TWI851921B - Pyrazine derivatives and their application in inhibiting SHP2 - Google Patents

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-labeled substance thereof, wherein the compound of formula (I) has a structure of: The pyrazine derivatives provided by the present invention have excellent SHP2 inhibitory activity and can be used to prevent and/or treat diseases or conditions mediated by or dependent on non-receptor protein tyrosine phosphatase.

Description

Pyrazine derivatives and their application in inhibiting SHP2

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 its use as a protein tyrosine phosphatase 2 (SHP2) inhibitor in preventing and/or treating diseases related to abnormal protein tyrosine phosphatase 2 (SHP2) activity.

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.

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.

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.

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.

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

Solution for solving the problem: In order to solve the above technical problem, 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: , wherein: R ¹ and R ² are the same or different, and are independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO ₂ , a substituted or unsubstituted group: -NH ₂ , a C ₁ -C ₁₀ alkyl group, a C ₁ -C ₁₀ alkylamino group, a C ₁ -C ₁₀ alkoxy group, a C ₃ -C ₁₂ cycloalkyl group, a C ₃ -C ₁₂ cycloalkyloxy group, a 3-12 membered heterocyclic group, a C ₆ -C ₁₀ aryl group, a 5-10 membered heteroaryl group; or R ¹ and R ² form a 3-8 membered cycloalkyl group, a cycloalkenyl group or a heterocyclic group, and optionally, the 3-8 membered cycloalkyl group, the cycloalkenyl group or the heterocyclic group is selected from -OH, -NH ₂ , -CN, NO ₂ , a halogen atom, a C ₁ -C ₁₀ alkyl group, a C ₁ -C ₁₀ alkoxy group, a C ₁ -C ₁₀ alkylamino group, a C ₃ -C ₁₂ cycloalkyl group, a C ₆ -C ₁₀ aryl group, and a 5-10 membered heteroaryl group; X is selected from a chemical bond, -NH-, and -CONH-; is selected from C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, C ₄ -C ₁₂ cycloalkyl, 3-12 membered heterocyclic group, C ₆ -C ₁₄ bridged cyclic group or spirocyclic group, C ₆ -C ₁₄ bridged heterocyclic group or spiro heterocyclic group; wherein the 5-10 membered heteroaryl, 3-12 membered heterocyclic group, C ₆ -C ₁₄ bridged heterocyclic group or spiro heterocyclic group contains 1-3 hetero atoms or groups selected from N, NH, O, S, C(O), S(O); each R ³ is the same or different and is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO ₂ , a substituted or unsubstituted group of the following: C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkylamino, -C ₁ -C ₁₀ alkylamide, C ₁ -C ₁₀ alkoxy, -NH ₂ , C ₃ -C ₁₂ cycloalkyl, 3-12 membered heterocyclic group, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl group, wherein the substituent is selected from C ₁ -C ₁₀ alkyl, C ₃ -C ₁₂ cycloalkyl, 3-12 membered heterocyclic group, halogen atom, -NH ₂ , -CN, -COOH, -CONH ₂ , -CHO, -OH, -NO ₂ , hydroxy-C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ alkylamino, 5-10 membered heteroaryl, C ₆ -C or any two adjacent ^R3's form a 3-6 membered saturated or unsaturated ring, optionally, the 3-6 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 - C10} alkyl group, a _C1 - _C10 alkoxy group, a C3- _C12 cycloalkylamino group, a _{C1 - C10} alkylamino group, a _C3 - _C12 cycloalkyl group, a halogenated _C1 - _C10 alkylamino group, a _C6 - _C10 aryl group and a 5-10 membered heteroaryl group; ^R4 , ^R5 , ^R6 , ^R7 , ^R8 , ^R9 R ¹⁰ and R ¹¹ are each independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO ₂ , a substituted or unsubstituted group: -NH ₂ , a C ₁ -C ₁₀ alkyl group, a C ₁ -C ₁₀ alkylamino group, a C ₁ -C ₁₀ alkoxy group, a C ₃ -C ₁₂ cycloalkyl group, a C ₃ -C ₁₂ cycloalkyloxy group, a 3-12 membered heterocyclic group, a C ₆ -C ₁₀ aryl group, a 5-10 membered heteroaryl group, wherein the substitution is selected from a C ₁ -C ₁₀ alkyl group, a C ₃ -C ₁₂ cycloalkyl group, a 3-12 membered heterocyclic group, a halogen atom, -NH ₂ , -CN, -COOH, -CHO, -OH, -NO ₂ , a hydroxyl-C ₁ -C The present invention relates to a group consisting of: _a C ₁ -C ₁₀ alkyl group, a C 1 -C 10 alkoxy group, a C ₁ -C ₁₀ alkylamino group, a 5-10 membered heteroaryl group or a C ₆ -C ₁₀ aryl group; m is 0, 1, 2, 3 or 4; and n is 0, 1 or 2.

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.

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.

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 drug composition, or the above-mentioned drug preparation, which is used for preventing and treating diseases or conditions mediated by or dependent on non-receptor protein tyrosine phosphatase.

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 above-mentioned drug composition, or the above-mentioned drug preparation for preventing and/or treating diseases or conditions mediated by or dependent on non-receptor protein tyrosine phosphatase.

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 by or dependent on non-receptor protein tyrosine phosphatase.

The present invention also provides a method for preventing and/or treating diseases or conditions mediated by or dependent on non-receptor protein tyrosine phosphatase, comprising 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 drug compositions, or the above-mentioned drug preparations to a patient in need thereof.

The present invention also provides a pharmaceutical product comprising at least one additional therapeutic agent and any one of the above-mentioned compounds of formula (I) or its pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled substance, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation.

Effect of the invention: The pyrazine derivatives provided by the present invention have excellent SHP2 inhibitory activity, 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 SHP2 inhibitory activity. The pyrazine derivatives described in the present invention can be used to prevent and/or treat diseases or conditions mediated by or dependent on non-receptor protein tyrosine phosphatase.

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: wherein: ^R1 and ^R2 are the same or different and are independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, _-NO2 , a substituted or unsubstituted group: _-NH2 , a _C1 - _C10 alkyl group, a _C1 - _C10 alkylamino group, a _C1 - _C10 alkoxy group, a _C3 - _C12 cycloalkyl group, a _C3 - _C12 cycloalkyloxy group, a 3-12 membered heterocyclic group, a _C6 - _C10 aryl group, a 5-10 membered heteroaryl group; or ^R1 and ^R2 form a 3-8 membered cycloalkyl group, a cycloalkenyl group or a heterocyclic group, optionally, the 3-8 membered cycloalkyl group, the cycloalkenyl group or the heterocyclic group is selected from -OH, _-NH2 , -CN, _-NO2 , a halogen atom, a C ₁ -C ₁₀ alkyl group, a C ₁ -C ₁₀ alkoxy group, a C ₁ -C ₁₀ alkylamino group, a C ₃ -C ₁₂ cycloalkyl group, a C ₆ -C ₁₀ aryl group, and a 5-10 membered heteroaryl group; X is selected from a chemical bond, -NH-, and -CONH-; is selected from C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, C ₄ -C ₁₂ cycloalkyl, 3-12 membered heterocyclic group, C ₆ -C ₁₄ bridged cyclic group or spirocyclic group, C ₆ -C ₁₄ bridged heterocyclic group or spiro heterocyclic group; wherein the 5-10 membered heteroaryl, 3-12 membered heterocyclic group, C ₆ -C ₁₄ bridged cyclic group or spirocyclic group contains 1-3 heteroatoms or groups selected from N, NH, O, S, C(O), S(O); each R ³ is the same or different and is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO ₂ , an aminoacyl group, a substituted or unsubstituted group of the following: C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkylamino, -C ₁ -C ₁₀ alkylamide, C ₁ -C ₁₀ alkoxy, -NH ₂ , C ₃ -C ₁₂ cycloalkyl, 3-12 membered heterocyclic group, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl group, wherein the substituent is selected from C ₁ -C ₁₀ alkyl, C ₃ -C ₁₂ cycloalkyl, 3-12 membered heterocyclic group, halogen atom, -NH ₂ , -CN, -COOH, -CONH ₂ , -CHO, -OH, -NO ₂ , hydroxy-C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ alkylamino, 5-10 membered heteroaryl or C ₆ -C or any two adjacent ^R3's form a 3-6 membered saturated or unsaturated ring, optionally, the 3-6 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 -C10 alkyl} group, a C1-C10 alkoxy group, a C3- _C12 cycloalkylamino group, a _C1 - _C10 alkylamino group, a _C3 -C12 cycloalkyl group, a halogenated _C1 - _C10 alkylamino group, a _{C6 - C10} aryl group and a 5-10 membered heteroaryl group; ^R4 , R5, ^R6 , R7, R8, R9, R10, R11, R12, R13, ^R14 , R15, R16, R17 _, R18, R19, _R20 , R21, _R22 , R23, ^R24 , R25, R26, R27, R28, ^R29 , ^R30 , ^R31 , R32 ¹¹ are each independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO ₂ , a substituted or unsubstituted group: -NH ₂ , a C ₁ -C ₁₀ alkyl group, a C ₁ -C ₁₀ alkylamino group, a C ₁ -C ₁₀ alkoxy group, a C ₃ -C ₁₂ cycloalkyl group, a C ₃ -C ₁₂ cycloalkyloxy group, a 3-12 membered heterocyclic group, a C ₆ -C ₁₀ aryl group, a 5-10 membered heteroaryl group, a 3-12 membered heterocyclic group, wherein the substitution is selected from a C ₁ -C ₁₀ alkyl group, a C ₃ -C ₁₂ cycloalkyl group, a 3-12 membered heterocyclic group, a halogen atom, -NH ₂ , -CN, -COOH, -CHO, -OH, -NO ₂ , a hydroxyl-C ₁ -C The present invention relates to a group consisting of: _a C ₁ -C ₁₀ alkyl group, a C 1 -C 10 alkoxy group, a C ₁ -C ₁₀ alkylamino group, a 5-10 membered heteroaryl group or a C ₆ -C ₁₀ aryl group; m is 0, 1, 2, 3 or 4; and n is 0, 1 or 2.

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 a special definition, but should be understood according to the common meaning in this field.

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.

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

In this article, _Ca - _Cb 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" regarding the number of groups or atoms herein indicate all integers within the given range. For example, substituted by "1-3" substituents indicates substituted by 1, 2 or 3 substituents; "3-12-membered heterocyclic group" indicates that it includes 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered and 12-membered heterocyclic groups.

The term " _C1 - _C10 alkyl" refers alone or in combination to a saturated straight or branched alkyl group containing 1 to 10 carbon atoms, including, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, t-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, and the like. In some embodiments, preferably, "C ₁ -C ₁₀ alkyl" is any one of methyl, ethyl, n-propyl, isopropyl, and t-butyl. Similarly, the term "C _1-6 alkyl" alone or in combination represents a saturated straight or branched alkyl group containing 1 to 6 carbon atoms, for example, including methyl, ethyl, propyl, isopropyl, etc.

The term "C ₁ -C ₁₀ alkoxy" alone or in combination refers to the group C ₁ -C ₁₀ alkyl-O-, wherein "C ₁ -C ₁₀ alkyl" means as defined above, for example, it includes (but is not limited to) methoxy (-OCH ₃ ), ethoxy (-OCH ₂ CH ₃ ), n-propoxy (-OCH ₂ CH ₂ CH ₃ ), isopropoxy (-OCH(CH ₃ ) ₂ ), n-butoxy (-OCH ₂ CH ₂ CH ₂ CH ₃ ), sec-butoxy (-OCH(CH ₃ )CH ₂ CH ₃ ), isobutoxy (-OCH ₂ CH(CH ₃ ) ₂ ), t-butoxy (-OC(CH ₃ ) ₃ ), n-pentoxy (-OCH ₂ CH ₂ CH _{2 CH 3} ), neopentoxy (-OCH ₂ C(CH ₃ ) ₃ )wait.

The term "C ₃ -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, "C ₃ -C ₁₂ cycloalkyl" is preferably "C ₃ -C ₈ cycloalkyl".

The term "C ₃ -C ₁₂ cycloalkyloxy" alone or in combination represents the group C ₃ -C ₁₂ cycloalkyl-O-, wherein C ₃ -C ₁₂ cycloalkyl is as defined above.

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 aziridine, aziridine cyclobutyl, oxazolidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactam, valerolactamide, caprolactam, 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, succinimidyl or More preferably, the 3-12 membered heterocyclic group is .

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

The term "heteroaryl" refers to an aromatic cyclic group formed by replacing a carbon atom on the ring with at least one heteroatom selected from sulfur, oxygen or nitrogen. In some embodiments, the aromatic cyclic 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, oxazinyl, pyridin-2(1H)-onyl, pyridin-4(1H)-onyl, pyridin-6(1H)-onyl, pyridin-7(1H)-onyl, pyridin-8(1H)-onyl, pyridin-10(1H)-onyl, pyridin-11(1H)-onyl, pyridin-12(1H)-onyl, pyridin-13(1H)-onyl, pyridin-14(1H)-onyl, pyridin-15(1H)-onyl, pyridin-16(1H)-onyl, pyridin-17(1H)-onyl, pyridin-18(1H)-onyl, pyridin-19( 1H )-onyl, pyridin-21(1H)-onyl, pyridin-23(1H)-onyl, pyridin-24( 1H) -onyl, pyridin-21 ... )-keto, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, naphthyl, 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 benzothiazolyl, and the like. The hydrogen atoms on the "heteroaryl" are independently and optionally substituted with one or more substituents described herein.

The term "C _6-10 aryl group" means an aryl group having 6 to 10 carbon atoms, wherein the aryl group is as defined above.

The term "5-10 membered heteroaryl" refers to a heteroaryl group having 5-10 carbon atoms and heteroatoms, wherein the heteroaryl group is as defined above.

The "3-8 membered cycloalkyl" in the term "3-8 membered cycloalkyl, cycloalkenyl or heterocyclic group" refers to a saturated monocyclic or condensed cycloalkyl group having 3-8 carbon atoms, for example, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Among them, the "3-8 membered cycloalkenyl" is a partially unsaturated monocyclic or condensed cyclic group having 3-8 carbon atoms. Wherein "3-8 membered heterocyclic group" means a heterocyclic group having 3-8 carbon atoms and a heteroatom or a heteroatom group, wherein the heteroatom or heteroatom group is selected from N, NH, O, S(O) _m (wherein m is 0, 1, 2); for example, aziridinyl, aziridinyl cyclobutyl, oxadiazinyl cyclobutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, etc.; in some embodiments, "3-8 membered heterocyclic group" is preferably "3-6 membered heterocyclic group" or "5-6 membered heterocyclic group".

The term "-CONH-" means -C(=O)-NH-, which can specifically represent C(=O) and Connect or NH with Connected, preferably C(=O) and connected.

The term "amino" alone or in combination means a primary amine group (-NH ₂ ), a secondary amine group (-NH-) or a tertiary amine group ( ).

The term "C ₁ -C ₁₀ alkylamino" alone or in combination means an amino group as defined above, wherein the hydrogen atom of the amino group is substituted by at least one C ₁ -C ₁₀ alkyl group, wherein "C ₁ -C ₁₀ alkyl group" means as defined above. Correspondingly, the “C ₁ -C ₁₀ alkylamino” includes, for example, methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, 2-butylamino, t-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. Specific "C ₁ -C ₁₀ alkylamino" includes methylamino, ethylamino, isopropylamino, t-butylamino and the like.

The term "C ₃ -C ₁₂ cycloalkylamino" means, alone or in combination, an amino group as defined above, wherein the hydrogen atom of the amino group is substituted by at least one C ₃ -C ₁₂ cycloalkyl group, and "C ₃ -C ₁₂ cycloalkyl" means as defined above.

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) are all within the scope of the present invention.

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 S.M.Berge in J. Pharmaceutical Sciences (volume 66: pages 1-19, 1977). In the present invention, pharmaceutically acceptable non-toxic acid addition salts refer to salts formed by the compounds of the present invention and organic or inorganic acids. Pharmaceutically acceptable non-toxic base addition salts refer to salts formed by the compounds of the present invention and organic or inorganic bases.

The term "solvate" refers to a compound formed by one or more solvent molecules and the compound of the present invention. Solvents forming 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.

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

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

The term "isotopic derivative" refers to an isotopic derivative obtained by replacing the hydrogen atom in the general formula (I) with 1 to 6 deuterium atoms (D) or an isotopic derivative obtained by replacing the carbon atom in the general formula (I) with 1 to 3 carbon 14 atoms ( ¹⁴ C).

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

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

In a preferred embodiment, the compound of formula (I) has a structure shown in formula (I-1): X is selected from a chemical bond, -NH-, -CONH-; is selected from C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, C ₄ -C ₁₂ cycloalkyl, 3-12 membered heterocyclic group, C ₆ -C ₁₄ bridged cyclic group or spirocyclic group, C ₆ -C ₁₄ bridged heterocyclic group or spiro heterocyclic group; wherein the 5-10 membered heteroaryl, 3-12 membered heterocyclic group, C ₆ -C ₁₄ bridged heterocyclic group or spiro heterocyclic group contains 1-3 heteroatoms or groups selected from N, NH, O, S, C(O), S(O); each R ³ is the same or different and is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO ₂ , aminoacyl, substituted or unsubstituted C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkylamino, -C 1 -C 10 alkylamide, C ₁ -C ₁₀ alkoxy, -NH ₂ , C ₃ -C ₁₂ cycloalkyl, 3-12 membered heterocyclic group, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl, wherein the substitution is selected from C ₁ -C ₁₀ alkyl, C ₃ -C ₁₂ cycloalkyl, 3-12 membered heterocyclic group, halogen atom, -NH ₂ , _-CN , -COOH, -CONH ₂ , -CHO, -OH, -NO ₂ , hydroxy-C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C _{1 -C} or any two adjacent R ⁵ groups form a _3-6 membered saturated or unsaturated ring, optionally, the 3-6 membered saturated or unsaturated ring is substituted by 1 to 3 selected from the group consisting of -OH, _{-NH 2} , _-CN , a halogen atom, a C ₁ -C ₁₀ alkyl group, a C _{1 -C 10 alkoxy group, a C 3} -C ₁₂ cycloalkylamino group, a C ₁ -C _{10 alkylamino} group, a C ₃ -C ₁₂ cycloalkyl group, a halogenated C _{1 -C 10} alkylamino group, a C ₆ -C ₁₀ aryl group, and a 5-10 membered heteroaryl group; m is 0, 1, 2, 3 or 4; In a more preferred embodiment, in the structure represented by formula (I-1), the methyl group substituted on the tetrahydrofuran ring and the amine group are on the same side of the tetrahydrofuran ring.

In a preferred embodiment, a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled substance thereof is characterized in that: is selected from phenyl, naphthyl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group; wherein the 5-10 membered heteroaryl or 3-12 membered heterocyclic group contains 1-3 heteroatoms or groups arbitrarily selected from N, NH, O, S, C(O), Preferably, the 5-10 membered heteroaromatic ring is selected from thienyl, pyridyl, pyrimidinyl, pyrazinyl, oxazinyl, 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 2-hydroxy-2-nitro-1-oxo-2 ... More preferably, the 3-12 membered heterocyclic group is selected from butyrolactam, pyrrolidinyl, succinimidyl or any one of; each R ³ is the same or different, and is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO ₂ , an aminoacyl group, a substituted or unsubstituted group: a C ₁ -C ₁₀ alkyl group, a C ₁ -C ₁₀ alkylamino group, a -C ₁ -C ₆ alkylCONH ₂ , a C ₁ -C ₁₀ alkoxy group, -NH ₂ , wherein the substitution is substituted by one or more substituents selected from C ₁ -C ₁₀ alkyl group, a halogen atom, -NH ₂ , -CN, -OH, -NO ₂ ; or any two adjacent R ^5s form a 3-6 membered saturated or unsaturated ring, and optionally, the 3-6 membered saturated or unsaturated ring is substituted by 1-3 -OH, -NH ₂ , -CN, a halogen atom, a C ₁ -C ₁₀ alkyl group, or a C ₁ -C ₁₀ alkoxy group.

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

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.

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

In a more preferred embodiment, the above-mentioned drug composition further comprises: -a pharmaceutically acceptable carrier; -an adjuvant; and/or -a formulation agent.

The present invention also provides a method for preparing the above-mentioned pharmaceutical composition, which comprises mixing a compound of formula (I) 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.

The present invention also provides a pharmaceutical preparation, which includes any of the above-mentioned compounds of formula (I) or its 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, sugar tablets, tablets, water or oil suspensions, dispersible powders or granules, emulsions, 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 may contain one or more ingredients selected from the following: sweeteners, flavoring agents, coloring agents and preservatives to provide pleasing and palatable pharmaceutical preparations. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets in admixture. These excipients may be inert excipients, granulating and disintegrants, and lubricants. The tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time. For example, a water-soluble taste masking substance may be used.

Oral formulations may also be provided in the form of soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or in which the active ingredient is mixed with a water-soluble carrier.

The aqueous suspension contains the active substance and a suitable excipient for mixing to prepare an aqueous suspension. Such an excipient is a suspending agent; the dispersing agent or wetting agent may be a naturally occurring phospholipid. The aqueous suspension may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

Oil suspensions can be prepared by suspending the active ingredient in vegetable oil or mineral oil. The oil suspensions may contain a thickener, and the above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding antioxidants.

Dispersible powders and granules suitable for preparing an aqueous suspension by the addition of water provide the active ingredient and dispersants or wetting agents, suspending agents 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 the addition of antioxidants such as ascorbic acid.

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. Sweeteners may be used. Such preparations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical preparation of the present invention may be in the form of a sterile injectable aqueous solution. Acceptable solvents or solvents that may 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 or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred to administer the solution and microemulsion 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.

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 preparation aggregate that can be introduced outside the stomach. In addition, sterile fixed oil can be conveniently used as a solvent or suspension medium. In addition, fatty acids can also be used to prepare injections.

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

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 method of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal 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 regimens.

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 by or dependent on non-receptor protein tyrosine phosphatase (SHP2, Src Homolgy-2 phospahtase).

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 by or dependent on non-receptor protein tyrosine phosphatase.

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 drug composition, or the drug preparation in the preparation of drugs for preventing and/or treating diseases or conditions mediated by or dependent on non-receptor protein tyrosine phosphatase.

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, neural defects, mental defects and reproductive 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 may be alcoholism or migraine; the cardiovascular system defect may be aortic aneurysm, susceptible myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension; the blood system defect may be deep vein thrombosis; the immune and inflammatory diseases may be arthritis, multiple sclerosis, and liver cirrhosis; the infectious diseases may be hepatitis B, chronic hepatitis, osteopenia, and osteoporosis; the neurological defect may be Alzheimer's disease, Parkinson's disease, migraine, and vertigo; the mental defect may be anorexia nervosa, attention deficit hyperactivity disorder, dementia, severe depressive disorder, and mental illness; the reproductive defect may be age of menarche, endometriosis, infertility, etc.

The present invention also provides a method for preventing and/or treating diseases or conditions mediated by or dependent on non-receptor protein tyrosine phosphatase, 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 drug composition, or the drug preparation to a patient in need thereof.

The term "therapeutically effective amount" refers to an amount of a pharmaceutical active ingredient that is capable of inducing a biological or medicinal response in cells, tissues, organs or organisms (e.g., patients).

The term "administer" refers to the process of applying a pharmaceutical active ingredient (such as the compound of the present invention) or a pharmaceutical composition containing a pharmaceutical active ingredient (such as the pharmaceutical composition of the present invention) to a patient or its cells, tissues, organs, biological fluids, etc., so that the pharmaceutical active ingredient or the pharmaceutical composition comes into contact with the patient or its cells, tissues, organs, biological fluids, etc. Common administration methods 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.

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

The term "patient" (or subject) refers to humans or non-human animals (e.g., mammals).

The present invention also provides a pharmaceutical product comprising at least one additional therapeutic agent for preventing and/or treating diseases or conditions mediated by or dependent on non-receptor protein tyrosine phosphatase, and 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.

The compound of formula (I) or its pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled substance, or the drug composition, or the drug preparation of the present invention can be used in combination with the following compounds or antibodies, or with antibody drugs to form antibody-drug conjugates.

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 substance 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: (1) Compound Ia and Compound Ib react under the action of alkali to obtain Compound Ic, wherein A in Ib is a halogen atom, preferably chlorine, bromine or iodine, and X is a chemical bond; (2) Compound Ic is deprotected to obtain Compound Id; (3) Compound Id and Compound Ie react to obtain Compound If, wherein B in Compound Ie is a halogen atom, preferably chlorine, bromine or iodine; (4) Compound If and Ig react under the action of alkali to obtain Compound (I). The synthetic route diagram is as follows:

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.

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

In a preferred embodiment, in step (3), the catalyst for 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.

In a preferred embodiment, in step (4), the catalyst for 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.

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 synthetic route is as follows:

The present invention also provides another method for synthesizing compound (I), comprising: (1) reacting compound I-h with compound I-i to obtain compound I-j, wherein A in compound I-i is a halogen atom, preferably chlorine, bromine or iodine; (2) reacting compound I-j with compound I-k to obtain compound I-l, wherein X in compound I-l is -CONH-; (3) reacting compound I-l with compound I-g to obtain compound (I).

In a preferred embodiment, in step (1), the catalyst for 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.

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

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.

The synthesis roadmap is as follows:

The present invention is further described with reference to the following embodiments; however, these embodiments should not be construed as limiting the scope of the present invention.

Preparation of intermediate Int-1

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 three times, and the organic phase was dried over anhydrous sodium sulfate. The desiccant was filtered, and the filtrate was concentrated to obtain the crude product Int-1b ( 237 g, yield 100%), which was directly used in the next reaction. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.32 (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).

Under an ice-water bath, diisobutylaluminum hydroxide (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, the filtrate was diluted with dichloromethane, washed with water three times, and the organic phase was dried over anhydrous sodium sulfate. The desiccant was filtered, the filtrate was concentrated, and the residue was purified by silica gel column (eluted with petroleum ether/ethyl acetate = 10/1) to obtain Int- 1c (56 g, yield 54%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.61 (s, 1H), 4.08 (q, J = 8.0 Hz, 1H), 1.27 (d, J = 8.0 Hz 3H), 0.91 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H).

Under nitrogen protection, diisopropylamine (23.4 mL, 166 mmol) was dissolved in anhydrous tetrahydrofuran (220 mL), cooled to -20°C, n-butyl lithium (64 mL, 160 mmol, 2.5 M n-hexane solution) was added dropwise, and after reacting for 1 hour, an anhydrous tetrahydrofuran (50 mL) solution of N-tert-butyloxycarbonyl-4-piperidinylcarboxylic acid ethyl ester (27.5 g, 107 mmol) was added dropwise, and the temperature was raised to 0°C for 1 hour, and Int- 1c (20.5 mL, 102 mmol) was added, and the reaction was continued 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. The product was 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.

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 reaction was allowed to react 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 the crude product 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.

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, filtered through the desiccant, the filtrate was concentrated under reduced pressure, and column chromatography was performed to obtain Int- 1f (24 g, yield 57%). ¹ H NMR (400 MHz, CDCl ₃ ) 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 = 4.0 Hz, 3 H). MS m/z [M+H] ⁺ : 290.3, [MH] ^- : 288.3.

Sodium hydroxide (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, and a saturated ammonium chloride solution was added dropwise until no bubbles were generated, and ethyl acetate was added for separation, and the aqueous phase was extracted until no product was obtained, and the combined organic phases were washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered through the desiccant, the filtrate was concentrated under reduced pressure, and column chromatography gave Int- 1g (5 g, yield 64%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.08-4.14 (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).

Int- 1g (13.5 g, 49.7 mmol) was added to dichloromethane (160 mL), and Dess-Martin oxidant (42 g, 99 mmol) was added in batches at -10°C, and the reaction was carried out at 0°C for 16 hours. Ether (500 mL) was added, and a large amount of solid precipitated. The solid was filtered and washed once with ether (100 mL). The filtrate was washed once with a saturated sodium bicarbonate aqueous solution and a saturated sodium thiosulfate aqueous solution, and the organic phase was dried with anhydrous sodium sulfate. The desiccant was filtered, the filtrate was concentrated under reduced pressure, and Int- 1h (5.5 g, yield 41%) was obtained by column chromatography. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.19 (d, J = 8.0 Hz, 1H), 3.83-3.92 (m, 4H), 2.96-3.16 (m, 2H), 1.55-1.79 (m, 4H), 1.46 (s, 9H), 1.32 (d, J = 8.0 Hz, 3H).

Dissolve Int- 1h (20.0 g, 274.3 mmol) and R-(+)-tert-butylsulfenamide (33.2 g, 274.3 mmol) in tetrahydrofuran (350 mL) solution, add tetraethyl titanium ester (67.7 g, 297 mmol), replace with nitrogen, and react at 100°C for 20 hours. After cooling to -25°C, add methanol (30 mL), and add lithium borohydride (5.97 g, 274.3 mmol) in batches. After the addition is complete, react at -10°C for 45 minutes. Saturated ammonium chloride solution was added at -10°C, and a large amount of solid precipitated. The mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was separated, and the aqueous phase was extracted with ethyl acetate again until no product was obtained. The organic phase was washed once with saturated brine, dried with sodium sulfate, filtered through the desiccant, and the organic phase was concentrated under reduced pressure. Int- 1i (12.4 g, yield 59%) was obtained by column chromatography. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.15-4.19 (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 = 8.0 Hz, 3H). MS m/z [M+H] ⁺ : 375.3, [MH] ^- : 373.5.

Int- 1i (12.0 g, 32.1 mmol) was dissolved in methanol (150 mL), and a solution of HCl in dioxane (15 mL, 4 M) was added. The temperature was raised to 40°C, and the reaction was stirred for 1 hour to stop the reaction. The reaction solution was cooled to room temperature, reduced pressure and concentrated to obtain Int -1 (7.85 g, yield 100%). ¹ H NMR (400 MHz, DMSO): δ 9.25 (br, 2H), 8.38 (br, 3H), 4.20-4.23 (m, 1H), 3.81 (d, J = 8.0 Hz, 1H), 3.62 (d, J = 8.0 Hz, 1H), 3.46 (br, 1H), 3.1 4-3.23 (m, 2H), 2.84-2.92 (m, 2H), 1.69-2.01 (m, 4H), 1.22 (d, J = 8.0 Hz, 3H). MS m/z [M+H] ⁺ : 171.2.

Preparation of intermediate Int-2

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, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was concentrated by decompression and recrystallization to obtain the intermediate Int-2 (10.0 g, yield 77.6%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.74 (d,1H), 7.67 (d, 1H), 7.26 (t, 1H), 1.31 (s, 9H).

Embodiment 1

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 salt water, 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 (400 MHz, CDCl ₃ ): δ 7.23 (dd,1H), 7.45 (m, 2H), 7.35 (d, 1H), 6.29 (d, 1H), 3.95 (s, 3H), 1.34 (s, 9H).

Add 1a (1.0 g, 3.2 mmol) to 25% hydrochloric acid (10 mL) and reflux for 2 hours. Cool to room temperature, extract with dichloromethane, and concentrate the organic phase under reduced pressure to obtain crude 1b (0.5 g, yield 60.8%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.29 (m,4H), 6.29 (d, 1H), 3.95 (s, 3H).

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. The mixture was cooled to room temperature, water was added, and ethyl acetate was used for extraction. The organic phase was washed with saturated salt water, dried over sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 1c (300 mg, yield 41.8%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 (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).

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), and acetonitrile (2 mL) were added to the reaction bottle and refluxed for reaction overnight. 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 (400 MHz, CDCl ₃ ): δ 8.96 (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).

Embodiment 2

Tri-n-butyltin hydroxide (2.8 g, 9.6 mmol) was dissolved in tetrahydrofuran (20 mL). LDA (2M, 4.8 mL, 9.6 mmol) was added dropwise at 0°C and reacted for 1 hour. The temperature was then lowered to -78°C and a solution of 2a (1.0 g, 8.7 mmol) in tetrahydrofuran (5 mL) was slowly added. The reaction was continued for 4 hours after the addition was complete. 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 salt water, 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 (400 MHz, CDCl ₃ ): δ 8.71-8.73 (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).

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 (400 MHz, CDCl ₃ ) δ 8.60 (m,3H), 7.87 (d, 1H), 7.56 (m, 1H), 7.37 (m, 1H), 1.38 (s, 9H).

Add 2c (0.9 g, 2.9 mmol) to 25% hydrochloric acid (10 mL) and reflux for 2 hours. Cool to room temperature, extract with dichloromethane, and concentrate the organic phase under reduced pressure to obtain crude product 2d (0.5 g, yield 67.7%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.61 (m,3H), 7.50 (d, 1H), 7.41 (t, 1H), 7.17 (d, 1H).

Add 2d (0.5 g, 2.0 mmol), 2,5- dichloropyrazine (0.9 g, 5.8 mmol), and potassium carbonate (0.8 g, 5.8 mmol) to acetonitrile (10 mL), and heat to 80°C to react overnight. Cool to room temperature, add water, extract with ethyl acetate, wash the organic phase with saturated salt water, dry with sodium sulfate, filter, concentrate under reduced pressure, and separate by column chromatography to obtain 2e (300 mg, yield 41.7%). MS m/z [M+H] ⁺ : 368.9.

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), and acetonitrile (2 mL) were added to the reaction bottle and refluxed for reaction overnight. 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 (400 MHz, CDCl ₃ ) δ 8.64 (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).

Embodiment 3

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%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.68 (m,1H), 7.51 (s, 1H), 7.41 (m, 2H), 7.31 (m,1H), 3.95 (s, 3H), 1.33 (s, 9H).

3a (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 3b (0.5 g, yield 60.8%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45 (s, 1H), 7.42 (s, 1H), 7.20 (d, 2H), 7.02 (d, 1H), 3.88 (s, 3H).

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. 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 salt water, dried over sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 3c (300 mg, yield 41.8%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36 (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).

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), and acetonitrile (2 mL) were added to the reaction bottle and refluxed for reaction 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; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (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).

Embodiment 4

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 salt water, 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 (400 MHz, CDCl ₃ ) δ 7.67 (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).

Add 4a (1.2 g, 3.7 mmol) to 25% hydrochloric acid (10 mL) and reflux for 2 hours. Cool to room temperature, extract with dichloromethane, and concentrate the organic phase under reduced pressure to obtain crude 4b (0.6 g, yield 60.3%). MS m/z [M+H] ⁺ : 273.2.

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. The mixture was cooled to room temperature, water was added, and ethyl acetate was used for extraction. The organic phase was washed with saturated salt water, dried over sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 4c (300 mg, yield 35.4%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36 (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).

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), and acetonitrile (2 mL) were added to the reaction bottle and refluxed for reaction overnight. 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 (400 MHz, CDCl ₃ ): δ 8.42 (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).

Embodiment 5

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 salt water, 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 (400 MHz, CDCl ₃ ) 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 ).

Dissolve 5a (1.0 g, 2.9 mmol) in 25% hydrochloric acid (10 mL) and reflux for 2 hours. Cool to room temperature, extract with dichloromethane, and concentrate the organic phase under reduced pressure to obtain crude 5b (0.5 g, yield 59.7%). ¹ H NMR (400 MHz, CDCl ₃ ) 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).

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. 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 salt water, dried over sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 5c (280 mg, yield 40.3%). ¹ H NMR (400 MHz, CDCl ₃ ) 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).

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), and acetonitrile (2 mL) were added to the reaction bottle and refluxed for reaction overnight. 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 (400 MHz, CDCl ₃ ): 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), 3.53 (d, 1H), 3.01 (d, 1H), 2.02 (m, 1 H), 1.71(m, 1H), 1.68(m, 1H), 1.56 (m, 1H), 1.12 (d, 3H).

Embodiment 6

Int-2 (5.0 g, 15.9 mmol), pinacol diboron (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 salt water, 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 H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.72 (t,1H), 7.44 (t, 2H), 1.34 (s, 12H), 1.33 (s, 9H).

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, and ethyl acetate was extracted. The organic phase was washed with saturated salt water, 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.

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 and extracted with dichloromethane. 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.

Add 6c (0.5 g, 1.9 mmol), 2,5- dichloropyrazine (1.4 g, 9.6 mmol), potassium carbonate (560.3 mg, 3.8 mmol) to acetonitrile (5 mL), heat to 80°C and react overnight. Cool to room temperature, add water, extract with ethyl acetate, wash the organic phase with saturated salt water, dry with sodium sulfate, filter, concentrate under reduced pressure, and separate by column chromatography to obtain 6d (300 mg, yield 41.7%). MS m/z [M+H] ⁺ : 368.9.

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), and acetonitrile (2 mL) were added to the reaction bottle and refluxed for reaction overnight. 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%). ¹ H NMR (400 MHz, CDCl ₃ ): 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), 3.74 (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.

Embodiment 7

7a (500 mg, 1.80 mmol), oxazole (149 mg, 2.16 mmol), sodium acetate (40.4 mg, 0.18 mmol), Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene) (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 three times with ethyl acetate. 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 column chromatography was performed to obtain 7b (83 mg, yield: 15.1%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.85 (s, 1H), 7.70-7.63 (m, 2H), 7.42-7.33 (m, 2H).

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 a 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%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.92-7.90 (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).

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

7d (211 mg, 1.09 mmol), 2- bromo -5- chloropyrazine (19 mg, 0.1 mmol), Pd ₂ (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), and the mixture was reacted at 100°C for 16 hours under nitrogen protection. After the reaction, water was added, the mixture was 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%).

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 bottle 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, CDCl ₃ ) δ 8.45 (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.

Embodiment 8

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, the product was concentrated and column chromatography was performed to obtain 8a (75 mg, yield: 64%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.67 (d, J = 8.0 Hz,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).

8a (90 mg, 0.23 mmol) was added to hydrochloric acid (12M, 3 mL), and the reaction was carried out at 80-90°C for 2 hours. The reaction was detected by TLC. After the reaction was completed, the solution was concentrated and 2- bromo -5- chloropyrazine (43 mg, 0.23 mmol), Pd ₂ (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) were added. The reaction was carried out at 100°C for 16 hours under nitrogen protection. After the reaction was completed, the solution was directly concentrated and column chromatography was performed to obtain 8c (30 mg, yield: 29%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.35 (m, 1H), 8.08 (m, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.45 (s, 1H), 7.42 (d , J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 4.0 Hz, 1H), 7.24 (m, 1H), 7.23 (m, 1H), 5.36 (s, 2H).

8c (110.0 mg, 0.25 mmol), Int-1 (72.0 mg, 0.3 mmol), potassium phosphate (159 mg, 0.75 mmol), and 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 (400 MHz, CDCl ₃ ) δ 8.24 (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 =8.0 Hz, 1H), 3.73 (d, J = 12.0 Hz, 1H), 3.53-3.47 (m, 1H), 3. 43-3.36 (m, 1H), 3.04 (d, J = 4.0 Hz, 1H), 1.96-1.89 (m, 1H), 1.81-1.71 (m, 3H), 1.27 (d, J = 4.0 Hz, 3H); MS m/z [M+H] ⁺ : 581.6.

Embodiment 9

Add 9a (200 mg, 1.10 mmol), 9a-2 (266.2 mg, 1.66 mmol), Pd ₂ (dba) ₃ (50.4 mg, 0.06 mmol), BINAP (347.6 mg, 0.54mmol), Cs ₂ CO ₃ (1.08 g, 3.34mmol), and Dioxane (8 mL) to a 100 mL single-necked bottle. React at 100 °C for 16 h. For post-treatment, first cool the reaction solution to room temperature, add 50 mL of water, extract with ethyl acetate three times, combine the organic phases, wash once with a saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate, and purify by column to obtain 9b (100 mg, yield: 34.3%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.46-8.44 (m, 2H), 8.15-8.12 (m, 1H), 7.54-7.46 (m, 2H), 6.91-6.82 (m, 1H).

Add 9b (100 mg, 0.39 mmol), 9b-2 (105 mg, 1.16 mmol), Cs ₂ CO ₃ (251 mg, 3.34 mmol), and DMF (8 mL) to a 100 mL single-necked bottle. React at 130 °C for 16 h. For post-treatment, first cool the reaction solution to room temperature, add 50 mL of water, extract with ethyl acetate three times, combine the organic phases, wash once with a saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate, and purify by column to obtain 9c (90 mg, yield 70.4%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.26-8.25 (m, 2H), 7.26-7.43 (m, 3H), 6.72-6.71 (m, 1H), 1.23 (m, 9H).

Dissolve 9c (90 mg, 0.50 mmol) in acetonitrile (2 mL) and add concentrated hydrochloric acid (12 M, 6 mL) at 120 °C for 5 hours. Extract twice with water and ethyl acetate, wash once with saturated salt water, dry over sodium sulfate, filter through the desiccant, concentrate under reduced pressure, and use directly in the next reaction.

9d-2 (58.4 mg, 0.3 mmol), Xantphos (16 mg, 0.02 mmol), Pd ₂ (dba) ₃ (25 mg, 0.02 mmol), DIEA (106.7 mg, 0.82 mmol), and 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, filtered through the desiccant, concentrated under reduced pressure, and purified by column chromatography to obtain 9e (100 mg, yield 76%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.49-8.48 (m, 2H), 8.39-8.37 (m, 2H), 8.12 (s, 1H), 7.51-7.46 (m, 2H), 6.89-6.86 (m, 1H).

Compound 9e (80 mg, 0.20 mmol), Int-1 (61 mg, 0.25 mmol), DMF (5 mL), and potassium phosphate (256 mg, 1.25 mmol) were added to a 100 mL single-necked bottle, and the mixture was heated to 110 °C and reacted for 2 hours. Water was added, extracted with ethyl acetate, dried with sodium sulfate, filtered through the desiccant, concentrated under reduced pressure, and purified by column chromatography to obtain 9 (4 mg, yield 44%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39-8.38 (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.

Embodiment 10

Int-2 (5.0 g, 15.9 mmol), pinacol diboron (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 salt water, 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 H NMR (400 MHz, CDCl ₃ ) δ 7.72 (t,1H), 7.44 (t, 2H), 1.34 (s, 12H), 1.33 (s, 9H).

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 salt water, 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 (400 MHz, CDCl ₃ ) δ 8.69 (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).

10b (1.4 g, 3.9 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 10c (0.8 g, yield 68.0%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.85 (s, 1H), 8.16 (s, 1H), 7.38 (d, 2H), 7.16 (s, 1H), 6.83 (s, 1H), 6.70 (s, 1H).

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 salt water, dried with sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 10d (300 mg, yield 27.1%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.65 (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).

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), and acetonitrile (2 mL) were added to the reaction bottle and refluxed for reaction overnight. 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 (400 MHz, CDCl ₃ ) 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), 7.0 4 (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).

Embodiment 11

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-necked bottle and reacted 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 (400 MHz, DMSO- d ₆ ) δ 8.93-8.91 (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).

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). The mixture was heated to 130°C and reacted 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, filtered through a desiccant, concentrated under reduced pressure, and filtered through a column to obtain crude product 11c (4.2 g, yield 100%). ¹ H NMR (400 MHz, DMSO) δ 7.24 (d, J = 8.0 Hz, 1H), 6.93-6.88 (m, 2 H).

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

Dissolve 11d (1.3 g, 6.67 mmol) in dioxane (15 mL), then add N-diisopropylethylamine (1.4 g, 11.1 mmol), tris(dibenzylideneacetone)dipalladium (512 mg, 0.56 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (642 mg, 1.11 mmol), and react at 100°C for 16 hours under nitrogen protection. Cool to room temperature, reduce pressure, concentrate, and purify by column chromatography to obtain 11e (1.1 g, yield 54%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 (s, 1H), 7.98 (s, 1H), 7.34-7.30 (m, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H).

Add 11e (210 mg, 0.69 mmol) and 11a (150 mg, 0.63 mmol) to chlorobenzene (5 mL), replace with nitrogen, heat to 135°C and stir for 24 hours. Add petroleum ether to precipitate solid, filter to obtain solid 11f (240 mg, yield 76%), which is directly used in the next reaction.

11f (240 mg, 0.49 mmol), Int-1 (132 mg, 0.54 mmol), potassium phosphate (612 mg, 2.89 mmol) were added to dimethyl sulfoxide (13 mL), the atmosphere was replaced with nitrogen, and the temperature was raised to 85°C and stirred for 16 hours. Water was added to precipitate the solid, which was filtered and chromatographed on a silica gel column to obtain the target product 11 (110 mg, yield 36%). MS m/z [M+H] ⁺ 628.1; ¹ H NMR (400 MHz, DMSO) δ 12.61(s, 1H), 8.87 (d, J = 4.0 Hz, 1H), 8.47 (s, 1H), 8.27 (s, 1H), 7.95 (s, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.45 (t, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7. 7.17 (s, 1H), 6.85 (d, J = 8.0 Hz, 2H), 4.15-4.02 (m, 3H), 3.80 (d, J = 4.0 Hz , 1H), 3.61 (d, J = 8.0 Hz, 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 = 8.0 Hz, 3H).

Embodiment 12

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

Dissolve 11e (100 mg, 0.37 mmol) in anhydrous tetrahydrofuran (5 mL), add 12a in tetrahydrofuran dropwise to the reaction solution, and react at room temperature overnight. Reduce pressure, concentrate, and pass through a column to obtain 12b (90 mg, yield 60%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.80 (s, 1H), 8.98 (d, J = 4.8 Hz, 2H), 8.67 (d, J = 8.4 Hz, 1H), 8.33 (d, J = 1.2 Hz, 1H), 8.11 (d, J = 1.2 Hz, 1H), 7 .64 (t, J = 8.0 Hz, 1H), 7.59 – 7.47 (m, 2H).

Compound 12b (90 mg, 0.22 mmol) was added to a 100 mL single-necked bottle, followed by Int-1 (41 mg, 0.24 mmol), N,N-dimethylformamide (3 mL), and potassium phosphate (280 mg, 1.32 mmol), and the mixture was heated to 80 °C and reacted for 3 hours. The reaction solution was cooled to room temperature, 20 mL of water was added, and the mixture was extracted twice with ethyl acetate and washed three times with saturated salt water. The organic phase was dried over sodium sulfate, spun dry, and scraped to obtain 12 (20 mg, yield 18%). MS m/z [M+H] ⁺ : 546.1; ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.65 (s, 1H), 8.98 (d, J = 4.8 Hz, 2H), 8.28 (d, J = 8.4Hz, 1H), 8.18 (s, 2H), 7.53 (t, J = 4.8 Hz , 1H), 7.38 (t, J = 8.4 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 4.32 – 3.98 (m, 4H), 3.76 (d, J = 9.2 Hz, 1H), 3.24 – 3.03 (m, 2H), 2.11 – 2.04 (m, 1H), 1.95 – 1.73 (m, 3H), 1.44 (d, J = 6.4 Hz, 3H).

Embodiment 13

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. Filter and concentrate under reduced pressure to obtain 13b (240 mg, yield 100%). ¹ H NMR (400 MHz, DMSO): δ 12.29 (br, 1H), 4.06 (q, J = 8.0 Hz, 2H), 3.64 (t, J = 8.0 Hz, 2H), 2.76 (t, J = 8.0 Hz, 2H), 1.71-1.83 (m, 4H), 1.17 (t, J = 8.0 Hz, 3H).

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 the solid, which was filtered and passed through a column to obtain a white solid 13c (300 mg, yield 60%). ¹ H NMR (400 MHz, DMSO) δ 14.86 (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 = 8.0 Hz, 2H), 1.95-1.81 (m, 4H).

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), the atmosphere was replaced with nitrogen, the temperature was raised 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 (400 MHz, DMSO) δ 8.49 (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 = 8.0 Hz, 1H), 3.14 (s, 1H), 2.84 (s, 2H), 1.91-1.57 (m, 9H), 1.26 (s, 3H), 1.16 (d, J = 8.0 Hz, 3H).

Embodiment 14

14a-1 (290 mg, 1.0 mmol), 14a-2 (220 mg, 1.0 mmol), Pd(PPh ₃ ) ₄ (115 mg, 0.1 mmol), K ₂ CO ₃ (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 mixture 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 (400 MHz, DMSO) δ 7.55 (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 = 8.0 Hz,1H), 1.53 (t, J = 8.0 Hz,1H).

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), stirred at 130°C for 16 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 14c (70 mg, yield: 33.8%). ¹ H NMR (400 MHz, DMSO) δ 7.51 (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 = 8.0 Hz, 1H), 1.52 (t, J = 8.0 Hz, 1H).

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 the mixture was 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 (400 MHz, DMSO) δ 8.36 (s, 1H), 8.08 (s, 1H), 7.63 (d, J = 8.0 Hz,1H), 7.55 (s, 1H), 7.51 (t, J = 8.0 Hz,1H), 7.47 (s , 1H), 7.44 (d, J = 8.0 Hz,1H).

Add dimethyl sulfoxide (5 mL) to 14d (50 mg, 0.13 mmol), Int-1 (38 mg, 0.16 mmol), potassium phosphate (82 mg, 0.39 mmol), and stir at 80-90°C for 5 hours. Pour the reaction solution into ethyl acetate (100 mL). Wash three times with 10% brine (50 mL). Concentrate the organic phase and obtain 14 (60 mg, yield: 88.9%) by column chromatography, purity 99.1A% (254 nm). ¹ H NMR (400 MHz, DMSO) δ 8.23 (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 = 12.0 Hz, 1H), 3.49-3.47 (m, 1H), 3.39-3.34 (m, 1H), 3.03 (d, J = 8.0 Hz,1H), 1.93- 1.88 (m, 1H), 1.79-1.74 (m, 3H), 1.54 (t, J = 8.0 Hz, 3H), 1.26 (d, J = 4.0 Hz, 3H). MS m/z [M+H] ⁺ : 519.2.

Embodiment 15

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 ] palladium dichloride (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%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.74-7.63 (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.

15b (40 mg, 0.1 mmol) was added with hydrochloric acid (12M, 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), Pd ₂ (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 the mixture was stirred at 100-105°C for 16 hours under nitrogen protection. The reaction solution was concentrated and column chromatography was performed to obtain 15d (20 mg, yield: 45.4%). ¹ H NMR(400 MHz, CDCl ₃ ) δ 8.40(d, J = 4.0 Hz,1H), 8.12(d, J = 4.0 Hz,1H), 7.76(d, J = 8.0 Hz,1H), 7.66 (s, 1H), 7.62 (s, 1H), 7.59-7.39 (m, 2 H), 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.

Add 15d (50.0 mg, 0.11 mmol), Int-1 (30.0 mg, 0.12 mmol), potassium phosphate (70.0 mg, 0.33 mmol), and dimethyl sulfoxide (1.1 mL) to the reaction bottle and react at 80-90°C for 16 hours. After the reaction is complete, pour in ethyl acetate (100 mL) and wash three times with 10% brine (50 mL). After the organic phase is concentrated, column chromatography is performed to obtain 15 (38 mg, yield: 60%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (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 =12.0 Hz,1H), 3.69 (d, J = 8.0 Hz, 1H), 3.59-3.53 (m, 3H), 3.47 (m, 1H), 3.37 (m, 1H), 3.0 (d, J = 4.0 Hz, 1H), 2.15-2.09 (m, 4H), 1.89 (m, 1H), 1.78-1.64 (m, 3H), 1.24 (d, J = 8.0 Hz, 3H). MS m/z [M+H] ⁺ : 575.4.

Biological activity evaluation

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.

SHP2 allosteric inhibition experiments

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

Phosphatase reactions were performed at room temperature in flat-bottom, low-edge, non-binding surface 384-well black polystyrene plates (Corning, Cat#3575) 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.

The following assay was used to monitor the inhibition of SHP2 by the compounds of the present invention (at concentrations ranging from 0.0003 to 100 μM): 0.5 nM SHP2 was incubated with 0.5 μM 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 5 μL of 160 μM 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 340 nm and 450 nm, respectively. The inhibitor dose response curves were analyzed using normalized IC ₅₀ regression curves based on control normalization. The IC ₅₀ of the compounds listed in the examples of the present invention are listed in Table 2.

Table 2 IC ₅₀ values of compounds inhibiting SHP2 Embodiment Chemical structure _IC50 (nM) 1 A 2 A 3 A 4 A 5 A 6 B 7 B 8 B 9 B 10 A 11 A 12 A 13 A 14 A 15 A Note: A≤10 nM; 10 nM＜B≤50 nM.

without.

Claims (13)

A compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate or isotope-labeled substance thereof, wherein the structure of the compound of formula (I) is:

wherein: ^R1 and ^R2 are the same or different and are independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, _-NO2 , a substituted or unsubstituted group: _-NH2 , a _C1 - _C10 alkyl group, a _C1 - _C10 alkylamino group, a _C1 - _C10 alkoxy group, a _C3 - _C12 cycloalkyl group, a C3 _{- C12} cycloalkyloxy group, a 3-12 membered heterocyclic group, a _C6 - _C10 aryl group, a 5-10 membered heteroaryl group; or ^R1 and ^R2 form a 3-8 membered cycloalkyl group, a cycloalkenyl group or a heterocyclic group, optionally, the 3-8 membered cycloalkyl group, the cycloalkenyl group or the heterocyclic group is selected from -OH, _-NH2 , -CN, _NO2 , a halogen atom, a C ₁ -C ₁₀ alkyl group, a C ₁ -C ₁₀ alkoxy group, a C ₁ -C ₁₀ alkylamino group, a C ₃ -C ₁₂ cycloalkyl group, a C ₆ -C ₁₀ aryl group, and a 5-10 membered heteroaryl group; X is selected from a chemical bond, -NH-, and -CONH-;

is selected from _C6 - _C10 aryl, 5-10 membered heteroaryl, _C4 - _C12 cycloalkyl, 3-12 membered heterocyclic group, _C6 - _C14 bridged cyclic group or spirocyclic group, _C6 - _C14 bridged heterocyclic group or spiro heterocyclic group; wherein the 5-10 membered heteroaryl, 3-12 membered heterocyclic group, _C6 - _C14 bridged heterocyclic group or spiro heterocyclic group contains 1-3 hetero atoms or groups selected from N, NH, O, S, C(O), S(O); each ^R3 is the same or different and is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, _-NO2 , a substituted or unsubstituted group of the following: _C1 -C The substituent is selected from C ₁ -C _{10 alkyl, C 1 -C 10 alkylamino} , -C ₁ -C ₁₀ alkylamide, C ₁ -C ₁₀ alkoxy, -NH ₂ , C ₃ -C ₁₂ cycloalkyl, 3-12 membered heterocyclic group, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl, wherein the substituent is selected from C ₁ -C ₁₀ alkyl, C ₃ -C ₁₂ cycloalkyl, 3-12 membered heterocyclic group, halogen atom, -NH ₂ , -CN, -COOH, -CONH ₂ , -CHO, -OH, -NO ₂ , hydroxy-C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ alkylamino, 5-10 membered heteroaryl, C ₆ -C or any two adjacent ^R3's form a 3-6 membered saturated or unsaturated ring, optionally, the 3-6 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 - C10} alkyl group, a _C1 - _C10 alkoxy group, a C3- _C12 cycloalkylamino group, a _{C1 - C10} alkylamino group, a _C3 - _C12 cycloalkyl group, a halogenated _C1 - _C10 alkylamino group, a _C6 - _C10 aryl group and a 5-10 membered heteroaryl group; ^R4 , ^R5 , ^R6 , ^R7 , ^R8 , ^R9 R ¹⁰ and R ¹¹ are each independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO ₂ , a substituted or unsubstituted group: -NH ₂ , a C ₁ -C ₁₀ alkyl group, a C ₁ -C ₁₀ alkylamino group, a C ₁ -C ₁₀ alkoxy group, a C ₃ -C ₁₂ cycloalkyl group, a C ₃ -C ₁₂ cycloalkyloxy group, a 3-12 membered heterocyclic group, a C ₆ -C ₁₀ aryl group, a 5-10 membered heteroaryl group, wherein the substitution is selected from a C ₁ -C ₁₀ alkyl group, a C ₃ -C ₁₂ cycloalkyl group, a 3-12 membered heterocyclic group, a halogen atom, -NH ₂ , -CN, -COOH, -CHO, -OH, -NO ₂ , a hydroxyl-C ₁ -C The present invention relates to a group consisting of: _a C ₁ -C ₁₀ alkyl group, a C 1 -C 10 alkoxy group, a C ₁ -C ₁₀ alkylamino group, a 5-10 membered heteroaryl group or a C ₆ -C ₁₀ aryl group; m is 0, 1, 2, 3 or 4; and n is 0, 1 or 2. The compound of claim 1 or a pharmaceutically acceptable salt, ester, isomer, solvate or isotope-labeled substance thereof, wherein ^R1 and ^R2 form a 3-8 membered cycloalkyl, cycloalkenyl or heterocyclic group, and optionally, the 3-8 membered cycloalkyl, cycloalkenyl or heterocyclic group is substituted by any 1-3 selected from the group consisting of -OH, _-NH2 , -CN, _NO2 , a halogen atom, a _C1 - _C10 alkyl group, a _C1 - _C10 alkoxy group, a _{C1 - C10} alkylamino group, a _C3 -C12 cycloalkyl group, a _C6 - _C10 aryl group and a 5-10 membered heteroaryl group;

is selected from C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclic group, preferably C ₆ -C _10- membered aryl, 5-9-membered heteroaryl, wherein the 5-10-membered heteroaryl, 3-12-membered heterocyclic group contains 1-3 hetero atoms or groups selected from N, NH, O, S, and C(O); preferably, the 3-12-membered heterocyclic group is selected from aziridine, nitrogen heterocyclobutyl, oxygen heterocyclobutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxythiomorpholinyl, butyrolactam, valerolactamide, caprolactam, butyrolactone, valerolactonyl, caprolactone, succinimide or

any one of; each R ³ is the same or different and is independently selected from H, a halogen atom, -CN, -COOH, -CHO, -OH, -NO ₂ , a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a 3-12-membered heterocyclic group, a -C ₁ -C ₁₀ alkylamide, -NH ₂ , 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 substituted by any 1-3 selected from the group consisting of -OH, -NH ₂ , -CN, a halogen atom, a C ₁ -C ₆ alkyl group and a C ₁ -C ₆ alkoxy group. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, isomer, solvate or isotope-labeled substance thereof, wherein ^R1 and ^R2 form a cyclopentane ring, a tetrahydrofuran ring, a tetrahydropyrrole ring or a tetrahydrothiophene ring, and optionally, the cyclopentane ring, the tetrahydrofuran ring, the tetrahydropyrrole ring or the tetrahydrothiophene ring is substituted by any 1 to 3 selected from the group consisting of -OH, _-NH2 , a halogen atom, a _C1 - _C10 alkyl group and a _C1 - _C10 alkoxy group;

is selected from phenyl, naphthyl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group; wherein the 5-10 membered heteroaryl and 3-12 membered heterocyclic group contain 1-3 hetero atoms or groups arbitrarily selected from N, NH, O, and C(O); each R ³ is the same or different and is independently selected from H, a halogen atom, -C ₁ -C ₆ alkyl CONH ₂ , -COOH, -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl substituted with a hydroxyl group, C ₁ -C ₆ alkyl substituted with an amino group, C ₁ -C ₆ alkoxy, -NH ₂ , or any two adjacent R ³ form a 5- or 6-membered ring. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, isomer, solvate or isotope-labeled substance thereof, wherein:

is selected from phenyl, naphthyl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group; the 5-10 membered heteroaryl ring is selected from thienyl, pyridyl, pyrimidinyl, pyrazinyl, oxazinyl, 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, furanopyrazinyl, thienopyrazinyl, pyridopyrimidonyl, benzoxazolyl, and benzothiazolyl; the 3-12 membered heterocyclic group is selected from aziridine, azocyclobutyl, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxythiomorpholinyl, butyrolactam, valerolactam, caprolactam, butyrolactone, valerolactone, caprolactone, succinimide or

Any one of; the 3-12 membered heterocyclic group is selected from butyrolactam, pyrrolidinyl, succinimidyl or

any one of; each R ³ is the same or different and is independently selected from H, a halogen atom, -C ₁ -C ₆ alkyl CONH ₂ , -COOH, -CN, C ₁ -C ₆ alkyl, hydroxyl-substituted C ₁ -C ₆ alkyl, amino-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -NH ₂ , or any two adjacent R ³ form a 5-membered or 6-membered ring. The compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate or isotope-labeled substance thereof as described in claim 1, wherein the compound of formula (I) has a structure shown in formula (I-1):

Among them, R ³ , X and

is defined as in request item 1. The compound as described in claim 5 or a pharmaceutically acceptable salt, ester, isomer, solvate or isotope-labeled substance thereof, wherein:

selected from C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group, wherein the 5-10 membered heteroaryl or 3-12 membered heterocyclic group contains 1-3 hetero atoms or groups selected from N, NH, O, S, C(O), S(O); each R ³ is the same or different, and is independently selected from H, a halogen atom, -CN, -COOH, -CHO, -OH, -NO ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 3-12 membered heterocyclic group, -C ₁ -C ₁₀ alkylamide, -NH ₂ , or any two adjacent R ³ to form a 5-6 membered saturated or unsaturated ring, optionally, the 5-6 membered saturated or unsaturated ring is substituted by any 1-3 selected from the group consisting of -OH, -NH ₂ , -CN, a halogen atom, a C ₁ -C ₆ alkyl group and a C ₁ -C ₆ alkoxy group. The compound as described in claim 5 or a pharmaceutically acceptable salt, ester, isomer, solvate or isotope-labeled substance thereof, wherein:

Selected from C ₆ -C ₁₀ aryl, 5-6 membered heteroaryl or 5-12 membered heterocyclic group, wherein the 5-6 membered heteroaryl or 5-12 membered heterocyclic group contains 1-3 hetero atoms or groups selected arbitrarily from N, NH, O, C(O); each R ³ is the same or different, and is independently selected from H, a halogen atom, a 5-6 membered heterocyclic group, -C ₁ -C ₆ alkyl CONH ₂ , -COOH, -CN, C ₁ -C ₆ alkyl, a hydroxyl-substituted C _{1 -C 6 alkyl, an amino-substituted C 1 -C 6 alkyl ,} a C ₁ -C ₆ alkoxy group, -NH ₂ , or any two adjacent R ³ form a 5-membered or 6-membered ring. The compound as described in claim 5 or a pharmaceutically acceptable salt, ester, isomer, solvate or isotope-labeled substance thereof, wherein:

is phenyl, naphthyl; or is selected from thienyl, pyridyl, pyrimidinyl, pyrazinyl, oxazinyl, 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, oxazolo pyrimidinyl, isoxazolopyrimidinyl, imidazopyrazinyl, pyrazolopyrazine, pyrrolopyrazinyl, furanopyrazinyl, thienopyrazinyl, pyridopyrimidonyl, benzoxazolyl; or selected from aziridine, azocyclobutyl, oxacyclobutyl, 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 in; each R ³ is the same or different and is independently selected from H, a halogen atom, -C ₁ -C ₆ alkyl CONH ₂ , -COOH, -CN, C ₁ -C ₆ alkyl, a 6-membered oxygen-containing heterocyclic group, a hydroxyl-substituted C ₁ -C ₆ alkyl, an amino-substituted C ₁ -C ₆ alkyl, a C ₁ -C ₆ alkoxy group, -NH ₂ , or any two adjacent R ³ form a 5-membered or 6-membered ring; in the structure shown in formula (I-1), the methyl group substituted on the tetrahydrofuran ring and the amino group are on the same side of the tetrahydrofuran ring. A compound selected from the following or a pharmaceutically acceptable salt, ester, isomer, solvate or isotope-labeled substance thereof:

A pharmaceutical composition comprising a compound as described in any one of claims 1 to 9 or a pharmaceutically acceptable salt, ester, isomer, solvate or isotope-labeled substance thereof. A pharmaceutical preparation, comprising a compound as described in any one of claims 1 to 9 or a pharmaceutically acceptable salt, ester, isomer, solvate or isotope label thereof, or a pharmaceutical composition as described in claim 10, 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. Use of a compound as described in any one of claims 1 to 9 or a pharmaceutically acceptable salt, ester, isomer, solvate or isotope label thereof, or a pharmaceutical composition as described in claim 10, or a pharmaceutical preparation as described in claim 11 in the preparation of a drug for preventing and/or treating a disease or condition mediated or dependent on non-receptor protein tyrosine phosphatase. A pharmaceutical product comprising at least one additional therapeutic agent and a compound as described in any one of claims 1 to 9 or a pharmaceutically acceptable salt, ester, isomer, solvate or isotope-labeled substance thereof, or a pharmaceutical composition as described in claim 10, or a pharmaceutical preparation as described in claim 11.