WO2021043077A1 - Substituted pyrazine compound and preparation method therefor and use thereof - Google Patents

Abstract

(I) The present invention relates to a substituted pyrazine compound used as an SHP2 phosphatase inhibitor. Specifically, the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt, an ester, a stereoisomer, a tautomer, a polymorph, a solvate, an isotopically labeled compound, a metabolite, or a prodrug thereof, a preparation method therefor, a pharmaceutical composition containing the compound, and use thereof in the prevention and treatment of SHP2 phosphatase-related diseases.

Description

A substituted pyrazine compound, its preparation method and application Invention field

The present invention relates to the field of medicinal chemistry, and in particular to a substituted pyrazine compound used as an inhibitor of SHP2 (src homology 2 domain containing phosphotyrosine phosphatase 2), a preparation method thereof, a pharmaceutical composition and its use in the treatment of SHP2 enzyme-related diseases ( Also referred to as "SHP2 phosphatase related diseases" or "SHP2 related diseases").

Background of the invention

SHP2 is a protein tyrosine phosphatase encoded by the gene PTPN11. It is an intracellular non-receptor member of the PTP family and catalyzes the dephosphorylation of protein tyrosine. SHP2 has two N-terminal SH2 (Srchomology 2) domains (N-SH2 and C-SH2), a protein tyrosine phosphatase (PTP) catalytic domain, and a proline-rich group and tyrosine C-terminal tail of phosphorylation site. These two SH2 domains control the subcellular localization and functional regulation of SHP2. In the inactivated state, SHP2 is in a self-inhibited state, and the combination of N-SH2 and PTP inhibits phosphatase activity. However, under the stimulation of growth factors, cytokines or inflammatory factors, such as platelet-derived growth factor (PDGF) and FGF, the phosphorylated tyrosine residues Tyr542 and Tyr580 bind to N-SH2, and the structure of PTP Exposure of the catalytically active site of the domain, and then release the self-inhibition state, activate the PTP activity of SHP2, thereby triggering the signal transduction cascade initiated by tyrosine phosphorylation.

SHP2 is widely expressed in the human body and participates in multiple signaling pathways such as Ras-Erk, PI3K-Akt, Jak-Stat, Met, FGFR, EGFR and NF-kB, and regulates cell proliferation, differentiation, migration, apoptosis and other physiological functions . The activating mutant of SHP2 is related to the occurrence of many diseases, such as Noonan syndrome, breast cancer, and melanoma. Overexpression of SHP2 can increase the risk of chronic myelogenous leukemia, mastocytosis, malignant glioma, lung cancer and breast cancer, suggesting that SHP2 has a wide range of roles in different types of cancers and different stages of cancer development.

It has been found that compounds such as pyrimidinones, pyrazines, carboxylic acids, quinones, quinolines and indoles have the function of inhibiting the activity of SHP2, but there is still an urgent need for new SHP2 inhibitors in this field, especially those with high SHP2 inhibitor with activity and other excellent properties. We were pleasantly surprised to find that a class of pyrazine compounds have higher SHP2 phosphatase inhibitory activity and better cardiac safety (lower hERG inhibition), showing good application prospects.

Summary of the invention

In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled compound, metabolism Substance or prodrug:

among them:

X is a direct bond or selected from S, O, NH and CH ₂ ;

Y is a direct key or

W ¹ , W ² and W ³ are each independently selected from CH and N;

R ^{1 is} selected from H, -OH, -NH ₂ , C _1-6 alkyl and C _3-6 cycloalkyl;

Each occurrence of R ² is independently selected from H, halogen, -OH, -OC _1-6 alkyl, -OC _3-6 cycloalkyl, -CN, C _1-6 alkyl, C _3-6 Cycloalkyl, C _2-6 alkenyl, -S(=O) _g -(C _1-6 alkyl), -S(=O) _g NH ₂ , -NH ₂ , -NH(C _1-6 alkane Group), -N(C _1-6 alkyl) ₂ , 3-12 membered heterocyclyl, C _6-10 aryl and 5-12 membered heteroaryl, wherein the alkyl, cycloalkyl, alkenyl , Heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more selected from halogen, =0, -OH, -OC _1-6 alkyl, -CN, C _1-6 alkyl, -S (=O) _g -(C _1-6 alkyl), _{-NH 2} , -NH(C _1-6 alkyl) and -N(C _1-6 alkyl) ₂ substituents;

Alternatively, any two R ² together with the atoms to which they are connected form a 5-10 membered hydrocarbon ring, a 5-10 membered heterocyclic ring, a 5-6 membered heteroaromatic ring or a benzene ring, wherein the hydrocarbon ring, heterocyclic ring, heteroaromatic ring The ring and the benzene ring are each optionally selected by one or more selected from -NH ₂ , -NH (C _1-6 alkyl), -N (C _1-6 alkyl) ₂ , halogen, -CN, =O, -OH, -OC _1-6 alkyl, halogenated C _1-6 alkyl and C _1-6 alkyl substituent substitution;

Or, when X is NH or CH ₂ , any one of R ² and X together with the atoms to which they are connected forms a 5-10 membered hydrocarbon ring, a 5-10 membered heterocyclic ring, a 5-6 membered heteroaromatic ring or a benzene ring, wherein The hydrocarbon ring, heterocyclic ring, heteroaromatic ring and benzene ring are each optionally selected from -NH ₂ , -NH (C _1-6 alkyl), -N (C _1-6 alkyl). _2. Substituent substitution of halogen, -CN, =O, -OH, -OC _1-6 alkyl, halogenated C _1-6 alkyl and C _{1-6 alkyl;}

R ^4a , R ^4b , R ^5a , R ^5b , R ^6a , R ^6b , R ^7a and R ^7b are each independently selected from H, halogen, =O, -CN, -OH, -COOH, -CONH ₂ , -C (O) O-(C _1-6 alkyl), C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -S(=O) _g -(C _1-6 alkyl), 3-6 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, The heterocyclic group, aryl group, heteroaryl group is optionally selected by one or more selected from -NH ₂ , -OH, =O, halogen, -CN, -OC _1-4 alkyl, -NH (C _1-6 Alkyl) and -N(C _1-6 alkyl) ₂ substituents;

Alternatively, any two of R ^4a , R ^4b , R ^5a , R ^5b , R ^6a , R ^6b , R ^7a and R ^7b form a C _3-10 hydrocarbon ring or 4- 12-membered heterocyclic ring;

Alternatively, R ^4a , R ^7a and R ³ together with the atoms to which they are attached form azaadamantane, optionally with one or more selected from F, Cl, Br, -OH, =O, -CN, -C( O) Substituent substitution of O(C _1-6 alkyl) and C _{1-6 alkyl;}

R ^8a and R ^8b are each independently selected from H, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-12 aryl and 5-12 membered heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, heteroaryl and aryl are each optionally substituted by one or Multiple selected from -N(R ^z ) ₂ , -NH ₂ , halogen, -CN, -OH, =O, -OC _1-6 alkyl, C _1-6 alkyl, halogenated C _1-6 alkyl , C _3-6 cycloalkyl, 3-12 membered heterocyclic group, C _6-10 aryl and 5-10 membered heteroaryl substituents;

Or R ^8a and R ^8b together with the connected atoms (or direct bonds) form a C _3-8 hydrocarbon ring or a 3-12 membered heterocyclic ring, wherein the hydrocarbon ring and the heterocyclic ring are each optionally selected by one or more From -N(R ^z ) ₂ , -NH ₂ , halogen, -CN, =O, -OH, -OC _1-6 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 Substituents of membered heterocyclic group, C _6-10 aryl group, 5-10 membered heteroaryl group;

且R ^8a和R ^8b同时为H时，R ³选自-CN、-C _1-6亚烷基-R ^z、-C _1-6亚烷基-OR ^z、C _3-6环烷基、C _2-6烯基、C _2-6炔基和苯基，其中所述的亚烷基、环烷基、烯基、炔基和苯基各自任选地被一个或多个选自卤素、-CN、＝O、-OR ^z、-OH、-N(R ^z) ₂、-NH ₂、C _1-6烷基、C _3-6环烷基、3-6元杂环基、苯基和5-6元杂芳基的取代基取代； When Y is a direct key or

And when R ^8a and R ^{8b are} both H, R ^{3 is} selected from -CN, -C _1-6 alkylene-R ^z , -C _1-6 alkylene-OR ^z , C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl and phenyl, wherein the alkylene, cycloalkyl, alkenyl, alkynyl and phenyl are each optionally selected from halogen, -CN, =O, -OR ^z , -OH, -N(R ^z ) ₂ , -NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, phenyl And 5-6 membered heteroaryl substituents;

且R ^8a、R ^8b不同时为H时，R ³选自H、卤素、-OR ^z、-OH、-CN、-C(O)OR ^z、-COOH、-CON(R ^z) ₂、-CONH ₂、-C _1-6烷基、-C _1-6亚烷基-R ^z、-C _1-6亚烷基-OR ^z、-C _1-6亚烷基-OH、-C _1-6亚烷基-N(R ^z) ₂、C _3-6环烷基、3-12元的杂环基、C _2-6烯基、C _2-6炔基、C _6-12芳基、5-12元的杂芳基、-S(＝O) _g-(C _1-6烷基)、-NH ₂和-N(R ^z) ₂，其中所述的烷基、亚烷基、环烷基、杂环基、烯基、炔基、杂芳基和芳基各自任选地被一个或多个选自卤素、-CN、＝O、-OR ^z、-OH、-N(R ^z) ₂、-COOH、-NHR ^z、-NH ₂、C _1-6烷基、C _3-6环烷基、3-12元杂环基、C _6-10芳基、5-10元杂芳基、-C(O)OR ^z、-C(O)N(R ^z) ₂、-C(O)NH ₂和-NO ₂的取代基取代； When Y is

And when R ^8a and R ^{8b are} not H at the same time, R ^{3 is} selected from H, halogen, -OR ^z , -OH, -CN, -C(O)OR ^z , -COOH, -CON(R ^z ) ₂ ,- CONH ₂ , -C _1-6 alkylene, -C _1-6 alkylene-R ^z , -C _1-6 alkylene-OR ^z , -C _1-6 alkylene-OH, -C _{1- 6} alkylene-N(R ^z ) ₂ , C _3-6 cycloalkyl, 3-12 membered heterocyclic group, C _2-6 alkenyl, C _2-6 alkynyl, C _6-12 aryl, 5-12 membered heteroaryl, -S(=O) _g -(C _1-6 alkyl), -NH ₂ and -N(R ^z ) ₂ , wherein the alkyl, alkylene, ring Alkyl, heterocyclyl, alkenyl, alkynyl, heteroaryl and aryl are each optionally selected by one or more selected from halogen, -CN, =0, -OR ^z , -OH, -N (R ^z ) ₂ , -COOH, -NHR ^z , -NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclic group, C _6-10 aryl, 5-10 membered heteroaryl -C(O)OR ^z , -C(O)N(R ^z ) ₂ , -C(O)NH ₂ and -NO ₂ substituents;

R ^z is optionally selected from -CN, -NH-C _1-6 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclyl, C _{2-6 at each occurrence} Alkenyl, C _2-6 alkynyl, C _6-12 aryl and 5-12 membered heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, heteroaryl and The aryl groups are each optionally substituted by one or more selected from -NH ₂ , halogen, -CN, =O, -NO ₂ , -OH, -OC _1-6 alkyl, C _1-6 alkyl, halogenated C _{Substituents of 1-6} alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclic group, C _6-10 aryl and 5-10 membered heteroaryl;

g is 0, 1 or 2;

n is 0, 1, 2, 3, 4, or 5.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvent Compounds, isotopically-labeled compounds, metabolites or prodrugs, and one or more pharmaceutically acceptable carriers.

In yet another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled compound, Use of the metabolite or prodrug or the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention or treatment of SHP2 phosphatase-related diseases.

In a further aspect, the present invention provides a method for preventing or treating SHP2 phosphatase-related diseases, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual in need thereof, Esters, stereoisomers, tautomers, polymorphs, solvates, isotopically labeled compounds, metabolites or prodrugs, or pharmaceutical compositions of the present invention.

In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled compound, The metabolite or prodrug or the pharmaceutical composition of the present invention is used to prevent or treat SHP2 phosphatase related diseases.

In one embodiment, the SHP2 phosphatase-related disease is a disease that is sensitive or responsive to SHP2 phosphatase inhibition. In a further embodiment, the SHP2 phosphatase-related disease is a tumor-like disease, including but not limited to solid and hematological malignancies.

In another aspect, the present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, or isotope-labeled compound , Metabolites or prodrugs, or the pharmaceutical composition of the present invention combined with another treatment method for the prevention or treatment of SHP2 phosphatase-related diseases, the additional treatment method includes but not limited to: radiotherapy, chemotherapy, immunotherapy Therapies or combinations thereof.

Brief description of the drawings

Figure 1 shows the volume change of the subcutaneously transplanted tumor in the mouse model of Test Example 4.

Figure 2 shows the changes in the body weight of the mice in Test Example 4.

Fig. 3 shows the volume change of the subcutaneously transplanted tumor in the mouse model of Test Example 5.

Figure 4 shows the changes in the body weight of the mice in Test Example 5.

Detailed description of the invention

General terms and definitions

Unless otherwise defined below, the meanings of all technical and scientific terms used herein are intended to be the same as those commonly understood by those skilled in the art. The reference to the technology used herein is intended to refer to the technology generally understood in the art, including those technical changes or equivalent technology substitutions that are obvious to those skilled in the art. Although it is believed that the following terms are well understood by those skilled in the art, the following definitions are still set forth to better explain the present invention.

The terms "including", "comprising", "having", "containing" or "involving" and other variants herein are inclusive or open-ended, and do not exclude other unlisted elements or method steps . Those skilled in the art should understand that the above-mentioned terms such as "including" encompass the meaning of "consisting of".

The term "about" means within ±10% of the stated value, preferably within ±5%, more preferably within ±2%.

Unless otherwise stated, concentrations are by weight and ratios (including percentages) are by moles.

The term "one (species) or more (species)" or similar expressions "at least one (species)" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 (species) Or more (species).

When the lower limit and the upper limit of a numerical range are disclosed, any numerical value and any included range falling within the range are specifically disclosed. In particular, each value range of the values disclosed herein (in the form "about a to b", or equivalent, "about a to b", or equivalent, "about ab"), should be understood to mean encompassing Each value and range in the wider range.

For example, the expression "C _1-6 "should be understood to cover any sub-range and each point value therein, such as C _2-5 , C _3-4 , C _1-2 , C _1-3 , C _1-4 , C _1-5 and so on, and C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ and so on. For example, the expression “C _3-10 ”should also be understood in a similar manner, for example, it can cover any sub-range and point value contained therein, such as C _3-9 , C _6-9 , C _6-8 , C _{6- 7.} C _7-10 , C _7-9 , C _7-8 , C _8-9, etc. and C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ and so on. For another example, the expression "3-10 yuan" should be understood to cover any sub-range and each point value, such as 3-4 yuan, 3-5 yuan, 3-6 yuan, 3-7 yuan, 3-8 yuan. Yuan, 3-9 Yuan, 4-5 Yuan, 4-6 Yuan, 4-7 Yuan, 4-8 Yuan, 5-7 Yuan, 5-8 Yuan, 6-7 Yuan, etc. and 3, 4, 5, 6 , 7, 8, 9, 10 yuan, etc. For another example, the expression "5-10 yuan" should also be understood in a similar way, for example, it can cover any sub-range and point value contained therein, such as 5-6 yuan, 5-7 yuan, 5-8 yuan, 5- 9 yuan, 5-10 yuan, 6-7 yuan, 6-8 yuan, 6-9 yuan, 6-10 yuan, 7-8 yuan, etc. and 5, 6, 7, 8, 9, 10 yuan, etc.

The term "alkyl", when used alone or in combination with other groups herein, refers to a saturated linear or branched hydrocarbon group. As used herein, the term "C _1-6 alkyl" refers to a saturated linear or branched hydrocarbon group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6 carbon atoms). For example, "C _1-6 alkyl" can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, new Pentyl or n-hexyl, etc.

As used herein, the term "alkylene" refers to a saturated linear or branched divalent hydrocarbon group. For example, as used herein, the term "C _1-6 alkylene" refers to a linear or branched divalent hydrocarbon group having 1 to 6 carbon atoms saturated. Including but not limited to methylene, ethylene, propylene or butylene.

The term "cycloalkyl", when used alone or in combination with other groups herein, refers to a saturated or partially saturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl) , Cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutene, cyclopentene, cyclohexene; or bicyclic, including spirocyclic, fused or bridged systems ( Such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.). For example, the term "C _{3 "-12} cycloalkyl" refers to a cycloalkyl having 3-12 ring carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9 or 10).

The term "hydrocarbon ring", when used herein alone or in combination with other groups, refers to a saturated or saturated or having, for example, 3-10 (suitably 5-8, more suitably 5-6) ring carbon atoms Unsaturated (that is, having one or more double bonds and/or triple bonds in the ring) monocyclic or polycyclic hydrocarbon ring, including but not limited to cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclohexyl ring , Cycloheptyl ring, cyclooctyl ring, cyclononyl ring, cyclohexenyl ring, etc.

The term "halogen" group, when used alone or in combination with other groups herein, means F, Cl, Br, or I.

The term "alkenyl", as used herein alone or in combination with other groups, refers to a straight or branched chain hydrocarbon group having one or more carbon-carbon double bonds. For example, as used herein, the term "C _2-6 alkenyl" refers to a straight or branched hydrocarbon group having 2-6 carbon atoms and one, two or three carbon-carbon double bonds, preferably containing one carbon-carbon Double bond C _2-6 alkenyl. Examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2- Hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl, etc.

The term "alkynyl", as used herein alone or in combination with other groups, refers to a straight or branched chain hydrocarbon group having one or more carbon-carbon triple bonds. For example, as used herein, the term "C _2-6 alkynyl" refers to a straight or branched hydrocarbon group having 2-6 carbon atoms and one, two or three carbon-carbon triple bonds, preferably containing one carbon-carbon _{C 2-6} alkenyl with triple bond. Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like.

The term "heterocyclic group" or "heterocyclic ring", when used alone or in combination with other groups herein, means having, for example, 3-15 (suitably 3-8, more suitably 3-6) A monocyclic or bicyclic non-aromatic ring system of ring atoms (for example, 3-15 members, 3-8 members, 3-6 members), wherein at least one ring atom (for example, 1 or 2) is selected from N, O, P And S heteroatoms, and the remaining ring atoms are C. The ring system may be a fused ring system, a bridged ring system or a spiro ring system. The ring system can be saturated (also can be understood as the corresponding "heterocycloalkyl") or unsaturated (that is, having one or more double bonds and/or triple bonds in the ring). The term also covers situations where the C atom may be (=O) substituted and/or the S atom on the ring may be substituted by 1 or 2 (=O). Examples of heterocyclic groups include, but are not limited to: oxirane, sulfiethane, azaethyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydrofuranyl, Hydrothienyl, dioxolyl, pyrrolidinyl, pyrrolidone, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, 1,4- Thioxanyl, 1,4-dioxanyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl, etc.

The term "aryl" or "aromatic ring", when used alone or in combination with other groups herein, refers to an all-carbon monocyclic or fused-ring polycyclic (such as bicyclic) aromatic group with a conjugated π-electron system Or aromatic ring. As used herein, the term "C _6-10 aryl" refers to an aromatic group containing 6-10 carbon atoms. Examples include, but are not limited to, phenyl, naphthyl, and the like.

The term "heteroaryl" or "heteroaromatic ring", when used alone or in combination with other groups herein, refers to an aromatic group or aromatic ring with a conjugated π-electron system, one or more of which (such as 1, 2, or 3) ring atoms are heteroatoms selected from N, O, P and S, and the remaining ring atoms are C. Heteroaryl or heteroaromatic rings can be characterized by the number of ring atoms. For example, a 5-10 membered heteroaryl group may contain 5-10 (e.g., 5, 6, 7, 8, 9 or 10) ring atoms, especially 5, 6, 9, 10 ring atoms. And in each case, the heteroaryl or heteroaromatic ring may optionally be further benzo-fused. For example, examples of heteroaryl groups are thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazinyl, isoxazolyl, isothiazolyl, oxadiazolyl, three Azolyl, thiadiazolyl, etc., and their benzo derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, benzofuranyl, Benzothienyl, indolyl, isoindolyl, etc., and their benzo derivatives.

The term "hydroxy" means -OH.

The term "cyano" means -CN.

The term "nitro" means -NO ₂ .

The term "amino" means -NH ₂ .

The terms "substituted", "substituted" and "suitable substitution" mean that one or more (eg, one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the indicated group , Provided that the normal valence of the specified atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are only permissible when such combinations form stable compounds.

If a substituent is described as "optionally... substituted", the substituent can be (1) unsubstituted, or (2) substituted. If an atom or group is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the atom or group may be independently selected, optional substituents Substitute. If substituents are described as being "independently selected from" or "each independently being", then each substituent is independently selected from each other. Therefore, each substituent may be the same or different from another (other) substituent. For example, when a certain substituent or substitution position or different substituents or substitution positions have R groups (such as but not limited to R ² and/or R ^z ) that may be the same or different symbols are selected, between R groups They can be selected independently, that is, they can be the same or different. The same is true for the selection of values such as g and n.

Unless otherwise specified, as used herein, the point of attachment of a substituent can be from any suitable position of the substituent.

When a bond of a substituent is shown as a bond connecting two atoms through a ring, then such a substituent may be bonded to any ring-forming atom in the substitutable ring.

The present invention also includes all pharmaceutically acceptable isotope-labeled compounds, which are the same as the compounds of the present invention, except that one or more atoms have the same atomic number but the atomic mass or mass number is different from the predominant atomic mass in nature. Or atomic substitution of mass number. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (such as deuterium ( ² H), tritium ( ³ H)); isotopes of carbon (such as ¹³ C and ¹⁴ C); Isotopes (e.g. ³⁷ Cl); isotopes of iodine (e.g. ¹²⁵ I); isotopes of nitrogen (e.g. ¹³ N and ¹⁵ N); isotopes of oxygen (e.g. ¹⁷ O and ¹⁸ O); isotopes of phosphorus (e.g. ³² P); and Isotopes of sulfur (for example ³⁴ S).

The term "stereoisomer" means an isomer formed due to at least one asymmetric center. In compounds with one or more (for example, one, two, three, or four) asymmetric centers, it can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual The diastereomers. Certain individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention may exist in a mixture of two or more structurally different forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It should be understood that the scope of the present invention encompasses all such things in arbitrary proportions (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%). %) isomers or mixtures thereof.

或虚楔形

描绘本发明的化合物的碳-碳键。使用实线以描绘键连至不对称碳原子的键欲表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键欲表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则本发明的化合物可以以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。 Solid lines (——) and solid wedge shapes can be used in this article

Virtual wedge

Depicts the carbon-carbon bonds of the compounds of the invention. The use of a solid line to depict the bond to an asymmetric carbon atom is intended to indicate that it includes all possible stereoisomers at that carbon atom (e.g., specific enantiomers, racemic mixtures, etc.). The use of real or imaginary wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist. When present in a racemic mixture, real and imaginary wedges are used to define relative stereochemistry, rather than absolute stereochemistry. Unless otherwise specified, the compounds of the present invention may be stereoisomers (including cis and trans isomers, optical isomers (such as R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformational isomers, atropisomers and mixtures thereof) exist in the form of. The compounds of the present invention can exhibit more than one type of isomerism, and are composed of mixtures thereof (for example, racemic mixtures and diastereomeric pairs).

The present invention also covers all possible crystalline forms or polymorphs of the compounds of the present invention, which can be a single polymorph or a mixture of more than one polymorph in any ratio.

It should also be understood that certain compounds of the present invention may exist in free form for treatment, or, when appropriate, in the form of their pharmaceutically acceptable derivatives. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which can be directly administered to patients in need thereof. Or indirectly provide the compound of formula (I) or its metabolites. Therefore, when the "compound of the present invention" is referred to herein, it is also intended to encompass the above-mentioned various derivative forms of the compound.

The pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include hydrochloride, acetate, aspartate, benzoate, bicarbonate/carbonate, glucoheptonate, gluconate, nitrate, orotate, palmitic acid Salt and other similar salts. Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, magnesium salts, and other similar salts. For a review of suitable salts, see, for example, "Remington's Pharmaceutical Sciences", Mack Publishing Company, Easton, Pa., (2005); and "Handbook of Pharmaceutical Salts: Properties, Selection and Application" (Handbook of Pharmaceutical Salts: Properties, Selection) , And Use), Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

As used herein, the term "ester" means an ester derived from the compounds described herein, which includes physiologically hydrolyzable esters (compounds of the invention that can be hydrolyzed under physiological conditions to release the free acid or alcohol form) . The compound of the present invention may itself be an ester.

The compound of the present invention may exist in the form of a solvate (preferably a hydrate), wherein the compound of the present invention contains a polar solvent as a structural element of the compound's crystal lattice, especially, for example, water, methanol or ethanol. The amount of polar solvent, especially water, can be present in a stoichiometric or non-stoichiometric ratio.

Those skilled in the art will understand that since nitrogen requires available lone pairs of electrons to oxidize to oxides, not all nitrogen-containing heterocycles can form N-oxides. Those skilled in the art will recognize nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for the preparation of N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, alkyl Hydrogen peroxide such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane to oxidize heterocycles and tertiary amines. These methods for the preparation of N-oxides have been widely described and reviewed in the literature, see for example: TLGilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750 (ARKatritzky and AJBoulton, Eds., Academic Press ); and GWHCheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol.22, pp 390-392 (ARKatritzky and AJBoulton, Eds., Academic Press).

Also included within the scope of the present invention are metabolites of the compounds of the present invention, that is, substances formed in the body when the compounds of the present invention are administered. The metabolites of compounds can be identified by techniques well known in the art, and their activity can be characterized by experimental methods. Such products can be produced by, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by a method in which the compounds of the present invention are contacted with a mammal for a time sufficient to produce their metabolites.

The present invention further includes within its scope the prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have less or no pharmacological activity when administered to or on the body. It can be converted into the compound of the present invention having the desired activity by, for example, hydrolytic cleavage. Usually such prodrugs will be functional group derivatives of the compound, which are easily converted into the desired therapeutically active compound in vivo. For other information on the use of prodrugs, please refer to "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of the present invention can be used, for example, by using certain parts known to those skilled in the art as "pro-moiety (for example, "Design of Prodrugs", described in H. Bundgaard (Elsevier, 1985))" It is prepared by substituting appropriate functional groups existing in the compounds of the present invention.

The present invention also encompasses the compounds of the present invention containing protecting groups. In any process of preparing the compounds of the present invention, protection of sensitive groups or reactive groups on any relevant molecule may be necessary and/or desirable, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, such as those described in T.W. Greene & P.G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 2006, and these references are incorporated herein by reference. Using methods known in the art, the protecting group can be removed at an appropriate subsequent stage.

The invention also encompasses methods of preparing the compounds described herein. It should be understood that the compounds of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the field of synthetic organic chemistry, or variations thereof known to those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction can be carried out in a solvent or solvent mixture suitable for the reagents and materials used and suitable for achieving the conversion.

The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that can effectively treat one or more symptoms of the target disorder or condition.

As used herein, the term "effective amount" (for example, "therapeutically effective amount" or "prophylactically effective amount") refers to the amount of the active ingredient that will achieve the desired effect to a certain extent after administration, such as one that relieves the condition being treated One or more symptoms or to prevent the appearance of a disease or its symptoms.

Unless otherwise specified, as used herein, the term "treating" means reversing, alleviating, inhibiting the progression of one or more symptoms of the disorder or condition to which such term is applied, or preventing such Or one or more symptoms of such a disorder or condition.

"Individual" as used herein includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from diseases such as those described herein. In the present invention, "non-human animals" include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs). , Cats, cows, pigs, etc.).

Detailed description of the invention

Compound of the present invention

In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled compound, metabolism Substance or prodrug:

among them:

X is a direct bond or selected from S, O, NH and CH ₂ ;

Y is a direct key or

W ¹ , W ² and W ³ are each independently selected from CH and N;

R ^{1 is} selected from H, -OH, -NH ₂ , C _1-6 alkyl and C _3-6 cycloalkyl;

Each occurrence of R ² is independently selected from H, halogen, -OH, -OC _1-6 alkyl, -OC _3-6 cycloalkyl, -CN, C _1-6 alkyl, C _3-6 Cycloalkyl, C _2-6 alkenyl, -S(=O) _g -(C _1-6 alkyl), -S(=O) _g NH ₂ , -NH ₂ , -NH(C _1-6 alkane Group), -N(C _1-6 alkyl) ₂ , 3-12 membered heterocyclic group, C _6-10 aryl group and 5-12 membered heteroaryl group. Preferably, R ² is independent of each occurrence Ground is selected from H, halogen, -OH, -OC _1-6 alkyl, -CN, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, -S(=O) _g -(C _1-6 alkyl), _{-NH 2} , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , 3-12 membered heterocyclic group, C _6-10 aryl And 5-12 membered heteroaryl groups, wherein each of the alkyl, cycloalkyl, alkenyl, heterocyclyl, aryl and heteroaryl groups is optionally selected from halogen, =0,- OH, -OC _1-6 alkyl, -CN, C _1-6 alkyl, -S(=O) _g -(C _1-6 alkyl) _{, -NH 2} , -NH(C _1-6 alkyl) ) And -N(C _1-6 alkyl) ₂ substituents;

Alternatively, any two R ² together with the atoms to which they are connected form a 5-10 membered hydrocarbon ring, a 5-10 membered heterocyclic ring, a 5-6 membered heteroaromatic ring or a benzene ring, wherein the hydrocarbon ring, heterocyclic ring, heteroaromatic ring The ring and the benzene ring are each optionally selected by one or more selected from -NH ₂ , -NH (C _1-6 alkyl), -N (C _1-6 alkyl) ₂ , halogen, -CN, =O, -OH, -OC _1-6 alkyl, halogenated C _1-6 alkyl and C _1-6 alkyl substituent substitution;

Or, when X is NH or CH ₂ , any one of R ² and X together with the atoms to which they are connected forms a 5-10 membered hydrocarbon ring, a 5-10 membered heterocyclic ring, a 5-6 membered heteroaromatic ring or a benzene ring, wherein The hydrocarbon ring, heterocyclic ring, heteroaromatic ring and benzene ring are each optionally selected from -NH ₂ , -NH (C _1-6 alkyl), -N (C _1-6 alkyl). _2. Substituent substitution of halogen, -CN, =O, -OH, -OC _1-6 alkyl, halogenated C _1-6 alkyl and C _{1-6 alkyl;}

R ^4a , R ^4b , R ^5a , R ^5b , R ^6a , R ^6b , R ^7a and R ^7b are each independently selected from H, halogen, =O, -CN, -OH, -COOH, -CONH ₂ , -C (O) O-(C _1-6 alkyl), C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -S(=O) _g -(C _1-6 alkyl), 3-6 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, The heterocyclic group, aryl group, heteroaryl group is optionally selected by one or more selected from -NH ₂ , -OH, =O, halogen, -CN, -OC _1-4 alkyl, -NH (C _1-6 Alkyl) and -N(C _1-6 alkyl) ₂ are substituted by one or more substituents selected from -NH ₂ , -OH, halogen, -CN, -OC _1-4 alkyl, -NH (C _1-6 alkyl) and -N(C _1-6 alkyl) ₂ substituents;

Alternatively, any two of R ^4a , R ^4b , R ^5a , R ^5b , R ^6a , R ^6b , R ^7a and R ^7b form a C _3-10 hydrocarbon ring or 4- 12-membered heterocyclic ring;

Alternatively, R ^4a , R ^7a and R ³ together with the atoms to which they are attached form azaadamantane, optionally with one or more selected from F, Cl, Br, -OH, =O, -CN, -C( O) Substituent substitution of O(C _1-6 alkyl) and C _{1-6 alkyl;}

R ^8a and R ^8b are each independently selected from H, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-12 aryl and 5-12 membered heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, heteroaryl and aryl are each optionally substituted by one or Multiple selected from -N(R ^z ) ₂ , -NH ₂ , halogen, -CN, -OH, =O, -OC _1-6 alkyl, C _1-6 alkyl, halogenated C _1-6 alkyl , C _3-6 cycloalkyl, 3-12 membered heterocyclic group, C _6-10 aryl and 5-10 membered heteroaryl substituents; preferably, the alkyl, cycloalkyl, alkene Group, alkynyl group, heterocyclic group, heteroaryl group and aryl group are each optionally selected from one or more groups -N(R ^z ) ₂ , -NH ₂ , halogen, -CN, -OH, =O,- Substituents of OC _1-6 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclic group, C _6-10 aryl and 5-10 membered heteroaryl;

Or R ^8a and R ^8b together with the connected atoms (or direct bonds) form a C _3-8 hydrocarbon ring or a 3-12 membered heterocyclic ring, wherein the hydrocarbon ring and the heterocyclic ring are each optionally selected by one or more From -N(R ^z ) ₂ , -NH ₂ , halogen, -CN, =O, -OH, -OC _1-6 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 Substituents of membered heterocyclic group, C _6-10 aryl group, 5-10 membered heteroaryl group;

且R ^8a和R ^8b同时为H时，R ³选自-CN、-C _1-6亚烷基-R ^z、-C _1-6亚烷基-OR ^z、C _3-6环烷基、C _2-6烯基、C _2-6炔基和苯基，其中所述的亚烷基、环烷基、烯基、炔基和苯基各自任选地被一个或多个选自卤素、-CN、＝O、-OR ^z、-OH、-N(R ^z) ₂、-NH ₂、C _1-6烷基、C _3-6环烷基、3-6元杂环基、苯基和5-6元杂芳基的取代基取代； When Y is a direct key or

And when R ^8a and R ^{8b are} both H, R ^{3 is} selected from -CN, -C _1-6 alkylene-R ^z , -C _1-6 alkylene-OR ^z , C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl and phenyl, wherein the alkylene, cycloalkyl, alkenyl, alkynyl and phenyl are each optionally selected from halogen, -CN, =O, -OR ^z , -OH, -N(R ^z ) ₂ , -NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, phenyl And 5-6 membered heteroaryl substituents;

且R ^8a、R ^8b不同时为H时，R ³选自H、卤素、-OR ^z、-OH、-CN、-C(O)OR ^z、-COOH、-CON(R ^z) ₂、-CONH ₂、-C _1-6烷基、-C _1-6亚烷基-R ^z、-C _1-6亚烷基-OR ^z、-C _1-6亚烷基-OH、-C _1-6亚烷基-N(R ^z) ₂、C _3-6环烷基、3-12元的杂环基、C _2-6烯基、C _2-6炔基、C _6-12芳基、5-12元的杂芳基、-S(＝O) _g-(C _1-6烷基)、-NH ₂和-N(R ^z) ₂，其中所述的烷基、亚烷基、环烷基、杂环基、烯基、炔基、杂芳基和芳基各自任选地被一个或多个选自卤素、-CN、＝O、-OR ^z、-OH、-N(R ^z) ₂、-NHR ²、-NH ₂、 C _1-6烷基、C _3-6环烷基、3-12元杂环基、C _6-10芳基、5-10元杂芳基、-C(O)OR ^z、-COOH、-C(O)N(R ^z) ₂、-C(O)NH ₂和-NO ₂的取代基取代，优选的，其中所述的烷基、亚烷基、环烷基、杂环基、烯基、炔基、杂芳基和芳基各自任选地被一个或多个选自卤素、-CN、＝O、-OR ^z、-OH、-N(R ^z) ₂、-NH ₂、C _1-6烷基、C _3-6环烷基、3-12元杂环基、C _6-10芳基、5-10元杂芳基、-C(O)OR ^z、-C(O)N(R ^z) ₂、-C(O)NH ₂和-NO ₂的取代基取代； When Y is

And when R ^8a and R ^{8b are} not H at the same time, R ^{3 is} selected from H, halogen, -OR ^z , -OH, -CN, -C(O)OR ^z , -COOH, -CON(R ^z ) ₂ ,- CONH ₂ , -C _1-6 alkylene, -C _1-6 alkylene-R ^z , -C _1-6 alkylene-OR ^z , -C _1-6 alkylene-OH, -C _{1- 6} alkylene-N(R ^z ) ₂ , C _3-6 cycloalkyl, 3-12 membered heterocyclic group, C _2-6 alkenyl, C _2-6 alkynyl, C _6-12 aryl, 5-12 membered heteroaryl, -S(=O) _g -(C _1-6 alkyl), -NH ₂ and -N(R ^z ) ₂ , wherein the alkyl, alkylene, ring Alkyl, heterocyclyl, alkenyl, alkynyl, heteroaryl and aryl are each optionally selected by one or more selected from halogen, -CN, =0, -OR ^z , -OH, -N (R ^z ) ₂ , -NHR ² , -NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclic group, C _6-10 aryl, 5-10 membered heteroaryl,- Substituents of C(O)OR ^z , -COOH, -C(O)N(R ^z ) ₂ , -C(O)NH ₂ and -NO ₂ are substituted, preferably, wherein the alkyl and alkylene Group, cycloalkyl group, heterocyclic group, alkenyl group, alkynyl group, heteroaryl group and aryl group are each optionally selected by one or more selected from halogen, -CN, =O, -OR ^z , -OH, -N (R ^z ) ₂ , -NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclic group, C _6-10 aryl, 5-10 membered heteroaryl, -C (O) OR ^z , -C(O)N(R ^z ) ₂ , -C(O)NH ₂ and -NO ₂ substituents;

R ^z is optionally selected from -CN, -NH-C _1-6 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclyl, C _{2-6 at each occurrence} Alkenyl, C _2-6 alkynyl, C _6-12 aryl and 5-12 membered heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, heteroaryl and The aryl groups are each optionally substituted by one or more selected from -NH ₂ , halogen, -CN, =O, -NO ₂ , -OH, -OC _1-6 alkyl, C _1-6 alkyl, halogenated C _{Substituents of 1-6} alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl; preferably, R ^z appears every time When selected from -CN, C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclic group, C _2-6 alkenyl, C _2-6 alkynyl, C _6-12 aryl And 5-12 membered heteroaryl groups, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, heteroaryl and aryl groups are each optionally selected from one or more -NH ₂ , Halogen, -CN, =O, -NO ₂ , -OH, -OC _1-6 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclic group, C _{6- Substituents of 10} aryl and 5-10 membered heteroaryl;

g is 0, 1 or 2;

n is 0, 1, 2, 3, 4, or 5.

In some embodiments, R ^{1 is} selected from H, -OH, -NH ₂ , C _1-3 alkyl and C _3-6 cycloalkyl; in some preferred embodiments, R ^{1 is} selected from H, -NH _2. -CH ₃ and cyclopropyl; in some more preferred embodiments, R ^{1 is} selected from -CH ₃ and cyclopropyl; in further preferred embodiments, R ^{1 is} selected from -CH ₃ .

In some embodiments, X is selected from a direct bond and S; in some preferred embodiments, X is a direct bond.

选自

在一些更优选的实施方案中，

选自

In some embodiments, W ³ is CH, and W ¹ and W ² are each independently selected from CH and N; in some preferred embodiments,

Selected from

In some more preferred embodiments,

Selected from

In some embodiments, ^{each occurrence of R 2} is independently selected from H, halogen, -OH, -OC _1-6 alkyl, -O-halo C _1-6 alkyl, -OC _3-6 Cycloalkyl, -CN, C _1-3 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, halogenated C _1-3 alkyl, -NH ₂ , -NH(C _1-3 Alkyl), -N(C _1-3 alkyl) ₂ , -S(=O) _g -(C _1-3 alkyl) and -S(=O) _g NH ₂ ; preferably, R ^{2 is} in each Each occurrence is independently selected from H, halogen, -OH, -OC _1-6 alkyl, -CN, C _1-3 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, halogen Substitute C _1-3 alkyl and -NH ₂ ; In some preferred embodiments, ^{each occurrence of R 2} is independently selected from H, F, Cl, Br, -OH, -CN, C _1-3 Alkyl, -OCH ₃ , -OCHF ₂ , -OCF ₃ , -O-cyclopropyl, -CF ₃ , -CHF ₂ , cyclopropyl, hydroxy substituted azetidinyl, pyrrolyl, morpholinyl , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ CN, -NH ₂ , -S-CH ₃ , -S(=O) ₂ CH ₃ and -S(=O) ₂ NH ₂ ; preferred , R ² is independently selected from H, F, Cl, Br, -OH, C _1-3 alkyl, -OCHF ₂ , -CF ₃ , -CHF ₂ , cyclopropyl, hydroxy substituted at each occurrence Azetidinyl, pyrrolyl, morpholinyl, -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ CN and -NH ₂ ; preferably, ^{each occurrence of R 2} is independently selected from H, F, Cl, Br, -OH, -CN, C _1-3 alkyl, -OCH ₃ , -OCHF ₂ , -OCF ₃ , -O-cyclopropyl, -CF ₃ , -CHF ₂ , cyclopropyl Group, pyrrolyl, morpholinyl, -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ CN, -NH ₂ , -S-CH ₃ , -S(=O) ₂ CH ₃ and -S(= O) ₂ NH ₂ ; Preferably, ^{each occurrence of R 2} is independently selected from H, F, Cl, Br, -OH, C _1-3 alkyl, -OCHF ₂ , -CF ₃ , -CHF ₂ , Cyclopropyl, pyrrolyl, morpholinyl, -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ CN and -NH ₂ ;

进一步优选的，R ²在每次出现时各自独立地选自F、Cl、Br、-CH ₃、-CF ₃、-CN、-NH ₂和

进一步优选的，R ²在每次出现时各自独立地选自F、Cl、Br、-OH、-OCH ₃、-OCHF ₂、-OCF ₃、-O-环丙基、-CH ₃、-CF ₃、-CN、-NH ₂、-NHCH ₃、-N(CH ₃) ₂、-S-CH ₃、-S(＝O) ₂CH ₃和-S(＝O) ₂NH ₂；进一步优选的，R ²在每次出现时各自独立地选自F、Cl、Br、-CH ₃、-CF ₃、-CN和-NH ₂。 In a further preferred embodiment, ^{each occurrence of R 2} is independently selected from F, Cl, Br, -OH, -OCH ₃ , -OCHF ₂ , -OCF ₃ , -O-cyclopropyl, -CH ₃ , -CF ₃ , -CN, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -S-CH ₃ , -S(=O) ₂ CH ₃ , -S(=O) ₂ NH ₂ with

Further preferably, ^{each occurrence of R 2} is independently selected from F, Cl, Br, -CH ₃ , -CF ₃ , -CN, -NH ₂ and

More preferably, ^{each occurrence of R 2} is independently selected from F, Cl, Br, -OH, -OCH ₃ , -OCHF ₂ , -OCF ₃ , -O-cyclopropyl, -CH ₃ , -CF ₃ , -CN, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -S-CH ₃ , -S(=O) ₂ CH ₃ and -S(=O) ₂ NH ₂ ; further preferred , R ² is independently selected from F, Cl, Br, -CH ₃ , -CF ₃ , -CN and -NH ₂ at each occurrence.

选自

R ²在每次出现时各自独立地选自F、Cl、Br、-OH、-OCH ₃、-OCHF ₂、-OCF ₃、-O-环丙基、-CH ₃、-CF ₃、 -CN、-NH ₂、-NHCH ₃、-N(CH ₃) ₂、-S-CH ₃、-S(＝O) ₂CH ₃和-S(＝O) ₂NH ₂，n为1、2或3。在一些优选的实施方案中，

选自

In some embodiments,

Selected from

Each occurrence of R ² is independently selected from F, Cl, Br, -OH, -OCH ₃ , -OCHF ₂ , -OCF ₃ , -O-cyclopropyl, -CH ₃ , -CF ₃ , -CN , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -S-CH ₃ , -S(=O) ₂ CH ₃ and -S(=O) ₂ NH ₂ , n is 1, 2 or 3 . In some preferred embodiments,

Selected from

In some embodiments, any two R ² together with the atoms to which they are attached form a 5-7 membered hydrocarbon ring, a 5-7 membered heterocyclic ring, or a 5-6 membered heteroaromatic ring, wherein the hydrocarbon ring and the heterocyclic ring are each any Optionally by one or more selected from -NH ₂ , F, Cl, -CN, =O, -OH, -OC _1-3 alkyl, halogenated C _1-3 alkyl and C _1-3 alkyl Substituents are substituted; in some embodiments, any two R ² together with the atoms to which they are attached form a 5-7 membered hydrocarbon ring or a 5-7 membered heterocyclic ring, wherein the hydrocarbon ring and the heterocyclic ring are each optionally substituted by one Or more substituents selected from -NH ₂ , F, Cl, -CN, =O, -OH, -OC _1-3 alkyl, halo C _1-3 alkyl and C _1-3 alkyl;

In some preferred embodiments, any two R ² together with the atoms to which they are attached form a 5-6 membered hydrocarbon ring, a 5-6 membered heterocyclic ring, or a 5-membered heteroaromatic ring, wherein the hydrocarbon ring and the heterocyclic ring are each Is optionally substituted with one or more substituents selected from the group consisting of -NH ₂ , F, Cl, =0, -OH, -OCH ₃ and -CH ₃ ; in some preferred embodiments, any two R ² and them The connected atoms together form a 5-6 membered hydrocarbon ring or a 5-6 membered heterocyclic ring, wherein the hydrocarbon ring and the heterocyclic ring are each optionally selected by one or more selected from -NH ₂ , F, Cl, =O,- Substituents of OH, -OCH ₃ and -CH ₃ are substituted.

In some embodiments, when X is NH or CH ₂ , any one of R ² and X together with the atoms to which they are attached form a 5-7 membered hydrocarbon ring or a 5-7 membered heterocyclic ring, wherein the hydrocarbon ring and the heterocyclic ring Each is optionally substituted by one or more selected from -NH ₂ , F, Cl, -CN, =O, -OH, -OC _1-3 alkyl, halo C _1-3 alkyl and C _1-3 alkane In some preferred embodiments, when X is NH or CH ₂ , any one of R ² and X together with the atoms to which they are attached form a 5-6 membered hydrocarbon ring or a 5-6 membered heterocyclic ring, Wherein the hydrocarbon ring and the heterocyclic ring are each optionally substituted with one or more substituents selected from -NH ₂ , F, Cl, =0, -OH, -OCH ₃ and -CH ₃ ; in some embodiments , When X is NH, any one of R ² and X together with the atom to which they are connected forms a morpholine ring.

In some embodiments, R ^4a , R ^4b , R ^5a , R ^5b , R ^6a , R ^6b , R ^7a and R ^7b are each independently selected from H, F, Cl, =O, -CN, -C(O ) O(C _1-4 alkyl), C _1-3 alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from halogen, =0, -OH and -NH ₂ ; in In some preferred embodiments, R ^4a , R ^4b , R ^5a , R ^5b , R ^6a , R ^6b , R ^7a and R ^7b are each independently selected from H, F, Cl, -CH ₃ and -C(O) O(C _1-3 alkyl); In some more preferred embodiments, R ^4a , R ^4b , R ^5a , R ^5b , R ^6a , R ^6b , R ^7a and R ^7b are each independently selected from H,- CH ₃ and -C(O)OCH ₃ ; In a further preferred embodiment, R ^4a , R ^4b , R ^5a , R ^5b , R ^6a , R ^6b , R ^7a and R ^7b are all H.

In some embodiments, any two of R ^4a , R ^4b , R ^5a , R ^5b , R ^6a , R ^6b , R ^7a , R ^7b together with the atoms (or direct bonds) to which they are connected form a C _4-8 hydrocarbon Ring or 4-8 membered heterocyclic ring; in some preferred embodiments ^{, any two of R 4a} , R ^5a , R ^6a , and R ^7a together with the atoms to which they are connected form a C _4-8 hydrocarbon ring or 4-8 membered ring Heterocycle; In a further preferred embodiment, R ^4a and R ^7a together with the atoms to which they are attached form a 4-6 membered nitrogen-containing heterocyclic ring, or R ^5a and R ^6a together with the atoms to which they are attached form a C _4-6 hydrocarbon Ring; In a further preferred embodiment, R ^5a and R ^6a together with the atoms to which they are attached form a cyclopenta ring, and R ^4a , R ^4b , R ^5b , R ^6a , R ^7a , R ^7b are all H.

In some embodiments, R ^4a , R ^7a and R ³ together with the atoms to which they are attached form azaadamantane; in some preferred embodiments, R ^4a , R ^7a and R ³ together with the atoms to which they are attached form nitrogen Heteroadamantane, and R ^4b , R ^5a , R ^5b , R ^6a , R ^6b , and R ^7b are all H.

且R ^8a和R ^8b同时为H时，R ³选自-CN、-C _1-3亚烷基-R ^z、-C _1-3亚烷基-OR ^z、C _3-6环烷基、C _2-4烯基、C _2-4炔基和苯基，其中所述的亚烷基、环烷基、烯基、炔基和苯基各自任选地被一个或多个选自F、Cl、-CN、＝O、-OR ^z、-OH、-N(R ^z) ₂、-NH ₂、C _1-4烷基、C _3-6环烷基、4-6元杂环基、苯基和5-6元杂芳基的取代基取代；在一些优选的实施方案中，当Y为直接键或

且R ^8a和R ^8b同时为H时，R ³选自-CH ₂CH＝CH ₂、-CH＝CH ₂、-CH ₂C＝CH、-C＝CH、-CH ₂R ^z、-CH ₂-OR ^z、-CN、环丙基、环丁基、环丁烯基、环戊基、环己基和苯基，其中所述苯基任选地被一个或两个选自F、Cl、-CN、-OH、-OCH ₃、-N(CH ₃) ₂、-NH(CH ₃)、-NH ₂和吡唑基的取代基取代；优选地，当Y为直接键或

且R ^8a和R ^8b同时为H时，R ³选自-CH ₂CH＝CH ₂、-CH＝CH ₂、-CH ₂C＝CH、-C＝CH、-CH ₂R ^z、-CH ₂-OR ^z、-CN、环丙基、环丁基、环戊基、环己基和苯基，其中所述苯基任选地被一个或两个选自F、Cl、-CN、-OH、-OCH ₃、-N(CH ₃) ₂、-NH(CH ₃)、-NH ₂和吡唑基的取代基取代。 In some embodiments, when Y is a direct bond or

And when R ^8a and R ^{8b are} both H, R ^{3 is} selected from -CN, -C _1-3 alkylene-R ^z , -C _1-3 alkylene-OR ^z , C _3-6 cycloalkyl, C _2-4 alkenyl, C _2-4 alkynyl and phenyl, wherein the alkylene, cycloalkyl, alkenyl, alkynyl and phenyl are each optionally selected from one or more of F, Cl, -CN, =O, -OR ^z , -OH, -N(R ^z ) ₂ , -NH ₂ , C _1-4 alkyl, C _3-6 cycloalkyl, 4-6 membered heterocyclic group, Phenyl and 5-6 membered heteroaryl substituents; in some preferred embodiments, when Y is a direct bond or

And when R ^8a and R ^{8b are} both H, R ^{3 is} selected from -CH ₂ CH=CH ₂ , -CH=CH ₂ , -CH ₂ C=CH, -C=CH, -CH ₂ R ^z , -CH ₂ -OR ^z , -CN, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclohexyl and phenyl, wherein said phenyl is optionally selected from F, Cl,- CN, -OH, -OCH ₃ , -N(CH ₃ ) ₂ , -NH(CH ₃ ), -NH ₂ and pyrazolyl substituents are substituted; preferably, when Y is a direct bond or

And when R ^8a and R ^{8b are} both H, R ^{3 is} selected from -CH ₂ CH=CH ₂ , -CH=CH ₂ , -CH ₂ C=CH, -C=CH, -CH ₂ R ^z , -CH ₂ -OR ^z , -CN, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl, wherein said phenyl is optionally selected from F, Cl, -CN, -OH, -OCH ₃ , -N(CH ₃ ) ₂ , -NH(CH ₃ ), -NH ₂ and pyrazolyl substituents are substituted.

且R ^8a、R ^8b不同时为H时，R ³选自H、F、Cl、Br、-OR ^z、-OH、-CN、C _1-6烷基、-C _1-4亚烷基-R ^z、-C _1-4亚烷基-OR ^z、C _3-6环烷基、C _2-4烯基、C _2-4炔基、苯基、3-8元的杂环基(例如3-6元的杂环基)和5-6元杂芳基，其中所述的烷基、亚烷基、环烷基、烯基、炔基、苯基、杂环基和杂芳基各自任选地被一个或多个选自F、Cl、-CN、＝O、-OR ^z、-OH、-N(R ^z) ₂、-NHR ^z、-NH ₂、C _1-4烷基、C _3-6环烷基、3-6元杂环基、苯基、5-6元杂芳基的取代基取代；在一些优选的实施方案中，当Y为

且R ^8a、R ^8b不同时为H时，R ³选自H、F、Cl、-CF ₃、-CHF ₂、-CH ₂F、-OH、-OCH ₃、-CH ₂CH＝CH ₂、-CH＝CH ₂、-CH ₂C≡CH、-C＝CH、-CH ₃、-CH ₂CH ₃、-CH ₂NHCH ₃、-CH ₂R ^z、-CH ₂-OR ^z、-CH ₂-OH、-CN、环丙基、环丁基、环戊基、氧杂环丁烷基、

吗啉基、四氢吡喃基、吡啶基、嘧啶基、噁唑基、噻唑基、吡唑基、噻吩基和苯基，其中所述吡啶基、嘧啶基、噁唑基、噻唑基、吡唑基、噻吩基和苯基任选地被一个或两个选自F、Cl、-CN、-OH、-OCH ₃、-N(CH ₃) ₂、-NH(CH ₃)、-NH ₂和吡唑基的取代基取代；优选的，R ³选自H、F、Cl、-CF ₃、-CHF ₂、-OH、-OCH ₃、-CH ₂CH＝CH ₂、-CH＝CH ₂、-CH ₂C＝CH、-C＝CH、-CH ₃、-CH ₂R ^z、-CH ₂-OR ^z、-CH ₂-OH、-CN、环丙基、环丁基、环戊基、吗啉基、四氢吡喃基、吡啶基、嘧啶基、噻唑基、吡唑基、噻吩基和苯基，其中所述吡啶基、嘧啶基、噻唑基、吡唑基、噻吩基和苯基任选地被一个或两个选自F、Cl、-CN、-OH、-OCH ₃、-N(CH ₃) ₂、-NH(CH ₃)、-NH ₂和吡唑基的取代基取代。 In some embodiments, when Y is

And when R ^8a and R ^{8b are} not H at the same time, R ^{3 is} selected from H, F, Cl, Br, -OR ^z , -OH, -CN, C _1-6 alkyl, -C _1-4 alkylene- R ^z , -C _1-4 alkylene -OR ^z , C _3-6 cycloalkyl, C _2-4 alkenyl, C _2-4 alkynyl, phenyl, 3-8 membered heterocyclic group (e.g. 3-6 membered heterocyclyl) and 5-6 membered heteroaryl, wherein the alkyl, alkylene, cycloalkyl, alkenyl, alkynyl, phenyl, heterocyclyl and heteroaryl groups are each Optionally by one or more selected from F, Cl, -CN, =O, -OR ^z , -OH, -N(R ^z ) ₂ , -NHR ^z , -NH ₂ , C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl substituents are substituted; in some preferred embodiments, when Y is

And when R ^8a and R ^{8b are} not H at the same time, R ^{3 is} selected from H, F, Cl, -CF ₃ , -CHF ₂ , -CH ₂ F, -OH, -OCH ₃ , -CH ₂ CH=CH ₂ , -CH=CH ₂ , -CH ₂ C≡CH, -C=CH, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ NHCH ₃ , -CH ₂ R ^z , -CH ₂ -OR ^z , -CH ₂ -OH, -CN, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl,

Morpholinyl, tetrahydropyranyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl, pyrazolyl, thienyl and phenyl, wherein the pyridyl, pyrimidinyl, oxazolyl, thiazolyl, pyridyl The azole group, thienyl group and phenyl group are optionally selected by one or two selected from F, Cl, -CN, -OH, -OCH ₃ , -N(CH ₃ ) ₂ , -NH(CH ₃ ), -NH ₂ And pyrazolyl substituents; preferably, R ^{3 is} selected from H, F, Cl, -CF ₃ , -CHF ₂ , -OH, -OCH ₃ , -CH ₂ CH=CH ₂ , -CH=CH ₂ , -CH ₂ C=CH, -C=CH, -CH ₃ , -CH ₂ R ^z , -CH ₂ -OR ^z , -CH ₂ -OH, -CN, cyclopropyl, cyclobutyl, cyclopentyl , Morpholinyl, tetrahydropyranyl, pyridyl, pyrimidinyl, thiazolyl, pyrazolyl, thienyl and phenyl, wherein the pyridyl, pyrimidinyl, thiazolyl, pyrazolyl, thienyl and benzene The group is optionally substituted by one or two substituents selected from F, Cl, -CN, -OH, -OCH ₃ , -N(CH ₃ ) ₂ , -NH(CH ₃ ), -NH ₂ and pyrazolyl replace.

In some embodiments, ^{each occurrence of R z} is optionally selected from -CN, -NH-C _1-4 alkyl, C _1-4 alkyl, -NH-C _1-4 alkyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, phenyl and heteroaryl are each optionally substituted by one Or more selected from -NH ₂ , F, Cl, -CN, -CH ₃ , -CH ₂ CH ₃ , =O, -OH, -OC _1-3 alkyl, -CF ₃ , -CHF ₂ , phenyl And C _3-6 cycloalkyl substituents; preferably, R ^z is optionally selected from -CN, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocycle at each occurrence Group, phenyl group and 5-6 membered heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, phenyl group and heteroaryl group are each optionally selected from one or more groups -NH ₂ , F , Cl, -CN, -CH ₃ , -CH ₂ CH ₃ , =O, -OH, -OC _1-3 alkyl, -CF ₃ , -CHF ₂ , phenyl and C _3-6 cycloalkyl substitution In some preferred embodiments, R ^z is optionally selected from -CN, -CH ₃ , -CH ₂ CH ₃ , -NHCH ₃ , isopropyl, benzyl, -CF ₃ ,- CHF ₂ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, azetidine Alkyl, pyrazolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, furyl, pyrazinyl, pyrimidinyl, pyridyl and phenyl, wherein the piperazinyl, nitrogen Etanyl, pyrazolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, furanyl, pyrazinyl, pyrimidinyl, pyridyl and phenyl are each optionally substituted by one or Two substituents selected from F, Cl, -CN, -CH ₃ , -CH ₂ CH ₃ , -OH and -OCH ₃ ; preferably, R ^z is optionally selected from -CN, -CH each time it appears ₃ , -CH ₂ CH ₃ , isopropyl, benzyl, -CF ₃ , -CHF ₂ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperazinyl, oxetanyl Group, tetrahydropyranyl, pyrrolidinyl, azetidinyl, pyrazolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, furyl, pyrazinyl, pyrimidinyl , Pyridyl and phenyl, wherein the piperazinyl, azetidinyl, pyrazolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, furyl, pyrazinyl , Pyrimidinyl, pyridyl and phenyl are each optionally substituted with one or two substituents selected from F, Cl, -CN, -CH ₃ , -CH ₂ CH ₃ , -OH and -OCH ₃ .

In some embodiments, R ^8a and R ^8b are each independently selected from H, C _1-3 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, benzene ring, and 5-6 membered heteroaryl. Group, wherein the alkyl group, cycloalkyl group, heterocyclic group, heteroaryl group and benzene ring are each optionally selected by one or more selected from -NH ₂ , F, Cl, -CN, -CH ₃ ,- CH ₂ CH ₃ , =O, -OH, -OC _1-3 alkyl, -CF ₃ , -CHF ₂ and C _3-6 cycloalkyl substituents are substituted; in some preferred embodiments, R ^8a , R ^8b are each independently selected from H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CF ₃ , -CHF ₂ , -CH ₂ F, isopropyl, cyclopropyl, cyclobutyl, ring Oxyethyl, oxetanyl, phenyl, pyridyl, pyridazinyl, thienyl, thiazolyl, oxazolyl, furyl, pyrazolyl, imidazolyl, pyrrolyl and pyrimidinyl, wherein Phenyl, pyridyl, pyridazinyl, thienyl, thiazolyl, oxazolyl, furyl, pyrazolyl, imidazolyl, pyrrolyl and pyrimidinyl are each optionally selected from one or more -NH ₂ , Substituents of F, Cl, -CN, -CH ₃ , -CH ₂ CH ₃ , -OH, -OC _1-3 alkyl, -CF ₃ and -CHF ₂ ; preferably, R ^8a and R ^8b are each independent Selected from H, -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -CHF ₂ , isopropyl, cyclopropyl, cyclobutyl, oxirane, oxetanyl, phenyl, pyridine Group, pyridazinyl, thienyl, thiazolyl, oxazolyl, furyl, pyrazolyl, imidazolyl, pyrrolyl, wherein the phenyl, pyridyl, pyridazinyl, thienyl, thiazolyl, oxazole Group, furyl, pyrazolyl, imidazolyl, pyrrolyl are each optionally selected from one or more of -NH ₂ , F, Cl, -CN, -CH ₃ , -CH ₂ CH ₃ , -OH,- OC _1-3 alkyl, -CF ₃ and -CHF ₂ substituents; in a more preferred embodiment, R ^8a and R ^8b are each independently selected from H, -CH ₃ , -CH ₂ CH ₃ , isopropyl Group, cyclopropyl, -CH ₂ OCH ₃ , -CF ₃ , -CH ₂ F, -CHF ₂ , 2-methylfuryl, thiazolyl, pyridyl and pyrimidinyl, preferably, R ^8a and R ^8b are each Independently selected from H, -CH ₃ , isopropyl, cyclopropyl, -CF ₃ , 2-methylfuranyl, thiazolyl, pyridyl and pyrimidinyl; in a further preferred embodiment, R ^8a , R ^8b Each is independently selected from H, -CH ₃ , isopropyl and cyclopropyl.

且R ^8a和R ^8b同时为H时，R ³选自-CH ₂CH＝CH ₂、-CH＝CH ₂、-CH ₂C＝CH、-C＝CH、-CH ₂R ^z、-CH ₂-OR ^z、-CN、环丙基、环丁基、环丁烯基、环戊基、环己基和苯基，其中所述苯基任选地被一个或两个选自F、Cl、-CN、-OH、-OCH ₃、-N(CH ₃) ₂、-NH(CH ₃)、-NH ₂和吡唑基的取代基取代，R ^z在每次出现时任选自-CN、-CH ₃、-CH ₂CH ₃、-NHCH ₃、异丙基、苄基、-CF ₃、-CHF ₂、环丙基、环丁基、环戊基、环己基、吗啉基、哌嗪基、氧杂环丁烷基、四氢呋喃基、四氢吡喃基、吡咯烷基、氮杂环丁烷基、吡唑基、噻吩基、噻唑基、噁唑基、咪唑基、三氮唑基、呋喃基、吡嗪基、嘧啶基、吡啶基和苯基，其中所述的哌嗪基、氮杂环丁烷基、吡唑基、噻吩基、噻唑基、噁唑基、咪唑基、三氮唑基、呋喃基、吡嗪基、嘧啶基、吡啶基和苯基各自任选地被一个或两个选自F、Cl、-CN、-CH ₃、-CH ₂CH ₃、-OH和-OCH ₃的取代基取代。在一些优选的实施方案中，当Y为直接键或

且R ^8a和R ^8b同时为H时，R ³选自-CH ₂CH＝CH ₂、-CH＝CH ₂、-CH ₂C＝CH、-C＝CH、-CH ₂-O-苄基、-CH ₂OCH ₃、-CH ₂OC ₂H ₅、-CH ₂-O-CH(CH ₃) ₂、-CH ₂OCHF ₂、-CH ₂-环丙基、-CH ₂-环丁基、-CH ₂-环戊基、-CH ₂-环己基、-CH ₂-O-异丙基、-CN、-CH(NH ₂)-CH ₃、-CH ₂-NH-CH ₃、环丙基、环丁基、环丁烯基、环戊基、环己基、苯基、苄基、

In some embodiments, when Y is a direct bond or

And when R ^8a and R ^{8b are} both H, R ^{3 is} selected from -CH ₂ CH=CH ₂ , -CH=CH ₂ , -CH ₂ C=CH, -C=CH, -CH ₂ R ^z , -CH ₂ -OR ^z , -CN, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclohexyl and phenyl, wherein said phenyl is optionally selected from F, Cl,- CN, -OH, -OCH ₃ , -N(CH ₃ ) ₂ , -NH(CH ₃ ), -NH ₂ and pyrazolyl substituents are substituted, and R ^z is optionally selected from -CN,- CH ₃ , -CH ₂ CH ₃ , -NHCH ₃ , isopropyl, benzyl, -CF ₃ , -CHF ₂ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperazinyl , Oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, azetidinyl, pyrazolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, Furanyl, pyrazinyl, pyrimidinyl, pyridinyl and phenyl, wherein the piperazinyl, azetidinyl, pyrazolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazide The azole group, furyl group, pyrazinyl group, pyrimidinyl group, pyridyl group and phenyl group are each optionally selected by one or two selected from F, Cl, -CN, -CH ₃ , -CH ₂ CH ₃ , -OH and- Substituents of OCH ₃ are substituted. In some preferred embodiments, when Y is a direct bond or

And when R ^8a and R ^{8b are} both H, R ^{3 is} selected from -CH ₂ CH=CH ₂ , -CH=CH ₂ , -CH ₂ C=CH, -C=CH, -CH ₂ -O-benzyl, -CH ₂ OCH ₃ , -CH ₂ OC ₂ H ₅ , -CH ₂ -O-CH(CH ₃ ) ₂ , -CH ₂ OCHF ₂ , -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl,- CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, -CH ₂ -O-isopropyl, -CN, -CH(NH ₂ )-CH ₃ , -CH ₂ -NH-CH ₃ , cyclopropyl, Cyclobutyl, cyclobutenyl, cyclopentyl, cyclohexyl, phenyl, benzyl,

且R ^8a为H，R ^8b选自-CH ₃、-CH ₂CH ₃、异丙基、环丙基、-CH ₂OCH ₃、-CF ₃、-CH ₂F、-CHF ₂、2-甲基呋喃基、噻唑基、吡啶基和嘧啶基，R ³选自H、F、Cl、-CF ₃、-CHF ₂、-CH ₂F、-OH、-OCH ₃、-CH ₂CH＝CH ₂、-CH＝CH ₂、-CH ₂C＝CH、-C＝CH、-CH ₃、-CH ₂CH ₃、-CH ₂NHCH ₃、-CH ₂R ^z、-CH ₂-OR ^z、-CH ₂-OH、-CN、环丙基、环丁基、环戊基、氧杂环丁烷基、

吗啉基、四氢吡喃基、吡啶基、嘧啶基、噁唑基、噻唑基、吡唑基、噻吩基和苯基，R ^z在每次出现时任选自-CN、-CH ₃、-CH ₂CH ₃、-NHCH ₃、异丙基、苄基、-CF ₃、-CHF ₂、环丙基、环丁基、环戊基、环己基、吗啉基、哌嗪基、氧杂环丁烷基、四氢呋喃基、四氢吡喃基、吡咯烷基、氮杂环丁烷基、吡唑基、噻吩基、噻唑基、噁唑基、咪唑基、三氮唑基、呋喃基、吡嗪基、嘧啶基、吡啶基和苯基，其中所述的哌嗪基、氮杂环丁烷基、吡唑基、噻吩基、噻唑基、噁唑基、咪唑基、三氮唑基、呋喃基、吡嗪基、嘧啶基、吡啶基和苯基各自任选地被一个或两个选自F、Cl、-CN、-CH ₃、-CH ₂CH ₃、-OH和-OCH ₃的取代基取代。在一些优选的实施方案中，Y为

且R ^8a为H，R ^8b选自-CH ₃、-CH ₂CH ₃、异丙基、环丙基、-CH ₂OCH ₃、-CF ₃、-CH ₂F、-CHF ₂、2-甲基呋喃-5-基、噻唑-2-基、吡啶-3-基、嘧啶-2-基和嘧啶-5-基，R ₃选自H、F、Cl、-CF ₃、-CHF ₂、-CH ₂F、-OH、-OCH ₃、-CH ₂CH＝CH ₂、-CH＝CH ₂、-CH ₂C＝CH、-C＝CH、-CH ₃、-CH ₂CH ₃、-CH ₂NHCH ₃、-CH ₂-OH、-CN、环丙基、环丁基、环戊基、

In some embodiments, Y is

And R ^8a is H, R ^{8b is} selected from -CH ₃ , -CH ₂ CH ₃ , isopropyl, cyclopropyl, -CH ₂ OCH ₃ , -CF ₃ , -CH ₂ F, -CHF ₂ , 2-methan Furanyl, thiazolyl, pyridyl and pyrimidinyl, R ^{3 is} selected from H, F, Cl, -CF ₃ , -CHF ₂ , -CH ₂ F, -OH, -OCH ₃ , -CH ₂ CH=CH ₂ , -CH=CH ₂ , -CH ₂ C=CH, -C=CH, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ NHCH ₃ , -CH ₂ R ^z , -CH ₂ -OR ^z , -CH ₂ -OH, -CN, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl,

Morpholinyl, tetrahydropyranyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl, pyrazolyl, thienyl and phenyl, R ^z is optionally selected from -CN, -CH ₃ , -CH ₂ CH ₃ , -NHCH ₃ , isopropyl, benzyl, -CF ₃ , -CHF ₂ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperazinyl, oxa Cyclobutanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, azetidinyl, pyrazolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, furanyl, Pyrazinyl, pyrimidinyl, pyridyl and phenyl, wherein the piperazinyl, azetidinyl, pyrazolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, Furanyl, pyrazinyl, pyrimidinyl, pyridinyl and phenyl are each optionally selected from one or two of F, Cl, -CN, -CH ₃ , -CH ₂ CH ₃ , -OH and -OCH ₃ Substituents are substituted. In some preferred embodiments, Y is

And R ^8a is H, R ^{8b is} selected from -CH ₃ , -CH ₂ CH ₃ , isopropyl, cyclopropyl, -CH ₂ OCH ₃ , -CF ₃ , -CH ₂ F, -CHF ₂ , 2-methan Furan-5-yl, thiazol-2-yl, pyridin-3-yl, pyrimidin-2-yl and pyrimidin-5-yl, R _{3 is} selected from H, F, Cl, -CF ₃ , -CHF ₂ ,- CH ₂ F, -OH, -OCH ₃ , -CH ₂ CH=CH ₂ , -CH=CH ₂ , -CH ₂ C=CH, -C=CH, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ NHCH ₃ , -CH ₂ -OH, -CN, cyclopropyl, cyclobutyl, cyclopentyl,

In some embodiments, R ^8a and R ^8b together with the atoms (or direct bonds) to which they are attached form a C _3-8 hydrocarbon ring and a 3-6 membered heterocyclic ring, wherein the hydrocarbon ring and the heterocyclic ring are each optionally By one or more selected from -NH ₂ , F, Cl, -CN, -CH ₃ , -CH ₂ CH ₃ , =O, -OH, -OC _1-3 alkyl, -CF ₃ and -CHF ₂ Substituents are substituted; in some preferred embodiments, R ^8a and R ^8b together with the atoms (or direct bonds) to which they are attached form a cyclopropane, cyclobutane, cyclopentane, or 3-6 membered heterocycle; in some more In a preferred embodiment, R ^8a and R ^8b together with the atoms (or direct bonds) to which they are attached form cyclopropane, cyclobutane, cyclopentane or oxetane.

In some embodiments, g is 0 or 2.

In some embodiments, n is 0, 1, 2, or 3; in some preferred embodiments, n is 2 or 3; in some more preferred embodiments, n is 2.

In some embodiments, the compound of formula (I) of the present invention has the structure of formula (II):

Wherein, each group is as defined above.

In some preferred embodiments, the compound of formula (I) of the present invention has the structure of formula (III):

Wherein, each group is as defined above.

Those skilled in the art should understand that the present invention covers compounds obtained by any combination of the various embodiments. Embodiments obtained by combining technical features or preferred technical features in one embodiment with technical features or preferred technical features in other embodiments are also included in the scope of the present invention.

In some preferred embodiments, the present invention provides compounds or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotopically labeled compounds, metabolites Or prodrugs, wherein the compound is selected from:

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I)-(III) (ie formula (I), (II) or (III), the same below) or a pharmaceutically acceptable compound thereof Salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotopically-labeled compounds, metabolites or prodrugs and one or more pharmaceutically acceptable carriers.

In yet another aspect, the present invention provides compounds of formula (I)-(III) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotopes thereof Use of the labeled compound, metabolite or prodrug or the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention or treatment of SHP2 phosphatase-related diseases.

In a further aspect, the present invention provides a method for preventing or treating SHP2 phosphatase-related diseases, the method comprising administering a compound of formula (I)-(III) or a pharmaceutically acceptable compound thereof to an individual in need Salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotopically-labeled compounds, metabolites or prodrugs or the pharmaceutical composition of the present invention.

In another aspect, the present invention provides compounds of formula (I)-(III) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, isotopes thereof The labeled compound, metabolite or prodrug or the pharmaceutical composition of the present invention is used to prevent or treat SHP2 phosphatase related diseases.

In some embodiments, the SHP2 phosphatase-related disease is a disease that is sensitive or responsive to SHP2 phosphatase inhibition. In a further embodiment, the SHP2 phosphatase-related disease is a tumor-like disease, including but not limited to solid and hematological malignancies.

In another aspect, the present invention further provides compounds of formula (I)-(III) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, Isotope-labeled compounds, metabolites or prodrugs or the pharmaceutical composition of the present invention are combined with other treatment methods for the prevention or treatment of SHP2 phosphatase-related diseases, and the additional treatment methods include but are not limited to: radiotherapy, Chemotherapy, immunotherapy or a combination thereof.

Preparation method of the present invention

Another aspect of the present invention also relates to a method for preparing the compound of the present invention, the method comprising:

1. Reacting a compound of formula S-1 with a compound of formula S-2 to generate a compound of M-1;

2. Reacting the compound of formula M-1 with the compound of formula S-3 to produce the compound of formula M-2;

3. Deprotection and functional group conversion of the compound of formula M-2 to produce the compound of formula (I);

Wherein, LG ¹ and LG ² each independently represent a halogen leaving group, or a C _1-6 alkylsulfonate leaving group optionally substituted by halogen (for example, a trifluoromethanesulfonate leaving group) Group); In addition, LG ² can also be a hydroxyl group;

R ^c represents H or a leaving group;

R ^f is a hydroxymethyl group or a functional group that can be converted into a hydroxymethyl group through one or more reactions;

PG ¹ represents a protecting group for H or an amino group (for example, methyl, tert-butoxycarbonyl, tert-butyldimethylsilyl, triisopropylsilyl, benzyl and methoxymethyl);

The remaining groups are as defined above.

In some preferred embodiments, LG ¹ represents halogen, such as iodine or bromine;

In some preferred embodiments, LG ² represents halogen (such as bromine or chlorine) or hydroxyl;

In some preferred embodiments, R ^{c is} selected from H, halogen, boronic acid group, boronic acid ester group, substituted silicon group, substituted metal group, or C _1-6 alkyl sulfonic acid optionally substituted by halogen Ester group. In a more preferred embodiment, R ^c is a boronic acid group or a boronic acid ester group.

In some preferred embodiments, R ^f represents H, F, Cl, Br, I, protected or unprotected hydroxymethyl or ester groups (for example -COOC ₂ H ₅ );

In step 1, the reaction is carried out in the presence of a metal catalyst. In some preferred embodiments, the metal catalyst is a metal palladium catalyst or a copper catalyst, such as tetrakis(triphenylphosphine)palladium, palladium acetate, tris(dibenzylideneacetone)dipalladium, [1,1'-bis(di Phenylphosphino)ferrocene]palladium dichloride, 1,2-bis(diphenylphosphineethane)palladium dichloride and bis(triphenylphosphine)palladium dichloride or cuprous iodide, etc.

In step 2, the reaction is carried out in the presence of a base and/or a metal catalyst. In some preferred embodiments, the base is an inorganic base, such as potassium phosphate. In other preferred embodiments, the metal catalyst is a metal palladium catalyst, such as palladium tetrakistriphenylphosphine, palladium acetate, tris(dibenzylideneacetone)dipalladium, 1,1′-bis(diphenylphosphine)dipalladium Palladium ferrocene chloride, 1,2-bis-diphenylphosphine ethane palladium chloride, and bis(triphenylphosphine) palladium dichloride, etc.

Alternatively, the reaction is carried out in the presence of a condensation reagent and a base. In some preferred embodiments, the base is an organic base, such as DBU. In other preferred embodiments, the condensation reagent is BOP, HATU or PyBOP, etc., preferably BOP.

In step 3, the method of functional group conversion includes but is not limited to the following reactions: 1) reduction reaction (reagents used such as LiBH ₄ , DIBAL-H); 2) metal-catalyzed coupling reaction; 3) hydrolysis reaction; The deprotection reaction can be carried out under acid or catalytic hydrogenolysis conditions. In some preferred embodiments, the acid is an organic acid, preferably trifluoroformic acid. In other preferred embodiments, the metal catalyst used in method 2) is palladium on carbon or palladium hydroxide on carbon.

The starting materials of the preparation method of the present invention can be from commercial sources or can be prepared according to known methods.

Those skilled in the art should understand that one or more steps in the above route can be omitted according to the desired product structure. Those skilled in the art can also appropriately adjust the order of the reaction steps as needed, and add or omit the protection/deprotection reaction steps.

The compounds of formula (II) and formula (III) of the present invention can be synthesized by similar methods with reference to the above-mentioned embodiments.

Pharmaceutical compositions, preparations and kits

The present invention also provides a pharmaceutical composition comprising a compound of formula (I)-(III) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvent Compounds (such as hydrates), isotopically-labeled compounds, metabolites or prodrugs, and one or more pharmaceutically acceptable carriers, and may optionally further include one or more for the treatment of SHP2 phosphatase-related The second therapeutic agent for the disease.

A further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, which method comprises combining a compound of formula (I)-(III) or a pharmaceutically acceptable salt, ester, or stereoisomer thereof , Tautomers, polymorphs, solvates, isotopically-labeled compounds, metabolites or prodrugs, or their mixtures in combination with one or more pharmaceutically acceptable carriers. The method may further include mixing one or more second therapeutic agents for the treatment of SHP2 phosphatase related diseases.

The pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, and mineral oil. Oil, sesame oil, etc. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. It is also possible to use physiological saline and aqueous glucose and glycerol solutions as liquid carriers, especially for injections. Pharmaceutically acceptable carriers include pharmaceutical excipients. Suitable pharmaceutical excipients include, but are not limited to, starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol , Water, ethanol, etc. The composition may also contain a small amount of wetting agents, emulsifiers, lubricants, stabilizers or pH buffering agents, etc. as needed. Oral preparations may contain standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).

The pharmaceutical composition can be administered in any form as long as it achieves prevention, alleviation, prevention, or cure of symptoms in human or animal patients. For example, various suitable dosage forms can be prepared according to the route of administration.

When administered orally, the pharmaceutical composition can be made into any orally acceptable preparation form, including but not limited to tablets, capsules, granules, pills, syrups, oral solutions, oral suspensions and oral emulsions Wait. When applied transdermally or topically, the pharmaceutical composition can be made into an appropriate ointment, lotion or liniment form, wherein the active ingredient can be suspended or dissolved in one or more carriers.

The pharmaceutical composition can also be administered in the form of injection, including injection, sterile powder for injection and concentrated solution for injection.

In other embodiments, the administration of the compound or pharmaceutical composition of the present invention may be combined with another treatment method. The additional treatment method can be selected from, but not limited to: radiotherapy, chemotherapy, immunotherapy, or a combination thereof. The compound or pharmaceutical composition of the present invention may be administered before, during, or after the implementation of the additional treatment method. The implementation of other treatment methods and the administration of the compound or pharmaceutical composition of the present invention can be carried out simultaneously, or in close connection before and after, or can be carried out at intervals of time. The method and order of administration can be selected according to the specific treatment situation. Adjustment.

Another aspect of the present invention also relates to a pharmaceutical preparation comprising a compound of formula (I)-(III), its pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph As active ingredients, solvates, isotopically-labeled compounds, metabolites or prodrugs, or mixtures thereof, or the pharmaceutical composition of the present invention. In some embodiments, the form of the formulation is a solid formulation, a semi-solid formulation, a liquid formulation, or a gaseous formulation.

A further object of the present invention is to provide a product, for example, in the form of a kit. The articles used herein are intended to include, but are not limited to, kits and packaging. The article of the present invention comprises: (a) a first container; (b) a pharmaceutical composition located in the first container, wherein the composition comprises: a first therapeutic agent, including: a compound of formula (I)-(III) Or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled compound, metabolite or prodrug thereof, or a mixture thereof; and (c ) An optional package insert stating that the pharmaceutical composition can be used to treat tumor conditions (as defined above). In other embodiments, the package insert states that the pharmaceutical composition can be used in combination with a second therapeutic agent to treat tumor conditions.

The package insert is a trademark, label, label, etc., which enumerate information related to the pharmaceutical composition in the first container. The information listed is usually determined by the regulatory agency (such as the U.S. Food and Drug Administration) that governs the area where the product is to be sold. Preferably, the package insert specifically lists the indications for which the pharmaceutical composition is approved. The package insert can be made of any material, and the information contained in or on the package can be read from the material. Preferably, the package instruction is a printable material (for example, paper, plastic, cardboard, foil, adhesive paper or plastic, etc.), on which the required information can be formed (for example, printed or applied).

Treatment methods and uses

Another object of the present invention is to provide a method for preventing or treating SHP2 phosphatase-related diseases, the method comprising administering to an individual in need an effective amount of a compound of formula (I)-(III) or its pharmaceutically acceptable Accepted salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites or prodrugs, or mixtures thereof, or pharmaceutical compositions of the present invention.

According to some embodiments of the present invention, the SHP2 phosphatase-related disease is a disease that is sensitive or responsive to SHP2 phosphatase inhibition. In a further embodiment, the SHP2 phosphatase-related disease is a tumor-like disease, including but not limited to solid and hematological malignancies. In a further embodiment, the tumor-like disorders include but are not limited to breast cancer, colorectal cancer, colon cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, and bronchioloalveolar cancer) and prostate cancer, and cholangiocarcinoma , Bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulvar cancer, and leukemia ( Including chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) and chronic myelogenous leukemia (CML)), multiple myeloma and lymphoma.

In some preferred embodiments, the disease is a solid tumor, such as breast cancer, colorectal cancer, colon cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioloalveolar cancer) and prostate cancer, and cholangiocarcinoma , Bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulvar cancer. In a further preferred embodiment, the compound of the present invention can be used in combination with radiochemotherapy or immunotherapy to prevent or treat cancer.

The dosage regimen can be adjusted to provide the best desired response. For example, when the medicine is administered in the form of injection, it can be administered as a single bolus injection, bolus injection, and/or continuous infusion, and so on. For example, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgent need of the treatment situation. It should be noted that the dose value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. Generally, the dose of treatment varies, depending on the considerations, such as: the age, gender and general health of the patient to be treated; the frequency of treatment and the nature of the desired effect; the degree of tissue damage; the symptomatic Duration; and other variables that can be adjusted by individual physicians. It should be further understood that for any particular individual, the specific dosing regimen should be adjusted over time according to the needs of the individual and the professional judgment of the person administering the composition or supervising the administration of the composition. The administration amount and administration schedule of the pharmaceutical composition can be easily determined by a person of ordinary skill in the clinical field. For example, the composition or compound of the present invention may be administered in divided doses from 4 times a day to once every 3 days, and the dosage may be, for example, 0.01 to 1000 mg/time. The required dose can be administered in one or more times to obtain the desired result. The pharmaceutical composition according to the present invention can also be provided in a unit dosage form.

Beneficial effect

The present invention provides a new type of highly active SHP2 inhibitor, which can achieve at least one of the following technical effects:

(1) High inhibitory activity on SHP2 phosphatase.

(2) Excellent physical and chemical properties (such as solubility, physical and/or chemical stability).

(3) Excellent pharmacokinetic properties (such as good bioavailability, appropriate half-life and duration of action).

(4) Excellent safety (lower toxicity and/or fewer side effects, wider therapeutic window), etc.

detailed description

Example

Examples and test examples are listed below to further illustrate the present invention in detail, but they do not limit the scope of the present invention, and changes can be made without departing from the scope of the present invention.

Mass spectrometry (MS) was measured using Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.

Preparative high performance liquid chromatography (HPLC) uses Shimadzu LC-8A preparative liquid chromatograph (YMC, ODS, 250×20mm chromatographic column).

Thin-layer chromatography purification uses GF 254 (0.4～0.5nm) silica gel plate produced in Yantai.

The reaction is monitored by thin-layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS). The developing solvent systems used include but are not limited to: dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and petroleum For the ether and ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, or triethylamine is added for adjustment.

Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as the stationary phase. The eluent system includes but is not limited to the dichloromethane and methanol system and the n-hexane and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

If there are no special instructions in the examples, the reaction temperature is room temperature (20°C to 30°C).

Unless otherwise specified, the reagents used in the examples were purchased from companies such as Acros Organics, Aldrich Chemical Company, Nanjing Yaoshi Technology, or Shanghai Shuya Pharmaceutical Technology.

The abbreviations used in this article have the following meanings:

Example 1: Preparation of ethyl 6-(2,3-dichlorophenyl)-3-hydroxy-5-methylpyrazine-2-carboxylate (IM-1)

Step 1: Preparation of ethyl 3-hydroxy-5-methylpyrazine-2-carboxylate (1-2)

1,2-Propane diamine (23.4 g, 315 mmol) was dissolved in ethanol (500 mL), cooled to 0° C., then diethyl carbonylmalonate (50 g, 287 mmol) was slowly added dropwise, and the addition was completed within 30 minutes. Stir at this temperature for 1 hour, and then raise the temperature to 85° C. to react for 24 hours. After the reaction, it was concentrated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-50%) to obtain a solid, which was slurried with MTBE (100 mL) and filtered to obtain compound 1-2 (14g, yield 27%) .

Step 2: Preparation of ethyl 6-bromo-3-hydroxy-5-methylpyrazine-2-carboxylate (1-3)

Dissolve 1-2 (18.0g, 98.8mmol) in dichloromethane (150mL), slowly add N-bromosuccinimide (17.6g, 98.8mmol) under ice bath conditions, move to room temperature and react for 2 hours . After the reaction, it was concentrated and purified by silica gel column chromatography (dichloromethane/petroleum ether=0-50%) to obtain the title compound (21.2 g, yield 82%).

The third step: Preparation of ethyl 6-(2,3-dichlorophenyl)-3-hydroxy-5-methylpyrazine-2-carboxylate (IM-1)

Combine 1-3 (4.1g, 15.3mmol), 2,3-dichlorophenylboronic acid (4.39g, 22.9mmol), potassium carbonate (10.6g, 76.6mmol) and bistriphenylphosphorus palladium dichloride (1.08g , 1.53mmol) was added to a mixed solvent of toluene (120mL) and ethanol (180mL), evacuated, replaced with nitrogen three times, and the system was heated to 90°C for 18 hours. After the raw materials have reacted, they are cooled to room temperature, concentrated to remove a large amount of ethanol and toluene, water is added, and the pH of the system is adjusted to about 2 with 3N HCl. The reaction solution was filtered through Celite pad, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-30%) to obtain the title compound (2.9g, yield) Rate 57%).

Example 2: (R)-4-(1-aminoethyl)-1-(5-(2,3-dichlorophenyl)-3-(hydroxymethyl)-6-methylpyrazine-2 -Yl)piperidine-4-carbonitrile (TM1) preparation

The first step: Preparation of (S, E)-N-ethylene-2-methylpropyl-2-sulfinamide (2-2)

Dissolve (S)-tert-butylsulfinamide (0.50g, 4.13mmol) in dry THF (15mL), add acetaldehyde (363mg, 8.25mmol, 1.6mL) and tetraisopropyl titanate (2.34g) , 8.25mmol, 2.4mL), replaced with nitrogen three times, and reacted at 25°C for 18 hours. After the reaction is complete, add water to quench the reaction, extract three times with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (ethyl acetate/petroleum ether=0-30%) to obtain the title compound (0.50g, yield 82%).

The second step: 4-cyano-4-((R)-1-((S)-1,1-dimethylethylsulfonamido)ethyl)piperidine-1-carboxylic acid tert-butyl ester (2-3) Preparation

4-Cyanopiperidine-1-carboxylic acid tert-butyl ester (3.86g, 18.3mmol) was dissolved in THF (15mL), protected by nitrogen, cooled to -78°C, and LiHMDS (3.38g, 20.2mmol, 20mL) was added dropwise ), react at this temperature for 30 minutes, then add 2-2 (0.90 g, 6.11 mmol), continue the reaction at this temperature for 2 hours, and then slowly rise to room temperature for 5 hours. After the reaction, the reaction was quenched by adding saturated ammonium chloride, extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-50%) ) To obtain the title compound (1.00 g, yield 46%).

The third step: Preparation of (R)-4-(1-aminoethyl)piperidine-4-carbonitrile hydrochloride (2-4)

Dissolve 2-3 (0.90g, 2.52mmol) in HCl (4M in 1,4-dioxane, 5mL), and react at 25°C for 2 hours. After the reaction, it was directly concentrated to obtain the title compound (0.45 g, yield 94%).

The fourth step: (R)-3-(4-(1-aminoethyl)-4-cyanopiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methyl Preparation of ethyl pyrazine-2-carboxylate (2-5)

Dissolve IM-1 (100mg, 0.31mmol) in DMF (3mL), add 2-4 (56.2mg, 0.37mmol), Carter condensing agent (274.4mg, 0.62mmol) and DBU (232.9mg, 1.53mmol) in sequence , Replaced with nitrogen three times, heated to 25°C for 2 hours. After the reaction, it was concentrated and purified by silica gel column chromatography (ethyl acetate/petroleum ether=0-50%) to obtain the title compound (50 mg, yield 35%).

The fifth step: (R)-4-(1-aminoethyl)-1-(5-(2,3-dichlorophenyl)-3-(hydroxymethyl)-6-methylpyrazine-2 -Yl)piperidine-4-carbonitrile (TM1) preparation

2-5 (50.0 mg, 0.11 mmol) was dissolved in THF (3 mL), protected by nitrogen, LiBH4 (1.62 mmol, 0.5 mL) was added at 0°C, and the mixture was moved to room temperature to react for 1 hour. After the reaction, the reaction was quenched by adding 2N dilute hydrochloric acid and concentrated. The crude product was prepared by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous formic acid) to obtain the title compound (24.1 mg, yield 52%).

MS m/z(ESI): 420.1[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.16 (s, 1H), 7.74 (m, 1H), 7.57-7.30 (m, 2H), 5.36 (s, 1H), 4.51 (s, 2H), 3.99-3.84(m, 2H), 3.07-2.86(m, 3H), 2.21(s, 3H), 2.17-2.09(m, 1H), 1.97-1.87(m, 1H), 1.83-1.65(m, 2H) ), 1.25-1.12 (d, J=6.0Hz, 3H).

Example 3: (3-(4-(aminomethyl)-4-((benzyloxy)methyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)-5- Preparation of methylpyrazin-2-yl)methanol (TM2)

Step 1: Synthesis of tert-butyl 4-((benzyloxy)methyl)-4-cyanopiperidine-1-carboxylate (3-2)

Dissolve 4-cyanopiperidine-1-carboxylic acid tert-butyl ester (8.73g, 41.5mmol) in dry THF (150mL), cool to -78°C under nitrogen protection, and slowly add LDA (2M in THF, 21mL), after the addition, react at this temperature for 1 hour. After benzyl chloromethyl ether (5g, 31.9mmol) was dissolved in dry THF (20mL), it was slowly added to the solution. After the addition, the temperature was raised to room temperature and reacted for 2 hours. After the reaction was completed, 100 mL saturated sodium bicarbonate solution was added to quench the reaction, extracted with dichloromethane (100 mL×3), the combined organic phase was washed with saturated brine (100 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and reduced The solvent was evaporated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 3-2 (6 g, yield 86%).

Step 2: Synthesis of 4-((benzyloxy)methyl)piperidine-4-carbonitrile (3-3)

Dissolve 3-2 (100 mg, 0.30 mmol) in dichloromethane (10 mL), add TFA (10 mL), and stir at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated to dryness under reduced pressure to obtain compound 3-3 trifluoroacetate (65 mg, yield 62%).

The third step: 3-(4-((benzyloxy)methyl)-4-cyanopiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazine Synthesis of -2-carboxylic acid ethyl ester (3-4)

Except that 3-3 was used in this step instead of 2-4 in the fourth step in Example 2, a method similar to that described in the fourth step in Example 2 was used to synthesize 3-4.

The fourth step: (3-(4-(aminomethyl)-4-((benzyloxy)methyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)-5- Synthesis of methylpyrazin-2-yl)methanol (TM2)

Dissolve 3-4 (20.1mg, 0.037μmol) in dichloromethane (10mL), slowly add DIBAL-H (1M in hexane, 0.5mL) under ice-bath conditions, and slowly warm up to room temperature after the addition is complete 1 hour. After the completion of the reaction, a saturated sodium bicarbonate solution (10 mL) was added to the reaction solution, and after thorough stirring, a solid precipitated, filtered, and the filtrate was separated. The aqueous phase was extracted with dichloromethane (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was subjected to reverse-phase HPLC (mobile phase A: acetonitrile, mobile phase B: The title compound (3.24 mg, yield 17%) was prepared by 0.05% formic acid aqueous solution).

MS m/z(ESI): 501.1[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 8.54 (s, 1H), 7.63 (dd, J=7.6, 1.5 Hz, 1H), 7.44-7.28 (m, 7H), 4.64 (s, 2H), 4.58 (s, 2H), 3.57(s, 2H), 3.43-3.38(m, 2H), 3.29-3.21(m, 2H), 2.92(s, 2H), 2.24(s, 3H), 1.78-1.66(m , 4H).

Example 4: (3-(4-(Aminomethyl)-4-(methoxymethyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methyl Preparation of pyrazin-2-yl)methanol (TM3)

Step 1: Synthesis of tert-butyl 4-cyano-4-(hydroxymethyl)piperidine-1-carboxylate (4-1)

Dissolve 3-2 (2g, 6.05mmol) in EtOH (50mL), add 10% palladium on carbon (400mg), and heat to 70°C for 6 hours in a hydrogen environment. After the reaction was completed, it was filtered, the filtrate was concentrated, and the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 4-1 (550 mg, yield 38%).

Step 2: Synthesis of tert-butyl 4-cyano-4-(methoxymethyl)piperidine-1-carboxylate (4-2)

Dissolve 4-1 (200mg, 0.83mmol) in dry THF (10mL), add NaH (166mg, 4.16mmol, 60%) under ice bath, and stir at this temperature for 1 hour, then add methyl iodide (236mg , 1.66mmol), after the addition, warm up to room temperature and react for 2 hours. After the completion of the reaction, the reaction was quenched with 10 mL of water, extracted with dichloromethane (10 mL×3), the combined organic phase was washed with saturated brine (10 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. Dry solvent gave compound 4-2 (110 mg, yield 52%).

Steps 3 to 5: (3-(4-(aminomethyl)-4-(methoxymethyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)- Synthesis of 5-methylpyrazin-2-yl)methanol (TM3)

Except that 4-2 was used in the third step instead of 3-2 in the second step in Example 3, TM3 was synthesized by a method similar to that described in the second to fourth steps in Example 3.

MS m/z(ESI): 425.1[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 8.55 (s, 1H), 7.63 (dd, J = 7.6, 1.2 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.34 (dd, J =7.6, 1.2Hz, 1H), 4.66 (s, 2H), 3.52 (s, 2H), 3.48-3.39 (m, 5H), 3.40-3.33 (m, 2H), 2.96 (s, 2H), 2.25 ( s, 3H), 1.84-1.61 (m, 4H).

Example 5: (3-(4-(aminomethyl)-4-(ethoxymethyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methyl Preparation of pyrazin-2-yl)methanol (TM4)

Except that ethyl iodide was used in the first step of this example instead of methyl iodide in the second step of Example 4, TM4 was synthesized by a method similar to that described in the second to fifth steps of Example 4.

MS m/z(ESI): 439.1[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 8.54 (s, 1H), 7.64 (dd, J = 7.6, 1.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.34 (dd, J =7.6, 1.2Hz, 1H), 4.66 (s, 2H), 3.60-3.56 (m, 4H), 3.51-3.43 (m, 2H), 3.40-3.33 (m, 2H), 3.05 (s, 2H), 2.25(s, 3H), 1.82-1.69(m, 4H), 1.24(t, J=6.8Hz, 3H).

Example 6: (3-(4-(aminomethyl)-4-((2-chlorothiazol-4-yl)methyl)piperidin-1-yl)-6-(2,3-dichlorobenzene (Yl)-5-methylpyrazin-2-yl)methanol (TM5) preparation

Step 1: Preparation of (2-chlorothiazol-4-yl)methanol (6-2)

Dissolve ethyl 2-chlorothiazole-4-carboxylate (2.0g, 10.4mmol) in dichloromethane (50mL), cool to 0°C and slowly add DIBAL-H (2M in hexane, 10mL), after the addition is complete React at this temperature for 30 minutes. After the reaction was completed, saturated sodium bicarbonate solution (100 mL) was slowly added to the reaction solution to quench the reaction, extracted with dichloromethane (100 mL×3), and the organic phases were combined and washed with saturated sodium chloride solution (100 mL×2). The phase was dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 6-2 (1.2 g, yield 77%).

Step 2: Preparation of (2-chlorothiazol-4-yl)methanesulfonate (6-3)

Dissolve 6-2 (1.2g, 8.02mmol) in dichloromethane (20mL), add triethylamine (0.81g, 8.02mmol), slowly add methanesulfonyl chloride (0.92g, 8.02mmol) under stirring, After the addition is complete, stir at room temperature for 30 minutes. After the reaction is complete, add water (20 mL) to the reaction solution to quench the reaction, stir thoroughly and separate the layers. The organic phase is dried with anhydrous sodium sulfate and filtered, and the solvent is evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 6-3 (1.3 g, yield 71%).

The third step: Preparation of 1-tert-butyl 4-ethyl 4-((2-chlorothiazol-4-yl)methyl)piperidine-1,4-dicarboxylate (6-4)

Under the protection of nitrogen, dissolve ethyl N-tert-butoxycarbonyl-4-piperidinecarboxylate (0.28g, 1.09mmol) in anhydrous THF (20mL), cool to -78℃, and slowly add LDA (0.6mL , 2M in THF), keep stirring for 0.5 hours after adding. 6-3 (0.19g, 1.12mmol) was slowly added to the reaction solution, and after the addition, the temperature was naturally raised to room temperature and reacted for 4 hours. After the reaction was completed, a saturated ammonium chloride solution was added to the reaction solution. After thorough stirring, an appropriate amount of DCM was added, and the layers were separated after thorough stirring. The organic phase was dried and concentrated and purified by column chromatography to obtain compound 6-4 (0.21g, yield 50 %).

Step 4: Preparation of 1-(tert-butoxycarbonyl)-4-((2-chlorothiazol-4-yl)methyl)piperidine-4-carboxylic acid (6-5)

6-4 (0.15 g, 0.38 mmol) was dissolved in 10 mL of methanol, sodium hydroxide aqueous solution (5 mL, 1 M) was added, and the reaction was heated to 60° C. for 4 hours. After the reaction is completed, cool to 0°C, adjust the pH to 4～5 with 2M dilute hydrochloric acid, and then add DCM for extraction. The organic phase is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated and purified by column chromatography to obtain compound 6-5( 100mg, yield 72%).

Step 5: Preparation of tert-butyl 4-carbamoyl-4-((2-chlorothiazol-4-yl)methyl)piperidine-1-carboxylate (6-6)

Dissolve 6-5 (100mg, 0.28mmol), ammonium chloride (29.7mg, 0.55mmol), EDCI (63.8mg, 0.33mmol) and HOBT (44.9mg, 0.33mmol) in dichloromethane (10mL), and then DIPEA (107.4 mg, 0.83 mmol) was added, and after the addition, the mixture was stirred at room temperature for 4 hours. After the reaction was completed, water (20 mL) was added, and the mixture was stirred thoroughly and then separated. The aqueous phase was extracted with dichloromethane (20 mL). The combined organic phase was washed with saturated brine (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and reduced. The solvent was evaporated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 6-6 (80 mg, yield 80%).

Step 6: Preparation of tert-butyl 4-((2-chlorothiazol-4-yl)methyl)-4-cyanopiperidine-1-carboxylate (6-7)

6-6 (40.1 mg, 0.11 mmol) was added to dichloromethane (10 mL), TEA (45.0 mg, 444.60 μmol) was added, and then TFAA (70.04 mg, 333.45 μmol) was added slowly, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, water (20 mL) was added, and the mixture was stirred thoroughly and then separated. The aqueous phase was extracted with dichloromethane (20 mL). The combined organic phase was washed with saturated brine (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and reduced. The solvent was evaporated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 6-7 (30 mg, yield 78%).

Steps 7 to 9: (3-(4-(aminomethyl)-4-((2-chlorothiazol-4-yl)methyl)piperidin-1-yl)-6-(2,3 -Dichlorophenyl)-5-methylpyrazin-2-yl)methanol (TM5)

Except that 6-7 was used in the seventh step instead of 3-2 in the second step in Example 3, TM5 was synthesized by a method similar to that described in the second to fourth steps in Example 3.

MS m/z(ESI): 512.1[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 7.63 (dd, J = 7.6, 1.2 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.35 (dd, J = 7.6, 1.2 Hz, 1H ), 7.28(s, 1H), 4.66(s, 2H), 3.45-3.42(m, 4H), 2.93(s, 2H), 2.68(s, 2H), 2.25(s, 3H), 1.68-1.64( m, 4H).

Example 7: 4-(Aminomethyl)-1-(5-(2,3-dichlorophenyl)-3-(hydroxymethyl)-6-methylpyrazin-2-yl)piperidine- Preparation of 4-nitrile (TM6)

The first step: the preparation of 4-(aminomethyl)-4-cyanopiperidine-1-carboxylic acid benzyl ester (7-1)

Benzyl 4-cyanopiperidine-1-carboxylate (7-0) (2g, 8.19mmol) was dissolved in tetrahydrofuran (30mL), the temperature was reduced to -78°C, and LiHMDS (1M in THF, 13.10mL) was added dropwise, After reacting at -78°C for 1 hour, add paraformaldehyde (516.30mg, 17.2mmol), naturally increase the temperature to 25°C and react for 16 hours. After LC-MS detects the reaction is complete, add saturated ammonium chloride solution, extract with ethyl acetate, and combine the organic phases. After drying and concentrating, 7-1 was prepared by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% formic acid aqueous solution) (1.4 g, yield 62%).

Step 2: Preparation of 4-(((tert-butoxycarbonyl)amino)methyl)-4-cyanopiperidine-1-carboxylic acid benzyl ester (7-2)

Dissolve 7-1 (5.58g, 20.4mmol) in dichloromethane (100mL), add di-tert-butyl dicarbonate (6.68g, 30.6mmol) and triethylamine (4.13g, 40.8mmol), react at 25°C for 1.5 After hours, LC-MS detected that the reaction was complete, water was added to the reaction solution, extracted with dichloromethane, the organic phases were combined, dried and concentrated to obtain 7-2 (7.6 g, yield 99%), which was directly used in the next reaction.

The third step: preparation of ((4-cyanopiperidin-4-yl)methyl) tert-butyl carbamate (7-3)

Dissolve 7-2 (1g, 2.68mmol) in methanol (70mL), add 10% Pd/C (0.2g), replace with hydrogen, and react at 25℃ for 30 minutes under the protection of a hydrogen balloon. LC-MS detects that the reaction is complete The reaction solution was filtered through Celite, and the filtrate was concentrated to obtain 7-3 (0.64 g, yield 99%), which was directly used in the next reaction.

The fourth step: 3-(4-(((tert-butoxycarbonyl)amino)methyl)-4-cyanopiperidin-1-yl)-6-(2,3-dichlorophenyl)-5- Preparation of ethyl methylpyrazine-2-carboxylate (7-4)

Dissolve IM-1 (200mg, 0.61mmol) in DMF (6mL), add 7-3 (175mg, 0.73mmol), BOP (407mg, 0.92mmol) and DBU (196mg, 1.22mmol), react at 25°C for 1 hour, After the completion of the reaction detected by LC-MS, water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, dried and concentrated, and purified by preparative TLC (dichloromethane: methanol = 20:1) to obtain solid 7-4 (120 mg, yield) 36%).

The fifth step: 3-(4-(aminomethyl)-4-cyanopiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazine-2-carboxy Preparation of ethyl ester (7-5)

Dissolve 7-4 (150mg, 0.27mmol) in dichloromethane (4mL), add trifluoroacetic acid (2mL), and react for 1 hour at 25°C. After the completion of the reaction is detected by LC-MS, the reaction solution is concentrated to obtain 7-5 Trifluoroacetate (150mg, yield 98%), directly used in the next reaction.

The sixth step: 4-(aminomethyl)-1-(5-(2,3-dichlorophenyl)-3-(hydroxymethyl)-6-methylpyrazin-2-yl)piperidine- Preparation of 4-nitrile (TM6)

Dissolve 7-5 (70mg, 0.12mmol) in dry tetrahydrofuran (3mL), lower the temperature to 0°C, add LiBH ₄ (2M, 0.31mL) dropwise, and react at 0°C for 10 minutes. LC-MS detects that the reaction is complete. Concentrated and purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous formic acid) to obtain the title compound (6 mg, yield 12%).

MS m/z(ESI): 405.8[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.74 (dd, J = 7.6, 1.2 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.42 (dd, J = 7.6, 1.2 Hz, 1H), 5.35 (s, 1H), 4.51 (d, J = 4.0 Hz, 2H), 3.89 (d, J = 13.6 Hz, 2H), 3.03 (t, J = 12.4 Hz, 2H), 2.84 (s, 2H), 2.21 (s, 3H), 2.00 (d, J=13.6 Hz, 1H), 1.74-1.64 (m, 2H).

Example 8: 4-(Aminomethyl)-1-(5-((2,3-dichlorophenyl)thio)-3-(hydroxymethyl)-6-methylpyrazin-2-yl ) Preparation of piperidine-4-carbonitrile (TM7)

The first step: 6-bromo-3-(4-(((tert-butoxycarbonyl)amino)methyl)-4-cyanopiperidin-1-yl)-5-methylpyrazine-2-carboxy Preparation of Ethyl Acid (8-1)

Dissolve 1-3 (0.75g, 2.87mmol) in DMF (10mL), add 8-0 (0.82g, 3.42mmol), BOP (1.65g, 3.73mmol) and DBU (0.66g, 4.31mmol) at 25°C Reacted for 1 hour. After the completion of the reaction was detected by LC-MS, water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, dried and concentrated, and purified by preparative TLC (petroleum ether: ethyl acetate=1:1) to obtain a solid 8- 1 (194 mg, yield 14%).

The second step: 3-(4-(((tert-butoxycarbonyl)amino)methyl)-4-cyanopiperidin-1-yl)-6-((2,3-dichlorophenyl)sulfur Yl)-5-methylpyrazine-2-carboxylic acid ethyl ester (8-2)

Dissolve 8-1 (50mg, 0.10mmol) in dioxane (8mL), add 2,3-dichlorothiophenol (22.3mg, 0.12mmol), potassium phosphate (66.0mg, 0.31mmol), iodide Cuprous (19.7mg, 0.11mmol) and 1,10-phenanthroline (18.9mg, 0.10mmol) were replaced with nitrogen and heated to 100°C for 12 hours. After the reaction was completed by LC-MS, the reaction solution was filtered and the filtrate was concentrated After purification by preparative TLC (petroleum ether: ethyl acetate = 3:1 (V: V)), a solid 8-2 (55 mg, yield 91%) was obtained.

The third step: 4-(aminomethyl)-1-(5-((2,3-dichlorophenyl)sulfanyl)-3-(hydroxymethyl)-6-methylpyrazin-2-yl ) Preparation of piperidine-4-carbonitrile (TM7)

Dissolve 8-2 (45mg, 77.52μmol) in tetrahydrofuran (8mL), lower the temperature to 0°C, add LiBH ₄ (2M, 0.58mL) dropwise, react at 0°C for 30 minutes, then warm up to 25°C for 30 minutes, LC-MS After detecting the completion of the reaction, the reaction solution was added dropwise to 3M hydrochloric acid and stirred at 25°C for 30 minutes. LC-MS detected that the Boc removal reaction was complete. The reaction solution was subjected to HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoro Aqueous acetic acid) was purified to obtain the trifluoroacetate salt of the title compound (5 mg, yield 12%).

MS m/z(ESI): 437.8[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 7.43 (dd, J = 7.6, 1.2 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.01 (dd, J = 7.6, 1.2 Hz, 1H) ), 4.59 (s, 2H), 3.99 (d, J = 13.6 Hz, 2H), 3.31-3.21 (m, 4H), 2.51 (s, 3H), 2.14-2.04 (m, 2H), 1.94-1.84 ( m, 2H).

Example 9: 4-(Aminomethyl)-1-(5-(2,3-dichloropyridin-4-yl)-3-(hydroxymethyl)-6-methylpyrazin-2-yl) Preparation of piperidine-4-carbonitrile (TM8)

The first step: 3-(4-(((tert-butoxycarbonyl)amino)methyl)-4-cyanopiperidin-1-yl)-6-(2,3-dichloropyridin-4-yl) Preparation of ethyl-5-methylpyrazine-2-carboxylate (9-1)

Dissolve 8-1 (80.1mg, 0.17mmol) in dioxane (10mL), add (2,3-dichloropyridin-4-yl)boronic acid (63.6mg, 0.33mmol), potassium carbonate (114.6mg, 0.83mmol) and bis(triphenylphosphorus) palladium dichloride (11.6mg, 0.17mmol), replaced with nitrogen, heated to 90°C for 2 hours, LC-MS detected that the reaction was complete, the reaction solution was concentrated, and the reaction solution was concentrated by preparative TLC (petroleum Ether: ethyl acetate = 2:1 (V: V)) was purified to obtain a solid 9-1 (48 mg, yield 53%).

The second step: 4-(aminomethyl)-1-(5-(2,3-dichloropyridin-4-yl)-3-(hydroxymethyl)-6-methylpyrazin-2-yl) Preparation of piperidine-4-carbonitrile (TM8)

Dissolve 9-1 (48.1mg, 0.0875mmol) in tetrahydrofuran (8mL), lower the temperature to 0°C, add LiBH ₄ (2M in THF, 0.91mL) dropwise, raise the temperature to 25°C and react for 30 minutes. LC-MS detects that the reaction is complete Then the reaction solution was added dropwise to 3M hydrochloric acid and stirred at 25°C for 30 minutes. After LC-MS detected the reaction was complete, the reaction solution was purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the title compound The trifluoroacetate salt (3mg, yield 6%).

MS m/z(ESI): 406.8[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.51 (d, J = 4.8 Hz, 1H), 8.28 (s, 3H), 7.57 (d, J = 4.8 Hz, 1H), 5.48 (s, 1H) , 4.54(s, 2H), 4.02(d, J=13.6Hz, 2H), 3.27(s, 2H), 3.07(t, J=12.4Hz, 2H), 2.25(s, 3H), 2.12(d, J=13.6Hz, 2H), 1.88-1.78 (m, 2H).

Example 10: (3-(4-(Aminomethyl)-4-(cyclopropylmethyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methyl Preparation of pyrazin-2-yl)methanol (TM9)

Except that bromomethylcyclopropane was used in the first step in this example instead of the benzyl chloromethyl ether in the first step in Example 3, the crude TM9 was synthesized by a method similar to that described in Example 3. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous formic acid) to obtain compound TM9.

MS m/z(ESI): 434.9[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 7.63 (dd, J = 8.0, 1.6 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.34 (dd, J = 8.0, 1.6 Hz, 1H ), 4.66(s, 2H), 4.62(br, 2H), 3.50-3.34(m, 4H), 3.06(s, 2H), 2.22(s, 3H), 1.85-1.76(m, 2H), 1.76 1.66 (m, 2H), 1.50 (d, J = 6.8 Hz, 2H), 0.78-0.68 (m, 1H), 0.61-0.53 (m, 2H), 0.19-0.11 (m, 2H).

Example 11: (3-(4-(aminomethyl)-4-(prop-2-yn-1-yl)piperidin-1-yl)-6-(2,3-dichlorophenyl)- Preparation of 5-methylpyrazin-2-yl)methanol (TM10)

Except that 3-bromopropyne was used in the first step in this example to replace the benzyl chloromethyl ether in the first step in Example 3, the crude TM10 was synthesized by a method similar to that described in Example 3. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous formic acid) to obtain compound TM10.

MS m/z(ESI): 418.9[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.55 (br, 1H), 7.63 (dd, J = 7.6, 1.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.34 (d, J=7.6, 1.2Hz, 1H), 4.66 (s, 2H), 3.56-3.45 (m, 2H), 3.38-3.31 (m, 2H), 3.10 (s, 2H), 2.54 (s, 2H), 2.25 (s, 3H), 1.88-1.68 (m, 4H).

Example 12: (3-(4-(aminomethyl)-4-(cyclobut-1-en-1-yl)piperidin-1-yl)-6-(2,3-dichlorophenyl) Preparation of -5-methylpyrazin-2-yl)methanol (TM11)

Step 1: Preparation of tert-butyl 4-cyano-4-(1-hydroxycyclobutyl)piperidine-1-carboxylate (12-2)

Dissolve 3-1 (4g, 19.0mmol) in THF (100mL), cool to -78°C, add LDA (26.6mmol, 13.3mL, 2M in THF) dropwise, stir at -78°C for 30 minutes, add ring Butanone (2.13g, 30.4mmol), then naturally heated and stirred. After TLC monitoring showed that the reaction was completed, the reaction was quenched by adding saturated sodium bicarbonate solution (50 mL), extracted with ethyl acetate (20 mL x 3), and the organic phases were combined, dried with anhydrous sodium sulfate, filtered with suction, and concentrated. The resulting crude product was passed through a column Chromatography (ethyl acetate: petroleum ether = 1:3) was purified to obtain solid compound 12-2 (5.10 g, yield 95%).

Step 2: Preparation of tert-butyl 4-cyano-4-(cyclobut-1-en-1-yl)piperidine-1-carboxylate (12-3)

Dissolve 12-2 (1.5 g, 5.35 mmol) in pyridine (16 mL), add POCl ₃ (4 mL), and heat to 80° C. and stir. After TLC monitoring showed that the reaction was complete, the system was cooled to room temperature, diluted with ethyl acetate (100 mL), and the organic phase was washed sequentially with 1N HCl (20 mL x 2) and saturated sodium chloride solution (20 mL). The organic phase was dried with anhydrous sodium sulfate, filtered with suction, and concentrated to obtain the crude compound 12-3 (1.0 g, yield 71%), which was directly used in the next reaction without further purification.

Steps 3 to 5: (3-(4-(aminomethyl)-4-(cyclobut-1-en-1-yl)piperidin-1-yl)-6-(2,3-di Synthesis of chlorophenyl)-5-methylpyrazin-2-yl)methanol (TM11)

Except that 12-3 was used in the third step instead of 3-2 in the second step in Example 3, the crude TM11 was synthesized by a method similar to that described in the second to fourth steps in Example 3. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 432.9[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.74 (dd, J = 7.6, 1.2 Hz, 1H), 7.68 (br, 3H), 7.48 (t, J = 7.6 Hz, 1H), 7.41 (dd, J=7.6, 1.2Hz, 1H), 6.09 (s, 1H), 4.51 (s, 1H), 4.50 (s, 2H), 3.70-3.59 (m, 2H), 3.12-3.00 (m, 2H), 2.90 -2.80(m, 2H), 2.47-2.41(m, 2H), 2.38-2.30(m, 2H), 2.18(s, 3H), 1.92-1.82(m, 2H), 1.70-1.57(m, 2H) .

Example 13: (3-(4-(aminomethyl)-4-cyclobutylpiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazine-2 -Based) methanol (TM12) preparation

Step 1: Preparation of tert-butyl 4-cyano-4-cyclobutylpiperidine-1-carboxylate (13-1)

Dissolve 12-3 (500 mg, 1.91 mmol) in MeOH (5 mL), add 10% Pd/C (201 mg), replace with hydrogen three times, and stir at room temperature. After TLC monitoring showed that the reaction was completed, it was filtered through a pad of diatomaceous earth and concentrated. The resulting crude compound 13-1 (250 mg, yield 50%) was used directly in the next step without further purification.

Steps 2 to 4: (3-(4-(aminomethyl)-4-cyclobutylpiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methyl Synthesis of pyrazin-2-yl)methanol (TM12)

Except that 13-1 was used in the second step instead of 3-2 in the second step in Example 3, the crude TM12 was synthesized by a method similar to that described in the second to fourth steps in Example 3. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 434.9[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.76 (dd, J = 8.0, 1.6 Hz, 1H), 7.61 (br, 3H), 7.50 (t, J = 8.0 Hz, 1H), 7.76 (dd, J = 7.6, 1.2 Hz, 1H), 5.36 (s, 1H), 4.52 (d, J = 4.4 Hz, 2H), 3.71-3.58 (m, 2H), 3.21-3.04 (m, 2H), 2.98-2.84 (m, 2H), 2.64-2.55(m, 1H), 2.20(s, 3H), 1.97-1.72(m, 5H), 1.72-1.56(m, 3H), 1.56-1.44(m, 2H).

Example 14: (3-(4-(aminomethyl)-4-benzylpiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazine-2- Base) methanol (TM13) preparation

Step 1: Preparation of tert-butyl 4-benzyl-4-cyanopiperidine-1-carboxylate (14-2)

Except that benzyl bromide was used in this step instead of the benzyl chloromethyl ether in the first step in Example 3, 14-2 was synthesized by a method similar to that described in the first step in Example 3.

Step 2: Preparation of tert-butyl 4-(aminomethyl)-4-benzylpiperidine-1-carboxylate (14-3)

Under ice-water bath, dissolve 14-2 (0.50g, 1.66mmol) in MeOH (10mL), add cobalt chloride hexahydrate (0.79g, 3.33mmol) and sodium borohydride (0.25g, 6.66mmol), stir and react 1 hour. LC-MS showed that the reaction was complete. The reaction system was first adjusted to acidity, then the pH of the system was adjusted to 10 with potassium carbonate aqueous solution, extracted with dichloromethane, dried over sodium sulfate, and concentrated to dryness to obtain compound 14-3 (0.40g, yield 79%), which was used directly Next reaction.

The third step: Preparation of (4-benzylpiperidin-4-yl)methylamine hydrochloride (14-4)

14-3 (0.40 g, 1.31 mmol) was dissolved in HCl (4 mL, 4N in 1,4-dioxane), and the reaction was stirred at room temperature for 2 hours. TLC showed that the reaction was complete. Concentrate under reduced pressure to obtain the title compound (0.28 g, yield 89%).

Steps 4 to 5: (3-(4-(aminomethyl)-4-benzylpiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methylpyridine Preparation of azin-2-yl)methanol (TM13)

Except that 14-4 was used in the fourth step instead of 3-3 in the third step in Example 3, the crude TM13 was synthesized by a method similar to that described in the third to fourth steps in Example 3. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 471.1[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.87 (br, 3H), 7.76-7.71 (dd, J = 7.6, 1.2 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.44 7.38 (dd, J=7.6, 1.2 Hz, 1H), 7.37-7.31 (m, 2H), 7.30-7.19 (m, 3H), 4.47 (s, 2H), 3.58-3.46 (m, 2H), 3.42- 3.30 (m, 2H), 2.90-2.75 (m, 4H), 2.18 (s, 3H), 1.65-1.45 (m, 4H).

Example 15: (3-(4-(aminomethyl)-4-phenylpiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazine-2- Preparation of methanol (TM14)

Step 1: Synthesis of tert-butyl 4-(2-bromophenyl)-4-cyanopiperidine-1-carboxylate (15-2)

2-(2-Bromophenyl)acetonitrile (2.12g, 10.8mmol) was dissolved in DMF (40mL), cooled to 0℃, NaH (0.86g, 21.6mmol, 60%) was added, moved to room temperature and 25℃ for 15 minutes Add tert-butyl N,N-bis(2-chloroethyl)carbamate (2.75g, 11.4mmol), and react at 80°C for 15 hours. After the reaction is completed, add 10 mL of water to quench the reaction, extract with ethyl acetate (60 mL x 3), combine the organic phases and wash with saturated brine (60 mL x 2), dry the organic phase with anhydrous sodium sulfate, filter, and evaporate under reduced pressure The crude product was obtained by dry solvent, and the crude product was purified by silica gel column chromatography to obtain compound 15-2 (470 mg, yield 12%).

Step 2: Synthesis of tert-butyl 4-(aminomethyl)-4-phenylpiperidine-1-carboxylate (15-3)

Dissolve 15-2 (300 mg, 0.82 mmol) in NH ₃ /MeOH (10 mL), add Raney Ni (241 mg), _{replace with H 2} three times, and react at 25° C. for 14 hours. After the completion of the reaction, the solvent was evaporated under reduced pressure to obtain crude compound 15-3 (200 mg), which was directly used in the next reaction.

The third step: Synthesis of (4-phenylpiperidin-4-yl)methylamine (15-4)

15-3 (200mg, 0.69mmol) was dissolved in dichloromethane (5ml) and trifluoroacetic acid (3mL), and reacted at 25°C for 1 hour. After the reaction, it was directly concentrated to obtain 15-4 trifluoroacetate (130 mg, yield 62%).

The fourth step: 3-(4-(aminomethyl)-4-phenylpiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazine-2-carboxy Synthesis of Ethyl Acid (15-5)

Dissolve IM-1 (90.1mg, 0.28mmol) in DMF (3mL), add 15-4 trifluoroacetate (52.4mg, 0.17mmol), Carter condensing agent (243.2mg, 0.55mmol) and DBU in turn (346.4mg, 2.28mmol) at 25°C for 1 hour. After the reaction, it was concentrated to obtain the crude product 15-5 (100 mg). The crude product was directly used in the next reaction without further purification.

The fifth step: (3-(4-(aminomethyl)-4-phenylpiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazine-2- Synthesis of base) methanol (TM14)

15-5 (100.0 mg, 0.20 mmol) was dissolved in dichloromethane (5 mL), DIBAL-H (1M in hexane, 1.5 mL) was added at 0°C, and the reaction was continued for 1 hour. After the reaction, the reaction was quenched by adding trifluoroacetic acid and concentrated. The crude product was purified by reverse-phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetic acid salt of the title compound (3.8 mg, yield 3.3%).

MS m/z(ESI): 457.2[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.73 (dd, J=7.6, 1.2 Hz, 1H), 7.59-7.31 (m, 10H), 5.36 (s, 1H), 4.51 (s, 2H), 3.64-3.44(m, 2H), 3.14-3.01(m, 4H), 2.43-2.26(m, 2H), 2.16(s, 3H), 2.10-1.88(m, 2H).

Example 16: (3-(4-(Aminomethyl)-4-(cyclohexylmethyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methylpyridine Preparation of azin-2-yl)methanol (TM15)

Step 1: Synthesis of tert-butyl 4-cyano-4-(cyclohexylmethyl)piperidine-1-carboxylate (16-2)

In a three-neck flask, dissolve 4-cyanopiperidine-1-carboxylic acid tert-butyl ester (1.2g, 5.71mmol) in THF (25mL), replace with nitrogen, and cool to -78°C. Add LDA (THF Medium 2M, 5.71 mL), stirred at -78°C for 0.5 hour. Bromomethylcyclohexane (1.01 g, 5.71 mmol) was dissolved in THF (25 mL) and slowly added to the reaction system. Warm to room temperature and react for 2 hours. After the reaction was completed, the _{reaction was quenched by adding 20 mL saturated NH 4} Cl aqueous solution, extracted with ethyl acetate (60 mL×3), the combined organic phase was washed with saturated brine (60 mL×2), the organic phase was dried over anhydrous sodium sulfate, and filtered The solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 16-2 (1.5 g, yield 86%).

Step 2: Synthesis of tert-butyl 4-(aminomethyl)-4-(cyclohexylmethyl)piperidine-1-carboxylate (16-3)

Dissolve 16-2 (331 mg, 1.08 mmol) in MeOH (8 mL), add cobalt chloride hexahydrate (179 mg, 0.76 mmol), slowly add NaBH ₄ (288 mg, 7.61 mmol), and react at room temperature at 25°C for 2 hours. After the reaction was completed, the diatomite was suction filtered, and the filtrate was evaporated to dryness under reduced pressure to obtain compound 16-3 (230 mg), which was directly used in the next reaction without purification.

The third step: Synthesis of (4-(cyclohexylmethyl)piperidin-4-yl)methylamine (16-4)

16-3 (230mg, 0.74mmol) was dissolved in HCl (4M in 1,4-dioxane, 4mL) and reacted at 25°C for one hour. After the reaction, it was directly concentrated to obtain 16-4 hydrochloride (130 mg, yield 71%).

The fourth step: 3-(4-(aminomethyl)-4-(cyclohexylmethyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazine Synthesis of -2-carboxylic acid ethyl ester (16-5)

Dissolve IM-1 (60.1mg, 0.18mmol) in DMF (3mL), add 16-4 hydrochloride (45.3mg, 0.18mmol), Carter condensing agent (162.1mg, 0.37mmol) and DBU (230.9mg) in sequence , 1.52mmol), react at 25°C for 2 hours. After the reaction, it was concentrated and purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain 16-5 (18.2 mg, yield 19%).

The fifth step: (3-(4-(aminomethyl)-4-(cyclohexylmethyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methylpyridine Synthesis of azin-2-yl)methanol (TM15)

16-5 (18.2 mg, 0.035 mmol) was dissolved in dichloromethane (6 mL), placed in an ice-water bath at 0°C, DIBAL-H (1M in hexane, 0.7 mL) was added, and the reaction was continued for 1 hour. After the reaction, the reaction was quenched by adding trifluoroacetic acid and concentrated. The crude product was purified by reverse-phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate (1.41) of the title compound. mg, yield 6.8%).

MS m/z(ESI): 477.2[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.78-7.65 (m, 4H), 7.49 (t, J = 7.6 Hz, 1H), 7.41 (dd, J = 7.6, 1.2 Hz, 1H), 4.50 ( s, 2H), 3.59-3.48 (m, 4H), 2.92 (d, J=5.7Hz, 2H), 2.19 (s, 3H), 1.78-1.55 (m, 9H), 1.30-1.19 (m, 3H) , 1.18-1.08 (m, 2H), 1.08-0.90 (m, 3H).

Example 17: (3-(4-(aminomethyl)-4-((difluoromethoxy)methyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)- Preparation of 5-methylpyrazin-2-yl)methanol (TM40)

The first step: the preparation of 1-benzyl 4-methyl 4-cyanopiperidine-1,4-dicarboxylate (17-1)

Under the protection of nitrogen, dissolve 4-cyanopiperidine-1-carboxylic acid benzyl ester (7-0) (2.78g, 11.38mmol) in THF (20mL), cool to -78℃, and slowly add LiHMDS( 23mmol, 23mL, 1M in THF), after the addition, stir at this temperature for 0.5 hours, then slowly add methyl chloroformate (2.15g, 22.76mmol), after the addition, the temperature is naturally raised to 25°C and reacted for 4 hours. After the reaction was completed, saturated ammonium chloride solution was added to the reaction solution. After stirring well, DCM (20mL) was added. After stirring, the layers were separated. The organic phase was dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude product. Purified by silica gel column chromatography to obtain compound 17-1 (1.7 g, yield 49%).

Step 2: Preparation of 4-cyano-4-(hydroxymethyl)piperidine-1-carboxylic acid benzyl ester (17-2)

Dissolve 17-1 (1.5g, 4.96mmol) in THF (10mL), cool to 0°C, slowly add NaBH ₄ (0.9g, 24.81mmol), and stir at 0°C for 1 hour after the addition. After the reaction is complete, DCM and appropriate amount of water were added to the reaction solution, stirred well and filtered, the filter cake was washed twice with DCM, the filtrate was separated, the aqueous phase was extracted three times with DCM, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated to dryness under reduced pressure to obtain crude product 17-2 (0.2 g), which was directly used in the next step.

The third step: Preparation of 4-cyano-4-((difluoromethoxy)methyl)piperidine-1-carboxylic acid benzyl ester (17-3)

Dissolve 17-2 (200mg, 0.73mmol) in acetonitrile (10mL), add CuI (28mg, 0.15mmol), heat to 50°C, slowly add 2-fluorosulfonyl difluoroacetic acid (260mg, 1.46mmol), The reaction was carried out at this temperature overnight. After the reaction was completed, the reaction solution was concentrated, DCM (10 mL) and saturated sodium bicarbonate solution (10 mL) were added, and the layers were separated after thorough stirring. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was obtained by dry solvent, and the crude product was purified by silica gel column chromatography to obtain 17-3 (200 mg, yield 85%).

Fourth step: Preparation of 4-((difluoromethoxy)methyl)piperidine-4-carbonitrile (17-4)

Dissolve 17-3 (200mg, 0.62mmol) in MeOH (30mL), add 10% Pd/C (75mg), react in hydrogen at 25°C for 1 hour, filter the reaction solution with Celite, and concentrate the filtrate to obtain crude product 17 -4 (80mg, yield 68%), directly used in the next reaction.

Step 5 to Step 6: (3-(4-(aminomethyl)-4-((difluoromethoxy)methyl)piperidin-1-yl)-6-(2,3-dichloro Preparation of phenyl)-5-methylpyrazin-2-yl)methanol (TM40)

Except that 17-4 was used in the fifth step instead of 3-3 in the third step in Example 3, the crude TM40 was synthesized by a method similar to that described in the third to fourth steps in Example 3. The crude product was reversed Phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) purification to obtain the trifluoroacetic acid salt of the title compound.

MS m/z(ESI): 461.1[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 8.54 (s, 1H), 7.64 (dd, J = 7.8, 1.6 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.34 (dd, J = 7.8, 1.6 Hz, 1H), 6.48 (t, J = 74.8 Hz, 1H), 4.67 (s, 2H), 4.01 (s, 2H), 3.48-3.30 (m, 2H), 3.41-3.33 (m, 2H), 3.04(s, 2H), 2.24(s, 3H), 1.86-1.70(m, 4H).

Example 18: 1-(4-(Aminomethyl)-1-(5-(2,3-dichlorophenyl)-3-(hydroxymethyl)-6-methylpyrazin-2-yl) Preparation of piperidin-4-yl)cyclobutanol (TM85)

Except that 12-2 was used in this example instead of 13-1 in the second step in Example 13, the crude TM85 was synthesized by a method similar to that described in the second to fourth steps in Example 13. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 451.2[M+H] ⁺

¹ H NMR (400MHz, DMSO) δ 7.74 (dd, J = 8.0, 1.6 Hz, 1H), 7.63 (br, 3H), 7.49 (t, J = 8.0 Hz, 1H), 7.43 (dd, J = 8.0 , 1.6Hz, 1H), 6.14 (s, 1H), 4.52 (s, 2H), 3.82-3.68 (m, 2H), 3.09-2.93 (m, 4H), 2.42- 2.29 (m, 2H), 2.20 ( s, 3H), 2.01-1.88 (m, 2H), 1.89-1.77 (m, 1H), 1.77-1.55 (m, 4H), 1.51-1.36 (m, 1H).

Example 19: (3-(4-(aminomethyl)-4-cyclopropylpiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazine-2 -Based) methanol (TM20) preparation

Step 1: Preparation of 1-benzyl-4-cyclopropylpiperidine-4-carbonitrile (19-2)

Dissolve 19-1 (2.10g, 9.05mmol) and cyclopropylacetonitrile (0.92g, 11.31mmol) in THF (50mL), protect with nitrogen, cool to 0°C, and add NaHMDS (2M in THF, 31.86mmol, 15.93) mL), after the dripping is completed, the temperature is naturally increased for 24h. After the reaction, the reaction was quenched by adding saturated ammonium chloride, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography to obtain 19-2 (0.46g, yield 21 %).

Step 2: Preparation of ((1-benzyl-4-cyclopropylpiperidin-4-yl)methyl) tert-butyl carbamate (19-3)

Dissolve 19-2 (0.40g, 1.66mmol) in methanol (10mL), add cobalt chloride hexahydrate (0.79g, 3.33mmol), cool to 0°C, add sodium borohydride (0.31g, 8.32mmol) to In the reaction system, the temperature was raised to 25°C for 4 hours. The reaction system was first quenched with 1N dilute hydrochloric acid, and then the pH was adjusted to about 10 with potassium carbonate aqueous solution. Subsequently, di-tert-butyl dicarbonate (0.36 g, 1.66 mmol) was added to the reaction system, and the reaction was carried out at 25° C. for 2 h. After the reaction was completed, 20 mL of water was added and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over sodium sulfate and filtered and concentrated. The crude product was subjected to silica gel column chromatography to obtain 19-3 (0.34 g, yield 59%).

The third step: Preparation of ((4-cyclopropylpiperidin-4-yl)methyl) tert-butyl carbamate (19-4)

Add 19-3 (240mg, 0.70mmol), isopropanol (9mL), water (3mL), acetic acid (1mL) and 10% palladium hydroxide/charcoal (48mg) into the autoclave, seal it, and replace it with hydrogen three times. The system pressure was increased to 1Mpa and reacted at 75°C for 4h. After the reaction, the filtrate was filtered through a pad of Celite, and the filtrate was concentrated to obtain the crude product. The crude product was adjusted to pH 10 with potassium carbonate aqueous solution, extracted with DCM, and concentrated to obtain the crude product, which was purified by a preparation plate to obtain 19-4 (75 mg, yield 42%).

Step 4 to Step 6: (3-(4-(aminomethyl)-4-cyclopropylpiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methyl Preparation of pyrazin-2-yl)methanol (TM20)

Except that 19-4 was used in the fourth step instead of 7-3 in the fourth step in Example 7, the crude TM20 was synthesized by a method similar to that described in the fourth to sixth steps in Example 7. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 421.3[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.80-7.70 (m, 4H), 7.48 (t, J = 7.6 Hz, 1H), 7.40 (dd, J = 7.6, 1.2 Hz, 1H), 5.33 ( s, 1H), 4.49 (s, 2H), 3.65-3.55 (m, 2H), 3.18-3.06 (m, 2H), 3.07-2.95 (m, 2H), 2.18 (s, 3H), 1.60-1.35 ( m, 4H), 0.95-0.80 (m, 1H), 0.45-0.35 (m, 4H).

Example 20: (3-(4-(aminomethyl)-4-cyclopentylpiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazine-2 -Based) methanol (TM21) preparation

Step 1 to Step 2: Preparation of tert-butyl 4-cyano-4-(cyclopent-1-en-1-yl)piperidine-1-carboxylate (20-2)

Except that cyclopentanone was used in the first step instead of the cyclobutanone in the first step in Example 12, 20-2 was synthesized by a method similar to that described in the first to second steps in Example 12.

Steps 3 to 6: (3-(4-(aminomethyl)-4-cyclopentylpiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methyl Synthesis of pyrazin-2-yl)methanol (TM21)

Except that 20-2 was used in the third step instead of 12-3 in the first step in Example 13, the crude TM21 was synthesized by a similar method as described in the first to fourth steps in Example 13. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 449.2[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.85-7.70 (m, 4H), 7.49 (t, J=7.6Hz, 1H), 7.43-7.39 (m, 1H), 4.50 (s, 2H), 3.65-3.55(m, 2H), 3.23-3.10(m, 2H), 3.03-2.95(m, 2H), 2.19(s, 3H), 2.15-2.04(m, 1H), 1.75-1.45(m, 10H) ), 1.35-1.20 (m, 2H).

Example 21: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazine- Preparation of 2-base) methanol (TM131)

The first step: the preparation of 4-(methoxy(methyl)carbamoyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (21-2)

21-1 (25.0 g, 102.75 mmol), HATU (46.9 g, 123.31 mmol) and DIPEA (66.4 g, 513.77 mmol) were dissolved in DMF (250 mL) and reacted at 25°C for 30 minutes. Subsequently, dimethylhydroxylamine hydrochloride (12.0 g, 123.31 mmol) was added, and the reaction was carried out at 25° C. for 15 hours. After the reaction was completed, saturated ammonium chloride was added for quenching, and ethyl acetate was added for extraction. The organic phases were combined, dried and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain 21-2 (25.0 g, yield 85%).

Step 2: Preparation of tert-butyl 4-acetyl-4-methylpiperidine-1-carboxylate (21-3)

21-2 (20.0 g, 69.8 mmol) was dissolved in THF (250 mL), the temperature was lowered to 0° C., and methylmagnesium bromide (93 mL, 279.0 mmol, 3N in THF) was slowly added dropwise within half an hour. After the addition, the temperature was slowly raised to 25°C to react for 16 hours. After the reaction was completed, the reaction solution was slowly added dropwise to a saturated aqueous ammonium chloride solution on ice, and ethyl acetate was added for extraction. The organic phases were combined, dried and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 21-3 (10.6 g, yield 63%).

The third step: preparation of 4-(1-(1,1-dimethylethylsulfonamido)ethyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (21-4)

Dissolve 21-3 (5.10g, 21.13mmol) in tetraisopropyl titanate (51mL), add tert-butylsulfinamide (5.12g, 42.27mmol), replace with nitrogen, heat up to 90°C and react for 16 hours, cool After reaching room temperature, saturated sodium chloride solution was added, extracted with ethyl acetate, the organic phases were combined, dried and concentrated under reduced pressure. The residue was dissolved in methanol (70 mL), sodium borohydride (2.3 g, 60.96 mmol) was slowly added in an ice bath, and the temperature was raised to 25° C. to react for 2 hours. After the reaction was completed, the temperature was lowered to 0°C, saturated ammonium chloride was added to quench the reaction, extracted with ethyl acetate, organically dried, concentrated under reduced pressure and subjected to column chromatography to obtain 21-4 (4.3g, yield 59%).

Step 4: Preparation of 1-(4-methylpiperidin-4-yl)ethan-1-amine hydrochloride (21-5)

21-4 (4.3g, 12.35mmol) was dissolved in dioxane hydrochloride solution (4M, 70mL), and reacted at 25°C for 2 hours. The reaction solution was concentrated to obtain crude solid 21-5 (2.65 g, yield 99%), which was directly used in the next reaction.

Step 5 to Step 6: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methyl Preparation of pyrazine-2-yl)methanol (TM131)

Except that 21-5 was used in the fifth step instead of 3-3 in the third step in Example 3, the crude TM131 was synthesized by a method similar to that described in the third to fourth steps in Example 3. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 409.1[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.80-7.65 (m, 4H), 7.49 (t, J=7.6Hz, 1H), 7.44-7.39 (m, 1H), 5.36 (s, 1H), 4.50 (s, 2H), 3.75-3.60 (m, 2H), 3.20-3.02 (m, 3H), 2.19 (s, 3H), 1.75-1.40 (m, 4H), 1.16 (d, J=4.0Hz, 3H), 1.00(s, 3H).

Example 22: (3-(4-(aminomethyl)-4-((tetrahydrofuran-3-yl)methyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)- Preparation of 5-methylpyrazin-2-yl)methanol (TM86)

Except that in the first step of this example, 3-(iodomethyl)tetrahydrofuran was used instead of the benzyl chloromethyl ether in the first step of Example 3, a method similar to that described in Example 3 was used to synthesize three of the target compounds. Fluoroacetate.

MS m/z(ESI): 465.1[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.84-7.66 (m, 4H), 7.49 (t, J = 7.6 Hz, 1H), 7.41 (dd, J = 7.6, 1.2 Hz, 1H), 5.33 ( s, 1H), 4.50 (s, 2H), 3.93 (t, J=7.6 Hz, 1H), 3.79-3.69 (m, 1H), 3.69-3.59 (m, 2H), 3.41-3.31 (m, 3H) , 3.14 (t, J = 8.2 Hz, 1H), 2.95 (d, J = 5.1 Hz, 2H), 2.19 (s, 3H), 2.16-2.04 (m, 2H), 1.69-1.41 (m, 7H).

Example 23: (3-(4-(aminomethyl)-4-(pyrazin-2-ylmethyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)-5 -Methylpyrazin-2-yl) methanol (TM82) preparation

Except that 2-(chloromethyl)pyrazine was used in the first step of this example to replace the benzyl chloromethyl ether in the first step of Example 3, the method similar to that described in Example 3 was used to synthesize the title compound. Trifluoroacetate.

MS m/z(ESI): 473.1[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.71-8.63 (m, 2H), 8.59 (d, J = 2.4 Hz, 1H), 7.95 (s, 3H), 7.75 (dd, J = 7.6, 1.2 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.42 (dd, J = 7.6, 1.2 Hz, 1H), 5.38 (s, 1H), 4.49 (s, 2H), 3.49-3.39 (m , 4H), 3.08 (s, 2H), 2.95-2.89 (m, 2H), 2.19 (s, 3H), 1.66-1.56 (m, 4H).

Example 24: (3-(4-(aminomethyl)-4-(pyrimidin-2-ylmethyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)-5- Preparation of methylpyrazin-2-yl)methanol (TM84)

Except that 2-(chloromethyl)pyrimidine was used in the first step of this example instead of the benzyl chloromethyl ether in the first step of Example 3, the third of the title compound was synthesized by a method similar to that described in Example 3. Fluoroacetate.

MS m/z(ESI): 473.2[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.82 (d, J = 4.8 Hz, 2H), 7.96 (s, 3H), 7.75 (dd, J = 7.6, 1.2 Hz, 1H), 7.52-7.46 ( m, 2H), 7.45-7.40 (m, 1H), 5.30 (s, 1H), 4.49 (s, 3H), 3.48-3.42 (m, 5H), 2.99-2.92 (m, 2H), 2.19 (s, 3H), 1.68-1.55 (m, 4H).

Example 25: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(2,3-dichloropyridin-4-yl)-5-methyl Preparation of pyrazin-2-yl)methanol (TM87)

The first step: 6-bromo-3-(4-(1-((tert-butoxycarbonyl)amino)ethyl)-4-methylpiperidin-1-yl)-5-methylpyrazine-2- Preparation of ethyl carboxylate (25-1)

Dissolve 1-3 (2.66g, 10.19mmol) in DMF (40mL), add 21-5 (2.63g, 12.23mmol), DIPEA (8.42mL, 50.94mmol) and Carter condensing agent (6.76g, 15.28mmol) in sequence , The temperature was raised to 60°C for 1 hour. After the reaction was completed, di-tert-butyl dicarbonate (3.34g, 15.28mmol) was added, and stirring was continued for 2 hours. After the reaction was completed, water was added, extracted with ethyl acetate, the organic phases were combined, dried and concentrated, and the crude product was purified by column chromatography to obtain 25-1 (3.30g, yield 67%).

The second step: 3-(4-(1-((tert-butoxycarbonyl)amino)ethyl)-4-methylpiperidin-1-yl)-6-(2,3-dichloropyridine-4- Yl)-5-methylpyrazine-2-carboxylic acid ethyl ester (25-2)

Dissolve 25-1 (5.20g, 10.71mmol) in 1,4-dioxane (100mL) and water (20mL), add (2,3-dichloropyridin-4-yl)boronic acid (3.08g, 16.07mmol), potassium carbonate (7.40g, 53.56mmol), [1,1'-bis(diphenylphosphine)ferrocene] dichloropalladium dichloromethane complex (0.87g, 1.07mmol), nitrogen After replacement, the temperature was raised to 90° C. and reacted for 3 hours. After the reaction was completed, water was added, extracted with ethyl acetate, the organic phases were combined, dried and concentrated, and purified by column chromatography to obtain 25-2 (3.59 g, yield 61%).

The third step: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(2,3-dichloropyridin-4-yl)-5-methyl Preparation of pyrazin-2-yl)methanol (TM87)

25-2 (40mg, 0.072mmol) was dissolved in hydrogen chloride dioxane solution (1mL, 4M), and reacted at 25°C for 1 hour. After the reaction was completed, the reaction solution was concentrated to obtain a solid. The solid was dissolved in dichloromethane (5mL), cooled to 0°C, DIBAL-H (1M in hexane, 0.288mL) was added dropwise, reacted at 0°C for 10 minutes, LC-MS detected that the reaction was complete, and methanol was added to quench the reaction. After being concentrated to dryness, the crude product was prepared by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous formic acid) to prepare the title compound (4 mg, yield 13%).

MS m/z(ESI): 410.2[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 8.53 (s, 1H), 8.41 (d, J = 4.8 Hz, 1H), 7.45 (d, J = 4.8 Hz, 1H), 4.66 (s, 2H), 3.77-3.71(m, 2H), 3.26-3.16(m, 3H), 2.27(s, 3H), 1.78-1.53(m, 4H), 1.29(d, J=6.8Hz, 3H), 1.12(s, 3H).

Example 26: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(4,5-dichloropyridin-3-yl)-5-methyl Preparation of pyrazin-2-yl)methanol (TM88)

The first step: 3-(4-(1-((tert-butoxycarbonyl)amino)ethyl)-4-methylpiperidin-1-yl)-6-(4,5-dichloropyridine-3- Preparation of ethyl)-5-methylpyrazine-2-carboxylate (26-2)

Dissolve 26-1 (112.8mg, 0.41mmol) in water (1mL) and 1,4-dioxane (5mL), add sodium carbonate (109.2mg, 1.03mmol) and bistriphenylphosphonium dichloride Palladium (28.9mg, 41.20umol), 25-1 (100.0mg, 0.21mmol) was added, and the reaction was carried out at 95°C for 14 hours under nitrogen protection. After the completion of the reaction, the reaction solution was concentrated and purified by column chromatography to obtain 26-2 (80 mg, 70%).

The second step: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(4,5-dichloropyridin-3-yl)-5-methyl Preparation of pyrazin-2-yl)methanol (TM88)

Except that 26-2 was used in this example instead of 25-2 in the third step of Example 25, a method similar to that described in the third step of Example 25 was used to synthesize the crude TM88. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 410.2[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.87 (s, 1H), 8.59 (s, 1H), 7.71 (s, 3H), 5.39 (s, 1H), 4.51 (s, 2H), 3.79- 3.66 (m, 2H), 3.20-3.08 (m, 3H), 2.23 (s, 3H), 1.69-1.53 (m, 3H), 1.50-1.41 (m, 1H), 1.16 (d, J = 6.8 Hz, 3H), 1.01(s, 3H).

Example 27: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(2-bromo-3-chloropyridin-4-yl)-5-methyl Preparation of pyrazine-2-yl)methanol (TM89)

The first step: 3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(2-bromo-3-chloropyridin-4-yl)-5-methyl Ethyl pyrazine-2-carboxylate

Dissolve 25-2 (45mg, 0.08mmol) in an acetic acid solution (33%wt, 5mL) of hydrobromic acid, heat up to 70°C and react for 16 hours. After LC-MS detects that the reaction is complete, the reaction solution is concentrated to obtain 27-1. Used directly in the next reaction.

The second step: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(2-bromo-3-chloropyridin-4-yl)-5-methyl Preparation of pyrazine-2-yl)methanol (TM89)

Dissolve 27-1 in dichloromethane (5 mL), lower the temperature to 0°C, add DIBAL-H (1M in hexane, 0.32 mL) dropwise, and react at 0°C for 10 minutes. LC-MS detects the completion of the reaction and adds methanol to quench the reaction. After concentration to dryness, the crude product is purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous formic acid) to obtain the title compound (6 mg, yield 16%) .

MS m/z(ESI): 454.1[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 8.47 (d, J = 4.8 Hz, 1H), 8.37 (s, 1H), 7.58 (d, J = 4.8 Hz, 1H), 4.49 (s, 2H), 3.77-3.62 (m, 2H), 3.17-3.03 (m, 2H), 2.91 (dd, J = 13.2, 6.4 Hz, 1H), 2.21 (s, 3H), 1.66-1.49 (m, 3H), 1.44- 1.33(m, 1H), 1.07(d, J=6.8Hz, 3H), 0.96(s, 3H).

Example 28: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(3-chloro-2-methoxypyridin-4-yl)-5 -Methylpyrazin-2-yl) methanol (TM90) preparation

Except that 28-1 was used in the first step of this example to replace the (2,3-dichloropyridin-4-yl)boronic acid in the second step of Example 25, the second step to the third step of Example 25 were used. The crude product of TM90 was synthesized in a similar manner as described. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 406.2[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 8.15 (d, J = 5.2 Hz, 1H), 6.99 (d, J = 5.2 Hz, 1H), 4.66 (s, 2H), 4.04 (s, 3H), 3.77-3.62(m, 2H), 3.26-3.13(m, 3H), 2.27(s, 3H), 1.78-1.49(m, 4H), 1.30(d, J=6.8Hz, 3H), 1.12(s, 3H).

Example 29: (6-(6-amino-2,3-dichloropyridin-4-yl)-3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)- Preparation of 5-methylpyrazin-2-yl)methanol (TM91)

Except that 29-1 was used in the first step of this example to replace the (2,3-dichloropyridin-4-yl)boronic acid in the second step of Example 25, the second step to the third step of Example 25 were used. The title compound was synthesized in a similar manner as described.

MS m/z(ESI): 425.3[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 8.38 (s, 1H), 6.72 (s, 2H), 6.42 (s, 1H), 4.48 (s, 2H), 3.72-3.60 (m, 2H), 3.15 -3.01 (m, 2H), 2.87 (q, J = 6.4 Hz, 1H), 2.22 (s, 3H), 1.66-1.48 (m, 3H), 1.45-1.32 (m, 1H), 1.05 (d, J =6.8Hz, 3H), 0.94 (s, 3H).

Example 30: (3-(4-(aminomethyl)-4-(pyridin-3-ylmethyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)-5- Preparation of methylpyrazin-2-yl)methanol (TM23)

A method similar to that described in Example 3 was used to synthesize the crude product of TM23 except that 3-bromomethylpyridine was used in the first step of this example instead of the benzyl chloromethyl ether in the first step of Example 3. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 472.1[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 8.69-8.60 (m, 2H), 8.25 (d, J=7.6 Hz, 1H), 7.91-7.80 (m, 1H), 7.64 (dd, J=7.6, 1.2Hz, 1H), 7.42(t, J=7.6Hz, 1H), 7.33(dd, J=7.6, 1.2Hz, 1H), 4.63(s, 2H), 3.67-3.54(m, 2H), 3.47- 3.41(m, 2H), 3.09(s, 2H), 3.07(s, 2H), 2.24(s, 3H), 1.78-1.69(m, 4H).

Example 31: (3-(4-allyl-4-(aminomethyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazine-2 -Based) methanol (TM18) preparation

Except that in the first step of this example, 3-bromopropene was used instead of the benzyl chloromethyl ether in the first step of Example 3, the crude TM18 was synthesized by a method similar to that described in Example 3. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 421.1[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 7.64 (dd, J = 7.6, 1.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.34 (dd, J = 7.6, 1.2 Hz, 1H ), 5.95-5.84(m, 1H), 5.26(d, J=3.6Hz, 1H), 5.23(s, 1H), 4.66(s, 2H), 3.53-3.35(m, 4H), 2.99(s, 2H), 2.37 (d, J = 7.6 Hz, 2H), 2.25 (s, 3H), 1.76-1.67 (m, 4H).

Example 32: (4-(1-aminoethyl)-1-(5-(2,3-dichlorophenyl)-3-(hydroxymethyl)-6-methylpyrazin-2-yl) Preparation of piperidin-4-yl)methanol (TM92)

The first step: Preparation of (E)-N-ethylene-2-methylpropyl-2-sulfinamide (32-2)

Except that 32-1 was used in the first step of this Example instead of 2-1 in the first step of Example 2, 32-2 was synthesized by a method similar to that described in the first step of Example 2.

The second step: 1-tert-butyl 4-ethyl 4-(1-(1,1-dimethylethylsulfonamido)ethyl)piperidine-1,4-dicarboxylate (32- 3) Preparation

Ethyl N-tert-butoxycarbonyl-4-piperidinecarboxylate (1.70g, 6.61mmol) was dissolved in THF (15mL), protected by nitrogen, cooled to -78°C, and LDA (2M in THF, 4.29mL) was added dropwise , React at this temperature for 30 minutes, then add 32-2 (1.26 g, 8.59 mmol), continue the reaction at this temperature for 2 hours, and then slowly rise to room temperature to react for 5 hours. After the reaction, the reaction was quenched by adding saturated ammonium chloride, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 32-3 (0.75g, yield 28%) ).

The third step to the fifth step: (4-(1-aminoethyl)-1-(5-(2,3-dichlorophenyl)-3-(hydroxymethyl)-6-methylpyrazine- Preparation of 2-yl)piperidin-4-yl)methanol (TM92)

Except that 32-3 was used in the third step instead of 2-3 in the third step in Example 2, the crude TM92 was synthesized by a method similar to that described in the third to fifth steps in Example 2. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 425.1[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 7.64 (dd, J = 7.6, 1.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.34 (dd, J = 7.6, 1.2 Hz, 1H ), 4.66(s, 2H), 3.92-3.84(m, 2H), 3.72-3.55(m, 2H), 3.26-3.24(m, 2H), 3.16-3.09(m, 1H), 2.25(s, 3H) ), 2.01-1.97 (m, 1H), 1.85-1.73 (m, 1H), 1.66-1.59 (m, 2H), 1.40 (d, J=6.8Hz, 3H).

Example 33: (3-(4-(1-aminoethyl)-4-(aminomethyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methyl Preparation of pyrazin-2-yl)methanol (TM93)

Except that 33-1 was used in the first step of this example instead of 3-3 in the third step of Example 3, the crude TM93 was synthesized by a method similar to that described in the third to fourth steps of Example 3. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 424.3[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.95 (brs, 6H), 7.75 (dd, J = 7.6, 1.2 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.42 (dd, J=7.6, 1.2Hz, 1H), 5.43 (s, 1H), 4.52 (s, 2H), 3.63-3.54 (m, 3H), 3.29-3.21 (m, 3H), 3.10-3.07 (m, 1H) , 2.20 (s, 3H), 1.84-1.77 (m, 2H), 1.64-1.58 (m, 2H), 1.21 (d, J = 6.8 Hz, 3H).

Example 34: (3-(4-(1-aminopropyl)-4-methylpiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazine- Preparation of 2-base) methanol (TM94)

Except that ethylmagnesium bromide was used in the first step of this example to replace the methylmagnesium bromide in the second step of Example 21, it was synthesized by a method similar to that described in the second to sixth steps in Example 21. Crude product of TM94. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 423.3[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.74 (dd, J = 7.6, 1.2 Hz, 1H), 7.69 (s, 3H), 7.49 (t, J = 7.6 Hz, 1H), 7.41 (dd, J=7.6, 1.2Hz, 1H), 5.34 (brs, 1H), 4.50 (s, 2H), 3.68-3.62 (m, 2H), 3.20-3.01 (m, 2H), 2.922.83 (m, 1H) , 2.19 (s, 3H), 1.79-1.69 (m, 1H), 1.64-1.60 (m, 3H), 1.54-1.47 (m, 1H), 1.44-1.34 (m, 1H), 1.05-1.00 (m, 6H).

Example 35: (3-(4-(aminomethyl)-4-(pyridin-2-ylmethyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)-5- Preparation of methylpyrazin-2-yl)methanol (TM22)

Except that 2-chloromethylpyridine was used in the first step of this example to replace the benzyl chloromethyl ether in the first step of Example 3, the crude TM22 was synthesized by a method similar to that described in Example 3. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 472.1[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.58 (d, J = 4.4 Hz, 1H), 8.08 (s, 3H), 7.87-7.79 (m, 1H), 7.74 (dd, J = 7.6, 1.2 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.45-7.40 (m, 2H), 7.38-7.33 (m, 1H), 4.49 (s, 2H), 3.44-3.38 (m, 4H) , 3.04 (s, 2H), 2.88 (d, J = 5.2 Hz, 2H), 2.19 (s, 3H), 1.65-1.55 (m, 4H).

Example 36: (3-(4-(aminomethyl)-4-(thiazol-5-ylmethyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)-5- Preparation of methylpyrazin-2-yl)methanol (TM95)

Except that in the first step of this example, 2-bromo-5-(bromomethyl)thiazole was used instead of the benzyl chloromethyl ether in the first step of Example 3, a method similar to that described in Example 3 was adopted. The crude product of TM95 was synthesized. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 478.1[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.05 (s, 1H), 7.87 (s, 3H), 7.78 (s, 1H), 7.75 (dd, J = 7.6, 1.2 Hz, 1H), 7.49 ( t, J=7.6Hz, 1H), 7.42(dd, J=7.6, 1.2Hz, 1H), 5.37(s, 1H), 4.49(s, 2H), 3.56-3.42(m, 4H), 3.16(s , 2H), 2.91-2.79 (m, 2H), 2.19 (s, 3H), 1.73-1.63 (m, 2H), 1.62-1.52 (m, 2H).

Example 37: (3-(4-(aminomethyl)-4-((1,6-dihydropyrimidin-4-yl)methyl)piperidin-1-yl)-6-(2,3- Preparation of dichlorophenyl)-5-methylpyrazin-2-yl)methanol (TM96)

Except that 4-(chloromethyl)pyrimidine was used in the first step of this example to replace the benzyl chloromethyl ether in the first step of Example 3, the crude product of TM96 was synthesized by a method similar to that described in Example 3 . The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 475.3[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ + D ₂ O) δ 7.99 (s, 1H), 7.73 (dd, J = 7.6, 1.2 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.39 (dd, J=7.6, 1.2 Hz, 1H), 4.98 (s, 1H), 4.54-4.47 (m, 2H), 4.21-4.12 (m, 2H), 3.52-3.44 (m, 2H), 3.33- 3.21 (m, 2H), 3.00 (s, 2H), 2.30-2.22 (m, 2H), 2.19 (s, 3H), 1.72-1.58 (m, 4H).

Example 38: 3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(2,3-dichloro-4-methoxyphenyl)-5- Preparation of methylpyrazin-2-yl)methanol (TM97)

Except that 38-1 was used in the first step of this example to replace the (2,3-dichloropyridin-4-yl)boronic acid in the second step of Example 25, the second step to the third step of Example 25 were used. The crude product of TM97 was synthesized in a similar manner as described. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 439.2[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.69 (s, 3H), 7.38 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 5.31 (s, 1H) , 4.49(s, 2H), 3.95(s, 3H), 3.76-3.57(m, 2H), 3.21-3.17(m, 1H), 3.16-2.98(m, 2H), 2.18(s, 3H), 1.69 -1.39(m, 4H), 1.16(d, J=6.4Hz, 3H), 1.00(s, 3H).

Example 39: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(3-chloro-2-fluoropyridin-4-yl)-5-methyl Preparation of pyrazine-2-yl)methanol (TM98)

The first step: 3-(4-(1-((tert-butoxycarbonyl)amino)ethyl)-4-methylpiperidin-1-yl)-6-(3-chloro-2-fluoropyridine-4 -Yl)-5-methylpyrazine-2-carboxylic acid ethyl ester (39-2)

Except that 39-1 was used in this step instead of (2,3-dichloropyridin-4-yl)boronic acid in the second step of Example 25, 39 was synthesized by a method similar to that described in the second step of Example 25. -2.

The second step: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(3-chloro-2-fluoropyridin-4-yl)-5-methyl Preparation of pyrazine-2-yl)methanol (TM98)

Add 39-2 (40mg, 74.62μmol) and dichloromethane (5mL) into the reaction flask, cool the ice water to 0～5℃, drop DIBAL-H (1M in hexane, 0.45mL), keep warm for 5～10 Reaction at °C for 2 hours. After the reaction was completed, methanol (1 mL) was added dropwise, dichloromethane (10 mL) and water (2 mL) were added, the organic phase was extracted and separated, dried and concentrated. The residue was dissolved in dichloromethane (1 mL) and added to the reaction flask, TFA (1 mL) was added dropwise, and reacted at 25°C for 1 hour. After the completion of the reaction, the reaction solution was concentrated to dryness, and the crude product was purified by reverse-phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound (10.8 mg, yield 28%) ).

MS m/z(ESI): 394.3[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.30 (d, J = 5.2 Hz, 1H), 7.74 (br, 3H), 7.51 (d, J = 5.2 Hz, 1H), 5.42 (s, 1H) , 4.51 (s, 2H), 3.85-3.70 (m, 2H), 3.20-3.09 (m, 3H), 2.24 (s, 3H), 1.71-1.45 (m, 4H), 1.16 (d, J = 6.8 Hz , 3H), 1.01(s, 3H).

Example 40: 4-(1-aminoethyl)-1-(5-(2,3-dichlorophenyl)-3-(hydroxymethyl)-6-methylpyrazin-2-yl)piper Preparation of pyridin-4-ol (TM99)

The first step: Preparation of tert-butyl 4-ethylenepiperidine-1-carboxylate (40-2)

Add ethyltriphenylphosphonium bromide (19.6g, 52.7mmol) and THF (250mL) into the reaction flask, reduce the temperature to -78°C, add n-BuLi (2.5M in hexane, 22mL) dropwise, after the addition is complete After the reaction was incubated for 1 hour, the temperature was raised to -20°C, and a solution of N-tert-butoxycarbonyl-4-piperidone (10.0 g, 50.2 mmol) in THF (50 mL) was added dropwise, and the reaction was incubated for 2 hours. After the reaction was completed, water was added, petroleum ether was used for extraction and liquid separation, the organic phase was dried and concentrated, and the crude product was purified by column chromatography to obtain 40-2 (5.60 g, yield 50%).

The second step: Preparation of 2-methyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (40-3)

Add 40-2 (5.20g, 24.61mmol) and dichloromethane (120mL) into the reaction flask, add m-chloroperoxybenzoic acid (6.37g, 36.91mmol) in batches at 25°C, and react at room temperature for 3 hours. After the completion of the reaction, saturated sodium sulfite (40ml) was added to quench the reaction, separated, the organic phase was washed with saturated sodium bicarbonate, the DCM phase was separated, washed with brine, dried and concentrated to obtain 40-3 (5.40g, yield 96%). Used directly in the next reaction.

The third step: Preparation of tert-butyl 4-(1-azidoethyl)-4-hydroxypiperidine-1-carboxylate (40-4)

40-3 (2.00 g, 8.80 mmol), DMF (20 mL), NH ₄ Cl (0.71 g, 13.20 mmol), NaN ₃ (0.74 g, 11.38 mmol) were added to the reaction flask, and the temperature was raised to 100° C. for 6 hours. After the reaction was completed, it was cooled to room temperature, water was added, and methyl tert-butyl ether was extracted. The organic phase was washed twice with water and dried and concentrated to dryness to obtain crude product 40-4 (2.20 g, yield 92%), which was directly used in the next reaction.

Step 4: Preparation of tert-butyl 4-(1-aminoethyl)-4-hydroxypiperidine-1-carboxylate (40-5)

Add 40-4 (2.00g, 7.40mmol), MeOH (60mL), and 10% Pd/C (270mg) into the autoclave. After replacing the air with nitrogen, add hydrogen to a pressure of 0.5MPa, and heat up to 40°C to react approximately 12 hours. After the reaction was completed, the palladium carbon was filtered off, and the filtrate was concentrated to dryness to obtain 40-5 (1.28 g, yield 71%).

Step 5 to Step 7: 4-(1-aminoethyl)-1-(5-(2,3-dichlorophenyl)-3-(hydroxymethyl)-6-methylpyrazine-2 -Yl)piperidin-4-ol (TM99) preparation

Except that 40-5 was used in the fifth step instead of 3-2 in the second step in Example 3, the crude TM99 was synthesized by a method similar to that described in the second to fourth steps in Example 3. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 411.3[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.74 (dd, J = 7.6, 1.2 Hz, 1H), 7.68 (s, 3H), 7.51-7.40 (m, 2H), 5.34 (s, 1H), 5.15(s, 1H), 4.50(s, 2H), 3.78-3.67(m, 2H), 3.24-3.13(m, 3H), 2.19(s, 3H), 1.78-1.57(m, 4H), 1.17( d, J=6.8Hz, 3H).

Example 41: (3-(4-(1-aminoethyl)-4-methoxypiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazine Preparation of -2-yl)methanol (TM100)

The first step: the preparation of 4-(1-azidoethyl)-4-methoxypiperidine-1-carboxylic acid tert-butyl ester (41-1)

Add 40-4 (1.80 g, 6.66 mmol) and DMF (5 mL) into the reaction flask, cool to 0° C., add NaH (0.66 g, 16.65 mmol, 60%) in batches, and stir for 10 minutes. Add iodomethane (2.36g, 16.65mmol) dropwise, and react at room temperature for 2 hours. After the reaction was completed, the temperature was lowered to 0°C, saturated ammonium chloride was added to quench the reaction, the reaction was quenched with methyl tert-butyl ether, the organic phase was washed with water, dried and concentrated to obtain crude product 41-1 (1.80g, yield 95%), which was used directly Next reaction.

Steps 2 to 5: (3-(4-(1-aminoethyl)-4-methoxypiperidin-1-yl)-6-(2,3-dichlorophenyl)-5- Preparation of methylpyrazin-2-yl)methanol (TM100)

Except that 41-1 was used in the second step instead of 40-4 in the fourth step in Example 40, the crude TM100 was synthesized by a method similar to that described in the fourth to seventh steps in Example 40. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 425.3[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.80-7.67 (m, 4H), 7.48 (t, J = 7.6 Hz, 1H), 7.42 (dd, J = 7.6 Hz, 1H), 5.36 (s, 1H), 4.52(s, 2H), 3.75-3.58(m, 3H), 3.21(s, 3H), 3.19-3.05(m, 2H), 2.19(s, 3H), 1.91-1.61(m, 4H) , 1.17 (d, J = 6.8 Hz, 3H).

Example 42: (3-(4-(aminomethyl)-4-(oxazol-4-ylmethyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)-5 -Methylpyrazin-2-yl) methanol (TM149) preparation

The first step: Preparation of oxazol-4-yl methyl methanesulfonate (42-2)

Dissolve oxazol-4-ylmethanol (1.30g, 13.12mmol) in DCM (20mL), cool to 0°C, add triethylamine (1.99g, 19.68mmol), and slowly add methylsulfonyl chloride (1.65 g, 14.43mmol), after the addition, stir at 0°C for 10 minutes, and then slowly warm up to room temperature to react for 1 hour. After the completion of the reaction, water (20 mL) was added to the reaction solution, fully stirred and then separated, the organic phase was dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated, and purified by silica gel column chromatography to obtain 42-2 (1.10 g).

Step 2: Preparation of tert-butyl 4-cyano-4-(oxazol-4-ylmethyl)piperidine-1-carboxylate (42-3)

Under the protection of nitrogen, dissolve N-tert-butoxycarbonyl-4-cyanopiperidine (650mg, 3.09mmol) in THF (20mL), cool to -78℃, and slowly add LDA (2M in THF, 3.7mL) ), after the addition, stir at this temperature for 0.5 hours, then slowly add 42-2 (500 mg, 2.82 mmol), and after the addition, naturally warm to room temperature and react for 4 hours. After the reaction was completed, saturated ammonium chloride solution (20mL) was added to the reaction solution. After stirring well, DCM (40mL) was added. After stirring well again, the layers were separated. The organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated and silica gel Purified by column chromatography, 42-3 (310 mg) was obtained.

Steps 3 to 5: (3-(4-(aminomethyl)-4-(oxazol-4-ylmethyl)piperidin-1-yl)-6-(2,3-dichlorobenzene Preparation of 5-methylpyrazin-2-yl)methanol (TM149)

Except that 42-3 was used in the third step instead of 3-2 in the second step in Example 3, the crude TM149 was synthesized by a method similar to that described in the second to fourth steps in Example 3. The crude product was reversed Purified by HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous formic acid) to obtain the title compound.

MS m/z(ESI): 462.2[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 8.54 (s, 1H), 8.20 (s, 1H), 7.87 (s, 1H), 7.64 (dd, J = 7.6, 1.2 Hz, 1H), 7.42 (t , J=7.6Hz, 1H), 7.34(dd, J=7.6, 1.6Hz, 1H), 4.66(s, 2H), 3.54-3.37(m, 4H), 2.99(s, 2H), 2.87(s, 2H), 2.25(s, 3H), 1.72-1.69(m, 4H).

Example 43: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-((2,3-dichloropyridin-4-yl)sulfanyl)- Preparation of 5-methylpyrazin-2-yl)methanol (TM114)

The first step: 3-(4-(1-((tert-butoxycarbonyl)amino)ethyl)-4-methylpiperidin-1-yl)-6-((2,3-dichloropyridine-4 -Yl)thio)-5-methylpyrazine-2-carboxylic acid ethyl ester (43-2)

Add 43-1 (83.4mg, 0.46mmol) to 1,4-dioxane (5mL), add potassium phosphate (196.8mg, 0.93mmol), cuprous iodide (59.0mg, 0.31mmol), 1 , 10-phenanthroline (55.7mg, 0.31mmol), then add 25-1 (150mg, 0.31mmol), under nitrogen protection, react at 98℃ for 16hr, filter, concentrate the filtrate, and separate by silica gel column chromatography (petroleum Ether: ethyl acetate=3:1) to obtain solid 43-2 (90mg, yield 50%).

The second step: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-((2,3-dichloropyridin-4-yl)sulfanyl)- Preparation of 5-methylpyrazin-2-yl)methanol (TM114)

Except that 43-2 was used in the second step of this example instead of 25-2 in the third step of Example 25, the crude TM114 was synthesized by a method similar to that described in the third step of Example 25. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 442.1[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.11 (d, J = 5.4 Hz, 1H), 7.68 (s, 3H), 6.67 (d, J = 5.4 Hz, 1H), 5.53 (s, 1H) , 4.47 (s, 2H), 3.89 (t, J = 14.0 Hz, 2H), 3.27-3.05 (m, 3H), 2.42 (s, 3H), 1.62-1.40 (m, 4H), 1.14 (d, J =6.8Hz, 3H), 1.01(s, 3H).

Example 44: (3-(4-(aminomethyl)-4-((methylamino)methyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)-5- Preparation of methylpyrazin-2-yl)methanol (TM173)

The first step: the preparation of 4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-4-cyanopiperidine-1-carboxylic acid benzyl ester (44-1)

Dissolve 7-2 (0.5g, 1.33mmol) in anhydrous tetrahydrofuran (5mL), cool to 0°C, add NaH (0.11g, 2.66mmol, 60%), stir for 10min, add methyl iodide (0.38g, 2.66mmol), after the addition, stir at 0°C for 10 minutes, and then slowly warm up to room temperature to react for 1 hour. After the reaction is complete, add water (15mL) and ethyl acetate (15mL) to the reaction solution, stir well and separate the liquids. The organic phase is dried with anhydrous sodium sulfate and filtered. The filtrate is concentrated to obtain crude product 44-1 (0.5g). Used directly in the next reaction.

Steps 2 to 4: 3-(4-cyano-4-((methylamino)methyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)-5- Preparation of ethyl methylpyrazine-2-carboxylate (44-4)

Except that 44-1 was used in the second step of this Example instead of 7-2 in the third step of Example 7, a similar method as described in the third to fifth steps of Example 7 was used to synthesize 44-4.

The fifth step: (3-(4-(aminomethyl)-4-((methylamino)methyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)-5- Preparation of methylpyrazin-2-yl)methanol (TM173)

Except that 44-4 was used in the fifth step of this example instead of 3-4 in the fourth step of Example 3, the crude product of TM173 was synthesized by a similar method as described in the fourth step of Example 3. The crude product was subjected to reversed-phase HPLC. (Mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) The trifluoroacetic acid salt of the title compound was purified.

MS m/z(ESI): 424.3[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 7.63 (dd, J = 7.6, 1.2 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.33 (dd, J = 7.6, 1.6 Hz, 1H ), 4.68(s, 2H), 3.55-3.39(m, 4H), 3.30(s, 2H), 3.26(s, 2H), 2.64(s, 3H), 2.09(s, 3H), 1.69-1.64( m, 4H).

Example 45: (6-((2-amino-3-chloropyridin-4-yl)sulfanyl)-3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl) Preparation of pyrazin-2-yl)methanol (TM174)

The first step: 6-bromo-3-(4-(1-((tert-butoxycarbonyl)amino)ethyl)-4-methylpiperidin-1-yl)pyrazine-2-carboxylic acid methyl ester ( 45-2) Preparation

Compound 45-1 (3.7 g, 12.50 mmol), compound 21-5 (2.35 g, 13.13 mmol) and DIPEA (8.08 g, 62.50 mmol) were added to NMP (52.5 mL) and reacted at 25° C. for 3 hr. LC-MS monitored the reaction to be complete. Then, di-tert-butyl dicarbonate (3 g, 13.75 mol) was added to the reaction solution, and the reaction was continued at 25° C. for 2 hours. Water and ethyl acetate were added to extract the product. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by thin layer chromatography to obtain compound 45-2 (2.5g, yield 44%) ).

Steps 2 to 3: (6-((2-amino-3-chloropyridin-4-yl)thio)-3-(4-(1-aminoethyl)-4-methylpiperidine- Preparation of 1-yl)pyrazin-2-yl)methanol (TM174)

Except that sodium 2-amino-3-chloropyridine-4-thiophenol was used in the second step of this example to replace 2,3-dichloropyridine-4-thiophenol (43-1) in the first step of Example 43 In addition, the crude product of TM174 was synthesized by a method similar to that described in the first to second steps in Example 43. The crude product was prepared by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous formic acid) to obtain the title Compound.

MS m/z(ESI): 409.1[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 8.51 (s, 1H), 8.30 (s, 1H), 7.60 (d, J = 5.6 Hz, 1H), 6.04 (d, J = 5.6 Hz, 1H), 4.66(s, 2H), 3.87-3.76(m, 2H), 3.28-3.15(m, 3H), 1.79-1.51(m, 4H), 1.29(d, J=6.8Hz, 3H), 1.12(s, 3H).

Example 46: (3-(4-(1-amino-2-fluoroethyl)-4-methylpiperidin-1-yl)-6-((2-amino-3-chloropyridin-4-yl )Sulfanyl)-5-methylpyrazin-2-yl)methanol (TM164) preparation

Step 1: Preparation of tert-butyl 4-(2-bromoacetyl)-4-methylpiperidine-1-carboxylate (46-1)

Under the protection of nitrogen, 21-3 (5.00 g, 20.72 mmol) was added to THF (50 mL), the temperature was lowered to -78° C., LDA (2M in tetrahydrofuran, 34.19 mL) was added dropwise, and the temperature was maintained and stirred for 10 minutes after dropping. Then TMSC1 (7.43g, 68.37mmol) was dropped into the system, the temperature was controlled at -78°C, and the dropping was completed and stirred for 1 hour. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution, extracted twice with methyl tert-butyl ether, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain an oily substance. The oil was dissolved in THF (25 mL), sodium carbonate (4.39 g, 41.44 mmol) was added, the temperature was lowered to 0° C., NBS (4.06 g, 22.79 mmol) was added in portions, and then the temperature was raised to 25° C. to react for 4 hours. After the completion of the reaction, methyl tert-butyl ether and 10% sodium carbonate aqueous solution were added to the reaction solution. After stirring, the solution was separated. The organic phase was washed once with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to column chromatography. Purified to obtain 46-1 (6.60 g, yield 99%).

Step 2: Preparation of tert-butyl 4-(2-fluoroacetyl)-4-methylpiperidine-1-carboxylate (46-2)

Add 46-1 (6.60g, 20.61mmol), 18-crown-6 (6.86g, 25.97mmol), anhydrous potassium fluoride (3.23g, 55.65mmol) into toluene (100mL), and heat to 85°C for reaction 6. hour. After the reaction is completed, cool to room temperature, add water to the system, separate the organic phase, wash once with brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dry to obtain crude product 46-2 (4.68g), which is used directly in the next step reaction.

Steps 3 to 4: Preparation of 2-fluoro-1-(4-methylpiperidin-4-yl)ethan-1-amine hydrochloride (46-4)

Except that 46-2 was used in the third step instead of 21-3 in the third step in Example 21, 46-4 was synthesized by a method similar to that described in the third to fourth steps in Example 21.

The fifth step: 6-bromo-3-(4-(1-((tert-butoxycarbonyl)amino)-2-fluoroethyl)-4-methylpiperidin-1-yl)-5-methylpyridine Preparation of oxazine-2-carboxylic acid ethyl ester (46-5)

Except that 46-4 was used in this step instead of 21-5 in the first step in Example 25, 46-5 was synthesized by a method similar to that described in the first step in Example 25.

Step 6 to Step 7: (3-(4-(1-amino-2-fluoroethyl)-4-methylpiperidin-1-yl)-6-((2-amino-3-chloropyridine) -4-yl)sulfanyl)-5-methylpyrazin-2-yl)methanol (TM164)

Except that in the sixth step of this example, 2-amino-3-chloropyridine-4-thiophenol sodium was used to replace the 2,3-dichloropyridine-4-thiophenol (43-1) in the first step in Example 43. In addition, the crude product of TM164 was synthesized by a method similar to that described in the first to second steps in Example 43, and the crude product was purified by reverse-phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) The trifluoroacetate salt of the title compound was obtained.

MS m/z(ESI): 441.0[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.11 (s, 3H), 7.67 (d, J = 5.6 Hz, 1H), 6.82 (s, 2H), 5.81 (d, J = 5.6 Hz, 1H) , 4.86-4.76(m, 1H), 4.69-4.64(m, 1H), 4.47(s, 2H), 3.85-3.83(m, 2H), 3.44-3.38(m, 1H), 3.21(m, 2H) , 2.41 (s, 3H), 1.72-1.67 (m, 2H), 1.58-1.50 (m, 2H), 1.09 (s, 3H).

Example 47: (3-(4-(1-amino-2-fluoroethyl)-4-methylpiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methyl Preparation of pyrazine-2-yl)methanol (TM175)

Except that in the first step of this example, 46-5 and 2,3-dichlorophenylboronic acid were used to replace 25-1 and (2,3-dichloropyridin-4-yl)boronic acid in the second step of Example 25, respectively. Instead, the crude product of TM175 was synthesized by a method similar to that described in the second to third steps in Example 25, and the crude product was subjected to reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) The trifluoroacetate salt of the title compound was purified.

MS m/z(ESI): 426.9[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 7.64 (dd, J = 7.8, 1.6 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.34 (dd, J = 7.8, 1.6 Hz, 1H ), 4.85-4.69 (m, 2H), 4.66 (s, 2H), 3.73-3.62 (m, 2H), 3.49-3.39 (m, 1H), 3.22 (m, 2H), 2.25 (s, 3H), 1.88-1.79(m, 2H), 1.65(m, 2H), 1.20(s, 3H).

Example 48: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-((2-chloropyridin-3-yl)sulfanyl)-5-methyl Preparation of pyrazine-2-yl)methanol (TM151)

Except that sodium 2-chloropyridine-3-thiophenolate was used in the first step of this example instead of 43-1 in the first step of Example 43, the same as those described in the first to second steps of Example 43 were used. The crude product of TM151 was synthesized in a similar way. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 408.0[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 8.22 (dd, J = 4.8, 1.6 Hz, 1H), 7.49 (dd, J = 7.8, 1.6 Hz, 1H), 7.27 (dd, J = 7.8, 4.8 Hz) , 1H), 4.56 (s, 2H), 3.81-3.66 (m, 2H), 3.25-3.13 (m, 3H), 2.50 (s, 3H), 1.76-1.49 (m, 4H), 1.28 (d, J =7.2Hz, 3H), 1.11(s, 3H).

Example 49: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-5-methyl-6-((2-(trifluoromethyl)pyridine-3 -Yl)thio)pyrazin-2-yl)methanol (TM152) preparation

Except that sodium 2-(trifluoromethyl)pyridine-3-thiophenolate was used in the first step of this example instead of 43-1 in the first step of Example 43, the same methods as those used in the first to second steps of Example 43 were used. The crude product of TM152 was synthesized in a similar way as described in step. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous sodium bicarbonate solution) to obtain the title compound.

MS m/z(ESI): 442.1[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 8.48 (d, J = 4.8 Hz, 1H), 7.69 (d, J = 4.8 Hz, 1H), 7.49 (d, J = 4.8, 4.8 Hz, 1H), 4.55 (s, 2H), 3.68-3.66 (m, 2H), 3.18-3.12 (m, 2H), 2.84-2.19 (m, 1H), 2.47 (s, 3H), 1.68-1.46 (m, 4H), 1.12(d, J=6.8Hz, 3H), 1.01(s, 3H).

Example 50: (3-(4-(1-aminoethyl)-4-(fluoromethyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methyl Preparation of pyrazin-2-yl)methanol (TM109)

Step 1: Preparation of 1-(tert-butyl)4-ethyl 4-(fluoromethyl)piperidine-1,4-dicarboxylate (50-2)

Ethyl N-Boc-4-piperidinecarboxylate (5.0g, 19.43mmol) was dissolved in THF (40mL), cooled to -78℃, LDA (2M in tetrahydrofuran, 16.5mL) was added dropwise, and reacted at -78℃ for 1 hour . Subsequently, fluorobromomethane (2.8g, 24.93mmol) was added dropwise, the temperature was maintained for 1 hour, and the temperature was raised to 25°C for 1 hour. After the reaction was completed, saturated ammonium chloride solution was added to the reaction solution, extracted three times with ethyl acetate, the organic phases were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain 50-2 (2.1g, yield 37 %).

Step 2: Preparation of tert-butyl 4-(fluoromethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (50-3)

50-2 (2.2g, 7.60mmol) was dissolved in THF (20mL), the temperature was lowered to 0°C, lithium aluminum hydride (283.7mg, 8.36mmol) was slowly added, and the reaction was carried out at 0°C for 1 hour. After the completion of the reaction, water (2mL), 10% NaOH aqueous solution (2mL) and water (6mL) were sequentially added to the reaction solution, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to obtain crude product 50-3 (1.8g), directly Used in the next reaction.

The third step: preparation of tert-butyl 4-(fluoromethyl)-4-formylpiperidine-1-carboxylate (50-4)

50-3 (1.18 g, 4.52 mmol) was dissolved in dichloromethane (20 mL), pyridinium chlorochromate (2.84 g, 13.55 mmol) was added, and the reaction was carried out at 20°C for 16 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain 50-4 (0.80 g, yield 68%).

The fourth step: (E)-4-(((tert-butylsulfinyl)imino)methyl)-4-(fluoromethyl)piperidine-1-carboxylic acid tert-butyl ester (50-5) preparation

Dissolve 50-4 (0.80g, 3.26mmol) in dichloromethane (30mL), add cesium carbonate (3.19g, 9.78mmol) and tert-butylsulfinamide (0.59g, 4.89mmol), and react at 25°C for 16 hours After the completion of the reaction was detected by LC-MS, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 50-5 (1.00 g, yield 87%).

Step 5: Preparation of tert-butyl 4-(1-((tert-butylsulfinyl)amino)ethyl)-4-(fluoromethyl)piperidine-1-carboxylate (50-6)

50-5 (1.0 g, 2.87 mmol) was dissolved in THF (10 mL), the temperature was lowered to -78°C, methyl lithium (1M in tetrahydrofuran, 6.0 mL) was added dropwise, and the reaction was carried out at -78°C for 15 minutes. After the completion of the reaction, saturated ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate three times, the organic phases were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain crude product 50-6 (1.0 g), which was directly used in the next reaction.

Step 6: Preparation of 1-(4-(fluoromethyl)piperidin-4-yl)ethan-1-amine (50-7)

50-6 (1.4g, 3.84mmol) was dissolved in MeOH (15mL), added to HCl (2M in ethyl acetate, 15mL), and reacted at 25°C for 1 hour. After the reaction, it was concentrated under reduced pressure to obtain the crude product 50-7 hydrochloride (0.6 g), which was directly used in the next reaction.

Steps 7 to 8: (3-(4-(1-aminoethyl)-4-(fluoromethyl)piperidin-1-yl)-6-(2,3-dichlorophenyl)- Preparation of 5-methylpyrazin-2-yl)methanol (TM109)

Except that 50-7 was used in the seventh step instead of 3-3 in the third step in Example 3, the crude product of TM109 was synthesized by a method similar to that described in the third to fourth steps in Example 3. The crude product was reversed Phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous sodium bicarbonate) purification to obtain the title compound.

MS m/z(ESI): 427.0[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.73 (dd, J = 8.0, 1.6 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.42 (dd, J = 8.0, 1.6 Hz, 1H), 5.30 (t, J = 6.0 Hz, 1H), 4.71-4.51 (m, 2H), 4.50 (d, J = 6.0 Hz, 2H), 3.63-3.53 (m, 2H), 3.23-3.09 (m , 2H), 2.84 (m, 1H), 2.18 (s, 3H), 1.77-1.49 (m, 4H), 1.02 (d, J = 6.4 Hz, 3H).

Example 51: (6-((2-Amino-3-chloropyridin-4-yl)thio)-3-(4-(1-aminoethyl)-4-(fluoromethyl)piperidine-1 -Yl)-5-methylpyrazin-2-yl)methanol (TM167)

The first step: 6-bromo-3-(4-(1-((tert-butoxycarbonyl)amino)ethyl)-4-(fluoromethyl)piperidin-1-yl)-5-methylpyridine Preparation of oxazine-2-carboxylic acid ethyl ester (51-1)

Except that 50-7 was used in this step instead of 21-5 in the first step in Example 25, 51-1 was synthesized by a method similar to that described in the first step in Example 25.

Steps 2 to 3: (6-((2-amino-3-chloropyridin-4-yl)thio)-3-(4-(1-aminoethyl)-4-(fluoromethyl) Preparation of piperidin-1-yl)-5-methylpyrazin-2-yl)methanol (TM167)

Except that in the second step of this example, 2-amino-3-chloropyridine-4-thiophenol sodium was used to replace the 2,3-dichloropyridine-4-thiophenol (43-1) in the first step of Example 43. In addition, the crude product of TM167 was synthesized by a method similar to that described in the first to second steps in Example 43, and the crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% sodium bicarbonate aqueous solution) Get the title compound.

MS m/z(ESI): 441.1[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 7.58 (d, J = 5.6 Hz, 1H), 5.87 (d, J = 5.6 Hz, 1H), 4.73 (d, J = 47.6 Hz, 2H), 4.63 ( s, 2H), 3.84-3.71 (m, 2H), 3.29-3.21 (m, 2H), 3.01 (m, 1H), 2.48 (s, 3H), 1.85-1.65 (m, 4H), 1.21 (d, J=6.8Hz, 3H).

Example 52: (3-(4-(1-aminoethyl)-4-(difluoromethyl)piperidin-1-yl)-6-(2,3-dichloropyridin-4-yl)- Preparation of 5-methylpyrazin-2-yl)methanol (TM176)

Step 1: Preparation of 1-(tert-butyl)4-ethyl 4-formylpiperidine-1,4-dicarboxylate (52-2)

Dissolve 52-1 (1.0g, 2.78mmol) in DCM (20mL), add PCC (1.7g, 8.35mmol), and react at 20°C for 24 hours. After the reaction is complete, the reaction solution is concentrated under reduced pressure to obtain a crude product. The crude product is passed through the column Analytical purification yields 52-2 (0.7g, yield 89%).

Step 2: Preparation of 1-(tert-butyl)4-ethyl 4-(difluoromethyl)piperidine-1,4-dicarboxylate (52-3)

52-2 (4.6g, 16.12mmol) was dissolved in diethylaminosulfur trifluoride (13.09g, 80.61mmol), and then reacted at 20°C for 18 hours. After the completion of the reaction, the reaction solution was slowly added dropwise to the cold saturated sodium bicarbonate solution, ethyl acetate was added to dilute the layers, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, dried, and concentrated under reduced pressure to obtain the crude product 52- 3 (4.5g), directly used in the next reaction.

Steps 3 to 7: Preparation of 1-(4-(difluoromethyl)piperidin-4-yl)ethan-1-amine (52-8)

Except that 52-3 was used in the third step instead of 50-2 in the second step in Example 50, the salt of the title compound 52-8 was synthesized by a method similar to that described in the second to sixth steps in Example 50 Acid salt.

Step 8 to Step 10: (3-(4-(1-aminoethyl)-4-(difluoromethyl)piperidin-1-yl)-6-(2,3-dichloropyridine-4 -Yl)-5-methylpyrazin-2-yl)methanol (TM176)

Except that 52-8 was used in the eighth step instead of 21-5 in the first step in Example 25, the crude product of TM176 was synthesized by a method similar to that described in the first to third steps in Example 25. The crude product was reversed Phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) purification to obtain the trifluoroacetic acid salt of the title compound.

MS m/z(ESI): 446.0[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.50 (d, J = 4.8 Hz, 1H), 7.92 (s, 3H), 7.57 (d, J = 4.8 Hz, 1H), 6.41 (t, J = 54.4Hz, 1H), 5.45 (s, 1H), 4.52 (s, 2H), 3.72-3.47 (m, 5H), 2.23 (s, 3H), 1.98-1.73 (m, 4H), 1.30 (d, J =6.9Hz, 3H).

Example 53: (3-(4-(1-aminoethyl)-4-(difluoromethyl)piperidin-1-yl)-6-((2,3-dichloropyridin-4-yl) Preparation of (thio)-5-methylpyrazin-2-yl)methanol (TM177)

Except that 52-9 was used in this example instead of 25-1 in the first step in Example 43, the crude product of TM177 was synthesized by a method similar to that described in the first to second steps in Example 43. The crude product was reversed. Phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous trifluoroacetic acid) purification to obtain the trifluoroacetic acid salt of the title compound.

MS m/z(ESI): 478.0[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.11 (d, J = 5.2 Hz, 1H), 7.92 (s, 3H), 6.67 (d, J = 5.2 Hz, 1H), 6.40 (t, J = 54Hz, 1H), 5.54 (s, 1H), 4.50 (s, 2H), 3.78-3.51 (m, 5H), 2.43 (s, 3H), 1.97-1.74 (m, 4H), 1.31 (d, J= 6.8Hz, 3H).

Example 54: 1-(4-((5-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)-3-methylpyrazine -2-yl)sulfanyl)-3-chloropyridin-2-yl)azetidine-3-ol (TM178)

The first step: (1-(1-(5-bromo-3-(hydroxymethyl)-6-methylpyrazin-2-yl)-4-methylpiperidin-4-yl)ethyl)amino Preparation of tert-butyl formate (54-1)

Dissolve 25-1 (5.7g, 11.74mmol) in dichloromethane (100mL), lower the temperature to -78°C, add DIBAL-H (1M in hexane, 35mL), after the addition, raise to 0°C and react for 15 minutes . After the reaction was completed, the temperature was lowered to -78°C, and an aqueous potassium sodium tartrate solution (20% wt, 100 mL) was added for quenching. After rising to room temperature, the reaction system was vigorously stirred for 2 hours. Extract with dichloromethane, combine the organic phases and dry and concentrate to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 54-1 (2.16 g, yield 39%).

The second step: (1-(1-(5-((2,3-dichloropyridin-4-yl)sulfanyl)-3-(hydroxymethyl)-6-methylpyrazin-2-yl) Preparation of tert-butyl 4-methylpiperidin-4-yl)ethyl)carbamate (54-2)

Except that 54-1 was used in this step instead of 25-1 in the first step in Example 43, compound 54-2 was synthesized by a method similar to that described in the first step in Example 43.

The third step: (1-(1-(5-((3-chloro-2-(3-hydroxyazetidin-1-yl)pyridin-4-yl)thio)-3-(hydroxymethyl (Yl)-6-methylpyrazin-2-yl)-4-methylpiperidin-4-yl)ethyl) tert-butyl carbamate (54-3)

Dissolve 54-2 (30.00mg, 55.30umol) in isopropanol (2mL), add azetidine-3-ol (8.08mg, 110.59umol) and DIPEA (28.59mg, 221.19umol), and react in microwave The reactor was heated to 120°C and reacted for 2 hours. After the completion of the reaction was detected by LC-MS, the reaction solution was concentrated and purified by thin layer chromatography to obtain compound 54-3 (12 mg, yield 37%).

The fourth step: 1-(4-((5-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(hydroxymethyl)-3-methylpyrazine -2-yl)sulfanyl)-3-chloropyridin-2-yl)azetidine-3-ol (TM178)

54-3 (12mg, 20.72umol) was dissolved in DCM (2mL), TFA (0.5mL) was added, and the reaction was carried out at 20°C for 0.5 hours. After the completion of the reaction was detected by LC-MS, the reaction solution was concentrated. The crude product was subjected to reversed-phase HPLC (mobile phase A: Acetonitrile, mobile phase B: 0.05% aqueous formic acid) The formate salt of the title compound (5 mg, yield 44%) was purified.

MS m/z(ESI): 479.0[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.38 (s, 1H), 7.79 (d, J = 5.6 Hz, 1H), 5.90 (d, J = 5.2 Hz, 1H), 4.53-4.45 (m, 1H), 4.46 (s, 2H), 4.38-4.31 (m, 2H), 3.90-3.82 (m, 4H), 2.99-2.96 (m, 2H), 2.93 (dd, J=12.4, 6.4Hz, 1H) , 2.40 (s, 3H), 1.66-1.32 (m, 4H), 1.08 (d, J = 6.8 Hz, 3H), 0.97 (s, 3H).

Example 55: (3-(4-(1-amino-2-fluoroethyl)-4-methylpiperidin-1-yl)-6-((2-amino-3-chloropyridin-4-yl ) Preparation of thio)pyrazin-2-yl)methanol (TM179).

Except that 46-4 was used in the first step of this example to replace 21-5 in the first step of Example 45, the crude TM179 was synthesized by a method similar to that described in the first to third steps of Example 45 The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetic acid salt of the title compound.

MS m/z(ESI): 427.1[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.36 (s, 1H), 8.20 (s, 3H), 7.72 (d, J = 6.0 Hz, 1H), 7.30 (brs, 1H), 6.04 (d, J=6.0Hz, 1H), 4.86-4.76 (m, 1H), 4.75-4.65 (m, 1H), 4.52 (s, 2H), 3.88-3.76 (m, 2H), 3.47-3.33 (m, 2H) , 3.23 (t, J = 11.6 Hz, 2H), 1.68-1.46 (m, 4H), 1.10 (s, 3H).

Example 56: (3-(4-(1-amino-2-methoxyethyl)-4-methylpiperidin-1-yl)-6-((2-amino-3-chloropyridine-4 -Yl)thio)pyrazin-2-yl)methanol (TM180) preparation

The first step: Preparation of tert-butyl 4-methyl-4-(oxiran-2-yl)piperidine-1-carboxylate (56-2)

Under the protection of nitrogen, add trimethylsulfoxide iodide (12.2g, 55.4mmol) into DMSO (50mL), cool the ice water to 0℃; add NaH (1.27g, 55.4mmol) in batches, and keep the temperature for 10~ React at 20°C for 0.5 hours; add tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate (7.00 g, 30.8 mmol) all at once and keep at 10-20°C and react for 4 hours. The ice water was cooled to 0°C, water (150ml) and ethyl acetate (200ml) were added in sequence and stirred for 10 minutes. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain compound 56-2 The crude product (5.37g) was used directly in the next step.

Step 2: Preparation of tert-butyl 4-(1-hydroxy-2-methoxyethyl)-4-methylpiperidine-1-carboxylate (56-3)

Compound 56-2 (1.40 g, 5.80 mmol) was dissolved in MeOH (60 mL), MeONa (10.44 g, 58.0 mmol, 30% MeOH solution) was added, and then stirred at 40° C. for 5 h. LC-MS showed that the raw materials had disappeared, cooled to room temperature, quenched the reaction with 1N HCl, extracted with ethyl acetate, combined the organic phases, dried over anhydrous sodium sulfate, filtered off with suction, and concentrated to obtain crude compound 56-3 (1.4g). Used directly in the next step.

Step 3: Preparation of tert-butyl 4-(2-methoxyacetyl)-4-methylpiperidine-1-carboxylate (56-4)

Compound 56-3 (300 mg, 1.10 mmol) was dissolved in DCM (20 mL), sodium bicarbonate (277 mg, 3.30 mmol) and Dess-Martin reagent (710 mg, 1.65 mmol) were added, and then stirred at room temperature for 5 h. LC-MS showed that the raw materials had disappeared, cooled to room temperature, quenched the reaction with saturated sodium sulfite solution, extracted with dichloromethane, combined the organic phases, dried over anhydrous sodium sulfate, filtered off with suction, and concentrated to obtain crude compound 56-4 (250mg). Used directly in the next step.

The fourth step: Preparation of (Z)-4-(1-(oximino)-2-methoxyethyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (56-5)

Compound 56-4 (230 mg, 0.85 mmol) was dissolved in EtOH (10 mL), hydroxylamine hydrochloride (118 mg, 1.70 mmol) and triethylamine (257 mg, 2.54 mmol) were added, and then stirred at 60° C. for 2 h. LC-MS showed that the raw materials had disappeared, cooled to room temperature, diluted with ethyl acetate, washed with 1N hydrochloric acid solution, combined the organic phases, dried over anhydrous sodium sulfate, filtered off with suction, and concentrated to obtain crude compound 56-5 (230mg), directly Used in the next step.

Step 5: Preparation of tert-butyl 4-(1-amino-2-methoxyethyl)-4-methylpiperidine-1-carboxylate (56-6)

Compound 56-5 (230 mg, 0.85 mmol) was dissolved in MeOH (10 mL), Raney nickel (94 mg, 1.61 mmol) was added, replaced with a hydrogen balloon three times, and stirred at room temperature for 10 hours. LC-MS showed that the raw material had disappeared. It was filtered through a pad of diatomaceous earth and concentrated to obtain crude compound 56-6 (200 mg), which was used directly in the next step without further purification.

Step 6: Preparation of 2-methoxy-1-(4-methylpiperidin-4-yl)ethan-1-amine (Compound 56-7)

Compound 56-6 (200 mg, 0.73 mmol) was dissolved in DCM (10 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. LC-MS showed that the raw material had disappeared, and it was concentrated to obtain the crude trifluoroacetate salt of compound 56-7 (200 mg, yield 95%), which was used directly in the next step without further purification.

Seventh to ninth steps: (3-(4-(1-amino-2-methoxyethyl)-4-methylpiperidin-1-yl)-6-((2-amino-3-chloro Preparation of pyridin-4-yl)thio)pyrazin-2-yl)methanol (TM180).

Except that in the seventh step of this example, 56-7 trifluoroacetate was used instead of 21-5 in the first step of Example 45, the same as those described in the first to third steps of Example 45 were used. The crude product of TM180 was synthesized by the method described above, and the crude product was purified by reverse-phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetic acid salt of the title compound.

MS m/z(ESI): 439.1[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 8.27 (s, 1H), 7.61 (d, J = 5.6 Hz, 1H), 6.04 (d, J = 5.6 Hz, 1H), 4.65 (s, 2H), 3.77-3.70(m, 1H), 3.58(dd, J=9.2, 3.2Hz, 1H), 3.36(s, 3H), 3.33-3.20(m, 4H), 2.80(dd, J=8.8, 3.2Hz, 1H), 1.81-1.66 (m, 2H), 1.61-1.51 (m, 2H), 1.05 (s, 3H).

Example 57: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-((7-chloro-1H-indazol-6-yl)sulfanyl) Preparation of -5-methylpyrazin-2-yl)methanol (TM181)

Step 1: Preparation of 2-ethylhexyl 3-((7-chloro-1H-indazol-6-yl)thio)propionate (57-2)

Combine 57-1 (1.76g, 7.61mmol), 2-ethylhexyl 3-mercaptopropionate (2.49g, 11.42mmol), DIPEA (1.97g, 15.23mmol), Xantphos (0.44g, 0.76mmol) and three (Dibenzylideneacetone)dipalladium (0.38g, 0.38mmol) was dissolved in 1,4-dioxane (20mL), replaced with nitrogen three times, and heated at 100°C to react for 2 hours. After the reaction was completed, the solvent was removed by concentration, ethyl acetate (50 mL) was added to dissolve, and the mixture was washed with saturated brine (50 mL). The organic phase was dried and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 57-2 (2.66 g, yield 85%).

Step 2: Preparation of sodium 7-chloro-1H-indazole-6-thiolate (57-3)

Dissolve 57-2 (0.44 g, 1.20 mmol) in tetrahydrofuran (5 mL), add ethanol solution of sodium ethoxide (0.8 g, 2.39 mmol, 20% wt), and stir at room temperature for 0.5 hours. After the reaction, dichloromethane (10 mL) was added to precipitate a large amount of solid. Filtration gave compound 57-3 (0.12 g, 50%).

The third step: (1-(1-(5-((7-chloro-1H-indazol-6-yl)sulfanyl)-3-(hydroxymethyl)-6-methylpyrazin-2-yl )-4-methylpiperidin-4-yl)ethyl) tert-butyl carbamate (57-4)

Except that 57-3 was used in this step instead of 2,3-dichloropyridine-4-thiol in the second step of Example 54, a method similar to that described in the second step of Example 54 was used to synthesize compound 57- 4.

The fourth step: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-((7-chloro-1H-indazol-6-yl)sulfanyl) Preparation of -5-methylpyrazin-2-yl)methanol (TM181)

Except that 57-4 was used in this step to replace 54-3 in the fourth step in Example 54, the crude product of TM181 was synthesized by a method similar to that described in the fourth step in Example 54. The crude product was subjected to reversed-phase HPLC (mobile Phase A: Acetonitrile, mobile phase B: 0.05% trifluoroacetic acid in water) was purified to obtain the trifluoroacetic acid salt of the title compound.

MS m/z(ESI): 447.0[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.60 (s, 1H), 8.16 (s, 1H), 7.65 (s, 4H), 6.73 (d, J = 8.2 Hz, 1H), 5.29 (s, 1H), 4.41 (s, 2H), 3.73-3.69 (m, 2H), 3.15-3.09 (m, 3H), 2.51 (s, 3H), 1.56-1.15 (m, 4H), 1.14 (d, J= 6.6Hz, 3H), 0.99(s, 3H).

Example 58: (3-(4-(1-aminoethyl)-4-ethylpiperidin-1-yl)-6-(2,3-dichloropyridin-4-yl)-5-methyl Preparation of pyrazin-2-yl)methanol (TM111)

Except that 58-1 was used in the first step of this example instead of 21-5 in the first step of Example 25, the crude product of TM111 was synthesized by a method similar to that described in the first to third steps of Example 25. Purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetic acid salt of the title compound.

MS m/z(ESI): 424.1[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 8.41 (d, J = 4.8 Hz, 1H), 7.45 (d, J = 4.8 Hz, 1H), 4.67 (s, 2H), 3.733.63 (m, 2H) ), 3.48-3.42(m, 1H), 3.28-3.20(m, 2H), 2.28(s, 3H), 1.82-1.59(m, 6H), 1.31(d, J=6.8Hz, 3H), 0.95( t, J=7.6Hz, 3H).

Example 59: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-((7-chloro-1-methyl-1H-indazole-6- Yl)thio)-5-methylpyrazin-2-yl)methanol and (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-((7 -Preparation of chloro-2-methyl-2H-indazol-6-yl)thio)-5-methylpyrazin-2-yl)methanol (TM182A and TM182B).

Step 1: Preparation of 6-bromo-7-chloro-1-methyl-1H-indazole and 6-bromo-7-chloro-2-methyl-2H-indazole (59-1A and 59-1B)

Dissolve 57-1 (1.7 g, 7.34 mmol) in tetrahydrofuran (20 mL), lower the temperature to 0°C, and add sodium hydride (337.7 mg, 8.81 mmol, 60% wt). After stirring for 0.5 hours, methyl iodide (1.6 g, 11.02 mmol) was added, the temperature was slowly raised to room temperature, and the reaction was conducted for 1 hour. After the reaction was completed, saturated brine was added for quenching. After extraction with ethyl acetate, the organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain solid products 59-1A and 59-1B (0.4g, 0.2g, total yield 67%).

Steps 2 to 5: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-((7-chloro-1-methyl-1H-indyl) (Azol-6-yl)thio)-5-methylpyrazin-2-yl)methanol and (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6 -Preparation of ((7-chloro-2-methyl-2H-indazol-6-yl)thio)-5-methylpyrazin-2-yl)methanol (TM182A and TM182B).

Except that 59-1A and 59-1B were used in the second step in this embodiment to replace 57-1 in the first step in embodiment 57, the method similar to that described in the first to fourth steps in embodiment 57 was adopted. The crude products of TM182A and TM182B were synthesized respectively. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous ammonium bicarbonate solution) to obtain the title compound. The characteristic data of the obtained products are as follows.

Product I:

MS m/z(ESI): 461.0[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 8.25 (s, 1H), 7.53 (d, J = 8.6 Hz, 1H), 6.78 (d, J = 8.6 Hz, 1H), 4.53 (s, 2H), 4.22 (s, 3H), 3.66-3.54 (m, 2H), 3.12 (m, 2H), 2.75 (q, J = 6.6 Hz, 1H), 2.45 (s, 3H), 1.67-1.56 (m, 3H) , 1.49-1.45 (m, 1H), 1.09 (d, J=6.6 Hz, 3H), 0.99 (s, 3H).

Product II:

MS m/z(ESI): 461.0[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.08 (s, 1H), 7.72 (s, 3H), 7.61 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 8 Hz, 1H), 5.35(s, 1H), 4.43(s, 2H), 4.33(s, 3H), 3.79-3.72(m, 2H), 3.16-3.10(m, 3H), 2.40(s, 3H), 1.65-1.53( m, 3H), 1.44-1.40 (m, 1H), 1.15 (d, J = 6.8 Hz, 3H), 1.00 (s, 3H).

Example 60: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-((8-chloroimidazo[1,2-a]pyridine-7- Preparation of (yl)thio)pyrazin-2-yl)methanol (TM183)

Step 1 to Step 2: Preparation of 8-chloroimidazo[1,2-a]pyridine-7-thiolate (60-3)

Except that 60-1 was used in the first step instead of 57-1 in the first step in Example 57, the compound 60-3 was synthesized by a method similar to that described in the first to second steps in Example 57.

The third step to the fourth step: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-((8-chloroimidazo[1,2-a] Preparation of pyridin-7-yl)thio)pyrazin-2-yl)methanol (TM183)

Except that 60-3 was used in the third step to replace the sodium 2-amino-3-chloropyridine-4-thiophenate in the second step in Example 45, the same as those described in the second to third steps in Example 45 were used. The crude product of TM183 was synthesized in a similar way. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 433.1[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.53 (d, J = 7.2 Hz, 1H), 8.31 (s, 1H), 8.16 (s, 1H), 7.84-7.76 (m, 4H), 6.76 ( d, J = 7.2 Hz, 1H), 4.50 (s, 3H), 3.81-3.74 (m, 2H), 3.21-3.12 (m, 3H), 1.65-1.55 (m, 3H), 1.45-1.41 (m, 1H), 1.15 (d, J = 6.6 Hz, 3H), 1.01 (s, 3H).

Example 61: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-((8-chloro-[1,2,4]triazolo[4 ,3-a]Pyridin-7-yl)thio)pyrazin-2-yl)methanol (TM184)

Step 1 to Step 2: Preparation of 8-chloro-[1,2,4]triazolo[4,3-a]pyridine-7-thiolate (61-3)

Except that 61-1 was used in the first step instead of 57-1 in the first step in Example 57, the compound 61-3 was synthesized by a method similar to that described in the first to second steps in Example 57.

The third step to the fourth step: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-((8-chloro-[1,2,4] three Preparation of azolo[4,3-a]pyridin-7-yl)thio)pyrazin-2-yl)methanol (TM184)

Except that 61-3 was used in the third step instead of the sodium 2-amino-3-chloropyridine-4-thiophenol in the second step in Example 45, the same as those described in the second to third steps in Example 45 were used. The crude product of TM184 was synthesized in a similar way. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 434.1[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 9.17 (s, 1H), 8.34 (s, 1H), 8.31 (d, J = 7.8 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 4.65(s, 2H), 3.85-3.72(m, 2H), 3.35-3.10(m, 3H), 1.80-1.50(m, 4H), 1.30(d, J=7.6Hz, 3H), 1.13(s, 3H).

Example 62: (R)-(3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(2,3-dichloropyridin-4-yl)- 5-methylpyrazin-2-yl)methanol (TR87) and (S)-(3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(2 , 3-Dichloropyridin-4-yl)-5-methylpyrazin-2-yl)methanol (TS87)

Chiral separation of TM87 is performed to obtain TR87 and TS87. The chiral purification chromatographic conditions are as follows:

Column CHIRALCEL OZ-H(OZH00CD-VF004) Column specifications 0.46cm I.D.×15cm L Injection volume 40ul Mobile phase ACN/DEA=100/0.1(V/V) Flow rate 1.0ml/min Detection wavelength UV 254nm temperature 35°C HPLC model: Shimadzu LC-20AD

The peak 1 retention time was 8.560 min, and the peak 2 retention time was 10.306 min.

Peak 1:

MS m/z(ESI): 410.2[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.49 (d, J = 4.8 Hz, 1H), 7.57 (d, J = 4.8 Hz, 1H), 5.33 (t, J = 5.6 Hz, 1H), 4.49 (d, J=5.6Hz, 2H), 3.73-3.68 (m, 2H), 3.19-3.06 (m, 2H), 2.51-2.50 (m, 2H), 2.20 (s, 3H), 1.56-1.26 (m , 4H), 0.92 (d, J = 6.8 Hz, 3H), 0.88 (s, 3H).

Peak 2:

MS m/z(ESI): 410.2[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.49 (d, J = 4.8 Hz, 1H), 7.57 (d, J = 4.8 Hz, 1H), 5.33 (t, J = 5.6 Hz, 1H), 4.49 (d, J=5.6Hz, 2H), 3.73-3.68 (m, 2H), 3.19-3.06 (m, 2H), 2.51-2.50 (m, 2H), 2.20 (s, 3H), 1.56-1.26 (m , 4H), 0.92 (d, J = 6.8 Hz, 3H), 0.88 (s, 3H).

Example 63: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-((3-chloropyridin-4-yl)sulfanyl)-5-methyl Preparation of pyrazine-2-yl)methanol (TM185)

Except that sodium 3-chloropyridine-4-thiophenate was used in this example instead of 43-1 in the first step of Example 43, TM185 was synthesized by a method similar to that described in the first to second steps of Example 43. The crude product. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous sodium bicarbonate solution) to obtain the title compound.

MS m/z(ESI): 408.1[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.57 (s, 1H), 8.27 (d, J = 5.2 Hz, 1H), 7.77 (s, 3H), 6.69 (d, J = 5.2 Hz, 1H) , 4.48(s, 2H), 3.94-3.80(m, 2H), 3.22-3.08(m, 3H), 2.44(s, 3H), 1.70-1.35(m, 4H), 1.16(d, J=7.6Hz , 3H), 1.02(s, 3H).

Example 64: (3-(4-(1-aminoethyl)-4-cyclopropylpiperidin-1-yl)-6-(2,3-dichloropyridin-4-yl)-5-methyl Preparation of pyrazine-2-yl)methanol (TM104)

Step 1 to Step 3: Preparation of 1-(4-cyclopropylpiperidin-4-yl)ethan-1-amine hydrochloride (64-4)

Except that 64-1 was used in the first step of this Example to replace 50-4 in the fourth step of Example 50, the compound 64-4 was synthesized by a method similar to that described in the fourth to sixth steps of Example 50.

Step 4 to Step 6: 3-(4-(1-aminoethyl)-4-cyclopropylpiperidin-1-yl)-6-(2,3-dichloropyridin-4-yl)- Preparation of 5-methylpyrazin-2-yl)methanol (TM104)

Except that 64-4 was used in this example instead of 21-5 in the first step of Example 25, the crude TM104 was synthesized by a method similar to that described in the first to third steps of Example 25. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) to obtain the trifluoroacetate salt of the title compound.

MS m/z(ESI): 436.1[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.50 (d, J = 4.8 Hz, 1H), 7.70 (s, 3H), 7.56 (d, J = 4.8 Hz, 1H), 5.38 (s, 1H) , 4.49 (s, 2H), 3.75-3.68 (m, 3H), 3.25-3.08 (m, 2H), 2.21 (s, 3H), 1.64-1.59 (m, 2H), 1.41-1.18 (m, 5H) , 0.85-0.78 (m, 1H), 0.43-0.35 (m, 4H).

Example 65: (3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl)-6-(4-chloro-5-methoxypyridin-3-yl)-5 -Methylpyrazin-2-yl) methanol (TM128) preparation

Except that 65-1 was used in the first step of this example to replace the (2,3-dichloropyridin-4-yl)boronic acid in the second step of Example 25, the second step to the third step of Example 25 were used. The trifluoroacetate salt of the title compound was synthesized in a similar manner as described.

MS m/z(ESI): 406.1[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 8.14 (d, J = 4.8 Hz, 1H), 6.99 (d, J = 4.8 Hz, 1H), 4.66 (s, 2H), 4.04 (s, 3H), 3.72-3.68 (m, 2H), 3.30-3.15 (m, 3H), 2.26 (s, 3H), 1.72-1.55 (m, 4H), 1.29 (d, J = 7.6 Hz, 3H), 1.11 (s, 3H).

Example 66: 6-((2-Amino-3-chloropyridin-4-yl)thio)-(3-(4-(1-aminoethyl)-4-cyclopropylpiperidin-1-yl )-5-methylpyrazin-2-yl)methanol (TM172) preparation

Except that in the first step of this example, 2-amino-3-chloropyridine-4-thiophenol sodium and compound 64-5 were used to replace the 2,3-dichloropyridine-4-sulfide in the first step of Example 43 In addition to phenol (43-1) and compound 25-1, the crude product of TM172 was synthesized by a method similar to that described in the first to second steps in Example 43. The crude product was subjected to reverse-phase HPLC (mobile phase A: acetonitrile, mobile phase). Phase B: 0.05% trifluoroacetic acid in water) was purified to obtain the trifluoroacetic acid salt of the title compound.

MS m/z(ESI): 449.1[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.72 (s, 3H), 7.66 (d, J = 5.2 Hz, 1H), 6.76 (brs, 2H), 5.78 (d, J = 5.2 Hz, 1H) , 4.46 (s, 2H), 3.82-3.67 (m, 3H), 3.35-3.10 (m, 2H), 2.40 (s, 3H), 1.68-1.55 (m, 2H), 1.36-1.26 (m, 5H) , 0.86-0.80 (m, 1H), 0.41-0.34 (m, 4H).

Example 67: (6-((2-amino-3-chloropyridin-4-yl)sulfanyl)-3-(4-(1-aminoethyl)-4-methylpiperidin-1-yl) Preparation of -5-methylpyrazin-2-yl)methanol (TM150)

Except that in the first step of this example, 2-amino-3-chloropyridine-4-thiophenol sodium was used instead of 2,3-dichloropyridine-4-thiophenol (43-1) in the first step of Example 43. In addition, the crude product of TM150 was synthesized by a method similar to that described in the first to second steps in Example 43, and the crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% trifluoroacetic acid aqueous solution) The trifluoroacetate salt of the title compound was obtained.

MS m/z(ESI): 423.0[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.69 (s, 3H), 7.66 (d, J = 5.2 Hz, 1H), 6.87 (brs, 2H), 5.81 (d, J = 5.2 Hz, 1H) , 5.49 (brs, 1H), 4.47 (s, 2H), 3.86-3.82 (m, 2H), 3.21-3.12 (m, 3H), 2.41 (s, 3H), 1.57-1.41 (m, 4H), 1.15 (d, J=6.4Hz, 3H), 1.01 (s, 3H).

Example 68: (3-(4-(1-amino-2-fluoroethyl)-4-(fluoromethyl)piperidin-1-yl)-6-((2-amino-3-chloropyridine- Preparation of 4-yl)thio)-5-methylpyrazin-2-yl)methanol (TM186)

Step 1: Preparation of tert-butyl 4-(fluoromethyl)-4-(1-hydroxyethyl)piperidine-1-carboxylate (68-1)

Dissolve 50-4 (1.12g, 4.57mmol) in THF (20mL), add methylmagnesium bromide (3M in 2-methyltetrahydrofuran, 2.30mL) dropwise, react at 20°C for 4 hours, LC-MS detects that the reaction is complete Afterwards, saturated ammonium chloride solution was added dropwise to the reaction solution, extracted with ethyl acetate three times, the organic phases were combined, dried and concentrated under reduced pressure to obtain crude product 68-1 (1.18 g), which was directly used in the next reaction.

Step 2: Preparation of tert-butyl 4-acetyl-4-(fluoromethyl)piperidine-1-carboxylate (68-2)

Dissolve 68-1 (1.18g, 4.52mmol) in DCM (20mL), add PCC (2.84g, 13.55mmol), and react at 20°C for 16 hours. After the completion of the reaction is detected by LC-MS, the reaction solution is concentrated to obtain a crude product. It was purified by column chromatography to obtain 68-2 (0.80 g, yield 68%).

Steps 3 to 9: (3-(4-(1-amino-2-fluoroethyl)-4-(fluoromethyl)piperidin-1-yl)-6-((2-amino-3 -Chloropyridin-4-yl)thio)-5-methylpyrazin-2-yl)methanol (TM186)

Except that 68-2 was used in the third step instead of 21-3 in the first step in Example 46, the crude TM186 was synthesized by a method similar to that described in the first to seventh steps in Example 46. The crude product was purified by reverse phase HPLC (mobile phase A: acetonitrile, mobile phase B: 0.05% aqueous formic acid) to obtain the formate salt of the title compound.

MS m/z(ESI): 458.8[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 8.46 (s, 1H), 7.58 (d, J = 5.6 Hz, 1H), 5.88 (d, J = 5.6 Hz, 1H), 4.85 to 4.65 (m, 4H) ), 4.63 (s, 2H), 3.87-3.72 (m, 2H), 3.49-3.34 (m, 3H), 2.48 (s, 3H), 1.90-1.78 (m, 4H).

Biological Examples

The structures of the control compounds SHP099 and TNO-155 used in the biological examples are as follows:

Test example 1: SHP2 (protein phosphatase) in vitro enzyme activity inhibition test test system:

Kinase: Recombinant full-length human PTPN11 (SHP2), Active (SignalChem Catalog: P38-20G)

Substrate: 6,8-Difluoro-4-methylumbelliferyl phosphate (DiFMUP) (Invitrogen Catalog: D6567)

Activating peptide: IRS1_pY1172(dPEG8)pY1222(BPS Bioscience Catalog: 79319-2)

Termination reagent: bpv(phen) (Abcam Catalog: ab141436)

Test parameters:

SHP2 concentration: 0.5nM; DiFMUP concentration: 200μM; IRS-1 concentration: 0.5μM; bpv: 160μM

Buffer system: 60mM Hepes pH7.2; 75mM NaCl; 75mM KCl; 0.05% P20; 1mM EDTA; 5mM DTT

Compound incubation and enzyme activation time: 60 minutes at room temperature

Reaction time between enzyme and substrate: 30 minutes at room temperature

Microplate reader parameters: BMG PHERAstar Fluorescence, excitation wavelength 340nm, emission wavelength 450nm

experiment procedure:

Incubate the mixture of the test compound and the phosphatase SHP2 and the activation peptide IRS-1 in a buffer system for 60 minutes at room temperature, add the substrate DiFMUP to start the reaction, after incubating at room temperature for 30 minutes, add bpv to stop the reaction, and put the reaction plate into the enzyme In the calibration instrument, the end point method is used to read the fluorescence value of each well in the plate.

data processing:

The vehicle group (containing 0.5nM SHP2, 200μM DiFMUP, 0.5μM IRS-1, 160μM bpv, 0.05% DMSO) was used as the negative control and the reaction buffer group (200μM DiFMUP, 0.5μM IRS-1, 160μM bpv, 0.05% DMSO) As a blank control, calculate the relative inhibitory activity of each concentration group, the inhibition rate=100%-(fluorescence value of the test group-fluorescence value of the blank group)/(fluorescence value of the solvent group-fluorescence value of the blank group)*100%. The curve was fitted according to the four-parameter model, and the half inhibitory concentration (IC ₅₀ ) of the compound was calculated.

test results:

The compound's inhibition of SHP2 activity was determined according to the above method, and the results are shown in Table 1.

Table 1. SHP2 phosphatase activity inhibition test results

Example IC ₅₀ (nM) Example 2 46.5 Example 3 235.6 Example 4 48.9 Example 5 88.1 Example 6 53.8 Example 7 68.7 Example 10 21.2 Example 11 71.6 Example 12 126.1 Example 14 67.9 Example 15 22.3 Example 17 24.7 Example 18 62.0 Example 19 29.4 Example 20 62.3 Example 21 14.2 Example 22 28.6 Example 24 26.8 Example 25 23.8 Example 26 32.3 Example 27 22.3 Example 28 47.1 Example 29 27.6 Example 30 25.2 Example 31 21.4 Example 33 30.8 Example 35 40.7 Example 36 27.7 Example 37 8.9 Example 42 30.6 Example 43 7.7 Example 44 16.3 Example 45 3.3 Example 46 12.2

Example 47 19.5 Example 49 25.2 Example 50 22.8 Example 51 19.9 Example 54 19.9 Example 55 1.1 Example 56 4.8 Example 57 8.4 Example 59 6.8 and 14.2 Example 60 8.9 Example 62 22.7 and 18.1 Example 67 8.2

in conclusion:

In the SHP2 phosphatase activity inhibition test, the compound of the present invention showed strong inhibitory activity.

Test Example 2: Inhibition test of compound on the proliferation activity of KYSE-520 cells (human esophageal squamous cell carcinoma)

Test system:

Cell name/manufacturer: KYSE-520/JCRB Cell Bank

Luminescent Cell Viability Assay，Promega Kit name/manufacturer:

Luminescent Cell Viability Assay, Promega

Test parameters:

Number of cells: 1500 cells/well

Plating medium: KYSE-520: 1640+10% FBS

Dosing medium: KYSE-520: 1640+10% FBS

Compound incubation conditions: 37°C, 5% CO ₂

Incubation time: 5d

Detection temperature: RT

BMG PHERAstar FS Luminescent

experiment procedure:

The cells were cultured in a medium containing 10% fetal bovine serum and placed at 37°C and 5% CO ₂ for culture. Pour an appropriate amount of cells into a 96-well plate and culture overnight in an incubator to allow the cells to adhere to the wall. The next day, the medium was removed, complete medium containing the pre-diluted compound was added, and incubated at 37°C for 5 days. On the fifth day, the detection reagent CellTiter-GLo was added to each well, and the relative luminescence unit (RLU) of each well was detected by chemiluminescence.

data processing:

CellTiter-Glo with cell-free medium was used to obtain the background value. Cell viability=(sample RLU-background RLU)/(vehicle RLU-background RLU)×100%, maximum inhibition rate=100%-maximum _{concentration of} cell viability, according to the four-parameter model to fit the curve, calculate the half inhibitory concentration of the compound (IC ₅₀ ).

test results:

The compound's inhibitory activity on the proliferation of KYSE-520 was determined according to the above method, and the results are shown in Table 2.

Table 2. Inhibition results of compounds on KYSE-520 cell proliferation activity

Example KYSE-520, IC ₅₀ (μM) Example 4 3.65±0.26 Example 10 3.67±0.31 Example 11 3.61±0.19 Example 15 2.02±0.12 Example 17 2.43±0.84

Example 19 2.52±0.22 Example 21 0.66±0.13 Example 24 2.79±0.1 Example 25 1.22±0.38 Example 26 2.30±0.83 Example 27 2.44±0.40 Example 28 2.55±0.79 Example 35 2.59±0.17 Example 36 2.11±0.53 Example 45 0.22±0.06 Example 51 1.07±0.32 Example 56 0.29±0.00 Example 57 0.98±0.11 Example 58 1.94±0.34 Example 62 1.31±0.3 and 0.92±0.14 Example 63 1.19±0.26 Example 67 1.12±0.42

in conclusion:

The compound of the present invention has strong cell proliferation inhibitory activity against KYSE-520.

Test Example 3: Biochemical hERG inhibition test

Test system:

Kit: Predictor ^TM hERG Fluorescence Polarization Assay, ThermoFisher, PV5366

Test parameters:

hERG concentration: 1X

Tracer concentration: 1nM

Incubation time: 2h

BMG PHERAstar FS FP

experiment procedure:

Add different concentrations of the compound of the present invention to the microplate containing hERG cell membrane, then add the tracer Tracer with high hERG affinity, incubate the microplate at 25°C for 2 hours, then use a multifunctional microplate reader to detect Fluorescence polarization (excitation wavelength: 540; emission wavelength: 590/590) value (mP) changes.

data processing:

According to the ratio of the data, the percentage inhibition rate (%) of the compound of the present invention on hERG at different concentrations is calculated, and the range _{of the half maximum inhibitory concentration (IC 50) of the compound is judged.} Percent inhibition rate (%)=(1-(mP of test compound-30μM mP of E4031)/(mP of experiment buffer-30μM E4031))*100

test results:

The above method was used to determine the compound's inhibition of hERG, and the results are shown in Table 3.

Table 3. hERG inhibition test results

Example IC ₅₀ (μM) Example 7 ＞10 Example 25 ＞10 Example 28 ＞10 Example 45 ＞10 Example 52 ＞10 Example 54 ＞10

Example 62 ＞10 and ＞10 Example 66 ＞10 Example 67 ＞10

in conclusion:

The test results show that the compound of the present invention has a low affinity with hERG, and the IC _{50 of} competition with the affinity tracer Tracer is greater than or close to 10 μM.

Test Example 4: Tumor inhibition test on KYSE-520 transplanted tumor model

Test purpose: To construct an animal model of CDX xenograft tumor by subcutaneously inoculating KYSE-520 cells in nu-nu mice, orally once a day after tumor formation, to evaluate the efficacy of different test compounds in vivo.

Test equipment and reagents:

Main reagents:

KYSE-520 cells were cultured in a monolayer in vitro, and the culture conditions were RPMI 1640 medium with 10% fetal bovine serum and cultured in an incubator _{at 37°C and 5% CO 2 air.} Use trypsin for digestion and passaging twice a week. When the cells are in the exponential growth phase, the cells are collected and counted.

The KYSE-520 cell line cultured to the logarithmic growth phase was prepared into a single cell suspension (cells were resuspended in PBS, mixed with phenol red-free matrigel 1:1, and the final cell density was 5×10 ⁷ /ml). Nude mice were inoculated with 0.1ml and subcutaneously inoculated into the right axillary of nude mice to construct a nude mouse xenograft model of esophageal cancer. When the tumor grew to 130mm ³ , the nude mice were randomly divided into 6 groups for administration. The dosing schedule is shown in the table As shown in 1 (orally administered once a day for 20 days), the vehicle is 5% DMSO + 5% Solutol + 90% H ₂ O.

Monitor the animal's health and death every day. Routine inspections include observing the effects of drug treatment on the daily behavior of animals, such as behavioral activities, food (water) intake, physical signs or other abnormalities, and make corresponding records.

The mice were weighed twice a week and the tumor volume was measured, and the data was recorded. Tumor volume (V) calculation formula: V=1/2×a×b ² , where a and b represent length and width respectively. The volume of the transplanted tumor and the weight of the mouse are shown in Figure 1 and Figure 2, respectively.

Evaluation of tumor growth inhibition rate TGI (%) for the effectiveness of anti-tumor drugs, where TGI (%) _{(tumor volume)} = [1-(T _Vt -T _V0 )/(C _Vt -C _V0 ) when the tumor does not regress ]×100%, T _V0 is the average tumor volume of the test compound group at the time of grouping, T _Vt is the average tumor volume of the test compound group at day t after administration; C _V0 is the average tumor volume of the vehicle group at the time of grouping; C _Vt It is the average tumor volume of the vehicle group at day t after administration; when the tumor has subsided, TGI (%) _{(tumor volume)} = 100%-(T _Vt- T _V0 )/T _V0 × 100%.

If the tumor is smaller than the initial volume, that is, when Vt<V0, it is defined as partial tumor regression (PR); if the tumor disappears completely, it is defined as complete tumor regression (CR).

test results:

Table 1. Efficacy of test compounds on KYSE-520 cell xenograft tumor model (calculated by tumor volume)

Note: ^* P<0.05 indicates a significant difference compared with the vehicle group.

Test Conclusions:

The above data shows that after continuous oral administration for 20 days, the compound of the embodiment of the present invention has a significant anti-tumor effect, and the efficacy is better than that of the positive compound SHP099 administered at the same dose; and the mice have better tolerance.

Test Example 5: Tumor inhibition test on NCI-H358 transplanted tumor model

Test purpose: To construct a subcutaneous xenograft mouse model by subcutaneously inoculating human non-small cell lung cancer cell NCI-H358 into the right scapula of Balb/c-nu mice. After tumor formation, it was administered orally once a day to evaluate different effects. Test compound in vivo efficacy.

Test equipment and reagents:

Main reagents:

Test operation:

The NCI-H358 cells were cultured in a monolayer in vitro under the conditions of RPMI1640 medium plus 10% fetal bovine serum and cultured in an incubator _{at 37°C and 5% CO 2.} Use pancreatin-EDTA for digestion and passage 2-3 times a week. When the cells are in the exponential growth phase, the cells are collected, counted, and inoculated.

Before the tumor cell inoculation, the test mice were identified by the earrings with special mouse numbers.

Each mouse's right scapula was subcutaneously inoculated with 1×10 ⁶ NCI-H358 cells (suspended in 0.1ml PBS + Matrigel). The average tumor volume is expected to be ~200mm ³ on the seventh day. According to the measurement results on the seventh day, 30 mice with regular tumor shapes and uniform volume were screened out, and they were randomly divided into 5 groups and administered according to the test protocol (The dosing schedule is shown in Table 2 (orally administered once a day for 20 days)), the vehicle is 5% DMSO + 5% Solutol + 90% H ₂ O.

Weigh the weight of the mice and measure the tumor volume 3 times a week, and record the data. Tumor volume (V) calculation formula: V=1/2×a×b ² , where a and b represent length and width respectively. The volume of the transplanted tumor and the weight of the mouse are shown in Figure 3 and Figure 4, respectively.

Evaluation of tumor growth inhibition rate TGI (%) for the effectiveness of anti-tumor drugs, where TGI (%) _{(tumor volume)} = [1-(T _Vt -T _V0 )/(C _Vt -C _V0 ) when the tumor does not regress ]×100%, T _V0 is the average tumor volume of the test compound group at the time of grouping, T _Vt is the average tumor volume of the test compound group at day t after administration; C _V0 is the average tumor volume of the vehicle group at the time of grouping; C _Vt It is the average tumor volume of the vehicle group at day t after administration; when the tumor has subsided, TGI (%) _{(tumor volume)} = 100%-(T _Vt- T _V0 )/T _V0 × 100%.

If the tumor is smaller than the initial volume, that is, when Vt<V0, it is defined as partial tumor regression (PR); if the tumor disappears completely, it is defined as complete tumor regression (CR).

test results:

Table 2: The efficacy of test compounds on NCI-H358 cell xenograft tumor model (calculated by tumor volume)

Note: ^* P<0.05 indicates a significant difference compared with the vehicle group.

Test Conclusions:

The above data shows that after continuous oral administration for 20 days, the compound of the embodiment of the present invention has a significant tumor-inhibiting effect, the drug effect is better than TNO-155 administered at the same dose, and the mice are well tolerated.

In short, the present invention provides a series of highly active SHP2 phosphatase inhibitors with novel structures, which have demonstrated good efficacy in mouse KYSE-520 CDX model and NCI-H358 CDX model, and have great potential for development. Become a drug for tumor diseases.

The foregoing embodiments do not limit the solution of the application in any way. In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other publications) is incorporated herein by reference in its entirety.

Claims (25)

The compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled compound, metabolite or prodrug thereof:

among them: X is a direct bond or selected from S, O, NH and CH ₂ ; Y is a direct key or

W ¹ , W ² and W ³ are each independently selected from CH and N; R ^{1 is} selected from H, -OH, -NH ₂ , C _1-6 alkyl and C _3-6 cycloalkyl; Each occurrence of R ² is independently selected from H, halogen, -OH, -OC _1-6 alkyl, -OC _3-6 cycloalkyl, -CN, C _1-6 alkyl, C _3-6 Cycloalkyl, C _2-6 alkenyl, -S(=O) _g -(C _1-6 alkyl), -S(=O) _g NH ₂ , -NH ₂ , -NH(C _1-6 alkane Group), -N(C _1-6 alkyl) ₂ , 3-12 membered heterocyclic group, C _6-10 aryl group and 5-12 membered heteroaryl group. Preferably, R ² is independent of each occurrence Ground is selected from H, halogen, -OH, -OC _1-6 alkyl, -CN, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, -S(=O) _g -(C _1-6 alkyl), _{-NH 2} , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , 3-12 membered heterocyclic group, C _6-10 aryl And 5-12 membered heteroaryl groups, wherein each of the alkyl, cycloalkyl, alkenyl, heterocyclyl, aryl and heteroaryl groups is optionally selected from halogen, =0,- OH, -OC _1-6 alkyl, -CN, C _1-6 alkyl, -S(=O) _g -(C _1-6 alkyl) _{, -NH 2} , -NH(C _1-6 alkyl) ) And -N(C _1-6 alkyl) ₂ substituents; Alternatively, any two R ² together with the atoms to which they are connected form a 5-10 membered hydrocarbon ring, a 5-10 membered heterocyclic ring, a 5-6 membered heteroaromatic ring or a benzene ring, wherein the hydrocarbon ring, heterocyclic ring, heteroaromatic ring The ring and the benzene ring are each optionally selected by one or more selected from -NH ₂ , -NH (C _1-6 alkyl), -N (C _1-6 alkyl) ₂ , halogen, -CN, =O, -OH, -OC _1-6 alkyl, halogenated C _1-6 alkyl and C _1-6 alkyl substituent substitution; Or, when X is NH or CH ₂ , any one of R ² and X together with the atoms to which they are connected forms a 5-10 membered hydrocarbon ring, a 5-10 membered heterocyclic ring, a 5-6 membered heteroaromatic ring or a benzene ring, wherein The hydrocarbon ring, heterocyclic ring, heteroaromatic ring and benzene ring are each optionally selected from -NH ₂ , -NH (C _1-6 alkyl), -N (C _1-6 alkyl). _2. Substituent substitution of halogen, -CN, =O, -OH, -OC _1-6 alkyl, halogenated C _1-6 alkyl and C _{1-6 alkyl;} R ^4a , R ^4b , R ^5a , R ^5b , R ^6a , R ^6b , R ^7a and R ^7b are each independently selected from H, halogen, =O, -CN, -OH, -COOH, -CONH ₂ , -C (O) O-(C _1-6 alkyl), C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -S(=O) _g -(C _1-6 alkyl), 3-6 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, The heterocyclic group, aryl group, heteroaryl group is optionally selected by one or more selected from -NH ₂ , -OH, =O, halogen, -CN, -OC _1-4 alkyl, -NH (C _1-6 Alkyl) and -N(C _1-6 alkyl) ₂ are substituted by one or more substituents selected from -NH ₂ , -OH, halogen, -CN, -OC _1-4 alkyl, -NH (C _1-6 alkyl) and -N(C _1-6 alkyl) ₂ substituents; Alternatively, any two of R ^4a , R ^4b , R ^5a , R ^5b , R ^6a , R ^6b , R ^7a and R ^7b form a C _3-10 hydrocarbon ring or 4- 12-membered heterocyclic ring; Alternatively, R ^4a , R ^7a and R ³ together with the atoms to which they are attached form azaadamantane, optionally with one or more selected from F, Cl, Br, -OH, =O, -CN, -C( O) Substituent substitution of O(C _1-6 alkyl) and C _{1-6 alkyl;} R ^8a and R ^8b are each independently selected from H, halogen, C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-12 aryl and 5-12 membered heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, heteroaryl and aryl are each optionally substituted by one or Multiple selected from -N(R ^z ) ₂ , -NH ₂ , halogen, -CN, -OH, =O, -OC _1-6 alkyl, C _1-6 alkyl, halogenated C _1-6 alkyl , C _3-6 cycloalkyl, 3-12 membered heterocyclic group, C _6-10 aryl and 5-10 membered heteroaryl substituents; preferably, the alkyl, cycloalkyl, alkene Group, alkynyl group, heterocyclic group, heteroaryl group and aryl group are each optionally selected from one or more groups -N(R ^z ) ₂ , -NH ₂ , halogen, -CN, -OH, =O,- Substituents of OC _1-6 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclic group, C _6-10 aryl and 5-10 membered heteroaryl; Or R ^8a and R ^8b together with the connected atoms (or direct bonds) form a C _3-8 hydrocarbon ring or a 3-12 membered heterocyclic ring, wherein the hydrocarbon ring and the heterocyclic ring are each optionally selected by one or more From -N(R ^z ) ₂ , -NH ₂ , halogen, -CN, =O, -OH, -OC _1-6 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 Substituents of membered heterocyclic group, C _6-10 aryl group, 5-10 membered heteroaryl group; When Y is a direct key or

And when R ^8a and R ^{8b are} both H, R ^{3 is} selected from -CN, -C _1-6 alkylene-R ² , -C _1-6 alkylene-OR ^z , C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl and phenyl, wherein the alkylene, cycloalkyl, alkenyl, alkynyl and phenyl are each optionally selected from halogen, -CN, =O, -OR ^z , -OH, -N(R ^z ) ₂ , -NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, phenyl And 5-6 membered heteroaryl substituents; When Y is

And when R ^8a and R ^{8b are} not H at the same time, R ^{3 is} selected from H, halogen, -OR ^z , -OH, -CN, -C(O)OR ^z , -COOH, -CON(R ^z ) ₂ ,- CONH ₂ , -C _1-6 alkylene, -C _1-6 alkylene-R ^z , -C _1-6 alkylene-OR ^z , -C _1-6 alkylene-OH, -C _{1- 6} alkylene-N(R ^z ) ₂ , C _3-6 cycloalkyl, 3-12 membered heterocyclic group, C _2-6 alkenyl, C _2-6 alkynyl, C _6-12 aryl, 5-12 membered heteroaryl, -S(=O) _g -(C _1-6 alkyl), -NH ₂ and -N(R ^z ) ₂ , wherein the alkyl, alkylene, ring Alkyl, heterocyclyl, alkenyl, alkynyl, heteroaryl and aryl are each optionally selected by one or more selected from halogen, -CN, =0, -OR ^z , -OH, -N (R ^z ) ₂ , -COOH, -NHR ^z , -NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclic group, C _6-10 aryl, 5-10 membered heteroaryl Group, -C(O)OR ^z , -C(O)N(R ^z ) ₂ , -C(O)NH ₂ and -NO ₂ substituents, preferably, the alkyl and alkylene Group, cycloalkyl group, heterocyclic group, alkenyl group, alkynyl group, heteroaryl group and aryl group are each optionally selected by one or more selected from halogen, -CN, =O, -OR ^z , -OH, -N (R ^z ) ₂ , -NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclic group, C _6-10 aryl, 5-10 membered heteroaryl, -C (O) OR ^z , -C(O)N(R ^z ) ₂ , -C(O)NH ₂ and -NO ₂ substituents; R ^z is optionally selected from -CN, -NH-C _1-6 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclyl, C _{2-6 at each occurrence} Alkenyl, C _2-6 alkynyl, C _6-12 aryl and 5-12 membered heteroaryl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, heteroaryl and The aryl groups are each optionally substituted by one or more selected from -NH ₂ , halogen, -CN, =O, -NO ₂ , -OH, -OC _1-6 alkyl, C _1-6 alkyl, halogenated C _{Substituents of 1-6} alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl; preferably, R ^z appears every time When selected from -CN, C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclic group, C _2-6 alkenyl, C _2-6 alkynyl, C _6-12 aryl And 5-12 membered heteroaryl groups, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, heteroaryl and aryl groups are each optionally selected from one or more -NH ₂ , Halogen, -CN, =O, -NO ₂ , -OH, -OC _1-6 alkyl, C _1-6 alkyl, C _3-6 cycloalkyl, 3-12 membered heterocyclic group, C _{6- Substituents of 10} aryl and 5-10 membered heteroaryl; g is 0, 1 or 2; n is 0, 1, 2, 3, 4, or 5. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled compound, metabolism Substance or prodrug, Wherein, R ^{1 is} selected from H, -OH, -NH ₂ , C _1-3 alkyl and C _3-6 cycloalkyl; Preferably, R ^{1 is} selected from H, -NH ₂ , -CH ₃ and cyclopropyl; More preferably, R ^{1 is} selected from -CH ₃ and cyclopropyl; More preferably, R ^{1 is} selected from -CH ₃ . The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, or isotope-labeled compound thereof , Metabolites or prodrugs, X is selected from direct bond and S; Preferably, X is a direct bond. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, or isotope thereof Labeled compounds, metabolites or prodrugs, Wherein, W ³ is CH, and W ¹ and W ² are each independently selected from CH and N; Preferably,

Selected from

More preferably,

Selected from

The compound of formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, or isotope thereof Labeled compounds, metabolites or prodrugs, Wherein, ^{each occurrence of R 2} is independently selected from H, halogen, -OH, -OC _1-6 alkyl, -O-halo C _1-6 alkyl, -OC _3-6 cycloalkyl, -CN, C _1-3 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, halogenated C _1-3 alkyl, -NH ₂ , -NH (C _1-3 alkyl), -N(C _1-3 alkyl) ₂ , -S(=O) _g -(C _1-3 alkyl) and -S(=O) _g NH ₂ ; preferably, each occurrence of ^{R 2} Independently selected from H, halogen, -OH, -OC _1-6 alkyl, -CN, C _1-3 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, halogenated C _{1- 3} alkyl and -NH ₂ ; Preferably, ^{each occurrence of R 2} is independently selected from H, F, Cl, Br, -OH, -CN, C _1-3 alkyl, -OCH ₃ , -OCHF ₂ , -OCF ₃ , -O -Cyclopropyl, -CF ₃ , -CHF ₂ , cyclopropyl, hydroxy-substituted azetidinyl, pyrrolyl, morpholinyl, -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ CN , -NH ₂ , -S-CH ₃ , -S(=O) ₂ CH ₃ and -S(=O) ₂ NH ₂ ; preferably, ^{each occurrence of R 2} is independently selected from H, F, Cl, Br, -OH, C _1-3 alkyl, -OCHF ₂ , -CF ₃ , -CHF ₂ , cyclopropyl, hydroxy substituted azetidinyl, pyrrolyl, morpholinyl, -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ CN and -NH ₂ ; Preferably, ^{each occurrence of R 2} is independently selected from H, F, Cl, Br, -OH, -CN, C _1-3 alkyl, -OCH ₃ , -OCHF ₂ , -OCF ₃ , -O -Cyclopropyl, -CF ₃ , -CHF ₂ , cyclopropyl, pyrrolyl, morpholinyl, -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ CN, -NH ₂ , -S-CH ₃ , -S(=O) ₂ CH ₃ and -S(=O) ₂ NH ₂ ; preferably, ^{each occurrence of R 2} is independently selected from H, F, Cl, Br, -OH, C _{1- 3 alkyl, -OCHF 2, -CF 3, -CHF} 2, cyclopropyl, pyrrolyl, _{morpholinyl, -NHCH 3, -N (CH 3} ) 2, -CH 2 CN , and -NH _2; More preferably, ^{each occurrence of R 2} is independently selected from F, Cl, Br, -OH, -OCH ₃ , -OCHF ₂ , -OCF ₃ , -O-cyclopropyl, -CH ₃ , -CF ₃ , -CN, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -S-CH ₃ , -S(=O) ₂ CH ₃ , -S(=O) ₂ NH ₂ and

Further preferably, ^{each occurrence of R 2} is independently selected from F, Cl, Br, -CH ₃ , -CF ₃ , -CN, -NH ₂ and

More preferably, ^{each occurrence of R 2} is independently selected from F, Cl, Br, -OH, -OCH ₃ , -OCHF ₂ , -OCF ₃ , -O-cyclopropyl, -CH ₃ , -CF ₃ , -CN, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -S-CH ₃ , -S(=O) ₂ CH ₃ and -S(=O) ₂ NH ₂ ; further preferred , R ² is independently selected from F, Cl, Br, -CH ₃ , -CF ₃ , -CN and -NH ₂ at each occurrence. The compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, or isotope thereof according to any one of claims 1 to 5 Labeled compounds, metabolites or prodrugs, among them,

Selected from

Each occurrence of R ² is independently selected from F, Cl, Br, -OH, -OCH ₃ , -OCHF ₂ , -OCF ₃ , -O-cyclopropyl, -CH ₃ , -CF ₃ , -CN , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -S-CH ₃ , -S(=O) ₂ CH ₃ and -S(=O) ₂ NH ₂ , n is 1, 2 or 3 ； Preferably,

Selected from

The compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, or isotope thereof according to any one of claims 1 to 6 Labeled compounds, metabolites or prodrugs, Wherein, any two R ² together with the atoms to which they are connected form a 5-7 membered hydrocarbon ring, a 5-7 membered heterocyclic ring or a 5-6 membered heteroaromatic ring, wherein the hydrocarbon ring and the heterocyclic ring are each optionally substituted by one Or more substituents selected from -NH ₂ , F, Cl, -CN, =O, -OH, -OC _1-3 alkyl, halo C _1-3 alkyl and C _1-3 alkyl; Any two R ² together with the atoms to which they are connected form a 5-7 membered hydrocarbon ring or a 5-7 membered heterocyclic ring, wherein the hydrocarbon ring and the heterocyclic ring are each optionally selected from -NH ₂ , F , Cl, -CN, =O, -OH, -OC _1-3 alkyl, halogenated C _1-3 alkyl and C _1-3 alkyl substituents; Preferably, any two R ² together with the atoms to which they are attached form a 5-6 membered hydrocarbon ring, a 5-6 membered heterocyclic ring or a 5-membered heteroaromatic ring, wherein the hydrocarbon ring and the heterocyclic ring are each optionally substituted by one or Multiple substituents selected from -NH ₂ , F, Cl, =O, -OH, -OCH ₃ and -CH ₃ ; Preferably, any two R ² together with the atoms to which they are attached form a 5-6 membered hydrocarbon ring or a 5-6 membered heterocyclic ring, wherein each of the hydrocarbon ring and the heterocyclic ring is optionally selected from -NH _2. Substituents of F, Cl, =O, -OH, -OCH ₃ and -CH ₃ are substituted. The compound of formula (I) according to any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, or isotope thereof Labeled compounds, metabolites or prodrugs, Wherein, when X is NH or CH ₂ , any one of R ² and X together with the atoms to which they are connected forms a 5-7 membered hydrocarbon ring or a 5-7 membered heterocyclic ring, wherein the hydrocarbon ring and the heterocyclic ring each optionally With one or more substituents selected from -NH ₂ , F, Cl, -CN, =O, -OH, -OC _1-3 alkyl, halo C _1-3 alkyl and C _1-3 alkyl replace; Preferably, when X is NH or CH ₂ , any one of R ² and X together with the atoms to which they are connected forms a 5-6 membered hydrocarbon ring or a 5-6 membered heterocyclic ring, wherein the hydrocarbon ring and the heterocyclic ring are each optionally Ground is substituted by one or more substituents selected from -NH ₂ , F, Cl, =0, -OH, -OCH ₃ and -CH ₃ ; or, when X is NH, any one of R ₂ and X is The connected atoms together form a morpholine ring. The compound of formula (I) according to any one of claims 1-8 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, or isotope thereof Labeled compounds, metabolites or prodrugs, Wherein, R ^4a , R ^4b , R ^5a , R ^5b , R ^6a , R ^6b , R ^7a and R ^7b are each independently selected from H, F, Cl, =O, -CN, -C(O)O(C _1-4 alkyl) and C _1-3 alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from halogen, =0, -OH and -NH ₂ ; Preferably, R ^4a , R ^4b , R ^5a , R ^5b , R ^6a , R ^6b , R ^7a and R ^7b are each independently selected from H, F, Cl, -CH ₃ and -C(O)O(C _{1 -3} alkyl); More preferably, R ^4a , R ^4b , R ^5a , R ^5b , R ^6a , R ^6b , R ^7a and R ^7b are each independently selected from H, -CH ₃ and -C(O)OCH ₃ ; More preferably, R ^4a , R ^4b , R ^5a , R ^5b , R ^6a , R ^6b , R ^7a and R ^7b are all H. The compound of formula (I) according to any one of claims 1-9, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, or isotope thereof Labeled compounds, metabolites or prodrugs, Wherein, any two of R ^4a , R ^4b , R ^5a , R ^5b , R ^6a , R ^6b , R ^7a , and R ^7b form a C _4-8 hydrocarbon ring or 4- 8-membered heterocyclic ring; Preferably, ^{any two of R 4a} , R ^5a , R ^6a , and R ^7a together with the atoms to which they are connected form a C _4-8 hydrocarbon ring or a 4-8 membered heterocyclic ring; More preferably, R ^4a and R ^7a together with their connected atoms form a 4-6 membered nitrogen-containing heterocyclic ring, or R ^5a and R ^6a together with their connected atoms form a C _4-6 hydrocarbon ring; More preferably, R ^5a and R ^6a together with the atoms to which they are connected form a cyclopentane ring, and R ^4a , R ^4b , R ^5b , R ^6a , R ^7a , and R7 ^b are all H. The compound of formula (I) according to any one of claims 1-10 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, or isotope thereof Labeled compounds, metabolites or prodrugs, Wherein, R ^4a , R ^7a and R ³ form azaadamantane together with the atoms to which they are connected; Preferably, R ^4a , R ^7a and R ³ together with the atoms to which they are connected form azaadamantane, and R ^4b , R ^5a , R ^5b , R ^6a , R ^6b and R ^7b are all H. The compound of formula (I) according to any one of claims 1-11 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, or isotope thereof Labeled compounds, metabolites or prodrugs, Among them, when Y is a direct key or

And when R ^8a and R ^{8b are} both H, R ^{3 is} selected from -CN, -C _1-3 alkylene-R ^z , -C _1-3 alkylene-OR ^z , C _3-6 cycloalkyl, C _2-4 alkenyl, C _2-4 alkynyl and phenyl, wherein the alkylene, cycloalkyl, alkenyl, alkynyl and phenyl are each optionally selected from one or more of F, Cl, -CN, =O, -OR ^z , -OH, -N(R ^z ) ₂ , -NH ₂ , C _1-4 alkyl, C _3-6 cycloalkyl, 4-6 membered heterocyclic group, Substituents of phenyl and 5-6 membered heteroaryl groups; Preferably, when Y is a direct bond or

And when R ^8a and R ^{8b are} both H, R ^{3 is} selected from -CH ₂ CH=CH ₂ , -CH=CH ₂ , -CH ₂ C≡CH, -C≡CH, -CH ₂ R ^z , -CH ₂ -OR ^z , -CN, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclohexyl and phenyl, wherein said phenyl is optionally selected from F, Cl,- CN, -OH, -OCH ₃ , -N(CH ₃ ) ₂ , -NH(CH ₃ ), -NH ₂ and pyrazolyl substituents are substituted; preferably, when Y is a direct bond or

And when R ^8a and R ^{8b are} both H, R ^{3 is} selected from -CH ₂ CH=CH ₂ , -CH=CH ₂ , -CH ₂ C≡CH, -C≡CH, -CH ₂ R ^z , -CH ₂ -OR ^z , -CN, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl, wherein said phenyl is optionally selected from F, Cl, -CN, -OH, -OCH ₃ , -N(CH ₃ ) ₂ , -NH(CH ₃ ), -NH ₂ and pyrazolyl substituents are substituted. The compound of formula (I) according to any one of claims 1-12 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, or isotope thereof Labeled compounds, metabolites or prodrugs, Where, when Y is

And when R ^8a and R ^{8b are} not H at the same time, R ^{3 is} selected from H, F, Cl, Br, -OR ^z , -OH, -CN, -C _1-6 alkyl, -C _1-4 alkylene -R ^z , -C _1-4 alkylene -OR ^z , C _3-6 cycloalkyl, C _2-4 alkenyl, C _2-4 alkynyl, phenyl, 3-8 membered heterocyclic group ( For example, 3-6 membered heterocyclic group) and 5-6 membered heteroaryl group, wherein the alkyl group, alkylene group, cycloalkyl group, alkenyl group, alkynyl group, phenyl group, heterocyclic group and heteroaryl group Each is optionally selected by one or more selected from F, Cl, -CN, =O, -OR ^z , -OH, -N(R ^z ) ₂ , -NHR ^z , -NH ₂ , C _1-4 alkyl , C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl substituents; Preferably, when Y is

And when R ^8a and R ^{8b are} not H at the same time, R ^{3 is} selected from H, F, Cl, -CF ₃ , -CHF ₂ , -CH ₂ F, -OH, -OCH ₃ , -CH ₂ CH=CH ₂ , -CH=CH ₂ , -CH ₂ C≡CH, -C≡CH, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ NHCH ₃ , -CH ₂ R ^z , -CH ₂ -OR ^z , -CH ₂ -OH, -CN, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl,

Morpholinyl, tetrahydropyranyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl, pyrazolyl, thienyl and phenyl, wherein the pyridyl, pyrimidinyl, oxazolyl, thiazolyl, pyridyl The azole group, thienyl group and phenyl group are optionally selected by one or two selected from F, Cl, -CN, -OH, -OCH ₃ , -N(CH ₃ ) ₂ , -NH(CH ₃ ), -NH ₂ And pyrazolyl substituents; preferably, R ^{3 is} selected from H, F, Cl, -CF ₃ , -CHF ₂ , -OH, -OCH ₃ , -CH ₂ CH=CH ₂ , -CH=CH ₂ , -CH ₂ C≡CH, -C≡CH, -CH ₃ , -CH ₂ R ^z , -CH ₂ -OR ^z , -CH ₂ -OH, -CN, cyclopropyl, cyclobutyl, cyclopentyl , Morpholinyl, tetrahydropyranyl, pyridyl, pyrimidinyl, thiazolyl, pyrazolyl, thienyl and phenyl, wherein the pyridyl, pyrimidinyl, thiazolyl, pyrazolyl, thienyl and benzene The group is optionally substituted by one or two substituents selected from F, Cl, -CN, -OH, -OCH ₃ , -N(CH ₃ ) ₂ , -NH(CH ₃ ), -NH ₂ and pyrazolyl replace. The compound of formula (I) according to any one of claims 1-13 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, or isotope thereof Labeled compounds, metabolites or prodrugs, Wherein, R ^z is optionally selected from -CN, -NH-C _1-4 alkyl, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl each time. And 5-6 membered heteroaryl groups, wherein the alkyl group, cycloalkyl group, heterocyclic group, phenyl group and heteroaryl group are each optionally selected by one or more selected from -NH ₂ , F, Cl,- Substituents of CN, -CH ₃ , -CH ₂ CH ₃ , =O, -OH, -OC _1-3 alkyl, -CF ₃ , -CHF ₂ , phenyl and C _3-6 cycloalkyl; preferably Wherein, R ^z is optionally selected from -CN, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl at each occurrence, wherein The alkyl group, cycloalkyl group, heterocyclic group, phenyl group and heteroaryl group are each optionally selected by one or more selected from -NH ₂ , F, Cl, -CN, -CH ₃ , -CH ₂ CH _3. Substituents of =0, -OH, -OC _1-3 alkyl, -CF ₃ , -CHF ₂ , phenyl and C _{3-6 cycloalkyl;} Preferably, ^{each occurrence of R z} is selected from -CN, -CH ₃ , -CH ₂ CH ₃ , -NHCH ₃ , isopropyl, benzyl, -CF ₃ , -CHF ₂ , cyclopropyl, ring Butyl, cyclopentyl, cyclohexyl, morpholinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, azetidinyl, pyrazolyl, thiophene Group, thiazolyl, oxazolyl, imidazolyl, triazolyl, furyl, pyrazinyl, pyrimidinyl, pyridyl and phenyl, wherein the piperazinyl, azetidinyl, pyrazole Group, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, furyl, pyrazinyl, pyrimidinyl, pyridyl and phenyl are each optionally one or two selected from F, Cl, -CN, -CH ₃ , -CH ₂ CH ₃ , -OH and -OCH ₃ substituents; preferably, R ^z is optionally selected from -CN, -CH ₃ , -CH ₂ CH ₃ , each occurrence Isopropyl, benzyl, -CF ₃ , -CHF ₂ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperazinyl, oxetanyl, tetrahydropyranyl, Pyrrolidinyl, azetidinyl, pyrazolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, furyl, pyrazinyl, pyrimidinyl, pyridyl and phenyl, where The piperazinyl, azetidinyl, pyrazolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, furyl, pyrazinyl, pyrimidinyl, pyridyl and benzene group each optionally substituted with one or two substituents selected from _{F, Cl, -CN, -CH 3} , -CH 2 CH 3, -OH and -OCH ₃ substituents. The compound of formula (I) according to any one of claims 1-14 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, or isotope thereof Labeled compounds, metabolites or prodrugs, Wherein, R ^8a and R ^8b are each independently selected from H, C _1-3 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, benzene ring and 5-6 membered heteroaryl, wherein The alkyl, cycloalkyl, heterocyclyl, heteroaryl and benzene rings are each optionally selected from one or more of -NH ₂ , F, Cl, -CN, -CH ₃ , -CH ₂ CH ₃ , =O, -OH, -OC _1-3 alkyl, -CF ₃ , -CHF ₂ and C _3-6 cycloalkyl substituents; Preferably, R ^8a and R ^8b are each independently selected from H, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CF ₃ , -CHF ₂ , -CH ₂ F, isopropyl, cyclopropyl , Cyclobutyl, oxiranyl, oxetanyl, phenyl, pyridyl, pyridazinyl, thienyl, thiazolyl, oxazolyl, furyl, pyrazolyl, imidazolyl, pyrrolyl and Pyrimidyl, wherein the phenyl, pyridyl, pyridazinyl, thienyl, thiazolyl, oxazolyl, furyl, pyrazolyl, imidazolyl, pyrrolyl and pyrimidinyl are each optionally substituted by one or more Substituted by substituents selected from -NH ₂ , F, Cl, -CN, -CH ₃ , -CH ₂ CH ₃ , -OH, -OC _1-3 alkyl, -CF ₃ and -CHF ₂ ; preferably, R ^8a and R ^8b are each independently selected from H, -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -CHF ₂ , isopropyl, cyclopropyl, cyclobutyl, oxirane, and oxetan Group, phenyl, pyridyl, pyridazinyl, thienyl, thiazolyl, oxazolyl, furyl, pyrazolyl, imidazolyl, pyrrolyl, wherein the phenyl, pyridyl, pyridazinyl, thienyl , Thiazolyl, oxazolyl, furyl, pyrazolyl, imidazolyl, pyrrolyl are each optionally one or more selected from -NH ₂ , F, Cl, -CN, -CH ₃ , -CH ₂ CH _3. Substituents of -OH, -OC _1-3 alkyl, -CF ₃ and -CHF _2; More preferably, R ^8a and R ^8b are each independently selected from H, -CH ₃ , -CH ₂ CH ₃ , isopropyl, cyclopropyl, -CH ₂ OCH ₃ , -CF ₃ , -CH ₂ F, -CHF _2. 2-Methylfuranyl, thiazolyl, pyridyl and pyrimidinyl; preferably, R ^8a and R ^8b are each independently selected from H, -CH ₃ , isopropyl, cyclopropyl, -CF ₃ , 2- Methylfuryl, thiazolyl, pyridyl and pyrimidinyl More preferably, R ^8a and R ^8b are each independently selected from H, -CH ₃ , isopropyl and cyclopropyl. The compound of formula (I) according to any one of claims 1-15 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, or isotope thereof Labeled compounds, metabolites or prodrugs, Wherein, R ^8a and R ^8b together with the atoms (or direct bonds) to which they are connected form a C _3-8 hydrocarbon ring and a 3-6 membered heterocyclic ring, wherein the hydrocarbon ring and the heterocyclic ring are each optionally substituted by one or more One substituent selected from -NH ₂ , F, Cl, -CN, -CH ₃ , -CH ₂ CH ₃ , =O, -OH, -OC _1-3 alkyl, -CF ₃ and -CHF ₂ ; Preferably, R ^8a and R ^8b together with the atoms (or direct bonds) to which they are connected form a cyclopropane, cyclobutane, cyclopentane or 3-6 membered heterocycle: More preferably, R ^8a and R ^8b together with the atoms (or direct bonds) to which they are attached form cyclopropane, cyclobutane, cyclopentane or oxetane. The compound of formula (I) according to any one of claims 1-16, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, or isotope thereof A labeled compound, metabolite, or prodrug, where g is 0 or 2. The compound of formula (I) according to any one of claims 1-17, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, or isotope thereof Labeled compounds, metabolites or prodrugs, Wherein, n is 0, 1, 2 or 3; Preferably, n is 2 or 3; More preferably, n is 2. The compound of formula (I) according to any one of claims 1-18, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, or isotope thereof A labeled compound, metabolite or prodrug, wherein the compound has the structure shown in formula (II):

Wherein, R ² , R ³ , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^8b , W ¹ , W ² , W ³ and n are as defined in any one of claims 1-18. The compound of formula (I) according to any one of claims 1-19, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, or isotope thereof A labeled compound, metabolite or prodrug, wherein the compound has the structure shown in formula (III):

Wherein, R ² , R ³ , R ^8a , R ^8b , W ¹ , W ² , W ³ and n are as defined in any one of claims 1-18. The compound of formula (I) according to any one of claims 1-20 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, or isotope thereof A labeled compound, metabolite or prodrug, wherein the compound is selected from:

A pharmaceutical composition comprising the compound according to any one of claims 1-21 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, or solvate thereof Compounds, isotope-labeled compounds, metabolites or prodrugs, and one or more pharmaceutically acceptable carriers. The compound of any one of claims 1-21 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled compound, metabolism The use of the drug or prodrug or the pharmaceutical composition of claim 22 in the preparation of a medicament for the prevention or treatment of SHP2 phosphatase-related diseases. A method for preventing or treating SHP2 phosphatase-related diseases, the method comprising administering to an individual in need the compound of any one of claims 1-21 or a pharmaceutically acceptable salt, ester, Stereoisomers, tautomers, polymorphs, solvates, isotopically-labeled compounds, metabolites or prodrugs, or the pharmaceutical composition of claim 22. The compound of any one of claims 1-21 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, isotope-labeled compound, metabolism The drug or prodrug or the pharmaceutical composition according to claim 22 is used to prevent or treat SHP2 phosphatase related diseases.

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