Novel bicyclic PD-L1 inhibitor as well as preparation method and medical application thereof

Abstract

The invention relates to the field of medicinal chemistry, and discloses a pyridino heterocyclic derivative with PD-1 / PD-L1 inhibitory activity as well as a preparation method and application of the pyridino heterocyclic derivative. The invention also discloses a composition containing the pyridino-heterocyclic derivative with the PD-1 / PD-L1 inhibitory activity or the pharmaceutically acceptable salt of the pyridino-heterocyclic derivative and the pharmaceutically acceptable carrier, and application of the pyridino-heterocyclic derivative or the pharmaceutically acceptable salt and the pharmaceutically acceptable carrier in preparation of a PD-1 / PD-L1 inhibitor. The compound can be used for treating tumors.

Description

Novel bicyclic PD-L1 inhibitors and their preparation methods and medical uses Technical Field

[0001] The present application belongs to the field of medicinal chemistry, and specifically relates to a class of biphenyl derivatives with PD-1 / PD-L1 inhibitory activity, their preparation methods, and pharmaceutical compositions containing these compounds and their use in treating tumors. Technical Background

[0002] In recent years, tumor immunotherapy has become a hot topic in the field of cancer treatment. Unlike traditional treatments that directly target tumor cells, tumor immunotherapy harnesses the body's own immune system to kill tumor cells. Activation of immune checkpoint pathways inhibits T cell activation, preventing overactivation of the immune system, maintaining immune tolerance, and preventing the development of autoimmune diseases. Tumors overactivate immune checkpoint pathways by inducing the body and certain lymphocytes to induce immune escape. Among these immune checkpoints, overactivation of PD-1 / PD-L1 plays a crucial role in tumor progression. Blocking the PD-1 / PD-L1 interaction can reactivate the immune system and kill tumor cells, showing good efficacy in the clinical treatment of melanoma, colon cancer, non-small cell lung cancer and other tumors (Clinical and Translational Oncology, 2019, 21: 702-712; Lung Cancer: Targets and Therapy, 2017: 8; Hum Vaccin Immunother, 2014, 10(11): 3111-3116; Journal of Medicinal Chemistry, 2020, 63(22): 13825-13850).

[0003] To date, multiple PD-1 / PD-L1-targeting mAbs have been approved by the FDA for tumor immunotherapy, and hundreds of mAbs are currently undergoing active clinical trials. Although these monoclonal antibodies have improved the prognosis of many cancer patients, only a small number of patients can achieve a lasting response due to the development of intrinsic and acquired drug resistance. The use of monoclonal antibodies can also cause serious immune-related adverse events (irAEs), common side effects include skin inflammation, colitis, hepatitis, hypothyroidism, and hypophysitis. In addition, large molecule drugs have disadvantages such as poor tissue permeability, complex preparation, high cost, and poor patient compliance. Therefore, the development of small molecule inhibitors is expected to solve the problems of the above-mentioned monoclonal antibodies.

[0004] Compared with monoclonal antibodies, small molecule drugs have the following obvious advantages: 1) simple administration method, more suitable for oral administration, can adjust the drug half-life, and avoid serious immunotherapy-related adverse events; 2) have good membrane permeability, can be directly exposed to the tumor microenvironment or cross physiological barriers; 3) can directly act on intracellular targets that large molecules cannot reach; 4) easy to obtain and more flexible in dosage form and dosage; 5) low production cost, no need for refrigeration, and convenient storage and transportation.

[0005] Currently, there are no PD-1 / PD-L1 small molecule inhibitors on the market, so the development of inhibitors that block PD-1 / PD-L1 protein-protein interactions has important practical significance and potential application prospects.

[0006] Summary of the Invention

[0007] Purpose of the invention: In response to the technical problems existing in the above-mentioned prior art, the present application provides pyridoheterocyclic derivatives with PD-1 / PD-L1 inhibitory activity, their preparation methods and pharmaceutical applications as PD-1 / PD-L1 protein-protein interaction inhibitors.

[0008] Technical solution: The present application discloses a pyridoheterocyclic derivative or a pharmaceutically acceptable salt thereof as shown in the general formula (I):

[0009] in:

[0010] Ar stands for

[0011] L represents -(CH2) m -, -O-, -NH-, -CH2O-, -CF2O-, -CH2NH-, -CONH-, -HNCO-, -NHCH2-, -OCF2-, -OCH2- or -CH=CH-, wherein m represents 0, 1 or 2;

[0012] X 1 、X 2 Each represents N or CH;

[0013] T and V respectively represent and -S-; among which R 5 represents H, C1-C6 alkyl or C3-C7 cycloalkyl;

[0014] U represents CH or N;

[0015] n represents 0, 1, 2, or 3;

[0016] R 1 and R 3Each independently represents H, D, halogen, CN, C1-C3 haloalkyl, C1-C3 alkyl or cyclopropyl;

[0017] R 2 represents H, substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl or substituted C3-C7 heterocycloalkyl, wherein the substituent is H, OH, NH2, COOH, amide, ester, alkoxy or aldehyde, which may be monosubstituted or polysubstituted, and the heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O and S;

[0018] R 4 Represents H, halogen, CN, CF3, OH, NH2, -O(CH2) p R 6 , substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl or substituted C3-C7 heterocycloalkyl, the substituents are H, OH, NH2, COOH, amide, ester, alkoxy, which may be monosubstituted or polysubstituted, wherein p represents 1, 2, 3 or 4, and the heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, and S;

[0019] R 6 Represents NR 7 R 8 , OR 7 or substituted C4-C6 nitrogen heterocycloalkyl, wherein R 7 represents H or C1-C3 alkyl, R 8 represents a substituted C1~C6 alkyl group, the C4-C6 azacycloalkyl group is tetrahydropyrrol-1-yl, piperidin-1-ylmorpholine-1-ylpiperazin-1-yl or azetidine-1-yl, and the substituents are OH, NH2, COOH, amide, ester, alkoxy, and can be monosubstituted or polysubstituted.

[0020] in:

[0021] Ar preferably represents

[0022] L represents -(CH2) m -, -CH2O-, -CF2O-, -CONH-, -NHCO- or -OCH2-, wherein m represents 0;

[0023] X 1 and X 2 Each represents N or CH;

[0024] T and V respectively represent -CH2-, -O-, -NH- or

[0025] U stands for N;

[0026] n represents 0 or 1;

[0027] R 1 and R 3 Each represents H, D, F, Cl, Br, CN, CH3 or CF3;

[0028] R 2 Represents H, Where q represents 0 or 1, R 9 and R 10 Each represents H, OH, COOH, CH2COOH, CH2NH2, CH2OH, CH2CH2OH, F, Cl, Br, CH3, CH2CH3;

[0029] R 11 Represents OH, NH2, NHCH3, CH3, OCH3, OCH2CH3, OCH(CH3)2;;

[0030] R 12 Represents CONH2, NHCOCH3, OH, CH2OH, CH2CH2OH, COOH, COOCH3, COOCH2CH3, COOCH(CH3)2;

[0031] R 13 represents H, CH3, CH2CH3, CH2OH, CH2CH2OH;

[0032] R 4 Represents H, F, Cl, Br, CN, CF3, OH, NH2 or -O(CH2) p R 6 , where p represents 2, 3 or 4, R 6 Represents OH, where R 9 、R 10 、R 11 、R 12 and R 13 The definition of R is the same as before. 14 represents CH3, CH2CH3, CH2CH2OH, formyl or acetyl, R 15 and R 16 Each represents H, OH, COOH, NH2, CH3, CH2CH3, CH2OH, CH2CH2OH, CONH2, cyclopropyl, COOCH3, COOCH2CH3 or COOCH(CH3)2, W represents -CH2-, -O-, -NH-, r represents 0 or 1.

[0033] Among them, more preferred are:

[0034] Ar stands for

[0035] L represents -CH2O- and -NHCO-;

[0036] X1 represents CH or N, X2 represents CH;

[0037] T generation or -CH2-;

[0038] U stands for N;

[0039] V represents -CH2-;

[0040] n=0 or 1.

[0041] R 1 and R 3 Each represents F, Cl, Br, CN, CH3 or CF3.

[0042] R 2 Representative: H.

[0043] R 4 Represents H, F, Cl, CN, CF3, OH, NH2 or -O(CH2)3R 6 , where R 6 Represents OH, CONH2, CH2OH, COOH, COOCH3, COOCH2CH3 or

[0044] More preferably, the compound is any one of the following compounds:

[0045] The pharmaceutically acceptable salt is an acid addition salt formed by the compound of general formula (I) and the following acids: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.

[0046] Use of a pyridoheterocycle-containing compound or a pharmaceutically acceptable salt thereof in the preparation of a PD-L1 inhibitor drug for treating tumors.

[0047] The compounds (I) of the present invention are divided into types IA, IB, IC, ID, IE and IF, and their synthesis methods are described as follows:

[0048] When Ar represents X1 and X2 each represent CH, and L represents -(CH2) m -, m = 0, T represents C = O, U represents N, V ​​represents CH2, n = 0, the synthetic route of formula IA is:

[0049] where R 1 、R 2 、R 3 and R 4 The definition of is the same as above.

[0050] Compound II and compound III are reacted by suzuki reaction to prepare compound IV, wherein the solvent used is selected from toluene, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAc), ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, water or a mixed solvent consisting of any two solvents, preferably a mixed solvent of 1,4-dioxane and water; the base used is selected from sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate, carbon Potassium hydrogen carbonate, sodium carbonate, potassium carbonate or triethylamine, preferably potassium carbonate; the catalyst used is selected from [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf)Cl2), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), bis(triphenylphosphine)palladium dichloride (Pd(PPh3)2Cl2), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) or palladium acetate (Pd(OAc)2), preferably Pd(PPh3)4. The reaction temperature is selected from 50 to 120°C, preferably 60 to 100°C.

[0051] Compound V is prepared from compound IV via a Sandmeyer reaction, wherein the diazotizing agent used is selected from tertiary 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 composed 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.

[0052] Compound VII is prepared from compound VI, where the acid-binding agent used is selected from triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, sodium methoxide, sodium ethoxide or potassium tert-butoxide, 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, preferably tetrahydrofuran or DMF.

[0053] Compound IA is prepared by a 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 mixed solvent consisting of any two solvents, preferably a mixed solvent of 1,4-dioxane and water. The base 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.

[0054] When Ar represents X1 represents N, X2 represents CH, and L represents -(CH2) m -, m = 0, T represents CH2, U represents N, V ​​represents CH2, n = 1, the synthesis route of formula IB is:

[0055] where R 1 、R 2 、R 3 and R 4 The definition of is the same as above.

[0056] Compound IX is prepared from compound VIII, where the acid-binding agent used is selected from triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide 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, preferably tetrahydrofuran or DMF.

[0057] Compound IB is prepared by suzuki reaction of compound IX and compound V, wherein 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 consisting of any two solvents, preferably a mixed solvent of 1,4-dioxane and water; the base 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.

[0058] When Ar represents X1 represents N, X2 represents CH, and L represents -(CH2) m -, m = 0, T is CH2, U represents N, V ​​represents CH2, n = 1, the synthesis route of formula IC is:

[0059] where R 1 、R 2 、R 3 and R 4 The definition of is the same as above.

[0060] Compound X is reacted with SOCl2 in methanol to prepare XI; the reaction temperature is selected from 50 to 120°C, preferably 60 to 100°C.

[0061] Compound XII is prepared by reduction of compound XI, wherein the solvent used is selected from tetrahydrofuran, ethanol, DMF or 1,4-dioxane, preferably methanol; and the reducing agent is selected from lithium aluminum tetrahydride, sodium borohydride or potassium borohydride, preferably lithium aluminum tetrahydride.

[0062] Compound XIV is prepared by a Suzuki reaction of Compound XII and Compound XIII. The solvent used is selected from toluene, DMF, DMAc, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, water, or a mixed solvent composed of any two solvents, preferably a mixed solvent of 1,4-dioxane and water. The base 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.

[0063] Compound IC is prepared by reacting compound IX with compound XIV, wherein 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 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 (Xantphos) or 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (Brett-Phos), preferably t-BuXPhos; the base 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, preferably toluene. The reaction temperature is selected from 50 to 120°C, preferably 60 to 100°C.

[0064] When Ar represents X1 represents N, X2 represents CH, L represents -CH2O-, T is CH2, U represents N, V ​​represents CH2, n=1, and the synthesis route of formula ID is:

[0065] where R 1 、R 2 、R 3 and R 4 The definition of is the same as above.

[0066] Compound XV is prepared by a Suzuki reaction of Compound XII and Compound III. The solvent used is selected from toluene, DMF, DMAc, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, water, or a mixed solvent composed of any two solvents, preferably a mixed solvent of 1,4-dioxane and water. The base 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.

[0067] Compound ID is prepared by reacting compound IX and compound XV, where 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 base used is selected from sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate or sodium carbonate, preferably cesium carbonate; and the solvent used is selected from tetrahydrofuran, 1,4-dioxane, toluene or a mixed solvent of any two of them, preferably toluene.

[0068] When Ar represents X1 represents N, X2 represents CH, L represents -CH2O-, T represents CH2, U represents N, V ​​represents NCH3, n=1, and the synthetic route of formula IE is:

[0069] where R 1 、R 2 、R 3 and R 4 The definition of is the same as above.

[0070] Compound XVII is prepared by reacting compound XVI with iodomethane under alkaline conditions, wherein the solvent used is selected from acetone, DMF, acetonitrile or tetrahydrofuran, or a mixed solvent composed of the above solvents, preferably DMF; the base used is selected from sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, or lithium hydroxide, preferably sodium hydride.

[0071] Compound XVII is reacted with an amine compound to undergo a reductive amination reaction to prepare 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 mixed solvent of the above solvents, preferably a mixed solvent of dichloromethane and methanol. The reducing agent used is selected from sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, or hydrosulfite, preferably sodium triacetoxyborohydride.

[0072] The target compound XIX is prepared by reacting compound XVIII under acidic conditions, wherein the solvent used is selected from ethyl acetate, acetone, dichloromethane, acetonitrile, tetrahydrofuran or a mixed solvent composed 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.

[0073] The target compound XX is prepared by reacting compound XIX with paraformaldehyde. The solvent used is selected from methanol, ethanol, ethyl acetate, acetone, dichloromethane, DMF, acetonitrile, tetrahydrofuran, or a mixed solvent of the above solvents, preferably methanol; the base used is selected from triethylamine, dimethylaminopyridine (DMAP), or N,N-diisopropylethylamine, preferably triethylamine.

[0074] Compound IE is prepared by reacting compound XX with compound XV. The catalyst used is selected from Pd(PPh3)4, Pd(dppf)Cl2, Pd(PPh3)2Cl2, Pd(OAc)2, or Pd2(dba)3, preferably Pd(OAc)2; the ligand used is selected from t-BuXPhos, X-Phos, Xantphos, or Brett-Phos, preferably t-BuXPhos; the base used is selected from sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate, or sodium carbonate, preferably cesium carbonate; and the solvent used is selected from tetrahydrofuran, 1,4-dioxane, toluene, or a mixture of any two of them, preferably toluene. The reaction temperature is selected from 50 to 120°C, preferably 60 to 100°C.

[0075] When Ar represents X1 represents N, X2 represents CH, L represents -NHCO-, T represents CH2, U represents N, V ​​represents CH2, n=1, and the synthetic route of formula IF is:

[0076] where R 1 、R 2 、R 3 and R 4 The definition of is the same as above.

[0077] Compound XXI is prepared by reacting compound VIII with di-tert-butyl dicarbonate under alkaline conditions, wherein the solvent used is selected from acetone, dichloromethane, DMF, acetonitrile, tetrahydrofuran or a mixed solvent composed of the above solvents, preferably tetrahydrofuran; the base used is selected from DMAP, triethylamine, N,N-diisopropylethylamine, potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate or lithium hydroxide, preferably triethylamine.

[0078] Compound XXII is prepared from compound XXI using a solvent selected from acetone, dichloromethane, DMF, acetonitrile, tetrahydrofuran, or a mixture thereof, preferably DMF; a cyanide donor selected from zinc cyanide, cuprous cyanide, or potassium ferrocyanide, preferably zinc cyanide; and a catalyst 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.

[0079] Compound XXIII is prepared by hydrolysis of compound XXII under alkaline conditions. The solvent used is selected from methanol, ethanol, water, acetonitrile, tetrahydrofuran, acetone, dichloromethane, DMF, acetonitrile, or a mixture thereof, preferably a mixture of ethanol and water. The base used is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, or lithium hydroxide, preferably potassium hydroxide. The reaction temperature is selected from 0 to 120°C, preferably 60 to 100°C.

[0080] Compound XXIV is prepared by reacting compound IV and XXIII, wherein 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-yl-oxytripyrrolidinophosphine hexafluorophosphate (PyBOP), preferably HATU; the acid binding agent 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 composed of the above solvents, preferably DMF; the reaction temperature is selected from 0 to 80°C, preferably 25 to 50°C.

[0081] The target compound XXV is prepared by reacting compound XXIV under acidic conditions, wherein the solvent used is selected from ethyl acetate, acetone, dichloromethane, acetonitrile, tetrahydrofuran or a mixed solvent composed 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.

[0082] Compound IF is prepared from compound XXV, where the acid-binding agent is selected from triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate or sodium hydride, preferably sodium hydride; and the solvent is selected from dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, ethyl acetate, DMF or a mixed solvent of any two, preferably tetrahydrofuran or DMF.

[0083] The present application also discloses a pharmaceutical composition comprising a compound of the above-mentioned general formula (I) (including chiral isomers) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The compound can be added with a pharmaceutically acceptable carrier to prepare common pharmaceutical preparations, such as tablets, capsules, syrups, suspensions, and injections, and can be supplemented with common pharmaceutical excipients such as flavorings, sweeteners, liquid or solid fillers, or diluents.

[0084] The use of the compound of general formula (I) and its hydrates, solvates or crystals described in the present application in the preparation of PD-1 / PD-L1 protein-protein interaction inhibitor drugs is also within the scope of protection of the present application.

[0085] Furthermore, the PD-1 / PD-L1 protein-protein interaction inhibitors can be used to treat cancer or tumors, for example, to prepare drugs for treating non-small cell lung cancer, colon cancer, melanoma, breast cancer, liver cancer and other cancers.

[0086] Pharmacological experiments have shown that the pyrido-heterocyclic derivatives of this application can effectively inhibit the PD-1 / PD-L1 interaction in homogeneous time-resolved fluorescence (HTRF) experiments. The pyrido-heterocyclic derivatives of this application have excellent activity, and therefore the development of biphenyl inhibitors of PD-1 / PD-L1 has great practical significance and potential application prospects.

[0087] Beneficial effects: Compared with the prior art, this application has the following significant advantages:

[0088] (1) The novel pyrido-heterocyclic derivatives of the present application can significantly inhibit the interaction between PD-1 and PD-L1, and their activity is superior to that of the known PD-1 / PD-L1 inhibitor BMS-202.

[0089] (2) The synthetic route of the pyrido-heterocyclic derivatives of the present application is ingeniously designed, simple and easy to implement, the raw materials are cheap and easily available, the synthetic process is safe and environmentally friendly, and it is easy to scale up production.

[0090] (3) It has a wide range of applications. Drugs with it as an active ingredient can be used to treat a variety of cancers or tumors related to the immune checkpoint PD-1 / PD-L1. BRIEF DESCRIPTION OF THE DRAWINGS

[0091] FIG1 shows the body weight growth curve of rats in a continuous administration toxicity test of the compound of the present invention.

[0092] FIG2 shows the animal tumor growth curve of the compound of the present invention in a BALB / c mouse 4T1 subcutaneous transplanted tumor model. DETAILED DESCRIPTION

[0093] Example 1

[0094] 2-(5-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-1-oxoisoindolin-2-yl)acetic acid ethyl ester (IA-1: R 1 =CH3, R 3 =F,R 4 =H, T represents C=O)

[0095] Synthesis of 2'-fluoro-2-methyl-[1,1'-biphenyl]-3-amine (IV-1)

[0096] 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-necked flask. Potassium carbonate (5.21 g, 37.69 mmol) dissolved in water (2.5 mL) was added to the reaction solution. Pd(PPh3)4 (0.39 g, 0.34 mmol) was added, and the mixture was heated to 80°C under nitrogen for 10 hours. TLC confirmed the complete reaction of the starting material, then heating was stopped and the mixture was cooled to room temperature. The palladium catalyst and insoluble matter were removed by filtration, and the mixture was diluted with water (25 mL) and extracted with ethyl acetate (25 mL × 3). The organic phases were combined, washed with saturated aqueous NaCl (25 mL × 3), and dried over anhydrous magnesium sulfate. The product was filtered and the solvent was evaporated under reduced pressure. 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.

[0097] 1 H NMR (300MHz, DMSO-d6) δ7.48-7.35(m,1H,ArH),7.34-7.22(m,3H,ArH),6.98(t,J=7.7Hz,1H,ArH),6.7 0(dd,J=8.0Hz,1.4Hz,1H,ArH),6.42(dd,J=7.5Hz,1.3Hz,1H,ArH),5.00(s,2H,NH2),1.85(s,3H,CH3).

[0098] Synthesis of 2-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (V-1)

[0099] Compound IV-1 (2.00 g, 9.94 mmol) was dissolved in methanol (20 mL) and water (10 mL). Hydrochloric acid (9.92 mL, 3 mmol / mL) was slowly added dropwise. The reaction mixture was stirred at 25°C until clear. The temperature was then lowered to 0°C, and a sodium nitrate (4.96 mL, 2.2 mmol / mL) aqueous solution was slowly added dropwise. Stirring was continued at 0°C for 30 minutes. Diboronic acid pinacol ester (7.56 g, 29.85 mmol) was dissolved in methanol (20 mL) and slowly added dropwise to the reaction mixture. A large amount of gas was generated. The mixture was brought to room temperature and stirred for 2 hours. Completion of the reaction was monitored by TLC (petroleum ether:ethyl acetate = 30:1). 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 solvent was removed by filtration and evaporation under reduced pressure. The residue was purified by column chromatography (petroleum ether to petroleum ether:ethyl acetate = 200:1) to afford 1.88 g of a yellow solid powder (yield 60.4%). mp 94.0-95.0°C.

[0100] 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)

[0101] 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-necked flask. Potassium carbonate (0.92 g, 6.60 mmol) was dissolved in water (1.0 mL) and added to the reaction mixture. Pd(PPh3)4 (0.27 g, 0.25 mmol) was then added under nitrogen. The reaction mixture was heated to 80°C and allowed to react for 12 hours. TLC (petroleum ether:ethyl acetate = 4:1) monitored the complete reaction of the starting materials. Heating was discontinued and the mixture was cooled to room temperature. The palladium catalyst and insoluble matter were removed by filtration, and 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 solvent was removed by filtration under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 15:1 to 3:1) to afford 0.40 g of a white solid powder (yield 50.9%). mp 190-192°C.

[0102] 1H NMR(300MHz,DMSO-d6)δ8.63(s,1H,ArH),7.76(d,J=7.8Hz,1H,ArH),7.60(s,1H,ArH), 7.49(d,J=7.6Hz,2H,ArH),7.44-7.26(m,6H,ArH),4.46(s,2H,CH2),2.01(s,3H,CH3).

[0103] Synthesis of ethyl 2-(5-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-1-oxoisoindolin-2-yl)acetate (IA-1)

[0104] Compound VII (0.50 g, 1.58 mmol) was added to 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 allowed to react at room temperature. After monitoring for complete reaction, the reaction was quenched with saturated ammonium chloride solution. 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 afford 0.63 g of a white solid in a 98.7% yield. mp 100-101°C.

[0105] 1 H NMR(300MHz,DMSO-d6)δ7.81(d,J=7.8Hz,1H,ArH),7.67-7.62(m,1H,ArH),7.57-7.47(m,2H,ArH),7.43-7.30(m,6H,Ar H),4.61(s,2H,NCH2),4.44(s,2H,NCH2),4.19(q,J=7.1Hz,2H,CH2CH3),2.03(s,3H,CH3),1.25(t,J=7.1Hz,3H,ArCH3).

[0106] Example 2

[0107] Ethyl 3-(5-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-1-oxoisoindolin-2-yl)propanoate (IA-2:

[0108] R 1 =CH3, R 3 =F,R 4 =H, T represents C=O)

[0109] Using compound VII (0.50 g, 1.58 mmol) and ethyl 3-bromopropionate (0.34 g, 1.89 mmol) as raw materials, the operation was the same as compound IA-1 to obtain 0.40 g of colorless viscous liquid with a yield of 60.6%.

[0110] 1 H NMR(300MHz,DMSO-d6)δ7.77(d,J=7.7Hz,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=7.1Hz,2H,CH2CH3),3.82(t,J=7.0Hz,2H,NCH2CH2),2.73(t,J=7.0Hz,2H,COCH2),2.01(s,3H,ArCH3),1.19(t,J=7.1Hz,3H,CH2CH3).

[0111] Example 3

[0112] Ethyl 2-(5-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-1-oxoisoindolin-2-yl)propanoate (IA-3: R 1 =CH3, R 3 =F,R 4 =H, T represents C=O)

[0113] Compound VII (0.50 g, 1.58 mmol) and ethyl 2-bromopropionate (0.34 g, 1.89 mmol) were used as starting materials and the same procedures as for compound IA-1 were followed to obtain 0.58 g of a white solid in an 88.3% yield. mp 50-52°C.

[0114] 1 H NMR(300MHz,DMSO-d6)δ7.80(d,J=7.8Hz,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=7.3Hz,1H,CH 3CH), 4.62 (d, J=7.0Hz, 2H, NCH2), 4.16 (q, J=7.1Hz, 2H, CH2CH3), 2.02 (s, 3H, ArCH3), 1.56 (d, J=7.4Hz, 3H, CHCH3), 1.22 (t, J=7.0Hz, 3H, CH2CH3).

[0115] Example 4

[0116] 2-(5-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-1-oxoisoindolin-2-yl)acetic acid (IA-4: R 1 =CH3, R 3 =F,R 4 =H, T represents C=O)

[0117] Compound IA-1 (30 mg, 0.16 mmol) was added to 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 completion of the reaction as monitored by TLC, the methanol was evaporated under reduced pressure and the pH was adjusted to 5-6 with 2 M HCl. A white solid precipitated and was filtered to yield 20 mg of an off-white solid product (72.1% yield). mp 164-166°C.

[0118] 1 H NMR(400MHz,DMSO-d6)δ12.95(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).

[0119] HRMS(ESI):m / z[M+H] + Calcd for C 23 H 19 FNO3:376.1349; Found:376.1350.

[0120] Example 5

[0121] 3-(5-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-1-oxoisoindolin-2-yl)propanoic acid (IA-5: R 1 =CH3, R 3 =F,R 4 =H, T represents C=O)

[0122] Compound IA-2 (50 mg, 0.12 mmol) and LiOH (10 mg, 0.24 mmol) in water (0.5 mL) were used as starting materials. The same procedure as for compound IA-4 was followed to give 40 mg of a yellow solid product in a 92.2% yield. mp 56-58°C.

[0123] 1 H NMR (300MHz, DMSO-d6) δ7.77(d,J=7.8Hz,1H,ArH),7.63(s,1H,ArH),7.50(d,J=7.7Hz,2H,ArH),7.44-7.28(m ,6H,ArH),4.58(s,2H,NCH2),3.78(t,J=6.9Hz,2H,NCH2CH2),2.65(t,J=7.0Hz,2H,COCH2),2.01(s,3H,CH3).

[0124] HRMS(ESI):m / z[M+H] + Calcd for C 24 H 21 FNO3:390.1505; Found:390.1503.

[0125] Example 6

[0126] 2-(5-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-1-oxoisoindolin-2-yl)propanoic acid (IA-6: R 1 =CH3, R 3 =F,R 4 =H, T represents C=O)

[0127] Compound IA-3 (50 mg, 0.12 mmol) and LiOH (10 mg, 0.24 mmol) in water (0.5 mL) were used as starting materials. The same procedure as for compound IA-4 was followed to give 30 mg of a white solid product in a 64.2% yield. mp 140-142°C.

[0128] 1 H NMR(300MHz,DMSO-d6)δ7.78(d,J=7.8Hz,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, CHCH3), 4.72-4.52 (m, 2H, CH2), 2.02 (s, 3H, ArCH3), 1.51 (d, J = 7.3Hz, 3H, CH3).

[0129] HRMS(ESI):m / z[M+H] + Calcd for C 24 H 21 FNO3:390.1505; Found:390.1502.

[0130] Example 7

[0131] 5-(2'-Fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-2-(2-hydroxyethyl)isoindol-1-one (IA-7: R 1 =CH3, R 3 =F,R 4 =H, T represents C=O)

[0132] Compound IA-1 (60 mg, 0.12 mmol) was added to 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 for complete reaction, the reaction was quenched with saturated ammonium chloride solution. A white solid precipitated, which was removed by filtration and washed with EA. The filtrate was concentrated and purified to afford 24 mg of a yellow solid in a 56.8% yield. mp 86-88°C.

[0133] 1 H NMR (300MHz, DMSO-d6) δ7.77(d,J=7.8Hz,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,NCH2),3.68-3.60(m,4H,CH2CH2),2.01(s,3H,CH3).

[0134] HRMS(ESI):m / z[M+H] + Calcd for C 23 H 21 FNO2:362.1556; Found:362.1556.

[0135] Example 8

[0136] 2-(5-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-1-oxoisoindolin-2-yl)acetamide (IA-8: R 1 =CH3, R 3 =F,R 4 =H, T represents C=O)

[0137] Compound IA-2 (100 mg, 0.27 mmol) was added to a 25 mL three-necked flask and dissolved in THF. A small amount of DMF was added dropwise, followed by the slow dropwise addition of thionyl chloride (95 mg, 0.78 mmol). The temperature was raised to 55°C for reaction. The reaction was monitored for complete reaction. The mixture was then returned to room temperature and transferred to -20°C. Ammonia was slowly added dropwise, and the pH was adjusted to 8. The reaction was monitored for complete reaction and the formation of new spots. 10 mL of water was added, and the mixture was extracted with EA (10 mL × 3), washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and purified by column chromatography to afford 42 mg of a light brown solid (42.0% yield). The mp was greater than 250°C.

[0138] 1 H NMR(300MHz,DMSO-d6)δ7.77(d,J=7.8Hz,1H,ArH),7.61(d,J=7.6Hz,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).

[0139] HRMS(ESI):m / z[M+H] + Calcd for C 23 H 20 FN2O2:375.1509; Found:375.1511.

[0140] Example 9

[0141] 2-(5-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)isoindolin-2-yl)ethan-1-ol (IA-9: R 1 =CH3, R 3 =F,R 4 =H, T represents CH2)

[0142] Compound IA-7 (30 mg, 0.08 mmol) was added to 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 addition, the mixture was refluxed at 68°C for 3 h. After monitoring the reaction completion, saturated ammonium chloride solution was added to quench the reaction. A white solid precipitated, which was removed by filtration and washed with EA. The filtrate was concentrated and purified to afford 14 mg of a brown solid in a 48.5% yield. mp 80-82°C.

[0143] 1H NMR(300MHz,Chloroform-d)δ7.36-7.29(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,CH2CH2OH),2.05(s,3H,CH3).

[0144] HRMS(ESI):m / z[M+H] + Calcd for C 23 H 23 FNO:348.1764; Found:348.1762.

[0145] Example 10

[0146] ethyl 2-(2-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (IB-1: R 1 =CH3, R 3 =F,R 4 =H)

[0147] Ethyl 2-(2-chloro-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (IX-1)

[0148] To a 25 mL eggplant-shaped flask, 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride VIII (0.50 g, 2.43 mmol) was added and dissolved in THF. NaH (0.20 g, 4.86 mmol) was added at 0°C. Ethyl bromoacetate (0.49 g, 2.93 mmol) was added dropwise to the reaction solution. The reaction was allowed to react at room temperature. TLC confirmed the complete reaction of the starting material. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (10 mL × 3), washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography to obtain 0.60 g of a light brown solid in a yield of 97.2%. mp 58-60°C.

[0149] 1H NMR(300MHz,Chloroform-d)δ7.45-7.37(m,5H,ArH),7.28-7.22(m,4H,ArH),4.24(q,J=7.1Hz,2H,CH2CH3),3.82(s ,2H,NCH2),3.47(s,2H,COCH2),3.09-3.05(m,2H,NCH2CH2),3.02-2.97(m,2H,NCH2CH2),1.31(t,J=7.2Hz,3H,CH3).

[0150] Synthesis of ethyl 2-(2-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (IB-1)

[0151] 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-necked flask. Potassium carbonate (0.37 g, 2.75 mmol) was dissolved in water (0.5 mL) and added to the reaction solution. Under nitrogen protection, Pd(PPh3)4 (0.14 g, 0.10 mmol) was added and the temperature was raised to 80°C for 12 hours. TLC (petroleum ether:ethyl acetate = 8:1) monitored the complete reaction of the raw materials. Heating was stopped and the mixture was cooled to room temperature. The palladium catalyst and insoluble matter were removed by filtration, and 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 product was filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 10:1) to obtain 180 mg of a yellow solid (yield 44.6%). mp 46-48°C.

[0152] 1 H NMR(300MHz,Chloroform-d)δ7.46-7.37(m,5H,ArH),7.28-7.22(m,4H,ArH),4.29(q,J=7.2Hz,2H,CH2CH3),3.95(s,2H,NCH2),3. 55(s,2H,COCH2),3.23(t,J=5.9Hz,2H,NCH2CH2),3.11(t,J=5.9Hz,2H,NCH2CH2),2.10(s,3H,ArCH3),1.36(t,J=7.2Hz,3H,CH3).

[0153] Example 11

[0154] 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, R 3 =F,R 4 =H)

[0155] Compound IB-1 (80 mg, 0.20 mmol) dissolved in ethanol (2 mL) was added to a 10 mL eggplant-shaped flask. 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 completion of the reaction as monitored by TLC, the methanol was evaporated under reduced pressure and the pH was adjusted to 5-6 with 2M HCl. A white solid precipitated, which was filtered and dried to yield 7 mg of a yellow solid (9.4% yield). mp 188-190°C.

[0156] 1 H NMR (300MHz, DMSO-d6) δ8.29(d,J=8.0Hz,1H,ArH),7.58(d,J=8.0Hz,1H,ArH),7.48-7.29(m,7H,ArH),4.23(s,2H,NCH2),3.74(t,J=6.7Hz,2H, NCH2), 3.26 (s, 2H, COCH2), 3.19 (t, J = 6.4Hz, 2H, NCH2), 2.08 (s, 3H, CH3).

[0157] HRMS(ESI):m / z[M+H] + Calcd for C 23 H 22 FN2O2:377.1665; Found:377.1667.

[0158] Example 12

[0159] 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, R 3 =F,R 4 =H)

[0160] Compound IB-1 (100 mg, 0.25 mmol) was added to 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. The reaction was monitored for complete reaction. The reaction was quenched with saturated ammonium chloride solution. A white solid precipitated and was removed by filtration. The solid was washed with EA, and the filtrate was concentrated and purified to afford 50 mg of a yellow solid in a 27.9% yield. mp 66-68°C.

[0161] 1 H NMR(300MHz,Chloroform-d)δ7.43-7.38(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 =5.4Hz,2H,CH2OH),3.13(t,J=5.6Hz,2H,NCH2CH2),2.98(t,J=5.8Hz,2H,NCH2CH2),2.80(t,J=5.3Hz,2H,NCH2),2.10(s,3H,CH3).

[0162] HRMS(ESI):m / z[M+H] + Calcd for C 23 H 23 FN2O:363.1873; Found:363.1872.

[0163] Example 13

[0164] ethyl 2-(2-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (IC-1: R 1 =CH3, )

[0165] Synthesis of methyl 3-bromo-2-methylbenzoate (XI-1)

[0166] To a 50 mL eggplant-shaped flask, 3-bromo-2-methylbenzoic acid X-1 (0.30 g, 1.40 mmol) and 5 mL of methanol were added dropwise. Thionyl chloride (0.20 mL, 2.79 mmol) was slowly added dropwise in an ice bath. After completion, the mixture was heated under reflux at 70°C for 1 h. TLC (petroleum ether:ethyl acetate = 8:1) monitored the reaction. The mixture was concentrated under reduced pressure to give 0.32 g of a white solid powder (99.0% yield). mp3 1.0-33.0°C.

[0167] 1H NMR (300MHz, Chloroform-d) δ7.72(d,J=8.5Hz,1H,ArH),7.68(d,J=8.6Hz,1H,ArH),7.09(t,J=7.8Hz,1H,ArH),3.90(s,3H,OCH3),2.63(s,3H,CH3).

[0168] Synthesis of (3-bromo-2-methylphenyl)methanol (XII-1)

[0169] Compound XI-1 (10.50 g, 46.10 mmol) and anhydrous tetrahydrofuran (50.00 mL) were placed in a three-necked flask under N2 protection and cooled to 0°C. LiAlH4 (3.10 g, 55.30 mmol) was slowly added portionwise. After addition, the ice bath was removed and the mixture was stirred at room temperature for 30 minutes. TLC (petroleum ether:ethyl acetate = 8:1) confirmed the complete reaction of the starting materials. Saturated NH4Cl solution was slowly added dropwise until no bubbles formed. The mixture was diluted with ethyl acetate (100 mL) and filtered to remove insoluble matter. The organic phase was washed with water (50 mL x 2) and saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure to yield 9.22 g of a white solid powder in a 98.9% yield. mp 103.0-104.0°C.

[0170] 1 H NMR (300MHz, DMSO-d6) δ7.49(d,J=8.0Hz,1H,ArH),7.39(d,J=7.7Hz,1H,ArH),7. 12(t,J=7.7Hz,1H,ArH),5.26(br,1H,CH2OH),4.52(s,2H,CH2),2.30(s,3H,CH3).

[0171] Synthesis of (3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenyl)methanol (XIV-1)

[0172] 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-necked flask. Potassium carbonate (962 mg, 6.96 mmol) dissolved in water (1 mL) was added to the reaction mixture. Pd(PPh3)4 (144 mg, 0.15 mmol) was added under nitrogen, and the mixture was heated to 80°C for 12 hours. TLC (petroleum ether:ethyl acetate = 8:1) monitored the complete reaction. Heating was discontinued, and the mixture was cooled to room temperature. The palladium catalyst and insoluble matter were removed by filtration, and 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 residue was filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1-15:1) to obtain 440 mg of a light brown oil in a yield of 69.07%.

[0173] 1 H NMR (300MHz, DMSO-d6) δ7.38(dd,J=7.6Hz,1.4Hz,1H,ArH),7.20(t,J=7.6Hz,1H,ArH),7.06(dd,J=7.6Hz,1.5Hz,1H,A rH),6.92(d,J=8.1Hz,1H,ArH),6.78-6.70(m,2H,ArH),4.55(s,2H,CH2OH),4.29(s,4H,OCH2,OCH2),2.14(s,3H,CH3).

[0174] Synthesis of ethyl 2-(2-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (IC-1)

[0175] 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-necked 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 under nitrogen protection, and the temperature was raised to 80°C for 12 hours. TLC (petroleum ether:ethyl acetate = 4:1) was used to monitor the reaction. Heating was stopped and the mixture was cooled to room temperature. The palladium catalyst and insoluble matter were removed by filtration, and the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated aqueous NaCl (10 mL × 3), and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, the solvent was evaporated under reduced pressure, and the product was purified by column chromatography (petroleum ether:ethyl acetate=20:1-10:1) to obtain 110 mg of a yellow viscous liquid with a yield of 49.21%.

[0176] 1 H NMR(300MHz,Chloroform-d)δ7.42(dd,J=6.4Hz,2.7Hz,1H,ArH),7.23-7.19(m,3H,ArH),6.90(d, J=8.2Hz,1H,ArH),6.83(d,J=1.8Hz,1H,ArH),6.79(dd,J=8.2Hz,1.9Hz,1H,ArH),6.59(d,J=8.3H z,1H,ArH),5.37(s,2H,OCH2),4.30(s,4H,OCH2CH2O),4.26(q,J=7.1Hz,2H,CH2CH3),3.76(s,2H, NCH2),3.46(s,2H,CH2CO),3.00(s,4H,NCH2CH2),2.28(s,3H,ArCH3),1.30(t,J=7.1Hz,3H,CH3).

[0177] Example 14

[0178] Ethyl 2-(2-((2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-1: R 1 =CH3, R 3 =F,R 4 =H)

[0179] Synthesis of (2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methanol (XV-1)

[0180] Compound XII-1 (2.00 g, 9.95 mmol), 2-fluorophenylboronic acid III-1 (2.09 g, 14.92 mmol), and 1,4-dioxane (45 mL) were added sequentially to a three-necked flask. Potassium carbonate (3.85 g, 27.85 mmol) dissolved in water (4.5 mL) was added to the reaction mixture. Pd(PPh3)4 (0.57 g, 0.50 mmol) was added under nitrogen, and the mixture was heated to 80°C for 12 hours. Complete reaction was 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 matter were removed by filtration, and the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), and dried over anhydrous magnesium sulfate. The solvent was removed by filtration and vacuum distillation. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 15:1) to obtain 2.05 g of a colorless oily liquid (yield: 95.3%). mp 40-42°C.

[0181] 1 H NMR (300MHz, DMSO-d6) δ7.52-7.42(m,2H,ArH),7.35-7.25(m,4H,ArH),7.11(d,J=7.6Hz,1H,ArH),5.20(s,1H,OH),4.58(s,2H,CH2),2.06(s,3H,CH3).

[0182] Synthesis of ethyl 2-(2-((2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-1)

[0183] 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 sequentially added to a three-necked flask. Cesium carbonate (0.43 g, 1.33 mmol) was added to the reaction mixture under nitrogen. Pd(OAc)2 (0.01 g, 0.07 mmol) was added and the mixture was heated to 80°C for 12 hours. Complete reaction was 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 matter were removed by filtration, and 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 and the solvent was evaporated under reduced pressure. 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 with a yield of 51.8%.

[0184] 1H NMR(300MHz,Chloroform-d)δ7.54(dd,J=7.3Hz,1.7Hz,1H,ArH),7.43-7.35(m,1H,ArH),7.30-7.13(m,6H,ArH),6.64(d,J=8.3Hz,1H,ArH),5.43(s,2H ,OCH2),4.27(q,J=7.1Hz,2H,CH2CH3),3.78(s,2H,NCH2),3.49(s,2H,NCH2),3.03(s,4H,NCH2CH2),2.25(s,3H,ArCH3),1.34(t,J=7.1Hz,3H,CH2CH3).

[0185] Example 15

[0186] ethyl 2-(2-((2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-2: R 1 =CH3, R 3 =CH3,R 4 =H)

[0187] Synthesis of (2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methanol (XV-2)

[0188] 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 followed to obtain 2.00 g of a white solid in a 94.7% yield. mp 48-50°C.

[0189] 1 H NMR(300MHz,DMSO-d6)δ7.43(d,J=7.5Hz,1H,ArH),7.32-7.23(m,4H,ArH),7.08-7.03(m,1H,ArH),6.9 8(d,J=7.5Hz,1H,ArH),5.17(t,J=5.3Hz,1H,OH),4.58(s,2H,CH2),2.00(s,3H,CH3),1.94(s,3H,CH3).

[0190] Synthesis of ethyl 2-(2-((2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-2)

[0191] Using compounds IX-1 (120 mg, 0.47 mmol) and XV-2 (120 mg, 0.57 mmol) as raw materials, the operation was the same as ID-1 to obtain 67 mg of a yellow viscous liquid with a yield of 32.9%.

[0192] 1 H NMR(300MHz,Chloroform-d)δ7.45(dd,J=7.7Hz,1.5Hz,1H,ArH),7.27(s,1H,ArH),7.2 5-7.18(m,4H,ArH),7.13-7.08(m,2H,ArH),6.61(d,J=8.4Hz,1H,ArH),5.38(s,2H,OCH 2),4.24(q,J=7.1Hz,2H,CH2CH3),3.87(s,2H,NCH2),3.54(s,2H,COCH2),3.11-2.86(m ,4H,NCH2CH2),2.07(s,3H,ArCH3),2.06(s,3H,ArCH3),1.31(t,J=7.1Hz,3H,CH2CH3).

[0193] Example 16

[0194] Ethyl 2-(2-((2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-3: R 1 =CH3, R 3 =Cl,R 4 =H)

[0195] Synthesis of (2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)methanol (XV-3)

[0196] 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 followed to obtain 500 mg of a white solid in a yield of 86.4%. mp 74-76°C.

[0197] 1 H NMR(400MHz,DMSO-d6)δ7.56-7.54(m,1H,ArH),7.46-7.39(m,3H,ArH),7.29-7.22( m,2H,ArH),7.01(dd,J=7.6Hz,1.4Hz,1H,ArH),4.56(s,2H,CH2),1.96(s,3H,CH3).

[0198] Synthesis of ethyl 2-(2-((2'-chloro-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-3)

[0199] Using compound IX-1 (170 mg, 0.73 mmol) and XV-3 (136 mg, 0.88 mmol) as raw materials, the operation was the same as compound ID-1 to obtain 150 mg of yellow viscous liquid with a yield of 51.8%.

[0200] 1 H NMR(300MHz,Chloroform-d)δ7.57-7.55(m,2H,ArH),7.28-7.20(m,3H,ArH),7.18-7.13(m,2H,ArH),7.06(dd,J =7.6Hz,1.5Hz,1H,ArH),6.53(d,J=8.4Hz,1H,ArH),5.38(s,2H,OCH2),4.17(t,J=7.1Hz,2H,OCH2CH3),3.69(s, 2H,NCH2),3.39(s,2H,NCH2CO),2.93(s,4H,NCH2CH2),2.06(s,3H,ArCH3),1.22(d,J=7.1Hz,3H,CH3).

[0201] Example 17

[0202] Ethyl 2-(2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-4: R 1 =CH3, R 3 =H,R 4 =H)

[0203] Synthesis of (2-methyl-[1,1'-biphenyl]-3-yl)methanol (XV-4)

[0204] 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 followed to obtain 320 mg of a white solid in a 64.9% yield. mp 63-65°C.

[0205] 1H NMR(300MHz,DMSO-d6)δ7.48-7.35(m,4H,ArH),7.30-7.21(m,3H,ArH),7.09(dd ,J=7.6Hz,1.5Hz,1H,ArH),5.16(s,1H,OH),4.56(s,2H,CH2),2.12(s,3H,CH3).

[0206] Synthesis of ethyl 2-(2-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-4)

[0207] Using compound IX-1 (150 mg, 0.59 mmol) and XV-4 (140 mg, 0.71 mmol) as raw materials, the operation was the same as compound ID-1 to obtain 115 mg of colorless viscous liquid with a yield of 46.9%.

[0208] 1 H NMR(300MHz,Chloroform-d)δ7.47-7.36(m,4H,ArH),7.35-7.29(m,3H,ArH),7.24-7.20(m,2H,ArH),6.60(d,J=8.3Hz,1H,ArH),5.39(s,2H,OCH 2),4.24(q,J=7.1Hz,2H,CH2CH3),3.80(s,2H,NCH2),3.49(s,2H,CH2CO),3.03(s,4H,NCH2CH2),2.27(s,3H,ArCH3),1.32(t,J=7.1Hz,3H,CH3).

[0209] Example 18

[0210] Ethyl 2-(2-((2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-5: R 1 =Cl, R 3 =F,R 4 =H)

[0211] Synthesis of methyl 3-bromo-2-chlorobenzoate (XI-2)

[0212] Using 3-bromo-2-chlorophenylboronic acid X-2 (5.00 g, 21.23 mmol) and thionyl chloride (3.10 mL, 42.47 mmol) as raw materials, the same operation as compound XI-1 was performed to obtain 5.29 g of light brown oil with a yield of 99.88%.

[0213] 1 H NMR (300MHz, DMSO-d6) δ8.18(dd,J=8.0Hz,1.6Hz,1H,ArH),7.96(dd,J=7.7Hz,1.6Hz,1H,ArH),7.61(t,J=7.9Hz,1H,ArH),4.08(s,3H,CH3).

[0214] Synthesis of (3-bromo-2-chlorophenyl)methanol (XII-2)

[0215] Compound XI-2 (5.29 g, 21.20 mmol) was reduced with LiAlH4 (0.80 g, 21.20 mmol) using the same procedure as compound XII-1 to give 4.60 g of a white solid powder in a 97.9% yield. mp 56-58°C.

[0216] 1 H NMR(300MHz,DMSO-d6)δ7.66(d,J=7.9Hz,1H,ArH),7.56(d,J=7.5Hz,1H,ArH),7 .31(t,J=7.7Hz,1H,ArH),5.55(t,J=5.7Hz,1H,OH),4.58(d,J=5.5Hz,2H,CH2).

[0217] Synthesis of (2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)methanol (XV-5)

[0218] Compound XV-2 (0.50 g, 2.26 mmol) and III-1 (0.38 g, 2.71 mmol) were used as starting materials and the same procedure as for compound XV-1 was followed to give 0.32 g of a light brown solid in a 59.9% yield. mp 44-46°C.

[0219] 1 H NMR (300MHz, DMSO-d6) δ7.84(d,J=7.7Hz,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).

[0220] Synthesis of ethyl 2-(2-((2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-5)

[0221] Using compound IX-1 (150 g, 0.59 mmol) and XV-5 (170 mg, 0.71 mmol) as raw materials, the operation was the same as compound ID-1 to obtain 116 mg of colorless viscous liquid with a yield of 43.3%.

[0222] 1 H NMR(300MHz,Chloroform-d)δ7.59(dd,J=7.4Hz,1.9Hz,1H,ArH),7.44-7.27(m,4H,ArH),7.25-7.12(m,3H,ArH),6.64(d,J=8.3Hz,1H,ArH) ,5.52(s,2H,OCH2),4.23(q,J=7.1Hz,2H,CH2CH3),3.75(s,2H,COCH2),3.45(s,2H,NCH2),2.98(s,4H,NCH2CH2),1.29(t,J=7.1Hz,3H,CH3).

[0223] Example 19

[0224] Ethyl 2-(2-((2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-6: R 1 =Cl, R 3 =CH3,R 4 =H)

[0225] Synthesis of (2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)methanol (XV-6)

[0226] Compounds XII-2 (0.50 g, 2.26 mmol) and III-2 (0.37 g, 2.71 mmol) were used as starting materials and the same procedure as for compound XV-1 was followed to give 0.32 g of a light brown solid in a 59.9% yield. mp 44-46°C.

[0227] 1 H NMR (400MHz, DMSO-d6) δ7.63-7.51(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).

[0228] Synthesis of ethyl 2-(2-((2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-6)

[0229] Using compound IX-1 (150 mg, 0.59 mmol) and XV-6 (165 mg, 0.71 mmol) as raw materials, the operation was the same as compound ID-1 to obtain 117 mg of colorless viscous liquid with a yield of 44.0%.

[0230] 1 H NMR(300MHz,Chloroform-d)δ7.56(dd,J=7.7Hz,1.7Hz,1H,ArH),7.34-7.27(m,3H,A rH),7.25-7.21(m,2H,ArH),7.20-7.12(m,2H,ArH),6.67-6.65(d,J=8.3Hz,1H,ArH) ,5.51(s,2H,OCH2),4.22(q,J=7.1Hz,2H,CH2CH3),3.78(s,2H,NCH2),3.47(s,2H,CH 2CO), 2.99 (s, 4H, NCH2CH2), 2.12 (s, 3H, ArCH3), 1.32-1.30 (t, J = 7.1Hz, 3H, CH2CH3).

[0231] Example 20

[0232] Ethyl 2-(2-((2,2'-dichloro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-7: R 1 =Cl, R 3 =Cl,R 4 =H)

[0233] Synthesis of (2,2'-dichloro-[1,1'-biphenyl]-3-yl)methanol (XV-7)

[0234] Using compound XII-2 (0.50 g, 2.26 mmol) and III-3 (0.42 g, 2.71 mmol) as raw materials, the operation was the same as compound XV-1 to obtain 0.31 g of light brown oil with a yield of 54.2%.

[0235] 1 H NMR(300MHz,DMSO-d6)δ7.88-7.82(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).

[0236] Synthesis of ethyl 2-(2-((2,2'-dichloro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-7)

[0237] Using compound IX-I (150 mg, 0.59 mmol) and XV-7 (165 mg, 0.71 mmol) as raw materials, the operation was the same as compound ID-1 to obtain 130 mg of colorless viscous liquid with a yield of 46.8%.

[0238] 1 H NMR(300MHz,Chloroform-d)δ7.60(dd,J=7.6Hz,1.8Hz,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=7.1Hz,2H,CH2CH3),3.76(s,2H,NCH2),3.45(s,2H,COCH2),2.98(s,4H,NCH2CH2),1.30(t,J=7.1Hz,3H,CH3).

[0239] Example 21

[0240] Ethyl 2-(2-((2-chloro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-8: R 1 =Cl, R 3 =H,R 4 =H)

[0241] Synthesis of (2-chloro-[1,1'-biphenyl]-3-yl)methanol (XV-8)

[0242] Compounds XII-2 (0.50 g, 2.26 mmol) and III-4 (0.41 g, 2.71 mmol) were used as starting materials and the same procedure as for compound XV-1 was used to obtain 0.41 g of a pale yellow solid in an 83.1% yield. mp 76-78°C.

[0243] 1H NMR (400MHz, DMSO-d6) δ7.59(dd,J=7.6Hz,1.7Hz,1H,ArH),7.49-7.38(m,6H,ArH),7.28(dd,J=7.6Hz,1.8Hz,1H,ArH),5.48(s,1H,OH),4.63(s,2H,CH2).

[0244] Synthesis of ethyl 2-(2-((2-chloro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-8)

[0245] Using compound IX-1 (150 mg, 0.59 mmol) and XV-8 (155 mg, 0.71 mmol) as raw materials, the operation was the same as compound ID-1 to obtain 187 mg of colorless viscous liquid with a yield of 72.7%.

[0246] 1 H NMR(300MHz,Chloroform-d)δ7.55(dd,J=6.9Hz,2.5Hz,1H,ArH),7.46-7.37(m,6H,ArH),7.34-7.28(m,2H,ArH),6.65(d,J=8.4Hz,1H,ArH) ,5.52(s,2H,OCH2),4.23(q,J=7.2Hz,2H,CH2CH3),3.81(s,2H,NCH2),3.49(s2H,COCH2),3.02(s,4H,NCH2CH2),1.30(t,J=7.1Hz,3H,CH3).

[0247] Example 22

[0248] Ethyl 2-(2-((2,2'-difluoro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-9: R 1 =F, R 3 =F,R 4 =H)

[0249] Synthesis of methyl 3-bromo-2-fluorobenzoate (XI-3)

[0250] Starting from 3-bromo-2-chlorophenylboronic acid X-3 (5.00 g, 21.23 mmol) and thionyl chloride (3.10 mL, 42.47 mmol), the same procedure as for compound XI-1 was used to obtain 5.30 g of a pale yellow solid in a 99.6% yield. mp 35-36°C.

[0251] 1 H NMR (300MHz, DMSO-d6) δ7.94 (ddd, J=8.1Hz, 6.4Hz, 1.8Hz, 1H, ArH), 7.83 (ddd, J=8 .1Hz, 6.6Hz, 1.7Hz, 1H, ArH), 7.25 (td, J=7.9Hz, 1.0Hz, 1H, ArH), 3.83 (s, 3H, CH3).

[0252] Synthesis of (3-bromo-2-fluorophenyl)methanol (XII-3)

[0253] Compound XI-3 (5.30 g, 22.74 mmol) was reduced with LiAlH4 (0.86 g, 22.74 mmol) using the same procedure as compound XII-1 to give 4.30 g of a pale yellow solid in a 92.2% yield. mp 34-35°C.

[0254] 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)

[0255] Compound XII-3 (0.50 g, 2.44 mmol) and III-1 (0.41 g, 2.93 mmol) were used as starting materials and the same procedure as for compound XV-1 was followed to obtain 0.37 g of a white solid in a yield of 68.9%. mp 50-52°C.

[0256] 1 H NMR (300MHz, DMSO-d6) δ7.49-7.32(m,3H,ArH),7.28-7.18(m,4H,ArH),4.53(s,2H,CH2).

[0257] Synthesis of ethyl 2-(2-((2,2'-difluoro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-9)

[0258] Using compound IX-1 (150 mg, 0.59 mmol) and XV-9 (156 mg, 0.71 mmol) as raw materials, the operation was the same as compound ID-1 to obtain 100 mg of colorless viscous liquid with a yield of 38.7%.

[0259] 1H NMR(300MHz,Chloroform-d)δ7.56-7.51(m,1H,ArH),7.42-7.33(m,4H,ArH),7.22-7.13(m,3H,ArH),6.61(d,J=8.4Hz,1H,ArH),5.48(s, 2H,OCH2),4.23(q,J=7.2Hz,2H,CH2CH3),3.79(s,2H,NCH2),3.48(s,2H,CH2CO),3.02-2.99(m,4H,NCH2CH2),1.31(t,J=7.1Hz,3H,CH3).

[0260] Example 23

[0261] Ethyl 2-(2-((2-fluoro-2'-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-10: R 1 =F, R 3 =CH3,R 4 =H)

[0262] Synthesis of (2-Fluoro-2'-methyl-[1,1'-biphenyl]-3-yl)methanol (XV-10)

[0263] Using compound XII-3 (0.50 g, 2.44 mmol) and III-2 (0.40 g, 2.93 mmol) as raw materials, the operation was the same as compound XVII-1 to obtain 0.34 g of colorless oil with a yield of 63.7%.

[0264] 1 H NMR(300MHz,DMSO-d6)δ7.51(td,J=7.3Hz,1.9Hz,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).

[0265] Synthesis of ethyl 2-(2-((2-fluoro-2'-methyl-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-10)

[0266] Using compound IX-1 (150 mg, 0.59 mmol) and XV-10 (153 mg, 0.71 mmol) as raw materials, the operation was the same as compound ID-1 to obtain 130 mg of colorless viscous liquid with a yield of 50.8%.

[0267] 1 H NMR(300MHz,Chloroform-d)δ7.54-7.48(m,1H,ArH),7.31-7.28(m,2H,ArH),7.24-7.15(m,5H,ArH),6.61(d,J=8.3Hz,1H,ArH),5.46(s,2H,OCH2 ),4.23(q,J=7.1Hz,2H,CH2CH3),3.79(s,2H,NCH2),3.48(s,2H,CH2CO),3.00(s,4H,NCH2CH2),2.21(s,3H,ArCH3),1.31(t,J=7.1Hz,3H,CH2CH3).

[0268] Example 24

[0269] Ethyl 2-(2-((2'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-11: R 1 =F, R 3 =Cl,R 4 =H)

[0270] Synthesis of (2'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)methanol (XV-11)

[0271] Compounds XII-3 (0.50 g, 2.44 mmol) and III-3 (0.46 g, 2.93 mmol) were used as starting materials and the same procedure as for compound XV-1 was followed to give 0.34 g of a colorless oil in a yield of 58.9%. mp 34-35°C.

[0272] 1 H NMR (300MHz, DMSO-d6) δ7.62-7.51(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).

[0273] Synthesis of ethyl 2-(2-((2'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-11)

[0274] Using compound IX-1 (150 mg, 0.59 mmol) and XV-11 (167 mg, 0.71 mmol) as raw materials, the operation was the same as compound ID-1 to obtain 104 mg of colorless viscous liquid with a yield of 38.8%.

[0275] 1 H NMR(300MHz,Chloroform-d)δ7.58-7.52(m,2.0Hz,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= 8.4Hz,1H,ArH),5.47(s,2H,OCH2),4.23(q,J=7.1Hz,2H,CH2CH3),3.77(s,2H ,NCH2),3.46(s,2H,CH2CO),2.99(s,4H,NCH2CH2),1.30(t,J=7.1Hz,3H,CH3).

[0276] Example 25

[0277] Ethyl 2-(2-((2-fluoro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-12: R 1 =F, R 3 =H,R 4 =H)

[0278] Synthesis of (2-Fluoro-[1,1'-biphenyl]-3-yl)methanol (XV-12)

[0279] Compounds XII-3 (0.50 g, 2.44 mmol) and III-4 (0.45 g, 2.93 mmol) were used as starting materials and the same procedure as for compound XV-1 was followed to obtain 0.37 g of a white solid in a yield of 75.1%. mp 84-86°C.

[0280] 1 H NMR (300MHz, DMSO-d6) δ7.54-7.44(m,5H,ArH),7.43-7.36(m,2H,ArH),7.27(t,J=7.6Hz,1H,ArH),5.32(t,J=5.7Hz,1H,OH),4.60(d,J=5.2Hz,2H,CH2).

[0281] Synthesis of ethyl 2-(2-((2-fluoro-[1,1'-biphenyl]-3-yl)methoxy)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (ID-12)

[0282] Using compound IX-1 (150 mg, 0.59 mmol) and XV-12 (143 mg, 0.71 mmol) as raw materials, the operation was the same as compound ID-1 to obtain 149 mg of colorless viscous liquid with a yield of 60.2%.

[0283] 1 H NMR(300MHz,Chloroform-d)δ7.57-7.55(m,1H,ArH),7.49-7.38(m,6H,ArH),7.23-7.16(m,2H,ArH),6.61(d,J=8.4Hz,1H,ArH),5.47(s, 2H,OCH2),4.27(q,J=7.1Hz,2H,CH2CH3),3.83(s,2H,NCH2),3.51(s,2H,COCH2),3.06-3.01(m,4H,NCH2CH2),1.32(t,J=7.1Hz,3H,CH3).

[0284] Example 26

[0285] 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, R 3 =F,R 4 =H)

[0286] Compound ID-1 (60 mg, 0.14 mmol) was added to 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 completion of the reaction as monitored by TLC, the methanol was evaporated under reduced pressure and the pH was adjusted to 5-6 with 2 M HCl. A white solid precipitated and was filtered to yield 30 mg of the product (53.5% yield). mp 130-132°C.

[0287] 1H NMR (300MHz, DMSO-d6) δ7.50-7.40(m,3H,ArH),7.32-7.25(m,4H,ArH),7.18-7.16(m,1H,ArH),6.66(d,J=8. 3Hz,1H,ArH),5.34(s,2H,OCH2),3.67(s,4H,NCH2,CH2COOH),2.92-2.79(m,4H,NCH2CH2),2.11(s,3H,CH3).

[0288] HRMS(ESI):m / z[M+H] + Calcd for C 24 H 24 FN2O3:407.1771; Found:407.1768.

[0289] Example 27

[0290] 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, R 3 =F,R 4 =H)

[0291] Compound ID-1 (80 mg, 0.18 mmol) was added to a 25 mL eggplant-shaped flask and dissolved in THF. Lithium aluminum hydride (14 mg, 0.37 mmol) was slowly added at 0°C. The reaction was monitored for complete reaction. The reaction was quenched with saturated ammonium chloride solution. A white solid precipitated and was removed by filtration. The solid was washed with EA and the filtrate was concentrated and purified to afford 34 mg of a yellow solid in a 41.5% yield. mp 72-74°C.

[0292] 1 H NMR(300MHz,Chloroform-d)δ7.54(d,J=7.3Hz,1H,ArH),7.45-7.32(m,2H,ArH),7.30-7.14(m,5H,ArH),6.67(d,J=8.3Hz,1H,ArH),5.44 (s,2H,OCH2),3.81(t,J=5.3Hz,2H,CH2OH),3.76(s,2H,NCH2),3.06-2.95(m,4H,NCH2CH2),2.85(t,J=5.3Hz,2H,NCH2),2.26(s,3H,CH3).

[0293] HRMS(ESI):m / z[M+H]+ Calcd for C 24 H 26 FN2O2:393.1978; Found:393.1975.

[0294] Example 28

[0295] 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, R 3 =CH3,R 4 =H)

[0296] Compound ID-2 (100 mg, 0.23 mmol) and LiAlH4 (18 mg, 0.47 mmol) were used as starting materials and the same procedure as for compound ID-13 was followed to obtain 34 mg of a yellow solid in a 41.5% yield. mp 96-98°C.

[0297] 1 H NMR(300MHz,Chloroform-d)δ7.47(d,J=7.6Hz,1H,ArH),7.27-7.21(m,5H,ArH),7.16-7.08(m,2H,ArH),6.61(d,J=8.4Hz,1H,ArH),5.39(s,2 H,OCH2),3.73(t,J=5.3Hz,2H,CH2OH),3.64(s,2H,NCH2),2.96-2.90(m,4H,NCH2CH2),2.76(t,J=5.3Hz,2H,NCH2),2.09(s,3H),2.06(s,3H).

[0298] HRMS(ESI):m / z[M+H] + Calcd for C 25 H 29 N2O2:389.2229; Found:389.2230.

[0299] Example 29

[0300] 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, R 3 =Cl,R 4 =H)

[0301] Compound ID-3 (150 mg, 0.37 mmol) and LiAlH4 (24 mg, 0.73 mmol) were used as starting materials and the same procedure as compound ID-13 was followed to obtain 100 mg of a yellow solid in a 66.6% yield. mp 108-110°C.

[0302] 1 H NMR(300MHz,Chloroform-d)δ7.58-7.50(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=8.4Hz,1H),Ar H,5.50-5.39(m,2H,OCH2),3.79(t,J=5.3Hz,2H,CH2OH),3.72(s,2H,NCH2) ,3.02-2.97(m,4H,NCH2CH2),2.83(t,J=5.3Hz,2H,NCH2),2.19(s,3H,CH3).

[0303] HRMS(ESI):m / z[M+H] + Calcd for C 24 H 26 ClN2O2:409.1683; Found:409.1687.

[0304] Example 30

[0305] 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, R 3 =H,R 4 =H)

[0306] Compound ID-4 (100 mg, 0.26 mmol) and LiAlH4 (20 mg, 0.53 mmol) were used as starting materials and the same procedure as for compound ID-12 was followed to give 55 mg of a yellow solid in a 55.6% yield. mp 152-154°C.

[0307] 1H NMR(300MHz,Chloroform-d)δ7.48-7.36(m,4H,ArH),7.35-7.28(m,3H,ArH),7.23(s,2H,ArH),6.62(d,J=8.3Hz,1H,ArH),5.39(s,2H, OCH2),3.74(t,J=5.3Hz,2H,CH2OH),3.66(s,2H,NCH2),3.00-2.92(m,4H,NCH2CH2),2.77(t,J=5.3Hz,2H,CH2CH2OH),2.28(s,3H,CH3).

[0308] HRMS(ESI):m / z[M+H] + Calcd for C 24 H 27 N2O2:375.2073; Found:375.2074.

[0309] Example 31

[0310] 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, R 3 =F,R 4 =H)

[0311] Compound ID-5 (106 mg, 0.23 mmol) and LiAlH4 (18 mg, 0.47 mmol) were used as starting materials and the same procedure as compound ID-13 was followed to obtain 76 mg of a yellow solid in a 79.0% yield. mp 116-118°C.

[0312] 1 H NMR(300MHz,Chloroform-d)δ7.60(dd,J=7.5Hz,2.0Hz,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 =8.4Hz,1H,ArH),5.52(s,2H,OCH2),3.75(t,J=5.3Hz,2H,CH2OH),3.69(s,2H,NCH2),2.99-2.93(m,4H,NCH2CH2),2.79(t,J=5.3Hz,2H,CH2CH2OH).

[0313] HRMS(ESI):m / z[M+H] + Calcd for C 23 H 23 ClFN2O2:413.1432; Found:413.1432.

[0314] Example 32

[0315] 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, R 3 =CH3,R 4 =H)

[0316] Compound ID-6 (60 mg, 0.13 mmol) and LiAlH4 (10 mg, 0.27 mmol) were used as starting materials and the same procedure as for compound ID-13 was followed to obtain 30 mg of a white solid in a 55.2% yield. mp 88-90°C.

[0317] 1 H NMR(300MHz,Chloroform-d)δ7.56(dd,J=7.6Hz,1.7Hz,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=8.5Hz,1 H,ArH),5.51(s,2H,OCH2),3.74(t,J=5.3Hz,2H,CH2OH),3.68(s,2H,NCH2),2 .96-2.93(m,4H,NCH2CH2),2.78(t,J=5.3Hz,2H,CH2CH2OH),2.11(s,3H,CH3).

[0318] HRMS(ESI):m / z[M+H] + Calcd for C 24 H 26 ClN2O2:409.1683; Found:409.1682.

[0319] Example 33

[0320] 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, R 3 =Cl,R 4 =H)

[0321] Compound ID-7 (120 mg, 0.26 mmol) and LiAlH4 (19 mg, 0.51 mmol) were used as starting materials and the same procedure as for compound ID-13 was followed to obtain 64 mg of a yellow solid in a 58.5% yield. mp 110-112°C.

[0322] 1 H NMR(300MHz,Chloroform-d)δ7.61(dd,J=7.7Hz,1.8Hz,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 =8.4Hz,1H,ArH),5.52(s,2H,OCH2),3.75(t,J=5.3Hz,2H,CH2OH),3.69(s,2H,NCH2),2.99-2.93(m,4H,NCH2CH2),2.79(t,J=5.3Hz,2H,CH2CH2OH).

[0323] HRMS(ESI):m / z[M+H] + Calcd for C 23 H 23 Cl2N2O2:429.1137; Found:429.1141.

[0324] Example 34

[0325] 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, R 3 =H,R 4 =H)

[0326] Compound ID-8 (187 mg, 0.43 mmol) and LiAlH4 (27 mg, 0.46 mmol) were used as starting materials and the same procedure as compound ID-13 was followed to obtain 80 mg of a white solid in a 47.3% yield. mp 148-150°C.

[0327] 1H NMR(300MHz,Chloroform-d)δ7.39(dd,J=6.9Hz,2.5Hz,1H,ArH),7.26-7.21(m,2H,ArH),7.17-7.06(m,5H,ArH),6.48(d,J=8.5Hz,1H, ArH),5.35(s,2H,OCH2),3.55(t,J=5.3Hz,2H,CH2OH),3.47(s,2H,NCH2),2.80-2.70(m,4H,NCH2CH2),2.58(t,J=5.3Hz,2H,CH2CH2OH).

[0328] HRMS(ESI):m / z[M+H] + Calcd for C 23 H 24 ClN2O2:395.1526; Found:395.1522.

[0329] Example 35

[0330] 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, R 3 =F,R 4 =H)

[0331] Compound ID-9 (100 mg, 0.23 mmol) and LiAlH4 (17 mg, 0.46 mmol) were used as starting materials and the same procedure as for compound ID-13 was followed to obtain 60 mg of a brown solid in a 66.4% yield. mp 60-62°C.

[0332] 1 H NMR(300MHz,Chloroform-d)δ7.57-7.52(m,1H,ArH),7.43-7.32(m,3H,ArH),7.25-7.13(m,4H,ArH),6.62(d,J=8.3Hz,1H,ArH), 5.48(s,2H,OCH2),3.74(t,J=5.3Hz,2H,CH2OH),3.66(s,2H,NCH2),2.95-2.92(m,4H,NCH2CH2),2.77(t,J=5.3Hz,2H,CH2CH2OH).

[0333] HRMS(ESI):m / z[M+H] + Calcd for C23 H 23 F2N2O2:397.1728; Found:397.1730.

[0334] Example 36

[0335] 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, R 3 =CH3,R 4 =H)

[0336] Compound ID-10 (130 mg, 0.30 mmol) and LiAlH4 (23 mg, 0.59 mmol) were used as starting materials and the same procedure as for compound ID-13 was followed to afford 90 mg of an off-white solid in a 76.7% yield. mp 62-64°C.

[0337] 1 H NMR(300MHz,Chloroform-d)δ7.56-7.48(m,1H,ArH),7.31-7.29(m,3H,ArH),7.25-7.18(m,4H,ArH),6.62(d,J=8.3Hz,1H,ArH),5.47(s,2H,OC H2),3.73(t,J=5.3Hz,2H,CH2OH),3.66(s,2H,NCH2),2.98-2.89(m,4H,NCH2CH2),2.77(t,J=5.3Hz,2H,CH2CH2OH),2.21(d,J=1.4Hz,3H,CH3).

[0338] HRMS(ESI):m / z[M+H] + Calcd for C 24 H 26 FN2O2:393.1978; Found:393.1981.

[0339] Example 37

[0340] 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, R 3 =Cl,R 4 =H)

[0341] Compound ID-11 (104 mg, 0.23 mmol) and LiAlH4 (17 mg, 0.46 mmol) were used as starting materials and the same procedure as for compound ID-13 was followed to afford 60 mg of a pale yellow solid in a 74.0% yield. mp 68-70°C.

[0342] 1 H NMR(300MHz,Chloroform-d)δ7.59-7.54(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=8.3H z,1H,ArH),5.48(s,2H,OCH2),3.74(t,J=5.3Hz,2H,CH2OH),3.68(s,2H,NCH2),2.97-2.92(m,4H,NCH2CH2),2.78(t,J=5.3Hz,2H,CH2CH2OH).

[0343] HRMS(ESI):m / z[M+H] + Calcd for C 23 H 23 ClFN2O2:413.1432; Found:413.1430.

[0344] Example 38

[0345] 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, Synthesis of (R3=H, R4=H)

[0346] Compound ID-11 (149 mg, 0.35 mmol) and LiAlH4 (17 mg, 0.46 mmol) were used as starting materials, and the same procedure as for compound ID-13 was followed to afford 70 mg of an off-white solid in a 52.3% yield. mp 72-74°C.

[0347] 1H NMR(300MHz,Chloroform-d)δ7.57-7.36(m,7H,ArH),7.25-7.17(m,2H,ArH),6.62(d,J=8.4Hz,1H,ArH),5.48(s,2H,OCH2 ),3.74(t,J=5.3Hz,2H,CH2OH),3.68(s,J=2.9Hz,2H,NCH2),2.99-2.90(m,4H,NCH2CH2),2.77(t,J=5.3Hz,2H,CH2CH2OH).

[0348] HRMS(ESI):m / z[M+H] + Calcd for C 23 H 24 FN2O2:379.1822; Found:379.1822.

[0349] Example 39

[0350] 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, R 3 =F,R 4 =H)

[0351] Compound ID-5 (400 mg, 0.88 mmol) was added to 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, the reaction was complete, and the methanol was evaporated under reduced pressure. The pH was adjusted to 5-6 with 2M HCl solution. A white solid precipitated and was filtered to give 262 mg of the product (69.8% yield). mp 101-108°C.

[0352] 1 H NMR(300MHz,Chloroform-d)δ7.59-7.52(m,1H,ArH),7.41-7.27(m,4H,ArH),7.22-7.01(m,3H,ArH),6.64( d,J=8.4Hz,1H,ArH),5.46(s,2H,OCH2),4.18(s,2H,NCH2),3.59(s,2H,COCH2),3.38-3.05(m,4H,NCH2CH2).

[0353] HRMS(ESI):m / z[M+H] +Calcd for C 23 H 21 ClFN2O3:427.1225Found:427.1223.

[0354] During the preparation of ID-26, a by-product was obtained, which was structurally identified as ID-27, m / z: 369.10 (M+H). 1 H-NMR(400MHz, DMSO-d6)δ:7.66(dd,1H,J=7.6&1.6Hz),7.53~7.47(m,1H),7.48~7.44(t,1H,J=15.2&7.6Hz),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(t,1H,J=10.4&5.2Hz),2.70~2.67(t,1H,J=10.4&5.2Hz)

[0355] Example 40

[0356] 2-(7-((2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-1-methyl-1,4-dihydropyridin[2,3-d]pyrimidin-3(2H)-yl)acetate (IE-1: R 1 =CH3, R 3 =CH3,R 4 =H)

[0357] Synthesis of tert-butyl (6-chloro-3-formylpyridin-2-yl)(methyl)carbamate (XVII)

[0358] Compound XVI (100 mg, 0.39 mmol) was added to a 25 mL eggplant-shaped flask and dissolved in DMF (10 mL). CHI (49 μL, 0.78 mmol) was slowly added dropwise to the reaction mixture, cooled to 0°C, and 60% NaH (18 mg, 0.469 mmol) was added portionwise. After addition, the mixture was stirred in an ice bath for 30 minutes and allowed to react at room temperature overnight. TLC (petroleum ether:ethyl acetate = 15:1) indicated near-completed starting material. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude product. Purification by column chromatography afforded 0.09 g of a colorless liquid in an 85.2% yield.

[0359] 1H NMR(300MHz,Chloroform-d)δ9.90(s,1H,CHO),8.13(d,J=8.1Hz,1H,ArH),7.29(d,J=8.1Hz,1H,ArH),3.44(s,3H,NCH3),1.43(s,9H,CH3).

[0360] Synthesis of ((2-((tert-Butoxycarbonyl)(methyl)amino)-6-chloropyridin-3-yl)methyl)glycine methyl ester (XVIII-1)

[0361] To a 25 mL eggplant-shaped flask were added compound XVII (0.70 g, 2.73 mmol), glycine methyl ester hydrochloride (0.69 g, 5.47 mmol) and dichloromethane (10 mL). After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (1.16 g, 5.47 mmol) was added portionwise at 0°C. After the addition was complete, the mixture was reacted at room temperature for 4 hours. After the reaction of the raw materials was completed as monitored by TLC, 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 combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude oil. 0.35 g of a colorless liquid was obtained by column chromatography (yield: 37.4%).

[0362] 1 H NMR(300MHz,Chloroform-d)δ7.95(d,J=8.0Hz,1H,ArH),7.29(d,J=8.2Hz,1H,ArH),4.86(br,1H,N H)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).

[0363] Synthesis of ((6-chloro-2-(methylamino)pyridin-3-yl)methyl)glycine methyl ester (XIX-1)

[0364] Compound XVIII-1 (0.67 g, 1.95 mmol) was added to a 50 mL eggplant-shaped flask and dissolved in ethyl acetate (5 mL). A solution of ethyl acetate and hydrogen chloride was added and allowed to react at room temperature for 12 hours. A white solid precipitated and was filtered to obtain 0.34 g of the white solid, a yield of 71.6%. mp 110-112°C.

[0365] 1H NMR (300MHz, DMSO-d6) δ9.67 (s, 2H, NH·HCl), 7.58 (d, J=7.7Hz, 1H, ArH), 6.60 (d, J=7.6Hz ,1H,ArH),4.11(s,2H,ArCH2),4.03(s,2H,CH2CO),3.72(s,3H,OCH3),2.79(s,3H,NHCH3).

[0366] Synthesis of methyl 2-(7-chloro-1-methyl-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl)acetate (XX-1)

[0367] 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, triethylamine (249 μl, 1.80 mmol) was added and stirred for 10 minutes. Paraformaldehyde (0.03 g, 1.08 mmol) was added and allowed to react at room temperature for 8 hours. After TLC monitoring of the reaction, the organic solvent was removed by concentration under reduced pressure. Water was added and the mixture was 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 afford a crude oil. Column chromatography afforded 0.20 g of a colorless liquid in a yield of 87.4%.

[0368] 1 H NMR(300MHz,Chloroform-d)δ7.01(d,J=7.5Hz,1H,ArH),6.50(d,J=7.5Hz,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)

[0369] Synthesis of methyl 2-(7-((2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-1-methyl-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl)acetate (IE-1)

[0370] 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 sequentially to a three-necked flask. Cesium carbonate (430 mg, 1.33 mmol) was then added. Under nitrogen, Pd(OAc)2 (15 mg, 0.07 mmol) was added and the temperature was raised to 80°C for 12 hours. TLC (petroleum ether:ethyl acetate = 4:1) confirmed the complete reaction. Heating was discontinued and the mixture was cooled to room temperature. The palladium catalyst and insoluble matter were removed by filtration, and the mixture was diluted with water (10 mL). Extraction was performed 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. Filtration and evaporation of the solvent under reduced pressure removed the residue. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 10:1) to afford 150 mg of a colorless, transparent liquid in a yield of 51.79%.

[0371] 1 H NMR(400MHz,Chloroform-d)δ(ppm):7.56-7.35(m,2H,ArH),7.29(d,J=1.8Hz,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=4.1Hz,2H,NCH2),3. 42(dd,J=3.1Hz,2.6Hz,2H,COCH2),3.03(q,J=3.8Hz,2.7Hz,3H,ArCH3),2.60(s,3H,NCH3),2.11(s,3H,ArCH3).

[0372] Example 41

[0373] (R)-2-(7-((3'-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-1-methyl-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl)acetate (IE-2: R 1 =CH3, R 3 =CH3, )

[0374] To a 50 mL sealed tube were added compound XV-2 (0.43 g, 0.64 mmol), XX-1 (0.25 g, 0.93 mmol), Cs2CO3 (0.61 g, 1.56 mmol), Pd(OAc)2 (0.02 g, 0.09 mmol), t-BuXPhos (0.08 g, 0.19 mmol), and toluene (10 mL). N2 was then added for protection and the mixture was refluxed at 80°C for 36 hours. After most of the starting materials had reacted, as monitored by TLC, the mixture was filtered through celite and concentrated under reduced pressure to afford the crude product. Column chromatography afforded 110 mg of a pale yellow oil, which was then purified to afford 90 mg of the product, in a yield of 16.8%.

[0375] 1 H NMR(300MHz,Chloroform-d)δ7.50(d,J=7.5Hz,1H,ArH),7.30-7.21(m,2H,ArH),7.15-7.09(m,2H,ArH),6.90(d,J=7.9Hz,1H,ArH),6.81 (d,J=7.5Hz,1H,ArH),6.12(d,J=7.9Hz,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 / 2CH2),2.86-2.81(m,2H,CH2),2.71-2.64(m, 1H,1 / 2CH2),2.50-2.43(m,1H,1 / 2CH2),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).

[0376] Example 42

[0377] 2-(7-((2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-1-methyl-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl)acetic acid (IE-3: R 1 =CH3, R 3 =CH3,R 4 =H)

[0378] Compound IE-1 (0.20 g, 0.46 mmol) was added to a 10 mL eggplant-shaped flask and dissolved in methanol (2 mL). 2M LiOH (1 mL) was added and stirred at room temperature for 4 hours. After completion of the reaction as monitored by TLC, the methanol was evaporated under reduced pressure and the pH was adjusted to 5-6 with 1M HCl solution. A white solid precipitated and was filtered. The crude product was slurried three times with dichloromethane to yield 70 mg of a white solid product in a 36.5% yield. mp 132-134°C.

[0379] 1 H NMR(400MHz,Chloroform-d)δ7.59-7.38(m,2H,ArH),7.32(d,J=1.8Hz,1H,ArH),7.30-7.23(m,2H,ArH),7.15 -7.12(m,3H,ArH),6.01-5.97(m,1H,ArH),5.53(s,2H,OCH2),4.16(s,2H,NCH2N),3.72(q,J=4.1Hz,2H,NCH2), 3.45(dd,J=3.1Hz,2.6Hz,2H,COCH2),3.06(s,3H,ArCH3),2.63(s,3H,NCH3),2.14(s,3H,ArCH3).

[0380] HRMS(ESI):m / z[M+H] + Calcd for C 25 H 28 N3O3:418.2030; Found:418.2132.

[0381] Example 43

[0382] (R)-2-(7-((3'-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-1-methyl-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl)acetic acid (IE-4: R 1 =CH3, R 3 =CH3, )

[0383] Compound IE-2 (90 mg, 0.16 mmol) and 2M LiOH (1 mL) were used as starting materials, and the same procedures as those for IE-3 were followed to obtain 80 mg of an off-white solid product in a 54.7% yield. mp 162-164°C.

[0384] 1H NMR (300MHz, DMSO-d6) δ7.43(d,J=7.5Hz,1H,ArH),7.26(d,J=8.1Hz,1H,ArH),7.2(d,J=8.5Hz,1H,ArH),7.15(d,J=7.8Hz,1H,ArH),7.04(d,J=7.5Hz, 1H, ArH), 6.97 (d, J=8.2Hz, 1H, ArH), 6.69 (d, J=7.6Hz, 1H, ArH), 6.01 (d, J= 7.8Hz,1H,ArH),5.36(s,2H,OCH2),4.25(s,1H,OH),4.16(s,2H,NCH2N),4.- 0-4.13(m,3H,OCH2CH2,CH),3.82(s,2H,ArCH2N),3.32(s,4H,CHCH2N,NCH2),2.97(s,3H,NCH3),2.90-2.79(m,1H,1 / 2NCH2CH2),2.79-2.68(m,3H,1 / 2 NCH2CH2,NCH2CH2),2.67-2.58(m,1H,1 / 2CH2CH2CH),2.02(s,3H,ArCH3),1.85(s,3H,ArCH3),1.99-1.91(m,2H,CH2),1.70-1.65(m,1H,1 / 2CH2CH2CH).

[0385] HRMS(ESI):m / z[M+H] + Calcd for C 32 H 41 N4O5:561.3077; Found:561.3079.

[0386] Example 44

[0387] 2-(2-((2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)carbamoyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetic acid ethyl ester (IF-1: R 1 =Cl, R 3 =F,R 4 =H)

[0388] Synthesis of tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-acetate (XXI)

[0389] To a 25 mL eggplant-shaped flask, add 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride VIII (250 mg, 1.22 mmol), dissolve in 5 mL of DCM, and dropwise add triethylamine (508 μl, 3.66 mmol). Add (Bco)2O (399 mg, 1.83 mmol). Monitor the reaction for complete reaction, dilute with 5 mL of water, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter, remove the solvent, and evaporating under reduced pressure. The crude product is purified to yield 320 mg of a white solid, a 97.7% yield. mp 66-68°C.

[0390] 1 H NMR(300MHz,Chloroform-d)δ7.39(d,J=8.1Hz,1H,ArH),7.18(d,J=8.1Hz,1H,ArH),4.57(s, 2H,NCH2),3.74(t,J=5.9Hz,2H,NCH2CH2),2.99(t,J=6.0Hz,2H,NCH2CH2),1.50(s,9H,CH3).

[0391] Synthesis of tert-butyl 2-cyano-7,8-dihydro-1,6-naphthyridine-6(5H)-acetate (XXII)

[0392] Compound XXI (500 mg, 1.86 mmol) and zinc cyanide (240 mg, 2.05 mmol) were placed in a three-necked flask and dissolved in 5 mL of DMF. Under nitrogen, Pd(PPh3)4 (215 mg, 0.19 mol) was added and the mixture was heated to 120°C for 10 hours. TLC (petroleum ether:ethyl acetate = 2:1) monitored the reaction for complete reaction. Heating was discontinued and the mixture was cooled to room temperature. The palladium catalyst and insoluble matter were removed by filtration, and 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. Filtration and evaporation of the solvent under reduced pressure removed the residue, which was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 5:1) to afford 300 mg of a white solid in a 62.2% yield. mp 112-114°C.

[0393] 1 H NMR(300MHz,Chloroform-d)δ7.54(s,2H,ArH),4.66(s,2H,NCH2),3.77(t,J=6.0Hz,2H,NCH2CH2),3.04(t,J=6.0Hz,2H,NCH2CH 2) ,1.49(s,9H,CH3).

[0394] Synthesis of 6-(2-(tert-Butoxy)-2-oxoethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylic acid (XXIII)

[0395] Compound XXII (1.00 g, 3.86 mol) was dissolved in methanol, and a KOH solution (1.08 g, 19.28 mol) was added. The reaction temperature was raised to 80°C for 12 hours. TLC (dichloromethane:methane = 10:1) confirmed the complete reaction. 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 solvent was removed by filtration and evaporated under reduced pressure. The residue was separated by column chromatography (dichloromethane:methanol = 25:1 to 5:1) to obtain 630 mg of a white solid, with a yield of 58.7%. mp 162-164°C.

[0396] 1 H NMR (300MHz, Chloroform-d) δ8.05(s,1H,ArH),7.66(s,1H,ArH),4.69(s,2H,NCH2),3.78(s,2H,NCH2CH2),3.06(s,2H,NCH2CH2),1.50(s,9H,CH3).

[0397] Synthesis of 2-chloro-2'-fluoro-[1,1'-biphenyl]-3-amine (IV-2)

[0398] 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-necked flask. Potassium carbonate (1.87 g, 13.6 mmol) dissolved in water was added to the reaction mixture. Under nitrogen, Pd(PPh3)4 (0.28 g, 0.20 mmol) was added and the temperature was raised to 80°C for 10 hours. TLC (petroleum ether:ethyl acetate = 15:1) monitored the reaction for complete reaction. Heating was discontinued and the mixture was cooled to room temperature. The palladium catalyst and insoluble matter were removed by filtration, and 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. Filtration and evaporation of the solvent under reduced pressure removed the solvent. The residue was purified by column chromatography to yield 0.97 g of a white solid powder in a 91.4% yield. mp 78-80°C.

[0399] 1H NMR(300MHz,DMSO-d6)δ7.43-7.40(m,1H,ArH),7.32-7.22(m,3H,ArH),7.08(dd,J=8.1Hz,7.4Hz, 1H, ArH), 6.85 (dd, J = 8.1Hz, 1.6Hz, 1H, ArH), 6.50 (dd, J = 7.4Hz, 1.6Hz, 1H, ArH), 5.48 (s, 2H, NH).

[0400] Synthesis of tert-butyl 2-((2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-)carboxylate (XXIV)

[0401] 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 mixture was allowed to react at room temperature for 12 hours. TLC (dichloromethane:methanol = 25:1) monitored the reaction, and the reaction was stopped. The mixture was diluted with 5 mL of water and extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by filtration under reduced pressure, and the residue was purified by column chromatography to yield 580 mg of a white solid in a 67.1% yield. mp 134-136°C.

[0402] 1 H NMR(300MHz,Chloroform-d)δ10.86(s,1H,NH),8.70(dd,J=8.3Hz,1.6Hz,1H,ArH),8.13(d, J=7.9Hz,1H,ArH),7.63(d,J=8.0Hz,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=7.6Hz,1.6Hz,1H,ArH),4.68(s, 2H,NCH2),3.79(t,J=5.9Hz,2H,NCH2CH2),3.07(t,J=6.0Hz,2H,NCH2CH2),1.51(s,9H,CH3).

[0403] Synthesis of N-(2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide (XXV)

[0404] 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. TLC (dichloromethane:methanol = 15:1) monitored the reaction to determine complete reaction. The solvent was then evaporated under reduced pressure to yield 616 mg of a pale yellow solid, a yield of 99.9%. The mp was greater than 250°C.

[0405] 1 H NMR (400MHz, DMSO-d6) δ10.72(s,1H,NH),8.45(m,1H,ArH),8.11(d,J=8.0Hz,1H,ArH),8.00(d,J=8.0Hz,1H,ArH),7.50-7.55(m,2H,ArH ),7.43-7.33(m,3H,ArH),7.25(dd,J=7.6Hz,1.6Hz,1H,ArH),4.44(s,2H,NCH2),3.54(s,2H,NCH2CH2),3.24(t,J=6.2Hz,2H,NCH2CH2).

[0406] Synthesis of ethyl 2-(2-((2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)carbamoyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetate (IF-1): Compound XXV (250 mg, 0.66 mmol) was dissolved in THF. 60% NaH (31.5 mg, 1.31 mmol) was slowly added dropwise under ice-cooling. The mixture was brought to room temperature and allowed to react for 30 minutes. Ethyl bromoacetate (87 μl, 0.79 mmol) was then slowly added dropwise. TLC (dichloromethane:methanol = 25:1) monitored the complete reaction of the starting material and stopped the reaction. The reaction was quenched with saturated NH4Cl solution, diluted with 5 mL of water, and extracted with ethyl acetate (5 mL x 3). The product was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was separated by column chromatography to yield 126 mg of a pale yellow solid (41.11% yield). mp 158-160°C.

[0407] 1H NMR(400MHz,Chloroform-d)δ10.86(s,1H,NH),8.70(d,J=8.2Hz,1H,ArH),8.08(d,J=7.9Hz,1H,ArH),7.55(d, J=7.9Hz,1H,ArH),7.44-7.36(m,2H,ArH),7.34-7.29(m,1.7Hz,1H,ArH),7.23-7.15(m,2H,ArH),7.14-7.09(m, 1H, ArH), 4.28 (q, J = 7.1Hz, 2H, CH3CH2), 3.99 (s, 2H, NCH2), 3.53 (s, 2H, COCH2), 3.22-3.07 (m, 4H, NCH2CH2), 1.31 (t, J = 7.1Hz, 3H, CH3).

[0408] Example 45

[0409] N-(2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)-6-(2-hydroxyethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide (IF-2: R 1 =Cl, R 3 =F,R 4 =H)

[0410] Compound IF-1 (60 mg, 0.13 mmol) was dissolved in THF. LiAlH₄ (10 mg, 0.26 mmol) was added under an ice bath, and the reaction was allowed to proceed to room temperature. TLC (dichloromethane:methanol = 25:1) monitored the reaction to be complete, and the reaction was stopped. The reaction was quenched with saturated NH₄Cl solution, diluted with 5 mL of water, and extracted with ethyl acetate (5 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was isolated by column chromatography to yield 36 mg of a white solid (54.6% yield). mp 88-90°C.

[0411] 1H NMR(300MHz,Chloroform-d)δ10.85(s,1H,NH),8.70(d,J=8.4Hz,1H,ArH),8.09(d,J=7 .9Hz,1H,ArH),7.57(d,J=7.9Hz,1H,ArH),7.40(t,J=7.7Hz,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=5.3Hz,2H,CH2OH),3.16(t,J =5.4Hz,2H,NCH2CH2),3.04(t,J=5.7Hz,2H,NCH2CH2),2.84(t,J=5.3Hz,2H,CH2CH2OH).

[0412] HRMS(ESI):m / z[M+H] + Calcd for C 23 H 22 ClFN3O2:426.1385; Found:426.1382.

[0413] Example 46

[0414] 2-(2-((2-chloro-2'-fluoro-[1,1'-biphenyl]-3-yl)carbamoyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)acetic acid (IF-3: R 1 =Cl, R 3 =F,R 4 =H)

[0415] Compound IF-1 (60 mg, 0.13 mmol) was dissolved in ethanol, and a NaOH solution (10 mg, 0.26 mmol) was added. The mixture was stirred at room temperature. TLC (dichloromethane:methanol = 5:1) confirmed the complete reaction and the reaction was stopped. The mixture was diluted with 5 mL of water and extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by filtration under reduced pressure, and the residue was purified by column chromatography to yield 42 mg of a white solid. Yield: 74.5%. mp: 224-226°C.

[0416] 1H NMR(300MHz,DMSO-d6)δ10.75(s,1H,NH),8.49(d,J=8.2Hz,1H,ArH),8.01-7.90(m,1H,ArH),7.81-7.69(m,1H,ArH),7.54-7.45 (m,2H,ArH),7.40-7.28(m,3H,ArH),7.24-7.13(m,1H,ArH),3.84(s,2H,NCH2),3.14(s,2H,COCH2),3.03-2.88(m,4H,NCH2CH2).

[0417] HRMS(ESI):m / z[M+H] + Calcd for C 23 H 20 ClFN3O3:440.1177; Found:440.1172.

[0418] Example 47

[0419] Evaluation of the inhibitory activity of the compounds of the present application on PD-1 / PD-L1 protein-protein interaction

[0420] Experimental purpose: Use the PD-1 / PD-L1 binding assay kit (CISBIO) to detect the activity of the compound of formula (I) as an inhibitor of PD-1 / PD-L1 interaction.

[0421] Experimental principle: HTRF (Homogeneous Time-Resolved Fluorescence) is a technology used to detect analytes in pure liquid systems. It mainly uses the energy transfer of two fluorescent groups, which are energy donors europium (Eu+) and energy acceptors. When the donor is externally excited (such as a flash lamp or laser), if it is within a close enough distance to the acceptor, it can transfer energy resonance to the acceptor, and the acceptor is excited to emit a specific wavelength. Using HTRF technology, this assay can simply and quickly characterize compounds and antibody blockers in a high-throughput format. By using a fluorescent marker labeled with Eu+ + The interaction between PD-L1 and PD-1 can be detected by using anti-Tag1 labeled with Europium (HTRF energy donor) and anti-Tag2 labeled with XL665 (HTRF energy acceptor). + Eu and XL665 bind to PD-L1 and PD-1 through antibodies to form a complex. When PD-L1 and PD-1 are close to each other, Eu +Excitation by external laser light triggers fluorescence resonance energy transfer (FRET) to XL665, which in turn emits specific light at 665 nm. This specific signal is proportional to the extent of the PD1 / PD-L1 interaction. Therefore, compounds or antibodies that block the PD-1 / PD-L1 interaction will result in a decrease in the HTRF signal.

[0422] Experimental materials: PD-1 / PD-L1 binding assay kits purchased from CISBIO; 96-well plates: purchased from CISBIO.

[0423] Testing instrument: Perkin Elmer, model: EnVision.

[0424] Test compound: Compound of formula (I), dissolved in DMSO and diluted in diluent buffer; DMSO concentration does not exceed 0.5%.

[0425] Experimental process: Use PD-1 / PD-L1 binding assay kits. Set up negative group, positive group and drug administration group, with 2 replicates in each group. For the positive control group, 2 μL diluent was added to the 96-well plate; 4 μL PD-L1 and 4 μL PD-1 diluted according to the instructions; for the negative control group, 6 μL diluent and 4 μL PD-L1 were added to the 96-well plate; for the drug administration group, 2 μL of the test compound (I) (or the positive compound BMS-202), 4 μL PD-L1 and 4 μL PD-1 were added to the 96-well plate in sequence. Seal the plate with a sealing film, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature for 15 minutes. Then, Anti-Tag-Eu3 diluted in Buffer was added. + Mix equal volumes of Anti-tag-XL665, then add 10 μL of the mixture to each well, seal the plate, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature for 2 hours. Remove the sealing film and use EnVision to read the fluorescence intensity at 665 nm and 615 nm, and calculate the ratio = Signal 665 nm / Signal 620 nm * 10 4 The IC values ​​of the compounds were calculated using Graphpad. 50 In this experiment, BMS-202 from BMS's WO2015034820 patent was selected as the positive drug. The activity data are shown in Table 1.

[0426] Values ​​represent IC<0.07 μM 50 ; B represents 0.07-1μM; C represents >1μM.

[0427] Table 1 Blockade of hPD-1 / hPD-L1 by compounds at the protein level

[0428] The experimental results show that the compounds of the present application have significant inhibitory activity on the PD-1 / PD-L1 protein-protein interaction. 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 better inhibitory activity than compound BMS-202 in document WO2015034820. This shows that the biphenyl compounds of the present application can be used as immune checkpoint PD-1 / PD-L1 inhibitors.

[0429] Acute toxicity test of compound of Example 48

[0430] Test samples: Compound ID-18, Compound ID-26, Compound ID-27.

[0431] Animal species and number: SD rats; 6 rats per group (half male and half female);

[0432] Administration: oral gavage;

[0433] Animal grouping and dosage: vehicle 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);

[0434] Dosing frequency: 1 dose.

[0435] Test process:

[0436] Post-dose cage observation on the day of dosing (D1): Observation frequency and duration: Each group of animals were cage-observed for acute toxic reactions for 4 hours after dosing. Animals showing obvious abnormalities underwent detailed clinical observation. Death, morbidity, respiration, secretions, feces, diet, and drinking water were observed, and changes in rat weight during the dosing period were recorded. Detailed clinical observations included, but were not limited to, behavioral activity, skin, fur, eyes, ears, nose, abdomen, external genitalia, anus, limbs, feet, and respiration. After the observation period, all animals were euthanized, and all animals underwent dissection and gross observation.

[0437] Experimental Results: Compounds ID-18, ID-26, and ID-27 were administered orally to SD rats at doses of 500, 1000, and 2000 mg / kg. No animals in each group were observed to be dying or near death, and no changes related to the test article were observed in the animals' gross appearance. Under the conditions of this study, the maximum tolerated dose (MTD) of compounds ID-24, ID-26, and ID-27 was greater than or equal to 2000 mg / kg, respectively.

[0438] 14-Day Repeated Dosage Safety Study of the Compound of Example 49

[0439] Test samples: Compound ID-18, Compound ID-26, Compound ID-27.

[0440] Animal species and number: SD rats; 6 rats per group (half male and half female);

[0441] Administration: oral gavage;

[0442] Animal groups and dosage: vehicle blank group, compound ID-18 group (300 mg / kg), compound ID-26 (300 mg / kg), compound ID-27 (300 mg / kg);

[0443] Dosage frequency: once a day for 14 days.

[0444] Test process:

[0445] After administration, the acute toxic reaction was observed for 4 hours by the cage, and animals with obvious abnormal performance were observed in detail. General clinical observation included 2 times a day during the test (1 time in the morning and 1 time in the afternoon). Death, morbidity, respiration, secretions, feces, diet, drinking water, etc. were observed, and the weight changes of rats during administration were recorded. Detailed clinical observation content included but was not limited to behavioral activity, skin, fur, eyes, ears, nose, abdomen, external genitalia, anus, limbs, feet, and respiration. After the administration, each group of animals was euthanized, and all animals were dissected and grossly observed.

[0446] The animal body weight growth curve during the administration period is shown in Figure 1.

[0447] Experimental results: For compound ID-18, compound ID-26, and compound ID-27, during the 14-day dosing period, animals in all dose groups had normal water and food intake, normal activities, and normal body weights, with no obvious abnormalities.

[0448] Example 50 Study on the pharmacodynamic effects of 4T1 breast cancer cell xenograft model

[0449] Model establishment and dosing regimen:

[0450] Animal species and number: Balb / c Nude; 6 animals per group;

[0451] Test samples: Compound ID-24, Compound ID-26, Compound ID-27

[0452] Test groups: blank solvent control group;

[0453] Compound ID-18 (10 mg / kg, ig, QD × 21 days);

[0454] Compound ID-26 (10 mg / kg, ig, QD × 21 days);

[0455] Compound ID-27 (10 mg / kg, ig, QD × 21 days);

[0456] Animal model establishment: Breast cancer tumor cells 4T1 in the logarithmic growth phase were cultured and collected in vitro, and 2×10 6 The number of cells / mouse was subcutaneously inoculated into the right back of nude mice, and the tumor was grown to 50-70 mm. 3 Tumor-bearing nude mice were randomly divided into groups. Subsequently, each group of animals was dosed, and the day of the first dose was defined as the first day of the experiment;

[0457] Dosing frequency: once a day;

[0458] General status observation: Observation time and frequency: once a day; Observation indicators or content: including but not limited to the animal's drug administration site, physical appearance, general behavior, mental state, death, and other abnormal manifestations. After the experiment, the animals were euthanized.

[0459] Tumor volume calculation: V = 1 / 2 × long diameter × short diameter 2 (mm 3 ).

[0460] Experimental results:

[0461] In the following table, “+” indicates a tumor inhibition rate of <20%; “++” indicates a tumor inhibition rate of 20% to 60%; and “+++” indicates a tumor inhibition rate of >60%.

[0462] Tumor inhibition rate of the compound:

[0463] The animal tumor growth curve of the compound of the present invention in the BALB / c mouse 4T1 subcutaneous transplanted tumor model is shown in FIG2 .

[0464] The above data show that compound ID-18, compound ID-26, and compound ID-27 have significant tumor-inhibiting effects. During the dosing test period, the experimental animals had normal water and food intake, normal activities, and normal body weight, and did not show any toxicity.

[0465] The efficacy and safety of the compound of the present invention are significantly better than those of BMS-202, indicating that the compound of the present invention has better therapeutic advantages and potential application value.

[0466] Example 51 Preliminary Study on Capsule Formulation of Compound ID-18

[0467] Recipe composition:

[0468] Capsule preparation method:

[0469] Mixing: Add the weighed compound ID-18, starch, and sodium starch glycolate into a wet mixer granulator and mix.

[0470] Preparation of adhesive solution: Weigh purified water, slowly add an appropriate amount of starch while stirring, and stir and disperse evenly to prepare an adhesive - starch slurry.

[0471] Preparation of soft material: Use a wet mixing granulator, control the stirring speed and shearing speed, slowly add starch slurry, stir, shear, and prepare the soft material.

[0472] Granulation: The prepared soft material is granulated using a swing granulator with a 24-mesh screen to obtain wet granules.

[0473] Drying: Add the wet granules into a fluidized bed granulator to obtain dry granules.

[0474] Granulation: The dry granules are sieved and sized using an oscillating granulator, and the granules obtained are weighed.

[0475] Mixing: Add the granules after granulation into the Wanxiang mixer, and after mixing is completed, add magnesium stearate and mix thoroughly to obtain mixed granules.

[0476] Filling: Use a filling machine to fill the mixed granules into gelatin hollow capsules, screen out qualified capsules, and obtain capsules to be packaged.

[0477] Obtain capsule samples with neat appearance.

Claims

1. A compound represented by general formula I, a hydrate, a solvate or a pharmaceutically acceptable salt thereof: in: Ar stands for L represents -(CH2) m -, -O-, -NH-, -CH2O-, -CF2O-, -CH2NH-, -CONH-, -HNCO-, -NHCH2-, -OCF2-, -OCH2- or -CH=CH-, wherein m represents 0, 1 or 2; X 1 、X 2 Each represents N or CH; T and V respectively represent and -S-; among which 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 3 Each independently represents H, D, halogen, CN, C1-C3 haloalkyl, C1-C3 alkyl or cyclopropyl; R 2 represents H, substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl or substituted C3-C7 heterocycloalkyl, wherein the substituent is H, OH, NH2, COOH, amide, ester, alkoxy or aldehyde, which may be monosubstituted or polysubstituted, and the heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O and S; R 4 Represents H, halogen, CN, CF3, OH, NH2, -O(CH2) p R 6 , substituted C1-C6 alkyl, substituted C3-C7 cycloalkyl or substituted C3-C7 heterocycloalkyl, the substituents are H, OH, NH2, COOH, amide, ester, alkoxy, which may be monosubstituted or polysubstituted, wherein p represents 1, 2, 3 or 4, and the heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O, and S; R 6 Represents NR 7 R 8 , OR 7 or substituted C4-C6 nitrogen heterocycloalkyl, wherein R 7 represents H or C1-C3 alkyl, R 8 represents a substituted C1~C6 alkyl group, the C4-C6 azacycloalkyl group is tetrahydropyrrol-1-yl, piperidin-1-ylmorpholine-1-ylpiperazin-1-yl or azetidine-1-yl, and the substituents are OH, NH2, COOH, amide, ester, alkoxy, and can be monosubstituted or polysubstituted.

2. The compound according to claim 1, its hydrate, solvate or pharmaceutically acceptable salt, characterized in that in: Ar stands for L represents -(CH2) m -, -CH2O-, -CF2O-, -CONH-, -NHCO- or -OCH2-, wherein m represents 0; X 1 and X 2 Each represents N or CH; T and V respectively represent -CH2-, -O-, -NH- or U stands for N; n represents 0 or 1; R 1 and R 3 Each represents H, D, F, Cl, Br, CN, CH3 or CF3; R 2 Represents H, Where q represents 0 or 1, R 9 and R 10 Each represents H, OH, COOH, CH2COOH, CH2NH2, CH2OH, CH2CH2OH, F, Cl, Br, CH3, CH2CH3; R 11 Represents OH, NH2, NHCH3, CH3, OCH3, OCH2CH3, OCH(CH3)2;; R 12 represents CONH2, NHCOCH3, OH, CH2OH, CH2CH2OH, COOH, COOCH3, COOCH2CH3, COOCH(CH3)2; R 13 represents H, CH3, CH2CH3, CH2OH, CH2CH2OH; R 4 Represents H, F, Cl, Br, CN, CF3, OH, NH2 or -O(CH2) p R 6 , where p represents 2, 3 or 4, R 6 Represents OH, where R 9 、R 10 、R 11 、R 12 and R 13 The definition of R is the same as before. 14 represents CH3, CH2CH3, CH2CH2OH, formyl or acetyl, R 15 and R 16 Each represents H, OH, COOH, NH2, CH3, CH2CH3, CH2OH, CH2CH2OH, CONH2, cyclopropyl, COOCH3, COOCH2CH3 or COOCH(CH3)2, W represents -CH2-, -O-, -NH-, r represents 0 or 1.

3. The compound according to claim 1 or 2, or a hydrate, solvate or pharmaceutically acceptable salt thereof, characterized in that: Where Ar represents L represents -CH2O- or -NHCO-; X1 represents CH or N; X2 represents CH; T stands for or -CH2-; U stands for N; V represents -CH2- or n = 0 or 1; R 1 and R 3 Each represents H, F, Cl, Br, CN, CH3 or CF3; R 2 Represents H, Where q represents 0 or 1; R 9 and R 10 Each represents H, OH, COOH, CH2COOH, CH2OH, CH3 or CH2CH3; R 11 represents OH, NH2, NHCH3, OCH3 or OCH2CH3; R 12 represents CONH2, NHCOCH3, OH, CH2OH, COOH, COOCH3, COOCH2CH3; R 13 represents H, CH3, CH2CH3, CH2OH or CH2CH2OH; R 4 Represents H, F, Cl, Br, CN, CF3, OH, NH2 or -O(CH2) p R 6 , where p represents 2, 3 or 4, R 6 Represents OH, COOH, CH2OH, NH2, NHCH3, CONH2, NHCOCH3, COOCH3, COOCH2CH3 or where R 15 and R 16 Each represents H, OH, CH3, CH2OH, CONH2, COOCH3 or COOCH2CH3; W represents CH2, O, NH or N-CH3; r represents 0 or 1.

4. The compound according to any one of claims 1 to 3, or a hydrate, solvate or pharmaceutically acceptable salt thereof, characterized in that: Ar stands for L represents -CH2O- and -NHCO-; X1 represents CH or N, X2 represents CH; T generation or -CH2-; U stands for N; V represents -CH2-; n=0 or 1.

5. The compound according to any one of claims 1 to 4, or a hydrate, solvate or pharmaceutically acceptable salt thereof, characterized in that: R 1 and R 3 Each represents F, Cl, Br, CN, CH3 or CF3.

6. The compound according to any one of claims 1 to 5, or a hydrate, solvate or pharmaceutically acceptable salt thereof, characterized in that: where R 2 Representative: H.

7. The compound according to any one of claims 1 to 6, or a hydrate, solvate or pharmaceutically acceptable salt thereof, characterized in that: R 4 Represents H, F, Cl, CN, CF3, OH, NH2 or -O(CH2)3R 6 , where R 6 Represents OH, CONH2, CH2OH, COOH, COOCH3, COOCH2CH3 or 8. A compound selected from any one of the following formulae, a hydrate, a solvate or a pharmaceutically acceptable salt thereof:

9. The compound according to claim 8, its hydrate, solvate or pharmaceutically acceptable salt, characterized in that The compound is IA-9, IB-2, ID-13, ID-14, ID-18, ID-19, ID-21, ID-22, ID-26, ID-27, ID-28, ID-30 or IE-4.

10. The compound, hydrate, solvate or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, characterized in that: The pharmaceutically acceptable salt is an acid addition salt formed by the compound of general formula I of claim 1 and the following acids: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.

11. The method for preparing the compound according to claim 1, comprising the steps of: When Ar represents X1 and X2 each represent CH, and L represents -(CH2) m -, m = 0, T represents C = O, U represents N, V ​​represents CH2, n = 0, the synthetic route of formula IA is: When Ar represents X1 represents N, X2 represents CH, and L represents -(CH2) m -, m = 0, T represents CH2, U represents N, V ​​represents CH2, and n = 1, the synthetic route of formula IB is: When Ar represents X1 represents N, X2 represents CH, and L represents -(CH2) m -, m = 0, T is CH2, U represents N, V ​​represents CH2, n = 1, the synthesis route of formula IC is: When Ar represents X1 represents N, X2 represents CH, L represents -CH2O-, T is CH2, U represents N, V ​​represents CH2, and when n=1, the synthetic route of formula ID is: When Ar represents X1 represents N, X2 represents CH, L represents -CH2O-, T represents CH2, U represents N, V ​​represents NCH3, and when n=1, the synthetic route of formula IE is: or, When Ar represents X1 represents N, X2 represents CH, L represents -HNCO-, T represents CH2, U represents N, V ​​represents CH2, and when n=1, the synthetic route of formula IF is:

12. A pharmaceutical composition, characterized in that 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 preparation 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 preparation of an anti-tumor drug.

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

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