Novel bicyclic PD-L1 inhibitors, their manufacturing methods and pharmaceutical uses

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] The present invention relates to the field of medicinal chemistry, specifically to biphenyl derivatives with PD-1 / PD-L1 inhibitory activity, methods for preparing them, pharmaceutical compositions containing these compounds, and their use in tumor treatment.

[0002] In recent years, tumor immunotherapy has become a focus of attention in the field of tumor treatment. 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 the body's normal immune tolerance, and preventing the development of autoimmune diseases. Tumors induce immune evasion by overactivating immune checkpoint pathways themselves and by some lymphocytes. Among these immune checkpoints, overactivation of PD-1 / PD-L1 plays an important role in tumor development. Blocking the PD-1 / PD-L1 interaction reactivates the immune system to kill tumor cells and shows 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, multiple mAbs targeting PD-1 / PD-L1 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 of patients achieve a durable response due to the development of inherent 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, large molecule drugs have drawbacks, such as poor tissue penetration, complex manufacturing, high cost, and poor patient compliance. Therefore, the development of small molecule inhibitors is expected to resolve the above-mentioned issues with monoclonal antibodies.

[0004] Compared with monoclonal antibodies, small molecule drugs have the following obvious advantages: 1) They are simple to administer, more suitable for oral administration, and the half-life of the drug can be tailored to avoid serious adverse events associated with immunotherapy. 2) They have excellent membrane permeability, allowing them to be directly exposed to the tumor microenvironment or pass through physiological barriers. 3) They can act directly on intracellular targets that large molecules cannot reach. 4) They are easily available, allowing for more flexible selection of dosage forms and dosages. 5) They have low production costs, do not require refrigeration, and are easy to store and transport.

[0005] Currently, there are no commercially available small molecule inhibitors of PD-1 / PD-L1, so the development of inhibitors that block the PD-1 / PD-L1 protein interaction is of great practical significance and has promising potential applications. Summary of the Invention [Problem to be solved by the invention]

[0006] Objective of the invention: In response to the technical problems in the prior art, the present invention provides pyridoheterocyclic derivatives with PD-1 / PD-L1 inhibitory activity, methods for preparing the same, and pharmaceutical uses thereof as inhibitors of PD-1 / PD-L1 protein-protein interaction.

[0007] Technical Solution: The present invention discloses a pyrido heterocyclic derivative represented by general formula I or a pharmaceutically acceptable salt thereof: [ka] (where, Ar is [ka] , [ka] , or [ka] indicates, L is -(CH2) m -, -O-, -NH-, -CHO-, -CFO-, -CHNH-, -CONH-, -HNCO-, -NHCH-, -OCF-, -OCH-, or -CH=CH-, where m is 0, 1, or 2; X 1 , X 2 each independently represents N or CH, T and V are respectively [ka] , [ka] , -O-, [ka] , and -S-, where R 5 represents H, C1-C6 alkyl, or C3-C7 cycloalkyl, U represents 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, a substituted C1-C6 alkyl, a substituted C3-C7 cycloalkyl, or a substituted C3-C7 heterocycloalkyl, wherein the substituent is H, OH, NH2, COOH, an amide, an ester group, an alkoxy, or an aldehyde group, and may be mono- or polysubstituted, and the heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, and S; R 4 are H, halogens, CN, CF3, OH, NH2, -O(CH2) p R 6 , substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl, or substituted C3-C7 heterocycloalkyl, wherein the substituents are H, OH, NH2, COOH, an amide, an ester group, or an alkoxy, and may be mono- or polysubstituted, wherein p is 1, 2, 3, or 4, and the heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, and S; R 6 is NR 7 R 8 , OR 7 or a substituted C4-C6 azacycloalkyl, where R 7 represents H or C1-C3 alkyl, and R 8 represents a substituted C1-C6 alkyl, the C4-C6 azacycloalkyl being tetrahydropyrrol-1-yl, piperidin-1-ylmorpholin-1-ylpiperazin-1-yl, or azetidin-1-yl, and the substituent is OH, NH2, COOH, an amide, an ester group, or an alkoxy, and may be mono- or polysubstituted.

[0008] where: Ar is preferably [ka] or [ka] indicates, L is -(CH2) m -, -CH2O-, -CF2O-, -CONH-, -NHCO-, or -OCH2-, where m is 0; X 1 and X 2 each independently represents N or CH, T and V are respectively [ka] , -CH2-, -O-, -NH-, or [ka] indicates, U indicates N, n represents 0 or 1; R 1 and R 3 respectively represent H, D, F, Cl, Br, CN, CH3, or CF3, R 2 H, [ka] or [ka] where q represents 0 or 1, and R 9 and R 10 respectively represent H, OH, COOH, CH2COOH, CH2NH2, CH2OH, CH2CH2OH, F, Cl, Br, CH3, and CH2CH3, R 11 represents OH, NH2, NHCH3, CH3, OCH3, OCH2CH3, OCH(CH3)2, R 12 indicates CONH2, NHCOCH3, OH, CH2OH, CH2CH2OH, COOH, COOCH3, COOCH2CH3, COOCH(CH3)2, R 13 represents H, CH3, CH2CH3, CH2OH, CH2CH2OH, R 4is H, F, Cl, Br, CN, CF3, OH, NH2, or -O(CH2) p R 6 where p is 2, 3, or 4; R 6 OH, [ka] , [ka] or [ka] where R 9 , R 10 , R 11 , R 12 , and R 13 is defined as above, and R 14 represents CH3, CH2CH3, CH2CH2OH, formyl, or acetyl, and R 15 and R 16 respectively represent H, OH, COOH, NH2, CH3, CH2CH3, CH2OH, CH2CH2OH, CONH2, cyclopropyl, COOCH3, COOCH2CH3 or COOCH(CH3)2; W represents -CH2-, -O-, -NH-, [ka] , or [ka] and r represents 0 or 1.

[0009] Here, more preferably, Ar is [ka] indicates, L represents -CHO- and -NHCO-; X 1 represents CH or N, and X 2 indicates CH, T is [ka] or -CH2-, U indicates N, V represents -CH2-, n is 0 or 1.

[0010] R 1 , and R 3 respectively represent F, Cl, Br, CN, CH3, or CF3. R 2 H, [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , or [ka] Shows.

[0011] R 4 is H, F, Cl, CN, CF3, OH, NH2, or -O(CH2)3R6 where R 6 is OH, CONH2, CH2OH, COOH, COOCH3, COOCH2CH3, or [ka] Shows.

[0012] More preferably, the compound is any 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 pharmaceutically acceptable salts are acid addition salts formed between a compound of general formula I and an acid selected from the group consisting of 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, and ferulic acid.

[0014] 1. Use of a compound containing a pyrido heterocycle or a pharmaceutically acceptable salt thereof in the manufacture of a PD-L1 inhibitor medicament for treating tumors.

[0015] The compounds (I) of the present invention are divided into types such as IA, IB, IC, ID, IE, and IF, and their synthesis methods are respectively described as follows.

[0016] Ar is [ka] indicates an X 1 and X 2 are each independently CH, and L is -(CH2) m -, m is 0, T is C=O, U is N, V ​​is CH2, and n is 0, the synthetic route for formula IA is as follows: [ka] (where R 1 , R 2 , R 3 , and R 4 The definition of is as above.)

[0017] Compound IV is prepared by 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 mixture of any two solvents, preferably a mixture 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)Cl), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh)), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh)Cl), tris(dibenzylideneacetone)dipalladium(0) (Pd(dba)), or palladium acetate (Pd(OAc)), preferably Pd(PPh). The reaction temperature is selected from 50 to 120°C, preferably 60 to 100°C.

[0018] Compound V is produced by the Sandmeyer reaction of compound IV. The diazotization 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 solvents, preferably a mixed solvent of methanol and water. The reaction temperature is selected from -25 to 80°C, preferably 0 to 25°C.

[0019] Compound VI is used to prepare Compound VII. The acid binder used is selected from triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium methanolate, 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 mixture of any two of these, preferably tetrahydrofuran or DMF.

[0020] Compound IA is produced by Suzuki reaction of Compound VII with 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 mixture of any two of these solvents, preferably a mixture 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] indicates an X 1 indicates N, and X 2 represents CH, and L represents -(CH2) m -, m is 0, T is CH2, U is N, V ​​is CH2, and n is 1, the synthetic route for formula IB is as follows: [ka] (where R 1 , R 2 , R 3 , and R 4 The definition of is as 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 methanolate, 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 mixture of any two of these, preferably tetrahydrofuran or DMF.

[0023] Compound IB is produced by 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] indicates an X 1 indicates N, and X 2 represents CH, and L represents -(CH2)m When U represents -, m is 0, T is CH2, U represents N, V ​​represents CH2, and n = 1, the synthetic route to formula IC is as follows: [ka] (where R 1 , R 2 , R 3 , and R 4 The definition of is as above.)

[0025] Compound X is reacted with SOCl2 in methanol to produce XI. The reaction temperature is selected from the range of 50 to 120°C, preferably 60 to 100°C.

[0026] Compound XI is reduced to prepare compound XII. The solvent used is selected from tetrahydrofuran, ethanol, DMF, or 1,4-dioxane, and is preferably methanol. The reducing agent used is selected from lithium aluminum tetrahydride, sodium borohydride, or potassium borohydride, and is preferably lithium aluminum tetrahydride.

[0027] Compound XIV is produced by 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 mixture of any two of these solvents, preferably a mixture 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 IX is reacted with compound XIV to produce compound IC. 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 ligand used is triphenylphosphine, 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-BuXPhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantph 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] indicates an X 1 indicates N, and X 2 represents CH, L represents -CH2O-, T is CH2, U represents N, V ​​represents CH2, and n is 1, the synthetic route for formula ID is as follows: [ka] (where R 1 , R 2 , R 3 , and R 4 The definition of is as above.)

[0030] Compound XV is produced by Suzuki reaction of compound XII with 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 mixture of any two of these solvents, preferably a mixture 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 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. 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] indicates an X 1 indicates N, and X 2represents CH, L represents -CH2O-, T represents CH2, U represents N, V ​​represents NCH3, and n is 1, the synthetic route for formula IE is as follows: [ka] (where R 1 , R 2 , R 3 , and R 4 The definition of is as above.)

[0033] Compound XVII is prepared from compound XVI and methyl iodide under alkaline conditions. The solvent used is selected from acetone, DMF, acetonitrile, tetrahydrofuran, or a mixture of the above solvents, preferably DMF, and 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 XVII is subjected to a reductive amination reaction with an amine compound to produce the target compound XVIII. The solvent used is selected from toluene, DMF, dichloromethane, dichloroethane, chloroform, methanol, 1,4-dioxane, tetrahydrofuran, ethanol, acetonitrile, acetone, or a mixture of the above solvents, preferably a mixture 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 mixture of the above solvents, preferably ethyl acetate. The acid used is selected from saturated ethyl acetate hydrogen chloride solution, saturated 1,4-dioxane hydrogen chloride solution, hydrochloric acid, trifluoroacetic acid, or trifluoromethanesulfonic acid, preferably saturated ethyl acetate hydrogen chloride solution.

[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 mixture of the above solvents, preferably methanol. The alkali used is selected from triethylamine, dimethylaminopyridine (DMAP), or N,N-diisopropylethylamine, preferably triethylamine.

[0037] Compound XX is reacted with compound XV to produce compound IE. 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. 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] indicates an X 1 indicates N, and X 2 represents CH, L represents -NHCO-, T represents CH2, U represents N, V ​​represents CH2, and n is 1, the synthetic route for formula IF is as follows: [ka] (where R 1 , R 2 , R 3 , and R 4 The definition of is as above.)

[0039] Compound XXI is prepared from compound VIII and di-tert-butyl dicarbonate under alkaline conditions. The solvent used is selected from acetone, dichloromethane, DMF, acetonitrile, tetrahydrofuran, or a mixture of the above solvents, preferably tetrahydrofuran, and 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 hydrogen carbonate, or lithium hydroxide, preferably triethylamine.

[0040] Compound XXII is produced using compound XXI. The solvent used is selected from acetone, dichloromethane, DMF, acetonitrile, tetrahydrofuran, or a mixed solvent 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 XXII is hydrolyzed under alkaline conditions to produce compound XXIII. The solvent used is selected from methanol, ethanol, water, acetonitrile, tetrahydrofuran, acetone, dichloromethane, DMF, acetonitrile, or a mixed solvent 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 IV and XXIII are reacted to produce compound XXIV. 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 (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (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 of the above solvents, preferably DMF; and 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 mixture of the above solvents, preferably ethyl acetate, and the acid used is selected from saturated ethyl acetate hydrogen chloride solution, saturated 1,4-dioxane hydrogen chloride solution, hydrochloric acid, trifluoroacetic acid, or trifluoromethanesulfonic acid, preferably saturated ethyl acetate hydrogen chloride solution.

[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, and the solvent used is selected from dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, ethyl acetate, DMF, or a mixed solvent of any two thereof, preferably tetrahydrofuran or DMF.

[0045] The present invention also discloses a pharmaceutical composition comprising the compound of general formula (I) (including chiral isomers) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The compound may be added to a pharmaceutically acceptable carrier to prepare a common pharmaceutical preparation, such as a tablet, capsule, syrup, suspension, or injection, and common pharmaceutical auxiliary materials such as flavorings, sweeteners, liquid or solid fillers, or diluents may also be added.

[0046] The use of the compound of general formula (I) of the present invention and its hydrate, solvate or crystal in the manufacture of a drug for inhibiting PD-1 / PD-L1 protein-protein interaction is also within the scope of protection of the present invention.

[0047] Furthermore, the PD-1 / PD-L1 protein-protein interaction inhibitors herein can be used in the manufacture of a medicament for treating cancer or tumors, for example, treating cancers such as non-small cell lung cancer, colon cancer, melanoma, breast cancer, liver cancer, etc.

[0048] Pharmacological experiments have shown that the pyridoheterocyclic derivatives of the present invention can produce excellent inhibitory effects on PD-1 / PD-L1 interaction in homogeneous time-resolved fluorescence (HTRF) experiments. Because the pyridoheterocyclic derivatives of the present invention have excellent activity, the development of biphenyl inhibitors of PD-1 / PD-L1 is expected to be of great practical significance and potential application. [Effects of the Invention]

[0049] Beneficial Effects: Compared with the prior art, the present invention has the following obvious advantages:

[0050] (1) The novel pyridoheterocyclic derivatives of the present invention can significantly inhibit the PD-1 / PD-L1 interaction, and their activity is superior to that of the known PD-1 / PD-L1 inhibitor BMS-202.

[0051] (2) The synthetic route of the pyridoheterocyclic derivatives of the present invention is uniquely designed, simple and easy to implement, the raw materials are inexpensive and readily available, and the synthetic process is safe, environmentally friendly, and easy to scale up.

[0052] (3) It has a wide range of applications, and as an active ingredient, it can be used as a drug to treat various cancers and tumors related to the immune checkpoint PD-1 / PD-L1. [Brief explanation of the drawings]

[0053] [Figure 1] 1 shows the weight gain curve of rats in a sustained administration toxicity test of the compound of the present invention. [Figure 2] 1 shows the animal tumor growth curves of the compounds of the present invention in a BALB / c mouse 4T1 subcutaneously transplanted tumor model. DETAILED DESCRIPTION OF THE INVENTION

[0054] Example 1 2-(5-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-1-oxoisoindolin-2-yl)ethyl acetate (IA-1:R 1 =CH3, [ka] , R 3 =F, R 4 =H, T represents C=O) 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 added sequentially to a three-neck flask. Potassium carbonate (5.21 g, 37.69 mmol) dissolved in water (2.5 mL) was added to the reaction mixture, and Pd(PPh3)4 (0.39 g, 0.34 mmol) was added. The mixture was heated to 80 °C under nitrogen protection for 10 h. Upon completion of the reaction as monitored by TLC, heating was discontinued and the mixture was cooled to room temperature. The palladium catalyst and insoluble materials were removed by suction filtration, diluted with water (25 mL), and extracted with ethyl acetate (25 mL × 3). The combined organic phases were washed with saturated aqueous NaCl (25 mL × 3) and dried over anhydrous magnesium sulfate. The mixture was filtered under suction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 15:1) to obtain 2.59 g of a yellow solid powder (yield 95.6%). MP: 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), and a solution of hydrochloric acid (9.92 mL, 3 mmol / mL) was slowly added dropwise. The reaction mixture was stirred at 25 °C until the mixture became clear. The temperature was then lowered to 0 °C, and an aqueous solution of NaNO (4.96 mL, 2.2 mmol / mL) was slowly added dropwise. After the addition was completed, the mixture was stirred at 0 °C for 30 minutes. Then, a solution of bis(pinacolato)diboron (7.56 g, 29.85 mmol) in methanol (20 mL) was slowly added dropwise to the reaction mixture, generating a large amount of gas. After the addition was completed, the mixture was returned to room temperature and stirred for 2 hours. TLC (petroleum ether:ethyl acetate = 30:1) showed that the starting materials had completely reacted. The mixture was extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 2), and dried over anhydrous sodium sulfate. The mixture was filtered with suction, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 200:1) to obtain 1.88 g of a yellow solid powder (60.4% yield). The mp was 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)isoindol-1-one (VII) Compound 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-neck 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 reacted for 12 h. Upon completion of the reaction, as monitored by TLC (petroleum ether:ethyl acetate = 4:1), heating was discontinued and the mixture was cooled to room temperature. The palladium catalyst and insoluble materials were removed by suction filtration, diluted with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated aqueous NaCl (10 mL x 3), and dried over anhydrous magnesium sulfate. The mixture was filtered under suction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 15:1 to 3:1) to obtain 0.40 g of a 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-oxoisoindolin-2-yl)ethyl acetate (IA-1) Compound VII (0.50 g, 1.58 mmol) was placed in a 25 mL eggplant-shaped flask and dissolved in THF. NaH (0.12 g, 3.16 mmol) was added at 0 °C. Ethyl bromoacetate (0.32 g, 1.89 mmol) was added dropwise to the mixture and the reaction was allowed to proceed at room temperature. After monitoring, the starting materials were completely reacted, and saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with EA (10 mL x 3), washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and purified by column chromatography to give 0.63 g of a white solid (98.7% yield). mp 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 (IA-2:R 1 =CH3, [ka] , R 3 =F, R 4 =H, T represents C=O) Compound VII (0.50 g, 1.58 mmol) and 3-bromoethylpropionate (0.34 g, 1.89 mmol) were used as starting materials, and 0.40 g of a colorless viscous liquid was obtained (yield 60.6%) in the same manner as in the preparation of compound IA-1. 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 (IA-3:R 1 =CH3, [ka] , R 3 =F, R 4 =H, T represents C=O) Compound VII (0.50 g, 1.58 mmol) and 2-bromoethyl propionate (0.34 g, 1.89 mmol) were used as starting materials, and 0.58 g of a white solid (88.3% yield) was obtained in the same manner as for compound IA-1. The reaction temperature was 50-52°C. 1 H 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-oxoisoindolin-2-yl)acetic acid (IA-4:R 1 =CH3, [ka] , R 3 =F, R 4 =H, T represents C=O) Compound IA-1 (30 mg, 0.16 mmol) was placed in a 10 mL eggplant-shaped flask and dissolved in methanol (2 mL). A solution of LiOH (8 mg, 0.20 mmol) in water (0.5 mL) was added and stirred at room temperature for 4 hours. After TLC showed the reaction was complete, the methanol was removed under reduced pressure, and the pH was adjusted to 5-6 with 2 M HCl solution. A white solid precipitated and was filtered with suction to obtain 20 mg of off-white solid product (72.1% yield). 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 for C 23 H 19 FNO3: 376.1349; Found: 376.1350. Example 5

[0058] 3-(5-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-1-oxoisoindolin-2-yl)propionic acid (IA-5:R 1 =CH3, [ka] , R 3 =F, R 4 =H, T represents C=O) Compound IA-2 (50 mg, 0.12 mmol) and a solution of LiOH (10 mg, 0.24 mmol) in water (0.5 mL) were used as starting materials, and the procedure was repeated to obtain compound IA-4, yielding 40 mg of a yellow solid product (92.2% yield). The reaction temperature was 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-oxoisoindolin-2-yl)propionic acid (IA-6:R 1 =CH3, [ka] , R 3=F, R 4 =H, T represents C=O) Compound IA-3 (50 mg, 0.12 mmol) and a solution of LiOH (10 mg, 0.24 mmol) in water (0.5 mL) were used as starting materials, and the procedure was repeated to obtain compound IA-4, yielding 30 mg of a white solid product (64.2% yield). The reaction temperature was 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)isoindol-1-one (IA-7:R 1 =CH3, [ka] , R 3 =F, R 4 =H, T represents C=O) Compound IA-1 (60 mg, 0.12 mmol) was placed in a 25 mL eggplant-shaped flask and dissolved in THF. Lithium aluminum hydride (8 mg, 0.24 mmol) was slowly added at 0 °C. After monitoring, the starting materials were completely reacted. Saturated ammonium chloride solution was added to quench the reaction, precipitating a white solid. The white solid was removed by suction filtration and washed with EA. The filtrate was concentrated, separated, and purified to give 24 mg of a yellow solid (56.8% yield). The reaction temperature was 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-oxoisoindolin-2-yl)acetamide (IA-8:R 1 =CH3, [ka] , R 3 =F, R 4 =H, T represents C=O) Compound IA-2 (100 mg, 0.27 mmol) was added to a 25 mL three-neck flask and dissolved in THF. A small amount of DMF was added dropwise, followed by the slow addition of thionyl chloride (95 mg, 0.78 mmol). The temperature was raised to 55 °C and the reaction was continued. After monitoring, the starting materials were completely reacted, the temperature was returned to room temperature, and the reaction mixture was transferred to -20 °C. Ammonia water was slowly added dropwise to adjust the pH to 8. After monitoring, the starting materials were completely reacted and a new spot was 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, and purified by column chromatography to obtain 42 mg of a light brown solid (42.0% yield). 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)oxoisoindolin-2-yl)ethan-1-ol (IA-9:R 1 =CH3, [ka] , R 3 =F, R 4 =H, T represents CH2) Compound IA-7 (30 mg, 0.08 mmol) was placed in a 25 mL eggplant-shaped flask and dissolved in THF. 1 M borane-tetrahydrofuran complex (0.46 mL, 0.48 mmol) was slowly added at 0 °C. After the dropwise addition, the mixture was refluxed at 68 °C for 3 h. After monitoring, the starting materials were completely reacted. A saturated ammonium chloride solution was added to quench the reaction, precipitating a white solid. The white solid was removed by suction filtration and washed with EA. The filtrate was concentrated, separated, and purified to give 14 mg of a brown solid (48.5% yield). The reaction temperature was 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-naphthyridin-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-naphthyridin-6(5H)-yl)ethyl acetate (IX-1) 2-Chloro-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride VIII (0.50 g, 2.43 mmol) was placed in a 25 mL eggplant-shaped flask and dissolved in THF. NaH (0.20 g, 4.86 mmol) was added at 0 °C, and ethyl bromoacetate (0.49 g, 2.93 mmol) was added dropwise to the reaction mixture. The mixture was allowed to react at room temperature. After TLC showed complete reaction, saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL x 3), washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and filtered under reduced pressure. The solvent was removed under reduced pressure. The residue was purified by column chromatography to give 0.60 g of a light brown solid (97.2% yield). 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-naphthyridin-6(5H)-yl)ethyl acetate (IB-1) Compound 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-neck flask. Potassium carbonate (0.37 g, 2.75 mmol) dissolved in water (0.5 mL) 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 for 12 h. Upon completion of the reaction, as monitored by TLC (petroleum ether:ethyl acetate = 8:1), heating was stopped and the mixture was cooled to room temperature. The palladium catalyst and insoluble materials were removed by suction filtration. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 3), and dried over anhydrous magnesium sulfate. The mixture was filtered under suction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 10:1) to give 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-naphthyridin-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 placed in a 10 mL eggplant-shaped flask and dissolved in ethanol (2 mL). A solution of LiOH (17 mg, 0.40 mmol) in water (0.3 mL) was added and stirred at room temperature for 4 hours. After TLC showed the reaction was complete, the ethanol was removed under reduced pressure, and the pH was adjusted to 5-6 with 2 M HCl solution. A white solid precipitated, which was suction filtered and baked to give 7 mg of a yellow solid product (9.4% yield). The reaction temperature was 188-190°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-naphthyridin-6(5H)-yl)ethan-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 placed in a 25 mL eggplant-shaped flask and dissolved in 3 mL of THF. Lithium aluminum hydride (19 mg, 0.50 mmol) was slowly added at 0 °C. After monitoring, the starting materials were completely reacted. Saturated ammonium chloride solution was added to quench the reaction, precipitating a white solid. The white solid was removed by suction filtration and washed with EA. The filtrate was concentrated, separated, and purified to give 50 mg of a yellow solid (27.9% yield). The reaction temperature was 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-naphthyridin-6(5H)-yl)ethyl acetate (IC-1:R 1 =CH3, [ka] ) synthesis Synthesis of methyl 3-bromo-2-methylbenzoate (XI-1) A 50 mL eggplant-shaped flask was charged with 3-bromo-2-methylbenzoic acid X-1 (0.30 g, 1.40 mmol) and 5 mL of methanol. Thionyl chloride (0.20 mL, 2.79 mmol) was slowly added dropwise in an ice bath. After the addition was complete, the mixture was heated to 70 °C and refluxed for 1 hour. TLC (petroleum ether:ethyl acetate = 8:1) showed that the starting materials had reacted completely. The mixture was concentrated under reduced pressure to give 0.32 g of a white solid powder (99.0% yield). The mp was 31.0-33.0 °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-neck flask. Under N2 protection, the temperature was lowered to 0 °C, and LiAlH4 (3.10 g, 55.30 mmol) was slowly added batchwise. After the addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 30 min. TLC (petroleum ether:ethyl acetate = 8:1) showed that the starting materials were completely reacted. Saturated NH4Cl solution was slowly added dropwise until no more bubbles were generated. The mixture was then diluted with ethyl acetate (100 mL). The insoluble material was removed by suction filtration. The organic phase was washed with water (50 mL x 2) and saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, suction filtered, and the solvent was removed under reduced pressure to give 9.22 g of a white solid powder (98.9% yield). The mp was 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-boronic acid XIII-1 (537 mg, 2.98 mmol), and 1,4-dioxane (10 mL) were added sequentially to a three-neck flask. Potassium carbonate (962 mg, 6.96 mmol) dissolved in water (1 mL) was added to the reaction mixture. Under nitrogen protection, Pd(PPh3)4 (144 mg, 0.15 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. Upon completion of the reaction, monitored by TLC (petroleum ether:ethyl acetate = 8:1), heating was stopped and the mixture was cooled to room temperature. The palladium catalyst and insoluble materials were removed by suction filtration, diluted with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 3), and dried over anhydrous magnesium sulfate. After suction filtration, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate=20:1 to 15:1) to obtain 440 mg of a pale brown oil (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. O.C. 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-naphthyridin-6(5H)-yl)ethyl acetate (IC-1) Compound 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 added sequentially to a three-neck flask. Cesium carbonate (307 mg, 0.94 mmol) was added to the reaction mixture. Under nitrogen protection, Pd(OAc)2 (11 mg, 0.05 mmol) was added, and the mixture was heated to 80 °C under nitrogen protection for 12 h. Upon completion of the reaction, monitored by TLC (petroleum ether:ethyl acetate = 4:1), heating was stopped and the mixture was cooled to room temperature. The palladium catalyst and insoluble materials were removed by suction filtration. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated aqueous NaCl (10 mL x 3), and dried over anhydrous magnesium sulfate. The drying agent was removed by suction filtration, the solvent was distilled off under reduced pressure, and the residue 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-naphthyridin-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-neck flask. Potassium carbonate (3.85 g, 27.85 mmol) dissolved in water (4.5 mL) was added to the reaction mixture. Under nitrogen protection, Pd(PPh3)4 (0.57 g, 0.50 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. Upon completion of the reaction, monitored by TLC (petroleum ether:ethyl acetate = 8:1), heating was discontinued and the mixture was cooled to room temperature. The palladium catalyst and insoluble materials were removed by suction filtration, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 3), and dried over anhydrous magnesium sulfate. The mixture was filtered under suction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 15:1) to give 2.05 g (95.3% yield) of a colorless oily liquid. 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-naphthyridin-6(5H)-yl)ethyl acetate (ID-1) Compound IX-1 (0.17 g, 0.67 mmol), XV-1 (0.17 g, 0.80 mmol), t-BuXphos (0.06 g, 0.13 mmol), and toluene (5 mL) were added sequentially to a three-neck flask. Cesium carbonate (0.43 g, 1.33 mmol) was added to the reaction mixture. Under nitrogen protection, Pd(OAc)2 (0.01 g, 0.07 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. Upon completion of the reaction, monitored by TLC (petroleum ether:ethyl acetate = 4:1), heating was stopped and the mixture was cooled to room temperature. The palladium catalyst and insoluble materials were removed by suction filtration. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 3), and dried over anhydrous magnesium sulfate. The mixture was filtered under suction, the solvent was distilled off 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-naphthyridin-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) Compound XII-1 (2.00 g, 9.95 mmol) and III-2 (2.03 g, 14.92 mmol) were used as starting materials, and the same procedure as for compound XV-1 was used to obtain 2.00 g of a white solid (yield 94.7%). The reaction temperature was 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-naphthyridin-6(5H)-yl)ethyl acetate (ID-2) Compounds IX-1 (120 mg, 0.47 mmol) and XV-2 (120 mg, 0.57 mmol) were used as starting materials, and the same procedure as for ID-1 was carried out to obtain 67 mg of a yellow viscous liquid (yield 32.9%). 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-naphthyridin-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) Compound XII-1 (500 mg, 2.49 mmol) and III-3 (580 mg, 3.73 mmol) were used as starting materials, and the same procedure as for compound XV-1 was used to obtain 500 mg of a white solid (yield 86.4%). The reaction temperature was 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-naphthyridin-6(5H)-yl)ethyl acetate (ID-3) Compound IX-1 (170 mg, 0.73 mmol) and XV-3 (136 mg, 0.88 mmol) were used as starting materials, and the same procedure as for compound ID-1 was carried out to obtain 150 mg of a yellow viscous liquid (yield 51.8%). 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-naphthyridin-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) Compound XII-1 (500 mg, 2.49 mmol) and III-4 (470 mg, 2.98 mmol) were used as starting materials, and the same procedure as for compound XV-1 was used to obtain 320 mg of a white solid (yield 64.9%). The reaction temperature was 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-naphthyridin-6(5H)-yl)ethyl acetate (ID-4) Compound IX-1 (150 mg, 0.59 mmol) and XV-4 (140 mg, 0.71 mmol) were used as starting materials, and 115 mg of a colorless viscous liquid (yield 46.9%) was obtained in the same manner as for 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-naphthyridin-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 starting materials, 5.29 g of a light brown oil was obtained (yield 99.88%) 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 reduced with LiAlH (0.80 g, 21.20 mmol) in the same manner as for compound XII-1, to give 4.60 g of a white solid powder (97.9% yield). mp 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) Compound XV-2 (0.50 g, 2.26 mmol) and III-1 (0.38 g, 2.71 mmol) were used as starting materials, and 0.32 g of a light brown solid (yield 59.9%) was obtained in the same manner as for compound XV-1. The reaction temperature was 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-naphthyridin-6(5H)-yl)ethyl acetate (ID-5) Compound IX-1 (150 g, 0.59 mmol) and XV-5 (170 mg, 0.71 mmol) were used as starting materials, and 116 mg of a colorless viscous liquid (yield 43.3%) was obtained in the same manner as for 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-naphthyridin-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) Compound XII-2 (0.50 g, 2.26 mmol) and III-2 (0.37 g, 2.71 mmol) were used as starting materials, and 0.32 g of a light brown solid (59.9% yield) was obtained in the same manner as for compound XV-1. The reaction temperature was 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-naphthyridin-6(5H)-yl)ethyl acetate (ID-6) Compound IX-1 (150 mg, 0.59 mmol) and XV-6 (165 mg, 0.71 mmol) were used as starting materials, and 117 mg of a colorless viscous liquid (yield 44.0%) was obtained in the same manner as for 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-naphthyridin-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) Compound XII-2 (0.50 g, 2.26 mmol) and III-3 (0.42 g, 2.71 mmol) were used as starting materials, and 0.31 g of a pale brown oil was obtained (yield 54.2%) in the same manner as in the preparation of 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-naphthyridin-6(5H)-yl)ethyl acetate (ID-7) Compound IX-1 (150 mg, 0.59 mmol) and XV-7 (165 mg, 0.71 mmol) were used as starting materials, and 130 mg of a colorless viscous liquid (yield 46.8%) was obtained in the same manner as for 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-naphthyridin-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) Compound XII-2 (0.50 g, 2.26 mmol) and III-4 (0.41 g, 2.71 mmol) were used as starting materials, and 0.41 g of a pale yellow solid (yield 83.1%) was obtained in the same manner as for compound XV-1. The reaction temperature was 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-naphthyridin-6(5H)-yl)ethyl acetate (ID-8) Compound IX-1 (150 mg, 0.59 mmol) and XV-8 (155 mg, 0.71 mmol) were used as starting materials, and 187 mg of a colorless viscous liquid was obtained (yield 72.7%) in the same manner as for 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-naphthyridin-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) 3-Bromo-2-chlorophenylboronic acid X-3 (5.00 g, 21.23 mmol) and thionyl chloride (3.10 mL, 42.47 mmol) were used as starting materials, and the procedure for preparing compound XI-1 was repeated to obtain 5.30 g of a pale yellow solid (99.6% yield). The reaction temperature was 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 reduced with LiAlH (0.86 g, 22.74 mmol) in the same manner as for compound XII-1, to give 4.30 g of a pale yellow solid (92.2% yield). The reaction temperature was 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) Compound XII-3 (0.50 g, 2.44 mmol) and III-1 (0.41 g, 2.93 mmol) were used as starting materials, and 0.37 g of a white solid (yield 68.9%) was obtained in the same manner as for compound XV-1. The reaction temperature was 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-naphthyridin-6(5H)-yl)ethyl acetate (ID-9) Compound IX-1 (150 mg, 0.59 mmol) and XV-9 (156 mg, 0.71 mmol) were used as starting materials, and 100 mg of a colorless viscous liquid (yield 38.7%) was obtained in the same manner as for 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-naphthyridin-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) Compound XII-3 (0.50 g, 2.44 mmol) and III-2 (0.40 g, 2.93 mmol) were used as starting materials, and the same procedure as for compound XV-1 was carried out to obtain 0.34 g of a colorless oil (yield 63.7%). 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-naphthyridin-6(5H)-yl)ethyl acetate (ID-10) Compound IX-1 (150 mg, 0.59 mmol) and XV-10 (153 mg, 0.71 mmol) were used as starting materials, and 130 mg of a colorless viscous liquid (yield 50.8%) was obtained in the same manner as for 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-naphthyridin-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) Compounds XII-3 (0.50 g, 2.44 mmol) and III-3 (0.46 g, 2.93 mmol) were used as starting materials, and 0.34 g of a colorless oil (58.9% yield) was obtained in the same manner as for compound XV-1. The reaction temperature was 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-naphthyridin-6(5H)-yl)ethyl acetate (ID-11) Compound IX-1 (150 mg, 0.59 mmol) and XV-11 (167 mg, 0.71 mmol) were used as starting materials, and 104 mg of a colorless viscous liquid (yield 38.8%) was obtained in the same manner as for 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-naphthyridin-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) Compound XII-3 (0.50 g, 2.44 mmol) and III-4 (0.45 g, 2.93 mmol) were used as starting materials, and 0.37 g of a white solid (75.1% yield) was obtained in the same manner as for compound XV-1. The reaction temperature was 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-naphthyridin-6(5H)-yl)ethyl acetate (ID-12) Compound IX-1 (150 mg, 0.59 mmol) and XV-12 (143 mg, 0.71 mmol) were used as starting materials, and 149 mg of a colorless viscous liquid was obtained (yield 60.2%) in the same manner as for 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-naphthyridin-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 placed in a 10 mL eggplant-shaped flask and dissolved in ethanol (2 mL). A solution of NaOH (11 mg, 0.28 mmol) in water (0.3 mL) was added and stirred at room temperature for 4 hours. After TLC showed the reaction was complete, the ethanol was removed under reduced pressure, and the pH was adjusted to 5-6 with 2 M HCl solution. A white solid precipitated and was filtered with suction to obtain 30 mg of the white solid product (53.5% yield). The reaction temperature was 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-naphthyridin-6(5H)-yl)ethan-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 placed in a 25 mL eggplant-shaped flask and dissolved in THF. Lithium aluminum hydride (14 mg, 0.37 mmol) was slowly added at 0 °C. After monitoring, the starting materials were completely reacted. Saturated ammonium chloride solution was added to quench the reaction, precipitating a white solid. The white solid was removed by suction filtration and washed with EA. The filtrate was concentrated, separated, and purified to give 34 mg of a yellow solid (41.5% yield). The reaction temperature was 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-naphthyridin-6(5H)-yl)ethan-1-ol (ID-15:R 1 =CH3, [ka] , R 3 =CH3, R 4 Synthesis of =H) Compound ID-2 (100 mg, 0.23 mmol) and LiAlH (18 mg, 0.47 mmol) were used as starting materials, and the procedure for compound ID-13 was repeated to obtain 34 mg of a yellow solid (41.5% yield). The mp was 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-naphthyridin-6(5H)-yl)ethan-1-ol (ID-16:R 1 =CH3, [ka] , R 3 =Cl, R 4 Synthesis of =H) Compound ID-3 (150 mg, 0.37 mmol) and LiAlH (24 mg, 0.73 mmol) were used as starting materials, and the procedure for compound ID-13 was repeated to obtain 100 mg of a yellow solid (yield 66.6%). The reaction temperature was 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-naphthyridin-6(5H)-yl)ethan-1-ol (ID-17:R 1 =CH3, [ka] , R 3 =H, R 4 Synthesis of =H) Compound ID-4 (100 mg, 0.26 mmol) and LiAlH (20 mg, 0.53 mmol) were used as starting materials, and the procedure for compound ID-12 was repeated to obtain 55 mg of a yellow solid (yield: 55.6%). The mp was 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-naphthyridin-6(5H)-yl)ethan-1-ol (ID-18:R 1 =Cl, [ka] , R 3 =F, R 4 Synthesis of =H) Compound ID-5 (106 mg, 0.23 mmol) and LiAlH (18 mg, 0.47 mmol) were used as starting materials, and the procedure for compound ID-13 was repeated to obtain 76 mg of a yellow solid (79.0% yield). The reaction temperature was 116-118°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-naphthyridin-6(5H)-yl)ethan-1-ol (ID-19:R 1 =Cl, [ka] , R 3 =CH3, R 4 Synthesis of =H) Compound ID-6 (60 mg, 0.13 mmol) and LiAlH (10 mg, 0.27 mmol) were used as starting materials, and the procedure for compound ID-13 was repeated to obtain 30 mg of a white solid (yield 55.2%). The reaction temperature was 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-naphthyridin-6(5H)-yl)ethan-1-ol (ID-20:R 1 =Cl, [ka] , R 3 =Cl, R 4 Synthesis of =H) Compound ID-7 (120 mg, 0.26 mmol) and LiAlH (19 mg, 0.51 mmol) were used as starting materials, and the procedure for obtaining compound ID-13 was repeated to obtain 64 mg of a yellow solid (yield: 58.5%). The reaction temperature was 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-naphthyridin-6(5H)-yl)ethan-1-ol (ID-21:R 1 =Cl, [ka] , R 3 =H, R 4 Synthesis of =H) Compound ID-8 (187 mg, 0.43 mmol) and LiAlH (27 mg, 0.46 mmol) were used as starting materials, and the procedure for compound ID-13 was repeated to obtain 80 mg of a white solid (47.3% yield). The reaction temperature was 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-naphthyridin-6(5H)-yl)ethan-1-ol (ID-22:R 1 =F, [ka] , R 3 =F, R 4 Synthesis of =H) Compound ID-9 (100 mg, 0.23 mmol) and LiAlH (17 mg, 0.46 mmol) were used as starting materials, and the procedure for compound ID-13 was repeated to obtain 60 mg of a brown solid (yield 66.4%). The reaction temperature was 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-naphthyridin-6(5H)-yl)ethan-1-ol (ID-23:R 1 =F, [ka] , R 3 =CH3, R 4 Synthesis of =H) Compound ID-10 (130 mg, 0.30 mmol) and LiAlH (23 mg, 0.59 mmol) were used as starting materials, and 90 mg of a nearly white solid was obtained (76.7% yield) in the same manner as for 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-naphthyridin-6(5H)-yl)ethan-1-ol (ID-24:R 1 =F, [ka] , R 3 =Cl, R 4 Synthesis of =H) Compound ID-11 (104 mg, 0.23 mmol) and LiAlH (17 mg, 0.46 mmol) were used as starting materials, and the procedure for obtaining compound ID-13 was repeated to obtain 60 mg of a pale yellow solid (74.0% yield). 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-naphthyridin-6(5H)-yl)ethan-1-ol (ID-25:R 1 =F, [ka] , R 3 =H, R 4 Synthesis of =H) Compound ID-11 (149 mg, 0.35 mmol) and LiAlH (17 mg, 0.46 mmol) were used as starting materials, and 70 mg of a nearly white solid was obtained (yield 52.3%) in the same manner as for 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-naphthyridin-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 placed in a 10 mL eggplant-shaped flask and dissolved in ethanol (3 mL). A solution of NaOH (69 mg, 1.76 mmol) in water (0.2 mL) was added and stirred at room temperature for 4 hours. After TLC showed the reaction was complete, the ethanol was removed under reduced pressure, and the pH was adjusted to 5-6 with 2 M HCl solution. A white solid precipitated and was filtered off with suction to obtain 262 mg (69.8% yield) of the white solid product. The reaction temperature was 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). In 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]pyrimidin-3(2H)-yl)methyl acetate (IE-1:R 1 =CH3, [ka] , R 3 =CH3, R 4 Synthesis of =H) Synthesis of tert-butyl (6-chloro-3-formylpyridin-2-yl)(methyl)carbamate (XVII) Compound XVI (100 mg, 0.39 mmol) was added to a 25 mL eggplant-shaped flask and dissolved in DMF (10 mL). CHCl (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 batchwise. After the addition was complete, the mixture was stirred in an ice bath for an additional 30 min and then allowed to react at room temperature overnight. As monitored by TLC (petroleum ether:ethyl acetate = 15:1), the mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was purified by column chromatography to give 0.09 g (85.2% yield) of a colorless liquid. 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-chloropyridin-3-yl)methyl)glycine methyl ester (XVIII-1) Compound XVII (0.70 g, 2.73 mmol), glycine methyl ester hydrochloride (0.69 g, 5.47 mmol), and dichloromethane (10 mL) were added to a 25 mL eggplant-shaped flask and stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (1.16 g, 5.47 mmol) was added batchwise at 0 °C. After the dropwise addition, the mixture was allowed to react at room temperature for 4 hours. TLC monitoring showed that the starting materials had completely reacted. 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 × 3). The organic phases were mixed, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oily crude product. This was separated by column chromatography to obtain 0.35 g of a colorless liquid (37.4% yield). 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)pyridin-3-yl)methyl)glycine methyl ester (XIX-1) Compound XVIII-1 (0.67 g, 1.95 mmol) was placed in a 50 mL recovery flask and dissolved in ethyl acetate (5 mL). A solution of hydrogen chloride in ethyl acetate was added and the mixture was allowed to react at room temperature for 12 hours. A white solid precipitated and was filtered with suction to obtain 0.34 g of a white solid (71.6% yield). The reaction temperature was 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]pyrimidin-3(2H)-yl)methyl acetate (XX-1) Compound XIX-1 (0.25 g, 0.90 mmol) was added to a 25 mL eggplant-shaped flask and dissolved in methanol (5 mL). 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 reacted at room temperature for 8 hours. After complete reaction, the mixture was concentrated under reduced pressure to remove the organic solvent. Water was added and extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude oil. This was separated by column chromatography to give 0.20 g of a colorless liquid (87.4% yield). 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]pyrimidin-3(2H)-yl)methyl acetate (IE-1) Compound 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 to a three-neck flask in this order. Cesium carbonate (430 mg, 1.33 mmol) was then added. Under nitrogen protection, Pd(OAc) (15 mg, 0.07 mmol) was added and the mixture was heated to 80 °C for 12 h. Upon completion of the reaction, as monitored by TLC (petroleum ether:ethyl acetate = 4:1), heating was stopped and the mixture was cooled to room temperature. The palladium catalyst and insoluble materials were removed by suction filtration. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 3), and dried over anhydrous magnesium sulfate. After suction filtration, the solvent was distilled off 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-hydroxypyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-1-methyl-1,4-dihydropyridine[2,3-d]pyrimidin-3(2H)-yl)methyl acetate (IE-2:R 1 =CH3, [ka] , R 3 =CH3, [ka] ) synthesis Compound XV-2 (0.43 g, 0.64 mmol), XX-1 (0.25 g, 0.93 mmol), CsCO (0.61 g, 1.56 mmol), Pd(OAc) (0.02 g, 0.09 mmol), t-BuXPhos (0.08 g, 0.19 mmol), and toluene (10 mL) were added to a 50 mL sealed tube. The mixture was protected with N and refluxed at 80 °C for 36 h. After TLC showed that most of the starting materials had reacted completely, the mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give the crude product, which was purified by column chromatography to give 110 mg of a pale yellow oil (90 mg, 16.8% yield). 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,

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[0096] (R)-2-(7-((3'-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-1-methyl-1,4-dihydropyridine[2,3-d]pyrimidin-3(2H)-yl)acetic acid (IE-4:R 1 =CH3, [ka] , R 3 =CH3,

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[0097] 2-(2-((2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)carbamoyl)-7,8-dihydro-1,6-naphthyridin-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) 2-Chloro-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride VIII (250 mg, 1.22 mmol) was placed in a 25 mL eggplant-shaped flask and dissolved in 5 mL DCM. Triethylamine (508 μL, 3.66 mmol) was added dropwise, followed by (Bco)2O (399 mg, 1.83 mmol). After monitoring, the reaction mixture was completely reacted. The mixture was diluted with 5 mL of water, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered under suction, and the solvent was removed under reduced pressure. The crude product was purified to yield 320 mg of a white solid (97.7% yield). 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 t-butyl 2-cyano-7,8-dihydro-1,6-naphthyridine-6(5H)-acetate (XXII) Compound XXI (500 mg, 1.86 mmol) and zinc cyanide (240 mg, 2.05 mmol) were added to a three-neck flask and dissolved in 5 mL of DMF. Under nitrogen protection, Pd(PPh3)4 (215 mg, 0.19 mmol) was added and the mixture was heated to 120 °C for 10 h. When the reaction was complete as monitored by TLC (petroleum ether:ethyl acetate = 2:1), heating was stopped and the mixture was cooled to room temperature. The palladium catalyst and insoluble materials were removed by suction filtration, the mixture was diluted with 5 mL of water, and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The mixture was suction filtered, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 5:1) to give 300 mg of a white solid (62.2% yield). 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 added to an aqueous solution of potassium hydroxide (1.08 g, 19.28 mol). The mixture was heated to 80°C and reacted for 12 hours. When the reaction was complete, as monitored by TLC (dichloromethane:methane = 10:1), the reaction was stopped and cooled to room temperature. The pH was adjusted to neutral with dilute hydrochloric acid, diluted with 5 mL of water, and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The mixture was filtered with suction, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 25:1 to 5:1) to obtain 630 mg of a white solid (58.7% yield). 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 added sequentially to a three-neck flask. Potassium carbonate (1.87 g, 13.6 mmol) dissolved in water was added to the reaction mixture. Under nitrogen protection, Pd(PPh3)4 (0.28 g, 0.20 mmol) was added, and the mixture was heated to 80 °C for 10 h. Upon completion of the reaction as monitored by TLC (petroleum ether:ethyl acetate = 15:1), heating was discontinued and the mixture was cooled to room temperature. The palladium catalyst and insoluble materials were removed by suction filtration, diluted with 5 mL of water, and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The mixture was filtered under suction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give 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 tert-butyl 2-((2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-)formate (XXIV) Compound 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 reaction was allowed to proceed at room temperature for 12 hours. The reaction was stopped when the starting materials were completely reacted, as monitored by TLC (dichloromethane:methanol = 25:1). The mixture was diluted with 5 mL of water and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The mixture was filtered with suction, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give 580 mg of a white solid (67.1% yield). 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 solution of hydrogen chloride in 1,4-dioxane was slowly added dropwise. When the raw materials were completely reacted as monitored by TLC (dichloromethane:methanol=15:1), the solvent was distilled off under reduced pressure to give 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-naphthyridin-6(5H)-yl)ethyl acetate (IF-1) Compound XXV (250 mg, 0.66 mmol) was dissolved in THF and slowly added with 60% NaH (31.5 mg, 1.31 mmol) in an ice bath. After the addition was complete, the mixture was cooled to room temperature and allowed to react for 30 minutes. Ethyl bromoacetate (87 μL, 0.79 mmol) was then slowly added dropwise to the reaction mixture. The reaction was stopped when the starting materials were completely reacted as monitored by TLC (dichloromethane:methanol = 25:1). The reaction was quenched with saturated NHCl solution, diluted with 5 mL of water, extracted with ethyl acetate (5 mL x 3), dried over anhydrous sodium sulfate, and filtered under reduced pressure. The solvent was removed under reduced pressure. The residue was purified by column chromatography to give 126 mg of a pale yellow solid (41.11% yield). 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 LiAlH4 (10 mg, 0.26 mmol) was added in an ice bath. The mixture was then cooled to room temperature and reacted. The reaction was stopped when the starting materials were 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 under suction. The solvent was removed under reduced pressure. The residue was purified by column chromatography to yield 36 mg of a white solid (54.6% yield). 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

[0100] Evaluation of the inhibitory activity of the compounds of the present invention against PD-1 / PD-L1 protein interaction Experimental Objective: To detect the inhibitory activity of the compound of formula (I) on PD-1 / PD-L1 interaction using a PD-1 / PD-L1 binding assay kit (CISBIO). Experimental principle: Homogeneous time-resolved fluorescence (HTRF) is a technique used to detect analytes in pure liquid systems. It is primarily driven by the energy donor europium (Eu + It utilizes energy transfer between two fluorescent groups, a donor and an energy acceptor. When the donor is externally excited (e.g., by a flash lamp or laser) and is within a sufficiently close distance from the acceptor, the energy is transferred to the acceptor via resonance, and the acceptor is excited and emits 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 observed by Eu + It can be detected using anti-Tag1 (HTRF energy donor) labeled with europium (Eu) and anti-Tag2 (HTRF energy acceptor) labeled with XL665. Tag1 and Tag2 are used to label PD-L1 and PD-1 proteins, respectively. + XL665 and XL665 bind to PD-L1 and PD-1, respectively, via their antibodies to form complexes. When PD-L1 and PD-1 bind to each other in close proximity, Eu + After being excited by an external laser, XL665 undergoes fluorescence resonance energy transfer to XL665, which specifically emits at 665 nm. This specific 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 was a PD-1 / PD-L1 binding assay kit purchased from CISBIO. The 96-well plate was purchased from CISBIO. Test equipment: Perkin Elmer, Model: EnVision. Test compound: Compound of formula (I). Dissolved in DMSO and diluted with diluent buffer. DMSO concentration was adjusted not to exceed 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 the instructions, and 4 μL of PD-1 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 of formula (I) (or the positive compound BMS-202), 4 μL of PD-L1, and 4 μL of PD-1 were added sequentially to a 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. Anti-Tag-Eu3 diluted in buffer was then added. + Equal amounts of Anti-tag-XL665 and Anti-tag-XL665 were mixed uniformly, and 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 compounds was calculated using Graphpad. 50 In this experiment, BMS-202 described in WO2015034820 patent of BMS company was selected as a positive drug, and the activity data is shown in Table 1. IC values ​​<0.07 μM 50 represents 0.07 to 1 μM, B represents 0.07 to 1 μM, and C represents >1 μM. [Table 2] The experimental results show that the compounds of the present invention have significant inhibitory activity against PD-1 / PD-L1 protein interaction, and among them, 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 have superior inhibitory activity to compound BMS-202 in 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 compounds

[0101] Test samples: Compound ID-18, Compound ID-26, Compound ID-27. Animal species and number: SD rats, 6 per group (half male, half female) Administration method: oral gavage 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: 1 dose Testing Process Cageside observations after drug administration on the day of administration (D1): Observation frequency and duration: Animals in each group were cageside observed for acute toxicity for 4 hours after administration. Animals exhibiting obvious abnormal behavior were subjected to detailed clinical observations. Observations included mortality, onset of symptoms, respiration, secretions, feces, and diet and drinking water status. Changes in rat 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, animals in each group were euthanized, and all animals were dissected and examined. Experimental Results: Compound ID-18, Compound ID-26, and Compound ID-27 were administered to SD rats by single intragastric administration at doses of 500, 1000, and 2000 mg / kg. No animals died or became moribund in any group. General observation of the animals in each dose group revealed no general changes related to the test article. Under the conditions of this study, the maximum tolerated dose (MTD) of Compound ID-24, Compound ID-26, and Compound ID-27 was ≥ 2000 mg / kg, respectively. Example 49: Safety test of compound administered repeatedly for 14 days

[0102] Test samples: Compound ID-18, Compound ID-26, Compound ID-27. Animal species and number: SD rats, 6 per group (half male, half female) Administration method: oral gavage Animal grouping and dosage: solvent blank group, compound ID-18 group (300 mg / kg), compound ID-26 (300 mg / kg), compound ID-27 (300 mg / kg) Dosage frequency: Once daily for 14 days Testing Process After administration, animals were observed for acute toxicity for 4 hours at the cageside, and animals showing obvious abnormal behavior were subjected to detailed clinical observations. General clinical observations were conducted twice daily (once in the morning and once in the afternoon) throughout the study period. Observations included mortality, onset of symptoms, respiration, secretions, feces, and diet and drinking water status. Changes in rat 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 from each group were euthanized, and all animals were dissected and subjected to general observations. The weight gain curve of the animals during the administration period is shown in FIG. Experimental Results: Within the administration cycle (14 days) of Compound ID-18, Compound ID-26, and Compound ID-27, animals in all dose groups had normal access to water and food, were generally active, had normal body weight, and had no obvious abnormalities. Example 50: Study on the pharmacodynamic effects of breast cancer tumor cell 4T1 xenograft tumor model

[0103] Model creation and dosing regimen Animal species and number: Balb / c nude, 6 animals 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) Preparation of animal model: 4T1 breast cancer cells in the logarithmic growth phase were cultured in vitro and harvested. 0.1 mL of the cells was injected into the right dorsal region of nude mice. 6 Cells were inoculated subcutaneously at 100 cells / animal, and tumor volumes were 50-70 mm 3 Once tumors had grown to 100%, the nude mice bearing the tumors were randomly divided into groups. Animals in each group were then administered drugs, with the first day of administration being defined as the first day of the study. Dosage frequency: once daily General observation: Time and frequency of observation: once a day; Observation criteria or contents: including but not limited to the local area of ​​administration, signs of appearance, general behavior, mental state, death, and other abnormal symptoms. The animals were euthanized after the experiment. Tumor volume calculation: V = 1 / 2 × major axis × minor axis 2 (mm 3 ) Test Results: In the table below, "+" means that the tumor inhibition rate is less than 20%, "++" means that the tumor inhibition rate is between 20% and 60%, and "+++" means that the tumor inhibition rate is greater than 60%. [Table 3] FIG. 2 shows the animal tumor growth curves of the compounds of the present invention in a BALB / c mouse 4T1 subcutaneously transplanted tumor model. The above data indicate that Compound ID-18, Compound ID-26, and Compound ID-27 have significant tumor inhibitory effects. During the administration test period, the experimental animals were able to consume water and food normally, were generally active, had 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 better therapeutic advantages and potential application value. Example 51 Preliminary Study on Capsule Formulation of Compound ID-18

[0104] [Table 4] How the capsules are made: mixture: The weighed compound ID-18, starch, and sodium carboxymethyl starch were added to a wet mix granulator and mixed. Preparation of binder solution: Purified water was weighed, and an appropriate amount of starch was slowly added while stirring, followed by stirring to disperse the starch uniformly, to obtain a starch slurry as a binder. Softwood production: Using a wet mixer granulator, the stirring speed and shear rate were controlled, and the starch slurry was slowly added, stirred, and sheared to obtain soft material. Granulation: The softwood thus produced was granulated using a 24-mesh sieve in a swing granulator to obtain wet particles. Drying: The wet particles were added to a fluid bed granulator to obtain dry particles. Graining: The dried particles were sized using a sieve in a swing granulator to obtain sized particles, which were then weighed. mixture: The sized particles were added to a universal mixer, and after mixing, magnesium stearate was added and finally mixed to obtain final mixed particles. filling: The final mixed particles were filled into gelatin hollow capsules using a filling machine and eligible capsules were selected for packaging. We obtained capsule samples that looked beautiful.

Claims

1. A compound represented by general formula I, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof. 【Chemical 1】 (where, Ar is 【Chemistry 2】 、 【Chemistry 3】 , or 【Chemistry 4】 indicates, L is -(CH ２ ) ｍ -, -O-, -NH-, -CH ２ O-, -CF ２ O-, -CH ２ NH-, -CONH-, -HNCO-, -NHCH ２ -, -OCF ２ -, -OCH ２ - or -CH=CH-, where m is 0, 1, or 2; X １ , X ２ each independently represents N or CH, T and V are respectively 【Chemistry 5】 、 【Chemistry 6】 , -O-, 【Chemistry 7】 , and -S-, where R ５ is H, C １ ~C ６ alkyl of, or C ３ ~C ７ represents a cycloalkyl group of the formula: U represents CH or N; n represents 0, 1, 2, or 3; R １ and R ３ are H, D, halogen, CN, and C, respectively. １ ~C ３ Haloalkyl, C １ ~C ３ represents an alkyl or cyclopropyl group represented by the formula: R ２ is H, substituted C １ ~C ６ Alkyl, substituted C ３ ~C ７ Cycloalkyl or substituted C ３ ~C ７ represents heterocycloalkyl, wherein the substituents are H, OH, NH ２ , COOH, an amide, an ester group, an alkoxy, or an aldehyde group, which may be mono- or polysubstituted, and said heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, and S; R ４ is H, halogen, CN, CF ３ , OH, NH ２ , -O(CH ２ ) ｐ R ６ , substitution C １ ~C ６ Alkyl, substituted C ３ ~C ７ Cycloalkyl or substituted C ３ ~C ７ represents heterocycloalkyl, wherein the substituents are H, OH, NH ２ , COOH, an amide, an ester group, an alkoxy, which may be mono- or polysubstituted, where p is 1, 2, 3 or 4, and said heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O and S; R ６ is NR ７ R ８ , OR ７ , or substitution C ４ ~C ６ where R ７ is H or C １ ~C ３ represents alkyl, and R ８ is a substitution C １ ~C ６ represents alkyl, and ４ ~C ６ Azacycloalkyl is tetrahydropyrrol-1-yl, piperidin-1-ylmorpholin-1-ylpiperazin-1-yl, or azetidin-1-yl, wherein the substituents are OH, NH ２ , COOH, amide, ester group, alkoxy, which may be mono- or polysubstituted.

2. Ar is 【Chemistry 8】 or 【Chemistry 9】 indicates, L is -(CH ２ ) ｍ -, -CH ２ O-, -CF ２ O—, —CONH—, —NHCO—, or —OCH ２ -, where m is 0, X １ and X ２ each independently represents N or CH; T and V are respectively 【Chemistry 10】 , -CH ２ -, -O-, -NH-, or 【Chemistry 11】 indicates, U represents N, n represents 0 or 1; R １ and R ３ are H, D, F, Cl, Br, CN, and CH ３ , or CF ３ indicates, R ２ H, 【Chemistry 12】 or 【Chemistry 13】 where q represents 0 or 1, and R ９ and R １０ are H, OH, COOH, and CH ２ COOH, CH ２ NH ２ , C.H. ２ OH, CH ２ CH ２ OH, F, Cl, Br, CH ３ , C.H. ２ CH ３ indicates, R １１ represents OH, NH ２ , NHCH ３ , CH ３ , OCH ３ , OCH ２ CH ３ , OCH(CH ３ ) ２ and indicates R １２ is CONH ２ , NHCOCH ３ , OH, CH ２ OH, CH ２ CH ２ OH, COOH, COOCH ３ , COOCH ２ CH ３ , COOCH (CH ３ ) ２ indicates, R １３ is H, CH ３ , C.H. ２ CH ３ , C.H. ２ OH, CH ２ CH ２ represents OH, R ４ are H, F, Cl, Br, CN, and CF ３ , OH, NH ２ , or —O(CH ２ ) ｐ R ６ where p is 2, 3, or 4; R ６ Ha, OH, 【Chemistry 14】 、 【Chemistry 15】 or 【Chemistry 16】 where R ９ , R １０ , R １１ , R １２ , and R １３ is defined as above, and R １４ is CH ３ , C.H. ２ CH ３ , C.H. ２ CH ２ OH, formyl, or acetyl; R １５ and R １６ are H, OH, COOH, and NH, respectively. ２ , C.H. ３ , C.H. ２ CH ３ , C.H. ２ OH, CH ２ CH ２ OH, CONH ２ , cyclopropyl, COOCH ３ , COOCH ２ CH ３ or COOCH (CH ３ ) ２ and W represents —CH ２ -, -O-, -NH-, 【Chemistry 17】 , or 【Chemistry 18】 and r represents 0 or 1, or a hydrate, solvate, or pharmaceutically acceptable salt thereof according to claim 1 .

3. Ar is 【Chemistry 19】 or 【Chemistry 20】 indicates, L is -CH ２ represents -O- or -NHCO-, X １ represents CH or N, X ２ indicates CH, T is, 【Chemical 21】 or -CH ２ - indicates U represents N, V is -CH ２ - or 【Chemical 22】 indicates, n is 0 or 1; R １ and R ３ are H, F, Cl, Br, CN, and CH ３ , or CF ３ indicates, R ２ H, 【Chemical 23】 or 【Chemistry 24】 where q represents 0 or 1; R ９ and R １０ are H, OH, COOH, and CH ２ COOH, CH ２ OH, CH ３ , or CH ２ CH ３ indicates, R １１ OH, NH ２ , NHCH ３ , OCH ３ , or OCH ２ CH ３ indicates, R １２ is CONH ２ , NHCOCH ３ , OH, CH ２ OH, COOH, COOCH ３ , COOCH ２ CH ３ indicates, R １３ is H, CH ３ , C.H. ２ CH ３ , C.H. ２ OH or CH ２ CH ２ represents OH, R ４ are H, F, Cl, Br, CN, and CF ３ , OH, NH ２ , or —O(CH ２ ) ｐ R ６ where p is 2, 3, or 4; R ６ OH, COOH, CH ２ OH, NH ２ , NHCH ３ , C.O.N.H. ２ , NHCOCH ３ , COOCH ３ , COOCH ２ CH ３ , or 【Chemistry 25】 where R １５ and R １６ are H, OH, and CH ３ , C.H. ２ OH, CONH ２ , COOCH ３ , or COOCH ２ CH ３ indicates, W is CH ２ , O, NH or N—CH ３ indicates, 3. The compound according to claim 1, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein r represents 0 or 1.

4. Ar is 【Chemical 26】 indicates, L is -CH ２ represents -O- and -NHCO-, X １ represents CH or N, and X ２ indicates CH, T is, 【Chemical 27】 or -CH ２ - indicates U represents N, V is -CH ２ - indicates The compound, its hydrate, solvate, or pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein n represents 0 or 1.

5. R １ and R ３ are F, Cl, Br, CN, and CH ３ , or CF ３ The compound according to any one of claims 1 to 4, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein

6. R ２ H, 【Chemical 28】 、 【Chemical 29】 、 【Chemistry 30】 、 【Chemical 31】 、 【Chemical 32】 、 【Chemical 33】 、 【Chemical 34】 、 【Chemistry 35】 , or 【Chemical 36】 The compound according to any one of claims 1 to 5, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein

7. R ４ are H, F, Cl, CN, and CF ３ , OH, NH ２ , or —O(CH ２ ) ３ R ６ where R ６ OH, CONH ２ , C.H. ２ OH, COOH, COOCH ３ , COOCH ２ CH ３ , or 【Chemical 37】 The compound according to any one of claims 1 to 6, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein

8. Any compound selected from the following formulae, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof: 【Chemical 38】 【Chemical 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemical 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 【Chemistry 50】 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemical 54】 【Chemistry 55】 【Chemical Formula 56】 【Chemical 57】 【Chemistry 58】 【Chemical Formula 59】 【Chemistry 60】 【Hua 61】

9. The compound, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, according to claim 8, wherein the compound is 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.

10. The compound, its hydrate, solvate, or pharmaceutically acceptable salt according to any one of claims 1 to 9, characterized in that the pharmaceutically acceptable salt is an acid addition salt formed between the compound of general formula I of claim 1 and an acid selected from the group consisting of 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, and ferulic acid.

11. Ar is 【Hua 62】 indicates X １ and X ２ each independently represents CH, and L represents -(CH ２ ) ｍ -, m is 0, T is C=O, U is N, V ​​is CH ２ and n is 0, the following route: 【Chemistry 63】 synthesizing formula IA with Ar is 【Hua 64】 indicates X １ indicates N, and X ２ represents CH, and L represents -(CH ２ ) ｍ -, m is 0, and T is CH ２ U represents N, V ​​represents CH ２ and n is 1, the following route: 【Chemistry 65】 synthesizing formula I-B with Ar is 【Hua 66】 indicates X １ indicates N, and X ２ represents CH, and L represents -(CH ２ ) ｍ -, m is 0, and T is CH ２ where U represents N and V represents CH ２ and n is 1, the following route: 【Chemical 67】 synthesizing formula IC by Ar is 【Chemistry 68】 indicates X １ indicates N, and X ２ represents CH, and L represents -CH ２ O-, and T is CH ２ where U represents N and V represents CH ２ and n is 1, the following route: 【Chemical Formula 69】 synthesizing formula ID with Ar is 【Chemistry 70】 indicates X １ indicates N, and X ２ represents CH, and L represents -CH ２ O-, and T is CH ２ where U represents N and V represents NCH ３ and n is 1, the following route: 【Chemical 71】 or synthesizing formula IE by Ar is 【Chemical 72】 indicates X １ indicates N, and X ２ represents CH, L represents -HNCO-, and T represents CH ２ U represents N, V ​​represents CH ２ and n is 1, the following route: 【Chemical 73】 2. A method for preparing the compound of claim 1, comprising the step of synthesizing the compound of formula IF by:

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. Use of the compound according to any one of claims 1 to 10, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, in the manufacture of a PD-1 / PD-L1 inhibitor drug.

14. Use of the compound according to any one of claims 1 to 10, or a hydrate, solvate, or pharmaceutically acceptable salt thereof in the manufacture of an antitumor drug.

15. A method for treating a tumor, comprising administering a therapeutically effective amount of the compound according to any one of claims 1 to 10, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, to a patient in need thereof.

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