Coumarin-3-carboxamide derivatives, preparation methods thereof, and applications thereof in the preparation of antitumor drugs

Abstract

The present invention discloses coumarin-3-carboxamide derivatives, their preparation methods, and their use in the preparation of anti-tumor drugs. The coumarin-3-carboxamide derivatives or pharmaceutically acceptable salts thereof have the structural formula shown in Formula (I): wherein R1 is hydrogen, an alkoxy group, or an amine group; R2 is hydrogen or a halogen atom; and m and n are 0 to 5. This invention is based on the development potential and value of coumarin derivatives in tumor treatment. The inventors of the present invention have studied coumarin-based anti-tumor drugs and discovered a series of coumarin derivatives with outstanding anti-tumor activity that can be used to treat breast cancer, oral cancer, or cervical cancer. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and in particular relates to a coumarin-3-carboxamide derivative, a preparation method thereof, and an application thereof in the preparation of anti-tumor drugs. Background Art

[0002] Although the research and development of anti-tumor drugs has made new progress and new anti-tumor drugs are constantly emerging, existing anti-tumor drugs still have difficult problems to overcome, such as weak tumor selectivity, severe toxic side effects, and easy drug resistance. Therefore, the research and development of new anti-tumor drugs remains one of the important contents of new drug research and development.

[0003] Coumarins are a class of 1,2-benzopyrone compounds widely distributed in nature. They possess a wide range of biological activities, including anti-inflammatory, antibacterial, antioxidant, antithrombotic, and anti-tumor properties. In terms of anti-tumor activity, various natural and synthetic coumarin derivatives have demonstrated outstanding effects. Summary of the Invention

[0004] The object of the present invention is to provide a coumarin-3-carboxamide derivative with clear activity, low toxicity and good anti-tumor effect.

[0005] The first object of the present invention is to provide a coumarin-3-carboxamide derivative or a pharmaceutically acceptable salt thereof, the structural formula of which is shown in formula (I):

[0006]

[0007] Wherein R1 is hydrogen, alkoxy or amino; R2 is hydrogen or halogen atom; m and n are 0 to 5.

[0008] Preferably, the alkoxy group is ethoxy or benzyloxy; and the amine group is diethylamine.

[0009] Preferably, the halogen atom is a bromine atom.

[0010] Preferably, m is 0-2, and n is 0-3.

[0011] Preferably, the coumarin-3-carboxamide derivative is:

[0012]

[0013] More preferably, the coumarin-3-carboxamide derivatives are 9b-e, 9k-l, 9n-o, 10d-e, 10g, 10i-j and 10n.

[0014] The second object of the present invention is to provide a method for preparing the coumarin-3-carboxamide derivative, wherein the coumarin-3-carboxamide derivative is prepared by condensing an amine derivative as shown in formula (II) and a carboxylic acid derivative as shown in formula (III);

[0015]

[0016] The third object of the present invention is to provide the use of the coumarin-3-carboxamide derivative or its pharmaceutically acceptable salt in the preparation of anti-tumor drugs.

[0017] The fourth object of the present invention is to provide an antitumor drug comprising an effective amount of the above-mentioned coumarin-3-carboxamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0018] The anti-tumor agent is anti-breast cancer, oral cancer or cervical cancer.

[0019] The present invention is based on the development potential and value of coumarin derivatives in tumor treatment. The inventors of the present invention have studied coumarin anti-tumor drugs and discovered a series of coumarin derivatives with outstanding anti-tumor activity, which can be used to treat breast cancer, oral cancer or cervical cancer. DETAILED DESCRIPTION

[0020] The following examples are provided to further illustrate the present invention, but are not intended to limit the present invention.

[0021] The preparation method of coumarin-3-carboxamide derivatives is as follows:

[0022] The synthetic routes and methods are shown in Synthetic Formulas 1-5. Using various substituted salicylaldehydes 1 and diethyl malonate as starting materials, anhydrous ethanol as solvent, and piperidine as the catalyzer, a Knoevenagel condensation reaction occurs to produce intermediate 2. Alternatively, intermediate 2a is reacted with various bromides in the presence of potassium carbonate in anhydrous N,N-dimethylformamide (DMF) to produce the corresponding alkylated intermediates 2d-e. In anhydrous dichloromethane (DCM) as solvent, under nitrogen protection, various alkylenediamines 3 are reacted with di-tert-butyl dicarbonate at 0°C, followed by room temperature, to produce the corresponding Boc-protected intermediate 4. Compounds 2b-e are refluxed with 4a-d, respectively, in anhydrous ethanol under nitrogen protection to produce intermediate 5. Intermediate 5 is then de-Boc-protected by trifluoroacetic acid (TFA) in anhydrous DCM at room temperature to produce intermediate 6. At the same time, lenalidomide was reacted with different cyclic dianhydrides 7 in anhydrous DMF as solvent under microwave conditions at 60°C to obtain intermediate 8. Finally, in anhydrous DMF as solvent at room temperature, intermediate 8 was condensed with intermediate 6 in the presence of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIPEA) to obtain coumarin derivatives 9 and 10.

[0023]

[0024] Synthetic route of intermediates 2a-e of formula 1

[0025]

[0026] Synthetic route of intermediates 4a-d of formula 2

[0027]

[0028] Synthetic route of intermediates 5a-n and 6a-n of formula 3

[0029]

[0030] Synthetic route of intermediate 8a-c of formula 4

[0031]

[0032] Synthesis route examples of intermediates 9a-o, 10a-n of formula 5:

[0033] The technical solution of the present invention is further illustrated below through specific examples.

[0034] (1) Synthesis of Compound 2:

[0035]

[0036] Differently substituted salicylaldehydes 1 (1.0 eq., 5.0 mmol) and diethyl malonate (2.0 eq., 10.0 mmol) were dissolved in anhydrous ethanol (10 mL) and mixed thoroughly. A catalytic amount of piperidine (1.0 mL) was then slowly added dropwise. The reaction mixture was stirred at room temperature for 2 h, and the reaction progress was monitored by thin-layer chromatography (TLC). After completion of the reaction, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to afford compounds 2a-c.

[0037] 2a: 1 H NMR (400MHz, CDCl3) δ8.68 (s, 1H), 7.55 (d, J = 9.3Hz, 1H), 6.89 (d, J = 2.1Hz, 1H), 6.78 (dd, J = 9.3, 2.0Hz, 1H), 4.28 (q, J = 7.1Hz, 2H), 1.30 (t, J = 7.1Hz, 3H).

[0038] 2b: 1 H NMR (400MHz, CDCl3) δ8.68 (s, 1H), 7.59 (d, J = 8.3Hz, 1H), 6.66 (dd, J = 8.4, 2.2Hz, 1H), 6.54 (d, J = 2. 2Hz, 1H), 4.28 (q, J = 7.1Hz, 2H), 3.52 ( q, J = 7.0Hz, 4H), 1.30 ( t, J = 7.1Hz, 3H), 1.16 ( t, J = 7.0Hz, 6H).

[0039] 2c: 1 H NMR (400MHz, CDCl3) δ8.50 (s, 1H), 7.49 (d, J = 8.7Hz, 1H), 6.87 (dd, J = 8.7, 2.4Hz, 1H), 6.79 (d, J = 2. 3Hz, 1H), 4.39 (q, J = 7.1Hz, 2H), 4.12 ( q, J = 7.0Hz, 2H), 1.47 ( t, J = 7.0Hz, 3H), 1.40 ( t, J = 7.1Hz, 3H).

[0040] Under nitrogen, compound 2a (1.0 eq., 1.0 mmol) and KCO (1.2 eq., 1.2 mmol) were added sequentially to anhydrous DMF (5 mL). After stirring for several minutes, ethyl bromide or benzyl bromide (1.4 eq., 1.4 mmol) were added dropwise under nitrogen. The mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the mixture was diluted with a large amount of distilled water, resulting in the precipitation of a large amount of solid. The solid was filtered, washed with distilled water (10.0 mL), and dried to yield compounds 2d-e.

[0041] 2d: 1 H NMR (400MHz, CDCl3) δ8.50 (s, 1H), 7.49 (d, J = 8.7Hz, 1H), 6.87 (dd, J = 8.7, 2.4Hz, 1H), 6.79 (d, J = 2. 3Hz, 1H), 4.39 (q, J = 7.1Hz, 2H), 4.12 ( q, J = 7.0Hz, 2H), 1.47 ( t, J = 7.0Hz, 3H), 1.40 ( t, J = 7.1Hz, 3H).

[0042] 2e: 1 H NMR (400MHz, CDCl3) δ8.68(s,1H),7.60(d,J=8.7Hz,1H),7.42(dq,J=6.9,1.0Hz,2H),7.39–7.32(m,2H),7.32–7.25(m,1H ), 6.90 (dd, J = 8.8, 2.4Hz, 1H), 6.86 (d, J = 2.4Hz, 1H), 5.07 (t, J = 1.0Hz, 2H), 4.28 (q, J = 7.1Hz, 2H), 1.30 (t, J = 7.1Hz, 3H).

[0043] (2) Synthesis of compound 4:

[0044]

[0045] Under nitrogen, various alkylenediamines 3 (10.0 eq., 20.0 mmol) were added to anhydrous DCM (15.0 mL). A solution of di-tert-butyl dicarbonate (1.0 eq., 2.0 mmol, 0.46 mL) in DCM (10.0 mL) was slowly added dropwise at 0°C for 2 h. The reaction was then transferred to room temperature and allowed to continue for 24 h. After completion, the organic layer was washed with saturated sodium chloride solution (25.0 mL x 3) and then with distilled water (25.0 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to yield compounds 4a-d.

[0046] 4a: 1H NMR (400MHz, CDCl3) δ4.90 (s, 1H), 3.26–3.11 (m, 2H), 2.78 (t, J = 5.9Hz, 2H), 1.43 (s, 9H).

[0047] 4b: 1 H NMR (400MHz, CDCl3) δ4.98 (s, 1H), 3.18 (q, J = 6.2Hz, 2H), 2.74 (t, J = 6.6Hz, 2H), 1.85 (s, 2H), 1.63–1.56 (m, 2H), 1.41 (s, 9H).

[0048] 4c: 1 H NMR (400MHz, CDCl3) δ4.70 (s, 1H), 3.11 (d, J = 5.9Hz, 2H), 2.69 (td, J = 6.6, 3.0Hz, 2H), 1.53–1.45 (m, 6H), 1.41 (d, J = 2.8Hz, 9H).

[0049] 4d: 1 H NMR (400MHz, CDCl3) δ4.62 (s, 1H), 3.12–3.04 (m, 2H), 2.69–2.62 (m, 2H), 1.50–1.38 (m, 16H), 1.32 (q, J = 8.2, 6.9Hz, 2H).

[0050] (3) Synthesis of compound 5:

[0051]

[0052] Under nitrogen, compound 2b-e (1.0 eq., 1.0 mmol) and intermediate 4 (1.2 eq., 1.2 mmol) were dissolved in anhydrous ethanol (10.0 mL) and reacted at reflux for 9 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain intermediate 5.

[0053] 5a: 1 H NMR (400MHz, CDCl3) δ8.96(s,1H),8.69(s,1H),7.42(d,J=8.9Hz,1H),6.64(dd,J=9.2,1.9Hz,1H),6.49(s,1H),5. 07(s,1H),3.55(q,J=5.6Hz,2H),3.45(q,J=7.1Hz,4H),3.35(d,J=5.2Hz,2H),1.43(s,9H),1.24(t,J=7.1Hz,6H).

[0054] 5b: 1 H NMR(400MHz,CDCl3)δ8.86(t,J=5.4Hz,1H),8.69(s,1H),7.42(d,J=8.9Hz,1H),6.64(dd,J=9.0,2.4Hz,1H),6.49(d,J=2.3Hz,1H),5.25(s,1H),3.47(dq,J=14.2,6.8Hz,6H),3.18(q,J=6.1Hz,2H),1.76(q,J=6.5Hz,2H),1.44(s,9H),1.23(t,J=7.1Hz,6H).

[0055] 5c: 1 H NMR(400MHz,CDCl3)δ8.81(t,J=5.5Hz,1H),8.69(s,1H),7.42(d,J=9.0Hz,1H),6.64(dd,J=9.0,2.3Hz,1H),6.49(d,J=2.1Hz,1H),4.60(s,1H),3.44(t,J=7.1Hz,6H),3.16(d,J=6.0Hz,2H),1.66–1.54(m,4H),1.43(s,9H),1.24(d,J=7.1Hz,6H).

[0056] 5d: 1 H NMR(400MHz,CDCl3)δ8.80(t,J=5.3Hz,1H),8.69(s,1H),7.42(d,J=8.9Hz,1H),6.64(dd,J=9.0,2.4Hz,1H),6.49(d,J=2.3Hz,1H),4.58(s,1H),3.44(p,J=6.9Hz,6H),3.12(q,J=5.9Hz,2H),1.66–1.59(m,2H),1.55–1.49(m,2H),1.43(s,12H),1.23(t,J=7.1Hz,6H).

[0057] 5e: 1 H NMR(400MHz,CDCl3)δ10.94(s,1H),9.84(d,J=0.7Hz,1H),7.68(d,J=2.4Hz,1H),7.60(dd,J=8.9,2.5Hz,1H),6.91(d,J=8.9Hz,1H),1.31–1.24(m,6H).

[0058] 5f: 1H NMR(400 MHz,CDCl3)δ8.81(s,1H),7.81(d,J=2.0 Hz,1H),7.74(dd,J=8.8,2.2Hz,1H),7.29(d,J=8.8 Hz,1H),5.04(s,1H),3.52(q,J=6.5 Hz,2H),3.24–3.10(m,2H),1.78(p,J=6.4 Hz,3H),1.44(s,9H).

[0059] 5g: 1 H NMR(400 MHz,CDCl3)δ8.80(s,1H),7.80(d,J=2.0 Hz,1H),7.72(dd,J=8.8,2.1Hz,1H),7.28(s,1H),4.64–4.48(m,1H),3.47(dq,J=13.0,6.6 Hz,2H),3.21–3.03(m,2H),1.63(q,J=7.4 Hz,2H),1.55(q,J=7.8,7.2 Hz,2H),1.41(s,9H).

[0060] 5h: 1 H NMR(400 MHz,CDCl3)δ8.82(s,1H),7.57(d,J=8.7 Hz,1H),6.92(dd,J=8.7,2.4Hz,1H),6.84(d,J=2.3 Hz,1H),5.01(s,1H),4.13(q,J=7.0 Hz,2H),3.57(q,J=5.9 Hz,2H),3.36(q,J=5.8 Hz,2H),1.47(t,J=7.0 Hz,3H),1.43(s,9H).

[0061] 5i: 1 H NMR(400 MHz,CDCl3)δ8.82(s,1H),7.56(d,J=8.7 Hz,1H),6.92(dd,J=8.7,2.3Hz,1H),6.84(d,J=2.0 Hz,1H),4.20(q,J=7.1 Hz,1H),4.13(q,J=6.9 Hz,2H),3.51(q,J=6.4Hz,2H),3.20–3.15(m,3H),1.77(t,J=6.5 Hz,2H),1.29–1.26(m,3H).

[0062] 5j: 1H NMR(400 MHz,CDCl3)δ8.81(s,1H),7.56(d,J=8.7 Hz,1H),6.91(dd,J=8.7,2.1Hz,1H),6.83(d,J=1.8 Hz,1H),4.62(s,1H),4.12(q,J=7.0 Hz,2H),3.45(q,J=6.6 Hz,2H),3.15(dt,J=10.7,5.7 Hz,2H),1.60–1.50(m,4H),1.42(s,9H),1.30–1.25(m,3H).

[0063] 5k: 1 H NMR(400 MHz,CDCl3)δ8.92(s,1H),8.82(s,1H),7.58(d,J=8.7 Hz,1H),7.43–7.35(m,5H),7.01(dd,J=8.7,2.4 Hz,1H),6.92(d,J=2.3 Hz,1H),5.16(s,2H),5.00(s,1H),3.57(q,J=5.9 Hz,2H),3.41–3.32(m,2H),1.68(s,2H),1.44(s,9H).

[0064] 5l: 1 H NMR(400MHz,CDCl3)δ8.83(s,2H),7.58(d,J=7.6Hz,1H),7.45–7.34(m,5H),7.05–6.98(m,1H),6.93(s,1H),5.17(s,2H),5.13(s,1H),3.52(q,J=6.1Hz,2H),3.23–3.12(m,2H),1.77(p,J=6.1Hz,2H),1.45(s,9H).

[0065] 5m: 1 H NMR(400MHz,CDCl3)δ8.82(s,1H),8.77(t,J=5.6Hz,1H),7.58(d,J=8.7Hz,1H),7.45–7.34(m,5H),7.00(dd,J=8.7,2.4Hz,1H),6.92(d,J=2.3Hz,1H),5.16(s,2H),4.60(s,1H),3.46(q,J=6.7Hz,2H),3.20–3.11(m,2H),1.73(s,1H),1.68–1.54(m,4H),1.43(s,9H).

[0066] 5n: 1H NMR (400MHz, CDCl3) δ8.83(s,1H),8.76(t,J=5.1Hz,1H),7.58(d,J=8.7Hz,1H),7.47–7.32(m,5H),7.04–6.97(m,1H),6.92(d ,J=1.6Hz,1H),5.16(s,2H),3.44(q,J=6.8Hz,2H),3.12(q,J=6.7Hz,2H),1.67–1.60(m,5H),1.56–1.50(m,2H),1.43(s,11H).

[0067] (4) Synthesis of Compound 6:

[0068]

[0069] Intermediates 5a-n (1.0 eq., 0.5 mmol) were added to anhydrous DCM and stirred thoroughly to dissolve. Excess trifluoroacetic acid (3 mL) was slowly added dropwise to the system and allowed to react at room temperature for 2 h. After completion of the reaction, DCM (20.0 mL) was added for dilution. The pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate. The organic layer was separated and extracted with DCM (25.0 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield compound 6.

[0070] 6a: 1 H NMR (400MHz, DMSO-d6) δ8.84(t,J=6.0Hz,1H),8.67(s,1H),7.83(s,2H),7.70(d,J=9.0Hz,1H),6.81(dd,J=9.0,2.4Hz ,1H),6.62(d,J=2.2Hz,1H),3.54(q,J=6.1Hz,2H),3.47(t,J=7.0Hz,4H),2.98(q,J=5.7Hz,2H),1.14(t,J=7.0Hz,6H).

[0071] 6b: 1 H NMR (400MHz, DMSO-d6) δ8.75(t,J=6.0Hz,1H),8.65(s,1H),7.69(d,J=9.1Hz,1H),6.81(dd,J=9.0,2.4Hz,1H),6.62(d,J= 2.2Hz,1H),3.51–3.46(m,4H),3.37(q,J=6.5Hz,3H),2.78(t,J=7.3Hz,2H),1.77(p,J=6.8Hz,2H),1.14(t,J=7.0Hz,6H).

[0072] 6c: 1 H NMR(400MHz,DMSO-d6)δ8.69(q,J=6.0,4.5Hz,1H),8.66(d,J=2.8Hz,1H),7.78(s,2H),7.69(dd,J=9.0,2.9Hz,1H),6.81(dd,J=9.0,2.1Hz,1H),6.62(s,1H),3.48(q,J=6.7Hz,4H),3.32(d,J=5.5Hz,2H),2.81(s,2H),1.56(s,4H),1.16–1.10(m,6H).

[0073] 6d: 1 H NMR(400MHz,DMSO-d6)δ8.65(s,2H),7.76(s,2H),7.68(d,J=9.0Hz,1H),6.80(dd,J=9.0,2.4Hz,1H),6.61(d,J=2.2Hz,1H),3.48(q,J=7.0Hz,4H),3.32–3.27(m,2H),2.82–2.76(m,2H),1.54(dq,J=14.4,7.5Hz,4H),1.34(p,J=7.4,6.8Hz,2H),1.14(t,J=7.0Hz,6H).

[0074] 6e: 1 H NMR(400MHz,DMSO-d6)δ8.86(s,1H),8.29(d,J=2.0Hz,1H),7.91(s,1H),7.50(d,J=8.9Hz,1H),3.57(q,J=5.7Hz,2H),3.01(t,J=6.0Hz,2H).

[0075] 6f: 1 H NMR(400MHz,DMSO-d6)δ8.81(s,1H),8.27(d,J=2.2Hz,1H),7.90(dd,J=8.8,2.3Hz,1H),7.49(d,J=8.9Hz,1H),3.39(q,J=6.3Hz,2H),2.90–2.72(m,2H),1.81(p,J=7.0Hz,2H),1.30(s,2H).

[0076] 6g: 1H NMR(400 MHz,DMSO-d6)δ8.55(s,1H),8.27–8.23(m,1H),7.88(dd,J=8.8,2.4Hz,1H),7.66(d,J=11.9 Hz,1H),3.68–3.59(m,2H),1.75–1.64(m,2H),1.60(q,J=7.7,7.0Hz,2H),1.23(s,2H).

[0077] 6h: 1 H NMR(400 MHz,DMSO-d6)δ8.86(s,1H),7.92(d,J=8.8 Hz,1H),7.11(d,J=2.0Hz,1H),7.04(dd,J=8.7,2.3 Hz,1H),4.19(q,J=6.9 Hz,2H),3.56(q,J=6.0 Hz,2H),3.00(t,J=6.0 Hz,2H),1.37(t,J=7.0 Hz,3H).

[0078] 6i: 1 H NMR(400 MHz,DMSO-d6)δ8.82(s,1H),7.91(d,J=8.6 Hz,1H),7.10(s,1H),7.07–6.99(m,1H),4.18(q,J=6.9 Hz,2H),3.39(d,J=5.9 Hz,2H),2.83(q,J=6.0 Hz,2H),1.81(p,J=6.8 Hz,2H),1.37(t,J=7.0 Hz,3H),1.30–1.22(m,2H).

[0079] 6j: 1 H NMR(400 MHz,DMSO-d6)δ8.82(s,1H),8.68(t,J=5.8 Hz,1H),7.90(d,J=8.8 Hz,1H),7.09(d,J=2.1 Hz,1H),7.03(dd,J=8.7,2.3 Hz,1H),4.17(q,J=6.9 Hz,2H),3.34(d,J=5.7 Hz,2H),2.82(d,J=4.1 Hz,2H),1.58(s,4H),1.36(t,J=6.9 Hz,3H).

[0080] 6k: 11H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 8.2 Hz, 2H), 7.93 (d, J = 8.7 Hz, 1H), 7.50–7.34 (m, 5H), 7.21 (d, J = 2.3 Hz, 1H), 7.13 (dd, J = 8.7, 2.4 Hz, 1H), 5.27 (s, 2H), 3.48 (q, J = 6.1 Hz, 2H), 2.89 (t, J = 6.2 Hz, 2H), 1.84 (s, 2H).

[0081] 6l: 1 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.76 (t, J = 6.0 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.50–7.33 (m, 6H), 7.21 (d, J = 2.3 Hz, 1H), 7.12 (dd, J = 8.7, 2.3 Hz, 1H), 5.27 (s, 2H), 2.79 (t, J = 7.4 Hz, 2H), 1.81 (p, J = 6.8 Hz, 2H).

[0082] 6m: 1 1H NMR (400MHz, DMSO-d6) δ 8.83 (s, 1H), 8.70 (t, J = 5.8Hz, 1H), 7.93 (d, J = 8.8Hz, 1H), 7.75 (s, 2H), 7.50–7.34 (m, 5H), 7.21 (s, 1H), 7.15–7.10 (m, 1H), 5.27 (s, 2H), 3.34 (d, J = 6.3Hz, 2H), 2.82 (s, 2H), 1.57 (s, 4H).

[0083] 6n: 1 1H NMR (400MHz, DMSO-d6) δ 8.82 (s, 1H), 8.65 (t, J = 5.6Hz, 1H), 7.96–7.70 (m, 3H), 7.51–7.34 (m, 5H), 7.20 (s, 1H), 7.12 (dd, J = 8.7, 2.0Hz, 1H), 5.26 (s, 2H), 3.30 (d, J = 6.7Hz, 2H), 2.77 (t, J = 7.5Hz, 2H), 1.56 (dp, J = 14.2, 7.3Hz, 4H), 1.36 (dd, J = 14.4, 7.3Hz, 2H).

[0084] (5) Synthesis of compound 8:

[0085]

[0086] Lenalidomide (1.0 eq., 1.0 mmol, 259.3 mg) and different cyclic dianhydrides 7 (1.5 eq., 1.5 mmol) were dissolved in anhydrous DMF (8.0 mL) and reacted at 60°C under 500 W microwave conditions for 48 h. After completion of the reaction, the solvent was partially recovered under reduced pressure, and methanol (10.0 mL) was added to precipitate a large amount of solid, which was filtered to obtain compound 8.

[0087] 8a: 1 H NMR (400MHz, DMSO-d6) δ12.17(s,1H),11.03(s,1H),9.86(s,1H),7.81(dd,J=6.8,2.1Hz,1H),7.49(d,J=7.3Hz,2H),5.15(dd,J=13.3,5.1Hz,1H), 4.41–4.28(m,2H),2.97–2.88(m,1H),2.62(dd,J=10.3,3.6Hz,3H),2.56 –2.52(m,2H),2.31(td,J=13.2,4.4Hz,1H),2.03(dq,J=10.1,2.9Hz,1H).

[0088] 8b: 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.87(s,1H),7.82(dd,J=6.9,1.5Hz,1H),7.49(d,J=6.9Hz,2H),5.14(dd,J=13.3,5.1Hz,1H),4.43–4.31(m,2H ),2.96–2.87(m,1H),2.64–2.57(m,1H),2.40(t,J=7.5Hz,2H),2.25(t,J=7 .2Hz,2H),2.02(dd,J=9.8,4.2Hz,1H),1.88(s,1H),1.81(q,J=7.3Hz,2H).

[0089] 8c: 1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),9.83(s,1H),7.81(dd,J=7.0,1.7Hz,1H), 7.53–7.46(m,2H),5.14(dd,J=13.3,5.1Hz,1H),4.42–4.30(m,2H),2.92(ddd,J =18.3,13.7,5.4Hz,1H),2.64–2.57(m,1H),2.35(h,J=9.1,8.3Hz,3H),2.23(t, J=7.0Hz,2H),2.02(dq,J=10.1,2.9Hz,1H),1.58(ddt,J=27.9,13.8,7.0Hz,4H).

[0090] (5) Synthesis of compounds 9 and 10:

[0091]

[0092] Compounds 6a-n (1.1 eq., 0.11 mmol), 8a-c (1.0 eq., 0.1 mmol), HATU (1.0 eq., 0.1 mmol, 38.0 mg), and DIPEA (5.0 eq., 0.5 mmol, 0.08 mL) were dissolved in anhydrous DMF (2.0 mL) and reacted at room temperature for 4 h. After completion, the reaction was quenched with distilled water (1.0 mL). The solvent was partially recovered under reduced pressure, and saturated brine (10.0 mL) was added. The mixture was then extracted with ethyl acetate (10.0 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1) to afford compounds 9 and 10.

[0093] 9a: 1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),9.87(s,1H),8.72(t,J=5.8Hz,1H),8.65(s,1H),8.64–8.61(m,1H),8.42(d,J=8.2Hz,1H),8.05(t,J=5.5Hz,1H),7.82(dd,J=6.8,2.0Hz,1H),7.67(d,J=9.1Hz,1H),7.47(d,J=7.4Hz,2H),7.44–7.38(m,1H),6.80(dd,J=9.1,2.4Hz,1H),6.60(d,J=2.2Hz,1H),5.14(dd,J=13.2,5.2Hz,1H),4.42–4.29(m,2H),3.48(q,J=6.8Hz,4H),3.24–3.19(m,2H),2.96–2.87(m,1H),2.63–2.58(m,3H),2.43(t,J=7.3Hz,2H),2.33(tt,J=13.0,6.3Hz,1H),2.03(ddd,J=9.4,5.2,2.6Hz,1H),1.14(t,J=7.0Hz,6H),0.89–0.79(m,1H). 13 C NMR(100MHz,DMSO-d6)δ173.00,171.56,171.18,170.76,167.93,162.59,157.30,152.49,147.80,132.68,131.68,128.55,120.36,110.19,107.67,95.88,51.57,44.40(2C),31.29,30.46,12.38(2C).

[0094] 9b: 1H NMR(400MHz,DMSO-d6)δ8.72(t,J=5.8Hz,1H),8.64(s,1H),7.99(t,J=5.4Hz,1H),7.82(dd,J=7.1,1.6Hz,1H),7.64(d,J=9.0Hz,1H),7.50–7.43(m,2H),6.77(dd,J=9.1,2.3Hz,1H),6.55(d,J=2.2Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.43–4.31(m,2H),3.59(d,J=6.3Hz,1H),3.47(t,J=7.0Hz,4H),3.41–3.36(m,2H),3.22(q,J=6.0Hz,2H),3.16–3.08(m,1H),2.96–2.86(m,1H),2.60(d,J=16.8Hz,1H),2.37(q,J=7.6Hz,3H),2.15(t,J=7.3Hz,2H),2.07–1.97(m,1H),1.83(q,J=7.3Hz,2H),1.13(t,J=7.0Hz,6H). 13 C NMR(100MHz,DMSO-d6)δ172.87,171.94,171.07,167.85,162.51,161.63,157.21,152.41,147.72,133.81,133.58,132.63,131.56,128.55,125.13,118.87,110.09,109.33,107.61,95.79,53.42,51.55,46.52,44.33(2C),41.69,38.55,31.22,22.65,21.22,18.02,16.72,12.32(2C).

[0095] 9c: 1H NMR(400 MHz,DMSO-d6)δ11.02(s,1H),9.87(s,1H),8.70(t,J=5.8 Hz,1H),8.64(s,1H),7.95(t,J=5.6 Hz,1H),7.82(dd,J=6.5,2.4 Hz,1H),7.67(d,J=9.1Hz,1H),7.51–7.45(m,2H),6.80(dd,J=9.1,2.6 Hz,1H),6.61(d,J=2.3 Hz,1H),5.14(dd,J=13.3,5.1 Hz,1H),4.43–4.27(m,2H),3.48(q,J=7.0 Hz,4H),3.32–3.28(m,2H),3.10(q,J=6.5 Hz,2H),2.96–2.86(m,1H),2.65–2.57(m,3H),2.43(t,J=7.2 Hz,2H),2.32(tt,J=13.3,6.7 Hz,1H),2.07–1.99(m,1H),1.62(p,J=6.7 Hz,2H),1.14(t,J=7.1Hz,6H). 13 C NMR(100 MHz,DMSO-d6)δ172.95,171.25,171.14,170.76,167.90,162.28,161.73,157.25,152.43,147.71,133.85,133.55,132.67,131.61,128.68,125.03,118.92,110.14,109.45,107.68,95.87,51.55,46.49,44.37(2C),36.69,36.27,31.34,31.24,30.48,29.46,22.73,12.36(2C).

[0096] 9d: 1H NMR(400 MHz,DMSO-d6)δ11.01(s,1H),9.80(s,1H),8.70(t,J=5.8 Hz,1H),8.64(s,1H),7.90(t,J=5.6 Hz,1H),7.83(dd,J=6.7,2.1 Hz,1H),7.67(d,J=9.1Hz,1H),7.52–7.45(m,2H),6.80(dd,J=9.1,2.4 Hz,1H),6.61(d,J=2.2 Hz,1H),5.13(dd,J=13.3,5.1 Hz,1H),4.37(q,J=17.5 Hz,2H),3.48(q,J=7.0 Hz,4H),3.29(d,J=6.6 Hz,2H),3.10(q,J=6.5Hz,2H),2.91(ddd,J=18.6,13.6,5.3 Hz,1H),2.63–2.55(m,1H),2.39–2.29(m,3H),2.15(t,J=7.3 Hz,2H),2.05–1.98(m,1H),1.83(p,J=7.3 Hz,2H),1.63(p,J=6.8 Hz,2H),1.14(t,J=7.0 Hz,6H). 13 C NMR(100 MHz,DMSO-d6)δ172.86,171.65,171.07,171.03,167.85,162.27,161.69,157.22,152.41,147.66,133.81,133.65,132.66,131.56,128.60,125.22,118.94,110.12,109.42,107.65,95.86,51.55,46.51,44.34(2C),36.71,36.18,35.11,34.65,31.22,29.44,22.64,21.21,12.32(2C).

[0097] 9e: 1H NMR(400 MHz,DMSO-d6)δ9.85(s,1H),8.64(d,J=5.3 Hz,2H),7.90(t,J=5.6Hz,1H),7.83(dd,J=6.4,2.5 Hz,1H),7.67(d,J=8.9 Hz,1H),7.50–7.45(m,2H),6.79(dd,J=9.1,2.3 Hz,1H),6.61(d,J=2.2 Hz,1H),5.14(dd,J=13.3,5.2 Hz,1H),4.35(q,J=17.6 Hz,2H),3.47(q,J=7.0 Hz,4H),3.29(d,J=6.1 Hz,2H),3.07(q,J=6.4 Hz,2H),2.92(ddd,J=18.5,13.6,5.3 Hz,1H),2.65–2.57(m,3H),2.42(t,J=7.3 Hz,2H),2.33(qd,J=13.2,4.3 Hz,1H),2.08–1.99(m,1H),1.50(dq,J=11.0,7.0,6.5 Hz,2H),1.42(dd,J=9.0,5.7 Hz,2H),1.13(t,J=7.0 Hz,6H). 13 C NMR(100 MHz,DMSO-d6)δ172.91,171.11,171.01,170.75,167.88,162.13,161.83,157.22,152.41,147.69,133.84,133.50,132.65,131.58,128.65,124.98,118.88,110.14,109.43,107.68,95.86,51.52,46.43,44.35(2C),38.59,38.25,31.36,31.23,30.45,26.73,22.72,12.34(2C).

[0098] 9f: 1H NMR(400 MHz,DMSO-d6)δ11.01(s,1H),9.80(s,1H),8.64(d,J=5.7 Hz,2H),7.88–7.80(m,2H),7.66(d,J=9.0 Hz,1H),7.48(d,J=7.2 Hz,2H),6.79(dd,J=9.0,2.3 Hz,1H),6.60(d,J=2.1 Hz,1H),5.14(dd,J=13.3,5.1 Hz,1H),4.45–4.29(m,2H),3.66–3.54(m,1H),3.47(q,J=6.9 Hz,4H),3.31–3.26(m,2H),3.17–3.10(m,1H),3.09–3.03(m,2H),2.91(ddd,J=18.2,13.7,5.3 Hz,1H),2.60(d,J=16.9 Hz,1H),2.37(q,J=7.7 Hz,3H),2.13(t,J=7.3Hz,2H),2.02(dd,J=11.4,5.9 Hz,1H),1.82(p,J=7.3 Hz,2H),1.46(dq,J=25.7,7.4 Hz,4H),1.13(t,J=7.1 Hz,6H). 13 C NMR(100 MHz,DMSO-d6)δ172.91,171.50,171.10,171.06,167.87,162.15,161.82,157.21,152.41,147.68,133.82,133.66,132.66,131.58,128.60,125.23,118.94,110.14,109.41,107.67,95.85,53.39,51.55,46.53,44.35(2C),41.67,38.61,38.17,35.16,34.64,31.24,26.78,26.75,22.66,21.27,18.02,16.73,12.34.(2C)

[0099] 9g: 1H NMR(400 MHz,DMSO-d6)δ11.02(s,1H),9.84(s,1H),8.64(d,J=5.6 Hz,2H),7.87(t,J=5.5 Hz,1H),7.83(dd,J=6.4,2.3 Hz,1H),7.67(d,J=9.0 Hz,1H),7.48(d,J=6.6 Hz,2H),6.78(dd,J=9.0,2.1 Hz,1H),6.59(d,J=1.8 Hz,1H),5.15(dd,J=13.3,5.1 Hz,1H),4.42–4.27(m,2H),3.47(q,J=6.9 Hz,4H),3.27(q,J=6.6 Hz,2H),3.04(q,J=6.5 Hz,2H),2.92(ddd,J=18.0,13.7,5.2 Hz,1H),2.66–2.57(m,3H),2.41(t,J=7.2 Hz,2H),2.32(qd,J=13.3,4.3 Hz,1H),2.08–1.99(m,1H),1.49(q,J=7.3 Hz,2H),1.41(q,J=6.9 Hz,2H),1.30(dd,J=16.0,9.6Hz,4H),1.13(t,J=7.0 Hz,6H). 13 CNMR(100 MHz,DMSO-d6)δ172.98,171.17,171.00,170.78,167.91,162.13,161.89,157.24,152.41,147.72,133.87,133.49,132.67,131.62,128.70,124.98,118.91,110.15,109.45,107.70,95.86,51.51,46.44,44.38(2C),38.45,31.42,31.26,30.49,28.93,28.88,23.91,22.75,12.37(2C).

[0100] 9h: 1H NMR(400 MHz,DMSO-d6)δ11.02(s,1H),9.78(s,1H),8.64(s,2H),7.82(d,J=6.8Hz,2H),7.67(d,J=9.0 Hz,1H),7.48(d,J=6.9 Hz,2H),6.79(d,J=10.4 Hz,1H),6.60(s,1H),5.14(dd,J=13.2,4.9 Hz,1H),4.42–4.30(m,2H),3.50–3.45(m,4H),3.27(s,2H),3.04(q,J=5.8,4.8 Hz,2H),2.95–2.86(m,1H),2.60(d,J=16.6 Hz,1H),2.40–2.31(m,3H),2.13(t,J=6.9 Hz,2H),2.02(d,J=10.8 Hz,1H),1.86–1.77(m,2H),1.53–1.47(m,2H),1.41(d,J=8.9 Hz,2H),1.30(d,J=7.0 Hz,5H),1.13(t,J=6.9 Hz,6H). 13 C NMR(100 MHz,DMSO-d6)δ172.99,171.53,171.17,171.11,167.93,162.16,161.89,157.24,152.42,147.70,133.85,133.66,132.69,131.62,128.66,125.25,118.99,110.16,109.44,107.70,95.87,53.50,51.57,46.54,44.39(2C),41.77,38.40,35.21,34.67,31.28,28.95,28.91,23.97,22.71,21.32,18.08,16.76,12.38(2C).

[0101] 9i: 1H NMR(400 MHz,DMSO-d6)δ11.04(s,1H),9.80(s,1H),8.63(d,J=7.7 Hz,2H),7.80(d,J=5.8 Hz,2H),7.67(d,J=9.1 Hz,1H),7.48(d,J=7.0 Hz,2H),6.78(d,J=9.1 Hz,1H),6.60(s,1H),5.15(dd,J=13.3,5.0 Hz,1H),4.44–4.28(m,2H),3.46(q,J=6.8 Hz,4H),3.27(q,J=6.5 Hz,2H),3.02(q,J=6.3 Hz,2H),2.98–2.86(m,1H),2.60(d,J=16.4 Hz,1H),2.42–2.30(m,3H),2.08(t,J=6.4 Hz,2H),2.05–1.99(m,1H),1.51(dd,J=16.9,9.6 Hz,6H),1.40(q,J=6.9 Hz,2H),1.25(dt,J=12.7,7.6 Hz,5H),1.12(t,J=7.0 Hz,6H). 13 C NMR(100 MHz,DMSO-d6)δ172.95,171.57,171.14,170.72,167.90,163.40,161.74,160.70,156.07,147.81,136.01,133.83,133.50,132.65,131.65,128.62,128.30,128.12,118.88,114.95,114.19,112.28,101.16,70.24,56.63,53.41,51.54,46.49,44.14(2C),40.15,39.94,39.73,39.52,39.31,39.10,38.89,31.25,30.44,22.72,18.04,16.74,12.58(2C).

[0102] 9j: 1H NMR(400 MHz,DMSO-d6)δ11.02(s,1H),9.94(s,1H),8.81(s,1H),8.75(t,J=5.8Hz,1H),8.24(d,J=2.3 Hz,1H),8.09(t,J=5.6 Hz,1H),7.88(dd,J=8.9,2.4 Hz,1H),7.81(dd,J=6.8,1.9 Hz,1H),7.49–7.42(m,3H),5.13(dd,J=13.2,5.0 Hz,1H),4.36(q,J=17.6 Hz,2H),3.42–3.38(m,2H),3.24(q,J=6.1 Hz,2H),2.92(ddd,J=17.7,13.4,5.0 Hz,1H),2.62(d,J=6.8Hz,2H),2.60(s,1H),2.43(t,J=7.1 Hz,2H),2.39–2.26(m,1H),2.07–1.99(m,1H). 13 C NMR(100 MHz,DMSO-d6)δ173.87,171.70,171.56,169.63,167.55,166.65,160.07,152.78,146.05,135.51,135.22,132.85,131.92,131.12,126.20,122.94,120.49,118.71,117.41,117.29,115.28,53.30,46.73,39.45,37.01,36.86,31.55,30.81,22.99.

[0103] 9k: 1H NMR(400 MHz,DMSO-d6)δ11.02(s,1H),9.82(s,1H),8.82(s,1H),8.78–8.73(m,1H),8.26–8.19(m,1H),8.01(t,J=5.4 Hz,1H),7.86(dd,J=8.8,2.3 Hz,1H),7.80(dd,J=7.3,1.5 Hz,1H),7.49–7.42(m,3H),5.13(dd,J=13.6,5.2 Hz,1H),4.43–4.29(m,2H),3.40(q,J=5.8 Hz,2H),3.24(q,J=6.2 Hz,2H),2.98–2.86(m,1H),2.39–2.35(m,2H),2.33(d,J=4.9 Hz,1H),2.14(t,J=7.3 Hz,2H),2.06–1.97(m,1H),1.86–1.77(m,2H). 13 C NMR(100 MHz,DMSO-d6)δ173.35,171.53,171.10,169.83,168.45,163.56,161.72,152.68,146.75,135.71,134.82,132.68,131.72,131.21,126.53,123.09,120.56,118.84,117.53,117.22,116.58,53.80,46.62,39.88,37.21,36.49,35.32,30.31,25.99,20.19.

[0104] 9l: 1H NMR(400 MHz,DMSO-d6)δ11.03(s,1H),9.92(s,1H),8.80(s,1H),8.74(t,J=5.9Hz,1H),8.25(d,J=2.3 Hz,1H),7.99(t,J=5.7 Hz,1H),7.88(dd,J=8.9,2.4 Hz,1H),7.82(dd,J=6.3,2.3 Hz,1H),7.50–7.45(m,3H),5.14(dd,J=13.3,5.1 Hz,1H),4.43–4.28(m,2H),3.67–3.53(m,2H),3.34–3.28(m,2H),2.92(ddd,J=17.8,13.8,5.2 Hz,1H),2.63(d,J=6.5 Hz,2H),2.60(s,1H),2.43(t,J=7.1 Hz,2H),2.33(qd,J=12.9,4.0Hz,1H),2.08–1.98(m,1H),1.64(p,J=6.5 Hz,2H). 13 C NMR(100 MHz,DMSO-d6)δ173.34,171.77,171.38,171.09,168.28,161.24,160.10,153.13,146.30,136.52,134.01,133.80,132.82,132.31,129.01,125.95,120.58,120.42,119.27,118.71,116.94,53.76,46.79,42.06,37.21,36.45,31.43,30.63,29.39,22.87.

[0105] 9m: 1H NMR(400 MHz,DMSO-d6)δ11.01(s,1H),9.88(s,1H),8.80(s,1H),8.24(d,J=2.5 Hz,1H),7.88(dd,J=8.9,2.4 Hz,1H),7.83(dd,J=6.6,2.3 Hz,1H),7.48(dd,J=8.1,3.0 Hz,3H),5.13(dd,J=13.4,5.1 Hz,1H),4.46–4.31(m,2H),3.59(dd,J=6.4,2.4Hz,2H),3.34–3.30(m,2H),2.97–2.85(m,1H),2.65–2.56(m,1H),2.38(t,J=7.3 Hz,2H),2.15(t,J=7.4 Hz,2H),2.03(dd,J=7.5,5.0 Hz,1H),1.83(p,J=7.4 Hz,2H),1.75–1.59(m,3H). 13 C NMR(100 MHz,DMSO-d6)δ173.37,172.36,171.52,171.40,168.33,161.31,160.12,153.16,146.33,136.57,133.99,132.86,132.33,129.02,125.66,120.59,120.43,119.39,118.75,116.98,112.71,54.30,43.26,37.30,36.43,35.35,34.92,31.46,29.39,22.83,21.56.

[0106] 9n: 1H NMR(400 MHz,DMSO-d6)δ11.03(s,1H),9.92(s,1H),8.80(s,1H),8.65(t,J=5.9Hz,1H),8.25(d,J=2.2 Hz,1H),7.94(t,J=5.6 Hz,1H),7.88(dd,J=8.8,2.3 Hz,1H),7.82(dd,J=5.9,2.9 Hz,1H),7.48(dd,J=5.5,2.8 Hz,3H),5.14(dd,J=13.2,5.1Hz,1H),4.35(q,J=17.5 Hz,2H),3.64–3.55(m,2H),3.33–3.26(m,2H),2.92(ddd,J=18.0,13.7,5.3 Hz,1H),2.65–2.57(m,3H),2.42(t,J=7.2 Hz,2H),2.36–2.25(m,1H),2.12–1.97(m,1H),1.55–1.48(m,2H),1.47–1.40(m,2H). 13 C NMR(100 MHz,DMSO-d6)δ173.46,171.68,171.44,171.21,168.41,161.28,160.25,153.17,146.31,136.61,134.05,133.88,132.85,132.35,129.10,125.50,120.62,120.53,119.37,118.79,117.04,53.86,51.89,46.87,42.17,38.55,31.51,30.24,26.87,26.72,22.91.

[0107] 9o: 1H NMR(400 MHz,DMSO-d6)δ11.02(s,1H),9.87(s,1H),8.78(s,1H),8.66(t,J=5.8Hz,1H),8.27–8.21(m,1H),7.90–7.85(m,2H),7.82(d,J=6.8 Hz,1H),7.50–7.44(m,3H),5.13(dd,J=12.8,4.6 Hz,1H),4.44–4.31(m,2H),3.59(dt,J=6.2,3.2 Hz,2H),3.32–3.28(m,2H),2.91(t,J=12.7 Hz,1H),2.60(d,J=17.4 Hz,2H),2.37(d,J=6.7 Hz,2H),2.13(t,J=7.0Hz,2H),2.05–1.99(m,1H),1.85–1.79(m,2H),1.51(d,J=6.3 Hz,2H),1.44(d,J=6.2 Hz,2H). 13 C NMR(100 MHz,DMSO-d6)δ173.53,171.10,169.79,169.53,167.55,166.71,160.07,152.78,147.06,136.41,134.82,132.85,132.42,132.12,126.30,122.94,120.49,118.71,117.41,117.29,115.32,54.30,46.73,41.83,40.10,35.49,35.82,30.81,27.10,26.72,25.99,20.19.

[0108] 10a: 1H NMR(400 MHz,DMSO-d6)δ11.02(s,1H),9.92(s,1H),8.81(s,1H),8.63(d,J=4.3 Hz,1H),8.43(d,J=8.4 Hz,1H),7.88(d,J=8.7 Hz,1H),7.81(dd,J=6.9,2.0 Hz,1H),7.49–7.40(m,3H),7.06(d,J=2.3 Hz,1H),7.01(dd,J=8.7,2.3 Hz,1H),5.14(dd,J=13.3,5.1 Hz,1H),4.36(q,J=17.6 Hz,2H),4.17(q,J=6.9 Hz,2H),3.61–3.56(m,2H),3.23(d,J=6.0 Hz,2H),3.10(t,J=7.4 Hz,3H),2.61(d,J=7.9 Hz,3H),2.43(t,J=7.2Hz,2H),2.33(qd,J=13.1,4.3 Hz,1H),2.09–1.97(m,1H),1.36(t,J=6.9 Hz,3H). 13 C NMR(100 MHz,DMSO-d6)δ173.37,171.80,171.56,169.63,168.25,163.69,161.38,160.97,156.88,147.37,134.05,132.85,131.92,130.19,126.20,122.94,117.29,115.74,113.35,112.66,100.90,64.71,53.70,46.73,42.45,36.81,31.86,30.55,29.01,22.79,16.82.

[0109] 10b: 1H NMR(400 MHz,DMSO-d6)δ11.02(s,1H),9.82(s,1H),8.81(s,1H),8.72(t,J=5.8 Hz,1H),8.01(t,J=5.3 Hz,1H),7.85(d,J=8.7 Hz,1H),7.81(dd,J=7.1,1.8 Hz,1H),7.50–7.42(m,2H),7.02(d,J=2.3 Hz,1H),6.98(dd,J=8.7,2.3 Hz,1H),5.13(dd,J=13.3,5.1 Hz,1H),4.43–4.29(m,2H),4.15(q,J=7.0 Hz,2H),3.58(p,J=6.8 Hz,2H),3.24(t,J=6.0 Hz,2H),2.91(ddd,J=18.1,13.4,5.4 Hz,1H),2.65–2.55(m,1H),2.35(q,J=6.0,5.0 Hz,3H),2.15(t,J=7.4 Hz,2H),2.06–1.98(m,1H),1.82(p,J=7.4 Hz,2H),1.36(t,J=6.9 Hz,3H). 13 C NMR(100 MHz,DMSO-d6)δ173.35,171.53,171.20,169.93,168.55,163.49,161.88,160.17,156.98,148.79,134.65,132.25,131.75,130.52,126.79,122.66,117.89,116.44,114.55,113.76,100.82,64.52,53.30,46.21,42.05,36.01,32.49,31.32,30.81,25.99,20.19,16.72.

[0110] 10c: 1H NMR(400 MHz,DMSO-d6)δ11.03(s,1H),9.92(s,1H),8.81(s,1H),7.88(d,J=8.8 Hz,1H),7.82(dd,J=6.5,2.4 Hz,1H),7.48(q,J=4.7 Hz,2H),7.08(d,J=2.1 Hz,1H),7.01(dd,J=8.7,2.3 Hz,1H),5.14(dd,J=13.2,5.2 Hz,1H),4.36(q,J=17.5 Hz,2H),4.17(q,J=6.9Hz,2H),3.58(t,J=5.9 Hz,2H),3.10(d,J=6.2 Hz,2H),2.97–2.86(m,1H),2.62(t,J=7.0 Hz,3H),2.43(t,J=7.1 Hz,2H),2.31(td,J=13.3,4.3 Hz,1H),2.08–1.98(m,1H),1.63(p,J=6.9Hz,2H),1.36(t,J=7.0 Hz,3H). 13 C NMR(100 MHz,DMSO-d6)δ173.30,171.71,171.36,171.06,168.25,163.93,161.84,161.10,156.40,148.03,134.00,133.79,132.80,131.42,128.98,125.35,118.86,114.94,114.18,112.22,100.79,64.20,53.72,46.77,42.02,37.45,36.45,31.42,30.64,29.47,22.86,16.89.

[0111] 10d: 1H NMR(400 MHz,DMSO-d6)δ11.02(s,1H),9.87(s,1H),8.81(s,1H),8.72(t,J=5.7 Hz,1H),7.94(t,J=5.5 Hz,1H),7.88(d,J=8.8 Hz,1H),7.83(dd,J=6.6,2.0 Hz,1H),7.48(d,J=7.0 Hz,2H),7.08(d,J=2.0 Hz,1H),7.01(dd,J=8.7,2.3 Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4.45–4.30(m,2H),4.17(q,J=6.9 Hz,2H),3.59(dt,J=10.6,5.3 Hz,2H),3.10(d,J=5.3 Hz,2H),2.91(ddd,J=18.2,13.7,5.2 Hz,1H),2.60(d,J=16.3 Hz,1H),2.36(dt,J=11.5,5.9Hz,3H),2.15(t,J=7.3 Hz,2H),2.05–1.98(m,1H),1.83(p,J=7.4 Hz,2H),1.64(p,J=6.6 Hz,2H),1.36(t,J=7.0 Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ173.53,171.50,171.80,171.63,168.55,163.67,161.38,161.08,156.58,148.39,134.05,133.95,132.92,131.39,128.88,125.94,118.29,114.63,113.85,112.56,100.76,64.21,53.20,46.65,42.52,37.64,36.89,31.44,30.76,29.38,25.62,22.91,16.12.

[0112] 10e: 1H NMR(400 MHz,DMSO-d6)δ11.03(s,1H),9.93(s,1H),8.81(s,1H),7.89(d,J=8.8 Hz,1H),7.82(dd,J=6.0,2.7 Hz,1H),7.48(q,J=4.0,3.6 Hz,2H),7.10–7.06(m,1H),7.02(dd,J=8.7,2.3 Hz,1H),5.14(dd,J=13.2,5.1 Hz,1H),4.36(q,J=17.6 Hz,2H),4.21–4.14(m,2H),3.30(q,J=6.6 Hz,2H),3.08–3.04(m,2H),3.00–2.85(m,1H),2.60(t,J=7.5 Hz,3H),2.41(t,J=7.2 Hz,2H),2.31(td,J=12.8,3.8 Hz,1H),2.07–1.98(m,1H),1.51(p,J=7.1,6.6 Hz,2H),1.43(q,J=8.0,7.2 Hz,2H),1.36(t,J=7.0 Hz,3H). 13 CNMR(100 MHz,DMSO-d6)δ173.66,171.48,171.89,170.86,168.95,162.75,161.32,161.28,157.13,147.97,135.08,133.24,132.52,131.21,127.40,125.96,118.66,115.02,113.95,112.78,101.21,64.36,53.46,46.05,42.91,37.55,35.98,31.83,30.59,27.06,25.45,23.06,15.82.

[0113] 10f: 1H NMR(400 MHz,DMSO-d6)δ11.02(s,1H),9.82(s,1H),8.80(s,1H),8.64(t,J=5.7 Hz,1H),7.88(d,J=8.8 Hz,1H),7.82(dd,J=6.8,1.9 Hz,1H),7.48(d,J=6.9 Hz,2H),7.08(d,J=1.9 Hz,1H),7.04–6.99(m,1H),5.14(dd,J=13.3,5.3 Hz,1H),4.45–4.29(m,2H),4.17(q,J=6.8 Hz,2H),3.60(dd,J=6.4,2.0 Hz,2H),3.10–3.04(m,2H),2.90(d,J=10.2 Hz,1H),2.69–2.55(m,1H),2.41–2.28(m,3H),2.13(t,J=7.4 Hz,2H),2.05–1.99(m,1H),1.86–1.76(m,2H),1.57–1.47(m,2H),1.47–1.40(m,2H),1.36(t,J=7.0 Hz,3H). 13 C NMR(100 MHz,DMSO-d6)δ173.95,171.60,171.42,170.38,168.44,163.52,161.28,160.85,157.08,146.92,134.55,133.74,131.89,131.06,127.56,125.82,117.94,115.18,113.28,112.61,101.98,63.87,53.27,46.23,42.59,38.60,35.24,31.92,30.68,27.83,26.11,25.49,22.89,16.24.

[0114] 10g: 1H NMR(400 MHz,DMSO-d6)δ11.02(s,1H),9.89(s,1H),8.82(s,1H),8.72(t,J=5.8 Hz,1H),8.06(t,J=5.5 Hz,1H),7.90(d,J=8.8 Hz,1H),7.81(dd,J=7.0,1.8 Hz,1H),7.50–7.34(m,7H),7.18(d,J=2.3 Hz,1H),7.11(dd,J=8.7,2.4 Hz,1H),5.26(s,2H),5.14(dd,J=13.3,5.1 Hz,1H),4.43–4.28(m,2H),3.39(q,J=6.2 Hz,2H),3.24(q,J=5.9 Hz,2H),2.91(ddd,J=17.7,13.7,5.3 Hz,1H),2.65–2.57(m,3H),2.43(t,J=7.2Hz,2H),2.33(qd,J=13.2,4.3 Hz,1H),2.07–1.99(m,1H). 13 C NMR(100 MHz,DMSO-d6)δ172.93,171.75,171.27,171.13,167.87,162.10,161.84,157.22,152.40,147.67,133.81,133.75,132.68,131.58(2C),128.64(2C),125.27,119.01,110.13,109.45,107.68,95.86,53.54,51.52,46.49,44.35,38.81,38.32,35.70,35.25,31.25,28.88,25.04,24.92,23.92.

[0115] 10h: 1H NMR(400 MHz,DMSO-d6)δ11.02(s,1H),9.74(s,1H),8.82(s,1H),8.72(t,J=5.8 Hz,1H),7.98(t,J=5.5 Hz,1H),7.88(d,J=8.8 Hz,1H),7.81(dd,J=7.3,1.6 Hz,1H),7.50–7.34(m,7H),7.14(d,J=2.3 Hz,1H),7.08(dd,J=8.7,2.3 Hz,1H),5.24(s,2H),5.14(dd,J=13.3,5.1 Hz,1H),4.42–4.29(m,2H),3.40(q,J=6.0 Hz,2H),3.24(q,J=6.0 Hz,2H),2.91(ddd,J=17.7,13.7,5.4 Hz,1H),2.60(d,J=17.6 Hz,1H),2.36(q,J=8.4,7.5 Hz,3H),2.15(t,J=7.3Hz,2H),2.06–1.98(m,1H),1.82(p,J=7.4 Hz,2H). 13 CNMR(100 MHz,DMSO-d6)δ172.88,171.97,171.09,171.02,167.85,163.36,161.71,160.72,156.02,147.84,135.97,133.78,133.52,132.63,131.58,128.58(2C),128.25,128.07(2C),125.10,118.88,114.88,114.11,112.23,101.08,70.19,51.54,46.48,38.22,35.10,34.68,31.22,29.04,22.65,21.20.

[0116] 10i: 1H NMR(400 MHz,DMSO-d6)δ11.03(s,1H),9.87(s,1H),8.81(s,1H),8.71(t,J=5.8Hz,1H),7.97(t,J=5.6 Hz,1H),7.90(d,J=8.8 Hz,1H),7.82(dd,J=6.6,2.2 Hz,1H),7.48(dq,J=4.6,2.9,2.2 Hz,4H),7.39(dt,J=22.8,7.1 Hz,3H),7.19(d,J=2.2Hz,1H),7.11(dd,J=8.7,2.3 Hz,1H),5.26(s,2H),5.14(dd,J=13.3,5.1 Hz,1H),4.42–4.29(m,2H),3.34–3.29(m,2H),3.11(q,J=6.4 Hz,2H),2.92(ddd,J=17.8,13.6,5.3 Hz,1H),2.62(t,J=7.1 Hz,3H),2.43(t,J=7.2 Hz,2H),2.33(qd,J=13.1,4.2 Hz,1H),2.07–1.99(m,1H),1.64(p,J=6.7 Hz,2H). 13 CNMR(100 MHz,DMSO-d6)δ172.96,171.30,171.14,170.76,167.91,163.37,161.49,160.83,156.07,147.73,136.02,133.85,133.54,132.67,131.62,128.69,128.63(2C),128.29,128.11(2C),125.02,118.93,115.08,114.19,112.34,101.17,70.23,51.55,46.48,36.87,36.23,31.32,31.24,30.47,29.34,22.73.

[0117] 10j: 1H NMR(400 MHz,DMSO-d6)δ11.02(s,1H),9.81(s,1H),8.81(s,1H),8.72(t,J=5.8 Hz,1H),7.90(dd,J=10.1,5.3 Hz,2H),7.83(dd,J=6.9,1.9 Hz,1H),7.48(d,J=7.2 Hz,4H),7.38(dt,J=22.9,7.1 Hz,3H),7.19(d,J=2.3 Hz,1H),7.10(dd,J=8.7,2.4Hz,1H),5.26(s,2H),5.14(dd,J=13.3,5.1 Hz,1H),4.45–4.28(m,2H),3.34–3.29(m,2H),3.11(q,J=6.4 Hz,2H),2.91(ddd,J=18.3,13.6,5.3 Hz,1H),2.60(d,J=16.7 Hz,1H),2.41–2.29(m,3H),2.15(t,J=7.3 Hz,2H),2.06–1.99(m,1H),1.84(p,J=7.3 Hz,2H),1.64(p,J=6.7 Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ172.90,171.71,171.10,171.04,167.87,163.35,161.48,160.80,156.05,147.71,136.00,133.81,133.65,132.67,131.59,128.59(2C),128.26,128.07(2C),125.23,118.97,115.04,114.16,112.31,101.16,70.21,59.80,51.55,46.52,36.90,36.14,35.14,34.67,31.23,29.34,22.66,21.24.

[0118] 10k: 1H NMR(400 MHz,DMSO-d6)δ11.03(s,1H),9.85(s,1H),8.81(s,1H),8.63(t,J=5.7 Hz,1H),7.93–7.88(m,2H),7.83(dd,J=6.5,2.4 Hz,1H),7.50–7.34(m,7H),7.19(d,J=2.2 Hz,1H),7.11(dd,J=8.7,2.3 Hz,1H),5.26(s,2H),5.15(dd,J=13.3,5.1 Hz,1H),4.43–4.27(m,2H),3.33–3.28(m,2H),3.07(q,J=6.4 Hz,2H),2.92(ddd,J=18.0,13.7,4.5 Hz,1H),2.65–2.57(m,3H),2.42(t,J=7.2 Hz,2H),2.33(qd,J=13.2,4.4 Hz,1H),2.08–1.99(m,1H),1.47(dq,J=29.7,7.3 Hz,4H). 13 C NMR(100 MHz,DMSO-d6)δ172.95,171.14,171.04,170.76,167.89,163.36,161.36,160.93,156.04,147.72,136.01,133.85,133.51,132.65,131.61,128.67,128.62(2C),128.28,128.09(2C),124.99,118.90,115.06,114.19,112.34,101.17,70.22,51.52,46.44,38.78,38.24,31.35,31.25,30.45,26.70,26.61,22.73.

[0119] 10l: 1H NMR(400 MHz,DMSO-d6)δ11.02(s,1H),9.79(s,1H),8.80(s,1H),8.64(t,J=5.7Hz,1H),7.89(d,J=8.8 Hz,1H),7.87–7.79(m,2H),7.50–7.34(m,7H),7.18(d,J=2.2 Hz,1H),7.10(dd,J=8.7,2.3 Hz,1H),5.26(s,2H),5.14(dd,J=13.3,5.1 Hz,1H),4.44–4.29(m,2H),3.33–3.28(m,2H),3.07(q,J=6.4 Hz,2H),2.91(ddd,J=17.7,13.7,5.3 Hz,1H),2.60(d,J=16.7 Hz,1H),2.41–2.29(m,3H),2.13(t,J=7.3 Hz,2H),2.06–2.00(m,1H),1.82(p,J=7.4Hz,2H),1.46(ddd,J=27.8,14.1,6.9 Hz,4H). 13 C NMR(100MHz,DMSO-d6)δ172.98,171.54,171.16,171.08,167.90,163.36,161.39,160.94,156.05,147.73,136.02,133.83,133.66,132.68,131.61,128.64(2C),128.31,128.13(2C),125.24,118.99,115.06,114.21,112.34,101.16,70.23,51.55,46.52,38.18,35.18,34.66,31.26,26.74,26.68,22.69,21.30.

[0120] 10m: 1H NMR(400 MHz,DMSO-d6)δ11.04(s,1H),9.85(s,1H),8.81(s,1H),8.63(t,J=5.7 Hz,1H),7.93–7.86(m,2H),7.82(dd,J=6.4,2.5 Hz,1H),7.50–7.33(m,7H),7.18(d,J=2.3 Hz,1H),7.10(dd,J=8.7,2.3 Hz,1H),5.25(s,2H),5.15(dd,J=13.3,5.1 Hz,1H),4.42–4.27(m,2H),3.29(q,J=6.8 Hz,2H),3.04(q,J=6.6 Hz,2H),2.92(ddd,J=18.1,13.7,5.4 Hz,1H),2.66–2.55(m,3H),2.41(t,J=7.3 Hz,2H),2.32(qd,J=13.3,4.5Hz,1H),2.03(dq,J=10.1,3.0Hz,1H),1.51(p,J=7.2 Hz,2H),1.42(p,J=7.0 Hz,2H),1.34–1.25(m,2H). 13 C NMR(100MHz,DMSO-d6)δ172.93,171.13,171.00,170.75,167.89,163.33,161.34,160.94,156.02,147.67,136.00,133.85,133.47,132.64,131.58,128.67,128.61(2C),128.28,128.09(2C),124.96,118.89,115.10,114.17,112.33,101.14,70.21,51.51,46.42,38.43,31.40,31.24,30.48,28.84,28.77,23.85,22.73.

[0121] 10n: 1H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.78(s,1H),8.80(s,1H),8.63(t,J=5.7Hz,1H),7.90(d,J=8.8Hz,1H),7.82(dt,J=8.2 ,4.1Hz,2H),7.50–7.33(m,7H),7.18(d,J=2.3Hz,1H),7.10(dd,J=8.7,2.4Hz,1H),5.25(s,2H),5.14(dd,J=13.3,5.1Hz,1H), 4.45–4.28(m,2H),3.33–3.27(m,2H),3.04(q,J=6.7Hz,2H),2.97–2.85(m,1H),2.60(d,J=17.8Hz,1H),2.40–2.29(m,3H),2. 13(t,J=7.3Hz,2H),2.06–1.98(m,1H),1.81(p,J=7.4Hz,2H),1.52(p,J=7.2Hz,2H),1.41(q,J=7.1Hz,2H),1.34–1.22(m,4H). 13 C NMR(100MHz,DMSO-d6)δ172.99,171.55,171.18,171.12,167.94,163.36,161.3 7,160.98,156.04,147.70,136.02,133.85,133.64,132.69,131.61,128.64(2C ),128.31,128.12(2C),125.23,119.00,115.06,114.19,112.34,101.15,70.24 ,51.58,46.55,38.41,35.23,34.69,31.29,28.91,28.83,23.94,22.71,21.33.

[0122] Example 2: Antitumor activity:

[0123] (1) Inhibitory activity on tumor cell proliferation:

[0124] The MTT method was used to detect the activity of the compounds of the present invention in inhibiting tumor cell proliferation. KB, Hela, MDA-MB-231 and MCF-7 cells were cultured at 4×10 3Cells were seeded into 96-well plates (190 μL) at a density of 10 cells / well and incubated at 37°C for 24 hours. 10 μL of compound culture medium at varying concentrations (final concentrations of 50, 25, 12.5, 6.25, 3.125, 1.5625, and 0.78125 μM) was added to each well of the 96-well plate, with triplicate wells set up for each group. The broad-spectrum anti-tumor drug 5-fluorouracil (5-FU) was used as a positive control (final concentrations of 50, 25, 12.5, 6.25, 3.125, 1.5625, and 0.78125 μM). After adding the test samples to the cells and culturing them under the same conditions for 72 hours, 10 μL of MTT solution (5 mg / mL) was added to each well. After culturing for 4 hours, the optical density (OD) of each well was measured at 540 / 655 nm using a microplate reader. The inhibitory rate of each compound on the above cell proliferation was calculated using the absorbance value. The formula is as follows:

[0125] I / %=(1-OD1 / OD)×100

[0126] Where: I is the cell proliferation inhibition rate (%); OD1 is the absorbance value of the cells in the drug-treated group; OD is the absorbance value of the cells in the blank control group. The obtained data were processed by Graphpad Prism 7 software to obtain the IC value of each compound. 50 Each group of experiments was repeated three times.

[0127] The experimental results are shown in Table 1. Most of the tested compounds have a certain degree of inhibitory activity against the proliferation of the four tumor cells. Among them, compounds 9b-e, 9k-l, 9o, 10d, 10g, 10i-j, and 10n have better activity against Hela than 5-FU. Among them, 9c and 9d have an IC of 100 for Hela. 50 The values reached 3.15 and 3.04 μM, respectively. Compounds 9n and 10e showed significantly better antiproliferative activity against MCF-7 cells than 5-FU. Therefore, these compounds may be used in the development of antitumor drugs.

[0128] Table 1 Inhibitory activity of compounds 9a-o and 10a-n on tumor cell proliferation

[0129]

[0130]

Claims

1. A coumarin-3-carboxamide derivative or a pharmaceutically acceptable salt thereof, wherein the structural formula is shown in any one of the following: 。 2. Use of compounds 9b, 9e, 9c, 9k, 9n, 9o, 10a, 10b, 10d, 10f, 10i, 10j, 10m, 10n or pharmaceutically acceptable salts thereof according to claim 1 in the preparation of anti-cervical cancer drugs.

3. Use of compounds 9d, 9l, 9f, 9m, 10g, 10h or pharmaceutically acceptable salts thereof according to claim 1 in the preparation of drugs for treating oral cancer or cervical cancer.

4. Use of the compound 9h, 10e or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of an anti-oral cancer drug.

5. Use of compounds 9c, 9d, 9j, 9k, 9l, 9n, 9o, 10a, 10b, 10c, 10d, 10e, 10f, 10g, 10h, 10k, 10m, 10n or pharmaceutically acceptable salts thereof according to claim 1 in the preparation of a drug for treating MDA-MB-231 breast cancer cells.

6. Use of the compound 9c, 9d, 9j, 9l, 9m, 9n, 10a, 10b, 10e, 10f, 10g, 10j, 10n or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a drug for treating MCF-7 breast cancer cells.

7. An anti-tumor drug, characterized in that: The invention comprises an effective amount of the coumarin-3-carboxamide derivative or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.

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