Preparation method and pharmaceutical use of phenylacrylamide RHBDD1 inhibitor

Abstract

The present invention relates to the field of medicine, and in particular to a class of compounds containing a phenylacrylamide structure or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compounds, and the use of the compounds in the preparation of drugs for treating diseases related to the function of intramembrane serine protease (Rhomboid domain containing 1, RHBDD1).

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a class of compounds containing a phenylacrylamide structure or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compounds, and the use of the compounds in the preparation of drugs for treating diseases related to the function of intramembrane serine protease (Rhomboid domain containing 1, RHBDD1). Background Art

[0002] RHBDD1 is an intramembrane serine protease and a member of the Rhomboid family. It is widely distributed in the biological world and has important regulatory functions. RHBDD1 can cleave tumor suppressor activated pathway protein 6 (TSAP6), apoptosis prerequisite protein BIK and transforming growth factor alpha (TGF-a).

[0003] RHBDD1 has a high protein expression level in a variety of tumor cells such as pancreatic adenocarcinoma, breast cancer, small cell lung cancer, renal cell carcinoma and colorectal cancer. Among them, colorectal cancer is a highly prevalent malignant tumor worldwide, and its occurrence and development are closely related to related oncogenes, tumor suppressor genes and growth factor pathways. The results of clinical correlation studies showed that the expression of RHBDD1 was significantly correlated with the survival, tumor differentiation, TNM stage and N grade of colorectal cancer patients. Endogenous mutation inactivation of RHBDD1 can inhibit tumor cell growth. Mechanistic studies have shown that RHBDD1 interacts with TGFα and can induce the cleavage and secretion of TGFα in an ADAM-independent manner. The secretion of TGFα further stimulates the EGFR / Raf / MEK / ERK signaling pathway, thereby participating in the occurrence and development of colorectal cancer. At present, there are no relevant reports on RHBDD1 inhibitors, and it is urgent to discover new RHBDD1 inhibitors. Summary of the invention

[0004] The present invention provides a class of compounds containing phenylacrylamide structure or pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition containing the class of compounds and use of the class of compounds in preparing drugs for treating diseases related to RHBDD1 function.

[0005] In order to solve the technical problem of the present invention, the present invention provides the following technical solutions:

[0006] The first aspect of the technical solution of the present invention is to provide a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof:

[0007]

[0008] Wherein, R1 is selected from the following structures:

[0009]

[0010] R2 is selected from hydrogen, substituted or unsubstituted C 1-4 Straight or branched chain oxaalkyl, C 3-6 Cyclomethoxy, C 4-8 Oxacycloalkoxy or

[0011] R3 is selected from hydrogen, methoxy, 2-methoxyethoxy or oxacyclohexane-4-ylmethoxy;

[0012] R4 is selected from hydrogen or methoxy.

[0013] Further, the compound according to claim 1 or a pharmaceutically acceptable salt thereof is characterized in that R2 is selected from hydrogen, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclohexylmethoxy, 2-methoxyethoxy, 3-methoxyethoxy, oxetane-3-ylmethoxy, oxolan-3-ylmethoxy, oxan-4-ylmethoxy, oxan-4-ylethoxy, N,N-diethylaminoethoxy, pyrrolidine-1- ethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 2-(pyridinylamido)ethoxy, 2-(2-oxopyrrolidin-1-yl)ethoxy, pyridin-4-ylmethoxy, pyridin-3-ylethoxy, pyridazin-4-ylmethoxy, thien-3-ylmethoxy, 3-fluoro-pyridin-4-ylmethoxy, 2-fluoro-pyridin-4-ylmethoxy.

[0014] As a preferred embodiment, the pharmaceutically acceptable salt is selected from organic acid salts or inorganic acid salts, including hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, malates, fumarates, tartrates or methanesulfonates.

[0015] As a preferred embodiment of the present invention, the compound of general formula (I) has the following structure:

[0016]

[0017]

[0018]

[0019] Another aspect of the technical solution of the present invention is to provide a method for synthesizing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, and the synthetic route is as follows:

[0020] Route (1):

[0021]

[0022] Reagents and conditions: (a) oxalyl chloride, N,N-dimethylformamide, dichloromethane, 0°C; (b) R1H, sodium hydride, tetrahydrofuran, 0°C.

[0023] Route (2):

[0024]

[0025] Reagents and conditions: (a) 2-iodopropane, potassium hydroxide, acetonitrile: water = 1:1, 90°C; (b) oxalyl chloride, N,N-dimethylformamide, dichloromethane, 0°C; 5,6-dihydro-2(1H)-pyridone, sodium hydride, tetrahydrofuran, 0°C; (c) anhydrous aluminum chloride, dichloromethane, 0°C; (d) R2OH, diisopropyl azodicarboxylate, triphenylphosphine, tetrahydrofuran, 0°C to room temperature;

[0026] Wherein R1, R2, R3, and R4 are defined as above.

[0027] Another aspect of the technical solution of the present invention is to provide a pharmaceutical composition, which comprises a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0028] Another aspect of the technical solution of the present invention is to provide the use of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating diseases related to the function of RHBDD1.

[0029] Another aspect of the technical solution of the present invention is to provide the use of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating tumors.

[0030] Beneficial technical effects

[0031] Examples 1-31 in the technical solution of the present invention all have significant inhibitory activity on RHBDD1 and show significant proliferation inhibition on tumor cells. DETAILED DESCRIPTION

[0032] Example 1

[0033] (E)-1-(3-(3,4,5-trimethoxyphenyl)acryloyl)quinolin-2(1H)one

[0034]

[0035] (1) Preparation of (E)-3-(3,4,5-trimethoxyphenyl)acryloyl chloride

[0036]

[0037] (E)-3,4,5-trimethoxycinnamic acid (0.100 g, 0.42 mmol) was dissolved in ultra-dry dichloromethane, and the mixture was cooled to 0°C under an argon atmosphere. Oxalyl chloride (274.4 mg, 2.1 mmol) and N,N-dimethylformamide (0.29 mg, 0.004 mmol) were slowly added, and the mixture was then moved to room temperature for 3 h. After the reaction of the raw materials was complete, the solvent was removed by distillation under reduced pressure to obtain a crude product of (E)-3-(3,4,5-trimethoxyphenyl)acryloyl chloride, which was used directly in the next step without further purification.

[0038] (2) Preparation of the title compound

[0039] Dissolve quinolin-2(1H)one (0.092g, 0.63mmol) in ultra-dry tetrahydrofuran, cool to 0℃, add 60% sodium hydride mineral oil mixture (0.027g, 0.69mmol) in two batches, and react for 40min under ice bath. Dissolve the crude (E)-3-(3,4,5-trimethoxyphenyl)acryloyl chloride (0.107g, 0.42mmol) obtained in the previous step in 1ml ultra-dry tetrahydrofuran, add dropwise to the system, and then move to room temperature to react for 1h. After the reaction is complete, add water to quench, extract with ethyl acetate, wash the ethyl acetate layer twice with 10ml saturated sodium chloride aqueous solution, and then distill under reduced pressure to remove the solvent. The petroleum ether and ethyl acetate system are separated by column chromatography to obtain 56mg of white solid, with a yield of 36.5% and a melting point of 76-78℃.

[0040] 1 H NMR(400MHz,Chloroform-d)δ8.28(d,J=8.5Hz,1H),8.04(d,J=8.5Hz,1H),7.90(d,J=16.1Hz,2H),7.75(s ,1H),7.58(t,J=7.6Hz,1H),7.33(d,J=8.8Hz,1H),6.82(m,2H),6.60(d,J=15.9Hz,1H),3.92(s,9H); calcd.For C21H19NO5(M+H) + 366.13139, found 366.25935.

[0041] Example 2

[0042] (E)-1-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0043]

[0044] (1) Preparation of (E)-3-(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)acryloyl chloride

[0045]

[0046] Dissolve (E)-3-(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)acrylic acid (0.100 g, 0.48 mmol) in ultra-dry dichloromethane, cool to 0°C under argon protection, slowly add oxalyl chloride (304.5 mg, 2.4 mmol) and N,N-dimethylformamide (0.29 mg, 0.004 mmol), and then move to room temperature to react for 3 hours. After the reaction of the raw materials is complete, the solvent is removed by distillation under reduced pressure to obtain crude (E)-3-(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)acryloyl chloride, which is used directly in the next step without further purification.

[0047] (2) Preparation of the title compound

[0048] Dissolve 5,6-dihydro-2(1H)-pyridone (69.8mg, 0.72mmol) in ultra-dry tetrahydrofuran, protect with argon, cool to 0℃, add 60% sodium hydride mineral oil mixture (0.031g, 0.79mmol) in two batches, and react for 40min under ice bath. Dissolve the crude (E)-3-(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)acryloyl chloride obtained in the previous step in 1ml ultra-dry tetrahydrofuran, add dropwise to the system, and then move to room temperature to react for 1h. After the reaction is complete, add water to quench, extract with ethyl acetate, wash the ethyl acetate layer twice with 10ml saturated sodium chloride aqueous solution, and then distill under reduced pressure to remove the solvent. The petroleum ether and ethyl acetate system are separated by column chromatography to obtain 45mg of white solid, with a yield of 32.8% and a melting point of 72-73℃.

[0049] 1H NMR(700MHz,Chloroform-d)δ7.65(d,J=15.6Hz,1H),7.37(d,J=15.5Hz,1H),7.13–7.06(m,2H),6.93(dt,J=9.2,4.2Hz,1H),6. 85(d,J=8.2Hz,1H),6.04(dt,J=9.7,1.9Hz,1H),4.30–4.25(m,4H),4.03(t,J=6.5Hz,2H),2.47(dq,J=6.2,4.3,3.1Hz,2H).HRMS calcd.For C16H15NO4(M+H) + 286.10193, found 286.10953.

[0050] Example 3

[0051] (E)-1-(3-(3-methoxy-4-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0052]

[0053] (1) Preparation of (E)-3-(3-methoxy-4-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)acryloyl chloride

[0054]

[0055] Dissolve (E)-3-(3-methoxy-4-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)acrylic acid (0.100 g, 0.32 mmol) in ultra-dry dichloromethane, cool to 0°C under argon protection, slowly add oxalyl chloride (205.8 mg, 1.6 mmol) and N,N-dimethylformamide (0.21 mg, 0.003 mmol), and then move to room temperature to react for 3 hours. After the reaction of the raw materials is complete, the solvent is removed by distillation under reduced pressure to obtain a crude product of (E)-3-(3-methoxy-4-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)acryloyl chloride, which is directly used in the next step without further purification.

[0056] (2) Preparation of the title compound

[0057] Dissolve 5,6-dihydro-2(1H)-pyridone (46.6 mg, 0.48 mmol) in ultra-dry tetrahydrofuran, protect with argon, cool to 0°C, add 60% sodium hydride mineral oil mixture (0.014 g, 0.35 mmol) in two batches, and react for 40 min under ice bath conditions. Dissolve the crude (E)-3-(3-methoxy-4-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)acryloyl chloride obtained in the previous step in 1 ml ultra-dry tetrahydrofuran, add dropwise to the system, and then move to room temperature to react for 1 h. After the reaction is complete, add water to quench, extract with ethyl acetate, wash the ethyl acetate layer twice with 5 ml saturated sodium chloride aqueous solution, and then distill under reduced pressure to remove the solvent. The petroleum ether and ethyl acetate system are separated by column chromatography to obtain 40 mg of white solid, with a yield of 32.4% and a melting point of 70-71°C.

[0058] 1 H NMR(400MHz,Chloroform-d)δ7.70(m,1H),7.40(d,J=15.9Hz,1H),7.11(s,2H),6.93(s,1H),6.85(s, 1H),6.04(s,1H),4.00(m,9H),3.40(s,2H),2.47(s,2H),1.81(s,3H),1.67(s,2H),1.35(s,2H).HRMS calcd.For C22H27NO5(M+H) + 386.19622, found 386.19562.

[0059] Example 4

[0060] (E)-1-(3-(3-methoxy-4-(2-methoxyethoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0061]

[0062] (1) Preparation of (E)-3-(3-methoxy-4-(2-methoxyethoxy)phenyl)acryloyl chloride

[0063]

[0064] Dissolve (E)-3-(3-methoxy-4-(2-methoxyethoxy)phenyl)acrylic acid (0.100 g, 0.39 mmol) in ultra-dry dichloromethane, cool to 0°C under argon protection, slowly add oxalyl chloride (251.7 mg, 1.98 mmol) and N,N-dimethylformamide (0.24 mg, 0.004 mmol), and then move to room temperature to react for 3 hours. After the reaction of the raw materials is complete, remove the solvent by distillation under reduced pressure to obtain crude (E)-3-(3-methoxy-4-(2-methoxyethoxy)phenyl)acryloyl chloride, which is directly used in the next step without further purification.

[0065] (2) Preparation of the title compound

[0066] Dissolve 5,6-dihydro-2(1H)-pyridone (46.6 mg, 0.48 mmol) in ultra-dry tetrahydrofuran, protect with argon, cool to 0°C, add 60% sodium hydride mineral oil mixture (0.014 g, 0.35 mmol) in two batches, and react for 40 min under ice bath conditions. Dissolve the crude (E)-3-(3-methoxy-4-(2-methoxyethoxy)phenyl)acryloyl chloride obtained in the previous step in 1 ml ultra-dry tetrahydrofuran, add dropwise to the system, and then move to room temperature to react for 1 h. After the reaction is complete, quench with water, extract with ethyl acetate, wash the ethyl acetate layer twice with 5 ml saturated sodium chloride aqueous solution, and then distill under reduced pressure to remove the solvent. The petroleum ether and ethyl acetate system are separated by column chromatography to obtain 43 mg of white solid, with a yield of 34.5% and a melting point of 72-73°C.

[0067] 1 H NMR(400MHz,Chloroform-d)δ7.71(d,J=15.5Hz,1H),7.41(d,J=15.5Hz,1H),7.16–7.08(m,2H),6.94-6.87(m,2H),6.04(d,J=9.7 HRMScalcd.For C18H21NO5(M+H) + 332.14865, found 332.14925.

[0068] Example 5

[0069] 1-(3-ethoxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one

[0070]

[0071] (1) Preparation of (E)-3-(3-isopropoxyphenyl)acrylic acid

[0072]

[0073] 3-Hydroxycinnamic acid (2.0 g, 12.19 mmol) was dissolved in 20 ml of acetonitrile: water = 1:1 solution, 2-iodopropane (2.48 g, 14.62 mmol) and potassium hydroxide (1.37 g, 24.38 mmol) were added in sequence, and the mixture was reacted at 90°C for 5 h under argon protection. After the reaction, the pH was adjusted to 2-3 with 1M hydrochloric acid aqueous solution, extracted with ethyl acetate, and the organic layer was washed twice with 25 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Concentrated, separated by column chromatography, the eluent was ethyl acetate, and dried to obtain 1.78 g of a white solid, with a yield of 70.8% and a melting point of 112-114°C.

[0074] 1 H NMR(400MHz,Chloroform-d)δ7.75(d,J=15.9Hz,1H),7.34–7.26(m,1H),7.12(d,J=7.7Hz,1H),7.06( s,1H),6.97–6.90(m,1H),6.43(d,J=16.0Hz,1H),4.58(m,1H),1.36(m,6H).MS(ESI)m / z207.14(M+H) + .

[0075] (2) Preparation of (E)-3-(3-isopropoxyphenyl)acryloyl chloride

[0076]

[0077] Dissolve (E)-3-(3-isopropoxyphenyl)acrylic acid (2.8 g, 13.58 mmol) in ultra-dry dichloromethane, cool to 0°C under argon protection, slowly add oxalyl chloride (8.62 g, 67.93 mmol) and N,N-dimethylformamide (9.9 mg, 0.136 mmol), and then move to room temperature to react for 3 hours. After the raw material reacts completely, remove the solvent by distillation under reduced pressure to obtain the crude (E)-3-(3-isopropoxyphenyl)acryloyl chloride, which is used directly in the next step without further purification. (3) Preparation of (E)-1-(3-isopropoxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one

[0078]

[0079] Dissolve 5,6-dihydro-2(1H)-pyridone (1.18 g, 12.22 mmol) in ultra-dry tetrahydrofuran, protect with argon, cool to 0°C, add 60% sodium hydride mineral oil mixture (358 mg, 14.94 mmol) in two batches, and react for 40 min under ice bath conditions. Add (E)-3-(3-isopropoxyphenyl)acryloyl chloride (2.8 g, 13.58 mmol) in ultra-dry tetrahydrofuran solution dropwise to the system, and then move to room temperature to react for 1 h. After the reaction is complete, quench with water, extract with ethyl acetate, wash the ethyl acetate layer twice with 10 ml saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, and then distill under reduced pressure to remove the solvent. The petroleum ether and ethyl acetate system are separated by column chromatography to obtain 1.2 g of yellow oil with a yield of 55.6%.

[0080] 1 H NMR(400MHz,Chloroform-d)δ7.71(d,J=15.5Hz,1H),7.49(d,J=15.6,1H),7.31-7.23(m,1H),7.16(d,J=7.6Hz,1H),7.10(d,J=2 .4Hz,1H),6.93(m,2H),6.05(m,1H),4.58(m,1H),4.05(t,J=6.4Hz,2H),2.51-2.45(m,2H),1.35(m,6H).MS(ESI)m / z286.22(M+H) + .

[0081] (4) Preparation of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one

[0082]

[0083] Dissolve (E)-1-(3-isopropoxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (750mg, 3.34mmol) in 20ml of ultra-dry dichloromethane, add anhydrous aluminum chloride (1.33g, 10.0mmol) at 0℃, and react for 2h. After the reaction, adjust the pH to 3-4 with 1M hydrochloric acid aqueous solution, extract with dichloromethane, wash the organic layer twice with 10ml saturated sodium chloride aqueous solution, and dry with anhydrous sodium sulfate. Concentrate, separate by column chromatography, eluent is ethyl acetate, and dry to obtain 800g of light yellow solid, with a yield of 98.8% and a melting point of 123-124℃.

[0084] 1H NMR(400MHz,Chloroform-d)δ7.67(dd,J=15.6,1.8Hz,1H),7.44(dd,J=15.7,1.8Hz,1H),7.24-7.16(m,1H),7.12-7.06(m,2H), 6.94(m,1H),6.90-6.84(m,1H),6.04(dd,J=9.7,1.9Hz,1H),4.03(td,J=6.5,1.7Hz,2H),2.47(m,2H).MS(ESI)m / z244.07(M+H) + .

[0085] (5) Preparation of the title compound

[0086] Ethanol (17.06 mg, 0.37 mmol) and triphenylphosphine (97.05 mg, 0.37 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (60.0 mg, 0.25 mmol) in ultra-dry tetrahydrofuran, and the mixture was cooled to 0°C with an ice bath. Diisopropyl azodicarboxylate (74.8 mg, 0.37 mmol) was added dropwise, and the mixture was moved to room temperature for 5 hours. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, and the eluent was ethyl acetate. The mixture was dried to obtain 20 mg of a white oil with a yield of 30.8%.

[0087] 1 H NMR(400MHz,Chloroform-d)δ7.75–7.67(m,1H),7.53–7.45(m,1H),7.27(m,1H),7.16(d,J=7.7Hz,1H),7.10(t, J=2.1Hz,1H),6.97–6.87(m,2H),6.04(m,1H),4.12-4.01(m,4H),2.48-2.45(m,2H),1.42(t,J=1.7Hz,3H).HRMS calcd.For C16H17NO3(M+H) + 272.12775, found 272.12812.

[0088] Example 6

[0089] (E)-1-(3-(3-propoxyphenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0090]

[0091] (1) Preparation of the title compound

[0092] 1-Propanol (18.2 mg, 0.31 mmol) and triphenylphosphine (81.3 mg, 0.31 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (50.0 mg, 0.21 mmol) in ultra-dry tetrahydrofuran, cooled to 0°C in an ice bath, and diisopropyl azodicarboxylate (62.7 mg, 0.31 mmol) was added dropwise. The mixture was moved to room temperature and reacted for 5 h. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, with ethyl acetate as the eluent, and dried to obtain 23 mg of a transparent oily substance with a yield of 26.0%.

[0093] 1 H NMR(400MHz,Chloroform-d)δ7.71(dd,J=15.5,2.8Hz,1H),7.48(dd,J=15.6,2.8Hz,1H),7.27(m,1H),7.15(d,J=7.7Hz,1H),7.10(s HRMS calcd.For C17H19NO3(M+H) + 286.14377, found 286.14346.

[0094] Example 7

[0095] (E)-1-(3-Isopropoxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one

[0096]

[0097] (1) Preparation of the title compound

[0098] Isopropanol (18.2 mg, 0.31 mmol) and triphenylphosphine (81.3 mg, 0.31 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (50.0 mg, 0.21 mmol) in ultra-dry tetrahydrofuran, and the mixture was cooled to 0°C with an ice bath. Diisopropyl azodicarboxylate (62.7 mg, 0.31 mmol) was added dropwise, and the mixture was moved to room temperature for 5 hours. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, and the eluent was ethyl acetate. The mixture was dried to obtain 25 mg of a yellow oil with a yield of 28.3.0%.

[0099] 1 H NMR(400MHz,Chloroform-d)δ7.71(d,J=15.5Hz,1H),7.49(d,J=15.6,1H),7.31–7.23(m,1H),7.16(d,J=7.6Hz,1H),7. 10(d,J=2.4Hz,1H),6.93(m,2H),6.05(m,1H),4.58(m,1H),4.05(t,J=6.4Hz,2H),2.51–2.45(m,2H),1.35(m,6H).HRMS calcd.ForC17H19NO3(M+H) + 286.14377, found 286.14365.

[0100] Example 8

[0101] (E)-1-(3-(3-(cyclopropylmethoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0102]

[0103] (1) Preparation of the title compound

[0104] Hydroxymethylcyclopropane (22.7 mg, 0.31 mmol) and triphenylphosphine (81.3 mg, 0.31 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (50.0 mg, 0.21 mmol) in ultra-dry tetrahydrofuran, cooled to 0°C, and diisopropyl azodicarboxylate (62.7 mg, 0.31 mmol) was added dropwise. The mixture was moved to room temperature and reacted for 5 h. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, with ethyl acetate as the eluent, and dried to obtain 27 mg of a transparent oily substance with a yield of 29.3.0%.

[0105] 1 H NMR(400MHz,Chloroform-d)δ7.71(dd,J=15.6,3.4Hz,1H),7.49(dd,J=15.6,3.4Hz,1H),7.27(p,J=4.3Hz,1H),7.19–7.14(m,1H),7.11(s,1H),6 .94(m,2H),6.08–6.01(m,1H),4.06-4.02(m,2H),3.83(m,2H),2.50-2.4 5(m,2H),1.28(s,1H),0.65(q,J=3.8Hz,2H),0.37(d,J=4.7Hz,2H).HRMS calcd.For C18H19NO3(M+H) + 298.14377, found 298.14345.

[0106] Example 9

[0107] (E)-1-(3-(3-(cyclobutylmethoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0108]

[0109] (1) Preparation of the title compound

[0110] Cyclobutylmethanol (31.9 mg, 0.37 mmol) and triphenylphosphine (97.1 mg, 0.37 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (60.0 mg, 0.25 mmol) in ultra-dry tetrahydrofuran, cooled to 0°C in an ice bath, and diisopropyl azodicarboxylate (72.9 mg, 0.37 mmol) was added dropwise. The mixture was moved to room temperature and reacted for 5 hours. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, and the eluent was ethyl acetate. The mixture was dried to obtain 25 mg of a transparent oily substance with a yield of 32.1% and a melting point of 80-81°C.

[0111] 1H NMR(700MHz,Chloroform-d)δ7.71(dd,J=15.6,1.9Hz,1H),7.49(dd,J=15.6,1.9Hz,1H),7.29–7.25(m,1H),7.11(d,J=2.5Hz,1H),6.96–6.89(m,2H ),6.07–6.03(m,1H),4.04(td,J=6.5,2.0Hz,2H),3.94(dd,J=6.5,1.9Hz, 2H),2.77(m,1H),2.48(m,2H),2.18–2.11(m,2H),1.99–1.85(m,4H).HRMS calcd.For C19H21NO3(M+H) + 312.15942, found 312.15887.

[0112] Example 10

[0113] (E)-1-(3-(3-(2-methoxyethoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0114]

[0115] (1) Preparation of the title compound

[0116] Ethylene glycol methyl ether (28.17 mg, 0.37 mmol) and triphenylphosphine (97.1 mg, 0.37 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (60.0 mg, 0.25 mmol) in ultra-dry tetrahydrofuran, cooled to 0°C, and diisopropyl azodicarboxylate (72.9 mg, 0.37 mmol) was added dropwise. The mixture was moved to room temperature and reacted for 5 hours. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, and the eluent was ethyl acetate. The mixture was dried to obtain 24 mg of a transparent oily substance with a yield of 31.9%.

[0117] 1H NMR(400MHz,Chloroform-d)δ7.70(dd,J=15.8,2.4Hz,1H),7.48(dd,J=15.5,2.4H z,1H),7.30–7.23(m,1H),7.18(d,J=7.7Hz,1H),7.13(s,1H),6.94(d,J=8.5Hz,2H ),6.04(d,J=9.7Hz,1H),4.14(p,J=2.6Hz,2H),4.04(td,J=6.6,2.3Hz,2H),3.76( dt,J=6.1,2.7Hz,2H),3.46(d,J=2.4Hz,3H),2.47(d,J=7.7Hz,2H).HRMScalcd.For C17H19NO4(M+H) + 302.13868, found 302.13831.

[0118] Embodiment 11

[0119] (E)-1-(3-(3-(3-methoxypropoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0120]

[0121] (1) Preparation of the title compound

[0122] 3-Methoxy-1-propanol (25.23 mg, 0.28 mmol) and triphenylphosphine (73.4 mg, 0.28 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (46.0 mg, 0.19 mmol) in ultra-dry tetrahydrofuran, cooled to 0°C with an ice bath, and diisopropyl azodicarboxylate (56.6 mg, 0.28 mmol) was added dropwise. The mixture was moved to room temperature and reacted for 5 h. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, and the eluent was ethyl acetate. The mixture was dried to obtain 25 mg of a transparent oily substance with a yield of 41.7%.

[0123] 1H NMR(400MHz,Chloroform-d)δ7.71(d,J=15.6Hz,1H),7.48(d,J=15.6Hz,1H),7.31–7.23(m,1H),7.16(d,J=7.6Hz,1H),7.11(s,1H) HRMS calcd.For C18H21NO4(M+H) + 316.15433, found 316.15393.

[0124] Example 12

[0125] (E)-1-(3-(3-(oxetan-3-ylmethoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0126]

[0127] (1) Preparation of the title compound

[0128] Cyclobutylmethanol (33.0 mg, 0.37 mmol) and triphenylphosphine (98.1 mg, 0.37 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (60.0 mg, 0.25 mmol) in ultra-dry tetrahydrofuran, cooled to 0°C, and diisopropyl azodicarboxylate (72.9 mg, 0.37 mmol) was added dropwise. The mixture was moved to room temperature and reacted for 5 h. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, with ethyl acetate as the eluent, and dried to obtain 47 mg of a transparent oily substance with a yield of 60.1%.

[0129] 1H NMR(400MHz,Chloroform-d)δ7.70(d,J=15.6Hz,1H),7.49(dd,J=15.7,1.8Hz,1H),7.31–7.25(m,1H),7.18(d,J=7.7Hz,1H),7.12(s,1H ),6.94(m,2H),6.04(m,1H),4.88(m,2H),4.58(m,2H),4.22(d,J=6.7Hz,2H),4.04(t,J=6.5Hz,2H),3.43(m,1H),2.54–2.41(m,2H).HRMS calcd.For C18H19NO4(M+H) + 314.13868, found 314.13812.

[0130] Example 13

[0131] (E)-1-(3-(3-((tetrahydrofuran-3-yl)methoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0132]

[0133] (1) Preparation of the title compound

[0134] 3-Tetrahydrofuran methanol (38.3 mg, 0.37 mmol) and triphenylphosphine (97.1 mg, 0.37 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (60.0 mg, 0.25 mmol) in ultra-dry tetrahydrofuran, and the mixture was cooled to 0°C with an ice bath. Diisopropyl azodicarboxylate (72.9 mg, 0.37 mmol) was added dropwise, and the mixture was moved to room temperature for 5 hours. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, and the eluent was ethyl acetate. The mixture was dried to obtain 17 mg of a transparent oily substance with a yield of 20.7%.

[0135] 1H NMR (400MHz, Chloroform-d) δ7.70 (dd, J=15.6, 2.1Hz, 1H), 7.48 (dd, J=15.6, 2. 1Hz,1H),7.32–7.24(m,1H),7.18-7.14(m,1H),7.10-7.01(m,1H),6.96-6.86(m, 2H),6.06-6.01(m,1H),4.04(td,J=6.5,2.0Hz,2H),3.99–3.85(m,4H),3.79(m, 1H),3.70(m,1H),2.74(m,1H),2.50–2.45(m,2H),2.12(m,1H),1.75(m,1H).HRMS calcd.ForC19H21NO4(M+H) + 328.15433, found 328.1539.

[0136] Embodiment 14

[0137] (E)-1-(3-(3-((tetrahydropyran-4-yl)methoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0138]

[0139] (1) Preparation of the title compound

[0140] Ethylene glycol methyl ether (32.98 mg, 0.28 mmol) and triphenylphosphine (73.4 mg, 0.28 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (46.0 mg, 0.19 mmol) in ultra-dry tetrahydrofuran, and the mixture was cooled to 0°C with an ice bath. Diisopropyl azodicarboxylate (56.6 mg, 0.28 mmol) was added dropwise, and the mixture was moved to room temperature for 5 hours. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, and the eluent was ethyl acetate. The mixture was dried to obtain 24 mg of a white oil with a yield of 37.9%.

[0141] 1H NMR(400MHz,Chloroform-d)δ7.71(d,J=15.7Hz,1H),7.49(d,J=15.6Hz,1H), 7.27(d,J=6.6Hz,1H),7.16(d,J=7.6Hz,1H),7.09(s,1H),6.99-6.87(m,2H), 6.05(d,J=9.7Hz,1H),4.03(m,4H),3.83(d,J=6.5Hz,2H),3.45(t,J=11.4Hz, 2H),2.48(d,J=6.1Hz,2H),2.06(s,2H),1.77(m,2H),1.51–1.43(m,1H).HRMS calcd.For C20H23NO4(M+H) + 342.16998, found 342.16983.

[0142] Embodiment 15

[0143] (E)-1-(3-(3-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0144]

[0145] (1) Preparation of the title compound

[0146] 2-Tetrahydropyran-4-ethanol (48.8 mg, 0.37 mmol) and triphenylphosphine (97.1 mg, 0.37 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (60.0 mg, 0.25 mmol) in ultra-dry tetrahydrofuran, cooled to 0°C, and diisopropyl azodicarboxylate (72.9 mg, 0.37 mmol) was added dropwise. The mixture was moved to room temperature and reacted for 5 hours. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, with ethyl acetate as the eluent, and dried to obtain 23 mg of a white solid with a yield of 25.9% and a melting point of 90-91°C.

[0147] 1H NMR(400MHz,Chloroform-d)δ7.72(dd,J=15.6,4.3Hz,1H),7.50(dd,J=15.7,4.3Hz,1H),7.30–7.24(m,1H),7.14(d,J=25.1Hz,2H),6.94(dt ,J=15.1,4.4Hz,2H),6.08–6.02(m,1H),4.11–3.90(m,6H),3.42(m,2H) ),2.51–2.47(m,2H),1.77–1.60(m,3H),1.53(m,2H),1.33(m,2H).HRMS calcd.For C21H25NO4(M+H) + 356.18563, found 356.18573.

[0148] Example 16

[0149] (E)-1-(3-(3-(cyclohexylmethoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0150]

[0151] (1) Preparation of the title compound

[0152] Cyclohexylmethanol (42.25 mg, 0.37 mmol) and triphenylphosphine (97.1 mg, 0.37 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (60.0 mg, 0.25 mmol) in ultra-dry tetrahydrofuran, cooled to 0°C in an ice bath, and diisopropyl azodicarboxylate (72.9 mg, 0.37 mmol) was added dropwise. The mixture was moved to room temperature and reacted for 5 hours. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, with ethyl acetate as the eluent, and dried to obtain 18 mg of a white solid with a yield of 21.2% and a melting point of 80-81°C.

[0153] 1H NMR(400MHz,Chloroform-d)δ7.72(d,J=15.7Hz,1H),7.53–7.45(m,1H),7.2 8–7.23(m,1H),7.15(d,J=7.8Hz,1H),7.10(s,1H),6.91(m,2H),6.05(d,J=9 .8Hz,1H),4.04(dt,J=6.4,3.6Hz,2H),3.80–3.75(m,2H),2.48(s,2H),1.91 -1.82(m,2H),1.81-1.66(m,3H),1.38-1.18(m,4H),1.17-1.03(m,2H).HRMS calcd.For C21H25NO3(M+H) + 340.19072, found 340.19019.

[0154] Embodiment 17

[0155] (E)-1-(3-(3-(2-(diethylamino)ethoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0156]

[0157] (1) Preparation of the title compound

[0158] Diethylaminoethanol (57.2 mg, 0.49 mmol) and triphenylphosphine (147.1 mg, 0.56 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (80.0 mg, 0.33 mmol) in ultra-dry tetrahydrofuran, cooled to 0°C, and diisopropyl azodicarboxylate (99.8 mg, 0.49 mmol) was added dropwise. The mixture was moved to room temperature and reacted for 5 h. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, with ethyl acetate as the eluent, and dried to obtain 45 mg of a light yellow oil with a yield of 39.8%.

[0159] 1H NMR(500MHz,Chloroform-d)δ7.72–7.65(m,1H),7.49–7.42(m,1H),7.28–7.22(m,1H),7.17–7.12(m,1H),7.11–7.06(m,1H),6.96–6.87(m HRMS calcd.For C20H26N2O3(M+H) + 343.20162, found 343.20117.

[0160] Embodiment 18

[0161] (E)-1-(3-(3-(2-(Pyrrolidin-1-yl)ethoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0162]

[0163] (1) Preparation of the title compound

[0164] N-(2-Hydroxyethyl)-pyrrolidine (56.4 mg, 0.49 mmol) and triphenylphosphine (147.1 mg, 0.56 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (80.0 mg, 0.33 mmol) in ultra-dry tetrahydrofuran, and the mixture was cooled to 0°C with an ice bath. Diisopropyl azodicarboxylate (99.8 mg, 0.49 mmol) was added dropwise, and the mixture was moved to room temperature for 5 hours. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, and the eluent was ethyl acetate. The mixture was dried to obtain 33 mg of a light yellow oil with a yield of 29.4%.

[0165] 1H NMR(500MHz,Chloroform-d)δ7.68(d,J=15.6Hz,1H),7.46(d,J=15.6Hz,1H),7.29–7.22(m,1H),7.17–7.05(m,2H),6.95–6.88(m,2H),6.02(dt HRMS calcd.For C20H24N2O3(M+H) + 341.18597, found 341.18564.

[0166] Embodiment 19

[0167] (E)-1-(3-(3-(2-(piperidin-1-yl)ethoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0168]

[0169] (1) Preparation of the title compound

[0170] N-Hydroxyethylpiperidine (53.2 mg, 0.41 mmol) and triphenylphosphine (93.6 mg, 0.35 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (50.0 mg, 0.21 mmol) in ultra-dry tetrahydrofuran, cooled to 0°C, and diisopropyl azodicarboxylate (63.7 mg, 0.31 mmol) was added dropwise. The mixture was moved to room temperature and reacted for 5 h. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, with ethyl acetate as the eluent, and dried to obtain 24 mg of a light yellow oil with a yield of 32.9%.

[0171] 1H NMR(500MHz,Chloroform-d)δ7.68(d,J=15.6Hz,1H),7.46(d,J=15.6Hz,1H),7. 29–7.22(m,1H),7.18–7.13(m,1H),7.09(dd,J=2.6,1.6Hz,1H),6.96–6.87(m,2H ),6.03(dt,J=9.7,1.9Hz,1H),4.13(t,J=6.0Hz,2H),4.02(t,J=6.5Hz,2H),2.79 (t,J=6.0Hz,2H),2.55–2.51(m,4H),2.46(m,2H),1.62(m,4H),1.45(m,2H).HRMS calcd.ForC21H26N2O3(M+H) + 355.20162, found 355.20123.

[0172] Embodiment 20

[0173] tert-Butyl (3-(3-oxo-3-(6-oxo-3,6-dihydropyridin-1(2H)-yl)propen-1-yl)phenoxy)methylpiperidine-1-carboxylate

[0174]

[0175] (1) Preparation of the title compound

[0176] N-Boc-4-piperidinol (491.5 mg, 2.28 mmol) and triphenylphosphine (677.7 mg, 2.58 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (370 mg, 1.52 mmol) in ultra-dry tetrahydrofuran, cooled to 0°C, and diisopropyl azodicarboxylate (461.1 mg, 2.28 mmol) was added dropwise. The mixture was moved to room temperature and reacted for 5 h. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, with ethyl acetate as the eluent, and dried to obtain 280 mg of a transparent oily substance with a yield of 41.8%.

[0177] 1H NMR(700MHz,Chloroform-d)δ7.71(d,J=15.6Hz,1H),7.48(d,J=15.7Hz,1H),7.27(d,J= 8.9Hz,1H),7.16(d,J=7.5Hz,1H),7.09(t,J=2.0Hz,1H),6.95(m,1H),6.89(m,1H),6.05( d,1.8Hz,1H),4.16(m,2H),4.04(t,J=6.4Hz,2H),3.82(d,J=6.3Hz,2H),2.75(m,2H),2. 48(m,2H),1.96(m,1H),1.85–1.81(m,2H),1.47(d,J=1.4Hz,9H),1.28–1.26(m,2H).HRMS calcd.For C25H32N2O5(M+H) + 441.2319, found 441.2395.

[0178] Embodiment 21

[0179] (E)-1-(3-(3-(2-morpholinoethoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0180]

[0181] (1) Preparation of the title compound

[0182] 2-Morpholinoethanol (41.3 mg, 0.31 mmol) and triphenylphosphine (82.6 mg, 0.31 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (50.0 mg, 0.21 mmol) in ultra-dry tetrahydrofuran, cooled to 0°C in an ice bath, and diisopropyl azodicarboxylate (63.7 mg, 0.31 mmol) was added dropwise. The mixture was moved to room temperature and reacted for 5 h. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, with ethyl acetate as the eluent, and dried to obtain 33 mg of a transparent oily substance with a yield of 44.1%.

[0183] 1H NMR(500MHz,Chloroform-d)δ7.68(d,J=15.6Hz,1H),7.47(d,J=15.6Hz,1H),7.30–7.2 3(m,1H),7.15(dp,J=7.5,0.7Hz,1H),7.10(dd,J=2.5,1.6Hz,1H),6.96–6.87(m,2H),6. 03(dt,J=9.7,1.8Hz,1H),4.12(t,J=5.7Hz,2H),4.02(t,J=6.5Hz,2H),3.78–3.70(m,4 H),2.80(t,J=5.6Hz,2H),2.58(t,J=4.7Hz,4H),2.46(tdd,J=6.3,4.2,1.9Hz,2H).HRMS calcd.For C20H24N2O4(M+H) + 357.18088, found 357.1803.

[0184] Embodiment 22

[0185] (E)-1-(3-(3-(Morpholinylpropoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0186]

[0187] (1) Preparation of the title compound

[0188] 3-(4-Morpholine)-1-propanol (24.5 mg, 0.15 mmol) and potassium carbonate (52.0 mg, 0.42 mmol) were added to an acetonitrile solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (30.0 mg, 0.13 mmol) in sequence, and the mixture was reacted at 60°C for 5 h. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, with ethyl acetate as the eluent, and dried to obtain 12 mg of a transparent oily substance with a yield of 27.0%.

[0189] 1H NMR(500MHz,Chloroform-d)δ7.69(d,J=15.6Hz,1H),7.47(d,J=15.6Hz,1H),7.29–7.23(m,1H),7.17–7.12(m,1H),7.09(dd,J=2.5,1.6Hz, HRMS calcd.For C21H26N2O4(M+H) + 371.19653, found 371.19604.

[0190] Embodiment 23

[0191] (E)-1-(3-(3-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0192]

[0193] (1) Preparation of the title compound

[0194] 1-Hydroxyethyl-4-methylpiperazine (70.66 mg, 0.49 mmol) and triphenylphosphine (147.1 mg, 0.56 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (80.0 mg, 0.33 mmol) in ultra-dry tetrahydrofuran, cooled to 0°C with an ice bath, and diisopropyl azodicarboxylate (99.8 mg, 0.49 mmol) was added dropwise. The mixture was moved to room temperature and reacted for 5 hours. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, and the eluent was ethyl acetate. The mixture was dried to obtain 43 mg of a transparent oily substance with a yield of 35.3%.

[0195] 1H NMR(500MHz,Chloroform-d)δ7.68(d,J=15.5Hz,1H),7.46(d,J=15.6Hz,1H),7.29–7.21(m,1H),7.19–7.10(m,1H),7.11–7.07(m,1H),6.96 –6.89(m,2H),6.03(m,1.9Hz,1H),4.11(td,J=5.8,1.7Hz,2H),4.02(t,J=6.5Hz,2H),2.81(t,J=5.8Hz,2H),2.62(s,4H),2.46(m,4H).HRMS calcd.For C21H27N3O3(M+H) + 370.21252, found 370.21219.

[0196] Embodiment 24

[0197] (E)-N-(2-(3-(3-oxo-3-(6-oxo-3,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)phenoxy)ethyl)picolinamide

[0198]

[0199] (1) Preparation of the title compound

[0200] N-(2-hydroxyethyl)picolinamide (52.2 mg, 0.31 mmol) and triphenylphosphine (82.6 mg, 0.31 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (50.0 mg, 0.21 mmol) in ultra-dry tetrahydrofuran, cooled to 0°C, and diisopropyl azodicarboxylate (63.7 mg, 0.31 mmol) was added dropwise. The mixture was moved to room temperature and reacted for 5 hours. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, and the eluent was ethyl acetate. The mixture was dried to obtain 24 mg of a transparent oily substance with a yield of 29.2%.

[0201] 1H NMR(400MHz,Chloroform-d)δ8.58(d,J=4.8Hz,1H),8.22(d,J=7.8Hz,1H),7.86(td ,J=7.8,1.7Hz,1H),7.70(d,J=15.6Hz,1H),7.52–7.40(m,2H),7.33–7.24(m,1H),7. 18(d,J=7.7Hz,1H),7.14(s,1H),6.94(m,2H),6.08–6.01(m,1H),4.19(t,J=5.2Hz, 2H),4.04(t,J=6.5Hz,2H),3.91(q,J=5.5Hz,2H),2.51–2.45(m,2H).HRMScalcd.For C22H21N3O4(M+H) + 392.16048, found 392.15988.

[0202] Embodiment 25

[0203] (E)-1-(3-(3-(2-(2-oxopyrrolidin-1-yl)ethoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0204]

[0205] (1) Preparation of the title compound

[0206] N-(2-hydroxyethyl)-2-pyrrolidone (63.3 mg, 0.49 mmol) and triphenylphosphine (147.2 mg, 0.56 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridine-2(1H)one (80.0 mg, 0.33 mmol) in ultra-dry tetrahydrofuran, cooled to 0°C with an ice bath, and diisopropyl azodicarboxylate (99.8 mg, 0.49 mmol) was added dropwise. The mixture was moved to room temperature and reacted for 5 hours. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, and the eluent was ethyl acetate. The mixture was dried to obtain 44 mg of a transparent oily substance with a yield of 37.6%.

[0207] 1H NMR(400MHz,Chloroform-d)δ7.70(d,J=15.8Hz,1H),7.48(d,J=15.7Hz,1H),7.30(d ,J=8.4Hz,1H),7.18(d,J=7.7Hz,1H),7.09(s,1H),6.96–6.86(m,2H),6.05(d,J=9.7 Hz,1H),4.14(t,J=5.2Hz,2H),4.04(t,J=6.4Hz,2H),3.70(d,J=5.3Hz,2H),3.60(t, J=7.1Hz,2H),2.49(s,2H),2.41(t,J=8.1Hz,2H),2.06–2.02(m,2H).HRMScalcd.For C20H22N2O4(M+H) + 355.16523, found 355.16476.

[0208] Embodiment 26

[0209] (E)-1-(3-(3-(4-methoxypyridinyl)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0210]

[0211] (1) Preparation of the title compound

[0212] 4-Hydroxymethylpyridine (53.47 mg, 0.33 mmol) and triphenylphosphine (147.2 mg, 0.56 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (80.0 mg, 0.33 mmol) in ultra-dry tetrahydrofuran, cooled to 0°C in an ice bath, and diisopropyl azodicarboxylate (99.8 mg, 0.49 mmol) was added dropwise. The mixture was moved to room temperature and reacted for 5 h. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, with ethyl acetate as the eluent, and dried to obtain 32 mg of a white solid with a yield of 29.0% and a melting point of 122-123°C.

[0213] 1H NMR(400MHz,Chloroform-d)δ8.66(s,2H),7.70(d,J=15.7Hz,1H),7.49(m,3H),7.32(t,J=8.0Hz,1H),7.23(d,J= 7.7Hz,1H),7.17(s,1H),6.96(t,J=6.9Hz,2H),6.06(m,1H),5.17(s,2H),4.05(t,J=6.4Hz,2H),2.49(s,2H).HRMS calcd.ForC20H18N2O3(M+H) + 335.13902, found 335.13889.

[0214] Embodiment 27

[0215] (E)-1-(3-(3-(2-(pyridin-3-yl)ethoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0216]

[0217] (1) Preparation of the title compound

[0218] 2-(3-pyridyl)ethanol (30.4mg, 0.25mmol) and triphenylphosphine (71.3mg, 0.27mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (40.0mg, 0.16mmol) in ultra-dry tetrahydrofuran, cooled to 0°C in an ice bath, and diisopropyl azodicarboxylate (50.5mg, 0.25mmol) was added dropwise. The mixture was moved to room temperature and reacted for 5h. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, and the eluent was ethyl acetate. The mixture was dried to obtain 24mg of a transparent oily substance with a yield of 43.1%.

[0219] 1H NMR (400MHz, Chloroform-d) δ8.58(s,1H),8.51(s,1H),7.74-7.64(m,3H),7.49-7.45(d,J=14.8Hz,1H),7.31(d,J=8.1Hz,1H),7.17(d,J=7.7H z,1H),7.09(s,1H),6.98-6.87(m,2H),6.07-6.02(s,1H),4.22(t,J=6.4Hz,2H),4.04(t,J=6.3Hz,2H),3.13(d,J=6.6Hz,2H),2.48(s,2H).HRMS calcd.For C21H20N2O3(M+H) + 349.15467, found 349.15408.

[0220] Embodiment 28

[0221] (E)-1-(3-(3-(pyridazin-4-ylmethoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0222]

[0223] (1) Preparation of the title compound

[0224] 4-pyridazinemethanol (27.5mg, 0.25mmol) and triphenylphosphine (71.3mg, 0.27mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (40.0mg, 0.16mmol) in ultra-dry tetrahydrofuran, cooled to 0℃, and diisopropyl azodicarboxylate (50.5mg, 0.25mmol) was added dropwise. The mixture was moved to room temperature and reacted for 5h. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, with ethyl acetate as the eluent, and dried to obtain 23mg of a white solid with a yield of 42.9% and a melting point of 160-161℃.

[0225] 1H NMR(400MHz,Chloroform-d)δ9.30(s,1H),9.23(s,1H),7.74–7.60(m,2H),7.49(d,J=15.9Hz,1H),7.31(d, J=7.6Hz,2H),7.17(s,1H),6.96(s,2H),6.04(d,J=9.9Hz,1H),5.16(s,2H),4.04(m,2H),2.48(m,2H).HRMS calcd.For C19H17N3O3(M+H) + 336.13192, found 336.13952.

[0226] Embodiment 29

[0227] (E)-1-(3-(3-(Thien-3-ylmethoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0228]

[0229] (1) Preparation of the title compound

[0230] 3-Thiophene methanol (24.6 mg, 0.25 mmol) and triphenylphosphine (71.3 mg, 0.27 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (40.0 mg, 0.16 mmol) in ultra-dry tetrahydrofuran, cooled to 0°C in an ice bath, and diisopropyl azodicarboxylate (50.5 mg, 0.25 mmol) was added dropwise. The mixture was moved to room temperature and reacted for 5 h. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, with ethyl acetate as the eluent, and dried to obtain 17 mg of a transparent oily substance with a yield of 21.0%.

[0231] 1 H NMR(400MHz,Chloroform-d)δ7.71(d,J=15.6Hz,1H),7.49(d,J=15.7Hz,1H),7.34(s,2H),7.30(d,J=8.0Hz,1H),7.19(d,J=7 .5Hz,3H),7.01–6.91(m,2H),6.05(d,J=9.7Hz,1H),5.10(s,2H),4.04(t,J=6.5Hz,2H),2.48(d,J=5.7Hz,2H).HRMScalcd.For C19H17NO3S(M+H) + 340.10019, found 340.09946.

[0232] Embodiment 30

[0233] (E)-1-(3-(3-(3-fluoropyridin-4-yl)methoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0234]

[0235] (1) Preparation of the title compound

[0236] (3-Fluoropyridin-4-yl)methanol (31.8 mg, 0.25 mmol) and triphenylphosphine (71.3 mg, 0.27 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (40.0 mg, 0.16 mmol) in ultra-dry tetrahydrofuran, cooled to 0°C with an ice bath, and diisopropyl azodicarboxylate (50.5 mg, 0.25 mmol) was added dropwise. The mixture was moved to room temperature and reacted for 5 hours. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, with ethyl acetate as the eluent, and dried to obtain 23 mg of a white solid with a yield of 40.8% and a melting point of 92-93°C.

[0237] 1 H NMR(400MHz,Chloroform-d)δ8.51–8.44(m,2H),7.70(d,J=15.7Hz,1H),7.55(s,1H),7.49(dd,J=15.6,2.5Hz,1H),7.36–7.20( m,2H),7.19(s,1H),6.96(t,J=9.4Hz,2H),6.05(d,J=9.8Hz,1H),5.21(s,2H),4.05(t,J=6.5Hz,2H),2.49(d,J=6.0Hz,2H).HRMS calcd.For C20H17FN2O3(M+H) + 353.12963, found 353.12903.

[0238] Embodiment 31

[0239] (E)-1-(3-(3-((2-fluoropyridin-4-yl)methoxy)phenyl)acryloyl)-5,6-dihydropyridin-2(1H)one

[0240]

[0241] (1) Preparation of the title compound

[0242] 2-Fluoro-4-pyridinemethanol (31.8 mg, 0.25 mmol) and triphenylphosphine (71.3 mg, 0.27 mmol) were added to a solution of 1-(3-hydroxyphenyl)acryloyl-5,6-dihydropyridin-2(1H)one (40.0 mg, 0.16 mmol) in ultra-dry tetrahydrofuran, cooled to 0°C with an ice bath, and diisopropyl azodicarboxylate (50.5 mg, 0.25 mmol) was added dropwise. The mixture was moved to room temperature and reacted for 5 h. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with 5 ml of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The mixture was concentrated and separated by column chromatography, with ethyl acetate as the eluent, and dried to obtain 25 mg of a white solid with a yield of 44.3% and a melting point of 150-151°C.

[0243] 1 H NMR(400MHz,Chloroform-d)δ8.26(s,1H),7.73(d,J=15.5,1H),7.52(d,J=15.6,1H),7.38–7.25(m,3H),7.19 (s,1H),7.08(s,1H),6.99(d,J=8.7Hz,2H),6.08(d,J=9.8Hz,1H),5.17(s,2H),4.08(m,2H),2.51(m,2H).HRMS calcd.For C20H17FN2O3(M+H) + 353.12963, found 353.12878.

[0244] Pharmacological experiments

[0245] Experimental Example 1: Verification of the inhibitory effect of compounds on the activity of intramembrane serine protease RHBDD1

[0246] Experimental purpose: To evaluate the inhibitory effect of the compounds of the present invention on the activity of intramembrane serine protease RHBDD1 in vitro.

[0247] Experimental method: A small molecule inhibition screening model targeting RHBDD1 was used (simulating the process of RHBDD1 hydrolyzing substrates in vivo). In vitro, the liposome simulating the cell membrane was used as the hydrolysis reaction carrier, and the transmembrane substrate Keren (with the fluorescent group FTIC) was used as the substrate. The fluorescence of the Keren fluorescent group was quenched in the liposome. When RHBDD1 performs the hydrolysis function to cut the substrate, the fluorescent group is released and the measured fluorescence value increases; when the compound is added to inhibit the RHBDD1 enzyme activity, the cutting of the fluorescent substrate Keren is inhibited and the fluorescence value decreases. Within a certain range, the fluorescence value is proportional to the RHBDD1 enzyme activity. Therefore, the inhibition of the compound on the RHBDD1 enzyme activity can be judged based on the change in the fluorescence value.

[0248] The reaction was carried out in a 384-well plate in 50 μL of the following system, incubated at 37°C in the dark for 4 h, and the fluorescence value (relative fluorescence unit, RFU) at 485 / 528 nm was measured using a Synergy H1 all-in-one microplate reader. The formula for calculating the inhibition rate is: Inhibition rate (%) = [1-(RFU 实验组 -RFU 体系 ) / (RFU 阴性对照 -RFU 体系 )] × 100%. GraphPad Prism was used to draw graphs, and cvxpt32 software was used to calculate IC 50 .

[0249] Table 1 Small molecule inhibitor screening model system for RHBDD1 target

[0250]

[0251] Experimental results: As shown in Table 2, the compounds of the present invention have a strong inhibitory effect on the activity of intramembrane serine protease RHBDD1. 50 The value is less than 1 μM, indicating that the compound of the present invention has a strong inhibitory effect on RHBDD1 enzyme activity.

[0252] Table 2 Inhibitory effect of the compounds of the present invention on RHBDD1 enzyme activity

[0253]

[0254]

[0255] Experimental Example 2: Verify the inhibitory effect of the compound on the proliferation of HCT116 and RKO cells.

[0256] Experimental purpose: This experiment uses the CCK-8 method to detect the inhibitory effect of compounds on HCT116 and RKO cell proliferation.

[0257] Experimental method: Cells in the logarithmic growth phase were cultured at 5x10 3 Cells / well were inoculated into 96-well plates, and 200ul PBS was added to the edge wells to prevent the volatilization of the culture medium. 12h after the cells were inoculated, 100ul of culture medium containing gradient concentrations of compounds was added, DMSO was used as a blank control, and 3 replicate wells were set for each concentration of compound. After 48h, the culture medium was discarded, and 100ul of culture medium containing 10% CCK-8 solution was added to each well. After incubation in a cell culture incubator for 1.5h in the dark, the OD value of absorbance at 450 / 630nm was measured by a microplate reader. According to the inhibition rate (%) = [1-(OD 给药 -OD 空 ) / (OD 对照 -OD空 )]×100% to calculate the inhibition rate, draw graphs with GraphPadPrism, and calculate IC50 with cvxpt32 software.

[0258] Experimental results: As shown in Table 3, the compounds of the present invention have a high inhibitory effect on the proliferation of HCT116 and RKO cells and are concentration-dependent. As shown in Table 3, the IC 50 The value is between 1-10 μM.

[0259] Table 3 Proliferation inhibition activity of the compounds of the present invention on HCT116 and RKO cells

[0260]

[0261]

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound structure is:

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The pharmaceutically acceptable salt is selected from an organic acid salt or an inorganic acid salt, and the organic acid salt or the inorganic acid salt is a hydrochloride, a hydrobromide, a sulfate, a phosphate, an acetate, a citrate, a malate, a fumarate, a tartrate or a methanesulfonate.

3. A method for preparing the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that: Here are the steps: Route (1): Reagents and conditions: (a) oxalyl chloride, N,N-dimethylformamide, dichloromethane, 0°C; (b) R1H, sodium hydride, tetrahydrofuran, 0°C, where R1 is When R2, R3, and R4 are methoxy groups; When R1 is When R2, R3, and R4 are selected from the following combinations: 1) R2 and R3 are R4 is hydrogen, 2) R2 is methoxy, R3 is 2-methoxyethoxy or oxacyclohexane-4-ylmethoxy, R4 is hydrogen, or, 3) R3 and R4 are hydrogen, R2 is ethoxy, n-propoxy, isopropoxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclohexylmethoxy, 2-methoxyethoxy, 3-methoxyethoxy, oxetane-3-ylmethoxy, oxolan-3-ylmethoxy, oxan-4-ylmethoxy, oxan-4-ylethoxy, N,N-diethylaminoethoxy, pyrrolidin-1-yl-ethoxy, piperidin-1-yl-ethoxy , 1-Boc-piperidin-4-methoxy, 2-morpholinylethoxy, 3-morpholinylethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 2-(pyridinamido)ethoxy, 2-(2-oxopyrrolidin-1-yl)ethoxy, pyridin-4-ylmethoxy, pyridin-3-ylethoxy, pyridazin-4-ylmethoxy, thien-3-ylmethoxy, 3-fluoro-pyridin-4-ylmethoxy, or 2-fluoro-pyridin-4-ylmethoxy; Route (2): Reagents and conditions: (a) 2-iodopropane, potassium hydroxide, acetonitrile: water = 1:1, 90°C; (b) oxalyl chloride, N,N-dimethylformamide, dichloromethane, 0°C; 5,6-dihydro-2(1H)-pyridone, sodium hydride, tetrahydrofuran, 0°C; (c) anhydrous aluminum chloride, dichloromethane, 0°C; (d) R2H, diisopropyl azodicarboxylate, triphenylphosphine, tetrahydrofuran, 0°C to room temperature; wherein R2 is selected from ethoxy, n-propoxy, isopropoxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclohexylmethoxy, 2-methoxyethoxy, 3-methoxyethoxy, oxetane-3-ylmethoxy, oxolan-3-ylmethoxy, oxahene-4-ylmethoxy, oxahene-4-ylethoxy, N,N-diethylaminoethoxy, pyrrolidin-1-yl-ethoxy, piperidin-1-yl-ethoxy, 1 -Boc-piperidin-4-methoxy, 2-morpholinylethoxy, 3-morpholinylethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 2-(pyridinamido)ethoxy, 2-(2-oxopyrrolidin-1-yl)ethoxy, pyridin-4-ylmethoxy, pyridin-3-ylethoxy, pyridazin-4-ylmethoxy, thien-3-ylmethoxy, 3-fluoro-pyridin-4-ylmethoxy, 2-fluoro-pyridin-4-ylmethoxy.

4. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

5. Use of the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease related to the function of RHBDD1.

6. Use of the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a tumor, wherein the tumor is related to the function of RHBDD1.

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