Novel bicyclic PD-L1 inhibitor, method for producing the same, and pharmaceutical use

Abstract

The present invention relates to the field of medicinal chemistry and discloses pyridoheterocyclic derivatives with PD-1 / PD-L1 inhibitory activity, and methods for preparing and using the same. The present invention also discloses a composition comprising the pyridoheterocyclic derivatives with PD-1 / PD-L1 inhibitory activity or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and its use in preparing PD-1 / PD-L1 inhibitors. The compounds of the present invention can be used to treat tumors.

Description

[Technical Field] 【0001】 This invention belongs to the field of medicinal chemistry and specifically relates to biphenyl derivatives having PD-1 / PD-L1 inhibitory activity, methods for producing these derivatives, pharmaceutical compositions containing these compounds, and their use in tumor treatment. Technical Background 【0002】 In recent years, tumor immunotherapy has become a focus in the field of oncology. Unlike conventional therapies that directly target tumor cells, tumor immunotherapy utilizes the body's own immune system to kill tumor cells. Activation of immune checkpoint pathways inhibits T cell activation, preventing overactivation of the human immune system, maintaining normal immune tolerance in the body, and avoiding the development of autoimmune diseases. Tumors cause tumor immune evasion by overactivating immune checkpoint pathways themselves and some lymphocytes. Of these immune checkpoints, overactivation of PD-1 / PD-L1 plays a crucial role in tumor development. Blocking the PD-1 / PD-L1 interaction reactivates the immune system and kills tumor cells, demonstrating excellent efficacy in treating tumors such as clinical melanoma, colon cancer, and non-small cell lung cancer (Clinical and Translational Oncology, 2019, 21: 702-712; Lung Cancer: Targets and Therapy, 2017: 8; Hum VaccinImmunother, 2014, 10(11): 3111-3116; Journal of Medicinal Chemistry, 2020, 63(22): 13825-13850). 【0003】 To date, several PD-1 / PD-L1 targeting mAbs have been approved by the FDA for use in tumor immunotherapy, and hundreds of mAbs are currently undergoing active clinical trials. While these monoclonal antibodies have improved the prognosis of many cancer patients, only a small number achieve a sustained response due to the development of intrinsic and acquired resistance. The use of monoclonal antibodies can also cause serious immune-related adverse events (irAEs), such as skin inflammation, colitis, hepatitis, hypothyroidism, and hypophysitis. Furthermore, macromolecular drugs have drawbacks such as low tissue permeability, complex manufacturing processes, high costs, and low patient compliance. Therefore, the development of small molecule inhibitors is expected to solve the problems of monoclonal antibodies mentioned above. 【0004】 Compared to monoclonal antibodies, small molecule drugs offer the following clear advantages: 1) They are easy to administer, more suitable for oral administration, and their half-life can be adjusted to avoid serious adverse events associated with immunotherapy. 2) They have excellent membrane permeability, allowing them to directly expose the tumor microenvironment or pass through physiological barriers. 3) They can directly act on intracellular targets that large molecules cannot reach. 4) They are readily available, offering greater flexibility in dosage form and administration. 5) They have lower production costs, do not require refrigeration, and are easy to store and transport. 【0005】 Currently, no PD-1 / PD-L1 small molecule inhibitors are commercially available. Therefore, the development of inhibitors that block PD-1 / PD-L1 protein interactions has great practical significance and holds promise for potential applications. [Overview of the Initiative] [Problems that the invention aims to solve] 【0006】 Objective of the Invention: In response to the technical problems present in the prior art described above, the present invention provides a pyridoheterocyclic derivative having PD-1 / PD-L1 inhibitory activity, a method for producing the same, and its pharmaceutically acceptable use as a PD-1 / PD-L1 protein-protein interaction inhibitor. 【0007】 Technical solution: The present invention discloses pyridoheterocyclic derivatives represented by general formula I or pharmaceutically acceptable salts thereof. [ka] (Here, Ar is [ka] , [ka] , or [ka] Show, L is -(CH2) m -, -O-, -NH-, -CH2O-, -CF2O-, -CH2NH-, -CONH-, -HNCO-, -NHCH2-, -OCF2-, -OCH2-, or -CH=CH-, where m represents 0, 1, or 2. X 1 , X 2 Each of these independently represents either N or CH. T and V are, respectively [ka] , [ka] 、-O-、 [ka] , and -S- are shown, where R 5 This represents H, C1-C6 alkyl, or C3-C7 cycloalkyl. U indicates CH or N. n represents 0, 1, 2, or 3. R 1 and R 3Each represents H, D, halogen, CN, C1-C3 haloalkyl, C1-C3 alkyl, or cyclopropyl, R 2 represents H, substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, or substituted C3-C7 heterocycloalkyl, wherein the substituent is H, OH, NH2, COOH, amide, ester group, alkoxy, or aldehyde group, and may be mono-substituted or multi-substituted, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, O, S, R 4 represents H, halogen, CN, CF3, OH, NH2, -O(CH2) p R 6 substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, or substituted C3-C7 heterocycloalkyl, wherein the substituent is H, OH, NH2, COOH, amide, ester group, alkoxy, and may be mono-substituted or multi-substituted, where p represents 1, 2, 3, or 4, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, O, S, R 6 represents NR 7 R 8 OR 7 or substituted C4-C6 azacycloalkyl, where R 7 represents H, or C1-C3 alkyl, and R<​​​​​​​​​​​​​​​​​​​​Show, L is -(CH2) m - represents -CH2O-, -CF2O-, -CONH-, -NHCO-, or -OCH2-, where m represents 0. X 1 and X 2 Each of these independently represents either N or CH. T and V are, respectively [ka] -CH2-, -O-, -NH-, or [ka] Show, U represents N, n represents 0 or 1. R 1 and R 3 These represent H, D, F, Cl, Br, CN, CH3, or CF3, respectively. R 2 H, [ka] or [ka] This shows that q represents 0 or 1, and R 9 and R 10 These represent H, OH, COOH, CH2COOH, CH2NH2, CH2OH, CH2CH2OH, F, Cl, Br, CH3, and CH2CH3, respectively. R 11 These represent OH, NH2, NHCH3, CH3, OCH3, OCH2CH3, and OCH(CH3)2. R 12 This represents CONH2, NHCOCH3, OH, CH2OH, CH2CH2OH, COOH, COOCH3, COOCH2CH3, COOCH(CH3)2, R 13 These represent H, CH3, CH2CH3, CH2OH, and CH2CH2OH. R 4These are H, F, Cl, Br, CN, CF3, OH, NH2, or -O(CH2) p R 6 This shows that, where p represents 2, 3, or 4, and R 6 , OH, [ka] , [ka] or [ka] Show, here, R 9 , R 10 , R 11 , R 12 , and R 13 It is defined in the same way as above, R 14 R represents CH3, CH2CH3, CH2CH2OH, formyl, or acetyl. 15 and R 16 These represent H, OH, COOH, NH2, CH3, CH2CH3, CH2OH, CH2CH2OH, CONH2, cyclopropyl, COOCH3, COOCH2CH3, or COOCH(CH3)2, respectively, and W represents -CH2-, -O-, -NH-, [ka] , or [ka] This indicates that r represents either 0 or 1. 【0009】 Here, moreover, Ar is [ka] Show, L represents -CH2O- and -NHCO-. X 1 This indicates CH or N, and X 2 CH indicates, T is [ka] Or, it shows -CH2-, U represents N, V represents -CH2-, n is either 0 or 1. 【0010】 R 1 , and R 3 These represent F, Cl, Br, CN, CH3, or CF3, respectively. R 2 H, [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , or [ka] This indicates. 【0011】 R 4 These are H, F, Cl, CN, CF3, OH, NH2, or -O(CH2)3R6 Show, here, R 6 These are OH, CONH2, CH2OH, COOH, COOCH3, COOCH2CH3, or [ka] This indicates. 【0012】 More preferably, the compound is one of the following compounds. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 【0013】 The aforementioned pharmaceutically acceptable salts are acid-added salts formed from a compound of general formula I with an acid such as hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or ferulic acid. 【0014】 The use of compounds containing pyridoheterocyclic compounds or pharmaceutically acceptable salts thereof in the manufacture of PD-L1 inhibitor drugs for the treatment of tumors. 【0015】 Compound (I) of the present invention is classified into types such as IA, IB, IC, ID, IE, and IF, and the synthesis methods for each are described below. 【0016】 Ar is [ka] Show, X 1 and X 2 Each of these independently represents CH, and L represents -(CH2) m When - is shown, m is 0, T is shown as C=O, U is shown as N, V ​​is shown as CH2, and n is 0, the synthesis pathway of equation IA is as follows: [ka] (Here, R 1 , R 2 , R 3 , and R 4 The definition is as stated above. 【0017】 Compound IV is prepared by the Suzuki reaction of Compound II and Compound III. The solvent used is selected from toluene, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, water, or a mixed solvent of any two of these solvents, preferably a mixed solvent of 1,4-dioxane and water. The alkali used is selected from sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate, potassium bicarbonate, sodium carbonate, potassium carbonate, or triethylamine, preferably potassium carbonate. The catalyst used is selected from [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (Pd(dppf)Cl2), tetrakis(triphenylphosphine)palladium(O)(Pd(PPh3)4), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), tris(dibenzylideneacetone)dipalladium(O)(Pd2(dba)3), or palladium acetate (Pd(OAc)2), preferably Pd(PPh3)4. The reaction temperature is selected from 50 to 120°C, preferably 60 to 100°C. 【0018】 Compound V is prepared by the Sandmeyer reaction of compound IV. The diazotizing reagent used is selected from tert-butyl nitrite (t-BuONO) and sodium nitrite, preferably sodium nitrite. The catalyst used is selected from dibenzoyl peroxide (BPO), azobisisobutyronitrile (AIBN), concentrated hydrochloric acid, or concentrated sulfuric acid, preferably hydrochloric acid. The solvent used is selected from tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, water, or a mixed solvent consisting of any two of these solvents, preferably a mixed solvent of methanol and water, and the reaction temperature is selected from -25 to 80°C, preferably 0 to 25°C. 【0019】 Compound VII is prepared using compound VI. The acid binder used is selected from triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium methanol, sodium ethoxide, or potassium tert-butoxide, preferably sodium hydride. The solvent used is selected from dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, ethyl acetate, DMF, or a mixed solvent of any two of these, preferably tetrahydrofuran or DMF. 【0020】 Compound IA is produced by the Suzuki reaction of compound VII and compound V. The solvent used is selected from toluene, DMF, DMAc, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, water, or a mixed solvent of any two of these solvents, preferably a mixed solvent of 1,4-dioxane and water. The alkali used is selected from sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate, potassium bicarbonate, sodium carbonate, potassium carbonate, or triethylamine, preferably potassium carbonate. The catalyst used is selected from Pd(PPh3)4, Pd(dppf)Cl2, Pd(PPh3)2Cl2, Pd(OAc)2, or Pd2(dba)3, preferably Pd(PPh3)4. The reaction temperature is selected from 50 to 120°C, preferably 60 to 100°C. 【0021】 Ar is [ka] Show, X 1 This indicates N, and X 2 represents CH, and L represents -(CH2) m When - is shown, m is 0, T is CH2, U is N, V ​​is CH2, and n is 1, the synthesis pathway of formula IB is as follows: [ka] (Here, R 1 , R 2 , R 3 , and R 4 The definition is as stated above. 【0022】 Compound IX is prepared using Compound VIII. The acid binder used is selected from triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium methanol, sodium ethoxide, potassium tert-butoxide, or sodium hydride, preferably sodium hydride. The solvent used is selected from dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, ethyl acetate, DMF, or a mixed solvent consisting of any two of these, preferably tetrahydrofuran or DMF. 【0023】 Compound IB is produced by the Suzuki reaction of compound IX and compound V. The solvent used is selected from toluene, DMF, DMAc, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, water, or a mixed solvent of any two of these solvents, preferably a mixed solvent of 1,4-dioxane and water. The alkali used is selected from sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate, potassium bicarbonate, sodium carbonate, potassium carbonate, or triethylamine, preferably potassium carbonate. The catalyst used is selected from Pd(PPh3)4, Pd(dppf)Cl2, Pd(PPh3)2Cl2, Pd(OAc)2, or Pd2(dba)3, preferably Pd(PPh3)4. 【0024】 Ar is [ka] Show, X 1 This indicates N, and X 2 represents CH, and L represents -(CH2)m When - is shown, m is 0, T is CH2, U is N, V ​​is CH2, and n is = 1, the composite path of formula IC is as follows: [ka] (Here, R 1 , R 2 , R 3 , and R 4 The definition is as stated above. 【0025】 Compound X and SOCl2 are reacted with methanol to produce XI. The reaction temperature is selected from 50 to 120°C, preferably from 60 to 100°C. 【0026】 Compound XII is produced by reducing compound XI. The solvent used is selected from tetrahydrofuran, ethanol, DMF, or 1,4-dioxane, preferably methanol, and the reducing agent used is selected from lithium aluminum tetrahydride, sodium borohydride, or potassium borohydride, preferably lithium aluminum tetrahydride. 【0027】 Compound XIV is produced by the Suzuki reaction of compound XII and compound XIII. The solvent used is selected from toluene, DMF, DMAc, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, water, or a mixed solvent of any two of these, preferably a mixed solvent of 1,4-dioxane and water. The alkali used is selected from sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate, potassium bicarbonate, sodium carbonate, potassium carbonate, or triethylamine, preferably potassium carbonate. The catalyst used is selected from Pd(PPh3)4, Pd(dppf)Cl2, Pd(PPh3)2Cl2, Pd(OAc)2, or Pd2(dba)3, preferably Pd(PPh3)4. The reaction temperature is selected from 50 to 120°C, preferably 60 to 100°C. 【0028】 Compound IC is produced by reacting compound IX with compound XIV. The catalyst used is selected from Pd(PPh3)4, Pd(dppf)Cl2, Pd(PPh3)2Cl2, Pd(OAc)2, or Pd2(dba)3, preferably Pd(OAc)2, and the ligands used are triphenylphosphine, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-BuXPhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantph The alkali used is selected from t-BuXPhos, or 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tris-i-propyl-1,1'-biphenyl (Brett-Phos), preferably t-BuXPhos; the alkali used is selected from sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate, or sodium carbonate, preferably cesium carbonate; the solvent used is selected from tetrahydrofuran, 1,4-dioxane, toluene, or a mixed solvent of any two of these, preferably toluene. The reaction temperature is selected from 50 to 120°C, preferably 60 to 100°C. 【0029】 Ar is [ka] Show, X 1 This indicates N, and X 2 When represents CH, L represents -CH2O-, T is CH2, U represents N, V ​​represents CH2, and n is 1, the synthesis pathway of formula ID is as follows: [ka] (Here, R 1 , R 2 , R 3 , and R 4 The definition is as stated above. 【0030】 Compound XV is produced by the Suzuki reaction of compound XII and compound III. The solvent used is selected from toluene, DMF, DMAc, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, water, or a mixed solvent of any two of these solvents, preferably a mixed solvent of 1,4-dioxane and water. The alkali used is selected from sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate, potassium bicarbonate, sodium carbonate, potassium carbonate, or triethylamine, preferably potassium carbonate. The catalyst used is selected from Pd(PPh3)4, Pd(dppf)Cl2, Pd(PPh3)2Cl2, Pd(OAc)2, or NiCl2(dppf), preferably Pd(PPh3)4. The reaction temperature is selected from 50 to 120°C, preferably 60 to 100°C. 【0031】 Compound ID is produced by the reaction of compound IX and compound XV. The catalyst used is selected from Pd(PPh3)4, Pd(dppf)Cl2, Pd(PPh3)2Cl2, Pd(OAc)2, or Pd2(dba)3, preferably Pd(OAc)2; the ligand used is selected from t-BuXPhos, X-Phos, Xantphos, or Brett-Phos, preferably t-BuXPhos; the alkali used is selected from sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate, or sodium carbonate, preferably cesium carbonate; and the solvent used is selected from tetrahydrofuran, 1,4-dioxane, toluene, or a mixed solvent of any two of these, preferably toluene. 【0032】 Ar is [ka] Show, X 1 This indicates N, and X 2When represents CH, L represents -CH2O-, T represents CH2, U represents N, V ​​represents NCH3, and n is 1, the synthesis pathway of formula IE is as follows: [ka] (Here, R 1 , R 2 , R 3 , and R 4 The definition is as stated above. 【0033】 Compound XVII is prepared using compound XVI and methyl iodide under alkaline conditions. The solvent used is selected from acetone, DMF, acetonitrile, or tetrahydrofuran, or a mixed solvent consisting of the above solvents, preferably DMF. The alkali used is selected from sodium hydride, sodium methanol, sodium ethoxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, or lithium hydroxide, preferably sodium hydride. 【0034】 Compound XVIII is produced by reductive amination of compound XVII with an amine compound. The solvent used is selected from toluene, DMF, dichloromethane, dichloroethane, chloroform, methanol, 1,4-dioxane, tetrahydrofuran, ethanol, acetonitrile, acetone, or a mixed solvent consisting of the above solvents, preferably a mixed solvent of dichloromethane and methanol. The reducing agent used is selected from sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, or sodium hydrosulfite, preferably sodium triacetoxyborohydride. 【0035】 Compound XVIII is reacted under acidic conditions to produce the target compound XIX. The solvent used is selected from ethyl acetate, acetone, dichloromethane, acetonitrile, tetrahydrofuran, or a mixed solvent consisting of the above solvents, preferably ethyl acetate. The acid used is selected from a hydrogen chloride solution of saturated ethyl acetate, a hydrogen chloride solution of saturated 1,4-dioxane, hydrochloric acid, trifluoroacetic acid, or trifluoromethanesulfonic acid, preferably a hydrogen chloride solution of saturated ethyl acetate. 【0036】 Compound XIX is reacted with polyoxymethylene to produce the target compound XX. The solvent used is selected from methanol, ethanol, ethyl acetate, acetone, dichloromethane, DMF, acetonitrile, tetrahydrofuran, or a mixed solvent consisting of the above solvents, preferably methanol. The alkali used is selected from triethylamine, dimethylaminopyridine (DMAP), or N,N-diisopropylethylamine, preferably triethylamine. 【0037】 Compound IE is produced by reacting compound XX with compound XV. The catalyst used is selected from Pd(PPh3)4, Pd(dppf)Cl2, Pd(PPh3)2Cl2, Pd(OAc)2, or Pd2(dba)3, preferably Pd(OAc)2; the ligand used is selected from t-BuXPhos, X-Phos, Xantphos, or Brett-Phos, preferably t-BuXPhos; the alkali used is selected from sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate, or sodium carbonate, preferably cesium carbonate; and the solvent used is selected from tetrahydrofuran, 1,4-dioxane, toluene, or a mixed solvent of any two of these, preferably toluene. The reaction temperature is selected from 50 to 120°C, preferably 60 to 100°C. 【0038】 Ar is [ka] Show, X 1 This indicates N, and X 2 When represents CH, L represents -NHCO-, T represents CH2, U represents N, V ​​represents CH2, and n is 1, the synthesis pathway of formula IF is as follows: [ka] (Here, R 1 , R 2 , R 3 , and R 4 The definition is as stated above. 【0039】 Compound XXI is prepared using compound VIII and di-tert-butyl dicarbonate under alkaline conditions. The solvent used is selected from acetone, dichloromethane, DMF, acetonitrile, tetrahydrofuran, or a mixed solvent consisting of the above solvents, preferably tetrahydrofuran. The alkali used is selected from DMAP, triethylamine, N,N-diisopropylethylamine, potassium tert-butoxide, sodium hydride, sodium methanol, sodium ethoxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, or lithium hydroxide, preferably triethylamine. 【0040】 Compound XXII is prepared using compound XXI. The solvent used is selected from acetone, dichloromethane, DMF, acetonitrile, tetrahydrofuran, or a mixed solvent consisting of the above solvents, preferably DMF. The cyano donor is selected from zinc cyanide, cuprous cyanide, or potassium ferrocyanide, preferably zinc cyanide. The catalyst used is selected from Pd(dppf)Cl2, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd2(dba)3, or Pd(OAc)2, preferably Pd(PPh3)4. The reaction temperature is selected from 50 to 150°C, preferably 80 to 120°C. 【0041】 Compound XXIII is produced by hydrolyzing compound XXII under alkaline conditions. The solvent used is selected from methanol, ethanol, water, acetonitrile, tetrahydrofuran, acetone, dichloromethane, DMF, acetonitrile, or a mixed solvent consisting of the above solvents, preferably a mixed solvent of ethanol and water. The alkali used is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, or lithium hydroxide, preferably potassium hydroxide. The reaction temperature is 0 to 120°C, preferably 60 to 100°C. 【0042】 Compound XXIV is produced by reacting compounds IV and XXIII. The condensing agent used is selected from carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), or hexafluorophosphate (benzotriazole-1-yloxy)tripyrrolidinophosphonium (PyBOP), preferably HATU. The acid binder is selected from N,N-diisopropylethylamine or triethylamine, preferably N,N-diisopropylethylamine. The solvent used is selected from acetone, dichloromethane, DMF, acetonitrile, tetrahydrofuran, or a mixed solvent consisting of the above solvents, preferably DMF. The reaction temperature is selected from 0 to 80°C, preferably 25 to 50°C. 【0043】 Compound XXIV is reacted under acidic conditions to produce the target compound XXV. The solvent used is selected from ethyl acetate, acetone, dichloromethane, acetonitrile, tetrahydrofuran, or a mixed solvent consisting of the above solvents, preferably ethyl acetate. The acid used is selected from a hydrogen chloride solution of saturated ethyl acetate, a hydrogen chloride solution of saturated 1,4-dioxane, hydrochloric acid, trifluoroacetic acid, or trifluoromethanesulfonic acid, preferably a hydrogen chloride solution of saturated ethyl acetate. 【0044】 Compound IF is prepared from compound XXV. The acid binder used is selected from triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, or sodium hydride, preferably sodium hydride. The solvent used is selected from dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, ethyl acetate, DMF, or a mixed solvent consisting of any two of these, preferably tetrahydrofuran or DMF. 【0045】 The present invention also discloses a pharmaceutical composition comprising the above-described compound of general formula (I) (including chiral isomers) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The compound may be used to produce common medicinal preparations, such as tablets, capsules, syrups, suspensions, and injections, by adding a pharmaceutically acceptable carrier, and common medicinal adjuncts such as flavorings, sweeteners, liquid or solid fillers, or diluents may be added. 【0046】 The use of the compound of general formula (I) of the present invention and its hydrate, solvate, or crystals in the manufacture of PD-1 / PD-L1 protein-protein interaction inhibitor drugs is also within the scope of protection of the present invention. 【0047】 Furthermore, the PD-1 / PD-L1 protein-protein interaction inhibitors described herein may be used in the manufacture of drugs to treat cancer or tumors, such as non-small cell lung cancer, colon cancer, melanoma, breast cancer, and liver cancer. 【0048】 Pharmacological experiments show that in homogeneous time-resolved fluorescence (HTRF) experiments, the pyridine heterocyclic ring system derivatives of the present invention can produce excellent inhibitory effects on the interaction of PD-1 / PD-L1. Since the pyridine heterocyclic ring system derivatives of the present invention have excellent activity, great practical significance and application potential can be expected for the development of biphenyl-based inhibitors of PD-1 / PD-L1. 【Effects of the Invention】 【0049】 Beneficial effects: Compared with the prior art, the present invention has the following obvious advantages. 【0050】 (1) The novel pyridine heterocyclic ring system derivatives of the present invention can significantly inhibit the interaction of PD-1 / PD-L1, and their activity is superior to that of the known PD-1 / PD-L1 inhibitor BMS-202. 【0051】 (2) The synthetic route of the pyridine heterocyclic ring system derivatives of the present invention is uniquely designed, simple and easy to implement, the raw materials are inexpensive and easily available, the synthetic process is safe and environmentally friendly, and large-scale production is easy. 【0052】 (3) The application range is wide, and as a drug with an active ingredient, it can be used for the treatment of various cancers and tumors related to the immune checkpoint PD-1 / PD-L1. 【Brief Description of the Drawings】 【0053】 [Figure 1] Shows the body weight gain curve of rats in the chronic administration toxicity test of the compounds of the present invention. [Figure 2] Shows the animal tumor growth curve of the compounds of the present invention in a BALB / c mouse 4T1 subcutaneous transplanted tumor model. 【Modes for Carrying Out the Invention】 【0054】 Example 1 2-(5-(2’-Fluoro-2-methyl-[1,1’-biphenyl]-3-yl)-1-oxoisoindolin-2-yl)ethyl acetate (I-A-1: R 1 =CH3, 【Chemical Structure】 , R 3 =F, R 4 =H, T represents C=O) synthesis Synthesis of 2’-fluoro-2-methyl-[1,1’-biphenyl]-3-amine (IV-1) 3-Bromo-2-methylaniline II-1 (2.50 g, 13.44 mmol), 2-fluorophenylboronic acid III-1 (2.26 g, 16.15 mmol), and 1,4-dioxane (25 mL) were sequentially added to a three-necked flask. A solution of potassium carbonate (5.21 g, 37.69 mmol) dissolved in water (2.5 mL) was added to the reaction solution, Pd(PPh3)4 (0.39 g, 0.34 mmol) was added, and the temperature was raised to 80 °C under nitrogen protection and reacted for 10 hours. As a result of monitoring by TLC, when the raw materials were completely reacted, heating was stopped and cooled to room temperature. Suction filtration was performed to remove the palladium catalyst and insoluble substances, water (25 mL) was added for dilution, and extraction was performed with ethyl acetate (25 mL × 3). The organic phases were mixed, washed with saturated NaCl aqueous solution (25 mL × 3), and dried over anhydrous magnesium sulfate. Suction filtration was performed, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 20:1~15:1) to obtain 2.59 g (yield 95.6%) of a yellow solid powder. m.p. 61.0~62.0 °C. 1 H NMR (300 MHz, DMSO-d6) δ 7.48 - 7.35 (m, 1H, ArH), 7.34 - 7.22 (m, 3H, ArH), 6.98 (t, J = 7.7 Hz, 1H, ArH), 6.70 (dd, J= 8.0 Hz, 1.4 Hz, 1H, ArH), 6.42 (dd, J = 7.5 Hz, 1.3 Hz, 1H, ArH), 5.00 (s, 2H, NH2), 1.85 (s, 3H, CH3). Synthesis of 2-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (V-1) Compound IV-1 (2.00 g, 9.94 mmol) was dissolved in methanol (20 mL) and water (10 mL). Hydrochloric acid solution (9.92 mL, 3 mmol / mL) was slowly added dropwise, and the mixture was stirred at 25°C until the reaction mixture became clear. The temperature was then lowered to 0°C, and an aqueous solution of NaNO2 (4.96 mL, 2.2 mmol / mL) was slowly added dropwise. After the addition was complete, the mixture was stirred at 0°C for 30 minutes. Then, bis(pinacolate)diborone (7.56 g, 29.85 mmol) dissolved in methanol (20 mL) was slowly added dropwise to the reaction mixture, generating a large amount of gas. After the addition was complete, the mixture was transferred to room temperature and stirred for 2 hours. Based on monitoring by TLC (petroleum ether:ethyl acetate = 30:1), once the reactants had completely reacted, the mixture was extracted with dichloromethane (20 mL x 2), the organic phase was mixed, washed with saturated sodium chloride solution (20 mL x 2), and dried over anhydrous sodium sulfate. The mixture was filtered by suction, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 200:1) to obtain 1.88 g of yellow solid powder (yield 60.4%). (mp 94.0~95.0°C). 1 H NMR (300 MHz, DMSO-d6) δ 7.70 (dd, J = 5.4 Hz, 3.7 Hz, 1H, ArH), 7.53 - 7.36 (m, 1H, ArH), 7.34 - 7.25 (m, 5H, ArH), 2.27 (s, 3H, ArCH3), 1.31 (s, 12H, CH3). Synthesis of 5-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)isoindole-1-one (VII) Compounds V (0.50 g, 2.36 mmol), VI (0.74 g, 2.48 mmol), and 1,4-dioxane (10 mL) were added sequentially to a three-necked flask. Potassium carbonate (0.92 g, 6.60 mmol) dissolved in water (1.0 mL) was added to the reaction mixture, and Pd(PPh3)4 (0.27 g, 0.25 mmol) was added under nitrogen protection. The reaction mixture was heated to 80°C and allowed to react for 12 hours. When the reaction was complete, as confirmed by TLC (petroleum ether:ethyl acetate = 4:1), heating was stopped and the mixture was cooled to room temperature. The palladium catalyst and insoluble matter were removed by suction filtration, diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was mixed, washed with saturated NaCl aqueous solution (10 mL x 3), and dried over anhydrous magnesium sulfate. The solution was filtered by suction, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 15:1~3:1) to obtain 0.40 g of white solid powder (yield 50.9%). (mp 190~192°C) 1 H NMR (300 MHz, DMSO-d6) δ 8.63 (s, 1H, ArH), 7.76 (d, J = 7.8 Hz, 1H, ArH), 7.60 (s, 1H, ArH), 7.49 (d, J = 7.6 Hz, 2H, ArH), 7.44 - 7.26 (m, 6H, ArH), 4.46 (s, 2H, CH2), 2.01 (s, 3H, CH3). Synthesis of 2-(5-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-1-oxoisoindorin-2-yl)ethyl acetate (IA-1) Compound VII (0.50 g, 1.58 mmol) was added to a 25 mL eggplant-shaped flask, dissolved in THF, and NaH (0.12 g, 3.16 mmol) was added at 0 °C. Ethyl bromoacetate (0.32 g, 1.89 mmol) was added dropwise to this mixture, and the reaction was carried out at room temperature. As a result of monitoring, when the raw materials completely reacted, saturated ammonium chloride solution was added to quench the reaction, and it was extracted with EA (10 mL × 3), washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and separated and purified by column chromatography to obtain 0.63 g (yield 98.7%) of a white solid. m.p. 100~101 °C. 1 H NMR (300 MHz, DMSO-d6) δ 7.81 (d, J = 7.8 Hz, 1H, ArH), 7.67 - 7.62 (m, 1H, ArH), 7.57 - 7.47 (m, 2H, ArH), 7.43 - 7.30 (m, 6H, ArH), 4.61 (s, 2H, NCH2), 4.44 (s, 2H, NCH2), 4.19 (q, J = 7.1 Hz, 2H, C H 2CH3), 2.03 (s, 3H, CH3), 1.25 (t, J = 7.1 Hz, 3H, ArCH3). Example 2 【0055】 3-(5-(2’-Fluoro-2-methyl-[1,1’-biphenyl]-3-yl)-1-oxoisoindolin-2-yl)ethyl propionate (I-A-2: R 1 =CH3, 【Chemical formula】 , R 3 =F, R 4 ​​​​​1H NMR (300 MHz, DMSO-d6) δ 7.77 (d, J = 7.7 Hz, 1H, ArH), 7.67 - 7.62 (m, 1H, ArH), 7.54 - 7.46 (m, 2H, ArH), 7.45 - 7.26 (m, 6H, ArH), 4.58 (s, 2H, NCH2), 4.10 (q, J = 7.1 Hz, 2H, C H 2CH3), 3.82 (t, J = 7.0 Hz, 2H, N CH 2CH2), 2.73 (t, J = 7.0 Hz, 2H, COCH2), 2.01 (s, 3H, ArCH3), 1.19 (t, J= 7.1 Hz, 3H, CH2C H 3). Example 3 【0056】 2-(5-(2'-Fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-1-oxoisoindolin-2-yl)ethyl propionate (I-A-3: R 1 =CH3, 【Chemical formula】 、R 3 =F, R 4 =H, T represents C=O) synthesis Using compound VII (0.50 g, 1.58 mmol) and 2-bromoethyl propionate (0.34 g, 1.89 mmol) as raw materials, in the same manner as compound I-A-1, 0.58 g (yield 88.3%) of a white solid was obtained. m.p. 50~52°C. 1 1H NMR (300 MHz, DMSO-d6) δ 7.80 (d, J = 7.8 Hz, 1H, ArH), 7.68 - 7.63 (m, 1H, ArH), 7.56 - 7.45 (m, 2H, ArH), 7.34 - 7.21 (m, 6H, ArH), 4.97 (q, J = 7.3 Hz, 1H, CH3C H ), 4.62 (d, J = 7.0 Hz, 2H, NCH2), 4.16 (q, J = 7.1 Hz, 2H, CH 2CH3), 2.02 (s, 3H, ArCH3), 1.56 (d, J = 7.4 Hz, 3H, CHC H 3), 1.22 (t, J= 7.0 Hz, 3H, CH2C H 3). Example 4 【0057】 2-(5-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-1-oxoisoindorin-2-yl)acetic acid (IA-4:R 1 =CH3, [ka] , R 3 =F, R 4 (where =H and T indicate C=O) Compound IA-1 (30 mg, 0.16 mmol) was added to a 10 mL round-bottom flask, dissolved in methanol (2 mL), and a solution of LiOH (8 mg, 0.20 mmol) in water (0.5 mL) was added. The mixture was stirred at room temperature for 4 hours. After monitoring by TLC to confirm the reaction was complete, the methanol was removed by distillation under reduced pressure. The pH was adjusted to 5-6 with 2 M HCl solution, and a white solid precipitated. The mixture was then filtered by suction to obtain 20 mg of a grayish-white solid product (yield 72.1%). The reaction temperature was 164-166°C. 1 H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H, OH), 7.82 - 7.74 (m, 1H, ArH), 7.66 - 7.58 (m, 1H, ArH), 7.53 - 7.43 (m, 2H, ArH), 7.41 - 7.23 (m, 6H, ArH), 4.58 (s, 2H, NCH2), 4.32 (s, 2H, NCH2), 2.00 (s, 3H, CH3). HRMS (ESI): m / z [M+H] + Calcd forC 23 H 19 FNO3: 376.1349; Found: 376.1350. Example 5 【0058】 3-(5-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-1-oxoisoindorin-2-yl)propionic acid (IA-5:R 1 =CH3, [ka] , R 3 =F, R 4 (where =H and T indicate C=O) Using a solution of compound IA-2 (50 mg, 0.12 mmol) and LiOH (10 mg, 0.24 mmol) in water (0.5 mL) as starting materials, 40 mg of a yellow solid product (yield 92.2%) was obtained in the same manner as with compound IA-4. (mp 56~58°C) 1 H NMR (300 MHz, DMSO-d6) δ 7.77 (d, J= 7.8 Hz, 1H, ArH), 7.63 (s, 1H, ArH), 7.50 (d, J = 7.7 Hz, 2H, ArH), 7.44 - 7.28 (m, 6H, ArH), 4.58 (s, 2H, NC H 2), 3.78 (t, J = 6.9 Hz, 2H, NC H 2CH2), 2.65 (t, J = 7.0 Hz, 2H, COC H 2), 2.01 (s, 3H, CH3). HRMS (ESI): m / z [M+H] + Calcd for C 24 H 21 FNO3: 390.1505; Found: 390.1503. Example 6 【0059】 2-(5-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-1-oxoisoindorin-2-yl)propionic acid (IA-6:R 1 =CH3, [ka] , R 3=F, R 4 (where =H and T indicate C=O) Using a solution of compound IA-3 (50 mg, 0.12 mmol) and LiOH (10 mg, 0.24 mmol) in water (0.5 mL) as starting materials, 30 mg of a white solid product (yield 64.2%) was obtained in the same manner as with compound IA-4. (Preparation temperature: 140-142°C) 1 H NMR (300 MHz, DMSO-d6) δ 7.78 (d, J= 7.8 Hz, 1H, ArH), 7.65 (s, 1H, ArH), 7.54 - 7.46 (m, 2H, ArH), 7.42 - 7.29 (m, 6H, ArH), 4.92 - 4.78 (m, 1H, C H CH3), 4.72 - 4.52 (m, 2H, CH2), 2.02 (s, 3H, ArCH3), 1.51 (d, J = 7.3 Hz, 3H, CH3). HRMS (ESI): m / z [M+H] + Calcd for C 24 H 21 FNO3: 390.1505; Found: 390.1502. Example 7 【0060】 5-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-2-(2-hydroxyethyl)isoindole-1-one (IA-7:R 1 =CH3, [ka] , R 3 =F, R 4 (where =H and T indicate C=O) Compound IA-1 (60 mg, 0.12 mmol) was added to a 25 mL round-bottom flask and dissolved in THF. Lithium aluminum hydride (8 mg, 0.24 mmol) was slowly added at 0°C. After monitoring, once the reaction was complete, saturated ammonium chloride solution was added to quench the reaction, precipitating a white solid. The white solid was removed by suction filtration, washed with EA, and the filtrate was concentrated, separated, and purified to obtain 24 mg of a yellow solid (yield 56.8%). (mp 86~88°C). 1 H NMR (300 MHz, DMSO-d6) δ 7.77 (d, J = 7.8 Hz, 1H, ArH), 7.63 (s, 1H, ArH), 7.52 - 7.45 (m, 2H, ArH), 7.40 - 7.25 (m, 6H, ArH), 4.90 (brs, 1H, OH), 4.63 (s, 2H, NC H 2), 3.68 - 3.60 (m, 4H, C H 2C H 2), 2.01 (s, 3H, C H 3). HRMS (ESI): m / z [M+H] + Calcd for C 23 H 21 FNO2: 362.1556; Found: 362.1556. Example 8 【0061】 2-(5-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-1-oxoisoindorin-2-yl)acetamide(IA-8:R 1 =CH3, [ka] , R 3 =F, R 4 (where =H and T indicate C=O) Compound IA-2 (100 mg, 0.27 mmol) was added to a 25 mL three-necked flask, dissolved with THF, a small amount of DMF was added dropwise, thionyl chloride (95 mg, 0.78 mmol) was slowly added dropwise, and the reaction was allowed to proceed by raising the temperature to 55°C. After monitoring, once the reacting elements were completely reacted, the temperature was reduced to room temperature, then to -20°C, aqueous ammonia was slowly added dropwise to adjust the pH to 8, and after monitoring, once the reacting elements were completely reacted and new spots were formed, 10 mL of water was added, and the mixture was extracted with EA (10 mL x 3), washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, separated and purified by column chromatography to obtain 42 mg of a light brown solid (yield 42.0%). The mp was higher than 250°C. 1 H NMR (300 MHz, DMSO-d6) δ 7.77 (d, J = 7.8 Hz, 1H, ArH), 7.61 (d, J = 7.6 Hz, 1H, ArH), 7.52 - 7.45 (m, 2H, ArH), 7.40 - 7.25 (m, 6H, ArH), 4.57 (s, 2H, NCH2), 4.16 (s, 2H, NCH2CO), 2.00 (s, 3H, CH3). HRMS (ESI): m / z [M+H] + Calcd for C 23 H 20 FN2O2: 375.1509; Found: 375.1511. Example 9 【0062】 2-(5-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)oxoisoindorin-2-yl)ethane-1-ol(IA-9:R 1 =CH3, [ka] , R 3 =F, R 4 Synthesis of (=H, T represents CH2) Compound IA-7 (30 mg, 0.08 mmol) was added to a 25 mL round-bottom flask and dissolved with THF. 1 M borane-tetrahydrofuran complex (0.46 ml, 0.48 mmol) was slowly added at 0°C. After the dropwise addition was complete, the reaction was carried out under reflux at 68°C for 3 hours. Upon monitoring, once the starting materials had completely reacted, saturated ammonium chloride solution was added to quench the reaction, precipitating a white solid. The white solid was removed by suction filtration, washed with EA, and the filtrate was concentrated, separated, and purified to obtain 14 mg of a brown solid (yield 48.5%). (mp 80~82°C). 1 H NMR (300 MHz, Chloroform-d) δ 7.36 - 7.29 (m, 4H, ArH), 7.25 - 7.13 (m, 6H, ArH), 4.25 (s, 4H, 2NCH2), 3.86 - 3.80 (m, 2H, CH2OH), 3.14 - 3.08 (m, 2H, C H 2CH2OH), 2.05 (s, 3H, CH3). HRMS (ESI): m / z [M+H] + Calcd for C 23 H 23 FNO: 348.1764; Found: 348.1762. Example 10 【0063】 2-(2-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (IB-1:R 1 =CH3, [ka] , R 3 =F, R 4 Synthesis of =H) 2-(2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (IX-1) 0.50 g, 2.43 mmol of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthirizine hydrochloride VIII was added to a 25 mL round-bottom flask, dissolved with THF, and NaH (0.20 g, 4.86 mmol) was added at 0°C. Ethyl bromoethyl (0.49 g, 2.93 mmol) was added dropwise to the reaction mixture, and the reaction was allowed to proceed at room temperature. After monitoring by TLC, once the starting materials had reacted completely, saturated ammonium chloride solution was added to quench the reaction, extracted with ethyl acetate (10 mL x 3), washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered by suction, the solvent was removed by distillation under reduced pressure, and the residue was separated and purified by column chromatography to obtain 0.60 g of a light brown solid (yield 97.2%). (mp 58~60°C) 1 H NMR (300 MHz, Chloroform-d) δ 7.45 - 7.37 (m, 5H, ArH), 7.28 - 7.22 (m, 4H, ArH), 4.24 (q, J = 7.1 Hz, 2H, C H 2CH3), 3.82 (s, 2H, NCH2), 3.47 (s, 2H, COCH2), 3.09 - 3.05 (m, 2H, NCH2C H 2), 3.02-2.97 (m, 2H, NC H 2CH2), 1.31 (t, J = 7.2 Hz, 3H, CH3). Synthesis of 2-(2-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (IB-1) Compounds IX-1 (0.25 g, 0.98 mmol), V-1 (10, 0.44 g, 1.47 mmol), and 1,4-dioxane (5 mL) were added sequentially to a three-necked flask. Potassium carbonate (0.37 g, 2.75 mmol) dissolved in (0.5 mL) water was added to the reaction mixture. Under nitrogen protection, Pd(PPh3)4 (0.14 g, 0.10 mmol) was added, and the mixture was heated to 80°C and reacted for 12 hours. Monitoring by TLC (petroleum ether:ethyl acetate = 8:1) confirmed that the starting materials had reacted completely. Heating was stopped, and the mixture was cooled to room temperature. The palladium catalyst and insoluble matter were removed by suction filtration, diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was mixed, washed with saturated brine (10 mL x 3), and dried over anhydrous magnesium sulfate. The solution was filtered by suction, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1~10:1) to obtain 180 mg of a yellow solid (yield 44.6%). (mp 46~48°C) 1 H NMR (300 MHz, Chloroform-d) δ 7.46 - 7.37 (m, 5H, ArH), 7.28 - 7.22 (m, 4H, ArH), 4.29 (q, J = 7.2 Hz, 2H, C H 2CH3), 3.95 (s, 2H, NCH2), 3.55 (s, 2H, COCH2), 3.23 (t, J = 5.9 Hz, 2H, NCH2C H 2), 3.11 (t, J = 5.9 Hz, 2H, NC H 2CH2), 2.10 (s, 3H, ArCH3), 1.36 (t, J = 7.2 Hz, 3H, CH3). Example 11 【0064】 2-(2-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)acetic acid (IB-2:R 1 =CH3, [ka] , R 3 =F, R 4 Synthesis of =H) Compound IB-1 (80 mg, 0.20 mmol) was added to a 10 mL round-bottom flask, dissolved in ethanol (2 mL), and a solution of LiOH (17 mg, 0.40 mmol) in water (0.3 mL) was added. The mixture was stirred at room temperature for 4 hours. After monitoring by TLC to confirm the reaction was complete, the ethanol was removed by distillation under reduced pressure. The pH was adjusted to 5-6 with 2 M HCl solution, and a white solid precipitated. The mixture was filtered by suction, baked, and yielded 7 mg of a yellow solid product (yield 9.4%). (mp188-190°C). 1 H NMR (300 MHz, DMSO-d6) δ 8.29 (d, J= 8.0 Hz, 1H, ArH), 7.58 (d, J = 8.0 Hz, 1H, ArH), 7.48 -7.29 (m, 7H, ArH), 4.23 (s, 2H, NCH2), 3.74 (t, J = 6.7 Hz, 2H, NCH2), 3.26 (s, 2H, COCH2), 3.19 (t, J = 6.4 Hz, 2H, NCH2), 2.08 (s, 3H, CH3). HRMS (ESI): m / z [M+H] + Calcd for C 23 H 22 FN2O2: 377.1665; Found: 377.1667. Example 12 【0065】 2-(2-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethane-1-ol(IB-3:R 1 =CH3, [ka] , R 3 =F, R 4 Synthesis of =H) Compound IB-1 (100 mg, 0.25 mmol) was added to a 25 mL round-bottom flask and dissolved in 3 mL of THF. Lithium aluminum hydride (19 mg, 0.50 mmol) was slowly added at 0°C. After monitoring, once the reaction was complete, saturated ammonium chloride solution was added to quench the reaction, causing a white solid to precipitate. The white solid was removed by suction filtration, washed with EA, and the filtrate was concentrated, separated, and purified to obtain 50 mg of a yellow solid (yield 27.9%). (mp 66~68°C). 1 H NMR (300 MHz, Chloroform-d) δ 7.43 - 7.38 (m, 1H, ArH), 7.36 - 7.29 (m, 3H, ArH), 7.24 - 7.11 (m, 5H, ArH), 3.79 (s, 2H, NCH2), 3.56 (t, J = 5.4 Hz, 2H, C H 2OH), 3.13 (t, J = 5.6 Hz, 2H, NCH2C H 2), 2.98 (t, J = 5.8 Hz, 2H, NC H 2CH2), 2.80 (t, J = 5.3 Hz, 2H, NC H 2), 2.10 (s, 3H, CH3). HRMS (ESI): m / z [M+H] + Calcd for C 23 H 23 FN2O: 363.1873; Found: 363.1872. Example 13 【0066】 2-(2-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethylacetate(IC-1:R 1 =CH3, [ka] ) synthesis Synthesis of methyl 3-bromo-2-methylbenzoate (XI-1) 0.30 g, 1.40 mmol of 3-bromo-2-methylbenzoic acid X-1 and 5 mL of methanol were added to a 50 mL round-bottom flask. Under ice bath conditions, 0.20 mL, 2.79 mmol of thionyl chloride was slowly added dropwise. After the addition was complete, the mixture was heated to 70°C and refluxed for 1 hour. Monitoring by TLC (petroleum ether:ethyl acetate = 8:1) confirmed that the starting materials had reacted completely. The mixture was then concentrated under reduced pressure to obtain 0.32 g of a white solid powder (yield 99.0%). (mp3 1.0~33.0°C) 1 H NMR (300 MHz, Chloroform-d) δ 7.72 (d, J = 8.5 Hz, 1H, ArH), 7.68 (d, J = 8.6 Hz, 1H, ArH), 7.09 (t, J = 7.8 Hz, 1H, ArH), 3.90 (s, 3H, OCH3), 2.63 (s, 3H, CH3). Synthesis of (3-bromo-2-methylphenyl)methanol (XII-1) Compound XI-1 (10.50 g, 46.10 mmol) and anhydrous tetrahydrofuran (50.00 mL) were added to a three-necked flask. Under N2 protection, the temperature was lowered to 0°C, and LiAlH4 (3.10 g, 55.30 mmol) was slowly added in batches. After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature for 30 minutes. Monitoring by TLC (petroleum ether:ethyl acetate = 8:1) confirmed that the starting materials had reacted completely. Saturated NH4Cl solution was slowly added dropwise until no more bubbles were generated. The mixture was diluted with ethyl acetate (100 mL), insoluble matter was removed by suction filtration, and the organic phases were washed with water (50 mL x 2) and saturated brine (50 mL x 2). The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by suction filtration under reduced pressure to obtain 9.22 g of white solid powder (yield 98.9%). (mp 103.0~104.0°C) 1 H NMR (300 MHz, DMSO-d6) δ 7.49 (d, J = 8.0 Hz, 1H, ArH), 7.39 (d, J= 7.7 Hz, 1H, ArH), 7.12 (t, J = 7.7 Hz, 1H, ArH), 5.26 (br,1H, CH2OH ), 4.52 (s, 2H, CH2), 2.30 (s, 3H, CH3). Synthesis of (3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenyl)methanol (XIV-1) Compound XII-1 (500 mg, 2.49 mmol), benzo-1,4-dioxane-6-boric acid XIII-1 (537 mg, 2.98 mmol), and 1,4-dioxane (10 mL) were added sequentially to a three-necked flask. Potassium carbonate (962 mg, 6.96 mmol) dissolved in water (1 mL) was added to the reaction mixture, and under nitrogen protection, Pd(PPh3)4 (144 mg, 0.15 mmol) was added. The temperature was then raised to 80°C and the reaction was allowed to proceed for 12 hours. Monitoring by TLC (petroleum ether:ethyl acetate = 8:1) confirmed that the reactants had reacted completely. Heating was stopped, and the mixture was cooled to room temperature. The palladium catalyst and insoluble matter were removed by suction filtration. The mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was mixed, washed with saturated brine (10 mL x 3), and dried over anhydrous magnesium sulfate. The solution was filtered by suction, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1~15:1) to obtain 440 mg of a light brown oily substance (yield 69.07%). 1 H NMR (300 MHz, DMSO-d6) δ 7.38 (dd, J = 7.6 Hz, 1.4 Hz, 1H, ArH), 7.20 (t, J = 7.6 Hz, 1H, ArH), 7.06 (dd, J= 7.6 Hz, 1.5 Hz, 1H, ArH), 6.92 (d, J= 8.1 Hz, 1H, ArH), 6.78 - 6.70 (m, 2H, ArH), 4.55 (s, 2H, C H 2OH), 4.29 (s, 4H, OC H 2, OC H 2), 2.14 (s, 3H, CH3). Synthesis of 2-(2-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (IC-1) Compounds IX-1 (120 mg, 0.47 mmol), XIV-1 (145 mg, 0.57 mmol), t-BuXphos (40 mg, 0.09 mmol), and toluene (5 mL) were sequentially added to a three-necked flask. Cesium carbonate (307 mg, 0.94 mmol) was added to the reaction mixture, and under nitrogen protection, Pd(OAc)2 (11 mg, 0.05 mmol) was added. Under nitrogen protection, the temperature was raised to 80°C and the reaction was allowed to proceed for 12 hours. Monitoring by TLC (petroleum ether:ethyl acetate = 4:1) confirmed that the reactants had reacted completely. Heating was stopped, and the mixture was cooled to room temperature. The palladium catalyst and insoluble matter were removed by suction filtration, diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was mixed, washed with saturated NaCl aqueous solution (10 mL x 3), and dried over anhydrous magnesium sulfate. The drying agent was removed by suction filtration, the solvent was removed by distillation under reduced pressure, and the solution was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 10:1) to obtain 110 mg of a yellow, viscous liquid (yield 49.21%). 1 H NMR (300 MHz, Chloroform-d) δ 7.42 (dd, J = 6.4 Hz, 2.7 Hz, 1H, ArH), 7.23 - 7.19 (m, 3H, ArH), 6.90 (d, J = 8.2 Hz, 1H, ArH), 6.83 (d, J = 1.8 Hz, 1H, ArH), 6.79 (dd, J = 8.2 Hz, 1.9 Hz, 1H, ArH), 6.59 (d, J = 8.3 Hz, 1H, ArH), 5.37 (s, 2H, OCH2), 4.30 (s, 4H, OC H 2C H 2O), 4.26 (q, J = 7.1 Hz, 2H, C H 2CH3), 3.76 (s, 2H, NCH2), 3.46 (s, 2H, C H2CO), 3.00 (s, 4H, NC H 2C H 2), 2.28 (s, 3H, ArC H 3), 1.30 (t, J = 7.1 Hz, 3H, CH3). Example 14 【0067】 2-(2-((2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-1:R 1 =CH3, [ka] , R 3 =F, R 4 Synthesis of =H) Synthesis of (2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methanol (XV-1) Compound XII-1 (2.00 g, 9.95 mmol), 2-fluorophenylboronic acid III-1 (2.09 g, 14.92 mmol), and 1,4-dioxane (45 mL) were added sequentially to a three-necked flask. Potassium carbonate (3.85 g, 27.85 mmol) dissolved in water (4.5 mL) was added to the reaction mixture, and under nitrogen protection, Pd(PPh3)4 (0.57 g, 0.50 mmol) was added. The temperature was then raised to 80°C and the reaction was allowed to proceed for 12 hours. Monitoring by TLC (petroleum ether:ethyl acetate = 8:1) confirmed that the starting materials had reacted completely. Heating was stopped, and the mixture was cooled to room temperature. The palladium catalyst and insoluble matter were removed by suction filtration. The mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phase was mixed, washed with saturated brine (50 mL x 3), and dried over anhydrous magnesium sulfate. The solution was filtered by suction, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1~15:1) to obtain 2.05 g of a colorless oily liquid (yield 95.3%). (mp 40~42°C) 1H NMR (300 MHz, DMSO-d6) δ 7.52 - 7.42 (m, 2H, ArH), 7.35 - 7.25 (m, 4H, ArH), 7.11 (d, J = 7.6 Hz, 1H, ArH), 5.20 (s, 1H, OH), 4.58 (s, 2H, CH2), 2.06 (s, 3H, CH3). Synthesis of 2-(2-((2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-1) Compounds IX-1 (0.17g, 0.67 mmol), XV-1 (0.17g, 0.80 mmol), t-BuXphos (0.06g, 0.13 mmol), and toluene (5 mL) were sequentially added to a three-necked flask. Cesium carbonate (0.43g, 1.33 mmol) was added to the reaction mixture, and under nitrogen protection, Pd(OAc)2 (0.01g, 0.07 mmol) was added. The temperature was then raised to 80°C and the reaction was allowed to proceed for 12 hours. Monitoring by TLC (petroleum ether:ethyl acetate = 4:1) confirmed that the starting materials had reacted completely. Heating was stopped, and the mixture was cooled to room temperature. The palladium catalyst and insoluble matter were removed by suction filtration. The mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was mixed, washed with saturated brine (10 mL x 3), and dried over anhydrous magnesium sulfate. The solution was filtered by suction, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 10:1) to obtain 0.15 g of a colorless, transparent liquid (yield 51.8%). 1 H NMR (300 MHz, Chloroform-d) δ 7.54 (dd, J = 7.3 Hz, 1.7 Hz, 1H, ArH), 7.43 - 7.35 (m, 1H, ArH), 7.30 - 7.13 (m, 6H, ArH), 6.64 (d, J = 8.3 Hz, 1H, ArH), 5.43 (s, 2H, OC H 2), 4.27 (q, J = 7.1 Hz, 2H, C H 2CH3), 3.78 (s, 2H, NCH 2), 3.49 (s, 2H, NC H 2), 3.03 (s, 4H, NC H 2C H 2), 2.25 (s, 3H, ArC H 3), 1.34 (t, J = 7.1 Hz, 3H, CH2C H 3). Example 15 【0068】 2-(2-((2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-2:R 1 =CH3, [ka] , R 3 =CH3, R 4 Synthesis of =H) Synthesis of (2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methanol (XV-2) Using compounds XII-1 (2.00 g, 9.95 mmol) and III-2 (2.03 g, 14.92 mmol) as starting materials, 2.00 g of a white solid (yield 94.7%) was obtained in the same manner as with compound XV-1. (mp 48~50°C) 1 H NMR (300 MHz, DMSO-d6) δ 7.43 (d, J = 7.5 Hz, 1H, ArH), 7.32 - 7.23 (m, 4H, ArH), 7.08 - 7.03 (m, 1H, ArH), 6.98 (d, J = 7.5 Hz, 1H, ArH), 5.17 (t, J = 5.3 Hz, 1H, OH), 4.58 (s, 2H, CH2), 2.00 (s, 3H, CH3), 1.94 (s, 3H, CH3). Synthesis of 2-(2-((2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-2) Using compounds IX-1 (120 mg, 0.47 mmol) and XV-2 (120 mg, 0.57 mmol) as raw materials, 67 mg of a yellow, viscous liquid (yield 32.9%) was obtained in the same manner as for ID-1. 1 H NMR (300 MHz, Chloroform-d) δ 7.45 (dd, J = 7.7 Hz, 1.5 Hz, 1H, ArH), 7.27 (s, 1H, ArH), 7.25 - 7.18 (m, 4H, ArH), 7.13 - 7.08 (m, 2H, ArH), 6.61 (d,J = 8.4 Hz, 1H, ArH), 5.38 (s, 2H, OC H 2), 4.24 (q, J = 7.1 Hz, 2H, C H 2CH3), 3.87 (s, 2H, NC H 2), 3.54 (s, 2H, COC H 2), 3.11 - 2.86 (m, 4H, NC H 2C H 2), 2.07 (s, 3H, ArCH3), 2.06 (s, 3H, ArCH3), 1.31 (t, J = 7.1 Hz, 3H, CH2C H 3). Example 16 【0069】 2-(2-((2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-3:R 1 =CH3, [ka] , R 3 =Cl, R 4 Synthesis of =H) Synthesis of (2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)methanol (XV-3) Using compounds XII-1 (500 mg, 2.49 mmol) and III-3 (580 mg, 3.73 mmol) as starting materials, 500 mg of a white solid (yield 86.4%) was obtained in the same manner as with compound XV-1. (Temperature: 74-76°C) 1 H NMR (400 MHz, DMSO-d6) δ 7.56 - 7.54 (m, 1H, ArH), 7.46 - 7.39 (m, 3H, ArH), 7.29 - 7.22 (m, 2H, ArH), 7.01 (dd, J = 7.6 Hz, 1.4 Hz, 1H, ArH), 4.56 (s, 2H, CH2), 1.96 (s, 3H, CH3). Synthesis of 2-(2-((2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-3) Using compounds IX-1 (170 mg, 0.73 mmol) and XV-3 (136 mg, 0.88 mmol) as starting materials, 150 mg of a yellow, viscous liquid (yield 51.8%) was obtained in the same manner as with compound ID-1. 1 H NMR (300 MHz, Chloroform-d) δ 7.57 - 7.55 (m, 2H, ArH), 7.28 - 7.20 (m, 3H, ArH), 7.18 - 7.13 (m, 2H, ArH), 7.06 (dd, J = 7.6 Hz, 1.5 Hz, 1H, ArH), 6.53 (d, J = 8.4 Hz, 1H, ArH), 5.38 (s, 2H, OC H 2), 4.17 (t, J = 7.1 Hz, 2H, OC H 2CH3), 3.69 (s, 2H, NC H 2), 3.39 (s, 2H, NC H 2CO), 2.93 (s, 4H, NC H 2C H 2), 2.06 (s, 3H, ArC H 3), 1.22 (d, J = 7.1 Hz, 3H, CH3). Example 17 【0070】 2-(2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-4:R 1 =CH3, [ka] , R 3 =H, R 4 Synthesis of =H) Synthesis of (2-methyl-[1,1'-biphenyl]-3-yl)methanol (XV-4) Using compounds XII-1 (500 mg, 2.49 mmol) and III-4 (470 mg, 2.98 mmol) as starting materials, 320 mg of a white solid (yield 64.9%) was obtained in the same manner as with compound XV-1. (mp 63-65°C) 1 H NMR (300 MHz, DMSO-d6) δ 7.48 - 7.35 (m, 4H, ArH), 7.30 - 7.21 (m, 3H, ArH), 7.09 (dd, J = 7.6 Hz, 1.5 Hz, 1H, ArH), 5.16 (s, 1H, OH), 4.56 (s, 2H, CH2), 2.12 (s, 3H, CH3). Synthesis of 2-(2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-4) Using compounds IX-1 (150 mg, 0.59 mmol) and XV-4 (140 mg, 0.71 mmol) as starting materials, 115 mg of a colorless, viscous liquid (yield 46.9%) was obtained in the same manner as with compound ID-1. 1H NMR (300 MHz, Chloroform-d) δ 7.47 - 7.36 (m, 4H, ArH), 7.35 - 7.29 (m, 3H, ArH), 7.24 - 7.20 (m, 2H, ArH), 6.60 (d, J = 8.3 Hz, 1H, ArH), 5.39 (s, 2H, OCH2), 4.24 (q, J = 7.1 Hz, 2H, C H 2CH3), 3.80 (s, 2H, NCH2), 3.49 (s, 2H, CH2CO), 3.03 (s, 4H, NC H 2C H 2), 2.27 (s, 3H, ArCH3), 1.32 (t, J = 7.1 Hz, 3H, CH3). Example 18 【0071】 2-(2-((2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-5:R 1 =Cl, [ka] , R 3 =F, R 4 Synthesis of =H) Synthesis of methyl 3-bromo-2-chlorobenzoate (XI-2) Using 3-bromo-2-chlorophenylboronic acid X-2 (5.00 g, 21.23 mmol) and thionyl chloride (3.10 mL, 42.47 mmol) as raw materials, 5.29 g of a light brown oily substance (yield 99.88%) was obtained in the same manner as for compound XI-1. 1 H NMR (300 MHz, DMSO-d6) δ 8.18 (dd, J = 8.0 Hz, 1.6 Hz, 1H, ArH), 7.96 (dd, J = 7.7 Hz, 1.6 Hz, 1H, ArH), 7.61 (t, J = 7.9 Hz, 1H, ArH), 4.08 (s, 3H, CH3). Synthesis of (3-bromo-2-chlorophenyl)methanol (XII-2) Compound XI-2 (5.29 g, 21.20 mmol) was used as a starting material and reduced with LiAlH4 (0.80 g, 21.20 mmol). A white solid powder of 4.60 g (yield 97.9%) was obtained in the same manner as with compound XII-1. (Preparation temperature: 56-58°C) 1 H NMR (300 MHz, DMSO-d6) δ 7.66 (d, J = 7.9 Hz, 1H, ArH), 7.56 (d, J = 7.5 Hz, 1H, ArH), 7.31 (t, J = 7.7 Hz, 1H, ArH), 5.55 (t, J = 5.7 Hz, 1H, OH), 4.58 (d, J = 5.5 Hz, 2H, CH2). Synthesis of (2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)methanol (XV-5) Using compounds XV-2 (0.50 g, 2.26 mmol) and III-1 (0.38 g, 2.71 mmol) as starting materials, 0.32 g of a light brown solid (yield 59.9%) was obtained in the same manner as with compound XV-1. (mp 44~46°C) 1 H NMR (300 MHz, DMSO-d6) δ 7.84 (d, J = 7.7 Hz, 1H, ArH), 7.73 - 7.61 (m, 2H, ArH), 7.57 - 7.46 (m, 4H, ArH), 5.68 (s, 1H, OH), 4.83 (s, 2H, CH2). Synthesis of 2-(2-((2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-5) Using compounds IX-1 (150 g, 0.59 mmol) and XV-5 (170 mg, 0.71 mmol) as starting materials, 116 mg of a colorless, viscous liquid (yield 43.3%) was obtained in the same manner as with compound ID-1. 1H NMR (300 MHz, Chloroform-d) δ 7.59 (dd, J = 7.4 Hz, 1.9 Hz, 1H, ArH), 7.44 - 7.27 (m, 4H, ArH), 7.25 - 7.12 (m, 3H, ArH), 6.64 (d, J = 8.3 Hz, 1H, ArH), 5.52 (s, 2H, OCH2), 4.23 (q, J = 7.1 Hz, 2H, C H 2CH3), 3.75 (s, 2H, COCH2), 3.45 (s, 2H, NCH2), 2.98 (s, 4H, NC H 2C H 2), 1.29 (t, J = 7.1 Hz, 3H, CH3). Example 19 【0072】 2-(2-((2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-6:R 1 =Cl, [ka] , R 3 =CH3, R 4 Synthesis of =H) Synthesis of (2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)methanol (XV-6) Using compounds XII-2 (0.50 g, 2.26 mmol) and III-2 (0.37 g, 2.71 mmol) as starting materials, 0.32 g of a light brown solid (yield 59.9%) was obtained in the same manner as with compound XV-1. (mp 44~46°C) 1 H NMR (400 MHz, DMSO-d6) δ 7.63 - 7.51 (m, 1H, ArH), 7.44 - 7.00 (m, 6H, ArH), 5.40 (s, 1H, OH), 4.65 (s, 2H, CH2), 2.03 (s, 3H, CH3). Synthesis of 2-(2-((2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-6) Using compounds IX-1 (150 mg, 0.59 mmol) and XV-6 (165 mg, 0.71 mmol) as starting materials, 117 mg of a colorless, viscous liquid (yield 44.0%) was obtained in the same manner as with compound ID-1. 1 H NMR (300 MHz, Chloroform-d) δ 7.56 (dd, J = 7.7 Hz, 1.7 Hz, 1H, ArH), 7.34 - 7.27 (m, 3H, ArH), 7.25 - 7.21 (m, 2H, ArH), 7.20 - 7.12 (m, 2H, ArH), 6.67 - 6.65 (d, J= 8.3 Hz, 1H, ArH), 5.51 (s, 2H, OCH2), 4.22 (q, J = 7.1 Hz, 2H, C H 2CH3), 3.78 (s, 2H, NCH2), 3.47 (s, 2H, CH2CO), 2.99 (s, 4H, NC H 2C H 2), 2.12 (s, 3H, ArCH3), 1.32 - 1.30 (t, J = 7.1 Hz, 3H, CH2C H 3). Example 20 【0073】 2-(2-((2,2'-dichloro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-7:R 1 =Cl, [ka] , R 3 =Cl, R 4 Synthesis of =H) Synthesis of (2,2'-dichloro-[1,1'-biphenyl]-3-yl)methanol (XV-7) Using compounds XII-2 (0.50 g, 2.26 mmol) and III-3 (0.42 g, 2.71 mmol) as raw materials, 0.31 g of a light brown oily substance (yield 54.2%) was obtained in the same manner as with compound XV-1. 1 H NMR (300 MHz, DMSO-d6) δ 7.88 - 7.82 (m, 1H, ArH), 7.82 - 7.76 (m, 1H, ArH), 7.70 - 7.62 (m, 3H, ArH), 7.57 - 7.51 (m, 1H, ArH), 7.47 - 7.41 (m, 1H, ArH), 5.71 (s, 1H, OH), 4.85 (s, 2H, CH2). Synthesis of 2-(2-((2,2'-dichloro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-7) Using compounds IX-1 (150 mg, 0.59 mmol) and XV-7 (165 mg, 0.71 mmol) as starting materials, 130 mg of a colorless, viscous liquid (yield 46.8%) was obtained in the same manner as with compound ID-1. 1 H NMR (300 MHz, Chloroform-d) δ 7.60 (dd, J = 7.6 Hz, 1.8 Hz, 1H, ArH), 7.51 - 7.46 (m, 1H, ArH), 7.35 -7.32 (m, 5H, ArH), 7.24 - 7.19 (m, 2H, ArH), 6.64 (d, J= 8.4 Hz, 1H, ArH), 5.52 (s, 2H, OCH2), 4.22 (q, J = 7.1 Hz, 2H, C H 2CH3), 3.76 (s, 2H, NCH2), 3.45 (s, 2H, COCH2), 2.98 (s, 4H, NC H 2C H 2), 1.30 (t, J = 7.1 Hz, 3H, CH3). Example 21 【0074】 2-(2-((2-chloro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-8:R 1 =Cl, [ka] , R 3 =H, R 4 Synthesis of =H) Synthesis of (2-chloro-[1,1'-biphenyl]-3-yl)methanol (XV-8) Using compounds XII-2 (0.50 g, 2.26 mmol) and III-4 (0.41 g, 2.71 mmol) as starting materials, a pale yellow solid of 0.41 g (yield 83.1%) was obtained in the same manner as with compound XV-1. (Temperature: 76-78°C) 1 H NMR (400 MHz, DMSO-d6) δ 7.59 (dd, J= 7.6 Hz, 1.7 Hz, 1H, ArH), 7.49 - 7.38 (m, 6H, ArH), 7.28 (dd, J = 7.6 Hz, 1.8 Hz, 1H, ArH), 5.48 (s, 1H, OH), 4.63 (s, 2H, CH2). Synthesis of 2-(2-((2-chloro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-8) Using compounds IX-1 (150 mg, 0.59 mmol) and XV-8 (155 mg, 0.71 mmol) as starting materials, 187 mg of a colorless, viscous liquid (yield 72.7%) was obtained in the same manner as with compound ID-1. 1H NMR (300 MHz, Chloroform-d) δ 7.55 (dd, J = 6.9 Hz, 2.5 Hz, 1H, ArH), 7.46 - 7.37 (m, 6H, ArH), 7.34 - 7.28 (m, 2H, ArH), 6.65 (d, J = 8.4 Hz, 1H, ArH), 5.52 (s, 2H, OCH2), 4.23 (q, J = 7.2 Hz, 2H, C H 2CH3), 3.81 (s, 2H, NCH2), 3.49 (s 2H, COCH2), 3.02 (s, 4H, NC H 2C H 2), 1.30 (t, J = 7.1 Hz, 3H, CH3). Example 22 【0075】 2-(2-((2,2'-difluoro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-9:R 1 =F, [ka] , R 3 =F, R 4 Synthesis of =H) Synthesis of methyl 3-bromo-2-fluorobenzoate (XI-3) Using 3-bromo-2-chlorophenylboronic acid X-3 (5.00 g, 21.23 mmol) and thionyl chloride (3.10 mL, 42.47 mmol) as starting materials, 5.30 g of a pale yellow solid (yield 99.6%) was obtained in the same manner as for compound XI-1. (Temperature: 35-36°C) 1 H NMR (300 MHz, DMSO-d6) δ 7.94 (ddd, J = 8.1 Hz, 6.4 Hz, 1.8 Hz, 1H, ArH), 7.83 (ddd, J = 8.1 Hz, 6.6 Hz, 1.7 Hz, 1H, ArH), 7.25 (td, J = 7.9 Hz, 1.0 Hz, 1H, ArH), 3.83 (s, 3H, CH3). Synthesis of (3-bromo-2-fluorophenyl)methanol (XII-3) Compound XI-3 (5.30 g, 22.74 mmol) was used as a starting material and reduced with LiAlH4 (0.86 g, 22.74 mmol). A pale yellow solid of 4.30 g (92.2% yield) was obtained in the same manner as with compound XII-1. (Temperature: 34-35°C) 1 H NMR (300 MHz, DMSO-d6) δ 7.65 - 7.55 (m, 1H, ArH), 7.53 - 7.43 (m, 1H, ArH), 7.17 (t, J = 7.8 Hz, 1H, ArH), 5.42 (t, J = 6.0 Hz, 1H, OH), 4.59 (s, 2H, CH2). Synthesis of (2,2'-difluoro-[1,1'-biphenyl]-3-yl)methanol (XV-9) Using compounds XII-3 (0.50 g, 2.44 mmol) and III-1 (0.41 g, 2.93 mmol) as starting materials, 0.37 g of a white solid (yield 68.9%) was obtained in the same manner as with compound XV-1. (Temperature: 50-52°C) 1 H NMR (300 MHz, DMSO-d6) δ 7.49 - 7.32 (m, 3H, ArH), 7.28 - 7.18 (m, 4H, ArH), 4.53 (s, 2H, CH2). Synthesis of 2-(2-((2,2'-difluoro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-9) Using compounds IX-1 (150 mg, 0.59 mmol) and XV-9 (156 mg, 0.71 mmol) as starting materials, 100 mg of a colorless, viscous liquid (yield 38.7%) was obtained in the same manner as with compound ID-1. 1H NMR (300 MHz, Chloroform-d) δ 7.56 - 7.51 (m, 1H, ArH), 7.42 - 7.33 (m, 4H, ArH), 7.22 - 7.13 (m, 3H, ArH), 6.61 (d, J = 8.4 Hz, 1H, ArH), 5.48 (s, 2H, OCH2), 4.23 (q, J = 7.2 Hz, 2H, C H 2CH3), 3.79 (s, 2H, NCH2), 3.48 (s, 2H, CH2CO), 3.02 - 2.99 (m, 4H, NC H 2C H 2), 1.31 (t, J = 7.1 Hz, 3H, CH3). Example 23 【0076】 2-(2-((2-fluoro-2'-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-10:R 1 =F, [ka] , R 3 =CH3, R 4 Synthesis of =H) Synthesis of (2-fluoro-2'-methyl-[1,1'-biphenyl]-3-yl)methanol (XV-10) Using compounds XII-3 (0.50 g, 2.44 mmol) and III-2 (0.40 g, 2.93 mmol) as starting materials, a colorless oily substance of 0.34 g (yield 63.7%) was obtained in the same manner as with compound XV-1. 1 H NMR (300 MHz, DMSO-d6) δ 7.51 (td, J = 7.3 Hz, 1.9 Hz, 1H, ArH), 7.34 -7.32 (m, 2H, ArH), 7.31 - 7.24 (m, 2H, ArH), 7.23 - 7.16 (m, 2H, ArH), 4.61 (s, 2H, CH2), 2.14 (s, 3H, CH3). Synthesis of 2-(2-((2-fluoro-2'-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-10) Using compounds IX-1 (150 mg, 0.59 mmol) and XV-10 (153 mg, 0.71 mmol) as starting materials, 130 mg of a colorless, viscous liquid (yield 50.8%) was obtained in the same manner as with compound ID-1. 1 H NMR (300 MHz, Chloroform-d) δ 7.54 - 7.48 (m, 1H, ArH), 7.31 - 7.28 (m, 2H, ArH), 7.24 - 7.15 (m, 5H, ArH), 6.61 (d, J = 8.3 Hz, 1H, ArH), 5.46 (s, 2H, OCH2), 4.23 (q, J = 7.1 Hz, 2H, C H 2CH3), 3.79 (s, 2H, NCH2), 3.48 (s, 2H, CH2CO), 3.00 (s, 4H, NC H 2C H 2), 2.21 (s, 3H, ArCH3), 1.31 (t, J = 7.1 Hz, 3H, CH2C H 3). Example 24 【0077】 2-(2-((2'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-11:R 1 =F, [ka] , R 3 =Cl, R 4 Synthesis of =H) Synthesis of (2'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)methanol (XV-11) Using compounds XII-3 (0.50 g, 2.44 mmol) and III-3 (0.46 g, 2.93 mmol) as starting materials, a colorless oily substance of 0.34 g (yield 58.9%) was obtained in the same manner as with compound XV-1. (Temperature: 34-35°C) 1 H NMR (300 MHz, DMSO-d6) δ 7.62 - 7.51 (m, 2H, ArH), 7.50 - 7.38 (m, 3H, ArH), 7.32 - 7.21 (m, 2H, ArH), 5.36 (s, 1H, OH), 4.61 (s, 2H, CH2). Synthesis of 2-(2-((2'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-11) Using compounds IX-1 (150 mg, 0.59 mmol) and XV-11 (167 mg, 0.71 mmol) as starting materials, 104 mg of a colorless, viscous liquid (yield 38.8%) was obtained in the same manner as with compound ID-1. 1 H NMR (300 MHz, Chloroform-d) δ 7.58 - 7.52 (m, 2.0 Hz, 1H, ArH), 7.50 - 7.47 (m, 1H, ArH), 7.35 - 7.32 (m, 3H, ArH), 7.25 - 7.16 (m, 3H, ArH), 6.61 (d, J = 8.4 Hz, 1H, ArH), 5.47 (s, 2H, OCH2), 4.23 (q, J = 7.1 Hz, 2H, C H 2CH3), 3.77 (s, 2H, NCH2), 3.46 (s, 2H, CH2CO), 2.99 (s, 4H, NC H 2C H 2), 1.30 (t, J = 7.1 Hz, 3H, CH3). Example 25 【0078】 2-(2-((2-fluoro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-12:R 1 =F, [ka] , R 3 =H, R 4 Synthesis of =H) Synthesis of (2-fluoro-[1,1'-biphenyl]-3-yl)methanol (XV-12) Using compounds XII-3 (0.50 g, 2.44 mmol) and III-4 (0.45 g, 2.93 mmol) as starting materials, 0.37 g of a white solid (yield 75.1%) was obtained in the same manner as with compound XV-1. (mp 84~86°C) 1 H NMR (300 MHz, DMSO-d6) δ 7.54 - 7.44 (m, 5H, ArH), 7.43 - 7.36 (m, 2H, ArH), 7.27 (t, J = 7.6 Hz, 1H, ArH), 5.32 (t, J = 5.7 Hz, 1H, OH), 4.60 (d, J = 5.2 Hz, 2H, CH2). Synthesis of 2-(2-((2-fluoro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (ID-12) Using compounds IX-1 (150 mg, 0.59 mmol) and XV-12 (143 mg, 0.71 mmol) as starting materials, 149 mg of a colorless, viscous liquid (yield 60.2%) was obtained in the same manner as with compound ID-1. 1H NMR (300 MHz, Chloroform-d) δ 7.57 - 7.55 (m, 1H, ArH), 7.49 - 7.38 (m, 6H, ArH), 7.23 - 7.16 (m, 2H, ArH), 6.61 (d, J = 8.4 Hz, 1H, ArH), 5.47 (s, 2H, OCH2), 4.27 (q, J = 7.1 Hz, 2H, C H 2CH3), 3.83 (s, 2H, NCH2), 3.51 (s, 2H, COCH2), 3.06 - 3.01 (m, 4H, NC H 2C H 2), 1.32 (t, J = 7.1 Hz, 3H, CH3). Example 26 【0079】 2-(2-((2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)acetic acid (ID-13:R 1 =CH3, [ka] , R 3 =F, R 4 Synthesis of =H) Compound ID-1 (60 mg, 0.14 mmol) was added to a 10 mL round-bottom flask, dissolved in ethanol (2 mL), and then a solution of NaOH (11 mg, 0.28 mmol) in water (0.3 mL) was added. The mixture was stirred at room temperature for 4 hours. After monitoring by TLC to confirm the reaction was complete, the ethanol was removed by distillation under reduced pressure, the pH was adjusted to 5-6 with 2 M HCl solution, a white solid precipitated, and the mixture was filtered by suction to obtain 30 mg of the white solid product (yield 53.5%). (mp 130-132°C) 1H NMR (300 MHz, DMSO-d6) δ 7.50 - 7.40 (m, 3H, ArH), 7.32 - 7.25 (m, 4H, ArH), 7.18 - 7.16 (m, 1H, ArH), 6.66 (d, J = 8.3 Hz, 1H, ArH), 5.34 (s, 2H, OCH2), 3.67 (s, 4H, NC H 2, C H 2COOH), 2.92 - 2.79 (m, 4H, NC H 2C H 2), 2.11 (s, 3H, CH3). HRMS (ESI): m / z [M+H] + Calcd for C 24 H 24 FN2O3: 407.1771; Found: 407.1768. Example 27 【0080】 2-(2-((2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethane-1-ol(ID-14:R 1 =CH3, [ka] , R 3 =F, R 4 Synthesis of =H) Compound ID-1 (80 mg, 0.18 mmol) was added to a 25 mL round-bottom flask and dissolved in THF. Lithium aluminum hydride (14 mg, 0.37 mmol) was slowly added at 0°C. After monitoring, once the reaction was complete, saturated ammonium chloride solution was added to quench the reaction, precipitating a white solid. The white solid was removed by suction filtration, washed with EA, and the filtrate was concentrated, separated, and purified to obtain 34 mg of a yellow solid (yield 41.5%). (mp 72~74°C). 1H NMR (300 MHz, Chloroform-d) δ 7.54 (d, J = 7.3 Hz, 1H, ArH), 7.45 - 7.32 (m, 2H, ArH), 7.30 - 7.14 (m, 5H, ArH), 6.67 (d, J = 8.3 Hz, 1H, ArH), 5.44 (s, 2H, OC H 2), 3.81 (t, J = 5.3 Hz, 2H, C H 2OH), 3.76 (s, 2H, NC H 2), 3.06 - 2.95 (m, 4H, NC H 2C H 2), 2.85 (t, J = 5.3 Hz, 2H, NC H 2), 2.26 (s, 3H, C H 3). HRMS (ESI): m / z [M+H] + Calcd for C 24 H 26 FN2O2: 393.1978; Found: 393.1975. Example 28 【0081】 2-(2-((2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethane-1-ol(ID-15:R 1 =CH3, [ka] , R 3 =CH3, R 4 Synthesis of =H) Using compound ID-2 (100 mg, 0.23 mmol) and LiAlH4 (18 mg, 0.47 mmol) as starting materials, 34 mg of yellow solid (yield 41.5%) was obtained in the same manner as with compound ID-13. (mp 96~98°C) 1H NMR (300 MHz, Chloroform-d) δ 7.47 (d, J = 7.6 Hz, 1H, ArH), 7.27 - 7.21 (m, 5H, ArH), 7.16 - 7.08 (m, 2H, ArH), 6.61 (d, J = 8.4 Hz, 1H, ArH), 5.39 (s, 2H, OC H 2), 3.73 (t, J = 5.3 Hz, 2H, C H 2OH), 3.64 (s, 2H, NC H 2), 2.96 - 2.90 (m, 4H, NC H 2C H 2), 2.76 (t, J = 5.3 Hz, 2H, NC H 2), 2.09 (s, 3H), 2.06 (s, 3H). HRMS (ESI): m / z [M+H] + Calcd for C 25 H 29 N2O2: 389.2229; Found: 389.2230. Example 29 【0082】 2-(2-((2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethane-1-ol(ID-16:R 1 =CH3, [ka] , R 3 =Cl, R 4 Synthesis of =H) Using compound ID-3 (150 mg, 0.37 mmol) and LiAlH4 (24 mg, 0.73 mmol) as starting materials, 100 mg of yellow solid (yield 66.6%) was obtained in the same manner as with compound ID-13. (Mid-temperature: 108-110°C) 1H NMR (300 MHz, Chloroform-d) δ 7.58 - 7.50 (m, 2H, ArH), 7.40 - 7.32 (m, 3H, ArH), 7.31 - 7.26 (m, 2H, ArH), 7.19 - 7.17 (m, 1H, ArH), 6.67 (d, J = 8.4 Hz, 1H, ArH), 5.50 - 5.39 (m, 2H, OC H 2), 3.79 (t, J = 5.3 Hz, 2H, C H 2OH), 3.72 (s, 2H, NC H 2), 3.02 - 2.97 (m, 4H, NC H 2C H 2), 2.83 (t, J = 5.3 Hz, 2H, NC H 2), 2.19 (s, 3H, CH3). HRMS (ESI): m / z [M+H] + Calcd for C 24 H 26 ClN2O2: 409.1683; Found:409.1687. Example 30 【0083】 2-(2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethane-1-ol(ID-17:R 1 =CH3, [ka] , R 3 =H, R 4 Synthesis of =H) Using compound ID-4 (100 mg, 0.26 mmol) and LiAlH4 (20 mg, 0.53 mmol) as starting materials, 55 mg of yellow solid (yield 55.6%) was obtained in the same manner as with compound ID-12. (Temperature: 152-154°C) 1H NMR (300 MHz, Chloroform-d) δ 7.48 - 7.36 (m, 4H, ArH), 7.35 - 7.28 (m, 3H, ArH), 7.23 (s, 2H, ArH), 6.62 (d, J = 8.3 Hz, 1H, ArH), 5.39 (s, 2H, OCH2), 3.74 (t, J = 5.3 Hz, 2H, CH2OH), 3.66 (s, 2H, NCH2), 3.00 - 2.92 (m, 4H, NC H 2C H 2), 2.77 (t, J = 5.3 Hz, 2H, C H 2CH2OH), 2.28 (s, 3H, CH3). HRMS (ESI): m / z [M+H] + Calcd for C 24 H 27 N2O2: 375.2073; Found: 375.2074. Example 31 【0084】 2-(2-((2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethane-1-ol(ID-18:R 1 =Cl, [ka] , R 3 =F, R 4 Synthesis of =H) Using compound ID-5 (106 mg, 0.23 mmol) and LiAlH4 (18 mg, 0.47 mmol) as starting materials, 76 mg of yellow solid (yield 79.0%) was obtained in the same manner as with compound ID-13. (mp116~118°C) 1H NMR (300 MHz, Chloroform-d) δ 7.60 (dd, J = 7.5 Hz, 2.0 Hz, 1H, ArH), 7.44 - 7.27 (m, 5H, ArH), 7.21 - 7.18 (m, 1H, ArH), 7.17 - 7.12 (m, 1H, ArH), 6.66 (d, J = 8.4 Hz, 1H, ArH), 5.52 (s, 2H, OCH2), 3.75 (t, J = 5.3 Hz, 2H, CH2OH), 3.69 (s, 2H, NCH2), 2.99 - 2.93 (m, 4H, NC H 2C H 2), 2.79 (t, J = 5.3 Hz, 2H, C H 2CH2OH). HRMS (ESI): m / z [M+H] + Calcd for C 23 H 23 ClFN2O2: 413.1432; Found: 413.1432. Example 32 【0085】 2-(2-((2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethane-1-ol(ID-19:R 1 =Cl, [ka] , R 3 =CH3, R 4 Synthesis of =H) Using compound ID-6 (60 mg, 0.13 mmol) and LiAlH4 (10 mg, 0.27 mmol) as starting materials, 30 mg of a white solid (yield 55.2%) was obtained in the same manner as with compound ID-13. (mp 88~90°C) 1H NMR (300 MHz, Chloroform-d) δ 7.56 (dd, J = 7.6 Hz, 1.7 Hz, 1H, ArH), 7.34 - 7.26 (m, 4H, ArH), 7.24 - 7.21 (m, 1H, ArH), 7.20 - 7.12 (m, 2H, ArH), 6.66 (d, J = 8.5 Hz, 1H, ArH), 5.51 (s, 2H, OCH2), 3.74 (t, J = 5.3 Hz, 2H, CH2OH), 3.68 (s, 2H, NCH2), 2.96 - 2.93 (m, 4H, NC H 2C H 2), 2.78 (t, J = 5.3 Hz, 2H, C H 2CH2OH), 2.11 (s, 3H, CH3). HRMS (ESI): m / z [M+H] + Calcd for C 24 H 26 ClN2O2: 409.1683; Found: 409.1682. Example 33 【0086】 2-(2-((2,2'-dichloro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethane-1-ol(ID-20:R 1 =Cl, [ka] , R 3 =Cl, R 4 Synthesis of =H) Using compound ID-7 (120 mg, 0.26 mmol) and LiAlH4 (19 mg, 0.51 mmol) as starting materials, 64 mg of a yellow solid (yield 58.5%) was obtained in the same manner as with compound ID-13. (Mid-temperature: 110-112°C) 1H NMR (300 MHz, Chloroform-d) δ 7.61 (dd, J = 7.7 Hz, 1.8 Hz, 1H, ArH), 7.51 - 7.46 (m, 1H, ArH), 7.38 - 7.27 (m, 5H, ArH), 7.25- 7.20 (m, 1H, ArH), 6.66 (d, J = 8.4 Hz, 1H, ArH), 5.52 (s, 2H, OCH2), 3.75 (t, J = 5.3 Hz, 2H, C H 2OH), 3.69 (s, 2H, NCH2), 2.99 - 2.93 (m, 4H, NC H 2C H 2), 2.79 (t, J= 5.3 Hz, 2H, C H 2CH2OH). HRMS (ESI): m / z [M+H] + Calcd for C 23 H 23 Cl2N2O2: 429.1137; Found: 429.1141. Example 34 【0087】 2-(2-((2-chloro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethane-1-ol(ID-21:R 1 =Cl, [ka] , R 3 =H, R 4 Synthesis of =H) Using compound ID-8 (187 mg, 0.43 mmol) and LiAlH4 (27 mg, 0.46 mmol) as starting materials, 80 mg of a white solid (yield 47.3%) was obtained in the same manner as with compound ID-13. (temperature: 148-150°C) 1H NMR (300 MHz, Chloroform-d) δ 7.39 (dd, J = 6.9 Hz, 2.5 Hz, 1H, ArH), 7.26 - 7.21 (m, 2H, ArH), 7.17 - 7.06 (m, 5H, ArH), 6.48 (d, J = 8.5 Hz, 1H, ArH), 5.35 (s, 2H, OCH2), 3.55 (t, J= 5.3 Hz, 2H, CH2OH), 3.47 (s, 2H, NCH2), 2.80 - 2.70 (m, 4H, NC H 2C H 2), 2.58 (t, J = 5.3 Hz, 2H, C H 2CH2OH). HRMS (ESI): m / z [M+H] + Calcd for C 23 H 24 ClN2O2: 395.1526; Found:395.1522. Example 35 【0088】 2-(2-((2,2'-difluoro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethane-1-ol(ID-22:R 1 =F, [ka] , R 3 =F, R 4 Synthesis of =H) Using compound ID-9 (100 mg, 0.23 mmol) and LiAlH4 (17 mg, 0.46 mmol) as starting materials, 60 mg of a brown solid (yield 66.4%) was obtained in the same manner as with compound ID-13. (mp 60~62°C) 1H NMR (300 MHz, Chloroform-d) δ 7.57 - 7.52 (m, 1H, ArH), 7.43 - 7.32 (m, 3H, ArH), 7.25 - 7.13 (m, 4H, ArH), 6.62 (d, J = 8.3 Hz, 1H, ArH), 5.48 (s, 2H, OCH2), 3.74 (t, J = 5.3 Hz, 2H, CH2OH), 3.66 (s, 2H, NCH2), 2.95 - 2.92 (m, 4H, NC H 2C H 2), 2.77 (t, J = 5.3 Hz, 2H, C H 2CH2OH). HRMS (ESI): m / z [M+H] + Calcd for C 23 H 23 F2N2O2: 397.1728; Found: 397.1730. Example 36 【0089】 2-(2-((2-fluoro-2'-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethane-1-ol(ID-23:R 1 =F, [ka] , R 3 =CH3, R 4 Synthesis of =H) Using compound ID-10 (130 mg, 0.30 mmol) and LiAlH4 (23 mg, 0.59 mmol) as starting materials, 90 mg of a nearly white solid (yield 76.7%) was obtained in the same manner as with compound ID-13. (mp 62~64°C) 1H NMR (300 MHz, Chloroform-d) δ 7.56 - 7.48 (m, 1H, ArH), 7.31 - 7.29 (m, 3H, ArH), 7.25 - 7.18 (m, 4H, ArH), 6.62 (d, J = 8.3 Hz, 1H, ArH), 5.47 (s, 2H, OCH2), 3.73 (t, J = 5.3 Hz, 2H, CH2OH), 3.66 (s, 2H, NCH2), 2.98 - 2.89 (m, 4H, NC H 2C H 2), 2.77 (t, J = 5.3 Hz, 2H, C H 2CH2OH), 2.21 (d, J = 1.4 Hz, 3H, CH3). HRMS (ESI): m / z [M+H] + Calcd for C 24 H 26 FN2O2: 393.1978; Found:393.1981. Example 37 【0090】 2-(2-((2'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethane-1-ol(ID-24:R 1 =F, [ka] , R 3 =Cl, R 4 Synthesis of =H) Using compound ID-11 (104 mg, 0.23 mmol) and LiAlH4 (17 mg, 0.46 mmol) as starting materials, 60 mg of a pale yellow solid (yield 74.0%) was obtained in the same manner as with compound ID-13. (mp 68~70°C) 1H NMR (300 MHz, Chloroform-d) δ 7.59 - 7.54 (m, 1H, ArH), 7.51 - 7.47 (m, 1H, ArH), 7.38 - 7.30 (m, 3H, ArH), 7.26 - 7.18 (m, 3H, ArH), 6.62 (d, J = 8.3 Hz, 1H, ArH), 5.48 (s, 2H, OCH2), 3.74 (t, J = 5.3 Hz, 2H, CH2OH), 3.68 (s, 2H, NCH2), 2.97 - 2.92 (m, 4H, NC H 2C H 2), 2.78 (t, J= 5.3 Hz, 2H, C H 2CH2OH). HRMS (ESI): m / z [M+H] + Calcd for C 23 H 23 ClFN2O2: 413.1432; Found:413.1430. Example 38 【0091】 2-(2-((2-fluoro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethane-1-ol(ID-25:R 1 =F, [ka] , R 3 =H, R 4 Synthesis of =H) Using compound ID-11 (149 mg, 0.35 mmol) and LiAlH4 (17 mg, 0.46 mmol) as starting materials, 70 mg of a nearly white solid (yield 52.3%) was obtained in the same manner as with compound ID-13. (mp 72~74°C) 1H NMR (300 MHz, Chloroform-d) δ 7.57 - 7.36 (m, 7H, ArH), 7.25 - 7.17 (m, 2H, ArH), 6.62 (d, J = 8.4 Hz, 1H, ArH), 5.48 (s, 2H, OCH2), 3.74 (t, J = 5.3 Hz, 2H, CH2OH), 3.68 (s, J = 2.9 Hz, 2H, NCH2), 2.99 - 2.90 (m, 4H, NC H 2C H 2), 2.77 (t, J = 5.3 Hz, 2H, C H 2CH2OH). HRMS (ESI): m / z [M+H] + Calcd for C 23 H 24 FN2O2: 379.1822; Found: 379.1822. Example 39 【0092】 2-(2-((2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)acetic acid (ID-26:R 1 =Cl, [ka] , R 3 =F, R 4 Synthesis of =H) Compound ID-5 (400 mg, 0.88 mmol) was added to a 10 mL round-bottom flask, dissolved in ethanol (3 mL), and then a solution of NaOH (69 mg, 1.76 mmol) in water (0.2 mL) was added. The mixture was stirred at room temperature for 4 hours. After monitoring by TLC to confirm the reaction was complete, the ethanol was removed by distillation under reduced pressure, the pH was adjusted to 5-6 with 2 M HCl solution, a white solid precipitated, and the mixture was filtered by suction to obtain 262 mg of the white solid product (yield 69.8%). (mp 101-108°C) 1H NMR (300 MHz, Chloroform-d) δ 7.59 - 7.52 (m, 1H, ArH), 7.41 - 7.27 (m, 4H, ArH), 7.22 - 7.01 (m, 3H, ArH), 6.64 (d, J = 8.4 Hz, 1H, ArH), 5.46 (s, 2H, OCH2), 4.18 (s, 2H, NCH2), 3.59 (s, 2H, COCH2), 3.38 - 3.05 (m, 4H, NC H 2C H 2). During the production of ID-26, a by-product was obtained, and its structure was identified as ID-27. m / z: 369.10 (M+H). 1 H-NMR (400 MHz, DMSO-d6) δ: 7.66 (dd, J =7.6 &1.6Hz, 1H), 7.53-7.47 (m, 1H), 7.48-7.44 (m, 1H), 7.41-7.30 (m, 5H), 6.71 (d, 1H, J =8.4Hz), 5.44 (s, 2H), 3.78 (s, 2H), 3.01-2.98 (m, 1H), 2.70-2.67 (m, 1H). Example 40 【0093】 2-(7-((2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-1-methyl-1,4-dihydropyridine[2,3-d]pyrimidine-3(2H)-yl)methylacetate(IE-1:R 1 =CH3, [ka] , R 3 =CH3, R 4 Synthesis of =H) Synthesis of (6-chloro-3-formylpyridine-2-yl)(methyl)carbamate tert-butyl(XVII) Compound XVI (100 mg, 0.39 mmol) was added to a 25 mL round-bottom flask and dissolved in DMF (10 mL). CH3I (49 μL, 0.78 mmol) was slowly added dropwise to the reaction mixture. The temperature was lowered to 0°C, and 60% NaH (18 mg, 0.469 mmol) was added in batches. After the dropwise addition was complete, the mixture was stirred in an ice bath for a further 30 minutes and allowed to react overnight at room temperature. When the reaction was almost complete, as confirmed by TLC (petroleum ether:ethyl acetate = 15:1), the mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate (10 mL x 2), the organic phase was mixed, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain 0.09 g of a colorless liquid (yield 85.2%). 1 H NMR (300 MHz, Chloroform-d) δ 9.90 (s, 1H, CHO), 8.13 (d, J = 8.1 Hz, 1H, ArH), 7.29 (d, J= 8.1 Hz, 1H, ArH), 3.44 (s, 3H, NCH3), 1.43 (s, 9H, CH3). Synthesis of ((2-((tert-butoxycarbonyl)(methyl)amino)-6-chloropyridine-3-yl)methyl)glycine methyl ester (XVIII-1) Compound XVII (0.70 g, 2.73 mmol), glycine methyl hydrochloride (0.69 g, 5.47 mmol), and dichloromethane (10 mL) were added to a 25 mL round-bottom flask. The mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (1.16 g, 5.47 mmol) was added in batches at 0°C. After the dropwise addition was complete, the mixture was allowed to react at room temperature for 4 hours. When the starting materials had reacted completely, as confirmed by TLC monitoring, saturated sodium carbonate was added dropwise to adjust the pH to 7. Water (5 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phase was mixed, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain an oily crude product, which was separated by column chromatography to obtain 0.35 g of a colorless liquid (yield 37.4%). 1H NMR (300 MHz, Chloroform-d) δ 7.95 (d, J = 8.0 Hz, 1H, ArH), 7.29 (d, J = 8.2 Hz, 1H, ArH),4.86 (br, 1H, NH) 3.78 (s, 3H, OCH3), 3.75 (s, 2H, ArCH2), 3.42 (s, 2H, CH2CO), 3.28 (s, 3H, NCH3), 1.46 (s, 9H, CH3). Synthesis of ((6-chloro-2-(methylamino)pyridine-3-yl)methyl)glycine methyl ester (XIX-1) Compound XVIII-1 (0.67 g, 1.95 mmol) was added to a 50 mL round-bottom flask, dissolved in ethyl acetate (5 mL), and a hydrogen chloride solution of ethyl acetate was added. The mixture was reacted at room temperature for 12 hours to precipitate a white solid, which was then filtered by suction to obtain 0.34 g of white solid (yield 71.6%). (mp 110~112°C) 1 H NMR (300 MHz, DMSO-d6) δ 9.67 (s, 2H,N H ·HCl), 7.58 (d, J= 7.7 Hz, 1H, ArH), 6.60 (d, J = 7.6 Hz, 1H, ArH), 4.11 (s, 2H, ArCH2), 4.03 (s, 2H, CH2CO), 3.72 (s, 3H, OCH3), 2.79 (s, 3H, NHC H 3). Synthesis of 2-(7-chloro-1-methyl-1,4-dihydropyridine[2,3-d]pyrimidine-3(2H)-yl)methylacetate (XX-1) Compound XIX-1 (0.25 g, 0.90 mmol) was added to a 25 mL round-bottom flask, dissolved in methanol (5 mL), and under nitrogen protection, triethylamine (249 μL, 1.80 mmol) was added and stirred for 10 minutes. Polyoxymethylene (0.03 g, 1.08 mmol) was added and the mixture was reacted at room temperature for 8 hours. After monitoring by TLC, when the starting materials had reacted completely, the mixture was concentrated under reduced pressure, the organic solvent was removed, water was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phase was mixed, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain an oily crude product, which was separated by column chromatography to obtain 0.20 g of a colorless liquid (yield 87.4%). 1 H NMR (300 MHz, Chloroform-d) δ 7.01 (d, J= 7.5 Hz, 1H,ArH), 6.50 (d, J = 7.5 Hz, 1H,ArH), 4.28 (s, 2H, NCH2N), 3.97 (s, 2H, ArCH2), 3.75 (s, 3H, OCH3), 3.43 (s, 2H, CH2CO), 3.05 (s, 3H, NCH3) Synthesis of 2-(7-((2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-1-methyl-1,4-dihydropyridine[2,3-d]pyrimidine-3(2H)-yl)methylacetate (IE-1) Compounds XX-1 (170 mg, 0.67 mmol), XV-2 (173 mg, 0.80 mmol), t-BuXphos (57 mg, 0.13 mmol), and toluene (5 mL) were added sequentially to a three-necked flask. Then, cesium carbonate (430 mg, 1.33 mmol) was added, and under nitrogen protection, Pd(OAc)2 (15 mg, 0.07 mmol) was added. The mixture was heated to 80°C and reacted for 12 hours. Monitoring by TLC (petroleum ether:ethyl acetate = 4:1) confirmed that the reactants had reacted completely. Heating was stopped, and the mixture was cooled to room temperature. The palladium catalyst and insoluble matter were removed by suction filtration, diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was mixed, washed with saturated brine (10 mL x 3), and dried over anhydrous magnesium sulfate. The solution was filtered by suction, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 10:1) to obtain 150 mg of a colorless, transparent liquid (yield 51.79%). 1 H NMR (400 MHz, Chloroform-d) δ (ppm): 7.56 - 7.35 (m, 2H, ArH), 7.29 (d, J = 1.8 Hz, 1H, ArH), 7.27 - 7.20 (m, 2H, ArH), 7.12 - 7.08 (m, 3H, ArH), 5.98 - 5.96 (m, 1H, ArH), 5.50 - 5.32 (s, 2H, OCH2), 3.79 (s, 3H, CH3), 4.13(s, 2H, NCH2N), 3.69 (q, J = 4.1 Hz, 2H, NCH2), 3.42 (dd, J = 3.1 Hz, 2.6 Hz, 2H, COCH2), 3.03 (q, J = 3.8 Hz, 2.7 Hz, 3H, ArCH3), 2.60 (s, 3H, NCH3), 2.11 (s, 3H, ArCH3). Example 41 【0094】 (R)-2-(7-((3'-(3-(3-hydroxypyrrolidine-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-1-methyl-1,4-dihydropyridine[2,3-d]pyrimidine-3(2H)-yl)methylacetate (IE-2:R 1 =CH3, [ka] , R 3 =CH3, [ka] ) synthesis Compounds XV-2 (0.43 g, 0.64 mmol), XX-1 (0.25 g, 0.93 mmol), and Cs2CO3 (0.61 g, 1.56 mmol) were added to a 50 mL sealed tube. Pd(OAc)2 (0.02 g, 0.09 mmol), t-BuXPhos (0.08 g, 0.19 mmol), and toluene (10 mL) were added, and the mixture was protected by introducing N2. The mixture was refluxed at 80°C for 36 hours. After monitoring by TLC, when most of the starting materials had reacted completely, the mixture was filtered by suction using diatomaceous earth, and the liquid was concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography to obtain 110 mg of a pale yellow oily substance, which was then purified to obtain 90 mg of a pale yellow oily substance (yield 16.8%). 1H NMR (300 MHz, Chloroform-d) δ 7.50 (d, J = 7.5 Hz, 1H, ArH), 7.30 - 7.21 (m, 2H, ArH), 7.15 - 7.09 (m, 2H, ArH), 6.90 (d, J = 7.9 Hz, 1H, ArH), 6.81 (d, J = 7.5 Hz, 1H, ArH), 6.12 (d, J = 7.9 Hz, 1H, ArH), 5.44 (s, 2H, OCH2), 4.45 (s, 1H, OH), 4.31 (s, 2H, NCH2N), 4.19 - 4.08 (m, 2H, OCH2), 4.02 (s, 2H, NCH2), 3.82 (s, 3H, OCH3), 3.54 (s, 2H, COCH2), 3.11 (s, 3H, NCH3), 2.93 - 2.90 (m, 1H,1 / 2C H 2), 2.86 - 2.81 (m, 2H, CH2), 2.71 - 2.64 (m, 1H, 1 / 2C H 2), 2.50 - 2.43 (m, 1H, 1 / 2C H 2), 2.34 - 2.24 (m, 3H, 1 / 2CH2, CH2), 2.15 (s, 3H, ArCH3), 1.99 (s, 3H, ArCH3), 2.00 - 1.83 (m, 2H, CH2). Example 42 【0095】 2-(7-((2,2'-ジメチル-[1,1'-ビフェニル]-3-イル)メトキシ)-1-メチル-1,4-ジヒドロピリジン[2,3-d]ピリミジン-3(2H)-イル)phthalic acid (IE-3:R 1 =CH3、 【change】 R 3 =CH3、R 4 =H) synthesis Compound IE-1 (0.20 g, 0.46 mmol) was added to a 10 mL round-bottom flask, dissolved with methanol (2 mL), and 2 M LiOH (1 mL) was added. The mixture was stirred at room temperature for 4 hours. After monitoring by TLC to confirm the reaction was complete, the methanol was removed by distillation under reduced pressure. The pH was adjusted to 5-6 with 1 M HCl solution, and a white solid precipitated. The mixture was filtered by suction, and the crude product was slurryed three times with dichloromethane to obtain 70 mg of a white solid product (yield 36.5%). The reaction temperature was 132-134°C. 1 H NMR (400 MHz, Chloroform-d) δ7.59 - 7.38 (m, 2H, ArH), 7.32 (d, J = 1.8 Hz, 1H, ArH), 7.30 - 7.23 (m, 2H, ArH), 7.15 - 7.12 (m, 3H, ArH), 6.01 - 5.97 (m, 1H, ArH), 5.53 (s, 2H, OCH2), 4.16 (s, 2H, NCH2N), 3.72 (q, J= 4.1 Hz, 2H, NCH2), 3.45 (dd, J = 3.1 Hz, 2.6 Hz, 2H, COCH2), 3.06 (s, 3H, ArCH3), 2.63 (s, 3H, NCH3), 2.14 (s, 3H, ArCH3). HRMS (ESI): m / z [M+H] + Calcd forC 25 H 28 N3O3:418.2030; Found: 418.2132. Example 43 【0096】 (R)-2-(7-((3'-(3-(3-hydroxypyrrolidine-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-1-methyl-1,4-dihydropyridine[2,3-d]pyrimidine-3(2H)-yl)acetic acid (IE-4:R 1 =CH3, [ka] , R 3 =CH3, 【change】 ) synthesis Compound IE-2 (90 mg, 0.16 mmol) and 2M LiOH (1 mL) were used as raw materials, IE-3 was used as raw materials, and 80 mg of off-white solid product (yield 54.7%) was obtained. mp162~164℃. 1 H NMR (300 MHz, DMSO-d6) δ 7.43 (d, J = 7.5 Hz, 1H, ArH), 7.26 (d, J = 8.1 Hz, 1H, ArH), 7.2 (d, J = 8.5 Hz, 1H, ArH), 7.15 (d, J = 7.8 Hz, 1H, ArH), 7.04 (d, J = 7.5 Hz, 1H, ArH), 6.97 (d, J = 8.2 Hz, 1H, ArH), 6.69 (d, J = 7.6 Hz, 1H, ArH), 6.01 (d, J = 7.8 Hz, 1H, ArH), 5.36 (s, 2H, OCH2), 4.25 (s, 1H, OH), 4.16 (s, 2H, NCH2N), 4.13 - 4.00 (m, 3H, OC H 2CH2, CH), 3.82 (s, 2H, ArCH2N), 3.32 (s, 4H, CHC H 2N, NC H 2), 2.97 (s, 3H, NCH3), 2.90 - 2.79 (m, 1H, 1 / 2NC H 2CH2), 2.79 - 2.68 (m, 3H, 1 / 2NC H 2CH2, NCH2C H 2), 2.67 - 2.58 (m, 1H, 1 / 2CH2C H 2CH), 2.02 (s, 3H, ArCH3), 1.85 (s, 3H, ArCH3), 1.99 - 1.91 (m, 2H, CH2), 1.70 - 1.65 (m, 1H, 1 / 2CH2C H 2CH). HRMS (ESI): m / z [M+H] + Calcd for C32 H 41 N4O5: 561.3077; Found: 561.3079. Example 44 【0097】 2-(2-((2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (IF-1:R 1 =Cl, [ka] , R 3 =F, R 4 Synthesis of =H) Synthesis of 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-t-butyl acetate(XXI) 250 mg, 1.22 mmol of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthirizine hydrochloride VIII was added to a 25 mL round-bottom flask, dissolved in 5 mL of DCM, triethylamine (508 μL, 3.66 mmol) was added dropwise, and (Bco)2O (399 mg, 1.83 mmol) was added. After monitoring, once the starting materials had completely reacted, 5 mL of water was added to dilute, the mixture was washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered by suction, and the solvent was removed by distillation under reduced pressure. The crude product was purified to obtain 320 mg of a white solid (yield 97.7%). (mp 66~68°C). 1 H NMR (300 MHz, Chloroform-d) δ 7.39 (d, J = 8.1 Hz, 1H, ArH), 7.18 (d, J = 8.1 Hz, 1H, ArH), 4.57 (s, 2H, NCH2), 3.74 (t, J = 5.9 Hz, 2H, NC H 2CH2), 2.99 (t, J = 6.0 Hz, 2H, NCH2C H 2), 1.50 (s, 9H, CH3). Synthesis of 2-cyano-7,8-dihydro-1,6-naphthyridine-6(5H)-t-butyl(XXII) acetate Compound XXI (500 mg, 1.86 mmol) and zinc cyanide (240 mg, 2.05 mmol) were added to a three-necked flask, dissolved in 5 mL of DMF, and under nitrogen protection, Pd(PPh3)4 (215 mg, 0.19 m) ol) was added. The mixture was heated to 120°C and reacted for 10 hours. Monitoring by TLC (petroleum ether:ethyl acetate = 2:1) confirmed that the starting materials had completely reacted. Heating was stopped, and the mixture was cooled to room temperature. The palladium catalyst and insoluble matter were removed by suction filtration. The mixture was diluted with 5 mL of water, extracted with ethyl acetate (5 mL x 3), and the organic phase was mixed. The mixture was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by suction filtration and reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1-5:1) to obtain 300 mg of a white solid (yield 62.2%). (mp 112-114°C) 1 H NMR (300 MHz, Chloroform-d) δ 7.54 (s, 2H, ArH), 4.66 (s, 2H, NCH2), 3.77 (t, J = 6.0 Hz, 2H, NC H 2CH2), 3.04 (t, J = 6.0 Hz, 2H, NCH2C H 2) , 1.49 (s, 9H, CH3). Synthesis of 6-(2-(tert-butoxy)-2-oxoethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylic acid (XXIII) Compound XXII (1.00 g, 3.86 mol) was dissolved in methanol, and an aqueous solution of KOH (1.08 g, 19.28 mol) was added. The mixture was heated to 80°C and reacted for 12 hours. Monitoring by TLC (dichloromethane:methane = 10:1) confirmed that the reactants had completely reacted. The reaction was stopped and the mixture was cooled to room temperature. The pH was adjusted to neutral with dilute hydrochloric acid, diluted with 5 mL of water, extracted with ethyl acetate (5 mL x 3), the organic phase was mixed, washed with saturated brine, and dried over anhydrous magnesium sulfate. The mixture was filtered by suction, the solvent was removed by distillation under reduced pressure, and the residue was separated by column chromatography (dichloromethane:methanol = 25:1-5:1) to obtain 630 mg of a white solid (yield 58.7%). (mp 162-164°C) 1 H NMR (300 MHz, Chloroform-d) δ 8.05 (s, 1H, ArH), 7.66 (s, 1H, ArH), 4.69 (s, 2H, NCH2), 3.78 (s, 2H, NC H 2CH2), 3.06 (s, 2H, NCH2C H 2), 1.50 (s, 9H, CH3). Synthesis of 2-chloro-2'-fluoro-[1,1'-biphenyl]-3-amine (IV-2) 3-Bromo-2-chloroaniline II-2 (1.00 g, 4.80 mmol), 2-fluorophenylboronic acid III-1 (1.02 g, 7.30 mmol), and 20 mL of 1,4-dioxane were sequentially added to a three-necked flask. Potassium carbonate (1.87 g, 13.6 mmol) dissolved in water was added to the reaction mixture, and under nitrogen protection, Pd(PPh3)4 (0.28 g, 0.20 mmol) was added. The mixture was heated to 80°C and reacted for 10 hours. When the reaction was complete, as confirmed by TLC (petroleum ether:ethyl acetate = 15:1), heating was stopped and the mixture was cooled to room temperature. The palladium catalyst and insoluble matter were removed by suction filtration, diluted with 5 mL of water, extracted with ethyl acetate (5 mL x 3), the organic phase was mixed, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solution was filtered by suction, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography to obtain 0.97 g of a white solid powder (yield 91.4%). (mp 78~80°C) 1 H NMR (300 MHz, DMSO-d6) δ 7.43 - 7.40 (m, 1H, ArH), 7.32 - 7.22 (m, 3H, ArH), 7.08 (dd, J = 8.1 Hz, 7.4 Hz, 1H, ArH), 6.85 (dd, J = 8.1 Hz, 1.6 Hz, 1H, ArH), 6.50 (dd, J = 7.4 Hz, 1.6 Hz, 1H, ArH), 5.48 (s, 2H, NH). Synthesis of 2-((2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-) tert-butyl(XXIV) formate Compounds XXIII (500 mg, 1.80 mmol) and IV-2 (397 mg, 1.80 mmol) were dissolved in dichloromethane, and HATU (820 mg, 2.16 mmol) and DIPEA (697 mg, 5.39 mmol) were added. The mixture was reacted at room temperature for 12 hours. The reaction was stopped when the starting materials had completely reacted, as monitored by TLC (dichloromethane:methanol = 25:1). The mixture was diluted with 5 mL of water, extracted with ethyl acetate (5 mL x 3), the organic phase was mixed, washed with saturated brine, and dried over anhydrous magnesium sulfate. The mixture was filtered by suction, the solvent was removed by distillation under reduced pressure, and the residue was separated and purified by column chromatography to obtain 580 mg of a white solid (yield 67.1%). (mp 134~136°C). 11 H NMR (300 MHz, Chloroform-d) δ 10.86 (s, 1H, NH), 8.70 (dd, J = 8.3 Hz, 1.6 Hz, 1H, ArH), 8.13 (d, J = 7.9 Hz, 1H, ArH), 7.63 (d, J = 8.0 Hz, 1H, ArH), 7.45 - 7.37 (m, 2H, ArH), 7.30 - 7.34 (m, 1H, ArH), 7.24 - 7.20 (m, 1H, ArH), 7.19 - 7.13 (m, 1H, ArH), 7.11 (dd, J = 7.6 Hz, 1.6 Hz, 1H, ArH), 4.68 (s, 2H, NCH2), 3.79 (t, J = 5.9 Hz, 2H, NC H 2CH2), 3.07 (t, J = 6.0 Hz, 2H, NCH2C H 2), 1.51 (s, 9H, CH3). Synthesis of N-(2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-formamide (XXV) Compound XXIV (580 mg, 1.21 mmol) was dissolved in methanol, and a 1,4-dioxane solution of hydrogen chloride was slowly added dropwise. After monitoring by TLC (dichloromethane:methanol = 15:1) and confirming that the starting materials had completely reacted, the solvent was removed by distillation under reduced pressure to obtain 616 mg of a pale yellow solid (yield 99.9%). The mp was higher than 250°C. 1 H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H, NH), 8.45 (m, 1H, ArH), 8.11 (d, J = 8.0 Hz, 1H, ArH), 8.00 (d, J = 8.0 Hz, 1H, ArH), 7.50 - 7.55 (m, 2H, ArH), 7.43 - 7.33 (m, 3H, ArH), 7.25 (dd, J = 7.6 Hz, 1.6 Hz, 1H, ArH), 4.44 (s, 2H, NCH2), 3.54 (s, 2H, NC H 2CH2), 3.24 (t, J = 6.2 Hz, 2H, NCH2C H 2). Synthesis of 2-(2-((2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-yl)ethyl acetate (IF-1) Compound XXV (250 mg, 0.66 mmol) was dissolved in THF, and 60% NaH (31.5 mg, 1.31 mmol) was slowly added under ice bath conditions. After the addition was complete, the mixture was transferred to room temperature and allowed to react for 30 minutes. Ethyl bromoethyl (87 μL, 0.79 mmol) was slowly added dropwise to the reaction mixture. The reaction was stopped when the starting materials had completely reacted, as monitored by TLC (dichloromethane:methanol = 25:1). The reaction was quenched with saturated NH4Cl solution, diluted with 5 mL of water, extracted with ethyl acetate (5 mL x 3), dried over anhydrous sodium sulfate, and filtered by suction. The solvent was removed by distillation under reduced pressure, and the residue was separated by column chromatography to obtain 126 mg of pale yellow solid (yield 41.11%). (mp 158~160°C) 1H NMR (400 MHz, Chloroform-d) δ 10.86 (s, 1H, NH), 8.70 (d, J = 8.2 Hz, 1H, ArH), 8.08 (d, J = 7.9 Hz, 1H, ArH), 7.55 (d, J = 7.9 Hz, 1H, ArH), 7.44 - 7.36 (m, 2H, ArH), 7.34 - 7.29 (m, 1.7 Hz, 1H, ArH), 7.23 - 7.15 (m, 2H, ArH), 7.14 - 7.09 (m, 1H, ArH), 4.28 (q, J = 7.1 Hz, 2H, CH3C H 2), 3.99 (s, 2H, NCH2), 3.53 (s, 2H, COCH2), 3.22 - 3.07 (m, 4H, NC H 2C H 2), 1.31 (t, J = 7.1 Hz, 3H, CH3). Example 45 【0098】 N-(2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)-6-(2-hydroxyethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-formamide(IF-2:R 1 =Cl, [ka] , R 3 =F, R 4 Synthesis of =H) Compound IF-1 (60 mg, 0.13 mmol) was dissolved in THF, and after adding LiAlH4 (10 mg, 0.26 mmol) under ice bath conditions, the reaction was carried out at room temperature. The reaction was stopped when the reactants had completely reacted, as monitored by TLC (dichloromethane:methanol = 25:1). The reaction was quenched with saturated NH4Cl solution, diluted with 5 mL of water, extracted with ethyl acetate (5 mL x 3), dried over anhydrous sodium sulfate, filtered by suction, the solvent was removed by distillation under reduced pressure, and the residue was separated by column chromatography to obtain 36 mg of a white solid (yield 54.6%). (mp 88~90°C) 1 H NMR (300 MHz, Chloroform-d) δ 10.85 (s, 1H, NH), 8.70 (d, J = 8.4 Hz, 1H, ArH), 8.09 (d, J = 7.9 Hz, 1H, ArH), 7.57 (d, J = 7.9 Hz, 1H, ArH), 7.40 (t, J = 7.7 Hz, 2H, ArH), 7.35 - 7.28 (m, 1H, ArH), 7.23 - 7.09 (m, 2H, ArH), 3.88 (s, 2H, NCH2), 3.79 (t, J = 5.3 Hz, 2H, C H 2OH), 3.16 (t, J = 5.4 Hz, 2H, NCH2C H 2), 3.04 (t, J = 5.7 Hz, 2H, NC H 2CH2), 2.84 (t, J = 5.3 Hz, 2H, C H 2CH2OH). HRMS (ESI): m / z [M+H] + Calcd for C 23 H 22 ClFN3O2:426.1385; Found: 426.1382. Example 46 【0099】 2-(2-((2-クロロ-2'-フルオロ-[1,1'-ビフェニル]-3-イル)カルバモイル)-7,8-ジヒドロ-1,6-ナフチリジン-6(5H)-イル)phthalic acid (IF-3:R 1 =Cl、 【change】 R 3 =F、R 4 =H) synthesis Compound IF-1 (60 mg, 0.13 mmol) was dissolved in ethanol, and an aqueous solution of NaOH (10 mg, 0.26 mmol) was added. The mixture was stirred at room temperature. The reaction was stopped when the starting materials had completely reacted, as monitored by TLC (dichloromethane:methanol = 5:1). The mixture was diluted with 5 mL of water, extracted with ethyl acetate (5 mL x 3), the organic phase was mixed, washed with saturated brine, and dried over anhydrous magnesium sulfate. The mixture was filtered by suction, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography to obtain 42 mg of a white solid (yield 74.5%). (mp 224~226°C). 1 H NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1H, NH), 8.49 (d, J = 8.2 Hz, 1H, ArH), 8.01 - 7.90 (m, 1H, ArH), 7.81 - 7.69 (m, 1H, ArH), 7.54 - 7.45 (m, 2H, ArH), 7.40 - 7.28 (m, 3H, ArH), 7.24 - 7.13 (m, 1H, ArH), 3.84 (s, 2H, NCH2), 3.14 (s, 2H, COCH2), 3.03 - 2.88 (m, 4H, NC H 2C H 2). HRMS (ESI): m / z [M+H] + Calcd for C 23 H 20 ClFN3O3:440.1177; Found: 440.1172. Example 47 【0100】 Evaluation of the inhibitory activity of the compound of the present invention on PD-1 / PD-L1 protein interaction. Experimental Objective: To detect the inhibitory activity of compound (I) on PD-1 / PD-L1 interaction using the PD-1 / PD-L1 binding assay kit (CISBIO). Experimental principle: Homogeneous time-resolved fluorescence (HTRF) is a technique used to detect samples in pure liquid systems. This is primarily done using europium (Eu) as an energy donor. + This assay utilizes the energy transfer between two fluorescent groups, which can be divided into a donor and an energy acceptor. When the donor is excited externally (e.g., by a flash lamp or laser), if it is close enough to the acceptor, the energy is transferred to the acceptor via resonance, exciting the acceptor and causing it to emit a specific wavelength. This assay, utilizing HTRF technology, allows for easy and rapid characterization of compounds and antibody blockers in a high-throughput format. The interaction between PD-L1 and PD-1 is Eu + Detection is possible using anti-Tag1 (HTRF energy donor) labeled with europium and anti-Tag2 (HTRF energy acceptor) labeled with XL665. Tag1 and Tag2 are used to label PD-L1 protein and PD-1 protein, respectively, and Eu + XL665 and XL665 bind to PD-L1 and PD-1 respectively via antibodies to form a complex. When PD-L1 and PD-1 bind close to each other, Eu + After being excited by an external laser, it induces fluorescence resonance energy transfer to XL665, the latter which specifically emits at 665 nm. This particular signal is directly proportional to the degree of PD1 / PD-L1 interaction. Therefore, compounds or antibodies that block PD-1 / PD-L1 interaction result in a decrease in the HTRF signal. Experimental materials: The kit is a PD-1 / PD-L1 binding assay kit purchased from CISBIO. The 96-well plate was also purchased from CISBIO. Test equipment: Perkin Elmer, Model: EnVision. Test compound: The compound of formula (I). It was dissolved in DMSO and diluted with diluent buffer. The DMSO concentration was kept below 0.5%. Experimental Procedure: A PD-1 / PD-L1 binding assay kit was used. Negative, positive, and treatment groups were set up, with two duplicate wells in each group. For the positive control group, 2 μL of diluent, 4 μL of PD-L1 diluted according to instructions, and 4 μL of PD-L1 were added to a 96-well plate. For the negative control group, 6 μL of diluent and 4 μL of PD-L1 were added to a 96-well plate. For the treatment group, 2 μL of the test compound (or positive compound BMS-202) of formula (I), 4 μL of PD-L1, and 4 μL of PD-L1 were sequentially added to the 96-well plate. The plate was sealed with sealing film, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 15 minutes. Next, Anti-Tag-Eu3 diluted in Buffer was added. + Equal amounts of Anti-tag-XL665 were homogeneously mixed, then 10 μL of the mixture was added to each well, the plate was sealed, centrifuged at 1000 rpm for 1 minute, and incubated at room temperature for 2 hours. The sealing film was removed, and the fluorescence intensity at 665 nm and 615 nm was read using EnVision, with the ratio = Signal 665 nm / Signal 620 nm * 10 4 The IC of the compound was calculated using Graphpad. 50 The following was calculated. In this experiment, BMS-202, as described in BMS's patent WO2015034820, was selected as the positive drug, and Table 1 is provided for activity data. The value is for IC <0.07μM 50 This represents a range of 0.07 to 1 μM, where B represents 0.07 to 1 μM and C represents > 1 μM. [Table 2] Experimental results demonstrate that the compounds of the present invention exhibit significant inhibitory activity against PD-1 / PD-L1 protein interactions. Among these, compounds IA-9, IB-2, ID-13, ID-14, ID-18, ID-19, ID-21, ID-22, ID-26, ID-27, ID-28, ID-30, and IE-4 exhibit superior inhibitory activity compared to compound BMS-202 described in reference WO2015034820. This indicates that the biphenyl compounds of the present invention can be used as immune checkpoint PD-1 / PD-L1 inhibitors. Example 48: Acute toxicity test of a compound 【0101】 Test samples: Compound ID-18, Compound ID-26, Compound ID-27. Animal species and number: SD rats, 6 individuals per group (half male, half female) Method of administration: Forced oral administration Animal grouping and dosage: Solvent blank group, Compound ID-18 group (500 mg / kg, 1000 mg / kg, 2000 mg / kg), Compound ID-26 (500 mg / kg, 1000 mg / kg, 2000 mg / kg), Compound ID-27 (500 mg / kg, 1000 mg / kg, 2000 mg / kg) Dosage frequency: Single dose Testing process Cage-side observation after drug administration on the day of administration (D1): Observation frequency and duration: Acute toxic reactions in each group of animals were observed cage-side for 4 hours after administration, and detailed clinical observations were performed on animals showing obvious abnormal behavior. Death, onset of symptoms, respiration, secretions, feces, food and drinking water status were observed, and changes in the rats' body weight during the administration period were recorded. Detailed clinical observations included, but were not limited to, behavior, skin, hair, eyes, ears, nose, abdomen, external genitalia, anus, limbs, feet, and respiration. After the observation period, the animals in each group were euthanized, and all animals were dissected and generally observed. Experimental Results: Compounds ID-18, ID-26, and ID-27 were administered to SD rats by single intragastric injection at doses of 500, 1000, and 2000 mg / kg. No animals died or were mortally ill in any group. General observations of the animals in each dose group showed no general changes related to the test substances. Under the conditions of this study, the maximum tolerated dose (MTD) for compounds ID-24, ID-26, and ID-27 was ≥ 2000 mg / kg, respectively. Example 49 Safety test when the compound is administered repeatedly for 14 days. 【0102】 Test samples: Compound ID-18, Compound ID-26, Compound ID-27. Animal species and number: SD rats, 6 individuals per group (half male, half female) Method of administration: Forced oral administration Animal grouping and dosage: Solvent blank group, compound ID-18 group (300 mg / kg), compound ID-26 group (300 mg / kg), compound ID-27 group (300 mg / kg) Dosage frequency: Once daily for 14 days. Testing process After administration, acute toxic reactions were observed cageside for 4 hours, and detailed clinical observations were performed on animals exhibiting obvious abnormal behavior. General clinical observations were conducted twice a day (once in the morning and once in the afternoon) during the study period. Death, onset of illness, respiration, secretions, feces, food and drinking water conditions were observed, and changes in the rats' body weight during the administration period were recorded. Detailed clinical observations included, but were not limited to, behavior, skin, hair, eyes, ears, nose, abdomen, external genitalia, anus, limbs, feet, and respiration. After administration, animals in each group were euthanized, and all animals were dissected and generally observed. Figure 1 shows the weight gain curve of the animals during the administration period. Experimental results: During the 14-day administration cycle of compounds ID-18, ID-26, and ID-27, animals in all dose groups were able to consume water and food normally, exhibited normal activity levels, maintained normal body weight, and showed no apparent abnormalities. Example 50: Study on the pharmacodynamic effects of a 4T1 xenograft tumor model of breast cancer tumor cells. 【0103】 Model creation and dosing plan Animal species and quantity: Balb / c Nude, 6 individuals per group Test samples: Compound ID-24, Compound ID-26, Compound ID-27 Test group: Blank solvent control group. Compound ID-18 (10mg / kg, ig, QD x 21 days) Compound ID-26 (10mg / kg, ig, QD x 21 days) Compound ID-27 (10mg / kg, ig, QD x 21 days) Creation of an animal model: Logarithmic breast cancer tumor cells 4T1 were cultured and harvested in vitro, and 0.1 mL was placed in 2 × 10⁶ cells on the right dorsal side of nude mice. 6 Subcutaneous inoculation was performed using cells / animals, and the tumor volume was 50-70 mm. 3 Once the mice had grown to a certain size, nude mice with tumors were randomly divided into groups. The animals in each group were then administered the drug, with the first administration day defined as the first day of the experiment. Dosage frequency: Once a day Observation of general condition: Time and frequency of observation: Once a day; Indicators or content of observation: Includes, but is not limited to, the local area of ​​administration, outward signs, general behavior, mental state, death, and other abnormal symptoms. Animals were euthanized after the experiment. Tumor volume calculation: V = 1 / 2 × major axis × minor axis 2 (mm 3 ) Experimental results: In the table below, "+" means the tumor inhibition rate is less than 20%, "++" means the tumor inhibition rate is between 20% and 60%, and "+++" means the tumor inhibition rate is greater than 60%. [Table 3] Figure 2 shows the animal tumor growth curves of the compounds of the present invention in a BALB / c mouse 4T1 subcutaneous transplant tumor model. The data above demonstrates that compounds ID-18, ID-26, and ID-27 exhibit significant tumor-inhibiting effects. During the administration cycle, the experimental animals were able to consume water and food normally, performed normal activities, maintained normal body weight, and showed no signs of toxicity. The efficacy and safety of the compounds of the present invention are significantly better than those of BMS-202, indicating that the compounds of the present invention have superior therapeutic benefits and potential application value. Example 51: Preliminary study on a capsule formulation of compound ID-18 【0104】 [Table 4] Capsule manufacturing method: mixture: The weighed compound ID-18, starch, and carboxymethyl starch sodium were added to a wet mixing granulator and mixed. Preparation of binder solution: Purified water was weighed, and an appropriate amount of starch was slowly added while stirring. The mixture was then stirred again to ensure uniform dispersion, obtaining a starch slurry which served as a binder. Manufacturing of soft materials: Using a wet mixing granulator, the stirring speed and shearing speed were controlled, and the starch slurry was slowly added, stirred, and sheared to obtain a soft material. Granulation: The manufactured soft material was granulated using a 24-mesh sieve in a swing granulator to obtain wet particles. Drying: Wet particles were added to a fluidized bed granulator to obtain dry particles. Graining: The dried particles were sized using a sieve in a swing granulator to obtain the sized particles, which were then weighed. mixture: The sizing particles were added to a universal mixer, and after mixing was complete, magnesium stearate was added and mixed one last time to obtain the final mixed particles. filling: The final mixed particles were filled into gelatin hollow capsules using a filling machine, and qualified capsules were selected for packaging. I obtained a sample of a capsule that looked very nice.

Claims

[Claim 1] A compound, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, which is any of the following selected from I-A-9, I-B-2, I-D-13, I-D-14, I-D-18, I-D-19, I-D-21, I-D-22, I-D-26, I-D-27, I-D-28, I-D-30, or I-E-4. 【Chemistry 1】 [Claim 2] The compound according to claim 1, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, wherein the compound is I-D-18, I-D-26, or I-D-27. [Claim 3] The compound, its hydrate, solvate, or pharmaceutically acceptable salt according to claim 1, characterized in that the pharmaceutically acceptable salt is an acid-added salt formed with the compound according to claim 1 and an acid such as hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or ferulic acid. [Claim 4] The following path: 【Chemistry 2】 (Here, R1 represents a methyl group, R3 represents F, and R4 represents H.) R2 is, 【change】 (This indicates...) Then, the step of synthesizing equation I-A, The following route: 【Transformation 3】 (Here, R1 represents a methyl group, R3 represents F, and R4 represents H.) R2 is, 【change】 (This indicates...) Then, the step of synthesizing equation I - B, The following route: The following route: 【Chemistry 4】 (Here, R1 represents a methyl group, Cl, F, or H; R3 represents F, H, or a methyl group; R4 represents H; R2 represents H, 【change】 、 【change】 , or 【change】 (This indicates...) The step of synthesizing equation I-D, or, The following route: 【Transformation 5】 (Here, R1 represents a methyl group, R3 represents a methyl group, and R2 represents, 【change】 Show, R4 represents -O(CH2)pR6, where p represents 3, and R6 represents, 【change】 (This indicates...) A method for producing the compound according to claim 1, comprising the step of synthesizing formula I-E. [Claim 5] A pharmaceutical composition comprising a compound according to any one of claims 1 to 3, a hydrate, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [Claim 6] Use of a compound according to any one of claims 1 to 3, its hydrate, solvate, or pharmaceutically acceptable salt thereof in the manufacture of a PD-1 / PD-L1 inhibitor drug. [Claim 7] Use of a compound according to any one of claims 1 to 3, its hydrate, solvate, or pharmaceutically acceptable salt thereof in the manufacture of an antitumor drug.

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