Pyrazine derivatives and their application in inhibiting SHP2

Abstract

The present 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 structure of the compound of formula (I) is: The pyrazine derivative provided by the present invention 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.

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] SHP2 is a non-receptor protein tyrosine phosphatase encoded by PTPN11, which consists of two N-terminal SH2 domains and one protein phosphatase domain. SHP2 protein is mainly located in the cytoplasm. In the basal state, it is in an autoinhibitory conformation. The N-terminal SH2 domain interacts with the phosphatase domain to hide its catalytic site. After receiving upstream signals, it is activated to an activated conformation, exposing the catalytic site and exerting the phosphatase function.

[0003] SHP2 is a key node connecting multiple important oncogenic signaling pathways in cells, such as JAK / STAT, PI3K / AKT, RAS / RAF / MAPK, PD-1 / PD-L1, etc. SHP2 protein mutation or overexpression is associated with a variety of diseases and tumors.

[0004] SHP2 mutations mainly occur in Noonan syndrome (50%), Leopard syndrome (80%), monocytic leukemia (35%), myelodysplastic syndrome (10%), B-cell acute lymphoblastic leukemia (7%), acute myeloid leukemia (4%), etc.; SHP2 mutations have also been found in solid tumors such as lung cancer, colorectal cancer, melanoma, liver cancer, breast cancer, etc.; abnormally activated growth factors, cytokines, etc. need to transmit signals through SHP2, and wild-type SHP2 activity is also crucial in many types of tumors; SHP2 is also downstream of immune checkpoints such as PD-1 and BTLA, and has a certain effect on the function of macrophages in the tumor microenvironment, and is involved in the mechanism of tumor immune escape, and also has important functions in the direction of tumor immunity.

[0005] Due to the important role of SHP2 in tumors, research on SHP2 catalytic site inhibitors has been going on for decades. However, the phosphatase domain of SHP2 is highly conserved and positively charged, and no drug has been advanced to the clinical stage. Summary of the invention

[0006] Problem that the invention aims to solve

[0007] 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 object of the present invention is to provide a pyrazine derivative, which has excellent SHP2 inhibitory activity and can be used to prevent and / or treat non-receptor protein tyrosine phosphatase-mediated or dependent diseases or conditions.

[0008] Solutions for solving problems

[0009] 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:

[0010]

[0011] in:

[0012] 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 Form a 3-8 membered cycloalkyl, cycloalkenyl or heterocyclic group, optionally, the 3-8 membered cycloalkyl, cycloalkenyl or heterocyclic group is selected from -OH, -NH2, -CN, NO2, a halogen atom, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 substituted by any 1 to 3 of the group consisting of aryl and 5-10 membered heteroaryl;

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

[0014] Selected from C6-C 10 Aryl, 5-10 membered heteroaryl, C4-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 14Bridged 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);

[0015] Every R 3 are the same or different and are 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 Alkylamide, 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, -CONH2, -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 3 Form a 3-6 membered saturated or unsaturated ring, optionally, the 3-6 membered saturated or unsaturated ring is selected from -OH, -NH2, -CN, a halogen atom, 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 any 1 to 3 of the group consisting of aryl and 5-10 membered heteroaryl;

[0016] R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11are independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, substituted or unsubstituted groups: -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;

[0017] m is 0, 1, 2, 3 or 4;

[0018] n is 0, 1 or 2.

[0019] 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.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] Effects of the Invention

[0027] The 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 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

[0028] 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:

[0029]

[0030] in:

[0031] R 1 and R 2 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: -NH2, C1-C 10 Alkyl, C1-C 10 Alkylamino, C1-C 10 Alkoxy, C3-C12 Cycloalkyl, C3-C 12 Cycloalkyloxy, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl; or R 1 and R 2 Form a 3-8 membered cycloalkyl, cycloalkenyl or heterocyclic group, optionally, the 3-8 membered cycloalkyl, cycloalkenyl or heterocyclic group is selected from -OH, -NH2, -CN, -NO2, a halogen atom, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C3-C 12 Cycloalkyl, C6-C 10 substituted by any 1 to 3 of the group consisting of aryl and 5-10 membered heteroaryl;

[0032] X is selected from a chemical bond, -NH-, -CONH-;

[0033] 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);

[0034] Every R 3 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 Alkylamide, 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, -CONH2, -CHO, -OH, -NO2, hydroxyl-C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10Alkylamino, 5-10 membered heteroaryl or C6-C 10 One or more substituents in the aryl group; or any two adjacent R 3 Form a 3-6 membered saturated or unsaturated ring, optionally, the 3-6 membered saturated or unsaturated ring is selected from -OH, -NH2, -CN, a halogen atom, 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 any 1 to 3 of the group consisting of aryl and 5-10 membered heteroaryl;

[0035] R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 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, 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;

[0036] m is 0, 1, 2, 3 or 4;

[0037] n is 0, 1 or 2.

[0038] In order to describe the content of the present invention more clearly, all the terms involved are defined as follows. In addition, a specific term should not be considered as uncertain or unclear without special definition, but should be understood according to the common meaning in the art.

[0039] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence state of the particular atom is normal and the compound after the substitution is stable.

[0040] The term "optional", "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, methyl is optionally substituted with halogen, which means that the methyl group may be unsubstituted, monosubstituted or polysubstituted with halogen. The term "halogen atom" refers to fluorine, chlorine, bromine or iodine, either alone or in combination, especially fluorine, chlorine or bromine.

[0041] In this article, C a -C b , means that the moiety has an integer number of carbon atoms in a given range. For example, "C1-C6" means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. The numerical ranges given in the form of "ab", "a to b" or "a to b" herein for the number of groups or the number of atoms indicate all integers within a given range. For example, "substituted by 1-3" substituents indicates that it is substituted by 1, 2 or 3 substituents; "3-12 membered heterocyclyl" indicates that it includes 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 membered heterocyclyls.

[0042] The term "C1-C 10 “Alkyl”, alone or in combination, represents a saturated straight or branched chain alkyl group containing 1 to 10 carbon atoms, for example, 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. In some embodiments, preferably, “C1-C 10 "Alkyl" is any of methyl, ethyl, n-propyl, isopropyl, and tert-butyl. Similarly, the term "C 1-6The term "alkyl" alone or in combination refers to a saturated straight or branched chain alkyl group containing 1 to 6 carbon atoms, including, for example, methyl, ethyl, propyl, isopropyl, and the like.

[0043] 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, for example, 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.

[0044] The term "C3-C 12 "Cycloalkyl" refers to a monocyclic or polycyclic cycloalkyl group having 3 to 12 carbon atoms, alone or in combination, including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. In some embodiments, "C3-C 12 The "cycloalkyl group" is preferably a "C3-C8 cycloalkyl group".

[0045] 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.

[0046] The term "3-12 membered heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic heterocyclic group containing 3-12 carbon atoms and heteroatoms or heteroatom groups (i.e., the sum of the number of carbon atoms and heteroatoms is 3-12), wherein the heteroatoms or heteroatom groups are selected from N, NH, O, C(O), S(O), m (wherein m is 0, 1 or 2). For example, the 3-12 membered heterocyclic group includes aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactamyl, valerolactamyl, caprolactamyl, butyrolactone, valerolactonyl, caprolactone, succinimide or In some embodiments, the "3-12 membered heterocyclic group" is preferably a "5-12 membered heterocyclic group" or a "5-7 membered heterocyclic group"; preferably, the 3-12 membered heterocyclic group includes butyrolactam, pyrrolidinyl, succinimide or More preferably, the 3-12 membered heterocyclic group is

[0047] 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.

[0048] The term "heteroaryl" refers to an aromatic ring group formed by replacing the carbon atoms on the ring with at least one heteroatom selected from sulfur, oxygen or nitrogen. In some embodiments, the aromatic ring group can be a 5-7 membered monocyclic or 7-12 membered bicyclic group. In some embodiments, 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) -one, pyridin-4 (1H) -one, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, naphthyl, benzothienyl , indolyl, 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.

[0049] The term "C 6-10 "Aryl" means an aromatic group having 6 to 10 carbon atoms, wherein aryl is as defined above.

[0050] The term "5-10 membered heteroaryl" denotes a heteroaryl group having 5 to 10 carbon atoms and heteroatoms, wherein heteroaryl is as defined above.

[0051] The term "3-8 membered cycloalkyl", "cycloalkenyl or heterocyclic group" means a saturated monocyclic or condensed ring cycloalkyl group having 3-8 carbon atoms, for example, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Among them, "3-8 membered cycloalkenyl" is a partially unsaturated monocyclic or condensed ring group having 3-8 carbon atoms. Among them, "3-8 membered heterocyclic group" means a heterocyclic group having 3-8 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, etc.; in some embodiments, "3-8 membered heterocyclyl" is preferably "3-6 membered heterocyclyl" or "5-6 membered heterocyclyl".

[0052] The term "-CONH-" means -C(=O)-NH-, which can specifically mean C(=O) and Connected or NH and Connected, preferably C(=O) and connected.

[0053] The term "amino" alone or in combination means a primary amino group (-NH2), a secondary amino group (-NH-) or a tertiary amino group.

[0054] 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 "C1-C 10 “Alkylamino” includes, for example, 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.

[0055] The term "C3-C12 "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.

[0056] 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.

[0057] 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: 1-19 pages, 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. Pharmaceutically acceptable non-toxic base addition salts represent salts formed by the compounds of the present invention and organic or inorganic bases.

[0058] 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.

[0059] The term "ester" is used to refer to organic esters, including, for example, monoesters, diesters, triesters, and more generally polyesters.

[0060] 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.

[0061] 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.

[0062] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be construed in an open and non-exclusive sense, ie, "including but not limited to".

[0063] 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.

[0064] In a preferred embodiment, the compound of formula (I) has the structure shown in formula (I-1):

[0065]

[0066] X is selected from a chemical bond, -NH-, -CONH-;

[0067] 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);

[0068] Every R 3 are the same or different and are 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 Alkylamide, 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, -CONH2, -CHO, -OH, -NO2, hydroxyl-C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkylamino, 5-10 membered heteroaryl, C6-C10 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 selected from -OH, -NH2, -CN, a halogen atom, 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 1 to 3 of the group consisting of aryl and 5-10 membered heteroaryl;

[0069] m is 0, 1, 2, 3 or 4;

[0070] In a more preferred embodiment, in the structure represented by formula (I-1), the methyl group and the amino group substituted on the tetrahydrofuran ring are on the same side of the tetrahydrofuran ring.

[0071] In a preferred embodiment, a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled substance thereof, characterized in that:

[0072] is selected from phenyl, naphthyl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

[0073] 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),

[0074] 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;

[0075] Every R 3 are the same or different and are 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-C6 alkylCONH2, 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.

[0076] In a more preferred embodiment, the compound of formula (I) is selected from the compounds shown in Table 1.

[0077] Table 1:

[0078]

[0079]

[0080]

[0081]

[0082]

[0083] 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.

[0084] In some embodiments of the present invention, the above-mentioned pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0085] In a more preferred embodiment, the above pharmaceutical composition further comprises:

[0086] - a pharmaceutically acceptable carrier;

[0087] - adjuvants; and / or

[0088] -excipient.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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).

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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).

[0106] 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.

[0107] 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.

[0108] The term "patient" (or subject) refers to a human or a non-human animal (eg, a mammal).

[0109] 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.

[0110] 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.

[0111] 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 scheme of the present invention, which are specifically described as follows:

[0112] (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;

[0113] (2) Compound Ic is deprotected to obtain compound Id;

[0114] (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;

[0115] (4) Compound If and Ig react under the action of a base to obtain compound (I).

[0116] The synthetic route is as follows:

[0117]

[0118] 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.

[0119] In a preferred embodiment, in step (2), the catalyst for the deprotection reaction is a protonic acid or a Lewis acid, preferably aluminum trichloride.

[0120] 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.

[0121] 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.

[0122] The present invention also provides another method for preparing compound Ic, wherein compound I-aa and compound Ib are reacted to obtain compound Ic, and the reaction catalyst is a coupling reaction catalyst, preferably tetrakis(triphenylphosphine)palladium. The synthesis route is as follows:

[0123]

[0124] The present invention also provides another method for synthesizing compound (I), comprising

[0125] (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;

[0126] (2) Compound Ij reacts with compound Ik to obtain compound Il, wherein X in compound Il is -CONH-;

[0127] (3) Compound Il and compound Ig are reacted to obtain compound (I).

[0128] 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.

[0129] 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.

[0130] 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.

[0131] The synthetic route is as follows:

[0132]

[0133] 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.

[0134] Preparation of intermediate Int-1

[0135]

[0136] To a solution of Int-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 Int-1b (237 g, yield 100%), which was directly used in the next step. 1 H NMR (400 MHz, CDCl3) δ4.32 (q, J = 8.0 Hz, 1H), 3.71 (s, 3H), 1.39 (d, J = 8.0 Hz 3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H).

[0137]

[0138] Under ice-water bath, diisobutylaluminum hydride (367 mL, 0.55 mol, 1.5 M toluene solution) was added dropwise to a solution of Int-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 give Int-1c (56 g, yield 54%). 1 H NMR (400MHz, CDCl3) 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).

[0139]

[0140] 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 Int-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 Int-1d (32.6 g, yield 72%). MS m / z [M+H] + :446.7.

[0141]

[0142] Under ice-water bath, lithium borohydride (2.3 g, 107 mmol) was added in batches to a solution of Int-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 Int-1e (30.2 g, yield 100%), which was used directly in the next step. MS m / z[M+H] + :404.5,[MH] - :402.4.

[0143]

[0144] Int-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, and 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, and the filtrate was concentrated under reduced pressure. Int-1f (24 g, yield 57%) was obtained by column chromatography. 1 H NMR (400 MHz, CDCl 33 )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.

[0145]

[0146] Sodium hydrogen (2.3 g, 57.44 mmol) was added to tetrahydrofuran (80 mL), cooled to -15 ° C, a solution of Int-1f (8.3 g, 28.72 mmol) in tetrahydrofuran (50 mL) was added dropwise, and a solution of p-toluenesulfonyl chloride (1.72 g, 9 mmol) in tetrahydrofuran (15 mL) 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 combined organic phases were 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 Int-1g (5 g, yield 64%) was obtained by column chromatography. 1 H NMR (400MHz, CDCl3) 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=8.0 Hz,3H).

[0147]

[0148] Int-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. The solid 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 Int-1h (5.5g, yield 41%) was obtained by column chromatography. 1 H NMR (400MHz, CDCl3) 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 = 8.0Hz, 3H).

[0149]

[0150] Int-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 reaction was carried out 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 reaction was carried out at -10°C for 45 minutes. Saturated ammonium chloride solution was added at -10°C, and a large amount of solid precipitated. The solid was 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 Int-1i (12.4 g, yield 59%). 1 H NMR (400MHz, CDCl3) δ4.15-4.19(m,1H),3.63-3.88(m,4H),3.30-3.44(m,2H),2.92(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). MS m / z[M+H] + :375.3,[MH] - :373.5.

[0151]

[0152] Int-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 Int-1 (7.85 g, yield 100%). 1 H NMR (400MHz, DMSO): 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). MS m / z[M+H] + :171.2.

[0153] Preparation of intermediate Int-2

[0154]

[0155] 1-Bromo-3-fluoro-2-trifluorotoluene (Int-1a, 10.0 g, 41.1 mmol), cesium carbonate (26.8 g, 82.3 mmol), tert-butyl mercaptan (4.4 g, 49.3 mmol), N,N-dimethylformamide (100 mL) were added to the reaction bottle and reacted at 50°C overnight. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and recrystallized to obtain the intermediate Int-2 (10.0 g, yield 77.6%). 1 H NMR (400MHz, CDCl3): δ7.74(d,1H),7.67(d,1H),7.26(t,1H),1.31(s,9H).

[0156] Example 1

[0157]

[0158]

[0159] Int-2 (1.5 g, 4.8 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (1.0 g, 4.8 mmol), potassium phosphate (4.0 g, 19.1 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (0.7 g, 0.9 mmol) were added to water (20 mL) and 1,4-dioxane (80 mL), replaced with nitrogen, and refluxed for 6 hours. After the reaction was complete, water was added, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 1a (1.2 g, yield 79.7%). 1 H NMR (400MHz, CDCl3): δ7.23(dd,1H),7.45(m,2H),7.35(d,1H),6.29(d,1H),3.95(s,3H),1.34(s,9H).

[0160]

[0161] 1a (1.0 g, 3.2 mmol) was added to 25% hydrochloric acid (10 mL), refluxed for 2 hours, cooled to room temperature, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure to obtain crude product 1b (0.5 g, yield 60.8%). 1 H NMR (400MHz, CDCl3) δ7.29(m,4H),6.29(d,1H),3.95(s,3H).

[0162]

[0163] 1b (0.5 g, 1.9 mmol), 2,5-dichloropyrazine (1.4 g, 9.6 mmol), potassium carbonate (530.3 mg, 3.8 mmol) were added to acetonitrile (5 mL), and the temperature was raised to 80°C for overnight reaction. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried with sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 1c (300 mg, yield 41.8%). 1 H NMR (400MHz, CDCl3) δ8.35(d,1H),8.05(d,1H),7.70(m,1H),7.58(m,2H),7.39(d,1H), 6.33(d,1H),3.95(s,3H).

[0164]

[0165] 1c (100.0 mg, 0.27 mmol), Int-1 (138.0 mg, 0.81 mmol), 1,8-diazabicycloundec-7-ene (164.0 mg, 1.1 mmol), acetonitrile (2 mL) were added to the reaction bottle and refluxed for overnight reaction. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was prepared to obtain 1 (20.0 mg, yield 14.7%). MS m / z [M+H] + :505.2; 1 H NMR(400MHz, CDCl3): δ8.96(d,1H),8.41(d,1H),8.25(d,1H),7.73(d,1H),7.47(t,1H),7.26(d,1H),7.14(d,1H),6.30(d,1H),4.07(t, 1H),3.91(m,6H),3.69(d,1H),3.54(m,2H),2.92(d,1H),1.76(m,1H),1.64(m,1H),1.57(m,1H),1.51(m,1H),1.08(d,3H).

[0166] Example 2

[0167]

[0168]

[0169] Tri-n-butyltin hydroxide (2.8 g, 9.6 mmol) was dissolved in tetrahydrofuran (20 mL), and LDA (2M, 4.8 mL, 9.6 mmol) was added dropwise at 0°C and reacted for 1 hour. The temperature was lowered to -78°C, and a solution of 2a (1.0 g, 8.7 mmol) in tetrahydrofuran (5 mL) was slowly added. After the addition, the reaction was continued for 4 hours. Saturated potassium fluoride solution (20 mL) was added and the temperature was raised to room temperature and stirred for 1 hour. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 2b (1.5 g, yield 46.5%). 1 H NMR (400MHz, CDCl3): δ8.71-8.73(m,1H),8.57(d,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,9H).

[0170]

[0171] Int-2 (1.5 g, 4.8 mmol), 2b (1.5 g, 4.0 mmol), tetrakistriphenylphosphine palladium (0.55 g, 0.47 mmol) were dissolved in xylene (10 mL), replaced with nitrogen, and reacted at 140°C overnight. After the reaction was complete, water was added, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 2c (0.9 g, yield 60.2%). 1 H NMR (400MHz, CDCl3) δ8.60(m,3H),7.87(d,1H),7.56(m,1H),7.37(m,1H),1.38(s, 9H).

[0172]

[0173] 2c (0.9 g, 2.9 mmol) was added to 25% hydrochloric acid (10 mL), refluxed for 2 hours, cooled to room temperature, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure to obtain crude product 2d (0.5 g, yield 67.7%). 1 H NMR (400MHz, CDCl3) δ8.61(m,3H),7.50(d,1H),7.41(t,1H),7.17(d,1H).

[0174]

[0175] 2d (0.5 g, 2.0 mmol), 2,5-dichloropyrazine (0.9 g, 5.8 mmol), potassium carbonate (0.8 g, 5.8 mmol) were added to acetonitrile (10 mL), and the temperature was raised to 80°C for overnight reaction. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried with sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 2e (300 mg, yield 41.7%). MS m / z[M+H] + :368.9.

[0176]

[0177] 2e (100.0 mg, 0.27 mmol), Int-1 (92.3 mg, 0.54 mmol), 1,8-diazabicycloundec-7-ene (206.4 mg, 1.36 mmol), acetonitrile (2 mL) were added to the reaction bottle and refluxed for overnight reaction. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was prepared to obtain 2 (5.5 mg, yield 4.0%). MS m / z [M+H] + :503.2; 1 H NMR(400MHz, CDCl3)δ8.64(d,2H),8.59(d,1H),8.24(s,1H),8.18(s,1H),7.39(q,2H),7.20(d,1H),5.35(m,1H),4.19(t,1H),3.93(m,2H),3. 82(d,1H),3.69(d,1H),3.48(m,1H),3.36(m,1H),3.27(m,1H),3.00(s,1H),2.02(m,1H),1.89(m,1H),1.77(m,2H),1.24(d,3H).

[0178] Example 3

[0179]

[0180] Int-2 (2.4 g, 7.7 mmol), 1-methyl-1H-pyrazole-4-boronic acid (1.0 g, 7.7 mmol), potassium phosphate (4.0 g, 19.1 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (1.1 g, 1.5 mmol) were added to water (20 mL) and 1,4-dioxane (80 mL), replaced with nitrogen, and refluxed for 6 hours. After the reaction was complete, water was added, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 3a (1.9 g, yield 78.8%). 1H NMR (400MHz, CDCl3) δ7.68(m,1H),7.51(s,1H),7.41(m,2H),7.31(m,1H),3.95(s,3H), 1.33(s,9H).

[0181]

[0182] 3a (1.0 g, 3.2 mmol) was added to 25% hydrochloric acid (10 mL), refluxed for 2 hours, cooled to room temperature, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure to obtain crude product 3b (0.5 g, yield 60.8%). 1 H NMR (400MHz, CDCl3) δ7.45(s,1H),7.42(s,1H),7.20(d,2H),7.02(d,1H),3.88(s,3H).

[0183]

[0184] 3b (0.5 g, 1.9 mmol), 2,5-dichloropyrazine (1.4 g, 9.6 mmol), potassium carbonate (530.3 mg, 3.8 mmol) were added to acetonitrile (5 mL), and the temperature was raised to 80°C for overnight reaction. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried with sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 3c (300 mg, yield 41.8%). 1 H NMR (400MHz, CDCl3) δ8.36(d,1H),8.09(d,1H),7.63(m,1H),7.53(m,1H),7.49(s,1H), 7.42(m,2H),3.96(s,3H).

[0185]

[0186] 3c (100.0 mg, 0.27 mmol), Int-1 (138.0 mg, 0.81 mmol), 1,8-diazabicycloundec-7-ene (164.0 mg, 1.1 mmol), acetonitrile (2 mL) were added to the reaction bottle and refluxed overnight. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was prepared to obtain 3 (5.0 mg, yield 3.7%). MS m / z [M+H] + :505.2; 1H NMR(400MHz, CDCl3)δ8.22(d,1H),8.17(d,1H),7.50(s,1H),7.41(s,1H),7.26(t,1H),7.10(t,2H),4.21(q,1H),3.97(m,1H),3.95(m,4H),3. 83(d,1H),3.72(d,1H),3.53(m,1H),3.32(m,1H),3.02(d,1H),2.01(m,1H),1.79(m,1H),1.76(m,1H),1.72(m,1H),1.26(d,3H).

[0187] Example 4

[0188]

[0189]

[0190] Int-2 (1.4 g, 4.5 mmol), 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester (1.0 g, 4.5 mmol), potassium phosphate (2.4 g, 11.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (163.5 mg, 0.2 mmol) were added to water (20 mL) and 1,4-dioxane (80 mL), replaced with nitrogen, and refluxed for 6 hours. After the reaction was complete, water was added, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 4a (1.2 g, yield 81.7%). 1 H NMR (400MHz, CDCl3) δ7.67(m,1H),7.52(s,1H),7.43(s,1H), 7.39(m,1H),7.32(m,1H),4.21(q,2H),1.53(t,3H),1.33(s,9H).

[0191]

[0192] 4a (1.2 g, 3.7 mmol) was added to 25% hydrochloric acid (10 mL) and refluxed for 2 hours. The mixture was cooled to room temperature, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure to obtain crude product 4b (0.6 g, yield 60.3%). MS m / z [M+H] + :273.2.

[0193]

[0194] 4b (0.6 g, 2.2 mmol), 2,5-dichloropyrazine (1.0 g, 6.6 mmol), potassium carbonate (910.3 mg, 6.6 mmol) were added to acetonitrile (5 mL), and the temperature was raised to 80°C for overnight reaction. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried with sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 4c (300 mg, yield 35.4%). 1 H NMR (400MHz, CDCl3) δ8.36(d,1H),8.08(d,1H),7.63(dd,1H),7.55(s,1H),7.51(m,1H), 7.44(m,2H),4.23(q,3H),1.54(t,3H).

[0195]

[0196] 4c (100.0 mg, 0.26 mmol), Int-1 (88.5 mg, 0.52 mmol), 1,8-diazabicycloundec-7-ene (200.0 mg, 1.3 mmol), acetonitrile (2 mL) were added to the reaction bottle and refluxed for overnight reaction. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was prepared to obtain 4 (34.6 mg, yield 25.7%). MS m / z [M+H] + :519.3; 1 H NMR(400MHz, CDCl3): δ8.42(d,1H),8.25(d,1H),7.88(s,1H),7.49(s,1H),7.43(t,1H),7.21(d,1H),7.04(d,1H),4.17(q,2H),4.11(t, 1H),3.96(m,2H),3.74(d,1H),3.54(d,1H),3.39(m,2H),3.04(d,1H),1.73(m,2H),1.54(m,2H),1.38(t,3H),1.11(d,3H).

[0197] Example 5

[0198]

[0199]

[0200] Int-2 (1.3 g, 4.2 mmol), 1-(2-hydroxyethyl)-1H-pyrazole-4-boronic acid pinacol ester (1.0 g, 4.2 mmol), potassium phosphate (2.2 g, 10.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (153.0 mg, 0.2 mmol) were added to water (10 mL) and 1,4-dioxane (40 mL), replaced with nitrogen, and refluxed for 6 hours. After the reaction was complete, water was added, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 5a (1.2 g, yield 82.9%). 1 H NMR (400MHz, CDCl3) δ (ppm) 7.69 (dd, 1H), 7.55 (s, 1H), 7.48 (s, 1H), 7.42 (m, 1H), 7.31 (m, 1H), 4.28 (t, 2H), 4.05 (t, 2H), 1.33 (s, 9H).

[0201]

[0202] 5a (1.0 g, 2.9 mmol) was dissolved in 25% hydrochloric acid (10 mL), refluxed for 2 hours, cooled to room temperature, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure to obtain crude product 5b (0.5 g, yield 59.7%). 1 H NMR (400MHz, CDCl3) δ (ppm) 7.83 (d, 1H), 7.56 (s, 1H), 7.51 (s, 1H), 7.44 (t, 1H), 7.21 (d, 1H), 4.31 (t, 2H), 4.05 (t, 2H).

[0203]

[0204] 5b (0.5 g, 1.7 mmol), 2,5-dichloropyrazine (1.4 g, 9.6 mmol), potassium carbonate (530.3 mg, 3.8 mmol) were added to acetonitrile (5 mL), and the temperature was raised to 80°C for overnight reaction. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried with sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 5c (280 mg, yield 40.3%). 1 H NMR (400MHz, CDCl3) δ (ppm) 8.33 (s, 2H), 7.75 (d, 1H), 7.49 (s, 2H), 7.37 (t, 1H), 7.15 (d, 1H), 4.24 (t, 2H), 3.96 (s, 2H).

[0205]

[0206] 5c (100.0 mg, 0.25 mmol), Int-1 (85.0 mg, 0.5 mmol), 1,8-diazabicycloundec-7-ene (266.0 mg, 1.7 mmol), acetonitrile (2 mL) were added to the reaction bottle and refluxed for overnight reaction. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was prepared to obtain 5 (5.1 mg, yield 3.8%). MS m / z [M+H] + :535.2; 1 H NMR(400MHz, CDCl3): δ(ppm)8.39(s,1H),8.22(s,1H),7.80(s,1H),7.48(s,1H),7.41(t,1H),7.19(d,1H),7.03(d, 1H),4.18(t,2H),4.09(m,1H),4.02(m,1H),3.94(m,2H),3.77(t,2H),3.72(d,2H),3.5 3(d,1H),3.01(d,1H),2.02(m,1H),1.71(m,1H),1.68(m,1H),1.56(m,1H),1.12(d,3H).

[0207] Example 6

[0208]

[0209]

[0210] Int-2 (5.0 g, 15.9 mmol), biboronic acid pinacol ester (8.0 g, 31.9 mmol), potassium acetate (6.3 g, 63.9 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (1.1 g, 1.6 mmol) were added to 1,4-dioxane (100 mL), replaced with nitrogen, and reacted at 80°C overnight. After the reaction was complete, water was added, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 6a (3.6 g, yield 62.6%). 1 HNMR (400MHz, CDCl3) δ (ppm) 7.72 (t, 1H), 7.44 (t, 2H), 1.34 (s, 12H), 1.33 (s, 9H).

[0211]

[0212] 6a (2.5 g, 6.9 mmol), 2-bromopyrimidine (1.0 g, 6.3 mmol), potassium phosphate (4.0 g, 18.9 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (460.0 mg, 0.6 mmol) were added to water (10 mL) and 1,4-dioxane (50 mL), replaced with nitrogen, and refluxed overnight. After the reaction was complete, water was added, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 6b (1.3 g, yield 66.2%). MS m / z[M+H] + :313.1.

[0213]

[0214] 6b (1.0 g, 3.2 mmol) was added to 25% hydrochloric acid (10 mL) and refluxed for 2 hours. The mixture was cooled to room temperature, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure to obtain crude product 6c (0.5 g, yield 60.9%). MS m / z [M+H] + :256.9.

[0215]

[0216] 6c (0.5 g, 1.9 mmol), 2,5-dichloropyrazine (1.4 g, 9.6 mmol), potassium carbonate (560.3 mg, 3.8 mmol) were added to acetonitrile (5 mL), and the temperature was raised to 80°C for overnight reaction. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried with sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 6d (300 mg, yield 41.7%). MS m / z[M+H] + :368.9.

[0217]

[0218] 6d (100.0 mg, 0.27 mmol), Int-1 (138.0 mg, 0.81 mmol), 1,8-diazabicycloundec-7-ene (164.0 mg, 1.1 mmol), acetonitrile (2 mL) were added to the reaction bottle and refluxed for overnight reaction. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was prepared to obtain 6 (40.0 mg, yield 29.3%). 1H NMR (400MHz, CDCl3): δ (ppm) 8.82 (d,2H),8.17(d,2H),7.73(m,4H),4.23(s,1H),4.07(m,2H),3.91(s,1H),3.7 4(d,1H),3.23(m,2H),3.13(s,1H),1.89(s,1H),1.75(s,3H),1.28(d,3H);MS m / z[M+H] + :503.1.

[0219] Example 7

[0220]

[0221]

[0222] 7a (500 mg, 1.80 mmol), oxazole (149 mg, 2.16 mmol), palladium acetate (40.4 mg, 0.18 mmol), Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) (208 mg, 0.36 mmol), potassium tert-butoxide (403.4 mg, 3.60 mmol) were added to toluene (8 mL), replaced with nitrogen, and reacted at 110° C. for 16 hours. After the reaction was complete, 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 the organic phase was concentrated and subjected to column chromatography to obtain 7b (83 mg, yield: 15.1%). 1 H NMR (400MHz, CDCl3): δ7.85 (s, 1H), 7.70-7.63 (m, 2H), 7.42-7.33 (m, 2H).

[0223]

[0224] 7b (250.0 mg, 1.08 mmol), tert-butyl mercaptan (300.0 mg, 3.27 mmol), cesium carbonate (703.4 mg, 2.16 mmol), N,N-dimethylformamide (10 mL) were added to the reaction bottle and reacted at 130°C for 16 hours. After the reaction was complete, 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 the organic phase was concentrated and column chromatography was performed to obtain 7c (300 mg, yield: 82.4%). 1H NMR (400MHz, CDCl3) δ7.92-7.90(m,1H),7.82(s,1H),7.70-7.68(m,1H),7.61-7.57(m,1H),7.31(s,1H),1.39(m,9H).

[0225]

[0226] 7c (300 mg, 0.99 mmol) was added to hydrochloric acid (12 M, 12 mL) and acetonitrile (4 mL), reacted at 90 °C for 6 hours, extracted twice with water and ethyl acetate, washed once with saturated brine, dried over sodium sulfate, the desiccant was filtered out, and concentrated to dryness under reduced pressure. The obtained 7d was directly used in the next step reaction.

[0227]

[0228] 7d (211 mg, 1.09 mmol), 2-bromo-5-chloropyrazine (19 mg, 0.1 mmol), Pd2(dba)3 (91.2 mg, 0.09 mmol), Xantphos (57 mg, 0.09 mmol), diethylisopropylamine (39 mg, 0.29 mmol) were added to 1,4-dioxane (10 mL), nitrogen was protected, and the reaction was carried out at 100° C. for 16 hours. After the reaction was completed, water was added, extracted with ethyl acetate, dried with sodium sulfate, and the organic phase was concentrated and column chromatography was performed to obtain 7e (90 mg, yield: 25.2%).

[0229]

[0230] 7e (90.0 mg, 0.25 mmol), Int-1 (73.0 mg, 0.30 mmol), potassium phosphate (320.0 mg, 1.51 mmol), N,N-dimethylformamide (5 mL) were added to the reaction flask and reacted at 90°C for 4 hours. After the reaction was complete, water was added, extracted with ethyl acetate, and dried over sodium sulfate. The organic phase was concentrated and column chromatography was performed to obtain 7 (36 mg, yield: 29.1%). 1 H NMR (400 MHz, CDCl3) δ8.45(s,1H),8.34-8.32(m,2H),7.67-7.55(m,2H),7.45(s,1H),7.39-7.36(m,1H), 4.12-4.09(m,1H),3.96-3.90(m,2H),3.71-3.66(m,1H),3.53-3.51(m,2H),3 .46-3.43(m,1H),2.96-2.94(m,1H),1.82-1.49(m,4H),1.12-1.10(m,3H); MS m / z[M+H]+ :492.3.

[0231] Example 8

[0232]

[0233] Int-2 (108 mg, 0.3 mmol), 1-benzyl-1H-pyrazole-4-boronic acid pinacol ester (34.6 mg, 0.3 mmol), tetrakis(triphenylphosphine)palladium (34.6 mg, 0.03 mmol), potassium carbonate (83 mg, 0.6 mmol) were added to 1,4-dioxane (1.5 mL) and water (1.5 mL), replaced with nitrogen, and reacted at 100-105° C. for 16 hours. After the reaction was complete, 8a (75 mg, yield: 64%) was obtained by column chromatography after concentration. 1 H NMR (400MHz, CDCl3) δ7.67 (d, J = 8.0Hz, 1H), 7.57(s,1H),7.42(s,1H),7.39-7.37(m,2H),7.35-7.30(m,3H),7.25-7.23(m,3H),5.36(s,2H),1.32(s,9H).

[0234]

[0235] 8a (90 mg, 0.23 mmol) was added to hydrochloric acid (12 M, 3 mL), reacted at 80-90 ° C for 2 hours, detected by TLC, concentrated after the reaction, added 2-bromo-5-chloropyrazine (43 mg, 0.23 mmol), Pd2(dba)3 (21 mg, 0.023 mmol), Xantphos (26 mg, 0.046 mmol), diethylisopropylamine (89 mg, 0.63 mmol) and 1,4-dioxane (2.3 mL), protected by nitrogen, reacted at 100 ° C for 16 hours. After the reaction, it was directly concentrated and column chromatography was performed to obtain 8c (30 mg, yield: 29%). 1 H NMR (400MHz, CDCl3): δ8.35(m,1H),8.08(m,1H),7.62(d,J=8.0Hz,1H), 7.60(s,1H),7.49(t,J=8.0Hz,1H),7.45(s,1H),7.42(d,J=8.0Hz,1H),7.36(d,J=8.0Hz, 1H), 7.34 (d, J = 4.0Hz, 1H), 7.24 (m, 1H), 7.23 (m, 1H), 5.36 (s, 2H).

[0236]

[0237] 8c (110.0 mg, 0.25 mmol), Int-1 (72.0 mg, 0.3 mmol), potassium phosphate (159 mg, 0.75 mmol), isopropanol (2.5 mL) were added to the reaction bottle and reacted at 80-85° C. for 16 hours. After the reaction was complete, the product was directly concentrated and column chromatography was performed to obtain 8 (90 mg, yield: 62%). 1 H NMR(400MHz, CDCl3)δ8.24(m,1H),8.20(m,1H),7.60 (s,1H),7.46(m,1H),7.42-7.33(m,3H),7.28-7.26(m,3H),7.16(s,1H),7.14(s,1H),5.39( s,2H),4.24-4.21(m,1H),4.00-3.90(m,2H),3.85(d,J=8.0Hz,1H),3.73(d,J=12.0Hz,1H), 3.53-3.47(m,1H),3.43-3.36(m,1H),3.04(d,J=4.0Hz,1H),1.96-1.89(m,1H),1.81-1.71(m,3H),1.27(d,J=4.0Hz,3H); MS m / z[M+H] + :581.6.

[0238] Example 9

[0239]

[0240] 9a (200 mg, 1.10 mmol), 9a-2 (266.2 mg, 1.66 mmol), Pd2(dba)3 (50.4 mg, 0.06 mmol), BINAP (347.6 mg, 0.54 mmol), Cs2CO3 (1.08 g, 3.34 mmol), Dioxane (8 mL) were added to a 100 mL single-mouth bottle. The reaction was carried out at 100 °C for 16 h. After treatment, 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 a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and purified by column to obtain 9b (100 mg, yield: 34.3%). 1 H NMR (400MHz, CDCl3) δ8.46-8.44(m,2H),8.15-8.12(m,1H),7.54-7.46(m,2H),6.91-6.82(m,1H).

[0241]

[0242] 9b (100 mg, 0.39 mmol), 9b-2 (105 mg, 1.16 mmol), Cs2CO3 (251 mg, 3.34 mmol), and DMF (8 mL) were added to a 100 mL single-mouth bottle. The mixture was reacted at 130 °C for 16 h. 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 9c (90 mg, 70.4% yield). 1 H NMR (400MHz, CD3OD) δ8.26-8.25 (m,2H),7.26-7.43(m,3H),6.72-6.71(m,1H),1.23(m,9H).

[0243]

[0244] 9c (90 mg, 0.50 mmol) was dissolved in acetonitrile (2 mL), concentrated hydrochloric acid (12 M, 6 mL), and reacted at 120°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.

[0245]

[0246] 9d-2 (58.4 mg, 0.3 mmol), Xantphos (16 mg, 0.02 mmol), Pd2(dba)3 (25 mg, 0.02 mmol), DIEA (106.7 mg, 0.82 mmol), Dioxane (8 mL) were added to the bottle in the previous step, and the mixture was reacted at 100°C for 16 hours under nitrogen protection. 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 chromatography to obtain 9e (100 mg, yield 76%). 1 H NMR (400MHz, CDCl3) δ8.49-8.48(m, 2H),8.39-8.37(m,2H),8.12(s,1H),7.51-7.46(m,2H),6.89-6.86(m,1H).

[0247]

[0248] Compound 9e (80 mg, 0.20 mmol) was added to a 100 mL single-mouth bottle, followed by Int-1 (61 mg, 0.25 mmol), DMF (5 mL), and potassium phosphate (256 mg, 1.25 mmol), and the mixture was heated to 110°C and reacted for 2 hours. Water was added, the mixture was extracted with ethyl acetate, dried over sodium sulfate, the desiccant was filtered, the mixture was concentrated under reduced pressure, and purified by column chromatography to obtain 9 (4 mg, yield 44%). 1 H NMR (400MHz, CDCl3) δ8.39-8.38(m,2H),8.31(s,1H),8.25(s,1H),7.54-7.52(m,1H),7.45-7.42(m,1H),7.04-7.02(m,1H),6.85-6.83( m,1H),4.33-4.27(m,1H),4.21-4.12(m,2H),3.96-3.93(m,1H),3.81-3.79(m,1H),3.45-3.30(m,2H),3.16-3.14(m,2H),1.92-1.69(m, 4H),1.29-1.27(m,3H); MS m / z[M+H] + :518.2.

[0249] Example 10

[0250]

[0251] Int-2 (5.0 g, 15.9 mmol), biboronic acid pinacol ester (8.0 g, 31.9 mmol), potassium acetate (6.3 g, 63.9 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (1.1 g, 1.6 mmol) were added to 1,4-dioxane (100 mL), replaced with nitrogen, and reacted at 80°C overnight. After the reaction was complete, water was added, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 10a (3.6 g, yield 62.6%). 1 HNMR (400MHz, CDCl3) δ7.72(t,1H),7.44(t,2H),1.34(s,12H),1.33(s,9H).

[0252]

[0253] 10a (2.0 g, 5.5 mmol), 5-bromopyrazolo[1,5-a]pyrimidine (1.0 g, 5.1 mmol), potassium phosphate (3.5 g, 16.7 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (400.0 mg, 0.5 mmol) were added to water (10 mL) and 1,4-dioxane (50 mL), replaced with nitrogen, and refluxed overnight. After the reaction was complete, water was added, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 10b (1.4 g, yield 71.7%). 1 H NMR (400MHz, CDCl3) δ8.69(dd,1H),8.17(d,1H),7.85(d,1H),7.56(t,1H),7.45(d,1H),6.83(d,1H),6.73(dd,1H),1.38(s,9H).

[0254]

[0255] 10b (1.4 g, 3.9 mmol) was added to 25% hydrochloric acid (10 mL), refluxed for 2 hours, cooled to room temperature, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure to obtain a crude product 10c (0.8 g, yield 68.0%). 1 H NMR (400MHz, CDCl3) δ8.85(s,1H),8.16(s,1H),7.38(d,2H),7.16(s,1H),6.83(s,1H),6.70(s,1H).

[0256]

[0257] 10c (0.8 g, 2.7 mmol), 2,5-dichloropyrazine (1.2 g, 8.1 mmol), potassium carbonate (1.1 g, 8.1 mmol) were added to acetonitrile (10 mL), and the temperature was raised to 80°C for overnight reaction. The mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried with sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 10d (300 mg, yield 27.1%). 1 HNMR (400MHz, CDCl3) δ8.65(dd,1H),8.30(d,1H),8.11(m,2H),7.74(d,1H), 7.59(t,1H),7.51(d,1H),6.81(d,1H),6.68(dd,1H).

[0258]

[0259] 10d (100.0 mg, 0.24 mmol), Int-1 (83.5 mg, 0.5 mmol), 1,8-diazabicycloundec-7-ene (186.8 mg, 1.23 mmol), acetonitrile (2 mL) were added to the reaction bottle and refluxed for overnight reaction. After the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was prepared to obtain 10 (10.0 mg, yield 7.5%). MS m / z [M+H] + :542.2; 1 H NMR(400MHz, CDCl3)δ(ppm)8.96(d,1H),8.29(s,1H),8.24(s,1H),8.22(d,1H),7.53(t,1H),7.36(m,2H), 7.04(d,1H),6.71(d,1H),4.30(m,1H),4.23(d,1H),3.97(d,1H),3.85(d,1H),3.61(d,1H),3.55( t,1H),3.35(m,1H),3.23(m,1H),2.05(m,1H),1.86(m,1H),1.81(m,1H),1.73(m,1H),1.30(d,3H).

[0260] Embodiment 11

[0261]

[0262]

[0263] 2-Aminopyridine (500 mg, 5.31 mmol), triethyl methanetricarboxylate (2.5 g, 11.68 mmol) and xylene (500 mg, 0.18 mmol) were added to a 100 mL single-mouth bottle in sequence and incubated at 140°C for 3 h. After post-treatment, 11a (1 g, yield 74%) was obtained by slurrying with ether, ethyl acetate and methanol. 1 H NMR (400MHz, DMSO-d6) δ8.93-8.91 (m,1H),8.20-8.15(m,1H),7.70-7.37(m,2H),4.16-4.11(m,2H),1.24-1.20(m,3H).

[0264]

[0265] 11b (3.0 g, 16.75 mmol) was added to NN dimethylformamide (30 mL), followed by tert-butyl mercaptan (3.0 g, 33.50 mmol) and cesium carbonate (10.9 g, 33.50 mmol), and the mixture was heated to 130°C for 24 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 crude product 11c (4.2 g, yield 100%) was obtained by column chromatography. 1 H NMR (400MHz, DMSO) δ7.24 (d, J = 8.0Hz, 1H), 6.93-6.88 (m, 2H).

[0266]

[0267] Disperse 11c (4.2 g, 16.75 mmol) in concentrated hydrochloric acid (30 mL), protect with nitrogen, heat to 85°C, stir and react for 1.5 hours, cool to room temperature, continue stirring for 1.5 hours, filter, wash the filter cake with n-hexane twice, and obtain crude product 11d (1.6 g, yield 50%), which is directly used in the next step.

[0268]

[0269] 11d (1.3 g, 6.67 mmol) was dissolved in dioxane (15 mL), and then N-diisopropylethylamine (1.4 g, 11.1 mmol), tris[dibenzylideneacetone]dipalladium (512 mg, 0.56 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (642 mg, 1.11 mmol) were added, and the temperature was raised to 100°C under nitrogen protection for 16 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column to obtain 11e (1.1 g, yield 54%). 1 H NMR (400MHz, CDCl3) δ8.39 (s, 1H), 7.98 (s, 1H), 7.34-7.30 (m, 1H), 7.08 (d, J = 8.0Hz, 1H), 6.86 (d, J = 8.0Hz, 1H).

[0270]

[0271] 11e (210 mg, 0.69 mmol) and 11a (150 mg, 0.63 mmol) were added to chlorobenzene (5 mL), replaced with nitrogen, heated to 135°C and stirred for 24 hours. Petroleum ether was added to precipitate solids, which were filtered to obtain solid 11f (240 mg, yield 76%), which was directly used in the next step.

[0272]

[0273] Add 11f (240 mg, 0.49 mmol), Int-1 (132 mg, 0.54 mmol), potassium phosphate (612 mg, 2.89 mmol) to dimethyl sulfoxide (13 mL), replace with nitrogen, heat to 85 ° C and stir for 16 hours. Add water to precipitate solid, filter to obtain solid, and obtain the target product 11 (110 mg, yield 36%) by silica gel column chromatography. MS m / z [M+H] + 628.1; 1 H NMR (400MHz, DMSO) δ12.61(s,1H),8.87(d,J=4.0Hz,1H),8.47(s,1H),8.27(s,1H),7.95(s, 1H),7.89(d,J=8.0Hz,2H),7.45(t,J=8.0Hz,2H),7.33(d,J=8.0Hz,2H),7.7.17(s,1H), 6.85(d,J=8.0Hz,2H),4.15-4.02(m,3H),3.80(d,J=4.0Hz,1H),3.61(d,J=8.0Hz,1H), 3.36-3.30(m,2H),3.18(s,1H),1.78-1.55(m,4H),1.26(s,2H),1.17(d,J=8.0Hz,3H).

[0274] Example 12

[0275]

[0276] Pyrimidine-2-carboxylic acid (400 mg, 3.2 mmol) and dichlorothionyl (2 mL) were added to a 50 mL single-mouth bottle and reacted at 80 °C for 3 hours. After post-treatment, the product was concentrated under reduced pressure to obtain 12a, which was used directly in the next step.

[0277]

[0278] 11e (100 mg, 0.37 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and 12a in tetrahydrofuran was added dropwise to the reaction solution, and reacted at room temperature overnight. The mixture was concentrated under reduced pressure and filtered to obtain 12b (90 mg, yield 60%). 1 H NMR (400MHz, CDCl3) δ10.80(s,1H),8.98(d,J=4.8Hz,2H),8.67(d,J=8.4Hz,1H),8.33(d,J=1.2Hz,1H),8.11(d, J=1.2Hz,1H),7.64(t,J=8.0Hz,1H),7.59–7.47(m,2H).

[0279]

[0280] Compound 12b (90 mg, 0.22 mmol) was added to a 100 mL single-mouth bottle, followed by Int-1 (41 mg, 0.24 mmol), N,N-dimethylformamide (3 mL), and potassium phosphate (280 mg, 1.32 mmol), and heated to 80 °C for 3 hours. The reaction solution was cooled to room temperature, 20 mL of water was added, extracted twice with ethyl acetate, washed three times with saturated brine, and the organic phase was dried over sodium sulfate, spin-dried, and scraped to obtain 12 (20 mg, yield 18%). MS m / z[M+H] + :546.1; 1 H NMR (400MHz, CDCl3) δ10.65(s,1H),8.98(d,J=4.8Hz,2H),8.28(d,J=8.4Hz,1H),8.18(s,2H), 7.53(t,J=4.8Hz,1H),7.38(t,J=8.4Hz,1H),6.93(d,J=8.0Hz,1H),4.32–3.98(m,4H), 3.76(d,J=9.2Hz,1H),3.24–3.03(m,2H),2.11–2.04(m,1H),1.95–1.73(m,3H),1.44(d,J=6.4Hz,3H).

[0281] Example 13

[0282]

[0283]

[0284] Under nitrogen protection, 11a (240 mg, 1.0 mmol) and palladium carbon (50 mg) were added to methanol (5 mL), replaced with hydrogen, and reacted at room temperature and pressure for 16 hours. Filtered and concentrated under reduced pressure to obtain 13b (240 mg, yield 100%). 1 H NMR (400MHz, DMSO): δ12.29(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).

[0285]

[0286] 13b (240 mg, 1.0 mmol) and 11e (305 mg, 1.0 mmol) were added to chlorobenzene (6 mL), replaced with nitrogen, heated to 135°C and stirred for 24 hours. Petroleum ether was added to precipitate solids, which were filtered and passed through a column to obtain white solid 13c (300 mg, yield 60%). 1 H NMR(400MHz,DMSO)δ14.86(s,1H),11.90(s,1H),8.68(s,1H),8.48(s, 1H),7.97-7.93(m,1H),7.76-7.71(m,2H),3.89-3.86(m,2H),2.90(t,J=8.0Hz,2H),1.95-1.81(m,4H).

[0287]

[0288] 13c (200 mg, 0.40 mmol), Int-1 (147 mg, 0.60 mmol), potassium phosphate (509 mg, 2.40 mmol) were added to dimethyl sulfoxide (5 mL), replaced with nitrogen, heated to 85 ° C and stirred for 16 hours. Water was added to precipitate the solid, which was filtered and passed through a column to obtain the target product 13 (140 mg, yield 55%). MS m / z [M+H] + :632.2; 1 H NMR(400MHz, DMSO)δ8.49(s,1H),8.29(s,1H),7.68(m,1H),7.49(m,1H),6.93(m,1H),4.17-4.05(m,3H), 3.83-3.78(m,3H),3.60(d,J=8.0Hz,1H),3.14(s,1H),2.84(s,2H),1.91-1.57(m,9H),1.26(s,3H),1.16(d,J=8.0Hz,3H).

[0289] Embodiment 14

[0290]

[0291] 14a-1 (290 mg, 1.0 mmol), 14a-2 (220 mg, 1.0 mmol), Pd(PPh3)4 (115 mg, 0.1 mmol), K2CO3 (238 mg, 2.0 mmol) were added to DMF (1 mL) and stirred at 100-105°C for 16 hours. The reaction solution was poured into ethyl acetate (100 mL). The reaction solution was washed three times with 10% brine (50 mL). The organic phase was concentrated and column chromatography was performed to obtain 14b (190 mg, yield: 81.8%). MS m / z [M+H]+ :259.3; 1 H NMR (400MHz, DMSO) δ7.55(s,1H),7.46(s,1H), 7.45-7.44(m,1H),7.16-7.14(m,1H),7.12-7.09(m,1H),4.22(q,J=8.0Hz,1H),1.53(t,J=8.0 Hz,1H).

[0292]

[0293] 14b (190 mg, 0.74 mmol), 14b-2 (480 mg, 2.2 mmol), cesium carbonate (715 mg, 2.2 mmol), N,N-dimethylformamide (2 mL) were added and stirred at 130°C for 16 hours. The reaction solution was poured into ethyl acetate (100 mL). The product was washed three times with 10% brine (50 mL). The organic phase was concentrated and column chromatography was performed to obtain 14c (70 mg, yield: 33.8%). 1 H NMR(400MHz,DMSO)δ7.51(s,1H),7.43(s,1H),7.26-7.25(m,2H),7.11-7.10(m,1H), 7.12-7.09(m,1H),4.21(q,J=8.0Hz,1H),1.52(t,J=8.0Hz,1H).

[0294]

[0295] 14c (70 mg, 0.25 mmol), 14c-2 (52 mg, 0.28 mmol), Pd(dba)3 (11 mg, 0.01 mmol), Xantphos (15 mg, 0.02 mmol), diethylisopropylamine (96 mg, 0.75 mmol) were added to 1,4-dioxane (5 mL), and stirred at 100-105°C for 16 hours under nitrogen protection. The reaction solution was concentrated and column chromatography was performed to obtain 14d (50 mg, yield: 52%). MS m / z [M+H] + :385.0; 1 H NMR (400MHz, DMSO) δ8.36 (s, 1H), 8.08 (s, 1H), 7.63 (d, J = 8.0Hz, 1H), 7.55 (s, 1H), 7.51 (t, J = 8.0Hz, 1H), 7.47 (s, 1H), 7.44 (d, J = 8.0Hz, 1H).

[0296]

[0297] 14d (50 mg, 0.13 mmol), Int-1 (38 mg, 0.16 mmol), potassium phosphate (82 mg, 0.39 mmol), dimethyl sulfoxide (5 mL), stirred at 80-90 ° C for 5 hours. The reaction solution was poured into ethyl acetate (100 mL). Washed three times with 10% brine (50 mL). The organic phase was concentrated and column chromatography was performed to obtain 14 (60 mg, yield: 88.9%), with a purity of 99.1A% (254 nm). 1 H NMR(400MHz,DMSO)δ8.23(m,1H),8.19(m,1H),7.53(s,1H),7.44(s,1H), 7.29-7.25(m,1H),7.15-7.09(s,1H),4.25-4.20(m,3H),3.95-3.92(m,1H),3.84(d,J=8.0 Hz,1H),3.72(d,J=12.0Hz,1H),3.49-3.47(m,1H),3.39-3.34(m,1H),3.03(d,J=8.0Hz,1H), 1.93-1.88(m,1H),1.79-1.74(m,3H),1.54(t,J=8.0Hz,3H),1.26(d,J=4.0Hz,3H). MS m / z [M+H] + :519.2.

[0298] Embodiment 15

[0299]

[0300] 15a (92.4 mg, 0.4 mmol), 4-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (111.0 mg, 0.4 mmol), sodium carbonate (85.0 mg, 0.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (29 mg, 0.04 mmol) were added to water (1 mL) and N,N-dimethylformamide (1 mL), replaced with nitrogen, and reacted at 100-105°C for 16 hours. After the reaction was complete, the reaction solution was poured into ethyl acetate (100 mL) and washed three times with 10% brine (50 mL). The organic phase was concentrated and column chromatography was performed to obtain 15b (70 mg, yield: 45%). 1H NMR (400MHz, CDCl3) δ7.74-7.63(m,1H),7.54-7.52 (m,1H),7.47-7.44(m,1H),7.40-7.32(m,1H),7.24(m,1H),4.41-4.35(m,1H),4.13-4.10(m, 2H),3.60-3.51(m,2H),2.24-2.20(m,4H),1.33(s,9H). MS m / z[M+H] + :385.3

[0301]

[0302] 15b (40 mg, 0.1 mmol) was added with hydrochloric acid (12 M, 2 mL), stirred at 80 ° C for two hours, the reaction end point was detected by TLC, concentrated and desolvated, and then 2-bromo-5-chloropyrazine (19 mg, 0.1 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), Xantphos (12 mg, 0.02 mmol), diethylisopropylamine (38 mg, 0.3 mmol) and 1,4-dioxane (1 mL) were added, and nitrogen was protected and stirred at 100-105 ° C for 16 hours. The reaction solution was concentrated and column chromatography was performed to obtain 15d (20 mg, yield: 45.4%). 1 H NMR (400MHz, CDCl3) δ8.40(d,J=4.0Hz,1H),8.12(d,J=4.0Hz,1H),7.76(d,J=8.0Hz,1H),7.66(s,1H),7. 62(s,1H),7.59-7.39(m,2H),4.45-4.38(m,1H),4.18-4.12(m,2H),3.63-3.55(m,2H),2.20-2.09(m,4H). MS m / z[M+H] + :441.1

[0303]

[0304] 15d (50.0 mg, 0.11 mmol), Int-1 (30.0 mg, 0.12 mmol), potassium phosphate (70.0 mg, 0.33 mmol), dimethyl sulfoxide (1.1 mL) were added to the reaction flask and reacted at 80-90°C for 16 hours. After the reaction was complete, ethyl acetate (100 mL) was poured in and washed three times with 10% brine (50 mL). The organic phase was concentrated and column chromatography was performed to obtain 15 (38 mg, yield: 60%). 1HNMR(400MHz, CDCl3)δ8.22(s,1H),8.17(s,1H),7.54(s,1H),7.47(s,1H),7.28-7.24 (m,1H),7.14-7.09(m,2H),4.39-4.37(m,1H),4.20-4.18(m,1H),4.14-4.11(m,3H),3.92-3. 89(m,2H),3.82(d,J=12.0Hz,1H),3.69(d,J=8.0Hz,1H),3.59-3.53(m,3H),3.47(m,1H),3.37 (m,1H),3.0(d,J=4.0Hz,1H),2.15-2.09(m,4H),1.89(m,1H),1.78-1.64(m,3H),1.24(d,J=8.0Hz,3H). MS m / z[M+H] + :575.4.

[0305] Biological activity evaluation

[0306] 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.

[0307] SHP2 allosteric inhibition experiments

[0308] SHP2 is allosterically activated by activation of its Src Homology 2 (SH2) domain by a di-tyrosyl-phosphorylated peptide. The later 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.

[0309] 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.

[0310] 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):

[0311] 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 2.

[0312] Table 2 IC values ​​of compounds for inhibition of SHP2 50 value

[0313]

[0314]

[0315]

[0316]

[0317] Note: A≤10nM; 10nM<B≤50nM.

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 selected from -OH, -NH2, a halogen atom, a C1-C 10 Alkyl and C1-C 10 substituted by any 1 to 3 of the group consisting of alkoxy groups; X is selected from a chemical bond, -NH-, -CONH-; Selected from 5-12 membered heterocyclic groups; wherein the 5-12 membered heterocyclic groups contain 1-3 heteroatoms or groups selected from N, NH, O, S, C(O), S(O); Every R 3 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 Alkoxy, -NH2 or 5-6 membered heterocyclic group, the substitution is selected from halogen atoms, -NH2, -CN, -COOH, -CONH2, -CHO, -OH, -NO2 or C6-C 10 One or more substituents in the aryl group; or any two adjacent R 3 Form a 5-6 membered saturated or unsaturated ring, optionally, the 5-6 membered saturated or unsaturated ring is selected from -OH, -NH2, -CN, a halogen atom, C1-C 10 Alkyl and C1-C 10 substituted by any 1 to 3 of the group consisting of alkoxy groups; R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 Each is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, -NH2, C1-C 10 Alkyl or C1-C 10 Alkoxy; m is 0, 1, 2, 3 or 4; n is 1.

2. 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 selected from -OH, -NH2, a halogen atom, a C1-C 10 Alkyl and C1-C 10 substituted by any 1 to 3 of the group consisting of alkoxy groups; X is selected from a chemical bond, -NH-, -CONH-; Selected from 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); Every R 3 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 Alkoxy, -NH2 or 5-6 membered heterocyclic group, the substitution is selected from halogen atoms, -NH2, -CN, -COOH, -CONH2, -CHO, -OH, -NO2 or C6-C 10 One or more substituents in the aryl group; or any two adjacent R 3 Form a 5-6 membered saturated or unsaturated ring, optionally, the 5-6 membered saturated or unsaturated ring is selected from -OH, -NH2, -CN, a halogen atom, C1-C 10 Alkyl and C1-C 10 substituted by any 1 to 3 of the group consisting of alkoxy groups; R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 Each is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO2, -NH2, C1-C 10 Alkyl or C1-C 10 Alkoxy; m is 0, 1, 2, 3 or 4; n is 1.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The 5-12 membered heterocyclic group contains 1-3 heteroatoms or groups selected from N, NH, O, S, and C(O); Every R 3 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, a 5-6 membered heterocyclic group or -NH2, or any two adjacent R 3 A 5-6 membered saturated or unsaturated ring is formed, and optionally, the 5-6 membered saturated or unsaturated ring is substituted by any 1-3 selected from the group consisting of -OH, -NH2, -CN, a halogen atom, a C1-C6 alkyl group and a C1-C6 alkoxy group.

4. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein The 5-10 membered heteroaryl group contains 1-3 heteroatoms or groups selected from N, NH, O, S, and C(O); Every R 3 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, a 5-6 membered heterocyclic group or -NH2, or any two adjacent R 3 A 5-6 membered saturated or unsaturated ring is formed, and optionally, the 5-6 membered saturated or unsaturated ring is substituted by any 1-3 selected from the group consisting of -OH, -NH2, -CN, a halogen atom, a C1-C6 alkyl group and a C1-C6 alkoxy group.

5. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: Every R 3 are the same or different, and are independently selected from H, a halogen atom, -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 3 A 5-6 membered saturated or unsaturated ring is formed.

6. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, 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, benzothiophenyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinoline any one of 1,2-a]pyrazinyl, 4,7-diazaindole, pyrazolopyrimidinyl, imidazopyrimidinyl, oxazolopyrimidinyl, isoxazolopyrimidinyl, imidazopyrazinyl, pyrazolopyrazine, pyrrolopyrazinyl, furanopyrazinyl, thienopyrazinyl, pyridopyrimidonyl, benzoxazolyl, and benzothiazolyl.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The 5-12 membered heterocyclic group is selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactamyl, valerolactamyl, caprolactamyl, butyrolactonyl, valerolactonyl, caprolactonyl, succinimide or Any of .

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: The compound of formula (I) has the structure shown in formula (I-1): Among them, R 3 , X, m, and The definition as shown in claim 1 or 2.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein Every R 3 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, a 5-6 membered heterocyclic group, -NH2, or any two adjacent R 3 A 5-6 membered saturated or unsaturated ring is formed, and optionally, the 5-6 membered saturated or unsaturated ring is substituted by any 1-3 selected from the group consisting of -OH, -NH2, -CN, a halogen atom, a C1-C6 alkyl group and a C1-C6 alkoxy group.

10. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein is selected from 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl contains 1-3 heteroatoms or groups selected from N, NH, O, C(O); Every R 3 are the same or different, and are independently selected from H, a halogen atom, a 5-6 membered heterocyclic group, -COOH, -CN, a C1-C6 alkyl group, a hydroxy-substituted C1-C6 alkyl group, an amino-substituted C1-C6 alkyl group, a C1-C6 alkoxy group, -NH2, or any two adjacent R 3 A 5-6 membered saturated or unsaturated ring is formed.

11. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein is selected from 5-12 membered heterocyclic groups, wherein the 5-12 membered heterocyclic groups contain 1-3 heteroatoms or groups selected from N, NH, O, C(O); Every R 3 are the same or different, and are independently selected from H, a halogen atom, a 5-6 membered heterocyclic group, -COOH, -CN, a C1-C6 alkyl group, a hydroxy-substituted C1-C6 alkyl group, an amino-substituted C1-C6 alkyl group, a C1-C6 alkoxy group, -NH2, or any two adjacent R 3 A 5-6 membered saturated or unsaturated ring is formed.

12. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein 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, isoxazolopyrimidinyl, imidazopyrazinyl, pyrazolopyrazine, pyrrolopyrazinyl, furanopyrazinyl, thienopyrazinyl, pyridopyrimidonyl, benzoxazolyl; or selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactam, valerolactam, caprolactam, butyrolactone, valerolactonyl, caprolactone, succinimide or Any one of the heterocyclic groups; Every R 3 are the same or different, and are independently selected from H, a halogen atom, -COOH, -CN, a C1-C6 alkyl group, a 6-membered oxygen-containing heterocyclic group, a hydroxy-substituted C1-C6 alkyl group, an amino-substituted C1-C6 alkyl group, a C1-C6 alkoxy group, -NH2, or any two adjacent R 3 Form a 5-6 membered saturated or unsaturated ring; In the structure represented by formula (I-1), the methyl group and the amino group substituted on the tetrahydrofuran ring are located on the same side of the tetrahydrofuran ring.

13. A compound selected from the following or a pharmaceutically acceptable salt thereof:

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical preparation comprising the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 14, 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.

16. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, or a pharmaceutical preparation according to claim 15, for use in preventing and / or treating a disease or condition mediated or dependent on non-receptor protein tyrosine phosphatase.

17. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, or the pharmaceutical composition according to claim 14, or the pharmaceutical preparation according to claim 15, in the preparation of a medicament for preventing and / or treating a disease or condition mediated or dependent on non-receptor protein tyrosine phosphatase.

18. A pharmaceutical combination comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, or a pharmaceutical preparation according to claim 15, and at least one additional therapeutic agent.

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