Aromatic heterocycle-fused lactam compound and preparation method therefor, pharmaceutical composition, and use

Abstract

Disclosed in the present invention are an aromatic heterocycle-fused lactam compound and a preparation method therefor, a pharmaceutical composition, and a use. The compound has a structure as represented by formula I, and the compound contains a benzene ring- or pyridine ring-fused lactam backbone. The compound has a significant agonistic effect on casein lyase P, can effectively inhibit tumor cell growth, exhibits activity at a micromolar concentration level or below, or even at a nanomolar concentration level, can be applied to the treatment of various cancers, and has broad prospects of application.

Description

Aromatic heterocyclic lactam compounds, their preparation methods, pharmaceutical compositions and applications Technical Field

[0001] This invention relates to an aromatic heterocyclic lactam compound, and also to the preparation, pharmaceutical composition, and application of the above compound. Background Technology

[0002] Casein lyase P (ClpP) is an oligoserine protease widely found in eukaryotic and prokaryotic cells. In human cells, ClpP (hClpP) is mainly located in the mitochondrial matrix, where its primary function is to degrade damaged or misfolded proteins, maintaining normal mitochondrial function. Recent studies have revealed that hClpP is a unique target for antitumor drugs. Activation of hClpP can promote the degradation of its substrates, including various respiratory chain proteins, thereby affecting intracellular oxidative phosphorylation and leading to the death of malignant tumor cells. Therefore, developing novel hClpP agonists may be a new strategy for treating tumors. Summary of the Invention

[0003] Objectives of the Invention: The first objective of this invention is to provide an aromatic heterocyclic lactam compound; the second objective is to provide a method for preparing the above-mentioned compound; the third objective is to provide a pharmaceutical composition comprising the above-mentioned compound; and the fourth objective is to provide the use of the above-mentioned compound or a pharmaceutical composition thereof in casein lyase P agonists or anticancer drugs.

[0004] Technical solution: The aromatic heterocyclic lactam compounds of the present invention are compounds containing a benzene ring or a pyridine ring lactam skeleton, as shown in Formula I:

[0005] in:

[0006] A is selected from CH2, CD2, CF2; X, Y, Z are selected from CH or N; Q is selected from CH2, CH2CH2, CHR4;

[0007] R1 and R2 are selected from phenyl or mono-, di-, and tri-substituted phenyl groups, wherein the mono-, di-, and tri-substituted substituents are selected from halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkynyl, and C1-C4 alkoxy.

[0008] R3 is selected from the group consisting of a hydrogen atom, a carbamoyl group, a nitrogen mono- or di-C1-C4 alkylated carbamoyl group, a substituted or non-substituted aryl group, a substituted or non-substituted heteroaryl group, a substituted or non-substituted 5-8 membered saturated or unsaturated heterocycle containing at least one O or NH, a C1-C10 alkyl group, or a C1-C10 alkyl group in which at least one hydrogen is substituted by any one of the following groups: a hydroxyl group, an amino group, an amido group, a nitrogen mono- or di-C1-C4 alkylated amido group, a carbamoyl group, a nitrogen mono- or di-C1-C4 alkylated carbamoyl group, a sulfonamide group, a nitrogen mono- or di-C1-C4 alkylated sulfonamide group, an aminosulfonyl group, a nitrogen mono- or di-C1-C4 alkylated aminosulfonyl group, a C1-C6 alkoxy group, a substituted or non-substituted 5-8 membered saturated or unsaturated heterocycle containing at least one O or NH, [O(CH2) 1-6 ] 1-6 R5;

[0009] R4 is selected from the group consisting of a hydrogen, a substituted or non-substituted phenyl group, a substituted or non-substituted heteroaryl group, a substituted or non-substituted 5-8 membered saturated or unsaturated heterocycle containing at least one O or NH, a hydroxyl group, an amino group, a C1-C4 alkoxy group, a nitrogen mono- or di-C1-C4 alkylated alkylamino group, a carboxyl group, a carbamoyl group, a nitrogen mono- or di-C1-C4 alkylated carbamoyl group, a C1-C4 alkyl group, a C3-C8 cycloalkyl group, or a C1-C4 alkyl group and a C3-C8 cycloalkyl group in which at least one hydrogen is substituted by any one of the following groups: a hydroxyl group, an amino group, a C1-C4 alkoxy group, a nitrogen mono- or di-C1-C4 alkylated alkylamino group, a carboxyl group, a carbamoyl group, a nitrogen mono- or di-C1-C4 alkylated carbamoyl group, a C1-C4 amido group, a nitrogen C1-C4 alkylated amido group, a methanesulfonamide group, a trifluoromethanesulfonamide group, an aminosulfonyl group, a nitrogen C1-C4 alkylated aminosulfonyl group, a substituted or non-substituted 5-7 membered heteroaryl group containing 1-3 N, O, S, a substituted or non-substituted 5-8 membered saturated or unsaturated heterocycle containing at least one O or NH;

[0010] R5 is selected from the group consisting of a hydrogen, a substituted or non-substituted phenyl group, a substituted or non-substituted heteroaryl group, a substituted or non-substituted 5-8 membered saturated or unsaturated heterocycle containing at least one O or NH, a hydroxyl group, an amino group, a C1-C4 alkoxy group, a nitrogen mono- or di-C1-C4 alkylated alkylamino group, a carboxyl group, a carbamoyl group, a nitrogen mono- or di-C1-C4 alkylated carbamoyl group, a sulfonamide group, a nitrogen mono- or di-C1-C4 alkylated sulfonamide group, an aminosulfonyl group, a nitrogen mono- or di-C1-C4 alkylated aminosulfonyl group;

[0011] the substituents on the phenyl, heteroaryl and 5-8 membered saturated or unsaturated heterocyclic ring in R3-R5 are selected from halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, nitrogen mono- or di-C1-C4 alkylated alkylamino, carboxyl, carbamoyl, nitrogen mono- or di-C1-C4 alkylated carbamoyl, sulfonamido, nitrogen mono- or di-C1-C4 alkylated sulfonamido, aminosulfonyl, nitrogen mono- or di-C1-C4 alkylated aminosulfonyl, substituted or non-substituted 5-8 membered saturated or unsaturated heterocyclic ring containing at least one O or NH;

[0012] wherein the compound is further preferably selected from:

[0013] A is selected from CH2;

[0014] X, Y, Z are independently selected from CH or N;

[0015] Q is selected from CH2;

[0016] R1, R2 are selected from phenyl or mono-, di-, tri-substituted phenyl, the substituents being selected from fluorine, chlorine, bromine, C1-C4 alkyl, trifluoromethyl, cyano, methoxy, ethoxy, propoxy, isopropoxy;

[0017] R3 is selected from hydrogen, imidazole, dihydroimidazole, benzimidazole, pyrazole, carboxyl, carbamoyl, nitrogen methylcarbamoyl, hydroxymethyl, aminomethyl, acetamidomethyl, methanesulfonamidomethyl, carbamoylmethyl, nitrogen methylcarbamoylmethyl, [O(CH2) 1-6 ] 1-6 OH, [O(CH2) 1-6 ] 1-6 OCH3, [O(CH2) 1-6 ] 1-6 OEt;

[0018] wherein the arylheterocyclic ring and lactam compound is selected from any one of the following compounds:

[0019] wherein the compound further comprises a stereoisomer, a tautomer, an isotopologue, a prodrug, a solvate, a crystal, a pharmaceutically acceptable salt or a mixture thereof.

[0020] wherein the pharmaceutically acceptable salt is a salt of the compound with an acid selected from any one of the following: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, ferulic acid.

[0021] The pharmaceutically acceptable salts refer to salts of the compounds prepared from a compound having a specific substituent with a relatively non-toxic acid or base. When the compound contains a relatively acidic functional group, the base addition salt can be obtained by contacting the free form of such a compound with a sufficient amount of the base in a pure solution or in a suitable inert solvent. The pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compound contains a relatively basic functional group, the acid addition salt can be obtained by contacting the free form of such a compound with a sufficient amount of the acid in a pure solution or in a suitable inert solvent. Examples of the pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonate or bicarbonate), phosphoric acid (forming phosphate, monohydrogenphosphate, dihydrogenphosphate), sulfuric acid (forming sulfate or bisulfate), hydroiodic acid, phosphorous acid and the like; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and the like similar acids; and salts of organic acids including amino acids (such as arginine and the like), glucuronic acid and the like organic acids. When certain specific compounds contain both basic and acidic functional groups, they can be converted into either base or acid addition salts. Preferably, the salts are contacted with a base or an acid in a conventional manner to separate the parent compound, whereby the free form of the compound is regenerated. The free form of the compound is different from the form of various salts thereof in some physical properties, for example, solubility in polar solvents.

[0022] The pharmaceutically acceptable salts can be synthesized from the parent compound that contains an acidic or basic moiety by conventional chemical methods. Generally, such salts can be prepared by contacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two. Preferably, nonaqueous media, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, are used. The corresponding acid is salted out of the compound I prepared by the above method to obtain the pharmaceutically acceptable salt of the compound.

[0023] wherein the stereoisomer is an isomer introduced by the chiral C in the lactam ring, the chiral C contained in Q and R3, R4, R5.

[0024] wherein the prodrug is an ester, amide prodrug introduced by carboxyl, hydroxyl, amino, more preferably C1-C4 alkyl ester, C1-C4 carboxylic acid ester, C1-C4 alkyl amide.

[0025] The solvate is a small molecule bonded state formed by the compound and solvent molecules, more preferably a hydrate or alcohol; the solvate can further form a salt with the corresponding acid to obtain the salt of the solvate.

[0026] The isotopic compound is a compound in which hydrogen is replaced by deuterium.

[0027] The crystallization refers to the specific crystal structure formed by the compound during the crystallization process, including different crystal forms of the compound itself, as well as different crystal forms of its salts, solvates, and salts of solvates.

[0028] The preparation methods of the above-mentioned aromatic heterocyclic lactam compounds are selected from any of the following methods:

[0029] Method 1: When X, Y, and Z are CH, A and Q are CH2, and R3 is a hydrogen atom, the following steps are included:

[0030] (1) Compound 2 was obtained by protecting the amino group in compound 1 with a trifluoroacetyl group;

[0031] (2) Compound 2 reacts with formaldehyde under acid catalysis to form an imine, which is then cyclized to synthesize compound 3;

[0032] (3) The amine obtained after removing the trifluoroacetyl group from compound 3 was then protected with Boc to prepare compound 4;

[0033] (4) Compound 4 was oxidized to obtain compound 5;

[0034] (5) Compound 5 is coupled with substituted or unsubstituted benzylboronic acid or borate ester to prepare compound 6;

[0035] (6) Compound 7 was obtained by removing the Boc protecting group from compound 6;

[0036] (7) Compound 7 was reacted with benzyl halides or sulfonates with or without benzene ring substitution to prepare target compound 8;

[0037] Method 2: When X, Y, and Z are CH, A is CH2, Q is CH2CH2, and R3 is a hydrogen atom, the following steps are included:

[0038] (1) Compound 9 was reacted with hydroxylamine to prepare compound 10;

[0039] (2) Compound 10 was prepared into compound 11 by the Beckmann rearrangement reaction;

[0040] (3) Compound 11 was reacted with benzyl halides or sulfonates with or without benzene ring substitution to prepare target compound 12;

[0041] (4) Compound 12 is coupled with benzene ring substituted or non-substituted benzyl boronic acid or boronic ester to prepare target compound 13;

[0042] Method three: when X is N, Y, Z are CH, A and Q are CH2, R3 is hydrogen atom, comprising the following steps:

[0043] (1) Compound 14 is esterified to prepare 15;

[0044] (2) Compound 15 is brominated to prepare compound 16;

[0045] (3) The bromine atom in compound 16 is substituted with cyano to prepare compound 17;

[0046] (4) The amine obtained after selective reduction of cyano in compound 17 is subjected to intramolecular cyclization to prepare compound 18;

[0047] (5) Compound 18 is subjected to substitution reaction with benzene ring substituted or non-substituted benzyl halide or sulfonate to prepare compound 19;

[0048] (6) Compound 19 is subjected to oxidation reaction to prepare compound 20;

[0049] (7) Compound 20 is subjected to chlorination to prepare compound 21;

[0050] (8) Compound 21 is coupled with substituted or non-substituted benzyl boronic acid or boronic ester to prepare target compound 22;

[0051] Method four: when Y is N, X, Z are CH, A and Q are CH2, R3 is hydrogen atom, comprising the following steps:

[0052] (1) Compound 23 is esterified to prepare compound 24;

[0053] (2) Compound 24 is reacted with trimethylaluminum to prepare compound 25;

[0054] (3) The methyl in compound 25 is brominated to prepare compound 26;

[0055] (4) The bromine atom in compound 26 is substituted with cyano to prepare compound 27;

[0056] (5) The amine obtained after selective reduction of cyano in compound 27 is subjected to cyclization with ester group to prepare compound 28;

[0057] (6) Compound 28 is subjected to substitution reaction with benzene ring substituted or non-substituted benzyl halide or sulfonate to prepare compound 29;

[0058] (7) the target compound 30 is prepared by coupling compound 29 with substituted or unsubstituted benzyl boronic acid or borate ester;

[0059] Method five: when Z is N, X, Y are CH, A and Q are CH2, and R3 is hydrogen atom, comprising the following steps:

[0060] (1) compound 31 is reacted with compound 32 to synthesize compound 33;

[0061] (2) compound 33 is oxidized to synthesize compound 34;

[0062] (3) compound 34 is oxidized to synthesize compound 35;

[0063] (4) the nitric oxide in compound 35 is reduced to prepare compound 36;

[0064] (5) after removing the Boc protecting group in compound 36, the obtained amide is subjected to substitution reaction with benzene ring substituted or unsubstituted benzyl halide or sulfonate to prepare compound 37;

[0065] (6) the target compound 38 is prepared by coupling compound 37 with substituted or unsubstituted benzyl boronic acid or borate ester;

[0066] Method six: when X, Y, Z are CH, A and Q are CH2, and R3 is different substituent, comprising the following steps:

[0067] (1) compound 39 is subjected to esterification and amino protection to obtain compound 40;

[0068] (2) compound 40 is subjected to imine formation with formaldehyde under the catalysis of acid and then ring closure to prepare compound 41;

[0069] (3) the ester group in compound 41 is reduced to obtain alcohol, which is subjected to cyclization with amino acid methyl ester to obtain compound 42;

[0070] (4) compound 42 is oxidized to prepare compound 43;

[0071] (4) compound 43 is subjected to ring opening under the action of base to prepare compound 44;

[0072] (5) compound 44 is protected with TBS to prepare compound 45;

[0073] (6) compound 45 is subjected to substitution reaction with benzene ring substituted or unsubstituted benzyl halide or sulfonate to prepare compound 46;

[0074] (7) the target compound 47 is prepared by coupling compound 46 with substituted or unsubstituted benzyl boronic acid or borate ester;

[0075] (8) removing the TBS protecting group in compound 47 to obtain compound 48;

[0076] (9) converting the hydroxyl group in compound 48 into different substituents as needed to obtain target compound 49.

[0077] The present application also discloses a pharmaceutical composition comprising the above-mentioned aryl heterocycle and lactam compound and a pharmaceutically acceptable carrier.

[0078] The pharmaceutical composition can be in the form of tablets, capsules, powders, pills, granules, injections, oral liquids, syrups, inhalants, ointments, patches or suppositories.

[0079] The pharmaceutically acceptable carrier can be an excipient widely used in the field of pharmaceutical production. The excipient is mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method for the active ingredient to be dissolved at the desired rate after the subject is administered, or to promote the active ingredient to be effectively absorbed after the subject is administered with the composition. The pharmaceutical excipient can be an inert filler, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipient can include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption retardants, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavorings and sweeteners.

[0080] The preparation method of the pharmaceutical composition includes conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0081] The pharmaceutical composition described in the present application can be administered in the form of injection (intravenous), mucosal, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular). The pharmaceutical composition of the present application can also be in a controlled or sustained release dosage form (such as liposome or microsphere). Examples of solid oral preparations include, but are not limited to, powder, capsule, caplet, soft capsule and tablet. Examples of liquid preparations for oral or mucosal administration include, but are not limited to, suspension, emulsion, elixir and solution. Examples of topical preparations include, but are not limited to, emulsion, gel, ointment, cream, patch, paste, foam, lotion, drop or serum preparation. Examples of preparations for parenteral administration include, but are not limited to, injection solution, dry powder preparation that can be dissolved or suspended in a pharmaceutically acceptable carrier, injection suspension and injection emulsion. Examples of other suitable preparations of the pharmaceutical composition described include, but are not limited to, eye drops and other ophthalmic preparations; aerosols such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.

[0082] The above-mentioned aromatic heterocyclic lactam compound or pharmaceutical composition can also be applied in the preparation of a ClpP agonist drug.

[0083] The above-mentioned aromatic heterocyclic lactam compound or pharmaceutical composition can also be applied in the preparation of a drug for treating cancer.

[0084] The cancer is acute myeloid leukemia, breast cancer, lung cancer, liver cancer, ovarian cancer, bladder cancer, prostate cancer, uterine cancer, gastric cancer, testicular cancer, thyroid cancer, cervical cancer, osteosarcoma, neuroblastoma, colon cancer, brain tumor.

[0085] Invention principle:

[0086] D9 is a small molecule hClpP agonist discovered by Sieber et al. through high-throughput screening, which activates hClpP with an EC 50The value is 5-10 μM. Sieber et al. carried out a series of optimizations on this compound, but failed to improve the ability of the compound to activate hClp. Crystal structure shows that D9 can adopt two different conformations when it binds to hClpP, as shown in the above figure. By comparing the conformation of D9 and another small molecule hClpP agonist ONC201 which has entered clinical study, it can be found that the binding conformation of D9 is closer to that of ONC201. Therefore, the inventors replaced the oxadiazole ring in D9 with a benzene ring or a pyridine ring, and connected the amide group with the ortho position of the benzene ring or the pyridine ring, to design the compounds represented by general formula I. Due to conformational constraints, these compounds can more effectively mimic the binding conformation of ONC201, and the hydrophobic part of the lactam ring can bind to hClpP, thereby enhancing the binding ability of the compound.

[0087] Advantages: Compared with the prior art, the benzene ring or pyridine ring and lactam compound of the present application has the following remarkable advantages: the benzene ring or pyridine ring and lactam compound of the present application has a significant agonistic effect on casein protease P (ClpP), and can effectively inhibit the growth of tumor cells, and the activity reaches the level of micromolar concentration and below, and even reaches the level of nanomolar concentration. Compared with ONC201 and its derivatives, the compound in the present application has higher selectivity for hClpP, and has higher metabolic stability because it does not contain a tertiary amine which is prone to oxidation. The compound in the present application can be applied to the treatment of various cancers, and has a wide application prospect. DETAILED DESCRIPTION

[0088] The technical solutions of the present application are further described below in conjunction with examples. The reagents used can be purchased through conventional channels.

[0089] The synthesis method of compounds I-1 to I-17 is as follows:

[0090] Reagents and conditions: (a) (CF3CO)2O, TEA, THF, rt; (b) H2SO4, CH3COOH, CH2O, rt; (c) i. 2N NaOH, EtOH, H2O. ii. BOC2O, dioxane, rt; (d) NaBrO3, CAN, H2O, dioxane, rt; (e) substituted or unsubstituted benzyl boronic acid pinacol ester, K2CO3, Pd(dppf)Cl2, H2O, CH3CN, Ar, 100℃; (f) CF3COOH, DCM, rt; (g) substituted or unsubstituted benzyl bromide, NaH, THF, rt.

[0091] Example 1: N-(4-bromophenethyl)-2,2,2-trifluoroacetamide (2)

[0092] Dissolve 3 g of compound 1 (15.07 mmol, 1 eq) in anhydrous tetrahydrofuran, add 3.05 g of triethylamine (30.15 mmol, 2 eq), and cool the reaction solution to 0°C. Add 4.74 g of trifluoroacetic anhydride (22.61 mmol, 1.5 eq), and after the addition is complete, move the reaction solution to room temperature and react for 2-3 h. After the reaction is complete, as determined by TLC, evaporate the solvent, and separate the crude product by column chromatography to obtain 3.6 g of compound 2 at a yield of 81%. 1 H NMR (300 MHz, CDC13) δ 7.43 (m, 2H), 7.09 (m, 2H), 6.57 (s, 1H), 3.59 (m, 2H), 2.86 (t, J = 7.2 Hz, 2H).

[0093] Example 2: 1-(7-Bromo-3,4-dihydroisoquinolin-2(lH)-yl)-2,2,2-trifluoroethan-l-one (3)

[0094] Dissolve 2 g of compound 2 (3.39 mmol, 1 eq) in a mixed solvent of acetic acid and concentrated sulfuric acid (3:2). Add 0.3 g of paraformaldehyde (5.08 mmol, 1.5 eq) to the reaction solution, and react at room temperature overnight. After the reaction is complete, carefully dilute the reaction solution with water, adjust the pH to 7 with sodium bicarbonate, extract the reaction solution with 20 mL of ethyl acetate three times, wash the combined organic phase with saturated sodium bicarbonate solution and saturated brine once each, dry over anhydrous sodium sulfate, and evaporate the solvent. Purify the crude product by column chromatography to obtain 1.4 g of compound 3 at a yield of 68%. 1 H NMR (300 MHz, CDC13) δ 7.34 (m, 2H), 7.05 (m, 1H), 4.75 (s, 2H), 3.86 (t, J = 8.0 Hz, 2H), 2.91 (t, J = 8.0 Hz, 2H).

[0095] Example 3: tert-Butyl-7-bromo-3,4-dihydroisoquinoline-2(lH)-carboxylate (4)

[0096] Dissolve 1 g of compound 3 (3.26 mmol, 1 eq) in 9 mL of ethanol, add 9 mL of a 2N NaOH solution, and react at room temperature until the reaction is complete, as determined by TLC. Evaporate the ethanol from the solution, add 10 mL of dioxane to the remaining aqueous solution, and then add 0.78 g of Boc20 (3.58 mmol, 1.1 eq) and react at room temperature for 2 h. After the reaction is complete, add 10 mL of water to the reaction solution, extract with ethyl acetate three times, each time using 20 mL of solvent, combine the organic phase, wash with saturated brine once, and dry over anhydrous sodium sulfate. Filter off the drying agent, evaporate the solvent, and purify the crude product by column chromatography to obtain 0.76 g of compound 4 at a yield of 75%. 1H NMR (300 MHz, CDC13) δ 7.28-7.25 (m, 2H), 7.01 (d, J = 8.0 Hz, 1H), 4.53 (s, 2H), 3.63 (t, J = 6.6 Hz, 2H), 2.84 (t, J = 6.6 Hz, 2H), 1.48 (s, 9H).

[0097] Example 4: tert-Butyl-7-bromo-l-oxo-3,4-dihydroisoquinoline-2(lH)-carboxylate (5)

[0098] Dissolve 1 g of compound 4 (3.22 mmol, 1 eq) in 5 mL of dioxane, add 5 mL of water to the solution, then add 970 mg of sodium bromate (6.43 mmol, 2 eq) and 352 mg of cerium ammonium nitrate (0.64 mmol, 0.2 eq) respectively, and react at room temperature until TLC shows that the reaction is complete. Dilute the reaction solution with 30 mL of water, then extract with ethyl acetate three times, 20 mL each time. Wash the combined organic phase with saturated NaHC03solution and saturated brine once each, dry the organic phase over anhydrous sodium sulfate, filter out the drying agent, evaporate the solvent, and purify the crude product by column chromatography to obtain 0.94 g of compound 5 with a yield of 90%. 1 H NMR (300 MHz, CDC13) δ 7.28-7.25 (m, 2H), 7.01 (d, J = 8.0 Hz, 1H), 4.53 (s, 2H), 3.63 (t, J = 6.6 Hz, 2H), 2.84 (t, J = 6.6 Hz, 2H), 1.48 (s, 9H).

[0099] Example 5: tert-Butyl-7-benzyl-l-oxo-3,4-dihydroisoquinoline-2(lH)-carboxylate (6a)

[0100] Dissolve 500 mg of intermediate 5 (1.54 mmol, 1 eq) in a mixed solvent of 6 mL of dioxane and 2 mL of water, add 670 mg of benzylboronic acid pinacol ester (3.07 mmol, 2 eq), 640 mg of potassium carbonate (4.61 mmol, 3 eq), and 110 mg of Pd(dppf)Cl2(0.15 mmol, 0.1 eq) to the solution respectively, and replace the reaction system with argon three times after addition is complete. Stir at 100°C for 3 h. After TLC shows that the reaction is complete, cool the reaction solution and add 20 mL of water, extract with ethyl acetate three times, 20 mL each time, wash the combined organic phase with saturated brine once, then dry over anhydrous sodium sulfate, filter out the drying agent, concentrate the solution, and separate the residue by column chromatography to obtain 382 mg of compound 6a with a yield of 74%. 1H NMR (300 MHz, CDC13) δ 8.06 (d, J = 1.9 Hz, 1H), 7.33 - 7.16 (m, 7H), 4.01 (s, 2H), 4.01 - 3.95 (m, 2H), 2.98 (t, J = 6.2 Hz, 2H), 1.60 (s, 9H).

[0101] Example 6: tert-Butyl-7-(2-fluorobenzyl)-l-oxo-3,4-dihydroisoquinoline-2(lH)- carboxylate (6b)

[0102] Compound 6b was prepared from intermediate 5 and 2-fluorobenzylboronic acid pinacol ester using the same procedure as 6a. MS (ESI) m / z: [M + Na] + C 21 H 22 F NO3Na calcd 378.2, found 378.3.

[0103] Example 7: tert-Butyl-7-(3-fluorobenzyl)-l-oxo-3,4-dihydroisoquinoline-2(lH)- carboxylate (6c)

[0104] Compound 6c was prepared from intermediate 5 and 3-fluorobenzylboronic acid pinacol ester using the same procedure as 6a. MS (ESI) m / z: [M + Na] + C 21 H 22 F NO3Na calcd 378.2, found 378.3.

[0105] Example 8: tert-Butyl-7-(4-fluorobenzyl)-l-oxo-3,4-dihydroisoquinoline-2(lH)- carboxylate (6d)

[0106] Compound 6d was prepared from intermediate 5 and 4-fluorobenzylboronic acid pinacol ester using the same procedure as 6a. MS (ESI) m / z: [M + Na] + C 21 H 22 F NO3Na calcd 378.2, found 378.3.

[0107] Example 9: tert-Butyl-7-(2-methylbenzyl)-l-oxo-3,4-dihydroisoquinoline-2(lH)- carboxylate (6e)

[0108] Compound 6e was prepared from intermediate 5 and 2-methylbenzylboronic acid pinacol ester using the same procedure as 6a. MS (ESI) m / z: [M + Na] + C 22 H 25 NO3Na calcd 374.2, found 374.3.

[0109] Example 10: tert-Butyl-7-(3-methylbenzyl)-l-oxo-3,4-dihydroisoquinoline- 2(lH)-carboxylate (6f)

[0110] Compound 6f was prepared from intermediate 5 and 3-methylbenzylboronic acid pinacol ester using the same procedure as for 6a. MS (ESI) m / z: [M+Na] + C 22 H 25 NO3Na calcd 374.2, found 374.3.

[0111] Example 11: tert-Butyl-7-(4-methylbenzyl)-l-oxo-3,4-dihydroisoquinoline- 2(lH)-carboxylate (6g)

[0112] Compound 6g was prepared from intermediate 5 and 4-methylbenzylboronic acid pinacol ester using the same procedure as for 6a. MS (ESI) m / z: [M+Na] + C 22 H 25 NO3Na calcd 374.2, found 374.3.

[0113] Example 12: 7-Benzyl-3,4-dihydroisoquinolin-l(2H)-one (7a)

[0114] Compound 6a (300 mg) was dissolved in 2 ml of dichloromethane, 2 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature until TLC showed that the reaction was complete. The solvent was evaporated, and the residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound 7a which was used directly in the next step. MS (ESI) m / z: [M+Na] + C 16 H 15 NONa calcd 260.1, found 260.2.

[0115] Example 13: 7-(2-Fluorobenzyl)-3,4-dihydroisoquinolin-l(2H)-one (7b)

[0116] Compound 7b was prepared from 6b using the same procedure as for 7a. MS (ESI) m / z: [M+Na] + C 16 H 14 FNONa calcd 278.1, found 278.2.

[0117] Example 14: 7-(3-Fluorobenzyl)-3,4-dihydroisoquinolin-l(2H)-one (7c)

[0118] Compound 7c was prepared from 6c using the same procedure as 7a. MS (ESI) m / z: [M+Na] 278.1. + C 16 H 14 FNONa calcd 278.1, found 278.2.

[0119] Example 15: 7-(4-fluorobenzyl)-3,4-dihydroisoquinolin-l(2H)-one (7d)

[0120] Compound 7d was prepared from 6d using the same procedure as 7a. MS (ESI) m / z: [M+Na] 278.1. + C 16 H 14 FNONa calcd 278.1, found 278.2.

[0121] Example 16: 7-(2-methylbenzyl)-3,4-dihydroisoquinolin-l(2H)-one (7e)

[0122] Compound 7e was prepared from 6e using the same procedure as 7a. MS (ESI) m / z: [M+Na] 274.1. + C 17 H 17 NONa calcd 274.1, found 274.2.

[0123] Example 17: 7-(3-methylbenzyl)-3,4-dihydroisoquinolin-l(2H)-one (7f)

[0124] Compound 7f was prepared from 6f using the same procedure as 7a. MS (ESI) m / z: [M+Na] 274.1. + C 17 H 17 NONa calcd 274.1, found 274.2.

[0125] Example 18: 7-(4-methylbenzyl)-3,4-dihydroisoquinolin-l(2H)-one (7g)

[0126] Compound 7g was prepared from 6g using the same procedure as 7a. MS (ESI) m / z: [M+Na] 274.1. + C 17 H 17 NONa calcd 274.1, found 274.2.

[0127] Example 19: 2,7-dibenzyl-3,4-dihydroisoquinolin-l(2H)-one (I-l)

[0128] To a solution of 50 mg of compound 7a (0.21 mmol, 1 eq) in 3 mL of anhydrous tetrahydrofuran, 17 mg of NaH (0.42 mmol, 2 eq) was first added to the solution under stirring at room temperature, and 54 mg of benzyl bromide (0.42 mmol, 2 eq) was added after 15 minutes. After stirring at room temperature until TLC showed that the reaction was complete, 0.2 mL of water was added to quench the reaction, and the solvent was evaporated. The residue was separated by column chromatography, and then purified by semi-preparative HPLC to obtain 56 mg of compound I-1, with a yield of 81%. 1 H NMR (300 MHz, CD3OD) δ 7.87 (d, J = 1.9 Hz, 1H), 7.37 - 7.05 (m, 12H), 4.71 (s, 2H), 3.95 (s, 2H), 3.37 (t, J = 6.7 Hz, 2H), 2.79 (t, J = 6.7 Hz, 2H); 13 C NMR (75 MHz, CD3OD) δ 165.18, 140.89, 140.51, 137.15, 136.41, 132.47, 128.68, 128.54, 128.39, 128.21, 127.80, 127.56, 127.21, 127.18, 125.85, 50.01, 45.40, 41.07, 26.96; MS (ESI) m / z: [M+Na] + C 23 H 21 NONa calculated 350.1, found 350.2.

[0129] Example 20: 7-benzyl-2-(2-chlorobenzyl)-3,4-dihydroisoquinolin-l(2H)-one (I-2)

[0130] Compound I-2 was prepared from compound 7a and 2-chlorobenzyl bromide using the same method as I-1. 1 H NMR (300 MHz, CD3OD) δ 7.86 (d, J = 1.9 Hz, 1H), 7.48 - 7.11 (m, 11H), 4.88 (s, 2H), 4.00 (s, 2H), 3.52 (dd, J = 6.6 Hz, 2H), 2.95 (t, J = 6.6 Hz, 2H); 13 C NMR (75 MHz, CD3OD) δ 165.47, 140.88, 140.58, 136.53, 134.22, 133.12, 132.59, 129.36, 128.79, 128.65, 128.54, 128.52, 128.18, 127.77, 127.21, 127.02, 125.84, 48.00, 45.88, 41.04, 27.01; MS (ESI) m / z: [M+Na]+ C 23 H 20 ClNONa calculated 384.1, found 384.10.

[0131] Example 21 : 7-benzyl-2-(3-chlorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one (I-3)

[0132] Compound I-3 was prepared from compound 7a and 3-chlorobenzyl bromide using the same procedure as I-1. 1 H NMR (300 MHz, CD3OD) δ 7.87 (d, J = 1.9 Hz, 1H), 7.38 - 7.09 (m, 11H), 4.93 (s, 1H), 3.98 (s, 2H), 3.44 (t, J = 6.6 Hz, 2H), 2.87 (t, J = 6.6 Hz, 2H); 13 C NMR (75 MHz, CD3OD) δ 165.30, 140.87, 140.57, 139.67, 136.43, 134.17, 132.58, 129.93, 128.53, 128.51, 128.19, 127.80, 127.59, 127.29, 127.21, 125.89, 125.84, 49.63, 45.66, 41.04, 26.99; MS (ESI) m / z: [M+Na] + C 23 H 20 ClNONa calculated 384.1, found 384.10.

[0133] Example 22: 7-benzyl-2-(4-chlorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one (I-4)

[0134] Compound I-4 was prepared from compound 7a and 4-chlorobenzyl bromide using the same procedure as I-1. 1 H NMR (300 MHz, CD3OD) δ 7.87 (d, J = 1.9 Hz, 1H), 7.41 - 7.13 (m, 11H), 4.76 (s, 2H), 4.02 (s, 2H), 3.53 (t, J = 6.2 Hz, 2H), 2.95 (t, J = 6.2 Hz, 2H); 13C NMR (75 MHz, CD3OD) δ 166.45, 141.08, 140.57, 136.49, 136.08, 132.95, 132.56, 129.16, 128.56, 128.51, 128.43, 128.17, 127.76, 127.17, 125.83, 49.42, 45.60, 41.02, 27.02; MS (ESI) m / z: [M+Na] 384.1. + C 23 H 20 ClNONa calculated 384.1, found 384.10.

[0135] Example 23: 7-benzyl-2-(4-methylbenzyl)-3,4-dihydroisoquinolin-l(2H)-one (I-5)

[0136] Compound I-5 was prepared from compound 7a and 4-methylbenzyl bromide using the same procedure as for I-l. 1 H NMR (300 MHz, CDC13) δ 8.07 (d, J = 1.9 Hz, 1H), 7.37 - 7.05 (m, 13H), 4.77 (s, 2H), 4.04 (s, 2H), 3.48 (t, J = 6.6 Hz, 2H), 2.90 (t, J = 6.6 Hz, 2H), 2.36 (s, 3H). 13 C NMR (75 MHz, CDC13) δ 164.64, 140.84, 140.22, 137.13, 135.88, 134.44, 132.22, 129.43, 129.33, 128.93, 128.80, 128.58, 128.11, 127.17, 126.21, 50.17, 45.31, 41.70, 27.76, 21.16; MS (ESI) m / z: [M+Na] 364.3. + C 24 H 23 NONa calculated 364.2, found 364.3.

[0137] Example 24: 7-benzyl-2-(4-trifluoromethylbenzyl)-3,4-dihydroisoquinolin-l(2H)-one (I-6)

[0138] Compound I-6 was prepared from compound 7a and 4-trifluoromethylbenzyl bromide using the same procedure as for I-l. 1H NMR (300 MHz, CDC13) δ 8.05 (d, J = 1.9 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 7.34 - 7.16 (m, 6H), 7.12 (d, J = 7.7 Hz, 1H), 4.85 (s, 2H), 4.04 (s, 2H), 3.51 (d, J = 7.1 Hz, 2H), 2.96 (d, J = 7.1 Hz, 2H); 13 C NMR (75 MHz, CDC13) δ 164.85, 141.66, 140.74, 140.42, 135.80, 132.53, 129.75 (q, J F-C = 32.8 Hz), 129.06, 128.91, 128.82, 128.60, 128.24, 127.29, 126.26, 124.13 (q, J F-C = 270.1 Hz), 125.62 (q, J F-C = 3.7 Hz), 50.31, 45.85, 41.68, 27.74; MS (ESI) m / z: [M + Na] + C 24 H 20 F3NONa calcd 418.2, found 418.2.

[0139] Example 25: 7-benzyl-2-(4-fluorobenzyl)-3,4-dihydroisoquinolin-l(2H)-one (I-7)

[0140] Compound I-7 was prepared from compound 7a and 4-fluorobenzyl bromide using the same procedure as I-l. 1 H NMR (300 MHz, CDC13) δ 8.05 (d, J = 1.9 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 7.34 - 7.16 (m, 6H), 7.12 (d, J = 7.7 Hz, 1H), 4.85 (s, 2H), 4.04 (s, 2H), 3.51 (d, J = 7.1 Hz, 2H), 2.96 (d, J = 7.1 Hz, 2H); 13 C NMR (75 MHz, CDC13) δ 164.85, 141.66, 140.74, 140.42, 135.80, 132.53, 129.75 (q, J F-C = 32.8 Hz), 129.06, 128.91, 128.82, 128.60, 128.24, 127.29, 126.26, 124.13 (q, J F-C = 270.1 Hz), 125.62 (q, J F-C = 3.7 Hz), 50.31, 45.85, 41.68, 27.74; MS (ESI) m / z: [M + Na] F-C= 21.3 Hz), 49.31, 45.46, 41.03, 27.00; MS (ESI) m / z: [M+Na] 368.2. + C 23 H 20 FNONa calcd 368.2, found 368.2.

[0141] Example 26: 7-benzyl-2-(4-bromobenzyl)-3,4-dihydroisoquinolin-l(2H)-one (I-8)

[0142] Compound I-8 was prepared from compound 7a and 4-bromobenzyl bromide using the same procedure as I-l. 1 H NMR (300 MHz, CDC13) δ 8.05 (d, J = 1.9 Hz, 1H), 7.53 - 7.42 (m, 2H), 7.37 - 7.16 (m, 8H), 7.10 (d, J = 7.7 Hz, 1H), 4.75 (s, 2H), 4.04 (s, 2H), 3.48 (t, J = 6.6 Hz, 2H), 2.92 (t, J = 6.6 Hz, 2H); 13 C NMR (75 MHz, CDC13) δ 164.74, 140.76, 140.35, 136.58, 135.80, 132.43, 131.77, 129.82, 129.16, 128.91, 128.80, 128.59, 127.25, 126.24, 121.39, 50.01, 45.58, 41.68, 27.74; MS (ESI) m / z: [M+Na] 428.1. + C 23 H 20 BrNONa calcd 428.1, found 428.1.

[0143] Example 27: 7-benzyl-2-(4-methoxybenzyl)-3,4-dihydroisoquinolin-l(2H)-one (I-9)

[0144] Compound I-9 was prepared from compound 7a and 4-methoxybenzyl bromide using the same procedure as I-l. 1 H NMR (300 MHz, CDC13) δ 8.05 (d, J = 1.9 Hz, 1H), 7.53 - 7.42 (m, 2H), 7.37 - 7.16 (m, 8H), 7.10 (d, J = 7.7 Hz, 1H), 4.75 (s, 2H), 4.04 (s, 2H), 3.48 (t, J = 6.6 Hz, 2H), 2.92 (t, J = 6.6 Hz, 2H); 13C NMR (75 MHz, CDC13) δ 164.61, 159.00, 140.83, 140.23, 135.84, 132.23, 129.56, 129.46, 129.43, 128.92, 128.77, 128.57, 127.16, 126.20, 114.00, 55.30, 49.86, 45.23, 41.69, 27.74; MS (ESI) m / z: [M + Na] 380.2. + C 24 H 23 NO2Na calc 380.2, found 380.2.

[0145] Example 28: 7-(2-Fluorobenzyl)-2-(4-trifluoromethylbenzyl)-3,4-dihydroisoquinolin- 1(2H)-one (1-10)

[0146] Compound 1-10 was prepared from compound 7b and 4-trifluoromethylbenzyl bromide using the same procedure as for 1-1. 1 H NMR (300 MHz, CD3OD) δ 7.89 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 7.37 (dd, J = 7.8, 1.9 Hz, 1H), 7.33 - 7.16 (m, 3H), 7.16 - 7.01 (m, 2H), 4.86 (s, 2H), 4.05 (s, 2H), 3.55 (t, J = 6.6 Hz, 2H), 2.97 (t, J = 6.6 Hz, 2H); 13 C NMR (75 MHz, CD3OD) δ 165.37, 160.90 (d, J = 241.1 Hz), 141.88 (q, J = 1.3 Hz), 139.25, 136.73, 132.41, 130.90 (d, J = 4.5 Hz), 129.25 (q, J = 32.5 Hz), 128.55, 128.08 (d, J = 8.0 Hz), 127.98, 127.61, 127.51, 127.25, 125.25 (q, J = 3.7 Hz), 124.2 (q, J = 263.8 Hz), 124.05 (d, J = 3.6 Hz), 114.90 (d, J = 22.0 Hz), 55.30, 49.86, 45.23, 41.69, 27.74; MS (ESI) m / z: [M + Na] 380.2. F-C F-C F-C F-C F-C F-C F-C F-C F-C ​​​​​​​​= 19.8 Hz), 49.78, 45.82, 33.98, 27.02; MS (ESI) m / z: [M+Na] 436.1. + C 24 H 19 F4N Na calcd 436.1, found 436.2.

[0147] Example 29: 7-(3-fluorobenzyl)-2-(4-trifluoromethylbenzyl)-3,4-dihydroisoquinolin- 1(2H)-one (I-11)

[0148] Compound I-11 was prepared from compound 7c and 4-trifluoromethylbenzyl bromide using the same procedure as for I-1. 1 H NMR (300 MHz, CD3OD) δ 7.88 (d, J = 1.9 Hz, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 7.42 - 7.19 (m, 3H), 7.06 (m, 1H), 7.01 - 6.87 (m, 2H), 4.87 (s, 2H), 4.04 (s, 2H), 3.57 (t, J = 6.7 Hz, 2H), 2.99 (t, J = 6.7 Hz, 2H); 13 C NMR (75 MHz, CD3OD) δ 165.39, 143.71 (d, J = 7.1 Hz), 141.91 (q, J = 1.3 Hz), 139.83, 136.83, 132.63, 129.90, 129.78, 128.62, 127.99, 127.81, 127.36, 125.26 (q, J = 272.6 Hz), 124.38, 124.24 (q, J = 3.9 Hz), 118.98, 115.13 (d, J = 24.4 Hz), 112.53 (d, J = 24.4 Hz), 49.79, 45.83, 40.58, 27.03; MS (ESI) m / z: [M+Na] 436.1. F-C = 7.1 Hz), 141.91 (q, J F-C = 1.3 Hz), 139.83, 136.83, 132.63, 129.90, 129.78, 128.62, 127.99, 127.81, 127.36, 125.26 (q, J = 272.6 Hz), 124.38, 124.24 (q, J = 3.9 Hz), 118.98, 115.13 (d, J = 24.4 Hz), 112.53 (d, J = 24.4 Hz), 49.79, 45.83, 40.58, 27.03; MS (ESI) m / z: [M+Na] 436.1. F-C = 7.1 Hz), 141.91 (q, J F-C = 1.3 Hz), 139.83, 136.83, 132.63, 129.90, 129.78, 128.62, 127.99, 127.81, 127.36, 125.26 (q, J = 272.6 Hz), 124.38, 124.24 (q, J = 3.9 Hz), 118.98, 115.13 (d, J = 24.4 Hz), 112.53 (d, J = 24.4 Hz), 49.79, 45.83, 40.58, 27.03; MS (ESI) m / z: [M+Na] 436.1. F-C = 7.1 Hz), 141.91 (q, J F-C = 1.3 Hz), 139.83, 136.83, 132.63, 129.90, 129.78, 128.62, 127.99, 127.81, 127.36, 125.26 (q, J = 272.6 Hz), 124.38, 124.24 (q, J = 3.9 Hz), 118.98, 115.13 (d, J = 24.4 Hz), 112.53 (d, J = 24.4 Hz), 49.79, 45.83, 40.58, 27.03; MS (ESI) m / z: [M+Na] 436.1. + C 24 H 19 F4N Na calcd 436.1, found 436.1.

[0149] Example 30: 7-(4-fluorobenzyl)-2-(4-trifluoromethylbenzyl)-3,4-dihydroisoquinolin- 1(2H)-one (I-12)

[0150] Compound 1-12 was prepared from compound 7d and 4-trifluoromethylbenzyl bromide using the same procedure as for 1-1. 1 H NMR (300 MHz, CD3OD) δ 7.86 (d, J = 1.9 Hz, 1H), 7.70 - 7.61 (m, 2H), 7.56 - 7.47 (m, 2H), 7.34 (dd, J = 7.7, 1.9 Hz, 1H), 7.21 (m, 3H), 7.06 - 6.92 (m, 2H), 4.85 (s, 2H), 3.99 (s, 2H), 3.53 (t, J = 6.7 Hz, 2H), 2.95 (t, J = 6.7 Hz, 2H); 13 C NMR (75 MHz, CD3OD) δ 165.37, 161.60 (d, J F-C = 240.8 Hz), 141.88 (q, J F-C = 1.3 Hz), 140.41, 136.86 (d, J F-C = 3.2 Hz), 136.65, 132.54, 130.13 (d, J F-C = 8.9 Hz), 129.29 (q, J F-C = 32.8 Hz), 128.57, 127.99, 127.73, 127.31, 125.25 (q, J F-C = 3.8 Hz), 124.23 (q, J F-C = 272.6 Hz), 114.74 (d, J F-C = 21.4 Hz), 49.79, 45.84, 40.09, 27.01; MS (ESI) m / z: [M+Na] + C 24 H 19 F4NONa calcd 436.1, found 436.2.

[0151] Example 31: 7-(2-methylbenzyl)-2-(4-trifluoromethylbenzyl)-3,4-dihydroisoquinolin-1(2H)-one (1-13)

[0152] Compound 1-13 was prepared from compound 7e and 4-trifluoromethylbenzyl bromide using the same procedure as for 1-1. 1H NMR (300MHz, CD3OD) δ7.81(d,J=1.9Hz,1H),7.66(d,J=8.1Hz,2H),7.52(d,J=8.1Hz,2H),7.27(dd,J=7.7,1.9Hz,1H),7 .18(d,J=7.7Hz,1H),7.15(s,4H),4.85(s,2H),4.04(s,2H),3.55(t,J=6.6Hz,2H),2.97(t,J=6.6Hz,2H),2.23(s,3H); 13 C NMR(75MHz,CD3OD)δ165.46,141.89(q,J F-C =1.3Hz),139.79,138.40,136.42,136.24,132.43,129.85(q,J F-C =23.3Hz),128.43,127.99,127.62,127.12,126.33,125.75,125.24(q,J F-C =3.8Hz), 124.21(q,J F-C =271.1Hz),49.78,45.85,38.57,27.02,18.40; MS(ESI)m / z:[M+Na] + C 25 H 22 The calculated value of F3NONa is 432.2, and the measured value is also 432.2.

[0153] Example 32: 7-(3-methylbenzyl)-2-(4-trifluoromethylbenzyl)-3,4-dihydroisoquinoline-1(2H)-one (I-14)

[0154] Compound I-14 was prepared by reacting compound 7f with 4-trifluoromethylbenzyl bromide using the same method as I-1. 1 H NMR (300MHz, CD3OD) δ7.81(d,J=1.9Hz,1H),7.66(d,J=8.1Hz,2H),7.52(d,J=8.1Hz,2H),7.27(dd,J=7.8,1.9Hz,1H),7 .18(d,J=7.8Hz,1H),7.15(s,4H),4.85(s,2H),4.04(s,2H),3.55(t,J=6.6Hz,2H),2.97(t,J=6.6Hz,2H),2.23(s,3H); 13 C NMR(75MHz,CD3OD)δ165.46,141.89(q,J F-C= 1.3 Hz), 139.79, 138.40, 136.42, 136.24, 132.43, 129.85 (q, J F-C = 23.0 Hz), 128.43, 127.99, 127.62, 127.12, 126.33, 125.75, 125.24 (q, J F-C = 3.8 Hz), 124.21 (q, J F-C = 270.1 Hz), 49.78, 45.85, 38.57, 27.02, 18.40; MS (ESI) m / z: [M+Na] + C 25 H 22 C36H32F3NONa Calcd 432.2, Found 432.2.

[0155] Example 33: 7-(4-methylbenzyl)-2-(4-trifluoromethylbenzyl)-3,4-dihydroisoquinolin- 1(2H)-one (I-15)

[0156] Compound I-15 was prepared from compound 7g and 4-trifluoromethylbenzyl bromide using the same procedure as I-1. 1 H NMR (300 MHz, CD3OD) δ 7.86 (d, J = 1.9 Hz, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.33 (dd, J = 7.7, 1.9 Hz, 1H), 7.17 (d, J = 7.7 Hz, 1H), 7.08 (s, 3H), 4.84 (s, 2H), 3.95 (s, 2H), 3.52 (t, J = 6.8 Hz, 2H), 2.94 (t, J = 6.8 Hz, 2H), 2.28 (s, 3H); 13 C NMR (75 MHz, CD3OD) δ 165.45, 141.90 (q, J F-C = 1.3 Hz), 140.86, 137.77, 136.43, 135.39, 132.58, 129.28 (q, J F-C = 32.3 Hz), 128.78, 128.42, 127.98, 127.74, 127.16, 125.24 (q, J F-C = 3.7 Hz), 124.23 (q, J F-C = 268.5 Hz), 49.77, 45.84, 40.61, 27.01, 19.65; MS (ESI) m / z: [M+Na] + C 25 H 22 C36H32F3NONa Calcd 432.2, Found 432.2.

[0157] Example 34: 2,7-bis-(4-fluorobenzyl)-3,4-dihydroisoquinoline-1(2H)-one (I-16)

[0158] Compound I-16 was prepared by reacting compound 7d with 4-fluorobenzyl bromide using the same method as I-1. 1 H NMR (300MHz, CDCl3) δ8.02(d,J=1.9Hz,1H),7.39–6.91(m,11H),4.76(s,2H),4.00(s,2H),3.48(t,J=6.6Hz,2H),2.92(t,J=6.6Hz,2H). 13 C NMR(75MHz,CDCl3)δ164.62,162.23(d,J F-C =243.1Hz), 161.48(d,J F-C =242.2Hz), 140.12, 136.47 (d, J) F-C =3.4Hz), 135.97, 133.24 (d, J) F-C =3.2Hz), 132.27, 130.30 (d, J) F-C =7.8Hz), 129.77(d,J F-C =7.8Hz),129.32,128.66,127.33,115.57(d,J F-C =14.0Hz), 115.29(d,J F-C =14.0Hz),49.88,45.47,40.80,27.70; MS(ESI)m / z:[M+Na] + C 23 H 19 The calculated value of F2NONa is 386.1, and the measured value is 386.1.

[0159] Example 35: 7-(4-fluorobenzyl)-2-(4-chlorobenzyl)-3,4-dihydroisoquinoline-1(2H)-one (I-17)

[0160] Compound I-17 was prepared by reacting compound 7d with 4-chlorobenzyl bromide using the same method as I-1. 1 H NMR(300MHz, CDCl3)δ8.02(d,J=1.9Hz,1H),7.36–7.07(m,7H),7.05–6.92(m ,2H),4.76(s,2H),3.99(s,2H),3.47(t,J=6.6Hz,2H),2.92(t,J=6.6Hz,2H); 13C NMR (75 MHz, CDC13) δ 164.66, 161.42 (d, J = 242.1 Hz), 140.14, 136.47 (d, J = 3.2 Hz), 136.02 (d, J = 4.3 Hz), 133.29, 132.32, 130.30 (d, J = 8.1 Hz), 129.48, 129.26, 128.83, 128.66, 127.36, 115.49 (d, J = 20.6 Hz), 115.20, 49.96, 45.57, 40.80, 27.70; MS (ESI) m / z: [M+Na] 402.1. F-C F-C F-C F-C F-C + C 23 H 19 C1FNONa calcd 402.1, found 402.1.

[0161] The synthesis method of compound I-18 is as shown below:

[0162] Reagents and conditions: (a) NH4OH·HCl, CH3COOK, EtOH, argon, 80 °C, 2 h; (b) SOCl2, 50 °C, 2 h, 60%; (c) 4-trifluoromethylbenzyl bromide, NaH, THF, room temperature, 8 h; (d) benzyl boronic acid pinacol ester, K2CO3, Pd(dppf)Cl2, H2O, CH3CN, argon, 100 °C, 8 h, 60%.

[0163] Example 36: 7-bromo-3,4-dihydronaphthalen-1(2H)-one oxime (10)

[0164] 1 g of compound 9 (4.43 mmol, 1 eq) was dissolved in 20 mL of ethanol, 0.34 g of hydroxylamine hydrochloride (4.88 mmol, 1.1 eq) and 0.65 g of potassium acetate (6.66 mmol, 1.5 eq) were added to the solution respectively, the reaction system was replaced with argon for 3 times, after stirring at 80 °C for 2 h, the solvent was evaporated, the residue was washed with water and dried, and the obtained compound 10 was directly used in the next step reaction.

[0165] Example 37: 8-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (11)

[0166] ​​​​​To a solution of 1 g of compound 10 in 7.5 mL of thionyl chloride, the reaction was stirred at 50 °C for 2 h. The excess thionyl chloride was removed by evaporation. To the residue was added 20 mL of water, and the solution was neutralized to pH 7 with saturated NaHC03solution. The organic phase was extracted with ethyl acetate (3 x 20 mL), washed with saturated brine, dried over anhydrous Na2S04, filtered, and concentrated. The residue was purified by column chromatography to give 0.6 g of compound 11 in 60% yield. 1 H NMR (300 MHz, CDC13) δ 7.84 (d, J = 2.2 Hz, 1H), 7.69 (s, 1H), 7.52 (dd, J = 8.1, 2.2 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 3.14 (m, 2H), 2.83 (t, J = 7.1 Hz, 2H), 2.10 - 1.97 (m, 2H).

[0167] Example 38: 8-Bromo-2-(4-trifluoromethylbenzyl)-2,3,4,5-tetrahydro-lH- benzo[c]azepin-l-one (12)

[0168] To a solution of 200 mg of compound 11 (0.84 mmol, 1 eq) in 10 mL of anhydrous tetrahydrofuran was added 50 mg of NaH (1.25 mmol, 1.5 eq) at room temperature with stirring. After 15 min, 298 mg of p-trifluoromethylbenzyl bromide (1.25 mmol, 1.5 eq) was added to the reaction solution, and the stirring was continued until TLC showed that the reaction was complete. The reaction was quenched by adding 0.2 mL of water, and the solvent was removed by evaporation. The residue was separated by column chromatography to give compound 12. 1 H NMR (300 MHz, CDC13) δ 7.89 (d, J = 2.2 Hz, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.57 - 7.46 (m, 3H), 7.05 (d, J = 8.1 Hz, 1H), 4.84 (s, 2H), 3.22 (t, J = 6.8 Hz, 2H), 2.73 (t, J = 6.8 Hz, 2H), 1.87 (m, 2H).

[0169] Example 39: 8-Benzyl-2-(4-trifluoromethylbenzyl)-2,3,4,5-tetrahydro-lH- benzo[c]azepin-l-one (I-18)

[0170] To a solution of 100 mg of compound 12 (0.25 mmol, 1 eq) in 6 mL of a mixed solvent of dioxane and 2 mL of water, 109 mg of benzylboronic acid pinacol ester (0.50 mmol, 2 eq), 104 mg of potassium carbonate (0.76 mmol, 3 eq) and 19 mg of Pd(dppf)Cl2(0.025 mmol, 0.1 eq) were added, respectively. The reaction system was replaced with argon for 3 times, and reacted at 100 °C for 6 h. After the reaction was completed, the reaction solution was diluted with 20 mL of water, and extracted with 20 mL of ethyl acetate for 3 times. The organic phase was combined and washed with saturated brine once, and dried over anhydrous sodium sulfate. After the solid was removed by filtration, the filtrate was concentrated. The residue was separated by column chromatography, and then purified by semi-preparative HPLC to obtain I-18. 1 H NMR (300 MHz, CDCl3) δ 7.64 (m, 3H), 7.52 (d, J = 8.0 Hz, 2H), 7.43-7.27 (m, 2H), 7.32-7.18 (m, 4H), 7.08 (d, J = 7.7 Hz, 1H), 4.85 (s, 2H), 4.03 (s, 2H), 3.22 (t, J = 6.6 Hz, 2H), 2.74 (t, J = 6.6 Hz, 2H), 1.84 (m, 2H); 13 C NMR (75 MHz, CDCl3) δ 171.59, 142.30 (q, J F-C = 1.3 Hz), 140.71, 140.20, 135.65, 135.13, 131.55, 129.80 (q, J F-C = 33.7 Hz), 129.21, 129.01, 128.63, 128.57, 128.50, 126.24, 125.65 (q, J F-C = 3.7 Hz), 124.14 (q, J F-C = 271.1 Hz), 50.10, 46.05, 41.53, 29.81, 29.20; MS (ESI) m / z: [M+Na] + C 25 H 22 F3NONa calcd 432.2, found 432.2.

[0171] The synthesis method of compound I-19 is as shown below:

[0172] Reagents and conditions: (a) SOCl2, MeOH, 80 °C; (b) NBS, BPO, CCl4, 80 °C; (c) TMS CN, CsF, MeOH, rt; (d) CoCl2.6H2O, NaBH4, MeOH, 0 °C; (e) 4-trifluoromethylbenzyl bromide, NaH, THF, rt; (f) mCPBA, DCM, rt; (g) POCl3, Et3N, DCM, rt; (h) benzylboronic acid pinacol ester, K2CO3, Pd(dppf)Cl2, H2O, CH3CN, Ar, 100 °C.

[0173] Example 40: methyl 3-methylpiperidinecarboxylate (15)

[0174] Compound 14 (14.60 mmol, 1 eq) was dissolved in 20 mL of methanol, 3.47 g of sulfoxide chloride (29.20 mmol, 2 eq) was added dropwise at 0 °C, and the reaction system was raised to 80 °C after the dropwise addition was completed. The reaction was carried out until TLC showed that the reaction was complete. The excess methanol was evaporated, 50 mL of water was added to the residue, and the pH was neutralized to 7 with a saturated sodium bicarbonate solution. Then it was extracted with ethyl acetate for 3 times, each time 30 mL. The organic phase was combined and washed with saturated brine once, and then dried with anhydrous sodium sulfate. After filtering out the solid, the filtrate was concentrated, and the residue was purified by column chromatography to obtain 1.87 g of compound 15 with a yield of 85%. MS (ESI) m / z: [M+Na] + C8H9NO2Na calc 174.0, found 174.1.

[0175] Example 41: methyl 3-(bromomethyl)pyridinecarboxylate (16)

[0176] Compound 15 (13.24 mmol, 1 eq) was dissolved in 20 mL of carbon tetrachloride, and 0.48 g of dibenzoyl peroxide (1.99 mmol, 0.15 eq) and 2.38 g of N-bromosuccinimide (13.24 mmol, 1 eq) were added in turn. After refluxing overnight, the solvent was evaporated, and the crude product was separated by column chromatography to obtain 1.83 g of compound 16 with a yield of 60%. MS (ESI) m / z: [M+Na] + C8H8BrNO2Na calc 252.0, found 252.1.

[0177] Example 42: methyl 3-(cyanomethyl)pyridinecarboxylate (17)

[0178] To a solution of 1 g of compound 16 (4.35 mmol, 1 eq) in 10 mL of methanol, 3.3 g of cesium fluoride (21.74 mmol, 5 eq) and 2.2 g of trimethylsilyl cyanide (21.74 mmol, 5 eq) were added successively at room temperature and the reaction was left overnight. The solvent was evaporated and the crude was separated by column chromatography to obtain 0.34 g of compound 17 with a yield of 45%. MS (ESI) m / z: [M+Na] 199.2. + C9H8N2O2Na Calcd. 199.1, Found. 199.2.

[0179] Example 43: 6,7-dihydro-l,7-naphthyridin-8(5H)-one (18)

[0180] To a solution of 1 g of compound 17 (5.68 mmol, 1 eq) in 10 mL of methanol, 2.7 g of cobalt dichloride hexahydrate (11.36 mmol, 2 eq) was added at 0°C and after 5 min 2.1 g of sodium borohydride (56.82 mmol, 10 eq) was added slowly in portions and the reaction was left at this temperature until TLC showed the completion of the reaction. The reaction was quenched by the dropwise addition of 10 mL of saturated aqueous ammonium chloride solution and extracted three times with 30 mL of ethyl acetate each time. The organic phases were combined and washed once with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solid was filtered off and the filtrate was concentrated. The residue was purified by column chromatography to obtain 0.25 g of compound 18 with a yield of 30%. MS (ESI) m / z: [M+Na] 171.2. + C8H8N2ONa Calcd. 171.1, Found. 171.2.

[0181] Example 44: 7-(4-trifluoromethylbenzyl)-6,7-dihydro-l,7-naphthyridin-8(5H)-one (19a)

[0182] To a solution of 300 mg of compound 18 (2.03 mmol, 1 eq) in 10 mL of anhydrous tetrahydrofuran, 73 mg of NaH (3.04 mmol, 1.5 eq) was added at room temperature with stirring. After 15 min, 727 mg of p-trifluoromethylbenzyl bromide (3.04 mmol, 1.5 eq) was added to the reaction and stirring was continued until TLC showed the completion of the reaction. The reaction was quenched by the addition of 0.5 mL of water and the solvent was evaporated. The residue was separated by column chromatography to obtain 527 mg of compound 19a with a yield of 85%. MS (ESI) m / z: [M+Na] 329.2. + C 16 H 13 F3N2ONa Calcd. 329.1, Found. 329.2.

[0183] Example 45: 8-oxo-7-(4-trifluoromethylbenzyl)-5,6,7,8-tetrahydro-l,7-naphthyridine 1-oxide (20a)

[0184] To a solution of 500 mg compound 19a (1.63 mmol, 1 eq) in 10 mL of dichloromethane was added 282 mg of meta-chloroperoxybenzoic acid (1.63 mmol, 1 eq) and the reaction was stirred at room temperature until TLC showed the reaction was complete. The reaction was filtered through celite and the celite cake was washed with dichloromethane (10 mL x 2). The filtrate was washed with saturated sodium sulfite solution and saturated brine, respectively, and dried over anhydrous sodium sulfate. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by column chromatography to give 421 mg of compound 20a in 80% yield. MS (ESI) m / z: [M+Na] 345.2. + C 16 H 13 Calcd for C13H9ClF3N2O2Na, 345.1, found 345.2.

[0185] Example 46: 2-Chloro-7-(4-trifluoromethylbenzyl)-6,7-dihydro-l,7- naphthyridin-8(5H)-one (21a)

[0186] To a solution of 500 mg compound 20a (1.55 mmol, 1 eq) in 10 mL of dichloromethane was added 470 mg of triethylamine (4.66 mmol, 3 eq) and 475 mg of phosphorus oxychloride (3.11 mmol, 2 eq) sequentially with stirring at room temperature. After the addition was complete, the reaction was stirred at room temperature until TLC showed the reaction was complete. The reaction was poured into 20 mL of ice water and stirred well. The organic phase was separated and the aqueous phase was extracted with dichloromethane (30 mL x 3). The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to give 264 mg of compound 21a in 50% yield. MS (ESI) m / z: [M+Na] 363.1. + C 16 H 12 Calcd for C14H9ClF3N2ONa, 363.0, found 363.1.

[0187] Example 47: 2-Benzyl-7-(4-trifluoromethylbenzyl)-6,7-dihydro-l,7- naphthyridin-8(5H)-one (I-19)

[0188] To a solution of 100 mg of compound 21a (0.29 mmol, 1 eq) in a mixture of 4 mL of acetonitrile and 1 mL of water, 128 mg of benzylboronic acid pinacol ester (0.59 mmol, 2 eq), 122 mg of potassium carbonate (0.88 mmol, 3 eq) and 22 mg of Pd(dppf)Cl2(0.03 mmol, 0.1 eq) were added, respectively. After addition, the reaction system was replaced with argon for 3 times. Stirring was carried out at 100 °C until TLC showed that the reaction was completed. The reaction solution was cooled and 20 mL of water was added. Extraction was carried out with ethyl acetate for 3 times, 20 mL each time. The organic phase was combined and washed with saturated brine once. Then, it was dried over anhydrous sodium sulfate. The drying agent was filtered out and the solution was concentrated. The residue was separated by column chromatography and then purified by semi-preparative HPLC to obtain 80 mg of compound I-19, with a yield of 69%. MS (ESI) m / z: [M+Na] + C 23 H 19 F3N2ONa calculated 419.1, found 419.2.

[0189] The synthesis method of compound I-20 is as shown below:

[0190] Reagents and conditions: (a) SOCl2, MeOH, 80 °C; (b) trimethylaluminum, Pd(PPh3)4, THF, Ar, 80 °C; (c) NBS, BPO, CCl4, 80 °C; (d) TMSCN, CsF, MeOH, rt; (e) CoCl2·6H2O, NaBH4, MeOH, 0 °C; (f) 4-trifluoromethylbenzyl bromide, NaH, THF, rt; (g) benzylboronic acid pinacol ester, K2CO3, Pd(dppf)Cl2, H2O, CH3CN, Ar, 100 °C.

[0191] Example 48: 2-chloro-5-bromoisatnic acid methyl ester (24)

[0192] 2 g of compound 23 (8.46 mmol, 1 eq) was dissolved in 20 mL of methanol. 2.0 g of thionyl chloride (16.92 mmol, 2 eq) was slowly added dropwise at 0 °C. After the dropwise addition was completed, the reaction solution was warmed to 80 °C and stirred until TLC showed that the reaction was complete. The excess methanol was evaporated. 30 mL of water was added to the residue. The pH value was neutralized to 7 with a saturated sodium bicarbonate solution. Extraction was carried out with ethyl acetate for 3 times, 30 mL each time. The organic phase was combined and washed with saturated brine once. Then, it was dried over anhydrous sodium sulfate. After the solid was filtered out, the filtrate was concentrated. The residue was purified by column chromatography to obtain 1.74 g of compound 24, with a yield of 82%. 1 H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 7.64 (s, 1H), 3.95 (s, 3H).

[0193] Example 49: Methyl 2-chloro-5-methylisonicotinate (25)

[0194] Dissolve 2 g of compound 24 (7.98 mmol, 1 eq) in 30 mL of anhydrous tetrahydrofuran, add 0.7 g of tetrakis(triphenylphosphine)palladium (0.64 mmol, 0.08 eq), slowly drop 0.75 g of trimethylaluminum (10.38 mmol, 1.3 eq) under argon protection, after the drop is completed, the reaction solution is warmed to 80°C and stirred until the TLC reaction is complete, quench the reaction with 20 mL of water, separate the organic phase, the aqueous phase is extracted with ethyl acetate for 3 times, 30 mL each time, the organic phase is combined and washed with saturated brine once, then dried with anhydrous sodium sulfate, filter out the solid, then concentrate the filtrate, the residue is purified by column chromatography to obtain 0.89 g of compound 25, with a yield of 60%. 1 H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H), 7.76 (s, 1H), 3.96 (s, 3H), 2.55 (s, 3H).

[0195] Example 50: Methyl 5-(bromomethyl)-2-chloroisonicotinate (26)

[0196] Dissolve 1 g of compound 25 (5.40 mmol, 1 eq) in 10 mL of carbon tetrachloride, add 0.20 g of dibenzoyl peroxide (0.81 mmol, 0.15 eq) and 0.92 g of N-bromosuccinimide (5.40 mmol, 1 eq) to the solution in turn, after adding, reflux overnight, evaporate the solvent, separate the crude product by column chromatography to obtain 0.93 g of compound 26, with a yield of 65%. 1 H NMR (300 MHz, CDCl3) δ 8.54 (s, 1H), 7.83 (s, 1H), 4.88 (s, 2H), 4.02 (s, 3H).

[0197] Example 51: Methyl 2-chloro-5-(cyanomethyl)isonicotinate (27)

[0198] Dissolve 1 g of compound 26 (3.78 mmol, 1 eq) in 10 mL of methanol, add 2.87 g of cesium fluoride (18.90 mmol, 5 eq) and 1.87 g of trimethylsilyl cyanide (18.90 mmol, 5 eq) to the solution in turn, stir at room temperature until the TLC shows that the reaction is complete, evaporate the solvent, separate the crude product by column chromatography to obtain 0.40 g of compound 27, with a yield of 50%. 1 H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 7.92 (s, 1H), 4.15 (s, 2H), 4.01 (s, 3H).

[0199] Example 52: 7-chloro-3,4-dihydro-2,6-naphthyridin-l(2H)-one (28)

[0200] Compound 27 (500 mg, 2.37 mmol, 1 eq) was dissolved in 10 mL of methanol, 1.1 g of cobalt dichloride hexahydrate (4.75 mmol, 2 eq) was added at 0 °C, 897 mg of sodium borohydride (23.74 mmol, 10 eq) was added in portions after 5 min, and the reaction was stirred at this temperature until TLC showed that the reaction was complete. The reaction was quenched by dropwise addition of 10 mL of saturated aqueous ammonium chloride solution, and the reaction was diluted with 20 mL of water. The organic phase was extracted with ethyl acetate (30 mL x 3), washed with saturated brine once, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to give 173 mg of compound 28 with a yield of 40%. 1 H NMR (300 MHz, CDC13) δ 8.40 (s, 1H), 7.93 (s, 1H), 6.80 (s, 1H), 3.65 (dt, J = 6.6, 2.9 Hz, 2H), 3.03 (t, J = 6.6 Hz, 2H).

[0201] Example 53: 7-chloro-2-(4-trifluoromethylbenzyl)-3,4-dihydro-2,6-naphthyridin-l(2H)-one (29a)

[0202] Compound 28 (100 mg, 0.55 mmol, 1 eq) was dissolved in 5 mL of anhydrous tetrahydrofuran, and 20 mg of NaH (0.82 mmol, 1.5 eq) was added to the solution under stirring at room temperature. After 15 min, 197 mg of p-trifluoromethyl benzyl bromide (0.82 mmol, 1.5 eq) was added to the reaction solution, and the stirring was continued until TLC showed that the reaction was complete. The reaction was quenched by adding 0.5 mL of water to the reaction solution, and the solvent was removed by evaporation. The residue was separated by column chromatography to give 159 mg of compound 29a with a yield of 85%. MS (ESI) m / z: [M+Na] + C 16 H 12 ClF3N2ONa calcd 363.1, found 363.2.

[0203] Example 54: 7-benzyl-2-(4-trifluoromethylbenzyl)-3,4-dihydro-2,6-naphthyridin-l(2H)-one (I-20)

[0204] To a solution of 100 mg of compound 29a (0.29 mmol, 1 eq) in 4 mL of acetonitrile and 1 mL of water, 128 mg of benzylboronic acid pinacol ester (0.59 mmol, 2 eq), 122 mg of potassium carbonate (0.88 mmol, 3 eq) and 22 mg of Pd(dppf)Cl2(0.03 mmol, 0.1 eq) were added, respectively. After addition, the reaction system was replaced with argon for 3 times. After stirring at 100 °C until TLC showed that the reaction was complete, the reaction solution was cooled and 20 mL of water was added. It was extracted with ethyl acetate for 3 times, 20 mL each time. The organic phase was combined and washed with saturated brine once, then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solution was concentrated. The residue was separated by column chromatography first, and then purified by semi-preparative HPLC to obtain 77 mg of compound I-20, with a yield of 66%. MS (ESI) m / z: [M+Na] 419.1 Calc’d, 419.2 Found. + C 23 H 19 F3N2ONa Calc’d 419.1, Found 419.2.

[0205] The synthesis method of compound I-21 is as shown below:

[0206] Reagents and conditions: (a) LiHMDS, AcONH4, THF, Ar, 60 °C; (b) mCPBA, DCM, rt; (c) RuCl3, NaIO4, EA, water, rt; (d) PCI3, Et3N, DCM, rt; (e) i. TFA, rt, 2 h; ii. 4-trifluoromethylbenzyl bromide, NaH, THF, rt; (h) benzylboronic acid pinacol ester, K2CO3, Pd(dppf)Cl2, water, CH3CN, Ar, 100 °C.

[0207] Example 55: tert-butyl 3-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (33)

[0208] To a solution of 2 g of compound 33 (7.44 mmol, 1 eq) in 20 mL of dichloromethane was added 1.3 g of m-chloroperoxybenzoic acid (7.44 mmol, 1 eq) and stirred at room temperature until TLC showed the reaction was complete. The reaction was filtered through celite and the resulting filtrate was washed with saturated sodium sulfite and saturated brine once each, dried over anhydrous sodium sulfate, the solids were filtered off and the filtrate was concentrated. The residue was purified by column chromatography to give 1.80 g of compound 34 in 85% yield. 1 H NMR (300 MHz, CDC13) δ 8.39 (d, J = 2.4 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 4.59 (s, 2H), 3.75 (t, J = 6.0 Hz, 2H), 2.98 (t, J = 6.0 Hz, 2H), 1.50 (s, 9H).

[0209] Example 56: 6-(tert-Butoxycarbonyl)-3-chloro-5,6,7,8-tetrahydro-l,6- naphthyridine 1-oxide (34)

[0210] To a solution of 2 g of compound 33 (7.44 mmol, 1 eq) in 20 mL of dichloromethane was added 1.3 g of m-chloroperoxybenzoic acid (7.44 mmol, 1 eq) and stirred at room temperature until TLC showed the reaction was complete. The reaction was filtered through celite and the resulting filtrate was washed with saturated sodium sulfite and saturated brine once each, dried over anhydrous sodium sulfate, the solids were filtered off and the filtrate was concentrated. The residue was purified by column chromatography to give 1.80 g of compound 34 in 85% yield. 1 H NMR (300 MHz, CDC13) δ 8.39 (d, J = 2.4 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 4.59 (s, 2H), 3.75 (t, J = 6.0 Hz, 2H), 2.98 (t, J = 6.0 Hz, 2H), 1.50 (s, 9H).

[0211] Example 57: 6-(tert-Butoxycarbonyl)-3-chloro-5-oxo-5,6,7,8-tetrahydro-l,6- naphthyridine 1-oxide (35)

[0212] To a solution of 2 g of compound 34 (7.02 mmol, 1 eq) in 12 mL of ethyl acetate, 8 mL of water was added, followed by the addition of 6.0 g of sodium periodate (28.09 mmol, 4 eq) and 0.15 g of ruthenium trichloride (0.70 mmol, 0.1 eq), respectively. After the addition was completed, the reaction was stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 50 mL of water, and then extracted with ethyl acetate three times, 30 mL each time. The organic phase was combined and washed with saturated brine once, and then dried over anhydrous sodium sulfate. After the solid was removed by filtration, the filtrate was concentrated, and the residue was purified by column chromatography to obtain 1.51 g of compound 35 with a yield of 72%. 1 H NMR (300 MHz, CDCl3) δ 8.42 (s, 1H), 8.00 (s, 1H), 4.05 (s, 2H), 3.30 (s, 2H), 1.60 (s, 9H).

[0213] Example 58: tert-Butyl 3-chloro-5-oxo-7,8-dihydro-1,6-naphthyridine-6(5H)- carboxylate (36)

[0214] To a solution of 1 g of compound 35 (3.35 mmol, 1 eq) in 10 mL of dichloromethane, 1.0 g of triethylamine (10.04 mmol, 3 eq) and 0.9 g of phosphorus trichloride (6.70 mmol, 2 eq) were added in sequence with stirring at room temperature. After the addition was completed, the reaction was stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was poured into 30 mL of ice water and stirred thoroughly. The aqueous phase was extracted with dichloromethane three times, 30 mL each time. The organic phase was combined and washed with saturated brine once, and then dried over anhydrous sodium sulfate. After the solid was removed by filtration, the filtrate was concentrated, and the residue was purified by column chromatography to obtain 0.38 g of compound 36 with a yield of 40%. 1 H NMR (300 MHz, CDCl3) δ 8.63 (d, J = 2.5 Hz, 1H), 8.40 (d, J = 2.5 Hz, 1H), 4.09 (t, J = 6.5 Hz, 2H), 3.21 (t, J = 6.5 Hz, 2H), 1.61 (s, 9H).

[0215] Example 59: 3-chloro-6-(4-trifluoromethylbenzyl)-7,8-dihydro-1,6-naphthyridin-5(6H)- one (37a)

[0216] To a solution of 500 mg of compound 36 (1.77 mmol, 1 eq) in 4 mL of dichloromethane, 1 mL of trifluoroacetic acid was added dropwise with stirring at room temperature, and the reaction was continued to stir until TLC showed that the reaction was complete. The reaction was concentrated under reduced pressure, the residue was dissolved in 10 mL of dichloromethane and concentrated again under reduced pressure, the residue was dissolved in tetrahydrofuran and cooled to 0°C, 85 mg of sodium hydride (3.54 mmol, 2 eq) was added, 10 minutes later, 634 mg of p-trifluoromethyl benzyl bromide (2.65 mmol, 1.5 eq) was added and the reaction was allowed to stir overnight at room temperature. After the reaction was complete, the reaction was quenched with an aqueous solution of ammonium chloride and diluted with water, the aqueous phase was extracted with 20 mL of ethyl acetate three times, the organic phase was combined and washed with saturated brine once, then dried over anhydrous sodium sulfate, the solid was filtered off and the filtrate was concentrated, the residue was purified by column chromatography to obtain 434 mg of compound 37a with a yield of 72%. 1 H NMR (300 MHz, CDC13) δ 8.60 (d, J = 2.5 Hz, 1H), 8.40 (d, J = 2.5 Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 4.86 (s, 2H), 3.61 (t, J = 6.8 Hz, 2H), 3.18 (t, J = 6.8 Hz, 2H).

[0217] Example 60: 3-benzyl-6-(4-trifluoromethylbenzyl)-7,8-dihydro-l,6-naphthyridin-5(6H)-one (I-21)

[0218] To a solution of 200 mg of compound 37 (0.59 mmol, 1 eq) in 6 mL of acetonitrile and 2 mL of water, 257 mg of benzylboronic acid pinacol ester (1.17 mmol, 2 eq), 245 mg of potassium carbonate (1.76 mmol, 3 eq) and 44 mg of Pd(dppf)Cl2(0.06 mmol, 0.1 eq) were added respectively, the reaction system was replaced with argon for 3 times after addition was completed, the reaction was allowed to stir at 100°C until TLC showed that the reaction was complete, the reaction was cooled and 20 mL of water was added, the reaction was extracted with 20 mL of ethyl acetate three times, the organic phase was combined and washed with saturated brine once, then dried over anhydrous sodium sulfate, the drying agent was filtered off, the solution was concentrated, the residue was separated by column chromatography and purified by semi-preparative HPLC to obtain 63 mg of compound I-21 with a yield of 27%. 1H NMR (300 MHz, CD3OD) δ 8.59 (d, J = 2.2 Hz, 1H), 8.37 (d, J = 2.2 Hz, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.38 - 7.21 (m, 5H), 4.88 (s, 2H), 4.14 (s, 2H), 3.70 (t, J = 6.8 Hz, 2H), 3.23 (t, J = 6.8 Hz, 2H); 13 C NMR (75 MHz, CD3OD) δ 163.28, 155.05, 149.74, 141.35, 139.27, 137.87, 137.69, 128.59, 128.55, 128.13, 126.43, 125.30 (q, J F-C = 3.8 Hz), 49.76, 44.57, 37.82, 28.60; MS (ESI) m / z: [M+Na] + C 23 H 19 C19H15F3N2ONa Calcd 419.1, Found 419.2.

[0219] The synthesis method of compounds I-22, I-23, I-26 to I-30, I-47 to I-49 is as shown below:

[0220] Reagents and conditions: (a) i. SOCl2, MeOH, rt; ii. ClCOOCH3, NaHCO3, dioxane, H2O, rt; (b) paraformaldehyde, H2SO4, AcOH, rt; (c) LiBH4, THF, rt; (d) NaBrO3, CAN, dioxane, H2O, rt; (e) CH3ONa, MeOH, rt; (f) TBS-Cl, imidazole, DMF, rt; (g) benzyl bromide or substituted benzyl bromide, NaH, THF, rt; (h) i. benzylboronic acid pinacol ester or substituted benzylboronic acid pinacol ester, Cs2CO3, Pd(dppf)Cl2, H2O, dioxane, Ar, 100 °C; ii. TBAF, THF, rt.

[0221] Example 61: (R)-methyl 3-(4-bromophenyl)-2-((methoxycarbonyl)amino)propanoate (40a)

[0222] To a solution of compound 39a (10 g, 40.97 mmol, 1 eq) in 80 mL of methanol was added 7.3 g of chlorosulfuric acid (61.45 mmol, 1.5 eq) dropwise at 0 °C. After the addition was completed, the reaction was allowed to warm to room temperature and stirred overnight. The methanol was removed by reduced pressure concentration. The resulting white solid was dissolved in 100 mL of water and neutralized to pH 7 with saturated sodium bicarbonate solution. Then 3.5 g of sodium bicarbonate powder was added, followed by the dropwise addition of 4.6 g of methyl chloroformate (49.2 mmol, 1.2 eq) at room temperature. The reaction was stirred until TLC showed that the reaction was complete. The reaction was extracted with ethyl acetate (60 mL x 3). The organic phase was combined and washed with saturated brine once, dried over anhydrous sodium sulfate. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by column chromatography to give compound 40a (11 g, 85% yield). 1 H NMR (300 MHz, CDC13) δ 7.40 (d, J = 9.0 Hz, 2H), 7.00 (d, J = 9.0 Hz, 2H), 5.37 (d, J = 8.3 Hz, 1H), 4.68 - 4.53 (m, 1H), 3.71 (s, 3H), 3.64 (s, 3H), 3.04 (qd, J = 13.9, 6.0 Hz, 2H).

[0223] Example 62: (S)-3-(4-bromophenyl)-2-((methoxycarbonyl)amino)propanoic acid methyl ester (40b)

[0224] Compound 40b was synthesized from 39b according to the synthetic procedure of 40a. MS (ESI) m / z: [M+Na] + C 12 H 14 BrNO4Na Calcd 338.0, Found 338.1.

[0225] Example 63: (R)-7-bromo-3,4-dihydroisoquinoline-2,3(lH)-dicarboxylic acid dimethyl ester (41a)

[0226] To a solution of compound 40a (10 g, 40.97 mmol, 1 eq) in 80 mL of methanol was added 7.3 g of chlorosulfuric acid (61.45 mmol, 1.5 eq) dropwise at 0 °C. After the addition was completed, the reaction was allowed to warm to room temperature and stirred overnight. The methanol was removed by reduced pressure concentration. The resulting white solid was dissolved in 100 mL of water and neutralized to pH 7 with saturated sodium bicarbonate solution. Then 3.5 g of sodium bicarbonate powder was added, followed by the dropwise addition of 4.6 g of methyl chloroformate (49.2 mmol, 1.2 eq) at room temperature. The reaction was stirred until TLC showed that the reaction was complete. The reaction was extracted with ethyl acetate (60 mL x 3). The organic phase was combined and washed with saturated brine once, dried over anhydrous sodium sulfate. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by column chromatography to give compound 40a (11 g, 85% yield). 1H NMR (300 MHz, CDC13) δ 7.35 - 7.22 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H), 5.19 (m, 0.6H), 4.99 (m, 0.4H), 4.82 - 4.47 (m, 2H), 3.81 (s, 1.8H), 3.76 (s, 1.2H), 3.64 (s, 3H), 3.22 - 3.03 (m, 2H).

[0227] Example 64: (S)-7-bromo-3,4-dihydroisoquinoline-2,3(lH)-dicarboxylic acid dimethyl ester (41b)

[0228] Compound 41b was synthesized from 40b following the procedure for the synthesis of 41a. MS (ESI) m / z: [M+Na] 350.0. + C 13 H 14 BrNO4Na Calcd 350.0, Found 350.1.

[0229] Example 65: (R)-7-bromo-l,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one (42a)

[0230] To a solution of 8 g of compound 41a (24.38 mmol, 1 eq) in 40 mL of anhydrous tetrahydrofuran, 0.8 g of lithium borohydride (36.57 mmol, 1.5 eq) was added slowly at 0 °C, after the addition was completed, it was raised to room temperature and stirred overnight, then quenched with 30 mL of saturated aqueous ammonium chloride solution, after the tetrahydrofuran was evaporated, the residue was diluted with 100 mL of water, extracted with ethyl acetate for 3 times, 50 mL each time, the organic phase was combined and washed with saturated brine once, then dried over anhydrous sodium sulfate, after the solid was filtered off, the filtrate was concentrated, the residue was purified by column chromatography to give 4.8 g of compound 42a with a yield of 73%. 1 H NMR (300 MHz, CDC13) δ 7.35 - 7.22 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H), 5.19 (m, 0.6H), 4.99 (m, 0.4H), 4.82 - 4.47 (m, 2H), 3.81 (s, 1.8H), 3.76 (s, 1.2H), 3.64 (s, 3H), 3.22 - 3.03 (m, 2H).

[0231] Example 66: (S)-7-bromo-l,5,10,10a-tetrahydro-3H-oxazolo[3,4-b]isoquinolin-3-one (42b)

[0232] Compound 42b was synthesized from 41b following the procedure for the synthesis of 42a. MS (ESI) m / z: [M+Na] 350.0.+ C 11 H 10 BrNO2Na Calcd 290.0, Found 290.1.

[0233] Example 67: (R)-7-bromo-10,10a-dihydro-3H-oxazolo[3,4-b]isoquinoline-3,5(lH)- dione (43a)

[0234] Compound 43a was synthesized from 42a by the similar procedure as described in example 67. MS (ESI) m / z: [M+Na] 290.1. 1 H NMR (300 MHz, DMSO-d6) δ 8.03 (d, J = 3.0 Hz, 1H), 7.66 (dd, J = 6.0, 3.0 Hz, 1H), 7.26 (d, J = 6.0 Hz, 1H), 4.73 - 4.52 (m, 2H), 4.18 (m, 1H), 3.19 - 3.07 (m, 2H); MS (ESI) m / z: [M+Na] 290.1. + C 11 H8BrNO3Na Calcd 304.0, Found 304.1.

[0235] Example 68: (S)-7-bromo-10,10a-dihydro-3H-oxazolo[3,4-b]isoquinoline-3,5(lH)- dione (43b)

[0236] Compound 43b was synthesized from 42b by the similar procedure as described in example 43a. MS (ESI) m / z: [M+Na] 290.1. + C 11 H8BrNO3Na Calcd 304.0, Found 304.1.

[0237] Example 69: (R)-7-bromo-3-hydroxymethyl-3,4-dihydroisoquinolin-l(2H)-one (44a)

[0238] To a solution of compound 43a (6 g, 21.27 mmol, 1 eq) in 30 mL of methanol was added sodium methoxide (57 mg, 1.06 mmol, 0.05 eq) at room temperature. The reaction was stirred until TLC showed that the reaction was complete. The solvent was evaporated, and the crude product was purified by column chromatography to give 4.4 g of compound 44a in 80% yield. 1 H NMR (300 MHz, CD3OD) δ 8.05 (d, J = 2.2 Hz, 1H), 7.66 (dd, J = 8.1, 2.2 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 3.75 (m, 1H), 3.62 - 3.57 (m, 2H), 3.12 - 2.88 (m, 2H).

[0239] Example 70: (S)-7-bromo-3-hydroxymethyl-3,4-dihydroisoquinolin-1(2H)-one (44b)

[0240] Compound 44b was synthesized from 43b according to the synthetic method of 44a. MS (ESI) m / z: [M+Na] + C 10 H 10 BrNO2Na Calcd 278.0, Found 278.1.

[0241] Example 71: (R)-7-bromo-3-((tert-butyldimethylsilyloxy)methyl)-3,4- dihydroisoquinolin-1(2H)-one (45a)

[0242] To a solution of compound 44a (4 g, 15.62 mmol, 1 eq) in 20 mL of N,N- dimethylformamide was added imidazole (3.2 g, 46.86 mmol, 3 eq) and tert- butyldimethylsilyl chloride (3.5 g, 23.43 mmol, 1.5 eq) at 0 °C. After the addition was completed, the reaction was allowed to warm to room temperature and stirred until TLC showed that the reaction was complete. To the reaction was added 100 mL of water, and the mixture was extracted with ethyl acetate (40 mL x 3). The organic phase was combined and washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to give 4.5 g of compound 45a in 77% yield. 1 H NMR (300 MHz, CD3OD) δ 8.05 (d, J = 2.2 Hz, 1H), 7.66 (dd, J = 8.1, 2.2 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 3.75 (m, 1H), 3.62 - 3.57 (m, 2H), 3.12 - 2.88 (m, 2H).

[0243] Example 72: (S)-7-bromo-3-((tert-butyldimethylsilyloxy)methyl)-3,4- dihydroisoquinolin-1(2H)-one (45b)

[0244] Compound 45b was synthesized from 44b following the synthetic procedure of 45a. 1 H NMR (300 MHz, CDC13) δ 8.23 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 8.1, 2.2 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.33 (s, 1H), 3.89 - 3.54 (m, 3H), 2.94 - 2.72 (m, 2H), 0.91 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H).

[0245] Example 73: (R)-7-bromo-3-((tert-butyldimethylsilyloxy)methyl)-2-(4- (trifluoromethyl)benzyl)-3,4-dihydroisoquinolin-1(2H)-one (46a)

[0246] Compound 46a was synthesized from 45a following the synthetic procedure of 46b. 1 H NMR (300 MHz, CDC13) δ 8.23 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 8.1, 2.2 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.33 (s, 1H), 3.89 - 3.54 (m, 3H), 2.94 - 2.72 (m, 2H), 0.91 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H).

[0247] Example 74: (S)-7-bromo-3-((tert-butyldimethylsilyloxy)methyl)-2-(4- (trifluoromethyl)benzyl)-3,4-dihydroisoquinolin-1(2H)-one (46b)

[0248] Compound 46b was synthesized from 45b following the synthetic procedure of 46a. 1H NMR (300 MHz, CDC13) δ 8.25 (d, J = 2.1 Hz, 1H), 7.64 - 7.53 (m, 3H), 7.47 (d, J = 7.9 Hz, 2H), 7.06 (d, J = 8.1 Hz, 1H), 5.52 (d, J = 15.2 Hz, 1H), 4.28 (d, J = 15.2 Hz, 1H), 3.70 - 3.39 (m, 3H), 3.17 - 2.88 (m, 2H), 0.83 (br s, 9H), -0.07 (s, 3H), -0.08 (s, 3H).

[0249] Example 75: (R)-7-bromo-3-((tert-butyldimethylsilyloxy)methyl)-2-(4- chlorobenzyl)-3,4-dihydroisoquinolin-1 (2H)-one (46c)

[0250] Compound 46c was prepared from intermediate 45a and 4-chlorobenzyl bromide using the same procedure as 46a. 1 H NMR (300 MHz, CDC13) δ 8.25 (d, J = 2.1 Hz, 1H), 7.64 - 7.53 (m, 3H), 7.47 (d, J = 7.9 Hz, 2H), 7.06 (d, J = 8.1 Hz, 1H), 5.52 (d, J = 15.2 Hz, 1H), 4.28 (d, J = 15.2 Hz, 1H), 3.70 - 3.39 (m, 3H), 3.17 - 2.88 (m, 2H), 0.83 (br s, 9H), -0.07 (s, 3H), -0.08 (s, 3H).

[0251] Example 76: (R)-7-bromo-3-((tert-butyldimethylsilyloxy)methyl)-2-(4- fluorobenzyl)-3,4-dihydroisoquinolin-1 (2H)-one (46d)

[0252] Compound 46d was prepared from intermediate 45a and 4-fluorobenzyl bromide using the same procedure as 46a. MS (ESI) m / z: [M + Na]+ calculated 500.1, found 500.2. + C 23 H 29 BrFNO2SiNa calculated 500.1, found 500.2.

[0253] Example 77: (R)-7-benzyl-3-hydroxymethyl-2-(4-trifluoromethylbenzyl)-3,4- dihydroisoquinolin-1 (2H)-one (I-22)

[0254] To a solution of 1 g of compound 46a (1.89 mmol, 1 eq) in a mixture of 16 mL of dioxane and 4 mL of water, 0.8 g of benzylboronic acid pinacol ester (3.78 mmol, 2 eq), 1.8 g of cesium carbonate (5.68 mmol, 3 eq) and 111 mg of Pd(dppf)Cl2(0.15 mmol, 0.08 eq) were added, respectively. After addition, the reaction system was replaced with argon for 3 times. The reaction was stirred at 100 °C until TLC showed that the reaction was complete. The reaction solution was cooled and 50 mL of water was added. The organic phase was extracted with ethyl acetate for 3 times, 30 mL each time. The organic phase was combined and washed with saturated brine once, then dried over anhydrous sodium sulfate. The drying agent was removed by filtration. The solution was concentrated. The residue was dissolved in 10 mL of tetrahydrofuran. 2 mL of 1 M tetrabutylammonium fluoride solution in tetrahydrofuran was added to the solution under stirring at room temperature. The stirring was continued until TLC showed that the reaction was complete. The solvent was evaporated. The residue was separated by column chromatography and purified by semi-preparative HPLC to obtain 0.48 g of compound I-22, with a yield of 60%. 1 H NMR (300 MHz, CD3OD) δ 7.86 (d, J = 1.9 Hz, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.32 (dd, J = 7.7, 1.9 Hz, 1H), 7.28 - 7.12 (m, 6H), 5.45 (d, J = 15.5 Hz, 1H), 4.38 (d, J = 15.5 Hz, 1H), 3.97 (s, 2H), 3.70 - 3.61 (m, 1H), 3.59 - 3.35 (m, 2H), 3.20 - 2.95 (m, 2H); MS (ESI) m / z: [M+Na] + C 25 H 22 F3NO2Na Calcd 448.2, Found 448.2.

[0255] Example 78: (S)-7-benzyl-3-hydroxymethyl-2-(4-trifluoromethylbenzyl)-3,4- dihydroisoquinolin-1(2H)-one (I-23)

[0256] I-23 was prepared by the same method as I-22, first coupling intermediate 46b with benzylboronic acid pinacol ester, and then removing the TBS protecting group. 1H NMR (300 MHz, CD3OD) δ 7.86 (d, J = 1.9 Hz, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.32 (dd, J = 7.7, 1.9 Hz, 1H), 7.28 - 7.12 (m, 6H), 5.45 (d, J = 15.5 Hz, 1H), 4.38 (d, J = 15.5 Hz, 1H), 3.97 (s, 2H), 3.66 (m, 1H), 3.59 - 3.35 (m, 2H), 3.20 - 2.95 (m, 2H); MS (ESI) m / z: [M+Na] 448.2, 448.2. + C 25 H 22 F3NO2Na Calcd. 448.2, Found. 448.2.

[0257] Example 79: (R)-7-(3-fluorobenzyl)-3-hydroxymethyl-2-(4- trifluoromethylbenzyl)-3,4-dihydroisoquinolin-1(2H)-one (I-26)

[0258] Compound I-26 was prepared using the same procedure as I-22, coupling intermediate 46a with 3-fluorobenzylboronic acid pinacol ester first, then removing the TBS protecting group. 1 H NMR (300 MHz, CD3OD) δ 7.85 (d, J = 1.9 Hz, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.37 (dd, J = 7.7, 1.9 Hz, 1H), 7.33 - 7.17 (m, 2H), 7.05 (d, J = 7.7 Hz, 1H), 6.99 - 6.86 (m, 2H), 5.47 (d, J = 15.5 Hz, 1H), 4.41 (d, J = 15.5 Hz, 1H), 4.03 (s, 2H), 3.70 (m, 1H), 3.61 - 3.36 (m, 2H), 3.26 - 2.96 (m, 2H); MS (ESI) m / z: [M+Na] 448.2, 448.2. + C 25 H 21 F4NO2Na Calcd. 466.2, Found. 466.2.

[0259] Example 80: (R)-7-(4-fluorobenzyl)-3-hydroxymethyl-2-(4- trifluoromethylbenzyl)-3,4-dihydroisoquinolin-1(2H)-one (I-27)

[0260] Compound I-27 was prepared using the same procedure as I-22, coupling intermediate 46a with 4-fluorobenzylboronic acid pinacol ester first, then removing the TBS protecting group. 1H NMR (300 MHz, CD3OD) δ 7.83 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.35 (dd, J = 7.7, 1.9 Hz, 1H), 7.26 - 7.16 (m, 3H), 7.05 - 6.95 (m, 2H), 5.46 (d, J = 15.5 Hz, 1H), 4.41 (d, J = 15.5 Hz, 1H), 4.00 (s, 2H), 3.70 (m, 1H), 3.61 - 3.36 (m, 2H), 3.25 - 2.96 (m, 2H); MS (ESI) m / z: [M+Na] + C 25 H 21 F4NO2Na Calcd 466.2, Found 466.2.

[0261] Example 81: (R)-7-benzyl-3-hydroxymethyl-2-(4-chlorobenzyl)-3,4- dihydroisoquinolin-1(2H)-one (I-28)

[0262] Compound I-28 was prepared using the same procedure as I-22, coupling intermediate 46c with benzylboronic acid pinacol ester first, then removing the TBS protecting group. 1 H NMR (300 MHz, CD3OD) δ 7.84 (d, J = 1.9 Hz, 1H), 7.37 - 7.31 (m, 5H), 7.30 - 7.14 (m, 6H), 5.36 (d, J = 15.2 Hz, 1H), 4.28 (d, J = 15.2 Hz, 1H), 4.00 (s, 2H), 3.66 (m, 1H), 3.57 - 3.34 (m, 2H), 3.16 - 2.95 (m, 2H); MS (ESI) m / z: [M+Na] + C 24 H 22 ClNO2Na Calcd 414.1, Found 414.2.

[0263] Example 82: (R)-7-(3-fluorobenzyl)-3-hydroxymethyl-2-(4-chlorobenzyl)-3,4- dihydroisoquinolin-1(2H)-one (I-29)

[0264] Compound I-29 was prepared using the same procedure as I-22, coupling intermediate 46c with 3-fluorobenzylboronic acid pinacol ester first, then removing the TBS protecting group. 1H NMR (300 MHz, CD3OD) δ 7.84 (d, J = 1.9 Hz, 1H), 7.38 - 7.23 (m, 6H), 7.18 (d, J = 7.7 Hz, 1H), 7.03 (dd, J = 7.7, 1.5 Hz, 1H), 6.97 - 6.87 (m, 2H), 5.36 (d, J = 15.1 Hz, 1H), 4.28 (d, J = 15.1 Hz, 1H), 4.01 (s, 2H), 3.66 (m, 1H), 3.59 - 3.36 (m, 2H), 3.16 - 2.97 (m, 2H); MS (ESI) m / z: [M+Na] + C 24 H 21 ClNO2Na Calcd 432.1, Found 432.2.

[0265] Example 83: (R)-7-(4-fluorobenzyl)-3-hydroxymethyl-2-(4-chlorobenzyl)-3,4- dihydroisoquinolin-1(2H)-one (I-30)

[0266] Compound I-30 was prepared using the same procedure as I-22, coupling intermediate 46c with 4-fluorobenzylboronic acid pinacol ester first, then removing the TBS protecting group. 1 H NMR (300 MHz, CD3OD) δ 7.82 (d, J = 1.9 Hz, 1H), 7.37 - 7.29 (m, 5H), 7.24 - 7.14 (m, 3H), 7.03 - 6.94 (m, 2H), 5.36 (d, J = 15.1 Hz, 1H), 4.28 (d, J = 15.1 Hz, 1H), 3.98 (s, 2H), 3.66 (m, 1H), 3.58 - 3.35 (m, 2H), 3.15 - 2.96 (m, 2H); MS (ESI) m / z: [M+Na] + C 24 H 21 ClNO2Na Calcd 432.1, Found 432.2.

[0267] Example 84: (R)-7-benzyl-2-(4-fluorobenzyl)-3-hydroxymethyl-3,4-dihydroisoquinolin- 1(2H)-one (I-47)

[0268] I-47 was prepared using the same procedure as I-22, coupling intermediate 46d with benzylboronic acid pinacol ester first, then removing the TBS protecting group. MS (ESI) m / z: [M+Na] + C 24 H 22 FNO2Na Calcd 398.2, Found 398.2.

[0269] Example 85: (R)-7-(3-fluorobenzyl)-2-(4-fluorobenzyl)-3-hydroxymethyl-3,4-dihydroisoquinoline-1(2H)-one (I-48)

[0270] I-48 was prepared using the same method as I-22, first by coupling intermediate 46d with pinacol 3-fluorobenzylborate, followed by removal of the TBS protecting group. MS(ESI) m / z: [M+Na] + C 24 H 21 The calculated value of F2NO2Na is 416.2, and the measured value is also 416.2.

[0271] Example 86: (R)-2,7-bis(4-fluorobenzyl)-3-hydroxymethyl-3,4-dihydroisoquinoline-1(2H)-one (I-49)

[0272] I-49 was prepared using the same method as I-22, first by coupling intermediate 46d with pinacol 4-fluorobenzylborate, followed by removal of the TBS protecting group. MS(ESI) m / z: [M+Na] + C 24 H 21 The calculated value of F2NO2Na is 416.2, and the measured value is also 416.2.

[0273] Example 87: (R)-3-aminomethyl-7-benzyl-2-(4-trifluoromethylbenzyl)-3,4-dihydroisoquinoline-1(2H)-one (I-24)

[0274] 200 mg of compound I-22 (0.47 mmol, 1 eq) was dissolved in 10 mL of anhydrous tetrahydrofuran. At 0 °C, 185 mg of triphenylphosphine (0.70 mmol, 1.5 eq), 143 mg of diisopropyl azodicarbonate (0.70 mmol, 1.5 eq), and 104 mg of phthalimide (0.70 mmol, 1.5 eq) were added to this solution. The reaction mixture was stirred at 0 °C for 15 minutes under nitrogen protection, then heated to room temperature and stirred overnight. After the reaction was complete as monitored by TLC, 30 mL of water was added to the reaction mixture, and the mixture was extracted three times with 20 mL of ethyl acetate each time. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The solution was concentrated, and the residue was purified by column chromatography. The obtained imide was dissolved in 10 mL of ethanol, and 71 mg of hydrazine hydrate (1.41 mmol, 3 eq) was slowly added to this solution. The mixture was then refluxed until complete as monitored by TLC. After removing the solvent by vacuum distillation, 10 mL of dichloromethane was added to the residue to dissolve it. The insoluble matter was filtered off, and the filter cake was washed three times with 10 mL of dichloromethane each time. After the filtrate was evaporated to dryness, it was first separated by column chromatography and then purified by semi-preparative HPLC to obtain 80 mg of compound I-24, with a yield of 40%. 1H NMR (300 MHz, CD3OD) δ 7.88 (d, J = 1.9 Hz, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.44 (dd, J = 7.8, 1.9 Hz, 1H), 7.33 - 7.17 (m, 6H), 5.53 (d, J = 15.5 Hz, 1H), 4.28 (d, J = 15.5 Hz, 1H), 4.03 (s, 2H), 3.96 (m, 1H), 3.37 - 3.27 (m, 1H), 3.14 - 2.89 (m, 3H); MS (ESI) m / z: [M + Na] 447.2, 447.2. + C 25 H 23 F3N2ONa calcd 447.2, found 447.2.

[0275] Example 88: (S)-3-Aminomethyl-7-benzyl-2-(4-trifluoromethylbenzyl)-3,4- dihydroisoquinolin-1 (2H)-one (I-25)

[0276] I-25 was prepared from I-23 using the same procedure as I-24. 1 H NMR (300 MHz, CD3OD) δ 7.88 (d, J = 1.9 Hz, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.44 (dd, J = 7.8, 1.9 Hz, 1H), 7.33 - 7.17 (m, 6H), 5.53 (d, J = 15.5 Hz, 1H), 4.28 (d, J = 15.5 Hz, 1H), 4.03 (s, 2H), 3.96 (m, 1H), 3.37 - 3.27 (m, 1H), 3.14 - 2.89 (m, 3H); MS (ESI) m / z: [M + Na] 447.2, 447.2. + C 25 H 23 F3N2ONa calcd 447.2, found 447.2.

[0277] The synthesis of compound I-31 is shown in the following scheme:

[0278] Reagents and conditions: (a) Dess-Martin periodinane, CH2Cl2, RT; (b) oxone, DMF.

[0279] Example 89: (R)-7-Benzyl-1-oxo-2-(4-(trifluoromethyl)benzyl)-1,2,3,4- tetrahydroisoquinoline-3-carbaldehyde (50)

[0280] To a solution of 500 mg of compound I-22 (1.17 mmol, 1 eq) in 10 mL of dichloromethane, 1.1 g of Dess-Martin periodinane (2.35 mmol, 2 eq) was added under stirring at room temperature. After the addition was completed, the stirring was continued for 2 h. After TLC detection showed that the reaction was complete, the reaction mixture was filtered through celite, and the filter cake was washed with dichloromethane (20 mL x 3). The filtrate was evaporated to dryness, and the residue was purified by column chromatography to obtain 388 mg of compound 50, with a yield of 78%. 1 H NMR (300 MHz, CDCl3) δ 9.55 (s, 1H), 8.04 (d, J = 1.9 Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.33-7.18 (m, 6H), 7.09 (d, J = 7.7 Hz, 1H), 5.60 (d, J = 15.2 Hz, 1H), 4.29 (d, J = 15.2 Hz, 1H), 4.06-4.00 (m, 3H), 3.43-3.20 (m, 2H).

[0281] Example 90: (R)-7-benzyl-l-oxo-2-(4-trifluoromethylbenzyl)-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (I-31)

[0282] To a solution of 100 mg of compound 50 (0.24 mmol, 1 eq) in 5 mL of DMF, 145 mg of oxone (0.24 mmol, 1 eq) was added under stirring at room temperature. After the addition was completed, the reaction was continued until TLC detection showed that the reaction was complete. The reaction mixture was poured into 20 mL of water, and the pH was adjusted to 2 with 1N HCl. The aqueous phase was extracted with ethyl acetate (20 mL x 3), and the organic phase was evaporated to dryness. The residue was first separated by column chromatography, and then purified by semi-preparative HPLC to obtain 73 mg of compound I-31, with a yield of 70%. 1 H NMR (300 MHz, CD3OD) δ 7.88 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.33 (dd, J = 7.8, 1.9 Hz, 1H), 7.30-7.14 (m, 6H), 5.51 (d, J = 15.6 Hz, 1H), 4.37 (m, 1H), 4.23 (d, J = 15.6 Hz, 1H), 4.00 (s, 2H), 3.42-3.24 (m, 2H); MS (ESI) m / z: [M+Na] + C 25 H 20 C, 62.48; H, 4.48; N, 9.62. Found C, 62.48; H, 4.48; N, 9.62.

[0283] Example 91: (R)-7-benzyl-l-oxo-2-(4-trifluoromethylbenzyl)-l,2,3,4- tetrahydroisoquinoline-3-carboxamide (I-32)

[0284] Dissolve 100 mg of compound I-31 (0.23 mmol, 1 eq) in 5 mL of dichloromethane, add 0.1 mL of DIEA, 37 mg of HOBT (0.27 mmol, 1.2 eq) and 52 mg of EDCI (0.27 mmol, 1.2 eq) successively at 0 °C, add 30 μL of ammonia after stirring for 30 min, and add water after the addition is completed. The reaction solution is brought to room temperature, and stirring is continued until the reaction is completed as monitored by TLC. Dichloromethane is added to the reaction solution to dilute it, and washing is performed with 1 N aqueous HC1, 1 N aqueous NaOH and saturated brine. The organic phase is dried over anhydrous sodium sulfate, and the solvent is removed by rotary evaporation under reduced pressure. The residue is separated by column chromatography, and then purified by semi-preparative HPLC to obtain 49 mg of compound I-32 at a yield of 49%. 1 H NMR (300 MHz, CD3OD) δ 7.88 (d, J = 1.9 Hz, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H), 7.34 (dd, J = 7.7, 1.9 Hz, 1H), 7.31 - 7.13 (m, 6H), 5.56 (d, J = 15.6 Hz, 1H), 4.28 (m, 1H), 4.09 (d, J = 15.6 Hz, 1H), 4.01 (s, 2H), 3.47 - 3.14 (m, 2H); MS (ESI) m / z: [M+Na] + C 25 H 21 F3N2O2Na Calc. 461.2, Found 461.2.

[0285] Example 92: (R)-7-benzyl-N-methyl-l-oxo-2-(4-trifluoromethylbenzyl)-l,2,3,4- tetrahydroisoquinoline-3-carboxamide (I-33)

[0286] Compound I-33 is prepared from compound I-31 and methylamine hydrochloride by the same method as that for compound I-32. 1H NMR (300 MHz, CD3OD) δ 7.88 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.34 (dd, J = 7.7, 1.9 Hz, 1H), 7.31 - 7.11 (m, 6H), 5.49 (d, J = 15.5 Hz, 1H), 4.24 (m, 1H), 4.16 (d, J = 15.5 Hz, 1H), 4.01 (s, 2H), 3.45 - 3.10 (m, 2H), 2.59 (s, 3H); MS (ESI) m / z: [M+Na] 475.2. + C 26 H 23 F3N2O2Na Calcd 475.2, Found 475.2.

[0287] Example 93: (R)-7-benzyl-3-methylaminomethyl-2-(4-trifluoromethylbenzyl)-3,4- dihydroisoquinolin-1 (2H)-one (I-34)

[0288] To 200 mg of compound I-24 (0.47 mmol, 1 eq) dissolved in 5 mL of dichloromethane, 0.2 mL of triethylamine and 154 mg of Boc20 (0.71 mmol, 1.5 eq) were added successively, and the resulting solution was stirred at room temperature until the reaction was complete as monitored by TLC. The solvent was evaporated, and the product was purified by silica gel column chromatography to obtain the Boc-protected product. The product from the previous step was dissolved in 5 mL of N,N-dimethylformamide, and 17 mg of sodium hydride (0.71 mmol, 1.5 eq) was added to the solution at 0°C. After 5 minutes, 100 mg of iodomethane (0.71 mmol, 1.5 eq) dissolved in DMF was added, and the reaction solution was stirred at room temperature until the reaction was complete as monitored by TLC. To the reaction solution, 1 mL of saturated aqueous ammonium chloride solution was added to quench the reaction, and then 10 mL of water was added to dilute the solution. The aqueous phase was extracted with 20 mL of ethyl acetate three times, and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the residue was dissolved in 5 mL of methanol. After 2 mL of saturated methanolic HCl was added dropwise with stirring, the reaction was continued to be stirred until the reaction was complete as monitored by TLC. The solvent was evaporated, and the residue was purified by semi-preparative HPLC to obtain 52 mg of compound I-34 at a yield of 25%. 1H NMR (300 MHz, CD3OD) δ 7.89 (d, J = 1.9 Hz, 1H), 7.70 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.46 (dd, J = 7.8, 1.9 Hz, 1H), 7.33 - 7.16 (m, 6H), 5.60 (d, J = 15.6 Hz, 1H), 4.21 (d, J = 15.6 Hz, 1H), 4.07 - 3.99 (m, 3H), 3.32 (m, 1H), 3.20 - 2.96 (m, 3H), 2.69 (s, 3H); MS (ESI) m / z: [M+Na] 461.2. + C 26 H 25 F3N2ONa Calcd 461.2, Found 461.2.

[0289] Example 94: (R)-3-(lH-Benzo[d]imidazol-2-yl)-7-benzyl-2-(4- trifluoromethylbenzyl)-3,4-dihydroisoquinolin-l(2H)-one (I-35)

[0290] To a solution of 200 mg of compound I-31 (0.46 mmol, 1 eq) in 5 mL of dichloromethane, 176 mg of N,N-diisopropylethylamine (1.38 mmol, 3 eq), 208 mg of HATU (0.55 mmol, 1.2 eq) and 54 mg of o-phenylenediamine (0.51 mmol, 1.1 eq) were added successively at 0 °C, and the reaction was stirred at room temperature for 10 min. The reaction was diluted with 10 mL of dichloromethane, and then washed successively with 1 N aqueous HC1, 1 N aqueous NaOH and saturated brine. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by silica gel column chromatography, and the obtained product was dissolved in 3 mL of acetic acid. The reaction was stirred at 70 °C until the reaction was completed by TLC monitoring. The acetic acid was removed by evaporation, 5 mL of water was added to the residue, and the pH was adjusted to 8 with an aqueous NaHC03 solution. The product was extracted with ethyl acetate three times, each time with 10 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography and purified by semi-preparative HPLC to obtain 72 mg of compound I-35 with a yield of 31%. 1H NMR (300 MHz, CD3OD) δ 7.95 (d, J = 1.9 Hz, 1H), 7.65 - 7.54 (m, 6H), 7.51-7.48 (m, 2H), 7.36 (dd, J = 7.8, 1.9 Hz, 1H), 7.30 - 7.14 (m, 6H), 5.61 - 5.49 (m, 2H), 4.55 (d, J = 15.3 Hz, 1H), 4.00 (s, 2H), 3.84 - 3.38 (m, 2H); MS (ESI) m / z: [M+Na] + C 31 H 24 F3N3ONa calcd 534.2, found 534.2.

[0291] Example 95: (R)-3-(4,5-dihydro-lH-imidazol-2-yl)-7-benzyl-2-(4- trifluoromethylbenzyl)-3,4-dihydroisoquinolin-l(2H)-one (I-36)

[0292] Compound 50 (200 mg, 0.47 mmol, 1 eq) was dissolved in 5 mL of dichloromethane, 31 mg of ethylenediamine (0.52 mmol, 1.1 eq) was added at 0°C under nitrogen protection, after stirring for 30 minutes, 92 mg of N-bromosuccinimide (0.52 mmol, 1.1 eq) was added, and after the addition was completed, it was stirred at room temperature overnight. After TLC detection of the complete reaction, the reaction was quenched with 10 mL of saturated sodium bicarbonate solution and diluted with 10 mL of water, the aqueous phase was extracted with dichloromethane 3 times, 20 mL each time, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The residue was first separated by column chromatography, and then purified by semi-preparative HPLC to obtain 109 mg of compound I-36, with a yield of 50%. 1 H NMR (300 MHz, CD3OD) δ 7.91 (d, J = 1.9 Hz, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.45 (dd, J = 7.8, 1.9 Hz, 1H), 7.31 - 7.19 (m, 6H), 5.48 (d, J = 15.4 Hz, 1H), 4.91 (m, 1H), 4.40 (d, J = 15.4 Hz, 1H), 4.04 (s, 2H), 3.79 (br s, 4H), 3.58 (dd, J = 16.7, 6.9 Hz, 1H), 3.18 (dd, J = 16.7, 1.9 Hz, 1H); MS (ESI) m / z: [M+Na] + C 27 H 24 F3N3ONa calcd 486.2, found 486.2.

[0293] Example 96: (R)-3-(lH-imidazol-2-yl)-7-benzyl-2-(4-trifluoromethylbenzyl)- 3,4-dihydroisoquinolin-l(2H)-one (I-37)

[0294] Dissolve 100 mg of compound I-36 (0.22 mmol, 1 eq) in 3 mL of dimethyl sulfoxide, add 91 mg of 2-iodoxybenzoic acid (0.32 mmol, 1.5 eq) at room temperature with stirring, continue stirring until the reaction is complete by TLC monitoring. Add 10 mL of aqueous sodium bicarbonate solution to the reaction solution, extract with ethyl acetate 3 times, 20 mL each time, combine the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, remove the solvent by rotary evaporation under reduced pressure, and purify the residue by column chromatography first, and then by semi-preparative HPLC to obtain 65 mg of compound I-37 with a yield of 65%. 1 H NMR (300 MHz, CD3OD) δ 7.94 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.42 - 7.34 (m, 3H), 7.32 - 7.12 (m, 6H), 5.53 - 5.39 (m, 2H), 4.49 (d, J = 15.4 Hz, 1H), 4.02 (s, 2H), 3.67 (dd, J = 15.0, 6.0 Hz, 1H), 3.28 (dd, J = 15.0, 3.0 Hz, 1H); MS (ESI) m / z: [M+Na] + C 27 H 22 F3N3ONa Calcd 484.2, Found 484.2.

[0295] Example 97: (R)-7-benzyl-3-methoxymethyl-2-(4-trifluoromethylbenzyl)-3,4- dihydroisoquinolin-l(2H)-one (I-38)

[0296] Dissolve 100 mg of compound I-22 (0.23 mmol, 1 eq) in 5 mL of anhydrous tetrahydrofuran, add 11 mg of sodium hydride (0.47 mmol, 2 eq) at 0 °C, after 5 minutes add 67 mg of iodomethane (0.47 mmol, 2 eq) to the reaction solution and stir to room temperature overnight. After the reaction is complete by TLC detection, quench the reaction by adding 0.2 mL of water to the reaction solution, remove the solvent by evaporation, and purify the residue by column chromatography first, and then by semi-preparative HPLC to obtain 62 mg of compound I-38 with a yield of 60%. 1H NMR (300 MHz, CD3OD) δ 7.85 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 7.36 (dd, J = 7.8, 1.9 Hz, 1H), 7.32 - 7.15 (m, 6H), 5.43 (d, J = 15.5 Hz, 1H), 4.42 (d, J = 15.5 Hz, 1H), 4.01 (s, 2H), 3.82 (m, 1H), 3.43 - 3.25 (m, 2H), 3.23 (s, 3H), 3.17 (dd, J = 16.3, 6.0 Hz, 1H), 2.95 (dd, J = 16.3, 1.9 Hz, 1H); MS (ESI) m / z: [M+Na] 462.2, 462.2. + C 26 H 24 F3NO2Na calc. 462.2, found 462.2.

[0297] Example 98: (R)-7-benzyl-3-ethoxymethyl-2-(4-trifluoromethylbenzyl)-3,4- dihydroisoquinolin-1(2H)-one (I-39)

[0298] Compound I-39 was prepared from compound I-22 and iodoethane using the same procedure as compound I-38. 1 H NMR (300 MHz, CD3OD) δ 7.85 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 7.36 (dd, J = 7.8, 1.9 Hz, 1H), 7.32 - 7.15 (m, 6H), 5.43 (d, J = 15.5 Hz, 1H), 4.42 (d, J = 15.5 Hz, 1H), 4.01 (s, 2H), 3.82 (m, 1H), 3.43 - 3.25 (m, 2H), 3.23 (s, 3H), 3.17 (dd, J = 16.3, 6.0 Hz, 1H), 2.95 (dd, J = 16.3, 1.9 Hz, 1H); MS (ESI) m / z: [M+Na] 462.2, 462.2. + C 27 H 26 F3NO2Na calc. 476.2, found 476.2.

[0299] Example 99: (R)-7-benzyl-3-methoxymethoxymethyl-2-(4-trifluoromethylbenzyl)-3,4- dihydroisoquinolin-1(2H)-one (I-40)

[0300] Compound 1-40 was prepared from compound 1-22 and bromomethyl methyl ether using the same procedure as for compound 1-38. 1 H NMR (300 MHz, CD3OD) δ 7.86 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.35 (dd, J = 7.7, 1.9 Hz, 1H), 7.31 - 7.15 (m, 6H), 5.42 (d, J = 15.5 Hz, 1H), 4.51 - 4.41 (m, 3H), 4.01 (s, 2H), 3.88 (m, 1H), 3.55 - 3.39 (m, 2H), 3.28 - 3.16 (m, 4H), 2.99 (dd, J = 15.0, 2.0 Hz, 1H); MS (ESI) m / z: [M+Na] 521.3, 523.3. + C 27 H 26 F3NO3Na calc. 492.2, found 492.2.

[0301] Example 100: (R)-7-benzyl-3-(2-methoxyethoxymethyl)-2-(4- trifluoromethylbenzyl)-3,4-dihydroisoquinolin-l(2H)-one (1-41)

[0302] Compound 1-41 was prepared from compound 1-22 and l-iodo-2- methoxyethane using the same procedure as for compound 1-38. 1 H NMR (300 MHz, CD3OD) δ 7.86 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.35 (dd, J = 7.7, 1.9 Hz, 1H), 7.31 - 7.15 (m, 6H), 5.42 (d, J = 15.5 Hz, 1H), 4.51 - 4.41 (m, 3H), 4.01 (s, 2H), 3.88 (m, 1H), 3.55 - 3.39 (m, 2H), 3.28 - 3.16 (m, 4H), 2.99 (dd, J = 15.0, 2.0 Hz, 1H); MS (ESI) m / z: [M+Na] 521.3, 523.3. + C 28 H 28 F3NO3Na calc. 492.2, found 492.2.

[0303] Example 101: (R)-7-(3-fluorobenzyl)-3-(2-methoxyethoxymethyl)-2-(4- trifluoromethylbenzyl)-3,4-dihydroisoquinolin-l(2H)-one (1-42)

[0304] Compound 1-42 was prepared from compound 1-26 using the same procedure as for compound 1-41. 1 H NMR (300 MHz, CD3OD) δ 7.85 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.37 (dd, J = 7.7, 1.9 Hz, 1H), 7.34 - 7.17 (m, 2H), 7.09 - 6.87 (m, 3H), 5.42 (d, J = 15.5 Hz, 1H), 4.47 (d, J = 15.5 Hz, 1H), 4.02 (s, 2H), 3.86 (m, 1H), 3.53 - 3.37 (m, 6H), 3.28 (s, 3H), 3.25 (dd, J = 16.5, 6.0 Hz, 1H), 2.91 (dd, J = 16.5, 1.5 Hz, 1H); MS (ESI) m / z: [M+Na] 524.2, 526.2. + C 28 H 27 F4NO3Na calc 524.2, found 524.2.

[0305] Example 102: (R)-7-(4-fluorobenzyl)-3-(2-methoxyethoxymethyl)-2-(4- trifluoromethylbenzyl)-3,4-dihydroisoquinolin-1(2H)-one (1-43)

[0306] Compound 1-43 was prepared from compound 1-27 using the same procedure as for compound 1-41. 1 H NMR (300 MHz, CD3OD) δ 7.85 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.37 (dd, J = 7.7, 1.9 Hz, 1H), 7.34 - 7.17 (m, 2H), 7.09 - 6.87 (m, 3H), 5.42 (d, J = 15.5 Hz, 1H), 4.47 (d, J = 15.5 Hz, 1H), 4.02 (s, 2H), 3.86 (m, 1H), 3.53 - 3.37 (m, 6H), 3.28 (s, 3H), 3.25 (dd, J = 16.5, 6.0 Hz, 1H), 2.91 (dd, J = 16.5, 1.5 Hz, 1H); MS (ESI) m / z: [M+Na] 524.2, 526.2. + C 28 H 27 F4NO3Na calc 524.2, found 524.2.

[0307] Example 103: (R)-7-benzyl-3-(2-methoxyethoxymethyl)-2-(4-chlorobenzyl)- 3,4-dihydroisoquinolin-1(2H)-one (I-44)

[0308] Compound I-44 was prepared from compound I-28 using the same procedure as for compound I-41. 1 H NMR (300 MHz, CD3OD) δ 7.84 (d, J = 1.9 Hz, 1H), 7.38 - 7.12 (m, 11H), 5.32 (d, J = 15.2 Hz, 1H), 4.34 (d, J = 15.2 Hz, 1H), 4.00 (s, 2H), 3.83 (m, 1H), 3.48 - 3.35 (m, 6H), 3.28 (s, 3H), 3.20 (dd, J = 16.5, 6.0 Hz, 1H), 2.91 (dd, J = 16.5, 1.5 Hz, 1H); MS (ESI) m / z: [M + Na] 472.2. + C 27 H 28 ClNO3Na Calcd 472.2, Found 472.2.

[0309] Example 104: (R)-7-(3-fluorobenzyl)-3-(2-methoxyethoxymethyl)-2-(4- chlorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one (I-45)

[0310] Compound I-45 was prepared from compound I-29 using the same procedure as for compound I-41. 1 H NMR (300 MHz, CD3OD) δ 7.84 (d, J = 1.9 Hz, 1H), 7.38 - 7.12 (m, 11H), 5.32 (d, J = 15.2 Hz, 1H), 4.34 (d, J = 15.2 Hz, 1H), 4.00 (s, 2H), 3.83 (m, 1H), 3.48 - 3.35 (m, 6H), 3.28 (s, 3H), 3.20 (dd, J = 16.5, 6.0 Hz, 1H), 2.91 (dd, J = 16.5, 1.5 Hz, 1H); MS (ESI) m / z: [M + Na] 472.2. + C 27 H 27 ClFNO3Na Calcd 490.2, Found 490.2.

[0311] Example 105: (R)-7-(4-fluorobenzyl)-3-(2-methoxyethoxymethyl)-2-(4- chlorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one (I-46)

[0312] Compound I-46 was prepared from compound I-30 using the same procedure as for compound I-41. 1 H NMR (300 MHz, CD3OD) δ 7.82 (d, J = 1.9 Hz, 1H), 7.41 - 7.31 (m, 5H), 7.29 - 7.15 (m, 3H), 7.07 - 6.95 (m, 2H), 5.32 (d, J = 15.2 Hz, 1H), 4.36 (d, J = 15.2 Hz, 1H), 4.01 (s, 2H), 3.82 (m, 1H), 3.50 - 3.37 (m, 6H), 3.29 (s, 3H), 3.16 (dd, J = 16.5, 6.0 Hz, 1H), 2.99 (dd, J = 16.5, 1.5 Hz, 1H); MS (ESI) m / z: [M+Na] + C 27 H 27 ClFNO3Na Calcd 490.2, Found 490.2.

[0313] Example 106: (R)-7-benzyl-3-(2-methoxyethoxymethyl)-2-(4-fluorobenzyl)-3,4- dihydroisoquinolin-1(2H)-one (I-50)

[0314] Compound I-50 was prepared from compound I-47 using the same procedure as for compound I-41. MS (ESI) m / z: [M+Na] + C 27 H 28 FNO3Na Calcd 456.2, Found 456.2.

[0315] Example 107: (R)-7-(3-fluorobenzyl)-3-(2-methoxyethoxymethyl)-2-(4-fluorobenzyl)- 3,4-dihydroisoquinolin-1(2H)-one (I-51)

[0316] Compound I-51 was prepared from compound I-48 using the same procedure as for compound I-41. MS (ESI) m / z: [M+Na] + C 27 H 27 F2NO3Na Calcd 474.2, Found 474.2.

[0317] Example 108: (R)-7-(4-fluorobenzyl)-3-(2-methoxyethoxymethyl)-2-(4-fluorobenzyl)- 3,4-dihydroisoquinolin-1(2H)-one (I-52)

[0318] Compound I-52 was prepared from compound I-49 using the same procedure as for compound I-41. MS (ESI) m / z: [M+Na] +C 27 H 27 F2NO3Na Calc. 474.2, Found 474.2.

[0319] Example 109: (R)-7-benzyl-3-(2-(2-methoxyethoxy)ethoxymethyl)-2-(4- chlorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one (I-53)

[0320] Compound I-53 was prepared from compound I-22 and 1-bromo-2-(2- methoxyethoxy)ethane using the same procedure as compound I-41. 1 H NMR (300 MHz, CD3OD) δ 7.86 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 7.34 (dd, J = 7.7, 1.9 Hz, 1H), 7.31 - 7.13 (m, 6H), 5.42 (d, J = 15.5 Hz, 1H), 4.46 (d, J = 15.5 Hz, 1H), 3.99 (s, 2H), 3.88 - 3.77 (m, 1H), 3.54 - 3.39 (m, 10H), 3.31 (s, 3H), 3.24 - 2.88 (m, 2H); MS (ESI) m / z: [M+Na] + C 30 H 32 F3NO4Na Calc. 550.2, Found 550.2.

[0321] Reagents and conditions: (a) NaH, THF, 0 °C to rt; (b) H2, 10% Pd-C, MeOH.

[0322] Example 110: (R)-7-(4-fluorobenzyl)-3-(2-hydroxyethoxymethyl)-2-(4- trifluoromethylbenzyl)-3,4-dihydroisoindolin-1(2H)-one (I-54)

[0323] Compound 50 was prepared from I-27 and 2-bromoethyl benzyl ether using the same procedure as compound I-38. MS (ESI) m / z: [M+Na] + C 34 H 31 F4NO3Na Calc. 600.2, Found 600.2.

[0324] To a solution of 1.5 g of compound 50 in 30 mL of methanol was added 100 mg of 10% Pd-C and stirred at rt under hydrogen for 12 h. The solid was filtered off and the filtrate was concentrated and the residue was purified by column chromatography to give compound I-54.1 H NMR (300 MHz, CD3OD) δ 7.84 (d, J = 1.7 Hz, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.36 (dd, J = 7.7, 1.7 Hz, 1H), 7.27 - 7.16 (m, 3H), 7.06 - 6.96 (m, 2H), 5.45 (d, J = 15.6 Hz, 1H), 4.47 (d, J = 15.6 Hz, 1H), 4.00 (s, 2H), 3.94 - 3.82 (m, 1H), 3.64 - 3.36 (m, 6H), 3.26 - 2.97 (m, 2H); MS (ESI) m / z: [M+Na] + calcd for C 27 H 25 F4NO3Na 510.2, found 510.1.

[0325] Example 111: (R)-7-(4-fluorobenzyl)-3-(2-aminoethoxymethyl)-2-(4- trifluoromethylbenzyl)-3,4-dihydroisoindol-l(2H)-one (I-55)

[0326] Compound I-55 was synthesized from compound I-54 using the same method as I-24. MS (ESI) m / z: [M+Na] + calcd for C 27 H 26 F4N2O2Na 509.2, found 509.1.

[0327] Example 112: (R)-7-(4-fluorobenzyl)-3-(2-methylaminoethoxymethyl)-2-(4- trifluoromethylbenzyl)-3,4-dihydroisoindol-l(2H)-one (I-56)

[0328] Compound I-56 was synthesized from compound I-54 using the same method as I-34. MS (ESI) m / z: [M+Na] + calcd for C 28 H 28 F4N2O2Na 523.2, found 523.1.

[0329] Example 113: (R)-7-(4-fluorobenzyl)-3-(2-dimethylaminoethoxymethyl)-2-(4- trifluoromethylbenzyl)-3,4-dihydroisoindol-l(2H)-one (I-57)

[0330] To a solution of 0.2 g of compound I-55 in 10 mL of methanol was added 0.5 mL of 37% formaldehyde solution and 30 mg of 10% Pd-C, respectively. The mixture was stirred at room temperature under hydrogen atmosphere for 12 h. After filtration, the filtrate was concentrated. The residue was purified by column chromatography and then by semi-preparative HPLC to give compound I-57. MS (ESI) m / z: [M+Na] + calcd for C 29 H 30 F4N2O2Na 537.2, found 523.2.

[0331] Reagents and conditions: (a) MsCl, triethylamine, CH2Cl2, 0 °C to room temperature; (b) piperazine, potassium carbonate, 60 °C, DMF.

[0332] Example 114: (R)-7-(4-fluorobenzyl)-3-(2-(piperazin-l-yl)ethoxymethyl)-2-(4- trifluoromethylbenzyl)-3,4-dihydroisoindol-l(2H)-one (I-58)

[0333] To a solution of 0.6 g of compound I-54 in 15 mL of dichloromethane was added 0.2 g of methanesulfonyl chloride and 0.3 mL of triethylamine at 0 °C, respectively. The reaction was stirred at room temperature until TLC showed the reaction was complete, then concentrated. The residue was purified by column chromatography to give compound 52. MS (ESI) m / z: [M+Na] + calcd for C 28 H 27 F4NO5SNa 588.2, found 588.2.

[0334] To a solution of 0.2 g of compound 52 in 5 mL of DMF was added 0.1 g of piperazine and 0.1 g of potassium carbonate. The mixture was stirred at 60 °C until the reaction was complete. To the reaction was added 10 mL of water, and extracted with dichloromethane three times, 10 mL each time. The organic phase was combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by semi-preparative HPLC to give compound I-58. MS (ESI) m / z: [M+Na] + calcd for C 31 H 33 F4N3O2Na 578.3, found 578.2.

[0335] Example 115: (R)-7-(4-Fluorobenzyl)-3-(2-(4-methylpiperazin-l- yl)ethoxymethyl)-2-(4-trifluoromethylbenzyl)-3,4-dihydroisoindolin-l(2H)-one (I-59) Compound I-59 was synthesized using the same procedure as I-58 from compound 52 and 4-methylpiperazine. MS (ESI) m / z: [M + Na] + calcd for C 32 H 35 F4N3O2Na 592.3, found 592.2.

[0336] Example 116: (R)-7-(4-Fluorobenzyl)-3-(2-morpholinoethoxymethyl)-2-(4- trifluoromethylbenzyl)-3,4-dihydroisoindolin-l(2H)-one (I-60)

[0337] Compound I-60 was synthesized using the same procedure as I-58 from compound 52 and morpholine. MS (ESI) m / z: [M + Na] + calcd for C 31 H 32 F4N2O3Na 579.3, found 579.2.

[0338] Example 117: (R)-2-(2-(7-(4-Fluorobenzyl)-l-oxo-2-(4- trifluoromethylbenzyl)-l,2,3,4-tetrahydroisoquinolin-3-yl)methoxy-ethoxy- acetic acid (I-61)

[0339] Compound I-61 was synthesized using the same procedure as I-58 from compound I-54 and ethyl bromoacetate. MS (ESI) m / z: [M + Na] + calcd for C 29 H 27 F4NO5Na 568.2, found 568.2.

[0340] Example 118: (S)-2-(2-((R)7-(4-fluorobenzyl)-1-oxo-2-(4-trifluoromethylbenzyl)-1,2,3,4-tetrahydroisoquinoline-3-yl)methoxyethoxy-2-hydroxypropionic acid (I-62)

[0341] 0.2 g of compound I-54 was dissolved in 5 mL of anhydrous THF. 12 mg of NaH and 60 mg of (S)-2,3-epoxypropionate were added to the solution at 0 °C. The reaction mixture was stirred overnight at room temperature. 10 mL of water was added to the reaction mixture, and the mixture was extracted three times with 10 mL of ethyl acetate each time. The combined organic phases were dried over anhydrous sodium sulfate, and the solid was filtered off. The filtrate was concentrated, and the residue was dissolved in 10 mL of a 1:1 (v / v) mixture of methanol and water. 1 mL of 3N sodium hydroxide solution was added to this solution, and the mixture was stirred at room temperature until TLC showed complete reaction. The pH was adjusted to 4 with 3N hydrochloric acid, and the reaction mixture was extracted three times with 10 mL of ethyl acetate each time. The combined organic phases were dried over anhydrous sodium sulfate, and the solid was filtered off. The filtrate was concentrated, and the residue was purified by semi-preparative HPLC to give compound I-62. MS (ESI) m / z: [M+Na] + calcd for C 30 H 29 F4NO6Na 598.2, found 598.1.

[0342] Example 119: (R)-2-(2-((R)7-(4-fluorobenzyl)-1-oxo-2-(4-trifluoromethylbenzyl)-1,2,3,4-tetrahydroisoquinoline-3-yl)methoxyethoxy-2-hydroxypropionic acid (I-63)

[0343] Compound I-63 was synthesized from compound I-54 and methyl (R)-2,3-epoxypropionate using the same method as I-62. MS (ESI) m / z: [M+Na] + calcd for C 30 H 29 F4NO6Na598.2, found 598.1.

[0344] Example 120: Activity Evaluation of Compounds

[0345] 1. The ability of the compound to activate hClpP

[0346] Compound I acts as a ClpP agonist to activate ClpP hydrolysis of FITC-casein EC. 50 The values ​​were determined according to the method described in the literature (Cancer Cell 2019, 35, 721-737). The specific procedures are as follows:

[0347] (1) Compound preparation: The test compound was prepared as a 100 mM stock solution in DMSO, and 1 μl of each compound was diluted to 10 mM with 9 μl of DMSO.

[0348] (2) Compound dilution (2X, 50 μl / well): The compound of formula I was diluted to a concentration of 200 μM, 50 μM, 10 μM, 2 μM, 500 nM, 100 nM, 20 nM, and 2 nM, and the diluent was test buffer. 50 μl of the compound at different concentrations was added to each well, and two replicate wells were used. The final concentration was 100 μM, 25 μM, 5 μM, 1 μM, 250 nM, 50 nM, 10 nM, and 1 nM.

[0349] (3) Protein dilution (4X, 25 μl / well): The protein hClpP purified according to the literature method (Cancer Cell 2019, 35, 721-737.) was 14 mg / ml, which was converted to a concentration of 1000 μM. The protein was diluted to 4 μM with test buffer, and 25 μl of the protein was added to each well. Incubation was performed at 37°C for 0.5 h. The final concentration was 1 μM.

[0350] (4) FITC-Casein dilution (4X, 25 μl / well): The FITC-Casein stock solution was labeled according to the literature method (Cancer Cell 2019, 35, 721-737.) and was 200 mM. It was diluted to 16 μM with test buffer, and 25 μL of FITC-Casein was added to each well. The final concentration was 4 μM. It was immediately detected by machine.

[0351] (5) Control group setting: FITC-Casein and FITC-Casein+ClpP were used as negative controls. The positive drugs ONC201 and ONC212 were used as positive control groups, and the positive drugs ONC201 and ONC212 were synthesized according to the literature method (Angewandte Chemie International Edition 2014, 53, 6628-6631.).

[0352] (6) Fluorescence kinetics detection: The detection temperature was 37°C. The shaking plate was 3 s. The excitation light was 485±20 nm, and the emission light was 525±20 nm. The kinetic parameters were set to scan every 1 min for a total of 15 min.

[0353] The activity of the compound of formula I in inhibiting tumor cell growth was determined according to a conventional method. The specific operation is as follows:

[0354] Molm13 or MDA-MB-31 cells in the logarithmic growth phase were respectively inoculated at an appropriate cell concentration (1 x 10 3 -4 x 10 3The cells were inoculated in 96-well cell culture plates, and the volume of the cell suspension in each well was 200 μL, and five wells were set. At the same time of inoculating the cells, different compounds to be tested were added to each well to reach the corresponding action concentration (1% DMSO was used as a negative control), and according to the experimental requirements, after 3 days of incubation, 15 μL of CCK-8 reagent was added to each well in the dark, and the incubation was continued for 2-3 h (according to the color development degree of the negative control well), and then the 96-well cell culture plate was taken out to measure the absorbance at 450 nm wavelength on a full-wavelength enzyme marker, and the cell survival rate after the action of the compound was calculated by Graphpad Prism 7:

[0355] Survival rate (%) = average absorbance of the drug group ÷ average absorbance of the control group X 100

[0356] 2. Experimental results

[0357] Table 1. EC values of the compound hydrolysis of FITC-casein and the activity results of inhibiting the growth of Molm13 and MDA-MB-31 cells 50

[0358] As shown in Table 1, the compound designed by the application has a significant agonizing effect on casein protease P (ClpP), and can effectively inhibit the growth of tumor cells, and the activity reaches the micromolar concentration level and below, and even reaches the nanomolar concentration level. The inventors found through experiments that the compound with a benzene ring in the bicyclic skeleton has better activity in activating hClpP and inhibiting the growth of tumor cells than the compound with a pyridine ring; among them, the compound with phenyl, meta-fluorophenyl or para-fluorophenyl as R1 has better activity, the compound with para-fluoro, para-chloro, para-bromo or para-trifluoromethyl phenyl as R2 has better activity, and the hydrophilicity of R3 has a significant effect on the cell activity of the compound, and the better groups are hydroxyl and ether containing multiple oxygen atoms. Therefore, the aromatic heterocycle and lactam compound of the application can be applied to the treatment of various cancers, and has a wide application prospect.​

Claims

1. An aromatic heterocycle fused lactam compound, characterized by, The structure of the compound is shown in formula I: wherein: A is selected from CH2, CD2, CF2; X, Y, Z are independently selected from CH or N; Q is selected from CH2, CH2CH2, CHR4; R1, R2are selected from phenyl or mono-, di-, tri-substituted phenyl, the mono-, di-, tri- substituents being selected from halogen, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkynyl, C1-C4alkoxy; R3 is selected from hydrogen atom, carbamoyl group, nitrogen mono- or bis-C1-C4 alkylated carbamoyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted 5-8 membered saturated or unsaturated heterocycle containing at least one O or NH, C1-C10 alkyl group, or C1-C10 alkyl group in which at least one hydrogen atom is substituted by any of the following groups: hydroxyl, amino, amide group, nitrogen mono- or bis-C1-C4 alkylated amide group, carbamoyl group, nitrogen mono- or bis-C1-C4 alkylated carbamoyl group, sulfonamide group, nitrogen mono- or bis-C1-C4 alkylated sulfonamide group, aminosulfonyl group, nitrogen mono- or bis-C1-C4 alkylated aminosulfonyl group, C1-C6 alkoxy group, substituted or unsubstituted 5-8 membered saturated or unsaturated heterocycle containing at least one O or NH, [O(CH2)] 1-6 ] 1-6 R5; R4is selected from hydrogen, substituted or non-substituted phenyl, substituted or non- substituted heteroaryl, substituted or non-substituted 5-8 membered saturated or unsaturated heterocycle containing at least one O or NH, hydroxy, amino, C1-C4alkoxy, nitrogen mono- or di-C1-C4alkylated alkylamino, carboxy, carbamoyl, nitrogen mono- or di-C1-C4alkylated carbamoyl, C1-C4alkyl, C3-C8cycloalkyl, or C1-C4alkyl and C3-C8cycloalkyl wherein at least one hydrogen is substituted by any of the following substituents: hydroxy, amino, C1-C4alkoxy, nitrogen mono- or di-C1-C4alkylated alkylamino, carboxy, carbamoyl, nitrogen mono- or di-C1-C4alkylated carbamoyl, C1-C4amide, nitrogen C1-C4alkylated amide, methanesulfonamide, trifluoromethanesulfonamide, aminosulfonyl, nitrogen C1-C4alkylated aminosulfonyl, substituted or non-substituted 5-7 membered heteroaryl containing 1-3 N, O, S, substituted or non-substituted 5-8 membered saturated or unsaturated heterocycle containing at least one O or NH; R5is selected from hydrogen, substituted or non-substituted phenyl, substituted or non- substituted heteroaryl, substituted or non-substituted 5-8 membered saturated or unsaturated heterocycle containing at least one O or NH, hydroxy, amino, C1-C4alkoxy, nitrogen mono- or di-C1-C4alkylated alkylamino, carboxy, carbamoyl, nitrogen mono- or di-C1-C4alkylated carbamoyl, sulfonamide, nitrogen mono- or di-C1-C4alkylated sulfonamide, aminosulfonyl, nitrogen mono- or di-C1-C4alkylated aminosulfonyl; the substituents on the phenyl, heteroaryl and 5-8 membered saturated or unsaturated heterocycle in R3-R5are selected from halogen, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, nitrogen mono- or di-C1-C4alkylated alkylamino, carboxy, carbamoyl, nitrogen mono- or di-C1-C4alkylated carbamoyl, sulfonamide, nitrogen mono- or di-C1-C4alkylated sulfonamide, aminosulfonyl, nitrogen mono- or di-C1-C4alkylated aminosulfonyl, substituted or non-substituted 5-8 membered saturated or unsaturated heterocycle containing at least one O or NH.

2. The compound according to claim 1, wherein in the compounds: A is selected from CH2; X, Y, Z are independently selected from CH or N; Q is selected from CH2; R1, R2are selected from phenyl or mono-, di-, tri-substituted phenyl, the mono-, di-, tri- substituents being selected from fluorine, chlorine, bromine, C1-C4alkyl, trifluoromethyl, cyano, methoxy, ethoxy, propoxy, isopropoxy; R3is selected from the group consisting of hydrogen, imidazole, dihydroimidazole, benzimidazole, pyrazole, carboxyl, carbamoyl, N-methylcarbamoyl, hydroxymethyl, aminomethyl, acetamidomethyl, methanesulfonamidomethyl, carbamoylmethyl, N-methylcarbamoylmethyl, [O(CH2) 1-6 ] 1-6 OH, [O(CH2) 1-6 ] 1-6 OCH3, [O(CH2) 1-6 ] 1-6 OEt.

3. The compound according to claim 1, wherein the compounds selected from any of the following: 2,7-dibenzyl-3,4-dihydroisoquinolin-1(2H)-one (I-1); 7-benzyl-2-(2-chlorobenzyl)-3,4-dihydroisoquinolin-l(2H)-one (1-2); 7-benzyl-2-(3-chlorobenzyl)-3,4-dihydroisoquinolin-l(2H)-one (1-3); 7-benzyl-2-(4-chlorobenzyl)-3,4-dihydroisoquinolin-l(2H)-one (1-4); 7-benzyl-2-(4-methylbenzyl)-3,4-dihydroisoquinolin-l(2H)-one (1-5); 7-benzyl-2-(4-trifluoromethylbenzyl)-3,4-dihydroisoquinolin-l(2H)-one (1-6); 7-benzyl-2-(4-fluorobenzyl)-3,4-dihydroisoquinolin-l(2H)-one (1-7); 7-benzyl-2-(4-bromobenzyl)-3,4-dihydroisoquinolin-l(2H)-one (1-8); 7-benzyl-2-(4-methoxybenzyl)-3,4-dihydroisoquinolin-l(2H)-one (1-9); 7-(2-fluorobenzyl)-2-(4-trifluoromethylbenzyl)-3,4-dihydroisoquinolin-l(2H)-one (1-10); 7-(3-fluorobenzyl)-2-(4-trifluoromethylbenzyl)-3,4-dihydroisoquinolin-l(2H)-one (1-11); 7-(4-fluorobenzyl)-2-(4-trifluoromethylbenzyl)-3,4-dihydroisoquinolin-l(2H)-one (1-12); 7-(2-methylbenzyl)-2-(4-trifluoromethylbenzyl)-3,4-dihydroisoquinolin-l(2H)-one (1-13); 7-(3-methylbenzyl)-2-(4-trifluoromethylbenzyl)-3,4-dihydroisoquinolin-l(2H)-one (1-14); 7-(4-methylbenzyl)-2-(4-trifluoromethylbenzyl)-3,4-dihydroisoquinolin-l(2H)-one (1-15); 2,7-bis-(4-fluorobenzyl)-3,4-dihydroisoquinolin-l(2H)-one (1-16); 7-(4-fluorobenzyl)-2-(4-chlorobenzyl)-3,4-dihydroisoquinolin-l(2H)-one (1-17); 8-benzyl-2-(4-trifluoromethylbenzyl)-2,3,4,5-tetrahydro-lH-benzo[c]azepin-l-one (1-18); 2-benzyl-7-(4-trifluoromethylbenzyl)-6,7-dihydro-l,7-naphthyridin-8(5H)-one (1-19); 7-benzyl-2-(4-trifluoromethylbenzyl)-3,4-dihydro-2,6-naphthyridin-l(2H)-one (1-20); 3-benzyl-6-(4-trifluoromethylbenzyl)-7,8-dihydro-l,6-naphthyridin-5(6H)-one (1-21); (R)-7-benzyl-3-hydroxymethyl-2-(4-trifluoromethylbenzyl)-3,4-dihydroisoquinolin-l(2H)-one (1-22); (S)-7-benzyl-3-hydroxymethyl-2-(4-trifluoromethylbenzyl)-3,4-dihydroisoquinolin-l(2H)-one (1-23); (R)-3-Aminomethyl-7-benzyl-2-(4-trifluoromethylbenzyl)-3,4-dihydroisoquinolin-l(2H)-one (I-24); (S)-3-Aminomethyl-7-benzyl-2-(4-trifluoromethylbenzyl)-3,4-dihydroisoquinolin-l(2H)-one (I-25); (R)-7-(3-Fluorobenzyl)-3-hydroxymethyl-2-(4-trifluoromethylbenzyl)-3,4- dihydroisoquinolin-l(2H)-one (I-26); (R)-7-(4-Fluorobenzyl)-3-hydroxymethyl-2-(4-trifluoromethylbenzyl)-3,4- dihydroisoquinolin-l(2H)-one (I-27); (R)-7-Benzyl-3-hydroxymethyl-2-(4-chlorobenzyl)-3,4-dihydroisoquinolin-l(2H)-one (I-28); (R)-7-(3-Fluorobenzyl)-3-hydroxymethyl-2-(4-chlorobenzyl)-3,4-dihydroisoquinolin-l(2H)-one (I-29); (R)-7-(4-Fluorobenzyl)-3-hydroxymethyl-2-(4-chlorobenzyl)-3,4-dihydroisoquinolin-l(2H)-one (I-30); (R)-7-Benzyl-l-oxo-2-(4-trifluoromethylbenzyl)-l,2,3,4-tetrahydroisoquinoline-3- carboxylic acid (I-31); (R)-7-Benzyl-l-oxo-2-(4-trifluoromethylbenzyl)-l,2,3,4-tetrahydroisoquinoline-3- carboxamide (I-32); (R)-7-Benzyl-N-methyl-l-oxo-2-(4-trifluoromethylbenzyl)-l,2,3,4-tetrahydroisoquinoline-3-carboxamide (I-33); (R)-7-Benzyl-3-methylaminomethyl-2-(4-trifluoromethylbenzyl)-3,4- dihydroisoquinolin-l(2H)-one (I-34); (R)-3-(lH-Benzo[d]imidazol-2-yl)-7-benzyl-2-(4-trifluoromethylbenzyl)-3,4- dihydroisoquinolin-l(2H)-one (I-35); (R)-3-(4,5-Dihydro-lH-imidazol-2-yl)-7-benzyl-2-(4-trifluoromethylbenzyl)-3,4- dihydroisoquinolin-l(2H)-one (I-36); (R)-3-(lH-Imidazol-2-yl)-7-benzyl-2-(4-trifluoromethylbenzyl)-3,4- dihydroisoquinolin-l(2H)-one (I-37); (R)-7-Benzyl-3-methoxymethyl-2-(4-trifluoromethylbenzyl)-3,4- dihydroisoquinolin-l(2H)-one (I-38); (R)-7-Benzyl-3-ethoxymethyl-2-(4-trifluoromethylbenzyl)-3,4- dihydroisoquinolin-l(2H)-one (I-39); (R)-7-Benzyl-3-methoxymethoxymethyl-2-(4-trifluoromethylbenzyl)-3,4- dihydroisoquinolin-l(2H)-one (I-40); (R)-7-benzyl-3-(2-methoxyethoxymethyl)-2-(4-trifluoromethylbenzyl)-3,4- dihydroisoquinolin-1 (2H)-one (1-41); (R)-7-(3-fluorobenzyl)-3-(2-methoxyethoxymethyl)-2-(4-trifluoromethylbenzyl)- 3,4-dihydroisoquinolin-1 (2H)-one (1-42); (R)-7-(4-fluorobenzyl)-3-(2-methoxyethoxymethyl)-2-(4-trifluoromethylbenzyl)- 3,4-dihydroisoquinolin-1 (2H)-one (1-43); (R)-7-benzyl-3-(2-methoxyethoxymethyl)-2-(4-chlorobenzyl)-3,4-dihydroisoquinolin- 1 (2H)-one (1-44); (R)-7-(3-fluorobenzyl)-3-(2-methoxyethoxymethyl)-2-(4-chlorobenzyl)-3,4- dihydroisoquinolin-1 (2H)-one (1-45); (R)-7-(4-fluorobenzyl)-3-(2-methoxyethoxymethyl)-2-(4-chlorobenzyl)-3,4- dihydroisoquinolin-1 (2H)-one (1-46); (R)-7-benzyl-3-hydroxymethyl-2-(4-fluorobenzyl)-3,4-dihydroisoquinolin-1 (2H)- one (1-47); (R)-7-(3-fluorobenzyl)-3-hydroxymethyl-2-(4-fluorobenzyl)-3,4-dihydroisoquinolin- 1 (2H)-one (1-48); (R)-2,7-bis(4-fluorobenzyl)-3-hydroxymethyl-3,4-dihydroisoquinolin-1 (2H)-one (1-49); (R)-7-benzyl-3-(2-methoxyethoxymethyl)-2-(4-fluorobenzyl)-3,4-dihydroisoquinolin- 1 (2H)-one (1-50); (R)-7-(3-fluorobenzyl)-3-(2-methoxyethoxymethyl)-2-(4-fluorobenzyl)-3,4- dihydroisoquinolin-1 (2H)-one (1-51); (R)-2,7-bis(4-fluorobenzyl)-3-(2-methoxyethoxymethyl)-3,4-dihydroisoquinolin-1 (2H)-one (1-52); (R)-7-benzyl-3-(2-(2-methoxyethoxy)ethoxymethyl)-2-(4-trifluoromethylbenzyl)- 3,4-dihydroisoquinolin-1 (2H)-one (1-53); (R)-7-(4-fluorobenzyl)-3-(2-hydroxyethoxymethyl)-2-(4-trifluoromethylbenzyl)- 3,4-dihydroisoindolin-1 (2H)-one (1-54); (R)-7-(4-fluorobenzyl)-3-(2-aminoethoxymethyl)-2-(4-trifluoromethylbenzyl)- 3,4-dihydroisoindolin-1 (2H)-one (1-55); (R)-7-(4-fluorobenzyl)-3-(2-methylaminoethoxymethyl)-2-(4- trifluoromethylbenzyl)-3,4-dihydroisoindolin-1 (2H)-one (1-56); (R)-7-(4-Fluorobenzyl)-3-(2-(piperazin-l-yl)ethoxymethyl)-2-(4- trifluoromethylbenzyl)-3,4-dihydroisoindol-l(2H)-one (I-58); (R)-7-(4-Fluorobenzyl)-3-(2-(piperazin-l-yl)ethoxymethyl)-2-(4- trifluoromethylbenzyl)-3,4-dihydroisoindol-l(2H)-one (I-58); (R)-7-(4-Fluorobenzyl)-3-(2-(piperazin-l-yl)ethoxymethyl)-2-(4- trifluoromethylbenzyl)-3,4-dihydroisoindol-l(2H)-one (I-58); (R)-7-(4-Fluorobenzyl)-3-(2-(piperazin-l-yl)ethoxymethyl)-2-(4- trifluoromethylbenzyl)-3,4-dihydroisoindol-l(2H)-one (I-58); (R)-7-(4-Fluorobenzyl)-3-(2-(piperazin-l-yl)ethoxymethyl)-2-(4- trifluoromethylbenzyl)-3,4-dihydroisoindol-l(2H)-one (I-58); (R)-7-(4-Fluorobenzyl)-3-(2-(piperazin-l-yl)ethoxymethyl)-2-(4- trifluoromethylbenzyl)-3,4-dihydroisoindol-l(2H)-one (I-58); (R)-7-(4-Fluorobenzyl)-3-(2-(piperazin-l-yl)ethoxymethyl)-2-(4- trifluoromethylbenzyl)-3,4-dihydroisoindol-l(2H)-one (I-58).

4. The compound according to claim 1, wherein The compound also includes its stereoisomer, tautomer, isotopic compound, prodrug, solvate, crystal, pharmaceutically acceptable salt or mixture.

5. A process for preparing the compound of claim 1, which is characterized by, The preparation method is specifically as follows: when X, Y, Z are CH, A and Q are CH2, R3 is a hydrogen atom, comprising the steps of: (1) the amino group in compound 1 is protected by trifluoroacetyl to obtain compound 2; (2) compound 2 is reacted with formaldehyde to form an imine under the catalysis of an acid, and then cyclization to synthesize compound 3; (3) the amine obtained by removing the trifluoroacetyl group in compound 3 is protected by Boc to obtain compound 4; (4) compound 4 is subjected to an oxidation reaction to obtain compound 5; (5) compound 5 is coupled with substituted or non-substituted benzyl boronic acid or borate to obtain compound 6; (6) compound 7 is obtained by removing the Boc protecting group in compound 6; (7) compound 7 is subjected to a substitution reaction with benzene ring substituted or non-substituted benzyl halide or sulfonate to obtain the target compound 8; Alternatively, when X is N, Y, Z are CH, A and Q are CH2, R3is a hydrogen atom, comprising the steps of: (1) compound 9 is subjected to esterification to obtain 10; (2) compound 10 is subjected to bromination to obtain compound 11; (3) the bromine atom in compound 11 is substituted by a cyano group to obtain compound 12; (4) the amine obtained by selectively reducing compound 12 is subjected to intramolecular cyclization to obtain compound 13; (5) compound 13 is subjected to a substitution reaction with benzene ring substituted or non-substituted benzyl halide or sulfonate to obtain compound 14; (6) compound 14 is subjected to an oxidation reaction to obtain compound 15; (7) compound 15 is subjected to chlorination to obtain compound 16; (8) compound 16 is coupled with substituted or non-substituted benzyl boronic acid or borate to obtain the target compound 17; Alternatively, when Y is N, X, Z are CH, A and Q are CH2, R3is a hydrogen atom, comprising the steps of: (1) esterification of compound 18 to obtain compound 19; (2) reaction of compound 19 with trimethylaluminum to obtain compound 20; (3) methyl bromination of compound 20 to obtain compound 21; (4) substitution of bromine in compound 21 with cyano to obtain compound 22; (5) selective reduction of cyano in compound 22 to obtain amine and cyclization of the ester group to obtain compound 23; (6) substitution reaction of compound 23 with benzene ring substituted or non-substituted benzyl halide or sulfonate to obtain compound 24; (7) coupling of compound 24 with substituted or non-substituted benzyl boronic acid or boronic ester to obtain target compound 25; Alternatively, when Z is N, X, Y are CH, A and Q are CH2, R3 is a hydrogen atom, comprising the steps of: (1) reaction of compound 26 with compound 27 to synthesize compound 28; (2) synthesis of compound 29 from compound 28 through oxidation reaction; (3) synthesis of compound 30 from compound 29 through oxidation reaction; (4) synthesis of compound 31 from compound 30 through reduction reaction; (5) substitution reaction of amide obtained after removal of Boc protecting group in compound 31 with benzene ring substituted or non-substituted benzyl halide or sulfonate to obtain compound 32; (6) coupling of compound 32 with substituted or non-substituted benzyl boronic acid or boronic ester to obtain target compound 33; Alternatively, when X, Y, Z are CH, A is CH2, Q is CH2CH2, R3 is a hydrogen atom, comprising the steps of: (1) reaction of compound 34 with hydroxylamine to obtain compound 35; (2) synthesis of compound 36 from compound 35 through Beckmann rearrangement reaction; (3) reaction of compound 36 with benzene ring substituted or non-substituted benzyl halide or sulfonate to obtain target compound 37; (4) coupling of compound 37 with benzene ring substituted or non-substituted benzyl boronic acid or boronic ester to obtain target compound 38; Alternatively, when X, Y, Z are CH, A and Q are CH2, R3 is a different substituent, comprising the steps of: (1) esterification and amino protection of compound 39 to obtain compound 40; (2) imine formation of compound 40 with formaldehyde under acid catalysis and then ring closure to obtain compound 41; (3) cyclization of alcohol obtained after reduction of ester group in compound 41 with amino acid methyl ester to obtain compound 42; (4) synthesis of compound 43 from compound 42 through oxidation reaction; (4) ring opening of compound 43 under the action of base to obtain compound 44; (5) protection of hydroxyl group in compound 44 with TBS to obtain compound 45; (6) substitution reaction of compound 45 with benzene ring substituted or non-substituted benzyl halide or sulfonate to obtain compound 46; (7) coupling of compound 46 with substituted or non-substituted benzyl boronic acid or boronic ester to obtain compound 47; (8) removal of TBS protecting group in compound 47 to obtain compound 48; (9) conversion of hydroxyl group in compound 48 into different substituents to obtain target compound 49.

6. A pharmaceutical composition, characterized by, The lactam compound containing the aromatic heterocycle as claimed in claim 1 and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition of claim 6, wherein, The preparation form of the pharmaceutical combination is tablet, capsule, powder, pill, granule, injection, oral liquid, syrup, inhalant, ointment, patch or suppository.

8. Use of the aromatic heterocycle-lactam compound as claimed in claim 1 or the pharmaceutical composition as claimed in claim 6 in the preparation of a casein kinase I P agonist drug.

9. Use of the aromatic heterocycle-lactam compound as claimed in claim 1 or the pharmaceutical composition as claimed in claim 6 in the preparation of a drug for treating cancer.

10. Use according to claim 9, characterized in that, The cancer is acute myeloid leukemia, breast cancer, lung cancer, liver cancer, ovarian cancer, bladder cancer, prostate cancer, uterine cancer, stomach cancer, testicular cancer, thyroid cancer, cervical cancer, osteosarcoma, neuroblastoma, colon cancer, brain tumor.

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