Pyrazine derivatives and their application in inhibiting SHP2

Abstract

This invention relates to a pyrazine derivative and its application in inhibiting SHP2, a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label thereof, wherein the compound of formula (I) has the following structure: The novel pyrazine derivative provided by this invention has excellent activity in inhibiting SHP2 and can be used for the prevention and / or treatment of diseases or conditions mediated or dependent on non-receptor protein tyrosine phosphatase.

Description

Technical Field

[0001] The present invention belongs to the field of medicine and relates to a pyrazine derivative, a preparation method thereof and an application thereof in medicine, and specifically relates to a pyrazine derivative and an application thereof as a protein tyrosine phosphatase 2 (SHP2) inhibitor in preventing and / or treating diseases related to abnormal protein tyrosine phosphatase 2 (SHP2) activity. Background Art

[0002] Protein tyrosine phosphatase 2 (SHP2) belongs to the protein tyrosine phosphatase family and is involved in regulating cell proliferation, survival, differentiation, migration and apoptosis. In recent years, more and more studies have shown that protein tyrosine phosphatases, such as SHP2, play an important role in tumors. In particular, as the role of SHP2 in tumors becomes increasingly clear, studies have confirmed that inhibiting the abnormal activation of SHP2 in tumors has become a feasible anti-tumor strategy.

[0003] SHP2 is the first confirmed true oncogene in the protein tyrosine phosphatase superfamily. It plays an important role in multiple signaling pathways such as metabolism, differentiation, proliferation, migration and survival. SHP2 can regulate signaling pathways such as Ras-mitogen-activated protein kinase, Janus kinase-signal transducer and activator of transcription (JAK-STAT) or phosphoinositide 3-kinase-AKT and nuclear factor κB (NF-κB); SHP2 is also a major regulator of programmed cell death protein-1 (PD-1) and B, T lymphocyte attenuator (BTLA) immune checkpoint signaling pathways, which may be related to tumor immunosuppression; in addition, SHP2 rarely mutates in solid tumors, but is overexpressed in a variety of tumors such as head and neck cancer, non-small cell lung cancer, breast cancer, liver cancer, gastric cancer and thyroid cancer.

[0004] Recent studies have shown that the combination of SHP2 inhibitors and anaplastic lymphoma kinase (ALK) inhibitors can treat patients who are resistant to first-generation / second-generation anaplastic lymphoma kinase inhibitors and do not respond to third-generation anaplastic lymphoma kinase inhibitors. The combination of SHP2 inhibitors and mitogen-activated protein kinase kinase (MEK) or serine / threonine protein kinase (BRAF) inhibitors can treat patients with KRAS or serine / threonine protein kinase (BRAF) mutations who are resistant to mitogen-activated protein kinase kinase or serine / threonine protein kinase inhibitors. For triple-negative breast cancer, the effect of SHP2 inhibitors causes it to overexpress estrogen receptor α, and combination with endocrine therapy is also a potential treatment option for triple-negative breast cancer. SHP2 can also affect the proliferation of vascular smooth muscle cells and is closely related to the occurrence and development of atherosclerosis. Therefore, SHP2 is a potential drug target with broad application prospects. Summary of the invention

[0005] Problem that the invention aims to solve

[0006] So far, no drug for protein tyrosine phosphatase has been marketed, and the compounds in the prior art have poor activity in inhibiting SHP2 (such as WO2016 / 203406A1). The purpose of the present invention is to provide a new type of pyrazine derivative, which has excellent activity in inhibiting SHP2 and can be used to prevent and / or treat diseases or conditions mediated or dependent on non-receptor protein tyrosine phosphatase.

[0007] Solutions for solving problems

[0008] In order to solve the above technical problems, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled substance thereof, wherein the structure of the compound of formula (I) is:

[0009]

[0010] in:

[0011] R 1 and R 2 are the same or different and are independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, substituted or unsubstituted groups: -NH2, C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkyloxy, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl; or R 1 and R 2 To form a 3-8 membered saturated or unsaturated cycloalkyl or heterocyclic group, optionally, the 3-8 membered saturated or unsaturated cycloalkyl or heterocyclic group is substituted by 1-3 -OH, -NH2, -CN, NO2, halogen atoms, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 substituted by aryl or 5-10 membered heteroaryl;

[0012] R 3 is selected from H, D, -NH2;

[0013] X is selected from a chemical bond, -NH-, -CONH-;

[0014] Y is selected from N or CR 0 , where R 0 Selected from H, D, -OH, -CN, halogen atoms, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 12 Cycloalkylamino, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, 3-8 membered heterocyclic group, halogenated C1-C 10 Alkylamino, C6-C 10 Aryl or 5-10 membered heteroaryl, wherein the heterocyclic group or heteroaryl group optionally contains 1-4 heteroatoms selected from S, O, N or NH;

[0015] Every R 4 Each is the same or different and is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, -CONHR 14 or-NHCOR 15 , substituted or unsubstituted following groups: -NH2, C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl; wherein R 14 and R 15 Each independently selected from C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the substitution is selected from C1-C 10 Alkyl, halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 The aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group is substituted with one or more substituents, wherein the substituents are optionally substituted with 1-3 C1-C 10 Alkyl, halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C3-C 12 substituted by cycloalkyl;

[0016] Selected from C6-C 10 Aryl, 5-10 membered heteroaryl, C4-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 14 Bridged or spirocyclic groups, C6-C 14 bridged heterocyclic group or spiro heterocyclic group; wherein the 5-10 membered heteroaryl, 3-12 membered heterocyclic group, C6-C 14 The bridged heterocyclic group or spiro heterocyclic group contains 1 to 3 heteroatoms or groups selected from N, NH, O, S, C(O), S(O);

[0017] Every R 5 Each is the same or different and is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, or a substituted or unsubstituted group of the following: C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, -NH2, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, the substitution is selected from C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, hydroxyl-C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, 5-10 membered heteroaryl, C6-C 10 substituted by one or more substituents in an aryl or 3-12 membered heterocyclic group; or any two adjacent R 5 Form a 3-6 membered saturated or unsaturated ring, optionally, the 3-6 membered saturated or unsaturated ring is 1-3 -OH, -NH2, -CN, halogen atoms, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 12 Cycloalkylamino, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkylamino, C6-C 10 substituted by aryl or 5-10 membered heteroaryl;

[0018] R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R12 , R 13 Each is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, a substituted or unsubstituted group: -NH2, C1-C 10 Alkyl, C1-C10 alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkyloxy, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, the substitution is selected from C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, hydroxyl-C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, 5-10 membered heteroaryl or C6-C 10 The aromatic group is substituted by one or more substituents;

[0019] m is 0, 1, 2 or 3;

[0020] n is 0, 1, 2 or 3;

[0021] p is 0, 1 or 2.

[0022] The present invention also provides a pharmaceutical composition comprising any one of the above compounds of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled substance thereof.

[0023] The present invention also provides a pharmaceutical preparation, which comprises any one of the above-mentioned compounds of formula (I) or its pharmaceutically acceptable salts, esters, isomers, solvates, prodrugs or isotope labels or the above-mentioned pharmaceutical compositions, wherein the preparation is any one of tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalants, suspensions, dry suspensions, patches and lotions.

[0024] The present invention also provides a compound of formula (I) as described above or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled substance thereof, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation, which is used for preventing and treating diseases or conditions mediated or dependent on non-receptor protein tyrosine phosphatase.

[0025] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled substance thereof, or the pharmaceutical composition or the pharmaceutical preparation for preventing and / or treating diseases or conditions mediated or dependent on non-receptor protein tyrosine phosphatase.

[0026] Use of any of the above-mentioned compounds of formula (I) or their pharmaceutically acceptable salts, esters, isomers, solvates, prodrugs or isotope-labeled substances, or the above-mentioned pharmaceutical compositions, or the above-mentioned pharmaceutical preparations in the preparation of drugs for preventing and / or treating diseases or conditions mediated or dependent on non-receptor protein tyrosine phosphatases.

[0027] The present invention also provides a method for preventing and / or treating diseases or conditions mediated or dependent on non-receptor protein tyrosine phosphatases, which comprises the following steps: administering a therapeutically effective amount of any of the above-mentioned compounds of formula (I) or their pharmaceutically acceptable salts, esters, isomers, solvates, prodrugs or isotope labels, or the above-mentioned pharmaceutical compositions, or the above-mentioned pharmaceutical preparations to patients in need thereof.

[0028] The present invention also provides a drug combination, which comprises any one of the above-mentioned compounds of formula (I) or its pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation, and at least one additional therapeutic agent.

[0029] Effects of the Invention

[0030] The novel pyrazine derivatives provided by the present invention have excellent activity in inhibiting SHP2, for example, compared with the SHP2 inhibitors in the prior art (such as compound 96 in Table 9 of WO2016 / 203406A1), they have significantly better activity in inhibiting SHP2. The novel pyrazine derivatives described in the present invention can be used to prevent and / or treat diseases or conditions mediated or dependent on non-receptor protein tyrosine phosphatases. DETAILED DESCRIPTION

[0031] First, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled substance thereof, wherein the structure of the compound of formula (I) is:

[0032]

[0033] in:

[0034] R 1 and R 2Each is the same or different and is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, a substituted or unsubstituted group of the following: -NH2, C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkyloxy, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl; or R 1 and R 2 To form a 3-8 membered saturated or unsaturated cycloalkyl or heterocyclic group, optionally, the 3-8 membered saturated or unsaturated cycloalkyl or heterocyclic group is substituted by 1-3 -OH, -NH2, -CN, -NO2, halogen atoms, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 substituted by aryl or 5-10 membered heteroaryl;

[0035] R 3 Selected from H, D, -NH2;

[0036] X is selected from a chemical bond, -NH-, -CONH-;

[0037] Y is selected from N or CR 0 , where R 0 Selected from H, D, -OH, -CN, halogen atoms, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 12 Cycloalkylamino, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, 3-8 membered heterocyclic group, halogenated C1-C 10 Alkylamino, C6-C 10 Aryl or 5-10 membered heteroaryl, wherein the heterocyclic group or heteroaryl group optionally contains 1-4 heteroatoms selected from S, O, N or NH;

[0038] Every R 4 Each is the same or different and is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, -CONHR 14 or-NHCOR 15 , substituted or unsubstituted following groups: -NH2, C1-C 10 Alkyl, C1-C 10Alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl; wherein R 14 and R 15 Each independently selected from C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the substitution is selected from C1-C 10 Alkyl, halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 The aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group is substituted with one or more substituents, wherein the substituents are optionally substituted with 1-3 C1-C 10 Alkyl, halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C3-C 12 substituted by cycloalkyl;

[0039] Selected from C6-C 10 Aryl, 5-10 membered heteroaryl, C4-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 14 Bridged or spirocyclic groups, C6-C 14 Bridged heterocyclic group or spiro heterocyclic group; wherein the 5-10 membered heteroaryl, 3-12 membered heterocyclic group, C6-C1 bridged cyclic group or spiro cyclic group contains 1-3 heteroatoms or groups selected from N, NH, O, S, C(O), S(O);

[0040] Every R 5 Each is the same or different and is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, an aminoacyl group, or a substituted or unsubstituted group of the following: C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, -NH2, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, the substitution is selected from C1-C 10 Alkyl, C3-C12 Cycloalkyl, 3-12 membered heterocyclic group, halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, hydroxyl-C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, 5-10 membered heteroaryl or C6-C 10 One or more substituents in the aryl group; or any two adjacent R 5 Form a 3-6 membered saturated or unsaturated ring, optionally, the 3-6 membered saturated or unsaturated ring is 1-3 -OH, -NH2, -CN, halogen atoms, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 12 Cycloalkylamino, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkylamino, C6-C 10 substituted by aryl or 5-10 membered heteroaryl;

[0041] R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 Each is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, a substituted or unsubstituted group: -NH2, C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkyloxy, 3-12 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclic group, the substitution is selected from C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, hydroxyl-C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, 5-10 membered heteroaryl or C6-C 10 The aromatic group is substituted by one or more substituents;

[0042] m is 0, 1, 2 or 3;

[0043] n is 0, 1, 2 or 3;

[0044] p is 0, 1 or 2.

[0045] In order to describe the content of the present invention more clearly, all the terms involved are defined as follows:

[0046] The term "halogen atom" refers to fluorine, chlorine, bromine or iodine, specifically fluorine, chlorine or bromine, alone or in combination.

[0047] The term "C1-C 10 “Alkyl”, alone or in combination, means a saturated straight or branched alkyl group containing 1 to 10, especially 1 to 6 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3,-dimethyl-2-butyl, etc. Preferably, “C1-C 10 "Alkyl" is any of methyl, ethyl, n-propyl, isopropyl, and tert-butyl. Similarly, the term "C 1-6 The term "alkyl" alone or in combination refers to a saturated straight or branched chain alkyl group containing 1 to 6 carbon atoms, including methyl, ethyl, propyl, isopropyl, and the like.

[0048] The term "C1-C 10 "Alkoxy" alone or in combination means a group C1-C 10 Alkyl-O-, where "C1-C 10 "Alkyl" means as defined above, including, but not limited to, methoxy (-OCH3), ethoxy (-OCH2CH3), n-propoxy (-OCH2CH2CH3), isopropoxy (-OCH(CH3)2), n-butoxy (-OCH2CH2CH2CH3), sec-butoxy (-OCH(CH3)CH2CH3), isobutoxy (-OCH2CH(CH3)2), tert-butoxy (-OC(CH3)3), n-pentoxy (-OCH2CH2CH2CH2CH3), neopentoxy (-OCH2C(CH3)3), and the like.

[0049] The term "C3-C 12The term "cycloalkyl" refers alone or in combination to saturated or partially unsaturated monocyclic or polycyclic cycloalkyl groups having 3 to 12, especially 3 to 8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

[0050] The term "C3-C 12 "Cycloalkyloxy" alone or in combination means a group C3-C 12 Cycloalkyl-O-, wherein C3-C 12 Cycloalkyl is as defined above.

[0051] The term "3-12 membered heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic heterocyclyl containing 3-12, particularly 5-12, more particularly 5-7 carbon atoms and heteroatoms or heteroatom groups selected from N, NH, O, C(O), S(O), m (wherein m is 0, 1 or 2); the 3-12 membered heterocyclic group includes aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactam, valerolactam, caprolactam, butyrolactone, valerolacton, caprolactone, succinimide or etc. Preferably, the 3-12 membered heterocyclic group includes butyrolactam, pyrrolidinyl, succinimide or More preferably, the 3-12 membered heterocyclic group is

[0052] The term "aryl" refers to any stable 6-10 membered monocyclic or bicyclic aromatic group, including phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindanyl or biphenyl, etc. The hydrogen atoms on the "aryl" group are independently optionally substituted with one or more substituents described in the present invention.

[0053] The term "heteroaryl" refers to an aromatic ring group formed by replacing a carbon atom on the ring with at least one heteroatom selected from sulfur, oxygen or nitrogen, and the aromatic ring group can be a 5-7 membered monocyclic or 7-12 membered bicyclic group. In the present invention, the number of heteroatoms in the heteroaryl group is preferably 1, 2, 3 or 4, such as thienyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridin-2(1H)-onyl, pyridin-4(1H)-onyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, naphthyl, benzothiophenyl, indole, benzothiophene, benzophenone ... Indole, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolyl, isoquinolyl, quinazolinyl, indazolyl, indole [1,2-a] pyrazinyl, 4,7-diazaindole, pyrazolopyrimidinyl, imidazopyrimidinyl, oxazolopyrimidinyl, isoxazolopyrimidinyl, imidazopyrazinyl, pyrazolopyrazine, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, pyridopyrimidonyl, benzoxazolyl or benzothiazolyl, etc. The hydrogen atoms on the "heteroaryl" are independently optionally substituted with one or more substituents described herein.

[0054] The term "C 6-10 "Aryl" means an aromatic group having 6 to 10 carbon atoms, wherein aryl is as defined above.

[0055] The term "5-10 membered heteroaryl" denotes a heteroaromatic ring having 5 to 10 carbon atoms and heteroatoms, wherein the heteroaromatic ring is as defined above.

[0056] The term "3-8 membered saturated or unsaturated cycloalkyl or heterocyclic group" means a saturated or partially unsaturated monocyclic or condensed ring cycloalkyl group having 3-8, particularly 3-6, more particularly 5-6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.; or a heterocyclic group having 3-8, particularly 3-6, more particularly 5-6 carbon atoms and heteroatoms or heteroatom groups, wherein the heteroatoms or heteroatom groups are selected from N, NH, O, S(O), m (wherein m is 0, 1, or 2); for example, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, and the like.

[0057] The term "-CONH-" means -C(=O)-NH-, which can specifically mean C(=O) and Connected or NH and Connected, preferably C(=O) and connected.

[0058] The term "amino" alone or in combination means a primary amino group (-NH2), a secondary amino group (-NH-) or a tertiary amino group.

[0059] The term "C1-C 10 "Alkylamino" alone or in combination means an amino group as defined above, wherein the hydrogen atom of the amino group is replaced by at least one C1-C 10 Alkyl substituted, where "C1-C 10 "Alkyl" means as defined above, accordingly, "C1-C 10 “Alkylamino” includes methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, 2-butylamino, tert-butylamino, n-pentylamino, 2-pentylamino, 3-pentylamino, 2-methyl-2-butylamino, 3-methyl-2-butylamino, 3-methyl-1-butylamino, 2-methyl-1-butylamino, n-hexylamino, 2-hexylamino, 3-hexylamino, 2-methyl-2-pentylamino, 3-methyl-2-pentylamino, 4-methyl-2-pentylamino, 3-methyl-3-pentylamino, 2-methyl-3-pentylamino, 2,3-dimethyl-2-butylamino, 3,3-dimethyl-2-butylamino and the like. Particularly “C1-C 10 "Alkylamino" means methylamino, ethylamino, isopropylamino, tert-butylamino and the like.

[0060] The term "C3-C 12 "Cycloalkylamino" means, alone or in combination, an amino group as defined above, wherein the hydrogen atom of the amino group is replaced by at least one C3-C 12 Cycloalkyl substituted, "C3-C 12 "Cycloalkyl" means as defined above.

[0061] The term "isomer" includes all isomeric forms including enantiomers, diastereomers, tautomers and geometric isomers (including cis-trans isomers). Therefore, the single stereochemical isomers of the compounds designed in the present invention or mixtures of their enantiomers, diastereomers, tautomers or geometric isomers (or cis-trans isomers) all belong to the scope of the present invention.

[0062] The term "pharmaceutically acceptable salt" means that the compounds of the present invention exist in the form of their pharmaceutical salts, including acid addition salts and base addition salts. Pharmaceutically acceptable salts are described in pharmaceutically salts described by SM Berge in J. Pharmaceutical Sciences (volume 66: pages 1-19, 1977). In the present invention, pharmaceutically acceptable non-toxic acid addition salts represent salts formed by the compounds of the present invention and organic or inorganic acids, including but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc. Pharmaceutically acceptable non-toxic base addition salts refer to salts formed by the compounds of the present invention with organic or inorganic bases, including but not limited to alkali metal salts, such as lithium, sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic base salts, such as ammonium salts or N-containing organic bases. + (C 1-6 4-alkyl) salt, preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, magnesium carbonate, calcium carbonate, ammonia water, triethylamine, tetrabutylammonium hydroxide, etc.

[0063] The term "solvate" refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc. "Pharmaceutically acceptable salts" can be synthesized by general chemical methods.

[0064] The term "ester" is used to refer to organic esters, including monoesters, diesters, triesters, and more generally polyesters.

[0065] The term "prodrug" refers to a chemical derivative of the compound of the present invention, which is converted into the compound represented by the general formula I through a chemical reaction in vivo.

[0066] The term "isotopic derivative" refers to an isotopic derivative obtained by replacing the hydrogen atoms in the general formula (I) with 1 to 6 deuterium atoms (D), replacing the carbon atoms in the general formula (I) with 1 to 3 carbon 14 atoms ( 14 C) isotopic derivatives obtained by substitution.

[0067] The terms involved in the present invention are defined above. Those skilled in the art can also understand the above terms in combination with the prior art. The following is a further description based on the content of the present invention and the definitions of the terms.

[0068] In a preferred embodiment, the compound of formula (I) has the structure shown in formula (I-1):

[0069]

[0070] Among them, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , X, Y, m, n, p, and The definitions of are as given above for the compounds of formula (I).

[0071] In a preferred embodiment, the compound of formula (I) has the structure shown in formula (I-2):

[0072]

[0073] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , X, m, n, p, and The definitions of are as given above for the compounds of formula (I).

[0074] In a preferred embodiment, R 1 and R 2 are the same or different and are independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, substituted or unsubstituted groups: -NH2, C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkyloxy, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl; wherein the substituted -NH2, C1-C10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkyloxy, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclic group is selected from C1-C 10 Alkyl, C1-C 10 Alkylamino, halogen atoms, -NH2, -CN, -NO2, -OH, hydroxyl substituted C1-C 10 Alkylamino, C1-C 10 Alkoxy, C3-C8 alkylamino, C3-C 12 Cycloalkyl, 5-10 membered heteroaryl, C6-C 10 substituted by one or more substituents of aryl and 5-10 membered heterocyclic group; the heterocyclic group or heteroaryl group optionally contains 1-4 heteroatoms or heteroatom-containing groups, and the heteroatoms or heteroatom-containing groups are selected from S, O, N or C(O); or R 1 and R 2 To form a 3-8 membered saturated or unsaturated cycloalkyl or heterocyclic group, optionally, the 3-8 membered saturated or unsaturated cycloalkyl or heterocyclic group is substituted by 1-3 -OH, -NH2, -CN, NO2, halogen atoms, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 The saturated or unsaturated cycloalkyl or heterocyclic group is optionally substituted by a carbocyclic ring or a heterocyclic ring containing 1 to 3 heteroatoms or groups selected from N, NH, O, S, C(O), S(O).

[0075] In a more preferred embodiment, R 1 and R 2 The 5-6 membered heterocyclic group contains 1-3 heteroatoms selected from N, NH, O, and S. Optionally, the 5-6 membered heterocyclic group is substituted by 1-3 halogen atoms, -OH, -NH2, C1-C 10 Alkylamino, C1-C 10 Alkyl or C1-C 10 Alkoxy substituted.

[0076] In a preferred embodiment, the above compounds Selected from C6-C 10Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; wherein the 5-10 membered heteroaryl or 3-12 membered heterocyclyl contains 1-3 heteroatoms or groups selected from N, NH, O, S, C(O), S(O).

[0077] In a preferred embodiment, the compound of formula (I) has the structure shown in formula (I-3):

[0078]

[0079] Among them, R 1 and R 2 Forming a 5-6 membered heterocyclic group, the heterocyclic group contains 1-3 heteroatoms selected from N, NH, O, S, and optionally, the 5-6 membered heterocyclic group is substituted by 1-3 -OH, -NH2, C1-C6 alkyl or C1-C6 alkoxy groups;

[0080] Selected from C6-C 10 Aryl or 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryl contains 1-3 heteroatoms or groups selected from N, NH, O, S, C(O), S(O).

[0081] In a preferred embodiment, R 4 Each is the same or different and is independently selected from H, D, -NH2, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl.

[0082] In a preferred embodiment, R 5 are the same or different and are independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, -NH2, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; or two adjacent R 5 It can form a 3-6 membered saturated or unsaturated cyclic group, optionally, the 3-6 membered saturated or unsaturated cyclic group is substituted by 1-3 -OH, -NH2, -CN, halogen atoms, C1-C 10 Alkyl, C1-C 10Alkoxy, C3-C 12 Cycloalkylamino, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkylamino, C6-C 10 aryl or 5-10 membered heteroaryl.

[0083] In a preferred embodiment, each R 5 are the same or different and are independently selected from H, D, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, -NH2; or two adjacent R 5 A 5-6 membered saturated cyclic group may be formed, wherein the 5-6 membered saturated cyclic group may be substituted by 1-2 -OH, -NH2, -CN, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkylamino group, a C1-C6 alkylamino group, a C3-C6 cycloalkyl group, a halogenated C1-C6 alkylamino group, a C6-C 10 aryl or 5-6 membered heteroaryl.

[0084] In a preferred embodiment, R 1 and R 2 To form a 3-6 membered saturated or unsaturated cyclic group, optionally, the 3-6 membered saturated or unsaturated cycloalkyl or heterocyclic group is substituted by 1-3 -OH, -NH2, -CN, NO2, halogen atoms, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, C6-C 10 substituted by aryl or 5-10 membered heteroaryl;

[0085] R 3 Selected from H;

[0086] X is selected from a chemical bond, -NH-, -CONH-;

[0087] Y is selected from CR 0 , where R 0 Any one of H, D, -OH, -CN, halogen atoms, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 12 Cycloalkylamino, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkylamino;

[0088] Every R 4Each is the same or different and is independently selected from H, D, -NH2, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, a substituted or unsubstituted group of the following: C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, preferably, the 3-12 membered heterocyclic group is selected from aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactam, valerolactam, caprolactam, butyrolactone, valerolactonyl, caprolactone, succinimide or More preferably, the 3-12 membered heterocyclic group is selected from butyrolactam, pyrrolidinyl, succinimide or Any of;

[0089] Selected from C6-C 10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclic group; wherein the 5-10 membered heteroaryl, 3-12 membered heterocyclic group contains 1-3 heteroatoms or groups selected from N, NH, O, S, C(O);

[0090] Every R 5 Each is the same or different and is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, a substituted or unsubstituted group of the following: C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, -NH2, C3-C6 cycloalkyl, a 3-6 membered heterocyclic group, a C6-C 10 Aryl or 5-10 membered heteroaryl, or any two adjacent R 5 Form a 5-6 membered saturated ring, optionally, the 5-6 membered saturated ring is substituted by 1-3 -OH, -NH2, -CN, halogen atoms, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkylamino, C1-C6 alkylamino, C3-C6 cycloalkyl, halogenated C1-C6 alkylamino, C6-C 10 substituted by aryl or 5-10 membered heteroaryl;

[0091] R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 independently selected from H, D, halogen atoms, -CN, -COOH, -CHO, -OH, -NO2, -NH2, C1-C10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkyloxy, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl;

[0092] m is 1 or 2;

[0093] n is 1 or 2 or 3;

[0094] p is 0 or 1.

[0095] In a more preferred embodiment, R 1 and R 2 Forming a 5-6 membered saturated cyclic group, preferably a cyclohexane ring, a cyclopentane ring, a tetrahydrofuran ring, a tetrahydropyrrole ring, a tetrahydrothiophene ring, a tetrahydropyran ring, optionally, the 5-6 membered saturated cyclic group is substituted by 1-3 -OH, -NH2, -CN, NO2, a halogen atom, a methyl group, or a methoxy group;

[0096] R 3 Selected from H;

[0097] X is selected from a chemical bond, -NH-, -CONH-;

[0098] Y is selected from CR 0 , where R 0 Optionally selected from H, halogen atoms, C1-C6 alkyl, C1-C6 alkoxy;

[0099] Every R 4 Each is the same or different, and each is independently selected from H, -NH2, a halogen atom, -CN, a C1-C6 alkyl group, a C1-C6 alkylamino group, and a C1-C6 alkoxy group;

[0100] Selected from C6-C 10 Aryl, 5-10 membered heteroaryl, 5-12 membered heterocyclic group, preferably C6-C 10 Aryl, 5-9 membered heteroaryl; wherein the 5-10 membered heteroaryl, 5-12 membered heterocyclic group contains 1-3 heteroatoms or groups selected from N, NH, O, S, C(O);

[0101] Every R 5 are the same or different and are independently selected from H, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, a C1-C6 alkyl group, a C1-C6 alkoxy group, -NH2, or any two adjacent R 5Forming a 5-6 membered saturated ring, optionally, the 5-6 membered saturated ring is substituted by 1-3 -OH, -NH2, -CN, halogen atoms, C1-C6 alkyl, C1-C6 alkoxy;

[0102] R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 Independently selected from H, halogen atoms, -CN, -COOH, -CHO, -OH, -NO2, -NH2, C1-C6 alkyl, C1-C6 alkoxy;

[0103] m is 1 or 2;

[0104] n is 1 or 2;

[0105] p is 0 or 1.

[0106] In a more preferred embodiment, R 1 and R 2 Forming a cyclopentane, tetrahydrofuran, tetrahydropyrrole or tetrahydrothiophene ring, wherein the cyclopentane, tetrahydrofuran, tetrahydropyrrole or tetrahydrothiophene ring is optionally substituted by 1 to 3 -OH, -NH2, halogen atoms, methyl or methoxy groups;

[0107] R 3 Selected from H;

[0108] X is selected from a chemical bond, -NH-, -CONH-;

[0109] Y is selected from CR 0 , where R 0 Optionally selected from H, halogen atoms, C1-C6 alkyl, C1-C6 alkoxy;

[0110] Every R 4 Each is the same or different and is independently selected from H, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group;

[0111] is selected from phenyl, naphthyl or 5-10 membered heteroaryl or 5-12 membered heterocyclic group; wherein the 5-6 membered heteroaryl contains 1-3 heteroatoms selected from N, NH, O, S, and preferably, the 5-6 membered heteroaryl ring is selected from thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, benzothiophenyl, indolyl, benzimidazole any one of benzothiazolyl, benzofuranyl, quinolyl, isoquinolyl, quinazolinyl, indazolyl, indole [1,2-a] pyrazinyl, 4,7-diazaindole, pyrazolopyrimidinyl, imidazopyrimidinyl, oxazolopyrimidinyl, isoxazolopyrimidinyl, imidazopyrazinyl, pyrazolopyrazine, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, pyridopyrimidonyl, benzoxazolyl or benzothiazolyl; the 5-12 membered heterocyclic group is selected from butyrolactam, pyrrolidinyl, succinimidyl or Any of .

[0112] Every R 5 are the same or different and are independently selected from H, a halogen atom, -CONH2, -COOH, -CN, a C1-C6 alkyl group, a C1-C6 alkyl group substituted with a hydroxyl group, a C1-C6 alkyl group substituted with an amino group, a C1-C6 alkoxy group, -NH2, or any two adjacent R 5 to form cyclohexane or cyclopentane;

[0113] R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 All are H;

[0114] m is 1;

[0115] n is 1 or 2 or 3;

[0116] p is 1.

[0117] In a preferred embodiment, the compound of formula (I) has a structure shown in formula (I-4):

[0118]

[0119] X is selected from a chemical bond, -NH-, -CONH-;

[0120] R 4 Selected from H, D, halogen atoms, -CN, -COOH, -CHO, -OH, -NO2, -CONHR 14 or-NHCOR 15, substituted or unsubstituted following groups: -NH2, C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl; wherein R 14 and R 15 Each independently selected from C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the substitution is selected from C1-C 10 Alkyl, halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 The aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group is substituted with one or more substituents, wherein the substituents are optionally substituted with 1-3 C1-C 10 Alkyl, halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C3-C 12 substituted by cycloalkyl;

[0121] Selected from C6-C 10 Aryl, 5-10 membered heteroaryl, C4-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 14 Bridged or spirocyclic groups, C6-C 14 bridged heterocyclic group or spiro heterocyclic group; wherein the 5-10 membered heteroaryl, 3-12 membered heterocyclic group, C6-C 14 The bridged heterocyclic group or spiro heterocyclic group contains 1 to 3 heteroatoms or groups selected from N, NH, O, S, C(O), S(O);

[0122] Every R 5 Each is the same or different and is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, an aminoacyl group, or a substituted or unsubstituted group of the following: C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, -NH2, C3-C 12Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 aryl or 5-10 membered heteroaryl, the substitution is selected from C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, hydroxyl-C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, 5-10 membered heteroaryl, C6-C 10 substituted by one or more substituents in an aryl or 3-12 membered heterocyclic group; or any two adjacent R 5 Form a 3-6 membered saturated or unsaturated ring, optionally, the 3-6 membered saturated or unsaturated ring is 1-3 -OH, -NH2, -CN, halogen atoms, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 12 Cycloalkylamino, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkylamino, C6-C 10 substituted by aryl or 5-10 membered heteroaryl;

[0123] n is 0, 1, 2 or 3;

[0124] In a preferred embodiment, R 4 is selected from H, D, a halogen atom, -CN;

[0125] is selected from phenyl, naphthyl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0126] wherein the 5-10 membered heteroaryl group and the 3-12 membered heterocyclic group contain 1-3 heteroatoms or groups selected from N, NH, O, S, and C(O),

[0127] Preferably, the 5-10 membered heteroaromatic ring is selected from thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolyl, isoquinolyl, quinazolinyl, indazolyl, indole [1,2-a] pyrazinyl, 4,7-diazaindole, pyrazolopyrimidinyl, imidazopyrimidinyl, oxazolopyrimidinyl , any one of isoxazolopyrimidinyl, imidazopyrazinyl, pyrazolopyrazine, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, pyridopyrimidonyl, benzoxazolyl, and benzothiazolyl; the 3-12 membered heterocyclic group is selected from aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactam, valerolactam, caprolactam, butyrolactone, valerolactonyl, caprolactone, succinimide or More preferably, the 3-12 membered heterocyclic group is selected from butyrolactam, pyrrolidinyl, succinimidyl or Any of;

[0128] Every R 5 Each is the same or different and is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, an aminoacyl group, or a substituted or unsubstituted group of the following: C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, -NH2, the substitution is selected from C1-C 10 Alkyl, halogen atoms, -NH2, -CN, -OH, -NO2 or one or more substituents; or any two adjacent R 5 Form a 3-6 membered saturated or unsaturated ring, optionally, the 3-6 membered saturated or unsaturated ring is 1-3 -OH, -NH2, -CN, halogen atoms, C1-C 10 Alkyl, C1-C 10 Alkoxy substituted.

[0129] In a more preferred embodiment, in the structure shown in formula (I-4), the methyl and amino groups substituted on the tetrahydrofuran ring are flipped to the same side. In a more preferred embodiment, the compound of formula (I) is selected from:

[0130]

[0131]

[0132]

[0133]

[0134] The present invention also provides a pharmaceutical composition comprising any one of the above compounds of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled substance thereof.

[0135] In some embodiments of the present invention, the above-mentioned pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0136] In a more preferred embodiment, the above pharmaceutical composition further comprises:

[0137] - a pharmaceutically acceptable carrier;

[0138] - adjuvants; and / or

[0139] -excipient.

[0140] The present invention also provides a method for preparing the above-mentioned pharmaceutical composition, which comprises mixing a compound of formula (I) as described above or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled substance thereof with a pharmaceutically acceptable carrier, adjuvant (such as a diluent) and / or excipient.

[0141] The present invention also provides a pharmaceutical preparation, which includes any of the above-mentioned compounds of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label or pharmaceutical composition, and the preparation can be in a form suitable for oral administration, such as tablets, lozenges, lozenges, water or oil suspensions, dispersible powders or granules, leaves, hard or soft capsules or syrups. Oral compositions can be prepared according to any known method for preparing pharmaceutical compositions in the art, and such compositions can contain one or more ingredients selected from the following: sweeteners, flavoring agents, colorants and preservatives to provide pleasing and palatable pharmaceutical preparations. Tablets contain active ingredients and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets for mixing. These excipients can be inert excipients, granulating agents and disintegrants, and lubricants. These tablets can be uncoated or can be coated by known techniques for masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time. For example, water-soluble taste masking substances can be used.

[0142] Oral preparations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, or wherein the active ingredient is mixed with a water-soluble carrier.

[0143] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents; dispersants or wetting agents may be naturally occurring phospholipids. Aqueous suspensions may also contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweeteners.

[0144] Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil or mineral oil. Oil suspensions may contain a thickening agent, and may be supplemented with the above-mentioned sweeteners and flavoring agents to provide a palatable preparation. These compositions may be preserved by the addition of an antioxidant.

[0145] Dispersible powders and granules suitable for preparing aqueous suspensions can be prepared by adding water to provide the active ingredient and a dispersant or wetting agent, suspending agent or one or more preservatives for mixing, suitable dispersants or wetting agents and suspending agents can illustrate the above examples. Other excipients such as sweeteners, flavoring agents and coloring agents may also be included, and these compositions may be preserved by adding antioxidants such as ascorbic acid.

[0146] The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids. Available sweeteners. Such preparations may also contain a demulcent, a preservative, a colorant and an antioxidant.

[0147] The pharmaceutical preparations of the present invention may be in the form of sterile injectable aqueous solutions. Acceptable solvents or solvents that may also be used include water, Glee's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injection solution or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred that the solution and microemulsion be administered in a manner that maintains a constant circulating concentration of the compound of the present invention. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used, an example of which is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

[0148] The pharmaceutical preparation of the present invention can be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared according to known techniques using the above-mentioned suitable dispersants or wetting agents and suspending agents. The sterile injection preparation can also be a sterile injection solution or suspension prepared by a non-toxic diluent or formulation that can be introduced parenterally. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. In addition, fatty acids can also be used to prepare injections.

[0149] The compounds of this invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will melt to release the drug therein.

[0150] As is well known to those skilled in the art, the dosage of a drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, or the age of the patient, or the weight of the patient, or the health condition of the patient, or the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the best treatment method such as the mode of treatment, the daily dosage of the compound of formula (I) or the type of pharmaceutically acceptable salt can be verified according to traditional treatment plans.

[0151] The present invention also provides the above-mentioned compound of formula (I) or its pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label, or the pharmaceutical composition, or the pharmaceutical preparation, which is used for preventing and treating diseases or conditions mediated or dependent on non-receptor protein tyrosine phosphatase (SHP2, Src Homolgy-2phospahtase).

[0152] The present invention also provides the use of the above-mentioned compound of formula (I) or its pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label, or the pharmaceutical composition, or the pharmaceutical preparation for preventing and / or treating diseases or conditions mediated or dependent on non-receptor protein tyrosine phosphatase.

[0153] The present invention also provides the use of the above-mentioned compound of formula (I) or its pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label, or the pharmaceutical composition, or the pharmaceutical preparation in the preparation of drugs for preventing and / or treating diseases or conditions mediated or dependent on non-receptor protein tyrosine phosphatase.

[0154] Wherein, the above-mentioned non-receptor protein tyrosine phosphatase-mediated or dependent diseases or conditions are selected from cancer, central nervous system defects, cardiovascular system defects, blood system defects, immune or inflammatory diseases, infectious diseases, metabolic defects, neurological defects, mental defects and appreciation defects. Wherein, the cancer can be breast cancer, endometrial cancer, head and neck cancer, skin cancer, lung cancer, liver cancer, leukemia, ovarian cancer, cervical cancer, prostate cancer, bile duct cancer, esophageal cancer, pancreatic cancer, colorectal cancer, brain glioma, leiomyoma fallopian tube tumor, kidney cancer, myeloma, bone cancer, thyroid cancer. The central nervous system defect can be alcoholism or migraine; the cardiovascular system defect can be aortic aneurysm, susceptible myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension; the blood system defect can be deep vein thrombosis; the immune and inflammatory diseases can be arthritis, multiple sclerosis, and cirrhosis; the susceptible infectious diseases can be hepatitis B, chronic hepatitis, osteopenia, and osteoporosis; the neurological defect can be Alzheimer's disease, Parkinson's disease, migraine, and vertigo; the mental defect can be anorexia nervosa, attention deficit hyperactivity disorder, dementia, severe depressive disorder, and psychosis; the reproductive defect can be age of menarche, endometriosis, infertility, etc.

[0155] The present invention also provides a method for preventing and / or treating diseases or conditions mediated or dependent on non-receptor protein tyrosine phosphatases, which comprises the following steps: administering a therapeutically effective amount of the above-mentioned compound of formula (I) or its pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label, or the pharmaceutical composition, or the pharmaceutical preparation to a patient in need thereof.

[0156] The term "therapeutically effective amount" refers to a dose of a pharmaceutically active ingredient that is capable of inducing a biological or medical response in a cell, tissue, organ or organism (eg, a patient).

[0157] The term "administer" refers to the process of applying a pharmaceutically active ingredient (such as a compound of the present invention) or a pharmaceutical composition comprising a pharmaceutically active ingredient (such as a pharmaceutical composition of the present invention) to a patient or its cells, tissues, organs, biological fluids, etc., so as to bring the pharmaceutically active ingredient or pharmaceutical composition into contact with the patient or its cells, tissues, organs, biological fluids, etc. Common modes of administration include (but are not limited to) oral administration, subcutaneous administration, intramuscular administration, subperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration, etc.

[0158] The term "in need of" refers to the physician's or other caregiver's judgment that the patient needs or will benefit from a preventive and / or therapeutic procedure, which judgment is based on various factors within the physician's or other caregiver's area of ​​expertise.

[0159] The term "patient" (or subject) refers to a human or a non-human animal (eg, a mammal).

[0160] The present invention also provides a drug combination, which comprises the above-mentioned compound of formula (I) or its pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label, or the pharmaceutical composition, or the pharmaceutical preparation and at least one additional therapeutic agent for preventing and / or treating non-receptor protein tyrosine phosphatase-mediated or dependent diseases or conditions.

[0161] The above-mentioned compound of formula (I) of the present invention or its pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label, or the pharmaceutical composition, or the pharmaceutical preparation can be used in combination with, but not limited to, the following compounds or antibodies, or can be used in antibody-drug conjugated form with antibody drugs.

[0162] The present invention also provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled product thereof. Several typical synthetic routes of the compound of formula I are described below to further describe the technical solution of the present invention. Specifically, it can be seen from the reaction route shown below:

[0163] (1) Compound Ia and Compound Ib react under the action of a base to obtain Compound Ic, wherein A in Ib is a halogen atom, preferably chlorine, bromine or iodine, and X is a chemical bond;

[0164] (2) Compound Ic is deprotected to obtain compound Id;

[0165] (3) Compound Id reacts with compound Ie to obtain compound If, wherein B in compound Ie is a halogen atom, preferably chlorine, bromine or iodine;

[0166] (4) Compound If and Ig react under the action of a base to obtain compound (I).

[0167] The synthetic route of the reaction is as follows:

[0168]

[0169] In a preferred embodiment, in step (1), the catalyst for the reaction is cuprous iodide and a base, and the base is preferably sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide or lithium tert-butoxide.

[0170] In a preferred embodiment, in step (2), the catalyst for the deprotection reaction is a protonic acid or a Lewis acid, preferably aluminum trichloride.

[0171] In a preferred embodiment, in step (3), the catalyst of the reaction is an organic base or an inorganic base catalyst, wherein the inorganic base is preferably sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, and the organic base is preferably triethylamine, diethylamine, diisopropylamine or N,N-diisopropylethylamine.

[0172] In a preferred embodiment, in step (4), the catalyst of the reaction is an organic base or an inorganic base catalyst, wherein the inorganic base is preferably sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, and the organic base is preferably triethylamine, diethylamine, diisopropylamine or N,N-diisopropylethylamine.

[0173] The present invention also provides another method for preparing compound Ic, wherein compound Ia1 and compound Ib are reacted to obtain compound Ic, and the reaction catalyst is a coupling reaction catalyst, preferably tetrakis(triphenylphosphine)palladium. The reaction scheme is as follows:

[0174]

[0175] The present invention also provides another method for synthesizing compound (I), comprising

[0176] (1) Compound Ih reacts with compound Ii to obtain compound Ij, wherein A in compound Ii is a halogen atom, preferably chlorine, bromine or iodine;

[0177] (2) Compound Ij reacts with compound Ik to obtain compound Il, wherein X in compound Il is -CONH-;

[0178] (3) Compound Il and compound Ig are reacted to obtain compound (I).

[0179] In a preferred embodiment, in step (1), the catalyst of the reaction is an organic base or an inorganic base, wherein the inorganic base is preferably sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, and the organic base is preferably triethylamine, diethylamine, diisopropylamine or N,N-diisopropylethylamine.

[0180] In a preferred embodiment, in step (2), the reaction catalyst is thionyl chloride and / or an organic base, and the organic base is preferably triethylamine, diethylamine, diisopropylamine or N,N-diisopropylethylamine, pyridine or 4-dimethylaminopyridine.

[0181] In a preferred embodiment, in step (2), the reaction catalyst is an organic base, and the organic base is preferably triethylamine, diethylamine, diisopropylamine, N,N-diisopropylethylamine, pyridine or 4-dimethylaminopyridine.

[0182] The synthetic route of the reaction is as follows:

[0183]

[0184] The present invention is further described in the following examples; however, these examples should not be construed as limiting the scope of the present invention.

[0185] Example 1

[0186]

[0187] To a solution of 1a (104 g, 1.0 mol) in dichloromethane (600 mL), imidazole (102 g, 1.5 mol) was added, and a solution of tert-butyldimethylsilane (165 g, 1.1 mol) in dichloromethane (200 mL) was added dropwise under ice-water cooling, and the mixture was reacted at room temperature for 16 hours. The reaction solution was diluted with dichloromethane, washed with water 3 times, and the organic phase was dried over anhydrous sodium sulfate. The desiccant was filtered and the filtrate was concentrated to obtain a crude product of 1b (237 g, yield 100%), which was directly used for the next step reaction.

[0188] 1 H NMR (CDCl3, 400MHz): δ4.32 (q, J=8.0Hz, 1H), 3.71 (s, 3H), 1.39 (d, J=8.0Hz3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H).

[0189]

[0190] Under an ice-water bath, diisobutylaluminum hydride (367 mL, 0.55 mol, 1.5 M toluene solution) was added dropwise to a solution of 1b (120 g, 0.55 mol) in dichloromethane (600 mL) and the reaction was allowed to proceed for 16 hours. Methanol (100 mL) was added dropwise to quench the reaction, and diatomaceous earth was added and stirred evenly. The mixture was filtered, and the filtrate was diluted with dichloromethane, washed with water 3 times, and the organic phase was dried over anhydrous sodium sulfate. The desiccant was filtered, the filtrate was concentrated, and the residue was purified by silica gel column (eluted with petroleum ether / ethyl acetate = 10 / 1) to obtain 1c (56 g, yield 54%).

[0191] 1 H NMR (CDCl3, 400MHz): δ9.61 (s, 1H), 4.08 (q, J = 8.0Hz, 1H), 1.27 (d, J = 8.0Hz3H), 0.91 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H).

[0192]

[0193] Under nitrogen protection, diisopropylamine (23.4 mL, 166 mmol) was dissolved in anhydrous tetrahydrofuran (220 mL), cooled to -20 ° C, and n-butyl lithium (64 mL, 160 mmol, 2.5 M n-hexane solution) was added dropwise. After reacting for 1 hour, a solution of N-tert-butyloxycarbonyl-4-piperidinylcarboxylic acid ethyl ester (27.5 g, 107 mmol) in anhydrous tetrahydrofuran (50 mL) was added dropwise. The temperature was raised to 0 ° C for 1 hour, and 1c (20.5 mL, 102 mmol) was added. The reaction was reacted at 0 ° C for 3 hours. The reaction was quenched with 5% sodium bicarbonate solution, extracted with ethyl acetate 3 times, and the organic phase was dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and the residue was purified by silica gel column (petroleum ether / ethyl acetate = 2 / 1) to obtain 1d (32.6 g, yield 72%). MS m / z [M+H] + :446.7.

[0194]

[0195] Under ice-water bath, lithium borohydride (2.3 g, 107 mmol) was added in batches to a solution of 1d (31.7 g, 71 mmol) in tetrahydrofuran (600 mL). After the addition, the mixture was reacted at room temperature for 16 hours. The mixture was cooled to 0°C in an ice-water bath, and a saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with ethyl acetate three times, and the organic phase was dried over anhydrous sodium sulfate. The desiccant was filtered, and the filtrate was concentrated to obtain a crude product of 1e (30.2 g, yield 100%), which was used directly in the next step.

[0196] MS m / z[M+H] + :404.5,[MH] - :402.4

[0197]

[0198] 1e (59.0 g, 146 mmol) was dissolved in tetrahydrofuran (600 mL), tetrabutylammonium fluoride (35 g, 109 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction, ethyl acetate was added to separate the layers, the aqueous phase was extracted until there was no product, the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered, the filtrate was concentrated under reduced pressure, and 1f (24 g, yield 57%) was obtained by column chromatography.

[0199] 1 H NMR (CDCl3, 400MHz): δ 3.94-4.00 (m, 1H), 3.65-3.81 (m, 5H), 3.07-3.15 (m, 2H), 1.60-1.71 (m, 4H), 1.45 (s, 9H), 1.33 (d, J = 4.0Hz, 3H). MS m / z[M+H] +:290.3,[MH] - :288.3.

[0200]

[0201] Sodium hydrogen (2.3 g, 57.44 mmol) was added to tetrahydrofuran (80 mL), cooled to -15 ° C, 1f (8.3 g, 28.72 mmol) in tetrahydrofuran (50 mL) solution was added dropwise, and p-toluenesulfonyl chloride (1.72 g, 9 mmol) in tetrahydrofuran (15 mL) solution was added dropwise, and the reaction was continued for 16 hours. The reaction solution was cooled to -15 ° C, saturated ammonium chloride solution was added dropwise until no bubbles were generated, ethyl acetate was added to separate the layers, the aqueous phase was extracted until no product was produced, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered, and the filtrate was concentrated under reduced pressure. 1g (5 g, yield 64%) was obtained by column chromatography.

[0202] 1 H NMR (CDCl3, 400MHz): δ4.08-4.14 (m, 1H), 3.01-3.80 (m, 7H), 1.68-1.81 (m, 4H), 1.46 (s, 9H), 1.26 (d, J = 8.0Hz, 3H).

[0203]

[0204] 1g (13.5g, 49.7mmol) was added to dichloromethane (160mL), and Dess-Martin periodinane (42g, 99mmol) was added in batches at -10°C, and the reaction was carried out at 0°C for 16 hours. Ether (500mL) was added, and a large amount of solid precipitated. It was filtered and washed once with ether (100mL). The filtrate was washed once with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution, and the organic phase was dried over anhydrous sodium sulfate. The desiccant was filtered, the filtrate was concentrated under reduced pressure, and 1h (5.5g, yield 41%) was obtained by column chromatography.

[0205] 1 H NMR (CDCl3, 400MHz): δ4.19 (d, J = 8.0 Hz, 1H), 3.83-3.92 (m, 4H), 2.96-3.16 (m, 2H), 1.55-1.79 (m, 4H), 1.46 (s, 9H), 1.32 (d, J = 8.0 Hz, 3H).

[0206]

[0207] 1h (20.0 g, 274.3 mmol) and R-(+)-tert-butylsulfenamide (33.2 g, 274.3 mmol) were dissolved in tetrahydrofuran (350 mL) solution, tetraethyl titanate (67.7 g, 297 mmol) was added, nitrogen was replaced, and the mixture was reacted at 100°C for 20 hours. After cooling to -25°C, methanol (30 mL) was added, and lithium borohydride (5.97 g, 274.3 mmol) was added in batches. After the addition, the mixture was reacted at -10°C for 45 minutes. Saturated ammonium chloride solution was added at -10°C, and a large amount of solids precipitated. The solids were filtered, and the filter cake was washed with ethyl acetate. The filtrate was separated, and the aqueous phase was extracted with ethyl acetate until there was no product. The organic phase was washed once with saturated brine, dried with sodium sulfate, and the desiccant was filtered. The organic phase was concentrated under reduced pressure and separated by column chromatography to obtain 1i (12.4 g, yield 59%).

[0208] 1 H NMR(CDCl3,400MHz): δ4.15-4.19(m,1H),3.63-3.88(m,4H),3.30-3.44(m,2H),2.9 2(s,1H),1.80(s,2H),1.60(s,2H),1.44(s,9H),1.25(s,9H),1.20(d,J=8.0Hz,3H). LCMS m / z[M+H] + :375.3,[MH] - :373.5.

[0209]

[0210] 1i (12.0 g, 32.1 mmol) was dissolved in methanol (150 mL), and a dioxane solution of HCl (15 mL, 4 M) was added, and the mixture was heated to 40°C, stirred for 1 hour, and the reaction was stopped. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain 1j (7.85 g, yield 100%).

[0211] 1 H NMR (DMSO, 400MHz): δ9.25(br,2H),8.38(br,3H),4.20-4.23(m,1H),3.81(d,J=8.0Hz,1H),3.62(d,J=8 .0Hz,1H),3.46(br,1H),3.14-3.23(m,2H),2.84-2.92(m,2H),1.69-2.01(m,4H),1.22(d,J=8.0Hz,3H). LCMS m / z[M+H] + :171.2.

[0212]

[0213] 1k (50 g, 0.3448 mol) was dissolved in N,N-dimethylformamide (500 mL), tert-butyl mercaptan (87 g, 0.9374 mol) and cesium carbonate (224 g, 0.6696 mol) were added, and the temperature was raised to 120°C under nitrogen protection for 24 hours. The reaction mixture was diluted with ethyl acetate and quenched with water. The organic phase was separated and washed five times with saturated brine, dried over sodium sulfate, and the desiccant was filtered. The organic phase was concentrated under reduced pressure to obtain an oily product 1l, and the product was directly used for the next step without purification.

[0214]

[0215] 1l (1 g, 4.65 mmol) was added to concentrated hydrochloric acid (2 mL), and an aqueous solution (10 mL) of sodium nitrite (0.25 g, 5.26 mmol) was added dropwise at -5°C, and stirred for 30 minutes. An aqueous solution (10 mL) of potassium iodide (1.08 g, 9.3 mmol) was added dropwise at -5°C. The reaction was stopped after 10 minutes, ethyl acetate was added, washed with water, dried over sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. Solid 1m (1 g, yield 66.7%) was obtained by column chromatography.

[0216]

[0217] Cuprous iodide (5.84 mg, 0.03 mmol) and potassium carbonate (169.6 mg, 1.2 mmol) were added to toluene (4 mL), replaced with nitrogen, and then N, N'-dimethylethylenediamine (5.4 mg, 0.06 mmol), 1m (200 mg, 0.61 mmol), 2-pyrrolidone (64.7 mg, 0.76 mmol) were added, and refluxed for 16 hours. Ethyl acetate was added for extraction, washed with water, dried with sodium sulfate, filtered, the organic phase was concentrated under reduced pressure, and solid 1n (6.1 mg, yield rate 71.8%) was obtained by column chromatography.

[0218] 1 H NMR (DMSO, 400MHz): δ7.67 (d, J=8.0Hz, 1H), 7.46-7.42 (m, 2H), 3.70-3.67 (m ,2H),2.44-2.40(t,J=8.0Hz,2H),2.16-2.13(t,J=8.0Hz,2H),1.33(s,9H). LCMS m / z[M+H] + :284.7.

[0219]

[0220] Aluminum trichloride (424 mg, 3.3 mmol) was added to anhydrous dichloromethane (20 mL), stirred for 10 minutes, and 1n (300 mg, 1 mmol) was added. After 3 hours, the reaction solution was poured into ice water, extracted with dichloromethane, dried with sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to obtain an oily substance 1o (182 mg, yield 80%).

[0221] LCMS m / z[M+H] + :228.4

[0222]

[0223] 1o (286 mg, 1.26 mmol) was dissolved in isopropanol (5 mL), and then dichloropyrazine (376 mg, 2.5 mmol) and diisopropylamine (323 mg, 2.5 mmol) were added. The atmosphere was replaced with nitrogen and the reaction was continued at 80°C overnight. After cooling, the mixture was concentrated and subjected to column chromatography to obtain a yellow oily substance 1p (400 mg). LCMS m / z [M+H] + :340.3.

[0224]

[0225] 1p (413 mg, 1.22 mmol), 1j (417 mg, 2.5 mmol), N,N-diisopropylethylamine (317 mg, 2.5 mmol) were dissolved in N-methylpyrrolidone (5 mL). The mixture was replaced with nitrogen and reacted at 100°C overnight. The solvent was spin-dried to directly prepare trifluoroacetate, neutralized with sodium bicarbonate, extracted with dichloromethane, dried and concentrated, and freeze-dried to obtain the target product 1 (115 mg, 20% yield for the nth and oth steps).

[0226] 1 H NMR (DMSO, 400MHz): δ8.45(s,1H),8.27(s,1H),7.30-7.22(m,2H),6.82(d,J=8.0Hz,1H),4.09-4.06(m,1H),3.89(m,2H),3.69-3.67(m,3H), 3.50-3.48(m,2H),2.92-2.91(m,1H),2.43(d,J=8.0Hz,2H),2.15(m,2 H), 1.77 (m, 1H), 1.66 (m, 1H), 1.57-1.54 (m, 3H), 1.09 (d, J = 4.0Hz, 3H). MS m / z[M+H] + :474.7.

[0227] Example 2

[0228]

[0229]

[0230] 2a (1 g, 4.65 mmol) and 11 (0.64 g, 5.58 mmol) were dissolved in toluene (10 mL), and then sodium tert-butoxide (0.63 g, 6.51 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (28 mg) were added, and the atmosphere was replaced with nitrogen three times. Tris(dibenzylidene indeneacetone)dipalladium (39 mg) was added, and the mixture was reacted at 120° C. for 1 hour. After cooling to 20° C., water and ethyl acetate were added, and the layers were separated. The aqueous phase was extracted twice with ethyl acetate, dried over sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. 2b (660 mg, yield 48.5%) was obtained by column chromatography.

[0231] 1 H NMR (CDCl3, 400MHz): δ8.34(d,J=8.0Hz,1H),8.29(s,1H),8.20(d,J=4.0Hz,1H),8.09 (d,J=4.0Hz,1H),7.37(d,J=8.0Hz,1H),7.26-7.30(m,1H),7.19(s,1H),1.38(s,9H). LCMS m / z[M+H] + :294.1.

[0232]

[0233] 2b (0.44 g) was dissolved in concentrated hydrochloric acid (22 mL) and reacted at 50°C for 2 hours. The mixture was cooled to 20°C and quenched with sodium bicarbonate until neutral. The aqueous phase was extracted with ethyl acetate three times, dried over sodium sulfate, the desiccant was filtered, and the mixture was concentrated under reduced pressure. 2c (193 mg, yield 54.2%) was obtained by column chromatography.

[0234] LCMS m / z[M+H] + :238.0,[MH] - :236.0.

[0235]

[0236] 2c (160 mg, 0.675 mmol) was dissolved in acetonitrile (2 mL), and then 2,5-dichloropyrazine (201 mg, 1.35 mmol) and potassium carbonate (279 mg, 2.025 mmol) were added, and the temperature was raised to 80°C for 2 hours. The mixture was cooled to 20°C and filtered, and the filtrate was concentrated to dryness under reduced pressure, and 2d (62 mg, yield 26.3%) was obtained by column chromatography.

[0237] 1H NMR (DMSO, 400MHz): δ9.06 (s, 1H), 8.67 (d, J = 4.0Hz, 1H), 8.42 (d, J = 4.0Hz, 1H), 8 .40(d,J=4.0Hz,1H),8.08-8.11(m,2H),8.01(d,J=4.0Hz,1H),7.40-7.43(m,2H). LCMS m / z[M+H] + :350.0,[MH] - :348.0.

[0238]

[0239] 2d (462 mg, 1.83 mmol), 1j (622 mg, 3.66 mmol), N,N-diisopropylethylamine (944 mg, 7.32 mmol), N-methylpyrrolidone (10 mL) were added to the reaction bottle and reacted overnight at 120°C. The crude product was concentrated by oil pump and directly prepared and concentrated to obtain the target product 2 (150 mg, yield 23%).

[0240] 1 H NMR (DMSO, 400MHz): δ8.97 (s, 1H), 8.43 (d, J = 4.0Hz, 1H), 8.39 (d, J = 2.0Hz, 1H), 8.26 (d, J = 4.0Hz, 1H), 8. 09(dd,J1=4.0Hz,J2=2.0Hz,1H),7.98(d,J=2.0Hz,1H),7.76(dd,J1=4.0Hz,J2=2.0Hz,1H),7.19(t,J=8.0 Hz,1H),6.59(dd,J1=4.0Hz,J2=2.0Hz,1H),4.04-4.10(m,1H),3.85-3.93(m,2H),3.67(d,J=8.0Hz,1H), 3.48(d,J=8.0Hz,1H),3.38-3.46(m,2H),2.91(d,J=2.0Hz,1H),1.41-1.79(m,6H),1.08(d,J=2.0Hz,3H). MS m / z[M+H] + :484.2.

[0241] Example 3

[0242]

[0243]

[0244] 3a (530 mg, 7.68 mmol) was added to N,N-dimethylformamide (50 mL), and then 1m (5 g, 15.36 mmol), lithium tert-butoxide (1.23 g, 15.36 mmol), and iodide (146 mg, 0.768 mmol) were added, and the mixture was placed in a preheated oil bath at 140°C, reacted for 20 minutes, cooled to room temperature, and water was added. The mixture was extracted with ethyl acetate, dried over sodium sulfate, the desiccant was filtered, and the mixture was concentrated under reduced pressure. 3b (980 mg, yield 49%) was obtained after column chromatography.

[0245] 1 H NMR (CDCl3, 400MHz): δ7.92 (dd, J=8.0Hz, 1H), 7.81 (s, 1H), 7.78 (dd, J=8.0Hz, 1H), 7.36-7.32 (m, 2H), 1.38 (s, 9H).

[0246]

[0247] 3b (1.6 g, 5.99 mmol) was dissolved in toluene (32 mL), anhydrous aluminum chloride (3.2 g, 23.97 mmol) was added, and the mixture was stirred at room temperature for 1 hour under nitrogen protection. Ice water was added to quench the mixture, and the layers were extracted with ethyl acetate and dried over sodium sulfate. The desiccant was filtered and concentrated under reduced pressure to obtain a crude product 3c (2.1 g, yield 100%), which was directly used in the next step.

[0248]

[0249] 2,5-Dibromopyrazine (2.77 g, 11.94 mmol) was added to isopropanol (30 mL), and the mixture was heated to 88°C with stirring under nitrogen protection. (3c / isopropanol / N,N-diisopropylethylamine) (1.26 g, 5.97 mmol / 15 mL / 1.5 g, 11.94 mmol) was slowly added dropwise for 1 hour. The mixture was cooled and filtered, washed with ethyl acetate, washed with water, dried with sodium sulfate, the drying agent was filtered, concentrated under reduced pressure, and purified by column to obtain 3d (380 mg, yield 17.3%).

[0250] 1 H NMR (CDCl3, 400MHz): δ8.45 (s, 1H), 8.14 (s, 1H), 8.07 (d, J = 8.0Hz, 1H), 7.81 (s,1H),7.76(d,J=8.0Hz,1H),7.43(t,J=8.0Hz,1H),7.34(d,J=4.0Hz,1H).

[0251]

[0252] 3d (727 mg, 1.9375 mmol), 1j (1.1 g, 3.947 mmol), potassium phosphate (1.4 g, 6.6 mmol) were added to isopropanol (50 mL), the atmosphere was replaced with nitrogen, the temperature was raised to 95°C and stirred for 16 hours. The mixture was concentrated under reduced pressure, dichloromethane and water were added to separate the layers, extracted with dichloromethane twice, dried over sodium sulfate, the desiccant was filtered, the mixture was concentrated under reduced pressure to dryness, and the target product 3 (300 mg, yield 48%) was obtained by column chromatography.

[0253] 1 H NMR (DMSO, 400MHz): δ8.44(s,1H),8.32(s,1H),8.28(s,1H),7.71(d,J=8.0Hz,1H),7.46(s,1H),7.36(t,J=8.0Hz,1H),6.98(d,J=8.0Hz, 1H), 4.04 (m, 1H), 3.87 (m, 2H), 3.67 (d, J = 8.0Hz, 1H), 3.49-3.32 (m, 3H), 2.90 (d, J = 8.0Hz, 1H), 1.74-1.43 (m, 6H), 1.07 (d, J = 8.0Hz, 3H). LCMS m / z[M+H + ]:458.3.

[0254] Example 4

[0255]

[0256] 4a (22 mg, 0.31 mmol) was added to xylene (2 mL), and then 1m (100 mg, 0.31 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (10 mg, 0.031 mmol), potassium tert-butoxide (103 mg, 0.93 mmol), chloro(2-dicyclohexylphosphino-2',6'-di-I-propoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II)-methyl tert-butyl ether (10 mg, 0.031 mmol) were added, the temperature was raised to 120°C, the reaction was carried out for 18 hours, the reaction was concentrated, and 4b (41 mg, yield 50%) was obtained.

[0257]

[0258] 4c was obtained by following the method for synthesizing 3c.

[0259]

[0260] 4d was obtained by the method of synthesizing 3d.

[0261] 1H NMR (CDCl3, 400MHz): δ 8.45 (s, 1H), 7.95 (s, 1H), 7.18 (m, 2H), 7.01 (m, 1H), 3.39 (m, 4H), 1.96 (m, 4H).

[0262]

[0263] The target product 4 was obtained according to the method of synthesis 3.

[0264] 1 H NMR (DMSO, 400MHz): δ8.40(s,1H),8.19(s,1H),7.02(t,J=8.0Hz,1H),6.78(d,J=8.0Hz,1H),6.26(d,J=8.0 Hz,1H),4.09(m,1H),3.88(m,2H),3.68(d,J=8.0Hz,1H),3.49-3.26(m,7H),2.92(d,J=4.0Hz,1H),2.10(br s, 2H), 1.84 (m, 4H), 1.74-1.43 (m, 4H), 1.06 (d, J = 8.0Hz, 3H). LCMS m / z[M+H + ]:460.3.

[0265] Example 5

[0266]

[0267] 5a (1 g, 6.25 mmol) was added to toluene (16 mL), followed by hexabutylditin (3.61 g, 6.25 mmol) and tetrakistriphenylphosphine palladium (358 mg, 0.312 mmol). The temperature was raised to 115°C and the reaction was continued for 4.5 hours. The mixture was concentrated and column-filtered to obtain 5b (489 mg, yield 21%).

[0268]

[0269] 5b (389 mg, 1.046 mmol) was added to xylene (16 mL), and then 1m (340 mg, 1.046 mmol) and tetrakistriphenylphosphine palladium (60 mg, 0.0522 mmol) were added. The temperature was raised to 155°C for 2 hours, and the mixture was concentrated and passed through a column to obtain 5c (216 mg, yield 74%).

[0270]

[0271] 5c (100 mg, 0.3571 mmol) was dissolved in toluene (3.4 mL), and anhydrous aluminum chloride (218 mg, 1.428 mmol) was added. The mixture was stirred at room temperature for 1 hour under nitrogen protection, quenched with ice water, extracted with ethyl acetate, washed with water, dried over sodium sulfate, the desiccant was filtered out, and concentrated under reduced pressure to give a crude product of 5d.

[0272]

[0273] 2,5-Dibromopyrazine (195 mg, 0.7142 mmol) was dissolved in isopropanol (3 mL), and the temperature was raised to 88°C under nitrogen protection. A mixed solution of 5d (0.3571 mmol) / isopropanol (1.6 mL) / N,N-diisopropylethylamine (106 mg, 0.7142 mmol) was slowly added dropwise over 0.5 hours, and stirred at 88°C for 16 hours. The mixture was cooled, extracted with ethyl acetate, dried over sodium sulfate, the desiccant was filtered, concentrated under reduced pressure, and purified by column to obtain 5e (58 mg, yield 43%).

[0274] 1 H NMR (CDCl3, 400MHz): δ8.45(s,1H),8.03(s,1H),7.90(d,J=8.0Hz,1H),7.66(d,J= 8.0Hz,1H),7.42(s,1H),7.36(t,J=8.0Hz,1H),6.74(d,J=4.0Hz,1H),3.98(s,3H).

[0275]

[0276] 5e (500 mg, 1.316 mmol), 1j (1.1 g, 3.947 mmol), potassium phosphate (1.4 g, 6.6 mmol) were added to isopropanol (50 mL), replaced with nitrogen, heated to 95°C and stirred for 16 hours. Concentrated, water was added, extracted twice with dichloromethane, dried with sodium sulfate, the desiccant was filtered, concentrated to dryness under reduced pressure, and crystallized with ethyl acetate to obtain the target product 5 (300 mg, yield 48%).

[0277] 1H NMR (DMSO, 400MHz): δ8.45(d,J=4.0Hz,1H),8.27(d,J=4.0Hz,1H),7.79(s,1H),7.50(d,J=8.0Hz,1H),7.23(t,J=8.0Hz 1H),6.80(d,J=8.0Hz,1H),6.66(d,J=4.0Hz,1H),4.07(m,1H),3.90(m,5H),3.67(d,J=8.0Hz,1H), 3.46(d,J=8.0Hz,1H),3.39(m,2H),2.90(d,J=4.0Hz,1H),1.77-1.41(m,6H),1.07(d,J=8.0Hz,3H). LCMS m / z [M+H + ]:471.3.

[0278] Example 6

[0279]

[0280]

[0281] Diisopropylamine (4.65 g, 46 mmol) was dissolved in tetrahydrofuran (50 mL), and n-butyl lithium (18.4 mL, 46 mmol) was added under ice-water bath, and the mixture was reacted for 15 minutes under ice-water bath, and then n-butyltin hydride (13.35 g, 46 mmol) was added dropwise, and the reaction was continued for 20 minutes. The mixture was cooled to -78°C, and 2a (5 g, 44 mmol, in 100 mL THF) was slowly added dropwise, and the mixture was reacted at -78°C for 4 hours. The mixture was heated to -40°C, and saturated potassium fluoride aqueous solution was added dropwise to quench the mixture. The mixture was extracted with ethyl acetate, dried over sodium sulfate, the desiccant was filtered, and the mixture was concentrated under reduced pressure. The mixture was passed through a column to obtain 6b (7.4 g, yield 46%).

[0282] 1 H NMR (CDCl3, 400MHz): δ8.71-8.73 (m, 1H), 8.57 (d, J = 4.0Hz 1H),8.36-8.40(m,1H),1.54-1.62(m,6H),1.30-1.39(m,6H),1.16-1.20(m,6H),0.90(t,J=8.0Hz 9H).

[0283]

[0284] 6b (6.8 g, 18.4 mmol) and 1m (5 g, 15.3 mmol) were dissolved in xylene (50 mL), and tetrakis(triphenylphosphine)palladium (1.78 g, 1.3 mmol) was added. The mixture was replaced with nitrogen and heated to 150°C for 6 hours. After cooling, the solvent was dried and passed through a column to obtain 6c (4.2 g, yield 99%).

[0285]

[0286] 6c (500 mg, 1.8 mmol) was dissolved in toluene (5 mL), and then aluminum chloride (957 mg, 7.2 mmol) was added in batches under an ice-water bath, and the mixture was reacted at room temperature for 1 hour. Water was added to quench the mixture, and the mixture was extracted with ethyl acetate and dried over sodium sulfate. The desiccant was filtered and the mixture was concentrated under reduced pressure to obtain 6d, which was directly used in the next step.

[0287]

[0288] To isopropanol (5 mL) were added 6d (280 mg, 1.26 mmol), dichloropyrazine (376 mg, 2.5 mmol), and diisopropylamine (323 mg, 2.5 mmol), and the atmosphere was replaced with nitrogen three times. The temperature was raised to 80 °C and the reaction was carried out for 16 hours. After cooling, the solvent was dried and passed through a column to obtain 6e (400 mg, yield 95%).

[0289] 1 H NMR (CDCl3, 400MHz): δ8.95 (s, 1H), 8.71-8.72 (m, 1H), 8.61 (d, J = 4.0Hz 1H),8.40(s,1H),8.18(s,1H),7.78-7.80(m,1H),7.68-7.70(m,1H),7.47-7.51(m,1H).

[0290]

[0291] 6e (410 mg, 1.22 mmol) was dissolved in N-methylpyrrolidone (10 mL), and then 1j (417 mg, 2.5 mmol) and diisopropylamine (317 mg, 2.5 mmol) were added. The mixture was replaced with nitrogen three times, and the temperature was raised to 100°C for reaction for 16 hours. The solvent was directly dried and freeze-dried to obtain the target product 6 (120 mg, yield 21%).

[0292] 1H NMR (DMSO, 400MHz): δ8.92 (s, 1H), 8.79-8.80 (m, 1H), 8.71-8.72 (d, J = 4.0Hz1H), 8.46 (s, 1H), 8.30 ( s,1H),7.36-7.43(m,2H),7.00-7.02(m,1H),4.06-4.09(m,1H),3.89-3.91(m,2H),3.69(d,J=12.0Hz 1H),3.40-3.53(m,3H),2.92(d,J=4.0Hz 1H), 1.75-1.80 (m, 1H), 1.63-1.69 (m, 1H), 1.48-1.57 (m, 2H), 1.41 (s, 2H), 1.09 (d, J = 8.0Hz3H). MS m / z[M+H] + :469.4.

[0293] Example 7

[0294]

[0295]

[0296] Dissolve diisopropylamine (12 g, 86 mmol) in tetrahydrofuran (100 mL), replace with nitrogen three times, cool to -10 ° C in an ice-salt bath, add n-butyl lithium (36 mL, 86 mmol), and control the system temperature at -10 ° C. Add n-butyl tin hydride (26.6 g, 86 mmol) dropwise, control the temperature at -5 ° C, and react at -10 ° C for 20 minutes. Cool to -80 ° C again, add a tetrahydrofuran solution of 7a (10 g, 86 mmol) dropwise, stir at -80 ° C for 4 hours, add saturated potassium fluoride (10 mL) solution to quench, filter, separate, dry with sodium sulfate, filter the desiccant, concentrate under reduced pressure, and purify by column chromatography to obtain 7b (9 g, yield 28%).

[0297]

[0298] n-Butyl lithium (27.6 mL, 102 mmol) was added to diethyl ether (150 mL), the system was cooled to -68 °C, tetramethylpiperidine (9.8 g, 61.2 mmol) was added dropwise, and after 30 minutes of reaction, a tetrahydrofuran solution of 7c (10 g, 68 mmol) was added dropwise, and the reaction was continued at -68 °C for 2 hours. The reaction was quenched with water, extracted twice with ethyl acetate, and the organic phases were combined and concentrated to obtain a crude product 7d (15 g, yield 83%).

[0299] 1H NMR (CDCl3, 400MHz): 7.90 (d, J = 4.0 Hz, 1H), 7.74 (d, J = 4.0 Hz, 1H).

[0300]

[0301] 7d (10.08 g, 36.9 mmol) was dissolved in dioxane, and then 2-ethylhexyl 3-mercaptopropionate (10.46 g, 47.9 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.533 g, 0.92 mmol), N,N-diisopropylethylamine (14.31 g, 110 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.422 g, 0.46 mmol) were added. The system was replaced with nitrogen three times, the temperature was raised to 108°C, the reaction was carried out for 2 hours, the mixture was concentrated under reduced pressure, and 7e (10 g, yield 74%) was obtained by column chromatography. 1 H NMR (CDCl3, 400MHz): δ8.14 (s, J = 8.0Hz, 1H), 7.02 (d, J = 4.0Hz, 1H), 4.04-4.05 (m, 2H), 3.27 (t, J = 8.0Hz 2H), 2.74 (t, J = 8.0Hz 2H),1.53-1.60(m,1H),1.24-1.41(m,8H),0.86-0.90(m,6H).

[0302]

[0303] 7b (6.50 g, 17.5 mmol) and 7e (5.30 g, 14.5 mmol) were dissolved in xylene, and then cuprous iodide (0.21 g, 1.10 mmol) and tetrakistriphenylphosphine palladium (3.30 g, 1.09 mmol) were added, and the atmosphere was replaced with nitrogen three times, and the temperature was raised to 158°C and reacted for 8 hours. The temperature was then lowered to 120°C, and the reaction was continued for 16 hours, and water was added to quench, and the mixture was extracted with ethyl acetate twice, dried with sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 7f (1.5 g, yield 25.4%).

[0304]

[0305] Dissolve 7f (1.54 g, 0.1 mmol) in tetrahydrofuran, cool the system to -68°C, add dropwise a tetrahydrofuran solution of potassium tert-butoxide (1.27 g, 0.2 mmol), and naturally warm to room temperature overnight. Add 5% potassium carbonate (20 mL) aqueous solution, extract twice with ethyl acetate, add 5% potassium carbonate (20 mL) aqueous solution to the organic phase, and stir for 10 minutes. Separate the liquids, combine the aqueous phases, adjust the pH to 3 with 2N hydrochloric acid, then extract twice with ethyl acetate, combine the organic phases, wash once with saturated brine, dry with sodium sulfate, and concentrate under reduced pressure to obtain 7g (800 mg, yield 95%).

[0306] 1 H NMR (CDCl3, 400MHz): δ9.11 (s, 1H), 8.74-8.75 (m, 1H), 8.68 (s, 1H), 7.71 (d, J = 8.0Hz, 1H), 7.05 (d, J = 4.0Hz, 1H).

[0307]

[0308] 7g (800 mg, 3.6 mmol) was dissolved in acetonitrile (3 mL), and then 2,5-dichloropyrazine (1.69 g, 7.2 mmol) and potassium carbonate (990 mg, 7.2 mmol) were added, and the nitrogen was replaced three times. The system was heated to 85°C and reacted for 16 hours. Dichloromethane was added to the reaction system, filtered, and concentrated under reduced pressure to obtain 7h (630 mg, yield 46%).

[0309] 1 H NMR(CDCl3,400MHz): δ9.01(d,J=1.6Hz,1H),8.74-8.75(m,1H),8.71(d,J=1.6Hz,1H),8 .67(d,J=2.4Hz,1H),8.62(d,J=1.6Hz,1H),8.34(d,J=4.8Hz,1H),7.36(d,J=1.6Hz,1H).

[0310]

[0311] 7h (400 mg, 1.05 mmol) and 1j (529 mg, 1.88 mmol) were dissolved in isopropanol (10 mL), and potassium phosphate (1.8 g, 8.49 mmol) was added. The nitrogen atmosphere was replaced three times, and the system was heated to 88°C and reacted for 16 hours. The product 7 (81 mg, yield 16.3%) was prepared after filtration and concentration.

[0312] 1H NMR ((CD3)2SO, 400MHz): δ9.01(s,1H),8.83(s,1H),8.77(s,1H),8.39(s,1H),8.36(d,J=4.8Hz,1H),8.25(s,1H),7.40(d,J=4.8Hz,1H), 4.04-4.07(m,1H),3.89(m,2H),3.67(d,J=8.4Hz,1H),3.47-3.49(m,3H),2.91(d,J=4.0Hz,1H),1.50-1.78(m,6H),1.06(d,J=4.0Hz,3H). LCMS m / z[M+H + ]:470.3.

[0313] Example 8

[0314]

[0315]

[0316] 8a was synthesized according to the method for synthesizing 6c.

[0317]

[0318] 8b was synthesized according to the method for synthesizing 6d.

[0319]

[0320] 8b (1.6 g, 7.2 mmol) was dissolved in dioxane (60 mL), and then 2-amino-3-bromo-5-chloropyrazine (1.25 g, 7.2 mmol), potassium phosphate (1.9 g, 10.8 mmol), 1,10-phenanthroline (216 mg, 1.44 mmol) were added, and nitrogen was replaced 3 times. Finally, cuprous iodide (228 mg, 1.44 mmol) was added, and nitrogen was replaced 3 times. The temperature was raised to 100 ° C and the reaction was refluxed overnight. Cooled to room temperature, directly concentrated and passed through a column to obtain 8c (624 mg, yield 25%).

[0321]

[0322] 8 was synthesized according to the method of 7.

[0323] 1H NMR (DMSO, 400MHz): δ8.88(s,1H),8.77(s,1H),8.25(s,1H),7.69(s,1H),7.34(m,2H),6.73(m,1H),6.17(br s,2H),4.04(m,1H),3.83(m,2H),3.67(d,J=8.0Hz,1H),3.49(d,J=8.0Hz,1H),3. 34-3.27(m,2H),2.90(d,J=4.0Hz,1H),1.74-1.43(m,6H),1.06(d,J=8.0Hz,3H). LCMS m / z[M+H + ]:484.1.

[0324] Example 9

[0325]

[0326] Cool down to 0°C, add lithium diisopropylamide solution (64mL, 0.064mol, 1mol / L) to tetrahydrofuran (100mL). Add tributyltin hydride (18.6g, 0.064mol) dropwise at -5°C. After the addition, keep warm for 20 minutes, cool down to -78°C, add 9a (7.0g, 0.061mol) in three times, keep warm for 2 hours, warm to room temperature, add ammonium chloride to quench, extract with ethyl acetate, dry with sodium sulfate, filter the desiccant, concentrate under reduced pressure, and purify by column chromatography to obtain 9b (0.486g, yield 2.1%).

[0327]

[0328] 9b (70 mg, 0.189 mmol) was dissolved in xylene (2 mL), and then 1m (65 mg, 0.1986 mmol), tetrakistriphenylphosphine palladium (22 mg, 0.0189 mmol), and iodide (10 mg, 0.0189 mmol) were added. The reaction was carried out at 125°C for 2 hours, cooled to room temperature, and concentrated and column-filtered to obtain 9c (30 mg, yield 57%).

[0329]

[0330] 9d was synthesized according to the method for synthesizing 6d.

[0331]

[0332] 9e was synthesized according to the method for synthesizing 8c.

[0333]

[0334] 9 was synthesized according to the method for synthesizing 8.

[0335] 1 H NMR (DMSO, 400MHz): δ8.96 (d, J = 4.0Hz, 2H), 8.45 (s, 1H), 8.28 (s, 1H), 7.55 (m, 1H), 7.43 (d, J = 4.0Hz 1H),7.33(t,J=8.0Hz,1H),6.95(d,J=8.0Hz,1H),4.05(m,1H),3.88(m,2H),3.65(d,J=8.0Hz,1H), 3.48(d,J=8.0Hz,1H),3.34(m,2H),2.87(d,J=4.0Hz,1H),1.77-1.41(m,6H),1.07(d,J=8.0Hz,3H). LCMS m / z[M+H + ]:469.2.

[0336] Example 10

[0337]

[0338]

[0339] 1l (20.0 g, 93 mmol) was dissolved in concentrated hydrochloric acid (750 mL), heated to 55°C for 24 hours, concentrated under reduced pressure to 150 mL, cooled to room temperature, filtered, and dried to obtain 10a (10.0 g, yield 67%).

[0340] 1 H NMR (DMSO, 400MHz): δ6.84 (t, J=8.0Hz, 1H), 6.66 (dd, J1=8.0Hz, J2=4.0Hz, 1H), 6.53 (dd, J1=8.0Hz, J2=4.0Hz, 1H), 5.37 (br, 2H), 5.30 (br, 1H).

[0341] MS m / z[MH] - :157.9

[0342]

[0343] 10a (0.66 g, 3.4 mmol) was dissolved in dimethyl sulfoxide (10 mL), and then 2,5-dichloropyrazine (0.5 g, 3.4 mmol) and cesium carbonate (2.2 g, 6.7 mmol) were added, and the mixture was heated to 80°C for 6 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, washed with water three times, dried over sodium sulfate, the desiccant was filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 10b (0.39 g, yield 42%).

[0344] MS m / z[MH] - :270.1

[0345]

[0346] 2-Chloro-3-fluorobenzoic acid (64 mg, 0.37 mol) was added to thionyl chloride (3 mL), refluxed and stirred for 1.5 hours, and concentrated to obtain the acid chloride. Then dichloromethane (3 mL), pyridine (42 mg, 0.53 mol), 10b (50 mg, 0.18 mol), 4-dimethylaminopyridine (10 mg, 0.09 mol) were added, stirred at room temperature for 1 hour, quenched with water, extracted with dichloromethane, dried and concentrated to obtain the crude product 10c, which was directly used for the next step.

[0347] LCMS m / z[M+H] + :429.0,[MH] - :427.0

[0348]

[0349] 10c (430 mg, 1 mol) and 1j (187 mg, 1.2 mol) were dissolved in N-methylpyrrolidone (10 mL), and then N,N-diisopropylethylamine (645 mg, 5 mol) was added, and the mixture was heated to 120°C and stirred overnight. The mixture was concentrated by oil pump, and the crude product was directly prepared to obtain 10C (260 mg, yield 46%).

[0350] 1 H NMR (DMSO, 400MHz): δ10.41(s,1H),8.44(s,1H),8.27(s,1H),7.48-7.69(m,4H),7.28(t,J=8.0Hz,1H),6.79(d,J=8.0Hz,1H),4.04-4.10(m,1H),3 .88-3.90(m,2H),3.67(d,J=8.0Hz,1H),3.48(d,J=8.0Hz,1H),3.38-3.4 3(m,2H),2.91(d,J=4.0Hz,1H),1.52-1.77(m,6H),1.08(d,J=4.0Hz,3H). MS m / z[M+H] + :562.1.

[0351] Embodiment 11

[0352]

[0353]

[0354] 2-Aminopyridine (10.0 g, 0.1 mol) and 11a (49.0 g, 0.2 mol) were dissolved in xylene (100 mL), heated to 130°C for 16 hours, cooled to room temperature, filtered, and the filter cake was washed three times with methanol and dried to obtain 11b (3.80 g, yield 15%).

[0355] 1 H NMR (DMSO, 400MHz): δ 12.45 (br, 1H), 8.89 (d, J = 8.0Hz, 1H), 8.16 (t, J = 8.0Hz, 1H), 7.34-7.38 (m, 2H), 4.12 (q, J = 8.0Hz, 2H), 1.21 (t, J = 8.0Hz, 3H). MS m / z[M+H] + :235.5,[MH] - :233.2

[0356]

[0357] Under nitrogen protection, 11b (2.00 g, 8.5 mmol) and palladium carbon (0.2 g) were dissolved in methanol (20 mL), replaced with hydrogen, and reacted at room temperature and pressure for 3 hours. Filtered and concentrated under reduced pressure to obtain 11c (1.77 g, yield 87%).

[0358] 1 H NMR (DMSO, 400MHz): δ 12.29 (br, 1H), 4.06 (q, J = 8.0Hz, 2H), 3.64 (t, J = 8.0Hz, 2H), 2.76 (t, J = 8.0Hz, 2H), 1.71-1.83 (m, 4H), 1.17 (t, J = 8.0Hz, 3H). MS m / z[M+H] + :239.2,[MH] - :237.2.

[0359]

[0360] 11c (275 mg, 1.1 mmol) and 10b (271 mg, 1.0 mmol) were dissolved in chlorobenzene (6 mL), heated to 130°C for 5 hours, cooled to room temperature, filtered, and dried to obtain 11d (260 mg, yield 56%).

[0361] 1H NMR (DMSO, 400MHz): δ14.74 (s, 1H), 12.31 (s, 1H), 8.66 (d, J = 4.0Hz, 1H), 8.48 (br, 1H), 8.44(s,1H),7.47-7.51(m,2H),3.84(br,2H),2.88(t,J=8.0Hz,2H),1.78-1.90(m,4H). MS m / z[MH] - :462.3.

[0362]

[0363] 11d (200 mg, 0.43 mmol), 1j (190 mg, 0.79 mmol), potassium phosphate (0.34 mg, 1.6 mol) were added to N-methylpyrrolidone (8 mL), heated to 120°C and stirred for 16 hours. The reaction solution was cooled to room temperature and purified by reverse phase preparative column to obtain 11 (43 mg, yield 17%).

[0364] 1 H NMR (DMSO, 400MHz): δ12.8(br,1H),8.41(s,1H),8.30(br,1H),8.23(s,1H),7.17(s,1H),6.58(d,J=8.0Hz,1H) ,5.50(br,3H),3.50-4.10(m,9H),2.99(d,J=4.0Hz,1H),2.73(s,2H),1.52-1.85(m,8H),1.09(d,J=8.0Hz,3H). MS m / z[M+H] + :598.6.

[0365] Example 12

[0366]

[0367]

[0368] 12a (279 mg, 2.2 mol) was added to thionyl chloride (5 mL), stirred at reflux for 1.5 hours, and concentrated to obtain the acid chloride. Dichloromethane (5 mL), pyridine (262 mg, 3.32 mol), 10b (300 mg, 1.1 mol), 4-dimethylaminopyridine (68 mg, 0.55 mol) were added to the acid chloride, and stirred at room temperature for 1 hour. Water was added to quench, extracted with dichloromethane, dried and concentrated, and column chromatography was performed to obtain 12b (250 mg, yield 59%) as a white solid.

[0369] LCMS m / z[M+H] + :379.9

[0370]

[0371] 12b (250 mg, 0.66 mol) was dissolved in N-methylpyrrolidone (5 mL), and then 1j (224 mg, 1.2 mol) and N,N-diisopropylethylamine (340 mg, 2.64 mol) were added. The mixture was stirred at 120°C overnight and concentrated under reduced pressure. The crude product was directly used to obtain an off-white solid 12 (140 mg, yield 41%).

[0372] 1 H NMR(DMSO,400MHz): δ9.59(s,1H),8.44(s,1H),8.26(s,1H),7.90-7.93(m,2H),7 .26(t,J=8.0Hz,1H),6.79(d,J=4.0Hz,1H),6.69(d,J=8.0Hz,1H),4.06-4.08(m,1 H),3.98(s,3H),3.85-3.93(m,2H),3.67(d,J=8.0Hz,1H),3.48(d,J=8.0Hz,1H),3 .38-3.46(m,2H),2.91(d,J=4.0Hz,1H),1.24-1.76(m,6H),1.08(d,J=4.0Hz,3H). MS m / z[M+H] + :514.2.

[0373]

[0374]

[0375] 2-Chloro-4,5-difluorobenzoic acid (425 mg, 2.2 mol) was added to thionyl chloride (5 mL), refluxed and stirred for 1.5 hours, and concentrated under reduced pressure to obtain the acid chloride. Dichloromethane (5 mL), pyridine (262 mg, 3.32 mol), 4-dimethylaminopyridine (68 mg, 0.55 mol), 10b (300 mg, 1.1 mol) were added to the acid chloride, stirred at room temperature for 1 hour, quenched with water, extracted with dichloromethane, dried over sodium sulfate, filtered the desiccant, concentrated under reduced pressure, and column chromatography gave a white solid 13b (270 mg, yield 54.9%).

[0376] LCMS m / z[M+H] + :446.0,[MH] - :444.0.

[0377] Embodiment 13

[0378]

[0379] 13b (270 mg, 0.61 mol) was dissolved in N-methylpyrrolidone (5 mL), and then 1j (206 mg, 1.21 mol) and N,N-diisopropylethylamine (315 mg, 2.44 mol) were added. The temperature was raised to 120°C and stirred overnight. The mixture was concentrated under reduced pressure to directly obtain an off-white solid 13 (100 mg, yield 21%).

[0380] 1 H NMR(DMSO,400MHz): δ10.36(s,1H),8.44(s,1H),8.26(s,1H),7.82-7.89(m,2H ),7.50(d,J=8.0Hz,1H),7.27(t,J=8.0Hz,1H),6.77(d,J=8.0Hz,1H),4.06-4. 09(m,1H),3.85-3.92(m,2H),3.67(d,J=8.0Hz,1H),3.48(d,J=8.0Hz,1H),3.3 9-3.45(m,2H),2.91(d,J=4.0Hz,1H),1.46-1.77(m,6H),1.08(d,J=2.0Hz,3H).

[0381] MS m / z[M+H] + :580.1.

[0382] Embodiment 14

[0383]

[0384] Compound benzoxazole (575 mg, 4.82 mmol), lithium tert-butoxide (772 mg, 9.64 mmol), cuprous iodide (91.8 mg, 0.482 mmol) were added to a 100 mL three-necked flask, 1m (2 g, 7.225 mmol) was added, dissolved in N,N-dimethylformamide (15 mL), heated to 150 ° C under nitrogen protection, and stirred for 1.5 h. The reaction solution was cooled to room temperature, 50 mL of water was added, and ethyl acetate was added for extraction. The organic phase was washed with water 3 times, dried, concentrated, and passed through a column to obtain 14a (300 mg, yield: 20%).

[0385] 1 H NMR (CDCl3, 400MHz): δ8.03-8.05 (d, J = 8.0Hz 1H), 7.83-7.86 (m, 2H), 7.61-7.64 (m, 1H), 7.37-7.41 (m, 3H), 1.39 (s, 9H).

[0386]

[0387] 14a (100 mg, 0.315 mmol), anhydrous aluminum chloride (167.8 mg, 1.26 mmol) and toluene (3 mL) were added to a 50 mL three-necked flask and stirred at room temperature for 15 h. After adding 20 mL of water, the mixture was extracted with ethyl acetate and the organic phase was dried and spin-dried to obtain 14b, which was used directly in the next step.

[0388]

[0389] 2,5-Dibromopyrazine (3 g, 13.2 mmol) and isopropanol (15 mL) were added to a 50 mL three-necked flask, the temperature was raised to 60°C with stirring, 14b (580 mg, 2.20 mmol) and N,N-diisopropylethylamine (568.6 mg, 4.40 mmol) were added dropwise, the reaction was stirred overnight, and the organic phase was extracted with water and ethyl acetate, dried, concentrated, and filtered to obtain 14c (230 mg, yield: 25%). 1 H NMR (CDCl3, 400MHz): δ8.46 (s, 1H), 8.18-8.22 (m, 2H), δ7.82-7.86 (m, 2H), δ7.61-7.63 (m, 1H), δ7.46-7.50 (t, 1H), δ7.39-7.42 (m, 2H).

[0390]

[0391] 14d (230 mg, 0.55 mmol), isopropanol (10 mL), 1j (173 mg, 0.71 mmol), and potassium phosphate (700 mg, 3.3 mmol) were added to a 50 mL three-necked flask and heated at 95°C with stirring for 18 h. The reaction solution was cooled to room temperature and 30 mL of water was added. After extraction with dichloromethane, the organic phase was concentrated. The crude product was purified by column to obtain 14 (30 mg, yield 11%).

[0392] 1H NMR (CDCl3, 400MHz): δ8.29-8.31(d,J=8.0Hz 2H), 7.87-7.88(d,J=4.0Hz1H), 7.80-7.82(d,J=8.0Hz 1H), 7.70-7.72(d,J=8.0Hz 1H),7.43-7.50(m,2H),δ7.35-7.38(t,1H),7.10-7.12(d,J=8.0Hz 1H),4.22-4.25(m,1H),4.22-4.25(m,1H),4.05-4.13(m,2H),3.87-3.89(d,J=8.0Hz 1H),3.71-3.73(d,J=8.0Hz 1H), 3.36-3.44 (m, 2H), 3.01-3.03 (d, J = 8.0Hz 1H), 1.69-1.85 (m, 5H), 1.21-1.23 (d, J = 8.0Hz 3H). MS m / z[MH + ]:508.04. Example 15

[0393]

[0394] Compound 4-oxazolecarbonitrile (1.0 g, 10.63 mmol), palladium acetate (2.86 g, 12.8 mmol), 2-dicyclohexylphosphine-2′,6′-dimethoxy-biphenyl (218 mg, 0.53 mmol), 1,8-diazabicycloundec-7-ene (3.24 g, 21.26 mmol) were added to a 100 mL three-necked flask, and 1m (3.50 g, 12.8 mmol) was added, dissolved in N,N-dimethylformamide, heated to 130°C under nitrogen protection, and stirred for 48 h. The reaction solution was cooled to room temperature, 50 mL of water was added, and after extraction with dichloromethane, the organic phase was washed three times with water, concentrated and passed through a column to obtain 15a (630 mg, yield 20%).

[0395] 1 H NMR (CDCl3, 400MHz): δ8.31 (s, 1H), 7.88-7.90 (d, J = 8.0Hz 1H), 7.83-7.85 (d, J = 8.0Hz 1H), 7.35-7.39 (t, 1H), 1.36 (s, 9H).

[0396]

[0397] 15a (630 mg, 2.15 mmol), anhydrous aluminum chloride (1.20 g, 8.61 mmol) and toluene (8 mL) were added to a 50 mL three-necked flask and stirred at room temperature for 5 h. After adding 20 mL of water, the mixture was extracted with ethyl acetate and the organic phase was dried and spin-dried to obtain 15b, which was used directly in the next step.

[0398]

[0399] 2,5-Dibromopyrazine (3.0 g, 12.9 mmol) and isopropanol (15 mL) were added to a 50 mL three-necked flask, the temperature was raised to 60°C with stirring, 15b (509 mg, 2.15 mmol) and N,N-diisopropylethylamine (556 mg, 4.3 mmol) were added dropwise, the reaction was stirred overnight, 30 mL of water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated, and 15c (220 mg, yield: 25%) was obtained by column chromatography.

[0400] 1 H NMR (CDCl3, 400MHz): δ8.49 (s, 1H), δ8.36 (s, 1H), 8.24 (s, 1H), 8.09-8.11 (d, J = 8.0Hz 1H), 7.87-7.89 (d, J = 8.0Hz 1H), 7.49-7.53 (t, 1H).

[0401]

[0402] In a 50 mL three-necked flask, 15c (220 mg, 0.56 mmol), isopropanol (10 mL), 1j (176 mg, 0.71 mmol), and potassium phosphate (700 mg, 3.3 mmol) were added and heated at 95 °C with stirring for 18 h. The reaction solution was cooled to room temperature, 30 mL of water was added, and the mixture was extracted with dichloromethane. The mixture was concentrated and filtered to obtain 15 (16 mg, yield 6%).

[0403] 1H NMR (CDCl3, 400MHz): δ8.34(s,1H), δ8.30(s,1H),8.24(s,1H),7.77-7.79(d,J=8.0Hz 1H),7.25-7.29(t,1H),7.15-7.17(d,J=8.0Hz 1H),4.20-4.26(m,1H),3.93-4.03(m,2H),3.85-3.87(d,J=8.0Hz 1H),3.72-3.75(d,J=12.0Hz 1H),3.50-3.57(m,1H),3.40-3.46(m,1H),3.04-3.05(d,J=4.0Hz 1H), 1.90-1.94 (m, 1H), 1.71-1.82 (m, 3H), 1.52 (s, 2H), 1.27-1.29 (d, J = 8.0Hz 3H). MS m / z[MH + ]:483.4.

[0404] Example 16

[0405]

[0406]

[0407] 4-Methylthiazole (455 mg, 4.6 mmol), 1.4-dioxane (10 mL), 1m (1.25 g, 13.8 mmol), 2-(dicyclohexylphosphino)biphenyl (262 mg, 0.76 mmol), and cesium carbonate (2.42 g, 7.6 mmol) were added to a 100 mL single-mouth bottle. The mixture was reacted at 110 °C overnight. After post-treatment, the reaction solution was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, washed once with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and purified by column to obtain 16a (500 mg, yield: 44%).

[0408] 1 H NMR (400MHz, CDCl3) δ7.77(s,1H),7.72(dd,J=7.6,1.6Hz,1H),7.35(dd,J=7.6,1.6Hz,1H),7.28(t,J=7.6Hz,1H),2.31(s,3H),1.37(s,9H).

[0409]

[0410] 36b (500 mg, 1.68 mmol) was dissolved in acetonitrile (0.5 mL) and concentrated hydrochloric acid (12 M, 5 mL) and reacted at 110°C for 5 hours. The mixture was extracted twice with water and ethyl acetate, washed once with saturated brine, dried over sodium sulfate, the desiccant was filtered, concentrated under reduced pressure, and used directly in the next step.

[0411]

[0412] 2,5-Dibromopyrazine (454 mg, 3.5 mmol) was added to isopropanol (10 mL), and the mixture was heated to 70°C under nitrogen protection. N,N-diisopropylethylamine (671 mg, 2.82 mmol) and an isopropanol solution of 16b were slowly added dropwise for 1 hour, and then the temperature was raised to 80°C overnight. Water was added, and the mixture was extracted with ethyl acetate, dried over sodium sulfate, the desiccant was filtered, and the mixture was concentrated under reduced pressure and purified by column to obtain 16c (100 mg, yield 17.8%).

[0413] 1 H NMR (400MHz, CDCl3) δ8.78 (s, 1H), 8.23 ​​(s, 1H), 7.63 (dd, J = 7.6, 1.6Hz, 1H), 7.44–7.29 (m, 2H), 2.31 (s, 3H).

[0414]

[0415] Compound 16c (100 mg, 0.25 mmol) was added to a 100 mL single-mouth bottle, followed by 1j (61 mg, 0.25 mmol), N,N-dimethylformamide (2 mL), and potassium phosphate (318 mg, 1.5 mmol), and the mixture was heated to 110°C and reacted for 2 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate twice, washed with saturated brine three times, and the organic phase was dried over sodium sulfate, spin-dried, and scraped (twice) to obtain 16 (35 mg, yield 28%).

[0416] 1H NMR (400MHz, CDCl3) δ8.78 (s, 1H), 8.24 (dd, J = 21.5, 1.1Hz, 2H), 7.20-7.10 (m,2H),7.03-6.95(m,1H),4.25-4.14(m,1H),4.02-3.88(m,2H),3.83(d,J =8.8Hz,1H),3.70(d,J=8.8Hz,1H),3.53-3.31(m,J=22.8,13.0,9.2,3.5Hz ,2H),3.00(t,J=15.4Hz,1H),2.33(s,3H),1.97-1.73(m,4H),1.26(s,3H). LCMS m / z[M+H + ]:488.4.

[0417] Embodiment 17

[0418]

[0419]

[0420] 4-Cyanothiazole (600 mg, 5.5 mmol), 1.4-dioxane (30 mL), 1m (1.5 g, 4.6 mmol), 2-(dicyclohexylphosphino)biphenyl (300 mg, 0.92 mmol), and cesium carbonate (3.0 g, 9.2 mmol) were added to a 100 mL single-mouth bottle. The mixture was reacted at 110 °C for 5 hours. After post-treatment, the reaction solution was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, washed once with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and purified by column to obtain 17a (630 mg, yield: 44%).

[0421] 1 H NMR (400MHz, CDCl3) δ8.90(s,1H),7.82(dd,J=7.6,1.6Hz,1H),7.51(dd,J=7.6,1.6Hz,1H),7.37(t,J=7.6Hz,1H),1.38(s,9H).

[0422]

[0423] 17b (630 mg, 2.0 mmol) was dissolved in toluene (20 mL), and anhydrous aluminum chloride was added to react at room temperature for 5 hours. The mixture was extracted twice with water and ethyl acetate, washed once with saturated brine, dried over sodium sulfate, the desiccant was filtered, and the mixture was concentrated under reduced pressure and used directly in the next step.

[0424]

[0425] 2,5-Dibromopyrazine (387 mg, 3.0 mmol) and N,N-diisopropylethylamine (571 mg, 2.4 mmol) were added to acetonitrile (5 mL) under nitrogen protection, and the acetonitrile solution of 17b was added dropwise for 1 hour and reacted at room temperature for 1 hour. Water was added, extracted with ethyl acetate, dried with sodium sulfate, the desiccant was filtered, concentrated under reduced pressure, and purified by column to obtain 17c (70 mg, yield 14.3%).

[0426] 1 H NMR(400MHz, CDCl3)δ8.95(s,1H),8.50(d,J=1.2Hz,1H),8.24(d,J=1.2Hz,1H), 7.82(dd,J=7.6,1.6Hz,1H), 7.64(dd,J=7.6,1.6Hz,1H), 7.49(t,J=7.6Hz,1H).

[0427]

[0428] Compound 17d (70 mg, 0.17 mmol) was added to a 100 mL single-mouth bottle, followed by 1j (42 mg, 0.17 mmol), N,N-dimethylformamide (2 mL), and potassium phosphate (216 mg, 1.0 mmol), and the mixture was heated to 80°C and reacted for 2 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate twice, washed with saturated brine three times, and the organic phase was dried over sodium sulfate, spin-dried, and slurried (petroleum ether:ethyl acetate = 30:1) to obtain 17 (56 mg, yield 66.0%).

[0429] 1 H NMR (400MHz, CDCl3) δ8.91(s,1H),8.28(d,J=1.2Hz,1H),8.21(d,J=1.2Hz,1H),7.3 4(dd,J=7.6,1.2Hz,1H),7.23(d,J=7.6Hz,1H),7.10(dd,J=8.0,1.2Hz,1H),4.23-4. 14(m,1H),4.00-3.88(m,2H),3.82(d,J=8.8Hz,1H),3.70(d,J=8.8Hz,1H),3.55-3. 34(m,2H),3.01(d,J=4.6Hz,1H),1.94-1.85(m,1H),1.80-1.69(m,3H),1.25(s,3H). MSm / z[M+H] + :499.4.

[0430] Embodiment 18

[0431]

[0432]

[0433] 4-Methylthiazole (1.1 g, 11.0 mmol), N,N-dimethylformamide (20 mL), 1m (3.0 g, 9.2 mmol), copper trifluoroacetate (531 mg, 1.84 mmol), and lithium tert-butoxide (1.48 g, 18.4 mmol) were added to a 100 mL single-mouth bottle. The reaction was allowed to proceed overnight at 130 °C in nitrogen. After treatment, the reaction solution was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, washed once with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 18a (1.0 g, yield: 36.6%).

[0434] 1 H NMR (400MHz, CDCl3) δ8.14(dd,J=8.0,1.6Hz,1H),7.71(dd,J=7.6,1.6Hz,1H),7.31(dd,J=9.6,6.0Hz,1H),7.05(s,1H),2.53(s,3H),1.36(s,9H).

[0435]

[0436] 18a (1.0 g, 3.3 mmol) was dissolved in toluene (30 mL), and anhydrous aluminum chloride was added, and the mixture was reacted at room temperature for 5 hours. The mixture was extracted twice with water and ethyl acetate, washed once with saturated brine, dried over sodium sulfate, the desiccant was filtered, and the mixture was concentrated under reduced pressure and used directly in the next step.

[0437]

[0438] 2,5-Dibromopyrazine (2.38 g, 10 mmol) and N,N-diisopropylethylamine (1.0 g, 8.0 mmol) were added to acetonitrile (20 mL). Under nitrogen protection, the acetonitrile solution of 18b was slowly added dropwise for 1 hour, and then reacted at room temperature for 5 hours. Water was added, extracted with ethyl acetate, dried over sodium sulfate, the desiccant was filtered, concentrated under reduced pressure, and purified by column to obtain 18c (100 mg, yield 6.3%).

[0439] 1 H NMR (400MHz, CDCl3) δ8.45 (d, J=1.2Hz, 1H), 8.29 (dd, J=8.0, 1.6Hz, 1H), 8.09 (d, J=1. 2Hz,1H),7.73(dd,J=7.6,1.6Hz,1H),7.42(t,J=7.6Hz,1H),7.08(s,1H),2.54(s,3H).

[0440]

[0441] Compound 18c (100 mg, 0.25 mmol) was added to a 100 mL single-mouth bottle, followed by 1j (61 mg, 0.25 mmol), N,N-dimethylformamide (2 mL), and potassium phosphate (318 mg, 1.5 mmol), and the mixture was heated to 80°C and reacted for 2 hours. 20 mL of water was added, and the mixture was extracted twice with ethyl acetate, washed three times with saturated brine, and the organic phase was dried over sodium sulfate, spin-dried, and passed through a column to obtain 18 (50 mg, yield 41%).

[0442] 1 H NMR (400MHz, CDCl3) δ8.24(d,J=1.2Hz,1H),8.20(s,1H),7.96(dd,J=8.0,1.6Hz,1 H),7.22(t,J=8.0Hz,1H),7.10-7.03(m,2H),4.30-4.18(m,1H),4.10-3.94(m,2H) ,3.91(d,J=8.8Hz,1H),3.73(d,J=8.8Hz,1H),3.45-3.23(m,2H),3.12(d,J=4.0Hz ,1H),2.54(s,3H),1.96(d,J=9.6Hz,1H),1.87-1.74(m,3H),1.32(d,J=6.4Hz,3H). MS m / z[M+H] + :488.3.

[0443] Embodiment 19

[0444]

[0445]

[0446] Sulfuric acid (13 mL) was slowly added to a solution of 15a (2.0 g, 6.83 mmol) in ethanol (30 mL) and heated to reflux. After the reaction was completed, the reaction was cooled to room temperature, diluted with ethyl acetate (100 mL), and extracted with water. The organic phase was dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by column to obtain a light yellow solid 19a (0.5 g, yield: 26.3%).

[0447] 1H NMR(400MHz, CDCl3)δ8.35(s,1H),7.78(d,J=8.0Hz,1H),7.48(d,J=8.0Hz,1H), 7.23(t,J=8.0Hz,1H),4.43(q,J=7.2Hz,2H),4.02(s,1H),1.41(t,J=7.2Hz,3H).

[0448]

[0449] 2,5-Dibromopyrazine (1.68 g, 7.05 mmol) was dissolved in isopropanol (20 mL) and heated to 80 ° C under N2 protection. To the solution was added dropwise a solution of 19a (0.5 g, 1.73 mmol) and N,N-diisopropylethylamine (0.58 mL, 3.52 mmol) in isopropanol (20 mL) over 2 hours. After the addition was complete, the reaction was allowed to react for 1 hour. The reaction mixture was then concentrated and purified by column to give 19b (0.229 g, 29.5% yield) as a white solid.

[0450] 1 H NMR (400MHz, CDCl3) δ8.45(d,J=1.2Hz,1H),8.36(s,1H),8.16(d,J=1.2Hz,1H),8.10(dd,J=8.0,1.6Hz ,1H),7.80(dd,J=7.6,1.6Hz,1H),7.44(t,J=7.6Hz,1H),4.44(q,J=7.2Hz,2H),1.41(t,J=7.2Hz,3H).

[0451]

[0452] Ammonia (3 mL, 28% aqueous solution) was added to a solution of 19b (229 mg, 0.52 mmol) in tetrahydrofuran / methanol (2.0 mL / 3.0 mL) and stirred at room temperature for 2 days. After the reaction was completed, the reaction mixture was diluted with water, and the precipitate was filtered and dried to give 19c (128 mg, yield: 92%).

[0453] 1 H NMR (400MHz, CDCl3) δ8.46 (s, 1H), 8.36 (s, 1H), 8.17 (s, 1H), 8.05 (d, J = 8.0Hz, 1H), 7.81 (d, J = 7.6Hz, 1H), 7.46 (t, J = 8.0Hz, 1H).

[0454]

[0455] 19c (128 mg, 0.31 mmol), 1j (0.083 g, 0.342 mmol) and potassium phosphate (0.396 g, 1.86 mmol) were added to dry N,N-dimethylformamide (5 mL) and stirred overnight at 50 ° C under nitrogen. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The organic layer was dried, concentrated, and scraper purified to give 19 (70 mg, yield: 44.8%).

[0456] 1 H NMR (400MHz, MeOD-d4) δ8.58(s,1H),8.34(d,J=14.4Hz,2H),7.84(dd,J=7.6,1.2Hz,1H),7.37(t,J=8.0Hz,1H),7.16(dd,J=8.0,1.2Hz,1H),4.37– 4.19(m,3H),4.00(d,J=8.8Hz,1H),3.87(d,J=8.8Hz,1H),3.43–3.24(m, 3H),2.00(s,1H),1.95–1.83(m,3H),1.80–1.71(m,1H),1.34-132(m,4H). LC-MS[M+H] + :m / z=501.2.

[0457] Embodiment 20

[0458]

[0459]

[0460] Ethyl 4-oxazolecarboxylate (1.0 g, 7.08 mmol), 1m (2.3 g, 7.08 mmol), palladium acetate (0.079 g, 0.35 mmol), 2-(dicyclohexylphosphino)biphenyl (0.25 g, 0.71 mmol) and cesium carbonate (4.65 g, 14.17 mmol) were added to 25 mL of 1,4-dioxane solution and heated overnight at 110 ° C under nitrogen protection. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and purified by column chromatography to give a brown solid 20a (1.0 g, 41.4%).

[0461] 1 H NMR (400MHz,CDCl3) 1H NMR(400MHz, CDCl3) δ8.36(s,1H),7.93(dd,J=7.6,1.6Hz,1H),7.81(dd,J=7.6,1.6Hz ,1H),7.33(t,J=7.6Hz,1H),4.43(q,J=7.2Hz,2H),1.41(t,J=7.2Hz,3H),1.36(s,9H).

[0462]

[0463] At 0°C, aluminum chloride (1.57 g, 11.78 mmol) was slowly added to a toluene (30 mL) solution of 20a (1.0 g, 2.95 mmol), and the reaction mixture was stirred at room temperature for 4 hours under nitrogen protection. After the reaction was completed, the reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 20b. It can be used directly in the next step without further purification.

[0464]

[0465] 2,5-Dibromopyrazine (6.72 g, 28.2 mmol) was dissolved in isopropanol (20 mL) and heated to 80 ° C under nitrogen protection. To the solution was added dropwise a solution of 20b (2.0 g, 6.92 mmol) and N,N-diisopropylethylamine (2.328 mL, 14.08 mmol) in isopropanol (20 mL) over 2 hours, and the reaction was continued for 1 hour. After the reaction was completed, the reaction mixture was concentrated and purified to obtain a white solid 20c (0.950 g, yield: 30.6%).

[0466] 1 H NMR (400MHz, CDCl3) δ8.45(d,J=1.6Hz,1H),8.36(s,1H),8.16(d,J=1.6Hz,1H),8.10(dd,J=8.0,1.6Hz ,1H),7.80(dd,J=7.6,1.6Hz,1H),7.44(t,J=7.6Hz,1H),4.44(q,J=7.2Hz,2H),1.41(t,J=7.2Hz,3H).

[0467]

[0468] 20c (215 mg, 0.49 mmol), 1j (0.12 g, 0.49 mmol) and potassium phosphate (0.57 g, 2.71 mmol) were added to dry N,N-dimethylformamide (10 mL) and reacted at 80 ° C overnight under nitrogen protection. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The organic layer was dried, concentrated and scraped to obtain 20d (108 mg, yield: 45%).

[0469] 1 H NMR (400MHz, CDCl3) δ8.35(s,1H),8.24(d,J=1.2Hz,1H),8.18(d,J=1.2Hz,1H),7.79(dd,J=7 .6,1.6Hz,1H),7.20(t,J=8.0Hz,1H),7.09(dd,J=8.0,1.6Hz,1H),4.42(q,J=7.2Hz,2H),4.2 1-4.18(m,1H),4.02–3.91(m,2H),3.84(d,J=8.8Hz,1H),3.70(d,J=8.8Hz,1H),3.47-3.29(m ,2H),3.05(d,J=4.4Hz,1H),1.94-1.70(m,4H),1.40(t,J=7.2Hz,3H),1.26(d,J=6.4Hz,3H).

[0470]

[0471] 20d (0.1 g, 0.189 mmol) and lithium hydroxide (0.032 g, 0.76 mmol) were added to a mixed solution of methanol / water (0.5 mL / 2.0 mL) and reacted at room temperature for 4 hours. After the reaction was completed, the reaction mixture was diluted with water (2 mL) and the pH was adjusted to 7 with 1N hydrochloric acid aqueous solution. The solid was filtered, washed with water, and then washed with a small amount of cold methanol / dichloromethane (1 / 20) solution, and the solid was dried to obtain 20 (76 mg, yield: 80%).

[0472] 1H NMR (400MHz, MeOD-d4) δ8.29–8.27(m,3H),7.78(d,J=7.6Hz,1H),7.29(t,J=8.0Hz,1H),7.05(d,J=8.0Hz,1H),4.29-4.23(m,1H),4.13-4.06(m,2H) ,3.89(d,J=8.8Hz,1H),3.75(d,J=8.8Hz,1H),3.4-3.36(m,2H),3.05(d,J =4.8Hz,1H),1.91-1.69(m,4H),1.39–1.30(m,2H),1.25(d,J=6.4Hz,3H). LC-MS[M+H] + :m / z=502.1.

[0473] Embodiment 21

[0474]

[0475] 2-Cyanofuran (1 mL), N,N-dimethylformamide (10 mL), 1m (1.0 g, 3.1 mmol), palladium acetate (67 mg, 0.3 mmol), 2-(dicyclohexylphosphino)biphenyl (210 mg, 0.6 mmol), cesium carbonate (1.98 g, 6.1 mmol) were added to a 100 mL single-mouth bottle. The mixture was reacted at 110 °C for 5 hours. After post-treatment, the reaction solution was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, washed once with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and purified by column to obtain 21a (500 mg, yield: 59%).

[0476] 1 H NMR (400MHz, CDCl3) δ8.90(s,1H),7.82(dd,J=7.6,1.6Hz,1H),7.51(dd,J=7.6,1.6Hz,1H),7.37(t,J=7.6Hz,1H),1.38(s,9H).

[0477]

[0478] 21a (500 mg, 2.1 mmol) was dissolved in toluene (30 mL), and anhydrous aluminum chloride (1.7 g, 12.8 mmol) was added, and the mixture was reacted at room temperature for 3 hours. The mixture was extracted twice with water and ethyl acetate, washed once with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 21b, which was directly used in the next step.

[0479]

[0480] 2,5-Dibromopyrazine (1.6 g, 6.7 mmol) and N,N-diisopropylethylamine (670 mg, 5.4 mmol) were added to acetonitrile (20 mL), and the acetonitrile solution of 21b was slowly added dropwise under nitrogen protection for about 1 hour, and then reacted at room temperature for 5 hours. Water was slowly added, extracted with ethyl acetate, dried with sodium sulfate, filtered, concentrated under reduced pressure, and purified to obtain 21c (180 mg, yield 21%).

[0481]

[0482] Compound 21c (180 mg, 0.45 mmol) was added to a 100 mL single-mouth bottle, followed by 1j (110 mg, 0.45 mmol), N,N-dimethylformamide (5 mL), and potassium phosphate (572 mg, 2.7 mmol), and the mixture was heated to 80°C and reacted for 2 hours. 20 mL of water was added, the mixture was extracted twice with ethyl acetate, and washed three times with saturated brine. The organic phase was dried over sodium sulfate, concentrated, and purified to obtain 21 (40 mg, yield 18%).

[0483] 1 H NMR(400MHz, CDCl3)δ8.25(s,1H),8.20(s,1H),7.66(d,J=7.6Hz,1H),7.22(d,J=10.4Hz,3H),6.98(d,J=8.0Hz,1H),4.26-4.13(m,1H),4.01–3.87 (m,2H),3.82(d,J=8.8Hz,1H),3.70(d,J=8.8Hz,1H),3.57-3.30(m,2H), 3.00(d,J=4.4Hz,1H),1.97-1.82(m,1H),1.80-1.64(m,3H),1.24(s,3H). MS m / z[M+H] + :482.2.

[0484] Embodiment 22

[0485]

[0486] 10b (200 mg, 0.74 mmol) and phthalic anhydride (180 mg, 1.2 mmol) were added to acetic acid (2 mL) and reacted at 140°C in a sealed tube for 5 hours. Water was added, extracted with ethyl acetate, dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified to obtain 22a (250 mg, yield 80.6%).

[0487] 1H NMR (400MHz, CDCl3) δ8.40(s,1H),8.17(s,1H),8.02–7.93(m,2H),7.85–7.77(m,3H),7.48(m,2H).

[0488]

[0489] 22a (250 mg, 0.6 mmol), potassium phosphate (764 mg, 3.6 mmol) and 1j (145 mg, 0.6 mmol) were added to 10 mL of N,N-dimethylformamide, heated to 80 °C for 5 hours, water was added, extracted with ethyl acetate, dried over sodium sulfate, filtered, concentrated under reduced pressure and purified to obtain 22 (30 mg, yield: 9.1%).

[0490] 1 H NMR (DMSO, 400MHz): 8.25 (s, 1H), 7.79-7.63 (m,, 3H), 7.50-7.40 (m, 2H), 7.20 (t, J = 8.0Hz, 1H), 6.70 (d, J = 8.0Hz, 1H), 4.17-4.10 (m, 1H), 4.08-3.9 7(m,2H),3.81-3.76(d,J=8.8Hz,1H),3.60–3.56(d,J=8.8Hz,1H),3.25- 3.22(m,1H),3.17-3.14(m,1H),1.77-1.48(m,4H),1.15(d,J=6.4Hz,3H). MS m / z[M+H] + :554.2.

[0491] Embodiment 23

[0492]

[0493] Pyrazole [1,5-A] pyrimidine (547 mg, 4.6 mmol), N,N-dimethylformamide (8 mL, 1 m (1.5 g, 4.6 mmol, palladium acetate (103 mg, 0.46 mmol, lithium chloride (190 mg, 4.6 mmol, potassium carbonate (640 mg, 4.6 mmol) were added to a 30 mL sealed tube. The reaction was carried out at 120 ° C for 5 hours under nitrogen protection. After post-treatment, the reaction solution was first cooled to room temperature, 50 mL of water was added, and ethyl acetate was extracted three times. The organic phases were combined, washed once with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. Purification gave solid 23a (400 mg, yield: 25.6%).

[0494] 1H NMR (400MHz, CDCl3): δ8.73 (dd, J=7.2, 1.6Hz, 1H), 8.55 (d, J=2.4Hz, 2H), 7.81 (dd, J=7.6, 1.6Hz, 1H),7.65(dd,J=7.6,1.6Hz,1H),7.33(t,J=7.8Hz,1H),6.88(dd,J=7.2,4.0Hz,1H),1.38(s,9H).

[0495]

[0496] Dissolve 23a (400 mg, 1.3 mmol) in toluene (10 mL), add anhydrous aluminum chloride (335 mg, 2.52 mmol), and react at room temperature for 3 hours. Extract twice with water and ethyl acetate, wash once with saturated brine, dry with sodium sulfate, filter the desiccant, and concentrate under reduced pressure to obtain 23b, which is used directly in the next step.

[0497]

[0498] 2,5-Dichloropyrazine (257 mg, 1.38 mmol), 23b (330 mg, 1.26 mmol), potassium carbonate (350 mg, 2.52 mmol) were dissolved in N,N-dimethylformamide / acetonitrile (10 / 10 mL), protected by nitrogen, and then reacted at 80°C for 5 hours. Water was added, extracted with ethyl acetate, dried with sodium sulfate, the desiccant was filtered, concentrated under reduced pressure, and purified by column to obtain 23c (60 mg, yield 13%).

[0499] 1 H NMR (400MHz, CDCl3): δ8.74(dd,J=7.2,1.6Hz,1H),8.58(dd,J=4.0,1.6Hz,1H),8.54(s,1H),8.39(d,J=1.6Hz,1H),8.10(d ,J=1.6Hz,1H),7.95(dd,J=8.0,1.6Hz,1H),7.66(dd,J=7.6,1.6Hz,1H),7.44(t,J=7.6Hz,1H),6.92(dd,J=7.2,4.0Hz,1H).

[0500]

[0501] Compound 23c (60 mg, 0.16 mmol) was added to a 100 mL single-mouth bottle, followed by 1j (110 mg, 0.16 mmol), N,N-dimethylformamide (5 mL), and potassium phosphate (203 mg, 0.96 mmol), and the mixture was heated to 80°C and reacted for 2 hours. 20 mL of water was added, and the mixture was extracted twice with ethyl acetate. The organic phase was washed three times with saturated brine, dried over sodium sulfate, concentrated, and subjected to column chromatography to obtain 23 (20 mg, yield 24.5%).

[0502] 1 H NMR (400MHz, CDCl3): δ8.73 (dd, J=7.2, 1.6Hz, 1H), 8.57-8.49 (m, 2H), 8.21 (d, J=11.6 Hz,2H),7.62(dd,J=7.6,1.6Hz,1H),7.22(t,J=7.6Hz,1H),6.99(dd,J=8.0,1.2Hz,1H ),6.88(dd,J=7.2,4.0Hz,1H),4.29-4.21(m,1H),4.15-3.91(m,3H),3.74(d,J=9.0Hz ,1H),3.36-3.20(m,2H),2.04-1.96(m,1H),1.90-1.75(m,3H),1.37(d,J=6.4Hz,3H). MS m / z[M+H] + :508.3

[0503] Embodiment 24

[0504]

[0505] 24a (1.0 g, 12.0 mmol) was added to N-N-dimethylformamide (24 mL), followed by 1m (5.9 g, 18.0 mmol), cuprous iodide (457 mg, 2.4 mmol), and lithium tert-butoxide (1.15 g, 14.4 mmol). Under nitrogen protection, the temperature was raised to 145 °C and stirred for 3 hours. The mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate and washed once with saturated aqueous common salt solution, dried over anhydrous sodium sulfate, the desiccant was filtered, and the mixture was concentrated under reduced pressure. The mixture was passed through a column to obtain 24b (2.3 g, yield 67%).

[0506] 1 H NMR (400MHz, CDCl3) δ7.87(d,J=4.0Hz,1H),7.75(d,J=4.0Hz,1H),7.51(s,1H),7.30(t,J=8.0Hz,1H),2.27(s,3H),1.36(s,9H).

[0507]

[0508] 24b (2.0 g, 7.1 mmol) was dissolved in toluene (40 mL), and anhydrous aluminum chloride (5.68 g, 42.6 mmol) was added. The mixture was stirred at room temperature for 3 hours under nitrogen protection. Ice water was added to quench the mixture, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The desiccant was filtered and the mixture was concentrated under reduced pressure to obtain a crude product 24c, which was directly used in the next step.

[0509]

[0510] 2,5-Dibromopyrazine (5.06 g, 21.3 mmol) and N,N-diisopropylethylamine (1.84 mL, 14.2 mmol) were dissolved in isopropanol (50 mL). Under nitrogen protection, the temperature was raised to 70°C, and a solution of 24c (1.6 g, 7.1 mmol) in isopropanol (15 mL) was slowly added dropwise over 1 hour, and the temperature was raised to 80°C and stirred for 16 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, the desiccant was filtered, concentrated under reduced pressure, and purified by column to obtain 24d (600 mg, yield 22%). 1 H NMR (CDCl3, 400MHz): δ8.42 (s, 1H), 8.10 (s, 1H), 8.02 (d, J = 8.0Hz, 1H), 7.74 (d, J = 8.0Hz, 1H), 7.51 (s, 1H), 7.39 (t, J = 8.0Hz, 1H), 2.26 (s, 3H).

[0511]

[0512] 24d (600 mg, 1.57 mmol), 1j (495 mg, 2.04 mmol), potassium phosphate (2.0 g, 9.41 mmol) were added to isopropanol (20 mL), the atmosphere was replaced with nitrogen, the temperature was raised to 95°C and stirred for 36 hours. The mixture was cooled to room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, the desiccant was filtered, and the mixture was concentrated under reduced pressure to obtain the target product 24 (349 mg, yield 47%).

[0513] 1H NMR (400MHz, CDCl3): δ8.21(s,1H),8.15(s,1H),7.69(d,J=8.0Hz,1H),7.48(s,1H),7 .15(t,J=8.0Hz,1H),7.01(d,J=8.0Hz,1H),4.13-4.17(m,1H),3.84-3.94(m,2H),3.7 7(d,J=8.8Hz,1H),3.65(d,J=8.8Hz,1H),3.40-3.47(m,1H),3.30-3.36(m,1H),2.96( d,J=4.8Hz,1H),2.24(s,3H),1.81-1.88(m,1H),1.62-1.75(m,3H),1.19-1.21(m,5H). LCMS m / z[M+H + ]:472.2.

[0514] Embodiment 25

[0515]

[0516] 25a (4.8 g, 32.66 mmol) was added to N-N-dimethylformamide (160 mL), and sodium hydrogen (1.96 g, 48.99 mmol) was added in batches under an ice-water bath, stirred for 30 minutes, and then iodoethane (8.15 g, 52.26 mmol) was added, and the reaction was allowed to react at room temperature for 3 hours. Saturated aqueous ammonium chloride solution was added under an ice-water bath to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, the desiccant was filtered, and concentrated under reduced pressure to obtain 25b (4.3 g, yield 75%).

[0517] 1 H NMR (400MHz, CDCl3) δ7.25(m,1H),6.19(m,1H),4.08(m,2H),1.41(m,3H).

[0518]

[0519] 25b (4.3 g, 24.56 mmol) was added to toluene (125 mL), and then tetrakistriphenylphosphine palladium (1.42 g, 1.23 mmol) and hexabutyl ditin (14.25 g, 24.56 mmol) were added. Under nitrogen protection, the temperature was raised to 110°C and the reaction was carried out for 16 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and filtered to obtain 25c (2.6 g, yield 27%).

[0520] 1H NMR (400MHz, CDCl3) δ7.46 (d, J = 2.0 Hz, 1H), 6.30 (d, J = 2.0 Hz, 1H), 4.24 (m, 2H), 1.58 (m, 6H), 1.47 (m, 3H), 1.32 (m, 6H), 1.07 (m, 6H), 0.89 (m, 9H).

[0521]

[0522] 25c (2.5 g, 6.49 mmol) was added to xylene (65 mL), followed by 1m (1.8 g, 6.49 mmol) and tetrakistriphenylphosphine palladium (376 mg, 0.33 mmol), and the mixture was heated to 155°C for 2 hours under nitrogen protection. The mixture was cooled to room temperature, concentrated under reduced pressure, and filtered to obtain 25d (1.65 g, yield 85%).

[0523] 1 H NMR(400MHz, CDCl3)δ7.76(dd,J=6.0,1.6Hz,1H),7.62((dd,J=7.6,2.0Hz,1H),7.44(d, J=2.4Hz,1H),7.26(m,1H),6.73(d,J=2.4Hz,1H),4.22(m,2H),1.53(m,3H),1.35(s,9H).

[0524]

[0525] 25d (1.55 g, 5.26 mmol) was dissolved in toluene (50 mL), and anhydrous aluminum chloride (2.8 g, 21.03 mmol) was added under an ice-water bath, and the mixture was stirred at room temperature for 4 hours under nitrogen protection. The mixture was quenched with ice water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The desiccant was filtered and concentrated under reduced pressure to obtain a crude product 25e (1.25 g, yield 100%), which was directly used in the next step.

[0526]

[0527] 2,5-Dibromopyrazine (5 g, 21.03 mmol) was dissolved in isopropanol (10 mL), and the temperature was raised to 65°C under nitrogen protection. A mixed solution of 25e (1.25 g, 5.26 mmol) / isopropanol (10 mL) / N,N-diisopropylethylamine (1.36 g, 10.52 mmol) was slowly added dropwise over 1 hour, and stirring was continued at 65°C for 1 hour. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column to obtain 25f (500 mg, yield 25%).

[0528] 1H NMR (400MHz, CDCl3) δ8.44(s,1H),8.01(s,1H),7.91(m,1H),7.64(d,J=6.4Hz,1H),7.45 (d,J=2.0Hz,1H),7.35(t,J=7.6Hz,1H),6.73(d,J=2.1Hz,1H),4.23(m,2H),1.53(m,3H).

[0529]

[0530] 25f (450 mg, 1.14 mmol), 1j (360 mg, 1.48 mmol), potassium phosphate (1.45 g, 6.85 mmol) were added to isopropanol (12 mL), and the mixture was heated to 95°C and stirred for 48 hours under nitrogen protection. The mixture was concentrated under reduced pressure to obtain the target product 25 (200 mg, yield 36%).

[0531] 1 H NMR (400MHz, CDCl3) δ8.18(d,J=16.9Hz,2H),7.59(d,J=7.4Hz,1H),7.44(d,J=1.3Hz,1H),7.13(t,J=7.8Hz,1H),6.94(d,J=7.6Hz,1H),6.72(d,J=1 .4Hz,1H),4.27–4.09(m,3H),3.88(m,2H),3.72(m,2H),3.40(m,2H),2.96 (m,1H),1.84(m,1H),1.69(m,3H),1.51(m,4H),1.21(d,J=6.3Hz,3H).LCMS m / z[M+H] + :485.2.

[0532] Embodiment 26

[0533]

[0534]

[0535] 26a (5.0 g, 25.25 mmol) was added to 1,4-dioxane (150 mL), followed by sodium carbonate (8.0 g, 75.75 mmol), tris(dibenzylideneacetone)dipalladium (1.16 g, 1.26 mmol), 2-dicyclohexylphosphine-2′,6′-dimethoxy-biphenyl (1.04 g, 2.53 mmol), hexabutylditin (17.6 g, 30.30 mmol). Under nitrogen protection, the temperature was raised to 110°C for 16 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and passed through a column to obtain 26b (4.05 g, yield 39%).1 H NMR (400MHz, CDCl3) δ9.25(brs,1H),7.99(d,J=2.0Hz,1H),7.75(brs,1H),7.62(s,1H),1.58(m,6H),1.36(m,6H),1.19(m,6H),0.91(m,9H).

[0536]

[0537] 26b (4.0 g, 9.78 mmol) was added to xylene (50 mL), followed by 1m (2.8 g, 9.78 mmol) and tetrakistriphenylphosphine palladium (566 mg, 0.49 mmol), and the mixture was heated to 155°C for 2 hours under nitrogen protection. The mixture was cooled to room temperature, concentrated under reduced pressure, and filtered to obtain 26c (3.0 g, yield 96%).

[0538] 1 H NMR(400MHz, CDCl3)δ9.20(m,1H),8.44(m,1H),7.88(m,1H),7.78(m,1H),7.76 (dd,J=7.7,1.6Hz,1H),7.65(dd,J=7.7,1.6Hz,1H),7.36(m,1H),1.38(s,9H).

[0539]

[0540] 26c (2.8 g, 8.81 mmol) was dissolved in toluene (45 mL), and anhydrous aluminum chloride (4.7 g, 35.24 mmol) was added in batches, and the mixture was stirred at room temperature for 4 hours under nitrogen protection. Ice water was added to quench the mixture, and the layers were extracted with ethyl acetate and dried over sodium sulfate. The desiccant was filtered and the mixture was concentrated under reduced pressure to obtain a crude product 26d, which was directly used in the next step.

[0541]

[0542] 2,5-Dibromopyrazine (8.4 g, 35.24 mmol) was dissolved in isopropanol (60 mL), and the temperature was raised to 65°C under nitrogen protection. A mixed solution of 26d (2.2 g, 8.81 mmol) / isopropanol (15 mL) / N,N-diisopropylethylamine (2.27 g, 17.62 mmol) was slowly added dropwise over 1 hour, and the mixture was stirred at 65°C for 1 hour. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column to obtain 26e (700 mg, yield 20%).

[0543] 1H NMR (400MHz, CDCl3) δ9.20 (s, 1H), 8.48 (m, 2H), 8.14 (d, J = 1.3Hz, 1H), 7.88 (brs, 1H), 7.76 (m, 3H), 7.47 (t, J = 7.6Hz, 1H).

[0544]

[0545] 26e (700 mg, 1.67 mmol), 1j (528 mg, 2.17 mmol), potassium phosphate (2.13 g, 10.02 mmol) were added to isopropanol (36 mL), replaced with nitrogen, heated to 95°C and stirred for 20 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain the target product 26 (310 mg, yield 36%).

[0546] 1 H NMR (400MHz, CDCl3) δ9.09 (s, 1H), 8.39 (s, 1H), 8.15 (d, J = 21.3Hz, 2H), 7.76 (d, J = 17.1Hz, 2H), 7.36 (d, J = 7.3Hz, 1H), 7.14 (t, J = 7.8Hz, 1H), 6.94 (d ,J=7.7Hz,1H),4.12(m,1H),3.84(m,2H),3.74(m,1H),3.62(m,1H),3.36( m,2H),2.93(m,1H),1.86-1.77(m,1H),1.64(m,4H),1.16(d,J=6.3Hz,3H). LCMS m / z[M+H] + :508.2.

[0547] Embodiment 27

[0548]

[0549] 27a (73.0 g, 0.51 mol) was added to methanol (800 mL), and then aqueous ammonia (160 mL) was added, and the mixture was reacted at room temperature for 48 hours. The mixture was concentrated under reduced pressure to obtain a yellow solid 27b (64.0 g, yield 96%).

[0550]

[0551] 27b (56.0 g, 0.5 mol) was added to tetrahydrofuran (700 mL), and then pyridine (79.1 g) was added. The mixture was cooled in an ice-water bath, and TFFA (136.5 g) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 3 hours. Ethyl acetate was added, and the mixture was washed once with water, diluted hydrochloric acid and saturated brine. The organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered, and the filtrate was concentrated under reduced pressure. 27c (34.0 g, yield 72%) was obtained by column chromatography.

[0552]

[0553] 27c (30 g, 0.318 mol) was added to dioxane (50 mL), followed by 1m (104 g, 0.318 mol), palladium acetate (6.92 g, 0.0318 mol), 2-(dicyclohexylphosphino)biphenyl (11.14 g, 0.0318 mol), and cesium carbonate (209.3 g, 0.637 mol). The mixture was heated to 110° C. and stirred for 16 hours under nitrogen protection. The mixture was cooled to room temperature, concentrated under reduced pressure, and passed through a column to obtain 27d (15 g, yield 15.9%).

[0554] 1 H NMR (400MHz, CDCl3) δ8.35 (s, 1H), 7.95-7.88 (m, 2H), 7.41 (t, J = 8.0Hz, 1H), 1.41 (s, 9H).

[0555]

[0556] 27d (10.0 g, 34.13 mmol) was dissolved in toluene (150 mL), and anhydrous aluminum chloride (27.3 g, 204.78 mmol) was added. The mixture was stirred at room temperature for 4 hours under nitrogen protection. Ice water was added to quench the mixture, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The desiccant was filtered and concentrated under reduced pressure to obtain a crude product 27e, which was directly used in the next step.

[0557]

[0558] 2,5-Dibromopyrazine (20.3 g, 85.33 mmol) and 27d (8.0 g, 34.13 mmol) were added to acetonitrile (150 mL), and then N,N-diisopropylethylamine (8.82 g, 68.26 mmol) was added. The mixture was protected by nitrogen and stirred at room temperature for 2 hours.

[0559] The residue was concentrated under reduced pressure and purified by column to afford 27e (2.5 g, two-step yield 18.0%).

[0560]

[0561] 27e (2.5 g, 6.35 mmol), 1j (1.85 g, 7.62 mmol), potassium phosphate (8.09 g, 38.10 mmol) were added to N-N-dimethylformamide (50 mL), and the mixture was heated to 70°C and stirred for 4 hours under nitrogen protection. Water was added to precipitate solids, which were filtered and passed through a column to obtain the target product 27 (1.1 g, yield 37%).

[0562] 1 H NMR (400MHz, CDCl3) δ8.34(s,1H),8.31(m,1H),8.24(m,1H),7.80-7.78(m,1H),7.27(d,J=8.0Hz,1H),7.19-7.17(m,1H),4.27–4.21(m,1H),3 .98-3.97(m,2H),3.84(d,J=4.0Hz,1H),3.74(d,J=8.0Hz,1H),3.55-3.44(m,2H),3.04(d,J=4.0Hz,1H),1.95-1.74(m,6H),1.30(s,5H).LCMS m / z[M+H + ]:483.2.

[0563] Embodiment 28

[0564]

[0565] 28a (3.87 g, 45.92 mmol) was added to N-N-dimethylformamide (50 mL), followed by 1m (3.0 g, 9.18 mmol), palladium acetate (207 mg, 0.92 mmol), 2-(dicyclohexylphosphino)biphenyl (644 mg, 1.84 mmol), and cesium carbonate (5.97 g, 18.36 mmol). The mixture was heated to 110° C. and reacted for 16 hours under nitrogen protection. The mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, the desiccant was filtered, and the mixture was concentrated under reduced pressure. The mixture was passed through a column to obtain 28b (1.8 g, yield 69%).

[0566] 1 H NMR (400MHz, CDCl3) δ7.69(d,J=8.0Hz,1H),7.55(d,J=8.0Hz,1H),7.45(d,J=4.0Hz, 1H),7.40(d,J=4.0Hz,1H),7.29(t,J=4.0Hz,1H),7.15(t,J=4.0Hz,1H),1.43(s,9H).

[0567]

[0568] 28b (1.2 g, 4.23 mmol) was dissolved in toluene (50 mL), and anhydrous aluminum chloride (3.4 g, 25.35 mmol) was added. The mixture was stirred at room temperature for 3 hours under nitrogen protection. Ice water was added to quench the mixture, and the mixture was extracted with ethyl acetate and dried over sodium sulfate. The desiccant was filtered and concentrated under reduced pressure to obtain a crude product 28c, which was directly used in the next step.

[0569] 1 H NMR (400MHz, DMSO) δ7.45 (d, J = 4.0Hz, 1H), 7.38-7.35 (m, 3H), 7.21-7.15 (m, 2H), 4.02 (s, 1H).

[0570]

[0571] 2,5-Dibromopyrazine (2.52 g, 10.58 mmol) was dissolved in isopropanol (25 mL), and the temperature was raised to 80°C under nitrogen protection. A mixed solution of 28c (960 mg, 4.23 mmol) / isopropanol (25 mL) / N,N-diisopropylethylamine (1.1 g, 8.46 mmol) was slowly added dropwise over 1 hour, and the mixture was stirred at 80°C for 2 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column to obtain 28d (810 mg, yield 50%).

[0572] LCMS m / z[M+H+]:383.0.

[0573]

[0574] 28d (810 mg, 2.12 mmol), 1j (620 mg, 2.54 mmol), potassium phosphate (2.70 g, 12.72 mmol) were added to N-N-dimethylformamide (10 mL), the atmosphere was replaced with nitrogen, the temperature was raised to 100°C and stirred for 16 hours. Water was added to precipitate the solid, which was filtered and passed through a reverse phase column to obtain the target product 28 (150 mg, yield 15%).

[0575] 1H NMR (400MHz, CDCl3) δ8.34(s,1H),8.31(m,1H),8.24(m,1H),7.80-7.78(m,2H),7.27(d,J=8.0Hz,2H),7.19-7.17(m,1H),4.27-4.21(m,1H) ,3.98-3.97(m,2H),3.84(d,J=4.0Hz,1H),3.74(d,J=8.0Hz,1H),3.55-3.44(m,2H),3.04(d,J=4.0Hz,1H),1.95-1.74(m,6H),1.30(s,3H). LCMS m / z[M+H+]: 473.2.

[0576] Embodiment 29

[0577]

[0578] 1m (3.0 g, 9.2 mmol) was added to borane tetrahydrofuran complex (19.98 mL, 19.98 mmol), and then magnesium chips (0.225 g, 9.2 mmol) were added, and the reaction was carried out under ultrasound until the magnesium chips disappeared. Then water was slowly added dropwise, and the temperature was raised to 100 ° C and stirred for 2 hours. After cooling to room temperature, dilute hydrochloric acid was added, and ethyl acetate was extracted. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and slurried with dichloromethane and petroleum ether to obtain a white solid 29b (1.8 g, yield 80%).

[0579] 1 H NMR (400MHz, CDCl3) δ7.95 (dd, J=7.5, 1.7Hz, 1H), 7.76 (dd, J=7.6, 1.8Hz, 1H), 7.29 (t, J=7.5Hz, 1H), 5.40 (s, 2H), 1.34 (s, 9H).

[0580]

[0581] 29b (0.737 g, 3.02 mmol) was added to dioxane (15 mL), followed by water (5 mL), 6-bromopyrazolo[1,5-A]pyrimidine (0.6 g, 3.02 mmol), tetrakistriphenylphosphine palladium (0.349 g, 0.302 mmol), potassium carbonate (1.253 g, 9.06 mmol), and the mixture was heated to 110°C and stirred for 16 hours under nitrogen protection. The mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and passed through a column to obtain 29c (0.82 g, yield 85%).

[0582] 1H NMR (400MHz, CDCl3) δ8.74(d,J=1.5Hz,1H),8.58(d,J=2.1Hz,1H),8.17(d,J=2.3Hz,1 H),7.76(dd,J=7.2,2.2Hz,1H),7.42–7.32(m,2H),6.75(d,J=1.9Hz,1H),1.39(s,9H).

[0583]

[0584] 29c (0.82 g, 2.58 mmol) was dissolved in toluene (20 mL), and anhydrous aluminum chloride (1.376 g, 10.32 mmol) was added under an ice-water bath, and the mixture was stirred at room temperature for 4 hours under nitrogen protection. The mixture was quenched with ice water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product 29d, which was directly used in the next step.

[0585]

[0586] 2,5-Dibromopyrazine (2.455 g, 10.32 mmol) was dissolved in isopropanol (20 mL), and the temperature was raised to 80°C under nitrogen protection. A mixed solution of 29d (2.58 mmol) / isopropanol (30 mL) / N,N-diisopropylethylamine (1.7 mL, 10.32 mmol) was slowly added dropwise over 2 hours, and the mixture was stirred at 80°C for 1 hour. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column to obtain 29e (309 mg, yield 31%).

[0587] 1 H NMR (400MHz, CDCl3) δ8.77(dd,J=2.2,0.8Hz,1H),8.58(d,J=2.2Hz,1H),8.48(d,J=1.4Hz,1H),8.21(d,J=1. 4Hz,1H),8.19(d,J=2.3Hz,1H),7.75(dd,J=7.5,2.0Hz,1H),7.57–7.42(m,2H),6.77(dd,J=2.3,0.7Hz,1H).

[0588]

[0589] 29e (200 mg, 0.478 mmol), 1j (139 mg, 0.573 mmol), potassium phosphate (406 mg, 1.912 mmol) were added to N-N-dimethylformamide (10 mL), and the mixture was heated to 80°C and stirred for 4 hours under nitrogen protection. The mixture was cooled to room temperature, water was added, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and filtered to obtain the target product 29 (169 mg, yield 68%).

[0590] 1 H NMR (400MHz, CDCl3) δ8.74(d,J=1.4Hz,1H),8.57(d,J=2.2Hz,1H),8.27(d,J=1.2Hz,1H),8.21(d,J=1.1Hz ,1H),8.17(d,J=2.3Hz,1H),7.25-7.13(m,2H),7.04(dd,J=7.6,1.8Hz,1H),6.75(d,J=1.7Hz,1H),4.28-4 .15(m,1H),4.08-3.87(m,2H),3.82(d,J=8.8Hz,1H),3.70(d,J=8.8Hz,1H),3.52-3.45(m,1H),3.41-3.35 (m,1H),3.01(d,J=4.5Hz,1H),1.94-1.87(m,1H),1.84-1.64(m,3H),1.38(brs,2H),1.24(d,J=6.4Hz,3H). LCMS m / z[M+H + ]:508.3.

[0591] Embodiment 30

[0592]

[0593]

[0594] 30a (41.5 mg, 0.25 mmol) was dissolved in dichloromethane (3.0 mL), 2 drops of N-dimethylformamide were added, and then oxalyl chloride (1.0 mL) was slowly added under ice-water bath, and the reaction was stirred at room temperature for 4 hours under nitrogen protection. Concentration under reduced pressure gave the acid chloride. Dichloromethane (3.0 mL), 10b (68.0 mg, 0.25 mmol), N,N-diisopropylethylamine (0.164 mL.1.0 mmol) were added to the acid chloride, and the mixture was stirred at room temperature for 2 hours. Concentration under reduced pressure and column chromatography gave 30b (21.0 mg, yield 20%) as a white solid.

[0595] 1H NMR (400MHz, CDCl3) δ9.44(s,1H),8.74(dd,J=8.2,1.6Hz,1H),8.37(d,J=1.3Hz,1H),8.04(d,J=1.3Hz,1H),7.43(dd,J=7.7,1. 7Hz,1H),7.37(t,J=7.9Hz,1H),6.61(s,1H),4.19(t,J=6.2Hz,2H),2.85(t,J=6.4Hz,2H),2.16-1.98(m,2H),1.97-1.82(m,2H).

[0596]

[0597] 30b (83.0 mg, 0.198 mmol) was dissolved in N-N-dimethylformamide (5 mL), and then 1j (57.8 mg, 0.237 mmol) and potassium phosphate (168.1 mg, 0.792 mmol) were added. The mixture was heated to 80°C and stirred for 4 hours under nitrogen protection. The mixture was cooled to room temperature, water was added, extracted with dichloromethane, dried over anhydrous sodium sulfate, the desiccant was filtered, concentrated under reduced pressure, and passed through a column to obtain the target product 30 (40 mg, yield 37%).

[0598] 1 H NMR (400MHz, CDCl3) δ9.39(s,1H),8.44(dd,J=8.3,1.3Hz,1H),8.19(d,J=1.3Hz,1H),8.16(d,J=1.3Hz,1H),7. 16(t,J=8.1Hz,1H),6.79(dd,J=7.9,1.4Hz,1H),6.59(s,1H),4.20(t,J=6.1Hz,3H),4.01-3.85(m,2H),3.82(d, J=8.8Hz,1H),3.70(d,J=8.8Hz,1H),3.54-3.28(m,2H),3.01(d,J=4.3Hz,1H),2.84(t,J=6.4Hz,2H),2.14-2.0 1(m,2H),1.97-1.83(m,3H),1.82-1.63(m,3H),1.50-1.27(m,1H),1.25(d,J=6.4Hz,3H),1.13(d,J=6.1Hz,1H). LCMS m / z[M+H + ]:554.3.

[0599] Embodiment 31

[0600]

[0601] To a solution of 10b (400 mg, 1.48 mmol) in dichloroethane (10 mL), 3-oxabicyclo[3.1.0]hexane-2,4-dione (200 mg, 1.67 mmol) was added, and the mixture was heated to 100°C for 1.5 hours under nitrogen protection. After cooling to room temperature, N,N'-carbonyldiimidazole (360 mg, 2.22 mmol) was added, and the mixture was heated to 100°C for 4 hours under nitrogen protection, cooled to room temperature, and stirred overnight. After concentration under reduced pressure, 31b (300 mg, yield 46%) was obtained as a light yellow solid by column chromatography. 1 H NMR (400MHz, CDCl3): δ8.42(s,1H),8.17(s,1H),7.79-7.76(m,1H),7.48(t,J=8.0H z,1H),7.44-7.41(m,1H),2.76-2.70(m,2H),1.94-1.91(m,1H),1.75-1.71(m,1H).

[0602]

[0603] 31b (250 mg, 0.68 mmol), 1j (196 mg, 0.81 mmol), potassium phosphate (864 mg, 4.07 mmol) were added to N,N-dimethylformamide (5 mL), and the mixture was heated to 80°C and stirred for 4 hours under nitrogen protection. Water was added, extracted with dichloromethane, dried over anhydrous sodium sulfate, the desiccant was filtered, concentrated under reduced pressure, and passed through a column to obtain the target product 31 (50 mg, yield 18%).

[0604] 1 H NMR (400MHz, CDCl3): δ8.27(s,1H),8.23(s,1H),7.24(t,J=8.0Hz,1H),7. 14-7.10(m,2H),4.25-4.23(m,1H),4.02-3.95(m,2H),3.87(d,J=8.0Hz,1 H),3.73(d,J=8.0Hz,1H),3.51-3.40(m,2H),3.06-3.05(m,1H),2.74-2.6 8(m,2H),1.97-1.95(m,2H),1.81-1.72(m,4H),1.32(d,J=8.0Hz,3H).LCMS m / z[M+H + ]:500.3.

[0605] Embodiment 32

[0606]

[0607] 29b (0.584 g, 2.393 mmol) was added to dichloroethane (10 mL), followed by water (10 mL), 5-chloropyrazolo[1,5-a]pyrimidine (0.3676 g, 2.393 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.0875 g, 0.1197 mmol), sodium carbonate (1.268 g, 11.965 mmol), and the mixture was heated to 95°C and stirred for 16 hours under nitrogen protection. The mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, the desiccant was filtered, and the mixture was concentrated under reduced pressure. The mixture was passed through a column to obtain 32b (0.678 g, yield 89%).

[0608] 1 H NMR(400MHz,Chloroform-d)δ8.71(d,J=7.2Hz,1H),8.16(d,J=2.2Hz,1H),7.77(dd,J=7.7,1.6Hz,1H),7 .62(dd,J=7.7,1.6Hz,1H),7.37(t,J=7.7Hz,1H),7.16(d,J=7.2Hz,1H),6.78–6.73(m,1H),1.37(s,9H).

[0609]

[0610] 32b (0.68 g, 2.14 mmol) was dissolved in toluene (20 mL), and anhydrous aluminum chloride (1.14 g, 10.32 mmol) was added under an ice-water bath, and the mixture was stirred at room temperature for 4 hours under nitrogen protection. Ice water was added to quench the mixture, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The desiccant was filtered and concentrated under reduced pressure to obtain a crude product 32c, which was directly used in the next step.

[0611]

[0612] 2,5-Dibromopyrazine (2.04 g, 8.56 mmol) was dissolved in isopropanol (10 mL), and the temperature was raised to 80°C under nitrogen protection. A mixed solution of 32c (2.14 mmol) / isopropanol (25 mL) / N,N-diisopropylethylamine (1.414 mL, 8.56 mmol) was slowly added dropwise over 2 hours, and the mixture was stirred at 80°C for 1 hour. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column to obtain 32d (0.2 g, yield 22%).

[0613] 1H NMR (400MHz, CDCl3) δ8.73(d,J=7.3Hz,1H),8.46(d,J=1.4Hz,1H),8.19(d,J=2.3Hz,1H),8.15(d,J=1.4Hz, 1H),7.77(ddd,J=12.0,7.7,1.6Hz,2H),7.48(t,J=7.7Hz,1H),7.16(d,J=7.3Hz,1H),6.78(d,J=2.2Hz,1H).

[0614]

[0615] 32d (200 mg, 0.478 mmol), 1j (139 mg, 0.573 mmol), potassium phosphate (406 mg, 1.912 mmol) were added to N-N-dimethylformamide (10 mL), and the mixture was heated to 80°C and stirred for 4 hours under nitrogen protection. The mixture was cooled to room temperature, water was added, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and filtered to obtain the target product 32 (143 mg, yield 57%).

[0616] 1 H NMR (400MHz, CDCl3) δ7.45 (dd, J=7.6, 1.6Hz, 1H), 7.25 (t, J=7.8Hz, 1H), 7.16 (d,J=7.3Hz,1H),7.09(dd,J=8.0,1.6Hz,1H),6.76(dd,J=2.3,0.7Hz,1H),4. 25–4.15(m,1H),4.04–3.87(m,2H),3.83(d,J=8.8Hz,1H),3.70(d,J=8.8Hz,1 H),1.96–1.84(m,1H),1.82–1.64(m,3H),1.25(m,4H),1.13(d,J=6.1Hz,1H).

[0617] LCMS m / z [M+H + ]:508.3.

[0618] Embodiment 33

[0619]

[0620] Thiazole (300 mg, 3.5 mmol), 1m (1.4 g, 4.23 mmol), 2-(dicyclohexylphosphino)biphenyl (123.5 mg, 0.35 mmol), palladium acetate (158 mg, 0.70 mmol), cesium carbonate (2.27 g, 7.0 mmol) were added to dioxane (10 mL). The atmosphere was replaced with nitrogen three times and stirred at 110 ° C overnight. The reaction solution was cooled to room temperature, 50 mL of water was added, and ethyl acetate was extracted three times. The organic phases were combined, washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and purified by column to obtain an oil 33b (350 mg, yield: 35.2%).

[0621]

[0622] 33b (350 mg, 1.23 mmol) was dissolved in acetonitrile (0.5 mL), and concentrated hydrochloric acid (12 M, 5 mL) was added, and the mixture was reacted at 110°C for 5 hours. After adding water (10 mL), the mixture was extracted with ethyl acetate (20 mL) twice, washed once with saturated brine (20 mL), dried over sodium sulfate (5.0 g), filtered, and the filtrate was concentrated to dryness under reduced pressure and used directly in the next step.

[0623]

[0624] 2,5-Dibromopyrazine (454 mg, 3.5 mmol) was added to isopropanol (10 mL), nitrogen was protected, the temperature was raised to 80°C, N,N-diisopropylethylamine (671 mg, 2.82 mmol) and the isopropanol solution of 33c were slowly added dropwise for 1 hour, and then the temperature was raised to 80°C overnight. Water (20 mL) was added, and ethyl acetate (20 mL) was extracted twice, dried over sodium sulfate (5.0 g), filtered, and the filtrate was concentrated under reduced pressure and purified by column to obtain 33d (120 mg).

[0625]

[0626] Compound 33d (50 mg, 0.13 mmol), 1j (25.5 mg, 0.15 mmol), added N, N-dimethylformamide (2 mL), then potassium phosphate (166.5 mg, 0.78 mmol), heated to 110 ° C, reacted for 2 hours. Add 20 mL of water, extract twice with ethyl acetate (20 mL), wash three times with saturated brine (20 mL), the organic phase is dried with sodium sulfate (5.0 g), spin-dried, and passed through a normal phase column to prepare a plate scraper to obtain 33 (35 mg, yield 28%).

[0627] 1H NMR(400MHz, CDCl3)δ8.92(s,1H),8.29-9.24(m,2H),8.09(m,1H),7.35–6.3 4(m,1H),7.23–7.19(m,1H),7.06-7.04(m,1H),4.28-4.24(m,1H),4.03-3.98 (m,2H),3.92-3.89(m,1H),3.77-3.74(m,1H),3.53-3.52(m,1H),3.41-3.35( m,1H),3.12-3.11(m,1H),2.05-1.97(m,2H),1.80-1.78(m,2H),1.30(s,3H). LCMS m / z[M+H] + :488.4.

[0628] Embodiment 34

[0629]

[0630] Thiazole (175 mg, 1.8 mmol), 34a (500 mg, 1.5 mmol), cuprous iodide (58 mg, 0.3 mmol), cesium carbonate (1 g, 3 mmol) were added to dioxane (5 mL). The mixture was reacted at 140 °C for 48 hours. The reaction solution was cooled to room temperature, 50 mL of water was added, and ethyl acetate (30 mL) was extracted three times. The organic phases were combined, washed once with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate (5.0 g), and purified by column to obtain 34b (160 mg, yield 37.6%).

[0631]

[0632] 34b (160 mg, 0.56 mmol) was dissolved in acetonitrile (0.5 mL), and concentrated hydrochloric acid (12 M, 5 mL) was added, and the mixture was reacted at 110°C for 5 hours. After adding water (10 mL), the mixture was extracted with ethyl acetate (20 mL) twice, washed once with saturated brine (20 mL), dried over sodium sulfate (5.0 g), filtered, and the filtrate was concentrated to dryness under reduced pressure and used directly in the next step.

[0633]

[0634] 2,5-Dibromopyrazine (337.4 mg, 1.4 mmol) was added to isopropanol (10 mL), and the temperature was raised to 80°C under nitrogen protection. N,N-diisopropylethylamine (146 mg, 1.12 mmol) and isopropanol (2 mL) solution of 34c were slowly added dropwise for 1 hour, and then the temperature was raised to 80°C overnight. The temperature was lowered to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL) twice, dried over sodium sulfate (5.0 g), filtered, and the filtrate was concentrated under reduced pressure to dryness, and purified by column to obtain 34d (30 mg, yield 13.9%).

[0635]

[0636] Compound 34d (30 mg, 0.078 mmol) and 1j (20 mg, 0.086 mmol) were added with N,N-dimethylformamide (2 mL) and potassium phosphate (99 mg, 0.47 mmol), heated to 110°C and reacted for 2 hours. The mixture was cooled to room temperature and 20 mL of water was added. The mixture was extracted twice with ethyl acetate (20 mL), washed three times with saturated brine (20 mL), and the organic phase was dried with sodium sulfate (5.0 g) and purified by column to obtain 34 (12 mg, yield 32.5%).

[0637] 1 H NMR(400MHz, CDCl3)δ8.15(s,1H),8.10(s,1H),7.89-7.85(m,2H),7.41–7.40(m,1H),7.14-7.10(m,1H),6.97-9.65(m,1H),4.12-4.06 (m,1H),3.88-3.79(m,2H),3.73-3.71(m,1H),3.61-3.59(m,1H),3.40-3.25(m,2H),2.92-2.90(m,1H),1.82-1.62(m,4H),1.15(s,3H). LCMS m / z[M+H] + :474.2.

[0638] Embodiment 35

[0639]

[0640]

[0641] 10b (50 mg, 0.18 mmol), pyrimidine-2-carboxylic acid (27 mg, 0.22 mmol), N,N-carbonyldiimidazole (44 mg, 0.27 mmol), dichloroethane (5 mL) were added. The mixture was reacted at 130°C for 48 hours. The mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted twice with ethyl acetate (20 mL), washed once with saturated brine (20 mL), dried with sodium sulfate (5.0 g), filtered, concentrated to dryness under reduced pressure, and purified by column chromatography to obtain 35b (90 mg).

[0642]

[0643] Compound 35b (110 mg, 0.29 mmol), 1j (79 mg, 0.32 mmol), added N, N-dimethylformamide (5 mL), then potassium phosphate (370 mg, 1.78 mmol), heated to 110 ° C, reacted for 2 hours. Cooled to room temperature, added 20 mL of water, extracted twice with ethyl acetate (20 mL), washed once with saturated brine (20 mL), dried with sodium sulfate (5.0 g), filtered, concentrated under reduced pressure, and purified by column to obtain 35 (30 mg, yield: 20.1%)

[0644] 1 H NMR (400MHz, CD3OD) δ8.97-8.96(m,2H),8.29-8.17(m,1H),8.20-8.16(m,2H),7.67-7.65(m,1H),7.21-7.17(m,1H),6.73-6.70(m,1H),4.19 -1.13(m,1H),4.05-3.97(m,2H),3.82-3.80(m,1H),3.66-3.64(m,1H) ,3.41-3.25(m,3H),2.96-2.95(m,1H),1.80-1.57(m,4H),1.15(s,3H). LCMS m / z[M+H] + :512.2.

[0645] Embodiment 36

[0646]

[0647] 11b (100 mg, 0.41 mmol), 2-chloro-3-((5-chloropyrazin-2-yl)mercapto)aniline (133 mg, 0.49 mmol), chlorobenzene (15 ml) were added. The mixture was kept at 130°C overnight. The temperature was lowered and ethyl acetate (15 mL) was added. Solids precipitated and were filtered to obtain 36b (110 mg, yield 49%).

[0648]

[0649] 36b (60 mg, 0.13 mmol), 1j (26 mg, 0.15 mmol), dimethyl sulfoxide (15 mL), potassium phosphate (166 mg, 0.78 mmol), heated to 80 ° C overnight. Cool to room temperature, add saturated brine (75 mL), stir for 30 minutes, filter to obtain a solid. Purify by column to obtain 36 (60 mg, yield: 76%).

[0650] 1 H NMR(400MHz,DMSO-d6)δ13.96(s,1H),8.61-9.59(m,1H),8.48-8.42(m,2H),8. 22-8.21(m,1H),7.55-7.51(m,1H),6.94-6.92(m,1H),6.74-6.71(m,1H),6.47- 6.44(m,1H),4.09-4.05(m,1H),3.92-3.84(m,2H),3.68-3.66(m,1H),3.49-3.4 2(m,3H),2.91-2.90(m,1H),2.02-1.97(m,1H),1.78-1.45(m,4H),1.23(s,3H). LCMS m / z[M+H] + :594.3.

[0651] Embodiment 37

[0652]

[0653] 37a (69.0 mg, 0.5 mmol) was added to dry tetrahydrofuran (2.0 mL), and oxalyl chloride (0.127 mL, 1.75 mmol) was added dropwise, and refluxed under nitrogen for 3 hours. The solvent was removed under reduced pressure. The obtained oil was dissolved in dry tetrahydrofuran (1.0 mL), and a tetrahydrofuran solution (3.0 mL) of 10b (136.0 mg, 0.5 mmol) was slowly added, refluxed under nitrogen for 2 hours, and concentrated through a silica gel column with ethyl acetate / petroleum ether (0-30%) to obtain 37b (175.0 mg, yield 89%).

[0654] 1H NMR (400MHz, CDCl3) δ11.74(s,1H),8.72(s,1H),8.64(dd,J=8.3,1.5Hz,1H),8.42(d,J=1.4Hz,1H),8.17(d,J=1.4Hz,1H ),7.61(dd,J=8.1,1.3Hz,1H),7.58–7.51(m,2H),7.47(t,J=8.0Hz,1H),7.11(dd,J=8.4,0.9Hz,1H),7.05–6.97(m,1H).

[0655]

[0656] The target product 37 was obtained by the method of synthesizing 36.

[0657] 1 H NMR (400MHz, DMSO-d6) δ8.46(d,J=1.1Hz,1H),8.38(dd,J=8.2,1.2Hz,1H),8.28(d,J=1.2Hz,1H),7.99(dd,J=8 .0,1.8Hz,1H),7.47–7.30(m,1H),7.26(t,J=8.0Hz,1H),6.98(d,J=8.0Hz,1H),6.93–6.93(m,1H),6.82(t,J=7. 2Hz,1H),6.67(dd,J=8.0,1.3Hz,1H),4.21–4.08(m,1H),4.07–3.92(m,2H),3.76(d,J=8.8Hz,1H),3.57(d,J=8. 8Hz, 1H), 3.50–3.28 (m, 2H), 3.08 (d, J = 5.2Hz, 1H), 1.89–1.65 (m, 2H), 1.66–1.46 (m, 2H), 1.14 (d, J = 6.4Hz, 3H). LCMS[M+H] + :m / z=526.3.

[0658] Embodiment 38

[0659]

[0660] The target product 38 was obtained by the method of synthesizing 36.

[0661] 1H NMR (400MHz, DMSO-d6) δ8.52–8.38(m,2H),8.27(d,J=1.2Hz,1H),7.80(d,J=3.0Hz,1H),7.28–7.09(m,2H),6.74(d,J=8.9Hz,1H),6.63(dd,J= 7.9,1.3Hz,1H),4.26–3.98(m,3H),3.84(d,J=8.9Hz,1H),3.64(d,J=8.9Hz,1H),3.38–3.18(m,3H),1.87–1.49(m,4H),1.19(d,J=6.5Hz,3H). LCMS[M+H] + :m / z=560.2.

[0662] Embodiment 39

[0663]

[0664] The target product 39 was obtained by the method of synthesizing 36.

[0665] 1 H NMR (400MHz, DMSO-d6): δ9.43(s,1H),8.26(m,1H),8.23(s,1H),8.20(s,1H),7.2(t,J=8. 0Hz,1H),6.82(m,1H),4.26-4.20(m,3H),4.00-3.90(m,2H),3.85(d,J=8.0Hz,1H),3.73(d ,J=12.0Hz,1H),3.53-3.46(s,1H),3.42-3.36(s,1H),3.03(d,J=4.0Hz,1H),2.98(t,J=10 .0Hz,2H),2.73-2.66(m,2H),1.95-1.88(m,1H),1.83-1.69(m,3H),1.28(d,J=8.0Hz,3H). LCMS m / z[M+H] + :540.3

[0666] Embodiment 40

[0667]

[0668] 1m (100 mg, 0.3 mmol), 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester (101.9 mg, 0.45 mmol), tetrakistriphenylphosphine palladium (17.68 mg, 0.01 mmol), potassium carbonate (126.7 mg, 0.918 mmol) were added to a mixed solution of toluene (5 mL), water (1 mL), and ethanol (1 mL). The mixture was reacted at 100°C for 16 hours. The reaction solution was cooled to room temperature, 50 mL of water was added, and ethyl acetate (50 mL) was extracted three times. The organic phases were combined, washed once with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate (5.0 g), concentrated, and purified by column to obtain 40a (65 mg, yield 74%).

[0669] 1H NMR (400MHz, CDCl3): δ7.85(s,1H),7.81(s,1H),7.61-7.59(m,1H),7.49-7.47(m,1H),7 .28-7.24(m,1H),7.06-7.04(m,1H),4.30-4.24(m,2H),1.60-1.56(m,3H),1.40(s,9H).

[0670]

[0671] 40a (65 mg, 0.22 mmol) was dissolved in acetonitrile (0.5 mL), concentrated hydrochloric acid (12 M, 5 mL) was added, and the mixture was reacted at 120°C for 5 hours. After cooling to room temperature, 20 mL of water was added, and the mixture was extracted twice with ethyl acetate (20 mL), washed once with saturated brine (20 mL), dried over sodium sulfate (5.0 g), filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in dioxane (5 mL), 2-chloro-5-bromopyrazine (43 mg, 0.22 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (13 mg, 0.02 mmol), tris(dibenzylideneacetone)dipalladium (10 mg, 0.01 mmol), N,N-diisopropylethylamine (9 mg, 0.7 mmol) were added, and the mixture was reacted at 100°C for 16 hours under nitrogen protection. 50 mL of water was added, and the mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed once with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate (5.0 g), and purified by column to obtain 40b (55 mg, yield: 30%).

[0672]

[0673] 40b (55 mg, 0.15 mmol) and 1j (25.5 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (2 mL), potassium phosphate (166.5 mg, 0.78 mmol) was added, heated to 110°C, and reacted for 2 hours. After cooling to room temperature, 50 mL of water was added, and the mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed once with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate (5.0 g), and purified by column to obtain 40 (20 mg, yield 26%).

[0674] 1H NMR (400MHz, CDCl3): δ8.13(s,1H),8.09(s,1H),7.70(s,1H),7.66(s,1H),7.16(s ,1H),7.03-6.99(m,1H),6.77-6.75(m,1H),4.16-4.08(m,4H),3.83-3.80(m,2H), 3.74-3.72(m,1H),3.61-3.59(m,1H),3.38-3.26(m,1H).4.16-4.08(m,4H),2.92- 2.91(m,1H),1.80-1.77(m,1H),1.68-1.61(m,1H),1.46-1.42(m,3H),1.14(s,9H). LCMS m / z[M+H] + :485.3.

[0675] Embodiment 41

[0676]

[0677] 41a (0.83 g, 2.0 mmol) was added with concentrated hydrochloric acid (10 mL) and refluxed with stirring until the reaction was completed. The yellow solid obtained was concentrated under reduced pressure, and the ginger vinegar product and N,N-diisopropylethylamine (1.32 mL, 8.0 mmol) were dissolved in isopropanol (20 mL), heated to 80 ° C, and an isopropanol solution (15 mL) of 2,5-dibromopyrazine (1.9 g, 8.0 mmol) was added within 2 hours and stirred for one hour. Concentration and column chromatography (petroleum ether / ethyl acetate: 0-25%) gave 41b (0.27 g, yield: 32%).

[0678] 1H NMR (400MHz, DMSO-d6): δ12.27(s,1H),8.78(d,J=1.4Hz,1H),8.50(s,1H),8.49(d,J=1.4Hz,1H),8.05-7.94(m, 1H), 7.84 (dd, J=7.7, 1.6Hz, 1H), 7.75 (dd, J=7.7, 1.6Hz, 1H), 7.58 (t, J=7.7Hz, 1H), 6.73 (dd, J=3.5, 1.7Hz, 1H).

[0679]

[0680] 41b (0.075 g, 0.179 mmol), 1j (0.048 g, 0.197 mmol), potassium phosphate (0.152 g, 0.716 mmol), N,N-dimethylformamide (5 mL) were added, and stirred at 70-75°C for 1 hour. Concentration column chromatography (dichloromethane: methanol = 100% to 10:1) gave 41 (50 mg, yield: 55%).

[0681] 1 H NMR (400MHz, DMSO-d6): δ12.26(s,1H),8.50(s,1H),8.47(s,1H),8.33(s,1H),7.99(d,J=3.1Hz,1H),7 .43(dd,J=7.6,1.6Hz,1H),7.38(t,J=7.7Hz,1H),6.97(dd,J=7.8,1.7Hz,1H),6.72(d,J=3.5Hz,1H),4. 16-4.05(m,1H),4.01-3.85(m,2H),3.71(d,J=8.5Hz,2H),3.52(d,J=8.5Hz,1H),2.95(d,J=5.1Hz,1H), 1.87-1.74(m,1H),1.74-1.63(m,1H),1.63-1.44(m,2H),1.11(d,J=6.4Hz,3H),1.05(d,J=10.0Hz,2H). LCMS:[M+H] + =508.3.

[0682] Embodiment 42

[0683]

[0684]

[0685] 1m (326 mg, 1.0 mmol), 42a (238.1 mg, 1.0 mmol), tetrakistriphenylphosphine palladium (115 mg, 0.1 mmol), potassium carbonate (400 mg, 3.0 mmol) were dissolved in dioxane (10 mL) and water (1 mL), replaced with nitrogen three times, and stirred at 110°C for 16 hours. Concentrated and passed through a column (petroleum ether: ethyl acetate = 100% to 10:1) to obtain 42b (270 mg, yield: 87.1%).

[0686]

[0687] 42b (260 mg,) was added with concentrated hydrochloric acid (5 mL, 12 M), replaced with nitrogen three times, and stirred at 80°C for 2 hours. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate at 0-10°C, extracted with ethyl acetate (20 mL×6), dried, filtered, and concentrated to obtain 42c, which was used directly in the next step.

[0688] LCMS m / z[M+H] + :255.2.

[0689]

[0690] 42c (160 mg, 0.8 mmol), 2-chloro-5-bromopyrazine (152 mg, 0.8 mmol), tris(dibenzylideneacetone)dipalladium (36.6 mg, 0.04 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (46.2 mg, 0.08 mmol), N,N-diisopropylethylamine (310 mg, 2.4 mmol) were dissolved in dioxane (10 mL), replaced with nitrogen three times, and stirred at 110°C for 16 hours. The mixture was concentrated and passed through a column (petroleum ether:ethyl acetate = 100% to 10:1) to obtain 42d (180 mg, yield: 77%).

[0691] MS m / z[M+H] + :367.1.

[0692]

[0693] 42d (180 mg, 0.49 mmol), 1j (131 mg, 0.54 mmol), potassium phosphate (636 mg, 3.0 mmol), dimethyl sulfoxide (5 mL) were added, and stirred at 80-85°C for 16 hours. After cooling to room temperature, the reaction solution was poured into 10% brine (50 mL), stirred for 5 minutes, extracted with ethyl acetate (50 mL×3), concentrated, and column chromatography (dichloromethane: methanol = 100% to 10:1) to obtain 42 (30 mg, yield: 12.2%).

[0694] 1 H NMR (CDCl3, 400MHz): δ8.22(s,1H),8.17(s,1H),7.85(s,1H),7.79(s,1H),7.24(dd,1H) ,7.10(t,J=8.0Hz,1H),6.84(dd,1H),4.29(t,J=4.0Hz,2H),4.19-4.16(m,1H),4.04(t,J =4.0Hz,2H),3.93-3.88(m,2H),3.80(d,J=12.0Hz,1H),3.72-3.67(m,1H),3.43-3.32(m ,2H),2.98(d,J=4.0Hz,1H),1.85-1.83(m,1H),1.75-1.67(m,3H),1.23(d,J=8.0Hz,3H). LCMS m / z[M+H] + :501.2.

[0695] Embodiment 43

[0696]

[0697]

[0698] 43a (1.59 g, 10 mmol), 1l (2.15 g, 10 mmol), tris(dibenzylideneacetone)dipalladium (228 mg, 0.25 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (288 mg, 0.5 mmol), sodium tert-butoxide (1.44 g, 15 mmol), were added to toluene (20 mL), replaced with nitrogen three times, and stirred at 110°C for 16 hours. 43b (2.5 g, yield: 85.0%) was obtained by column chromatography (petroleum ether: ethyl acetate = 100% to 10:1).

[0699]

[0700] 43b (500 mg,) was added with concentrated hydrochloric acid (5 mL, 12 M). The atmosphere was replaced with nitrogen three times and stirred at 80°C for 2 hours. The mixture was cooled to room temperature and quenched with saturated sodium bicarbonate at 0-10°C. The mixture was extracted with ethyl acetate (100 mL × 3), dried, filtered, and concentrated to give 43c, which was used directly in the next step.

[0701] 1H NMR (CDCl3, 400MHz): δ 8.46 (s, 1H), 8.45 (s, 1H), 8.33 (dd, 1H), 7.7 (s, 1H), 7.15 (t, J = 8.0Hz, 1H), 7.02 (dd, 1H), 6.80 (t, J = 4.0Hz, 1H).

[0702]

[0703] 43c (237 mg, 1.0 mmol), 2-chloro-5-bromopyrazine (190 mg, 1.0 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (57 mg, 0.1 mmol), N,N-diisopropylethylamine (390 mg, 3.0 mmol), dioxane (4.5 mL) were added. Nitrogen was replaced three times and stirred at 110°C for 16 hours. Column (petroleum ether: ethyl acetate = 100% to 10:1) was used to obtain 43d (250 mg, yield: 71.4%).

[0704] LCMS m / z[M+H] + :350.2.

[0705]

[0706] 43d (200 mg, 0.57 mmol), 1j (153 mg, 0.63 mmol), potassium phosphate (726 mg, 6.0 mmol), dimethyl sulfoxide (5 mL) were added, and stirred at 80-85 ° C for 16 hours. The reaction solution was poured into 10% saline (50 mL), stirred for 5 minutes, and extracted with ethyl acetate (50 mL × 3). Passed through a normal phase silica gel column, dichloromethane: methanol = 100% to 10:1 to obtain 170 mg of solid, passed through a reverse phase column (water / acetonitrile = 100% to 60%), and 43 (40 mg yield: 14.5%) was obtained.

[0707] 1H NMR (CDCl3, 400MHz): δ8.47 (s, 1H), 8.46 (s, 1H), 8.43 (d, J = 8.0Hz, 1H), 8.17 (s ,1H),8.16(s,1H),7.7(s,1H),7.17(t,J=8.0Hz,1H),6.80(t,J=4.0Hz,1H),6.7 3(d,J=8.0Hz,1H),4.27-4.24(m,1H)4.12-3.95(m,3H),3.75(d,J=12.0Hz,1H) ,3.29-3.20(m,3H),2.0-1.98(m,1H),1.90-1.74(m,3H),1.38(d,J=4.0Hz,3H). LCMS m / z[M+H] + :484.3.

[0708] Embodiment 44

[0709]

[0710]

[0711] 1m (100 mg, 0.3 mmol), 44a (45 mg, 0.46 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (22 mg, 0.03 mmol), sodium tert-butoxide (59 mg, 0.6 mmol), toluene (3 mL) were added, and the mixture was reacted at 100°C for 16 h. The reaction solution was cooled to room temperature, 50 mL of water was added, and the mixture was extracted twice with ethyl acetate (20 mL), washed once with saturated brine (20 mL), dried over sodium sulfate (5.0 g), filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 44b (150 mg, yield 52%).

[0712] 1H NMR (400MHz, CDCl3): δ7.49(s,1H),7.39(s,1H),7.09-7.05(m,2H),6.35-6.33(m,1H),3.94(m,3H),1.39(m,9H).

[0713]

[0714] 44b (150 mg, 0.50 mmol) was dissolved in acetonitrile (2 mL), concentrated hydrochloric acid (12 M, 6 mL) was added, and the mixture was reacted at 120°C for 5 hours. 20 mL of water was added, and the mixture was extracted twice with ethyl acetate (20 mL), washed once with saturated brine (20 mL), dried over sodium sulfate (5.0 g), filtered, and concentrated to dryness under reduced pressure. The crude product was dissolved in dioxane (5 mL), and 2-chloro-5-bromopyrazine (99 mg, 0.50 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (29.3 mg, 0.05 mmol), tris(dibenzylideneacetone)dipalladium (46.5 mg, 0.05 mmol), and N,N-diisopropylethylamine (196.7 mg, 1.52 mmol) were added in sequence, and the mixture was reacted at 100°C for 16 hours under nitrogen protection. After cooling to room temperature, water (20 mL) was added, extracted twice with ethyl acetate (20 mL), washed once with saturated brine (20 mL), dried over sodium sulfate (5.0 g), filtered, concentrated under reduced pressure, and purified by column to obtain 44c (100 mg, yield: 56%).

[0715]

[0716] Compound 44c (100 mg, 0.25 mmol) and 1j (74 mg, 0.30 mmol) were added to N,N-dimethylformamide (5 mL), and potassium phosphate (322 mg, 1.52 mmol) was added, and the mixture was heated to 110°C and reacted for 2 hours. After cooling to room temperature, water (20 mL) was added, and the mixture was extracted twice with ethyl acetate (20 mL), washed once with saturated brine (20 mL), dried over sodium sulfate (5.0 g), filtered, concentrated under reduced pressure, and purified by column to obtain 44 (20 mg, yield 14%).

[0717] 1H NMR (400MHz, CDCl3) δ8.06-8.05(s,2H),7.32(s,1H),7.24(s,1H),6.84-6.80(s,1H),6.54-6.54(s,1H),6.34-6.32(m,1H),4.12-4. 06(m,1H),3.79(m,3H),3.72-3.70(m,1H),3.60.3.58(m,1H),3.38-3.19(m,3H),2.91-2.90(m,1H),1.81-1.66(m,4H),1.15(m,3H). LCMS m / z[M+H] + :486.3.

[0718] Biological activity evaluation

[0719] The compounds of the invention were evaluated for their ability to selectively inhibit SHP2 activity. The inhibitory properties of the compounds of the invention described herein can be demonstrated by testing in any of the following assays.

[0720] SHP2 allosteric inhibition experiments

[0721] SHP2 is allosterically activated by activation of its Src Homology 2 (SH2) domain by a di-tyrosyl-phosphorylated peptide. The latter activation step results in the release of the autoinhibitory interface of SHP2, which in turn renders the SHP2 protein tyrosine phosphatase (PTP) active and available for substrate recognition and reaction catalysis. The catalytic activity of SHP2 is monitored in a rapid fluorescence assay format using the surrogate substrate DiFMUP.

[0722] Phosphatase reactions were performed in flat-bottom, low-edge, non-binding surface 384-well black polystyrene plates (Corning, Cat#3575) at room temperature using a final reaction volume of 25 μL and the following assay buffer conditions: 60 mM HEPES, pH 7.2, 75 mM NaCl, 75 mM KCl, 1 mM EDTA, 0.05% P-20, 5 mM DTT.

[0723] The following experiment was used to monitor the inhibition of SHP2 by the compounds of the present invention (at concentrations ranging from 0.0003 to 100 μM):

[0724] Among them, 0.5nM SHP2 was incubated with 0.5μM peptide IRS1_pY1172(dPEG8)pY1222 (sequence: H2N-LN(pY)IDLDLV(dPEG8)LST(pY)ASINFQK-amide) (SEQ ID NO: 1) (WO2016 / 203406A1). After incubation at 25°C for 30-60 minutes, the alternative substrate DiFMUP (Invitrogen, cat#D6567) was added to the reaction and incubated at 25°C for 30 minutes. The reactants were then carefully diluted by adding 5μL of 160μM bpV(Phen) solution (Enzo Life Sciences cat#ALX-270-204). The fluorescence signal was monitored using a microplate reader (VARIOSKAN LUX, Thermo) with excitation and emission wavelengths of 340nm and 450nm, respectively. IC was normalized using control-based normalization 50 The IC values ​​of the compounds listed in the examples of the present invention are 50 Listed in Table 1.

[0725] Table 1 IC values ​​of compounds for inhibition of SHP2 50 value

[0726]

[0727]

[0728]

[0729]

[0730]

[0731]

[0732]

[0733]

[0734]

[0735] By comparing the test data in Table 1 with the activity data of the compounds in WO2016 / 203406A1, it can be seen that the novel pyrazine derivatives of the present invention have significantly better SHP2 inhibitory activity than the compounds in WO2016 / 203406A1 (such as compound 96 in Table 9).

[0736] The above describes the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art may make various modifications or variations within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the structure of the compound of formula (I) is: in: R 1 and R 2 To form a tetrahydrofuran ring, optionally, the tetrahydrofuran ring is substituted by 1-3 -OH, -NH2, -CN, NO2, halogen atoms, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 substituted by aryl or 5-10 membered heteroaryl; R 3 Selected from H, D; X is selected from a chemical bond, -NH-, -CONH-; Y is selected from CR 0 , where R 0 Selected from H, D, -OH, -CN, halogen atoms, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 12 Cycloalkylamino, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, 3-8 membered heterocyclic group, halogenated C1-C 10 Alkylamino, C6-C 10 Aryl or 5-10 membered heteroaryl, wherein the heterocyclic group or heteroaryl group optionally contains 1-4 heteroatoms selected from S, O, N or NH; Every R 4 Each is the same or different and is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, -CONHR 14 or-NHCOR 15 , substituted or unsubstituted following groups: -NH2, C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl; wherein R 14 and R 15 Each independently selected from C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the substitution is selected from C1-C 10 Alkyl, halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 The aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group is substituted with one or more substituents, wherein the substituents are optionally substituted with 1-3 C1-C 10 Alkyl, halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C3-C 12 substituted by cycloalkyl; Selected from C6-C 10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclic group; wherein the 5-10 membered heteroaryl, 3-12 membered heterocyclic group contains 1-3 heteroatoms or groups selected from N, NH, O, S, C(O), S(O); Every R 5 Each is the same or different and is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, an aminoacyl group, or a substituted or unsubstituted group of the following: C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, -NH2, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the substitution is selected from C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, hydroxyl-C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, 5-10 membered heteroaryl, C6-C 10 substituted by one or more substituents in an aryl or 3-12 membered heterocyclic group; or any two adjacent R 5 Form a 3-6 membered saturated or unsaturated ring, optionally, the 3-6 membered saturated or unsaturated ring is substituted by 1-3 -OH, -NH2, -CN, halogen atoms, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 12 Cycloalkylamino, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkylamino, C6-C 10 substituted by aryl or 5-10 membered heteroaryl; R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 Each is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, a substituted or unsubstituted group: -NH2, C1-C 10 Alkyl, C1-C10 alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkyloxy, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, the substitution is selected from C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, hydroxyl-C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, 5-10 membered heteroaryl or C6-C 10 The aromatic group is substituted by one or more substituents; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; p is 1.

2. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound of formula (I) has the structure shown in formula (I-1): Among them, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , X, Y, m, n, p, and The definition is as shown in claim 1.

3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound of formula (I) has the structure shown in formula (I-2): Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , X, m, n, p, and The definition is as shown in claim 1.

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 1 and R 2 To form a tetrahydrofuran ring, optionally, the tetrahydrofuran ring is substituted by 1-3 halogen atoms, -OH, -NH2, C1-C 10 Alkylamino, C1-C 10 Alkyl or C1-C 10 Alkoxy substituted.

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1, characterized in that: The compound of formula (I) has the structure shown in formula (I-3): Among them, R 1 and R 2 To form a tetrahydrofuran ring, optionally, the tetrahydrofuran ring is substituted by 1-3 halogen atoms, -OH, -NH2, C1-C 10 Alkylamino, C1-C 10 Alkyl or C1-C 10 Alkoxy substituted; in, R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 4 , R 5 , m, n, p and X are as defined in claim 1.

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: Every R 4 are the same or different and are independently selected from H, D, -NH2, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: Every R 5 are the same or different and are independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, -NH2, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; or any two adjacent R 5 Form a 3-6 membered saturated or unsaturated ring, optionally, the 3-6 membered saturated or unsaturated ring is substituted by 1-3 -OH, -NH2, -CN, halogen atoms, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 12 Cycloalkylamino, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkylamino, C6-C 10 aryl or 5-10 membered heteroaryl.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 7, characterized in that: Every R 5 are the same or different and are independently selected from H, D, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkylamino group, a C1-C6 alkoxy group, -NH2; or two adjacent R 5 A 5-6 membered saturated cyclic group may be formed, wherein the 5-6 membered saturated cyclic group may be substituted by 1-2 -OH, -NH2, -CN, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkylamino group, a C1-C6 alkylamino group, a C3-C6 cycloalkyl group, a halogenated C1-C6 alkylamino group, a C6-C 10 aryl or 5-6 membered heteroaryl.

9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, characterized in that: R 1 and R 2 To form a tetrahydrofuran ring, optionally, the tetrahydrofuran ring is substituted by 1-3 -OH, -NH2, -CN, NO2, halogen atoms, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, C6-C 10 substituted by aryl or 5-10 membered heteroaryl; R 3 Selected from H; X is selected from a chemical bond, -NH-, -CONH-; Y is selected from CR 0 , where R 0 Selected from H, D, -OH, -CN, halogen atoms, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 12 Cycloalkylamino, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkylamino; Every R 4 Each is the same or different and is independently selected from H, D, -NH2, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, a substituted or unsubstituted group: C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl; Selected from C6-C 10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl, wherein the 5-10 membered heteroaryl, 3-12 membered heterocyclyl contains 1-3 heteroatoms or groups selected from N, NH, O, S, C(O); Every R 5 Each is the same or different and is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, a substituted or unsubstituted group of the following: C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, -NH2, C3-C6 cycloalkyl, a 3-6 membered heterocyclic group, a C6-C 10 Aryl or 5-10 membered heteroaryl, or any two adjacent R 5 Form a 5-6 membered saturated ring, optionally, the 5-6 membered saturated ring is substituted by 1-3 -OH, -NH2, -CN, halogen atoms, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkylamino, C1-C6 alkylamino, C3-C6 cycloalkyl, halogenated C1-C6 alkylamino, C6-C 10 substituted by aryl or 5-10 membered heteroaryl; R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 independently selected from H, D, halogen atoms, -CN, -COOH, -CHO, -OH, -NO2, -NH2, C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkyloxy, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl; m is 1 or 2; n is 1 or 2 or 3; p is 1.

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 9, characterized in that: Selected from C6-C 10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclic radical, wherein the 5-10 membered heteroaryl contains 1-3 heteroatoms or groups selected from N, NH, O, S, C(O), and the 3-12 membered heterocyclic radical is selected from aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactamyl, valerolactamyl, caprolactamyl, butyrolactonyl, valerolactonyl, caprolactonyl, succinimide or Any of .

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 10, characterized in that: Selected from C6-C 10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclic group, wherein the 5-10 membered heteroaryl contains 1-3 heteroatoms or groups selected from N, NH, O, S, C(O), and the 3-12 membered heterocyclic group is selected from butyrolactam, pyrrolidinyl, succinimidyl or Any of .

12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, characterized in that: R 1 and R 2 Forming a tetrahydrofuran ring, optionally, the tetrahydrofuran ring is substituted by 1-3 -OH, -NH2, -CN, NO2, halogen atoms, methyl, methoxy; R 3 Selected from H; X is selected from a chemical bond, -NH-, -CONH-; Y is selected from CR 0 , where R 0 is selected from H, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group; Every R 4 Each is the same or different and is independently selected from H, -NH2, a halogen atom, -CN, a C1-C6 alkyl group, a C1-C6 alkylamino group, a C1-C6 alkoxy group; Selected from C6-C 10 Aryl, 5-10 membered heteroaryl, 5-12 membered heterocyclic group; wherein the 5-10 membered heteroaryl, 5-12 membered heterocyclic group contains 1-3 heteroatoms or groups selected from N, NH, O, S, C(O); Every R 5 are the same or different, and are independently selected from H, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, a C1-C6 alkyl group, a C1-C6 alkoxy group, -NH2, or any two adjacent R 5 Forming a 5-6 membered saturated ring, optionally, the 5-6 membered saturated ring is substituted by 1-3 -OH, -NH2, -CN, halogen atoms, C1-C6 alkyl, C1-C6 alkoxy; R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 Independently selected from H, halogen atoms, -CN, -COOH, -CHO, -OH, -NO2, -NH2, C1-C6 alkyl, C1-C6 alkoxy; m is 1 or 2; n is 1 or 2 or 3; p is 1.

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 12, characterized in that: Selected from C6-C 10 Aryl, 5-9 membered heteroaryl; wherein the 5-9 membered heteroaryl contains 1-3 heteroatoms or groups selected from N, NH, O, S, C(O).

14. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, characterized in that: R 1 and R 2 Forming a tetrahydrofuran ring, optionally, the tetrahydrofuran ring is substituted by 1-3 -OH, -NH2, halogen atoms, methyl, methoxy; R 3 Selected from H; X is selected from a chemical bond, -NH-, -CONH-; Y is selected from CR 0 , where R 0 is selected from H, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group; Every R 4 Each is the same or different and is independently selected from H, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group; Selected from phenyl, naphthyl, 5-10 membered heteroaryl or 5-12 membered heterocyclic group; wherein the 5-10 membered heteroaryl contains 1-3 heteroatoms selected from N, NH, O, S; Every R 5 are the same or different, and are independently selected from H, a halogen atom, -CONH2, -COOH, -CN, a C1-C6 alkyl group, a C1-C6 alkyl group substituted with a hydroxyl group, a C1-C6 alkyl group substituted with an amino group, a C1-C6 alkoxy group, -NH2, or any two adjacent R 5 to form cyclohexane or cyclopentane; R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 All are H; m is 1; n is 1 or 2 or 3; p is 1.

15. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 14, characterized in that: is selected from phenyl, naphthyl, 5-10 membered heteroaryl or 5-12 membered heterocyclyl; wherein the 5-10 membered heteroaryl is selected from thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl , isoquinolyl, quinazolinyl, indazolyl, indole [1,2-a] pyrazinyl, 4,7-diazaindole, pyrazolopyrimidinyl, imidazopyrimidinyl, oxazolopyrimidinyl, isoxazolopyrimidinyl, imidazopyrazinyl, pyrazolopyrazine, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, pyridopyrimidonyl, benzoxazolyl or benzothiazolyl, the 5-12 membered heterocyclic group is selected from butyrolactam, pyrrolidinyl, succinimidyl or Any of .

16. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: The compound of formula (I) has the structure shown in formula (I-4): X is selected from a chemical bond, -NH-, -CONH-; R 4 Selected from H, D, halogen atoms, -CN, -COOH, -CHO, -OH, -NO2, -CONHR 14 or-NHCOR 15 , substituted or unsubstituted following groups: -NH2, C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl; wherein R 14 and R 15 Each independently selected from C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the substitution is selected from C1-C 10 Alkyl, halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 The aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group is substituted with one or more substituents, wherein the substituents are optionally substituted with 1-3 C1-C 10 Alkyl, halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C3-C 12 substituted by cycloalkyl; Selected from C6-C 10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclic group; wherein the 5-10 membered heteroaryl, 3-12 membered heterocyclic group contains 1-3 heteroatoms or groups selected from N, NH, O, S, C(O), S(O); Every R 5 Each is the same or different and is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, an aminoacyl group, or a substituted or unsubstituted group of the following: C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, -NH2, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl, the substitution is selected from C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, halogen atom, -NH2, -CN, -COOH, -CHO, -OH, -NO2, hydroxyl-C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, 5-10 membered heteroaryl, C6-C 10 substituted by one or more substituents in an aryl or 3-12 membered heterocyclic group; or any two adjacent R 5 Form a 3-6 membered saturated or unsaturated ring, optionally, the 3-6 membered saturated or unsaturated ring is substituted by 1-3 -OH, -NH2, -CN, halogen atoms, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 12 Cycloalkylamino, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, halogenated C1-C 10 Alkylamino, C6-C 10 substituted by aryl or 5-10 membered heteroaryl; n is 0, 1, 2 or 3.

17. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 16, characterized in that: R 4 is selected from H, D, a halogen atom, -CN, an unsubstituted or halogen atom-substituted C1-C 10 alkyl; is selected from phenyl, naphthyl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; wherein the 5-10 membered heteroaryl and 3-12 membered heterocyclic group contain 1-3 heteroatoms or groups selected from N, NH, O, S, and C(O); Every R 5 Each is the same or different and is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, an aminoacyl group, or a substituted or unsubstituted group of the following: C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, -NH2, the substitution is selected from C1-C 10 Alkyl, halogen atoms, -NH2, -CN, -OH, -NO2 or one or more substituents; or any two adjacent R 5 Form a 3-6 membered saturated or unsaturated ring, optionally, the 3-6 membered saturated or unsaturated ring is substituted by 1-3 -OH, -NH2, -CN, halogen atoms, C1-C 10 Alkyl, C1-C 10 Alkoxy substituted.

18. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 17, characterized in that: is selected from phenyl, naphthyl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; wherein the 5-10 membered heteroaryl is selected from the group consisting of thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, benzothiophenyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolyl, isoquinolyl, quinazolinyl, indazolyl, indole [1,2-a] pyrazinyl, 4,7-diazaindole, pyrazolopyrimidinyl, imidazopyrimidinyl, oxazolopyrimidinyl, Any one of isoxazolopyrimidinyl, imidazopyrazinyl, pyrazolopyrazine, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, pyridopyrimidonyl, benzoxazolyl, and benzothiazolyl; the 3-12 membered heterocyclic group is selected from aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactam, valerolactam, caprolactam, butyrolactone, valerolactonyl, caprolactone, succinimide or Any of .

19. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 18, characterized in that: is selected from phenyl, naphthyl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; The 3-12 membered heterocyclic group is selected from butyrolactam, pyrrolidinyl, succinimidyl or Any of .

20. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: The compound of formula (I) is selected from:

21. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20.

22. A pharmaceutical preparation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21, wherein the preparation is any one of tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalants, suspensions, dry suspensions, patches, and lotions.

23. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 20, or a pharmaceutical composition as claimed in claim 21, or a pharmaceutical preparation as claimed in claim 22, for use in preventing and treating diseases or conditions mediated or dependent on non-receptor protein tyrosine phosphatases.

24. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, or a pharmaceutical composition according to claim 21, or a pharmaceutical preparation according to claim 22 in the preparation of a medicament for preventing and / or treating a disease or condition mediated or dependent on non-receptor protein tyrosine phosphatase.

25. A pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 20, or a pharmaceutical composition as claimed in claim 21, or a pharmaceutical formulation as claimed in claim 22, and at least one additional therapeutic agent.

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