Tricyclic ring-containing macrocyclic compounds and their use

Abstract

The present invention discloses a tricyclic ring-containing macrocyclic compound and its use, specifically, a compound represented by formula (II) and a pharmaceutically acceptable salt thereof. JPEG2025524018000134.jpg53163

Description

Technical Field

[0001] The present invention relates to a tricyclic ring-containing macrocyclic compound and its use, and specifically relates to a compound represented by formula (II) and a pharmaceutically acceptable salt thereof.

Background Art

[0002] This application claims the following priorities. CN2022108721559, filing date: July 22, 2022, CN2022113690989, filing date: November 3, 2022, CN2022116017524, filing date: December 13, 2022, CN2023102194528, filing date: March 8, 2023, CN202310562000X, filing date: May 16, 2023.

[0003] Kinase is related to cell proliferation, metabolism, differentiation, and apoptosis, and abnormal activation of multiple kinases leads to the onset of cancer. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) and belongs to the insulin receptor family. It is mainly expressed in the central nervous system and the peripheral nervous system and plays a role in the development and function of the nervous system.

[0004] ALK was initially discovered in anaplastic large-cell lymphoma (ALCL). The N-terminus of the normally expressed protein nucleophosmin (NPM) fuses with the ALK kinase domain to form the fusion protein NPM-ALK. Chromosomal translocation leads to the continuous activation of cells and ultimately forms tumors. Currently, various ALK fusion proteins have been identified. Here, the EML4-ALK fusion protein is found in 3-7% of NSCLC patients and is considered a potent factor driving tumors, so EML4-ALK has been established as an effective target for cancer treatment.

[0005] Currently, multiple ALK inhibitors are in clinical trials and have been approved for sale. Among them, Crizotinib and Lorlatinib have been approved by the FDA for the treatment of ALK-positive NSCLC patients. Unfortunately, although ALK inhibitors have been proven effective in early clinical trials, the treated patients develop ALK acquired resistance and metastatic brain cancer. Mutations in ALK (such as EML4-ALK-L1196M, EML4-ALK-L1198F, EML4-ALK-G1202R, EML4-ALK-G1202R-L1198F, and EML4-ALK-G1202R-L1196M, etc.) are the main causes of the current ALK drug resistance mechanism. Therefore, for the treatment of NSCLC patients, there is an urgent need for a new generation of inhibitors that can overcome the acquired resistance of existing ALK inhibitors.

Summary of the Invention

[0006] The present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof.

Chemical Formula

Chemical Formula

[0007] The present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

[0008] The present invention further provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

[0009] The present invention further provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

[0010] The present invention further provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

[0011] The present invention further provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

[0012] In some embodiments of the present invention, two R a groups on the same carbon atom are linked to form cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, oxolanyl, or pyrrolidinyl, and the cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, oxolanyl, or pyrrolidinyl is optionally substituted by 1, 2, or 3 halogens, and the other variables are as defined in the present invention.

[0013] In some embodiments of the present invention, two R aare linked to form cyclopropyl, cyclobutyl, oxetanyl or azetidinyl, and the other variables are as defined in the present invention.

[0014] In some embodiments of the present invention, two Rs on the same carbon atom as described above a are linked to form cyclopropyl or cyclobutyl, and the cyclopropyl or cyclobutyl is optionally substituted by one, two or three halogens, and the other variables are as defined in the present invention.

[0015] In some embodiments of the present invention, two Rs on the same carbon atom as described above a are linked to form cyclopropyl, and the other variables are as defined in the present invention. In some embodiments of the present invention, two Rs on the same carbon atom as described above a are linked to form cyclopropyl, cyclobutyl or oxetanyl, and the other variables are as defined in the present invention.

[0016] In some embodiments of the present invention, two Rs on different carbon atoms as described above a are linked to form cyclopropyl or cyclobutyl, and the cyclopropyl or cyclobutyl is optionally substituted by one, two or three halogens, and the other variables are as defined in the present invention.

[0017] In some embodiments of the present invention, two Rs on different carbon atoms as described above a are linked to form cyclobutyl, and the other variables are as defined in the present invention. In some embodiments of the present invention, each of the above Rs c is independently selected from F, Cl, Br, I and CH3, and the CH3 is optionally substituted by one, two or three halogens, and the other variables are as defined in the present invention.

[0018] In some embodiments of the present invention, each of the above Rs cis independently selected from F, Cl, Br, I, CH3, and CF3 respectively, and the other variables are as defined in the present invention. In some embodiments of the present invention, each of the above R c is independently selected from H, F, Cl, Br, I, and CH3 respectively, and the CH3 is optionally substituted by one, two, or three halogens, and the other variables are as defined in the present invention.

[0019] In some embodiments of the present invention, the above R c is independently selected from H, F, Cl, Br, I, CH3, and CF3 respectively, and the other variables are as defined in the present invention.

[0020] In some embodiments of the present invention, each of the above R d is independently selected from F, OH, NH2, CH3, and cyclopropyl respectively, and the other variables are as defined in the present invention.

[0021] In some embodiments of the present invention, each of the above R d is independently selected from H, F, OH, NH2, CH3, and cyclopropyl respectively, and the other variables are as defined in the present invention.

[0022] In some embodiments of the present invention, the above L2 is selected from CH2, CH2CH2, and C(CH3)2, and the CH2, CH2CH2, and C(CH3)2 are each independently optionally substituted by one, two, or three R a and the other variables are as defined in the present invention.

[0023] In some embodiments of the present invention, the above L2 is selected from CH2 and C(CH3)2, and the CH2 and C(CH3)2 are each independently optionally substituted by one, two, or three R a and the other variables are as defined in the present invention.

[0024] In some embodiments of the present invention, the above L2 is selected from CH2, CF2, C(CH3)2, and C(CF3)2, and the other variables are as defined in the present invention. In some embodiments of the present invention, the above L2 is selected from -CH2- and -C(CH3)2-, and the -CH2- and -C(CH3)2- are each independently 1, 2, or 3 R a optionally substituted by, and the other variables are as defined in the present invention.

[0025] In some embodiments of the present invention, the above L2 is selected from -CH2-, -CF2-, -C(CH3)2-, and -C(CF3)2-, and the other variables are as defined in the present invention. In some embodiments of the present invention, the above L2 is CH2, CF2, CH2CH2, C(CH3)2, C(CF3)2,

Chemical formula

[0026] In some embodiments of the present invention, the above L2 is CH2, CF2, CH2CH2, C(CH3)2, C(CF3)2,

Chemical formula

[0027] In some embodiments of the present invention, the above L2 is selected from a single bond, CH2, CH2CH2, and C(CH3)2, and the CH2, CH2CH2, and C(CH3)2 are each independently 1, 2, or 3 R a optionally substituted by, and the other variables are as defined in the present invention.

[0028] In some embodiments of the present invention, the above L2 is a single bond, CH2, CF2, CH2CH2, C(CH3)2, C(CF3)2, [Chemical formula] selected from the group consisting of, and the other variables are as defined in the present invention.

[0029] In some embodiments of the present invention, the above L3 is selected from CH2, CH2CH2, and C(CH3)2, and the CH2, CH2CH2, and C(CH3)2 are each independently optionally substituted by 1, 2, or 3 R a and the other variables are as defined in the present invention.

[0030] In some embodiments of the present invention, the above L3 is selected from CH2 and C(CH3)2, and the CH2 and C(CH3)2 are each independently optionally substituted by 1, 2, or 3 R a and the other variables are as defined in the present invention.

[0031] In some embodiments of the present invention, the above L3 is selected from CH2, CF2, C(CH3)2, and C(CF3)2, and the other variables are as defined in the present invention. In some embodiments of the present invention, the above L3 is selected from -CH2- and -C(CH3)2-, and the -CH2- and -C(CH3)2- are each independently optionally substituted by 1, 2, or 3 R a and the other variables are as defined in the present invention.

[0032] In some embodiments of the present invention, the above L3 is selected from -CH2-, -CF2-, -C(CH3)2-, and -C(CF3)2-, and the other variables are as defined in the present invention. In some embodiments of the present invention, the above L3 is CH2, CF2, CH2CH2, C(CH3)2, C(CF3)2, [Chemical formula] selected from, and other variables are as defined in the present invention.

[0033] In some embodiments of the present invention, the above L3 is CH2, CF2, CH2CH2, C(CH3)2, C(CF3)2,

Chemical formula

[0034] In some embodiments of the present invention, the above L3 is selected from a single bond, CH2, CH2CH2 and C(CH3)2, and the CH2, CH2CH2 and C(CH3)2 are each independently optionally substituted by 1, 2 or 3 R a and other variables are as defined in the present invention. In some embodiments of the present invention, the above L3 is a single bond, CH2, CF2, CH2CH2, C(CH3)2, C(CF3)2,

Chemical formula

[0035] In some aspects of the present invention, the above structural unit -L2-L3- is -CH2C(CH3)2-,

Chemical formula

[0036] In some aspects of the present invention, the above structural unit -L2-L3- is -CH2C(CH3)2-,

Chemical formula

[0037] In some embodiments of the present invention, the above structural unit -L2-L3- is -CH2C(CH3)2-,

Chemical formula

[0038] In some embodiments of the present invention, the above R1 is selected from O, S, NOH, NCN, NOCH3, NOCH2CH3 and NOCH2CH2OCH3, and the other variables are as defined in the present invention.

[0039] In some embodiments of the present invention, the above R1 is selected from O, NOH, NCN, NOCH3, NOCH2CH3 and NOCH2CH2OCH3, and the other variables are as defined in the present invention.

[0040] In some embodiments of the present invention, the above R1 is selected from O and S, and the other variables are as defined in the present invention. In some embodiments of the present invention, the above R1 is selected from NCN and NOCH3, and the other variables are as defined in the present invention.

[0041] In some embodiments of the present invention, the above R2 is H, F, Cl, Br, I, OH, NH2, CN, CH3 and

Chemical formula

Chemical formula

[0042] In some embodiments of the present invention, the above R2 is H, F, Cl, Br, I, OH, NH2, CN, CH3,

Chemical formula

[0043] In some embodiments of the present invention, the above R2 is selected from H, F, Cl, Br, I, OH, NH2, CN and CH3, and the other variables are as defined in the present invention. In some embodiments of the present invention, the above R2 is H, F, Cl, Br, I, OH, NH2, CN, CH3, cyclopropyl,

Chemical formula

Chemical formula

[0044] In some embodiments of the present invention, the above R2 is H, F, Cl, Br, I, OH, NH2, CN, CH3,

Chemical formula

[0045] In some embodiments of the present invention, the above R2 is H, F, Cl, Br, I, OH, NH2, CN, CH3,

Chemical formula

[0046] In some embodiments of the present invention, the above R2 is F, Cl, Br, I, OH, NH2, CN, CH3,

Chemical formula

[0047] In some embodiments of the present invention, the above R2 is C 2-5 selected from alkynyl, and the C 2-5 alkynyl is each independently optionally substituted by 1, 2 or 3 R d , and the other variables are as defined in the present invention. In some embodiments of the present invention, the above R2 is selected from ethynyl and propynyl, and the ethynyl and propynyl are each independently optionally substituted by 1, 2 or 3 R d , and the other variables are as defined in the present invention. In some embodiments of the present invention, the above R3 is H, F, Cl, Br, I, CH3, CH2F, CHF2, CF3 and

Chemical formula

[0048] In some embodiments of the present invention, the above R3 is selected from H, CH3 and CHF2, and the other variables are as defined in the present invention. In some embodiments of the present invention, the above R3 is selected from CHF2, and the other variables are as defined in the present invention.

[0049] In some embodiments of the present invention, the above T3 is selected from -O-, -CH2O-, =CH- and =CCH3-, and the other variables are as defined in the present invention. In some embodiments of the present invention, the above T3 is selected from O, CH2O, CH, and C(CH3), and the other variables are as defined in the present invention.

[0050] In some embodiments of the present invention, the above T4 is selected from -CH(CHF2)-, -N=, and -C(=O)-, and the other variables are as defined in the present invention. In some embodiments of the present invention, the above T4 is selected from CH(CHF2), N, and C(=O), and the other variables are as defined in the present invention.

[0051] In some embodiments of the present invention, the above ring A is selected from phenyl, pyridyl, and cyclohexenyl, and the phenyl, pyridyl, and cyclohexenyl are each independently optionally substituted by 1, 2, or 3 R c and the other variables are as defined in the present invention. In some embodiments of the present invention, the above ring A is selected from phenyl and pyridyl, and the phenyl and pyridyl are each independently optionally substituted by 1, 2, or 3 R c and the other variables are as defined in the present invention.

[0052] In some embodiments of the present invention, the above ring A is

Chemical formula

[0053] In some embodiments of the present invention, the above ring A is

Chemical formula

[0054] In some aspects of the present invention, the above structural unit [Chemistry] selected from, and other variables are as defined in the present invention.

[0055] In some embodiments of the present invention, the above structural unit [Chemistry] selected from, and other variables are as defined in the present invention.

[0056] In one embodiment of the present invention, the above structural unit [Chemistry] selected from, and other variables are as defined in the present invention.

[0057] In some embodiments of the present invention, the above structural unit [Chemistry] selected from, and other variables are as defined in the present invention.

[0058] In some embodiments of the present invention, the above structural unit [Chemistry] selected from, and other variables are as defined in the present invention.

[0059] In some embodiments of the present invention, the above structural unit [Chemistry] selected from, and other variables are as defined in the present invention.

[0060] In some embodiments of the present invention, the above structural unit [Chemical formula] selected from, and other variables are as defined in the present invention.

[0061] In some embodiments of the present invention, the above structural unit [Chemical formula] selected from, and other variables are as defined in the present invention.

[0062] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is [Chemical formula] selected from, provided that R1, R2, R3, T1, T2, L1, L2, L3, ring A and [Chemical formula] are as defined in the present invention, when R3 is not H, the carbon atom marked with "*" is a chiral carbon atom and exists in a single enantiomer of (R) or (S) or in a form enriched in one enantiomer.

[0063] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is [Chemical formula] selected from, provided that R3 is selected from F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b s, R1, R2, L2, L3, ring A and each R b are as defined herein.

[0064] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is [Chemical formula] selected from provided that R3 is selected from F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b groups, R1, R2, L2, L3, ring A and each R b are as defined herein.

[0065] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is [Chemical formula] selected from provided that R1 is selected from O, NOH, NCN, NOCH3, NOCH2CH3 and NOCH2CH2OCH3, R2 is selected from F, Cl, Br, I, OH, NH2, CN, C 1-4 alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 3-6 cycloalkyl, and the C 1-4 alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 3-6 cycloalkyl are each independently optionally substituted by 1, 2 or 3 R d groups, R3 is selected from F, Cl, Br, I and C 1-3 alkyl, and the C 1-3 alkyl is 1, 2 or 3 R bis optionally replaced by, Ring A is selected from phenyl and pyridyl, and said phenyl and pyridyl are each independently substituted by 1, 2 or 3 R c is optionally replaced by, The structural unit -L2-L3- is -CH2C(CH3)2-, [Chemical formula] selected from Each R b is independently selected from H, F, Cl, Br, I and OH, Each R c is independently selected from H, F, Cl, Br, I and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens, Each R d is independently selected from H, F, Cl, Br, I, OH, NH2, C 1-3 alkyl and C 3-6 cycloalkyl, said C 1-3 alkyl and C 3-6 cycloalkyl are each independently optionally substituted by 1, 2 or 3 halogens.

[0066] In some embodiments of the present invention, each R in the compound of the above formula (III-1) or (P-1) or its pharmaceutically acceptable salt d is as defined in formula (II) of the present invention. In some embodiments of the present invention, R1 in the compound of the above formula (III-1) or (P-1) or its pharmaceutically acceptable salt is selected from O, and the other variables are as defined in formula (III-1) or (P-1) of the present invention.

[0067] In some embodiments of the present invention, R2 in the compound of the above formula (III-1) or (P-1) or its pharmaceutically acceptable salt is F, Cl, Br, CN, C 1-4 alkyl, C 2-5Alkynyl and C 3-6 selected from cycloalkyl, said C 1-4 alkyl, C 2-5 alkynyl and C 3-6 cycloalkyl are each independently optionally substituted by one, two, or three R d and the other variables are as defined in formula (III-1) or (P-1) of the present invention. In some embodiments of the present invention, R2 in the compound of formula (III-1) or (P-1) above or a pharmaceutically acceptable salt thereof is C 2-5 selected from alkynyl, said C 2-5 alkynyl is optionally substituted by one, two, or three R d and the other variables are as defined in formula (III-1) or (P-1) of the present invention.

[0068] In some embodiments of the present invention, R3 in the compound of formula (III-1) or (P-1) above or a pharmaceutically acceptable salt thereof is selected from CHF2, and the other variables are as defined in formula (III-1) or (P-1) of the present invention. Some further embodiments of the present invention consist of any combination of the above variables.

[0069] The present invention further provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof. [Chemical formula] [Chemical formula] [Chemical formula]

[0070] The present invention further provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof. [Chemical formula] [Chemistry] [Chemistry]

[0071] The present invention further provides the use of the above-mentioned compound or its pharmaceutically acceptable salt in the manufacture of a medicament for treating ALK inhibitor-related diseases.

[0072] [Technical Effects] The compounds of the present invention exhibit higher kinase inhibitory activity against ALK kinase and its mutants, ROS1 and TRKB kinases, and also have a strong inhibitory effect on ALK mutant cells and TRKB phenotype cells. Here, the inhibition against ALK is stronger and the inhibition against TRKB is weaker, having excellent selectivity. The compounds of the present invention are hypertonic and low-efflux compounds, showing no significant inhibition against different subtypes of any P450 isozyme, and also showing good hepatocyte metabolic stability and having excellent pharmacokinetic properties.

[0073] [Definitions and Explanations] Unless otherwise explained, the following terms and phrases used in this specification have the following meanings. If a specific term or phrase is not specially defined, it should be understood as having an ordinary definition without being uncertain or unclear. When a trade name appears in this specification, it refers to the corresponding product or its active ingredient.

[0074] As used in this specification, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms, which are within the scope of reliable medical judgment, suitable for use in contact with human and animal tissues, with little toxicity, irritation, allergic reaction or other problems or complications, and meeting a reasonable benefit / risk ratio.

[0075] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, which are prepared with acids or bases that are relatively non-toxic compared to compounds having the specific substituents found in the present invention. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting these compounds with a sufficient amount of base in a single solution or in a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting these compounds with a sufficient amount of acid in a single solution or in a suitable inert solvent. Some specific compounds of the present invention contain both basic and acidic functional groups and can thus be converted into any base addition salt or acid addition salt.

[0076] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or basic groups. Usually, the method for producing such salts involves reacting these compounds in the form of free acids or bases with a stoichiometric amount of a suitable base or acid in water or an organic solvent, or a mixture of both.

[0077] The compounds of the present invention may exist in the form of specific geometric isomers or stereoisomers. 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, for example, mixtures rich in enantiomers or diastereomers, and all these mixtures are included within the scope of the present invention. Other asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and their mixtures are included within the scope of the present invention.

[0078]

Chemical formula

[0079] Unless otherwise specified, when a double bond structure exists in a compound, for example, a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and two different substituents are bonded to each atom on the double bond (when a nitrogen atom is included in the double bond, the lone pair of electrons bonded to the nitrogen atom is regarded as a substituent), in a double bond containing a nitrogen atom, between the atom on the double bond in the compound and its substituent [Chemical formula] as shown by, it represents the (Z)-isomer, (E)-isomer, or a mixture of both isomers of the compound.

[0080] Unless otherwise explained, the terms "rich in one isomer", "rich in isomers", "rich in one enantiomer", or "rich in enantiomers" mean that the content of one isomer or enantiomer is less than 100%, and the content of this isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0081] Unless otherwise explained, the term "isomer excess" or "enantiomer excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, when the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80%.

[0082] The optically active (R)- and (S)-isomers, as well as the D and L isomers, can be prepared by chiral synthesis or by means of chiral reagents or other conventional techniques. To obtain one enantiomer of a certain compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomers are resolved by conventional methods known in the art and recovered to obtain the pure enantiomer. Also, the separation of enantiomers and diastereomers is usually carried out using chromatography with a chiral stationary phase and optionally in combination with a chemical derivatization method (e.g., generating a carbamate from an amine).

[0083] The compounds of the present invention may contain unnatural proportions of atomic isotopes in one or more of the atoms that make up the compound. For example, the compound can be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), C-14 ( 14 C), etc. Or for example, deuterium can be substituted for hydrogen to form a deuterated drug, and the bond formed between deuterium and carbon is stronger than the bond formed between normal hydrogen and carbon. Compared with the non-deuterated drug, the deuterated drug has advantages such as reducing toxic side effects, enhancing drug stability, enhancing efficacy, and extending the biological half-life of the drug. The conversion of the isotope composition of the compounds of the present invention is included within the scope of the present invention regardless of whether it is radioactive.

[0084] The term "optionally" or "optionally and optionally" may appear depending on the following matters or circumstances but does not necessarily appear, and the description means that it includes the case where the matters or circumstances described therein occur and the case where they do not occur.

[0085] The term "substituted" refers to the substitution of any one or more hydrogen atoms in a particular atom by a substituent. If the particular valence state is normal and the compound after substitution is stable, the substituent may include deuterium and hydrogen variants. When the substituent is a ketone (i.e., =O), it means that two hydrogen atoms are substituted. When the substituent is =CH2, it means that two hydrogen atoms are substituted.

[0086] The term "optionally substituted" means that it may or may not be substituted. Unless otherwise defined, the type and number of substituents are arbitrary as long as they are chemically feasible. If any of the variables (e.g., R) appears one or more times in the composition or structure of the compound, its definition is independent in any case. Therefore, for example, when one group is substituted by 0 to 2 Rs, the above group is arbitrarily substituted by 2 or fewer Rs, and in any case, R has independent options. Also, combinations of substituents and / or their variants are only allowed if such combinations result in a stable compound.

[0087] When the number of linking groups is 0, for example, -(CRR)0- means that the linking group is a single bond. When the number of substituents is 0, this indicates the absence of substituents. For example, -A-(R)0 indicates that the structure is actually -A.

[0088] When the substituent is empty, it indicates the absence of substituents. For example, when X in A-X does not exist, it indicates that the structure is actually A. When one of the variables is a single bond, it means that the two groups it is bonded to are directly bonded. For example, when L in A-L-Z represents a single bond, the structure actually means A-Z.

[0089] When the listed linking groups do not specify the linking direction, the linking direction is arbitrary. For example,

Chemical formula

Chemical formula

Chemical formula

[0090] Unless otherwise specified, when a group has one or more bondable sites, any one or more sites of the group can be bonded to other groups via a chemical bond. When the bonding mode of the chemical bond is delocalized and there is an H atom at the bondable site, when the chemical bond is formed, the number of H atoms at the site decreases to a group with a corresponding valence according to the number of formed chemical bonds. The chemical bond by which the site is bonded to other groups is a solid straight-line bond (

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

[0091]

Chem.

Chem.

Chem.

[0092] Unless otherwise specified, the number of atoms in the ring is generally defined as the number of ring members. For example, "5- to 7-membered ring" refers to a "ring" of 5 to 7 atoms arranged around it. Unless otherwise specified, the term "halogeno" or "halogen" represents a fluorine, chlorine, bromine, or iodine atom, either by itself or as part of another substituent, unless otherwise specified.

[0093] Unless otherwise specified, "C 1-4 alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms, used alone or in combination with other terms. "C 1-4 alkyl" is used to represent a straight-chain or branched-chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The above C 1-4The alkyl group includes C4, C3, C 1-3 , C 1-2 and C 2-3 alkyl groups, etc., which may be monovalent, divalent or polyvalent. Examples of C 1-4 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0094] Unless otherwise specified, the term "C 1-3 alkyl" is used alone or in combination with other terms to represent a straight-chain or branched-chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms, and the term "C 1-3 alkyl" is used to represent a straight-chain or branched-chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl group includes C3, C 1-2 and C 2-3 alkyl groups, etc., which may be monovalent, divalent or polyvalent. Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0095] Unless otherwise defined, "C 2-5 alkenyl" is used alone or in combination with other terms to represent a hydrocarbon group composed of 2 to 5 carbon atoms containing at least one carbon-carbon double bond in a straight-chain or branched-chain form, and the carbon-carbon double bond may be at any position in the group. The C 2-5 alkenyl group includes C 2-4 , C 2-3 , C5, C4, C3 and C2 alkenyl groups, etc., and the C 2-5 alkenyl may be monovalent, divalent or polyvalent. Examples of C 2-5 alkenyl include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, butadienyl, pentadienyl, etc.

[0096] Unless otherwise defined, "C 2-5"Alkynyl" is used to represent a hydrocarbon group composed of 2 to 5 carbon atoms containing at least one carbon-carbon triple bond, either linear or branched, alone or in combination with other terms. The carbon-carbon triple bond may be at any position of the group. The said C 2-5 Alkynyl includes C 2-4 、C 2-3 、C5, C4, C3 and C2 alkynyl, etc. It may be monovalent, divalent or polyvalent. C 2-5 Examples of C alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, etc.

[0097] Unless otherwise defined, the term "C 1-3 alkoxy" represents an alkyl group containing 1 to 3 carbon atoms linked to the remainder of the molecule through an oxygen atom, either alone or in combination with other terms. It may be monovalent, divalent or polyvalent. The said C 1-3 alkoxy includes C 1-2 、C 2-3 、C3 and C2 alkoxy, etc. C 1-3 Examples of C alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy or isopropoxy), etc.

[0098] Unless otherwise explained, "C 3-6 cycloalkyl" represents a saturated monocyclic hydrocarbon group consisting of 3 to 6 carbon atoms, either alone or in combination with other terms. The said C 3-6 cycloalkyl includes C 3-5 、C 4-5 and C 5-6 cycloalkyl, etc., and it may be monovalent, divalent or polyvalent. C 3-6 Examples of C cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0099] Unless otherwise explained, "C 5-6"Cycloalkenyl" means a partially unsaturated monocyclic hydrocarbon group consisting of 5 to 6 carbon atoms each containing at least one carbon-carbon double bond, either alone or in combination with other terms. The said C 5-6 Cycloalkenyl includes, for example, C5 or C6 cycloalkenyl, which may be monovalent, divalent, or polyvalent. C 5-6 Examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, etc.

[0100] Unless otherwise specified, the term "4- to 6-membered heterocycloalkyl" means a saturated monocyclic group consisting of 4 to 6 ring atoms each, where 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the carbon atoms may optionally be oxidized (i.e., C(O)), the nitrogen atoms may optionally be quaternized, and the carbon and sulfur heteroatoms may optionally be oxidized (i.e., C(=O), NO, and S(=O) p、p is 1 or 2). Also, regarding the "4- to 6-membered heterocycloalkyl", the heteroatom can occupy the position where it is bonded to the heterocycloalkyl and the rest of the molecule. The 4- to 6-membered heterocycloalkyl includes 5- to 6-membered, 4-membered, 5-membered, and 6-membered heterocycloalkyls, etc. It may be monovalent, divalent, or polyvalent. Examples of 4- to 6-membered heterocycloalkyls include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxinyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, or hexahydropyridazinyl, etc., but are not limited thereto.

[0101] Unless otherwise specified, the terms "5- to 6-membered heteroaryl ring" and "5- to 6-membered heteroaryl" of the present invention are used interchangeably. The term "5- to 6-membered heteroaryl" represents a monocyclic group having a conjugated electron system composed of 5 to 6 ring atoms, and 1, 2, 3, or 4 of its ring atoms are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms. Here, the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p, where p is 1 or 2). The 5- to 6-membered heteroaryl may be bonded to the rest of the molecule via a heteroatom or a carbon atom. The 5- to 6-membered heteroaryl includes 5-membered and 6-membered heteroaryl. Examples of the 5- to 6-membered heteroaryl include pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (including 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furyl (including 2-furyl, 3-furyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.), pyrazinyl, or pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.).

[0102] The structure of the compound of the present invention can be confirmed by conventional methods well-known to those skilled in the art. When the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by the conventional technical means of those skilled in the art. For example, single-crystal X-ray diffraction (SXRD), the cultured single crystal was collected by a Bruker D8 venture diffractometer, the light source was CuKα radiation, the scanning method was φ / ω scanning. After collecting the relevant data, the absolute configuration can be confirmed by further direct method (Shelxs97) crystal structure analysis.

[0103] 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, embodiments combined with other chemical synthesis methods, and equivalent alternative methods well-known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0104] The present invention uses the following abbreviations: aq represents water, DCM represents dichloromethane, PE represents petroleum ether, DMSO represents dimethyl sulfoxide, EA and EtOAc both represent ethyl acetate, EtOH represents ethanol, MeOH represents methanol, DMF represents N,N-dimethylformamide, Boc represents a tert-butoxycarbonyl group, which is an amine protecting group, THF represents tetrahydrofuran, Boc2O represents di-tert-butyl dicarbonate, TFA represents trifluoroacetic acid, TEA represents triethylamine, HCl represents hydrochloric acid, mp represents melting point, FDPP represents pentafluorophenyl diphenylphosphinate, prep-HPLC represents preparative high performance liquid chromatography, THP represents 2-chloro-tetrahydro-2H-pyran, BRETTPHOS represents 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, and TBAF represents tetra-n-butylammonium fluoride. The solvents used in the present invention are commercially available. Compounds are named according to the normal naming principles in the art or using ChemDraw® software, and commercially available compounds are named in the supplier's catalog.

Modes for Carrying Out the Invention

[0105] Hereinafter, the present invention will be described in detail by way of examples, which do not mean any restrictive limitations on the present invention. The compounds of the present invention can be produced by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining with other chemical synthesis methods, and equivalent alternative methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention. Various changes and modifications to the specific embodiments of the present invention will be apparent to those skilled in the art without departing from the spirit and scope of the present invention.

[0106] Reference Example 1: Compound B-1

Chemical Structure

[0107] Step 1 Dissolve B-1-1 (90 g, 343.12 mmol) in dichloromethane (700 mL). Sequentially add sodium periodate (169.8 g, 793.86 mmol) and 6 mL of saturated sodium bicarbonate solution at 24 °C. After 5 minutes, add sodium bicarbonate (12 g, 142.85 mmol). After the addition is complete, remove the water bath and stir at room temperature for 2 hours. Then add magnesium sulfate (180 g, 1.50 mol). Filter the reaction mixture, wash the cake with dichloromethane (2 × 180 mL), collect the filtrate to obtain the crude product of the dichloromethane solution of B-1-2, and use it directly in the next step.

[0108] Step 2 Dropwise add diethylaminosulfur trifluoride (686.18 mmol, 90.66 mL) to the crude product of the dichloromethane solution of B-1-2 obtained in Step 1 at 24 °C, and stir at 20 °C for 14 hours. Quench the obtained reaction mixture by pouring it batchwise into a sodium bicarbonate solution dissolved in crushed ice little by little. Separate the layers, wash the organic phase successively with water (1000 mL) and saturated brine (500 mL), dry it over anhydrous sodium sulfate, filter it, and wash the filter residue with dichloromethane (150 mL). Concentrate the obtained filtrate under reduced pressure to obtain Compound B-1-3. 1 H NMR (400 MHz, CDCl3): δ ppm 5.88 - 5.55 (m, 1H), 4.25 - 4.22 (m, 1H), 4.16 - 4.11 (m, 1H), 4.10 - 4.06 (m, 1H), 1.47 (s, 3H), 1.39 (s, 3H).

[0109] Step 3 B-1-3 (22 g, 144.60 mmol) was dissolved in acetonitrile (190 mL) and H2O (10 mL), and bis(acetonitrile)dichloropalladium(II) (750.30 mg, 2.89 mmol) was added. The mixture was stirred at 60 °C for 5 h under a N2 atmosphere. After cooling to room temperature, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of B-1-4.

[0110] Step 4: Synthesis of B-1-5 The crude product of B-1-4 (22 g) was dissolved in dichloromethane (400 mL). Imidazole (11.81 g, 173.53 mmol) and tert-butyldimethylchlorosilane (23.97 g, 159.07 mmol) were sequentially added at 0 °C, and the temperature was raised to room temperature and stirred for 2 h. The reaction solution was diluted with dichloromethane (600 mL) and washed with 400 mL of water. The obtained organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 - 10:1) to obtain compound B-1-5. 1 H NMR (400 MHz, DMSO-d6): δ ppm 5.99 - 5.67 (m, 1H), 5.57 (d, J = 5.6 Hz, 1H), 3.74 - 3.53 (m, 3H), 0.84 (s, 9H), 0.02 (s, 6H).

[0111] Step 5: Synthesis of B-1-6 B-1-5 (26.2 g, 115.76 mmol) was dissolved in dichloromethane (400 mL), and pyridine (185.21 mmol, 14.95 mL) and trifluoromethanesulfonic anhydride (138.91 mmol, 22.92 mL) were sequentially added thereto at -30 °C to -20 °C. After the addition was completed, the mixture was stirred at 0 °C for 2 hours. The reaction solution was diluted with dichloromethane (400 mL) and washed with 300 mL of water. The obtained organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 10:1) to obtain compound B-1-6. 1 H NMR (400 MHz, CDCl3): δ ppm 6.20 - 5.85 (m, 1H), 4.93 - 4.82 (m, 1H), 4.03 - 3.97 (m, 2H), 0.91 (s, 9H), 0.11 (s, 6H).

[0112] Step 6: Synthesis of B-1-7 B-1-6 (28.94 g, 80.75 mmol) was dissolved in 1,4-dioxane (250 mL), and 4-methoxybenzylamine (96.90 mmol, 12.54 mL) and triethylamine (96.90 mmol, 13.49 mL) were sequentially added thereto, and the mixture was stirred at 90 °C for 8 hours. The reaction solution was cooled to room temperature, water (300 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (400 mL × 2). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the obtained filtrate was concentrated to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 10:1) to obtain compound B-1-7. 11H NMR (400 MHz, CDCl3): δ ppm 7.22 - 7.20 (m, 2H), 6.86 - 6.81 (m, 2H), 5.90 - 5.58 (m, 1H), 3.87 - 3.75 (m, 2H), 3.75 (s, 3H), 3.68 - 3.64 (m, 2H), 2.89 - 2.84 (m, 1H), 0.83 (s, 9H), 0.02 (s, 6H).

[0113] Step 6: Synthesis of B-1 B-1-7 (26.99 g, 78.12 mmol) was dissolved in tetrahydrofuran (280 mL), and then tetrabutylammonium fluoride solution (1 M, 78.12 mL) was added. The mixture was stirred at 24 °C for 2 hours. The reaction solution was diluted with ethyl acetate (500 mL × 3) and washed with 300 mL of water. The obtained organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. B-1 was obtained by separation and purification by column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1). 1 1H NMR (400 MHz, CDCl3): δ ppm 7.20 - 7.16 (m, 2H), 6.86 - 6.75 (m, 2H), 5.95 - 5.56 (m, 1H), 3.85 - 3.75 (m, 2H), 3.73 (s, 3H), 3.71 - 3.63 (m, 1H), 3.56 - 3.49 (m, 1H), 2.98 - 2.85 (m, 1H).

[0114] Reference Example 2: Compound B-2

Chemical Structure

[0115] Step 1: Synthesis of B-2-2 After dissolving B-2-1 (100 g, 644.52 mmol) in ethanol (1000 mL), diethyl fluoromalonate (172.24 g, 966.78 mmol) and sodium ethoxide (109.65 g, 1.61 mol) were sequentially added, and the temperature was raised to 90 °C and stirred for 6 hours. After the reaction solution was cooled to room temperature, water (1000 mL) was added for dilution, and the pH was adjusted to 3 with 2N hydrochloric acid solution. A solid precipitated, was filtered, the cake was collected, 1.5 L of acetonitrile was added and stirred, then filtered, 1.0 L of acetonitrile was further added to the cake and stirred, then filtered, and the cake was collected to obtain B-2-2. 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.84 (s, 1H), 4.23(q, J=7.0 Hz, 2H), 1.27(t, J=7.0 Hz, 3H); LCMS: m / z=242.1 [M+1] + 。

[0116] Step 2: Synthesis of B-2-3 Phosphorus oxychloride (11.4 mol, 1.06 L) was added to a reaction flask equipped with a buffer device, B-2-2 (110 g, 456.1 mmol) was added in one batch, replaced with nitrogen gas, then cooled to 0 °C, and N,N-diethylaniline (684.15 mmol, 109.43 mL) was slowly added dropwise. The temperature was raised to 100 °C and stirred for 3 hours. After the reaction solution was cooled to room temperature, 250 mL of acetonitrile was added for dilution, and then slowly added to 2 L of normal temperature water for quenching. The obtained solution was placed in an ice-water bath and stirred for 1 hour, filtered, the cake was collected, the obtained cake was dissolved in 1 L of dichloromethane, 500 mL of saturated sodium bicarbonate aqueous solution was added, stirred for 1 hour, and separated. The obtained organic phase was concentrated under reduced pressure to obtain B-2-3. 1 H NMR (400 MHz, CDCl3): δ ppm 8.65 (s, 1H), 4.43 (q, J=7.0 Hz, 2H), 1.43 (t, J=7.0 Hz, 3H); LCMS: m / z=278.0 [M+1] + 。

[0117] Step 3: Synthesis of B-2 B-2-3 (3.9 g, 14.03 mmol) was dissolved in tetrahydrofuran (50.0 mL), water (100.0 mL) and ethanol (150.0 mL), and then ammonium chloride (4.05 g, 75.74 mmol) was added. After purging with nitrogen gas, the solution was cooled to 0 °C, zinc powder (3.7 g, 56.1 mmol) was added in one portion, and the mixture was reacted at 0 °C for 2 hours. The reaction mixture was filtered, and the filtrate was extracted with dichloromethane (50 mL × 3). The obtained organic phase was washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (eluent: PE:EA = 1:0 to 3:1) to obtain B-2. 1 H NMR (400 MHz, CDCl3): δ ppm 8.65 (d, J = 3.2 Hz, 1H), 8.50 (s, 1H), 4.36 (q, 2H), 1.36 (t, 3H); LCMS: m / z = 244.0 [M+1] + 。

[0118] Reference Example 3: Compound B-3

Chemical Structure

[0119] Step 1: Synthesis of B-3-2 Thionyl chloride (74.44 mmol, 5.4 mL) was dissolved in acetonitrile (35 mL), and B-3-1 (5.0 g, 26.42 mmol) dissolved in acetonitrile (25 mL) was slowly added dropwise at -40 °C. After stirring uniformly, pyridine (142.48 mmol, 11.5 mL) was added, and the mixture was stirred at room temperature of about 15 °C for 2 hours. 150.0 mL of ethyl acetate was added to the reaction mixture, and the mixture was filtered. The filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by column chromatography (PE:EA = 1:1) to obtain compound B-3-2. 11H NMR (400 MHz, CDCl3): δ ppm 4.77 - 4.56 (m, 1H), 4.35 - 4.33 (m, 1H), 1.52 (s, 6H), 1.46 (s, 9H); LCMS: m / z = 258.1 [M+Na] + 。

[0120] Step 2: Synthesis of B-3 B-3-2 (1.0 g, 4.25 mmol) and ruthenium(III) chloride hydrate (4.4 mg, 19.7 μmol) were dissolved in acetonitrile (10.5 mL). Under a nitrogen gas atmosphere, sodium periodate (5.3 g, 24.8 mmol) dissolved in 10.5 mL of water was added at 0 °C, and the temperature was raised to about 20 °C (room temperature) and stirred for 16 hours. 100 mL of water was added to the reaction solution for dilution, and the mixture was extracted with dichloromethane (100 mL × 3). The obtained organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by column chromatography (PE:EA = 1:1) to obtain B-3. 1 1H NMR (400 MHz, CDCl3): δ ppm 4.23 (s, 2H), 1.59 (s, 9H), 1.56 (s, 6H); LCMS: m / z = 252.1 [M+1] + 。

[0121] Reference Example 4: Compound B-4

Chemical Structure

[0122] Step 1: Synthesis of B-4-2 B-4-1 (0.5 g, 14.03 mmol) and B-3 (0.74 g, 2.94 mmol) were dissolved in DMF (10.0 mL), and then potassium carbonate (1.02 g, 7.35 mmol) was added. The mixture was heated to 50 °C and stirred for 4 hours. 5 mL of dichloromethane was added to dilute the reaction solution, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE:EA = 10:1) to obtain B-4-2.1 1H NMR (400 MHz, CDCl3): δ ppm 7.49 - 7.44 (m, 1H), 7.12 - 7.04 (m, 1H), 6.89 - 6.84 (m, 1H), 3.91 (s, 2H), 3.84 (s, 3H), 1.36 (s, 6H), 1.33 (s, 9H); LCMS: m / z = 364.1 [M+Na] + 。

[0123] Step 2: Synthesis of B-4-3 Dissolve B-4-2 (0.3 g, 0.88 mmol) in tetrahydrofuran (4.0 mL), add LiBH4 (38.3 mg, 1.76 mmol) under the condition of 0 °C. After the addition, stir at room temperature for 18 hours. Quench the reaction system with 5.0 mL of water, then add 1 mL of 2 M sodium hydroxide solution, extract with dichloromethane (10 mL × 3). Wash the obtained organic phase with 5.0 mL of saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (PE:EA = 10:1) to obtain B-4-3. 1 1H NMR (400 MHz, CDCl3): δ ppm 7.09 - 7.05 (m, 1H), 6.97 - 6.90 (m, 1H), 6.86 - 6.79 (m, 1H), 4.73 - 4.71 (m, 1H), 4.71 - 4.67 (m, 2H), 4.03 (s, 2H), 1.43 (s, 6H), 1.41 (s, 9H); LCMS: m / z = 336.1 [M+Na] + 。

[0124] Step 3: Synthesis of B-4 B-4-3 (0.1 g, 0.32 mmol) was dissolved in dichloromethane (3.0 mL), N,N-diisopropylethylamine (0.96 mmol, 167 μL) was added, methanesulfonyl chloride (0.41 mmol, 32.0 μL) was added under the condition of 0 °C, and then the temperature was raised to 25 °C at room temperature and stirred for 18 h. 3 mL of 2 M hydrochloric acid solution was added under the condition of 0 °C to quench the reaction system, diluted with 15 mL of water, and extracted with dichloromethane (15 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE:EA = 10:1) to obtain B-4. 1 H NMR (400 MHz, CDCl3): δ ppm 7.03 - 6.98 (m, 1H), 6.93 - 6.86 (m, 1H), 6.79 - 6.72 (m, 1H), 4.53 (s, 2H), 3.96 (s, 2H), 1.37 (s, 6H), 1.33 (s, 9H); LCMS: m / z = 354.0 [M+Na] + 。

[0125] Reference Example 5: Compound B-5

Chemical Structure

[0126] Step 1: Synthesis of B-5-2 B-5-1 (7.07 g, 43.37 mmol), ethylene glycol monomethyl ether (3 g, 39.42 mmol) and triphenylphosphine (11.37 g, 43.37 mmol) were dissolved in tetrahydrofuran (85 mL). A solution of diisopropyl azodicarboxylate (51.25 mmol, 9.97 mL) in tetrahydrofuran (15 mL) was slowly added dropwise to the reaction solution under an ice bath, and the mixture was reacted at 0 °C for 10 minutes. Then, the temperature was slowly raised to 25 °C and stirred for 16 hours. Water (30 mL) was slowly added to the reaction solution to quench the reaction system, and the mixture was extracted with EA (200 mL × 2). The obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE:EA = 10:1~1:1) to obtain B-5-2. 1 H NMR (400 MHz, CDCl3) δ ppm 7.81 - 7.89 (m, 2 H), 7.72 - 7.79 (m, 2 H), 4.30 - 4.44 (m, 2 H), 3.67 - 3.82 (m, 2 H), 3.34 - 3.45 (s, 3 H); LCMS: m / z=222.0 [M+1] + 。

[0127] Step 2: Synthesis of B-5 B-5-2 was dissolved in DCM (10 mL), and then hydrazine hydrate (4.97 mmol, 302.10 μL, purity: 80%) was added, and the mixture was reacted at 25 °C for 16 hours. The reaction solution was filtered, and the obtained filtrate was concentrated under reduced pressure. DCM (20 mL) was added to the residue, stirred, filtered, and the filtrate was collected and concentrated under reduced pressure. After adding the residue to DCM (5 mL), a solution of hydrochloric acid ethyl acetate (4M, 5 mL) was further added, and the mixture was stirred for 20 minutes. The reaction solution was concentrated under reduced pressure. After adding ethyl acetate (20 mL) to the residue and concentrating, and then adding ethyl acetate (20 mL) to the residue again and concentrating, B-5 was obtained.

[0128] Reference Example 6: Compound B-6

Chemical Structure

[0129] Step 1: Synthesis of B-6-2 B-6-1 (5 g, 32.23 mmol) and pyridine hydrochloride (14.90 g, 128.93 mmol) were added to a round-bottom flask, heated to 145 °C and reacted for 1 hour. After the reaction solution was cooled to room temperature, water (200 mL) was added to the reaction solution, and then extracted with EA (500 mL × 2). The obtained organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the obtained filtrate was concentrated under reduced pressure to obtain B-6-2. 1 H NMR (400 MHz, CDCl3) δ ppm 10.20 (s, 1 H), 7.93 - 8.02 (m, 1 H), 7.83 - 7.87 (m, 1 H).

[0130] Step 2: Synthesis of B-6-3 After dissolving B-6-2 (3.0 g, 21.26 mmol) in DMF (30 mL), B-3 (4.86 g, 19.33 mmol) and potassium carbonate (6.68 g, 48.32 mmol) were sequentially added, and the temperature was raised to 50 °C and stirred for 14 hours. It was filtered, and the cake was washed with EA (20 mL). The obtained filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE:EA = 10:1~4:1) to obtain B-6-3. LCMS: m / z = 213.1 [M+1-100] + .

[0131] Step 3: Synthesis of B-6-4 B-6-3 (1.9 g, 6.08 mmol) was dissolved in EtOH (20 mL). Under a nitrogen gas atmosphere, sodium borohydride (1.15 g, 30.42 mmol) was added at 0 °C, and reacted at 25 °C for 3 hours. Water (10 mL) was added to the reaction solution at 0 °C and stirred for 0.5 hour to completely quench it. Then it was extracted with EA (200 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the obtained filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE:EA = 10:1~5:1) to obtain B-6-4. 11H NMR (400 MHz, CDCl3) δ ppm 7.95 (d, J = 3.01 Hz, 1 H), 7.57 (dd, J = 8.78, 3.01 Hz, 1 H), 6.62 (brs, 1 H), 5.37 (t, J = 5.52 Hz, 1 H), 4.48 (d, J = 5.52 Hz, 2 H), 4.25 (s, 2 H), 1.33 (s, 9 H), 1.25 (s, 6 H); LCMS: m / z = 315.1 [M+1] + 。

[0132] Step 4: Synthesis of B-6 Dissolve B-6-4 (1 g, 3.18 mmol) in DCM (20 mL), then add N,N-diisopropylethylamine (9.54 mmol, 1.66 mL). After cooling to 0 °C under a nitrogen gas atmosphere, slowly add methanesulfonyl chloride (6.81 mmol, 527.03 μL) dropwise, react at 0 °C for 1 hour, then warm to 25 °C and react for 2 hours. Slowly add the reaction solution dropwise to an ice-cold aqueous solution of saturated sodium bicarbonate (50 mL), extract with DCM (200 mL × 2), dry the obtained organic phase over anhydrous sodium sulfate, filter, and rotary evaporate the obtained filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE:EA = 10:1~5:1) to obtain B-6. 1 1H NMR (400 MHz, CDCl3) δ ppm 7.89 - 7.96 (m, 1 H), 7.45 - 7.48 (m, 1 H), 4.60 (s, 2 H), 4.35 (s, 2 H), 1.41 (s, 15H).

[0133] Reference Example 7: Compound B-7

Chemical Structure

[0134] Reference Example 8: Compound B-8 [Chem.] B-1-6 (5 g, 13.95 mmol) was dissolved in an ammonia dioxane solution (0.4 M, 100 mL), then triethylamine (2.33 mL, 16.74 mmol) was added. After purging with nitrogen gas, the reaction was carried out at 90 °C for 12 hours. After cooling the reaction solution to room temperature, 50 mL of water was added to the reaction solution, and the mixture was extracted with 50 mL of dichloromethane. After liquid separation, the organic phase was collected, and the aqueous phase was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed successively with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase: PE:EA = 1:0 to 10:1) to obtain B-8. 1 H NMR (400 MHz, CDCl3): δ ppm 5.95 - 5.55 (m, 1H), 3.89 - 3.61 (m, 2H), 3.13 - 2.87 (m, 1H), 0.91 (s, 9H), 0.08 (s, 6H).

[0135] Reference Example 9: Compound B-9 [Chem.]

[0136] Step 1: Synthesis of B-9-3 B-4-1 (760 mg, 4.47 mmol) and B-9-2 (899.03 mg, 4.47 mmol) were dissolved in 3 mL of dichloromethane. Next, triphenylphosphine (1.76 g, 6.70 mmol) was added, and after cooling to 0 °C, diisopropyl azodicarboxylate (7.15 mmol, 1.39 mL) was added. The temperature was slowly raised to 24 °C and the reaction was carried out for 12 hours. 10 mL of water was added to the reaction solution for quenching, and it was extracted with 10 mL of dichloromethane. After liquid separation, the organic phase was collected, and the aqueous phase was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase PE:EA = 1:0~1:1) to obtain B-9-3. 1 H NMR (400 MHz, CDCl3): δ ppm 7.61 (dd, J = 3.3, 8.9 Hz, 1H), 7.17 (ddd, J = 3.3, 7.5, 9.1 Hz, 1H), 6.84 (dd, J = 4.2, 9.2 Hz, 1H), 3.93 (s, 3H), 3.86 (s, 2H), 3.27 (d, J = 5.4 Hz, 2H), 1.46 (s, 9H), 0.75 - 0.68 (m, 2H), 0.65 - 0.59 (m, 2H); LCMS: m / z= 254.2[M-100+1] + 。

[0137] Step 2: Synthesis of B-9-4 B-9-3 (1.8 g, 3.01 mmol) and calcium chloride (333.52 mg, 3.01 mmol) were added to a reaction flask. Next, tetrahydrofuran (6 mL) and ethanol (12 mL) were added. The mixture was cooled to 0 °C under a nitrogen gas atmosphere, and sodium borohydride (227.38 mg, 6.01 mmol) was slowly added. The reaction was carried out at 24 °C for 12 hours. The reaction solution was slowly quenched with 20 mL of water, 2 M hydrochloric acid was added to adjust the pH value to 6 - 7, and the mixture was extracted with 20 mL of dichloromethane. After liquid separation, the organic phase was collected. The aqueous phase was extracted with dichloromethane (2 × 20 mL), and the organic phases were combined. The combined organic phases were washed successively with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase: PE:EA = 1:0 - 2:1) to obtain B-9-4. 1 H NMR (400 MHz, CDCl3) δ ppm 7.07 (dd, J = 3.1, 8.6 Hz, 1H), 6.92 (dt, J = 3.2, 8.5 Hz, 1H), 6.71 (dd, J = 4.3, 8.9 Hz, 1H), 6.33 (br s, 1H), 5.23 - 5.09 (m, 1H), 4.71 (s, 2H), 3.82 (s, 2H), 3.26 (br d, J = 4.5 Hz, 2H), 1.39 (s, 9H), 0.67 - 0.57 (m, 4H); LCMS: m / z = 348.2 [M+Na] + .

[0138] Step 3: Synthesis of B-9 B-9-4 (0.65 g, 2.00 mmol) was dissolved in dichloromethane (13 mL), cooled to 0 °C under an atmosphere of nitrogen gas, thionyl chloride (4.00 mmol, 290.19 μL) was added, and the mixture was reacted at 20 °C for 1 hour. 5 mL of water was added to the reaction solution to quench the reaction system, the pH value was adjusted to 7 - 8 with saturated sodium bicarbonate solution, 10 mL of dichloromethane was added for extraction, and after liquid separation, the organic phase was collected and the aqueous phase was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed successively with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase: PE:EA = 1:0 ~ 1:1) to obtain B-9. 1 H NMR (400 MHz, CDCl3) δ ppm 7.10 (dd, J = 2.9, 8.5 Hz, 1H), 6.97 (dt, J = 3.0, 8.4 Hz, 1H), 6.76 (dd, J = 4.2, 8.7 Hz, 1H), 5.15 - 5.04 (m, 1H), 4.64 (s, 2H), 3.86 (s, 2H), 3.27 (br d, J = 5.5 Hz, 2H), 1.43 (s, 9H), 0.75 - 0.60 (m, 4H); LCMS: m / z = 366.1 [M+Na] + 。

[0139] Reference Example 10: Compound B-10

Chemical Structure

[0140] Step 1: Synthesis of B-10-2 B-4-1 (2.0 g, 11.76 mmol) was dissolved in N,N-dimethylformamide (6.67 mL). Under a nitrogen gas atmosphere, 3-bromopropylene (1.56 g, 12.93 mmol), potassium carbonate (1.79 g, 12.93 mmol), and sodium iodide (1.94 g, 12.93 mmol) were sequentially added, and the reaction was carried out at 20 °C for 12 hours. 30 mL of water was added to the reaction solution to quench the reaction system, and the mixture was extracted with ethyl acetate (20 mL × 3). After liquid separation, the organic phase was collected, washed successively with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase: PE:EA = 1:0~6:1) to obtain B-10-2. 1 H NMR (400 MHz, CDCl3) δ ppm 7.53 (dd, J = 3.2, 8.8 Hz, 1H), 7.16 - 7.15 (m, 1H), 6.93 (dd, J = 4.0, 8.8 Hz, 1H), 6.07 - 6.03 (m, 1H), 5.50 (dd, J = 1.6, 17.2 Hz, 1H), 5.32 (dd, J = 1.6, 10.4 Hz, 1H), 4.61 (dd, J = 1.6, 3.2 Hz, 2H), 3.91 (s, 3H); LCMS: m / z= 211.2 [M+H] + 。

[0141] Step 2: Synthesis of B-10-3 B-10-2 (2.0 g, 9.51 mmol) was dissolved in toluene (40.0 mL). The temperature was lowered to 0 °C under an atmosphere of nitrogen gas, and a toluene solution of diisobutylaluminum hydride (1 M, 28.54 mL) was slowly added dropwise. The mixture was stirred at 0 °C for 1 hour. Saturated sodium tartrate (100 mL) was added to the reaction solution to quench the reaction system, and the mixture was extracted with ethyl acetate (100 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed successively with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase: PE:EA = 1:0 to 10:1) to obtain B-10-3. 1 H NMR (400 MHz, CDCl3) δ ppm 7.06 (dd, J = 3.2, 8.8 Hz, 1H), 6.93 (td, J = 3.2, 4.4 Hz, 1H), 6.81 (dd, J = 4.4, 4.8 Hz, 1H), 6.07 - 6.02 (m, 1H), 5.44 (dd, J = 1.6, 15.6 Hz, 1H), 5.33 (dd, J = 1.6, 10.4 Hz, 1H), 4.70 (d, J = 2.8 Hz, 2H), 4.57 (d, J = 5.2 Hz, 2H), 2.25 (s, 1H).

[0142] Step 3: Synthesis of B-10 B-10-3 (0.5 g, 2.74 mmol) was dissolved in dichloromethane (10.0 mL). Thionyl chloride (0.3 mL, 4.12 mmol) was added under an atmosphere of nitrogen gas, and the mixture was stirred at 20 °C for 0.5 hour. The resulting reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase: PE:EA = 1:0 to 20:1) to obtain B-10. 11H NMR (400 MHz, CDCl3) δ ppm 7.13 (dd, J = 3.2, 8.8 Hz, 1H), 6.97 (td, J = 3.2, 4.4 Hz, 1H), 6.83 (dd, J = 4.4, 4.8 Hz, 1H), 6.07 - 6.02 (m, 1H), 5.45 (dd, J = 1.6, 17.2 Hz, 1H), 5.33 (dd, J = 1.6, 10.4 Hz, 1H), 4.65 (s, 2H), 4.58 (dd, J = 1.6, 3.2 Hz, 2H).

[0143] Reference Example 11: Compound B-11 [Chemical formula]

[0144] Step 1: Synthesis of B-11-2 Imidazole (7.27 g, 106.82 mmol), triethylamine (53.41 mmol, 7.43 mL) and dichloromethane (50 mL) were added to the reaction flask, cooled to -65 °C under a nitrogen gas atmosphere, and a dichloromethane (50 mL) solution of thionyl chloride (32.05 mmol, 2.33 mL) and B-11-1 (5 g, 26.70 mmol) was slowly added dropwise. Then, the temperature was slowly raised to 25 °C and stirred for 12 hours. 20 mL of water was added to the reaction solution to quench the reaction system, and the mixture was extracted with dichloromethane (20 mL × 3). After liquid separation, the organic phase was collected, washed successively with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of B-11-2. 1 1H NMR (400 MHz, CDCl3) δ ppm 5.06 (dd, J = 1.2, 8.8 Hz, 1H), 4.15 (d, J = 8.8 Hz, 1H), 1.93 - 1.87 (m, 1H), 1.51 - 1.50 (m, 1H), 1.41 (s, 9H), 0.77 - 0.72 (m, 1H), 0.68 - 0.65 (m, 1H).

[0145] Step 2: Synthesis of B-11 B-11-2 (6.2 g, 26.58 mmol), water (31 mL) and acetonitrile (62 mL) were added to a reaction flask, cooled to 0 °C under a nitrogen gas atmosphere, and then sodium periodate (7.11 g, 33.22 mmol) and ruthenium(III) chloride (27.56 mg, 132.89 μmol) were added. After slowly warming to 20 °C, the mixture was stirred for 2 hours. The reaction solution was filtered, and the filtrate was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase: PE:EA = 1:0 to 3:1) to obtain B-11. 1 1H NMR (400 MHz, CDCl3) δ ppm 4.43 (s, 2H), 1.88 (t, J = 6.8 Hz, 2H), 1.54 (s, 9H), 0.77 (t, J = 6.8 Hz, 2H).

[0146] Reference Example 12: Compound B-12

Chemical Structure

[0147] Step 1: Synthesis of B-12-2 Imidazole (1.01 g, 14.91 mmol) was dissolved in dichloromethane (16 mL), cooled to -5 °C, and then a solution of thionyl chloride (0.32 mL, 4.47 mmol) in dichloromethane (5 mL) was slowly added. The mixture was stirred at -5 °C for 1 hour. Then the temperature was lowered to -10 °C, and a solution of B-12-1 (0.5 g, 2.48 mmol) in dichloromethane (4 mL) was added. The mixture was returned to room temperature and stirred for 2 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed successively with 10% citric acid solution (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE:EA = 1:0 to 1:1) to obtain B-12-2.1 1H NMR (400 MHz, CDCl3) δ ppm 4.95 (d, J = 8.8 Hz, 1H), 4.80 (d, J = 8.8 Hz, 1H), 2.12 - 2.08 (m, 2H), 1.93 - 1.83 (m, 2H), 1.67 - 1.64 (m, 2H), 1.58 (s, 9H).

[0148] Step 2: Synthesis of B-12 B-12-2 (0.51 g, 2.06 mmol) was dissolved in acetonitrile (15 mL), cooled to 0 °C under a nitrogen gas atmosphere, and then a solution of sodium periodate (2.56 g, 11.96 mmol) and ruthenium(III) chloride hydrate (2.7 mg, 10.31 μmol) in water (15 mL) was added. After slowly warming to 20 °C, the mixture was stirred for 16 hours. The reaction solution was filtered, and the filtrate was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of B-12, which was used directly in the reaction of the next step without purification. 1 1H NMR (400 MHz, CDCl3) δ ppm 4.82 (s, 2H), 2.89 - 2.86 (m, 2H), 2.22 - 2.16 (m, 2H), 1.78 - 1.73 (m, 2H), 1.51 (s, 9H).

[0149] Reference Example 13: Compound B-13

Chemical Structure

[0150] Step 1: Synthesis of B-13-2 B-13-1 (276.0 mg, 1.97 mmol) and B-12 (415.0 mg, 1.58 mmol) were dissolved in N,N'-dimethylformamide. Next, cesium carbonate (1.28 g, 3.94 mmol) was added, and the temperature was raised to 70 °C, followed by stirring for 16 hours. After the reaction solution was cooled to room temperature, water (50 mL) was added for quenching, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed successively with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE:EA = 10:0~5:1) to obtain B-13-2. 1 H NMR (400 MHz, CDCl3) δ ppm 7.51 (dd, J = 3.2, 8.4 Hz, 1H), 7.25 - 7.23 (m, 1H), 7.04 - 7.00 (m, 1H), 4.87 (s, 1H), 4.27 (s, 2H), 2.30 - 2.04 (m, 4H), 2.04 - 2.02 (m, 1H), 1.93 - 1.88 (m, 1H),1.42 (s, 9H).

[0151] Step 2: Synthesis of B-13-3 B-13-2 (350.0 mg, 1.08 mmol) was dissolved in methanol (5 mL), and sodium borohydride (60.0 mg, 1.59 mmol) was added at 0 °C, followed by reacting at 24 °C for 1 hour. The reaction system was quenched with a saturated ammonium chloride (20 mL) solution, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed successively with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of B-13-3, which was directly used in the reaction of the next step without purification. 11H NMR (400 MHz, CDCl3) δ ppm 7.05 - 7.03 (m, 1H), 6.94 - 6.92 (m, 1H), 6.84 (dd, J = 4.4, 8.8 Hz, 1H), 4.89 (s, 1H), 4.67 (s, 2H), 4.14 (s, 2H), 2.32 - 2.23 (m, 4H), 1.91 - 1.89 (m, 1H), 1.86 - 1.84 (m, 1H), 1.43 (s, 9H).

[0152] Step 2: Synthesis of B-13 B-13-3 (345.0 mg, 1.06 mmol) was dissolved in dichloromethane (10 mL), then N,N'-diisopropylethylamine was added. After cooling to 0 °C, methanesulfonyl chloride (250.0 μL, 3.23 mmol) was added dropwise, and the reaction was carried out at 24 °C for 16 hours. Water (20 mL) was added to the reaction solution to quench the reaction system, and the mixture was extracted with dichloromethane (15 mL × 3). The combined organic phases were successively washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of B-13. 1 1H NMR (400 MHz, CDCl3) δ ppm 7.09 (dd, J = 3.2, 8.4 Hz, 1H), 6.99 - 6.98 (m, 1H), 6.97 - 6.87 (m, 1H), 4.97 (s, 1H), 4.61 (s, 2H), 4.16 (s, 2H), 2.35 - 2.27 (m, 4H), 1.92 - 1.89 (m, 1H), 1.87 - 1.86 (m, 1H), 1.42 (s, 9H).

[0153] Reference Example 14: Compound B-14

Chemical Structure

[0154] Step 1: Synthesis of B-14-2 B-4-1 (5.45 g, 32.05 mmol), B-14-1 (5.0 g, 26.7 mmol), and triphenylphosphine (10.51 g, 40.06 mmol) were added to dichloromethane (60 mL). After cooling to 0 °C, diisopropyl azodicarboxylate (8.64 g, 42.73 mmol) was added, and the mixture was stirred at 20 °C for 4 hours. Water (100 mL) was added to the reaction solution for quenching, and the mixture was extracted with dichloromethane (100 mL × 2). The combined organic phases were successively washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE:EA = 1:0 to 10:1) to obtain B-14-2. 1 H NMR (400 MHz, CDCl3) δ ppm 7.50 (1H, J = 3.2 Hz, J = 8.4 Hz, dd), 7.15 - 7.10 (m, 1H), 6.74 (1H, J = 4.4 Hz, J = 8.4 Hz, dd), 4.88 - 4.84 (m, 1H), 4.43 - 4.39 (m, 1H), 3.89 (s, 3H), 2.95 - 2.94 (m, 2H), 2.09 - 2.05 (m, 2H), 1.33 (s, 9H).

[0155] Step 2: Synthesis of B-14-3 B-14-2 (2.0 g, 5.89 mmol) was dissolved in tetrahydrofuran (20 mL). Sodium borohydride (0.3 g, 13.77 mmol) was added at 0 °C, and the mixture was reacted at 24 °C for 30 hours. The reaction system was quenched with water (50 mL), and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were successively washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE:EA = 1:0 to 4:1) to obtain B-14-3. LCMS: m / z = 334.2 [M+Na] + 。

[0156] Step 3: Synthesis of B-14 B-14-3 (1.47 g, 4.72 mmol) was dissolved in dichloromethane (30 mL), then N,N'-diisopropylethylamine (3.29 mL, 18.89 mmol) was added. After cooling to 0 °C, methanesulfonyl chloride (763.5 μL, 9.86 mmol) was added dropwise, and the reaction was carried out at 20 °C for 16 h. Water (50 mL) was added to the reaction mixture to quench the reaction system, and the mixture was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed successively with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE:EA = 1:0 to 4:1) to obtain B-14. LCMS: m / z = 352.1 [M+Na] + 。

[0157] Reference Example 14: Compound B-15

Chemical formula

[0158] Step 1: Synthesis of B-15-1 B-6-2 (3.1 g, 21.97 mmol) and B-11 (6.02 g, 24.17 mmol) were dissolved in DMF (32 mL). Then, potassium carbonate (7.59 g, 54.93 mmol) was slowly added at 0 °C, and the temperature was slowly raised to 20 °C and stirred for 10 h. Saturated brine (30 mL) was added to quench the reaction system, the pH was adjusted to about 3 with 2N hydrochloric acid, and the mixture was extracted with ethyl acetate (30 mL). The aqueous phase was extracted with dichloromethane (20 mL × 6). The combined organic phases were dried over anhydrous sodium sulfate successively, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (developing solvent: PE:EA = 1:0 to 1:1) to obtain B-15-1. 11H NMR (400 MHz, CDCl3) δ ppm 10.39 (d, J = 3.1 Hz, 1 H), 8.19 (d, J = 3.3 Hz, 1 H), 7.84 (dd, J = 3.2, 7.4 Hz, 1 H), 5.04 (br s, 1H), 4.48 (s, 2 H), 1.46 - 1.36 (m, 9 H), 0.95 (s, 4 H); LCMS: m / z = 333.1 [M+Na] + 。

[0159] Step 2: Synthesis of B-15-2 B-15-1 (2.77 g, 8.93 mmol) was dissolved in tetrahydrofuran (30 mL). Under a nitrogen gas atmosphere, sodium borohydride (0.47 g, 12.5 mmol) was added at 0 °C, and the reaction was carried out at 0 °C for 1 hour. Water (15 mL) was added to the reaction solution at 0 °C and stirred for 0.5 hour to completely quench it. Then, 2N hydrochloric acid was added to adjust the pH to 6 - 7, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined. The organic phase was washed successively with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the obtained filtrate was concentrated under reduced pressure to obtain the crude product of B-15-2, which was directly used in the next step without purification. 1 1H NMR (400 MHz, CDCl3) ppm 7.86 (d, J = 2.9 Hz, 1 H), 7.34 (br s, 1H), 5.09 (br d, J = 2.8 Hz, 1H), 4.61 (br s, 2H), 4.30 (s, 2H), 1.43 (s, 9H), 0.96 - 0.89 (m, 4H); LCMS: m / z = 313.2 [M+1] + 。

[0160] Step 4: Synthesis of B-15 B-15-2 (2.5 g, 8.0 mmol) was dissolved in DCM (25 mL), then N,N-diisopropylethylamine (24.01 mmol, 4.18 mL) was added. After cooling to 0 °C under a nitrogen gas atmosphere, methanesulfonyl chloride (16.01 mmol, 1.24 mL) was slowly added dropwise, and the temperature was slowly raised to 20 °C and reacted for 12 hours. The reaction solution was evaporated under reduced pressure to remove the solvent, and the crude product was separated and purified by column chromatography (PE:EA = 9:1 to 1:1) to obtain B-15. 1 H NMR (400 MHz, CDCl3) ppm 7.92 (d, J = 2.9 Hz, 1H), 7.49 (dd, J = 2.9, 7.9 Hz, 1H), 5.21 - 4.82 (m, 1H), 4.60 (s, 2H), 4.39 (br s, 2H), 1.44 (br s, 9H), 0.92 (s, 4H); LCMS: m / z = 331.1 [M+1] + 。

[0161] Example 1

Chemical formula

[0162] Step 1: Synthesis of Compound 001-1 B-1 (7.26 g, 31.4 mmol) and B-2 (7.65 g, 31.4 mmol) were dissolved in DMSO (140.0 mL), then KF (6.38 g, 109.89 mmol) was added and reacted at 120 °C for 3 hours. The reaction solution was washed with 300 mL of water and extracted with ethyl acetate (500 mL × 3). The obtained organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. It was separated and purified by column chromatography (PE:EA = 1:0 to 1:1) to obtain 001-1. 11H NMR (400 MHz, CDCl3): δ ppm 8.36 - 8.30 (m, 1H), 8.23 (s, 1H), 7.17 - 7.14 (m, 2H), 6.92 - 6.51 (m, 3H), 4.97 - 4.86 (m, 1H), 4.66 - 4.57 (m, 1H), 4.33 - 4.20 (m, 2H), 4.10 - 4.03 (m, 1H), 3.96 - 3.89 (m, 1H), 3.81 - 3.70 (m, 5H), 1.26 (t, J=7.2 Hz, 3H); LCMS: m / z=439.1 [M+1] + 。

[0163] Step 2: Synthesis of Compound 001-2 001-1 (0.4 g, 0.91 mmol) was dissolved in DMSO (16 mL), and then cesium carbonate (1.19 g, 3.64 mmol) was added. The mixture was stirred at 26 °C for 1 hour. It was washed with 50 mL of water and extracted with ethyl acetate (100 mL × 3). The obtained organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. It was separated and purified by column chromatography (PE:EA = 1:0~1:1) to obtain 001-2. 1 1H NMR (400 MHz, CDCl3): δ ppm 8.31 (s, 1H), 8.14 (s, 1H), 7.36 (d, J=8.4 Hz, 2H), 6.88 (d, J=8.4 Hz, 2H), 6.16 - 6.08 (m, 1H), 6.08 - 5.76 (m, 1H), 4.55 - 4.47 (m, 1H), 4.41 - 4.32 (m, 2H), 4.25 -4.21 (m, 1H), 3.86 - 3.72 (m, 5H), 1.38 (t, J = 7.2 Hz, 3H); LCMS: m / z = 419.0 [M+H] + 。

[0164] Step 3: Synthesis of Compound 001-3 001-2 (0.448 g, 1.07 mmol) was dissolved in trifluoroacetic acid (8 mL) and stirred at 70 °C for 7 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, and the obtained crude product was separated and purified by column chromatography (PE:EA = 1:0 - 1:2) to obtain the trifluoroacetate salt of 001-3 1 H NMR (400 MHz, CDCl3): δ ppm 8.30 - 8.24 (m, 1H), 8.17 (s, 1H), 6.09 - 5.71 (m, 1H), 4.51 (dd, J = 2.0 Hz, J = 12.0 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 4.26 - 4.19 (m, 1H), 4.06 - 3.96 (m, 1H), 1.38 (t, J = 7.2 Hz, 3H); LCMS: m / z = 299.0 [M+H] + 。

[0165] Step 4: Synthesis of compound 001-4 001-3 (0.11 g, 0.37 mmol) and B-4 (0.15 g, 0.44 mmol) were dissolved in DMF (3 mL), and then cesium carbonate (0.36 g, 1.11 mmol) was added. The mixture was stirred at 26 °C for 3 hours. It was washed with 15 mL of water and extracted with ethyl acetate (50 mL × 3). The obtained organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. It was separated and purified by column chromatography (PE:EA = 3:1) to obtain 001-4. LCMS: m / z = 594.2 [M+H] + 。

[0166] Step 5: Synthesis of compound 001-5 001-4 (0.05 g, 84.23 μmol) was dissolved in tetrahydrofuran (2 mL), ethanol (4 mL) and methanol (2 mL). Next, lithium hydroxide (2 M, 4.0 mL) was added and the mixture was stirred at 30 °C for 20 h. The reaction solution was cooled to -20 °C, quenched by adding 4.2 mL of 2 M hydrochloric acid solution, and then diluted by adding 20 mL of water. It was extracted with dichloromethane (20 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the obtained crude product 001-5 was directly used in the next step without purification. LCMS: m / z = 588.2 [M+Na] + 。

[0167] Step 6: Synthesis of compound 001-6 The crude product of 001-5 (0.045 g) was dissolved in dichloromethane (4 mL), hydrochloric acid / 1,4-dioxane solution (4 M, 6.85 mL) was added, and the mixture was stirred at 20 °C for 1 h. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride crude product of crude product 001-6, which was directly used in the next step. LCMS: m / z = 466.1 [M+H] + 。

[0168] Step 7: Synthesis of compound 001-7 After 001-6 (38 mg, crude product of hydrochloride) was dissolved in dichloromethane (4 mL), N,N-diisopropylethylamine (731.5 μmol, 127.4 μL) and pentafluorophenyl diphenylphosphinate (42.6 mg, 111.0 μmol) were sequentially added, and the mixture was stirred at 20 °C for 3 h. 10 mL of 2 M sodium carbonate solution was added to the reaction solution, and it was extracted with dichloromethane (20 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin layer chromatography (mobile phase: DCM:MeOH = 10:1) to obtain 001-7. 11H NMR (400 MHz, CDCl3): δ ppm 9.29 - 9.24 (m, 1H), 8.26 - 8.24 (m, 1H), 8.14 - 8.11 (m, 1H), 7.03 - 6.95 (m, 2H), 6.90 - 6.84 (m, 1H), 6.21 - 5.93 (m, 1H), 5.92 - 5.87 (m, 1H), 4.79 - 4.67 (m, 1H), 4.40 - 4.26 (m, 2H), 4.26 - 4.20 (m, 1H), 4.03 - 3.96 (m, 1H), 3.92 - 3.87 (m, 1H), 1.81 - 1.76 (m, 3H), 1.62 (s, 3H); LCMS: m / z = 448.1 [M+H] + 。

[0169] Step 8: Synthesis of Compound 001-8 001-7 (0.5 g, 1.12 mmol) was dissolved in 1,2-dimethylbenzene (20 mL), then Lawesson's reagent (1.81 g, 4.47 mmol) was added, and the mixture was stirred at 140 °C for 5 h. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 mL × 3). The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (DCM:MeOH = 20:1) to obtain 001-8. LCMS: m / z = 464.1 [M+H] + 。

[0170] Step 9: Synthesis of Compound 001 001-8 (0.05 g, 107.9 μmol) was dissolved in DMF (5 mL), and then methoxyamine hydrochloride (144.2 mg, 1.73 mmol), mercury(II) oxide (187.0 mg, 863.05 μmol), and triethylamine (1.51 mmol, 210.22 μL) were added sequentially. The mixture was stirred at 60 °C for 3 hours. The reaction solution was diluted with dichloromethane and filtered. The obtained filtrate was washed with 10% sodium bicarbonate, and the aqueous phase was extracted with dichloromethane (10 mL × 2). After combining the organic phases, they were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin-layer chromatography (DCM:MeOH = 20:1) to obtain 001. 1 H NMR (400 MHz, CDCl3): δ ppm 8.52 (s, 1H), 8.08 (s, 1H), 7.08 (s, 1H), 7.02 - 6.99 (m, 1H), 6.98 - 6.94 (m, 1H), 6.89 - 6.80 (m, 1H), 6.18 - 6.00 (m, 1H), 5.99 - 5.96 (d, J=12 Hz, 1H), 4.69 - 4.66 (d, J=12 Hz, 1H), 4.37 - 4.28 (m, 1H), 4.25 - 4.19 (m, 1H), 4.17 - 4.13 (d, J=16 Hz,1H), 3.99 - 3.98 (m, 2H), 3.82 (s, 3H), 1.66 (s, 6H); LCMS: m / z = 477.1 [M+H] + 。

[0171] Example 2

Chemical Structure

[0172] Example 3

Chemical formula

[0173] Example 4

Chemical Structure

[0174] Step 1: Synthesis of Compound 004-1 B-6 (569.08 mg, 1.71 mmol) and 001-3 (510 mg, 1.71 mmol) were dissolved in DMF (25 mL), then cesium carbonate (2.23 g, 6.84 mmol) was added, and the mixture was stirred at 5 °C for 4 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with DCM (100 mL × 2). The obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by thin-layer chromatography (PE:EA = 2:1) to obtain 004-1. 1 H NMR (400 MHz, CDCl3): δ ppm 8.37 (br d, J = 6.00 Hz, 1 H), 8.28 (d, J = 2.25 Hz, 1 H), 8.09 (d, J = 1.50 Hz, 1 H), 7.90 (dd, J = 2.94, 1.56 Hz, 1 H), 5.78 - 6.25 (m, 1 H), 5.51 (d, J = 14.51 Hz, 1 H), 4.47 - 4.60 (m, 4 H), 4.38 - 4.46 (m, 2 H), 4.12 (qd, J = 7.13, 1.75 Hz, 1 H), 3.94 (br d, J = 11.76 Hz, 1 H), 1.40 (s, 15 H), 1.26 (td, J = 7.13, 1.63 Hz, 3 H); LCMS: m / z = 495.1 [M + H - 100] + 。

[0175] Step 2: Synthesis of Compound 004-2 004-1 (0.8 g, 1.345 mmol) was dissolved in tetrahydrofuran (30 mL), ethanol (60 mL) and methanol (30 mL). Then, lithium hydroxide (2 M, 67.3 mL) was added, and the mixture was stirred at 30 °C for 20 hours. The reaction solution was cooled to -20 °C, 70.0 mL of 2 M hydrochloric acid solution was added, and further diluted with 200 mL of water. The mixture was extracted with dichloromethane (200 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained crude product 004-2 was directly used in the next step without purification. LCMS: m / z = 489.2 [M + Na - 100] + 。

[0176] Step 3: Synthesis of Compound 004-3 Dissolve 004-2 (0.8 g, 1.41 mmol) in DCM (10 mL), then add a 1,4-dioxane (4 M, 10 mL) solution of hydrochloric acid, and stir at 25 °C for 1 hour. Concentrate the resulting reaction solution under reduced pressure. After adding EA (10 mL) to the residue to dissolve it and then concentrating, add EA (10 mL) again to dissolve it and then concentrate to obtain crude product 004-3, which was directly used in the reaction of the next step. LCMS: m / z = 467.1 [M+H] + 。

[0177] Step 4: Synthesis of Compound 004-4 Dissolve 004-3 in DCM (50 mL), add N,N-diisopropylethylamine (11.79 mmol, 2.05 mL) and pentafluorophenyldiphenylphosphinate (679.65 mg, 1.77 mmol), and stir at 25 °C for 2 hours. Add water (20 mL) to the reaction solution, extract with DCM (200 mL × 2), dry the obtained organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. Separate and purify the crude product by thin layer chromatography (DCM:MeOH = 10:1) to obtain 004-4. 1 H NMR (400 MHz, CDCl3): δ ppm 9.09 (s, 1 H), 8.22 - 8.36 (m, 1 H), 8.16 (s, 1 H), 8.00 (d, J = 2.88 Hz, 1 H), 7.35 (dd, J = 7.94, 2.69 Hz, 1 H), 5.83 - 6.24 (m, 1 H), 5.72 (dd, J = 15.38, 1.50 Hz, 1 H), 4.83 (d, J = 10.76 Hz, 1 H), 4.74 (d, J = 12.38 Hz, 1 H), 4.21 - 4.42 (m, 3 H), 3.90 (d, J = 10.63 Hz, 1 H), 1.77 (s, 3 H), 1.63 (s, 3 H); LCMS: m / z = 449.0 [M+H] + 。

[0178] Step 5: Synthesis of Compound 004 004-4 (0.09 g, 200.71 μmol) and Lawesson's reagent (324.73 mg, 802.86 μmol) were dissolved in 1,2-xylene (8 mL), and the temperature was raised to 140 °C under a nitrogen gas atmosphere and reacted for 5 hours. The reaction solution was cooled to room temperature, 50 mL of water was added to the reaction solution, and it was extracted with EA (60 mL × 3). After combining the organic phases, they were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by thin-layer chromatography (DCM:MeOH = 1:0 to 20:1) to obtain 004. 1 H NMR (400 MHz, CDCl3): δ ppm 10.37 (brs, 1 H), 8.54 (s, 1 H), 8.13 (s, 1 H), 8.02 (d, J = 3.01 Hz, 1 H), 7.41 (dd, J = 7.91, 3.14 Hz, 1 H), 6.03 - 6.19 (m, 1 H), 5.69 - 5.79 (m, 1 H), 4.66 - 4.81 (m, 2 H), 4.17 - 4.35 (m, 3 H), 3.96 (d, J = 11.04 Hz, 1 H), 2.03 (s, 3 H), 1.82 (s, 3 H); LCMS: m / z = 465.1 [M+H] + 。

[0179] Example 5

Chemical Structure

[0180] Example 6

Chemical Structure

[0181] Step 1: Synthesis of Compound 006-1 B-7 (0.5 g, 1.94 mmol) and B-1 (448.75 mg, 1.94 mmol) were dissolved in DMSO (10 mL). After that, KF (281.88 mg, 4.85 mmol) was added, and the mixture was stirred at 120 °C for 5 hours under a nitrogen gas atmosphere. The reaction solution was poured into 100 mL of ice water for quenching, and a solid precipitated. The solid obtained by filtration was dissolved in dichloromethane (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE:EA = 1:0~1:1) to obtain 006-1. 1 H NMR (400 MHz, CDCl3) δ ppm 8.33 (d, J = 7.8 Hz, 1H), 7.25 (s, 2H), 6.95 - 6.89 (m, 2H), 6.87 - 6.67 (m, 1H), 4.96 (d, J = 16.5 Hz, 1H), 4.70 (dd, J = 1.9, 16.5 Hz, 1H), 4.38 (qtd, J = 7.1, 10.8, 17.8 Hz, 3H), 4.16 - 4.10 (m, 1H), 4.06 - 3.99 (m, 1H), 3.88 - 3.75 (m, 4H), 2.61 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H); LCMS: m / z = 453.1 [M+H] + 。

[0182] Step 2: Synthesis of Compound 006-2 006-1 (700 mg, 1.55 mmol) was dissolved in DMF (49 mL). After being replaced with nitrogen gas, cesium carbonate (1.51 g, 4.64 mmol) was added, and the mixture was stirred at 50 °C for 12 hours. After the reaction solution was cooled to room temperature, 10 mL of water was added to quench the reaction system, and it was extracted with EA (20 mL × 4). The obtained organic phase was successively washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by thin-layer chromatography (PE:EA = 1:1) to obtain 006-2 11H NMR (400 MHz, CDCl3) δ ppm 8.04 (s, 1H), 7.36 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 6.09 (d, J = 14.8 Hz, 1H), 5.97 - 5.75 (m, 1H), 4.48 (m, 1H), 4.43 - 4.29 (m, 2H), 4.28 - 4.17 (m, 1H), 3.84 - 3.69 (m, 5H), 2.62 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H); LCMS: m / z = 433.1 [M+H] + 。

[0183] Step 3: Synthesis of Compound 006-3 006-2 (440 mg, 1.02 mmol) was dissolved in trifluoroacetic acid (1 mL), and the temperature was raised to 70 °C and stirred for 12 hours under a nitrogen gas atmosphere. After the reaction solution was cooled to room temperature, 50 mL of water was added to quench the reaction system, and it was extracted with EA (20 mL × 4). The obtained organic phase was washed successively with saturated sodium bicarbonate (20 mL × 3) and saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of 006-3, which was directly used in the reaction of the next step. LCMS: m / z = 313.1 [M+H] + 。

[0184] Step 4: Synthesis of Compound 006-4 006-3 (320 mg, 1.02 mmol), B-4 (340.02 mg, 1.02 mmol) and cesium carbonate (1.00 g, 3.07 mmol) were dissolved in DMF (1 mL), and reacted at 25 °C for 3 hours under a nitrogen gas atmosphere. The reaction system was quenched with 10 mL of water and extracted with EA (20 mL × 4). The EA phase was washed successively with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (PE:EA = 1:0~1:1) to obtain 006-4. 11H NMR (400 MHz, CDCl3) δ ppm 8.01 (s, 1H), 7.63 (br d, J = 7.1 Hz, 1H), 6.99 - 6.92 (m, 1H), 6.86 (dd, J = 4.3, 8.9 Hz, 1H), 6.12 - 5.77 (m, 2H), 4.58 - 4.46 (m, 2H), 4.45 - 4.35 (m, 3H), 4.28 - 4.22 (m, 1H), 4.20 (d, J = 8.8 Hz, 1H), 3.95 (br d, J = 8.8 Hz, 1H), 3.84 (br d, J = 11.4 Hz, 1H), 2.62 (s, 3H), 1.42 - 1.35 (m, 18H); LCMS: m / z = 608.5 [M+H] + 。

[0185] Step 5: Synthesis of Compound 006-5 006-4 (170 mg, 279.78 μmol) was dissolved in THF (2 mL), EtOH (4 mL) and MeOH (2 mL), then lithium hydroxide monohydrate (2 M, 4 mL) and sodium hydroxide (22.38 mg, 559.56 μmol) were added, and the reaction was carried out at 25 °C for 144 h under an atmosphere of nitrogen gas. The reaction solution was cooled to -20 °C, and 2 M hydrochloric acid was added to adjust the pH value to about 3. It was extracted with DCM (20 mL × 4), and the obtained organic phase was successively washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by thin layer chromatography (PE:EA = 1:1) to obtain 006-5. LCMS: m / z = 580.5 [M+H] + 。

[0186] Step 6: Synthesis of Compound 006-6 006-5 (100 mg, 172.54 μmol) was dissolved in trifluoroacetic acid (0.5 mL), and the reaction was carried out at 25 °C for 0.5 h under an atmosphere of nitrogen gas. The reaction solution was concentrated under reduced pressure to obtain a crude product 006-6. LCMS: m / z = 480.4 [M+H] + 。

[0187] Step 7: Synthesis of Compound 006 006-6 (83 mg, 173.11 μmol) and pentafluorophenyl diphenylphosphinate (99.78 mg, 259.67 μmol) were dissolved in DCM (2 mL), and N,N-diisopropylethylamine (1.73 mmol, 301.53 μL) was added under an atmosphere of nitrogen gas. The mixture was reacted at 25 °C for 12 hours. The reaction system was quenched with 10 mL of water and extracted with DCM (20 mL × 3). The DCM phase was washed successively with saturated sodium carbonate (20 mL × 3) and saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by thin-layer chromatography (DCM:MeOH = 20:1), and then further purified by prep-HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 m, mobile phase: phase A was water (10 mM ammonium bicarbonate), and phase B was acetonitrile; gradient: phase B increased from 10% to 70% in the first 4.0 minutes, was maintained for 1.0 minute, then decreased to 10% and was maintained for 3.0 minutes) to obtain 006. 1 H NMR (400 MHz, CDCl3) δ ppm 9.25 (s, 1H), 8.05 (s, 1H), 7.02 - 6.95 (m, 2H), 6.89 - 6.82 (m, 1H), 6.18 - 5.87 (m, 2H), 4.70 (m, 1H), 4.39 - 4.31 (m, 1H), 4.30 - 4.25 (m, 1H), 4.21 (d, J = 15.3 Hz, 1H), 3.99 - 3.89 (m, 2H), 2.64 (s, 3H), 1.80 (s, 3H), 1.63 (s, 3H); LCMS: m / z = 462.2 [M+H] + 。

[0188] Example 7

Chemical Structure

[0189] Step 1: Synthesis of Compound 007-2 007-1 (3g, 19.54 mmol), 2-chloro-tetrahydro-2H-pyran (7.14 mL, 78.14 mmol) and pyridinium 4-methylbenzenesulfonate (294.55 mg, 1.17 mmol) were dissolved in 30 mL of toluene, purged with nitrogen gas, and then heated at 100 °C for 12 hours to react. The solvent was removed by concentration under reduced pressure. Next, 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with 15 mL of dichloromethane. After liquid separation, the organic phase was collected, and the aqueous phase was extracted with dichloromethane (3 × 10 mL). The combined organic phases were successively washed with saturated brine (2 × 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase: PE:EA = 1:0~0:1) to obtain 007-2. 1 H NMR (400 MHz, CDCl3) δ ppm 8.28 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.28 (s, 1H), 5.85 (dd, J = 2.2, 10.6 Hz, 1H), 4.18 (td, J = 2.0, 11.7 Hz, 1H), 3.90 - 3.74 (m, 1H), 2.21 - 1.96 (m, 2H), 1.91 - 1.60 (m, 4H); LCMS: m / z = 238.1 [M+H] + 。

[0190] Step 2: Synthesis of compound 007-3 007-2 (600 mg, 2.52 mmol) and B-8 (682.64 mg, 3.03 mmol) were dissolved in 10 mL of 1,4-dioxane, and after purging with nitrogen gas, sodium tert-butoxide (485.18 mg, 5.05 mmol), palladium acetate (28.34 mg, 126.22 μmol), and BRETTPHOS (135.50 mg, 252.43 μmol) were added sequentially, and the mixture was heated at 80 °C for 12 hours to effect the reaction. The reaction solution was cooled to room temperature, 30 mL of water was added to the reaction solution for quenching, and the mixture was extracted with 20 mL of dichloromethane. After liquid separation, the organic phase was collected, and the aqueous phase was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed sequentially with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase: PE:EA = 1:0~1:1) to obtain 007-3. 1 H NMR (400 MHz, CDCl3) δ ppm 8.03 (d, J = 2.3 Hz, 1H), 7.82 (dd, J = 1.2, 8.6 Hz, 1H), 6.46 (dd, J = 2.3, 8.6 Hz, 1H), 6.27 - 5.90 (m, 1H), 5.77 - 5.62 (m, 1H), 4.89 (br d, J = 8.2 Hz, 1H), 4.66 - 4.43 (m, 1H), 4.22 - 4.14 (m, 1H), 4.00 (td, J = 1.8, 10.1 Hz, 1H), 3.86 - 3.73 (m, 2H), 2.11 - 2.07 (m, 2H), 1.86 - 1.75 (m, 4H), 0.93 (s, 9H), 0.11 (d, J = 7.2 Hz, 6H); LCMS: m / z =427.2 [M+H] + 。

[0191] Step 3: Synthesis of Compound 007-4 007-3 (490 mg, 1.15 mmol) and sodium acetate (612.50 mg, 7.47 mmol) were dissolved in acetic acid (12.5 mL), cooled to 0 °C under an atmosphere of nitrogen gas, pyridinium tribromide (551.06 mg, 1.72 mmol) was added, and the reaction was carried out at 25 °C for 2 hours. The reaction solution was quenched with 10 mL of saturated sodium thiosulfate (the potassium iodide test paper did not change to blue), 10 mL of water was added and stirred for 10 minutes, extracted with 20 mL of dichloromethane. After liquid separation, the organic phase was collected, and the aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed successively with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of 007-4, which was used directly in the next step without purification. LCMS: m / z = 505.1 [M+H] + 。

[0192] Step 4: Synthesis of Compound 007-5 007-4 (640 mg, 1.27 mmol) and TBAF (1 M, 1.45 mL) were dissolved in 10 mL of THF, and the reaction was carried out at 25 °C for 1 hour under an atmosphere of nitrogen gas. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase: PE:EA = 1:0 to 0:1) to obtain 007-5. 1 H NMR (400 MHz, CDCl3) δ ppm 8.10 (s, 1H), 8.00 (d, J = 4.2 Hz, 1H), 6.31 - 5.96 (m, 1H), 5.69 (br d, J = 7.3 Hz, 1H), 5.64 - 5.54 (m, 1H), 4.69 - 4.51 (m, 1H), 4.19 - 4.07 (m, 2H), 4.02 - 3.93 (m, 1H), 3.82 - 3.70 (m, 1H), 3.39 (t, J = 7.1 Hz, 1H), 2.38 (t, J = 8.2 Hz, 1H), 2.09 (br dd, J = 2.8, 6.4 Hz, 3H), 2.06 - 1.98 (m, 2H).

[0193] Step 5: Synthesis of Compound 007-6 007-5 (100 mg, 255.62 μmol) and cesium carbonate (108.27 mg, 332.30 μmol) were dissolved in 2.5 mL of 1,4-dioxane. Under an atmosphere of nitrogen gas, 2-(di-tert-butylphosphino)-1,1'-binaphthyl (20.37 mg, 51.12 μmol) and tris(dibenzylideneacetone)dipalladium(0) (23.41 mg, 25.56 μmol) were sequentially added, and the temperature was slowly raised to 88 °C and reacted for 15 hours. Next, 2-(di-tert-butylphosphino)-1,1'-binaphthyl (20.37 mg, 51.12 μmol) and tris(dibenzylideneacetone)dipalladium(0) (23.41 mg, 25.56 μmol) were added, and the reaction was carried out at 116 °C for 16 hours. The reaction solution was separated and purified by preparative thin-layer chromatography (EA:PE = 2:1) to obtain 007-6. 1 H NMR (400 MHz, CDCl3) δ ppm 7.97 (s, 1H), 7.52 - 7.29 (m, 1H), 6.04 - 5.67 (m, 1H), 5.62 (br dd, J = 2.6, 10.3 Hz, 1H), 5.20 (br s, 1H), 4.39 (br d, J = 11.1 Hz, 1H), 4.22 - 4.06 (m, 2H), 3.89 - 3.68 (m, 2H), 2.19 - 2.07 (m, 2H), 1.90 - 1.62 (m, 4H); LCMS: m / z = 311.1 [M+H] + 。

[0194] Step 6: Synthesis of compound 007-7 007-6 (40 mg, 128.91 μmol), B-4 (85.55 mg, 257.82 μmol), cesium carbonate (126.00 mg, 386.72 μmol) and tetrabutylammonium iodide (12.38 mg, 33.52 μmol) were dissolved in 0.8 mL of DMF, and heated at 40 °C for 16 h for reaction under a nitrogen gas atmosphere. The reaction solution was quenched with 5 mL of water, extracted with dichloromethane (1 mL × 3), and separated to obtain a crude product in the organic phase. The crude product was separated and purified by preparative thin layer chromatography (EA:PE = 10:1) to obtain 007-7. 1 H NMR (400 MHz, CDCl3) δ ppm 7.96 (s, 1H), 7.45 (s, 1H), 7.26 - 7.18 (m, 1H), 6.97 - 6.74 (m, 2H), 6.09 - 5.74 (m, 1H), 5.73 - 5.60 (m, 2H), 4.56 - 4.38 (m, 2H), 4.24 - 4.08 (m, 2H), 4.04 - 3.89 (m, 2H), 3.87 - 3.68 (m, 2H), 2.10 (br s, 2H), 1.82 - 1.58 (m, 4H), 1.45 - 1.39 (m, 9H), 1.36 - 1.29 (m, 6H); LCMS: m / z = 606.3 [M+H] + 。

[0195] Step 7: Synthesis of compound 007-8 After dissolving 007-7 (30 mg, 49.53 μmol) in 1.5 mL of dichloromethane, trifluoroacetic acid (0.5 mL, 6.75 mmol) was added, and the mixture was reacted at 25 °C for 2 h, concentrated under reduced pressure to remove the solvent and trifluoroacetic acid to obtain a crude product of the trifluoroacetate salt of 007-8, which was directly used in the next step without purification. 11H NMR (400 MHz, DMSO-d6) δ ppm 7.95 (s, 1H), 7.38 (s, 1H), 7.04 - 6.92 (m, 2H), 6.89 (dd, J = 2.7, 9.3 Hz, 1H), 6.48 - 6.08 (m, 1H), 5.25 (br d, J = 16.9 Hz, 1H), 4.66 (br d, J = 16.9 Hz, 1H), 4.49 (br d, J = 11.5 Hz, 1H), 4.11 - 3.99 (m, 2H), 3.75 - 3.66 (m, 2H), 1.15 - 1.10 (m, 6H); LCMS: m / z =422.2 [M+H] + 。

[0196] Step 8: Synthesis of Compound 007 007-8 (35.36 mg, crude product of trifluoroacetate) was dissolved in 2.1 mL of dichloromethane. A solution of N,N'-carbonyldiimidazole (25.60 mg, 157.86 μmol) in dichloromethane (0.7 mL) was added dropwise at 0 °C. After stirring well, N,N'-diisopropylethylamine (0.2 mL, 1.15 mmol) was added, and the temperature was slowly raised to 25 °C and reacted for 12 hours. 5 mL of 10% aqueous citric acid solution was slowly poured into the reaction solution to adjust the pH value to 6. Extraction was carried out with dichloromethane (1 mL × 2), and the organic phase was obtained by liquid separation. After concentration under reduced pressure, separation and purification were carried out by preparative thin-layer chromatography (PE:EA = 1:1). The obtained crude product was purified by preparative high-performance liquid chromatography (chromatography column: Waters Xbridge BEH C18 100×30 mm×10 m; mobile phase: phase A is water (10 mM ammonium bicarbonate), phase B is acetonitrile; gradient: phase B increases from 10% to 80% in the first 4 minutes, is maintained for 2.0 minutes, and then decreases to 10% in 2 minutes) to obtain 007. 11H NMR (400 MHz, CDCl3) δ ppm 10.30 (br s, 1H), 8.38 (s, 1H), 7.48 (s, 1H), 7.07 - 6.92 (m, 2H), 6.83 (dd, J = 4.4, 9.1 Hz, 1H), 6.10 - 5.80 (m, 1H), 5.76 (br d, J = 15.5 Hz, 1H), 4.68 (br d, J = 11.6 Hz, 1H), 4.35 - 4.16 (m, 3H), 4.07 (d, J = 8.9 Hz, 1H), 3.93 (d, J = 8.9 Hz, 1H), 1.77 (s, 3H), 1.67 (s, 3H); LCMS: m / z = 448.1 [M+H] + 。

[0197] Example 8

Chem.

[0198] Example 9

Chemical formula

[0199] Step 1: Synthesis of Compound 009-2 After dissolving 009-1 (5.0 g, 32.23 mmol) in ethyl acetate (50 mL), potassium carbonate (0.23 g, 1.61 mmol) was added, and the mixture was cooled to -5 °C under a nitrogen gas atmosphere. N-Bromosuccinimide (7.17 g, 40.28 mmol) was added, and then the temperature was slowly raised to 20 °C and stirred for 2 hours. The reaction solution was washed with 50 mL of saturated sodium bisulfite solution, extracted with ethyl acetate (2 × 50 mL), the organic phases were combined, washed successively with saturated brine (2 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase: PE:EA = 1:0~1:1) to obtain 009-2. 1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (t, J=7.03 Hz, 3 H), 4.18 (q, J=7.11 Hz, 2 H), 6.26 (s, 2 H), 12.15 (s, 1 H); LCMS: m / z =233.7, 235.7 [M+H]+ .

[0200] Step 2: Synthesis of Compound 009-3 009-2 (86.0 g, 367.4 mmol), diethyl fluoromalonate (98.2 g, 551.2 mmol) and sodium ethoxide (62.5 g, 918.6 mmol) were dissolved in ethanol (1000 mL), the temperature was raised to 78 °C and stirred for 6 hours. After cooling to room temperature, it was concentrated under reduced pressure to remove ethanol, 1 M hydrochloric acid solution was added dropwise to adjust the pH value to about 3, stirred at 25 °C for 1 hour, filtered, and the obtained cake was dried in a vacuum oven to obtain 009-3. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (t, J=7.03 Hz, 3 H), 4.25 (q, J=7.11 Hz, 2 H), 7.84 (s, 1 H), 9.63 (br s, 1 H); LCMS: m / z =319.7, 321.7 [M+H] + .

[0201] Step 3: Synthesis of Compound 009-4 009-3 (43.0 g, 134.3 mmol) was dissolved in phosphorus oxychloride (454.8 mL, 4.89 mol), N,N-diisopropylamine (32.2 mL, 201.5 mmol) was added dropwise at 0 °C, and the temperature was slowly raised to 100 °C and stirred for 3 hours. The reaction solution was cooled to room temperature, distilled under reduced pressure to recover most of the phosphorus oxychloride, the obtained solution was slowly added to water (450 mL) for quenching, a solid precipitated, filtered, the cake was washed with water (3×50 mL), and the filtrate was neutralized and then discarded. The obtained cake was redissolved in methyl tert-butyl ether (200 mL), stirred at 25 °C for 0.5 hour, filtered, and the cake was collected to obtain 009-4. LCMS: m / z =377.7, 379.7 [M+Na] + .

[0202] Step 4: Synthesis of Compound 009-5 009-4 (1.9 g, 5.32 mmol) was dissolved in ethanol (45 mL), tetrahydrofuran (45 mL) and water (30 mL). Then ammonium chloride (1.54 g, 28.77 mmol) was added, and zinc powder (1.39 g, 21.21 mmol) was added in one batch at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. The reaction mixture was filtered, and the filtrate was successively extracted with dichloromethane (2 × 30 mL), washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product, and the crude product was separated and purified by column chromatography (mobile phase: PE:EA = 1:0~3:1) to obtain 009-5. LCMS: m / z = 321.9 [M+H] + 。

[0203] Step 5: Synthesis of compound 009-6 009-5 (5.0 g, 15.5 mmol), B-1 (3.58 g, 15.5 mmol) and potassium fluoride (3.15 g, 54.26 mmol) were dissolved in dimethyl sulfoxide (50 mL), heated to 120 °C and stirred for 1 h. The reaction mixture was washed with 50 mL of water, extracted with ethyl acetate (2 × 50 mL), the organic phases were combined, successively washed with saturated brine (2 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase: PE:EA = 1:0~3:1) to obtain 009-6. LCMS: m / z = 517.1 [M+H] + 。

[0204] Step 6: Synthesis of compound 009-7 009-6 (1.4 g, 2.71 mmol) was dissolved in DMF (15 mL), purged with nitrogen gas, then cesium carbonate (2.65 g, 8.13 mmol) was added, and the mixture was stirred at 24 °C for 2 h. 10 mL of water was added to quench the reaction system, and it was extracted with EA (20 mL × 2). The obtained organic phase was successively washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by thin-layer chromatography (PE:EA = 1:1) to obtain 009-7. LCMS: m / z = 497.1 [M+H]+ .

[0205] Step 7: Synthesis of Compound 009-8 009-7 (1.1 g, 2.2 mmol) was dissolved in trifluoroacetic acid (2 mL), and the temperature was raised to 70 °C and stirred for 12 hours under an atmosphere of nitrogen gas. After the reaction solution was cooled to room temperature, 50 mL of water was added to quench the reaction system, and it was extracted with EA (20 mL × 3). The obtained organic phase was washed successively with saturated sodium bicarbonate (20 mL × 3) and saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 009-8. LCMS: m / z = 377.1 [M+H] + .

[0206] Step 8: Synthesis of Compound 009-9 009-8 (0.9 g, 2.4 mmol) and B-4 (1.2 g, 3.7 mmol) were dissolved in N,N-dimethylformamide (9 mL), then cesium carbonate (2.3 g, 7.2 mmol) was added, and it was stirred at 24 °C for 1.5 hours. 20 mL of water was added to quench the reaction system, and it was extracted with EA (40 mL × 2). The obtained organic phase was washed successively with saturated brine (40 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE:EA = 2:1) to obtain 009-9. LCMS: m / z = 694.2, 696.2 [M+Na] + .

[0207] Step 9: Synthesis of Compound 009-10 009-9 (0.5 g, 0.74 mmol) was dissolved in tetrahydrofuran (5 mL), methanol (5 mL) and ethanol (10 mL), lithium hydroxide monohydrate (2.5 g, 59.48 mmol) was added, and it was stirred at 24 °C for 72 hours. The pH value was adjusted to 7 - 8 with 2 M hydrochloric acid, extracted with dichloromethane (40 mL × 2), washed successively with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 009-10.

[0208] Step 10: Synthesis of Compound 009-11 009-10 (0.1 g, 155.2 μmol) was dissolved in ethyl acetate (1.0 mL), and after purging with nitrogen gas, a hydrochloric acid / ethyl acetate solution (4 M, 0.5 mL) was added, and the reaction was carried out at 20 °C for 1 hour. The resulting reaction solution was concentrated under reduced pressure to obtain a crude product of the hydrochloride salt of 009-11. LCMS: m / z = 544.0 [M+H] + .

[0209] Step 11: Synthesis of Compound 009 009-11 (42 mg, crude product of hydrochloride salt) was dissolved in DCM (0.8 mL), and after purging with nitrogen gas, pentafluorophenyldiphenylphosphinate (44.47 mg, 115.74 μmol) and N,N-diisopropylethylamine (149.58 mg, 1.16 mmol) were added, and the mixture was stirred at 24 °C for 12 hours. 10 mL of water was added to quench the reaction system, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed successively with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin-layer chromatography silica gel plate (dichloromethane:methanol = 20:1), and further purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 m, mobile phase: [phase A: water (10 mM ammonium bicarbonate); phase B: acetonitrile], gradient: phase B increases from 10% to 80% in the first 3 minutes, is maintained for 0.9 minutes, and gradually decreases from 80% to 10% in the last 0.6 minutes) to obtain 009. 11H NMR (400 MHz, CDCl3) δ ppm 9.15 (s, 1H), 8.04 (s, 1H), 7.05 - 6.94 (m, 2H), 6.86 (dd, J = 4.5, 8.9 Hz, 1H), 6.20 - 5.86 (m, 2H), 4.73 (d, J = 12.0 Hz, 1H), 4.43 - 4.34 (m, 1H), 4.32 - 4.26 (m, 1H), 4.24 (d, J = 15.1 Hz, 1H), 4.00 - 3.87 (m, 2H), 1.80 (s, 3H), 1.62 (s, 3H); LCMS: m / z =526.1 [M+H] + 。

[0210] Example 10

Chemical Structure

[0211] Example 11

Chem.

[0212] Step 1: Synthesis of Compound 011-1 001-3 (340 mg, 1.14 mmol) and B-9 (391.96 mg, 1.14 mmol) were dissolved in N,N-dimethylformamide (6 mL), and then cesium carbonate (1.11 g, 3.42 mmol) was added. The mixture was stirred at 24 °C for 12 hours under a nitrogen gas atmosphere. The reaction solution was quenched with 10 mL of water, 20 mL of ethyl acetate was added for extraction. After liquid separation, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were successively washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase: PE:EA = 1:0~1:1) to obtain 011-1. 11H NMR (400 MHz, CDCl3) δ ppm 8.30 (s, 1H), 8.10 (s, 1H), 6.93 (dt, J = 3.3, 8.4 Hz, 1H), 6.74 (td, J = 4.2, 8.9 Hz, 2H), 6.19 - 5.85 (m, 1H), 5.73 (d, J = 14.3 Hz, 1H), 4.61 - 4.51 (m, 2H), 4.43 (q, J = 7.1 Hz, 2H), 4.39 - 4.26 (m, 2H), 3.79 - 3.74 (m, 2H), 3.33 - 3.18 (m, 2H), 1.43 (t, J = 7.1 Hz, 3H), 1.38 (s, 9H), 0.56 - 0.46 (m, 4H); LCMS: m / z =606.5 [M+H] + 。

[0213] Step 2: Synthesis of Compound 011-2 Dissolve 011-1 (370 mg, 610.96 μmol) in tetrahydrofuran (8 mL), ethanol (16 mL) and methanol (8 mL), then add lithium hydroxide monohydrate solution (2 M, 16 mL) and sodium hydroxide (48.88 mg, 1.22 mmol), and stir at 30 °C for 12 hours under a nitrogen gas atmosphere. Adjust the pH value of the reaction solution to 3 - 4 with 2N hydrochloric acid, add 20 mL of dichloromethane for extraction, collect the organic phase after liquid separation, and extract the aqueous phase with dichloromethane (20 mL × 3). Combine the organic phases, wash successively with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. Purify the crude product by thin layer chromatography silica gel plate (PE:EA = 1:1) to obtain 011-2. 11H NMR (400 MHz, CDCl3) δ ppm 8.32 (s, 1H), 8.17 (s, 1H), 7.18 (dd, J = 3.1, 8.4 Hz, 1H), 6.96 (dt, J = 3.1, 8.4 Hz, 1H), 6.77 (dd, J = 4.3, 9.0 Hz, 1H), 6.23 - 5.90 (m, 1H), 5.70 (br d, J = 14.6 Hz, 1H), 4.70 (br s, 1H), 4.64 - 4.55 (m, 2H), 4.30 - 4.17 (m, 1H), 4.14 - 3.99 (m, 1H), 3.86 (br d, J = 9.5 Hz, 1H), 3.71 (br d, J = 9.5 Hz, 1H), 3.18 - 2.94 (m, 2H), 1.36 (s, 9H), 0.56 - 0.44 (m, 4H); LCMS: m / z =578.5 [M+H] + 。

[0214] Step 3: Synthesis of Compound 011-3 011-2 (110 mg, 190.46 μmol) was dissolved in dichloromethane (2.1 mL), then trifluoroacetic acid (9.42 mmol, 0.7 mL) was added and reacted at 24 °C for 1 hour. The obtained reaction solution was concentrated under reduced pressure to obtain a crude product of the trifluoroacetate salt of 011-3, which was directly used in the reaction of the next step. LCMS: m / z=478.4 [M+H] + 。

[0215] Step 4: Synthesis of Compound 011-4 011-3 (80 mg, crude product of trifluoroacetate) was dissolved in dichloromethane (2 mL). Under a nitrogen gas atmosphere, 1H-benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (130.80 mg, 251.34 μmol) and N,N-diisopropylethylamine (837.81 μmol, 145.93 μL) were added, and the mixture was stirred at 24 °C for 12 hours. 5 mL of water was added to the reaction solution to quench the reaction system, and the mixture was extracted with 10 mL of dichloromethane. After liquid separation, the organic phase was collected, and the aqueous phase was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed successively with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin-layer chromatography silica gel plate (DCM:MeOH = 20:1) to obtain 011-4. 1 H NMR (400 MHz, CDCl3) δ ppm 8.59 (br s, 1H), 8.31 (s, 1H), 8.12 (s, 1H), 6.97 - 6.88 (m, 2H), 6.82 (dd, J = 4.4, 8.8 Hz, 1H), 6.20 - 5.83 (m, 2H), 4.73 (br d, J = 10.0 Hz, 2H), 4.33 - 4.30 (m, 1H), 4.18 - 4.13 (m, 1H), 4.01 (br dd, J = 1.7, 14.1 Hz, 1H), 3.71 (d, J = 4.3 Hz, 1H), 3.38 (br d, J = 9.6 Hz, 1H), 2.95 (br dd, J = 2.6, 13.8 Hz, 1H), 0.88 - 0.65 (m, 4H); LCMS: m / z =460.4 [M+H] + 。

[0216] Step 5: Synthesis of Compound 011-5 011-4 (76 mg, 165.43 μmol) and Lawesson's reagent (267.64 mg, 661.70 μmol) were added to 1,2-xylene (2 mL), and the mixture was stirred at 140 °C for 7 hours under a nitrogen gas atmosphere. 10 mL of water was added to the reaction solution to quench the reaction system, and the mixture was extracted with 20 mL of dichloromethane. After liquid separation, the organic phase was collected, and the aqueous phase was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed successively with saturated sodium carbonate solution (20 mL × 3) and saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin-layer chromatography silica gel plate (PE:EA = 1:2) to obtain 011-5. 1 H NMR (400 MHz, CDCl3) δ ppm 10.17 (br s, 1H), 8.65 (s, 1H), 8.11 (s, 1H), 6.99 - 6.88 (m, 2H), 6.82 (dd, J = 4.5, 9.0 Hz, 1H), 6.21 - 5.85 (m, 2H), 4.80 (d, J = 9.4 Hz, 1H), 4.71 (d, J = 11.4 Hz, 1H), 4.45 - 4.22 (m, 3H), 4.16 (d, J = 15.3 Hz, 1H), 3.37 - 3.27 (m, 2H), 1.00 - 0.81 (m, 3H), 0.74 (td, J = 4.8, 9.5 Hz, 1H); LCMS: m / z =476.4 [M+H] + 。

[0217] Step 6: Synthesis of Compound 011 011-5 (35 mg, 73.61 μmol), methoxyamine hydrochloride (1.18 mmol, 89.42 μL), triethylamine (1.03 mmol, 143.44 μL) and mercury(II) oxide (136.79 mg, 631.56 μmol) were dissolved in N,N-dimethylformamide (3.5 mL) and stirred at 60 °C for 3 h under a nitrogen gas atmosphere. The mixture was filtered through diatomaceous earth, and the reaction solution was filtered. The cake was washed with dichloromethane solution (20 mL × 3), and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by prep-HPLC (column: Waters Xbridge BEH C18 50×2.1 mm×5 μm, mobile phase A: 10 mM aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile, the ratio of phase B increased from 10% to 80% in the first 4.5 min, maintained for 0.9 min, and gradually decreased to 10% in the last 0.6 min) to obtain Compound 011. After the reaction solution was filtered, the cake was added to hydrochloric acid (2 M, 30 mL) and soaked overnight. Then, the pH was adjusted to 10 with sodium hydroxide (2 M), sodium sulfide solid (1 g) was added to form a precipitate, and ferrous sulfate (1 g) was further added as a coprecipitant. After standing, the mixture was filtered, the cake was discarded, and the filtrate was adjusted to pH 7 - 8 with hydrochloric acid (1 M) and then discarded. 1 H NMR (400 MHz, CDCl3) δ ppm 8.85 (br s, 1H), 8.11 (s, 1H), 6.97 - 6.85 (m, 2H), 6.80 (br d, J = 3.5 Hz, 1H), 6.18 - 5.82 (m, 2H), 4.84 - 4.61 (m, 2H), 4.29 (br s, 2H), 4.15 - 4.04 (m, 1H), 3.99 - 3.90 (m, 1H), 3.86 (s, 3H), 3.29 (br d, J = 9.3 Hz, 1H), 2.85 - 2.66 (m, 1H), 0.93 - 0.63 (m, 4H); LCMS: m / z = 489.4 [M+H] + 。

[0218] Example 12

Chemical Structure

[0219] Step 1: Synthesis of Compound 012-2 012-1 (2.5 g, 14.92 mmol), 3,4-dihydro-2H-pyran (5.46 mL, 59.67 mmol), and pyridinium p-toluenesulfonate (224.9 mg, 0.89 mmol) were added to toluene (25 mL), and the mixture was stirred at 100 °C for 12 h under a nitrogen gas atmosphere. Then, 3,4-dihydro-2H-pyran (5.46 mL, 59.67 mmol) and pyridinium p-toluenesulfonate (112.5 mg, 0.45 mmol) were added, and the reaction was continued for 6 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting crude product was separated by column chromatography (mobile phase: PE:EA = 1:0~1:1) to obtain 012-2. 1 H NMR (400 MHz, CDCl3) δ ppm 7.85 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 5.89 (dd, J = 2.8, 11.2 Hz, 1H), 4.21 - 4.17 (m, 1H), 3.80 - 3.74 (m, 1H), 2.78 (s, 3H), 2.38 - 2.34 (m, 1H), 2.08 - 2.07 (m, 1H), 1.94 - 1.91 (m, 1H), 1.82 - 1.77 (m, 2H), 1.76 - 1.67 (m, 1H); LCMS: m / z = 252.1 [M+H] + 。

[0220] Step 2: Synthesis of Compound 012-3 To 012-2 (1.0 g, 3.97 mmol), B-8 (1.07 g, 4.77 mmol) and sodium tert-butoxide (0.76 g, 7.95 mmol), 1,4-dioxane (15 mL) was added. Under the atmosphere of nitrogen gas, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (0.21 g, 0.40 mmol) and palladium acetate (44.6 mg, 0.20 mmol) were added, and the mixture was stirred at 80 °C for 12 h. The reaction solution was cooled to room temperature, 20 mL of water was added to quench the reaction system, and the mixture was extracted with dichloromethane (20 mL×3). After liquid separation, the organic phase was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase: PE:EA = 1:0~0:1) to obtain 012-3. 1 H NMR (400 MHz, CDCl3) δ ppm 7.66 (d, J = 8.4 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H), 6.23 - 5.92 (m, 1H), 5.69-5.65 (m, 1H), 4.75 (dd, J = 5.6, 8.4 Hz, 1H), 4.55 - 4.40 (m, 1H), 4.20 - 4.17 (m, 1H), 3.97 - 3.79 (m, 1H), 3.78 - 3.72 (m, 2H), 2.67 (s, 3H), 2.10 - 2.05 (m, 1H), 1.90 - 1.87 (m, 1H), 1.78 - 1.63 (m, 3H), 0.92 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H); LCMS: m / z = 441.3 [M+H] + 。

[0221] Step 3: Synthesis of compound 012-4 012-3 (1.05 g, 2.38 mmol) and sodium acetate (1.27 g, 15.49 mmol) were added to acetic acid (25 mL), cooled to 0 °C under a nitrogen gas atmosphere, pyridinium tribromide (1.14 g, 3.57 mmol) was added, and the temperature was slowly raised to 25 °C and stirred for 2 hours. 200 mL of saturated sodium thiosulfate was added to the reaction solution to quench the reaction system, then 50 mL of water was added and stirred for 30 minutes. It was extracted with dichloromethane (50 mL), and after liquid separation, the organic phase was collected. The aqueous phase was extracted with dichloromethane (50 mL × 3), the organic phases were combined, washed successively with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 012-4. LCMS: m / z = 519.2, 521.2 [M+H] + 。

[0222] Step 4: Synthesis of compound 012-5 012-4 (1.2 g, 2.31 mmol) and tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 3.46 mL) were added to tetrahydrofuran (18.75 mL), and stirred at 20 °C for 12 hours under a nitrogen gas atmosphere. The obtained reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was separated and purified by column chromatography (mobile phase: PE:EA = 1:0~1:1) to obtain 012-5. 1 H NMR (400 MHz, CDCl3) δ ppm 7.93 (d, J = 2.4 Hz, 1H), 6.33 - 6.05 (m, 1H), 5.60 - 5.53 (m, 2H), 4.55 - 4.45 (m, 1H), 4.20 - 4.14 (m, 2H), 4.12 - 4.00 (m, 1H), 3.74 - 3.68 (m, 1H), 2.65 - 2.52 (m, 5H), 2.11 - 2.05 (m, 1H), 1.88 - 1.85 (m, 1H), 1.77 - 1.63 (m, 3H); LCMS: m / z = 405.1, 407.0 [M+H] + 。

[0223] Step 5: Synthesis of compound 012-6 012-5 (0.25 g, 0.62 mmol) and cesium carbonate (0.26 g, 0.80 mmol) were added to 1,4-dioxane (6.25 mL). Under an atmosphere of nitrogen gas, 2-(di-tert-butylphosphino)-1,1'-binaphthyl (0.1 g, 0.25 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.11 g, 0.12 mmol) were added. The temperature was slowly raised to 88 °C and stirred for 1 hour, then raised to 100 °C and stirred for 1 hour, and further raised to 115 °C and stirred for 12 hours. It was slowly cooled to room temperature, and the resulting reaction solution was concentrated under reduced pressure. The crude product was separated and purified by column chromatography (mobile phase: PE:EA = 1:0 to 0:1) to obtain 012-6. LCMS: m / z = 325.1 [M+H] + 。

[0224] Step 6: Synthesis of compound 012-7 012-6 (0.10 g, 0.31 mmol), B-4 (0.15 g, 0.46 mmol) and tetrabutylammonium iodide (29.6 mg, 0.08 mmol) were added to N,N-dimethylformamide (2.0 mL). Under an atmosphere of nitrogen gas, cesium carbonate (0.30 g, 0.93 mmol) was added. The temperature was raised to 40 °C and stirred for 16 hours. The reaction solution was cooled to room temperature, 10 mL of water was added to the reaction solution to quench the reaction system, and it was extracted with ethyl acetate (10 mL × 3). After liquid separation, the organic phase was collected, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was separated and purified by column chromatography (mobile phase: PE:EA = 1:0 to 0:1) to obtain 012-7. LCMS: m / z = 620.3 [M+H] + 。

[0225] Step 7: Synthesis of compound 012-8 012-7 (0.15 g, 0.24 mmol) was added to a hydrochloric acid ethyl acetate solution (4.0 M, 3.03 mL), and stirred at 20 °C for 0.5 hour. The resulting reaction solution was concentrated under reduced pressure to obtain a crude product of the hydrochloride salt of 012-8, which was directly used in the next step. LCMS: m / z = 436.1 [M+H] + 。

[0226] Step 8: Synthesis of Compound 012 012-8 (0.07 g, crude product of hydrochloride) was added to dichloromethane (3.5 mL), cooled to 0 °C under a nitrogen gas atmosphere, and a solution of N,N'-carbonyldiimidazole (48.1 mg, 0.30 mmol) in dichloromethane (0.7 mL) and 4-dimethylaminopyridine (5.4 mg, 0.45 mmol) were slowly added dropwise. The temperature was slowly raised to 25 °C and stirred for 12.0 hours. 10% aqueous citric acid solution (10 mL) was added to the reaction solution, the pH value was adjusted to about 6, extracted with dichloromethane (10 mL × 2), and after liquid separation, the organic phase was collected and concentrated under reduced pressure to obtain a crude product. The crude product was purified by a thin layer chromatography silica gel plate (PE:EA = 0:1), and further separated and purified by preparative high performance liquid chromatography (column model: Waters Xbridge Prep OBD C18 column, 150×40 mm×10 m; mobile phase: phase A (10 mM aqueous ammonium bicarbonate solution), phase B: acetonitrile, gradient: phase B increases from 25% to 65% in 8 minutes) to obtain 012. LCMS: m / z = 462.3 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ ppm 10.32 (s, 1H), 7.36 (s, 1H), 7.02 - 7.00 (m, 1H), 6.95 - 6.94 (m, 1H), 6.83 - 6.81 (m, 1H), 6.05 - 5.77 (m, 2H), 4.67 - 4.64 (m, 1H), 4.25 - 4.20 (m, 2H), 4.16 - 4.06 (m, 1H), 4.04 - 3.91 (m, 2H), 2.81 (s, 3H), 1.75 (s, 3H), 1.68 (s, 3H).

[0227] Example 13

Chemical Structure

[0228] Step 1: Synthesis of Compound 013-1 B-6 (0.26 g, 0.77 mmol) and 007-6 (0.12 g, 0.39 mmol) were dissolved in N,N-dimethylformamide (8 mL). Next, cesium carbonate (0.19 g, 0.58 mmol) was added, and the mixture was stirred at 5 °C for 4 hours, then warmed to 20 °C and reacted for 12 hours. 20 mL of water was added to the reaction solution to quench the reaction system, and the mixture was extracted with dichloromethane (100 mL × 2). After liquid separation, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin-layer chromatography (PE:EA = 0:1) to obtain 013-1. 1 H NMR (400 MHz, CDCl3) δ ppm 8.01 (br d, J = 8.1 Hz, 1H), 7.90 (s, 1H), 7.65 (br d, J = 8.1 Hz, 1H), 7.48 (s, 1H), 6.10 - 5.75 (m, 1H), 5.68 - 5.55 (m, 1H), 5.31 (s, 1H), 4.58 - 4.42 (m, 3H), 4.35 (s, 1H), 4.25 - 4.18 (m, 1H), 3.90 (br s, 1H), 3.77 (br s, 1H), 2.06 (s, 3H), 1.77 - 1.73 (m, 1H), 1.71 (br d, J = 2.8 Hz, 1H), 1.67 (br s, 1H), 1.62 - 1.55 (m, 2H), 1.43 (s, 9H), 1.39 (d, J = 9.7 Hz, 6H); LCMS: m / z = 607.4 [M+H] + 。

[0229] Step 2: Synthesis of compound 013-2 013-1 (0.1 g, 0.16 mmol) and hydrochloric acid methanol solution (4 M, 31.25 mL) were added to the reaction flask, and the mixture was stirred at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product of the hydrochloride salt of 013-2, which was directly used in the next step without purification. 11H NMR (400 MHz, CD3OD) δ ppm 9.04 (s, 1H), 7.93 (d, J = 2.8 Hz, 1H), 7.57 (s, 1H), 7.44 (dd, J = 2.3, 8.9 Hz, 1H), 6.21 (dt, J = 4.5, 55.2 Hz, 1H), 5.24 (br d, J = 17.4 Hz, 1H), 4.94 (br s, 1H), 4.70 (br d, J = 11.8 Hz, 1H), 4.54 - 4.47 (m, 1H), 4.44 - 4.38 (m, 1H), 4.28 - 4.14 (m, 2H), 1.50 (d, J = 2.6 Hz, 6H); LCMS: m / z = 423.2 [M+H] + 。

[0230] Step 3: Synthesis of Compound 013 Dissolve 013-2 (40 mg, crude product of hydrochloride) in dichloromethane (0.4 mL), cool to 0 °C, and then slowly add dropwise a solution of N,N'-carbonyldiimidazole (18.43 mg, 113.64 μmol) in dichloromethane (0.2 mL) and 4-dimethylaminopyridine (2.31 mg, 18.94 μmol), and stir at 25 °C for 3 hours. Add water (10 mL) to the reaction solution to quench the reaction system, extract with dichloromethane (10 mL × 3), separate the layers, combine the organic phases, wash successively with saturated brine (10 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by thin-layer chromatography (PE:EA = 0:1), and further separated and purified by preparative high-performance liquid chromatography [column: Phenomenex Luna C18 column, 100 × 30 mm × 3 μm; mobile phase: phase A (0.2% aqueous trifluoroacetic acid solution), phase B: acetonitrile, gradient: phase B increases from 40% to 70% in 8 minutes] to obtain 013. 11H NMR (400 MHz, CDCl3) δ ppm 9.95 (broad singlet, 1H), 8.40 (singlet, 1H), 7.95 (doublet, J = 2.9 Hz, 1H), 7.50 (singlet, 1H), 7.37 (doublet of doublets, J = 2.6, 7.9 Hz, 1H), 5.95 (doublet of triplets, J = 6.8, 55.5 Hz, 1H), 5.58 (broad doublet, J = 15.8 Hz, 1H), 4.86 (doublet, J = 10.6 Hz, 1H), 4.68 (broad doublet, J = 11.6 Hz, 1H), 4.30 - 4.17 (multiplet, 3H), 3.97 (doublet, J = 10.8 Hz, 1H), 1.77 (singlet, 3H), 1.68 (singlet, 3H); LCMS: m / z = 449.1 [M+H] + 。

[0231] Example 14

Chemical formula

[0232] Step 1: Synthesis of Compound 014-1 007-6 (0.14 g, 0.45 mmol), B-10 (0.14 g, 0.68 mmol) and cesium carbonate (0.29 g, 0.90 mmol) were dissolved in N,N-dimethylformamide (1.0 mL) and stirred at 20 °C for 12 hours. The resulting reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was separated and purified by thin layer chromatography (PE:EA = 0:1) to obtain 014-1. LCMS: m / z = 475.2 [M+H] + 。

[0233] Step 2: Synthesis of Compound 014-2 014-1 (0.16 g, 0.34 mmol) and 1,3-dimethylbarbituric acid (0.11 g, 0.67 mmol) were added to ethanol (3.0 mL). Under a nitrogen gas atmosphere, tetrakis(triphenylphosphine)palladium(0) was added, and the mixture was stirred at 40 °C for 12 hours. The resulting reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was separated and purified by thin-layer chromatography (PE:EA = 0:1) to obtain 014-2. LCMS: m / z = 435.2 [M+H] + 。

[0234] Step 3: Synthesis of compound 014-3 B-11 (80.3 mg, 0.32 mmol), 014-2 (0.14 g, 0.32 mmol) and cesium carbonate (0.26 g, 0.81 mmol) were added to N,N-dimethylformamide (3.0 mL), and the mixture was stirred at 70 °C for 12 hours. Water (10 mL) was added to the reaction solution to quench the reaction system, and the mixture was extracted with ethyl acetate (5 mL × 3). After liquid separation, the organic phases were combined, washed successively with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by thin-layer chromatography (ethyl acetate:methanol = 10:1) to obtain 014-3.

[0235] Step 4: Synthesis of compound 014-4 Ethyl acetate (0.2 mL) was added to 014-3 (80.0 mg, 0.13 mmol) and hydrochloric acid ethyl acetate solution (4 M, 0.83 mL), and the mixture was stirred at 20 °C for 1 hour. The resulting reaction solution was concentrated under reduced pressure to obtain a crude product of the hydrochloride salt of 014-4, which was directly used in the next step. LCMS: m / z = 420.1 [M+H] + 。

[0236] Step 5: Synthesis of compound 014 014-4 (45.0 mg, crude product of hydrochloride) and dichloromethane (0.5 mL) were added to a reaction flask, cooled to 0 °C under a nitrogen gas atmosphere, and a solution of N,N'-carbonyldiimidazole (48.0 mg, 0.3 mmol) in dichloromethane (0.1 mL) and 4-dimethylaminopyridine (36.2 mg, 0.3 mmol) were slowly added dropwise at 0 °C. Then, the temperature was slowly raised to 25 °C and stirred for 1 hour. Water (2 mL) was added to the reaction solution to quench the reaction system, and the mixture was extracted with dichloromethane (2 mL × 3). After liquid separation, the organic phases were combined, washed successively with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by thin-layer chromatography (dichloromethane:ethyl acetate = 1:1), and further separated and purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 column, 100 × 30 mm × 10 m; mobile phase: phase A (10 mM aqueous ammonium hydrogen carbonate solution), phase B: acetonitrile, gradient: phase B increased from 25% to 55% in 8 minutes) to obtain 014. 1 H NMR (400 MHz, CDCl3) δ ppm 10.36 (s, 1H), 8.31 (s, 1H), 7.48 (s, 1H), 6.94 - 6.90 (m, 2H), 6.76 - 6.74 (m, 1H), 5.96 - 5.80 (m, 2H), 4.68 (d, J = 10.8 Hz, 1H), 4.45 (d, J = 8.4 Hz, 1H), 4.26 - 4.25 (m, 2H), 4.23 (d, J = 8.4 Hz, 1H), 3.79 (d, J = 9.2 Hz, 1H), 2.27 - 2.23 (m, 1H), 1.15 - 1.05 (m, 2H), 0.99 - 0.96 (m, 1H); LCMS: m / z = 446.2 [M+H] + 。

[0237] Example 15

Chemical Structure

[0238] Step 1: Synthesis of Compound 015-1 006-3 (0.27 g, 0.86 mmol) and B-6 (0.43 g, 1.30 mmol) were dissolved in N,N-dimethylformamide (3.0 mL). Next, cesium carbonate (0.85 g, 2.59 mmol) was added, and the mixture was stirred at 25 °C for 3 hours. Water (10 mL) was added to the reaction solution to quench the reaction system, and the mixture was extracted with ethyl acetate (30 mL × 3). After liquid separation, the organic phases were combined, washed successively with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1~1:1) to obtain 015-1. 1 H NMR (400 MHz, CDCl3) δ ppm 8.39 - 8.32 (m, 1H), 8.01 (s, 1H), 7.91 (d, J = 3.1 Hz, 1H), 6.17 - 5.79 (m, 1H), 5.53 (d, J = 14.5 Hz, 1H), 4.67 - 4.60 (m, 1H), 4.58 - 4.51 (m, 2H), 4.50 - 4.39 (m, 3H), 4.37 - 4.25 (m, 1H), 3.96 - 3.87 (m, 1H), 2.64 - 2.58 (m, 3H), 1.45 - 1.36 (m, 19H); LCMS: m / z = 631.2 [M+Na] + 。

[0239] Step 2: Synthesis of Compound 015-2 015-1 (0.36 g, 0.59 mmol), an aqueous solution of lithium hydroxide monohydrate (2 M, 20 mL), and sodium hydroxide (47.3 mg, 1.18 mmol) were added to tetrahydrofuran (7.2 mL), methanol (7.2 mL), and ethanol (14.4 mL), and the mixture was stirred at 30 °C for 40 hours. Water (2 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (10 mL) and separated. The resulting aqueous phase was adjusted to pH approximately 3 with 2 M hydrochloric acid, extracted with dichloromethane (10 mL × 3), separated, the organic phases were combined, washed successively with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 015-2. LCMS: m / z = 581.3 [M+H] + 。

[0240] Step 3: Synthesis of Compound 015-3 015-2 (80 mg, 137.80 μmol) was added to trifluoroacetic acid (4 mL), and the mixture was stirred at 25 °C for 0.5 hour and concentrated under reduced pressure to obtain a crude product of 015-3, which was used directly in the next step. LCMS: m / z = 481.3 [M+H] + 。

[0241] Step 4: Synthesis of Compound 015 015-3 (80.0 mg, crude product) was dissolved in dichloromethane (2 mL), and then N,N-diisopropylethylamine (1.67 mmol, 290.03 μL) and pentafluorophenyldiphenylphosphinate (96.0 mg, 0.25 mmol) were added sequentially. The mixture was stirred at 25 °C for 12 h. The reaction system was quenched with 10 mL of water and extracted with dichloromethane (20 mL). After liquid separation, the organic phase was collected. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed successively with saturated sodium carbonate solution (20 mL × 3) and saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by thin-layer chromatography (PE:EA = 1:1), and further separated and purified by preparative high-performance liquid chromatography (column: Waters Xbridge Prep OBD C18 column 150 × 40 mm × 10 m; mobile phase: phase A was 10 mM aqueous ammonium bicarbonate solution, and phase B was acetonitrile; gradient: phase B increased from 25% to 55% in 8 min) to obtain 015. 1 H NMR (400 MHz, CDCl3) δ 8.95 (br s, 1H), 8.02 (br d, J = 27.9 Hz, 2H), 7.39 - 7.29 (m, 1H), 6.22 - 5.85 (m, 1H), 5.72 (br d, J = 15.4 Hz, 1H), 4.88 - 4.66 (m, 2H), 4.34 - 4.20 (m, 3H), 3.88 (br d, J = 10.1 Hz, 1H), 1.78 (br s, 3H), 1.62 (br d, J = 11.4 Hz, 6H); LCMS: m / z = 463.2 [M+H] + 。

[0242] Example 16

Chemical Structure

[0243] Step 1: Synthesis of Compound 016-1 006-3 (0.27 g, 0.86 mmol) and B-9 (0.31 g, 0.95 mmol) were dissolved in N,N-dimethylformamide (5.4 mL). Next, cesium carbonate (0.85 g, 2.59 mmol) was added, and the mixture was stirred at 25 °C for 12 hours. Water (10 mL) was added to the reaction solution to quench the reaction system, and the mixture was extracted with ethyl acetate (20 mL). The aqueous phase was further extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed successively with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1 to 1:1) to obtain 016-1. 1 H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.62 (br d, J = 6.3 Hz, 1H), 6.95 (dt, J = 3.1, 8.4 Hz, 1H), 6.76 (dd, J = 4.3, 9.0 Hz, 1H), 6.16 - 5.91 (m, 1H), 5.88 - 5.82 (m, 1H), 5.06 (br s, 1H), 4.56 - 4.47 (m, 2H), 4.43 (q, J = 7.1 Hz, 2H), 4.33 - 4.24 (m, 1H), 4.05 (d, J = 9.8 Hz, 1H), 3.90 - 3.78 (m, 2H), 2.62 (s, 3H), 1.45 - 1.41 (m, 12H), 0.87 (br dd, J = 5.1, 9.8 Hz, 1H), 0.80 - 0.68 (m, 3H); LCMS: m / z = 606.4 [M+H] + 。

[0244] Step 2: Synthesis of Compound 016-2 016-1 (0.37 g, 0.61 mmol), an aqueous solution of lithium hydroxide monohydrate (2 M, 24.7 mL), and sodium hydroxide (48.9 mg, 1.22 mmol) were dissolved in tetrahydrofuran (12.3 mL), methanol (12.3 mL), and ethanol (24.7 mL), and stirred at 35 °C for 55 hours. Water (2 mL) was added to the reaction mixture, and the mixture was washed with dichloromethane (20 mL) and separated. The resulting aqueous phase was adjusted to pH about 3 with 2 M hydrochloric acid, extracted with dichloromethane (20 mL × 3), separated, and the organic phases were combined, washed successively with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain 016-2. 1 1H NMR (400 MHz, CDCl3) δ 10.27 - 9.95 (m, 1H), 8.11 (s, 1H), 7.10 (dd, J = 2.9, 8.4 Hz, 1H), 6.97 (dt, J = 3.0, 8.4 Hz, 1H), 6.80 (dd, J = 4.3, 9.0 Hz, 1H), 6.15 - 5.86 (m, 1H), 5.66 (br d, J = 15.1 Hz, 1H), 4.95 - 4.78 (m, 2H), 4.63 - 4.51 (m, 2H), 4.15 - 3.90 (m, 6H), 1.41 (br s, 9H), 0.97 (br d, J = 6.5 Hz, 2H), 0.83 - 0.80 (m, 2H); LCMS: m / z = 578.3 [M+H] + 。

[0245] Step 3: Synthesis of compound 016-3 016-2 (0.17 g, 0.29 mmol) and TFA (13.5 mmol, 1 mL) were added to dichloromethane (2.0 mL), stirred at 25 °C for 0.5 hour, concentrated under reduced pressure to obtain a crude product of 016-3, and used directly in the next step. LCMS: m / z = 478.3 [M+H] + 。

[0246] Step 4: Synthesis of Compound 016 After dissolving 016-3 (95.0 mg, crude product) in dichloromethane (2 mL), N,N-diisopropylethylamine (1.99 mmol, 346.6 μL) and pentafluorophenyl diphenylphosphinate (114.7 mg, 0.30 mmol) were sequentially added, and the mixture was stirred at 25 °C for 2 hours. 5 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL). After liquid separation, the organic phase was collected. The aqueous phase was further extracted with dichloromethane (10 mL × 3), and the combined organic phases were washed successively with saturated sodium carbonate solution (20 mL × 3) and saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by thin-layer chromatography (PE:EA = 0:1), and further separated and purified by preparative high-performance liquid chromatography (column: Waters Xbridge Prep OBD C18 column, 150 × 40 mm × 10 m; mobile phase: phase A: 10 mM aqueous ammonium hydrogen carbonate solution, phase B: acetonitrile; gradient: phase B increases from 30% to 65% in 8 minutes) to obtain 016. 1 H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.01 (s, 1H), 6.98 - 6.85 (m, 2H), 6.73 (dd, J = 4.5, 9.0 Hz, 1H), 6.18 - 5.87 (m, 2H), 4.70 (br d, J = 11.4 Hz, 1H), 4.43 (d, J = 9.3 Hz, 1H), 4.33 - 4.22 (m, 2H), 4.14 (d, J = 15.3 Hz, 1H), 3.67 (d, J = 9.3 Hz, 1H), 2.58 (s, 3H), 2.28 - 2.16 (m, 1H), 1.08 - 0.97 (m, 2H), 0.84 - 0.74 (m, 1H) LCMS: m / z = 460.2 [M+H] + 。

[0247] Example 17

Chemical Structure

[0248] Example 18

Chemical formula

[0249] Step 1: Synthesis of Compound 018-1 009-8 (0.3 g, 0.8 mmol) was added to acetonitrile (0.2 mL), and after being replaced with nitrogen gas three times, (2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) methanesulfonate (67.3 mg, 0.08 mmol) and cesium carbonate (0.52 g, 1.6 mmol) were added. After slowly heating to 80 °C, a solution of propargyl (1 M, 2.39 mL) in acetonitrile (0.2 mL) was added, and the reaction was carried out for 12 hours. After cooling to room temperature, water (5.0 mL) was added to the reaction solution to quench the reaction system, and the mixture was extracted with dichloromethane (5.0 mL × 3). The organic phases were combined, washed successively with saturated brine (10.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain 018-1. LCMS: m / z = 337.2 [M+H] + 。

[0250] Step 2: Synthesis of Compound 018-2 018-1 (0.13 g, 0.39 mmol) and B-4 (0.19 g, 0.58 mmol) were dissolved in N,N’-dimethylformamide (2.0 mL), and then cesium carbonate (0.38 g, 1.16 mmol) was added. The mixture was stirred at 25 °C for 2 hours under a nitrogen gas atmosphere. Water (2.0 mL) was added to the reaction solution to quench the reaction system, and the mixture was extracted with ethyl acetate (10.0 mL × 3). The organic phases were combined, washed successively with saturated brine (10.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain 018-2. 11H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.68 - 7.53 (m, 1H), 7.02 - 6.91 (m, 1H), 6.90 - 6.79 (m, 1H), 6.13 - 5.77 (m, 2H), 4.55 - 4.36 (m, 5H), 4.28 - 4.15 (m, 2H), 4.04 - 3.93 (m, 1H), 3.91 - 3.79 (m, 1H), 2.18 (s, 3H), 1.62 - 1.56 (m, 3H), 1.41 (brs, 9H), 1.36 (brs, 3H), 1.32 (brs, 3H); LCMS: m / z = 632.3 [M+H] + 。

[0251] Step 3: Synthesis of Compound 018-3 018-2 (0.1 g, 0.16 mmol) was added to a mixed solution of ethanol (2 mL), tetrahydrofuran (1 mL) and methanol (1 mL), then lithium hydroxide (95.8 mg, 4.0 mmol) was added, and the reaction was carried out at 30 °C for 24 hours. Water (5 mL) was added to the reaction solution to quench the reaction system, the pH value was adjusted to about 5 with 2 M hydrochloric acid, and the mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phases were successively washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin layer chromatography (PE:EA = 1:1) to obtain 018-3. LCMS: m / z = 604.3 [M+H] + 。

[0252] Step 4: Synthesis of Compound 018-4 018-3 (55 mg, 91.12 μmol) was dissolved in dichloromethane (1 mL), then trifluoroacetic acid (0.3 mL) was added, and the reaction was carried out at 20 °C for 2 hours. The trifluoroacetic acid was evaporated under reduced pressure to remove, and the crude product of 018-4 was obtained, which was directly used in the reaction of the next step without purification. LCMS: m / z = 504.3 [M+H] + 。

[0253] Step 5: Synthesis of Compound 018 018-4 (50.0 mg, 99.31 μmol) was dissolved in dichloromethane (0.1 mL), and then N,N-diisopropylethylamine (0.5 mmol, 86.5 μL) and pentafluorophenyl diphenylphosphinate (57.2 mg, 0.15 mmol) were sequentially added, followed by stirring at 20 °C for 3 hours. 5 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were washed successively with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin-layer chromatography (PE:EA = 0:1), and then further purified by preparative high-performance liquid chromatography (column: Waters Xbridge Prep OBD C18 column, 150 × 40 mm × 10 m; mobile phase: phase A: 10 mM aqueous ammonium bicarbonate solution, phase B: acetonitrile; gradient: phase B increased from 35% to 65% in 8 minutes) to obtain 018. 1 H NMR (400 MHz, CDCl3) δ 9.20 (br s, 1H), 8.03 (s, 1H), 7.03 - 6.92 (m, 2H), 6.89 - 6.81 (m, 1H), 6.19 - 5.85 (m, 2H), 4.72 (br d, J = 11.9 Hz, 1H), 4.39 - 4.18 (m, 3H), 3.98 - 3.86 (m, 2H), 2.17 (s, 3H), 1.81 (s, 3H), 1.61 (s, 3H); LCMS: m / z = 486.3 [M+H] + 。

[0254] Example 19

Chemical Structure

[0255] Step 1: Synthesis of Compound 019-1 009-8 (0.3 g, 0.8 mmol) was added to acetonitrile (6.0 mL), and after purging three times with nitrogen gas, (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (67.3 mg, 0.08 mmol) and cesium carbonate (0.52 g, 1.6 mmol) were added. After slowly heating to 80 °C, a solution of (triisopropylsilyl)acetylene (535.4 μL, 2.39 mmol) in acetonitrile (6.0 mL) was added, and the mixture was reacted for 12 hours. The resulting reaction solution was evaporated under reduced pressure to remove acetonitrile, and was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain 019-1. LCMS: m / z = 479.3 [M+H] + 。

[0256] Step 2: Synthesis of Compound 019-2 019-1 (0.26 g, 0.54 mmol) and B-4 (0.22 g, 0.65 mmol) were dissolved in N,N-dimethylformamide (2.6 mL), and then cesium carbonate (0.53 g, 1.63 mmol) was added. The mixture was stirred at 20 °C for 2 hours. Water (10 mL) was added to the reaction solution to quench the reaction system, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed successively with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain 019-2. 11H NMR (400 MHz, CDCl3) δ ppm 8.04 (s, 1H), 7.70 - 7.56 (m, 1H), 7.00 - 6.91 (m, 1H), 6.89 - 6.80 (m, 1H), 6.13 - 5.78 (m, 2H), 4.53 - 4.40 (m, 5H), 4.31 - 4.22 (m, 1H), 4.18 (br d, J = 9.0 Hz, 1H), 4.00 - 3.91 (m, 1H), 3.86 (br d, J = 11.7 Hz, 1H), 1.42 - 1.38 (m, 12H), 1.37 - 1.31 (m, 9H), 1.19 (s, 18H), LCMS: m / z = 774.4 [M+H] + 。

[0257] Step 3: Synthesis of Compound 019-3 019-2 (0.13 g, 0.17 mmol) was added to a solution of ethanol (2.6 mL), tetrahydrofuran (1.3 mL) and methanol (1.3 mL), and then a mixed solvent solution of sodium hydroxide (2 M, 2.6 mL) was added. The mixture was stirred at 30 °C for 24 h. After the reaction solution was cooled to 0 °C, water (5 mL) was added to quench the reaction system. The pH value was adjusted to about 7 with 2 M hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed successively with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by thin layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 019-3. LCMS: m / z = 590.3 [M+H] + 。

[0258] Step 4: Synthesis of Compound 019-4 019-3 (35.0 mg, 59.4 μmol) was dissolved in dichloromethane (1 mL), and then trifluoroacetic acid (0.3 mL) was added. The mixture was stirred at 20 °C for 1 h. Trifluoroacetic acid was evaporated and removed under reduced pressure to obtain a crude product of 019-4, which was directly used in the next step reaction without purification. LCMS: m / z = 490.3 [M+H] + 。

[0259] Step 5: Synthesis of Compound 019 019-4 (25.0 mg, 51.1 μmol) was dissolved in dichloromethane (0.3 mL), and then pentafluorophenyldiphenylphosphinate (29.4 mg, 76.6 μmol) and N,N-diisopropylethylamine (33.0 mg, 255.4 μmol) were sequentially added, followed by stirring at 20 °C for 3 hours. Water (5 mL) was added to quench the reaction system, and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were washed successively with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:1), and then further purified by preparative high-performance liquid chromatography (column: Waters Xbridge BEH C18 column, 100 × 30 mm × 10 μm; mobile phase: phase A: 10 mM aqueous ammonium carbonate solution, phase B: acetonitrile; gradient: phase B increased from 35% to 65% in 8 minutes) to obtain 019. 1 H NMR (400 MHz, CDCl3) δ 9.19 (br s, 1H), 8.06 (br s, 1H), 7.08 - 6.72 (m, 3H), 6.23 - 5.79 (m, 2H), 4.73 (br d, J = 11.3 Hz, 1H), 4.44 - 4.17 (m, 3H), 4.05 - 3.82 (m, 2H), 3.46 (br s, 1H), 1.81 (br s, 3H), 1.62 (br s, 3H); LCMS: m / z = 472.3 [M+H] + 。

[0260] Example 20

Chemical Structure

[0261] Step 1: Synthesis of Compound 020-1 009-8 (0.4 g, 1.06 mmol) was added to acetonitrile (4.0 mL), and the mixture was purged with nitrogen gas three times. Then, (2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) methanesulfonate (89.8 mg, 0.106 mmol) and cesium carbonate (0.69 g, 2.12 mmol) were added. After slowly heating to 80 °C, a solution of cyclopropylacetylene (263.9 μL, 3.18 mmol) in acetonitrile (2.0 mL) was added, and the mixture was reacted for 12 hours. The resulting reaction solution was evaporated under reduced pressure to remove acetonitrile, and then separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain 020-1. LCMS: m / z = 363.2 [M+H] + 。

[0262] Step 2: Synthesis of compound 020-2 020-1 (0.24 g, 0.66 mmol) and B-4 (0.26 g, 0.79 mmol) were dissolved in N,N-dimethylformamide (4.0 mL), and then cesium carbonate (0.65 g, 1.99 mmol) was added. The mixture was stirred at 20 °C for 2 hours. Water (10 mL) was added to the reaction solution to quench the reaction system, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed successively with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 020-2. 1 H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.72 - 7.47 (m, 1H), 7.00 - 6.83 (m, 2H), 6.13 - 5.68 (m, 2H), 4.67 - 4.33 (m, 5H), 4.32 - 4.08 (m, 3H), 4.02 - 3.93 (m, 1H), 3.89 - 3.78 (m, 1H), 1.44 - 1.31 (m, 18H), 1.01 - 0.86 (m, 4H); LCMS: m / z = 658.4 [M+H] + 。

[0263] Step 3: Synthesis of Compound 020-3 020-2 (0.17 g, 0.26 mmol) was added to a solution of ethanol (3.4 mL), tetrahydrofuran (1.7 mL), and methanol (1.7 mL). Next, a mixed solvent solution of potassium hydroxide (2 M, 3.4 mL) and sodium fluoride (21.7 mg, 0.52 mmol) was added, and the mixture was stirred at 30 °C for 60 hours. Water (10 mL) was added to the reaction solution to quench the reaction system, and the pH value was adjusted to 3-4 with 2 M hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed successively with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain 020-3. LCMS: m / z = 630.3 [M+H] + 。

[0264] Step 4: Synthesis of Compound 020-4 020-3 (80.0 mg, 127.1 μmol) was dissolved in dichloromethane (1.6 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at 20 °C for 0.5 hour. It was evaporated under reduced pressure to remove trifluoroacetic acid to obtain a crude product of the trifluoroacetate salt of 020-4, which was directly used in the reaction of the next step without purification. LCMS: m / z = 530.3 [M+H] + 。

[0265] Step 5: Synthesis of Compound 020 020-4 (67.0 mg, crude product of trifluoroacetate) was dissolved in dichloromethane (1.4 mL), and then 1H-benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (98.8 mg, 189.8 μmol) and N,N-diisopropylethylamine (110.2 μL, 632.7 μmol) were added sequentially. The mixture was stirred at 20 °C for 2 hours. Water (5 mL) was added to quench the reaction system, and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were washed successively with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:1), and then by preparative high-performance liquid chromatography (column: Phenomenex Luna C18 column, 75 × 30 mm × 3 μm; mobile phase: phase A: 0.2% aqueous formic acid solution, phase B: acetonitrile; gradient: phase B increases from 25% to 60% in 8 minutes) to obtain 020. 1 H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.01 (s, 1H), 7.04 - 6.93 (m, 2H), 6.85 (br dd, J = 4.4, 9.5 Hz, 1H), 6.20 - 5.83 (m, 2H), 4.71 (br d, J = 12.0 Hz, 1H), 4.40 - 4.32 (m, 1H), 4.28 (td, J = 1.8, 12.0 Hz, 1H), 4.22 (d, J = 15.1 Hz, 1H), 3.99 - 3.92 (m, 1H), 3.91 - 3.83 (m, 1H), 1.81 (s, 3H), 1.61 (s, 3H), 1.33 - 1.22 (m, 1H), 0.98 - 0.92 (m, 2H), 0.91 - 0.85 (m, 2H); LCMS: m / z = 512.3 [M+H] + 。

[0266] Example 21

Chemical Structure

[0267] Step 1: Synthesis of Compound 021-1 009-8 (329.0 mg, 0.87 mmol) and B-13 (299.9 mg, 0.87 mmol) were dissolved in N,N'-dimethylformamide (10 mL). Then, cesium carbonate (0.85 g, 2.62 mmol) was added, and the mixture was stirred at 20 °C for 4 hours. Water (30 mL) was added to the reaction solution for quenching, and the mixture was extracted with ethyl acetate (20 mL × 4). The combined organic phases were successively washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE:EA = 1:0 to 3:1) to obtain 021-1. LCMS: m / z = 584.1 [M + H - Boc] + 。

[0268] Step 2: Synthesis of Compound 021-2 021-1 (0.54 g, 0.78 mmol) was added to a mixed solution of methanol (5 mL), tetrahydrofuran (5 mL), and ethanol (10 mL). A mixed solvent solution of sodium hydroxide (2 M, 10.55 mL) was added, and the mixture was reacted at 30 °C for 24 hours. 1 M hydrochloric acid was added to the reaction solution to adjust the pH value to 3 - 4, and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were successively washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE:EA = 10:1 to 1:1) to obtain 021-2. LCMS: m / z = 556.3 [M + H - Boc] + 。

[0269] Step 3: Synthesis of Compound 021-3 021-2 (320 mg, 487.5 μmol) was dissolved in ethyl acetate (3.5 mL). A solution of hydrochloric acid in ethyl acetate (4 M, 0.32 mL) was added, and the mixture was reacted at 20 °C for 16 hours. It was evaporated under reduced pressure to remove hydrogen chloride gas to obtain a crude product of 021-3, which was directly used in the reaction of the next step without purification. LCMS: m / z = 556.0 [M + H] + 。

[0270] Step 4: Synthesis of Compound 021 021-3 (168.0 mg, 283.3 μmol) was dissolved in dichloromethane (8.0 mL), and then N,N-diisopropylethylamine (1.42 mmol, 246.8 μL) and pentafluorophenyl diphenylphosphinate (163.3 mg, 0.42 mmol) were added sequentially, followed by stirring at 20 °C for 3 hours. 20 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were washed successively with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE:EA = 10:1 to 2:1), and further purified by preparative chiral chromatography (column: DAICEL CHIRALCEL OJ column, 250 × 30 mm × 10 μm; mobile phase: phase A: supercritical carbon dioxide, phase B: 0.1% aqueous ammonia / ethanol solution, gradient: B was 40%, isobaric elution) to obtain 021. 1 H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 8.03 (s, 1H), 7.02 - 6.95 (m, 2H), 6.91 - 6.88 (m, 1H), 6.19 - 5.92 (m, 1H), 5.85 (dd, J = 1.2 Hz, 15.2 Hz, 1H), 4.73 (d, J = 11.6 Hz, 1H), 4.49 (d, J = 9.2 Hz, 1H), 4.37 - 4.35 (m, 1H), 4.30 (dm, J = 11.6 Hz, 1H), 4.19 (d, J = 15.2 Hz, 1H), 3.98 (d, J = 9.2 Hz, 1H), 3.95 - 3.90 (m, 1H), 2.66 - 2.61 (m, 1H), 2.44 - 2.39 (m, 1H), 2.13 - 201 (m, 2H), 1.91 - 1.84 (m, 1H); LCMS: m / z = 538.0 [M+H] + , 540.0 [M+2+H] + 。

[0271] Example 22 [Chemical formula] 021 (50 mg, 92.9 μmol) was dissolved in N-methylpyrrolidone (2.0 mL), and after purging with nitrogen gas, cuprous cyanide (16.64 mg, 185.8 μmol) and tetrakis(triphenylphosphine)palladium(0) (21.5 mg, 18.6 μmol) were added, and the mixture was stirred at 120 °C for 16 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the cake was washed with ethyl acetate (5 mL). Water (20.0 mL) was added to the obtained filtrate, and extraction was performed with ethyl acetate (5 mL × 3). The organic phases were combined, washed successively with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by thin-layer chromatography (petroleum ether:ethyl acetate = 6:4), and then purified by preparative high-performance liquid chromatography (column: Xtimate C18 column, 150 × 40 mm × 5 μm; mobile phase: phase A: 0.1% aqueous hydrochloric acid solution, phase B: acetonitrile; gradient: phase B increases from 43% to 73% in 15 minutes) to obtain 022. 1 H NMR (400 MHz, CDCl3) δ ppm 9.09 (s, 1H), 8.08 (s, 1H), 7.02 - 6.95 (m, 2H), 6.91 - 6.89 (m, 1H), 6.23 - 5.95 (m, 1H), 5.86 - 5.82 (m, 1H), 4.79 - 4.76 (m, 1H), 4.51 - 4.49 (m, 1H), 4.42 - 4.25 (m, 2H), 4.25 - 4.22 (m, 1H), 3.99 - 3.95 (m, 2H), 2.67 - 2.64 (m, 1H), 2.42 - 2.41 (m, 1H), 2.11 - 1.99 (m, 2H), 1.90 - 1.85 (m, 1H); LCMS: m / z = 485.3 [M+H] + 。

[0272] Example 23 [Chemical formula]

[0273] Step 1: Synthesis of Compound 023-1 009-8 (0.3 g, 0.80 mmol) and B-14 (262.3 mg, 0.80 mmol) were dissolved in N,N'-dimethylformamide (3.0 mL). Next, a solution of cesium carbonate (0.78 g, 2.39 mmol) in N,N'-dimethylformamide (3.0 mL) was added, and the mixture was stirred at 20 °C for 3 hours. Water (10 mL) was added to the reaction solution for quenching, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were successively washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE:EA = 4:1~2:1) to obtain 023-1. LCMS: m / z = 670.2 [M+H] + ,672.2 [M+2+H] + 。

[0274] Step 2: Synthesis of Compound 023-2 023-1 (0.45 g, 0.67 mmol) was added to a mixed solution of methanol (5 mL), tetrahydrofuran (5 mL) and ethanol (10 mL). Then, a mixed solvent solution of sodium hydroxide (2 M, 9.06 mL) was added, and the mixture was reacted at 20 °C for 30 hours. 2 M hydrochloric acid was added to the reaction solution to adjust the pH value to 7~8, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were successively washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE:EA = 1:0~3:1) to obtain 023-2. LCMS: m / z = 542.0 [M+H-Boc] + ,m / z = 544.0 [M+H+2-Boc] + 。

[0275] Step 3: Synthesis of Compound 023-3 023-2 (0.23 g, 358.0 μmol) was dissolved in dichloromethane (10.0 mL), and then a 1,4-dioxane solution of hydrochloric acid (4 M, 5.75 mL) was added, and the reaction was carried out at 20 °C for 3 hours. Evaporation under reduced pressure was performed to remove hydrogen chloride gas, and the crude product of 023-3 was obtained and directly used in the reaction of the next step without purification. LCMS: m / z = 542.0 [M+H] + , m / z = 544.0 [M+2+H] + .

[0276] Step 4: Synthesis of Compound 023 023-3 (209.6 mg, 362.8 μmol) was dissolved in dichloromethane (16.0 mL), and then N,N-diisopropylethylamine (1.81 mmol, 316.0 μL) and pentafluorophenyl diphenylphosphinate (209.1 mg, 0.54 mmol) were sequentially added, and the mixture was stirred at 20 °C for 3 hours. 20 mL of water was added to the reaction solution, and extraction was performed with dichloromethane (20 mL × 2). The organic phases were combined, washed successively with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE:EA = 1:0~2:1), and then preparative chiral chromatography (column: DAICEL CHIRALCEL OD column, 250×30 mm×10 cm; mobile phase: phase A: supercritical carbon dioxide, phase B: 0.1% ammonia water ethanol solution, gradient: phase B is 40%, isobaric elution) was used for purification to obtain 023. 11H NMR (400 MHz, CDCl3) δ 9.03 (d, J = 10.4 Hz, 1H), 8.07 (s, 1H), 6.95 - 6.87 (m, 2H), 6.48 (dd, J = 4.8 Hz, J = 8.8 Hz, 1H), 6.21 - 5.92 (m, 2H), 5.00 - 4.97 (m, 1H), 4.90 - 4.87 (m, 1H), 4.78 - 4.75 (m, 1H), 4.41 - 4.33 (m, 2H), 4.26 - 4.22 (m, 1H), 3.13 - 3.07 (m, 1H), 2.85 - 2.79 (m, 1H), 2.31 - 2.25 (m, 1H), 1.95 - 1.90 (m, 1H); LCMS: m / z = 524.0, 526.0 [M+H] + 。

[0277] Example 24

Chemical Structure

[0278] Example 25

Chemical Structure

[0279] Step 1: Synthesis of Compound 025-1 To the reaction flask were added 009-8 (1.5 g, 3.02 mmol), cuprous cyanide (540.29 mg, 6.03 mmol) and N-methylpyrrolidone (30 mL), then cuprous iodide (574.46 mg, 3.02 mmol) was added. Under the atmosphere of nitrogen gas, the mixture was heated to 125 °C and reacted for 12 hours. Ammonia water (15.0 mL) was added to the reaction solution and stirred for 10 minutes to quench the reaction system. Water (15.0 mL) was added, and a solid precipitated. The obtained cake was dissolved in dichloromethane (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 025-1. 11H NMR (400 MHz, CDCl3) δ ppm 8.11 (br s, 1H), 7.48 - 7.30 (m, 2H), 6.89 (br d, J = 7.5 Hz, 2H), 6.21 - 5.70 (m, 2H), 4.71 - 4.12 (m, 4H), 3.81 (br s, 5H), 1.52 - 1.33 (m, 3H), LCMS: m / z =444.3 [M+H] + 。

[0280] Step 2: Synthesis of Compound 025-2 025-1 (1.2 g, 2.71 mmol) and trifluoroacetic acid (12 mL) were added to a reaction flask, and the mixture was heated to 90 °C and reacted for 2 hours under a nitrogen gas atmosphere. After the reaction solution was concentrated under reduced pressure to evaporate and remove trifluoroacetic acid, the pH value was adjusted to 7 - 8 with saturated sodium bicarbonate solution, dichloromethane (20.0 mL × 3) was added for extraction, the organic phases were combined, washed successively with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE:EA = 1:0~0:1) to obtain 025-2. 1 1H NMR (400 MHz, CDCl3) δ ppm 8.16 (s, 1H), 7.16 (br s, 1H), 6.03 - 5.72 (m, 1H), 4.53 (br d,J= 12.6 Hz, 1H), 4.42 (q,J= 6.9 Hz, 2H), 4.27 (br d,J= 12.1 Hz, 1H), 4.10 - 3.96 (m, 1H), 1.44 (t,J= 6.8 Hz, 3H), LCMS: m / z =324.2 [M+H] + 。

[0281] Step 3: Synthesis of Compound 025-3 025-2 (0.3 g, 928.06 μmol) was dissolved in N,N-dimethylformamide (3 mL), cooled to 0 °C, and then potassium carbonate (0.38 g, 2.78 mmol) was added. A solution of B-15 (0.46 g, 1.39 mmol) in N,N-dimethylformamide (1 mL) was added. After stirring at 0 °C for 1 hour under a nitrogen gas atmosphere, the temperature was slowly raised to 20 °C and stirred for 2 hours. The reaction solution was quenched with water (6 mL), extracted with ethyl acetate (6.0 mL × 3), the organic phases were combined, washed successively with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE:EA = 1:0 to 1:1) to obtain 025-3. 1 H NMR (400 MHz, CDCl3) δ ppm 8.38 (dd, J = 2.9, 8.1 Hz, 1H), 8.05 (s, 1H), 7.87 (d, J = 2.7 Hz, 1H), 6.25 - 5.93 (m, 1H), 5.46 - 5.28 (m, 1H), 5.14 - 4.79 (m, 2H), 4.66 (br d,J = 11.5 Hz, 1H), 4.58 (d, J= 14.2 Hz, 1H), 4.53 - 4.46 (m, 2H), 4.41 - 4.34 (m, 1H), 4.33 - 4.24 (m, 1H), 4.21 - 4.08 (m, 1H), 1.48 (t, J= 7.1 Hz, 3H), 1.45 - 1.29 (m, 9H), 1.12 - 1.00 (m, 1H), 0.95 - 0.78 (m, 3H), LCMS: m / z =618.3 [M+H] + 。

[0282] Step 4: Synthesis of Compound 025-4 025-3 (0.5 g, 0.81 mmol) was dissolved in ethanol (10 mL), tetrahydrofuran (5 mL) and methanol (5 mL), cooled to 0 °C, then lithium hydroxide monohydrate (2 M, 10 mL) was added, and it was stirred at 0 °C for 1 hour under a nitrogen gas atmosphere, and then the temperature was raised to 25 °C and reacted for 5 hours. Water (10 mL) was added to the reaction solution to quench the reaction system, then 2N hydrochloric acid was added to adjust the pH value to about 4, and it was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed successively with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (PE:EA = 1:0~1:1) to obtain 025-4. 1 H NMR (400 MHz, CDCl3) δ ppm 13.32 - 12.57 (m, 1H), 8.77 (d, J = 0.9 Hz, 1H), 8.27 (dd, J = 2.7, 8.4 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.30 (br s, 1H), 6.66 - 6.32 (m, 1H), 5.07 (br d, J = 14.6 Hz, 1H), 4.90 - 4.73 (m, 1H), 4.68 (br d, J = 12.1 Hz, 1H), 4.51 (br d, J = 14.4 Hz, 1H), 4.40 - 4.21 (m, 3H), 1.32 (br s, 9H), 0.84 - 0.67 (m, 4H), LCMS: m / z = 590.3 [M+H] + 。

[0283] Step 5: Synthesis of compound 025-5 025-4 (0.32 g, 0.54 mmol) was dissolved in dichloromethane (3.0 mL), cooled to 0 °C, then trifluoroacetic acid (1 mL) was added, and the temperature was slowly raised to 20 °C and stirred for 1 hour. It was evaporated under reduced pressure to remove trifluoroacetic acid in the reaction solution to obtain a crude product of 025-5, which was directly used in the reaction of the next step without purification. LCMS: m / z = 490.2 [M+H] + 。

[0284] Step 6: Synthesis of Compound 025 025-5 (265 mg, 0.54 mmol) was dissolved in dichloromethane (2.6 mL) and cooled to 0 °C under a nitrogen gas atmosphere. Then, 1H-benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (0.42 g, 0.81 mmol) and N,N-diisopropylethylamine (0.47 mL, 2.71 mmol) were added, and the temperature was slowly raised to 20 °C and stirred for 1.0 hour. Water (10.0 mL) was added to the reaction solution for quenching, and the mixture was extracted with dichloromethane (20.0 mL × 3). The combined organic phases were washed successively with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE:EA = 1:0 to 1:1), and then by preparative chromatography (column model: Waters Xbridge Prep OBD C18 150×40 mm×10 μm, mobile phase A: 10 mM aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile, gradient: phase B increases from 25% to 55% in 8.0 minutes). The obtained target eluate was concentrated under reduced pressure and further lyophilized to obtain 025. SFC chiral analysis and detection (column: Chiralcel OD-3, 50×4.6 mm I.D., 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: isopropanol [0.2% ammonia methanol solution (7M)], gradient: phase B increases from 5% to 50% in the first 1.2 minutes, maintained for 1 minute, and then phase B decreases from 50% to 5% in 0.8 minutes) showed ee = 100% (Rt = 1.609 minutes). 11H NMR (400 MHz, CDCl3) δ ppm 8.94 (s, 1H), 8.79 (s, 1H), 8.06 (br s, 1H), 7.99 (br d, J = 8.3 Hz, 1H), 6.68 - 6.33 (m, 1H), 5.47 (br d, J = 14.8 Hz, 1H), 5.05 (br t, J = 10.1 Hz, 1H), 4.91 (br d, J = 10.9 Hz, 1H), 4.72 (br d, J = 12.4 Hz, 1H), 4.52 - 4.38 (m, 2H), 3.74 (br d, J = 10.9 Hz, 1H), 1.96 - 1.80 (m, 1H), 1.06 - 0.96 (m, 2H), 0.89 - 0.77 (m, 1H), LCMS: m / z = 472.2 [M+H] + 。

[0285] Example 26

Chemical Structure

[0286] Step 1: Synthesis of Compound 026-1 Dissolve 025-2 (0.3 g, 0.93 mmol) in N,N-dimethylformamide (3 mL), cool to 0 °C, add potassium carbonate (0.38 g, 2.78 mmol), then add a solution of B-6 (463.28 mg, 1.39 mmol) in N,N-dimethylformamide (1 mL). Stir the reaction mixture at 0 °C for 1 hour under a nitrogen gas atmosphere, and then slowly warm to 20 °C and continue the reaction for 2 hours. Quench the reaction mixture with water (6 mL), extract with ethyl acetate (6 mL × 3), combine the organic phases, wash successively with saturated brine (10 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. Separate and purify the crude product by column chromatography (mobile phase: PE:EA = 1:0 to 1:1) to obtain 026-1. 11H NMR (400 MHz, CDCl3) δ ppm 8.37 (broad d, J = 5.4 Hz, 1H), 8.07 (s, 1H), 7.92 (d, J = 3.0 Hz, 1H), 6.18 - 5.85 (m, 1H), 5.47 (d, J = 14.4 Hz, 1H), 4.68 - 4.45 (m, 7H), 4.34 - 4.28 (m, 1H), 4.00 (broad d, J = 11.4 Hz, 1H), 1.50 - 1.45 (m, 3H), 1.43 (s, 9H), 1.40 (broad s, 3H), 1.39 (s, 3H), LCMS: m / z = 620.3 [M+H] + 。

[0287] Step 2: Synthesis of Compound 026-2 026-1 (0.44 g, 0.71 mmol) was dissolved in ethanol (8 mL), tetrahydrofuran (4 mL) and methanol (4 mL), cooled to 0 °C, then lithium hydroxide monohydrate (2 M, 8.80 mL) was added, and the reaction was carried out at 0 °C for 1 hour under an atmosphere of nitrogen gas. Next, the temperature was slowly raised to 25 °C and the reaction was carried out for 5 hours. Water (10 mL) was added to the reaction solution for quenching, 2N hydrochloric acid was added to adjust the pH value to about 4, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed successively with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (mobile phase: PE:EA = 1:0~1:1) to obtain 026-2. 11H NMR (400 MHz, CDCl3) δ ppm 13.14 - 12.54 (m, 1H), 8.81 (s, 1H), 8.23 (br d, J = 8.4 Hz, 1H), 8.03 (br s, 1H), 6.68 (br dd, J = 1.1, 9.8 Hz, 1H), 6.63 - 6.34 (m, 1H), 5.23 (br d, J = 15.0 Hz, 1H), 4.61 (br d, J = 12.0 Hz, 1H), 4.52 (br d, J = 14.8 Hz, 2H), 4.40 - 4.33 (m, 1H), 4.26 (br d, J = 10.6 Hz, 2H), 1.36 (s, 9H), 1.31 (s, 3H), 1.25 (s, 3H), LCMS: m / z = 592.3 [M+H] + 。

[0288] Step 3: Synthesis of Compound 026-3 026-2 (0.27 g, 0.46 mmol) was dissolved in dichloromethane (3 mL), cooled to 0 °C under a nitrogen gas atmosphere, trifluoroacetic acid (1 mL) was added, stirred at 0 °C for 0.2 h, warmed to 20 °C, and then reacted for 0.8 h. Evaporated under reduced pressure to remove dichloromethane and trifluoroacetic acid to obtain the crude product of 026-3. LCMS: m / z = 492.3 [M+H] + 。

[0289] Step 4: Synthesis of Compound 026 026-3 (224 mg, 0.46 mmol) was dissolved in dichloromethane (2.3 mL) and cooled to 0 °C under a nitrogen gas atmosphere. Then, 1H-benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (0.36 g, 0.68 mmol) and N,N-diisopropylethylamine (0.40 mL, 2.28 mmol) were added, and the temperature was slowly raised to 20 °C and stirred for 1.0 h. Water (10.0 mL) was added to the reaction solution for quenching, and the mixture was extracted with dichloromethane (20.0 mL × 3). The combined organic phases were washed successively with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (PE:EA = 1:0 to 1:1), and then purified by preparative chromatography (column model: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 m, mobile phase A: 10 mM aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile, gradient: phase B increases from 30% to 60% in 8.0 min). The obtained target eluate was concentrated under reduced pressure and further lyophilized to obtain 026. Chiral analysis and detection (chromatographic column: (S,S)-WHELK-O1, 50 × 4.6 mm I.D., 3.5 m; mobile phase A: supercritical carbon dioxide, mobile phase B: ethanol [0.2% ammonia methanol solution (7 M)], gradient: phase B increases from 5% to 50% in the first 1.2 min, maintained for 1 min, and then phase B decreases from 50% to 5% in 0.8 min) showed that the ee of compound 26 was 93.86%, Rt = 2.146 min, and the Rt of its enantiomer was 1.971 min. 11H NMR (400 MHz, CDCl3) δ ppm 8.91 (s, 1H), 8.80 (s, 1H), 8.11 (brs, 1H), 8.07 (brd, J = 8.8 Hz, 1H), 6.35 - 6.67 (m, 1H), 5.39 (br d, J = 14.8 Hz, 1H), 5.00 - 5.15 (m, 1H), 4.66 - 4.80 (m, 2H), 4.43 - 4.55 (m, 2H), 3.94 (br d, J = 10.8 Hz, 1H), 1.64 (s, 3H), 1.52 (s, 3H); LCMS: m / z = 474.2 [M+H] + 。

[0290] Example 27

Chem.

[0291] Biological test data Experimental Example 1: In vitro kinase inhibition activity test ALK, ALK L1196M 、ALK G1202R 、ALK G1202R / L1196M The test of the kinase inhibition activity of the compound against ALK, ROS1 and TRKB was completed by Wuhan Heyan Biopharmaceutical Technology Co., Ltd or Hefei PreceDo Biopharmaceutical Technology Co., Ltd.

[0292] Experimental method 1: Experimental materials: ALK Active, ALK (L1196M) Active, ALK (G1202R) Active and ALK (G1202R / L1196M) Active were purchased from Carna. SRC Substrate was purchased from SignalChem. IGF1R tide was purchased from SignalChem. ADP-Glo Kinase Assay was purchased from Promega. Kinase assay buffer III was purchased from SignalChem. Nivo multi-label analyzer (PerkinElmer).

[0293] ALK Kinase Inhibition Test Method: The test compound was diluted to 1 mM with 100% DMSO as the first concentration, and then serially diluted 5-fold to 8 concentrations with a pipette, i.e., diluted from 1 mM to 0.0128 μM. Each concentration point of the compound was further diluted 20-fold with 1× kinase buffer to prepare a compound working solution containing 5% DMSO. 1 μL of each concentration gradient working solution of the compound was added to a microplate, and two replicate wells were set up. 2 μL of ALK enzyme (15 ng / well), 2 μL of substrate and ATP mixture (25 μM ATP, 0.5 μg / μL SRC Substrate) were added to the microplate. At this time, the final concentration gradient of the compound was diluted from 10 μM to 0.128 nM, and the final concentrations of ATP and substrate were 10 μM and 0.2 μg / μL, respectively. The reaction system was reacted at 25°C for 1 hour. After the reaction, 5 μL of ADP-Glo reagent was added to each well and the reaction was continued at 25°C for 40 minutes. After the reaction, 10 μL of kinase detection reagent was added to each well and reacted at 25°C for 30 minutes. Then, chemiluminescence was read using a PerkinElmer Nivo multimode plate reader, and the integration time was 0.5 seconds.

[0294] ALK (L1196M) Kinase Inhibition Test Method: The method for preparing the working solution of the test compound was the same as that for ALK kinase. 2 μL of LALK (L1196M) enzyme (4 ng / well), 2 μL of substrate and ATP mixture (125 μM ATP, 0.5 μg / μL IGF1R tide) were added to the microplate. At this time, the final concentration gradient of the compound was diluted from 10 μM to 0.128 nM, and the final concentrations of ATP and substrate were 50 μM and 0.2 μg / μL, respectively. The subsequent steps were the same as those for ALK kinase.

[0295] ALK (G1202R) Kinase Inhibition Test Method: The method for preparing the working solution of the test compound is the same as that for ALK kinase. Add 2 μL of ALK (G1202R) enzyme (15 ng / well), 2 μL of the substrate and ATP mixture (125 μM ATP, 0.5 μg / μL SRC Substrate) to the microplate. At this time, dilute the final concentration gradient of the compound from 10 μM to 0.128 nM, and the final concentrations of ATP and the substrate are 50 μM and 0.2 μg / μL, respectively. The subsequent steps are the same as those for ALK kinase.

[0296] ALK (G1202R / L1196M) Kinase Inhibition Test Method: The method for preparing the working solution of the test compound is the same as that for ALK kinase. Add 2 μL of ALK (G1202R / L1196M) enzyme (5 ng / well), 2 μL of the substrate and ATP mixture (125 μM ATP, 0.5 μg / μL SRC Substrate) to the microplate. At this time, dilute the final concentration gradient of the compound from 10 μM to 0.128 nM, and the final concentrations of ATP and the substrate are 50 μM and 0.2 μg / μL, respectively. The subsequent steps are the same as those for ALK kinase.

[0297] ROS1 Kinase Inhibition Test Method: The method for preparing the working solution of the test compound is the same as that for ALK kinase. Add 2 μL of ROS1 (3.0 ng / well), 2 μL of the substrate and ATP mixture (50 μM ATP, 0.2 μg / μL IGF1R tide substrate) to the microplate. At this time, dilute the final concentration gradient of the compound from 10 μM to 0.128 nM, and the final concentrations of ATP and the substrate are 0.25 μM and 0.2 μg / μL, respectively. The subsequent steps are the same as those for ALK kinase.

[0298] TRKB Kinase Inhibition Test Method: The method for preparing the working solution of the test compound is the same as that for ALK kinase. Add 2 μL of TRKB (0.5 ng / well), 4 μL of substrate and ATP mixture (5 μM ATP, 0.5 μM SRC Substrate) to the microplate. At this time, dilute the final concentration gradient of the compound from 10 μM to 0.128 nM, and the final concentrations of ATP and substrate are 0.25 μM and 0.2 μg / μL, respectively. The subsequent steps are the same as those for ALK kinase.

[0299] Use the equation (Sample - Min) / (Max - Min)×100% to convert the raw data to the inhibition rate, and the IC 50 value was obtained by curve fitting using four parameters (obtained with the log(inhibitor) vs. response--Variable slope model in GraphPad Prism). The test results of Compounds 001 - 005 are as shown in Table 1 - 1.

[0300] Table 1 - 1: Kinase Half - Inhibitory Concentration IC 50 (nM)

Table 1

[0301] Experimental Method 2: Experimental Materials: ALK (G1202R / L1196M) Active and TRKB were purchased from Carna. IGF1 was purchased from GenScript. PolyE4Y1 was purchased from SIGMA. ADP - Glo TM Reagent was purchased from Promega. ATP was purchased from Promega. Kinase Detection Reagent was purchased from Promega. Microplate reader (PerkinElmer).

[0302] Reaction system: ALK (G1202R / L1196M), reaction system concentration: 8.63 nM, ATP concentration: 5.0 μM, substrate IGF1 concentration: 0.2 μg / μL, ALK (G1202R / L1196M) kinase buffer: 40 mM Tris-HCl (pH 7.5) + 20 mM magnesium chloride + 0.1 mg / mL BSA + 50 μM DTT.

[0303] TRKB reaction concentration: 4.47 nM, ATP concentration: 5.0 μM, substrate PolyE4Y1 concentration: 0.2 μg / μL, TRKB kinase buffer: 40 mM Tris-HCl (pH 7.5) + 20 mM magnesium chloride + 2.5 mM manganese chloride + 0.1 mg / mL BSA + 50 μM DTT.

[0304] ALK (G1202R / L1196M), TRKB detection method: 2 μL of kinase and 1 μL of compound were added to a 384-well plate. 2 μL of substrate / ATP mixture was added, and the plate was incubated in the dark at room temperature for 60 minutes. 5 μL of ADP-Glo TM Reagent was added, and the plate was incubated at room temperature for 40 minutes. 10 μL of Kinase Detection Reagent was added, and the plate was incubated at room temperature for 30 minutes. The plate was read using a microplate reader, and luminescence was recorded (integration time was set to 0.5 seconds).

[0305] The raw data was converted to inhibition rate using the equation (Sample - Min) / (Max - Min) × 100%, and the IC 50 value was obtained by curve fitting using four parameters (obtained with the log(inhibitor) vs. response - Variable slope model in GraphPad Prism). The test results of compound 006 - 024 are as shown in Table 1 - 2.

[0306] Table 1 - 2: Kinase half-maximal inhibitory concentration IC 50 (nM)

Table 2

[0307] Conclusion: The compounds of the present invention exhibit higher kinase inhibitory activities against ALK kinase and its mutants, ROS1 and TRKB kinases. Among them, it shows more efficient inhibition against ALK kinase and mutants, relatively weak inhibition against TRKB, and better selectivity.

[0308] Experimental Example 2: Cell Permeability Test Experimental Purpose: Using the MDCKII-MDR1 monolayer cell test system to evaluate the permeability and efflux ratio of the test compound, and to evaluate the potential of the compound to cross the blood-brain barrier and the potential to be effluxed in vitro by the P-gp transporter.

[0309] Experimental Method: MDCKII-MDR1 cells (manufactured by The Netherlands Cancer Institute) were seeded in a 96-well cell plate (manufactured by Corning) at a cell density of 2.5×10 5 cells / ml and cultured for 7 days to form a confluent monolayer. Hank's balanced salt buffer (pH 7.40 ± 0.05) containing 10 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid was used as the transport buffer (here, the transport buffer for Compound 005 is the transport buffer with an additional 1% BSA (bovine serum albumin)). The bidirectional transport of the test compound was tested at a concentration of 2 μM, and the concentration of DMSO in the culture system was controlled to be less than 1%. After adding the sample, the cell plate was cultured at 37 ± 1 °C, 5% CO2 and saturated humidity for 150 minutes. Quantitative analysis of all samples was performed using the LC-MS / MS method. The apparent permeability coefficient (P app , cm / s), efflux ratio (ER), and recovery rate were calculated using the following formulas.

[0310] The apparent permeability coefficient (P app , cm / s) was calculated using the following formula. P app =(dC r / d t )×V r / (A×C0). Here, dC r / d t is the cumulative concentration of the receptor end of the compound per unit time (μM / s), and V r is the volume of the solution at the receptor end (the volumes of the solution at the apical and basolateral ends are 0.075 mL and 0.250 mL, respectively), A is the relative surface area of the cell monolayer (0.0804 cm 2 ), and C0 is the starting concentration (nM) of the test compound at the dosing end or the peak area ratio of the control compound. The efflux ratio was calculated using the following formula. ER = P app (BA) / P app (AB). The recovery rate was calculated using the following formula. % Recovery rate = 100 × [(V r ×C r )+(V d ×C d )] / (V d ×C0). Here, C0 is the starting concentration (nM) of the test compound at the dosing end or the peak area ratio of the control compound, V d is the volume at the dosing end (the apical end is 0.075 mL and the basolateral end is 0.250 mL), and C d and C r are the final concentrations (nM) of the test compound at the dosing end and the receiving end, respectively, or the peak area ratio of the control compound.

[0311] The test results are as shown in Table 2. Table 2: MDCKII-MDR1 Test Results

Table 3

[0312] Conclusion: The compound of the present invention is a hypertonic and low-excretion compound.

[0313] Experimental Example 3: Anti-proliferative Activity Test Against Three Ba / F3 Cell Lines Ba / F3-EML4-ALK-G1202R, Ba / F3-EML4-ALK-G1202R-L1198F, Ba / F3-EML4-ALK-G1202R-L1196M

[0314] Experimental Materials (1) Cell lines (constructed by Hefei PreceDo Biopharmaceutical Technology Co., Ltd.) ALK G1202R / L1196M Cell lines: Ba / F3-EML4-ALK-G1202R / L1196M, TRKB cell line: Ba / F3-TEL-TRKB.

[0315] (2) Reagents: RPMI1640: Brand: VivaCell, Catalog number: C3010-0500, Fetal bovine serum: Brand: VivaCell, Catalog number: C04001-500, Penicillin-streptomycin solution: Brand: Gibco, Catalog number: 15140-122, CellTiterGlo: Brand: Promega, Catalog number: G7573, Trypan blue: Brand: Solarbio, Catalog number: C0040, 96-well plate (white): Brand: Biosharp, Catalog number: BS-MP-96W, 96-well drug plate: Brand: Beaver, Catalog number: 40196.

[0316] (3) Instruments: Cell counter, Manufacturer: Count star, Model: IC1000, Microplate reader, Manufacturer: Molecular Devices, Model: SpectraMax Paradigm, Carbon dioxide incubator, Thermo, Model: HERA cell vios 160i.

[0317] (4) Compound information: Compounds were prepared at a working concentration of 1 mM using DMSO.

[0318] Experimental methods (1) Cell culture: The cell lines were cultured in an incubator at 37 °C, 5% CO 2 and subcultured regularly. Cells in the logarithmic growth phase were seeded onto plates. (2) Preparation of compound storage plates: The test compound was prepared into a 10 mM solution (Stock Con.) using DMSO, and further into a 1 mM solution (Work Con.) using DMSO. 1 μL of the Stock solution and 9 μL of DMSO were taken to prepare 10 μL of the Work solution. (3) Preparation of 1000× compound stock plates (tubes): DMSO was serially diluted 3-fold from 1 μM to the lowest concentration, resulting in a total of 8 concentrations. (4) Preparation of 20× compound working solutions: 98 μL of cell culture medium was placed in a flat-bottomed 96-well transparent reagent plate, and 2 μL of the compound was aspirated from the 1000× compound stock plate and added to the cell culture medium in the 96-well transparent reagent plate. 2 μL of DMSO was added to the solvent control. After adding the compound or DMSO, pipetting was performed with a pipette to mix uniformly. (5) Cells were stained with trypan blue and counted. When the cell viability was 90% or more, the cell concentration was adjusted to an appropriate concentration. (6) 95 μL of cell suspension (2000 cells / well) per well was added to the compound detection cell plate, and a cell-free medium (containing 0.1% DMSO) was added to the Min control well. (7) Administration of the compound detection cell plate: 5 μL of the 20× compound working solution was added to the cell culture plate, and 5 μL of the DMSO-cell culture medium mixture was added to the Max control. The final DMSO concentration was 0.1%. (8) The culture plate was cultured in a 37 °C, 5% CO2 incubator for 72 hours. (9) According to the instructions of the Promega CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega-G7573), the following procedure was performed. The CellTiter-Glo buffer was thawed and allowed to return to room temperature. The CellTiter-Glo substrate was allowed to return to room temperature. The CellTiter-Glo buffer was added to the bottle of the CellTiter-Glo substrate to dissolve the substrate, and the CellTiter-Glo working solution was prepared. It was gently vortexed to dissolve thoroughly. The cell culture plate was taken out and left for 10 minutes to equilibrate to room temperature. 50 μL (equal to half the volume of the cell culture medium in each well) of the CellTiter-Glo working solution was added to each well. The culture plate was shaken on an orbital shaker for 2 minutes to induce cell lysis. The plate was left at room temperature for 10 minutes to stabilize the luminescence signal. The luminescence signal was detected using a SpectraMax Paradigm plate reader. The cell viability was detected by CellTiter-Glo luminescence.

[0319] Data analysis: By reading with a SpectraMax Paradigm, the corresponding fluorescence value RLU of each well was obtained. The cell growth inhibition rate data was processed using Inhibition Rate (Inh%) = 100 - (RLU Drug - RLU Min ) / (RLU Max - RLU Min ) × 100%. After calculating the inhibition rates corresponding to compounds at different concentrations in Excel, an inhibition rate curve was created using GraphPad Prism software, and related parameters including the maximum and minimum inhibition rates of the cells and the IC 50 value were calculated.

[0320] The experimental results are as shown in Table 3. Table 3: Half-maximal inhibitory concentration IC 50 (nM)

Table 4

[0321] Conclusion: The compounds of the present invention exhibit a strong inhibitory effect on ALK mutant cells and TRKB phenotype cells. Here, Compounds 010, 018, 019, and 020 show stronger inhibition against ALK mutant cells and relatively weak inhibition against TRKB phenotype cells, having excellent selectivity.

[0322] Experimental Example 4: In Vivo Pharmacokinetic Study in Mice

[0323] Experimental Purpose: Male CD-1 mice aged 7 - 9 weeks were used as test animals. After a single intravenous injection (IV) and intragastric administration (PO) of the compounds using the LC / MS / MS method, the plasma concentrations of the compounds at different time points were measured to study the pharmacokinetic behavior of the compounds of the present invention in the mouse body.

[0324] Experimental Method: Two groups of healthy mice (fasted) were administered by intravenous injection (IV) and intragastric administration (PO), with 2 mice / group. The intravenous injection solvent for Compounds 001, 005, and 006 was 10% dimethyl sulfoxide + 40% polyethylene glycol 400 + 50% water. After mixing the test compound and the solvent, it was vortexed and sonicated to prepare a clear solution of 0.5 mg / mL, with a pH value of 3.3 - 3.6. The mice were injected intravenously at a dose of 1.0 mg / kg. The oral administration solvent for Compounds 001, 005, and 006 was 0.5% sodium carboxymethylcellulose + 1% polyoxyethylene sorbitan monooleate. After mixing the test compound and the solvent, it was vortexed and sonicated to prepare a suspension containing homogeneous particles of 0.5 mg / mL, with a pH value of 6.8 - 7.0, and the oral administration dose for the mice was 5.0 mg / kg.

[0325] The intravenous injection solvent of Compound 010 is 10% dimethylacetamide + 70% polyethylene glycol 400 + 20% (aqueous solution of 10 hydroxypropyl-β-cyclodextrin). After mixing the test compound with the solvent, it was vortexed and sonicated to produce a clear solution of 1.0 mg / mL, and the intravenous injection dose for mice was 1.0 mg / kg. The oral administration solvent of Compound 010 is 5% dimethyl sulfoxide + 60% tri(caprylic acid / capric acid) glyceride + 30% polyethylene glycol 400 + 5% water. After mixing the test compound with the solvent, it was vortexed and sonicated to produce a suspension containing homogeneous particles of 0.5 mg / mL, and the oral administration dose for mice was 5.0 mg / kg.

[0326] The intravenous solvents of Compounds 019 and 020 are 10% dimethyl sulfoxide + 40% polyethylene glycol 400 + 50% water. After mixing the test compound with the solvent, it was vortexed and sonicated to produce a clear solution of 0.1 mg / mL, and the intravenous injection dose for mice was 0.5 mg / kg. The oral administration solvent of Compound 020 is 0.5% sodium carboxymethyl cellulose + 1% polyoxyethylene sorbitan monooleate. After mixing the test compound with the solvent, it was vortexed and sonicated to produce a homogeneous particle-containing suspension of 0.5 mg / mL, with a pH value of 7.08, and the oral intragastric administration dose for mice was 5.0 mg / kg. After administration, whole blood was collected at 0.083 h, 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 8.0 h, 12.0 h, and 24.0 h to prepare plasma, the drug concentration was analyzed by LC-MS / MS method, and the pharmacokinetic parameters were calculated using Phoenix WinNonlin 6.3. The experimental results are as shown in Table 4.

[0327] Table 4: Results of Pharmacokinetic Tests of Drugs in Mice

Table 5

[0328] Conclusion: The compound of the present invention has a long half-life, high exposure, high bioavailability, and excellent pharmacokinetic properties in mouse PK (pharmacokinetics).

[0329] Experimental Example 5: HMS CLint (liver) test

[0330] Experimental purpose: Test the metabolic stability of the compound of the present invention in human and mouse hepatocytes.

[0331] Experimental materials: (1) Test compound (10 mM), controls: 7-ethoxycoumarin (7-Ethoxycoumarin, 30 mM), 7-hydroxycoumarin (7-Hydroxycoumarin, 30 mM), Mouse hepatocytes, cell viability: 73.8%, supplier: Cat No.: BioreclamationIVTM005052, Human hepatocytes, cell viability: 94.6%, supplier: Cat No.: Bioreclamation IVTX008001.

[0332] (2) Buffer system: Thawing of medium: Williams medium E contains 5% fetal bovine serum, 30% Percoll solution and other adjuvants.

[0333] Culturing of medium: Williams medium E (without phenol red) containing 2 mM L-glutamine and 25 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid. Stop solution: Acetonitrile contains 200 ng / mL tolbutamide and rabelol as internal standards. Dilution solution: Ultra-pure water.

[0334] Experimental method 1) Accurately weigh the positive control compound and dissolve it in dimethyl sulfoxide (DMSO) to prepare a 30 mM solution. 2) The test compound at 10 mM and the control compound at 30 mM were diluted to 1 mM and 3 mM with DMSO on a 96-well plate. 3) The test compound at 1 mM and the positive control compound at 3 mM were diluted to quantitative solutions at 100 mM and 300 mM with acetonitrile. 4) The cryopreserved cells were thawed, separated and suspended in the culture medium, and then diluted with the pre-heated culture medium to 0.5×10 6 cells / mL. 5) 198 μL of the pre-heated cell suspension was added to a 96-well plate. 6) 100 μL of the stop solution (acetonitrile containing 200 ng / mL of tolbutamide and 200 ng / mL of labetalol as internal standards) was transferred to the pre-labeled 96-well plate. 7) 2 μL of the 100 μM test compound or 300 μM positive control quantitative solution was added in two portions to each well of the 96-well plate. 8) For the T0 sample, it was mixed to obtain a uniform suspension for about 1 minute, and then immediately 20 μL of each sample was transferred to a well containing 100 μL of ice-cold stop solution and then mixed. 9) All plates were cultured in a 95% humidity incubator at 5% CO2, 37 °C, and shaken at a constant speed of about 600 rpm to initiate the reaction. 10) The samples were mixed at 15 minutes, 30 minutes, 60 minutes and 90 minutes, and then 20 μL of each sample at each time point was transferred to a well containing 100 μL of ice-cold stop solution and then mixed. 11) The same components other than the cell suspension were added to each well to prepare medium control (MC) sample plates (designated as T0-MC and T90-MC) at T0 and T90. A final concentration table was created. 12) At each corresponding time point, the plate was taken out of the incubator and mixed with 100 μL of ice-cold stop solution to stop the reaction. 13) The plate was immediately vortexed and vortexed on a plate shaker at 500 rpm for 10 minutes. Then, all sample plates were centrifuged at 3220×g at 4 °C for 20 minutes. 14) After centrifugation, the supernatant in the sample plate at 35 μL / well was transferred to another pre-labeled 96-well plate containing 70 μL of ultrapure water according to the plate map. 15) The analysis plate was sealed and stored at 4 °C until LC-MS-MS analysis. The residual rates of the test compound and the control compound were determined by the following formula.

Equation

[0335] The disappearance rate constant k of the test compound and the control compound in hepatocytes was calculated by plotting time against the logarithm of the residual rate, and the half-life (T 1 / 2 ) and in vitro intrinsic clearance (CL int ) were determined. The formulas are as follows. T 1 / 2 = 0.693 / k, CL int(hep) = k / cell number per mL (million cells / mL), CL int(liver) = CL int(hep) × liver weight to body weight ratio × number of hepatocytes per 1 g of liver. The parameters and test results of the compounds of the present invention in the HMS test were as shown in Table 5.

[0336] Table 5 Parameters and test results of the compounds of the present invention in the HMS test

Table 6

[0337] Conclusion: The compounds of the present invention show moderate metabolism in human hepatocytes, faster metabolism in mice, and better stability.

[0338] Experimental Example 6: Cytochrome P450 Isozyme Inhibition Activity Test

[0339] Experimental Purpose: The inhibitory activity of the compounds of the present invention against different subtypes of cytochrome P450 isoenzymes in human liver microsomes is tested.

[0340] Experimental materials: Pooled human liver microsomes (HLM) were purchased from Corning Inc. (Steuben, New York, USA), diclofenac was the probe substrate (10 μM), sulfaphenazole was the positive control inhibitor, and 4'-hydroxydiclofenac was the metabolite.

[0341] Preparation of test system working solutions: Human liver microsomes: HLM stock solution 20.0 mg / mL, working solution 0.2 mg / mL, final concentration 0.1 mg / mL. Potassium phosphate buffer: 100 mM, cofactor working solution: magnesium chloride, NADP (nicotinamide adenine dinucleotide phosphate), G6P (glucose-6-phosphate), G6PDH (glucose-6-phosphate dehydrogenase) and phosphate buffer or magnesium chloride, NADPH (reduced nicotinamide adenine dinucleotide phosphate) powder and potassium phosphate buffer. Prepared in the appropriate ratio in the cofactor working solution.

[0342] Stop solution: An isotope-labeled 4'-hydroxydiclofenac-d4 stock solution was prepared with methanol, and then the stop solution was prepared with acetonitrile.

[0343] Experimental method: To the substrate-free control sample wells of the reaction plate, 100 μL of a mixture of human liver microsomes and potassium phosphate buffer was added, and to the sample wells at the zero time point, 98 μL of a mixture of human liver microsomes and potassium phosphate buffer was added. To the control without inhibitor (NIC), test compound, and positive control inhibitor sample wells of the reaction plate, 100 μL of a mixed solution of human liver microsomes and substrate was added. From the dilution plate, 2 μL of blank solvent, test compound working solution (in triplicate), and positive control inhibitor working solution (in duplicate) were added to the reaction plate respectively. The reaction plate was preheated at 37.0 °C for 10 minutes. 98 μL of cofactor working solution was added to the reaction plate to initiate the reaction. When the reaction time of each CYP enzyme was reached, 200 μL of stop solution was added to the reaction plate to stop the reaction. 4 μL of 5.0% substrate solution was added to the sample wells at the zero time point. The sample plate was placed in a centrifuge and centrifuged at 3220×g for 20 minutes. The supernatant was taken out, appropriate diluents were added at appropriate ratios, and the plate was shaken until uniformly mixed. The concentration of a specific metabolite in the sample was detected using liquid chromatography-tandem mass spectrometry (LC-MS / MS). Using SigmaPlot (V.11), a non-linear regression analysis of the average activity rate vs. concentration of the test compound was performed. The IC 50 values were calculated by a three-parameter or four-parameter inverse logarithmic equation. The experimental results are as shown in Table 6.

[0344] Table 6. Inhibition Results of the Compounds of the Present Invention against P450 Isozymes

Table 7

[0345] Conclusion: The compounds of the present invention do not significantly inhibit any different subtypes of P450 isozymes.

[0346] Experimental Example 7: Plasma Protein Binding Rate (PPB) Test

[0347] Experimental Purpose: The protein binding rate of the compound of the present invention in CD-1 mouse and human plasma is measured using equilibrium dialysis method.

[0348] Experimental method: Plasma samples of the compound are prepared with CD-1 mouse plasma and human plasma respectively, where the compound concentration is 2.00 μM, placed in a 96-well equilibrium dialysis device, and dialyzed with phosphate buffer solution at 37 °C for 6 hours. In this experiment, warfarin was used as a control compound. The concentrations of the test substances in plasma and dialysis buffer were measured by LC-MS / MS method, and the unbound rate (%Unbound), bound rate (%Bound) and recovery rate (%Recovery) of the compound were calculated respectively. The calculation formula is %Unbound = 100 × F C / T C , %Bound = 100 - %Unbound, %Recovery = 100 × (F C =T C ) / T0, where F C is the compound concentration at the buffer end of the dialysis plate, T C is the compound concentration at the plasma end of the dialysis plate, and T0 is the concentration of the compound in the plasma sample at the zero time point.

[0349] Experimental conclusion: The compound shows a higher binding rate in both CD-1 mouse and human plasma.

Claims

1. A compound represented by formula (II) or a pharmaceutically acceptable salt thereof. 【Chemical 1】 (However, [Chemical Formula 2] is selected from a single bond and a double bond, T １ is selected from C, and T ２ is selected from N, Or, T １ is selected from N, and T ２ is selected from C, T ３ is selected from O, N, NH, C(=O), C(R ３ ), ２ O, C(R ３ ), and C(R ３ ), ２ and is selected from T ４ is selected from N, NH, C(=O), C(R ３ ), ２ O, C(R ３ ), and C(R ３ ), ２ and is selected from L １ is selected from CH ２ and C(=O), and L ２ and L ３ each independently is selected from a single bond and C １－３ alkyl, and the C １－３ alkyl is optionally substituted by one, two or three R ａ groups R １ is selected from O, S and NR ４ and R ２ is selected from H, F, Cl, Br, I, OH, NH ２ , CN, C １－４ alkyl, C ２－５ alkenyl, C ２－５ alkynyl and C ３－６ cycloalkyl, and the C １－４ alkyl, C ２－５ alkenyl, C ２－５ alkynyl and C ３－６ cycloalkyl are each independently optionally substituted by 1, 2 or 3 R ｄ ; R ３ is selected from H, F, Cl, Br, I and C １－３ alkyl, said C １－３ alkyl is optionally substituted by one, two or three Rs ｂ and R ４ is selected from OH, CN and -(OCH ２ CH ２ ) ｎ -C １－３ alkoxy, and n is 0 or 1, Ring A is selected from phenyl, 5- to 6-membered heteroaryl, and C5-6 cycloalkenyl, and the phenyl, 5- to 6-membered heteroaryl, and C5-6 cycloalkenyl are each independently optionally substituted by 1, 2, or 3 R ｃ groups Each R ａ and each R ｂ is independently selected from H, F, Cl, Br, I, and OH, Alternatively, two Rs on the same carbon atom ａ are linked to form C ３－６ cycloalkyl or 4- to 6-membered heterocycloalkyl, and the C ３－６ cycloalkyl or 4- to 6-membered heterocycloalkyl is each independently optionally substituted by one, two or three halogens. Alternatively, two Rs on different carbon atoms are linked to form a C ａ cycloalkyl, and said C ３－６ cycloalkyl is optionally substituted by one, two or three halogens, ３－６ ​ Each R ｃ is independently selected from H, F, Cl, Br, I and C １－３ alkyl, and said C １－３ alkyl is optionally substituted by one, two or three halogens Each R ｄ is independently selected from H, F, Cl, Br, I, OH, NH ２ , C １－３ alkyl and C ３－６ cycloalkyl, wherein said C １－３ alkyl and C ３－６ cycloalkyl are each independently optionally substituted by one, two or three halogens, The condition is that T ４ is selected from C(R ３ ), ２ T is selected from C(R ３ ), ３ T is selected from C(R ２ O), T ２ is selected from C, T １ is selected from N, L １ is selected from CH ２ The ring A is selected from phenyl or 5- to 6-membered heteroaryl optionally substituted by 1, 2 or 3 R ｃ When R １ is selected from O, R ２ is F, Cl, Br, I, OH, NH ２ , CN, C １－４ alkyl, C ２－５ alkenyl, C ２－５ alkynyl and C ３－６ cycloalkyl, and the C １－４ alkyl, C ２－５ alkenyl, C ２－５ alkynyl and C ３－６ cycloalkyl are each independently optionally substituted by 1, 2 or 3 R ｄ ), the "hetero" of the 5- to 6-membered heteroaryl or 4- to 6-membered heterocycloalkyl represents 1, 2 or 3 heteroatoms or heteroatomic groups independently selected from O, NH, S, S(=O), N and C(=O).)

2. Each R ｃ is independently selected from H, F, Cl, Br, I, and CH ３ wherein said CH ３ is optionally substituted with one, two or three halogens, or each R ｃ is independently selected from H, F, Cl, Br, I, CH ３ and CF ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from.

3. Each R ｄ is independently selected from H, F, OH, NH ２ , CH ３ and cyclopropyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. L ２ and L ３ are each independently a single bond, CH ２ CH ２ CH ２ and C(CH ３ ) ２ selected from, said CH ２ CH ２ CH ２ and C(CH ３ ) ２ are each independently optionally substituted by 1, 2 or 3 R ａ or, L ２ and L ３ are each independently a single bond, CH ２ CF ２ CH ２ CH ２ C(CH ３ ) ２ C(CF ３ ) ２ ​ [Chemical Formula 3] The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from

5. Structural unit - L ２ -L ３ - is -CH ２ C(CH ３ ) ２ -, 【Chemical Formula 4】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from

6. R １ is O, NOH, NCN, NOCH ３ , NOCH ２ CH ３ and NOCH ２ CH ２ OCH ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from

7. R ２ is H, F, Cl, Br, I, OH, NH ２ , CN, CH ３ , cyclopropyl, [Chemical Formula 5] selected from, said CH ３ , cyclopropyl, 【Chemical Formula 6】 is independently replaced by one, two or three Rs ｄ optionally, or R ２ is H, F, Cl, Br, I, OH, NH ２ , CN, CH ３ , 【Chemical Formula 7】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from

8. R ３ is H, F, Cl, Br, I, CH ３ , CH ２ F, CHF ２ , CF ３ and 【Chemical Formula 8】 selected from, or R ３ is H, CH ３ and CHF ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from.

9. T ３ is O, CH ２ O, CH and C(CH ３ ) selected from the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. T ４ is the compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from CH(CHF ２ ), N and C(=O).

11. Ring A is selected from phenyl, pyridyl, and cyclohexenyl, and the phenyl, pyridyl, and cyclohexenyl are each independently optionally substituted by one, two, or three Rs ｃ or Ring A is 【Chemical Formula 9】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from

12. Structural unit 【Chemical 10】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from

13. Structural unit 【Chemical 11】 The compound according to claim 12 or a pharmaceutically acceptable salt thereof, selected from

14. The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, selected from the compounds represented by the following formula. 【Chemical Formula 12】 (However, R １ 、R ２ 、R ３ 、T １ 、T ２ 、L １ 、L ２ 、L ３ 、ring A and 【Chemical 13】 is as defined in any one of claims 1 to 13, R ３ When R is not H, the carbon atom marked with "*" is a chiral carbon atom and exists as a single enantiomer of (R) or (S) or in a form enriched in one enantiomer.)

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, selected from the compounds represented by the following formula. 【Chemical 14】 (However, R ３ is selected from F, Cl, Br, I, and C １－３ alkyl, and said C １－３ alkyl is optionally substituted by one, two or three R ｂ groups, R １ 、R ２ 、L ２ 、L ３ 、ring A and each R ｂ are as defined in claim 14.)

16. A compound represented by the following formula or a pharmaceutically acceptable salt thereof. 【Chemical Formula 15】 【Chemical 16】 【Chemical 17】

17. Use of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating an ALK inhibitor-related disease.

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