CN114195799A

CN114195799A - Pyrazine derivative and application thereof in inhibition of SHP2

Info

Publication number: CN114195799A
Application number: CN202010910913.2A
Authority: CN
Inventors: 孙海丰; 李家鹏; 张贵平; 王奎锋
Original assignee: Suzhou Genhouse Pharmaceutical Co ltd
Current assignee: Suzhou Genhouse Pharmaceutical Co ltd
Priority date: 2020-09-02
Filing date: 2020-09-02
Publication date: 2022-03-18
Also published as: TW202210488A

Abstract

The invention relates to a pyrazine derivative and application thereof in inhibiting SHP2, a compound of formula (I) or pharmaceutically acceptable salt, ester thereof,An isomer, solvate, prodrug or isotopic label, wherein the compound of formula (i) has the structure:

Description

Pyrazine derivative and application thereof in inhibition of SHP2

Technical Field

The invention belongs to the field of medicines, relates to a pyrazine derivative, a preparation method thereof and application thereof in medicines, and particularly relates to a pyrazine derivative and application thereof as a protein tyrosine phosphatase 2(SHP2) inhibitor in prevention and/or treatment of diseases related to abnormal activity of protein tyrosine phosphatase 2(SHP 2).

Background

SHP2 is a non-receptor protein tyrosine phosphatase encoded by PTPN11, consisting of 2N-terminal SH2 domains, 1 protein phosphatase domain. The SHP2 protein is mainly located in cytoplasm and is in self-inhibition conformation under a basic state, and the N-terminal SH2 domain interacts with a phosphatase domain to hide a catalytic site; upon receiving an upstream signal, it is activated to an activated conformation, exposing a catalytic site, and performing a 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. Mutation or overexpression of the SHP2 protein has been associated with a variety of diseases and tumors.

SHP2 mutations occurred mainly in noonan syndrome (50%), leopard syndrome (80%), monocytic leukemia (35%), myelodysplastic syndrome (10%), B-cell acute lymphocytic leukemia (7%), acute myelogenous leukemia (4%), etc.; the mutation of SHP2 is also found in solid tumors such as lung cancer, colorectal cancer, melanoma, liver cancer, breast cancer, etc.; abnormally activated growth factors, cytokines, etc. require signaling through SHP2, and wild-type SHP2 activity is also important in many types of tumors; SHP2 is also located at the downstream of immune check points such as PD-1 and BTLA, has certain influence on macrophage function in tumor microenvironment, participates in the mechanism of tumor immune escape, and has important function in the direction of tumor immunity.

Due to the important role of SHP2 in tumors, SHP2 catalytic site inhibitors have been studied for decades, but the phosphatase domain of SHP2 is highly conserved and positive, and no drugs have been advanced to the clinical stage.

Disclosure of Invention

Problems to be solved by the invention

No drug related to protein tyrosine phosphatase is available on the market, and the compounds in the prior art have poor activity in inhibiting SHP2 (such as WO2016/203406A 1). The invention aims to provide a pyrazine derivative which has excellent SHP2 inhibitory activity and can be used for preventing and/or treating diseases or symptoms mediated or dependent on non-receptor protein tyrosine phosphatase.

Means for solving the problems

In order to solve the above technical problems, the present invention provides a compound of formula (i), or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein the compound of formula (i) has the structure:

wherein:

R¹and R²Each of which is the same or different and is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO₂Substituted or unsubstituted groups of the following: -NH₂、C₁-C₁₀Alkyl radical, C₁-C₁₀Alkylamino radical, C₁-C₁₀Alkoxy radical, C₃-C₁₂Cycloalkyl radical, C₃-C₁₂Cycloalkyloxy, 3-12 membered heterocyclyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl; or R¹And R²Forming a 3-8 membered cycloalkyl, cycloalkenyl or heterocyclyl group, optionally, said 3-8 membered cycloalkyl, cycloalkenyl or heterocyclyl group is selected from-OH, -NH₂、-CN、NO₂Halogen atom, C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy radical、C₁-C₁₀Alkylamino radical, C₃-C₁₂Cycloalkyl radical, C₆-C₁₀Aryl and 5-10 membered heteroaryl, optionally substituted with 1-3 substituents;

x is selected from a chemical bond, -NH-, -CONH-;

is selected from C₆-C₁₀Aryl, 5-10 membered heteroaryl, C₄-C₁₂Cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₄Bridged or spiro ring group, C₆-C₁₄Bridged heterocyclic groups or spiro heterocyclic groups; wherein said 5-10 membered heteroaryl, 3-12 membered heterocyclyl, C₆-C₁₄The bridged heterocyclyl or spiroheterocyclyl group contains 1 to 3 heteroatoms or groups optionally selected from N, NH, O, S, C (O), S (O);

each R³Each of which is the same or different and is independently selected from H, D, halogen atom, -CN, -COOH, -CHO, -OH, -NO₂Substituted or unsubstituted groups of the following: c₁-C₁₀Alkyl radical, C₁-C₁₀Alkylamino, -C₁-C₁₀Alkyl amides, C₁-C₁₀Alkoxy, -NH₂、C₃-C₁₂Cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl, said substitution being by a group selected from C₁-C₁₀Alkyl radical, C₃-C₁₂Cycloalkyl, 3-to 12-membered heterocyclyl, halogen atom, -NH₂、-CN、-COOH、-CONH₂、 -CHO、-OH、-NO₂hydroxy-C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy radical, C₁-C₁₀Alkylamino, 5-10 membered heteroaryl, C₆-C₁₀Aryl or 3-12 membered heterocyclyl; or two R's which are arbitrarily adjacent³Forming a 3-6 membered saturated or unsaturated ring, optionally said 3-6 membered saturated or unsaturated ring is selected from the group consisting of-OH, -NH₂-CN, halogen atom, C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy radical, C₃-C₁₂Cycloalkylamino radical, C₁-C₁₀Alkylamino radical, C₃-C₁₂Cycloalkyl, halo C₁-C₁₀Alkylamino radical, C₆-C₁₀Aryl and 5-10 membered heteroaryl, optionally substituted with 1-3 substituents;

R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹each independently selected from H, D, halogen atom, -CN, -COOH, -CHO, -OH, -NO₂Substituted or unsubstituted groups of the following: -NH₂、C₁-C₁₀Alkyl, C1-C10 alkylamino, C₁-C₁₀Alkoxy radical, C₃-C₁₂Cycloalkyl radical, C₃-C₁₂Cycloalkyloxy, 3-12 membered heterocyclyl, C₆-C₁₀Aryl, 5-to 10-membered heteroaryl, said substitution being by a group selected from C₁-C₁₀Alkyl radical, C₃-C₁₂Cycloalkyl, 3-to 12-membered heterocyclyl, halogen atom, -NH₂、-CN、-COOH、 -CHO、-OH、-NO₂hydroxy-C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy radical, C₁-C₁₀Alkylamino, 5-10 membered heteroaryl or C₆-C₁₀Aryl is substituted by one or more substituents in the aryl;

m is 0, 1,2,3 or 4;

n is 0, 1 or 2.

The present invention also provides a pharmaceutical composition comprising a compound of formula (i) as described above or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof.

The invention also provides a pharmaceutical preparation, which comprises any one of the compounds of formula (I) or pharmaceutically acceptable salts, esters, isomers, solvates, prodrugs or isotopic labels thereof or the pharmaceutical composition, and 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 isotopic label thereof, or a pharmaceutical composition as described above, or a pharmaceutical formulation as described above, for use in the prevention and treatment of a non-receptor protein tyrosine phosphatase mediated or dependent disease or condition.

The invention also provides the use of a compound of formula (i) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof as described above, or a pharmaceutical composition as described above, or a pharmaceutical formulation as described above, for the prophylaxis and/or treatment of a disease or condition mediated or dependent on non-receptor protein tyrosine phosphatases.

Use of a compound of formula (i) as described above or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or a pharmaceutical composition as described above, or a pharmaceutical formulation as described above, in the manufacture of a medicament for the prophylaxis and/or treatment of a non-receptor protein tyrosine phosphatase mediated or dependent disease or condition.

The present invention also provides a method for the prevention and/or treatment of a non-receptor protein tyrosine phosphatase mediated or dependent disease or disorder comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (i) as described above or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or a pharmaceutical composition as described above, or a pharmaceutical formulation as described above.

The present invention also provides a pharmaceutical combination comprising a compound of formula (i) as described in any one of the above or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or a pharmaceutical composition as described above, or a pharmaceutical formulation as described above, and at least one additional therapeutic agent.

ADVANTAGEOUS EFFECTS OF INVENTION

The pyrazine derivative provided by the invention has excellent activity of inhibiting SHP2, and for example, compared with an SHP2 inhibitor (such as a compound 96 in a table 9 of WO2016/203406A1) in the prior art, the pyrazine derivative has obviously better activity of inhibiting SHP 2. The pyrazine derivatives provided by the invention can be used for preventing and/or treating diseases or symptoms which are not mediated or dependent on receptor protein tyrosine phosphatase.

Detailed Description

In a first aspect, the present invention provides a compound of formula (i), or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein the compound of formula (i) has the structure:

wherein:

R¹and R²Each of which is the same or different and is independently selected from H, D, halogen atom, -CN, -COOH, -CHO, -OH, -NO₂Substituted or unsubstituted groups of the following: -NH₂、C₁-C₁₀Alkyl radical, C₁-C₁₀Alkylamino radical, C₁-C₁₀Alkoxy radical, C₃-C₁₂Cycloalkyl radical, C₃-C₁₂Cycloalkyloxy, 3-12 membered heterocyclyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl; or R¹And R²Forming a 3-8 membered cycloalkyl, cycloalkenyl or heterocyclyl group, optionally, said 3-8 membered cycloalkyl, cycloalkenyl or heterocyclyl group is selected from-OH, -NH₂、-CN、-NO₂Halogen atom, C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy radical, C₁-C₁₀Alkylamino radical, C₃-C₁₂Cycloalkyl radical, C₆-C₁₀Aryl and 5-10 membered heteroaryl, optionally substituted with 1-3 substituents;

x is selected from a chemical bond, -NH-, -CONH-;

is selected from C₆-C₁₀Aryl, 5-10 membered heteroaryl, C₄-C₁₂Cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₄Bridged or spiro ring group, C₆-C₁₄Bridged heterocyclic groups or spiro heterocyclic groups; wherein said 5-10 membered heteroaryl, 3-12 membered heterocyclyl, C₆-C₁The bridged or spiro ring group contains 1-3 heteroatoms or groups selected from N, NH, O, S, C (O), S (O);

each R³Each of which is the same or different and is independently selected from H, D, halogen atom, -CN, -COOH, -CHO, -OH, -NO₂Aminoacyl, substituted or unsubstituted of the following groups: c₁-C₁₀Alkyl radical, C₁-C₁₀Alkylamino, -C₁-C₁₀Alkyl amides, C₁-C₁₀Alkoxy, -NH₂、C₃-C₁₂Cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl, said substitution being by a group selected from C₁-C₁₀Alkyl radical, C₃-C₁₂Cycloalkyl, 3-to 12-membered heterocyclyl, halogen atom, -NH₂、-CN、-COOH、 -CONH₂、-CHO、-OH、-NO₂hydroxy-C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy radical, C₁-C₁₀Alkylamino, 5-10 membered heteroaryl or C₆-C₁₀Aryl is substituted by one or more substituents in the aryl; or two R's which are arbitrarily adjacent³Forming a 3-6 membered saturated or unsaturated ring, optionally said 3-6 membered saturated or unsaturated ring is selected from the group consisting of-OH, -NH₂-CN, halogen atom, C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy radical, C₃-C₁₂Cycloalkylamino radical, C₁-C₁₀Alkylamino radical, C₃-C₁₂Cycloalkyl, halo C₁-C₁₀Alkylamino radical, C₆-C₁₀Aryl and 5-10 membered heteroaryl, optionally substituted with 1-3 substituents;

R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹each independentlySelected from H, D, halogen atom, -CN, -COOH, -CHO, -OH, -NO₂Substituted or unsubstituted groups of the following: -NH₂、C₁-C₁₀Alkyl radical, C₁-C₁₀Alkylamino radical, C₁-C₁₀Alkoxy radical, C₃-C₁₂Cycloalkyl radical, C₃-C₁₂Cycloalkyloxy, 3-12 membered heterocyclyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl, said substitution being selected from C₁-C₁₀Alkyl radical, C₃-C₁₂Cycloalkyl, 3-to 12-membered heterocyclyl, halogen atom, -NH₂、-CN、-COOH、-CHO、-OH、-NO₂hydroxy-C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy radical, C₁-C₁₀Alkylamino, 5-10 membered heteroaryl or C₆-C₁₀Aryl is substituted by one or more substituents in the aryl;

m is 0, 1,2,3 or 4;

n is 0, 1 or 2.

In order to more clearly describe the contents of the present invention, all terms referred to will now be defined as follows. Furthermore, a particular term should not be considered as ambiguous or unclear unless specifically defined, but rather construed according to ordinary meanings in the art.

The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, so long as the valence of the particular atom is normal and the substituted compound is stable.

The terms "optional," "optional," or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, methyl is optionally substituted by halogen, meaning that methyl may be unsubstituted, mono-or poly-substituted by halogen. The term "halogen atom" means fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine, alone or in combination.

Herein C_a-C_bIs that the moiety has an integer number of carbons in the given rangeAn atom. For example, "C₁-C₆By "is meant that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. Numerical ranges given herein in the form of "a-b", or "a-b" for the number of groups or atoms indicate all integers within the given range. For example, substituted with "1-3" substituents, meaning 1,2, or 3 substituents; "3-12 membered heterocyclyl" is meant to include 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-membered heterocyclyl.

The term "C₁-C₁₀Alkyl "represents a saturated straight-chain or branched alkyl group having 1 to 10 carbon atoms, alone or in combination, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-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, 3-dimethyl-2-butyl, 2-methyl-2-pentyl, 2-butyl, and the like, 3,3, -dimethyl-2-butyl, and the like. In some embodiments, preferably, "C" is₁-C₁₀The alkyl group "is any of methyl, ethyl, n-propyl, isopropyl, and tert-butyl. Similarly, the term "C_1-6Alkyl "alone or in combination means a saturated straight or branched chain alkyl group containing 1 to 6 carbon atoms, including, for example, methyl, ethyl, propyl, isopropyl, and the like.

The term "C₁-C₁₀Alkoxy "alone or in combination denotes the radical C₁-C₁₀alkyl-O-in which "C₁-C₁₀Alkyl represents as defined above, for example, it includes, but is not limited to, methoxy (-OCH)₃) Ethoxy (-OCH)₂CH₃) N-propoxy group (-OCH)₂CH₂CH₃) I-propoxy (-OCH (CH)₃)₂) N-butoxy (-OCH)₂CH₂CH₂CH₃) Sec-butoxy (-OCH (CH)₃)CH₂CH₃) Isobutoxy (-OCH)₂CH(CH₃)₂) T-butoxy (-OC (CH))₃)₃) N-pentyloxy (-OCH)₂CH₂CH₂CH₂CH₃) Neopentyloxy (-OCH)₂C(CH₃)₃) And the like.

The term "C₃-C₁₂Cycloalkyl "refers to monocyclic or polycyclic cycloalkyl groups having 3 to 12 carbon atoms, either alone or in combination, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. In some embodiments, "C₃-C₁₂Cycloalkyl is "preferably" C₃-C₈Cycloalkyl groups ".

The term "C₃-C₁₂Cycloalkyloxy "represents the radical C alone or in combination₃-C₁₂cycloalkyl-O-wherein C₃-C₁₂Cycloalkyl represents as defined above.

The term "3-12 membered heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic heterocyclyl group containing 3-12 carbon atoms and a heteroatom or heteroatom group selected from N, NH, O, C (O), S (O), i.e., the sum of the number of carbon atoms and heteroatoms is 3-12_m(wherein m is 0, 1 or 2). For example, the 3-12 membered heterocyclic group includes aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1-dioxothiomorpholinyl, butyrolactam, valerolactam, caprolactam, butyrolactone, valerolactam, caprolactone, succinimide, or

And the like. In some embodiments, "3-12 membered heterocyclyl" is preferably "5-12 membered heterocyclyl" or "5-7 membered heterocyclyl"; preferably, the 3-12 membered heterocyclic group includes butyrolactam, pyrrolidinyl, succinimide or

More preferably, the 3-12 membered heterocyclyl is

The term "aryl" denotes any stable 6-10 membered monocyclic or bicyclic aromatic group including phenyl, naphthyl, tetrahydronaphthyl, 2, 3-indanyl or biphenyl and the like. The hydrogen atoms on the "aryl" are independently optionally substituted with one or more substituents described herein.

The term "heteroaryl" denotes an aromatic ring radical formed by replacement of a carbon atom on the ring with at least one heteroatom selected from sulfur, oxygen or nitrogen. In some embodiments, the aromatic ring group may be a 5-7 membered monocyclic or 7-12 bicyclic group. In some embodiments, the number of heteroatoms in the heteroaryl group is preferably 1,2,3, or 4, such as thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridin-2 (1H) -onyl, pyridin-4 (1H) -onyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, naphthyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, indole [1,2-a ] pyrazinyl, 4, 7-diazaindole, pyrazolopyrimidyl, imidazopyrimidinyl, oxazolopyrimidyl, isoxazolopyrimidyl, imidazopyrazinyl, and the like, Pyrazolopyrazine, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, pyridopyrimidinyl, benzoxazolyl or benzothiazolyl and the like. The hydrogen atoms on the "heteroaryl" groups are independently optionally substituted with one or more substituents as described herein.

The term "C_6-10Aryl "denotes an aryl group having 6 to 10 carbon atoms, wherein aryl denotes as defined above.

The term "5-10 membered heteroaryl" denotes heteroaryl having 5-10 carbon atoms and heteroatoms, wherein heteroaryl is as defined above.

The term "3-8 membered cycloalkyl" in the term "3-8 membered cycloalkyl, cycloalkenyl or heterocyclyl" means a cyclic alkyl group havingSaturated monocyclic or fused ring cycloalkyl groups having 3 to 8 carbon atoms include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Wherein "3-8 membered cycloalkenyl" has a partially unsaturated monocyclic or fused ring group of 3-8 carbon atoms. Wherein "3-8 membered heterocyclyl" denotes a heterocyclyl having 3-8 carbon atoms and a heteroatom or heteroatom group selected from N, NH, O, S (O)_m(wherein m is 0, 1, 2); for example, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1-dioxothiomorpholinyl, and the like; in some embodiments "3-8 membered heterocyclyl" is preferably "3-6 membered heterocyclyl" or "5-6 membered heterocyclyl".

The term "—" CONH "denotes — C (═ O) -NH-, and may in particular denote C (═ O) and

to or from NH and

are preferably C (═ O) and

are connected.

The term "amino" denotes, alone or in combination, a primary amino group (-NH)₂) Secondary amino (-NH-) or tertiary amino

The term "C₁-C₁₀Alkylamino "represents, alone or in combination, an amino group as defined above, in which the hydrogen atom of the amino group is interrupted by at least one C₁-C₁₀Alkyl is substituted in which "C₁-C₁₀Alkyl "denotes as defined above. Accordingly, "C₁-C₁₀Alkylamino "includes, for example, methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, 2-butylAmino, tert-butylamino, n-pentylamino, 2-pentylamino, 3-pentylamino, 2-methyl-2-butylamino, 3-methyl-1-butylamino, 2-methyl-1-butylamino, n-hexylamino, 2-hexylamino group, 3-hexylamino group, 2-methyl-2-pentylamino group, 3-methyl-2-pentylamino group, 4-methyl-2-pentylamino group, 3-methyl-3-pentylamino group, 2, 3-dimethyl-2-butylamino group, 3-dimethyl-2-butylamino group and the like. In particular "C₁-C₁₀Alkylamino "is methylamino, ethylamino, isopropylamino, tert-butylamino, and the like.

The term "C₃-C₁₂Cycloalkylamino "denotes an amino group as defined above, alone or in combination, wherein the hydrogen atom of the amino group is interrupted by at least one C₃-C₁₂Cycloalkyl radicals substituted by "C₃-C₁₂Cycloalkyl "denotes as defined above.

The term "isomer" encompasses all isomeric forms including enantiomers, diastereomers, tautomers and geometric isomers (including cis-trans isomers). Thus, individual stereochemical isomers of the contemplated compounds of the present invention or mixtures of enantiomers, diastereomers, tautomers or geometric isomers (or cis-trans isomers) thereof are intended to be within the scope of the present invention.

The term "pharmaceutically acceptable salts" means that the compounds of the present invention exist in the form of their pharmaceutically acceptable salts, including acid addition salts and base addition salts. Pharmaceutically acceptable salts are described in pharmaceutical salts described in J.pharmaceutical Sciences (Vol.66: pp.1-19, 1977) by S.M.Berge. In the present invention, pharmaceutically acceptable non-toxic acid addition salts mean salts of the compounds of the present invention with organic or inorganic acids. Pharmaceutically acceptable non-toxic base addition salts mean salts of the compounds of the invention with organic or inorganic bases.

The term "solvate" refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N-dimethylformamide, dimethylsulfoxide, and the like. The "pharmaceutically acceptable salt" can be synthesized by a general chemical method.

The term "ester" is used to denote an organic ester, including, for example, monoesters, diesters, triesters, and more generally polyesters.

The term "prodrug" means a chemical derivative which is a compound of the present invention and is converted into a compound represented by the general formula I in vivo by a chemical reaction.

The term "isotopic derivative" means an isotopic derivative obtained by substituting the hydrogen atom in the general formula (I) with 1 to 6 deuterium atoms (D), the carbon atom in the general formula (I) being substituted with 1 to 3 carbon 14 atoms (I)¹⁴C) The resulting isotopic derivative by substitution.

The words "comprise" or "comprise" and variations thereof such as "comprises" or "comprising," are to be understood in an open, non-exclusive sense, i.e., "including but not limited to.

The terms related to the present invention are defined above, and those skilled in the art can also understand the above terms in combination with the prior art, and further description is made below based on the contents of the present invention and the definitions of the terms.

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

x is selected from a chemical bond, -NH-, -CONH-;

is selected from C₆-C₁₀Aryl, 5-10 membered heteroaryl, C₄-C₁₂Cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₄Bridged or spiro ring group, C₆-C₁₄Bridged heterocyclic groups or spiro heterocyclic groups; wherein the 5-10 membered heteroaryl, 3-12 membered heterocycleBase, C₆-C₁₄The bridged heterocyclyl or spiroheterocyclyl group contains 1 to 3 heteroatoms or groups optionally selected from N, NH, O, S, C (O), S (O);

each R³Each of which is the same or different and is independently selected from H, D, halogen atom, -CN, -COOH, -CHO, -OH, -NO₂Aminoacyl, substituted or unsubstituted of the following groups: c₁-C₁₀Alkyl radical, C₁-C₁₀Alkylamino, -C₁-C₁₀Alkyl amides, C₁-C₁₀Alkoxy, -NH₂、C₃-C₁₂Cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl, said substitution being by a group selected from C₁-C₁₀Alkyl radical, C₃-C₁₂Cycloalkyl, 3-to 12-membered heterocyclyl, halogen atom, -NH₂、-CN、-COOH、 -CONH₂、-CHO、-OH、-NO₂hydroxy-C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy radical, C₁-C₁₀Alkylamino, 5-10 membered heteroaryl, C₆-C₁₀Aryl or 3-12 membered heterocyclyl; or two R's which are arbitrarily adjacent⁵Forming a 3-6 membered saturated or unsaturated ring, optionally said 3-6 membered saturated or unsaturated ring is selected from the group consisting of-OH, -NH₂-CN, halogen atom, C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy radical, C₃-C₁₂Cycloalkylamino radical, C₁-C₁₀Alkylamino radical, C₃-C₁₂Cycloalkyl, halo C₁-C₁₀Alkylamino radical, C₆-C₁₀Aryl and 5-10 membered heteroaryl, substituted with 1-3 of the group;

m is 0, 1,2,3 or 4;

in a more preferred embodiment, in the structure represented by the formula (I-1), the substituted methyl group and the amino group on the tetrahydrofuran ring 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 isotopic label thereof,

selected from phenyl, naphthyl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

wherein said 5-10 membered heteroaryl, 3-12 membered heterocyclyl contains 1-3 heteroatoms or groups selected from N, NH, O, S, C (O),

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

Any one of (a); more preferably, the 3-12 membered heterocyclic group is selected from butyrolactam, pyrrolidinyl, succinimidyl or

Any one of (a);

each R³Each independently selected from H, D, each independentlyHalogen atom, -CN, -COOH, -CHO, -OH, -NO₂Aminoacyl, substituted or unsubstituted of the following groups: c₁-C₁₀Alkyl radical, C₁-C₁₀Alkylamino, -C₁-C₆Alkyl CONH₂、C₁-C₁₀Alkoxy, -NH₂Said substitution being selected from C₁-C₁₀Alkyl, halogen atom, -NH₂、-CN、 -OH、-NO₂Is substituted with one or more substituents of (1); or two R's which are arbitrarily adjacent⁵Forming a 3-6 membered saturated or unsaturated ring, optionally said 3-6 membered saturated or unsaturated ring being substituted by 1-3-OH, -NH₂-CN, halogen atom, C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy groups.

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

Table 1:

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

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

-a pharmaceutically acceptable carrier;

-an adjuvant; and/or

-an excipient.

The present invention also provides a process for the preparation of a pharmaceutical composition as described above which comprises mixing a compound of formula (i) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof as described above with a pharmaceutically acceptable carrier, adjuvant (e.g. diluent) and/or excipient.

The present invention also provides a pharmaceutical formulation comprising a compound of formula (i) as described in any of the above, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label or pharmaceutical composition thereof, which formulation may be in a form suitable for oral administration, for example as a tablet, dragee, lozenge, aqueous or oily suspension, dispersible powder or granule, lozenge, hard or soft capsule or syrup. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pleasant to the eye and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating and disintegrating agents, and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, water soluble taste masking substances may be used.

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

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents; the dispersing or wetting agent may be a naturally occurring phospholipid. Aqueous suspensions 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 may be formulated by suspending the active ingredient in a vegetable or mineral oil. Oil suspensions may contain thickening agents, and sweetening and flavoring agents as described above may be added to provide palatable preparations, and the compositions may be preserved by the addition of antioxidants.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent or one or more preservatives, suitable dispersing or wetting agents and suspending agents to illustrate the above. Other excipients such as sweetening, flavoring and coloring agents may also be present, and these compositions may be preserved by the addition of antioxidants such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily 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 formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical formulations of the present invention may be in the form of sterile injectable aqueous solutions, or may be presented in the form of an acceptable vehicle or solvent, such as water, grignard 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 an oil phase, the injection or microemulsion being injectable into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain such a constant concentration, a continuous intravenous delivery device may be used, an example of such a device being an intravenous pump of the model Deltec CADD-PLUS. TM.5400.

The pharmaceutical formulations of the present invention may be in the form of a sterile injectable aqueous or oleaginous suspension for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or carrier. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. In addition, fatty acids can also be prepared into injections.

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

As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound employed, or the age of the patient, or the weight of the patient, or the health condition of the patient, or the diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the optimum treatment regimen, such as the mode of treatment, the daily amount of compound (I) or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

The present invention also provides a compound of formula (i) as described above or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or a pharmaceutical composition thereof, or a pharmaceutical formulation thereof, for use in the prevention and treatment of a disease or condition mediated or dependent on non-receptor protein tyrosine phosphatase (SHP2, Src Homolgy-2 phosphatase).

The invention also provides the use of a compound of formula (i) as described above, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or a pharmaceutical composition as described above, or a pharmaceutical formulation as described above, for the prevention and/or treatment of a non-receptor protein tyrosine phosphatase mediated or dependent disease or condition.

The invention also provides the application of the compound with the formula (I) or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic marker thereof, or the pharmaceutical composition or the pharmaceutical preparation in preparing medicines for preventing and/or treating diseases or symptoms mediated or dependent by the non-receptor protein tyrosine phosphatase.

Wherein the non-receptor protein tyrosine phosphatase mediated or dependent disease or disorder is selected from the group consisting of cancer, central nervous system deficiency, cardiovascular system deficiency, blood system deficiency, immune or inflammatory disease, susceptibility to infection, metabolic deficiency, neurological deficiency, mental deficiency, and elevation deficiency. 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, renal cancer, myeloma, bone cancer, thyroid cancer. The central nervous system deficiency may be alcoholism or migraine; the cardiovascular system defect can be aortic aneurysm, susceptible myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension; the blood system defect may be deep vein thrombosis; the immune and inflammatory diseases can be arthritis, multiple sclerosis and liver cirrhosis; the susceptible disease can be hepatitis B, chronic hepatitis, osteopenia, and osteoporosis; the neurological deficit can be alzheimer's disease, parkinson's disease, migraine, vertigo; the mental deficiency may be anorexia nervosa, attention deficit hyperactivity disorder, dementia, major depressive disorder, psychosis; the reproductive deficiency may be menstrual onset age, endometriosis, infertility, etc.

The present invention also provides a method for the prevention and/or treatment of a non-receptor protein tyrosine phosphatase mediated or dependent disease or disorder comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (i) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof as described above, or said pharmaceutical composition, or said pharmaceutical formulation.

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

The term "administering" refers to the process of applying a pharmaceutically active ingredient (such as a compound of the invention) or a pharmaceutical composition comprising a pharmaceutically active ingredient (e.g., a pharmaceutical composition of the invention) to a patient or a cell, tissue, organ, biological fluid, etc. site thereof, such that the pharmaceutically active ingredient or pharmaceutical composition contacts the patient or the cell, tissue, organ, biological fluid, etc. site thereof. Common modes of administration include, but are not limited to, oral administration, subcutaneous administration, intramuscular administration, intraperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration, and the like.

The term "in need thereof refers to a judgment by a physician or other caregiver that a patient needs or will benefit from a prophylactic and/or therapeutic procedure, the judgment being made based on various factors of the physician or other caregiver in their area of expertise.

The term "patient" (or subject) refers to a human or non-human animal (e.g., a mammal).

The present invention also provides a pharmaceutical combination comprising a compound of formula (i) as described above or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or a pharmaceutical composition as described above, or a pharmaceutical formulation as described above, and at least one additional therapeutic agent for the prevention and/or treatment of a non-receptor protein tyrosine phosphatase mediated or dependent disease or condition.

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

The invention also provides a preparation method of the compound shown in the formula (I) or pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic marker thereof, and the technical scheme of the invention is further described by describing several typical synthetic routes of the compound shown in the formula I, which is specifically described as follows:

(1) reacting a compound I-a with a compound I-b under the action of alkali to obtain a compound I-c, wherein in the compound I-b, A is a halogen atom, preferably chlorine, bromine or iodine, and X is a chemical bond;

(2) deprotecting the compound I-c to obtain a compound I-d;

(3) reacting the compound I-d with the compound I-e to obtain a compound I-f, wherein B in the compound I-e is a halogen atom, preferably chlorine, bromine or iodine;

(4) reacting the compounds I-f and I-g under the action of alkali to obtain the compound (I).

The synthetic route is as follows:

in a preferred embodiment, in step (1), the catalyst for the reaction is cuprous iodide and a base, preferably sodium hydroxide, potassium 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 protic or 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 carbonate or 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 carbonate or sodium carbonate, and the organic base is preferably triethylamine, diethylamine, diisopropylamine or N, N-diisopropylethylamine.

The invention also provides another method for preparing the compound I-c, the compound I-c is obtained by reacting the compound I-aa with the compound I-b, and the reaction catalyst is a coupling reaction catalyst, preferably tetrakis (triphenylphosphine) palladium. The synthetic route is as follows:

the invention also provides another method for synthesizing the compound (I), which comprises

(1) Reacting the compound I-h with the compound I-I to obtain a compound I-j, wherein A in the compound I-I is a halogen atom, preferably chlorine, bromine or iodine;

(2) reacting the compound I-j with the compound I-k to obtain a compound I-l, wherein X in the compound I-l is-CONH-;

(3) reacting the compound I-l with the compound I-g to obtain the 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 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 thionyl chloride and/or an organic base, 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, preferably triethylamine, diethylamine, diisopropylamine, N-diisopropylethylamine, pyridine or 4-dimethylaminopyridine.

The synthetic route is as follows:

the following examples may further illustrate the present invention, however, these examples should not be construed as limiting the scope of the present invention.

Preparation of intermediate Int-1

To a solution of Int-1a (104g, 1.0mol) in dichloromethane (600mL) was added imidazole (102g, 1.5mol), and a solution of tert-butyldimethylsilane (165g, 1.1mol) in dichloromethane (200mL) was added dropwise with cooling in an ice-water bath and reacted at room temperature for 16 hours. The reaction solution was diluted with dichloromethane, washed with water 3 times, and the organic phase was dried over anhydrous sodium sulfate. The drying agent was filtered and the filtrate was concentrated to give crude Int-1b (237g, 100% yield) which was used directly in the next reaction.¹H NMR(400 MHz,CDCl₃)δ4.32(q,J＝8.0Hz,1H),3.71(s,3H),1.39(d,J＝8.0Hz 3H),0.89(s,9H),0.09 (s,3H),0.06(s,3H)。

To a solution of Int-1b (120g, 0.55mol) in dichloromethane (600mL) was added dropwise diisobutylaluminum hydride (367mL, 0.55mol, 1.5M in toluene) in an ice-water bath, and the reaction was carried out for 16 hours. The reaction was quenched dropwise with methanol (100mL) and celite was added and stirred well. Filtration, dilution of the filtrate with dichloromethane, washing with water 3 times and drying of the organic phase with anhydrous sodium sulfate. The drying agent was filtered, the filtrate was concentrated, and the residue was purified on silica gel column (petroleum ether/ethyl acetate 10/1 rinses) to give Int-1c (56 g, 54% yield).¹H NMR(400MHz,CDCl₃)δ9.61(s,1H),4.08(q,J＝8.0Hz,1H),1.27(d,J＝ 8.0Hz 3H),0.91(s,9H),0.10(s,3H),0.09(s,3H)。

Under the protection of nitrogen, diisopropylamine (23.4mL, 166mmol) was dissolved in anhydrous tetrahydrofuran (220mL), the temperature was reduced to-20 ℃, N-butyllithium (64mL, 160mmol, 2.5M N-hexane solution) was added dropwise, reaction was carried out for 1 hour, and then a solution of ethyl N-t-butoxycarbonyl-4-piperidinecarboxylate (27.5g, 107mmol) in anhydrous tetrahydrofuran (50mL) was added dropwiseThe reaction was carried out at 0 ℃ for 1 hour, and Int-1c (20.5mL, 102mmol) was added thereto and the reaction was carried out at 0 ℃ for 3 hours. The reaction was quenched with 5% sodium bicarbonate solution, extracted 3 times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, and the residue was purified by silica gel column (petroleum ether/ethyl acetate: 2/1) to give Int-1d (32.6g, 72% yield). MS M/z [ M + H ]]⁺:446.7。

Under ice-water bath, lithium borohydride (2.3g, 107mmol) was added in portions to a solution of Int-1d (31.7g, 71mmol) in tetrahydrofuran (600mL), and after the addition was completed, the reaction was carried out at room temperature for 16 hours. Cooling to 0 deg.C in ice water bath, adding saturated sodium bicarbonate solution to quench reaction, extracting with ethyl acetate for 3 times, and drying the organic phase with anhydrous sodium sulfate. The drying agent was filtered and the filtrate was concentrated to give crude Int-1e (30.2g, 100% yield) which was used directly in the next step. MS M/z [ M + H ]]⁺:404.5,[M-H]^-:402.4。

Int-1e (59.0g, 146mmol) was dissolved in tetrahydrofuran (600mL), tetrabutylammonium fluoride (35g, 109 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Adding saturated sodium bicarbonate solution into the reaction solution to quench the reaction, adding ethyl acetate for layering, extracting the aqueous phase until no product is produced, combining the organic phases and washing with saturated brine. The organic phase was dried over anhydrous sodium sulfate, the drying agent was filtered, the filtrate was concentrated under reduced pressure, and column chromatography gave Int-1f (24g, 57% yield).¹H NMR(400MHz,CDCl₃₃)δ 3.94-4.00(m,1H),3.65-3.81(m,5H),3.07-3.15(m,2H),1.60-1.71(m,4H),1.45(s,9H),1.33(d, J＝4.0Hz,3H)。MS m/z[M+H]⁺:290.3,[M-H]^-:288.3。

Mixing sodiumHydrogen (2.3g, 57.44mmol) was added to tetrahydrofuran (80mL), the temperature was reduced to-15 deg.C, a solution of Int-1f (8.3 g, 28.72mmol) in tetrahydrofuran (50mL) was added dropwise, and a solution of p-toluenesulfonyl chloride (1.72g, 9mmol) in tetrahydrofuran (15mL) was added dropwise and the reaction was continued for 16 h. Cooling the reaction liquid to-15 ℃, dropwise adding a saturated ammonium chloride solution until no bubbles are generated, adding ethyl acetate for layering, extracting a water phase until no product is generated, combining organic phases, and washing with saturated salt water. The organic phase was dried over anhydrous sodium sulfate, the drying agent was filtered, the filtrate was concentrated under reduced pressure, and column chromatography gave Int-1g (5g, 64% yield).¹H NMR(400MHz, CDCl₃)δ4.08-4.14(m,1H),3.01-3.80(m,7H),1.68-1.81(m,4H),1.46(s,9H),1.26(d,J＝8.0 Hz,3H).

Int-1g (13.5g, 49.7mmol) was added to dichloromethane (160mL), and Des-Martin oxidant (42g, 99mmol) was added in portions at-10 ℃ and reacted at 0 ℃ for 16 hours. Ether (500mL) was added, a large amount of solid precipitated, filtered, washed once with ether (100mL), the filtrate was washed once with a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium thiosulfate, and the organic phase was dried over anhydrous sodium sulfate. The drying agent was filtered, the filtrate was concentrated under reduced pressure, and isolated by column chromatography to give Int-1h (5.5g, 41% yield).¹H NMR(400MHz,CDCl3)δ4.19(d,J＝8.0Hz,1H),3.83-3.92(m,4H), 2.96-3.16(m,2H),1.55-1.79(m,4H),1.46(s,9H),1.32(d,J＝8.0Hz,3H)。

Int-1h (20.0g, 274.3mmol) and R- (+) -tert-butylsulfinamide (33.2g, 274.3mmol) were dissolved in a solution of tetrahydrofuran (350mL), and tetraethyl titanate (67.7g, 297mmol) was added, replaced with nitrogen, and reacted at 100 ℃ for 20 hours. After cooling to-25 ℃ methanol (30mL) was added and lithium borohydride (5.97g, 274.3mmol) was added in portions and after addition was complete the reaction was carried out at-10 ℃ for 45 min. Adding saturated ammonium chloride solution at-10 deg.C, precipitating a large amount of solid, vacuum filtering,the filter cake was washed with ethyl acetate, the filtrate was separated, the aqueous phase was extracted with ethyl acetate again until no product was produced, the organic phase was washed once with saturated brine, dried over sodium sulfate, filtered over a drying agent, concentrated under reduced pressure from the organic phase, and separated by column chromatography to give Int-1i (12.4g, 59% yield).¹H NMR (400MHz,CDCl₃)δ4.15-4.19(m,1H),3.63-3.88(m,4H),3.30-3.44(m,2H),2.92(s,1H),1.80 (s,2H),1.60(s,2H),1.44(s,9H),1.25(s,9H),1.20(d,J＝8.0Hz,3H)。MS m/z[M+H]⁺:375.3, [M-H]^-:373.5。

Int-1i (12.0g, 32.1mmol) was dissolved in methanol (150mL), HCl in dioxane (15mL, 4M) was added, the temperature was raised to 40 ℃ and the reaction was stirred for 1 hour to stop the reaction. The reaction was cooled to room temperature and concentrated under reduced pressure to give Int-1(7.85g, 100% yield).¹H NMR(400MHz,DMSO):δ9.25(br,2H),8.38(br,3H), 4.20-4.23(m,1H),3.81(d,J＝8.0Hz,1H),3.62(d,J＝8.0Hz,1H),3.46(br,1H),3.14-3.23(m, 2H),2.84-2.92(m,2H),1.69-2.01(m,4H),1.22(d,J＝8.0Hz,3H)。MS m/z[M+H]⁺:171.2。

Preparation of intermediate Int-2

1-bromo-3-fluoro-2-trifluorotoluene (Int-1a,10.0g, 41.1mmol), cesium carbonate (26.8g,82.3mmol), tert-butylmercaptan (4.4g,49.3mmol), N, N-dimethylformamide (100mL) was added to the reaction flask and reacted at 50 ℃ overnight. After the reaction, water was added to quench, ethyl acetate was used for extraction, the organic phase was concentrated under reduced pressure, and recrystallized to give Int-2 as an intermediate (10.0g, 77.6% yield).¹H NMR(400MHz,CDCl₃):δ7.74(d,1H),7.67(d,1H),7.26(t,1H),1.31(s,9H).

Example 1

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

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

1b (0.5g, 1.9mmol), 2, 5-dichloropyrazine (1.4g, 9.6mmol) and potassium carbonate (530.3mg, 3.8mmol) were added to acetonitrile (5mL) and the reaction was allowed to warm to 80 ℃ overnight. Cooling to room temperature, adding water, extracting with ethyl acetate, washing the organic phase with saturated brine, drying over sodium sulfate, filtering, concentrating under reduced pressure, and separating by column chromatography to give 1c (300mg, 41.8% yield).¹H NMR(400MHz,CDCl₃)δ8.35(d,1H),8.05(d,1H),7.70(m,1H),7.58(m,2H),7.39(d,1H), 6.33(d,1H),3.95(s,3H).

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

Example 2

Dissolving tri-n-butyltin hydride (2.8g, 9.6mmol) in tetrahydrofuran (20mL), dropwise adding LDA (2M,4.8 mL,9.6mmol) at 0 ℃, reacting for 1 hour, cooling to-78 ℃, slowly adding 2a (1.0g,8.7mmol) tetrahydrofuran (5mL), continuing to react for 4 hours after adding, adding saturated potassium fluoride solution (20mL), raising the temperature to room temperature, stirring for 1 hour, extracting with ethyl acetate, washing the organic phase with saturated common salt water, drying with sodium sulfate, filtering, concentrating under reduced pressure, and separating by column chromatography to obtain 2b (1.5g, yield 46.5%).¹H NMR(400MHz,CDCl₃):δ8.71-8.73(m,1H),8.57(d,1H),8.36-8.40 (m,1H),1.54-1.62(m,6H),1.30-1.39(m,6H),1.16-1.20(m,6H),0.90(t,9H).

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

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

2d (0.5g, 2.0mmol), 2, 5-dichloropyrazine (0.9g, 5.8mmol) and potassium carbonate (0.8g, 5.8mmol) were added to acetonitrile (10mL) and the mixture was allowed to warm to 80 ℃ for reaction overnight. Cooling to room temperature, adding water, extracting with ethyl acetate, washing the organic phase with saturated brine, drying over sodium sulfate, filtering, concentrating under reduced pressure, and separating by column chromatography to give 2e (300mg, 41.7% yield). MS M/z [ M + H ]]⁺:368.9.

To a reaction flask was added 2e (100.0mg, 0.27mmol), Int-1(92.3mg, 0.54mmol), 1, 8-diazabicycloundec-7-ene (206.4mg, 1.36mmol), acetonitrile (2mL) and the reaction was refluxed overnight. After completion of the reaction, concentration under reduced pressure and crude product were prepared to give 2(5.5mg, yield 4.0%). MS M/z [ M + H ]]⁺:503.2；¹H NMR(400MHz, CDCl₃)δ8.64(d,2H),8.59(d,1H),8.24(s,1H),8.18(s,1H),7.39(q,2H),7.20(d,1H),5.35(m, 1H),4.19(t,1H),3.93(m,2H),3.82(d,1H),3.69(d,1H),3.48(m,1H),3.36(m,1H),3.27(m, 1H),3.00(s,1H),2.02(m,1H),1.89(m,1H),1.77(m,2H),1.24(d,3H).

Example 3

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

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

3b (0.5g, 1.9mmol), 2, 5-dichloropyrazine (1.4g, 9.6mmol) and potassium carbonate (530.3mg, 3.8mmol) were added to acetonitrile (5mL) and the reaction was allowed to warm to 80 ℃ overnight. Cooling to room temperature, adding water, extracting with ethyl acetate, washing the organic phase with saturated brine, drying over sodium sulfate, filtering, concentrating under reduced pressure, and separating by column chromatography to give 3c (300mg, 41.8% yield).¹H NMR(400MHz,CDCl₃)δ8.36(d,1H),8.09(d,1H),7.63(m,1H),7.53(m,1H),7.49(s,1H), 7.42(m,2H),3.96(s,3H).

To a reaction flask were added 3c (100.0mg, 0.27mmol), Int-1(138.0mg, 0.81mmol), 1, 8-diazabicycloundec-7-ene (164.0mg, 1.1mmol), acetonitrile (2mL) and the reaction was refluxed overnight. After completion of the reaction, concentration under reduced pressure and crude product were prepared to give 3(5.0mg, yield 3.7%). MS M/z [ M + H ]]⁺:505.2；¹H NMR(400MHz, CDCl₃)δ8.22(d,1H),8.17(d,1H),7.50(s,1H),7.41(s,1H),7.26(t,1H),7.10(t,2H),4.21(q, 1H),3.97(m,1H),3.95(m,4H),3.83(d,1H),3.72(d,1H),3.53(m,1H),3.32(m,1H),3.02(d, 1H),2.01(m,1H),1.79(m,1H),1.76(m,1H),1.72(m,1H),1.26(d,3H).

Example 4

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

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

4b (0.6g, 2.2mmol), 2, 5-dichloropyrazine (1.0g, 6.6mmol) and potassium carbonate (910.3mg, 6.6mmol) were added to acetonitrile (5mL) and the reaction was allowed to warm to 80 ℃ overnight. Cooling to room temperature, adding water, extracting with ethyl acetate, washing the organic phase with saturated brine, drying over sodium sulfate, filtering, concentrating under reduced pressure, and separating by column chromatography to give 4c (300mg, 35.4% yield).¹H NMR(400MHz,CDCl₃)δ8.36(d,1H),8.08(d,1H),7.63(dd,1H),7.55(s,1H),7.51(m,1H), 7.44(m,2H),4.23(q,3H),1.54(t,3H).

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

Example 5

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

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

5b (0.5g, 1.7mmol), 2, 5-dichloropyrazine (1.4g, 9.6mmol) and potassium carbonate (530.3mg, 3.8mmol) were added to acetonitrile (5mL) and the reaction was allowed to warm to 80 ℃ overnight. Cooling to room temperature, addition of water, extraction with ethyl acetate, washing of the organic phase with saturated brine, drying over sodium sulfate, filtration, concentration under reduced pressure, column chromatography to give 5c (280mg, 40.3% yield).¹H NMR(400MHz,CDCl₃)δ(ppm)8.33(s,2H),7.75(d,1H),7.49(s,2H),7.37(t,1H),7.15(d, 1H),4.24(t,2H),3.96(s,2H).

To the reaction flask was added 5c (100.0mg, 0.25mmol), Int-1(85.0mg,0.5mmol), 1, 8-diazabicycloundec-7-ene (266.0mg, 1.7mmol), acetonitrile (2mL), was reacted overnight at reflux. After completion of the reaction, concentration under reduced pressure and crude product were prepared to give 5(5.1mg, yield 3.8%). MS M/z [ M + H ]]⁺:535.2；¹H NMR(400MHz,CDCl₃): δ(ppm)8.39(s,1H),8.22(s,1H),7.80(s,1H),7.48(s,1H),7.41(t,1H),7.19(d,1H),7.03(d, 1H),4.18(t,2H),4.09(m,1H),4.02(m,1H),3.94(m,2H),3.77(t,2H),3.72(d,2H),3.53(d, 1H),3.01(d,1H),2.02(m,1H),1.71(m,1H),1.68(m,1H),1.56(m,1H),1.12(d,3H).

Example 6

Int-2(5.0g, 15.9mmol), pinacol diboron (8.0g, 31.9mmol), potassium acetate (6.3g,63.9 mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (1.1g,1.6mmol) was added to 1, 4-dioxane (100mL), purged with nitrogen, and reacted at 80 ℃ overnight. After completion of the reaction, water was added, extraction was performed with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to column chromatography to give 6a (3.6g, yield 62.6%).¹H NMR (400MHz,CDCl₃)δ(ppm)7.72(t,1H),7.44(t,2H),1.34(s,12H),1.33(s,9H).

6a (2.5g, 6.9mmol), 2-bromopyrimidine (1.0g, 6.3mmol), potassium phosphate (4.0g,18.9mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (460.0mg,0.6mmol) was added to water (10mL) and 1, 4-dioxane (50mL), and the reaction was refluxed overnight, displaced with nitrogen. After the reaction is completed, adding water, extracting with ethyl acetate, washing the organic phase with saturated salt water, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with columnChromatography gave 6b (1.3g, 66.2% yield). MS M/z [ M + H ]]⁺:313.1。

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

6c (0.5g, 1.9mmol), 2, 5-dichloropyrazine (1.4g, 9.6mmol) and potassium carbonate (560.3mg, 3.8mmol) were added to acetonitrile (5mL) and the reaction was allowed to warm to 80 ℃ overnight. Cooling to room temperature, adding water, extracting with ethyl acetate, washing the organic phase with saturated brine, drying over sodium sulfate, filtering, concentrating under reduced pressure, and separating by column chromatography to give 6d (300mg, 41.7% yield). MS M/z [ M + H ]]⁺:368.9。

6d (100.0mg, 0.27mmol), Int-1(138.0mg, 0.81mmol), 1, 8-diazabicycloundec-7-ene (164.0mg, 1.1mmol), acetonitrile (2mL) were added to the reaction flask and the reaction was refluxed overnight. After completion of the reaction, concentration under reduced pressure and crude product were prepared to give 6(40.0mg, yield 29.3%).¹H NMR(400MHz,CDCl₃):δ(ppm)8.82 (d,2H),8.17(d,2H),7.73(m,4H),4.23(s,1H),4.07(m,2H),3.91(s,1H),3.74(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。

Example 7

7a (500mg, 1.80mmol), oxazole (149mg, 2.16mmol), palladium acetate (40.4mg, 0.18mmol), Xantphos (4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene) (208mg,0.36mmol) and potassium tert-butoxide (403.4 mg, 3.60mmol) were added to toluene (8mL) and reacted at 110 ℃ for 16 hours with nitrogen substitution. After completion of the reaction, 50mL of water was added, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the organic phase was concentrated and subjected to column chromatography to give 7b (83mg, yield: 15.1%).¹H NMR(400MHz,CDCl₃):δ7.85 (s,1H),7.70-7.63(m,2H),7.42-7.33(m,2H)。

To the reaction flask were added 7b (250.0mg, 1.08mmol), tert-butylmercaptan (300.0mg, 3.27mmol), cesium carbonate (703.4mg, 2.16mmol), N, N-dimethylformamide (10mL), and reacted at 130 ℃ for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 50mL of water was added, extraction was carried out with ethyl acetate three times, the organic phases were combined, washed once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography to give 7c (300mg, yield: 82.4%).¹H NMR(400MHz,CDCl₃)δ7.92-7.90(m,1H),7.82(s,1H),7.70-7.68(m,1H),7.61-7.57(m, 1H),7.31(s,1H),1.39(m,9H)。

7c (300mg, 0.99mmol) was added to hydrochloric acid (12M,12mL) and acetonitrile (4mL) and reacted at 90 ℃ for 6 hours, water and ethyl acetate were added and extracted 2 times, washed once with saturated brine, dried over sodium sulfate, filtered over a desiccant, concentrated to dryness under reduced pressure, and the resulting 7d was used directly in the next reaction.

Adding 7d (211mg, 1.09mmol), 2-bromo-5-chloropyrazine (19mg,0.1mmol), Pd₂(dba)₃(91.2mg, 0.09mmol), Xantphos (57mg, 0.09mmol), diethylisopropylamine (39mg, 0.29mmol) were added to 1, 4-dioxane (10mL) and reacted at 100 ℃ for 16h under nitrogen. After the reaction was completed, water was added, extracted with ethyl acetate, dried over sodium sulfate, and the organic phase was concentrated and subjected to column chromatography to give 7e (90mg, yield: 25.2%).

To the reaction flask were added 7e (90.0mg, 0.25mmol), Int-1(73.0mg, 0.30mmol), potassium phosphate (320.0 mg, 1.51mmol), N, N-dimethylformamide (5mL) and reacted at 90 ℃ for 4 hours. After the reaction was completed, water was added, extracted with ethyl acetate, and dried over sodium sulfate. The organic phase was concentrated and subjected to column chromatography to give 7(36mg, yield: 29.1%).¹H NMR(400 MHz,CDCl₃)δ8.45(s,1H),8.34-8.32(m,2H),7.67-7.55(m,2H),7.45(s,1H),7.39-7.36(m,1H), 4.12-4.09(m,1H),3.96-3.90(m,2H),3.71-3.66(m,1H),3.53-3.51(m,2H),3.46-3.43(m,1H), 2.96-2.94(m,1H),1.82-1.49(m,4H),1.12-1.10(m,3H)；MS m/z[M+H]⁺:492.3。

Example 8

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

Adding 8a (90mg, 0.23mmol) into hydrochloric acid (12M,3mL), reacting at 80-90 deg.C for 2 hr, detecting by TLC, concentrating after reaction, adding 2-bromo-5-chloropyrazine (43mg,0.23mmol), Pd₂(dba)₃(21mg, 0.023mmol), Xantphos (26mg, 0.046mmol), diethylisopropylamine (89mg, 0.63mmol) and 1, 4-dioxane (2.3 mL) were reacted under nitrogen at 100 ℃ for 16 h. After the reaction was completed, concentration was directly carried out, and column chromatography was carried out to obtain 8c (30mg, yield: 29%).¹H NMR(400MHz,CDCl₃):δ8.35(m,1H),8.08(m,1H),7.62(d,J＝8.0Hz,1H), 7.60(s,1H),7.49(t,J＝8.0Hz,1H),7.45(s,1H),7.42(d,J＝8.0Hz,1H),7.36(d,J＝8.0Hz, 1H),7.34(d,J＝4.0Hz,1H),7.24(m,1H),7.23(m,1H),5.36(s,2H)。

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

Example 9

To a 100mL single-necked flask was added 9a (200mg, 1.10mmol), 9a-2(266.2mg, 1.66mmol), Pd₂(dba)₃(50.4mg，0.06mmol)，BINAP(347.6mg，0.54mmol)，Cs₂CO₃(1.08g, 3.34mmol), Dioxane (8 mL). The reaction was carried out at 100 ℃ for 16 h. After-treatment, the reaction mixture was cooled to room temperature, 50mL of water was added, extraction was carried out with ethyl acetate three times, the organic phases were combined, washed once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and subjected to column purification to obtain 9b (100mg, yield: 34.3%).¹H NMR(400MHz,CDCl₃)δ8.46-8.44(m,2H),8.15-8.12(m, 1H),7.54-7.46(m,2H),6.91-6.82(m,1H).

To a 100mL single-necked flask was added 9b (100mg, 0.39mmol), 9b-2(105mg, 1.16mmol), Cs₂CO₃(251mg, 3.34mmol), DMF (8 mL). The reaction was carried out at 130 ℃ for 16 h. After-treatment, the reaction was cooled to room temperature, 50mL of water was added, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and purified by column chromatography to give 9c (90mg yield 70.4%).¹H NMR(400MHz,CD₃OD)δ8.26-8.25 (m,2H),7.26-7.43(m,3H),6.72-6.71(m,1H),1.23(m,9H).

9c (90mg, 0.50mmol) was dissolved in acetonitrile (2mL) and reacted with concentrated hydrochloric acid (12M, 6mL) at 120 ℃ for 5 hours. Water and ethyl acetate are added for extraction for 2 times, saturated salt solution is washed once, sodium sulfate is dried, a drying agent is filtered, and the drying agent is concentrated under reduced pressure and is directly used for the next reaction.

9d-2(58.4mg, 0.3mmol), Xantphos (16mg, 0.02mmol), Pd₂(dba)₃(25mg, 0.02mmol), DIEA (106.7mg, 0.82mmol), Dioxane (8mL) were added to the bottle from the previous stepUnder the protection of nitrogen, the reaction is carried out for 16 hours at 100 ℃. Water was added, extraction was performed with ethyl acetate, drying was performed with sodium sulfate, the drying agent was filtered, concentration was performed under reduced pressure to dryness, and purification by column chromatography gave 9e (100mg, yield 76%).¹H NMR(400MHz,CDCl₃)δ8.49-8.48(m, 2H),8.39-8.37(m,2H),8.12(s,1H),7.51-7.46(m,2H),6.89-6.86(m,1H).

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

Example 10

Int-2(5.0g, 15.9mmol), pinacol diboron (8.0g, 31.9mmol), potassium acetate (6.3g,63.9 mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (1.1g,1.6mmol) was added to 1, 4-dioxane (100mL), purged with nitrogen, and reacted at 80 ℃ overnight. After completion of the reaction, water was added, extraction was performed with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to column chromatography to obtain 10a (3.6g, yield 62.6%).¹H NMR (400MHz,CDCl₃)δ7.72(t,1H),7.44(t,2H),1.34(s,12H),1.33(s,9H).

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

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

10c (0.8g, 2.7mmol), 2, 5-dichloropyrazine (1.2g, 8.1mmol) and potassium carbonate (1.1g, 8.1mmol) were added to acetonitrile (10mL) and the mixture was allowed to warm to 80 ℃ for reaction overnight. Cooling to room temperature, adding water, extracting with ethyl acetate, washing the organic phase with saturated brine, drying over sodium sulfate, filtering, concentrating under reduced pressure, and separating by column chromatography to give 10d (300mg, yield 27.1%).¹H NMR(400MHz,CDCl₃)δ8.65(dd,1H),8.30(d,1H),8.11(m,2H),7.74(d,1H), 7.59(t,1H),7.51(d,1H),6.81(d,1H),6.68(dd,1H).

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

Example 11

To a 100mL single-necked flask were added 2-aminopyridine (500mg, 5.31mmol), triethyl methanetricarboxylate (2.5g, 11.68mmol) and xylene (500mg, 0.18mmol) in this order, and the mixture was heated at 140 ℃ for 3 h. After-treatment, slurried with diethyl ether, ethyl acetate, and methanol, respectively, to give 11a (1g, yield 74%).¹H NMR(400MHz,DMSO-d₆)δ8.93-8.91 (m,1H),8.20-8.15(m,1H),7.70-7.37(m,2H),4.16-4.11(m,2H),1.24-1.20(m,3H).

11b (3.0g, 16.75mmol) was added to N-N dimethylformamide (30mL), followed by tert-butylmercaptan (3.0g, 33.50mmol), cesium carbonate (10.9g, 33.50mmol), and the temperature was raised to 130 ℃ under nitrogen for 24 hours. Cooled to room temperature, water was added, extraction was carried out with ethyl acetate, the organic phase was washed with saturated brine 2 times, dried over anhydrous sodium sulfate, filtered over a drying agent, concentrated under reduced pressure, and passed through a column to give crude 11c (4.2g, yield 100%).¹H NMR(400MHz,DMSO) δ7.24(d,J＝8.0Hz,1H),6.93-6.88(m,2H).

11c (4.2g, 16.75mmol) was dispersed in concentrated hydrochloric acid (30mL), heated to 85 ℃ under nitrogen, stirred for 1.5 h, cooled to room temperature, and stirred for 1.5 h. Filtration and washing of the filter cake with n-hexane 2 times gave crude 11d (1.6 g, 50% yield) which was used directly in the next reaction.

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

11e (210mg, 0.69mmol) and 11a (150mg, 0.63mmol) were added to chlorobenzene (5mL), and the mixture was stirred at 135 ℃ for 24 hours under nitrogen substitution. Petroleum ether was added to precipitate a solid, which was filtered to give 11f (240mg, yield 76%) as a solid, which was used in the next reaction.

To dimethyl sulfoxide (13mL) were added 11f (240mg, 0.49mmol), Int-1(132mg, 0.54mmol), potassium phosphate (612mg, 2.89mmol), and the mixture was stirred at 85 ℃ for 16 hours under nitrogen substitutionThen (c) is performed. Water was added to the reaction solution to precipitate a solid, which was then filtered to obtain a solid, which was then subjected to silica gel column chromatography to obtain the objective product 11(110mg, yield 36%). MS M/z [ M + H ]]⁺628.1；¹H NMR (400MHz,DMSO)δ12.61(s,1H),8.87(d,J＝4.0Hz,1H),8.47(s,1H),8.27(s,1H),7.95(s, 1H),7.89(d,J＝8.0Hz,2H),7.45(t,J＝8.0Hz,2H),7.33(d,J＝8.0Hz,2H),7.7.17(s,1H), 6.85(d,J＝8.0Hz,2H),4.15-4.02(m,3H),3.80(d,J＝4.0Hz,1H),3.61(d,J＝8.0Hz,1H), 3.36-3.30(m,2H),3.18(s,1H),1.78-1.55(m,4H),1.26(s,2H),1.17(d,J＝8.0Hz,3H).

Example 12

A50 mL single-necked flask was charged with pyrimidine-2-carboxylic acid (400mg, 3.2mmol) and thionyl chloride (2 mL). The reaction was carried out at 80 ℃ for 3 hours. Working up and concentrating under reduced pressure to give 12a, which is used directly in the next step.

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

A100 mL single vial was charged with Compound 12b (90mg, 0.22mmol), Int-1(41mg, 0.24mmol), N, N-dimethylformamide (3mL), potassium phosphate (280mg, 1.32mmol) and heated to 80 ℃ for 3 hours. Cooling the reaction solution to room temperature, adding 20mL of water, extracting with ethyl acetate for 2 times, washing with saturated salt water for three times, drying with organic phase sodium sulfate, spin-drying, and scraping to obtainTo 12(20mg, yield 18%). MS M/z [ M + H ]]⁺:546.1；¹H NMR (400MHz,CDCl₃)δ10.65(s,1H),8.98(d,J＝4.8Hz,2H),8.28(d,J＝8.4Hz,1H),8.18(s,2H), 7.53(t,J＝4.8Hz,1H),7.38(t,J＝8.4Hz,1H),6.93(d,J＝8.0Hz,1H),4.32–3.98(m,4H), 3.76(d,J＝9.2Hz,1H),3.24–3.03(m,2H),2.11–2.04(m,1H),1.95–1.73(m,3H),1.44(d,J ＝6.4Hz,3H)。

Example 13

Under nitrogen, 11a (240mg, 1.0mmol) and palladium on carbon (50mg) were added to methanol (5mL), and the mixture was reacted under hydrogen replacement at normal temperature and pressure for 16 hours. Filtration and concentration under reduced pressure gave 13b (240mg, 100% yield).¹H NMR (400MHz,DMSO):δ12.29(br,1H),4.06(q,J＝8.0Hz,2H),3.64(t,J＝8.0Hz,2H),2.76(t,J ＝8.0Hz,2H),1.71-1.83(m,4H),1.17(t,J＝8.0Hz,3H).

To chlorobenzene (6mL) were added 13b (240mg, 1.0mmol) and 11e (305mg, 1.0mmol), and the mixture was stirred at 135 ℃ for 24 hours under nitrogen substitution. Petroleum ether was added to precipitate a solid, which was filtered to give a solid, which was then passed through a column to give 13c as a white solid (300mg, yield 60%).¹H NMR(400MHz,DMSO)δ14.86(s,1H),11.90(s,1H),8.68(s,1H),8.48(s, 1H),7.97-7.93(m,1H),7.76-7.71(m,2H),3.89-3.86(m,2H),2.90(t,J＝8.0Hz,2H),1.95-1.81 (m,4H).

To dimethyl sulfoxide (5mL) was added 13c (200mg, 0.40mmol), Int-1(147mg, 0).60mmol), potassium phosphate (509mg, 2.40mmol), nitrogen substitution, and stirring at 85 ℃ for 16 hours. Water was added to the reaction solution to precipitate a solid, which was then filtered to obtain a solid, which was then subjected to column chromatography to obtain the objective compound 13(140mg, yield 55%). MS M/z [ M + H ]]⁺:632.2；¹H NMR(400MHz, DMSO)δ8.49(s,1H),8.29(s,1H),7.68(m,1H),7.49(m,1H),6.93(m,1H),4.17-4.05(m,3H), 3.83-3.78(m,3H),3.60(d,J＝8.0Hz,1H),3.14(s,1H),2.84(s,2H),1.91-1.57(m,9H),1.26(s, 3H),1.16(d,J＝8.0Hz,3H).

Example 14

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

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

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

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

Example 15

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

15b (40mg,0.1mmol) hydrochloric acid (12M,2mL) was added, the mixture was stirred at 80 ℃ for two hours, the end of the reaction was checked by TLC, concentrated and desolventized, and then 2-bromo-5-chloropyrazine (19mg,0.1mmol), Pd, was added₂(dba)₃(9mg,0.01mmol), Xantphos (12mg,0.02mmol) and diethylisopropylamine (38mg,0.3mmol) were added to 1, 4-dioxane (1mL) and stirred at 105 ℃ for 16h under nitrogen. The reaction solution was concentrated and subjected to column chromatography to give 15d (20mg, yield: 45.4%).¹H NMR(400MHz,CDCl₃)δ8.40(d,J＝4.0Hz,1H),8.12(d,J＝4.0Hz,1H),7.76(d,J＝8.0Hz,1H), 7.66(s,1H),7.62(s,1H),7.59-7.39(m,2H),4.45-4.38(m,1H),4.18-4.12(m,2H),3.63-3.55(m, 2H),2.20-2.09(m,4H)。MS m/z[M+H]⁺:441.1

To the reaction flask were added 15d (50.0mg, 0.11mmol), Int-1(30.0mg, 0.12mmol), potassium phosphate (70.0 mg, 0.33mmol), dimethyl sulfoxide (1.1mL), and reacted at 80-90 ℃ for 16 hours. After completion of the reaction, ethyl acetate (100mL) and 10% saline (50mL) were poured and washed three times. The organic phase was concentrated and subjected to column chromatography to give 15(38mg, yield: 60%).¹H NMR(400MHz,CDCl₃)δ8.22(s,1H),8.17(s,1H),7.54(s,1H),7.47(s,1H),7.28-7.24 (m,1H),7.14-7.09(m,2H),4.39-4.37(m,1H),4.20-4.18(m,1H),4.14-4.11(m,3H),3.92-3.89 (m,2H),3.82(d,J＝12.0Hz,1H),3.69(d,J＝8.0Hz,1H),3.59-3.53(m,3H),3.47(m,1H),3.37 (m,1H),3.0(d,J＝4.0Hz,1H),2.15-2.09(m,4H),1.89(m,1H),1.78-1.64(m,3H),1.24(d,J＝ 8.0Hz,3H)。MS m/z[M+H]⁺:575.4。

Evaluation of biological Activity

The ability of the compounds of the invention to selectively inhibit SHP2 activity was evaluated. The inhibitory properties of the compounds of the invention described herein can be demonstrated by testing in any of the following experiments.

Experiment for allosteric inhibition of SHP2

SHP2 is allosterically activated by activation of the bis-tyrosyl-phosphorylated peptide with its Src Homology 2(SH2) domain. A later activation step results in the release of the self-inhibitory interface of SHP2, which in turn activates SHP2 Protein Tyrosine Phosphatase (PTP) and is available for substrate recognition and reaction catalysis. Catalytic activity of SHP2 was monitored in a rapid fluorescence assay format using the surrogate substrate, DiFMUP.

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

The inhibition of SHP2 by the compounds of the invention (varying concentrations from 0.0003 to 100. mu.M) was monitored using the following assay:

wherein 0.5nM SHP2 was combined with 0.5. mu.M peptide IRS1_ pY1172(dPEG8) pY1222 (sequence: H)₂N-LN (pY) IDLDLV (dPEG8) LST (pY) ASINFQK-amide) (SEQ ID NO:1) (WO2016/203406A 1). After incubation at 25 ℃ for 30-60 min, the surrogate substrate DiFMUP (Invitrogen, cat # D6567) was added to the reaction and incubated at 25 ℃ for 30 min. The reaction was then carefully diluted by adding 5. mu.L of 160. mu.M bpV (Phen) solution (Enzo Life Sciences cat # ALX-270-. The fluorescence signal was monitored using a microplate reader (variaskan LUX, Thermo) using excitation and emission wavelengths of 340nm and 450nm respectively. IC normalized using control-based normalization₅₀Regression curves, inhibitor dose response curves were analyzed. IC of the Compounds listed in the examples of the invention₅₀Are listed in table 2.

IC inhibition of SHP2 by the Compounds of Table 2₅₀Value of

q is noted; a is less than or equal to 10 nM; b is more than 10nM and less than or equal to 50 nM.

Claims

1. A compound of formula (i) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein the compound of formula (i) has the structure:

wherein:

R¹and R²Each of which is the same or different and is independently selected from H, D, a halogen atom, -CN, -COOH, -CHO, -OH, -NO₂Substituted or unsubstituted groups of the following: -NH₂、C₁-C₁₀Alkyl radical, C₁-C₁₀Alkylamino radical, C₁-C₁₀Alkoxy radical, C₃-C₁₂Cycloalkyl radical, C₃-C₁₂Cycloalkyloxy, 3-12 membered heterocyclyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl; or R¹And R²Forming a 3-8 membered cycloalkyl, cycloalkenyl or heterocyclyl group, optionally, said 3-8 membered cycloalkyl, cycloalkenyl or heterocyclyl group is selected from-OH, -NH₂、-CN、NO₂Halogen atom, C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy radical, C₁-C₁₀Alkylamino radical, C₃-C₁₂Cycloalkyl radical, C₆-C₁₀Aryl and 5-10 membered heteroaryl, optionally substituted with 1-3 substituents;

x is selected from a chemical bond, -NH-, -CONH-;

each R³Each of which is the same or different and is independently selected from H, D, halogen atom, -CN, -COOH, -CHO, -OH, -NO₂Substituted or unsubstituted groups of the following: c₁-C₁₀Alkyl radical, C₁-C₁₀Alkylamino, -C₁-C₁₀Alkyl amides, C₁-C₁₀Alkoxy, -NH₂、C₃-C₁₂Cycloalkyl, 3-12 membered heterocyclyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl, said substitution being by a group selected from C₁-C₁₀Alkyl radical, C₃-C₁₂Cycloalkyl, 3-to 12-membered heterocyclyl, halogen atom, -NH₂、-CN、-COOH、-CONH₂、-CHO、-OH、-NO₂hydroxy-C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy radical, C₁-C₁₀Alkylamino, 5-10 membered heteroaryl, C₆-C₁₀Aryl or 3-12 membered heterocyclyl; or two R's which are arbitrarily adjacent³Forming a 3-6 membered saturated or unsaturated ring, optionally said 3-6 membered saturated or unsaturated ring is selected from the group consisting of-OH, -NH₂-CN, halogen atom, C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy radical, C₃-C₁₂Cycloalkylamino radical, C₁-C₁₀Alkylamino radical, C₃-C₁₂Cycloalkyl, halo C₁-C₁₀Alkylamino radical, C₆-C₁₀Aryl and 5-10 membered heteroaryl, optionally substituted with 1-3 substituents;

R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹each independently selected from H, D, halogen atom, -CN, -COOH, -CHO, -OH, -NO₂Substituted or unsubstituted groups of the following: -NH₂、C₁-C₁₀Alkyl radical, C₁-C₁₀Alkylamino radical, C₁-C₁₀Alkoxy radical, C₃-C₁₂Cycloalkyl radical, C₃-C₁₂Cycloalkyloxy, 3-12 membered heterocyclyl, C₆-C₁₀Aryl, 5-to 10-membered heteroaryl, said substitution being by a group selected from C₁-C₁₀Alkyl radical, C₃-C₁₂Cycloalkyl, 3-to 12-membered heterocyclyl, halogen atom, -NH₂、-CN、-COOH、-CHO、-OH、-NO₂hydroxy-C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy radical, C₁-C₁₀Alkylamino, 5-10 membered heteroaryl or C₆-C₁₀Aryl is substituted by one or more substituents in the aryl;

m is 0, 1,2,3 or 4;

n is 0, 1 or 2.

2. The compound of claim 1, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopic label thereof, wherein,

R¹and R²Forming a 3-8 membered cycloalkyl, cycloalkenyl or heterocyclyl group, optionally, said 3-8 membered cycloalkyl, cycloalkenyl or heterocyclyl group is selected from-OH, -NH₂、-CN、NO₂Halogen atom, C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy radical, C₁-C₁₀Alkylamino radical, C₃-C₁₂Cycloalkyl radical, C₆-C₁₀Aryl and 5-10 membered heteroaryl, optionally substituted with 1-3 substituents;

is selected from C₆-C₁₀Aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl, preferably C₆-C₁₀Aryl, 5-9 membered heteroaryl, wherein said 5-10 membered heteroaryl, 3-12 membered heterocyclyl contains 1-3 heteroatoms or groups optionally selected from N, NH, O, S, C (O); preferably, the 3-12 membered heterocyclyl group is selected from aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1-dioxothiomorpholinyl, butyrolactam, valerolactam, caprolactam, butyrolactone, valerolactone, caprolactone, succinimide or mixtures thereof

Any one of (a);

each R³Each of which is the same or different and is independently selected from the group consisting of H, halogen atom, -CN, -COOH, -CHO, -OH, -NO₂、C₁-C₆Alkyl radical, C₁-C₆Alkoxy, 3-12 membered heterocyclyl, -C₁-C₁₀Alkylamides, -NH₂Or any two adjacent R³Forming a 5-6 membered saturated or unsaturated ring, optionally said 5-6 membered saturated or unsaturated ring is selected from the group consisting of-OH, -NH₂-CN, halogen atom, C₁-C₆Alkyl and C₁-C₆Any 1-3 of the group consisting of alkoxy.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopic label thereof, wherein,

R¹and R²Forming cyclopentane, tetrahydrofuran ring, tetrahydropyrrole ring, tetrahydrothiophene ring, optionally, the cyclopentane, tetrahydrofuran ring, tetrahydropyrrole ring, tetrahydrothiophene ring is selected from-OH、-NH₂Halogen atom, C₁-C₁₀Alkyl and C₁-C₁₀Alkoxy, optionally substituted with 1-3 of the group consisting of alkoxy;

selected from phenyl, naphthyl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; wherein said 5-10 membered heteroaryl, 3-12 membered heterocyclyl contains 1-3 heteroatoms or groups optionally selected from N, NH, O, C (O);

each R³Each of which is the same or different and is independently selected from the group consisting of H, halogen atom, -C₁-C₆Alkyl CONH₂、-COOH、-CN、C₁-C₆Alkyl, hydroxy substituted C₁-C₆Alkyl, amino substituted C₁-C₆Alkyl radical, C₁-C₆Alkoxy, -NH₂Or any two adjacent R³Forming a 5 or 6 membered ring.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopic label thereof, wherein,

the 5-10 membered heteroaromatic ring is selected from the group consisting of thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, indole [1,2-a ] indole]Pyrazinyl, 4, 7-diazaindole, pyrazolopyrimidinyl, imidazopyrimidinyl, oxazolopyrimidinyl, isoxazolopyrimidinyl, imidazopyrazinyl, pyrazoloAny one of pyrazine, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, pyridopyrimidinone, benzoxazolyl, benzothiazolyl; the 3-12 membered heterocyclic group is selected from aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1-dioxothiomorpholinyl, butyrolactam, valerolactam, caprolactam, butyrolactone, valerolactam, caprolactone, succinimide or

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

Any one of (a);

5. The compound of formula (i), or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof according to claim 1, wherein said compound of formula (i) has a structure represented by formula (i-1):

wherein R is³X and

is as defined in claim 1.

6. The compound of claim 5, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopic label thereof, wherein,

is selected from C₆-C₁₀Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl, wherein said 5-10 membered heteroaryl or 3-12 membered heterocyclyl contains 1-3 heteroatoms or groups optionally selected from N, NH, O, S, C (O), S (O);

7. The compound of claim 5, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopic label thereof, wherein,

is selected from C₆-C₁₀Aryl, 5-6 membered heteroaryl or 5-12 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 5-12 membered heterocyclyl contains 1-3 heteroatoms or groups optionally selected from N, NH, O, C (O);

each R³Each of which is the same or different, and each is independently selected from the group consisting of H, a halogen atom, a 5-6 membered heterocyclic group, -C₁-C₆Alkyl CONH₂、-COOH、-CN、C₁-C₆Alkyl, hydroxy substituted C₁-C₆Alkyl, amino substituted C₁-C₆Alkyl radical, C₁-C₆Alkoxy, -NH₂Or any two adjacent R³Forming a 5 or 6 membered ring.

8. The compound of claim 5, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopic label thereof, wherein,

is phenyl or naphthyl; or is selected from thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, thiazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, indole [1,2-a ] group]A heteroaryl group of any one of pyrazinyl, 4, 7-diazaindole, pyrazolopyrimidinyl, imidazopyrimidinyl, oxazolopyrimidinyl, isoxazolopyrimidinyl, imidazopyrazinyl, pyrazolopyrazine, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, pyridopyrimidinone, benzoxazolyl; or from aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1-dioxothiomorpholinyl, butyrolactam, valerolactam, caprolactam, butyrolactone, valerolactam, caprolactone, succinimide or

A heterocyclic group of any one of (1);

each R³Each being the same or different and each being independentIs selected from H, halogen atom, -C₁-C₆Alkyl CONH₂、-COOH、-CN、C₁-C₆Alkyl, 6-membered oxygen-containing heterocyclic group, hydroxy-substituted C₁-C₆Alkyl, amino substituted C₁-C₆Alkyl radical, C₁-C₆Alkoxy, -NH₂Or any two adjacent R³Forming a 5-or 6-membered ring;

in the structure represented by the formula (I-1), the methyl group and the amino group substituted on the tetrahydrofuran ring are on the same side of the tetrahydrofuran ring.

9. A compound selected from the group consisting of:

。

10. a pharmaceutical composition comprising a compound of any one of claims 1-9, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopic label thereof.

11. A pharmaceutical formulation comprising a compound of any one of claims 1-9 or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof or a pharmaceutical composition of claim 10, which formulation is any one of a tablet, capsule, injection, granule, powder, suppository, pill, cream, paste, gel, powder, oral solution, inhalation, suspension, dry suspension, patch, lotion.

12. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or a pharmaceutical composition according to claim 10, or a pharmaceutical formulation according to claim 11, for use as a medicament for the prevention and/or treatment of a non-receptor protein tyrosine phosphatase mediated or dependent disease or condition.

13. Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or a pharmaceutical composition according to claim 10, or a pharmaceutical formulation according to claim 11, in the manufacture of a medicament for the prevention and/or treatment of a non-receptor protein tyrosine phosphatase mediated or dependent disease or condition.

14. A method of preventing and/or treating a non-receptor protein tyrosine phosphatase mediated or dependent disease or disorder comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1-9, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or a pharmaceutical composition of claim 10, or a pharmaceutical formulation of claim 11.

15. A pharmaceutical combination comprising a compound of any one of claims 1-9, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or a pharmaceutical composition of claim 10, or a pharmaceutical formulation of claim 11, and at least one additional therapeutic agent.