Benzylamine derivatives, their preparation method and uses

Abstract

The present invention relates to benzylamine derivatives, their preparation methods and uses, and in particular to benzylamine derivatives represented by general formula (I) or pharmaceutically acceptable stereoisomers, salts, solvates or prodrugs thereof, which have strong binding ability to human PD-L1, can significantly inhibit PD-1 / PD-L1 interaction, and have significant anti-tumor effects in vivo. Accordingly, the present invention also relates to methods for preparing the benzylamine derivatives and their use in preparing therapeutic agents for PD-1 / PD-L1-associated diseases. [Formula 1] JPEG2023539043000149.jpg5357

Description

[Technical Field]

[0001] The present invention belongs to the field of biomedical technology and relates to benzylamine derivatives that can block PD-1 / PD-L1 interaction, and to methods for preparing the compounds and their use in the manufacture of medicaments for the treatment of PD-1 / PD-L1-related diseases. [Background technology]

[0002] This application claims priority from Chinese Patent Application No. 202010801978.3, filed on April 11, 2020. The disclosure of the Chinese Patent Application is incorporated herein by reference.

[0003] Tumor immunotherapy has made great progress in recent years. Unlike conventional treatments such as chemoradiotherapy and targeted therapy, tumor immunotherapy primarily kills tumors by overcoming immunosuppression within the patient and reactivating the patient's own immune cells.

[0004] Currently, immune checkpoint PD-1 / PD-L1 inhibitors have been one of the most notable advances in tumor immunotherapy. PD-1 (programmed cell death protein 1) is expressed on T cells, B cells, NK cells, and monocytes. Its ligand, PD-L1 (programmed cell death protein-ligand 1), is highly expressed on the surface of tumor cells and can bind to PD-1 on the surface of T cells. The binding of PD-1 and PD-L1 generates a negative regulatory signal that suppresses T cell immune activity, allowing tumor cells to evade immune system recognition and attack, enabling immune escape and survival. Blocking PD-1 / PD-L1 interaction has been well-documented through numerous preclinical studies and the launch of monoclonal antibodies, effectively restoring T cell immune function, enabling the immune system to recognize and eliminate tumor cells, and suppressing tumor growth.

[0005] Between 2014 and 2017, five monoclonal antibody PD-1 / PD-L1 inhibitors were available on the global market: pembrolizumab (Keytruda®), nivolumab (Opdivo®), atezolizumab (Tecentriq®), avelumab (Bavencio®), and durvalumab (Imfinzi®). In December 2018, domestic PD-1 inhibitors from Junshi Biosciences (toripalimab) and Innovent Biologics (sintilimab) received marketing approval from the CFDA. In December 2019, BeiGene's PD-1 inhibitor tislelizumab was approved for marketing. According to the FDA's clinical trials website (www.clinicaltrials.gov), as of September 2018, 2,250 clinical trials of monoclonal antibody PD-1 / PD-L1 inhibitors were being conducted worldwide to examine their combined effects with other anti-tumor drugs or to expand their indications.

[0006] However, the clinical application of PD-1 / PD-L1 inhibitors is severely limited by the high price of antibody drugs due to their high manufacturing costs, their susceptibility to immune-related side effects, poor stability, the need for low-temperature storage and transportation, the inconvenience of administration (oral administration is ineffective and requires intravenous injection), inadequate PK (small volume of distribution, long elimination half-life), and low efficacy rate (only 20-40% efficacy rate for most solid tumors).

[0007] Small molecule drugs have advantages such as low cost, effective oral administration, good stability, fewer side effects on the immune system, and easy tumor penetration for improved efficacy. Compared with monoclonal antibodies, small molecule drugs have a wider range of clinical applications.

[0008] Currently, research into PD-1 / PD-L1 small molecule inhibitors has only just begun, with most reported compounds still in the preclinical research stage, and no marketed drugs exist. It remains unclear whether existing compounds can successfully address the shortcomings of monoclonal antibodies in clinical applications. Therefore, efficient and novel small molecule inhibitors of PD-1 / PD-L1 remain a topic of ongoing research and development. Summary of the Invention [Problem to be solved by the invention]

[0009] One object of the present invention is to provide benzylamine derivatives or pharmaceutically acceptable stereoisomers, salts, solvates or prodrugs thereof that inhibit the PD-1 / PD-L1 interaction, as well as pharmaceutical compositions containing any of the foregoing components, methods for preparing the benzylamine derivatives, and their use in the manufacture of medicaments for the prevention and treatment of PD-1 / PD-L1-associated diseases. [Means for solving the problem]

[0010] In one aspect, the present application provides a benzylamine derivative of general formula (I), or a pharmaceutically acceptable stereoisomer, salt, solvate or prodrug thereof:

[0011] [ka]

[0012] During the ceremony, R is selected from the group consisting of hydrogen and C1-C8 alkyl; R1 is selected from the group consisting of hydrogen, deuterium, halogen, C1-C4 alkyl, deuterated C1-C4 alkyl, halogenated C1-C4 alkyl, and C1-C4 alkoxy; R2 is selected from the group consisting of:

[0013] [ka]

[0014] R6 is selected from the group consisting of halogen, C1-C4 alkyl, deuterated C1-C4 alkyl, halogenated C1-C4 alkyl, and C1-C4 alkoxy; R7 is located at the meta or ortho position relative to R6; R7 is hydrogen, —O—(CH2) n -R0, -CONH-R0 and -(CH2) n -R0, n is an integer from 1 to 4, and R0 is cyano, hydroxyl, carboxyl, amino, or a heteroatom-containing linear or cyclic hydrophilic substituent; R3 is selected from R8-CH2-, where R8 is hydrogen, cyano, C1-C4 alkyl, halogenated C1-C4 alkyl, C2-C4 alkenyl, -NR9R10, -CONR9R 10 , 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl and 5-10 membered heteroaryl, optionally C1-C4 alkyl, halogenated C1-C4 alkyl, C2-C4 alkenyl, -NR9R 10 , -CONR9R 10 , 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl are each independently cyano, halogen, carboxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylsulfonyl, 3- to 6-membered cycloalkyl, hydroxyl-substituted 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, hydroxyl-substituted 3- to 6-membered heterocycloalkyl, -CONR9R 10 and -NR9COR 10 and each occurrence of R and R is independently substituted with one or more substituents selected from the group consisting of 10 are each independently selected from the group consisting of hydrogen, deuterium, and C1-C4 alkyl; R4 is a hydroxyl, a carboxyl, an amino acid (preferably a hydrophilic amino acid) fragment, and -NR 10 R 11 and R 10 and R11 are each independently selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, and 3- to 6-membered cycloalkyl, and optionally the C1-C6 alkyl and 3- to 6-membered cycloalkyl are each independently substituted with one or more substituents selected from the group consisting of mercapto, hydroxyl, carboxyl, hydroxyl-substituted C1-C6 alkyl, C1-C6 amido, and 3- to 6-membered nitrogen-containing heterocycloalkyl; or R 10 and R 11 together with the N atom to which it is attached, form a 5-6 membered heterocycloalkyl, which may optionally be substituted with one or more groups selected from the group consisting of amino, hydroxyl, carboxyl, mercapto, and hydroxyl-substituted C1-C6 alkyl; R5 is selected from the group consisting of hydrogen, deuterium, cyano, halogen, C1-C4 alkyl, C2-C4 alkenyl, deuterated C1-C4 alkyl, halogenated C1-C4 alkyl, and C1-C4 alkoxy; Y and Z are each independently selected from the group consisting of carbon and nitrogen. [Effects of the Invention]

[0015] The compounds of the present invention have strong binding ability to human PD-L1, have the activity of significantly inhibiting the PD-1 / PD-L1 interaction, and have significant anti-tumor effects in vivo. [Brief explanation of the drawings]

[0016] [Figure 1] FIG. 1 shows the tumor growth curve over time when 15 mg / kg of compound 5 was intraperitoneally administered to PD-1 humanized mice. [Figure 2] FIG. 1 shows the time-course body weight accumulation curve when 15 mg / kg of Compound 5 was intraperitoneally administered to PD-1 humanized mice. DETAILED DESCRIPTION OF THE INVENTION

[0017] The drawings described in this specification are used to further explain the present invention and constitute a part of this application. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute undue limitations on the present invention.

[0018] In some embodiments, the benzylamine derivative is as shown in formula (IA).

[0019] [ka]

[0020] wherein R, R, R, R, R, R, R, and R are as defined above, and R is located at the para or meta position of -OR. In some preferred embodiments, R is located at the para position of -OR.

[0021] In some embodiments, the structure of the benzylamine derivative is as shown in formula (IB).

[0022] [ka]

[0023] wherein R, R1, R2, R3, R4 and R5 are as defined above, at least one of Z and Y is nitrogen, and R5 is located at the para or meta position of -OR3.

[0024] In some embodiments, the benzylamine derivative has a structure represented by formula (IC):

[0025] [ka]

[0026] In the formula, R, R1, R2, R3, R4, and R5 are as defined above, and R5 is located at the para or meta position of -OR3.

[0027] In some embodiments, R in any of formulas I, IA, IB, and IC is selected from the group consisting of hydrogen and methyl. In some preferred embodiments, R in any of formulas I, IA, IB, and IC is hydrogen.

[0028] In some embodiments, R1 in any of formulas I, IA, IB, and IC is selected from the group consisting of halogen, C1-C2 alkyl, and halogenated C1-C2 alkyl. In some embodiments, R 1 in any of formulae I, IA, IB, and IC is bromo, methyl, or trifluoromethyl. In some embodiments, R1 in any of formulas I, IA, IB, and IC is selected from the group consisting of halogen and C1-C2 alkyl. In some preferred embodiments, R1 in any of formulas I, IA, IB, and IC is bromo or methyl. In some embodiments, R 1 in any of formulas I, IA, IB, and IC is selected from the group consisting of fluoro, chloro, bromo, iodo, methoxy, methyl, cyano, deuterated methyl, and halogenated methyl.

[0029] In some embodiments, R2 in any of formulas I, IA, IB, and IC is selected from the group consisting of:

[0030] [ka]

[0031] R6 is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methoxy, methyl, cyano, deuterated methyl, and halogenated methyl. R7 is located in the meta or ortho position relative to R6, and R7 is hydrogen, -O-(CH2) n -R0, -CONH-R0 and -(CH2) n-R0, where n is an integer from 1 to 4, and R0 is selected from the group consisting of cyano, hydroxyl, carboxyl, amino, and heteroatom-containing linear or cyclic hydrophilic substituents.

[0032] In some embodiments, R2 in any of formulas I, IA, IB, and IC is selected from the group consisting of:

[0033] [ka]

[0034] In some embodiments, R3 in any of formulas I, IA, IB, and IC is selected from R8-CH2-, where R8 is selected from the group consisting of hydrogen, C1-C2 alkyl, phenyl, and 5-6 membered heteroaryl, and optionally, C1-C2 alkyl, phenyl, and 5-6 membered heteroaryl are each independently substituted with one cyano.

[0035] In some embodiments, R3 in any of formulas I, IA, IB, and IC is selected from the group consisting of:

[0036] [ka]

[0037] In some embodiments, R3 in any of formulas I, IA, IB, and IC is selected from the group consisting of:

[0038] [ka]

[0039] In some embodiments, R4 in any of Formulas I, IA, IB, and IC is a fragment of an amino acid and -NR 10 R 11 where R 10and R 11 are each independently selected from the group consisting of hydrogen, deuterium, and C1-C6 alkyl, optionally C1-C6 alkyl being substituted with one or more substituents selected from the group consisting of mercapto group, hydroxyl, carboxyl, hydroxyl-substituted C1-C4 alkyl, C1-C4 amido, and 5- to 6-membered nitrogen-containing heterocycloalkyl; or R 10 and R 11 together with the N atom attached thereto, form a 5-6 membered heterocycloalkyl, optionally substituted with one or more groups selected from the group consisting of amino, hydroxyl, carboxyl, mercapto, and hydroxyl-substituted C1-C4 alkyl; the amino acid fragment is selected from the fragment obtained by losing one hydrogen of the amino that shares a carbon atom with the carboxyl. In some preferred embodiments, the amino acid is selected from the group consisting of:

[0040] [ka]

[0041] In some preferred embodiments, the amino acids are selected from serine, hydroxyproline, and asparagine.

[0042] In some embodiments, R4 in any of formulas I, IA, IB, and IC is selected from the group consisting of:

[0043] [ka]

[0044] In some embodiments, R 4 in any of formulas I, IA, IB, and IC is selected from the group consisting of:

[0045] [ka]

[0046] In some embodiments, R5 in any of formulas I, IA, IB, and IC is selected from the group consisting of hydrogen, deuterium, halogen, C1-C2 alkyl, and C1-C2 alkoxy, such as hydrogen, chlorine, methoxy, or methyl. In some embodiments, R5 in any of formulas I, IA, IB, and IC is selected from the group consisting of fluorine, chlorine, bromine, iodine, methoxy, methyl, cyano, deuterated methyl, halogenated methyl, ethyl, vinyl, and ethoxy. In some embodiments, R5 in any of formulas I, IA, IB, and IC is selected from the group consisting of hydrogen, deuterium, halogen, and C1-C2 alkyl, such as hydrogen, chlorine, or methyl.

[0047] In some embodiments, in any of formulas I, IA, IB, and IC, R is hydrogen; R5 is selected from the group consisting of hydrogen, chlorine, and methyl, and R5 is in the para position of -OR3.

[0048] In some embodiments, in any of formulas I, IA, IB, and IC: R is selected from hydrogen and C1-C8 alkyl; R1 is selected from halogen and C1-C4 alkyl;

[0049] R2 is the following group

[0050] [ka]

[0051] R6 is selected from the group consisting of halogen, C1-C4 alkyl, deuterated C1-C4 alkyl, halogenated C1-C4 alkyl, and C1-C4 alkoxy; R7 is in the meta or ortho position relative to R6; R7 is hydrogen, —O—(CH2) n -R0, -CONH-R0, and -(CH2)n -R0, where n is an integer from 1 to 4, and R0 is cyano, hydroxyl, carboxyl, amino, or a heteroatom-containing linear or cyclic hydrophilic substituent;

[0052] R3 is selected from R8-CH2-, where R8 is selected from the group consisting of 6- to 10-membered aryl substituted with one or more cyano groups, and 5- to 10-membered heteroaryl optionally substituted with one or more cyano groups;

[0053] R4 is the following group

[0054] [ka]

[0055] wherein R5 is selected from the group consisting of halogen and C1-C4 alkyl, and R5 is in the para position of -OR3; Y and Z are each independently selected from the group consisting of carbon and nitrogen.

[0056] In some embodiments, in formula IA: R is selected from the group consisting of hydrogen and methyl; R1 is selected from the group consisting of halogen and C1-C2 alkyl;

[0057] R2 is selected from the group consisting of:

[0058] [ka]

[0059] R3 is selected from the group consisting of:

[0060] [ka]

[0061] R4 is selected from the group consisting of:

[0062] [ka]

[0063] R5 is selected from the group consisting of halogen and C1-C4 alkyl, and R5 is -OR 3 It is in the para rank.

[0064] In some embodiments, in any of formulas I, IA, IB, and IC: R is hydrogen; R1 is bromine or methyl; R2 is as follows:

[0065] [ka]

[0066] R3 is selected from the group consisting of:

[0067] [ka]

[0068] R4 is selected from the following:

[0069] [ka]

[0070] R5 is selected from the group consisting of hydrogen, chlorine and methyl, and R5 is in the para position to -OR3.

[0071] In some embodiments, the benzylamine derivative is selected from the following:

[0072] [ka]

[0073] [ka]

[0074] In some embodiments, the pharmaceutically acceptable salt of the benzylamine derivative is selected from the group consisting of salts formed with organic or inorganic acids (e.g., hydrochloride, sulfate, phosphate, hydrobromide, hydroiodide, nitrate, bisulfate, oxalate, formate, acetate, citrate, tartrate, sulfonate, benzoate, trifluoroacetate, maleate, or citrate, etc.), salts formed with alkali metals or alkaline earth metals (e.g., lithium, sodium, potassium, magnesium, and calcium or ammonium salts, etc.), and salts formed with organic bases (e.g., methylamine, ethylamine, triethylamine, piperidine, morpholine, etc.). In some embodiments, the pharmaceutically acceptable salt of the benzylamine derivative is their hydrochloride salt.

[0075] As used herein, the term "halogen" means fluorine, chlorine, bromine and iodine.

[0076] As used herein, the term "C1-C8 alkyl" means a straight-chain or branched alkyl containing 1 to 8 carbon atoms, including C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, and C1-C2 alkyl, representative examples of which are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, and the like.

[0077] As used herein, the term "C1-C4 alkoxy" refers to a group formed in the form of C1-C4 alkyl-O-, where "C1-C4 alkyl" is as defined above, such as C1-C3 alkoxy and C1-C2 alkoxy. Representative examples are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, and the like.

[0078] As used herein, the term "C2-C4 alkenyl" refers to a straight or branched chain hydrocarbon having at least one carbon-carbon double bond and containing 2 to 4 carbon atoms, representative examples of which include vinyl, propenyl, 2-propenyl, butenyl, 2-butenyl, butadienyl, etc.

[0079] As used herein, the term "deuterated" refers to a group obtained by replacing at least one hydrogen atom in the group with a deuterium isotope, for example, a deuterated C1-C4 alkyl.

[0080] As used herein, the term "halogenated" refers to a group obtained by substituting at least one hydrogen atom in a group with the aforementioned halogen, such as halogenated C1-C4 alkyl, halogenated C1-C4 alkoxy, etc. A representative example thereof is trifluoromethyl.

[0081] As used herein, the term "hydrophilic substituent" refers to a group that easily binds with water, and the hydrophilic group typically contains at least one hydrophilic functional group such as hydroxyl, amino, carboxyl, sulfonic acid group, or phosphate group. In some embodiments, the hydrophilic substituent is a linear or cyclic hydrophilic substituent containing a heteroatom. Specific examples include, but are not limited to, the following:

[0082] [ka]

[0083] As used herein, the term "3- to 6-membered cycloalkyl" refers to a saturated cyclic hydrocarbon containing 3 to 6 ring-forming carbon atoms, such as a 3-membered cycloalkyl, a 4-membered cycloalkyl, a 5-membered cycloalkyl, or a 6-membered cycloalkyl. Representative examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0084] As used herein, the term "3- to 6-membered heterocycloalkyl" refers to a saturated cyclic hydrocarbon containing 3 to 6 ring members, in which at least one (e.g., 1, 2, 3, or 4) ring member is a heteroatom selected from the group consisting of N, O, and S, such as a 3-membered heterocycloalkyl, a 4-membered heterocycloalkyl, a 5-membered heterocycloalkyl, or a 6-membered heterocycloalkyl. For example, a 3- to 6-membered nitrogen-containing heterocycloalkyl. Representative examples include ethylene oxide, butylene oxide, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperazinyl, oxazinyl, and the like.

[0085] As used herein, the term "6- to 10-membered aryl" refers to an aromatic group of 6 to 10 ring-forming carbon atoms, such as phenyl or naphthyl.

[0086] As used herein, the term "5-10-membered heteroaryl" refers to an aromatic group containing 5 to 10 ring members, wherein at least one (e.g., 1, 2, 3, or 4) ring member is a heteroatom selected from the group consisting of N, O, and S. The heteroaryl may be a monocyclic heteroaryl, a bicyclic heteroaryl, or a polycyclic heteroaryl, such as a 5- or 6-membered heteroaryl. Representative examples include furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, and the like.

[0087] As used herein, the term "C1-C4 alkylsulfonyl" refers to a group formed in the form of C1-C4 alkyl-SO2-, where "C1-C4 alkyl" is as defined above, and refers to, for example, C1-C3 alkylsulfonyl and C1-C2 alkylsulfonyl. A representative example is methanesulfonyl.

[0088] As used herein, the term "C1-C6 amide" refers to a group formed in the form of C1-C5 alkyl-CONH-, where "C1-C5 alkyl" is as defined above, such as C1-C4 alkylamide and C1-C2 alkylamide. Typical examples are formamide, acetamide, etc.

[0089] As used herein, the term "stereoisomer" refers to an isomer resulting from a difference in the spatial arrangement of atoms in a molecule, and includes cis-trans isomers, enantiomers, and diastereomers. The stereoisomers of the present invention include any of the above-mentioned stereoisomers of a benzylamine derivative, and a mixture in which one or more stereoisomers are formed in any ratio.

[0090] As used herein, the term "solvate" refers to a stable complex formed by the interaction between a benzylamine derivative described herein and a solvent (e.g., an organic solvent such as methanol or ethanol, or water) that forms a stable complex. In some embodiments, the solvent may function as a structural element of the crystal lattice of the benzylamine derivative. In some embodiments, the solvent may be present in stoichiometric or non-stoichiometric proportions.

[0091] As used herein, the term "prodrug" refers to a derivative of a benzylamine derivative described herein that contains a biologically reactive functional group that can be cleaved or reacted with other biochemical groups under biochemical conditions to produce a benzylamine derivative, including, but not limited to, phosphates, esters, amides, and ureides of the benzylamine derivatives described herein that are hydrolyzable under biochemical conditions.

[0092] In another aspect, the present invention provides a method for preparing a compound according to the first aspect, specifically as follows:

[0093] When the benzylamine derivative of general formula (I) has a structure represented by formula (IA), the preparation method thereof is selected from the following methods I to III.

[0094] [ka]

[0095] When the benzylamine derivative of general formula (I) has a structure represented by formula (IB), its preparation method is selected from the following Method IV or Method V.

[0096] [ka]

[0097] When the benzylamine derivative of general formula (I) has a structure represented by formula (IC), its preparation method is selected from the following Method VI or Method VII.

[0098] [ka]

[0099] Unless otherwise specified, the substituents appearing in the above compounds are as described in any one of the first aspects of the invention.

[0100] In another aspect, the present invention provides a pharmaceutical composition comprising a benzylamine derivative according to any one of the first aspect of the present invention, or a pharmaceutically acceptable stereoisomer, salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0101] A carrier refers to a substance used to improve the selectivity, efficacy, and / or safety of a drug when administered. It is primarily used to control the release of a drug and can also be used to improve the pharmacokinetic properties of a drug, particularly bioavailability. An excipient refers to a substance other than the active ingredient in a pharmaceutical formulation, and is primarily used to improve long-term stability, fill a solid formulation (hence often specifically referred to as a "filler"), or improve the effectiveness of the product (e.g., enhance absorption, reduce viscosity, improve solubility, etc.). Depending on the route of administration or dosage form, those skilled in the art can select appropriate carriers and excipients based on known theory and experience. In some embodiments, carriers or excipients include, but are not limited to, magnesium stearate, alumina, glycerol, lecithin, serum albumin, cellulose-based materials, PEG, beeswax, lanolin, potassium sorbate, lactose, starch, coconut oil, and vegetable oils.

[0102] The pharmaceutical composition of the present invention can be prepared in various forms depending on different administration routes.

[0103] In some embodiments, the pharmaceutical composition can be administered by any of the following methods: oral administration, inhalation spray, rectal administration, nasal administration, buccal administration, vaginal administration, topical administration, parenteral administration (including subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, ventricular / intraventricular, intrasternal and intracranial injection or infusion), or administration via an explanted container, of which oral, intraperitoneal or intravenous administration is preferred.

[0104] For oral administration, the benzylamine derivative, or its pharmaceutically acceptable stereoisomer, salt, solvate, or prodrug, can be formulated into any orally acceptable formulation, including, but not limited to, tablets, capsules, aqueous solutions, and suspensions. Common carriers for tablets include lactose, cornstarch, etc., and lubricants such as magnesium stearate can also be added. Common diluents for capsules include lactose, dried cornstarch, etc. Aqueous suspensions are usually prepared by mixing the active ingredient with suitable emulsifiers and suspending agents. If desired, sweeteners, flavors, or coloring agents can also be added to the oral formulations described above.

[0105] For rectal administration, the benzylamine derivative, or its pharmaceutically acceptable stereoisomer, salt, solvate, or prodrug, can generally be made into a suppository form, which is prepared by mixing the drug with a suitable non-irritating excipient. The excipient is solid at room temperature but melts at rectal temperature to release the drug. Such excipients include cocoa butter, beeswax, polyethylene glycol, etc.

[0106] When treating affected surfaces or organs that are amenable to topical administration, particularly those involving the eyes, skin, or lower enteric nervous system disorders, the benzylamine derivatives or pharmaceutically acceptable stereoisomers, salts, solvates, or prodrugs thereof can be formulated into different topical preparations depending on the affected surfaces or organs, specifically as follows:

[0107] For topical administration to the eye, the benzylamine derivative or its pharmaceutically acceptable stereoisomer, salt, solvate or prodrug can be formulated in the form of a fine powder suspension or solution, and the carrier used is isotonic sterile saline with a defined pH, with or without the addition of a preservative such as benzyl alkoxide chloride. In addition, for ophthalmic use, it can be formulated in the form of an ointment, such as petrolatum ointment.

[0108] For topical administration to the skin, the benzylamine derivative, or its pharmaceutically acceptable stereoisomer, salt, solvate, or prodrug, can be formulated into a suitable ointment, lotion, or cream in which the active ingredient is suspended or dissolved in one or more carriers. Carriers that can be used for ointments in the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax, water, etc. Carriers that can be used for lotions or creams include, but are not limited to, mineral oil, sorbitan monostearate, Tween 60, cetyl ester wax, cetyl aryl alcohol, 2-octyldodecanol, benzyl alcohol, and water, etc.

[0109] For topical administration to the lower intestinal tract, the benzylamine derivative, or a pharmaceutically acceptable stereoisomer, salt, solvate, or prodrug thereof, can be formulated as a rectal suppository, as described above, or in a suitable enema formulation. Additionally, topical transdermal patches can also be used.

[0110] In addition, benzylamine derivatives or their pharmaceutically acceptable stereoisomers, salts, solvates, or prodrugs can be administered in the form of sterile injectable preparations such as sterile injectable aqueous or oily suspensions or sterile injectable solutions. Usable carriers and solvents include water, Ringer's solution, isotonic sodium chloride solution, etc. Additionally, sterile, fixed oils such as monoglycerides and diglycerides can also be used as solvents or suspending media.

[0111] The above-mentioned various dosage forms of the drugs can be prepared according to conventional methods in the pharmaceutical field.

[0112] In another aspect, the present invention provides use of a benzylamine derivative, or a pharmaceutically acceptable stereoisomer, salt, solvate or prodrug thereof, or pharmaceutical composition thereof in the manufacture of a medicament for the prevention or treatment of a PD-1 / PD-L1 associated disease.

[0113] In another aspect, the present invention provides a benzylamine derivative, or a pharmaceutically acceptable stereoisomer, salt, solvate or prodrug thereof, or pharmaceutical composition thereof for use in the prevention or treatment of a PD-1 / PD-L1 associated disease.

[0114] In another aspect, the present invention provides a method for preventing or treating a PD-1 / PD-L1 associated disease, comprising administering to a subject in need thereof an effective amount of a benzylamine derivative, or a pharmaceutically acceptable stereoisomer, salt, solvate or prodrug thereof, or a pharmaceutical composition.

[0115] In another aspect, the present invention provides a method for inhibiting PD-1 / PD-L1 interaction, comprising administering to a subject in need thereof an effective amount of a benzylamine derivative, or a pharmaceutically acceptable stereoisomer, salt, solvate or prodrug thereof, or a pharmaceutical composition.

[0116] In another aspect, the present invention provides a method of increasing an immune response, comprising administering to a subject in need thereof an effective amount of a benzylamine derivative, or a pharmaceutically acceptable stereoisomer, salt, solvate or prodrug thereof, or a pharmaceutical composition.

[0117] The PD-1 / PD-L1 associated diseases described herein include tumors, infectious diseases, and autoimmune diseases.

[0118] In some embodiments, the tumor is one or more selected from the group consisting of a tumor of the digestive system, a tumor of the urinary system, a tumor of the blood system, a tumor of the nervous system, a tumor of the reproductive system, skin cancer, lung cancer, breast cancer, head and neck cancer, brain tumor, glioma, nasopharyngeal tumor, and the like.

[0119] In some embodiments, the infectious disease is selected from one or more infections caused by microorganisms, hi some embodiments, the infectious disease is an infection caused by bacteria and viruses.

[0120] In some embodiments, the autoimmune disease is selected from the group consisting of chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, pulmonary hemorrhagic nephritic syndrome, pemphigus (e.g., pemphigus vulgaris), pemphigoid, primary biliary cirrhosis, multiple cerebral sclerosis, acute idiopathic polyneuropathy, etc., systemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis, scleroderma, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune disease, Sjogren's syndrome, ankylosing spondylitis, polyarteritis nodosa, Wegener's granulomatosis, etc.

[0121] As used herein, the term "therapeutically effective amount" or "prophylactically effective amount" refers to an amount that is sufficient, within the scope of sound medical judgment, to treat or prevent a disease in a patient, but small enough to avoid significant side effects (at a reasonable benefit / risk ratio). A therapeutically effective amount of a compound will depend on factors such as the specific compound selected (which may take into account, for example, the potency, efficacy, and half-life of the compound), the selected route of administration, the disease being treated, the severity of the disease being treated, the age, size, weight, and physical condition of the patient being treated, the medical history of the patient being treated, the duration of treatment, the nature of concurrent treatment, the desired therapeutic effect, and the like, but can be routinely determined by one of ordinary skill in the art.

[0122] In addition, it should be noted that the specific dosage and method of use of a benzylamine derivative, or its pharmaceutically acceptable stereoisomer, salt, solvate, or prodrug, for each patient depends on many factors, such as the patient's age, weight, sex, natural health status, nutritional status, activity, administration time, drug metabolism rate, disease severity, and the subjective judgment of the treating physician. A dose ranging from 0.001 to 1000 mg / kg body weight / day is preferred.

[0123] Hereinafter, technical solutions in the embodiments of the present invention will be clearly and completely described with reference to the accompanying drawings. It should be apparent that the described embodiments are only a part of the embodiments of the present invention, but not all of the embodiments. The following description of at least one exemplary embodiment is merely exemplary in nature and is not intended to limit the present invention, its application, or uses in any way. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without any inventive efforts shall fall within the protection scope of the present invention. [Example]

[0124] [Example 1] (1) Synthesis of intermediate 1-1.

[0125] [ka]

[0126] 3-Bromo-2-methylbenzyl alcohol (2.51 g, 12.5 mmol), phenylboronic acid (2.29 g, 18.75 mmol), cesium acetate (5.99 g, 31.25 mmol), and PdCl(dppf) (0.917 g, 1.25 mmol) were reacted in 40 mL of THF under argon protection at reflux for 23 h, cooled, and concentrated. The residue was extracted three times with water and DCM. The organic phase was washed three times with water, concentrated, and purified by column chromatography to give 2.44 g of a brown solid in 98% yield. 1H NMR(400MHz,CDCl3):δ 7.44-7.32(m,4H),7.32-7.27(m,2H),7.26-7.23(m,1H),7.20(dd,J=7.6,1.2Hz,1H),4.77(s,2H),2.24(s,3H),1.70(s,1H). ESI-MS: m / z=181.11[M-OH] + .

[0127] (2) Synthesis of intermediate 1-2.

[0128] [ka]

[0129] 1-1 (1.51 g, 7.62 mmol) was dissolved in 30 mL of DCM and cooled to 0 °C in an ice bath. PBr3 (0.36 mL, 3.81 mmol) was added dropwise. After the addition, the resulting mixture was allowed to react for 20 min. Crushed ice was then added to quench the reaction. The mixture was extracted three times with DCM. The organic phase was washed once with saturated aqueous sodium bicarbonate, washed with water until neutral, dried over anhydrous Na2SO4, and filtered under suction. The filtrate was concentrated to dryness to give 1.32 g of a colorless oil in 66% yield. This was used directly in the next step without further purification. 1 H NMR (400MHz, CDCl3): δ 7.44-7.39(m,2H),7.38-7.32(m,2H),7.32-7.27(m,2H),7.22(d,J=2.8Hz,1H),7.21(s,1H),4.60(s,2H),2.30(s,3H). ESI-MS: m / z=181.10[M-Br] + .

[0130] (3) Synthesis of intermediate 1-3

[0131] [ka]

[0132] 2-Hydroxy-p-nitrobenzaldehyde (4.81 g, 28.78 mmol) was dissolved in 40 mL of DMF, followed by the addition of K2CO3 (5.97 g, 43.20 mmol), m-cyanobenzyl bromide (6.21 g, 31.68 mmol), and tetrabutylammonium iodide (50 mg, 0.14 mmol). The resulting mixture was reacted at room temperature for 4 hours, poured into 900 mL of ice water, and filtered under suction. The filter cake was washed with water until neutral, dried, dispersed in cyclohexane, ultrasonicated, and filtered under suction to give 8.05 g of a pale yellow powdery solid in 99% yield. This was used directly in the next step without further purification. 1 H NMR (400MHz, DMSO-d6): δ 10.49(s,1H),8.09(t,J=1.6Hz,2H),7.98-7.91(m,3H),7.86(d,J=7.6Hz,1H),7.66(t,J=7.8Hz,1H),5.51(s,2H). ESI-MS: m / z=281.06[MH] - .

[0133] (4) Synthesis of intermediate 1-4

[0134] [ka]

[0135] 1-3 (8.05 g, 28.52 mmol), Fe powder (5.59 g, 99.82 mmol), and NHCl (2.29 g, 42.81 mmol) were suspended in 100 mL of a 4:1 EtOH / HO mixed solvent and heated to reflux for 1.5 h. After 5 h of reaction, the mixture was cooled and suction filtered to remove insoluble materials. The filtrate was evaporated to dryness, water was added, and the mixture was sonicated and suction filtered to give 6.48 g of an orange powdery solid in 90% yield. This solid was used directly in the next step without further purification. 1H NMR (400MHz, DMSO-d6): δ 10.05 (s, 1H), 8.16-7.34 (m, 5H), 6.60-6.06 (m, 4H), 5.21 (s, 2H). ESI-MS: m / z=253.10[M+H] + .

[0136] (5) Synthesis of intermediate 1-5

[0137] [ka]

[0138] 1-2 (490 mg, 1.88 mmol) and 1-4 (567 mg, 2.25 mmol) were suspended in 15 mL of acetonitrile and 2 mL of DMF, and K2CO3 (392 mg, 2.84 mmol) was added. The mixture was refluxed for 11 h, concentrated, water was added, and the mixture was extracted three times with EA. The organic phase was washed with water until neutral, concentrated, and the residue was purified by column chromatography to give 460 mg of a pale yellow solid in a 57% yield. 1 H NMR(400MHz,CDCl3):δ 10.23(s,1H),7.75(d,J=8.4Hz,1H),7.72-7.66(m,2H),7.66-7.60(m,1 H),7.51(t,J=7.6Hz,1H),7.48-7.40(m,2H),7.40-7.35(m,1H),7.33-7. 27(m,3H),7.25-7.21(m,2H),6.32(dd,J=8.8,2.0Hz,1H),6.09(d,J=2. 0Hz, 1H), 5.14 (s, 2H), 4.67 (br, 1H), 4.40 (d, J=4.8Hz, 2H), 2.23 (s, 3H). ESI-MS: m / z=433.19[M+H] + .

[0139] (6) Synthesis of Compound 1

[0140] [ka]

[0141] 1-5 (100 mg, 0.23 mmol) and N-acetylethylenediamine (47 mg, 0.46 mmol) were dissolved in 2 mL of DCE and 0.5 mL of DMF, and glacial acetic acid (26 μL, 0.46 mmol) was added. The mixture was allowed to react for 24 h at 35 °C, followed by the addition of NaBH(OAc)3 (147 mg, 0.69 mmol). The resulting mixture was then added with water and extracted three times with DCM. The organic phase was washed three times with water, concentrated, purified by column chromatography, and recrystallized to give 42 mg of an earthy yellow powder. The yield was 35%. 1 H NMR(400MHz,DMSO-d6):δ 7.90(s,1H),7.80-7.76(m,3H),7.60(t,J=7.6Hz,1H),7.45(t,J=7.6Hz,2H),7.39-7.34(m,1H),7 .31-7.28(m,3H),7.19(t,J=7.6Hz,1H),7.10(dd,J=7.5,1.1Hz,1H),6.97(d,J=8.0Hz,1H),6.35(d ,J=2.0Hz,1H),6.15(dd,J=8.0,2.0Hz,1H),6.03(t,J=5.6Hz,1H),5.10(s,2H),4.23(d,J=5.6Hz,2 H),3.57(s,2H),3.11(q,J=6.4Hz,2H),2.52-2.50(m,2H),2.18(s,3H),1.81(br,1H),1.76(s,3H). ESI-HRMS: m / z calculated value (C 33 H 35 N4O2 + [M+H] + )519.2755, actual value 519.2754.

[0142] [Example 2]

[0143] [ka]

[0144] 1-5 (108 mg, 0.25 mmol) and ethanolamine (31 mg, 0.5 mmol) were dissolved in 3 mL of DCE, and glacial acetic acid (29 μL, 0.50 mmol) was added. The mixture was then incubated at room temperature for 12 hours. NaBH(OAc)3 (159 mg, 0.75 mmol) was then added and the reaction was continued for 12 hours. Water was then added, and the resulting mixture was extracted with a 10:1 mixture of DCM and MeOH. The organic phase was washed with water, concentrated, purified by column chromatography, and recrystallized to give 30 mg of an earth-yellow powder. The yield was 25%. 1 H NMR(400MHz,DMSO-d6):δ 7.90(s,1H),7.79(d,J=7.6Hz,2H),7.59(t,J=8.0Hz,1H),7.45(t,J=7.2Hz,2H),7.38-7.35(m ,1H),7.31-7.29(m,3H),7.19(t,J=7.6Hz,1H),7.10(d,J=7.2Hz,1H),6.96(d,J=8.0Hz,1H),6. 36(s,1H),6.15(d,J=7.8Hz,1H),6.03(t,J=5.6Hz,1H),5.10(s,2H),4.46(br,1H),4.23(d,J= 4.8Hz,2H),3.58(s,2H),3.44(t,J=5.2Hz,2H),2.53(t,J=6.0,2H),2.18(s,3H),1.90(br,1H). ESI-HRMS: m / z calculated value (C 31 H 31 N3NaO2 + [M+Na] + )500.2308, actual value 500.2307.

[0145] [Example 3]

[0146] [ka]

[0147] 1-5 (108 mg, 0.25 mmol) and 2-aminopropanediol (46 mg, 0.5 mmol) were dissolved in 2 mL of DCE and 0.5 mL of DMF. Glacial acetic acid (29 μL, 0.50 mmol) was added and the mixture was reacted at 35°C for 24 hours. NaBH(OAc)3 (159 mg, 0.75 mmol) was then added and the reaction was continued for another 24 hours. Water was then added, and the resulting mixture was extracted with a 10:1 mixture of DCM and MeOH. The organic phase was washed with water, concentrated, recrystallized, and purified to give 92 mg of an earth-yellow powder in 72% yield. 1 H NMR(400MHz,DMSO-d6):δ 8.31(br,2H),7.99(s,1H),7.88(d,J=8.0Hz,1H),7.79(d,J=7.6Hz,1H),7.57(t,J=8.0Hz,1H),7.47-7.44(m,2H),7.40-7 .35(m,1H),7.31(d,J=1.2Hz,1H),7.29(s,1H),7.26(d,J=7.6Hz,1H),7.19(t,J=7.6Hz,1H),7.10(d,J=7.6Hz,1H),7.07( d,J=8.4Hz,1H),6.40-6.35(m,2H),6.19(dd,J=8.0,1.6Hz,1H),5.41(br,1H),5.18-5.11(m,2H),4.25(d,J=5.2Hz,2H),4 .04(dd,J=43.6,12.8Hz,2H),3.78(dd,J=11.6,4.0Hz,1H),3.66(dd,J=11.2,7.2Hz,1H),3.19-3.16(m,1H),2.17(s,3H). ESI-HRMS: m / z calculated value (C 32 H 31 N3NaO4 + [M+Na] + )544.2207, actual value 544.2208.

[0148] [Example 4]

[0149] [ka]

[0150] 1-5 (216 mg, 0.50 mmol) and D-serine (105 mg, 1.0 mmol) were suspended in 2 mL of DMF, and glacial acetic acid (57 μL, 1.0 mmol) was added. The mixture was incubated at 35°C for 24 h. NaBH(OAc)3 (318 mg, 1.50 mmol) was then added and the reaction was continued for 24 h. Water was then added, and the resulting mixture was extracted with a 10:1 mixture of DCM and MeOH. The organic phase was washed with water and concentrated. The residue was purified by preparative liquid chromatography to give 180 mg of a pale yellow powder (69% yield). 1 H NMR(400MHz,DMSO-d6):δ 8.31(br,2H),7.99(s,1H),7.88(d,J=8.0Hz,1H),7.79(d,J=7.6Hz,1H),7.57(t,J=8.0Hz,1H),7.47-7.44(m,2H),7.40-7 .35(m,1H),7.31(d,J=1.2Hz,1H),7.29(s,1H),7.26(d,J=7.6Hz,1H),7.19(t,J=7.6Hz,1H),7.10(d,J=7.6Hz,1H),7.07( d,J=8.4Hz,1H),6.40-6.35(m,2H),6.19(dd,J=8.0,1.6Hz,1H),5.41(br,1H),5.18-5.11(m,2H),4.25(d,J=5.2Hz,2H),4 .04(dd,J=43.6,12.8Hz,2H),3.78(dd,J=11.6,4.0Hz,1H),3.66(dd,J=11.2,7.2Hz,1H),3.19-3.16(m,1H),2.17(s,3H). ESI-HRMS: m / z calculated value (C 32 H 31 N3NaO4 + [M+Na] + )544.2207, actual value 544.2208.

[0151] [Example 5] (1) Synthesis of Intermediate 5-1

[0152] [ka]

[0153] 1-1 (7.36 g, 37.14 mmol), phthalimide (6.56 g, 44.57 mmol), and PPh3 (13.64 g, 52.00 mmol) were added to a three-neck flask. Under Ar protection, 170 mL of anhydrous THF was added, cooled to 0 °C, and DEAD (9.06 g, 52.0 mmol) was added dropwise. After addition, the mixture was allowed to react at room temperature for 24 hours. The solvent was evaporated to dryness, and the residue was purified by column chromatography to obtain 11.21 g of a white solid in a 92% yield. 1 H NMR(400MHz,CDCl3):δ 7.92-7.86(m,2H),7.77-7.72(m,2H),7.43-7.38(m,2H),7.36-7.31(m,1H),7.3 0-7.26(m,2H),7.24-7.21(m,1H),7.20-7.12(m,2H),4.94(s,2H),2.34(s,3H). ESI-MS: m / z=328.13[M+H] + .

[0154] (2) Synthesis of intermediate 5-2

[0155] [ka]

[0156] 5-1 (11.21 g, 34.27 mmol) was dissolved in 210 mL of ethanol, and 85% hydrazine hydrate (3.63 g, 61.68 mmol) was added. The mixture was refluxed for 3 h, cooled, and 40 mL of 6 N aqueous HCl was added. The mixture was refluxed for 30 min. The reaction mixture was cooled to 0 °C and suction filtered to remove insoluble materials. The filtrate was concentrated and adjusted to pH 8-9 with saturated NaHCO3. The mixture was extracted with DCM. The organic phase was washed once with water, and the solvent was evaporated to dryness to give 6.5 g of a colorless oil in 96% yield. This was used directly in the next step without further purification. 1H NMR(400MHz,CDCl3):δ 7.43-7.37(m,2H),7.36-7.31(m,2H),7.30-7.27(m,2H),7.24(t,J=7.6Hz ,1H),7.15(dd,J=7.6,1.2Hz,1H),3.93(s,2H),2.22(s,3H),1.79(s,2H). ESI-MS: m / z = 198.13 [M+H] + .

[0157] (3) Synthesis of intermediate 5-3

[0158] [ka]

[0159] 4-Bromo-2-hydroxy-5-methylbenzaldehyde (430 mg, 2 mmol) was dissolved in 6 mL of acetonitrile, and K2CO3 (304 mg, 2.2 mmol), 5-chloromethylnicotinonitrile (336 mg, 2.2 mmol), and NaI (30 mg, 0.2 mmol) were added. The mixture was allowed to react at room temperature for 24 hours, diluted with 18 mL of water, filtered by suction to remove insoluble matter, and washed with water until neutral to give 649 mg of an earth-yellow powdery solid, which was used directly in the next step without further purification. 1 H NMR(400MHz,DMSO-d6):δ 10.37(s,1H),9.03(d,J=1.6Hz,1H),9.01(d,J=2.0Hz,1H),8.53(s,1H),7.68(s,1H),7.63(s,1H),5.40(s,2H),2.34(s,3H). ESI-MS: m / z=331.01[M+H] + .

[0160] (4) Synthesis of intermediate 5-4

[0161] [ka]

[0162] 5-2 (296 mg, 1.5 mmol), 5-3 (596 mg, 1.8 mmol), CsCO (733 mg, 2.25 mmol), BINAP (187 mg, 0.3 mmol), and Pd(OAc) (34 mg, 0.15 mmol) were suspended in 15 mL of dioxane and refluxed under Ar protection for 20 h. The mixture was concentrated, water was added, and the mixture was extracted with DCM. The organic phase was washed with water to neutrality and purified by column chromatography to give 300 mg of a pale yellow solid in 45% yield. 1 H NMR(400MHz,CDCl3):δ 10.21(s,1H),8.84(t,J=1.8Hz,2H),8.05(t,J=2.0Hz,1H),7.61(s,1H),7.46-7.42(m,2H),7.39-7.35(m,1H),7.3 3-7.30(m,2H),7.27-7.24(m,3H),6.08(s,1H),5.18(s,2H),4.50(br,1H),4.44(s,2H),2.25(s,3H),2.13(s,3H). ESI-MS: m / z=448.21[M+H] + .

[0163] (5) Synthesis of Compound 5

[0164] [ka]

[0165] 5-4 (750 mg, 1.68 mmol) and D-serine (350 mg, 3.36 mmol) were suspended in 12 mL of anhydrous DMF and 4 mL of anhydrous methanol. Glacial acetic acid (195 μL, 3.36 mmol) was added and the reaction was continued for 24 h at 35 °C. NaBH(OAc) (1.065 g, 5.04 mmol) was added and the reaction was continued for 24 h. Water was then added, and the resulting mixture was extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 350 mg of a white powdery solid in 39% yield. 1H NMR(400MHz,DMSO-d6):δ 8.88(dd,J=15.6,2.0Hz,2H),8.37(t,J=2.0Hz,1H),8.34(br,2H),7.48-7.44(m,2H),7.40-7.35(m,1H),7.35-7.34(m ,1H),7.33-7.32(m,1H),7.16(dd,J=7.6,1.8Hz,1H),7.12(t,J=7.2Hz,1H),7.07(dd,J=7.2,1.8Hz,1H),7.01(s,1H),6 .09(s,1H),5.72(t,J=5.6Hz,1H),5.38(br,1H),5.14(dd,J=18.8,13.2Hz,2H),4.35(d,J=5.6Hz,2H),4.04(dd,J=44.8 ,12.8Hz,2H),3.78(dd,J=11.2,4.4Hz,1H),3.64(dd,J=11.4,7.2Hz,1H),3.19-3.16(m,1H),2.19(s,3H),2.10(s,3H). ESI-HRMS: m / z calculated value (C 32 H 32 N4NaO4 + [M+Na] + )559.2316, actual value 559.2313.

[0166] [Example 6] (1) Synthesis of intermediate 6-1

[0167] [ka]

[0168] 2,4-Dihydroxy-6-methylbenzaldehyde (1.52 g, 10 mmol) was dissolved in 40 mL of DCM, and 2,6-dimethylpyridine (1.13 g, 10.5 mmol) and DMAP (245 mg, 2 mmol) were added. The mixture was cooled to 0 °C, and 15 mL of a DCM solution of TfO (2.96 g, 10.5 mmol) was added dropwise. The reaction was carried out at room temperature for 10 h after the addition. Water was then added, and the resulting mixture was extracted with DCM. The organic phase was washed with water, and the solvent was evaporated to dryness. The residue was purified by column chromatography to give 1.7 g of a colorless oil in 60% yield. 1 H NMR (400MHz, CDCl3): δ 12.16(s,1H),10.31(s,1H),6.76(d,J=2.4Hz,1H),6.67(d,J=2.4Hz,1H),2.67(s,3H). ESI-MS: m / z=285.00[M+H] + .

[0169] (2) Synthesis of intermediate 6-2

[0170] [ka]

[0171] 6-1 (220 mg, 0.77 mmol) was dissolved in 8 mL of acetonitrile, and K2CO3 (128 mg, 0.92 mmol), m-cyanobenzyl bromide (159 mg, 0.81 mmol), and tetrabutylammonium iodide (15 mg, 0.04 mmol) were added. The resulting mixture was reacted at room temperature for 6 h, concentrated, added with water, extracted with DCM, and the organic phase was washed with water to neutrality. The organic phase was concentrated and purified by column chromatography to give 286 mg of a pale yellow solid in 93% yield. 1 H NMR (400MHz, CDCl3): δ 10.64(s,1H),7.78-7.61(m,3H),7.60-7.52(m,1H),6.80(s,2H),5.20(s,2H),2.63(s,3H) (isomer ratio = 5:1). ESI-MS: m / z=400.03[M+H] + .

[0172] (3) Synthesis of intermediate 6-3

[0173] [ka]

[0174] 5-2 (99 mg, 0.5 mmol), 6-2 (200 mg, 0.5 mmol), Cs2CO3 (244 mg, 0.75 mmol), BINAP (62 mg, 0.1 mmol), and Pd(OAc)2 (11 mg, 0.05 mmol) were suspended in 5 mL of dioxane and reacted at reflux under Ar protection for 24 h. The mixture was concentrated, water was added, and the mixture was extracted with DCM. The organic phase was washed with water to neutrality and purified by column chromatography to give 131 mg of a pale yellow solid in 59% yield. 1 H NMR(400MHz,CDCl3):δ 10.46(s,1H),7.69-7.64(m,2H),7.63-7.59(m,1H),7.53-7.46(m,1H ),7.46-7.40(m,2H),7.39-7.34(m,1H),7.32-7.27(m,3H),7.24(d,J =2.0Hz,1H),7.23(s,1H),6.10(s,1H),5.99(d,J=2.0Hz,1H),5.11(s,2H),4.53(br,1H),4.38(d,J=3.2Hz,2H),2.57(s,3H),2.23(s,3H). ESI-MS: m / z=447.17[M+H] + .

[0175] (4) Synthesis of Compound 6

[0176] [ka]

[0177] 6-3 (131 mg, 0.29 mmol) and D-serine (62 mg, 0.58 mmol) were suspended in 4 mL of anhydrous DMF and 1 mL of DCE, and glacial acetic acid (34 μL, 0.58 mmol) was added. The mixture was incubated at 35 °C for 24 h. NaBH(OAc) (187 mg, 0.087 mmol) was then added and the reaction was continued for 24 h. Water was then added, and the mixture was extracted with a DCM / MeOH (10:1) mixture, washed with water, and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 48 mg of a white powdery solid in 31% yield. 1H NMR(400MHz,DMSO-d6):δ 8.20(br,2H),7.98(s,1H),7.88(d,J=8.0Hz,1H),7.78(d,J=7.8Hz,1H),7.56(dt,J=7.6,1.2Hz,1H),7.49-7.41(m,2H),7. 40-7.34(m,1H),7.32-7.28(m,2H),7.27-7.23(m,1H),7.18(t,J=7.6Hz,1H),7.10(dd,J=7.6,1.2Hz,1H),6.29(t,J=5.2Hz ,1H),6.24(d,J=1.6Hz,1H),6.12(d,J=1.6Hz,1H),5.37(br,1H),5.13(dd,J=14.8,13.2Hz,2H),4.24(d,J=5.6Hz,2H),4.1 0(s,2H),3.84(dd,J=11.6,4.4Hz,1H),3.61(dd,J=11.6,8.4Hz,1H),3.19(dd,J=8.0,4.4Hz,1H),2.21(s,3H),2.17(s,3H). ESI-HRMS: m / z calculated value (C 33 H 33 N3NaO4 + [M+Na] + )558.2363, actual value 558.2363.

[0178] [Example 7] (1) Synthesis of intermediate 7-1

[0179] [ka]

[0180] 6-1 (852 mg, 3 mmol) was dissolved in 24 mL of acetonitrile, and K2CO3 (954 mg, 6.90 mmol), 5-chloromethylnicotinonitrile hydrochloride (624 mg, 3.30 mmol), and NaI (45 mg, 0.3 mmol) were added. The mixture was reacted at room temperature for 12 hours, then at 45 °C for 9 hours. The mixture was concentrated, water was added, and the mixture was extracted with EA. The organic phase was washed with water, neutralized, and purified by column chromatography to give 780 mg of a pale yellow solid. The yield was 65%. 1H NMR (400MHz, CDCl3): δ 10.61 (s, 1H), 8.93 (s, 2H), 8.10 (s, 1H), 6.85 (s, 2H), 5.25 (s, 2H), 2.64 (s, 3H). ESI-MS: m / z=401.03[M+H] + .

[0181] (2) Synthesis of intermediate 7-2

[0182] [ka]

[0183] 5-2 (311 mg, 1.58 mmol), 7-1 (760 mg, 1.89 mmol), Cs2CO3 (772 mg, 2.37 mmol), BINAP (197 mg, 0.32 mmol), and Pd(OAc)2 (36 mg, 0.16 mmol) were suspended in 15 mL of dioxane and reacted at 85 °C for 20 h under Ar protection. The mixture was concentrated, water was added, and the mixture was extracted with DCM. The organic phase was washed with water to neutrality and purified by column chromatography to give 305 mg of a pale yellow solid in 43% yield. 1 H NMR(400MHz,DMSO-d6):δ 10.27(s,1H),9.00(d,J=2.0Hz,1H),8.96(d,J=2.0Hz,1H),8.45(t,J=2.0Hz,1H),7.49-7.42(m,2H),7.42-7.34(m,1H),7.34-7.29(m,2H) ),7.29-7.18(m,3H),7.14(dd,J=7.4,1.4Hz,1H),6.27(s,1H),6.16(s,1H),5.26(s,2H),4.39(d,J=5.2Hz,2H),2.41(s,3H),2.19(s,3H). ESI-MS: m / z=448.20[M+H] + .

[0184] (3) Synthesis of Compound 7

[0185] [ka]

[0186] 7-2 (269 mg, 0.60 mmol) and D-serine (126 mg, 1.20 mmol) were suspended in 8 mL of anhydrous DMF and 2 mL of DCE. Glacial acetic acid (70 μL, 1.20 mmol) was added and the mixture was incubated at 35 °C for 24 h. NaBH(OAc) (382 mg, 1.80 mmol) was then added and the reaction was continued for 24 h. Water was then added, and the resulting mixture was extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 119 mg of a white powdery solid in 37% yield. 1 H NMR(400MHz,DMSO-d6):δ 9.02(d,J=2.4Hz,1H),8.99(d,J=2.0Hz,1H),8.49(t,J=2.4Hz,1H),8.17(br,2H),7.48-7.42(m,2H),7.41-7.34(m,1H) ,7.34-7.28(m,2H),7.26(d,J=7.6Hz,1H),7.19(t,J=7.6Hz,1H),7.10(dd,J=7.6,1.6Hz,1H),6.31(t,J=5.6Hz,1H),6. 25(d,J=1.6Hz,1H),6.14(d,J=1.6Hz,1H),5.38(br,1H),5.18(dd,J=18.0,13.2Hz,2H),4.25(d,J=5.2Hz,2H),4.10(s, 2H),3.82(dd,J=11.6,4.4Hz,1H),3.61(dd,J=11.2,8.4Hz,1H),3.19(dd,J=8.0,4.4Hz,1H),2.22(s,3H),2.17(s,3H). ESI-HRMS: m / z calculated value (C 32 H 32 N4NaO4 + [M+Na] + )559.2316, actual value 559.2317.

[0187] [Example 8] (1) Synthesis of intermediate 8-1

[0188] [ka]

[0189] 2-Methoxy-4-nitrobenzaldehyde (2.05 g, 11.32 mmol), 2-amino-4-chlorobenzoic acid (0.97 g, 5.66 mmol), 1-fluoro-2,4,6-trismethylpyridine trifluoromethanesulfonate (4.91 g, 16.98 mmol), Pd(OAc) (249 mg, 1.11 mmol), and p-toluenesulfonic acid (3.89 g, 22.59 mmol) were suspended in 80 mL of glacial acetic acid and stirred at room temperature for 10 minutes. The reaction mixture was then heated to 90 °C for 24 hours, cooled, concentrated, and the residue was purified by column chromatography to give 1.50 g of a pale yellow solid in 67% yield. 1 H NMR (400MHz, CDCl3): δ 12.06(s,1H),10.41(s,1H),7.39(dd,J=2.0,0.8Hz,1H),7.23(d,J=2.0Hz,1H),4.03(s,3H). ESI-MS: m / z=198.05[M+H] + .

[0190] (2) Synthesis of intermediate 8-2

[0191] [ka]

[0192] 8-1 (684 mg, 3.47 mmol) was dissolved in 12 mL of DMF, and K2CO3 (574 mg, 4.15 mmol), m-cyanobenzyl bromide (715 mg, 3.65 mmol), and tetramethylammonium iodide (15 mg, 0.04 mmol) were added sequentially. The mixture was allowed to react at room temperature for 7 hours. The reaction mixture was poured into 300 mL of ice water and subjected to suction filtration. The filter cake was washed with water until neutral, dried, dispersed in cyclohexane, sonicated, and suction filtrated to obtain 1 g of a pale yellow powder in 93% yield. This product was used directly in the next step without further purification. 1H NMR (400MHz, DMSO-d6): δ 10.42 (s, 1H), 8.00 (s, 1H), 7.91-7.80 (m, 2H), 7.66-7.57 (m, 3H), 5.42 (s, 2H), 3.99 (s, 3H).

[0193] (3) Synthesis of intermediate 8-3

[0194] [ka]

[0195] 8-2 (900 mg, 2.88 mmol) was suspended in 30 mL of a 5:1 EtOH / HO mixture, and Fe (565 mg, 10.09 mmol) and NH4Cl (230 mg, 4.30 mmol) were added. The mixture was refluxed for 3.5 hours, filtered under suction to remove insoluble materials, and the filtrate was evaporated to dryness. The resulting mixture was purified by column chromatography to give 790 mg of an orange powdery solid in a 97% yield. 1 H NMR(400MHz,DMSO-d6):δ 10.09(s,1H),8.03(s,1H),7.88-7.83(m,1H),7.80(dt,J=8.0,1.4Hz,1H),7.62(t ,J=7.8Hz,1H),6.39(s,2H),5.87(dd,J=9.0,1.4Hz,2H),5.13(s,2H),3.74(s,3H). ESI-MS: m / z=283.11[M+H] + .

[0196] (4) Synthesis of intermediate 8-4

[0197] [ka]

[0198] 1-2 (290 mg, 1.11 mmol) was dissolved in 5 mL of DMF, and K2CO3 (184 mg, 1.33 mmol) and 8-3 (330 mg, 1.17 mmol) were added. The mixture was reacted at 85 °C for 35 minutes under microwave irradiation. Water was added, and the mixture was extracted with DCM. The organic phase was washed with water until neutral and concentrated. The residue was purified by column chromatography to give 150 mg of a pale yellow solid in 29% yield. 1 H NMR(400MHz,CDCl3):δ 10.32(s,1H),7.78(d,J=7.8Hz,1H),7.70(s,1H),7.59(dt,J=7.6,1.4Hz ,1H),7.48(t,J=7.8Hz,1H),7.45-7.40(m,2H),7.40-7.34(m,1H),7.32- 7.27(m,3H),7.24(d,J=2.0Hz,1H),7.23(s,1H),5.78(dd,J=18.2,1.8Hz ,2H),5.11(s,2H),4.69(br,1H),4.39(s,2H),3.85(s,3H),2.24(s,3H). ESI-MS: m / z=463.19[M+H] + .

[0199] (5) Synthesis of Compound 8

[0200] [ka]

[0201] 8-4 (189 mg, 0.41 mmol) and D-serine (86 mg, 0.82 mmol) were suspended in 4 mL of anhydrous DMF, and glacial acetic acid (47 μL, 0.82 mmol) was added. The mixture was incubated at 35 °C for 24 h. NaBH(OAc) (260 mg, 1.23 mmol) was then added and the reaction was continued for 24 h. Water was then added, and the resulting mixture was extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 136 mg of a white powdery solid in 60% yield. 1H NMR(400MHz,DMSO-d6):δ 8.16(br,2H),7.95(s,1H),7.84(d,J=8.0Hz,1H),7.78(d,J=8.0Hz,1H),7.56(t,J=7.8Hz,1H),7.48-7.43(m,2H),7 .40-7.34(m,1H),7.31-7.28(m,3H),7.20(t,J=7.6Hz,1H),7.12(dd,J=7.2,1.2Hz,1H),6.42(t,J=5.2Hz,1H),6.02 (d,J=3.2Hz,2H),5.31(br,1H),5.13(dd,J=16.4,13.2Hz,2H),4.28(d,J=5.2Hz,2H),4.09(dd,J=26.8,13.2Hz,2H) ,3.78(dd,J=11.2,4.4Hz,1H),3.73(s,3H),3.62(dd,J=11.6,7.6Hz,1H),3.12(dd,J=7.2,4.4Hz,1H),2.19(s,3H). ESI-HRMS: m / z calculated value (C 33 H 33 N3NaO5 + [M+Na] + )574.2312, actual value 574.2313.

[0202] [Example 9] (1) Synthesis of intermediate 9-1

[0203] [ka]

[0204] 5-2 (1 g, 5.07 mmol) was dissolved in 30 mL of DCM, DABCO (57 mg, 0.51 mmol) was added, and then BocO (553 mg, 2.54 mmol) was added. The mixture was allowed to react at room temperature overnight, and 30 mL of n-hexane was added. The mixture was then suction filtered and the filter cake was washed with a 1:1 mixture of n-hexane and DCM to obtain 660 mg of a white powdery solid in a 62% yield. 1H NMR(400MHz,DMSO-d6):δ 7.46-7.34(m,2H)(dd,J=10.0,4.6Hz,1H),7.40-7.34(m,1H),7.31-7.26(m,3H),7.23(t,J=7.4 Hz,1H),7.09(dd,J=7.2,1.6Hz,1H),6.39(t,J=5.8Hz,1H),4.29(d,J=6.0Hz,2H),2.14(s,3H). ESI-MS: m / z=421.21[M+H] + .

[0205] (2) Synthesis of intermediate 9-2

[0206] [ka]

[0207] 9-1 (907 mg, 2.16 mmol), 6-chloro-2-methoxy-pyridine-3-carbaldehyde (814 mg, 4.75 mmol), Cs2CO3 (2.10 g, 6.48 mmol), Sphos (266 mg, 0.65 mmol), and Pd(OAc)2 (73 mg, 0.33 mmol) were suspended in 25 mL of dioxane and reacted at reflux under Ar protection for 24 h. The mixture was concentrated, water was added, and the mixture was extracted with DCM. The organic phase was washed neutral with water and suction filtered to remove insoluble materials. The filtrate was concentrated and purified by column chromatography and preparative silica gel to give 364 mg of a pale yellow solid in 25% yield. 1 H NMR(400MHz,CDCl3):δ 10.07(s,1H),7.90(d,J=8.4Hz,1H),7.45-7.39(m,2H),7.38-7.33(m,1H),7.33-7.27(m,3H), 7.25-7.19(m,2H),6.05(d,J=8.4Hz,1H),5.32(br,1H),4.65(s,2H),3.98(s,3H),2.24(s,3H). ESI-MS: m / z=333.14[M+H] + .

[0208] (3) Synthesis of Compound 9

[0209] [ka]

[0210] 9-2 (157 mg, 0.47 mmol) and N-acetylethylenediamine (97 mg, 0.94 mmol) were dissolved in 4 mL of DCE and 1 mL of DMF, and the mixture was added with glacial acetic acid (54 μL, 0.94 mmol) and reacted at 35 °C for 24 h. NaBH(OAc) (300 mg, 1.41 mmol) was then added and the reaction was continued for 12 h. The resulting mixture was extracted with a DCM / MeOH (10:1) mixture, washed with water, and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 85 mg of a pale yellow solid in 43% yield. 1 H NMR(400MHz,CDCl3):δ 7.72(s,1H),7.47-7.39(m,3H),7.39-7.32(m,1H),7.32-7.27(m,3H),7.24-7.16(m,2H),6.54(br,1H),5.94(d,J=8.0Hz,1H),4.79( t,J=5.2Hz,1H),4.46(d,J=5.2Hz,2H),3.93(s,3H),3.88(s,2H),3.54-3.47(m,2H),2.95(t,J=4.8Hz,2H),2.22(s,3H),2.02(s,3H). ESI-HRMS: m / z calculated value (C 25 H 30 N4NaO2 + [M+Na] + )441.2261, actual value 441.2259.

[0211] [Example 10] (1) Synthesis of Intermediate 10-1

[0212] [ka]

[0213] 2-Hydroxy-p-nitrobenzaldehyde (2.47 g, 14.78 mmol) was dissolved in 30 mL of DMF, and K2CO3 (2.15 g, 15.56 mmol) was added. After stirring at room temperature for 30 minutes, 5-chloromethylnicotinonitrile (2.48 g, 16.29 mmol) and NaI (222 mg, 1.48 mmol) were added and the mixture was allowed to react at room temperature for 19 hours. The reaction solution was poured into 1 L of water, suction filtered, and neutralized with water. The filter cake was dried to give 4.05 g of a pale yellow powdery solid in 97% yield, which was used directly in the next step without further purification. 1 H NMR(400MHz,DMSO-d6):δ 10.50(s,1H),9.06(d,J=2.0Hz,1H),9.05(d,J=2.0Hz,1H),8.59(t,J=2.0Hz,1H),8.12(d,J=1.2Hz,1H),8.00-7.93(m,2H),5.57(s,2H). ESI-MS: m / z=284.07[M+H] + .

[0214] (2) Synthesis of Intermediate 10-2

[0215] [ka]

[0216] 10-1 (4.75 g, 16.77 mmol) was suspended in 185 mL of a 5:1 EtOH / HO mixture, and Fe (3.29 g, 58.75 mmol) and NHCl (1.36 g, 25.43 mmol) were added. The mixture was refluxed for 1.5 hours, filtered under suction to remove insoluble matter, and the filtrate was evaporated to dryness. Water was added, and the mixture was sonicated and filtered under suction to obtain 4.12 g of an orange-yellow powdery solid in 97% yield. 1 H NMR (400MHz, DMSO-d6): δ 10.02(s,1H),9.02(s,1H),9.00(s,1H),8.49(s,1H),7.46(d,J=8.4Hz,1H),6.43(s,2H),6.26(s,2H),5.24(s,2H). ESI-MS: m / z=252.09[M−H] - .

[0217] (3) Synthesis of intermediate 10-3

[0218] [ka]

[0219] 1-2 (2.48 g, 9.50 mmol) and 10-2 (2.52 g, 9.95 mmol) were dissolved in a mixture of 51 mL of MeCN and 17 mL of DMF, and K2CO3 (1.58 g, 11.4 mmol) was added. The mixture was reacted at 60 °C for 10 h, concentrated, added with water, extracted with EA, and the organic phase was washed with water until neutral. The mixture was purified by column chromatography to give 1 g of a yellow-white solid in a 24% yield. 1 H NMR (400 MHz, DMSO-d): δ 10.06(s,1H),9.00(d,J=2.0Hz,1H),8.98(d,J=2.0Hz,1H),8.48(t,J=2.0Hz,1 H),7.51(d,J=8.8Hz,1H),7.49-7.43(m,2H),7.40-7.35(m,2H),7.33-7.30(m,2 H),7.28(dd,J=7.6,1.2Hz,1H),7.23(t,J=7.6Hz,1H),7.14(dd,J=7.4,1.4Hz, 1H),6.38(s,1H),6.37(s,1H),5.29(s,2H),4.41(d,J=5.2Hz,2H),2.20(s,3H). ESI-MS: m / z=434.19[M+H] + .

[0220] (4) Synthesis of Compound 10

[0221] [ka]

[0222] 10-3 (133 mg, 0.31 mmol) and D-serine (65 mg, 0.62 mmol) were dissolved in 2.5 mL of anhydrous DMF, and glacial acetic acid (35 μL, 0.62 mmol) was added. The mixture was then reacted at 35 °C for 24 h. NaBH(OAc) (195 mg, 0.92 mmol) was then added and the reaction was continued for 24 h. Water was then added, and the resulting mixture was extracted with a DCM / MeOH (10:1) mixture, washed with water, and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 73 mg of a white solid in 45% yield. 1 H NMR(400MHz,DMSO-d6):δ 9.00(dd,J=10.4,2.4Hz,2H),8.51(t,J=2.0Hz,1H),7.48-7.44(m,2H),7.39-7.35(m,1H),7.32-7.31(m,1H) ),7.31-7.29(m,1H),7.28-7.25(m,1H),7.19(t,J=7.6Hz,1H),7.09(t,J=8.0Hz,2H),6.41-7.25(m,2H),6.2 1(dd,J=8.4,1.6Hz,1H),5.32(br,1H),5.20(dd,J=19.6,12.8Hz,2H),4.26(d,J=5.2Hz,2H),4.03(dd,J=46 .4,13.2Hz,2H),3.77(dd,J=11.2,4.4Hz,1H),3.64(dd,J=11.4,7.2Hz,1H),3.17-3.14(m,1H),2.18(s,3H). ESI-HRMS: m / z calculated value (C 31 H 30 N4NaO4 + [M+Na] + )545.2159, actual value 545.2157.

[0223] [Example 11] (1) Synthesis of Intermediate 11-1

[0224] [ka]

[0225] 1-2 (418 mg, 1.6 mmol) and 4-amino-5-chloro-2-methoxybenzaldehyde (312 mg, 1.68 mmol) were dissolved in 15 mL of MeCN, K2CO3 (265 mg, 1.92 mmol) was added, and the mixture was refluxed for 18 hours, concentrated, water was added, and the mixture was extracted with EA. The organic phase was washed with water until neutral and purified by column chromatography to give 277 mg of a pale yellow solid in a 47% yield. 1 H NMR(400MHz,CDCl3):δ 10.14(s,1H),7.79(s,1H),7.47-7.40(m,2H),7.40-7.34(m,1H),7.34-7.28(m,3H), 7.28-7.23(m,2H),6.14(s,1H),5.22(br,1H),4.48(s,2H),3.87(s,3H),2.26(s,3H). ESI-MS: m / z=366.13[M+H] + .

[0226] (2) Synthesis of Compound 11

[0227] [ka]

[0228] 11-1 (150 mg, 0.41 mmol) and D-serine (86 mg, 0.82 mmol) were dissolved in 3 mL of anhydrous DMF, and glacial acetic acid (47 μL, 0.82 mmol) was added. The mixture was then reacted at 35 °C for 24 h. NaBH(OAc) (195 mg, 0.92 mmol) was then added and the reaction was continued for 24 h. Water was then added, and the resulting mixture was extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 110 mg of a pale yellow solid (59% yield). 1H NMR (400 MHz, DMSO-d): δ 7.47-7.43(m,2H),7.40-7.34(m,1H),7.30(s,2H),7.29-7.26(m,2H),7.20( t,J=7.6Hz,1H),7.09(d,J=8.0Hz,1H),6.23(s,1H),6.05(t,J=5.6Hz,1H),4. 48(d,J=5.6Hz,2H),3.93(dd,J=21.6,13.2Hz,2H),3.75(dd,J=11.6,4.8Hz,1 H),3.67(s,3H),3.65-3.60(m,1H),3.15(dd,J=6.8,4.4Hz,1H),2.23(s,3H). ESI-HRMS: m / z calculated value (C 25 H 27 ClN2NaO4 + [M+Na] + )477.1552, actual value 477.1553.

[0229] [Example 12]

[0230] [ka]

[0231] 9-2 (347 mg, 1.04 mmol) and D-serine (219 mg, 2.08 mmol) were dissolved in 6 mL of anhydrous DMF, and glacial acetic acid (119 μL, 2.08 mmol) was added. The mixture was then reacted at 35 °C for 24 h. NaBH(OAc) (664 mg, 3.12 mmol) was then added and the reaction was continued for 24 h. Water was then added, and the resulting mixture was extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 154 mg of a white solid in a 36% yield. 1H NMR(400MHz,DMSO-d6):δ 8.17(br,2H),7.46-7.42(m,2H),7.40-7.35(m,2H),7.35-7.30(m,1H),7.31-7.25(m, 2H),7.24-7.16(m,2H),7.08(dd,J=7.6,0.8Hz,1H),6.08(d,J=8.0Hz,1H),5.46(br,1 H),4.50(d,J=5.6Hz,2H),3.92(dd,J=20.0,11.2Hz,2H),3.81(s,3H),3.76(dd,J=11. 6,4.4Hz,1H),3.64(dd,J=11.4,7.0Hz,1H),3.16(dd,J=6.8,4.4Hz,1H),2.20(s,3H). ESI-HRMS: m / z calculated value (C 24 H 27 N3NaO4 + [M+Na] + )444.1894, actual value 444.1892.

[0232] [Example 13] (1) Synthesis of intermediate 13-1

[0233] [ka]

[0234] 4-Bromo-3-chlorobenzaldehyde (2.53 g, 11.52 mmol), 2-amino-4-chlorobenzoic acid (0.99 g, 5.76 mmol), 1-fluoro-2,4,6-trimethylpyridine trifluoromethanesulfonate (5 g, 17.29 mmol), Pd(OAc) (259 mg, 1.15 mmol), and p-toluenesulfonic acid (3.97 g, 23.05 mmol) were suspended in 115 mL of glacial acetic acid, stirred at room temperature for 10 minutes, and then reacted at 90 °C for 24 hours. The mixture was cooled and concentrated, and the residue was purified by column chromatography to give 1.50 g of a pale yellow solid (55% yield). 1 H NMR (400MHz, DMSO-d6): δ 11.33 (s, 1H), 10.20 (s, 1H), 7.73 (s, 1H), 7.38 (s, 1H). ESI-MS: m / z=234.90[M+H] + .

[0235] (2) Synthesis of intermediate 13-2

[0236] [ka]

[0237] 13-1 (471 mg, 2 mmol) was dissolved in 7 mL of MeCN, and K2CO3 (304 mg, 2.2 mmol), 5-chloromethylnicotinonitrile (336 mg, 2.2 mmol), and NaI (60 mg, 0.4 mmol) were added. The mixture was allowed to react at room temperature for 22 hours. The reaction mixture was poured into 30 mL of water, suction filtered, and the filter cake was washed until neutral and dried to give 663 mg of a pale yellow powdery solid in 94% yield. This solid was used directly in the next step without further purification. 1 H NMR (400MHz, DMSO-d6): δ 10.32(s,1H),9.04(d,J=2.0Hz,1H),9.01(d,J=2.0Hz,1H),8.54(t,J=2.0Hz,1H),7.85(s,1H),7.82(s,1H),5.45(s,2H). ESI-MS: m / z=350.95[M+H] + .

[0238] (3) Synthesis of intermediate 13-3

[0239] [ka]

[0240] 5-2 (354 mg, 1.80 mmol), 13-2 (527 mg, 1.50 mmol), Cs2CO3 (732 mg, 2.25 mmol), BINAP (187 mg, 0.30 mmol), and Pd(OAc)2 (34 mg, 0.15 mmol) were suspended in 15 mL of dioxane and reacted at 85 °C for 24 h under Ar protection. The mixture was concentrated, water was added, and the mixture was extracted with DCM. The organic phase was washed with water to neutrality and purified by column chromatography to give 345 mg of a pale yellow solid in 49% yield. 1 H NMR(400MHz,DMSO-d6):δ 10.05(s,1H),8.93(d,J=2.0Hz,1H),8.86(d,J=2.0Hz,1H),8.37(t,J=2.0Hz,1H),7.61(s,1H),7.49-7.43(m,2H),7.41-7.35(m,1H) ,7.35-7.31(m,2H),7.19-7.14(m,1H),7.11(s,1H),7.11-7.08(m,2H),6.29(s,1H),5.27(s,2H),4.58(d,J=6.0Hz,2H),2.22(s,3H). ESI-MS: m / z=468.13[M+H] + .

[0241] (4) Synthesis of compound 13

[0242] [ka]

[0243] 13-3 (436 mg, 0.93 mmol) and D-serine (196 mg, 1.86 mmol) were dissolved in 6 mL of anhydrous DMF, and glacial acetic acid (109 μL, 1.86 mmol) was added. The mixture was allowed to react at 35 °C for 24 h. NaBH(OAc) (594 mg, 2.79 mmol) was then added and the reaction was continued for 24 h. Water was then added, and the resulting mixture was extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 106 mg of a white solid in a 20% yield. 1H NMR(400MHz,DMSO-d6):δ 8.91(d,J=1.6Hz,1H),8.86(d,J=2.0Hz,1H),8.37(s,1H),8.17(br,2H),7.46(t,J=7.2Hz,2H),7 .40-7.34(m,2H),7.34-7.29(m,2H),7.16-7.03(m,3H),6.24(s,1H),6.09(t,J=5.8Hz,1H),5.34( br,1H),5.16(dd,J=18.4,13.2Hz,2H),4.43(d,J=5.6Hz,2H),4.01(dd,J=33.6,13.2Hz,2H),3.7 5(dd,J=11.2,4.4Hz,1H),3.63(dd,J=11.2,6.8Hz,1H),3.17(dd,J=6.6,4.6Hz,1H),2.19(s,3H). ESI-HRMS: m / z calculated value (C 31 H 29 N4NaO4 + [M+Na] + )579.1770, actual value 549.1766.

[0244] [Example 14] (1) Synthesis of intermediate 14-1

[0245] [ka]

[0246] 5-2 (473 mg, 2.40 mmol), 4-bromo-2-methoxy-5-methylbenzaldehyde (458 mg, 2.0 mmol), Cs2CO3 (977 mg, 3.0 mmol), BINAP (249 mg, 0.40 mmol), and Pd(OAc)2 (45 mg, 0.20 mmol) were suspended in 15 mL of dioxane and reacted at reflux under Ar for 24 h. The mixture was concentrated, water was added, and the mixture was extracted with EA. The organic phase was washed with water to neutrality and purified by column chromatography to give 405 mg of a pale yellow solid in 59% yield. 1H NMR(400MHz,DMSO-d6):δ 9.97(s,1H),7.47-7.41(m,2H),7.40-7.32(m,2H),7.33-7.25(m,3H),7.22(t,J=7.6Hz,1H),7.11(dd,J=7.2, 1.2Hz,1H), 6.69(t,J=5.8Hz,1H),6.05(s,1H),4.54(d,J=5.6Hz,2H),3.71(s,3H),2.25(s,3H),2.14(s,3H). ESI-MS: m / z=346.18[M+H] + .

[0247] (2) Synthesis of Compound 14

[0248] [ka]

[0249] 14-1 (257 mg, 0.74 mmol) and D-serine (156 mg, 1.48 mmol) were dissolved in 5 mL of anhydrous DMF, and glacial acetic acid (85 μL, 1.48 mmol) was added. The mixture was then reacted at 35 °C for 24 h. NaBH(OAc) (473 mg, 2.23 mmol) was then added and the reaction was continued for 24 h. Water was then added, and the resulting mixture was extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 159 mg of a white solid in a 49% yield. 1H NMR(400MHz,DMSO-d6):δ 8.18(br,2H),7.47-7.43(m,2H),7.40-7.33(m,1H),7.32-7.26(m,3H),7.19(t,J=7.6H z,1H),7.08(d,J=7.5Hz,1H),6.94(s,1H),6.10(s,1H),5.68(t,J=5.6Hz,1H),5.36(br, 1H),4.41(d,J=5.2Hz,2H),3.95(dd,J=27.2,13.2Hz,2H),3.77(dd,J=11.2,4.4Hz,1H) ,3.65(s,3H),3.63-3.58(m,1H),3.13(dd,J=7.2,4.4Hz,1H),2.24(s,3H),2.09(s,3H). ESI-HRMS: m / z calculated value (C 26 H 30 N2NaO4 + [M+Na] + )457.2098, actual value 457.2096.

[0250] [Example 15] (1) Synthesis of intermediate 15-1

[0251] [ka]

[0252] 9-1 (660 mg, 1.57 mmol), 2-chloro-4-methoxypyridine-5-carbaldehyde (448 mg, 2.61 mmol), Cs2CO3 (1.36 g, 4.18 mmol), Sphos (161 mg, 0.39 mmol), and Pd(OAc)2 (44 mg, 0.20 mmol) were suspended in 25 mL of dioxane and reacted at reflux under Ar for 24 h. The reaction mixture was then concentrated, water was added, and the mixture was extracted with DCM. The organic phase was washed neutral with water and filtered under suction to remove insoluble materials. The filtrate was concentrated and purified by column chromatography and preparative silica gel to give 143 mg of a pale yellow solid in a 16% yield. 1H NMR(400MHz,CDCl3):δ 10.04(s,1H),8.38(s,1H),7.44-7.39(m,2H),7.38-7.33(m,1H),7.31(dd,J=6.8,2.4Hz,1H),7.29-7.2 6(m,2H),7.25-7.20(m,2H),5.81(s,1H),5.77(br,1H),4.59(d,J=5.2Hz,2H),3.89(s,3H),2.24(s,3H). ESI-MS: m / z=333.16[M+H] + .

[0253] (2) Synthesis of Compound 15

[0254] [ka]

[0255] 15-1 (203 mg, 0.61 mmol) and D-serine (160 mg, 1.52 mmol) were dissolved in 4 mL of anhydrous DMF, and glacial acetic acid (87 μL, 1.52 mmol) was added. The mixture was then reacted at 35°C for 24 hours. NaBH(OAc)3 (388 mg, 1.83 mmol) was then added and the reaction was continued for 24 hours. Water was then added, and the resulting mixture was extracted with n-butanol. The organic phase was concentrated to dryness, and the residue was purified by preparative liquid chromatography to give 104 mg of a white solid in a 40% yield. 1 H NMR(400MHz,DMSO-d6):δ 7.81(s,1H),7.45(t,J=7.4Hz,2H),7.36(t,J=7.2Hz,1H),7.30-7.26(m, 3H),7.19(t,J=7.4Hz,1H),7.12-7.07(m,2H),6.19(s,1H),5.39(br,1H) ,4.50(d,J=5.2Hz,2H),3.93(dd,J=21.2,13.6Hz,2H),3.81-3.75(m,4H),3.64(dd,J=11.4,7.0Hz,1H),3.18(dd,J=6.8,4.4Hz,1H),2.17(s,3H). ESI-HRMS: m / z calculated value (C 24 H 28N3O4 + [M+H] + )422.2074, actual value 422.2074.

[0256] [Example 16] (1) Synthesis of intermediate 16-1

[0257] [ka]

[0258] 4-Bromo-2-hydroxy-5-methylbenzaldehyde (430 mg, 2 mmol) was dissolved in 10 mL of MeCN, and KCO (304 mg, 2.2 mmol), benzyl bromide (376 mg, 2.2 mmol), and NaI (30 mg, 0.2 mmol) were added. The mixture was reacted at room temperature for 22 hours, and 30 mL of water was added. The mixture was suction filtered, and the filter cake was washed with water until neutral and dried to give 503 mg of a pale yellow powdery solid in a yield of 82%. 1 H NMR (400MHz, CDCl3): δ 10.45(s,1H),7.69(s,1H),7.45-7.33(m,5H),7.28(s,1H),5.14(s,2H),2.36(s,3H). ESI-MS: m / z=327.00 [M+Na] + .

[0259] (2) Synthesis of intermediate 16-2

[0260] [ka]

[0261] 5-2 (367 mg, 1.86 mmol), 16-1 (473 mg, 1.55 mmol), Cs2CO3 (758 mg, 2.33 mmol), BINAP (193 mg, 0.31 mmol), and Pd(OAc)2 (35 mg, 0.16 mmol) were suspended in 15 mL of dioxane and reacted under Ar at reflux for 24 h. The mixture was concentrated, water was added, and the mixture was extracted with EA. The organic phase was washed with water until neutral and purified by column chromatography to give 337 mg of a pale yellow solid in a 52% yield. 1 H NMR(400MHz,CDCl3):δ 10.29(s,1H),7.60(d,J=0.8Hz,1H),7.45-7.41(m,2H),7.40-7.33(m,5H),7.33-7.29(m,3H),7.29-7.26( m,1H),7.25-7.23(m,2H),6.14(s,1H),5.12(s,2H),4.39(s,2H),4.34(br,1H),2.22(s,3H),2.10(s,3H). ESI-MS: m / z=422.24[M+H] + .

[0262] (2) Synthesis of Compound 16

[0263] [ka]

[0264] 16-2 (297 mg, 0.70 mmol) and D-serine (148 mg, 1.41 mmol) were dissolved in 8 mL of anhydrous DMF and 2 mL of anhydrous methanol. Glacial acetic acid (80 μL, 1.41 mmol) was added and the mixture was allowed to react at 35°C for 24 hours. NaBH(OAc)3 (448 mg, 2.11 mmol) was added and the reaction was continued for 24 hours. Water was then added, and the resulting mixture was extracted with a 10:1 mixture of DCM / MeOH and washed with water. The organic phase was concentrated to dryness. The residue was purified by preparative liquid chromatography to give 36 mg of a white solid in a 10% yield. 1H NMR(400MHz,DMSO-d6):δ 8.16(br,2H),7.46(tt,J=8.2,1.6Hz,2H),7.41-7.37(m,1H),7.35-7.32(m,3H),7.31(t,J=1.2Hz,1H),7.30-7 .24(m,3H),7.21(dd,J=7.6,1.6Hz,1H),7.16(t,J=7.6Hz,1H),7.10(dd,J=7.4,1.4Hz,1H),6.97(s,1H),6.13(s ,1H),5.70(t,J=5.6Hz,1H),5.38(br,1H),4.98(s,2H),4.32(d,J=5.2Hz,2H),3.99(dd,J=36.2,13.0Hz,2H),3. 78(dd,J=11.4,4.4Hz,1H),3.66(dd,J=11.4,7.0Hz,1H),3.17(dd,J=7.2,4.4Hz,1H),2.20(s,3H),2.09(s,3H). ESI-HRMS: m / z Calculation Value (C 32 H 34 N2NaO4 + [M+Na] + )533.2411, measured value 533.2408.

[0265] [Example 17] (1) Synthesis of intermediate 17-1

[0266]

change

[0267] 4-Bromo-2-hydroxy-5-methylbenzaldehyde (430 mg, 2 mmol) was dissolved in 10 mL of MeCN, and K2CO3 (608 mg, 4.4 mmol), 3-bromomethylpyridine hydrobromide (556 mg, 2.2 mmol), and NaI (30 mg, 0.2 mmol) were added. The mixture was reacted at room temperature in the dark for 24 h. 3-Bromomethylpyridine hydrobromide (303 mg, 1.20 mmol) and K2CO3 (332 mg, 2.4 mmol) were added, and the reaction was continued for 12 h. 50 mL of water was then added, and the resulting mixture was extracted with EA. The organic phase was washed with water until neutral, and purified by column chromatography to give 180 mg of a pale yellow powdery solid in a 29% yield. 1 H NMR(400MHz,CDCl3):δ 10.41(s,1H),8.71(s,1H),8.64(d,J=4.0Hz,1H),7.83-7.79(m,1H),7.70( s, 1H), 7.37 (dd, J=8.0, 4.8Hz, 1H), 7.29 (s, 1H), 5.17 (s, 2H), 2.38 (s, 3H). ESI-MS: m / z = 306.01 [M+H] + .

[0268] (2) Synthesis of intermediate 17-2

[0269] [ka]

[0270] 5-2 (571 mg, 2.90 mmol), 17-1 (740 mg, 2.42 mmol), Cs2CO3 (1.18 g, 3.62 mmol), BINAP (301 mg, 0.48 mmol), and Pd(OAc)2 (55 mg, 0.24 mmol) were suspended in 20 mL of dioxane and reacted at reflux under Ar for 24 h. The mixture was concentrated, water was added, and the mixture was extracted with EA. The organic phase was washed with water until neutral and purified by column chromatography to give 386 mg of a pale yellow solid in a 38% yield. 1H NMR(400MHz,CDCl3):δ 10.23(s,1H),8.65(s,1H),8.59(d,J=4.4Hz,1H),7.77(d,J=8.0Hz,1H),7.60(s,1H),7.44(t,J=7.4Hz,2H),7.40-7.35(m,1H) ),7.34-7.27(m,4H),7.27-7.25(m,2H),6.14(s,1H),5.20-5.08(m,2H),4.43(s,2H),4.40(br,1H),2.25(s,3H),2.11(s,3H). ESI-MS: m / z=423.21[M+H] + .

[0271] (3) Synthesis of Compound 17

[0272] [ka]

[0273] 17-2 (310 mg, 0.73 mmol) and D-serine (154 mg, 1.47 mmol) were dissolved in 8 mL of anhydrous DMF and 2 mL of anhydrous methanol. Glacial acetic acid (85 μL, 1.47 mmol) was added and the mixture was reacted at 35°C for 24 h. NaBH(OAc)3 (467 mg, 2.20 mmol) was then added and the reaction was continued for 24 h. Water was then added and the resulting mixture was extracted with a DCM / MeOH (10 / 1) mixture and washed with water. The organic phase was concentrated to dryness. The residue was purified by preparative liquid chromatography to give 51 mg of a white solid in a 14% yield. 1H NMR(400MHz,DMSO-d6):δ 8.58(d,J=1.6Hz,1H),8.47(dd,J=4.8,1.6Hz,1H),8.26(br,2H),7.81(dt,J=8.0,2.0Hz,1H),7.49-7.42(m,2H),7.40-7.35(m,1H) ,7.34-7.31(m,2H),7.29(ddd,J=7.8,4.8,0.4Hz,1H),7.21(dd,J=7.6,1.2Hz,1H),7.16(t,J=7.6Hz,1H),7.09(dd,J=7.4,1.4Hz,1H ),6.98(s,1H),6.15(s,1H),5.69(t,J=5.6Hz,1H),5.38(br,1H),5.04(dd,J=15.6,13.2Hz,2H),4.35(d,J=5.2Hz,2H),3.99(dd,J=4 0.8,13.2Hz,2H),3.78(dd,J=11.4,4.4Hz,1H),3.65(dd,J=11.2,7.2Hz,1H),3.17(dd,J=7.0,4.6Hz,1H),2.21(s,3H),2.10(s,3H). ESI-HRMS: m / z Calculation Value (C 31 H 33 N3NaO4 + [M+Na] + )534.2363, measured value 534.2360.

[0274] [Example 18]

[0275]

change

[0276] 5-4 (313 mg, 0.7 mmol) and (R)-3-amino-4-hydroxybutyric acid (167 mg, 1.40 mmol) were suspended in 6 mL of anhydrous DMF and 2 mL of anhydrous methanol. Glacial acetic acid (80 μL, 1.40 mmol) was added and the mixture was reacted at 35 °C for 24 h. NaBH(OAc) (445 mg, 2.10 mmol) was then added and the reaction was continued for 24 h. Water was then added and the resulting mixture was extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 30 mg of a white powdery solid in an 8% yield. 1 H NMR(400MHz,DMSO-d6):δ 10.00(br,2H),8.91-8.80(m,2H),8.32(s,1H),7.45(t,J=7.4Hz,2H),7.39-7.33(m,3 H),7.16-7.04(m,3H),6.97(s,1H),6.08(s,1H),5.66(t,J=5.4Hz,1H),5.17-5.07(m, 2H),4.34(d,J=4.8Hz,2H),3.91(dd,J=68.0,12.8Hz,2H),3.58(dd,J=11.6,4.4Hz,1H ),3.47-3.39(m,1H),3.07-3.01(m,1H),2.19(s,3H),2.16-2.13(m,2H),2.11(s,3H). ESI-HRMS: m / z calculated value (C 33 H 34 N4NaO4 + [M+Na] + )573.2472, actual value 573.2472.

[0277] [Example 19] (1) Synthesis of intermediate 19-1

[0278] [ka]

[0279] 4-Bromo-2-hydroxy-5-methylbenzaldehyde (645 mg, 3 mmol) was dissolved in 9 mL of MeCN, and K2CO3 (647 mg, 4.68 mmol), 3-cyanobenzyl bromide (647 mg, 3.3 mmol), and NaI (45 mg, 0.3 mmol) were added. The mixture was allowed to react at room temperature for 24 hours. 40 mL of water was added, and the resulting mixture was filtered under vacuum. The filter cake was washed with water until neutral and then dried. After drying, the filter cake was suspended in cyclohexane, sonicated, and vacuum filtered to obtain 801 mg of a pale yellow solid in 81% yield. 1 H NMR (400MHz, DMSO-d6): δ 10.36(s,1H),8.01(s,1H),7.85(t,J=8.6Hz,2H),7.69-7.57(m,3H),5.35(s,2H),2.33(s,3H). ESI-MS: m / z=330.00[M+H] + .

[0280] (2) Synthesis of intermediate 19-2

[0281] [ka]

[0282] 5-2 (548 mg, 2.78 mmol), 19-1 (766 mg, 2.32 mmol), Cs2CO3 (1.13 g, 3.46 mmol), BINAP (289 mg, 0.46 mmol), and Pd(OAc)2 (52 mg, 0.23 mmol) were suspended in 15 mL of dioxane and reacted under Ar at reflux for 24 h. The mixture was concentrated, water was added, and the mixture was extracted with EA. The organic phase was washed with water until neutral and purified by column chromatography to give 382 mg of a pale yellow solid in a 37% yield. 1H NMR(400MHz,CDCl3):δ 10.25(s,1H),7.68(s,1H),7.67-7.58(m,3H),7.48(t,J=7.6Hz,1H),7.46-7.41(m,2H),7.39-7.35(m,1H),7.34-7.2 8(m,2H),7.28-7.23(m,3H),6.08(s,1H),5.14(s,2H),4.46(br,1H),4.41(d,J=4.8Hz,2H),2.24(s,3H),2.12(s,3H). ESI-MS: m / z=447.21[M+H] + .

[0283] (3) Synthesis of compound 19

[0284] [ka]

[0285] 19-2 (341 mg, 0.76 mmol) and D-serine (161 mg, 1.53 mmol) were dissolved in 7 mL of anhydrous DMF, and glacial acetic acid (87 μL, 1.53 mmol) was added. The mixture was then reacted at 35°C for 24 h. NaBH(OAc)3 (486 mg, 2.29 mmol) was then added and the reaction was continued for 24 h. Water was then added, and the resulting mixture was extracted with a DCM / MeOH (10 / 1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 320 mg of a white solid in 79% yield. 1H NMR(400MHz,DMSO-d6):δ 8.29(br,1H),7.87(s,1H),7.74-7.68(m,2H),7.47-7.43(m,3H),7.39-7.35(m,1H),7.33-7.28(m,2H),7.17 (dd,J=7.2,1.2Hz,1H),7.13(t,J=7.4Hz,1H),7.08(dd,J=7.2,1.6Hz,1H),6.99(s,1H),6.09(s,1H),5.70(t ,J=5.6Hz,1H),5.38(br,1H),5.12-5.02(m,2H),4.33(d,J=5.2Hz,2H),4.02(dd,J=40.4,13.0Hz,2H),3.79( dd,J=11.6,4.4Hz,1H),3.65(dd,J=11.2,7.2Hz,1H),3.18(dd,J=6.9,4.6Hz,1H),2.19(s,3H),2.10(s,3H). ESI-HRMS: m / z calculated value (C 33 H 33 N3NaO4 + [M+Na] + )558.2363, actual value 558.2364.

[0286] [Example 20] (1) Synthesis of Intermediate 20-1

[0287] [ka]

[0288] 4-Bromo-2-hydroxy-5-methylbenzaldehyde (660 mg, 3.07 mmol) was dissolved in 15 mL of MeCN, and KCO (467 mg, 3.38 mmol) and iodoethane (527 mg, 3.38 mmol) were added. The mixture was reacted at 60°C for 24 hours, concentrated, water was added, and the mixture was extracted with EA. The organic phase was washed with water until neutral and purified by column chromatography to give 537 mg of a yellow-white powdery solid in a 72% yield. 1H NMR (400MHz, CDCl3): δ 10.41(s,1H),7.66(s,1H),7.18(s,1H),4.12(q,J=7.4Hz,2H),2.35(s,3H),1.47(t,J=7.4Hz,3H). ESI-MS: m / z=243.01[M+H] + .

[0289] (2) Synthesis of Intermediate 20-2

[0290] [ka]

[0291] 5-2 (591 mg, 3.0 mmol), 20-1 (608 mg, 2.50 mmol), Cs2CO3 (1.22 g, 3.75 mmol), BINAP (311 mg, 0.50 mmol), and bPd(OAc)2 (56 mg, 0.25 mmol) were suspended in 15 mL of dioxane and reacted at reflux under Ar protection for 24 h. The mixture was concentrated, water was added, and the mixture was extracted with EA. The organic phase was washed with water until neutral and purified by column chromatography to give 350 mg of a pale yellow solid in a 39% yield. 1 H NMR(400MHz,CDCl3):δ 10.22(s,1H),7.58(d,J=0.8Hz,1H),7.46-7.40(m,2H),7.40-7.34(m,1H),7.34-7.27(m,3H),7.26(d,J=3.6Hz,1H),7.24(s, 1H),6.09(s,1H),4.44(d,J=4.0Hz,2H),4.39(br,1H),4.09(q,J=6.8Hz,2H),2.26(s,3H),2.09(s,3H),1.43(t,J=6.8Hz,3H). ESI-MS: m / z=360.21[M+H] + .

[0292] (3) Synthesis of Compound 20

[0293] [ka]

[0294] 20-2 (296 mg, 0.82 mmol) and D-serine (173 mg, 1.65 mmol) were dissolved in 5.5 mL of anhydrous DMF, and glacial acetic acid (94 μL, 1.65 mmol) was added. The mixture was then reacted at 35°C for 24 hours. NaBH(OAc)3 (523 mg, 2.47 mmol) was added, and the reaction was continued for 24 hours. Water was then added, and the resulting mixture was extracted with a 10:1 mixture of DCM / MeOH and washed with water. The organic phase was concentrated to dryness. The residue was purified by preparative liquid chromatography to give 290 mg of a white solid in a 79% yield. 1 H NMR(400MHz,DMSO-d6):δ 8.21(br,2H),7.47-7.43(m,2H),7.40-7.34(m,1H),7.30-7.26(m,3H),7.18(t,J=7.6Hz,1 H),7.08(dd,J=7.6,1.2Hz,1H),6.93(s,1H),6.06(s,1H),5.71(t,J=5.6Hz,1H),5.41(br,1 H),4.40(d,J=5.6Hz,2H),4.02-3.84(m,4H),3.78(dd,J=11.6,4.4Hz,1H),3.63(dd,J=11. 6,7.6Hz,1H),3.14(dd,J=7.2,4.4Hz,1H),2.23(s,3H),2.09(s,3H),1.24(t,J=7.0Hz,3H). ESI-HRMS: m / z calculated value (C 27 H 32 N2NaO4 + [M+Na] + )471.2254, actual value 471.2254.

[0295] [Example 21]

[0296] [ka]

[0297] 5-4 (339 mg, 0.76 mmol) and L-hydroxyproline (199 mg, 1.52 mmol) were suspended in 6.5 mL of anhydrous DMF, and glacial acetic acid (87 μL, 1.52 mmol) was added. The mixture was then reacted at 35°C for 24 h. NaBH(OAc)3 (482 mg, 2.27 mmol) was then added and the reaction was continued for 24 h. Water was then added, and the resulting mixture was extracted with a DCM / MeOH (10:1) mixture, washed with water, and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 150 mg of a white powdery solid in 35% yield. 1 H NMR(400MHz,DMSO-d6):δ 8.91(d,J=2.0Hz,1H),8.85(d,J=2.0Hz,1H),8.36(t,J=2.2Hz,1H),7.47-7.43(m,2H),7.40-7.35(m,1H),7.34-7.32(m,1H),7.3 2-7.31(m,1H),7.20(dd,J=7.6,1.6Hz,1H),7.14(t,J=7.6Hz,1H),7.08(dd,J=7.6,1.6Hz,1H),7.01(s,1H),6.11(s,1H),5.71(t, J=5.8Hz,1H),5.36(br,1H),5.15(dd,J=23.2,13.6Hz,2H),4.35(d,J=5.6Hz,2H),4.28-4.24(m,1H),4.13(dd,J=63.0,13.0Hz,2H ),3.71(t,J=8.2Hz,1H),3.33(dd,J=11.6,4.8Hz,1H),2.86(dd,J=11.6,3.2Hz,1H),2.20(s,3H),2.11(s,3H),2.08-1.98(m,2H). ESI-HRMS: m / z calculated value (C 34 H 34 N4NaO4 + [M+Na] + )585.2472, actual value 585.2471.

[0298] [Example 22]

[0299] [ka]

[0300] 5-4 (313 mg, 0.7 mmol) and (S)-(+)-4-amino-3-hydroxybutyric acid (167 mg, 1.40 mmol) were suspended in 6 mL of anhydrous DMF and 2 mL of anhydrous methanol. Glacial acetic acid (80 μL, 1.40 mmol) was added and the mixture was reacted at 35 °C for 24 h. NaBH(OAc) (445 mg, 2.10 mmol) was then added and the reaction was continued for 24 h. Water was then added and the resulting mixture was extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 97 mg of a white powdery solid in a 25% yield. 1 H NMR(400MHz,DMSO-d6):δ 8.90(d,J=2.0Hz,1H),8.83(d,J=2.0Hz,1H),8.29(t,J=2.2Hz,1H),7.48-7.42(m,2H),7.40-7.34(m,1H),7 .34-7.31(m,2H),7.17(dd,J=7.6,1.6Hz,1H),7.13(t,J=7.4Hz,1H),7.07(dd,J=7.4,1.8Hz,1H),6.96(s,1H) ),6.08(s,1H),5.57(t,J=5.6Hz,1H),5.11(s,2H),4.33(d,J=5.2Hz,2H),3.88(qui,J=5.6Hz,1H),3.76(dd ,J=17.0,13.0Hz,2H),2.68(d,J=5.6Hz,2H),2.29(ddd,J=32.2,15.2,5.6Hz,2H),2.20(s,3H),2.10(s,3H). ESI-HRMS: m / z calculated value (C 29 H 26 N3O + [M-C4H8NO3] + )432.2070, actual value 432.2069.

[0301] [Example 23]

[0302] [ka]

[0303] It is a by-product isolated in Example 22 in an amount of 38 mg. 1 H NMR(400MHz,CDCl3):δ 8.80(d,J=1.6Hz,2H),8.08(t,J=2.0Hz,1H),7.46-7.41(m,2H),7.39-7.34(m,1H),7.34-7.32(m,1H),7.32-7.31(m ,1H),7.30-7.27(m,1H),7.24(d,J=1.6Hz,1H),7.23(s,1H),6.96(s,1H),6.15(s,1H),5.09(s,2H),4.55(d,J=14.4H) z,1H),4.45(br,1H),4.34(d,J=14.4Hz,1H),4.32(s,2H),3.86(br,1H),3.50(dd,J=10.8,5.6Hz,1H),3.20(dd,J=1 0.8,2.0Hz,1H),2.69(dd,J=17.2,6.8Hz,1H),2.44(br,1H),2.39(dd,J=17.4,2.2Hz,1H),2.25(s,3H),2.08(s,3H). ESI-HRMS: m / z calculated value (C 33 H 33 N4O3 + [M+H] + )533.2547, actual value 533.2545.

[0304] [Example 24]

[0305] [ka]

[0306] 5-4 (313 mg, 0.7 mmol) and D-homoserine (167 mg, 1.40 mmol) were suspended in 6 mL of anhydrous DMF and 2 mL of anhydrous methanol. Glacial acetic acid (80 μL, 1.40 mmol) was added and the mixture was reacted at 35 °C for 24 h. NaBH(OAc) (445 mg, 2.10 mmol) was then added and the reaction was continued for 24 h. Water was then added and the resulting mixture was extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 230 mg of a white powdery solid in 60% yield. 1 H NMR(400MHz,DMSO-d6):δ 8.90(d,J=2.0Hz,1H),8.85(d,J=2.0Hz,1H),8.35(t,J=2.0Hz,1H),8.15(br,2H),7.48-7.42(m,2H),7 .40-7.36(m,1H),7.35-7.31(m,2H),7.17-7.10(m,2H),7.07(dd,J=6.8,2.0Hz,1H),7.01(s,1H),6.08 (s,1H),5.73(t,J=5.6Hz,1H),5.54(br,1H),5.13(dd,J=18.0,13.2Hz,2H),4.35(d,J=5.6Hz,2H),4.0 3-3.89(m,2H),3.56-3.44(m,2H),3.21(t,J=6.4Hz,1H),2.19(s,3H),2.11(s,3H),1.93-1.67(m,2H). ESI-HRMS: m / z calculated value (C 33 H 34 N4NaO4 + [M+Na] + )573.2472, actual value 573.2472.

[0307] [Example 25]

[0308] [ka]

[0309] 5-4 (313 mg, 0.7 mmol) and D-asparagine (185 mg, 1.40 mmol) were suspended in 8 mL of anhydrous DMF, and glacial acetic acid (80 μL, 1.40 mmol) was added. The mixture was then reacted at 35°C for 24 hours. NaBH(OAc)3 (445 mg, 2.10 mmol) was then added, and the reaction was continued for 24 hours. Water was then added, and the resulting mixture was extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 180 mg of a white powdery solid in a 46% yield. 1 H NMR(400MHz,DMSO-d6):δ 8.89(d,J=2.0Hz,1H),8.85(d,J=2.0Hz,1H),8.34(t,J=2.0Hz,1H),7.78(s,1H),7.49-7.43(m,2H),7.39-7. 35(m,1H),7.35-7.34(m,1H),7.33-7.32(m,1H),7.16-7.09(m,3H),7.07(dd,J=7.0,2.2Hz,1H),6.96(s,1H) ,6.07(s,1H),5.73(t,J=5.8Hz,1H),5.16(s,2H),4.34(d,J=5.2Hz,2H),4.04(dd,J=21.4,13.0Hz,2H),3.36 (dd,J=9.2,4.0Hz,1H),2.73(dd,J=16.6,3.8Hz,1H),2.43(dd,J=16.6,9.0Hz,1H),2.19(s,3H),2.11(s,3H). ESI-HRMS: m / z calculated value (C 33 H 33 N5NaO4 + [M+Na] + )586.2425, actual value 586.2422.

[0310] [Example 26] (1) Synthesis of intermediate 26-1

[0311] [ka]

[0312] 1-5 (108 mg, 0.25 mmol) and KOH (85%) (20 mg, 0.30 mmol) were dissolved in 3 mL of THF, and methyl benzenesulfonate (65 mg, 0.38 mmol) was added. The mixture was reacted at 35°C for 25 hours. Methyl benzenesulfonate (13 mg, 0.08 mmol) was added, and the reaction was continued for 15 hours. The reaction mixture was concentrated, water was added, and the mixture was extracted with DCM. The organic phase was washed with water and purified by recrystallization to give 70 mg of a pale yellow solid in a 63% yield. 1 H NMR(400MHz,CDCl3):δ 10.24(s,1H),7.75(d,J=8.8Hz,1H),7.69(s,1H),7.67-7.59(m,2H),7.51-7.41(m,3H),7.41-7.35(m,1H),7.34-7.29(m,2H),7.23-7.15( m,2H),6.94(dd,J=6.4,2.4Hz,1H),6.38(dd,J=8.8,2.0Hz,1H),6.09(d,J=2.4Hz,1H),5.14(s,2H),4.59(s,2H),3.19(s,3H),2.18(s,3H). ESI-MS: m / z=447.22 [M+H] + .

[0313] (2) Synthesis of Compound 26

[0314] [ka]

[0315] 26-1 (89 mg, 0.2 mmol) and D-serine (42 mg, 0.40 mmol) were suspended in 2 mL of anhydrous DMF, and glacial acetic acid (23 μL, 0.40 mmol) was added. The mixture was then reacted at 35°C for 24 h. NaBH(OAc)3 (131 mg, 0.6 mmol) was then added and the reaction was continued for 14 h. Water was then added, and the resulting mixture was extracted with a DCM / MeOH (10:1) mixture, washed with water, and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 64 mg of a pale yellow powdery solid in a 60% yield. 1H NMR(400MHz,DMSO-d6):δ 8.33(br,2H),7.98(s,1H),7.85(d,J=8.0Hz,1H),7.77(d,J=7.6Hz,1H),7.53(t,J=7.6Hz,1H),7.46(t,J=7.6Hz,2H), 7.41-7.35(m,1H),7.33-7.29(m,2H),7.17-7.11(m,2H),7.08(d,J=7.6Hz,1H),6.83(d,J=7.6Hz,1H),6.37(d,J=2.0Hz ,1H),6.25(dd,J=8.4,2.0Hz,1H),5.39(br,1H),5.21(dd,J=17.2,13.2Hz,2H),4.56(s,2H),4.06(dd,J=42.4,12.8Hz, 2H),3.78(dd,J=11.6,4.4Hz,1H),3.66(dd,J=11.2,7.2Hz,1H),3.18(dd,J=6.8,4.4Hz,1H),3.04(s,3H),2.14(s,3H). ESI-HRMS: m / z Calculation Value (C 33 H 33 N3NaO4 + [M+Na] + )558.2363, measured value 558.2361.

[0316] [Example 27]

[0317]

change

[0318] 26-1 (70 mg, 0.16 mmol) and ethanolamine (19 mg, 0.31 mmol) were dissolved in 2 mL of DCE and 0.5 mL of anhydrous DMF, and glacial acetic acid (18 μL, 0.31 mmol) was added. The mixture was incubated at 35 °C for 24 h. NaBH(OAc) (103 mg, 0.49 mmol) was then added and the reaction was continued for 12 h. Water was then added, and the resulting mixture was extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by column chromatography to give an oil. This oil was dissolved in DCM, and 3 mL of 1N HCl in ether was added dropwise. The mixture was stirred at room temperature for 30 min. The mixture was then vacuum filtered. The filter cake was purified again by preparative liquid chromatography to give 34 mg of a white solid (38% yield). 1 H NMR(400MHz,DMSO-d6):δ 9.00(s,2H),7.98(s,1H),7.83(d,J=7.6Hz,1H),7.80-7.74(m,1H),7.55(t,J=7.8Hz,1H),7.48- 7.42(m,2H),7.38-7.34(m,1H),7.32-7.27(m,3H),7.13(t,J=7.6Hz,1H),7.07(dd,J=7.4,1.0Hz, 1H),6.87(d,J=7.2Hz,1H),6.47(s,1H),6.35(d,J=5.6Hz,1H),5.59(br,6H),5.22(s,2H),4.60( s,2H),4.04(t,J=4.8Hz,2H),3.66(t,J=5.4Hz,2H),3.07(s,3H),2.96-2.85(m,2H),2.13(s,3H). ESI-HRMS: m / z calculated value (C 32 H 33 N3NaO2 + [M+Na] + )514.2465, actual value 514.2460.

[0319] [Example 28] (1) Synthesis of intermediate 28-1

[0320] [ka]

[0321] 3-Bromo-2-methylaniline (2.79 g, 15 mmol), phenylboronic acid (2.74 g, 22.5 mmol), cesium acetate (7.20 g, 37.51 mmol), and PdCl(dppf) (1.10 g, 1.50 mmol) were suspended in 48 mL of THF and reacted at reflux under argon protection for 24 h. The mixture was cooled and concentrated. Water was added to the residue, and the mixture was extracted with DCM. The organic phase was washed with water, concentrated, and purified by column chromatography to give 2.61 g of a brown solid in 95% yield. 1 H NMR (400MHz, CDCl3): δ 7.41-7.37(m,2H),7.36-7.27(m,3H),7.07(t,J=7.8Hz,1H),6.70(d,J=7.6Hz,2H),3.69(br,2H),2.06(s,3H). ESI-MS: m / z=184.12[M+H] + .

[0322] (2) Synthesis of intermediate 28-2

[0323] [ka]

[0324] 2-Hydroxy-4-hydroxymethylbenzaldehyde (683 mg, 4.49 mmol) was dissolved in 20 mL of MeCN, and KCO (683 mg, 4.94 mmol) and 5-chloromethylnicotinonitrile (755 mg, 4.95 mmol) were added. The mixture was reacted at 60 °C for 10 h. 230 mL of water was added, and the mixture was suction filtered. The filter cake was dried to give 1.01 g of a pale yellow powdery solid in 84% yield. This solid could be used directly in the next step without further purification. 1H NMR(400MHz,DMSO-d6):δ 10.41(d,J=0.8Hz,1H),9.04(dd,J=3.2,2.0Hz,2H),8.55(t,J=2.0,1H),7.71(d,J=7.6Hz,1H),7.29(d,J =0.8Hz,1H),7.08(ddd,J=8.0,1.2,0.8Hz,1H),5.49(t,J=5.6Hz,1H),5.39(s,2H),4.59(d,J=5.6Hz,2H). ESI-MS: m / z=269.10 [M+H] + .

[0325] (3) Synthesis of intermediate 28-3

[0326] [ka]

[0327] 28-2 (838 mg, 3.12 mmol) and pyridine (494 mg, 6.24 mmol) were dissolved in 20 mL of anhydrous DCM, 2 mL of anhydrous DMF was added, and 4 mL of anhydrous DCM solution of MsCl (537 mg, 4.69 mmol) was added dropwise at 0 °C. After the addition, the mixture was reacted at room temperature for 24 h, followed by the addition of water and extraction with DCM. The organic phase was washed with water, concentrated, and purified by column chromatography to give 565 mg of a pale yellow solid in 63% yield. 1 H NMR(400MHz,DMSO-d6):δ 10.42(d,J=0.4Hz,1H),9.04(dd,J=3.6,2.0Hz,2H),8.56(t,J=2.0Hz,1H),7.76(d,J =7.6Hz,1H),7.44(d,J=1.6Hz,1H),7.21(d,J=8.0Hz,1H),5.41(s,2H),4.83(s,2H). ESI-MS: m / z=287.05[M+H] + .

[0328] (4) Synthesis of intermediate 28-4

[0329] [ka]

[0330] 28-3 (397 mg, 1.38 mmol) was dissolved in 8 mL of MeCN, and 2.5 mL of DMF was added. K2CO3 (229 mg, 1.66 mmol), 28-1 (379 mg, 2.07 mmol), and NaI (42 mg, 0.28 mmol) were added. The mixture was reacted at 30 °C for 24 h, followed by addition of water and extraction with EA. The organic phase was washed with water until neutral, concentrated, and purified by column chromatography to give 188 mg of a pale yellow powdery solid (yield 31%). 1 H NMR(400MHz,CDCl3):δ 10.46(s,1H),8.87(d,J=2.4Hz,1H),8.85(d,J=2.0Hz,1H),8.06(t,J=2 .2Hz,1H),7.88(d,J=7.6Hz,1H),7.44-7.39(m,2H),7.37-7.29(m,3H), 7.17(d,J=8.0Hz,1H),7.09(t,J=7.8Hz,2H),6.72(d,J=7.6Hz,1H),6.4 6(d,J=8.0Hz,1H),5.24(s,2H),4.50(s,2H),4.19(br,1H),2.11(s,3H). ESI-MS: m / z=434.19[M+H] + .

[0331] (3) Synthesis of compound 28

[0332] [ka]

[0333] 28-4 (278 mg, 0.64 mmol) and D-serine (135 mg, 1.28 mmol) were suspended in 6 mL of anhydrous DMF and 2 mL of anhydrous MeOH. Glacial acetic acid (73 μL, 1.28 mmol) was added and the mixture was reacted at 35 °C for 24 h. NaBH(OAc) (408 mg, 1.93 mmol) was then added and the reaction was continued for 24 h. Water was then added and the resulting mixture was extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 78 mg of a white powdery solid in a 23% yield. 1 H NMR(400MHz,DMSO-d6):δ 9.02(d,J=2.4Hz,1H),8.98(d,J=2.0Hz,1H),8.50(t,J=2.0Hz,1H),7.43-7.38(m,2H),7.38-7.31(m,2H),7.29 -7.24(m,2H),7.20(s,1H),7.03(d,J=7.6Hz,1H),6.91(t,J=7.8Hz,1H),6.42(dd,J=7.6,0.8Hz,1H),6.37(d,J =8.0Hz,1H),5.76(t,J=6.0Hz,1H),5.27(dd,J=18.8,12.8Hz,2H),4.37(d,J=5.6Hz,2H),4.10(dd,J=20.6,13. 4Hz,2H), 3.75(dd,J=11.2,4.4Hz,1H),3.63(dd,J=11.2,6.8Hz,1H),3.19(dd,J=6.8,4.4Hz,1H),2.03(s,3H). ESI-HRMS: m / z calculated value (C 31 H 31 N4O4 + [M+H] + )523.2340, actual value 523.2338.

[0334] [Example 29] (1) Synthesis of intermediate 29-1

[0335] [ka]

[0336] 1-Bromo-3-methyl-2-(trifluoromethyl)benzene (10.25 g, 42.88 mmol), phenylboronic acid (7.32 g, 60.03 mmol), cesium acetate (20.58 g, 107.22 mmol), and PdCl(dppf) (3.15 g, 4.29 mmol) were suspended in 100 mL of THF and reacted at reflux under argon for 36 hours. The mixture was cooled and concentrated. Water was added to the residue, and the mixture was extracted with DCM. The organic phase was washed with water, concentrated, and purified by column chromatography to give 5.3 g of a colorless oil in a 52% yield. 1 H NMR (400MHz, CDCl3): δ 7.41-7.31 (m, 4H), 7.28-7.25 (m, 3H), 7.12-7.08 (m, 1H), 2.57 (q, J = 2.8Hz, 3H).

[0337] (2) Synthesis of intermediate 29-2

[0338] [ka]

[0339] 29-1 (4.48 g, 18.96 mmol) was dissolved in 70 mL of CCl4, NBS (3.37 g, 18.96 mmol) and 75% BPO (304 mg, 1.26 mmol) were added, and the mixture was refluxed for 11 hours. The mixture was then concentrated to dryness, water was added, and the mixture was extracted with DCM. The organic phase was washed with water, washed with brine, and then with anhydrous Na2SO4 で The mixture was dried and filtered under suction. The filtrate was concentrated to dryness. The residue was dissolved in 50 mL of DMF, potassium phthalimide (4.05 g, 21.87 mmol) was added, and the mixture was reacted at 80°C for 1.5 hours. The solvent was removed by evaporation under reduced pressure. Water was added to the residue, and the mixture was extracted with DCM. The organic phase was washed with water, concentrated, and purified by column chromatography to obtain 4.55 g of a white solid in 60% yield. 1H NMR(400MHz,CDCl3):δ 7.98-7.91(m,2H),7.82-7.77(m,2H),7.43-7.36(m,4H),7.31-7.27(m,2H),7.19(d,J=7.6Hz,1H),7.14(d,J=7.6Hz,1H),5.19(s,2H). ESI-MS: m / z=382.09[M+H] + .

[0340] (4) Synthesis of intermediate 29-3

[0341] [ka]

[0342] 29-2 (450 mg, 1.18 mmol) was dissolved in 7 mL of ethanol, and 85% hydrazine hydrate (125 mg, 2.12 mmol) was added. The mixture was refluxed for 3 h. After cooling, 1.38 mL of 6 N aqueous HCl was added, and refluxing was continued for 30 min. The reaction mixture was cooled and suction filtered to remove insoluble materials. The filtrate was concentrated, adjusted to pH 10 with 1 N NaOH, and extracted with DCM / MeOH (10 / 1). The organic phase was washed once with water, and the solvent was evaporated to dryness to give 290 mg of a colorless oil in 98% yield. This was used directly in the next step without further purification. 1 H NMR(400MHz,CDCl3):δ 7.57(d,J=7.6Hz,1H),7.51(t,J=7.6Hz,1H),7.42-7.33(m,3H),7.29-7.25(m,2H),7.19(d,J=7.6Hz,1H),4.08(q,J=1.6Hz,2H). ESI-MS: m / z=252.09[M+H] + .

[0343] (5) Synthesis of intermediate 29-4

[0344] [ka]

[0345] 29-3 (290 mg, 1.15 mmol), 5-3 (459 mg, 1.39 mmol), Cs2CO3 (564 mg, 1.73 mmol), BINAP (144 mg, 0.23 mmol), and Pd(OAc)2 (26 mg, 0.12 mmol) were suspended in 9 mL of dioxane and reacted under Ar protection at reflux for 16 h. The mixture was concentrated, water was added, and the mixture was extracted with EA. The organic phase was washed with water, neutralized, and purified by column chromatography to give 388 mg of a pale yellow solid in 67% yield. 1 H NMR(400MHz,CDCl3):δ 10.21(s,1H),8.82(d,J=1.6Hz,1H),8.79(d,J=2.0Hz,1H),7.99(t,J=2.0Hz,1H),7.63(s,1H),7.51-7.46(m, 2H),7.46-7.38(m,3H),7.30-7.27(m,3H),5.96(s,1H),5.10(s,2H),4.88(br,1H),4.73(s,2H),2.21(s,3H). ESI-MS: m / z=502.15[M+H] + .

[0346] (6) Synthesis of Compound 29

[0347] [ka]

[0348] 29-4 (358 mg, 0.71 mmol) and D-serine (150 mg, 1.43 mmol) were suspended in 6 mL of anhydrous DMF and 2 mL of anhydrous MeOH, and glacial acetic acid (82 μL, 1.43 mmol) was added. The mixture was then reacted at 35 °C for 24 h. NaBH(OAc) (454 mg, 2.44 mmol) was then added, followed by the addition of water. The resulting mixture was then extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 181 mg of a white powdery solid in 43% yield. 1H NMR(400MHz,DMSO-d6):δ 8.89(d,J=2.0Hz,1H),8.82(d,J=2.0Hz,1H),8.34(t,J=2.0Hz,1H),7.51(t,J=7.6Hz,1H),7.46-7.38(m ,4H),7.31(d,J=2.0Hz,1H),7.29(d,J=1.6Hz,1H),7.19(d,J=7.6Hz,1H),7.05(s,1H),6.09(t,J=5.6Hz, 1H),5.93(s,1H),5.32(br,1H),5.09(dd,J=17.8,13.2Hz,2H),4.57(d,J=4.0Hz,2H),4.03(dd,J=40.4, 13.2Hz,2H),3.78(dd,J=11.4,4.4Hz,1H),3.64(dd,J=11.6,7.2Hz,1H),3.19-3.16(m,1H),2.14(s,3H). ESI-HRMS: m / z calculated value (C 32 H 29 F3N4NaO4 + [M+Na] + )613.2033, actual value 613.2033.

[0349] [Example 30] (1) Synthesis of Intermediate 30-1

[0350] [ka]

[0351] 29-1 (473 mg, 2.0 mmol) was dissolved in 8 mL of CCl4, NBS (356 mg, 2 mmol) and 75% BPO (32 mg, 0.10 mmol) were added, and the mixture was refluxed for 10 hours. The mixture was then concentrated to dryness, water was added, and the mixture was extracted with DCM. The organic phase was washed with water, washed with saturated brine, dried over anhydrous Na2SO4, and subjected to suction filtration. The filtrate was purified by column chromatography to give 390 mg of a white solid in a 62% yield. 1H NMR (400MHz, CDCl3): δ 7.61-7.56(m,1H),7.51(t,J=7.6Hz,1H),7.40-7.36(m,3H),7.27-7.23(m,3H),4.73(q,J=1.6Hz,2H).

[0352] (2) Synthesis of Intermediate 30-2

[0353] [ka]

[0354] 30-1 (630 mg, 2 mmol) and 10-2 (532 mg, 2.10 mmol) were dissolved in a mixture of 10.5 mL of MeCN and 3.5 mL of DMF, and K2CO3 (332 mg, 2.40 mmol) was added. The mixture was reacted at 60 °C for 11 hours, concentrated, water was added, and the mixture was extracted with EA. The organic phase was washed with water until neutral, and purified by column chromatography to give 120 mg of a yellow-white solid in a 12% yield. 1 H NMR(400MHz,CDCl3):δ 10.19(s,1H),8.85(d,J=2.0Hz,2H),8.05(t,J=2.2Hz,1H),7.74(d,J=8.4Hz,1H),7.53(d,J=7.2Hz,1H),7.49(t,J=7.6Hz,1H),7.44-7.3 6(m,3H),7.30-7.23(m,3H),6.35(dd,J=8.4,1.6Hz,1H),6.06(d,J=2.0Hz,1H),5.16(s,2H),5.04(t,J=5.8Hz,1H),4.69(d,J=4.8Hz,2H). ESI-MS: m / z=488.14[M+H] + .

[0355] (3) Synthesis of Compound 30

[0356] [ka]

[0357] 30-2 (120 mg, 0.25 mmol) and D-serine (52 mg, 0.49 mmol) were suspended in 3 mL of anhydrous DMF, and glacial acetic acid (28 μL, 0.49 mmol) was added. The mixture was then reacted at 35°C for 24 h. NaBH(OAc)3 (157 mg, 0.74 mmol) was added and the reaction was continued for 24 h. Water was then added, and the resulting mixture was extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 56 mg of a white powdery solid in a 39% yield. 1 H NMR(400MHz,DMSO-d6):δ 9.00(d,J=2.0Hz,1H),8.99(d,J=2.0Hz,1H),8.50(t,J=2.0Hz,1H),8.21(br,2H),7.60-7.55(m,2H),7.47-7.3 7(m,3H),7.31-7.26(m,2H),7.22(t,J=4.0Hz,1H),7.10(d,J=8.0Hz,1H),6.72(t,J=5.6Hz,1H),6.35(d,J=1.6H) z,1H),6.13(dd,J=8.0,1.6Hz,1H),5.34(br,1H),5.19(dd,J=19.6,13.2Hz,2H),4.49(d,J=4.0Hz,2H),4.03(d d,J=44.0,13.2Hz,2H),3.76(dd,J=11.6,4.4Hz,1H),3.63(dd,J=11.6,7.2Hz,1H),3.16(dd,J=7.2,4.4Hz,1H). ESI-HRMS: m / z calculated value (C 31 H 27 F3N4NaO4 + [M+Na] + )599.1877, actual value 599.1876.

[0358] [Example 31] (1) Synthesis of Intermediate 31-1

[0359] [ka]

[0360] 2-Bromo-1-iodo-3-toluene (5 g, 16.8 mmol), phenylboronic acid (2.36 g, 19.35 mmol), cesium acetate (8.08 g, 42.09 mmol), and PdCl(dppf) (1.24 g, 1.69 mmol) were suspended in 40 mL of THF and reacted at reflux under argon protection for 36 h. The mixture was cooled and concentrated. Water was added to the residue, and the mixture was extracted with DCM. The organic phase was washed with water, concentrated, and purified by column chromatography to give 3.93 g of a colorless oil in 95% yield. 1 H NMR (400MHz, CDCl3): δ 7.61-7.58 (m, 1H), 7.48-7.31 (m, 6H), 7.26-7.23 (m, 1H), 7.16-7.10 (m, 1H), 2.49 (s, 3H).

[0361] (2) Synthesis of intermediate 31-2

[0362] [ka]

[0363] 31-1 (3.93 g, 15.90 mmol) was dissolved in 70 mL of CCl4, and NBS (2.83 g, 15.90 mmol) and 75% BPO (255 mg, 0.79 mmol) were added. The mixture was refluxed for 11 hours, concentrated to dryness, and water was added. The mixture was extracted with DCM. The organic phase was washed with water, concentrated, and purified by column chromatography to give 3.36 g of a white solid in a 65% yield. 1 H NMR (400MHz, CDCl3): δ 7.47-7.42(m,2H),7.41-7.39(m,2H),7.38-7.35(m,2H),7.33(t,J=7.6Hz,1H),7.25(dd,J=7.6,2.0Hz,1H),4.71(s,2H).

[0364] (3) Synthesis of intermediate 31-3

[0365] [ka]

[0366] 31-2 (860 mg, 2.64 mmol) and 10-2 (668 mg, 2.64 mmol) were dissolved in a mixture of 15 mL of MeCN and 5 mL of DMF, and K2CO3 (437 mg, 3.16 mmol) was added. The mixture was refluxed for 11 hours, then concentrated, water was added, and the mixture was extracted with EA. The organic phase was washed with water until neutral, and purified by column chromatography to give 200 mg of a pale yellow solid in a 15% yield. 1 H NMR(400MHz,DMSO-d6):δ 10.06(s,1H),9.00(d,J=1.6Hz,1H),8.97(d,J=1.6Hz,1H),8.47(s,1H),7.55-7.50(m,2H),7.50-7.44(m,2H),7.43-7.37( m,4H),7.33(dd,J=7.4,1.4Hz,1H),7.28(dd,J=7.2,1.6Hz,1H),6.34(d,J=10.4Hz,2H),5.29(s,2H),4.50(d,J=5.6Hz,2H). ESI-MS: m / z=498.08[M+H] + .

[0367] (4) Synthesis of Compound 31

[0368] [ka]

[0369] 31-3 (316 mg, 0.63 mmol) and D-serine (133 mg, 1.27 mmol) were suspended in 6 mL of anhydrous DMF, and glacial acetic acid (72 μL, 1.27 mmol) was added. The reaction was continued at 35 °C for 24 h. Subsequently, NaBH(OAc) (403 mg, 1.27 mmol) was added and the reaction was continued for 24 h. 90 mmol) was added and the reaction was continued for 24 h. Water was then added, and the resulting mixture was extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 153 mg of a white powdery solid in 41% yield. 1H NMR(400MHz,DMSO-d6):δ 9.00(d,J=2.0Hz,1H),8.98(d,J=2.0Hz,1H),8.50(t,J=2.0Hz,1H),8.22(br,1H),7.50-7.44(m,2H),7.44-7.40(m,1H) ,7.40-7.34(m,3H),7.32(dd,J=7.8,1.8Hz,1H),7.24(dd,J=7.2,2.0Hz,1H),7.09(d,J=8.4Hz,1H),6.66(t,J=5.8Hz,1H ),6.37(d,J=1.6Hz,1H),6.14(dd,J=8.2,1.8Hz,1H),5.31(br,1H),5.20(dd,J=19.6,13.2Hz,2H),4.37(d,J=6.0Hz,2H) ,4.04(dd,J=44.4,13.2Hz,2H),3.77(dd,J=11.2,4.4Hz,1H),3.63(dd,J=11.6,7.2Hz,1H),3.16(dd,J=7.2,4.4Hz,1H). ESI-HRMS: m / z Calculation Value (C 30 H 27 BrN4NaO4 + [M+Na] + )609.1108, measured value 609.1111.

[0370] [Example 32] (1) Synthesis of intermediate 32-1

[0371]

change

[0372] 3-Methyl-4-nitrobenzaldehyde (1.90 g, 11.52 mmol), 2-amino-4-chlorobenzoic acid (0.99 g, 5.76 mmol), 1-fluoro-2,4,6-trimethylpyridine trifluoromethanesulfonate (5 g, 17.29 mmol), Pd(OAc) (259 mg, 1.15 mmol), and p-toluenesulfonic acid (3.97 g, 23.05 mmol) were suspended in 115 mL of glacial acetic acid, stirred at room temperature for 10 minutes, and then reacted at 90 °C for 24 hours. The reaction system was cooled and concentrated, and the residue was purified by column chromatography to obtain 942 mg of a pale yellow solid in a 45% yield. 1 H NMR (400MHz, DMSO-d6): δ 11.31 (s, 1H), 10.33 (s, 1H), 7.69 (s, 1H), 7.52 (s, 1H), 2.40 (s, 3H). ESI-MS: m / z=180.03[M−H] - .

[0373] (2) Synthesis of intermediate 32-2

[0374] [ka]

[0375] 32-1 (578 mg, 3.19 mmol) was dissolved in 17 mL of MeCN and 3.5 mL of DMF, and K2CO3 (485 mg, 3.51 mmol), 5-chloromethylnicotinonitrile (535 mg, 3.51 mmol), and NaI (96 mg, 0.64 mmol) were added. The mixture was allowed to react at room temperature for 24 hours, after which 80 mL of water was added, suction filtered, and the filter cake was washed with water until neutral and dried to give 939 mg of a yellow-white powdery solid in 99% yield. This solid was used directly in the next step without further purification. 1 H NMR (400MHz, DMSO-d6): δ 10.44(s,1H),9.04(t,J=2.0Hz,1H),8.56(t,J=2.0Hz,1H),7.91(s,1H),7.82(s,1H),5.47(s,2H),2.45(s,3H). ESI-MS: m / z=296.07[MH] - .

[0376] (3) Synthesis of intermediate 32-3

[0377] [ka]

[0378] 32-2 (1.46 g, 4.91 mmol) was suspended in 55 mL of a 5:1 EtOH / HO mixture, and Fe (963 mg, 17.20 mmol) and NHCl (394 mg, 7.37 mmol) were added. The mixture was refluxed for 4 h, filtered under suction, and the insoluble material was removed. The filtrate was evaporated to dryness. Water was added, and the mixture was extracted with 20:1 DCM / MeOH. The organic phase was concentrated to dryness to give 1.30 g of an orange powdery solid in 99% yield. This solid was used directly in the next step without further purification. 1 H NMR(400MHz,DMSO-d6):δ 10.03(s,1H),9.02(d,J=2.0Hz,1H),8.99(d,J=2.0Hz,1H),8.48(t,J=2.0 Hz, 1H), 7.33 (s, 1H), 6.32 (s, 1H), 6.19 (s, 2H), 5.22 (s, 2H), 2.01 (s, 3H). ESI-MS: m / z=268.11 [M+H] + .

[0379] (4) Synthesis of intermediate 32-4

[0380] [ka]

[0381] 31-2 (815 mg, 2.50 mmol) and 32-3 (702 mg, 2.63 mmol) were dissolved in a mixture of 12 mL of MeCN and 4 mL of DMF, and K2CO3 (415 mg, 3.0 mmol) was added. The mixture was refluxed for 7.5 h, concentrated, water was added, and the mixture was extracted with EA. The organic phase was washed with water until neutral, and purified by column chromatography to give 180 mg of a pale yellow solid in a 14% yield. 1 H NMR(400MHz,CDCl3):δ 10.20(s,1H),8.82(d,J=2.0Hz,1H),8.80(d,J=2.0Hz,1H),7.99(t,J=2.2Hz,1H),7.62(d,J=0.4Hz,1H),7.49-7.42(m,3H),7.42-7. 37(m,2H),7.36-7.29(m,2H),7.28-7.24(m,1H),5.98(s,1H),5.13(s,2H),4.90(t,J=5.8Hz,1H),4.61(d,J=6.0Hz,2H),2.19(s,3H). ESI-MS: m / z=512.08[M+H] + .

[0382] (5) Synthesis of Compound 32

[0383] [ka]

[0384] 32-4 (180 mg, 0.35 mmol) and D-serine (74 mg, 0.70 mmol) were suspended in 3.5 mL of anhydrous DMF, and glacial acetic acid (40 μL, 0.70 mmol) was added. The mixture was then reacted at 35°C for 24 h. NaBH(OAc)3 (224 mg, 1.06 mmol) was added and the reaction was continued for 24 h. Water was then added, and the resulting mixture was extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 46 mg of a white powdery solid in a 22% yield. 1H NMR(400MHz,DMSO-d6):δ 8.89(d,J=1.6Hz,1H),8.83(d,J=1.6Hz,1H),8.34(s,1H),8.14(br,2H),7.48-7.39(m,5H), 7.30(t,J=7.6Hz,1H),7.20(t,J=7.6Hz,2H),7.03(s,1H),6.03-5.96(m,2H),5.29(br,1H),5 .12(dd,J=18.6,13.4Hz,2H),4.44(d,J=5.6Hz,2H),4.03(dd,J=40.0,13.0Hz,2H),3.77(dd ,J=11.4,4.2Hz,1H),3.64(dd,J=11.0,7.4Hz,1H),3.17(dd,J=6.8,4.4Hz,1H),2.13(s,3H). ESI-HRMS: m / z calculated value (C 31 H 29 BrN4NaO4 + [M+Na] + )623.1264, actual value 623.1265.

[0385] [Example 33] (1) Synthesis of intermediate 33-1

[0386] [ka]

[0387] 31-2 (400 mg, 1.23 mmol) and 1-4 (325 mg, 1.29 mmol) were dissolved in a mixture of 4.5 mL of MeCN and 2.5 mL of DMF, and K2CO3 (203 mg, 1.47 mmol) was added. The mixture was refluxed for 10 h, concentrated, water was added, and the mixture was extracted with EA. The organic phase was washed with water until neutral, and purified by column chromatography to give 155 mg of a pale yellow solid in a 25% yield. 1H NMR(400MHz,CDCl3):δ 10.24(s,1H),7.74(d,J=8.4Hz,1H),7.69-7.60(m,3H),7.50(t,J=7.6,1H),7.48-7.40(m,3H),7.41-7.34( m,2H),7.32-7.26(m,3H),6.35-6.30(m,1H),6.06(d,J=2.0Hz,1H),5.12(s,2H),4.99(br,1H),4.55(s,2H). ESI-MS: m / z=497.07[M+H] + .

[0388] (2) Synthesis of Compound 33

[0389] [ka]

[0390] 33-1 (152 mg, 0.31 mmol) and D-serine (64 mg, 0.61 mmol) were suspended in 3 mL of anhydrous DMF, and glacial acetic acid (35 μL, 0.61 mmol) was added. The mixture was then reacted at 35°C for 24 hours. NaBH(OAc)3 (194 mg, 0.92 mmol) was then added, and the reaction was continued for 24 hours. Water was then added, and the resulting mixture was extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 128 mg of a pale yellow solid in a 70% yield. 1H NMR(400MHz,DMSO-d6):δ 8.26(br,2H),7.98(s,1H),7.87(d,J=8.0Hz,1H),7.79(d,J=7.6Hz,1H),7.57(t,J=8.0Hz,1H),7.51- 7.29(m,6H),7.24(dd,J=7.2,1.6Hz,1H),7.08(d,J=8.4Hz,1H),6.64(t,J=6.0Hz,1H),6.34(d,J=1.6 Hz,1H),6.12(dd,J=8.0,1.6Hz,1H),5.33(br,1H),5.18-5.10(m,2H),4.35(d,J=5.6Hz,2H),4.03(dd ,J=40.4,12.8Hz,2H),3.78(dd,J=11.6,4.0Hz,1H),3.65(dd,J=11.2,7.2Hz,1H),3.18-3.15(m,1H). ESI-HRMS: m / z calculated value (C 28 H 22 BrNO + [M-C3H6NO3] + )481.0910, actual value 481.0911.

[0391] [Example 34] (1) Synthesis of intermediate 34-1

[0392] [ka]

[0393] 3-Bromo-2-methylbenzyl alcohol (3.25 g, 16.16 mmol), benzo-1,4-dioxane-6-boronic acid (3.64 g, 20.23 mmol), cesium acetate (7.75 g, 40.38 mmol), and PdCl(dppf) (1.19 g, 1.62 mmol) were suspended in 50 mL of THF and reacted at reflux under argon protection for 24 h. The mixture was cooled and concentrated. Water was added to the residue, and the mixture was extracted with DCM. The organic phase was washed with water, concentrated, and purified by column chromatography to give 4.05 g of a colorless oil in 98% yield. 1H NMR(400MHz,CDCl3):δ 7.36(dd,J=7.6,1.2Hz,1H),7.22(t,J=7.6Hz,1H),7.17(dd,J=7.6,1.6Hz,1H),6.89(d,J=8.4Hz,1H), 6.81(d,J=2.0Hz,1H),6.76(dd,J=8.0,2.0Hz,1H),4.76(s,2H),4.30(s,4H),2.25(s,3H),1.66(s,1H). ESI-MS: m / z=257.12[M+H] + .

[0394] (2) Synthesis of intermediate 34-2

[0395] [ka]

[0396] 34-1 (513 mg, 2.0 mmol) was dissolved in 10 mL of DCM and cooled to 0 °C in an ice bath. PBr (0.094 mL, 1.0 mmol) was added dropwise, and the reaction was continued for 20 min. The mixture was quenched by adding crushed ice and extracted three times with DCM. The organic phase was washed once with saturated sodium bicarbonate solution and then with water until neutral, dried over anhydrous NaSO, filtered under suction, and concentrated to dryness to give 550 mg of a colorless oil in 86% yield, which was used directly in the next step without further purification. 1 H NMR(400MHz,CDCl3):δ 7.35-7.29(m,1H),7.22-7.15(m,2H),6.93-6.89(m,1H),6.82-6.80(m,1H),6.78-6.74(m,1H),4.59(s,2H),4.31(s,4H),2.32(s,3H). ESI-MS: m / z=239.11[M-Br] + .

[0397] (3) Synthesis of intermediate 34-3

[0398] [ka]

[0399] 34-2 (550 mg, 1.72 mmol) and 1-4 (435 mg, 1.72 mmol) were dissolved in a mixture of 10 mL of MeCN and 3 mL of DMF, and K2CO3 (262 mg, 1.90 mmol) was added. The mixture was refluxed for 11 hours, concentrated, water was added, and the mixture was extracted with EA. The organic phase was washed with water until neutral, and purified by column chromatography to give 170 mg of a yellow-white solid in a 20% yield. 1 H NMR(400MHz,CDCl3):δ 10.23(s,1H),7.74(d,J=8.4Hz,1H),7.71-7.66(m,2H),7.63(d,J=7.8Hz,1H),7.5 1(t,J=7.8Hz,1H),7.25-7.22(m,1H),7.22-7.17(m,2H),6.91(d,J=8.4Hz,1H),6. 81(d,J=2.0Hz,1H),6.76(dd,J=8.2,2.2Hz,1H),6.31(dd,J=8.6,1.8Hz,1H),6.07 (d,J=1.6Hz,1H),5.14(s,2H),4.64(s,1H),4.38(s,2H),4.31(s,4H),2.24(s,3H). ESI-MS: m / z=491.20[M+H] + .

[0400] (4) Synthesis of Compound 34

[0401] [ka]

[0402] 34-3 (162 mg, 0.33 mmol) and D-serine (69 mg, 0.66 mmol) were suspended in 3 mL of anhydrous DMF, and glacial acetic acid (38 μL, 0.66 mmol) was added. The mixture was allowed to react at 35°C for 24 hours. NaBH(OAc)3 (210 mg, 0.99 mmol) was then added and the mixture was allowed to react for 24 hours. Water was then added, and the mixture was extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 91 mg of a pale yellow solid in a 48% yield. 1 H NMR(400MHz,DMSO-d6):δ 8.33(br,2H),7.99(s,1H),7.88(d,J=8.0Hz,1H),7.79(d,J=7.6Hz,1H),7.57(t,J=8.0Hz,1H),7.22(d,J=8.0 Hz,1H),7.15(t,J=7.6Hz,1H),7.07(d,J=8.0Hz,2H),6.92(d,J=8.0Hz,1H),6.80-6.67(m,2H),6.36-6.34(m, 2H),6.19(d,J=8.0Hz,1H),5.36(br,1H),5.18-5.10(m,2H),4.28(br,4H),4.23(d,J=4.4Hz,2H),4.03(dd,J= 43.6,13.2Hz,2H),3.77(dd,J=10.8,4.0Hz,1H),3.65(dd,J=11.2,8.0Hz,1H),3.17-3.14(m,1H),2.18(s,3H). ESI-HRMS: m / z calculated value (C 34 H 33 N3NaO6 + [M+Na] + )602.2262, actual value 602.2266.

[0403] [Example 35] (1) Synthesis of intermediate 35-1

[0404] [ka]

[0405] A three-necked flask was charged with 34-1 (3.46 g, 13.50 mmol), phthalimide (2.38 g, 16.18 mmol), and PPh3 (4.96 g, 18.91 mmol). 60 mL of anhydrous THF was added under Ar protection. The mixture was cooled to 0°C and DEAD (3.29 g, 18.89 mmol) was added. The mixture was then reacted at room temperature for 24 hours. The solvent was evaporated to dryness, and the residue was purified by column chromatography to give 5.02 g of a white solid (yield 97%). 1H NMR(400MHz,CDCl3):δ 7.89-7.87(m,2H),7.75-7.73(m,2H),7.21-7.16(m,1H),7.14(d,J=4.0Hz,1H),7.13(s,1H),6.88(d,J =8.0Hz,1H),6.80(d,J=2.0Hz,1H),6.74(dd,J=8.4,2.0Hz,1H),4.93(s,2H),4.30(s,4H),2.35(s,3H). ESI-MS: m / z=386.14[M+H] + .

[0406] (2) Synthesis of intermediate 35-2

[0407] [ka]

[0408] 35-1 (4.88 g, 12.66 mmol) was dissolved in 75 mL of ethanol, and 85% hydrazine hydrate (1.34 g, 22.75 mmol) was added. The mixture was refluxed for 6 hours, cooled, and 10 mL of 6 N aqueous HCl was added. The mixture was refluxed for 30 minutes, cooled, and subjected to suction filtration to remove insoluble materials. The filtrate was concentrated, adjusted to pH 10 with 1 N NaOH, and extracted with DCM / MeOH (10 / 1). The organic phase was washed with water, and the solvent was evaporated to dryness to give 3.20 g of a colorless oil in 99% yield. This was used directly in the next step without further purification. 1 H NMR(400MHz,CDCl3):δ 7.31(dd,J=7.6,1.2Hz,1H),7.21(t,J=7.6Hz,1H),7.12(dd,J=7.6,1.2Hz,1H),6.89(d,J=8.4Hz,1H), 6.80(d,J=2.0Hz,1H),6.75(dd,J=8.4,2.0Hz,1H),4.30(s,4H),3.91(s,2H),2.23(s,3H),1.56(s,2H). ESI-MS: m / z=256.13[M+H] + .

[0409] (3) Synthesis of intermediate 35-3

[0410] [ka]

[0411] 35-2 (420 mg, 1.64 mmol), 5-3 (654 mg, 1.97 mmol), Cs2CO3 (804 mg, 2.47 mmol), BINAP (205 mg, 0.33 mmol), and Pd(OAc)2 (37 mg, 0.16 mmol) were suspended in 11 mL of dioxane and reacted at 85 °C under Ar protection for 24 h. The mixture was concentrated, water was added, and the mixture was extracted with EA. The organic phase was washed with water to neutrality and purified by column chromatography to give 325 mg of a pale yellow solid in a 39% yield. 1 H NMR(400MHz,DMSO-d6):δ 10.06(s,1H),8.92(d,J=2.0Hz,1H),8.83(d,J=2.4Hz,1H),8.33(t,J=2.0Hz,1H) ,7.38(d,J=0.8Hz,1H),7.13-7.08(m,2H),7.07-7.05(m,1H),6.92(d,J=8.0Hz,1H ),6.81(d,J=2.0Hz,1H),6.77(dd,J=8.2,2.2Hz,1H),6.67(t,J=5.8Hz,1H),6.09( s,1H),5.21(s,2H),4.47(d,J=5.6Hz,2H),4.29(s,4H),2.23(s,3H),2.14(s,3H). ESI-MS: m / z=506.20[M+H] + .

[0412] (4) Synthesis of Compound 35

[0413] [ka]

[0414] 35-3 (288 mg, 0.57 mmol) and D-serine (120 mg, 1.14 mmol) were suspended in 6 mL of anhydrous DMF and 2 mL of anhydrous methanol. Glacial acetic acid (65 μL, 1.14 mmol) was added and the mixture was reacted at 35 °C for 24 h. NaBH(OAc) (362 mg, 1.71 mmol) was then added and the mixture was reacted for 24 h. Water was added and the mixture was extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 98 mg of a white powdery solid in a 29% yield. 1 H NMR(400MHz,DMSO-d6):δ 8.89(d,J=2.0Hz,1H),8.85(d,J=2.0Hz,1H),8.36(t,J=2.0Hz,1H),8.22(br,2H),7.11(dd,J=7.2,1.6Hz,1H),7.08(t,J=7.2Hz ,1H),7.03(dd,J=7.2,1.6Hz,1H),7.00(s,1H),6.91(d,J=8.0Hz,1H),6.81(d,J=2.0Hz,1H),6.77(dd,J=8.4,2.0Hz,1H),6.07( s,1H),5.69(t,J=5.6Hz,1H),5.31(br,1H),5.13(dd,J=18.8,13.2Hz,2H),4.32(d,J=5.2Hz,2H),4.28(s,4H),4.03(dd,J=44.0 ,13.2Hz,2H),3.77(dd,J=11.2,4.4Hz,1H),3.64(dd,J=11.6,7.2Hz,1H),3.16(dd,J=7.2,4.4Hz,1H),2.20(s,3H),2.10(s,3H). ESI-HRMS: m / z calculated value (C 34 H 34 N4NaO6 + [M+Na] + )617.2371, actual value 617.2377.

[0415] [Example 36] (1) Synthesis of intermediate 36-1

[0416] [ka]

[0417] 35-2 (418 mg, 1.64 mmol), 13-2 (480 mg, 1.37 mmol), Cs2CO3 (667 mg, 2.05 mmol), BINAP (170 mg, 0.27 mmol), and Pd(OAc)2 (31 mg, 0.14 mmol) were suspended in 14 mL of dioxane and reacted under Ar at reflux for 24 h. The mixture was concentrated, water was added, and the mixture was extracted with EA. The organic phase was washed with water until neutral and purified by column chromatography to give 559 mg of a pale yellow solid in 78% yield. 1 H NMR(400MHz,DMSO-d6):δ 10.04(s,1H),8.93(d,J=2.0Hz,1H),8.85(d,J=2.0Hz,1H),8.36(t,J=2.0Hz,1H),7.60(s,1H),7.14-7.03(m,4H),6.92(d,J=8.2Hz) ,1H),6.80(d,J=2.0Hz,1H),6.76(dd,J=8.2,2.2Hz,1H),6.26(s,1H),5.25(s,2H),4.56(d,J=6.0Hz,2H),4.29(s,4H),2.22(s,3H). ESI-MS: m / z=526.19[M+H] + .

[0418] (2) Synthesis of Compound 36

[0419] [ka]

[0420] 36-1 (340 mg, 0.65 mmol) and D-serine (135 mg, 1.28 mmol) were suspended in 6 mL of anhydrous DMF and 2 mL of anhydrous methanol. Glacial acetic acid (74 μL, 1.28 mmol) was added and the mixture was reacted at 35°C for 24 hours. NaBH(OAc)3 (410 mg, 1.93 mmol) was then added and the mixture was reacted for 24 hours. Water was added and the mixture was extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 135 mg of a white powdery solid in 34% yield. 1 H NMR(400MHz,DMSO-d6):δ 8.89(d,J=2.0Hz,1H),8.85(d,J=2.0Hz,1H),8.36(t,J=2.0Hz,1H),8.17(br,2H),7.37(s,1H),7.12-7.01(m ,3H),6.92(d,J=8.0Hz,1H),6.80(d,J=2.0Hz,1H),6.76(dd,J=8.2,2.2Hz,1H),6.22(s,1H),6.07(t,J=5.8Hz ,1H),5.38(br,1H),5.15(dd,J=18.0,13.2Hz,2H),4.40(d,J=5.6Hz,2H),4.28(s,4H),4.01(dd,J=33.6,13.2 Hz,2H),3.75(dd,J=11.2,4.4Hz,1H),3.64(dd,J=11.6,6.8Hz,1H),3.18(dd,J=6.8,4.4Hz,1H),2.20(s,3H). ESI-HRMS: m / z calculated value (C 33 H 31 ClN4NaO6 + [M+Na] + )637.1824, actual value 637.1825.

[0421] [Example 37: (Comparative Example 1)] (1) Synthesis of intermediate 37-1

[0422] [ka]

[0423] A three-necked flask was charged with 1-1 (2.18 g, 11 mmol), 2,4-dihydroxybenzaldehyde (1.38 g, 10 mmol), and PPh3 (2.89 g, 11 mmol). Under Ar protection, 100 mL of anhydrous THF was added, cooled to 0°C, and DIAD (2.22 g, 11 mmol) was added dropwise. The mixture was then reacted at room temperature for 24 hours. The solvent was evaporated to dryness, and the residue was purified by column chromatography to obtain 1.75 g of a yellow solid in a 55% yield. 1 H NMR(400MHz,CDCl3):δ 11.52(s,1H),9.75(s,1H),7.51-7.29(m,11H),6.68(dd,J=8.5,2.2Hz,1H),6.61(d,J=2.1Hz,1H),5.16(s,2H),2.27(s,3H). ESI-MS: m / z=319.13[M+H] + .

[0424] (2) Synthesis of intermediate 37-2

[0425] [ka]

[0426] 37-1 (318 mg, 1 mmol) was dissolved in 12 mL of acetonitrile, and K2CO3 (207 mg, 1.5 mmol), tetra-n-butylammonium iodide (18 mg, 0.05 mmol), and 5-chloromethylnicotinonitrile (183 mg, 1.2 mmol) were added. The mixture was allowed to react at 75 °C overnight. The reaction solution was concentrated, water was added, and the mixture was extracted with EA. The organic phase was washed with water until neutral and purified by column chromatography to give 226 mg of a yellow solid in a 52% yield. 1H NMR(400MHz,DMSO-d6):δ 10.26(s,1H),9.05-8.97(m,2H),8.56(s,1H),7.72(d,J=2.0Hz,1H),7.55-7.49(m,3H),7.45-7.38(m,1H),7.35 -7.28(m,3H),7.25(d,J=2.1Hz,1H),7.01(s,1H),6.89(d,J=2.1Hz,1H),5.45(s,2H),5.31(s,2H),2.25(s,3H). ESI-MS: m / z=435.16[M+H] + .

[0427] (3) Synthesis of Compound 37

[0428] [ka]

[0429] 37-2 (217 mg, 0.50 mmol) and D-serine (105 mg, 1 mmol) were dissolved in 5 mL of anhydrous DMF, and glacial acetic acid (58 μL, 1 mmol) was added. The mixture was then incubated at 35°C for 24 hours. NaBH(OAc)3 (318 mg, 1.5 mmol) was then added and the reaction was continued for 24 hours. Water was added, and the mixture was extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 138 mg of a white solid in a 53% yield. 1 H NMR (400 MHz, DMSO-d): δ 9.05(s,1H),9.01(s,1H),8.35(br,2H),7.49-7.40(m,3H),7.40-7.28(m,5H) ,7.20(d,J=2.1Hz,1H),6.88(s,1H),6.75(d,J=2.1Hz,1H),5.36-5.25(m,2H), 5.17(s,2H),4.07(d,J=5.2Hz,1H),4.00(d,J=7.2Hz,1H),3.73(d,J=6.8Hz,1 H),3.64(dd,J=11.4,7.2Hz,1H),3.17-3.14(m,1H),2.21(s,3H),1.93(s,1H). ESI-MS: m / z=524.25[M+H] + .

[0430] [Example 38: (Comparative Example 2)] (1) Synthesis of intermediate 38-1

[0431] [ka]

[0432] (5-Bromo-4-methylpyridin-3-yl)methanol (308 mg, 2.5 mmol) and CuCN (560 mg, 6.25 mmol) were added to a reactor and suspended in 8 mL of pyridine. The mixture was reacted at 160 °C for 24 hours, cooled, and the reaction mixture was added to 4 mL of concentrated aqueous ammonia and 12 mL of saturated ammonium chloride, followed by stirring at room temperature for 2 hours. The mixture was extracted with a dichloromethane / isopropanol (85:15) mixture. The extract was dried over anhydrous sodium sulfate and concentrated to dryness to give 305 mg of 5-hydroxymethyl-4-methylpyridine-3-carbonitrile, which was used directly in the next step. 5-Hydroxymethyl-4-methylpyridine-3-carbonitrile (305 mg, 2.06 mmol) was dissolved in 9 mL of DCM, thionyl chloride (0.3 mL, 4.12 mmol) was added, and the mixture was stirred at room temperature until the reaction was complete. The reaction mixture was concentrated to dryness, and EA was added. The organic phase was washed with saturated sodium bicarbonate solution and sodium chloride solution, concentrated to dryness, and purified by column chromatography to give 223 mg of an oil in 65% yield. 1 H NMR (400MHz, CDCl3): δ 9.08 (s, 1H), 8.75 (s, 1H), 4.52 (s, 2H), 2.45 (s, 3H).

[0433] (2) Synthesis of intermediate 38-2

[0434] [ka]

[0435] 37-1 (337 mg, 1.06 mmol) was dissolved in 12 mL of acetonitrile, and K2CO3 (220 mg, 1.59 mmol), tetra-n-butylammonium iodide (18 mg, 0.053 mmol), and intermediate 38-1 (211 mg, 1.27 mmol) were added sequentially. The reaction was allowed to proceed at 75°C overnight. The reaction solution was concentrated, water was added, and the mixture was extracted with EA. The organic phase was washed with water until neutral, and purified by column chromatography to give 357 mg of a pale yellow solid in a 75% yield. 1 H NMR(400MHz,DMSO-d6):δ 10.26(s,1H),8.97(s,1H),8.92(s,1H),7.87(d,J=2.3Hz,1H),7.54-7.47(m,3H),7.45-7.34(m,1H),7.35-7 .28(m,4H),6.89(d,J=2.1Hz,1H),6.69(d,J=2.1Hz,1H),5.45(s,2H),5.31(s,2H),2.55(s,3H),2.25(s,3H). ESI-MS: m / z=449.21[M+H] + .

[0436] (3) Synthesis of Compound 38

[0437] [ka]

[0438] 38-2 (224 mg, 0.50 mmol) and D-serine (105 mg, 1 mmol) were dissolved in 5 mL of anhydrous DMF, and glacial acetic acid (58 μL, 1 mmol) was added. The mixture was then reacted at 35°C for 24 hours. NaBH(OAc)3 (318 mg, 1.5 mmol) was added, and the reaction was continued for 24 hours. Water was added, and the mixture was extracted with a DCM / MeOH (10:1) mixture. The organic phase was washed with water and concentrated to dryness. The residue was purified by preparative liquid chromatography to give 132 mg of a white solid in 49% yield. 1H NMR(400MHz,DMSO-d6):δ 9.05(s,1H),9.01(s,1H),8.35(br,2H),7.47-7.39(m,3H),7.41-7.23(m,5H),7. 26(d,J=2.1Hz,1H),6.89(s,1H),6.75(d,J=2.1Hz,1H),5.36-5.25(m,2H),5.16( s,2H),4.07(d,J=5.2Hz,1H),4.03(d,J=7.2Hz,1H),3.71(d,J=6.8Hz,1H),3.64( dd,J=11.4,7.2Hz,1H),3.17-3.14(m,1H),2.56(s,3H),2.21(s,3H),1.95(s,1H) ESI-MS: m / z=538.25[M+H] + .

[0439] [Example 39] Activity of compounds inhibiting PD-1 / PD-L1 interaction The inhibitory activity of compounds against PD-1 / PD-L1 interaction was evaluated at the protein level using the PD-1 / PD-L1 Binding Assay Kit (Cisbio Company). The assay method for this kit is based on the principle of homogeneous time-resolved fluorescence (HTRF). The kit contains the relevant proteins, reagents, and buffers required for the experiment. The positive control compound BMS202 was purchased from MCE.

[0440] (1) Experimental method The experimental method and procedures were carried out according to the kit instructions, and were briefly described as follows.

[0441] Compounds were prepared in DMSO at the desired concentrations. Tag1-PD-L1, Tag2-PD-1 and compound solutions were diluted with dilution buffer to form working solutions, and anti-Tag1-EU 3+ Anti-Tag1-XL665 and anti-Tag2-XL665 were diluted with detection buffer to prepare working solutions. A white 384-shallow-well plate was used for the experiment. 2 μL of compound working solution, 4 μL of Tag1-PD-L1 working solution, and 4 μL of Tag2-PD-1 working solution were added to each well in sequence and incubated at room temperature for 15 minutes. Anti-Tag1-EU3+ 5μL of the working solution and 5μL of the anti-Tag2-XL665 working solution were thoroughly mixed to form a mixture of 10μL, which was then added to each well and incubated for 2.5 hours for detection. Control groups were also set up as follows: 2μL of compound working solution was replaced with 2μL of dilution buffer to form a positive control, and 2μL of compound working solution and 4μL of Tag1-PD-L1 working solution were replaced with 6μL of dilution buffer to form a negative control. Fluorescence intensities at emission wavelengths of 620nm and 665nm were detected using a TECAN Infinite F200 PRO under excitation light of 320nm. The HTRF value of each well was calculated as (fluorescence intensity at 665nm / fluorescence intensity at 620nm) x 10 4 The compound inhibition rate (%) was calculated using the formula: [1-(HTRF value of compound well - HTRF value of negative control well) / (HTRF value of positive control well - HTRF value of negative control well)] x 100%. The inhibition rate of each compound was determined at 8 to 10 concentrations, and the IC was calculated using Prism software. 50 was calculated.

[0442] (2) Experimental results The results of evaluating the inhibitory activity of compounds against PD-1 / PD-L1 interaction are shown in the table below.

[0443] [Table 1]

[0444] Example 40: Interaction of compounds with human PD-L1 protein (1) Experimental method In this experiment, human PD-L1 / AVI was captured by an SA chip using Fortebio's OctectRED biofilm interferometry (BLI) technology. The antigen PD-L1 / AVI was diluted to 10 μg / mL in running buffer (PBS + 0.02% Tween-20 + 2% DMSO) with a loading time of 300 s. Similarly, the analyte was diluted with running buffer to corresponding concentrations (20 nM, 10 nM, 5 nM, 2.5 nM, 1.25 nM, 0.625 nM, 0.3125 nM), with a buffer blank control. The binding time for human PD-L1 / AVI and the analyte was 180 s, and the dissociation time was 300 s. The chip was regenerated with 10 mM glycine-HCl (pH 1.7) solution, with three 5-s pulses. The data were fitted to a 1:1 binding model to determine the equilibrium dissociation constant, KD.

[0445] (1) Experimental results The results are shown in the table below. The compound had strong binding ability to human PD-L1, with an affinity KD value of nM or higher.

[0446] [Table 2]

[0447] [Example 41] Evaluation of compounds for in vitro IFN-γ secretion promoting activity (1) Experimental method Human peripheral blood mononuclear cells (PBMCs) were isolated from 10–15 ml of whole blood from healthy volunteers using laboratory human lymphocyte separation medium (TBD Sciences). The cells were washed twice with normal saline, resuspended in buffer (RPMI 1640 complete medium containing 10% FBS, SIGMA), and counted. PBMCs were dispersed and placed at 1 × 10 per well of a 96-well plate. 5Cells and 50 μL of buffer solution were placed in wells. Anti-CD3 antibody (SIGMA) and anti-CD28 antibody (SIGMA) were mixed at a 1:1 ratio to obtain an antibody mixture. The antibody mixture was added to the wells to a final antibody concentration of 0.8 μg / mL. Simultaneously, PDL1 / FC fusion protein (SINO BIOLOGICAL) was added to a final concentration of 10.0 μg / mL, and test compounds were diluted with buffer and added to the wells to a final concentration of 0.1 μM or 1 μM. The mixture was cultured for 72 hours at 37°C and 5% CO2. The supernatant was collected, and IFN-γ expression levels were measured using the ELISA MAX™ Human IFN-γ Standard Kit (BioLegend). The increase rate was calculated using the following formula: Increase rate (%) = (expression level after compound treatment - expression level after PDL1 treatment) / expression level after PDL1 treatment × 100%.

[0448] (2) Experimental results The results are shown in the table below. Compounds 5 and 10 were found to have a significant effect of promoting IFN-γ secretion at the cellular level, and the effect was superior to that of BMS202.

[0449] [Table 3]

[0450] [Example 42] Evaluation of compound cytotoxicity (1) Experimental method Raji (ATCC), raw (ATCC), and PBMCs cells were suspended in buffer (RPMI 1640 complete medium containing 10% FBS, SIGMA), and the cell density was counted. The cells were transferred to wells of a 96-well plate, and the cell density in each well was 1 × 10 4The cells were incubated with various concentrations of compounds (100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.125 μM) and buffer control solution (0.2% DMSO) at 37°C and 5% CO2 for 24 hours, with the cells adjusted to the number of cells per well. 100 μL of Cell Titer-Glo Luminescent Solution (Promega) was added to each well, and the cells were shaken at room temperature for 10 minutes. The system fluorescence was measured using a GloMax® Navigator System, and the cell death rate was calculated. The cell death rate (%) was calculated using the formula (1-RLU compound / RLU control) × 100%, and the IC was calculated from the inhibition curve. 50 It was decided that:

[0451] (2) Experimental results The experimental results are shown in the table below. The results show that most of the compounds have good safety to various cells, and only a few compounds show some toxicity.

[0452] [Table 4]

[0453] [Example 43] Evaluation of in vivo antitumor effect Based on the mechanism by which PD-1 / PD-L1 inhibitors exert their anti-tumor effects by activating the immune system and inhibiting PD-1 / PD-L1 interaction, the animal model used for in vivo efficacy experiments must be an animal with a healthy immune system. Furthermore, species differences in PD-1 / PD-L1 expression between animals and humans must be taken into consideration. Therefore, the in vivo anti-tumor pharmacodynamics evaluation model of the present invention employs PD-1-humanized mice, inoculated with PD-L1-humanized tumor cells. This evaluation model can more accurately reflect the in vivo efficacy of compounds.

[0454] (1) Experimental method Twenty-four PD-1-humanized mice (strain full name: C57BL / 6J-Pdcd1) were cultured at approximately 6 weeks of age. em1(hPDCD1) / Smoc) were purchased from the Shanghai Southern Model Animal Center, placed in an SPF animal breeding room, and observed for 1-2 weeks. After acclimatization to the breeding environment, the genetically modified colon cancer cell line MC38 (mouse PD-L1 knockout, human PD-L1 knockin) was subcutaneously inoculated into the groin area of ​​the hind legs of the mice. The inoculated cell dose was 1 × 10 6 The tumor volume was 50-150 mm. 3 Once the tumors reached the tumor size, the animals were randomly assigned to a vehicle group and a test group, each consisting of six animals, according to a random number table. The test group received an intraperitoneal injection of Compound 5 at 15 mg / kg, and the vehicle group received an intraperitoneal injection of the same volume of buffer as the test group. The administration frequency was once daily for three weeks. Tumor size and mouse weight were measured and recorded during the experiment, and the mice were sacrificed at the end of the experiment. Mouse weight and tumor growth curves were plotted.

[0455] (2) Experimental results The experimental results are shown in Figures 1 and 2. Compared with the control group, compound 5 was able to significantly inhibit tumor growth.

[0456] Various modifications of the present invention in addition to those described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. Each document cited in this application, including all patents, patent applications, journal articles, books, and any other publications, is hereby incorporated by reference in its entirety.

Claims

1. General formula (IA): 【Chemistry 1】 (In the formula, R is hydrogen; R 1 is selected from C 1 -C 2 alkyl; R 2 teeth, 【Chemistry 2】 and R 3 teeth, 【Transformation 3】 and R 4 teeth,: 【Chemistry 4】 selected from the group consisting of: R 5 is selected from the group consisting of hydrogen, deuterium, halogen, and C 1 -C 2 alkyl; R 5 is -OR 3 (It exists in the para position of or a pharmaceutically acceptable stereoisomer, salt, or solvate thereof.

2. The benzylamine derivative according to claim 1, wherein R 1 is methyl, or a pharmaceutically acceptable stereoisomer, salt, or solvate thereof.

3. R 5 2. The benzylamine derivative of claim 1, or a pharmaceutically acceptable stereoisomer, salt, or solvate thereof, wherein R is selected from the group consisting of hydrogen and methyl.

4. (2-((5-cyanopyridin-3-yl)methoxy)-5-methyl-4-(((2-methyl-[1,1′-biphenyl]-3-yl)methyl)amino)benzyl)-D-serine, (2-((5-cyanopyridin-3-yl)methoxy)-4-(((2-methyl-[1,1′-biphenyl]-3-yl)methyl)amino)benzyl)-D-serine, (5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-(((2-methyl-[1,1′-biphenyl]-3-yl)methyl)amino)benzyl)-D-serine, (R)-3-((2-((5-cyanopyridin-3-yl)methoxy)-5-methyl-4-(((2-methyl-[1,1'-biphenyl]-3-yl)methyl)amino)benzyl)amino)-4-hydroxybutyric acid, (2S,4R)-1-(2-((5-cyanopyridin-3-yl)methoxy)-5-methyl-4-(((2-methyl-[1,1′-biphenyl]-3-yl)methyl)amino)benzyl)-4-hydroxypyrrolidine-2-carboxylic acid, (S)-4-((2-((5-cyanopyridin-3-yl)methoxy)-5-methyl-4-(((2-methyl-[1,1'-biphenyl]-3-yl)methyl)amino)benzyl)amino)-3-hydroxybutyric acid, (S)-5-((2-((4-hydroxy-2-oxopyrrolidin-1-yl)methyl)-4-methyl-5-(((2-methyl-[1,1′-biphenyl]-3-yl)methyl)amino)phenoxy)methyl)nicotinonitrile, and (2-((5-cyanopyridin-3-yl)methoxy)-5-methyl-4-(((2-methyl-[1,1'-biphenyl]-3-yl)methyl)amino)benzyl)-D-asparagine 2. The benzylamine derivative of claim 1, wherein the benzylamine derivative is selected from the group consisting of:

5. The following method 【Transformation 5】 2. A process for preparing the benzylamine derivative according to claim 1, characterized in that it is selected from:

6. A benzylamine derivative according to any one of claims 1 to 4, or a pharmaceutically acceptable stereoisomer, salt, or solvate thereof; one or more pharmaceutically acceptable carriers or excipients; A pharmaceutical composition comprising:

7. Use of the benzylamine derivative according to any one of claims 1 to 4, or a pharmaceutically acceptable stereoisomer, salt, or solvate thereof, in the manufacture of a medicament for the prevention and treatment of diseases associated with PD-1 / PD-L1.

8. PD-1 / PD-L1-associated diseases include tumors, infectious diseases, and autoimmune diseases. the tumor is selected from the group consisting of a tumor of the digestive system, a tumor of the urinary system, a tumor of the blood, a tumor of the nervous system, a tumor of the reproductive system, skin cancer, lung cancer, breast cancer, head and neck cancer, brain tumor, glioma, and nasopharyngeal tumor; the infectious disease is selected from one or more infections caused by a microorganism; The autoimmune disease is selected from the group consisting of chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, pulmonary hemorrhagic nephritic syndrome, pemphigus, pemphigoid, primary biliary cirrhosis, multiple cerebral sclerosis, acute idiopathic polyneuropathy, systemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis, scleroderma, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia, autoimmune thyroid disease, Sjogren's syndrome, ankylosing spondylitis, polyarteritis nodosa, and Wegener's granulomatosis.

8. Use according to claim 7.

9. A pharmaceutical composition for use in the prevention or treatment of a PD-1 / PD-L1-associated disease, comprising the benzylamine derivative according to any one of claims 1 to 4, or a pharmaceutically acceptable stereoisomer, salt, or solvate thereof, or the pharmaceutical composition according to claim 6, for use in the prevention or treatment of a PD-1 / PD-L1-associated disease.

10. PD-1 / PD-L1-associated diseases include tumors, infectious diseases, and autoimmune diseases. the tumor is selected from the group consisting of a tumor of the digestive system, a tumor of the urinary system, a tumor of the blood, a tumor of the nervous system, a tumor of the reproductive system, skin cancer, lung cancer, breast cancer, head and neck cancer, brain tumor, glioma, and nasopharyngeal tumor; the infectious disease is selected from one or more infections caused by a microorganism; The autoimmune disease is selected from the group consisting of chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, pulmonary hemorrhagic nephritic syndrome, pemphigus, pemphigoid, primary biliary cirrhosis, multiple cerebral sclerosis, acute idiopathic polyneuropathy, systemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis, scleroderma, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia, autoimmune thyroid disease, Sjogren's syndrome, ankylosing spondylitis, polyarteritis nodosa, and Wegener's granulomatosis. The pharmaceutical composition according to claim 9 .

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