Pyrazine thio-biphenyl compounds and their applications

Abstract

A pyrazine thio-biphenyl compound and its application, specifically discloses the compound of formula (II) or a pharmaceutically acceptable salt thereof.

Description

[0001] This application claims the following priorities:

[0002] CN202011008309.7, filing date: September 23, 2020;

[0003] CN202110182212.6, filing date: February 9, 2021;

[0004] CN202110412812.7, filing date: April 16, 2021;

[0005] CN202110590591.2, filing date: May 28, 2021. Technical Field

[0006] The present invention relates to pyrazine thio - biphenyl compounds and their applications, and particularly to compounds of formula (II) or pharmaceutically acceptable salts thereof. Background Art

[0007] The phosphorylation of tyrosine kinases and the de - phosphorylation of tyrosine phosphatases are common signal transduction mechanisms in organisms, which jointly regulate the tyrosine phosphorylation level of intracellular proteins. Shp2 (SH2 domain - containing protein - tyrosine phosphatase - 2) is a non - transmembrane protein tyrosine phosphatase that plays a de - phosphorylation role and is an important member of the protein tyrosine phosphatase (PTP) family. Its molecule is encoded by the PTPN11 gene. It can not only positively regulate downstream signal transduction pathways through the catalytic activity of phosphatase, but also play a positive regulatory role as a phosphatase - independent adapter protein, and can also play a negative regulatory role under specific conditions, thus widely participating in the regulation of biological functions such as cell differentiation and migration and related signal transduction processes. PTPN11 mutation is considered a high - risk factor for juvenile myelomonocytic leukemia (JMML). At the same time, because of the abnormal activation and mutation of Shp2 in different types of leukemia, it is considered an oncogene of leukemia; in prostate cancer, breast cancer, pancreatic cancer, gastric cancer and glioma, Shp2 has also been reported to be in an over - activated state; in lung cancer, Shp2 promotes tumorigenesis and development as an oncogene by regulating multiple mechanisms. However, in the process of liver cancer occurrence, Shp2 plays the role of a tumor suppressor gene under the influence of a specific environment. In short, as an important nodal molecule, Shp2 plays an important regulatory role in the process of tumorigenesis and development and is a potential therapeutic target. Summary of the Invention

[0008] The present invention provides compounds of formula (II) or pharmaceutically acceptable salts thereof,

[0009]

[0010] wherein,

[0011] structural unit

[0012] E 1 is O or CH 2 ;

[0013] T 1 is N or CH;

[0014] R 1 is

[0015] R 11 、R 13 and R 14 are each independently C 1-3 alkyl;

[0016] R 12 is H or C 1-3 alkyl;

[0017] R 2 is F, Cl, Br or I;

[0018] R 3 is C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a ;

[0019] R 4 is H, F, Cl, Br, I or C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b ;

[0020] R a and R b are each independently F, Cl, Br, I, OH or NH 2 ;

[0021] n is 0, 1, 2 or 3;

[0022] m is 1, 2 or 3;

[0023] When n is 0, the structural unit structural unit

[0024] When n is 1, 2 or 3, the structural unit is the structural unit structural unit

[0025] The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0026]

[0027] wherein,

[0028] structural unit

[0029] R 1 is

[0030] R 11 、R 13 and R 14 are each independently C 1-3 alkyl;

[0031] R 12 is H or C 1-3 alkyl;

[0032] R 2 is F, Cl, Br or I;

[0033] R 3 is C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a ;

[0034] R 4 is H, F, Cl, Br, I or C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b ;

[0035] R a and R b are each independently F, Cl, Br, I, OH or NH 2 ;

[0036] m is 1, 2 or 3.

[0037] In some embodiments of the present invention, the above R 1 is and other variables are as defined in any technical solution of the present invention.

[0038] In some embodiments of the present invention, the above R 11 、R 13 and R 14 are each independently CH 3 and other variables are as defined in any technical solution of the present invention.

[0039] In some embodiments of the present invention, the above-mentioned R 12 is H or CH 3 , and other variables are defined as in any technical solution of the present invention.

[0040] In some embodiments of the present invention, the above-mentioned R 3 is CH 3 , and other variables are defined as in any technical solution of the present invention.

[0041] In some embodiments of the present invention, the above-mentioned R 4 is F, Cl, Br or I, and other variables are defined as in any technical solution of the present invention.

[0042] In some embodiments of the present invention, the above-mentioned structural unit Other variables are defined as in any technical solution of the present invention.

[0043] In some embodiments of the present invention, the above-mentioned structural unit Other variables are defined as in any technical solution of the present invention.

[0044] In some embodiments of the present invention, the above-mentioned structural unit Other variables are defined as in any technical solution of the present invention.

[0045] In some embodiments of the present invention, the above-mentioned structural unit Other variables are defined as in any technical solution of the present invention.

[0046] Some embodiments of the present invention are formed by any combination of the above variables.

[0047] In some embodiments of the present invention, the above-mentioned compound has the structure of formula (II-1)

[0048]

[0049] wherein,

[0050] R 11 , R 12 , R 2 , n, E 1 and the structural unit are defined as in any technical solution of the present invention.

[0051] In some embodiments of the present invention, the above-mentioned compound has the structure of formula (I-1) or (I-2)

[0052]

[0053] Among them,

[0054] R 11 、R 12 、R 13 、R 14 、R 2 and the structural unit are defined as in any technical solution of the present invention.

[0055] In some embodiments of the present invention, the above-mentioned compound has the structure of formula (I-1A), (I-1B), (I-2A), (II-1A) or (II-1B)

[0056]

[0057]

[0058] Among them,

[0059] n, m, E 1 、T 1 、R 11 、R 12 、R 13 、R 14 、R 2 、R 3 and R 4 are defined as in any technical solution of the present invention.

[0060] In some embodiments of the present invention, the above-mentioned compound has the structure of formula (I-1A-1), (I-2A-1), (II-1A-1) or (II-1B-1)

[0061]

[0062] Among them,

[0063] m, n, E 1 、T 1 、R 11 、R 12 、R 13 、R 14 、R 2 、R 3 and R 4 are defined as in any technical solution of the present invention.

[0064] The present invention also provides the following compounds or their pharmaceutically acceptable salts,

[0065]

[0066]

[0067] In some embodiments of the present invention, the above-mentioned compound is

[0068]

[0069]

[0070] In one technical solution of the present invention, the above-mentioned compound of the present invention is:

[0071]

[0072] In one technical solution of the present invention, the above-mentioned compound of the present invention is Compound 004,

[0073]

[0074] In one technical solution of the present invention, the compound of the present invention is a stereoisomer of Compound 004, or a formate of the stereoisomer. The retention time of the stereoisomer or its formate after chiral supercritical fluid chromatography analysis is 3.1 - 3.5 min, preferably 3.2 - 3.4 min, more preferably about 3.3 min; the conditions for the chiral supercritical fluid chromatography analysis are: chromatographic column: Chiralpak AS-3 (100 mm * 4.6 mm, 3 μm); mobile phase: carbon dioxide; [0.05% triethylamine, ethanol%]: 40% - 40%.

[0075] In one technical solution of the present invention, the above-mentioned compound of the present invention is another stereoisomer of Compound 004. The retention time of the stereoisomer after chiral supercritical fluid chromatography analysis is 4.3 - 4.7 min, preferably 4.4 - 4.6 min, more preferably about 4.5 min; the conditions for the chiral supercritical fluid chromatography analysis are: chromatographic column: Chiralpak AS-3 (100 mm * 4.6 mm, 3 μm); mobile phase: carbon dioxide; [0.05% triethylamine, ethanol%]: 40% - 40%.

[0076] In one technical solution of the present invention, the above-mentioned compound of the present invention is

[0077]

[0078] In one technical solution of the present invention, the compound of the present invention is a stereoisomer of compound 005; the retention time of the stereoisomer after chiral supercritical fluid chromatography analysis is 4.8 - 5.2 min, preferably 4.9 - 5.1 min, more preferably about 5.0 min; the conditions for the chiral supercritical fluid chromatography analysis are: chromatographic column: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); mobile phase: [0.1% ammonia water - ethanol]; ethanol%: 48% - 78%, 7 min.

[0079] In one technical solution of the present invention, the compound of the present invention is another stereoisomer of compound 005; the retention time of the stereoisomer after chiral supercritical fluid chromatography analysis is 5.6 - 6.0 min, preferably 5.7 - 5.9 min, more preferably about 5.8 min; the conditions for the chiral supercritical fluid chromatography analysis are: chromatographic column: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); mobile phase: [0.1% ammonia water - ethanol]; ethanol%: 48% - 78%, 7 min.

[0080] In one technical solution of the present invention, the compound of the present invention is

[0081]

[0082] In one technical solution of the invention, the above - mentioned compound is a stereoisomer of compound 006. The retention time of the stereoisomer after chiral supercritical fluid chromatography separation is 4.9 - 5.3 min, preferably 5.0 - 5.2 min, more preferably about 5.1 min; the conditions for the chiral supercritical fluid chromatography separation are: chromatographic column: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); mobile phase: [0.1% ammonia water - methanol]; methanol%: 40% - 40%.

[0083] In one technical solution of the invention, the above - mentioned compound is another stereoisomer of compound 006. The retention time of the stereoisomer after chiral supercritical fluid chromatography separation is 6.6 - 7.0 min, preferably 6.7 - 6.9 min, more preferably about 6.8 min; the conditions for the chiral supercritical fluid chromatography separation are: chromatographic column: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); mobile phase: [0.1% ammonia water - methanol]; methanol%: 40% - 40%.

[0084] In one technical solution of the present invention, the compound of the present invention is

[0085]

[0086] In one technical solution of the present invention, the compound of the present invention is a stereoisomer of compound 007; the retention time of the stereoisomer after chiral supercritical fluid chromatography separation is 6.6 - 7.0 min, preferably 6.7 - 6.9 min, more preferably about 6.8 min; the conditions for chiral supercritical fluid chromatography separation are: chromatographic column: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); mobile phase: [0.1% ammonia water - ethanol]; ethanol%: 48% - 78%, 10 min.

[0087] In one technical solution of the present invention, the compound of the present invention is another stereoisomer of compound 007; the retention time of the stereoisomer after chiral supercritical fluid chromatography separation is 7.1 - 7.5 min, preferably 7.2 - 7.4 min, more preferably about 7.4 min; the conditions for chiral supercritical fluid chromatography separation are: chromatographic column: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); mobile phase: [0.1% ammonia water - ethanol]; ethanol%: 48% - 78%, 10 min.

[0088] In one technical solution of the present invention, the compound of the present invention is

[0089]

[0090] In one technical solution of the present invention, the compound of the present invention is a stereoisomer of compound 008; the retention time of the stereoisomer after chiral supercritical fluid chromatography separation is 2.7 - 3.1 min, preferably 2.8 - 3.0 min, more preferably about 2.9 min; the conditions for chiral supercritical fluid chromatography separation are: chromatographic column: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); mobile phase: [0.1% ammonia water - ethanol]; ethanol%: 45% - 45%.

[0091] In one technical solution of the present invention, the compound of the present invention is another stereoisomer of compound 008; the retention time of the stereoisomer after chiral supercritical fluid chromatography separation is 3.6 - 4.0 min, preferably 3.7 - 3.9 min, more preferably about 3.9 min; the conditions for chiral supercritical fluid chromatography separation are: chromatographic column: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); mobile phase: [0.1% ammonia water - ethanol]; ethanol%: 45% - 45%.

[0092] In one technical solution of the present invention, the compound of the present invention is

[0093]

[0094] In one technical solution of the present invention, the compound of the present invention is a stereoisomer of compound 010; the retention time of the stereoisomer after chiral supercritical fluid chromatography separation is 2.3 - 2.7 min, preferably 2.4 - 2.6 min, more preferably about 2.6 min; the conditions for the chiral supercritical fluid chromatography separation are: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); mobile phase: [0.1% ammonia water - ethanol]; ethanol%: 40% - 40%.

[0095] In one technical solution of the present invention, the compound of the present invention is another stereoisomer of compound 010; the retention time of the stereoisomer after chiral supercritical fluid chromatography separation is 3.2 - 3.6 min, preferably 3.3 - 3.5 min, more preferably about 3.4 min; the conditions for the chiral supercritical fluid chromatography separation are: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); mobile phase: [0.1% ammonia water - ethanol]; ethanol%: 40% - 40%.

[0096] The second aspect of the present invention further provides a pharmaceutical composition, which comprises the compound defined in any of the above technical solutions or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0097] The present invention also provides a method for treating a disease related to SHP2 in a subject in need, which includes providing an effective dose of the compound defined in any of the above technical solutions or a pharmaceutically acceptable salt thereof or a pharmaceutical composition to the subject.

[0098] The present invention also provides the use of the above compound, its isomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition in the preparation of a drug for treating a disease related to SHP2.

[0099] Technical effects

[0100] The compound of the present invention exhibits good inhibitory activity against the protein tyrosine phosphatase SHP2 and will have excellent therapeutic effects in patients with SHP2 - abnormal tumors.

[0101] Definitions and explanations

[0102] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered indeterminate or unclear without a special definition, but should be understood in its ordinary meaning. When a trade name appears in this text, it is intended to refer to its corresponding product or its active ingredient.

[0103] As used herein, the term "pharmaceutically acceptable" pertains to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0104] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from compounds having specific substituents found in the present invention with relatively non-toxic acids or bases. When a compound of the present invention contains a relatively acidic functional group, the base addition salt can be obtained by contacting such a compound with a sufficient amount of a base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When a compound of the present invention contains a relatively basic functional group, the acid addition salt can be obtained by contacting such a compound with a sufficient amount of an acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, where the inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, where the organic acids include, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid and similar acids; also salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can thus be converted into either base or acid addition salts.

[0105] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds containing acid or base groups by conventional chemical methods. Generally, the preparation method of such salts is to react these compounds in the form of free acids or bases with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of both.

[0106] The compounds of the present invention can exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereomer-enriched mixtures, all of which mixtures are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are included within the scope of the present invention.

[0107] Unless otherwise specified, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.

[0108] Unless otherwise specified, the terms "cis-trans isomers" or "geometric isomers" are caused by the inability of double bonds or single bonds of ring carbon atoms to rotate freely.

[0109] Unless otherwise specified, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and are not mirror images of each other.

[0110] Unless otherwise specified, "(+)" indicates dextrorotation, "(-)" indicates levorotation, and "(±)" indicates racemization.

[0111] Unless otherwise specified, a solid wedge bond and a dashed wedge bond are used to represent the absolute configuration of a stereocenter, and a solid straight bond and a dashed straight bond are used to represent the relative configuration of a stereocenter. A wavy line is used to represent a solid wedge bond or a dashed wedge bond or a wavy line is used to represent a solid straight bond and a dashed straight bond

[0112] Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to different functional group isomers that are in dynamic equilibrium at room temperature and can rapidly interconvert. If tautomers are possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur through the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0113] Unless otherwise specified, an atom with "*" or "#" is a chiral atom or chiral center and exists in the form of a single (R) or (S) enantiomer or an enantiomer-rich form; for example, represents

[0114] Unless otherwise specified, the terms "enriched in one isomer", "isomer-enriched", "enriched in one enantiomer", or "enantiomer-enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of this isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0115] Unless otherwise specified, the terms "isomer excess" or "enantiomer excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, then the isomer or enantiomer excess (ee value) is 80%.

[0116] Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with an appropriate optically active acid or base, and then the diastereomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography that employs a chiral stationary phase and optionally in combination with chemical derivatization (such as forming a carbamate from an amine).

[0117] The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound can be labeled with a radioactive isotope, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). Also, for example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with the non-deuterated drug, the deuterated drug has advantages such as reducing toxic and side effects, increasing drug stability, enhancing efficacy, and prolonging the biological half-life of the drug. All isotopic compositions of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0118] The term "optional" or "optionally" means that the subsequently described event or condition may but does not have to occur, and this description includes the case where the described event or condition occurs and the case where the described event or condition does not occur.

[0119] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and variants of hydrogen, provided that the valence state of the particular atom is normal and the resulting compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.

[0120] The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents can be arbitrary based on what is chemically achievable.

[0121] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0 - 2 R's, the group may optionally be substituted with up to two R's, and each R in each case has independent options. In addition, combinations of substituents and / or their variants are only permitted if such combinations result in a stable compound.

[0122] When one of the variables is selected from a single bond, it means that the two groups it connects are directly linked. For example, in A - L - Z, when L represents a single bond, it means the structure is actually A - Z.

[0123] When a substituent is vacant, it means that the substituent is absent. For example, in A - X, when X is vacant, it means the structure is actually A. When it is not specified which atom of the listed substituent is bonded to the group being substituted, such a substituent can be bonded through any of its atoms. For example, a pyridyl group as a substituent can be connected to the group being substituted through any carbon atom on the pyridine ring.

[0124] When the listed linking group does not specify its linking direction, the linking direction is arbitrary. For example, in which the linking group L is -M - W -, at this time -M - W - can connect ring A and ring B in the same direction as the reading order from left to right to form or can connect ring A and ring B in the opposite direction to the reading order from left to right to form Combinations of the described linking groups, substituents and / or their variants are only permitted if such combinations result in a stable compound.

[0125] Unless otherwise specified, when a group has one or more connectable sites, any one or more of these sites of the group can be connected to other groups by chemical bonds. When the connection mode of the chemical bond is non-specific and there are H atoms at the connectable sites, then when connecting the chemical bonds, the number of H atoms at this site will correspondingly decrease with the number of connected chemical bonds to become a group with the corresponding valence. The chemical bond connecting the site to other groups can be represented by a straight solid line bond a straight dashed line bond or a wavy line For example, the straight solid line bond in -OCH 3 represents the connection to other groups through the oxygen atom in this group; the straight dashed line bond in represents the connection to other groups through both ends of the nitrogen atom in this group; the wavy line in represents the connection to other groups through the 1- and 2-carbon atoms in this phenyl group;

[0126]

[0127] Unless otherwise specified, the term "C 1-3 alkyl" is used to represent a saturated hydrocarbon group with a straight or branched chain consisting of 1 to 3 carbon atoms. The C 1-3 alkyl includes C 1-2 and C 2-3 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine). Examples of C 1-3 alkyl include but are not limited to methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0127] Unless otherwise specified, C n-n+m or C n -C n+m includes any specific case of having n to n + m carbons. For example, C 1-12 includes C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、C 7 、C 8 、C 9 、C 10 、C 11 、and C12 also includes any range from n to n + m, such as C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 and so on; similarly, n - to n + m - membered rings mean that the number of atoms in the ring is from n to n + m. For example, 3 - to 12 - membered rings include 3 - membered rings, 4 - membered rings, 5 - membered rings, 6 - membered rings, 7 - membered rings, 8 - membered rings, 9 - membered rings, 10 - membered rings, 11 - membered rings, and 12 - membered rings, and also include any range from n to n + m. For example, 3 - to 12 - membered rings include 3 - to 6 - membered rings, 3 - to 9 - membered rings, 5 - to 6 - membered rings, 5 - to 7 - membered rings, 6 - to 7 - membered rings, 6 - to 8 - membered rings, and 6 - to 10 - membered rings and so on.

[0128] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (such as a nucleophilic substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups, such as methanesulfonate, tosylate, p - bromobenzenesulfonate, p - toluenesulfonate, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, and so on.

[0129] The term "protecting group" includes, but is not limited to, "amino - protecting group", "hydroxy - protecting group", or "mercapto - protecting group". The term "amino - protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino - protecting groups include, but are not limited to: formyl; acyl groups, such as alkanoyl groups (such as acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert - butoxycarbonyl (Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and 9 - fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl (Bn), trityl (Tr), 1,1 - bis - (4′ - methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert - butyldimethylsilyl (TBS), and so on. The term "hydroxy - protecting group" refers to a protecting group suitable for preventing side reactions of the hydroxyl group. Representative hydroxy - protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert - butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p - methoxybenzyl (PMB), 9 - fluorenylmethyl (Fm), and diphenylmethyl (diphenylmethyl, DPM); silyl groups, such as trimethylsilyl (TMS) and tert - butyldimethylsilyl (TBS), and so on.

[0130] Unless otherwise specified, the conditions for supercritical fluid chromatography are as follows: for example, supercritical fluid chromatography (chromatographic column: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); mobile phase: [0.1% ammonia water - ethanol]; ethanol percentage: 48% - 78%, 7 min, where 7 min represents the time required for the ethanol concentration to increase from 48% to 78%.

[0131] The compounds of the present invention can be prepared by various synthetic methods well-known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and the equivalent substitution methods well-known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0132] The structures of the compounds of the present invention can be confirmed by conventional methods well-known to those skilled in the art. If the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), collecting diffraction intensity data of the cultivated single crystal with a Bruker D8 venture diffractometer, the light source is CuKα radiation, scanning mode: Scanning, after collecting relevant data, further using the direct method (Shelxs97) to analyze the crystal structure, the absolute configuration can be confirmed.

[0133] The solvents used in the present invention are commercially available. The following abbreviations are used in the present invention: aq represents water; eq represents equivalent, equal amount; NaCNBH 3 represents sodium cyanoborohydride; r.t. represents room temperature; mp represents melting point; DCM represents dichloromethane; MeOH represents methanol; SFC represents supercritical fluid chromatography; MMS represents the intrinsic hepatic clearance rate.

[0134] Compounds are named according to the conventional naming principles in the art or using software, and commercially available compounds use the supplier catalog names. Specific Embodiments

[0135] The present invention will be described in detail below through examples, but this does not mean any adverse limitation to the present invention. The present invention has been described in detail herein, and its specific embodiments have also been disclosed. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention, and they still fall within the protection scope of the present invention.

[0136] Example 1

[0137]

[0138]

[0139] Step 1: Synthesis of Compound 001-2:

[0140] Dissolve Compound 001-1 (5 g, 24.22 mmol, 1 eq) in acetonitrile (50 mL), add methylene iodide (9.73 g, 36.33 mmol, 2.93 mL, 1.5 eq), and slowly add tert-butyl nitrite (3.75 g, 36.33 mmol, 4.32 mL, 1.5 eq) at 0 °C. Heat the mixture to 20 °C and stir, then heat to 80 °C and stir for 1 hour. Concentrate the reaction solution under reduced pressure at 43 °C. Dissolve the concentrate in 80 mL of petroleum ether, filter, and finally dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Column chromatography: The crude product is separated by column chromatography (petroleum ether) to obtain Compound 001-2.

[0141] Step 2: Synthesis of Compound 001-3:

[0142] Under the protection of nitrogen, dissolve Compound 001-2 (5 g, 15.76 mmol, 1 eq) and dimethylphosphine oxide (1.23 g, 15.76 mmol, 1 eq) in dioxane (50 mL), add tris(dibenzylideneacetone)dipalladium (721.38 mg, 787.78 μmol, 0.05 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (455.82 mg, 787.78 μmol, 0.05 eq), and N,N-diisopropylethylamine (5.09 g, 39.39 mmol, 6.86 mL, 2.5 eq) at once, then heat to 60 °C and stir for 16 hours. Cool the reaction solution to 20 °C and concentrate it under reduced pressure at 43 °C. Dissolve the concentrate in 30 mL of water and 50 mL of ethyl acetate, extract and separate the layers, and extract the aqueous phase with ethyl acetate (30 mL, 30 mL, 30 mL) three times. Combine the organic phases, wash once with saturated sodium chloride solution (30 mL), and finally dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Separate and purify by high performance liquid chromatography (column: Phenomenex Genimi NX C18 150*40 mm*5 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile %: 22%-32%, 10 min) to obtain Compound 001-3. MS(ESI) m / z: 269.0 [M+H] + .

[0143] Step 3: Synthesis of Compound 001-4:

[0144] Under the protection of nitrogen, compound 001-3 (2.3 g, 8.60 mmol, 1 eq) and compound 001-3A (2.25 g, 10.32 mmol, 1.2 eq) were dissolved in dioxane (25 mL). N,N-Diisopropylethylamine (3.33 g, 25.80 mmol, 4.49 mL, 3 eq), tris(dibenzylideneacetone)dipalladium (787.38 mg, 859.86 μmol, 0.1 eq), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (497.53 mg, 859.86 μmol, 0.1 eq) were added at once, and then the temperature was raised to 110 °C and stirred for 5 hours. The reaction solution was cooled to 20 °C and concentrated under reduced pressure at 43 °C. The concentrate was dissolved in 50 mL of water and 50 mL of ethyl acetate, and the layers were separated by extraction. Meanwhile, the aqueous phase was extracted three times with ethyl acetate (50 mL, 30 mL, 30 mL). The organic phases were combined, washed once with saturated sodium chloride solution (30 mL), and finally dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was separated by column chromatography (0-10% methanol in dichloromethane). Compound 001-4 was obtained. MS(ESI) m / z: 405.2 [M+H] + 。

[0145] Step 4: Synthesis of compound 001-5:

[0146] Compound 001-4 (0.5 g, 1.23 mmol, 1 eq) was dissolved in tetrahydrofuran (5 mL). Potassium tert-butoxide (1 M, 1.85 mL, 1.5 eq) dissolved in tetrahydrofuran (5 mL) was added dropwise at -78 °C, and the mixture was stirred at -78 °C for 1 hour. The reaction solution was directly rotary evaporated to obtain the crude product. The obtained crude product was directly used in the next reaction without further purification. Compound 001-5 was obtained. MS(ESI) m / z: 221.0 [M+H] + 。

[0147] Step 5: Synthesis of compound 001-6:

[0148] Under nitrogen protection, compound 001-5 (270 mg, 1.22 mmol, 1 eq) and compound 001-5A (382.59 mg, 1.84 mmol, 1.5 eq) were dissolved in dioxane (3 mL). Tris(dibenzylideneacetone)dipalladium (112.05 mg, 122.36 μmol, 0.1 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (70.80 mg, 122.36 μmol, 0.1 eq), and N,N-diisopropylethylamine (474.43 mg, 3.67 mmol, 639.40 μL, 3 eq) were added in one portion. Then the temperature was raised to 110 °C and stirred for 5 hours. The reaction solution was cooled to 20 °C and concentrated under reduced pressure at 43 °C. The concentrate was dissolved in 30 mL of water and 30 mL of ethyl acetate, and extraction was carried out with phase separation. Meanwhile, the aqueous phase was extracted twice with ethyl acetate (30 mL, 30 mL, 30 mL). The organic phases were combined, washed once with saturated sodium chloride solution (30 mL), and finally dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was separated by column chromatography (0 - 10% methanol in dichloromethane) (TLC detection: DCM:MeOH = 10:1). Compound 001-6 was obtained. MS (ESI) m / z: 347.9 [M+H] + .

[0149] Step 6: Synthesis of compound 001-7:

[0150] Compound 001-6 (40 mg, 114.88 μmol, 1 eq) and compound 001-6A (47.29 mg, 172.32 μmol, 1.5 eq) were dissolved in a mixed solvent of dimethylacetamide (2 mL) and water (2 mL). Potassium carbonate (79.39 mg, 574.40 μmol, 5 eq) was added in one portion. Then the temperature was raised to 100 °C and stirred for 16 hours. The reaction solution was directly rotary evaporated to obtain the crude product. Compound 001-7 was obtained and directly used for the next reaction. MS (ESI) m / z: 586.3 [M+H] + .

[0151] Step 7: Synthesis of compound 001:

[0152] Compound 001-7 (45 mg, 76.77 μmol, 1 eq) was dissolved in hydrochloric acid / dioxane (4 M, 479.83 μL, 25 eq), and the mixture was stirred at 20 °C for 1 h. The reaction solution was directly concentrated in vacuo to obtain the crude product. It was separated and purified by high performance liquid chromatography (column: Phenomenex Gemini-NX C18 75*30mm*3μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile %: 0%-30%, 7 min) to obtain the formate of compound 001. MS (ESI) m / z: 482.1 [M+H] + 。 1 H NMR (400 MHz, CD 3 OD) δ ppm 1.32 - 1.35 (m, 3H), 1.71 (br d, J = 12.80 Hz, 1H), 1.80 - 1.90 (m, 3H), 1.95 (s, 3H), 1.99 (s, 3H), 3.09 - 3.25 (m, 2H), 3.41 (br d, J = 4.02 Hz, 1H), 3.87 (d, J = 9.29 Hz, 1H), 4.00 (d, J = 9.03 Hz, 1H), 4.18 - 4.38 (m, 3H), 6.95 (d, J = 7.53 Hz, 1H), 7.36 (m, 1H), 7.62 (s, 1H), 7.75 (m, 1H).

[0153] Example 2

[0154]

[0155] Step 1: Synthesis of compound 002-1:

[0156] Under the protection of nitrogen, compound 001-1 (200 mg, 968.68 μmol, 1 eq) was dissolved in acetonitrile (5 mL), and diiodomethane (73.00 mg, 774.94 μmol, 69.52 μL, 0.8 eq) was added in one portion. The temperature was raised to 60 °C, and tert-butyl nitrite (149.83 mg, 1.45 mmol, 172.82 μL, 1.5 cq) was slowly added, and then the temperature was raised to 80 °C and stirred for 1 h. The reaction solution was concentrated under reduced pressure at 43 °C. The concentrate was dissolved in 80 mL of petroleum ether, filtered, and finally the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography: The crude product was separated by column chromatography (petroleum ether = 100%). Compound 002-1 was obtained. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.33 (dd, J = 7.15, 2.13 Hz, 1H), 6.95 - 7.05 (m, 2H), 2.40 (s, 3H).

[0157] Step 2: Synthesis of Compound 002-2:

[0158] Dissolve Compound 002-1 (2.8 g, 11.79 mmol, 1 eq) in methanol (40 mL), and add ammonium acetate (1.82 g, 23.57 mmol, 2 eq) and iodobenzene diacetate (9.49 g, 29.47 mmol, 2.5 eq) all at once. Stir the mixture at 20 °C for 1 hour. Directly evaporate the reaction solution to dryness to obtain the crude product. The crude product is separated by column chromatography (0 - 10% methanol in dichloromethane) to obtain Compound 002-2. MS (ESI) m / z: 269.7 [M+H] + .

[0159] Step 3: Synthesis of Compound 002-3:

[0160] Under the protection of nitrogen, dissolve Compound 002-2 (1 g, 3.72 mmol, 1 eq) and Compound 001-3A (894.37 mg, 4.10 mmol, 1.1 eq) in dioxane (10 mL), and add diisopropylethylamine (1.44 g, 11.17 mmol, 1.95 mL, 3 eq), tris(dibenzylideneacetone)dipalladium(0) (340.98 mg, 372.36 μmol, 0.1 eq), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (215.45 mg, 372.36 μmol, 0.1 eq) all at once. Then heat the mixture to 110 °C and stir for 5 hours. Cool the reaction solution to 20 °C and concentrate it under reduced pressure at 43 °C. Dissolve the concentrate in 50 mL of water and 50 mL of ethyl acetate, extract and separate the layers. Meanwhile, extract the aqueous phase with ethyl acetate (50 mL, 30 mL, 30 mL) three times. Combine the organic phases, wash them once with saturated sodium chloride solution (30 mL), and finally dry the organic phases with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Column chromatography: The crude product is separated by column chromatography (0 - 10% methanol in dichloromethane) to obtain Compound 002-3. MS (ESI) m / z: 406.1 [M+H] + .

[0161] Step 4: Synthesis of Compound 002-4:

[0162] Under the protection of nitrogen, dissolve Compound 002-4 (100 mg, 246.30 μmol, 1 eq) in tetrahydrofuran (1.23 mL), and add potassium tert-butoxide (1 M, 1.23 mL, 1 eq) all at once at -78 °C. Stir the mixture at -78 °C for 1 hour. Directly evaporate the reaction solution to dryness to obtain the crude product. The obtained crude product is directly used in the next reaction without further purification to obtain Compound 002-4. MS (ESI) m / z: 221.9 [M+H]+.

[0163] Step 5: Synthesis of Compound 002-5:

[0164] Under the protection of nitrogen, dissolve Compound 002-4 (50 mg, 225.50 μmol, 1 eq) and Compound 001-5A (70.51 mg, 338.25 μmol, 1.5 eq) in dioxane (3 mL). Add diisopropylethylamine (87.43 mg, 676.51 μmol, 117.84 μL, 3 eq), tris(dibenzylideneacetone)dipalladium(0) (20.65 mg, 22.55 μmol, 0.1 eq), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (13.05 mg, 22.55 μmol, 0.1 eq) all at once. Then heat the mixture to 110 °C and stir for 5 hours. Cool the reaction mixture to 20 °C and concentrate it under reduced pressure at 43 °C. Dissolve the concentrate in 30 mL of water and 30 mL of ethyl acetate, extract and separate the layers. Meanwhile, extract the aqueous phase with ethyl acetate (30 mL × 3) three times. Combine the organic phases, wash them once with saturated sodium chloride solution (30 mL), and finally dry the organic phases over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is separated by column chromatography (0 - 10% methanol in dichloromethane). Compound 002-5 is obtained. MS(ESI) m / z: 348.9 [M+H]+.

[0165] Step 6: Synthesis of Compound 002-6:

[0166] Under the protection of nitrogen, dissolve Compound 002-5 (50 mg, 143.16 μmol, 1 eq) and Compound 001-6A (39.29 mg, 143.16 μmol, 1 eq) in dimethylacetamide (2 mL) and water (2 mL). Add potassium carbonate (59.36 mg, 429.48 μmol, 3 eq) all at once. Then heat the mixture to 100 °C and stir for 16 hours. Directly evaporate the reaction mixture to dryness to obtain Compound 002-6. MS(ESI) m / z: 587.1 [M+H]+.

[0167] Step 7: Synthesis of Compound 002:

[0168] Compound 002-6 (50 mg, 85.15 μmol, 1 eq) was dissolved in hydrochloric acid / methanol (4 M, 532.17 μL, 25 eq), and the mixture was stirred at 20 °C for 1 h. The reaction solution was directly concentrated in vacuo to obtain the crude product. It was separated and purified by high performance liquid chromatography (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile %: 0%-30%, 7 min). The formate of compound 002 was obtained. The formate of 002 was added to ethyl acetate (30 mL), washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain compound 002. MS (ESI) m / z: 483.1 [M+H] + . 1 HNMR (400 MHz, CD 3 OD) δ ppm 7.96 (d, J = 7.75 Hz, 1H), 7.63 (s, 1H), 7.37 (t, J = 8.00 Hz, 1H), 6.97 (d, J = 8.50 Hz, 1H), 4.63 (br s, 2H), 4.20 - 4.37 (m, 4H), 3.99 (m, 1H), 3.87 (m, 1H), 3.36 (s, 3H), 3.10 - 3.24 (m, 1H), 1.77 - 1.91 (m, 3H), 1.70 (m, 1H), 1.32 (m, 3H).

[0169] Example 3

[0170]

[0171] Step 1: Synthesis of compound 003-1:

[0172] Under the protection of nitrogen, compound 002-2 (1.9 g, 7.07 mmol, 1 eq) was dissolved in N,N-dimethylformamide (20 mL), and sodium hydride (424.45 mg, 10.61 mmol, 60% purity, 1.5 eq) was added at 0 °C at one time. The mixture was stirred at 0 °C for 10 min, then iodomethane (2.01 g, 14.15 mmol, 880.86 μL, 2 eq) was added, and the temperature was raised to 25 °C and stirred for hours. The reaction solution was added dropwise to 10 mL of ice water, diluted with 50 mL of ethyl acetate, separated, and the aqueous phase was washed with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure from the filtrate. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 0-50%) to obtain compound 003-1. MS (ESI) m / z: 283.9 [M+H] + .

[0173] Step 2: Synthesis of compound 003-2:

[0174] Under the protection of nitrogen, compound 003-1 (1.5 g, 5.31 mmol, 1 eq) and compound 001-3A (1.27 g, 5.84 mmol, 1.1 eq) were dissolved in dioxane (20 mL). Diisopropylethylamine (2.06 g, 15.92 mmol, 2.77 mL, 3 eq), tris(dibenzylideneacetone)dipalladium (486.08 mg, 530.81 μmol, 0.1 eq), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (307.14 mg, 530.81 μmol, 0.1 eq) were added at one time. Then the temperature was raised to 110 °C and stirred for 5 hours. The reaction solution was cooled to 20 °C and concentrated under reduced pressure at 43 °C. The concentrate was dissolved in 50 mL of water and 50 mL of ethyl acetate, and the layers were separated by extraction. Meanwhile, the aqueous phase was extracted three times with ethyl acetate (50 mL, 30 mL, 30 mL). The organic phases were combined, washed once with saturated sodium chloride solution (30 mL), and finally dried over anhydrous sodium sulfate. The organic phase was filtered, and the filtrate was concentrated under reduced pressure. Column chromatography: The crude product was separated by column chromatography (0-10% methanol in dichloromethane) to obtain compound 003-2. MS (ESI) m / z: 420.0 [M+H] + 。

[0175] Step 3: Synthesis of compound 003-3:

[0176] Under the protection of nitrogen, compound 003-2 (100 mg, 238.08 μmol, 1 eq) was dissolved in tetrahydrofuran (1 mL). Potassium tert-butoxide (1 M, 1.19 mL, 5 eq) was added at -78 °C at one time, and the mixture was stirred at -78 °C for 1 hour. The reaction solution was directly evaporated to dryness to obtain compound 003-3. MS (ESI) m / z: 235.9 [M+H]+.

[0177] Step 4: Synthesis of compound 003-4:

[0178] Under the protection of nitrogen, dissolve compound 003-3 (56 mg, 237.54 μmol, 1 eq) and compound 001-5A (74.27 mg, 356.30 μmol, 1.5 eq) in dioxane (3 mL). Add diisopropylethylamine (92.10 mg, 712.61 μmol, 124.12 μL, 3 eq), tris(dibenzylideneacetone)dipalladium (21.75 mg, 23.75 μmol, 0.1 eq), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (13.74 mg, 23.75 μmol, 0.1 eq) all at once. Then heat the mixture to 110 °C and stir for 5 hours. Cool the reaction solution to 20 °C and concentrate it under reduced pressure at 43 °C. Dissolve the concentrate in 30 mL of water and 30 mL of ethyl acetate, extract and separate the layers. Meanwhile, extract the aqueous phase with ethyl acetate (30 mL × 3) three times. Combine the organic phases, wash them once with saturated sodium chloride solution (30 mL), and finally dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is separated by column chromatography (0 - 10% methanol in dichloromethane) to obtain compound 003-4. MS(ESI) m / z: 362.9 [M+H] + 。

[0179] Step 5: Synthesis of compound 003-5:

[0180] Under the protection of nitrogen, dissolve compound 003-4 (85 mg, 233.98 μmol, 1 eq) and compound 001-6A (77.05 mg, 280.77 μmol, 1.2 eq) in dimethylacetamide (2 mL) and water (2 mL). Add potassium carbonate (97.01 mg, 701.93 μmol, 3 eq) all at once. Then heat the mixture to 100 °C and stir for 16 hours. Directly spin-dry the reaction solution to obtain the crude product. Compound 003-5 is obtained. MS(ESI) m / z: 601.1 [M+H] + 。

[0181] Step 6: Synthesis of compound 003:

[0182] Compound 003-5 (50 mg, 83.16 μmol, 1 eq) was dissolved in hydrogen chloride / methanol (4 M, 20.79 μL, 1 eq), and the mixture was stirred at 20 °C for 1 h. The reaction solution was directly evaporated to dryness to obtain the crude product. It was separated and purified by high performance liquid chromatography (Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile %: 5%-35%, 7 min) to obtain the formate of compound 003. The formate of 003 was added to ethyl acetate (30 mL), washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain compound 003. MS (ESI) m / z: 497.0 [M+H] + . 1 HNMR (400 MHz, CD 3 OD) δ ppm 7.92 (dd, J = 7.91, 1.38 Hz, 1H), 7.63 (s, 1H), 7.40 (t, J = 7.91 Hz, 1H), 7.00 (dd, J = 8.03, 1.51 Hz, 1H), 4.25 - 4.38 (m, 3H), 4.02 (d, J = 9.29 Hz, 1H), 3.90 (d, J = 9.29 Hz, 1H), 3.44 (d, J = 4.27 Hz, 1H), 3.36 (s, 3H), 3.07 - 3.24 (m, 2H), 2.57 (s, 3H), 1.79 - 1.90 (m, 3H), 1.68 - 1.76 (m, 1H), 1.35 (s, 3H).

[0183] Example 4

[0184]

[0185]

[0186] Step 1: Synthesis of compound 004-2:

[0187] Under the protection of nitrogen, compound 004-1 (5.0 g, 19.43 mmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (60 mL). After displacing nitrogen three times, the temperature was lowered to -78 °C. A solution of lithium diisopropylamide (2.0 M, 10.69 mL, 1.1 eq) in tetrahydrofuran was slowly added dropwise to the reaction mixture, and the mixture was stirred at -78 °C for 1 hour. Then, a solution of compound 004-2A in tetrahydrofuran was slowly added dropwise to the system, and the reaction was carried out at -78 °C for 30 minutes. Then, the reaction system was slowly warmed up to -25 °C and reacted for 15 hours. After the reaction was completed, it was quenched with 100 mL of saturated ammonium chloride solution and extracted three times with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. Column chromatography: The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 0 - 10%) to obtain compound 004-2. MS (ESI) m / z: 388.2 [M+Na] + 。

[0188] Step 2: Synthesis of compound 004-3:

[0189] Under the protection of nitrogen, compound 004-2 (6.91 g, 18.91 mmol, 1 eq) was dissolved in dioxane (80 mL) and methanol (32 mL). After adding aqueous sodium hydroxide solution (6 M, 16 mL, 5.08 eq), the temperature was raised to 100 °C and refluxed for 15 hours. After the reaction was completed, it was cooled to room temperature. The organic solvents were removed under reduced pressure, and the pH was adjusted to 3 - 4 with dilute hydrochloric acid (1.0 M). It was filtered, the filter cake was washed with water, and the washed filter cake was redissolved in ethyl acetate, dried over anhydrous sodium sulfate, and then dried by rotary evaporation to obtain compound 004-3. MS (ESI) m / z: 360.1 [M+Na] + 。

[0190] Step 3: Synthesis of compound 004-4:

[0191] Under the protection of nitrogen, compound 004-4 (6.10 g, 18.08 mmol, 1 eq) and polyphosphoric acid (40 mL, 1.0 eq) were added to a single-necked flask, and the reaction was carried out at 120 °C for 1 hour. After the reaction was completed, it was cooled to room temperature, and the reaction mixture was poured into ice water for quenching. The pH was slowly adjusted to 9 with aqueous sodium hydroxide solution (6 M) under an ice bath. Extraction was carried out three times with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The crude product was dissolved in dichloromethane (100 mL). Di-tert-butyl dicarbonate (6.12 g, 28.05 mmol, 6.44 mL, 3.0 eq) and triethylamine (5.68 g, 56.10 mmol, 7.81 mL, 6.0 eq) were added, and the reaction mixture was reacted at 25 °C for 2 hours. After the reaction was completed, water was added, and liquid separation was carried out. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain compound 004-4. MS(ESI) m / z: 342.1 [M+Na] + .

[0192] Step 4: Synthesis of compound 004-5:

[0193] Under the protection of nitrogen, compound 004-4 (2 g, 6.26 mmol, 1 eq) and compound 004-5A (2.28 g, 18.79 mol, 3.0 eq) were added to a single-necked flask, and then tetraethyl titanate (5 mL) was added. The reaction was refluxed at 100 °C for 18 hours. After the reaction was completed, it was cooled to room temperature, and the mixture was poured into ice water for quenching. Ethyl acetate (50 mL) was added and stirred for 1 hour. Liquid separation was carried out, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. Column chromatography: The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 0 - 20%), and compound 004-5 was obtained. MS(ESI) m / z: 445.1 [M+Na] + .

[0194] Step 5: Synthesis of compound 004-6:

[0195] Under the protection of nitrogen, compound 004-5 (2.54 g, 6.01 mmol, 1 eq) was dissolved in tetrahydrofuran (25 mL). After cooling to -20 °C, sodium borohydride (455 mg, 12.02 mmol, 2.0 eq) was added. The reaction system was gradually restored to 25 °C and reacted for 12 hours. After the reaction was completed, the reaction was quenched by adding water under an ice bath. After extraction with ethyl acetate (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain compound 004-6. MS(ESI) m / z: 447.1 [M+Na] + .

[0196] Step 6: Synthesis of Compound 004-7:

[0197] Dissolve Compound 004-6 (34 mg, 80 μmol, 1 eq) in dichloromethane (5 mL), and add trifluoroacetic acid (91.2 mg, 800 μmol, 59.23 μL, 10 eq). After the reaction mixture reacts at 25 °C for 2 hours, add potassium carbonate to neutralize the reaction system to neutrality, and rotary evaporate the solvent to obtain Compound 004-7. MS (ESI) m / z: 325.1 [M+H] + 。

[0198] Step 7: Synthesis of Compound 004-8:

[0199] Dissolve Compound 004-7 (25.9 mg, 80 μmol, 1 eq) and Compound 002-5 (27.6 mg, 80 μmol, 1 eq) in N,N-dimethylacetamide (4 mL) and water (4 mL), add potassium carbonate (57.38 mg, 415 μmol, 5 eq), and then react at 100 °C for 48 hours. After the reaction is completed, cool to room temperature, add water (10 mL), extract with ethyl acetate (10 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and rotary evaporate to remove the solvent. Column chromatography: The crude product is separated by column chromatography (dichloromethane:methanol = 0-10%) to obtain Compound 004-8. MS (ESI) m / z: 637.1 [M+H] + 。

[0200] Step 8: Synthesis of Compound 004:

[0201] Dissolve Compound 004-8 (23 mg, 36.1 μmol, 1 eq) in methanol (2 mL), and add hydrochloric acid methanol solution (4 M, 530 μL, 58.5 eq). After the reaction mixture reacts at 25 °C for 1 hour, directly rotary evaporate the solvent to obtain the crude product. The crude product is sent to preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX C18 75*30mm*3μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile%: 48%-78%, 7 min) for separation to obtain the formate of Compound 004. Add the formate of 004 to ethyl acetate (30 mL), wash with saturated sodium bicarbonate solution, dry over anhydrous sodium sulfate, filter, and rotary evaporate the filtrate to obtain Compound 004. MS (ESI) m / z: 533.2 [M+H] + 。 1 H NMR (400 MHz, CDCl 3) δ ppm 7.95 (dd, J = 7.78, 1.25 Hz, 1H), 7.68 (s, 1H), 7.28 (m, 2H), 7.04 (dd, J = 7.91, 1.38 Hz, 1H), 6.91 - 6.96 (m, 2H), 4.88 (s, 2H), 4.21 (m, 2H), 3.98 (s, 1H), 3.34 (s, 3H), 3.17 - 3.27 (m, 2H), 3.05 - 3.14 (d, J = 15.56 Hz, 1H), 2.75 (d, J = 15.56 Hz, 1H), 1.30 - 1.34 (m, 2H).

[0202] Step 9: Synthesis of Compounds 004 - 8A and 004 - 8B:

[0203] Compound 004 - 8 was subjected to chiral supercritical fluid chromatography for separation (column: Chiralpak AS - 3 (100 mm * 4.6 mm, 3 μm); mobile phase: carbon dioxide; [0.05% triethylamine, ethanol%]: 40% - 40%), and two isomers were obtained. Isomer 1 is 004 - 8A (retention time 2.557 min). MS(ESI) m / z: 637.1 [M + H] + . Isomer 2 is 004 - 8B (retention time 3.028 min), MS(ESI) m / z: 637.1 [M + H] + .

[0204] Step 10: Synthesis of Compound 004A:

[0205] Compound 004 - 8A (23 mg, 36.1 μmol, 1 eq) was dissolved in methanol (2 mL), and hydrochloric acid methanol solution (4 M, 530 μL, 58.5 eq) was added. After the reaction mixture was reacted at 25 °C for 1 hour, the solvent was directly evaporated to dryness to obtain the crude product. The crude product was subjected to high - performance liquid chromatography (column: Welch Xtimate C18 150 * 25 mm * 5 μm; mobile phase: [water (0.225% formic acid) - acetonitrile]; acetonitrile%: 10% - 40%, 7 min) for separation to obtain the formate of Compound 004A. MS(ESI) m / z: 533.2 [M + H] + .

[0206] 1 H NMR(400MHz,CD 31H NMR (400 MHz, CDCl₃) δ ppm 7.95 (dd, J = 7.78, 1.25 Hz, 1H), 7.64 (s, 1H), 7.50 (dd, J = 8.28, 5.27 Hz, 1H), 7.38 (t, J = 7.91, 1H), 7.15 - 7.02 (m, 2H), 6.99 (dd, J = 8.03, 1.51 Hz, 1H), 4.45 - 4.25 (m, 3H), 3.36 (s, 3H), 3.32 - 3.22 (m, 2H), 3.20 - 3.10 (m, 2H), 2.00 - 1.50 (m, 4H).

[0207] 1 1H NMR(400MHz,CDCl 3 )δ ppm 7.95 (dd, J = 7.78, 1.25 Hz, 1H), 7.68 (s, 1H), 7.28 (m, 2H), 7.04 (dd, J = 7.91, 1.38 Hz, 1H), 6.91 - 6.96 (m, 2H), 4.88 (s, 2H), 4.21 (m, 2H), 3.98 (s, 1H), 3.34 (s, 3H), 3.17 - 3.27 m, 2H), 3.05 - 314 (d, J = 15.56 Hz, 1H), 2.75 (d, J = 15.56 Hz, 1H), 1.30 - 1.34 (m, 2H).

[0208] The formate of 004A was analyzed by chiral supercritical fluid chromatography: (Column: Chiralpak AS - 3 (100 mm * 4.6 mm, 3 μm); Mobile phase: carbon dioxide; [0.05% triethylamine, ethanol%]: 40% - 40%) The retention time was 3.327 min.

[0209] Step 11: Synthesis of compound 004B:

[0210] Compound 004 - 8B (23 mg, 36.1 μmol, 1 eq) was dissolved in methanol (2 mL), and hydrochloric acid methanol solution (4 M, 530 μL, 58.5 eq) was added. After the reaction mixture was reacted at 25 °C for 1 hour, the solvent was directly evaporated to dryness to obtain the crude product. The crude product was separated by high - performance liquid chromatography (Column: Welch Xtimate C18 150 * 25 mm * 5 μm; Mobile phase: [water (0.225% formic acid) - acetonitrile]; Acetonitrile%: 10% - 70%, 7 min) to obtain the formate of compound 004B. MS (ESI) m / z: 533.2 [M + H] - .

[0211] 1 1H NMR(400MHz,CD 3OD) δ ppm 7.95 (dd, J = 7.78, 1.25 Hz, 1H), 7.64 (s, 1H), 7.54 (dd, J = 8.53, 5.02 Hz, 1H), 7.38 (t, J = 7.91, 1H), 7.18 - 7.05 (m, 2H), 6.99 (dd, J = 8.03, 1.25 Hz, 1H), 4.45 - 4.25 (m, 3H), 3.36 (s, 3H), 3.32 - 3.22 (m, 2H), 3.22 - 3.15 (m, 2H), 2.00 - 1.50 (m, 4H).

[0212] 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.95 (dd, J = 7.78, 1.25 Hz, 1H), 7.68 (s, 1H), 7.28 (m, 2H), 7.04 (dd, J = 7.91, 1.38 Hz, 1H), 6.91 - 6.96 (m, 2H), 4.88 (s, 2H), 4.21 (m, 2H), 3.98 (s, 1H), 3.34 (s, 3H), 3.17 - 3.27 (m, 2H), 3.05 - 3.14 (d, J = 15.56 Hz, 1H), 2.75 (m, 1H), 1.30 - 1.34 (m, 2H).

[0213] The formate of 004B was sent to chiral supercritical fluid chromatography for analysis: (Chromatographic column: Chiralpak AS - 3 (100 mm * 4.6 mm, 3 μm); Mobile phase: carbon dioxide; [0.05% triethylamine, ethanol%]: 40% - 40%) The retention time was 4.498 min.

[0214] Example 5

[0215]

[0216] Step 1: Synthesis of compound 005 - 2:

[0217] Compound 005 - 1 (500 mg, 1.17 mmol, 1 eq) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3.0 mL) was added. After the reaction mixture was reacted at 25 °C for 2 hours, potassium carbonate was added to neutralize the reaction system to neutrality, and the solvent was evaporated to dryness to obtain compound 005 - 2. MS (ESI) m / z: 327.1 [M + H] + .

[0218] Step 2: Synthesis of compound 005 - 3:

[0219] Compound 005-2 (380 mg, 1.16 mmol, 1 eq) and compound 002-5 (405 mg, 1.16 mmol, 1 eq) were dissolved in N,N-dimethylacetamide (10 mL) and water (10 mL). After adding potassium carbonate (995 mg, 5.8 mmol, 5 eq), the reaction was carried out at 100 °C for 48 h. After the reaction was completed, it was cooled to room temperature. After adding water (10 mL), it was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. Column chromatography: The crude product was separated by column chromatography (methylene chloride:methanol = 0 - 10%), and compound 005-3 was obtained. MS (ESI) m / z: 639.1 [M+H] + 。

[0220] Step 3: Synthesis of compound 005:

[0221] Compound 005-3 (250 mg, 391 μmol, 1 eq) was dissolved in methanol (10 mL), and hydrochloric acid methanol solution (4 M, 2.5 mL, 58.5 eq) was added. After the reaction mixture reacted at 25 °C for 1 h, the solvent was directly removed by rotary evaporation to obtain the crude product. The crude product was sent to supercritical fluid chromatography (chromatographic column: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); mobile phase: [0.1% ammonia water - ethanol]; ethanol%: 48% - 78%, 7 min). Compound 005A (5.032 min) and compound 005B (5.823 min) were separated. Compound 005A: MS (ESI) m / z: 535.1 [M+H] + 。 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.94 (dd, J = 7.78, 1.25 Hz, 1H), 7.65 (s, 1H) 7.38 - 7.34 (m, 2H), 7.00 - 6.97 (m, 1H), 6.91 - 6.55 (m, 2H), 4.48 - 4.40 (m, 1H), 4.37 - 4.26 (m, 1H), 4.09 (s, 1H), 3.45 - 3.37 (m, 2H), 3.35 (s, 3H), 1.96 - 1.93 (m, 2H), 1.85 - 1.82 (m, 2H). Compound 005B: MS (ESI) m / z: 535.1 [M+H] + 。 1 H NMR (400 MHz, CD 3OD) δ ppm 7.94 (dd, J = 7.78, 1.25 Hz, 1H), 7.65 (s, 1H), 7.38 - 7.34 (m, 2H), 7.00 - 6.97 (m, 1H), 6.91 - 6.66 - 6.55 (m, 2H), 4.48 - 4.40 (m, 1H), 4.37 - 4.26 (m, 1H), 4.09 (s, 1H), 3.45 - 3.37 (m, 2H), 3.35 (s, 3H), 1.96 - 1.93 (m, 2H), 1.85 - 1.82 (m, 2H).

[0222] Example 6

[0223]

[0224] Step 1: Synthesis of Compound 006 - 3:

[0225] Dissolve Compound 006 - 1 (7.13 g, 33.93 mmol, 1 eq) in tetrahydrofuran (160 mL). Add lithium diisopropylamide (2 M, 22.06 mL, 1.3 eq) when the temperature is lowered to -78 °C. React the reaction system at -78 °C for 1 hour. Add 006 - 2 (10 g, 37.32 mmol, 1.1 eq). React the system at -78 °C for another 1 hour, and then slowly warm it to 25 °C with stirring. After the reaction is completed, quench it with 25 mL of saturated ammonium chloride solution. Extract with ethyl acetate three times (150 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and rotary evaporate to remove the solvent. Column chromatography: The crude product is separated by column chromatography (petroleum ether:ethyl acetate = 0 - 10%) to obtain Compound 006 - 3. MS (ESI) m / z: 296.8 [M + H] + .

[0226] Step 2: Synthesis of Compound 006 - 4:

[0227] Under the protection of nitrogen, dissolve compound 006-3 (12.00 g, 30.21 mmol, 1 eq) in a mixed solution of N,N-dimethylacetamide (100 mL) and water (10 mL). Add dichloro bis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium (2.14 g, 3.02 mmol, 2.14 mL, 0.1 eq) and triethylamine (12.23 g, 120.82 mmol, 16.82 mL, 4 eq). Evacuate and refill the system with nitrogen three times, and then heat the mixture to 130 °C and react for 5 hours. Cool the reaction solution to room temperature, add 150 mL of water, and extract with ethyl acetate (200 mL × 3). Combine the organic phases, concentrate under reduced pressure until the volume of the concentrated solution is about 150 mL, wash with water 4 times, wash with saturated brine 2 times, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is separated by column chromatography (30% - 35% ethyl acetate in petroleum ether) to obtain compound 006-4, MS(ESI) m / z: 263.9 [M+H] + 。

[0228] Step 3: Synthesis of compound 006-5:

[0229] Dissolve compound 006-4 (8.83 g, 27.65 mmol, 1 eq) in tetraethyl orthotitanate (85 ml), add compound 004-5A (10.05 g, 82.94 mmol, 3 eq). Evacuate and refill the system with nitrogen three times, and then heat the mixture to 130 °C and react for 3 hours. After the reaction is completed, cool the reaction solution to room temperature, add the reaction solution to ice water, stir for 40 minutes, add the supernatant to a separatory funnel, and then extract with ethyl acetate (200 mL × 3). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is separated by column chromatography (25% - 35% ethyl acetate in petroleum ether) to obtain compound 006-5. MS(ESI) m / z: 322.9 [M- t Bu] + 。

[0230] Step 4: Synthesis of compound 006-6:

[0231] Dissolve compound 006-5 (7.34 g, 17.37 mmol, 1 eq) in tetrahydrofuran (70 ml), cool to 0 °C, and add sodium borohydride (1.31 g, 34.74 mmol, 2 eq) with stirring. The reaction system gradually returns to 25 °C and reacts for 16 hours. Add 150 mL of water to the reaction solution to quench the unreacted NaBH 4 , extract with ethyl acetate (200 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is purified by SFC to obtain compound 006-6. MS(ESI) m / z: 325.0 [M- tBu + .

[0232] Step 5: Synthesis of Compound 006-7:

[0233] Dissolve Compound 006-6 (1.10 g, 2.59 mmol, 1 eq) in dichloromethane (10 mL), add trifluoroacetic acid (3.84 g, 33.68 mmol, 2.49 mL, 13 eq), and react the mixture at 25 °C for 50 min. After the reaction, concentrate under reduced pressure to remove part of the trifluoroacetic acid, then add 30 ml of water to the concentrated solution, add 3 g of potassium carbonate to remove the excess trifluoroacetic acid, and extract with ethyl acetate (50 mL×3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and rotary evaporate to remove the solvent to obtain Compound 006-7. MS(ESI) m / z: 325.1 [M+H] + .

[0234] Step 6: Synthesis of Compound 006-8:

[0235] Dissolve Compound 006-7 (380 mg, 1.16 mmol, 1 eq) and Compound 002-5 (405 mg, 1.16 mmol, 1 eq) in N,N-dimethylacetamide (10 mL) and water (10 mL), add potassium carbonate (995 mg, 5.8 mmol, 5 eq), and react at 100 °C for 48 hours. After the reaction, cool to room temperature, add water (50 mL), and extract with ethyl acetate (50 mL×3). Combine the organic phases and wash with saturated brine (50 mL×3). Dry the organic phase over anhydrous sodium sulfate, filter, and rotary evaporate to remove the solvent. Column chromatography: The crude product is separated by column chromatography (dichloromethane:methanol = 0-10%) to obtain Compound 006-8. MS(ESI) m / z: 637.2 [M+H] + .

[0236] Step 7: Synthesis of Compound 006:

[0237] Dissolve Compound 006-8 (308 mg, 483 μmol, 1 eq) in methanol (10 mL), and add hydrochloric acid in methanol solution (4 M, 2.5 mL, 58.5 eq). After the reaction mixture reacts at 25 °C for 1 hour, directly rotary evaporate the solvent to obtain the crude product of 006. The crude product is sent to chiral supercritical fluid chromatography (chromatographic column: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 μm); mobile phase: [0.1% ammonia-methanol]; methanol%: 40%-40%). Compound 006A (5.115 min) and Compound 006B (6.812 min) are separated. Compound 006A: MS(ESI) m / z: 533.1 [M+H] + . 11H NMR (400 MHz, CD 3 OD) δ ppm 7.94 (d, J = 7.78 Hz, 1H), 7.65 (s, 1H), 7.37 (t, J = 7.91 Hz, 1H), 7.24 (dd, J = 7.91, 5.14 Hz, 1H), 7.19 - 7.10 (m, 1H), 7.00 - 6.93 (m, 2H), 4.39 - 4.25 (m, 2H), 3.98 (s, 1H), 3.35 (s, 3H), 3.30 - 3.10 (m, 3H), 2.79 (d, J = 15.31 Hz, 1H), 1.90 - 1.70 (m, 2H), 1.64 - 1.59 (m, 1H), 1.45 - 1.35 (m, 1H). Compound 006B: MS (ESI) m / z: 533.1 [M+H] + 。δ ppm 7.94 (d, J = 7.78 Hz, 1H), 7.65 (s, 1H), 7.37 (t, J = 7.91 Hz, 1H), 7.24 (dd, J = 7.91, 5.14 Hz, 1H), 7.19 - 7.10 (m, 1H), 7.00 - 6.93 (m, 2H), 4.39 - 4.25 (m, 2H), 3.98 (s, 1H), 3.35 (s, 3H), 3.30 - 3.10 (m, 3H), 2.79 (d, J = 15.31 Hz, 1H), 1.90 - 1.70 (m, 2H), 1.64 - 1.59 (m, 1H), 1.45 - 1.35 (m, 1H).

[0238] Example 7

[0239]

[0240]

[0241] Step 1: Synthesis of Compound 007-2:

[0242] Dissolve Compound 007-1 (500 mg, 1.23 mmol, 1 eq) in dichloromethane (5 mL), and add trifluoroacetic acid (3.0 mL). After the reaction mixture reacts at 25 °C for 2 hours, add potassium carbonate to neutralize the reaction system to neutral, and evaporate the solvent to dryness to obtain Compound 007-2. MS (ESI) m / z: 306.1 [M+H] + 。

[0243] Step 2: Synthesis of Compound 007-3:

[0244] Compound 007-2 (366 mg, 1.19 mmol, 1 eq) and compound 002-5 (420 mg, 1.20 mmol, 1 eq) were dissolved in N,N-dimethylacetamide (10 mL) and water (10 mL). After adding potassium carbonate (832 mg, 5.8 mmol, 5 eq), the reaction was carried out at 100 °C for 48 hours. After the reaction was completed, it was cooled to room temperature. After adding water (10 mL), it was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. Column chromatography: The crude product was separated by column chromatography (methylene chloride:methanol = 0-10%) to obtain compound 007-3. MS(ESI) m / z: 621.1 [M+H] + 。

[0245] Step 3: Synthesis of compound 007:

[0246] Compound 007-3 (238 mg, 391 μmol, 1 eq) was dissolved in methanol (10 mL). Hydrochloric acid methanol solution (4 M, 2.5 mL, 58.5 cq) was added. After the reaction mixture reacted at 25 °C for 1 hour, the solvent was directly removed by rotary evaporation to obtain the crude product. The crude product was sent to supercritical fluid chromatography (chromatographic column: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); mobile phase: [0.1% ammonia water - ethanol]; ethanol%: 48%-78%, 10 min). Compound 007A (6.802 min) and compound 007B (7.384 min) were separated. Compound 007A: MS(ESI) m / z: 516.1 [M+H] + 。Compound 007A: MS(ESI) m / z: 516.1 [M+H] + 。 1 H NMR(400 MHz, CD 3 OD) δ ppm 8.35 (d, J = 5.14 Hz, 1H) 7.95 (dd, J = 7.91 Hz, 1.38, 1H), 7.84 (d, J = 7.53 Hz, 2H), 7.63 (s, 1H), 7.37 (t, J = 7.91 Hz, 1H), 7.28 (dd, J = 7.40, 5.14 Hz, 1H), 7.00 (dd, J = 7.91, 1.38 Hz, 1H), 4.37 - 4.26 (m, 2H), 4.04 (s, 1H), 3.35 (s, 3H), 3.20 - 3.30 (m, 3H), 2.97 - 2.82 (m, 1H), 1.95 - 1.75 (m, 2H), 1.70 - 1.60 (m, 1H), 1.45 - 1.40 (m, 1H). Compound 007B: MS(ESI) m / z: 516.1 [M+H] - 。 11H NMR (400 MHz, CD 3 OD) δ ppm 8.35 (d, J = 5.14 Hz, 1H), 7.95 (dd, J = 7.91 Hz, 1.38, 1H), 7.84 (d, J = 7.53 Hz, 2H), 7.63 (s, 1H), 7.37 (t, J = 7.91 Hz, 1H), 7.28 (dd, J = 7.40, 5.14 Hz, 1H), 7.00 (dd, J = 7.91, 1.38 Hz, 1H), 4.37 - 4.26 (m, 2H), 4.04 (s, 1H), 3.35 (s, 3H), 3.20 - 3.30 (m, 3H), 2.97 - 2.82 (m, 1H), 1.95 - 1.75 (m, 2H), 1.70 - 1.60 (m, 1H), 1.45 - 1.40 (m, 1H).

[0247] Example 8

[0248]

[0249] Step 1: Synthesis of Compound 008 - 2:

[0250] Dissolve Compound 006 - 1 (19 g, 70.92 mmol, 1.1 eq) in tetrahydrofuran (160 mL). Add lithium diisopropylamide (2 M, 38.6 mL, 1.2 eq) when the temperature is lowered to -78 °C. React the reaction system at -78 °C for 1 hour. Add 008 - 1 (13.6 g, 64.50 mmol, 1.0 eq), and react the system at -78 °C for another 1 hour. Then slowly warm it to 25 °C with stirring. After the reaction is completed, quench it with 250 mL of saturated ammonium chloride solution, extract it three times with ethyl acetate (150 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and rotary evaporate to remove the solvent. Column chromatography: The crude product is separated by column chromatography (petroleum ether:ethyl acetate = 0 - 10%) to obtain Compound 008 - 2. MS (ESI) m / z: 297.9 [M - t Bu] + .

[0251] Step 2: Synthesis of Compound 008 - 3:

[0252] Under the protection of nitrogen, dissolve compound 008-2 (12.00 g, 30.21 mmol, 1 eq) in a mixed solution of N,N-dimethylacetamide (100 mL) and water (10 mL). Add dichloro bis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium (2.14 g, 3.02 mmol, 2.14 mL, 0.1 eq) and triethylamine (12.23 g, 120.82 mmol, 16.82 mL, 4 eq). Evacuate and refill the system with nitrogen three times, and then heat the mixture to 130 °C and react for 5 hours. Cool the reaction mixture to room temperature, add 150 mL of water, and extract with ethyl acetate (200 mL × 3). Combine the organic phases, concentrate under reduced pressure until the volume of the concentrated solution is about 150 mL, wash with saturated brine (200 mL × 6), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is separated by column chromatography (30% - 35% ethyl acetate in petroleum ether) to obtain 008-3, MS(ESI) m / z: 264.1 [M - t Bu] + .

[0253] Step 3: Synthesis of compound 008-4:

[0254] Dissolve 008-3 (18 g, 56.36 mmol, 1 eq) in tetraethyl orthotitanate (180 mL), add 004-5A (20.49 g, 169.08 mmol, 3 eq). Evacuate and refill the system with nitrogen three times, and then heat the mixture to 130 °C and react for 3 hours. After the reaction is completed, cool the reaction mixture to room temperature. Add the reaction mixture to ice water, stir for 40 minutes. Transfer the supernatant to a separatory funnel, and then extract with ethyl acetate (200 mL × 3). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is separated by column chromatography (25% - 35% ethyl acetate in petroleum ether) to obtain compound 008-4. MS(ESI) m / z: 323.2 [M - Boc] + .

[0255] Step 4: Synthesis of compound 008-5:

[0256] Dissolve 008-4 (18 g, 42.60 mmol, 1 eq) in tetrahydrofuran (70 mL), cool to 0 °C, and add sodium borohydride (3.22 g, 85.20 mmol, 2 eq) with stirring. The reaction system gradually returns to 25 °C and reacts for 16 hours. Add 150 mL of water to the reaction mixture to quench the unreacted NaBH 4, extracted with ethyl acetate (200 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by SFC (chromatographic column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 μm); mobile phase: [0.1% ammonia water - ethanol]; ethanol%: 25% - 25%). Compound 008-5 was separated. MS (ESI) m / z: 325.2 [M - Boc] + .

[0257] Step 5: Synthesis of compound 008-6:

[0258] Dissolve 008-5 (800 mg, 1.88 mmol, 1 eq) in dichloromethane (10 mL), add trifluoroacetic acid (3.84 g, 33.68 mmol, 2.49 mL, 13 eq), and react the mixture at 25 °C for 50 minutes. After the reaction, concentrate under reduced pressure to remove part of the trifluoroacetic acid, then add 30 ml of water to the concentrated solution, add 3 g of potassium carbonate to remove the excess trifluoroacetic acid, extract with ethyl acetate (50 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and rotary evaporate to remove the solvent to obtain compound 008-6. MS (ESI) m / z: 325.2 [M + H] + .

[0259] Step 6: Synthesis of compound 008-7:

[0260] Dissolve compound 008-6 (570 mg, 1.76 mmol, 1 eq) and compound 002-5 (767 mg, 2.20 mmol, 1.2 eq) in N,N-dimethylacetamide (10 mL) and water (10 mL), add potassium carbonate (607 mg, 4.39 mmol, 2.5 eq), and react at 100 °C for 48 hours. After the reaction, cool to room temperature, add water (50 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (50 mL×3), dry the organic phases over anhydrous sodium sulfate, filter, and rotary evaporate to remove the solvent to obtain compound 008-7. MS (ESI) m / z: 637.2 [M + H] + .

[0261] Step 7: Synthesis of compound 008:

[0262] Compound 008-7 (1.04 g, 1.63 mmol, 1 eq) was dissolved in methanol (10 mL), and hydrochloric acid methanol solution (4 M, 2.5 mL, 58.5 eq) was added. After the reaction mixture was reacted at 25 °C for 1 hour, the solvent was directly evaporated to dryness to obtain the crude product of 008. The crude product was sent to supercritical fluid chromatography (chromatographic column: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); mobile phase: [0.1% ammonia water - ethanol]; ethanol%: 45% - 45%). Compound 008A (2.921 min) and compound 008B (3.872 min) were separated. Compound 008A: MS (ESI) m / z: 533.1 [M + H]+. 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.94 (dd, J = 7.91, 1.38 Hz, 1H), 7.63 (s, 1H), 7.38 (t, J = 7.91 Hz, 1H), 7.30 - 7.20 (m, 2H), 7.00 - 6.95 (m, 2H), 4.35 - 4.28 (m, 2H), 4.03 (s, 1H), 3.36 (s, 3H), 3.32 - 3.25 (m, 2H), 3.21 (d, J = 16.06 Hz, 1H), 2.85 (d, J = 16.06 Hz, 1H), 1.92 - 1.77 (m, 2H), 1.65 - 1.60 (m, 1H), 1.50 - 1.43 (m, 1H). Compound 008B: MS (ESI) m / z: 533.1 [M + H] + 。 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.84 (dd, J = 7.91, 1.38 Hz, 1H), 7.63 (s, 1H), 7.42 (t, J = 7.91 Hz, 1H), 7.30 - 7.20 (m, 2H), 6.99 (t, J = 8.53 Hz, 1H), 6.86 (dd, J = 8.53, 1.51 Hz, 1H), 4.25 - 4.18 (m, 2H), 3.89 (s, 1H), 3.36 (s, 3H), 3.32 - 3.15 (m, 2H), 3.10 (d, J = 16.06 Hz, 1H), 2.65 (d, J = 16.06 Hz, 1H), 1.80 - 1.65 (m, 2H), 1.60 - 1.50 (m, 1H), 1.20 - 1.05 (m, 1H).

[0263] Example 9

[0264]

[0265]

[0266] Step 1: Synthesis of Compound 009-3:

[0267] At 0 °C, potassium tert-butoxide (17.43 g, 155.36 mmol, 3.5 eq) was dissolved in 1,2-dimethoxyethane (500 mL). After purging with nitrogen three times, a solution of 009-2 (13.00 g, 66.58 mmol, 1.5 eq) in 1,2-dimethoxyethane (500 mL) was slowly added dropwise at 0 °C. The temperature was controlled not to exceed 5 °C. The mixture was stirred at 0 °C for 1 hour, and then isopropanol (3.73 g, 62.14 mmol, 4.76 mL, 1.4 eq) was added at 0 °C. The mixture was stirred for another 30 minutes. Then, a solution of 009-1 (10 g, 44.39 mmol, 1 eq) in DME (500 mL) was added. The mixture was stirred at 0 °C for 1 hour and then warmed to 25 °C and stirred for 12 hours. After the reaction was completed, it was quenched with 200 mL of saturated ammonium chloride solution and extracted with ethyl acetate (500 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The crude product was purified by flash column chromatography (petroleum ether:ethyl acetate = 20:1 - 10:1) to obtain Compound 009-3.

[0268] Step 2: Synthesis of Compound 009-5:

[0269] Compound 009-3 (6.3 g, 26.66 mmol, 1 eq) was dissolved in tetrahydrofuran (250 mL). When the temperature was lowered to -78 °C, lithium diisopropylamide (2 M, 22.06 mL, 1.3 eq) was added. The reaction system was reacted at -78 °C for 1 hour. Then, 50 mL of a tetrahydrofuran solution of 009-4 (7.50 g, 27.99 mmol, 1.05 eq) was added, and the system was reacted at -78 °C for another 1 hour, and then slowly warmed to 25 °C with stirring. After the reaction was completed, it was quenched with 250 mL of saturated ammonium chloride solution and extracted three times with ethyl acetate (450 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 10 - 20%) to obtain Compound 009-5. MS(ESI) m / z: 369.0 [M - t Bu] + .

[0270] Step 3: Synthesis of Compound 009-6:

[0271] Under the protection of nitrogen, dissolve compound 009-5 (5.1 g, 12.05 mmol, 1 eq) in a mixed solution of N,N-dimethylacetamide (200 mL) and water (20 mL), add dichloro bis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium (0.85 g, 1.2 mmol, 0.1 eq) and triethylamine (4.88 g, 48.19 mmol, 6.71 mL, 4 eq), evacuate and refill the system with nitrogen three times, and heat to 130 °C for reaction for 5 hours. Cool the reaction solution to room temperature, add 150 ml of water, extract with ethyl acetate (200 mL×3), combine the organic phases, concentrate under reduced pressure until the volume of the concentrated solution is about 150 ml, wash with saturated brine (200 mL×6), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is separated by column chromatography (30% - 35% ethyl acetate in petroleum ether) to obtain 009-6, MS(ESI) m / z: 290.1 [M- t Bu] + .

[0272] Step 4: Synthesis of compound 009-7:

[0273] Dissolve 009-6 (4.2 g, 12.16 mmol, 1 eq) in tetraethyl titanate (100 mL), add 004-5A (4.42 g, 36.48 mmol, 3 eq), evacuate and refill the system with nitrogen three times, and then heat to 130 °C for reaction for 3 hours. After the reaction is completed, cool the reaction solution to room temperature, add the reaction solution to ice water, stir for 40 minutes, add the supernatant to a separatory funnel, and then extract with ethyl acetate (200 mL×3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is separated by column chromatography (10% - 20% ethyl acetate in petroleum ether) to obtain compound 009-7. MS(ESI) m / z: 449.1 [M+H] + .

[0274] Step 5: Synthesis of compound 009-8:

[0275] Dissolve 009-7 (4.5 g, 10.03 mmol, 1 eq) in tetrahydrofuran (70 mL), cool to 0 °C, and add sodium borohydride (379.51 mg, 10.03 mmol, 1 eq) with stirring. The reaction system gradually returns to 25 °C and reacts for 4 hours. Add 150 mL of water to the reaction solution to quench the unreacted NaBH 4, extracted with ethyl acetate (200 mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (column: Phenomenex Genimi NXC18 (150 mm * 40 mm, 5 μm); mobile phase: [water (0.225% formic acid) - acetonitrile]; acetonitrile%: 42% - 72%), and compound 009-8A and compound 009-8B were separated. MS (ESI) m / z: 451.1 [M+H] +

[0276] Step 6: Synthesis of compound 009-9A:

[0277] Dissolve 009-8A (0.4 g, 0.89 mmol, 1 eq) in dichloromethane (10 mL), add trifluoroacetic acid (384 g, 33.68 mmol, 2.49 mL, 13 eq), and the mixture was reacted at 25 °C for 50 minutes. After the reaction was completed, part of trifluoroacetic acid was removed by concentration under reduced pressure, then 30 ml of water was added to the concentrated solution, 3 g of potassium carbonate was added to remove the excess trifluoroacetic acid, and extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain compound 009-9A. MS (ESI) m / z: 351.1 [M+H] + 。

[0278] Step 7: Synthesis of compound 009-10A:

[0279] Dissolve compound 009-9A (300 mg, 0.860 mmol, 1 eq) and compound 002-5 (300 mg, 0.860 mmol, 1 eq) in N,N-dimethylacetamide (10 mL) and water (10 mL), add potassium carbonate (0.591 mg, 4.3 mmol, 5 eq), and react at 100 °C for 48 hours. After the reaction was completed, it was cooled to room temperature, 50 mL of water was added, and then extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), the organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. Column chromatography: The crude product was separated by column chromatography (dichloromethane: methanol = 0 - 10%) to obtain compound 009-10A. MS (ESI) m / z: 351.1 [M+H] + 。

[0280] Step 8: Synthesis of compound 009A:

[0281] Compound 009-10A (40 mg, 60.3 μmol, 1 eq) was dissolved in methanol (5 mL), and hydrochloric acid in methanol solution (4 M, 2.5 mL, 58.5 eq) was added. After the reaction mixture was reacted at 25 °C for 1 hour, the solvent was directly evaporated to dryness to obtain the crude product of 009A. The crude product was purified by preparative high performance liquid chromatography (column: Phenomenex Gemini-NX C18 (75 mm * 30 mm, 3 μm); mobile phase: [water (0.225% formic acid) - acetonitrile]; acetonitrile %: 5% - 35%), for 7 min. The formate of compound 009A was separated: MS (ESI) m / z: 560.0 [M + H] + . 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.98 - 7.86 (m, 1H), 7.51 (s, 1H), 7.48 - 7.34 (m, 2H), 7.00 - 6.97 (m, 1H), 6.91 - 6.55 (m, 2H), 4.71 - 4.65 (m, 1H), 4.61 (s, 2H), 4.35 (s, 1H), 3.37 (s, 3H), 3.10 - 3.02 (m, 1H), 2.44 - 2.34 (m, 1H), 2.27 - 2.15 (m, 2H), 2.12 - 2.01 (m, 3H), 1.91 - 1.83 (m, 1H), 1.64 - 1.57 (m, 1H).

[0282] Step 9: Synthesis of compound 009-9B:

[0283] 009-8B (0.4 g, 0.89 mmol, 1 eq) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (384 g, 33.68 mmol, 2.49 mL, 13 eq) was added. The mixture was reacted at 25 °C for 50 minutes. After the reaction was completed, part of the trifluoroacetic acid was removed by concentration under reduced pressure. Then, 30 ml of water was added to the concentrated solution, and 3 g of potassium carbonate was added to remove the excess trifluoroacetic acid. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain compound 009-9B. MS (ESI) m / z: 351.1 [M + H] + .

[0284] Step 10: Synthesis of compound 009-10B:

[0285] Compound 009-9B (300 mg, 0.860 mmol, 1 eq) and compound 002-5 (300 mg, 0.860 mmol, 1 eq) were dissolved in N,N-dimethylacetamide (10 mL) and water (10 mL). After adding potassium carbonate (0.591 mg, 4.3 mmol, 5 eq), the reaction was carried out at 100 °C for 48 h. After the reaction was completed, it was cooled to room temperature. Water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. Column chromatography: The crude product was separated by column chromatography (dichloromethane:methanol = 0-10%) to obtain compound 009-10B. MS (ESI) m / z: 351.1 [M+H] + 。

[0286] Step 11: Synthesis of compound 009B:

[0287] Compound 009-10B (20 mg, 60.3 μmol, 1 eq) was dissolved in methanol (5 mL), and hydrochloric acid methanol solution (4 M, 2.5 mL, 58.5 eq) was added. After the reaction mixture was reacted at 25 °C for 1 h, the solvent was directly removed by rotary evaporation to obtain the crude product of 009B. The crude product was separated by preparative high performance liquid chromatography (column: Phenomenex Gemini-NX C18 (75 mm*30 mm, 3 μm); mobile phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile %: 5%-35%), 7 min. The formate of compound 009B was obtained. MS (ESI) m / z: 5,60.0 [M+H] + 。 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.98-7.86 (m, 1H), 7.51 (s, 1H), 7.48-7.34 (m, 2H), 7.00-6.97 (m, 1H), 6.91-6.55 (m, 2H), 4.71-4.65 (m, 1H), 4.61 (s, 2H), 4.35 (s, 1H), 3.37 (s, 3H), 3.10-3.02 (m, 1H), 2.44-2.34 (m, 1H), 2.27-2.15 (m, 2H), 2.12-2.01 (m, 3H), 1.91-1.83 (m, 1H), 1.64-1.57 (m, 1H).

[0288] Example 10

[0289]

[0290]

[0291] Step 1: Synthesis of Compound 010-2:

[0292] Dissolve Compound 010-1 (8.5 g, 41.06 mmol, 1 eq) in dichloromethane (100 mL), add N-bromosuccinimide (7.31 g, 41.06 mmol, 1 eq), benzoyl peroxide (596.75 mg, 2.46 mmol, 0.06 eq). The system is evacuated and replaced with nitrogen three times, and then slowly heated to 80 °C for reaction for 5 h. After the reaction is completed, the reaction solution is cooled to room temperature, filtered, 200 mL of water is added to the filtrate, and extracted with ethyl acetate (100 mL × 3). The combined organic phases are washed with saturated brine (200 mL × 1), dried over anhydrous sodium sulfate, filtered, and the solvent is removed by rotary evaporation. The crude product is separated by flash column chromatography (3% - 5% ethyl acetate in petroleum ether) to obtain Compound 010-2.

[0293] Step 2: Synthesis of Compound 010-3:

[0294] Dissolve Compound 006-1 (4.35 g, 20.67 mmol, 1 eq) in tetrahydrofuran (120 mL). The system is evacuated and replaced with nitrogen three times. When the temperature is lowered to -78 °C, lithium diisopropylamide (2 M, 12.40 mL, 1.2 eq) is added, and the reaction system is reacted at -78 °C for 1 h. A solution of 010-2 (6.5 g, 22.73 mmol, 1.1 eq) in tetrahydrofuran (30 mL) is added. The system is reacted at -78 °C for another 1 h, and then slowly warmed to 25 °C with stirring and continued to react for 10 h. After the reaction is completed, it is quenched with 100 mL of saturated ammonium chloride solution and extracted three times with ethyl acetate (100 mL × 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the solvent is removed by rotary evaporation. Column chromatography: The crude product is separated by column chromatography (10% - 15% ethyl acetate in petroleum ether) to obtain Compound 010-3. MS(ESI) m / z = 358.9 [M- t Bu] + 。

[0295] Step 3: Synthesis of Compound 010-4:

[0296] Dissolve compound 010-3 (4.41 g, 10.62 mmol, 1 eq) in a mixed solution of N,N-dimethylacetamide (40 mL) and water (4 mL). Add dichloro bis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium (751.94 mg, 1.06 mmol, 751.94 μL, 0.1 eq) and triethylamine (4.30 g, 42.48 mmol, 5.91 mL, 4 eq). Evacuate and refill the system with nitrogen three times. Heat the reaction mixture to 130 °C and stir for 5 h. After completion of the reaction, cool the reaction mixture to room temperature, add 150 mL of water, and extract with ethyl acetate (200 mL × 3). Combine the organic phases, concentrate under reduced pressure until the volume of the concentrated solution is about 150 mL, wash with saturated brine (200 mL × 6), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is separated by column chromatography (15% - 25% ethyl acetate in petroleum ether) to obtain compound 010-4, MS(ESI) m / z: = 282.1 [M - t Bu] + .

[0297] Step 4: Synthesis of compound 010-5:

[0298] Dissolve compound 010-4 (2.35 g, 6.97 mmol, 1 eq) in tetraethyl orthotitanate (30 mL). Add 004-5A (2.53 g, 20.90 mmol, 3 eq). Evacuate and refill the system with nitrogen three times. Then heat the reaction mixture to 130 °C and stir for 3 h. After completion of the reaction, cool the reaction mixture to room temperature. Add the reaction mixture to ice water and stir for 40 min. Transfer the supernatant to a separatory funnel, and extract with ethyl acetate (100 mL × 3). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product is separated by column chromatography (25% - 35% ethyl acetate in petroleum ether) to obtain compound 010-5. MS(ESI) m / z: 341.1 [M - Boc] + .

[0299] Step 5: Synthesis of compound 010-6:

[0300] Dissolve compound 010-5 (2.68 g, 6.08 mmol, 1 eq) in tetrahydrofuran (30 mL). Cool the solution to 0 °C, and add sodium borohydride (460.30 mg, 12.17 mmol, 2 eq) with stirring. The reaction system gradually returns to 25 °C and stirs for 16 h. Add 100 mL of water to the reaction mixture to quench the unreacted NaBH 4, extracted with ethyl acetate (100 mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (45% - 55% ethyl acetate in petroleum ether) to separate and obtain Compound 010-6. MS (ESI) m / z: 343.1 [M - Boc] - .

[0301] Step 6: Synthesis of Compound 010-7:

[0302] Compound 010-6 (435.50 mg, 984.04 μmol, 1 eq) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1.57 g, 13.78 mmol, 1.02 mL, 14 eq) was added, and the mixture was reacted at 25 °C for 50 minutes. After the reaction was completed, part of the trifluoroacetic acid was removed by concentration under reduced pressure, then 30 mL of water was added to the concentrated solution, 3 g of potassium carbonate was added to remove the excess trifluoroacetic acid, extracted with ethyl acetate (50 mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain Compound 010-7. MS (ESI) m / z: 343.1 [M + H] + .

[0303] Step 7: Synthesis of Compound 010-8:

[0304] Compound 001-7 (330.00 mg, 963.66 μmol, 1 eq) and Compound 002-5 (403.88 mg, 1.16 mmol, 1.2 eq) were dissolved in N,N-dimethylacetamide (7 mL) and water (7 mL), potassium carbonate (399.55 mg, 2.89 mmol, 3 eq) was added, and the mixture was reacted at 80 °C for 16 hours. After the reaction was completed, it was cooled to room temperature, 50 mL of water was added, and then extracted with ethyl acetate (50 mL × 3), the organic phases were combined and washed with saturated brine (50 mL × 6), the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was subjected to column chromatography (4% - 8% dichloromethane in methanol) to separate and obtain Compound 010-8. MS (ESI) m / z: 655.2 [M + H] + .

[0305] Step 8: Synthesis of Compound 010:

[0306] Compound 010-8 (160 mg, 244.18 μmol, 1 eq) was dissolved in methanol (2 mL), and hydrochloric acid methanol solution (4 M, 1.86 mL, 30.43 eq) was added. After the reaction mixture was reacted at 25 °C for 1 hour, the solvent was directly evaporated to dryness to obtain the crude product of 010. The crude product was sent to supercritical fluid chromatography (chromatographic column: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); mobile phase: [0.1% ammonia water - ethanol]; ethanol%: 40% - 40%). Compound 010A (retention time: 2.561 min) and compound 010B (retention time: 3.389 min) were separated. Compound 010A: MS (ESI) m / z: 551.0 [M + H] + . 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.94 (dd, J = 7.91, 1.38 Hz, 1H), 7.61 (s, 1H), 7.35 (t, J = 7.91 Hz, 1H), 7.30 - 7.23 (m, 1H), 7.18 - 7.10 (m, 1H), 7.00 - 6.95 (m, 1H), 4.35 - 4.28 (m, 2H), 3.94 (s, 1H), 3.36 (s, 3H), 3.30 - 3.11 (m, 3H), 2.82 - 2.75 (m, 1H), 1.90 - 1.71 (m, 2H), 1.64 - 1.55 (m, 1H), 1.45 - 1.37 (m, 1H). Compound 010B: MS (ESI) m / z: 551.0 [M + H] + . 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.94 (dd, J = 7.91, 1.38 Hz, 1H), 7.61 (s, 1H), 7.35 (t, J = 7.91 Hz, 1H), 7.30 - 7.23 (m, 1H), 7.18 - 7.10 (m, 1H), 7.00 - 6.95 (m, 1H), 4.35 - 4.28 (m, 2H), 3.94 (s, 1H), 3.36 (s, 3H), 3.30 - 3.11 (m, 3H), 2.82 - 2.75 (m, 1H), 1.9 - 1.71 (m, 2H), 1.64 - 1.55 (m, 1H), 1.45 - 1.37 (m, 1H).

[0307] Biological test

[0308] Experimental example 1: In vitro evaluation

[0309] Reaction buffer:

[0310] 60 mM HEPES (pH 7.4), 1 mM EDTA, 75 mM KCl, 75 mM NaCl, 0.01% Brij-35, 5 mM DTT, and 10% DMSO (final).

[0311] Enzyme: PTPN11 / SHP2-FL (produced in RBC, no CAS number)

[0312] Recombinant human PTPN11 full-length (Genbank accession number #NM_002834; aa 2 - 597,

[0313] isoform 1 (canonical)) expressed in E. coli with N-terminal StrepII-TEV and C-terminal histidine tags. Mw = 71.93 kDa.

[0314] Activating peptide: H2N-LN(pY)IDLDLV(dPEG8)LST(pY)ASINFQK-amide (based on publication)

[0315] Substrate: DiFMUP [6,8-difluoro-7-hydroxy-4-methylcoumarin]

[0316] Final concentrations in the assay:

[0317] 0.35 μM activating peptide

[0318] 100 μM DiFMUP (6,8-difluoro-4-methylumbelliferyl phosphate)

[0319] Procedure:

[0320] 1. Prepare the designated enzyme / peptide and substrate in freshly prepared reaction buffer;

[0321] 2. Add the enzyme / peptide solution to the reaction wells;

[0322] 3. Deliver compounds in 100% DMSO to the enzyme solution by acoustic technology (Echo550; nanoliter range), incubate at room temperature for 30 minutes;

[0323] 4. Add the substrate solution to the reaction wells to initiate the reaction;

[0324] 5. Monitor enzyme activity (Ex / Em 355 / 460) as a time course measurement of the increase in fluorescence signal of the fluorescent substrate for 60 minutes at room temperature;

[0325] 6. Data analysis: Take the slope of the linear part of the time course measurement × (signal / minute) and calculate the % enzyme activity relative to the DMSO control; subtract the background slope of the enzyme basal activity (without peptide).

[0326] The in vitro screening test results of the compounds of the present invention are shown in Table 1.

[0327] Table 1. In vitro screening test results of the compounds of the present invention

[0328] Compound Number <![CDATA[PTPN11 / SHP2-FL(IC 50 nM)]]> Formate of Compound 001 21.8 Formate of Compound 002 12.6 Formate of Compound 003 72.4 Formate of Compound 004 2.84 Formate of Compound 004A 3.21 Formate of Compound 004B 2.61 Compound 005A 5.35 Compound 005B 3.66 Compound 006A 2.95 Compound 006B 2.22 Compound 008A 2.78 Compound 008B 2.43 Compound 010A 6.01 Compound 010B 5.81

[0329] Conclusion: The compounds of the present invention have certain inhibitory activity against PTPN11 / SHP2-FL.

[0330] Experimental Example 2: Evaluation of the cell activity of Compound H358

[0331] Experimental purpose:

[0332] This experiment aims to verify the inhibitory effect of the compounds of the present invention on the proliferation of NCI-H358 human non-small cell lung cancer cells with KRAS G12C mutation.

[0333] Experimental materials:

[0334] Cell line NCI-H358 (purchased from Procell), RPMI1640 medium, penicillin / streptomycin antibiotics purchased from Vicente, and fetal bovine serum purchased from Biosera. CellTiter-Glo (cell viability chemiluminescence detection reagent) reagent was purchased from Promega.

[0335] Experimental method:

[0336] Seed NCI-H358 cells into a white 96-well plate, 80 μL of cell suspension per well, which contains 4000 NCI-H358 cells. Place the cell plate in a carbon dioxide incubator and incubate overnight. Dilute the test compound 5-fold with a multichannel pipette to the 9th concentration, that is, dilute from 2000 μM to 5.12 nM, and set up a double-replicate experiment. Add 78 μL of medium to the middle plate, and then transfer 2 μL of the gradient-diluted compound per well to the middle plate according to the corresponding positions. After mixing, transfer 20 μL per well to the cell plate. The concentration range of the compound transferred to the cell plate is 10 μM to 0.026 nM. Place the cell plate in a carbon dioxide incubator and culture for 5 days. Prepare another cell plate and read the signal value on the day of adding the drug as the maximum value (Max value in the following equation) for data analysis. Add 25 μL of cell viability chemiluminescence detection reagent to each well of this cell plate and incubate at room temperature for 10 minutes to stabilize the luminescence signal. After the incubation of the cell plate with the compound is completed, use a multi-label analyzer to read the values.

[0337] Data analysis:

[0338] The original data is converted into the inhibition rate using the equation (Sample - Min) / (Max - Min)*100%, and the value of IC50 can be obtained by fitting a curve with four parameters (obtained in the "log(inhibitor) vs. response - Variable slope" mode in GraphPad Prism).

[0339] The results of the H358 cell activity screening test of the compounds of the present invention are shown in Table 2 below.

[0340] Table 2. Results of the in vitro screening test of the compounds of the present invention

[0341] Compound Number <![CDATA[H358(IC 50 nM)]]> Formate of Compound 004A 56.5 Formate of Compound 004B 19.2 Compound 006A 30 Compound 006B 18 Compound 010A 11.9 Compound 010B 7.9

[0342] Conclusion: The compounds of the present invention have good inhibitory activity against H358 cells.

[0343] Experimental Example 3: Pharmacokinetics evaluation of the compounds

[0344] Experimental purpose: To test the pharmacokinetics of the compounds in CD - 1 mice

[0345] Experimental materials: CD - 1 mice (male, 32 - 33 g)

[0346] Experimental operation:

[0347] The pharmacokinetic characteristics of the compounds after intravenous injection and oral administration in rodents were tested according to the standard protocol. In the experiment, the candidate compounds were formulated into clear solutions, and the mice were given a single intravenous injection and oral administration. The intravenous injection and oral solvent were aqueous solutions of hydroxypropyl - β - cyclodextrin or physiological saline solution in a certain proportion. Whole blood samples were collected within 24 hours, centrifuged at 3000 g for 15 minutes, and the plasma samples were obtained by separating the supernatant. Four volumes of acetonitrile solution containing internal standard were added to precipitate proteins. After centrifugation, the supernatant was taken, an equal volume of water was added, and then the supernatant was taken for injection after centrifugation. The plasma drug concentration was quantitatively analyzed by LC - MS / MS analysis method, and pharmacokinetic parameters such as peak concentration, peak time, clearance rate, half - life, area under the plasma concentration - time curve, bioavailability, etc. were calculated.

[0348] The results of the pharmacokinetics test of the compounds of the present invention are shown in Table 3 below.

[0349] Table 3 Pharmacokinetics test results

[0350]

[0351] Conclusion: The compounds of the present invention can significantly improve single or some of the pharmacokinetic indexes of mice.

[0352] Experimental Example 4: CYP inhibition experiment in human liver microsomes

[0353] The purpose of the research project is to evaluate the inhibitory effect of the test article on human liver microsomal cytochrome P450 isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) using a 5-in-1 probe substrate for CYP isozymes.

[0354] Pooled human liver microsomes (HLM) were purchased from Corning Inc. (Steuben, New York, USA) or XenoTech, LLC. (Lenexa, KS, USA) or other suppliers and stored at temperatures below -70 °C before use.

[0355] Serial dilutions of the test article working solutions were added to an incubation system containing human liver microsomes, probe substrates, and cofactors for the recycling system. A control containing solvent instead of the test article served as the enzyme activity control (100%). The concentration of the metabolite generated by the probe substrate in the samples was determined by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Nonlinear regression analysis of the mean percentage activity of the test article against concentration was performed using SigmaPlot (V.11). The IC 50 value was calculated using a three-parameter or four-parameter sigmoidal equation.

[0356] The test results are shown in Table 4:

[0357] Table 4

[0358]

[0359]

[0360] Conclusion: The compounds of the present invention show weak inhibitory effects on all five CYP isozymes.

[0361] Experimental Example 5: Inhibition Test of hERG Potassium Channels

[0362] 1. Experimental Purpose:

[0363] To detect the effect of Test Example 1 on hERG potassium channels using the whole-cell patch clamp method.

[0364] 2. Experimental Method

[0365] 2.1. Cell Culture

[0366] Cells stably expressing hERG potassium channels used in the experiment were from CHO-hERE of Aviva Biosciences. CHO-hERG was cultured in an environment of 5% CO 2 , 37 °C. The culture medium for CHO hERG is shown in Table 5.

[0367] Table 5 CHO hERG Culture Medium

[0368] Reagent Supplier Catalog Number Volume (mL) F12 Hams Invitrogen 31765-092 500 FBS Invitrogen 10099-141 50 G418 / Geneticin Invitrogen 10131-027 1 Hygromycin B Invitrogcn 10687-010 1

[0369] 2.2. Preliminary Preparation of Cells

[0370] Prepare CHO-hERG cells for the experiment by culturing them for at least two days and ensuring that the cell density reaches over 75%. Before the experiment starts, digest the cells with TrypLE and then resuspend and collect the cells with extracellular fluid.

[0371] 2.3. Preparation of Intracellular and Extracellular Fluids

[0372] The extracellular fluid needs to be prepared once a month. The intracellular fluid must be aliquoted and stored frozen at -20°C. The compositions of the intracellular and extracellular fluids are shown in Table 6.

[0373] Table 6 Compositions of Intracellular and Extracellular Fluids

[0374]

[0375]

[0376] 2.4. Preparation of Compounds

[0377] Dissolve the compound to be tested and the positive control Amitriptyline in DMSO to form a stock solution of a certain concentration, then dilute them according to different gradients, and finally add them to the extracellular fluid in a certain proportion to dilute to the concentration to be tested. Check visually for precipitation before the experiment starts. Finally, in the test solution and the positive control Amitriptyline, the concentration of DMSO should not exceed 0.3% at most.

[0378] 2.5. Voltage Stimulation Protocol

[0379] Maintain the clamping potential at -80 mV. First, apply a voltage stimulation of -50 mV for 80 ms to record the cell leakage current value. Then depolarize to +20 mV and maintain for 4800 ms to open the hERG channel. Then repolarize to -50 mV and maintain for 5000 ms to elicit and record the hERG tail current. Finally, restore the voltage to the clamping potential of -80 mV and maintain for 3100 ms. The above voltage stimulation is repeated every 15000 ms.

[0380] 2.6. QPatch HTX Whole-Cell Patch-Clamp Recording

[0381] hERG QPatch HTXThe experiment was conducted at room temperature. A whole-cell protocol, a voltage stimulation protocol, and a compound detection protocol were established on the software of QPatch Assay Software 5.2 (Sophion Bioscience).

[0382] First, 30 repeated voltage stimulations were performed, and this section was the baseline area for subsequent analysis. Then, 5 μL of extracellular fluid was added and repeated three times. The working concentrations of each compound were added in sequence, still with a 5 μL addition volume and repeated three times. Each test concentration incubated the cells for at least 5 minutes. During the entire recording process, all indicators needed to meet the data analysis acceptance criteria. If the criteria were not met, the cell would not be included in the analysis, and the compound would be retested. The above recording process was all automated by the Qpatch analysis software. The test concentrations of each compound were 0.24 μM, 1.20 μM, 6.00 μM, and 30.00 μM in sequence, and each concentration was repeated on at least two cells.

[0383] 2.7. Data analysis

[0384] In each complete current record, the inhibition percentage of each compound concentration was calculated based on the percentage of the peak current in the negative control. The dose-response relationship curve was fitted using the standard Hill equation, and the specific equation was as follows:

[0385] I (C) =I b +(I fr -I b )*c n / (IC 50 n +c n )

[0386] C is the compound test concentration, and n is the slope

[0387] Curve fitting and inhibition rate calculation were both completed by the Qpatch analysis software. If the inhibition rate at the lowest concentration exceeded half-maximal inhibition or the inhibition rate at the highest concentration did not reach half-maximal inhibition, the corresponding IC 50 of the compound was lower than the lowest concentration or the IC 50 value was greater than the highest concentration.

[0388] 2.8. Test results

[0389] The hERG IC50 value results of the compounds in the examples are shown in Table 7.

[0390] Table 7 hERG IC 50 value results of the compounds in the examples

[0391] Test Sample <![CDATA[hERG IC 50 (nM)]]> Formate of Compound 004A 8.20 Formate of Compound 004B 9.82 Compound 006A 10.3 Compound 006B 14.0

[0392] Conclusion: The compound of the present invention shows insignificant inhibition on hERG.

[0393] Experimental Example 6: In vitro microsomal stability experiment

[0394] 6.1. Experimental materials:

[0395] 6.1.1 Liver microsomes

[0396] Human and animal microsomes were purchased from Corning or Xenotech and stored in a -80 °C refrigerator.

[0397] 6.1.2 Reduced nicotinamide adenine dinucleotide phosphate (NADPH), supplier: Chem-impex international, product number: 00616

[0398] 6.1.3 Control compounds: Testosterone, Diclofenac, Propafenone

[0399] 6.2 Experimental procedures

[0400] 6.2.1 Preparation of working solutions

[0401] Stock solution: 10 mM DMSO solution

[0402] Preparation of working concentration: Diluted to 100 μM with 100% acetonitrile (organic phase content: 99% ACN, 1% DMSO)

[0403] 6.2.2 Experimental procedures

[0404] Prepare 2 96-well incubation plates, named T60 incubation plate and NCF60 incubation plate respectively.

[0405] Add 445 μL of microsomal working solution (liver microsome protein concentration is 0.56 mg / mL) to the T60 incubation plate and the NCF60 incubation plate respectively, and then place the above incubation plates in a 37 °C water bath for pre-incubation for about 10 minutes.

[0406] After the pre-incubation was completed, 5 μL of the test article or control compound working solution was added to each well of the T60 incubation plate and the NCF60 incubation plate, and mixed well. 50 μL of potassium phosphate buffer was added to each well of the NCF60 incubation plate to initiate the reaction; 180 μL of the termination solution (acetonitrile solution containing 200 ng / mL tolbutamide and 200 ng / mL labetalol) and 6 μL of the NADPH regeneration system working solution were added to the T0 termination plate, and 54 μL of the sample was taken from the T60 incubation plate to the T0 termination plate (T0 sample generated). 44 μL of the NADPH regeneration system working solution was added to each well of the T60 incubation plate to initiate the reaction. Only 54 μL of the microsome working solution, 6 μL of the NADPH regeneration system working solution and 180 μL of the termination solution were added to the Blank plate. Therefore, in the samples of the test article or control compound, the final concentrations of the compound, testosterone, diclofenac and propafenone in the reaction were 1 μM, the concentration of liver microsomes was 0.5 mg / mL, and the final concentrations of DMSO and acetonitrile in the reaction system were 0.01% (v / v) and 0.99% (v / v), respectively.

[0407] After incubation for an appropriate time (such as 5, 15, 30, 45 and 60 minutes), 180 μL of the termination solution (acetonitrile solution containing 200 ng / mL tolbutamide and 200 ng / mL labetalol) was added to the sample wells of each termination plate, and then 60 μL of the sample was taken from the T60 incubation plate to terminate the reaction.

[0408] All the sample plates were shaken well and centrifuged at 3220×g for 20 minutes, and then 80 μL of the supernatant was taken from each well and diluted to 240 μL with pure water for liquid chromatography-tandem mass spectrometry analysis.

[0409] The MMS results of the compounds of the present invention are shown in Table 8.

[0410] Table 8 MMS results of the compounds of the present invention

[0411] Test Sample MMS (mL / min / kg), H, M Formate of Compound 004A 19.7，67.9 Formate of Compound 004B 33.0，61.1 Compound 006A 31.2，100.8 Compound 006B 47.9，57.3

Claims

1. A compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein, Structural unit is E 1 is O or CH 2 ; T 1 is N or CH; R 1 For R 11 , R 13 and R 14 C 1-3 alkyl; R 12 is H or C 1-3 alkyl; R 2 is F, Cl, Br or I; R 3 is C 1-3 alkyl, said C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a substituents; R 4 is H, F, Cl, Br, I or C 1-3 alkyl, and said C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b substituents; R a and R b are each independently F, Cl, Br, I, OH or NH 2 ; n is 0, 1, 2 or 3; m is 1, 2 or 3; When n is 0, the structural unit is structural unit is When n is 1, 2 or 3, the structural unit is the structural unit The structural unit is 2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 11 , R 13 and R 14 are independently CH 3 .

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 12 is H or CH 3 .

4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein, R 1 For 5. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 3 is CH 3 .

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 4 is F, Cl, Br or I.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, Structural unit is 8. The compound or a pharmaceutically acceptable salt thereof according to claim 7, wherein, Structural unit is 9. The compound or a pharmaceutically acceptable salt thereof according to claim 8, wherein, Structural unit is 10. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has the structure of formula (II-1) wherein, R 11 、R 12 、R 2 、n、E 1 and structural units as defined in claim 1.

11. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has the structure of formula (II-1A), wherein, n, m, E 1 , T 1 , R 11 , R 12 , R 2 and R 4 as defined in claim 1.

12. The compound or a pharmaceutically acceptable salt thereof according to claim 11, wherein the compound has the structure of formula (II-1B), wherein, m, E 1 , T 1 , R 11 , R 12 , R 2 and R 4 as defined in claim 11 13. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has the structure of formula (I-1A), (I-1B) or (I-2A), wherein, R 11 、R 12 、R 13 、R 14 、R 2 、R 3 and R 4 as defined in claim 1.

14. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has the structure of formula (I-1A-1), (I-2A-1) or (II-1A-1) wherein, m, n, E 1 , T 1 , R 11 , R 12 , R 13 , R 14 , R 2 , R 3 and R 4 as defined in claim 1.

15. The compound or a pharmaceutically acceptable salt thereof according to claim 14, wherein the compound has the structure of formula (II-1B-1) wherein, m, E 1 , T 1 , R 11 , R 12 , R 2 and R 4 as defined in claim 14 16. A compound or a pharmaceutically acceptable salt thereof, the compound being:

17. The compound or a pharmaceutically acceptable salt thereof according to claim 16, the compound being:

18. A stereoisomer of the following compound, or a pharmaceutically acceptable salt of the stereoisomer, wherein, the retention time of the stereoisomer after chiral supercritical fluid chromatography analysis is 3.1 - 3.5 min; the conditions for the chiral supercritical fluid chromatography analysis are: chromatographic column: Chiralpak AS-3 with dimensions 100 mm * 4.6 mm, 3 μm; mobile phase: carbon dioxide; 40% ethanol containing 0.05% triethylamine.

19. The stereoisomer of the compound according to claim 18, or a pharmaceutically acceptable salt of the stereoisomer, wherein, the retention time of the stereoisomer after chiral supercritical fluid chromatography analysis is 3.2 - 3.4 min; the conditions for the chiral supercritical fluid chromatography analysis are: chromatographic column: Chiralpak AS-3 with dimensions 100 mm * 4.6 mm, 3 μm; mobile phase: carbon dioxide; 40% ethanol containing 0.05% triethylamine.

20. The stereoisomers of the compound according to claim 18, or a pharmaceutically acceptable salt of the stereoisomers, wherein, the retention time of the stereoisomers after chiral supercritical fluid chromatography analysis is 3.3 min; the conditions for the chiral supercritical fluid chromatography analysis are: chromatographic column: Chiralpak AS-3 of 100 mm * 4.6 mm, 3 μm; mobile phase: carbon dioxide; 40% ethanol containing 0.05% triethylamine.

21. The stereoisomers of the following formula compound, or a pharmaceutically acceptable salt of the stereoisomers, wherein, the retention time of the compound after chiral supercritical fluid chromatography analysis is 4.3 - 4.7 min; the conditions for the chiral supercritical fluid chromatography analysis are: chromatographic column: Chiralpak AS-3 of 100 mm * 4.6 mm, 3 μm; mobile phase: carbon dioxide; 40% ethanol containing 0.05% triethylamine.

22. The stereoisomers of the compound according to claim 21, or a pharmaceutically acceptable salt of the stereoisomers, wherein, the retention time of the compound after chiral supercritical fluid chromatography analysis is 4.4 - 4.6 min; the conditions for the chiral supercritical fluid chromatography analysis are: chromatographic column: Chiralpak AS-3 of 100 mm * 4.6 mm, 3 μm; mobile phase: carbon dioxide; 40% ethanol containing 0.05% triethylamine.

23. The stereoisomers of the compound according to claim 21, or a pharmaceutically acceptable salt of the stereoisomers, wherein, the retention time of the compound after chiral supercritical fluid chromatography analysis is 4.5 min; the conditions for the chiral supercritical fluid chromatography analysis are: Chiralpak AS-3 of 100 mm * 4.6 mm, 3 μm; mobile phase: carbon dioxide; 40% ethanol containing 0.05% triethylamine.

24. The stereoisomers of the following formula compound, or a pharmaceutically acceptable salt of the isomers, wherein, the retention time of the compound after chiral supercritical fluid chromatography separation is 4.9 - 5.3 min; the conditions for the chiral supercritical fluid chromatography separation are: chromatographic column: DAICEL CHIRALPAK AS of 250 mm * 30 mm, 10 μm; mobile phase: 40% methanol containing 0.1% ammonia water.

25. The stereoisomers of the compound according to claim 24, or a pharmaceutically acceptable salt of the stereoisomers, wherein, the retention time of the compound after chiral supercritical fluid chromatography separation is 5.0 - 5.2 min; the conditions for the chiral supercritical fluid chromatography separation are: chromatographic column: DAICEL CHIRALPAK AS of 250 mm * 30 mm, 10 μm; mobile phase: 40% methanol containing 0.1% ammonia water.

26. The stereoisomers of the compound according to claim 24, or a pharmaceutically acceptable salt of the stereoisomers, wherein, The retention time of the said compound after chiral supercritical fluid chromatography separation is 5.1 min; the conditions for the chiral supercritical fluid chromatography separation are as follows: chromatographic column: DAICEL CHIRALPAK AS with dimensions of 250 mm * 30 mm and 10 μm; mobile phase: 40% methanol containing 0.1% ammonia water.

27. The stereoisomers of the following formula compound, or a pharmaceutically acceptable salt of the said stereoisomers, wherein, The retention time of the said compound after chiral supercritical fluid chromatography separation is 6.6 - 7.0 min; the conditions for the chiral supercritical fluid chromatography separation are as follows: chromatographic column: DAICEL CHIRALPAK AS with dimensions of 250 mm * 30 mm and 10 μm; mobile phase: 40% methanol containing 0.1% ammonia water.

28. The stereoisomers of the compound according to claim 27, or a pharmaceutically acceptable salt of the said stereoisomers, wherein, The retention time of the said compound after chiral supercritical fluid chromatography separation is 6.7 - 6.9 min; the conditions for the chiral supercritical fluid chromatography separation are as follows: chromatographic column: DAICEL CHIRALPAK AS with dimensions of 250 mm * 30 mm and 10 μm; mobile phase: 40% methanol containing 0.1% ammonia water.

29. The stereoisomers of the compound according to claim 28, or a pharmaceutically acceptable salt of the said stereoisomers, wherein, The retention time of the said compound after chiral supercritical fluid chromatography separation is 6.8 min; the conditions for the chiral supercritical fluid chromatography separation are as follows: chromatographic column: DAICEL CHIRALPAK AS with dimensions of 250 mm * 30 mm and 10 μm; mobile phase: 40% methanol containing 0.1% ammonia water.

30. A pharmaceutical composition, which comprises the compound according to any one of claims 1 - 29 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

31. Use of the compound according to any one of claims 1 - 29 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 30 in the preparation of a drug for treating diseases related to SHP2.

32. The use according to claim 31, wherein the SHP2 - related disease is a solid tumor.

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