-1 (4 mL, 5.0 mmol) were dissolved in 4 mL of DMA. The mixture was heated to 85° C. and reacted for 15 h. After cooling to room temperature, the reaction solution was poured into 15 mL of ice water and a solid precipitated. The mixture was filtered under suction. The filter cake was dissolved in ethyl acetate and filtered. The filtrate was concentrated and separated by flash column chromatography (PE / EA=1 / 1) to give a yellow solid a12-2 (280 mg). Yield: 29%, LC-MS: ESI-MS (m / z): 361.1 [M+H] + .

[0164] Step 2: The intermediate a12-2 (85 mg, 0.24 mmol) obtained in the previous step was dissolved in 6 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 12 hours. The reaction was stopped. The reaction solution was concentrated to obtain trifluoroacetate a12-3 (20 mg). Yield: 30%, LC-MS: ESI-MS (m / z): 261.1 [M+H] + .

[0165] Step 3: Mix the intermediate a12-3 (20 mg, 0.08 mmol) obtained in the previous step with K 2 CO 3 (43 mg, 0.31 mmol) was mixed in 5 mL of acetonitrile, and 2-bromo-N-methylacetamide a12-4 (9 mg, 0.061 mmol) was added. The mixture was reacted at room temperature for 3 hours. The reaction was stopped. 20 mL of water was added to the reaction solution. The mixture was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by flash column chromatography (DCM / MeOH=10 / 1) to obtain a white solid a12 (35 mg). Yield: 96%, LC-MS: ESI-MS (m / z): 332.2 [M+H] + .

[0166] Synthesis of intermediate a13 [ka] Under nitrogen protection, intermediate a4-1 (50 mg, 0.10 mmol) was dissolved in 5 mL of DMF and added with Pd( t BuP) 3 (16 mg, 0.03 mmol) and zinc cyanide (18 mg, 0.16 mmol) were added. The mixture was heated to 100° C. and reacted for 1 hour. The completion of the reaction was confirmed by LC-MS. The reaction was stopped. 30 mL of saturated aqueous sodium dicarbonate solution was added to the reaction solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by thin layer chromatography to obtain a yellow solid a13 (30 mg). Yield: 69%, LCMS: ESI-MS (m / z): 378.0 [M+H] + .

[0167] Synthesis of intermediate a14 [ka] Step 1: Under nitrogen protection, intermediate a14-1 (1.0 g, 6.11 mmol), Pd 2 (dba) 3 (558 mg, 0.61 mmol), Xphos (581 mg, 1.22 mmol) and freshly prepared raw material a12-1 (8 mL, 12.0 mmol) were dissolved in 6 mL of DMA. The mixture was heated to 85° C. and reacted for 12 h. After cooling to room temperature, the reaction solution was poured into 35 mL of ice water. The mixture was extracted with ethyl acetate, concentrated and separated by flash column chromatography (PE / EA=2 / 1) to give a yellow solid a14-2 (120 mg). Yield: 8%, LC-MS: ESI-MS (m / z): 185.1 [M-56] + .

[0168] Step 2: The intermediate a14-2 (120 mg, 0.42 mmol) obtained in the previous step was dissolved in 6 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 0.5 hours. The reaction was stopped. The reaction solution was concentrated to obtain trifluoroacetate a14-3 (70 mg). Yield: 91%, LC-MS: ESI-MS (m / z): 141.1 [M+H] + .

[0169] Step 3: Under nitrogen protection, the trifluoroacetate salt a14-3 (100 mg, 0.71 mmol) obtained in the previous step, intermediate a1 (203 mg, 0.71 mmol) and Cs 2 CO 3 (1162 mg, 3.57 mmol) were mixed in 10 mL of 1,4-dioxane. Xantphos Pd G3 (68 mg, 0.071 mmol) was added. The mixture was heated to 100° C. and reacted for 3 h. The reaction was stopped and filtered. The filtrate was concentrated and separated by flash column chromatography to give a yellow solid a14 (70 mg). Yield: 26%, LC-MS: ESI-MS (m / z): 344.1 [M+H] + .

[0170] Synthesis of intermediate a15 [ka] Step 1: In an ice bath, intermediate a11-3 (1.3 g, 6.10 mmol) was dissolved in 13 mL of dichloromethane, and oxalyl chloride (1.54 g, 12.1 mmol) and 3 drops of anhydrous DMF were added dropwise. The reaction solution was stirred for 1 hour. 12 mL of ammonia water was added dropwise to the reaction solution. The mixture was heated to room temperature and reacted for another 1 hour. 30 mL of ice water was added to the reaction solution to quench the reaction. The mixture was extracted with dichloromethane, concentrated, and separated by column chromatography (PE / EA=1 / 1) to obtain a white solid a15-1 (1.1 g). Yield: 85%.

[0171] 1 H NMR (400 MHz, DMSO-d6 ) δ 8.72 (d, J = 7.8 Hz, 1H), 8.39 (s, 1H), 8.07 (s, 1H), 7.47 (s, 1H), 6.69 (s, 1H), 3.72-3.77 (m, 1H), 1.16 (d, J = 6.3 Hz, 6H).

[0172] Step 2: In an ice bath, the intermediate a15-1 (1.1 g, 5.16 mmol) obtained in the previous step was dissolved in 13 mL of anhydrous tetrahydrofuran, and NaH (1.2 g, 30.1 mmol, 60%) was added. The reaction solution was stirred for 30 minutes. CDI (2.5 g, 15.4 mmol) was added to the reaction solution. The mixture was heated to room temperature and reacted for another hour. The completion of the reaction was confirmed by LC-MS. 50 mL of ice water was added to the reaction solution. The mixture was extracted with dichloromethane, concentrated, and separated by column chromatography (PE / EA=1 / 1) to obtain a white solid a15-2 (1.0 g). Yield: 81%, LC-MS: ESI-MS (m / z): 240.0 [M+H] + .

[0173] Step 3: The intermediate a15-2 (1.0 g, 4.18 mmol) obtained in the previous step and DIEA (530 mg, 4.18 mmol) were dissolved in 15 mL of acetonitrile and POCl 3 (640 mg, 4.18 mmol) was added. The reaction solution was heated to 90° C. and reacted for 1 hour. The reaction was stopped and the mixture was cooled to room temperature. The reaction solution was poured into 40 mL of ice water. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by column chromatography (PE / EA=5 / 1) to obtain a white solid a15-3 (700 mg). Yield: 65%, LC-MS: ESI-MS (m / z): 258.0 [M+H] + .

[0174] Step 4: In an ice bath, intermediate a3-4 (408 mg, 1.55 mmol), intermediate a15-3 (400 mg, 1.55 mmol) and DIEA (802 mg, 6.19 mmol) were dissolved in 10 mL of dichloromethane. The mixture was reacted in an ice bath for 1 hour. The reaction was stopped. 30 mL of water was added to the reaction solution. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by flash column chromatography to obtain a white solid a15 (300 mg). Yield: 47%, LC-MS: ESI-MS (m / z): 371.0 [M+H] + .

[0175] Synthesis of intermediates a16, a18 to a22, a24, a27, a29, a31, a34, and a36 to a38 [ka] Step 1: Compound a16-1 (304 mg, 1.76 mmol), intermediate a1 (500 mg, 1.76 mmol) and Cs under nitrogen protection 2 CO 3 (2.86 g, 8.78 mmol) were mixed in 10 mL of 1,4-dioxane. Xantphos Pd G3 (166 mg, 0.17 mmol) was added. The mixture was heated to 100° C. for 2 h. The reaction was stopped. The mixture was filtered. The filtrate was concentrated and separated by flash column chromatography to give a yellow solid a16-2 (400 mg). Yield: 55%, LC-MS: ESI-MS (m / z): 376.2 [M+H] + .

[0176] Step 2: In an ice bath, the intermediate a16-2 (120 mg, 0.32 mmol) obtained in the previous step was dissolved in 2 mL of dichloromethane. 0.5 mL of pyridine was added, and 0.5 mL of trimethylsilyl trifluoromethanesulfonate was slowly added. The mixture was reacted at room temperature for 16 hours. The completion of the reaction was confirmed by LC-MS. 30 mL of saturated aqueous sodium dicarbonate was added to the system to quench the reaction. The mixture was extracted with dichloromethane. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by thin layer chromatography to obtain a yellow solid a16-3 (75 mg). Yield: 77%, LC-MS: ESI-MS (m / z): 276.2 [M+H] + .

[0177] Step 3: The intermediate a16-3 (21 mg, 0.077 mmol) obtained in the previous step and triethylamine (21 mg, 0.21 mmol) were dissolved in 2 mL of dichloromethane. Methylsulfonyl chloride (139 μL, 0.18 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction was stopped. 10 mL of ice water was added to the reaction solution. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by thin layer chromatography to obtain a white solid a16 (20 mg). Yield: 65%, LC-MS: ESI-MS (m / z): 354.0 [M+H] + .

[0178] Referring to the synthetic route of intermediate a16, the following intermediates were synthesized using similar framework structures. [Table 3] [Table 4] [Table 5]

[0179] Synthesis of intermediates a23, a30, a32, a33, a35, a39, and a41 [ka] In an ice bath, intermediate a16 (40 mg, 0.11 mmol) was dissolved in 3 mL of DMF. NaH (6 mg, 0.15 mmol) and iodoethane (20 mg, 0.13 mmol) were added. The mixture was warmed to room temperature and reacted for 2 hours. The completion of the reaction was confirmed by LC-MS. 30 mL of saturated aqueous sodium dicarbonate solution was added to the system to quench the reaction. The mixture was extracted with dichloromethane. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by column chromatography to obtain a yellow solid a23 (40 mg). Yield: 84%, LC-MS: ESI-MS (m / z): 382.1 [M+H] + .

[0180] Referring to the synthetic route of intermediate a23, the following intermediates were synthesized using similar framework structures. [Table 6] [Table 7]

[0181] Synthesis of intermediates a25 and a42 [ka] Step 1: Under nitrogen protection, raw material a25-1 (7.0 g, 27.7 mmol) and triethylamine (4.2 g, 41.5 mmol) were dissolved in 40 mL of dichloromethane. Methylsulfonyl chloride (3.21 g, 28.0 mmol) was added. The mixture was reacted at room temperature for 4 hours. The reaction was stopped and the solvent was removed under reduced pressure to give crude product a25-2 (10.8 g).

[0182] Step 2: The crude product a25-2 (10.8 g) obtained in the previous step and the raw material a25-3 (4.21 g, 27.7 mmol) were dissolved in 30 mL of DMF. NaH (1.11 g, 27.7 mmol) was added. The mixture was slowly heated to 80° C. and reacted for 12 hours. The completion of the reaction was confirmed by LC-MS. 100 mL of saturated saline was added to the system to quench the reaction. The mixture was extracted with dichloromethane. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product a25-4 (15 g). LC-MS: ESI-MS (m / z): 388.3 [M+H] + .

[0183] Step 3: The crude product a25-4 (15 g) obtained in the previous step and LiCl (2.52 g, 60.0 mmol) were dissolved in 40 mL of N,N-dimethylacetamide DMA. The mixture was heated to 150° C. and reacted for 2 hours. The reaction was stopped. 100 mL of ice water was added to the reaction solution. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by flash column chromatography to obtain a yellow solid a25-5 (6.42 g). Total yield in three steps: 71%, LC-MS: ESI-MS (m / z): 330.1 [M+H] + .

[0184] Step 4: Under hydrogen atmosphere (2 atm), the intermediate a25-5 (6.42 g, 19.5 mmol) from the previous step and Pd / C (1.28 g, 20%) were mixed in 40 mL of methanol. 2 mL of trifluoroacetic acid was added. The reaction was allowed to react at room temperature for 16 hours. The reaction was stopped. The mixture was filtered and concentrated to give a yellow oil a25 (4.5 g), which was used directly in the next reaction. LC-MS: ESI-MS (m / z): 164.2 [M+H] + .

[0185] Referring to the synthetic route of intermediate a25, the following intermediates were synthesized using similar framework structures. [Table 8]

[0186] Synthesis of intermediates a26 and a43 [ka] Under nitrogen protection, intermediate a25 (2.0 g, 12.3 mmol), intermediate a1 (3.47 g, 12.3 mmol) and Cs 2 CO 3 (8.01 g, 24.6 mmol) was mixed in 80 mL of 1,4-dioxane. Xantphos Pd G3 (1.14 g, 1.2 mmol) was added. The mixture was heated to 100° C. and reacted for 6 hours. The reaction was stopped. The mixture was filtered. The filtrate was concentrated and separated by flash column chromatography to give a brown solid a26 (970 mg). Yield: 23%, LC-MS: M+H + =367.3.

[0187] Referring to the synthetic route of intermediate a26, the following intermediates were synthesized using similar framework structures. [Table 9]

[0188] Synthesis of intermediate a28 [ka] Step 1: In an ice bath under nitrogen protection, raw materials a28-1 (250 mg, 1.45 mmol) and triethylamine (294 mg, 2.9 mmol) were dissolved in 5 mL of DMF. 3-Chloropropylsulfonyl chloride a28-2 (282 mg, 1.59 mmol) was added. The mixture was stirred for 30 minutes, and NaH (174 mg, 4.35 mmol) was added. The mixture was warmed to room temperature and reacted for 12 hours. The reaction was stopped by adding 30 mL of saturated NH 4Aqueous Cl solution was added to the system. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give crude product a28-3 (380 mg). Yield: 83%, LC-MS: M+Na + =299.0.

[0189] Step 2: The intermediate a28-3 (220 mg, 0.72 mmol) obtained in the previous step was dissolved in 7 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 2 hours. The reaction was stopped. The solvent was removed by evaporation under reduced pressure. 10 mL of water was added, and the mixture was freeze-dried to obtain a white solid a28-4 (150 mg). Yield: 65%, LC-MS: M+H + =177.1.

[0190] Step 3: Under nitrogen protection, intermediate trifluoroacetate a28-4 (100 mg, 0.34 mmol), intermediate a1 (212 mg, 0.75 mmol) and Cs 2 CO 3 (332 mg, 1.02 mmol) was mixed in 10 mL of 1,4-dioxane. Xantphos Pd G3 (35 mg, 0.034 mmol) was added. The mixture was heated to 100° C. and reacted for 3 hours. The reaction was stopped and the mixture was filtered. The filtrate was concentrated and separated by flash column chromatography to give a yellow solid a28 (50 mg). Yield: 35%, LC-MS: M+H + =380.1.

[0191] Synthesis of intermediate a40 [ka] Intermediate a40-1 was obtained by referring to the synthetic route of intermediate a16. Workup: Intermediate 1-(3-chloro-5-isopropylisoquinolin-8-yl)-N-methylazetidin-3-amine a40-1 (10 mg, 0.035 mmol) and triethylamine (11 mg, 0.11 mmol) were dissolved in 3 mL of dichloromethane. 1.0 mL of a dichloromethane solution of trifluoromethanesulfonic anhydride (20 mg, 0.07 mmol) was added dropwise. The mixture was reacted at room temperature for 2 hours. 30 mL of a saturated aqueous solution of sodium dicarbonate was added to the system to quench the reaction. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by thin layer chromatography (DCM / MeOH, 10 / 1) to give a pale yellow solid a40 (15 mg). Yield: 93%, LC-MS: M+H + =422.1.

[0192] Synthesis of intermediates b1 and b2 [ka] In an ice bath under nitrogen protection, the raw material tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate intermediate b1-1 (3.0 g, 14.0 mmol) was dissolved in 50 mL of ethanol. Sodium borohydride (0.78 g, 21.0 mmol) was added. The mixture was heated to room temperature and reacted for 4 hours. The completion of the reaction was confirmed by LC-MS. 50 mL of saturated aqueous ammonium chloride solution was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, concentrated, and separated by flash column chromatography (PE / EA=2 / 1) to obtain trans intermediate b1 and cis intermediate b2 (2.52 g). Yield: 90%, LCMS: ESI-MS (m / z): 164.0 [M-55] + .

[0193] Synthesis of intermediates b3-b5, b10-b12, x1 and x2 [ka] Under nitrogen protection, cis-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate b2 (800 mg, 3.63 mmol) was dissolved in 5 mL of 1,4-dioxane. 4 M of hydrochloric acid / dioxane (4.5 mL, 18.16 mmol) was slowly added dropwise. The mixture was reacted at room temperature for 2 hours, and the solvent was removed by evaporation under reduced pressure to give compound b3-1 (210 mg), which was used directly in the next step.

[0194] Cis-3-fluoropiperidin-4-ol hydrochloride b3-1 (840 mg, 5.4 mmol), 2-chloropyrimidin-4-amine b3-2 (700 mg, 5.4 mmol) and triethylamine (1.63 g, 16.2 mmol) were dissolved in 20 mL of isopropanol. The reaction system was sealed and reacted at 110° C. for 18 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and separated by column chromatography (DCM / MeOH=21 / 1) to obtain a yellow solid Cis-b3 (200 mg). Yield: 16%, LC-MS: ESI-MS (m / z): 283.9 [M+H] + .

[0195] Referring to the synthetic route of compound b3, the following intermediates were synthesized using similar framework structures. [Table 10] [Table 11] [Table 12]

[0196] Synthesis of intermediates b6-b8 [ka] In an ice bath, the raw material 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole b6-1 (200 mg, 1.03 mmol) was dissolved in 2 mL of DMF. 60% NaH (82 mg, 2.06 mmol) was added. The mixture was stirred for 1 h, and cyclopropanesulfonyl chloride (217 mg, 1.54 mmol) was added. The mixture was warmed to room temperature and stirred for 5 h. 30 mL of ice water was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product b6-2, which was used directly in the next step. LCMS: ESI-MS (m / z): 299.1 [M+H] + .

[0197] Under nitrogen protection, the crude product b6-2 (288 mg, 0.58 mmol) obtained in the previous step, 2-chloropyrimidin-4-amine b3-2 (50 mg, 0.39 mmol) and Cs were 2 CO 3 (252 mg, 0.77 mmol) was mixed in 6 mL of a mixture of 1,4-dioxane and water (v / v=5 / 1). 2 (57 mg, 0.077 mmol) was added. The mixture was heated to 100° C. and reacted for 6 hours. The completion of the reaction was confirmed by LC-MS. The mixture was filtered, and 20 mL of water was added to the filtrate. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by flash column chromatography (PE / EA=2 / 1) to obtain compound b6 (30 mg). Yield: 27%, LCMS: ESI-MS (m / z): 266.0 [M+H] + .

[0198] Referring to the synthetic route of compound b6, the following intermediates were synthesized using similar framework structures. [Table 13]

[0199] Synthesis of intermediates b9, x3 and x4 [ka] In an ice bath, cis intermediate b2 (600 mg, 2.72 mmol) was dissolved in 6 mL of anhydrous tetrahydrofuran. NaH (131 mg, 3.3 mmol) was added, and iodomethane (426 mg, 3.0 mmol) was added dropwise. The mixture was heated to room temperature and reacted for 3 hours. 20 mL of ice water was added to the system to quench the reaction. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by flash column chromatography (PE / EA=5 / 1) to give pale yellow solid b9-1 (600 mg). Yield: 94%, LCMS: ESI-MS (m / z): 134.0 [M-55] + .

[0200] Under nitrogen protection, cis intermediate b9-1 (600 mg, 2.56 mmol) was dissolved in 5 mL of dichloromethane. 2 mL of trifluoroacetic acid was slowly added dropwise. The mixture was reacted at room temperature for 2 hours. The solvent was removed by evaporation under reduced pressure to give compound b9-2 (340 mg), which was used directly in the next step.

[0201] Cis trifluoroacetate b9-2 (340 mg, 1.37 mmol), 2-chloropyrimidin-4-amine b3-2 (125 mg, 0.96 mmol) and cesium carbonate (896 mg, 2.72 mmol) were mixed in 8 mL of DMF. The reaction system was reacted at 100° C. for 1 hour. After cooling to room temperature, 30 mL of water was added to the system. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and separated by column chromatography (EtOAc) to obtain a white solid cis b9 (200 mg). Yield: 65%, LC-MS: ESI-MS (m / z): 227.1 [M+H] + .

[0202] Referring to the synthetic route of compound b9, the following intermediates were synthesized using similar framework structures. [Table 14] EXAMPLES

[0203] Preparation of target molecules P1-P5, P7-P9, P11-P19, P21-P51 [ka] Under nitrogen protection, intermediate a2 (70 mg, 0.185 mmol), Cs 2 CO 3 (180 mg, 0.55 mmol) and intermediate b3 (39 mg, 0.185 mmol) were mixed in 2 mL of 1,4-dioxane. 2 (dba) 3 CHCl 3 (56 mg, 0.055 mmol) and C-phos (24 mg, 0.055 mmol) were added. The mixture was heated to 100° C. and reacted for 12 hours. The completion of the reaction was confirmed by LC-MS. The mixture was filtered. The filtrate was concentrated and separated by HPLC preparative chromatography to obtain a yellow solid P1 (4.0 mg). Yield: 4%, LCMS: ESI-MS (m / z): 555.0 [M+H] + .

[0204] 1 HNMR (400 MHz, DMSO-d 6) δ 9.87 (s, 1H), 9.00 (s, 1H), 8.60 (s, 1H), 7.95 (d, J = 5.7 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 6.41 (d, J = 5.7 Hz, 1H), 6.34 (d, J = 8.1 Hz, 1H), 5.11 (d, J = 5.1 Hz, 1H), 4.74 - 4.58 (m, 1H), 4.58 - 4.52 (m, 1H), 4.38-4.30 (m, 1H), 4.17 (s, 2H), 4.08 (s, J = 6.7 Hz, 2H), 3.93 - 3.76 (m, 2H), 3.59 - 3.40 (m, 2H), 2.87 (s, 3H), 2.64 - 2.53 (m, 4H), 1.72-1.64 (m, 2H), 1.25 (dd, J = 6.7, 4.6 Hz, 6H).

[0205] Referring to the synthetic route of compound P1, the following target molecules were synthesized using similar backbone structures (unless otherwise stated, the compounds are in the cis configuration). [Table 15] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20] [Table 21] [Table 22] [Table 23]

Table 24

Table 25

Table 26

Table 27

Table 28

Table 29

Table 30

Table 31

Table 32

Table 33

Table 34

Table 35

Table 36

Table 37

Table 38

Table 39

Example

[0206] (Preparation of target molecule P6) [ka] 2-Chloro-8-methoxyquinazoline P6-1 (2.0 g, 10.3 mmol) was dissolved in 50 mL of acetonitrile, and N-bromosuccinimide (3.67 g, 20.6 mmol) was added. The mixture was stirred at room temperature for 2 hours. The completion of the reaction was confirmed by LC-MS. The solvent was removed by evaporation under reduced pressure, and 100 mL of water was added to the system. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (PE / EA=1 / 10) to give 5-bromo-2-chloro-8-methoxyquinazoline P6-2 (2.85 g). Yield: 80%, LCMS: ESI-MS (m / z): 272.9 [M+H] + .

[0207] 1 H NMR (400 MHz, CDCl 3 ) δ 9.54 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 4.08 (s, 3H).

[0208] The intermediate P6-2 (2.0 g, 10.3 mmol) obtained in the previous step was dissolved in 30 mL of dichloromethane, and boron tribromide (2.74 g, 10.9 mmol) was added. The mixture was reacted at room temperature for 12 hours. The completion of the reaction was confirmed by LC-MS. A saturated aqueous solution of sodium dicarbonate was slowly added to the reaction solution to quench the reaction. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (DCM / MeOH=20 / 1) to obtain 2,5-dibromo-8-hydroxyquinazoline P6-3 (2.8 g). Yield: 81%, LCMS: ESI-MS (m / z): 302.8 [M+H] + .

[0209] The intermediate P6-3 (2.8 g, 9.2 mmol) obtained in the previous step was dissolved in 46 mL of hydrochloric acid (1 M) / 1,4-dioxane solution, and the mixture was reacted at room temperature for 1 hour. The completion of the reaction was confirmed by LC-MS. The reaction solution was concentrated under reduced pressure, and a saturated aqueous solution of sodium dicarbonate was slowly added to the reaction solution to adjust the pH to about 8. The solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product P6-4 (2.7 g). LCMS: ESI-MS (m / z): 258.8 [M+H] + .

[0210] The crude product P6-4 (2.7 g) and DIEA (2.7 g, 20.8 mmol) obtained in the previous step were dissolved in 30 mL of dichloromethane, and N-phenylbistrifluoromethylsulfonamide P6-5 (5.57 g, 15.6 mmol) was added. The mixture was reacted at room temperature for 12 hours. The completion of the reaction was confirmed by LC-MS. The reaction solution was concentrated under reduced pressure. 100 mL of water was added to the reaction solution. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (PE / EA=1 / 1) to obtain compound P6-6 (3.2 g). Yield: 71%, LCMS: ESI-MS (m / z): 392.8 [M+H] + .

[0211] Under nitrogen protection, the intermediate P6-6 (1.0 g, 2.6 mmol) obtained in the previous step, K 2 CO 3 (706 mg, 5.2 mmol) and isopropenylboronic acid pinacol ester a1-3 (515 mg, 3.1 mmol) were dissolved in a mixture (11 mL) of 1,4-dioxane and water (v / v=10 / 1). 2(187 mg, 0.25 mmol) was added. The mixture was heated to 45° C. for 2 hours. The completion of the reaction was confirmed by LC-MS. The mixture was filtered. The filtrate was concentrated and separated by column chromatography (PE / EA=10 / 1) to give brown oil P6-7 (100 mg). Yield: 8%, LCMS: ESI-MS (m / z): 282.8 [M+H] + .

[0212] The intermediate P6-7 (100 mg, 0.21 mmol) obtained in the previous step and Cs 2 CO 3 (649 mg, 0.63 mmol) was dissolved in 5 mL of DMF. 1-(4-aminopyridin-2-yl)piperidin-4-ol P6-8 (49 mg, 0.25 mmol) was added. The mixture was heated to 110° C. and reacted for 12 hours. The completion of the reaction was confirmed by LC-MS. After cooling to room temperature, 50 mL of water was added to the reaction solution. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (DCM / MeOH=20 / 1) to obtain compound P6-9 (40 mg). Yield: 39%, LCMS: ESI-MS (m / z): 439.7 [M+H] + .

[0213] Under nitrogen protection, the intermediate P6-9 (40 mg, 0.091 mmol) obtained in the previous step and Cs 2 CO 3 (89 mg, 0.27 mmol) and intermediate a3-4 (36 mg, 0.14 mmol) were dissolved in 2 mL of 1,4-dioxane. Xantphos Pd G3 (17 mg, 0.018 mmol) was added. The mixture was heated to 100° C. and reacted for 6 hours. The completion of the reaction was confirmed by LC-MS. The mixture was filtered. The filtrate was concentrated and separated by HPLC preparative chromatography to obtain a yellow solid P6-10 (30 mg). Yield: 59%, LCMS: ESI-MS (m / z): 509.1 [M+H] + .

[0214] The intermediate P6-10 (20 mg, 0.04 mmol) obtained in the previous step was dissolved in 5 mL of ethyl acetate, and platinum dioxide (45 mg, 0.19 mmol) was added. The mixture was reacted at room temperature for 6 hours under a hydrogen atmosphere. The reaction solution was filtered. The filtrate was concentrated and separated by HPLC preparative chromatography to obtain the target compound P6 (1.0 mg). Yield: 5%, LC-MS: ESI-MS (m / z): 510.9 [M+H] + . EXAMPLES

[0215] [ka] Under nitrogen protection, intermediate a5 (100 mg, 0.30 mmol), Cs 2 CO 3 (196 mg, 0.60 mmol) and intermediate b3 (cis) (64 mg, 0.30 mmol) were mixed in 3 mL of 1,4-dioxane. 2 (dba) 3 CHCl 3 (31 mg, 0.03 mmol) was added. The mixture was heated to 100° C. and reacted for 16 hours. The completion of the reaction was confirmed by LC-MS. The mixture was filtered. The filtrate was concentrated and separated by flash column chromatography (DCM / MeOH=10 / 1) to obtain a yellow solid P10-1 (100 mg). Yield: 59%, LCMS: ESI-MS (m / z): 508.9 [M+H] + .

[0216] The intermediate P10-1 (100 mg, 0.60 mmol) obtained in the previous step was dissolved in 1 mL of tetrahydrofuran, and LiOH solution (3N, 0.5 mL) was added. The mixture was reacted at room temperature for 3 hours. The reaction was stopped. The reaction solution was concentrated under reduced pressure. Acetic acid was added to the system to adjust the pH to about 6. 10 mL of water was added. The mixture was extracted with ethyl acetate and concentrated under reduced pressure to obtain crude product P10-2 (50 mg). Yield: 23%, LCMS: ESI-MS (m / z): 495.1 [M+H] + .

[0217] Crude product P10-1 (10 mg, 0.039 mmol) and a solution of dimethylamine in tetrahydrofuran (1 mL, 1 M) were dissolved in 1 mL of DMF. DIEA (16 mg, 0.12 mmol) and HATU (3.0 mg, 0.06 mmol) were added. The mixture was stirred at room temperature for 16 hours. 5 mL of water was added to the system. The mixture was extracted with ethyl acetate, concentrated under reduced pressure, and separated by thin layer chromatography to obtain compound P10 (1.5 mg). Yield: 24%. [cis configuration]

[0218] 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.08 (s, 1H), 8.41 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 6.39 (d, J = 8.2 Hz, 1H), 6.33 (d, J = 6.3 Hz, 1H), 4.86 (s, 1H), 4.66 - 4.56 (m, 1H), 4.32 - 4.40 (m, 3H), 3.89 - 4.00 (m, 1H), 3.85-3.89 (m, 2H), 3.57 -3.65(m, 2H), 3.45-3.50 (m, 1H), 3.10 (s, 3H), 3.09-3.13 (m, 3H), 2.89 (s, 3H), 2.60(d, J = 6.0 Hz, 2H), 1.84-1.90(m, 1H), 1.80-1.82(m, 1H), 1.33 (dd, J = 6.7, 4.5 Hz, 6H).

[0219] Referring to the synthetic route of compound P10, the following target molecules were synthesized using similar backbone structures (unless otherwise stated, the compounds are in the cis configuration). [Table 40] EXAMPLES

[0220] (Preparation of target molecules H1-H2, H4-H5, H12, H23, H25, and H33-H34) [ka] Under nitrogen protection, intermediate a3 (35 mg, 0.10 mmol), Cs 2 CO 3 (48 mg, 0.15 mmol) and intermediate b6 (32 mg, 0.12 mmol) were mixed in 3 mL of 1,4-dioxane. 2 (dba) 3 CHCl 3 (10 mg, 0.01 mmol) and C-phos (4.5 mg, 0.01 mmol) were added. The mixture was heated to 100° C. and reacted for 12 hours. The completion of the reaction was confirmed by LC-MS. The mixture was filtered. The filtrate was concentrated and separated by HPLC preparative chromatography to obtain a yellow solid H1 (2.7 mg). Yield: 5%, LCMS: ESI-MS (m / z): 582.1 [M+H] + .

[0221] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.37 (d, J = 8.4 Hz, 1H), 9.10 (s, 1H), 8.77 (s, 1H), 8.70 (s, 1H), 8.51 (s, 1H), 8.43 (d, J = 5.9 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.25 (s, 1H), 6.45 (d, J = 8.1 Hz, 1H), 4.41 (t, J = 7.7 Hz, 2H), 3.98 (t, J = 6.9 Hz, 2H), 3.64 - 3.52 (m, 3H), 3.31 - 3.23 (m, 2H), 3.02 (s, 3H), 1.37 (d, J = 6.8 Hz, 6H), 1.30 (ddd, J = 21.4, 16.3, 9.3 Hz, 4H).

[0222] Referring to the synthetic route of compound H1, the following target molecules were synthesized using similar backbone structures. [Table 41] [Table 42] EXAMPLES

[0223] (Preparation of target molecules H3, H6 to H11, H13 to H22, H24, and H26 to H32) [ka] Under nitrogen protection, intermediate a3 (9 mg, 0.026 mmol), Cs 2 CO 3 (17 mg, 0.052 mmol) and intermediate b8 (7 mg, 0.026 mmol) were mixed in 1.5 mL of 1,4-dioxane. 2 (dba) 3 CHCl 3 (81 mg, 0.008 mmol) and C-phos (3.0 mg, 0.008 mmol) were added. The mixture was heated to 100° C. and reacted for 20 hours. The completion of the reaction was confirmed by LC-MS. The mixture was filtered. The filtrate was concentrated and separated by HPLC preparative chromatography to obtain a yellow solid H3 (5.0 mg). Yield: 44%, LCMS: ESI-MS (m / z): 437.3 [M+H] + .

[0224] Compound H3 (5 mg, 0.011 mmol) was dissolved in 1.5 mL of dichloromethane in an ice bath. Triethylamine (3 mg, 0.021 mmol) and n-propylsulfonyl chloride (3 mg, 0.021 mmol) were added. The mixture was warmed to room temperature and reacted for 1 hour. The reaction was stopped. 10 mL of water was added to the reaction solution. The mixture was extracted with ethyl acetate, concentrated, and separated by HPLC preparative chromatography to obtain compound H6 (2.1 mg). LCMS: ESI-MS (m / z): 584.0 [M+H] + .

[0225] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.43 (s, 1H), 9.11 (s, 1H), 8.77 (s, 1H), 8.70 (s, 1H), 8.53 (s, 1H), 8.44 (d, J = 5.9 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.25 (bs, 1H), 6.45 (d, J = 8.1 Hz, 1H), 4.43 - 4.39 (m, 2H), 3.98 -3.82 (m, 2H), 3.586-3.52 (m, 2H), 3.60 -3.57 (m, 3H), 3.29 -3.26 (m, 1H), 3.02 (s, 3H), 1.64 - 1.58 (m, 2H), 1.38 (d, J = 6.8 Hz, 6H), 0.96 - 0.90 (m, 3H).

[0226] Referring to the synthetic route of compound H6, the following target molecules were synthesized using similar backbone structures. [Table 43] [Table 44] [Table 45] [Table 46] [Table 47] [Table 48] [Table 49] EXAMPLES

[0227] Inhibitory Effects of Compounds of the Present Disclosure on Kinase EGFR Activity EGFR wild type and its mutants (EGFR wt To detect the effects of small molecule inhibitors on the kinase activity of EGFR-L858R, EGFR-L858R-T790M-C797S, and EGFR-L858R-C797S), we used the mobility shift assay (MSA) method.

[0228] 10 μL of kinase solution was added to the compound wells and positive control Max wells at 2.5x final concentration, and 10 μL of 1x kinase buffer was added to the negative control Min wells. The mixture was centrifuged at 1000 rpm for 30 seconds, the reaction plate was shaken to mix the solution well, and then incubated at room temperature for 10 minutes. A mixture of ATP and kinase substrate was prepared in 1x kinase buffer at 5 / 3x final concentration. The reaction was started by adding a mixture of ATP and substrate (15 μL, 5 / 3x final concentration). The 384-well plate was centrifuged at 1000 rpm for 30 seconds, shaken to mix the solution well, and then incubated at room temperature for the corresponding time. The kinase reaction was stopped by adding 30 μL of stop detection solution, and the mixture was centrifuged at 1000 rpm for 30 seconds, and then shaken to mix well. The conversion was read using a Caliper EZ Reader.

[0229] Calculation formula: %Inhibition = (Conversion %_Maximum - Conversion %_Sample) / (Conversion %_Maximum - Conversion %_Min) x 100 where % Conversion_Sample is the conversion read from the sample; % Conversion_Min is the average of the negative control wells and represents the conversion read from wells with no enzyme activity; % Conversion_Max is the average of the positive control wells and represents the conversion read from wells with no compound inhibition.

[0230] (Fitting of dose-effect curves) Dose-effect curves were fitted using log(inhibitor) vs. response-variable slope in the analysis software GraphPad Prism 5, where the IC of each compound was calculated on enzyme activity using the log value of the concentration as the X-axis and the % inhibition as the Y-axis. 50 Got the value.

[0231] The formula is Y = lower limit + (upper limit - lower limit) / (1 + 10^((LogIC 50 -X) * Hill Slope). Table 1: Inhibition test results of compounds against EGFR (wild type), EGFR (L858R), EGFR (L858R / C797S), and EGFR (L858R / T790M / C797S) [Table 50] [Table 51] [Table 52] ND = Not Detected

[0232] The above results indicate that the molecules disclosed herein have good inhibitory effects on osimertinib-resistant mutants of EGFR, and relatively weak inhibition of wild-type EGFR, i.e., high selectivity. [ka] (Control group A; WO2021133809) EXAMPLES

[0233] The effects of small molecule inhibitors on proliferation of five Ba / F3 cell lines (Ba / F3-FL-EGFR, Ba / F3-FL-EGFR-L858R, Ba / F3-FL-EGFR-L858R-T790M-C797S, Ba / F3-TEL-EGFR-L858R-C797S and Ba / F3-FL-EGFR-del19-C797S) were detected using Promega CellTiter-Glo reagent.

[0234] The cell lines were incubated in an incubator (37°C, 5% CO 2 ). Cells were passaged periodically and cells in logarithmic growth phase were used for plating. 95 μL of cell suspension was added to each well of the cell plate and culture medium without cells (containing 0.1% DMSO) was added to the Min control well. Compound detection cell plate substance addition: 5 μL of 20x compound working solution was added to the cell culture plate as shown in the table below. 5 μL of DMSO-cell culture medium mixture was added to the Max control well, resulting in a final DMSO concentration of 0.1%. 5 μL of DMSO-cell culture medium mixture was added to the Max control well. The final DMSO concentration was 0.1%.

[0235] The compounds to be tested were added as per the table below. [Table 53]

[0236] The culture plate was placed in an incubator (37°C, 5% CO 2 ) for 72 hours. Cell viability was detected by CellTiter-Glo luminescent assay. Data Analysis: The cell growth inhibition rate (inhibition rate) data was processed using the following formula: Inhibition rate (inhibition%) = 100-(RLU 薬剤 -RLU 最小値 ) / (RLU 最大値 -RLU 最小値 ) * 100%. [In the formula, RLU 薬剤represents the relative luminescence units of the cells to which the drug was added, and RLU 最小値 represents the luminescence units of the culture medium, RLU 最大値 represents the relative luminescence units of cells to which DMSO was added].

[0237] The inhibition rates corresponding to different compound concentrations were calculated by EXCEL, and then the inhibition rate curves were plotted using GraphPad Prism software to obtain the maximum and minimum cell inhibition rates, as well as the IC 50 Relevant parameters including the values ​​were calculated.

[0238] Table 2: Antiproliferative inhibitory effects of representative compounds on BaF3 cells transfected with the kinases EGFRwt, EGFR(L858R), EGFR(L858R / C797S), EGFR(L858R / T790M / C797S) and EGFR(del19 / C797S). [Table 54] [Table 55] [Table 56] [Table 57] ND = Not Detected

[0239] The above results show that the compounds disclosed herein have good anti-proliferative effects on L858R-related and osimertinib-resistant EGFR mutants, and have relatively weak inhibitory effects on wild-type EGFR. Some compounds are significantly superior to the control molecules. EXAMPLES

[0240] The effects of small molecule inhibitors on proliferation of three Ba / F3 cell lines (Ba / F3-FL-EGFR-del19, Ba / F3-FL-EGFR-del19-T790M, Ba / F3-FL-EGFR-del19-T790M-C797S) were detected using Promega CellTiter-Glo reagent.

[0241] The cell lines were incubated in an incubator (37°C, 5% CO 2 ). Cells were passaged periodically and cells in logarithmic growth phase were used for plating. 95 μL of cell suspension was added to each well of the cell plate, and cell-free culture medium (containing 0.1% DMSO) was added to the Min control well. Compound detection cell plate addition: 5 μL of 20× compound working solution was added to the cell culture plate. 5 μL of DMSO-cell culture medium mixture was added to the Max control well to give a final DMSO concentration of 0.1%. 5 μL of DMSO-cell culture medium mixture was added to the Max control well to give a final DMSO concentration of 0.1%.

[0242] The culture plate was placed in an incubator (37°C, 5% CO 2 ) for 72 hours. Cell viability was detected by CellTiter-Glo luminescent assay. Data Analysis: The cell growth inhibition rate (inhibition rate) data was processed using the following formula: Inhibition rate (inhibition%) = 100-(RLU 薬剤 -RLU 最小値 ) / (RLU 最大値 -RLU 最小値 ) * 100%. [In the formula, RLU 薬剤 represents the relative luminescence units of the cells treated with the drug, RLU 最小値 represents the luminescence units of the culture medium, RLU 最大値 represents the relative luminescence units of cells to which DMSO was added].

[0243] The inhibition rates corresponding to different compound concentrations were calculated by EXCEL, and then the inhibition rate curves were plotted using GraphPad Prism software to obtain the maximum and minimum cell inhibition rates, as well as the IC 50 Relevant parameters including the values ​​were calculated. Table 3: Antiproliferative inhibitory effects of representative compounds on BaF3 cells transfected with kinases EGFR(del19), EGFR(del19 / T790M) and EGFR(del19 / T790M / C797S). [Table 58]

[0244] The above results indicate that the compounds disclosed herein have good antiproliferative effects against del19-associated and osimertinib-resistant mutants of EGFR. EXAMPLES

[0245] The liver microsomal stability studies of the compounds were as follows: The compounds of the present disclosure were subjected to liver microsome stability test. The compounds to be tested were incubated with different species of liver microsomes with or without the addition of NADPH. The final concentration of the compounds to be tested in the test system was 1 μM. The final concentration of NADPH was 1 mM, and the final concentration of liver microsomes was 0.5 mg / ml. At different time points within 60 minutes, the compound concentration in the incubation supernatant was detected, and pharmacokinetic parameters (such as intrinsic clearance) were calculated. The results show that the molecules of the present disclosure have good metabolic stability, especially in the human body. [Table 59] EXAMPLES

[0246] In vivo efficacy assay in BALB / c nude mice. The details were as follows: BaF3(del19 / T790M / C797S) tumor cells were cultured and inoculated into 6-8 week old female BALB / c nude mice (body weight about 20 g), and all mice were subcutaneously inoculated. The mice were kept under SPF grade laboratory environment, and all mice had free access to commercially certified standard chow. The average tumor volume of the mice was about 150 mm 3 When the mice reached adulthood, the test compounds were orally administered daily. The doses were as follows: blank group, vehicle (DMSO / Solutol / H 2 0, 5 / 10 / 85). The dose of the dosing group was 100 mg / kg, twice a day; the dose of the osimertinib group was 25 mg / kg, once a day. The tumor volume was measured three times a week using a two-dimensional caliper, and the animals were weighed daily. After 13 consecutive days of dosing, the inhibition rate (TGI / 100%) was calculated based on the final tumor volume. The volume calculation formula is as follows: V=1 / 2a * b 2 , where a represents the long axis of the tumor and b represents the short axis of the tumor. [Table 60] $ means that the dose was 50 mg / kg for the first 4 days and 100 mg / kg from the 5th day onwards.

[0247] The results indicate that the molecules disclosed herein have good in vivo efficacy, have excellent inhibitory effects on osimertinib-resistant tumor cells, can overcome drug resistance, and provide clinical benefits.

Claims

1. Formula (I): 【Chemistry 1】 (I) or a pharma- ceutically acceptable salt, isotopic substitute, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof. [In the formula, structure: 【Chemistry 2】 Here is the structure: 【Chemistry 3】 wherein the structure: 【Chemistry 4】 But the structure: 【Chemistry 5】 When X is selected from CH and N, Y is CH ２ , C═O and C═S; and the structure: 【Chemistry 6】 But the structure: 【Chemistry 7】 when X is C and Y is CH; Z is selected from CH and N; Ring A is a 4-8 membered heterocyclyl; Ring B has the structure: 【Chemistry 8】 Selected from: L is a chemical bond, -S(=O)(=M)-, -N(R Ｎ )-S(=O)(=M)-, -S(=O)(=M)-N(R Ｎ ) -, -N(R Ｎ )-C(=O)-, -C(=O)-N(R Ｎ ) -, -CH(R Ｎ )-C(=O)-, -C(=O)-CH(R Ｎ ) -, -CH(R Ｎ )-S(=O)(=M)- and -S(=O)(=M)-CH(R Ｎ )-selected from; R １ and R ２ are independently H, halogen, C １～６ Alkyl and C １～６ haloalkyl; R ３ and R ４ are independently H, OR ａ , C １～６ Alkyl and C １～６ haloalkyl; R ５ is H, halogen, C １～６ Alkyl and C １～６ haloalkyl; R ６ is -C ０～６ Alkylene-OR ａ , -C ０～６ Alkylene -NR ｂ R ｃ , C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, 4-6 membered heterocyclyl, C ６～１０ selected from aryl and 5-6 membered heteroaryl; R ７ is H, -C １～６ Alkylene -CN, -C １～６ Alkylene-OR ａ , -C １～６ Alkylene -NR ｂ R ｃ , C １～６ Alkyl, C １～６ Haloalkyl and -S(=O)(=M)-R ８ Selected from: where M is O or NH; R Ｎ is H, C １～６ Alkyl and C １～６ haloalkyl; Or, R Ｎ and R ６ is connected to C １～６ Alkylene, C ２～６ Alkenylene or C ２～６ Forming an alkynylene; R ８ is -C ０～６ Alkylene-OR ａ , -C ０～６ Alkylene -NR ｂ R ｃ , C １～６ Alkyl, -C １～６ Alkylene-C ３～６ Cycloalkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, 4-6 membered heterocyclyl, C ６～１０ aryl and 5- to 6-membered heteroaryl, which are selected from one or more of R ａ and R ａ , R ｂ and R ｃ are independently H, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ cycloalkyl and 4- to 6-membered heterocyclyl; or R ｂ and R ｃ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl; X, Y, Z, ring A, ring B, L, R １ ~R ８ , R Ｎ , R ａ , R ｂ and R ｃ each group in may be substituted with one or more deuterium atoms until fully deuterized; However, L is -CH(R Ｎ )-S(=O)(=M)-, and the ring in which X, Y and Z are located is a benzene ring, then B has the structure: 【Chemistry 9】 is.]

2. The ring in which X, Y and Z are located has the structure: 【Chemistry 10】 2. A compound of formula (I) according to claim 1, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, selected from:

3. Ring A has the structure: 【Chemistry 11】 3. A compound of formula (I) according to claim 1 or 2, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, selected from:

4. Ring B has the structure: 【Chemistry 12】 4. The compound of formula (I) according to any one of claims 1 to 3, wherein:

5. Ring B has the structure: 【Chemistry 13】 4. The compound of formula (I) according to any one of claims 1 to 3, wherein:

6. L is -S(=O)(=M)-, -N(R Ｎ )-S(=O)(=M)-,-N(R Ｎ )-C(=O)-,-CH(R Ｎ )-C(=O)- and -CH(R Ｎ )-S(=O)(=M)-; or L is selected from -N(R Ｎ )-S(=O)(=M)- or -CH(R Ｎ 6. The compound of formula (I) according to any one of claims 1 to 5, wherein R(R) is -S(=O)(=M)-, or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

7. R １ and R ２ One of the groups is a halogen, and the other group is H, halogen and C. １～６ alkyl; or R １ and R ２ is F and the other is selected from H, F and Me; or R １ and R ２ and the other is H; or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

8. R ３ and R ４ One of the two is OR ａ and the other is H and C １～６ alkyl; or R ３ and R ４ is OH or OMe, and the other is selected from H and Me, or a pharma- ceutically acceptable salt, isotopic form, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

9. R ５ is selected from H and Me, or a pharma- ceutically acceptable salt, isotopic substitute, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

10. The following structure: 【Chemistry 14】 【Chemistry 15】 or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein each group is as defined in any one of claims 1 to 9.

11. Formula (II): 【Chemistry 16】 (II) or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof. [In the formula, structure: 【Chemistry 17】 Here is the structure: 【Chemistry 18】 wherein the structure: 【Chemistry 19】 But the structure: 【Chemistry 20】 When X is selected from CH and N, Y is CH ２ , C═O and C═S; and the structure: 【Chemistry 21】 But the structure: 【Chemical 22】 when X is C and Y is CH; Z is selected from CH and N; Ring A is a 4-8 membered heterocyclyl; L is -S(=O)(=M)-, -N(R Ｎ )-S(=O)(=M)-, -S(=O)(=M)-N(R Ｎ ) -, -N(R Ｎ )-C(=O)-, -C(=O)-N(R Ｎ ) -, -CH(R Ｎ )-C(=O)-, -C(=O)-CH(R Ｎ ) -, -CH(R Ｎ )-S(=O)(=M)- and -S(=O)(=M)-CH(R Ｎ )-selected from; R ５ is H, halogen, C １～６ Alkyl and C １～６ haloalkyl; R ６ is OR ａ , N.R. ｂ R ｃ , C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, 4-6 membered heterocyclyl, C ６～１０ selected from aryl and 5-6 membered heteroaryl; R ７ is H, C １～６ Alkyl, C １～６ Haloalkyl and -S(=O)(=M)-R ８ Selected from: where M is O or NH; R Ｎ is H, C １～６ Alkyl and C １～６ haloalkyl; Or, R Ｎ and R ６ is connected to C １～６ Alkylene, C ２～６ Alkenylene or C ２～６ Forming an alkynylene; R ８ is OR ａ , N.R. ｂ R ｃ , C １～６ Alkyl, -CH ２ -C ３～６ Cycloalkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, 4-6 membered heterocyclyl, C ６～１０ aryl and 5- to 6-membered heteroaryl, which are selected from one or more of R ａ and R ａ , R ｂ and R ｃ are independently H, C １～６ Alkyl and C １～６ haloalkyl; or R ｂ and R ｃ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl.

12. Formula (III): 【Chemistry 23】 (III) or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof. [In the formula, Ring A is a 4-8 membered heterocyclyl; L is -S(=O)(=M)-, -N(R Ｎ )-S(=O)(=M)-, -S(=O)(=M)-N(R Ｎ ) -, -N(R Ｎ )-C(=O)-, -C(=O)-N(R Ｎ ) -, -CH(R Ｎ )-C(=O)-, -C(=O)-CH(R Ｎ ) -, -CH(R Ｎ )-S(=O)(=M)- and -S(=O)(=M)-CH(R Ｎ )-selected from; R ５ is H, halogen, C １～６ Alkyl and C １～６ haloalkyl; R ６ is OR ａ , N.R. ｂ R ｃ , C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, 4-6 membered heterocyclyl, C ６～１０ selected from aryl and 5-6 membered heteroaryl; R ７ is H, C １～６ Alkyl, C １～６ Haloalkyl and -S(=O)(=M)-R ８ Selected from: where M is O or NH; R Ｎ is H, C １～６ Alkyl and C １～６ haloalkyl; Or, R Ｎ and R ６ is connected to C １～６ Alkylene, C ２～６ Alkenylene or C ２～６ Forming an alkynylene; R ８ is OR ａ , N.R. ｂ R ｃ , C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, 4-6 membered heterocyclyl, C ６～１０ aryl and 5- to 6-membered heteroaryl, which are selected from one or more of R ａ and R ａ , R ｂ and R ｃ are independently H, C １～６ Alkyl and C １～６ haloalkyl; or R ｂ and R ｃ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl.

13. Ring A is of the following formula: 【Chemistry 24】 Selected from: L is -S(=O)(=M)-, -N(R Ｎ )-S(=O)(=M)-, -S(=O)(=M)-N(R Ｎ ) -, -N(R Ｎ )-C(=O)-, -C(=O)-N(R Ｎ ) -, -CH(R Ｎ )-C(=O)-, -C(=O)-CH(R Ｎ ) -, -CH(R Ｎ )-S(=O)(=M)- and -S(=O)(=M)-CH(R Ｎ )-selected from; R ５ is selected from H and Me; R ６ But, Me, Et, Pr, CH ２ CF ３ , cyclopropyl, OH, NH ２ , NHMe, NMe ２ , furan-2-yl, and pyridin-4-yl; R ７ is H, trifluoroethyl and -S(=O)(=M)-R ８ Selected from: where M is O or NH; R Ｎ But, H, C １～６ Alkyl and C １～６ haloalkyl; Or, R Ｎ and R ６ are connected, C １～６ Alkylene, C ２～６ Alkenylene or C ２～６ Forming an alkynylene; R ８ But, Me, Et, Pr, CH ２ CF ３ , cyclopropyl, OH, NH ２ , NHMe, NMe ２ , pyran-4-yl, furan-2-yl, and pyridin-4-yl; R ａ , R ｂ and R ｃ are independent, H, C １～６ Alkyl and C １～６ haloalkyl; or R ｂ and R ｃ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl; 13. The compound of claim 12, or a pharma- ceutically acceptable salt, isotopic substitute, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof.

14. Ring A is a 4- to 8-membered heterocyclyl; L is -S(=O)(=M)-, -CH(R Ｎ )-C(=O)- and -CH(R Ｎ )-S(=O)(=M)-; R ５ But, H, C １～６ Alkyl or C １～６ haloalkyl; R ６ But, OR ａ , N.R. ｂ R ｃ , C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ selected from cycloalkyl and 4- to 6-membered heterocyclyl; R ７ is H, trifluoroethyl and -S(=O)(=M)-R ８ Selected from: where M is O or NH; R Ｎ But, H, C １～６ Alkyl and C １～６ haloalkyl; Or, R Ｎ and R ６ are connected, C １～６ Alkylene, C ２～６ Alkenylene or C ２～６ Forming an alkynylene; R ８ But, OR ａ , N.R. ｂ R ｃ , C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ selected from cycloalkyl and 4- to 6-membered heterocyclyl; R ａ , R ｂ and R ｃ are independent, H, C １～６ Alkyl and C １～６ haloalkyl; or R ｂ and R ｃ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl; 13. The compound of claim 12, or a pharma- ceutically acceptable salt, isotopic substitute, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof.

15. Ring A is a 4- to 8-membered heterocyclyl; L is -S(=O)(=M)-, -CH(R Ｎ )-C(=O)- and -CH(R Ｎ )-S(=O)(=M)-; R ５ But H and C １～６ alkyl; R ６ But, N.R. ｂ R ｃ , C １～６ Alkyl and C １～６ haloalkyl; R ７ is H, trifluoroethyl and -S(=O)(=M)-R ８ Selected from: where M is O or NH; R Ｎ But, H, C １～６ Alkyl and C １～６ haloalkyl; R ８ But, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ cycloalkyl and pyran-4-yl; R ｂ and R ｃ are independent, H, C １～６ Alkyl and C １～６ haloalkyl, 13. The compound of claim 12, or a pharma- ceutically acceptable salt, isotopic substitute, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof.

16. Ring A is of the formula: 【Chemistry 25】 Selected from: L is -S(=O)(=M)-, -CH(R Ｎ )-C(=O)- and -CH(R Ｎ )-S(=O)(=M)-; R ５ is H; R ６ Me and NH ２ Selected from: R ７ is H and -S(=O)(=M)-R ８ Selected from: where M is O; R Ｎ But, H, C １～６ Alkyl and C １～６ haloalkyl; R ８ is selected from Me, Et, Pr, cyclopropyl and pyran-4-yl; 13. The compound of claim 12, or a pharma- ceutically acceptable salt, isotopic substitute, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof.

17. Formula (IV): 【Chemistry 26】 (IV) or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof. [In the formula, Ring A is a 4-8 membered heterocyclyl; L is -S(=O)(=M)-, -N(R Ｎ )-S(=O)(=M)-, -S(=O)(=M)-N(R Ｎ ) -, -N(R Ｎ )-C(=O)-, -C(=O)-N(R Ｎ ) -, -CH(R Ｎ )-C(=O)- and -C(=O)-CH(R Ｎ )-selected from; R １ and R ２ are independently H, halogen, C １～６ Alkyl and C １～６ haloalkyl; R ３ and R ４ are independently H, OR ａ , C １～６ Alkyl and C １～６ haloalkyl; R ５ is H, halogen, C １～６ Alkyl and C １～６ haloalkyl; R ６ is OR ａ , N.R. ｂ R ｃ , C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, 4-6 membered heterocyclyl, C ６～１０ selected from aryl and 5-6 membered heteroaryl; where M is O or NH; R Ｎ is H, C １～６ Alkyl and C １～６ haloalkyl; Or, R Ｎ and R ６ is connected to C １～６ Alkylene, C ２～６ Alkenylene or C ２～６ Forming an alkynylene; R ａ , R ｂ and R ｃ are independently H, C １～６ Alkyl and C １～６ haloalkyl; or R ｂ and R ｃ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl.

18. Ring A is of the following formula: 【Chemistry 27】 Selected from: L is -S(=O)(=M)-, -N(R Ｎ )-S(=O)(=M)-, -S(=O)(=M)-N(R Ｎ ) -, -N(R Ｎ )-C(=O)-, -C(=O)-N(R Ｎ ) -, -CH(R Ｎ )-C(=O)- and -C(=O)-CH(R Ｎ )-selected from; R １ and R ２ are independently H, halogen, C １～６ Alkyl and C １～６ haloalkyl; R ３ and R ４ are independent, H, OR ａ , C １～６ Alkyl and C １～６ haloalkyl; R ５ But, H, C １～６ Alkyl and C １～６ haloalkyl; R ６ But, OR ａ , N.R. ｂ R ｃ , C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, 4-6 membered heterocyclyl, C ６～１０ selected from aryl and 5-6 membered heteroaryl; where M is O or NH; R Ｎ But, H, C １～６ Alkyl and C １～６ haloalkyl; Or, R Ｎ and R ６ are connected, C １～６ Alkylene, C ２～６ Alkenylene or C ２～６ Forming an alkynylene; R ａ , R ｂ and R ｃ are independent, H, C １～６ Alkyl and C １～６ haloalkyl; or R ｂ and R ｃ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl; 18. The compound of claim 17, or a pharma- ceutically acceptable salt, isotopic substitute, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof.

19. Formula (V), (V-1) or (V-2): 【Chemistry 28】 or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof. [In the formula, L is -S(=O)(=M)-, -N(R Ｎ )-S(=O)(=M)-, -S(=O)(=M)-N(R Ｎ ) -, -N(R Ｎ )-C(=O)-, -C(=O)-N(R Ｎ ) -, -CH(R Ｎ )-C(=O)- and -C(=O)-CH(R Ｎ )-selected from; R １ and R ２ are independently H, halogen, C １～６ Alkyl and C １～６ haloalkyl; R ３ and R ４ are independently H, OR ａ , C １～６ Alkyl and C １～６ haloalkyl; R ５ is H, halogen, C １～６ Alkyl and C １～６ haloalkyl; R ６ is OR ａ , N.R. ｂ R ｃ , C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, 4-6 membered heterocyclyl, C ６～１０ selected from aryl and 5-6 membered heteroaryl; where M is O or NH; R Ｎ is H, C １～６ Alkyl and C １～６ haloalkyl; Or, R Ｎ and R ６ is connected to C １～６ Alkylene, C ２～６ Alkenylene or C ２～６ Forming an alkynylene; R ａ , R ｂ and R ｃ are independently H, C １～６ Alkyl and C １～６ haloalkyl; or R ｂ and R ｃ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl.

20. L is -S(=O)(=M)-, -N(R Ｎ )-S(=O)(=M)-,-N(R Ｎ )-C(=O)- and -CH(R Ｎ )-C(=O)-; R １ and R ２ One of the groups is a halogen, and the other group is H, a halogen, and C. １～６ alkyl; R ３ and R ４ One of the two is OR ａ and the other is H and C １～６ alkyl; R ５ But, H, C １～６ Alkyl and C １～６ haloalkyl; R ６ But, OR ａ , N.R. ｂ R ｃ , C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ selected from cycloalkyl and 5-6 membered heteroaryl; where M is O or NH; R Ｎ But, H, C １～６ Alkyl and C １～６ haloalkyl; Or, R Ｎ and R ６ are connected, C １～６ Alkylene, C ２～６ Alkenylene or C ２～６ Forming an alkynylene; R ａ , R ｂ and R ｃ are independent, H, C １～６ Alkyl and C １～６ haloalkyl; or R ｂ and R ｃ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl; 20. The compound of claim 19, or a pharma- ceutically acceptable salt, isotopic substitute, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof.

21. Formula (VI), (VI-1) or (VI-2): 【Chemical 29】 or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof. [In the formula, M is O or NH; R １ and R ２ are independently H, halogen, C １～６ Alkyl and C １～６ haloalkyl; R ３ and R ４ are independently H, OR ａ , C １～６ Alkyl and C １～６ haloalkyl; R ５ is H, halogen, C １～６ Alkyl and C １～６ haloalkyl; R ６ is OR ａ , N.R. ｂ R ｃ , C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, 4-6 membered heterocyclyl, C ６～１０ selected from aryl and 5-6 membered heteroaryl; R Ｎ is H, C １～６ Alkyl and C １～６ haloalkyl; Or, R Ｎ and R ６ is connected to C １～６ Alkylene, C ２～６ Alkenylene or C ２～６ Forming an alkynylene; Here, R ａ , R ｂ and R ｃ are independently H, C １～６ Alkyl and C １～６ haloalkyl; or R ｂ and R ｃ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl.

22. M is O or NH; R １ and R ２ One of the groups is a halogen, and the other group is H, a halogen, and C. １～６ alkyl; R ３ and R ４ One of the two is OR ａ and the other is H and C １～６ alkyl; R ５ But H and C １～６ alkyl; R ６ But, OR ａ , N.R. ｂ R ｃ , C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ selected from cycloalkyl and 5-6 membered heteroaryl; R Ｎ But H and C １～６ alkyl; Or, R Ｎ and R ６ are connected, C １～６ Forming an alkylene; Here, R ａ , R ｂ and R ｃ are independent, H, C １～６ Alkyl and C １～６ haloalkyl, 22. The compound of claim 21, or a pharma- ceutically acceptable salt, isotopic substitute, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof.

23. M is O; R １ and R ２ is F and the other is selected from H, F and Me; R ３ and R ４ is OH or OMe, and the other is selected from H and Me; R ５ is selected from H and Me; R ６ But, Me, Et, Pr, CH ２ CF ３ , cyclopropyl, NMe ２ , furan-2-yl, and pyridin-4-yl; R Ｎ is selected from H and Me; Or, R Ｎ and R ６ are connected, C １～４ Forming an alkylene 22. The compound of claim 21, or a pharma- ceutically acceptable salt, isotopic substitute, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof.

24. M is O or NH; R １ and R ２ One of the groups is halogen, C １～６ Alkyl and C １～６ haloalkyl, and the other is H; R ３ and R ４ One of the two is OR ａ , C １～６ Alkyl and C １～６ haloalkyl, and the other is H; R ５ H, halogen, C １～６ Alkyl and C １～６ haloalkyl; R ６ But, OR ａ , N.R. ｂ R ｃ , C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, 4-6 membered heterocyclyl, C ６～１０ selected from aryl and 5-6 membered heteroaryl; R Ｎ But, H, C １～６ Alkyl and C １～６ haloalkyl; Or, R Ｎ and R ６ are connected, C １～６ Alkylene, C ２～６ Alkenylene or C ２～６ Forming an alkynylene; Here, R ａ , R ｂ and R ｃ are independent, H, C １～６ Alkyl and C １～６ haloalkyl; or R ｂ and R ｃ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl; 22. The compound of claim 21, or a pharma- ceutically acceptable salt, isotopic substitute, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof.

25. M is O or NH; R １ and R ２ One of the groups is halogen and C １～６ alkyl, and the other is H; R ３ and R ４ One of the two is OR ａ and the other is H; R ５ But, H, C １～６ Alkyl and C １～６ haloalkyl; R ６ But, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ selected from cycloalkyl and 4- to 6-membered heterocyclyl; R Ｎ But, H, C １～６ Alkyl and C １～６ haloalkyl; Here, R ａ H, C １～６ Alkyl and C １～６ haloalkyl, 22. The compound of claim 21, or a pharma- ceutically acceptable salt, isotopic substitute, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof.

26. M is O; R １ and R ２ one of which is halogen (or F) and the other is H; R ３ and R ４ One of the two is OR ａ and the other is H; R ５ But H and C １～４ alkyl; R ６ But, C １～４ Alkyl and C １～４ haloalkyl; R Ｎ But, H, C １～４ Alkyl and C １～４ haloalkyl; or C １～４ is alkyl; Here, R ａ But H and C １～４ selected from alkyl, 22. The compound of claim 21, or a pharma- ceutically acceptable salt, isotopic substitute, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof.

27. Formula (VII), (VII-1) or (VII-2): 【Chemistry 30】 or a pharma- ceutically acceptable salt, isotopic substitution, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof. [In the formula, L is -S(=O)(=M)-, -N(R Ｎ )-S(=O)(=M)-, -S(=O)(=M)-N(R Ｎ ) -, -N(R Ｎ )-C(=O)-, -C(=O)-N(R Ｎ ) -, -CH(R Ｎ )-C(=O)-, -C(=O)-CH(R Ｎ ) -, -CH(R Ｎ )-S(=O)(=M)- and -S(=O)(=M)-CH(R Ｎ )-selected from; R ５ is H, halogen, C １～６ Alkyl and C １～６ haloalkyl; R ６ is OR ａ , N.R. ｂ R ｃ , C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, 4-6 membered heterocyclyl, C ６～１０ selected from aryl and 5-6 membered heteroaryl; R ７ is H, C １～６ Alkyl, C １～６ Haloalkyl and -S(=O)(=M)-R ８ Selected from: where M is O or NH; R Ｎ is H, C １～６ Alkyl and C １～６ haloalkyl; Or, R Ｎ and R ６ is connected to C １～６ Alkylene, C ２～６ Alkenylene or C ２～６ Forming an alkynylene; R ８ is OR ａ , N.R. ｂ R ｃ , C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, 4-6 membered heterocyclyl, C ６～１０ aryl and 5- to 6-membered heteroaryl, which are selected from one or more of R ａ and R ａ , R ｂ and R ｃ are independently H, C １～６ Alkyl and C １～６ haloalkyl; or R ｂ and R ｃ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl.

28. L is -N(R Ｎ )-S(=O)(=M)- and -CH(R Ｎ )-S(=O)(=M)-; R ５ But, C １～６ Alkyl and C １～６ haloalkyl; R ６ But, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ selected from cycloalkyl and 4- to 6-membered heterocyclyl; R ７ -S(=O)(=M)-R ８ and where M is O or NH; R Ｎ But, H, C １～６ Alkyl and C １～６ haloalkyl; R ８ But, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ cycloalkyl and 4- to 6-membered heterocyclyl, which are selected from one or more of R ａ and R ａ But, H, C １～６ Alkyl and C １～６ haloalkyl, 28. The compound of claim 27, or a pharma- ceutically acceptable salt, isotopic substitute, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof.

29. L is -N(R Ｎ )-S(=O)(=M)- and -CH ２ -S(=O)(=M)-; R ５ But, C １～６ Alkyl and C １～６ haloalkyl; R ６ But, C １～６ Alkyl and C １～６ haloalkyl; R ７ But -S(=O)(=M)-R ８ and where M is O or NH; R Ｎ But, C １～６ Alkyl and C １～６ haloalkyl; R ８ But, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ cycloalkyl and 4- to 6-membered heterocyclyl; 28. The compound of claim 27, or a pharma- ceutically acceptable salt, isotopic substitute, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof.

30. L is -N(R Ｎ ) -S(=O) ２ - and -CH ２ -S(=O) ２ - selected from; R ５ But, C １～６ Alkyl and C １～６ haloalkyl; R ６ But, C １～６ Alkyl and C １～６ haloalkyl; R ７ But -S(=O) ２ -R ８ and Here, R Ｎ But, C １～６ Alkyl and C １～６ haloalkyl; R ８ But, C １～６ Alkyl, C １～６ Haloalkyl and C ３～６ cycloalkyl, 28. The compound of claim 27, or a pharma- ceutically acceptable salt, isotopic substitute, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof.

31. L is -N(R Ｎ ) -S(=O) ２ - and -CH ２ -S(=O) ２ - selected from; R ５ C １～４ is alkyl; R ６ C １～４ is alkyl; R ７ -S (=O) ２ -R ８ and Here, R Ｎ C １～４ is alkyl; R ８ But, C １～４ Alkyl and C ３～６ cycloalkyl, 28. The compound of claim 27, or a pharma- ceutically acceptable salt, isotopic substitute, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof.

32. formula: 【Chemistry 31】 【Chemistry 32】 【Chemical Formula 33】 【Chemical 34】 【Chemistry 35】 【Chemical 36】 【Chemical 37】 【Chemical Formula 38】 【Chemical Formula 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 or a tautomer, stereoisomer, prodrug, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

33. 33. A pharmaceutical composition comprising a compound according to any one of claims 1 to 32, or a pharma- ceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, or isotopic substitution thereof, and a pharma- ceutically acceptable excipient; or, further comprising another therapeutic agent.

34. 34. Use of a compound according to any one of claims 1 to 32, or a pharma- ceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic substitution thereof, in the manufacture of a medicament for treating and / or preventing diseases mediated by EGFR protein and its mutants.

35. A method for treating and / or preventing a disease mediated by EGFR protein and its mutants in a subject, comprising administering to the subject a compound according to any one of claims 1 to 32 or a pharma- ceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic substitution thereof, or a pharmaceutical composition according to claim 33.

36. A compound according to any one of claims 1 to 32 or a pharma- ceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic substitution thereof, or a pharmaceutical composition according to claim 33, for use in the treatment and / or prevention of a disease mediated by an EGFR protein and a mutant thereof.

37. 37. The use of claim 34, or the method of claim 35, or the compound or composition for use of claim 36, wherein the EGFR mutant is selected from one or more of the L858R mutant, the del19 mutant, the T790M mutant, and the C797S mutant; and optionally the disease is selected from lung cancer, colon cancer, urothelial cancer, breast cancer, prostate cancer, brain cancer, ovarian cancer, gastric cancer, pancreatic cancer, head and neck cancer, bladder cancer and mesothelioma, or non-small cell lung cancer.

Images