CN116693454A - A kind of substituted cyanoquinolinone compound and its preparation method and application - Google Patents

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a substituted cyano quinolinone compound and a preparation method and application thereof. The substituted cyano quinolinone compound has remarkable inhibition effect on phosphodiesterase type I, has remarkable treatment effect on phosphodiesterase related diseases, animal models such as pulmonary fibrosis and enteritis, and can be developed into a new target candidate drug for inflammatory diseases such as pulmonary fibrosis and enteritis. In addition, the preparation method of the substituted cyano quinolinone compound is simple, the reaction condition is mild, and the method is very suitable for large-scale industrialized production.

Description

A kind of substituted cyanoquinolinone compound and its preparation method and application

technical field

The invention belongs to the technical field of biomedicine. More specifically, it relates to a substituted cyanoquinolinone compound and its preparation method and application.

Background technique

Phosphodiesterase (PDE) is a family of super enzymes that can degrade the second messengers cAMP (cyclic adenosine monophosphate) and cGMP (cyclic guanosine monophosphate) in vivo. The two nucleotides, cAMP and cGMP, can activate protein kinase A and protein kinase G, and then mediate downstream signaling pathways to control important physiological processes in the body. Therefore, PDE inhibitors can regulate various important physiological processes in the body by regulating the concentrations of cAMP and cGMP.

PDE1 is a subfamily of the PDE superenzyme family that can simultaneously hydrolyze cAMP and cGMP, including three subtypes, namely PDE1A, PDE1B and PDE1C: PDE1A is mainly expressed in the whole brain and rodent heart; PDE1B is mainly expressed in brain tissue PDE1C is mainly expressed in cardiac tissue and vascular smooth muscle, and is mainly regulated by the Ca ²⁺ /calmodulin binding domain specifically, mediating calcium and cyclic nucleotide signaling pathways. Studies have shown that changes in the signaling pathway regulated by PDE1 are associated with the central nervous system, and can be used to regulate mental disorders, movement disorders, cognitive functions, and Alzheimer's disease; some studies have also shown that PDE1 is associated with cardiac insufficiency Related, can be used to regulate heart failure, cardiac remodeling and dysfunction; other studies have shown that PDE1 is associated with lung, kidney, hematology, gastrointestinal tract, liver, fertility, cancer and metabolic disorders (Samidurai, A.; Xi, L.; Das, A.; Iness, AN; Vigneshwar, NG; Li, P.; et al. ). However, the current research on PDE1 is still limited, and there are not many types of PDE1 inhibitors, and no PDE1 inhibitors are currently on the market as drugs.

Contents of the invention

The technical problem to be solved by the present invention is to overcome the defects and deficiencies of the few types of existing PDE1 inhibitors, and provide a substituted cyanoquinolinone compound.

The purpose of the present invention is to provide the preparation method of described substituted cyanoquinolinone compound.

Another object of the present invention is to provide the application of the substituted cyanoquinolinone compounds in the preparation of drugs for phosphodiesterase-related diseases.

Another object of the present invention is to provide the application of the substituted cyanoquinolinones in the preparation of phosphodiesterase inhibitors.

Another object of the present invention is to provide a phosphodiesterase inhibitor.

The above object of the present invention is achieved through the following technical solutions:

A substituted cyanoquinolinone compound, the substituted cyanoquinolinone compound has a formula (I) structure:

Wherein, R ₁ is C _1-8 alkyl or substituted C _{1-8 alkyl, and the substituent of said substituted C 1-8 alkyl} is phenyl or substituted phenyl, C _3-8 cycloalkyl or N-containing , O, S one or more heterocyclic groups;

_R2 is phenyl or substituted phenyl, heterocyclic group containing one or more of N, O, S, amino or substituted amino, C _3~8 cycloalkyl, C _1~8 alkyl, indene full or substituted indane;

R ₃ is hydrogen, amino or substituted amino, piperazinyl or pyridine substituted piperazinyl;

The substituent of the substituted amino group is C _1-5 alkyl or substituted C _1-5 alkyl, the substituent of the substituted C _1-5 alkyl is phenyl or substituted phenyl, pyridyl, halogenated pyridine Base, benzobisoxazolyl, tetrahydropyranyl, piperidine or substituted piperidinyl, C _1~5 alkyl substituted amino, C _3~8 cycloalkyl, morpholinyl or substituted morpholinyl, Tetrahydrofuryl; the substituent of the substituted piperidinyl or substituted morpholinyl is C _2-4 alkanonyl, C _1-5 alkyl, pyridyl, halogenated phenyl;

The substituent of the substituted phenyl is C _1-5 alkyl, halogen; the substituent of the substituted indane is methylcarboxylate.

Preferably, the R ₁ is C _1-5 alkyl or substituted C _1-5 alkyl, and the substituent of the substituted C _1-5 alkyl is phenyl, halogenated phenyl, C _3-6 cycloalkane base or pyridyl;

_R2 is phenyl or substituted phenyl, amino or substituted amino, C _3-6 cycloalkyl, morpholinyl, C _1-5 alkyl, indane or substituted indane;

R ₃ is hydrogen, amino or substituted amino, piperazinyl or pyridine substituted piperazinyl;

The substituent of the substituted amino group is C _1-5 alkyl or substituted C _1-5 alkyl, the substituent of the substituted C _1-5 alkyl is phenyl or substituted phenyl, pyridyl, halogenated pyridine Base, benzobisoxazolyl, tetrahydropyranyl, piperidine or substituted piperidinyl, C _1~5 alkyl substituted amino, C _3~8 cycloalkyl, morpholinyl or substituted morpholinyl, Tetrahydrofuryl; the substituent of the substituted piperidinyl or substituted morpholinyl is C _2-4 alkanonyl, C _1-5 alkyl, pyridyl, halogenated phenyl;

The substituent of the substituted phenyl is C _1-3 alkyl, halogen; the substituent of the substituted indane is methylcarboxylate.

More preferably, the _R is selected from any of the following structures:

The _R2 is selected from any of the following structures:

The _R3 is hydrogen or any of the following structures:

Further, the substituted cyanoquinolinone compound can also be a pharmaceutically acceptable salt or solvate thereof

In addition, the present invention also provides a preparation method for the substituted cyanoquinolinone compound, specifically comprising the following steps:

S1. Heat amino-substituted bromoxynil and R ₂ MgBr to reflux, add hydrochloric acid in an ice bath after the reaction is complete, and perform post-treatment to obtain the compound of formula (II);

S2. Mixing the compound of formula (II) obtained in step S1 with phosphorus pentachloride and cyanoacetic acid for ring-forming reaction, and post-processing to obtain the compound of formula (III);

S3. Completely react the compound of formula (III) obtained in step S2 with R ₁ Br and an alkaline reagent, and post-process to obtain the compound of formula (IV);

S4. The compound of formula (IV) obtained in step S3 is reacted with R ₃ NH ₂ through Buchwald-Hartwig aryl amination reaction to obtain the compound of formula (I). The structural formulas of the compounds of formulas (I)-(IV) are as follows:

Further, in step S1, the heating and refluxing temperature is 50-150° C.; the heating and refluxing time is 6-12 hours.

Furthermore, in step S1, the reaction time after adding hydrochloric acid is 1-6h.

Preferably, in step S1, the post-treatment includes the following steps: concentrating under reduced pressure to remove the solvent, adjusting the pH to be neutral, extracting with ethyl acetate, collecting the organic layer for drying, concentrating under reduced pressure to remove the solvent, drying, and purifying by column chromatography, Instantly.

Further, in step S2, the temperature of the ring-forming reaction is 60-80° C., and the reaction time is 0.5-4 h.

Preferably, in step S2, the post-treatment includes the following steps: adding water to dilute the reaction system, extracting with DCM, collecting the organic phase to dry, concentrating under reduced pressure to remove the solvent, redissolving in DCM, adding NaOH to stir, and beating with EA to obtain the product.

Furthermore, in step S3, the reaction is carried out at room temperature (15-35° C.), and the reaction time is 4-10 h.

Preferably, in step S3, the post-treatment includes the following steps: adding water to dilute the reaction system, extracting with EA, collecting the organic phase for drying, concentrating under reduced pressure to remove the solvent, and purifying by column chromatography to obtain the product.

Further, in step S4, the reaction temperature is 90-150° C., and the reaction time is 6-10 h.

Preferably, in step S4, the post-treatment includes the following steps: filtering with diatomaceous earth to remove the catalyst, collecting the organic phase, concentrating under reduced pressure to remove the solvent, and purifying by column chromatography to obtain the final product.

Preferably, during the reaction process of steps S1-S4, an organic solvent needs to be added for the reaction, and the organic solvent is selected from tetrahydrofuran (THF), dichloromethane, N,N-dimethylformamide (DMF), toluene, diethyl ether, medium one or more of .

The present invention proves through experiments that the substituted cyanoquinolinone compounds have a significant inhibitory effect on phosphodiesterase type I, can significantly improve the pathological conditions of bleomycin-induced pulmonary fibrosis rats, and improve dextran sulfate Pathological changes in rats with sodium-induced enteritis.

Therefore, the present invention also claims the use of the substituted cyanoquinolinone compound in the preparation of phosphodiesterase-related disease medicines.

Preferably, the phosphodiesterase-related diseases include pulmonary fibrosis, enteritis, heart failure, schizophrenia, vascular dementia, neurodegenerative diseases (such as Alzheimer's disease, etc.), pulmonary hypertension.

In addition, the present invention also claims the use of the substituted cyanoquinolinone compounds in the preparation of phosphodiesterase inhibitors.

Moreover, the present invention also provides a phosphodiesterase inhibitor, the phosphodiesterase inhibitor uses the substituted cyanoquinolinone compound as the main functional ingredient.

Further, the phosphodiesterase is PDE1. At present, PDE1 inhibitors in the prior art are mainly used for central nervous system diseases, and are rarely used for peripheral diseases. The present invention proves for the first time through experiments that it has a good improvement effect on peripheral diseases such as pulmonary fibrosis and enteritis.

The present invention has the following beneficial effects:

The substituted cyanoquinolinone compound of the present invention has a significant inhibitory effect on phosphodiesterase type I, has a significant therapeutic effect on phosphodiesterase-related diseases, and has a significant therapeutic effect on animal models such as pulmonary fibrosis and enteritis, and can develop into pulmonary New target drug candidates for inflammatory diseases such as fibrosis and enteritis. Moreover, the preparation method of the substituted cyanoquinolinone compound of the present invention is simple, the reaction conditions are mild, and it is very suitable for large-scale industrial production.

Description of drawings

Fig. 1 is the statistical chart of the test result of respiratory function index in embodiment 4.

FIG. 2 is a western blot diagram and data statistics diagram of α-SMA expression in rat lung tissue in Example 4. FIG.

Fig. 3 is a pathological section diagram of rat enteritis induced by dextran sodium sulfate in Example 5.

Detailed ways

The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments, but the embodiments do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the technical field.

Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

The preparation of embodiment 1 compound 8

The preparation of the compound 8 specifically comprises the following steps:

S1. Preparation of compound 8a: Dissolve 2-amino-4-bromoxynil (648mg, 3mmol) in 10mL THF, stir in an ice bath, add p-tolylmagnesium bromide (1mol/L) in THF dropwise Solution 9mL, after the dropwise addition, reflux reaction at 70°C for 10h, and the next day, slowly add 4mol/L hydrochloric acid 10mL to the reaction system under ice bath conditions, and react for 6h. Remove the solvent by evaporation, add water to adjust the pH of the solution to neutral, extract three times with ethyl acetate, collect the organic layer, dry over anhydrous sodium sulfate, remove the solvent by rotary evaporation under reduced pressure, dry, and purify by column chromatography to obtain a yellow oil (600mg , 75%), which is compound 8a;

S2. Preparation of compound 8b: Dissolve phosphorus pentachloride (434mg, 2.08mmol) and cyanoacetic acid (180mg, 2.1mmol) in 20mL of dichloromethane, and add compound 8a obtained in step S1 dropwise at 60°C ( 600mg, 2.08mmol) DCM solution, reacted for 0.5h, diluted the reaction system with water, extracted twice with DCM, collected the organic phase, dried over anhydrous sodium sulfate, removed the solvent by rotary evaporation under reduced pressure, redissolved with DCM, added NaOH (100mg , 2.5mmol) was stirred for 1h, and was beaten with EA to obtain a white solid (459mg, 65%), which was compound 8b;

S3. Preparation of compound 8c: Dissolve compound 8b (212mg, 0.625mmol), benzyl bromide (117mg, 0.69mmol) and potassium carbonate (104mg, 0.75mmol) obtained in step S2 in 10mL DMF, and stir the reaction at room temperature for 4h , after the reaction was finished, the reaction system was diluted with water, extracted twice with EA, the organic phase was collected, dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation under reduced pressure, and purified by column chromatography to obtain a white solid (109 mg, 41%), namely is compound 8c;

S4. Preparation of Compound 8: Compound 8c (90mg, 0.21mmol), n-butylamine (18mg, 0.25mmol), Pd ₂ (dba) ₃ (10mg, 0.0105mmol), 1,1'-linked Naphthalene-2,2'-bisdiphenylphosphine (BINAP, 13mg, 0.021mmol) and NaOBu-t (36mg, 0.315mmol) were dissolved in toluene (10mL), reacted at 95°C for 9h under the protection of argon, and monitored the reaction by TLC. After the end, the catalyst was removed by filtration with diatomaceous earth, the organic phase was collected, the solvent was removed by rotary evaporation under reduced pressure, and purified by column chromatography to obtain a yellow solid (39 mg, 44%), which was compound 8.

The preparation of embodiment 2 substituted cyanoquinolinone compounds

Referring to the preparation method of Compound 8 in Example 1, Compounds 1-7 and 9-47 were prepared using different raw materials according to their structures. The structures of compounds 1-47 are as follows:

The structure of compound 1～47 in table 1

The NMR data are as follows:

Compound 1: ¹ H NMR (400MHz, CDCl ₃ ) δ7.61–7.55(m,1H),7.49(d,J=8.0Hz,1H),7.45–7.30(m,10H),7.18(t,J= 7.5Hz,1H),5.65(s,2H),2.50(s,3H). ¹³ CNMR(126MHz,CDCl ₃ )δ160.07,159.12,140.40,140.37,135.44,133.77,130.63,129.95,129.65,129.00,1 28.79, 127.74,126.85,123.00,119.91,115.64,115.06,106.57,46.81,21.50.HRMS(ESI-TOF)m/z[M+H] ⁺ calcd for C ₂₄ H ₁₈ N ₂ O 351.1492,found 351.1486.

Compound 2: ¹ H NMR (400MHz, CDCl ₃ ) δ7.57(dd, J=11.4, 4.4Hz, 1H), 7.43(dt, J=17.9, 8.7Hz, 4H), 7.34(d, J=6.3Hz , 2H), 7.30(d, J=6.5Hz, 4H), 7.19(t, J=7.7Hz, 1H), 5.63(s, 2H), 2.50(s, 3H). ¹³ C NMR (126MHz, CDCl ₃ )δ158.92,158.35,140.38,138.53,135.27,135.07,134.12,132.53,131.65,129.65,129.16,129.04,127.81,127.06,126.83,123.29,119.55, 115.81, 114.76, 106.76, 46.88, 20.15. HRMS (ESI-TOF ) m/z[M+H] ⁺ calcdfor C ₂₄ H ₁₇ N ₂ OCl 385.1102; found 385.1102.

Compound 3: ¹ H NMR (400MHz, CDCl ₃ ) δ7.82(dd, J=8.2, 1.3Hz, 1H), 7.51(ddd, J=8.6, 7.3, 3.7Hz, 1H), 7.31(t, J= 7.5Hz, 4H), 7.23(dd, J＝11.1, 8.0Hz, 3H), 5.50(s, 2H), 4.07–3.90(m, 4H), 3.81–3.67(m, 4H). ¹³ C NMR (126MHz ( ESI-TOF) m _/ z [M+ H] ⁺ calcd for C ₂₁ H ₁₉ N ₃ O ₂ 346.1550; found 346.1562.

Compound 4: ¹ H NMR (400MHz, CDCl ₃ ) δ7.84(d, J=7.1Hz, 1H), 7.51-7.43(m, 1H), 7.35-7.29(m, 3H), 7.27(s, 2H) ,7.25(s,1H),7.21–7.15(m,1H),5.50(s,2H),3.77–3.39(m,4H),1.71(dt,J＝14.5,7.4Hz,4H),0.92(t ,J＝7.4Hz,6H). ¹³ CNMR(101MHz,DMSO-d6)δ164.79,160.88,140.56,136.86,133.76,129.14,127.87,127.63,126.95,122.69,118.09,117.35,116.72 ,94.38,54.89,45.67, 40.56, 40.35, 40.14, 39.93, 39.72, 39.51, 39.30, 21.10, 11.55. HRMS (ESI-TOF) m/z[M+H] ⁺ calcd for C ₂₃ H ₂₅ N ₃ O 360.2070; found 360.2082.

Compound 5: ¹ H NMR (400MHz, CDCl ₃ ) δ7.85(d, J=8.2Hz, 1H), 7.47(t, J=7.8Hz, 1H), 7.35–7.28(m, 3H), 7.27(s ,2H),7.25(s,1H),7.18(t,J=7.6Hz,1H),5.51(s,2H),3.70(q,J=7.1Hz,4H),1.26(t,J=7.1Hz ,6H). ¹³ C NMR (101MHz, DMSO-d6) δ164.24, 160.80, 140.45, 136.83, 133.82, 129.16, 127.73, 127.64, 126.96, 122.79, 118.47, 117.20, 116.61, 95.53, 47.28, 45.66, 40.53, 40.32, 40.12, 39.91, 39.70, 39.49, 39.28, 13.46. HRMS (ESI-TOF) m/z[M+H] ⁺ calcd for C ₂₁ H ₂₁ N ₃ O 332.1757; found 332.1771.

Compound 6: ¹ H NMR (400MHz, CDCl ₃ ) δ7.65(d, J=7.4Hz, 1H), 7.54(t, J=7.9Hz, 1H), 7.51–7.39(m, 4H), 7.36(dd ,J=10.5,3.9Hz,2H),7.33–7.29(m,4H),7.19(t,J=7.7Hz,1H),5.58(dd,J=57.5,15.6Hz,2H),3.69(s, 3H),3.66–3.60(m,1H),3.43–3.12(m,2H),2.55(ddd,J＝13.3,8.6,4.8Hz,1H). ¹³ C NMR(126MHz,CDCl ₃ )δ173.35,159.83, 159.56, 155.92, 145.89, 139.79, 135.35, 132.95, 130.55, 129.55, 128.98, 127.75, 127.41, 127.22, 126.93, 125.61, 122.81, 120.38, 119.03, 11 6.24, 115.38, 107.64, 64.73, 53.32, 47.44, 38.01, 31.55. HRMS(ESI-TOF) m/z[M+H] ⁺ calcd for C ₂₈ H ₂₂ N ₂ O ₃ 435.1703; found 435.1700.

Compound 7: ¹ H NMR (400MHz, CDCl ₃ ) δ7.45–7.31(m, 5H), 7.28(d, J=7.0Hz, 4H), 7.24(s, 1H), 7.11(t, J=7.4Hz ,1H),6.93–6.86(m,2H),5.59(dd,J=40.6,15.6Hz,2H),5.38(t,J=9.4Hz,1H),3.27(t,J=8.3Hz,2H) , 2.79 (dd, J=17.5, 10.7Hz, 1H), 2.50 (td, J=20.4, 10.2Hz, 1H). ¹³ C NMR (126MHz, CDCl ₃ ) δ161.30, 158.95, 144.13, 142.82, 140.68, 135.44, 133.07, 128.99, 128.89, 127.73, 127.60, 127.20, 126.85, 125.27, 124.03, 122.17, 117.56, 116.21, 115.16, 108.71, 51.58, 46.89, 33.07, 32.00 .HRMS(ESI-TOF)m/z[M+H] ⁺ calcd for C ₂₆ H ₂₀ N ₂ O 377.1648; found 377.1653.

Compound 8: ¹ H NMR (500MHz, CDCl ₃ ) δ7.37–7.29 (m, 8H), 7.28 (d, J=1.9Hz, 1H), 7.15 (d, J=9.0Hz, 1H), 6.34 (dd ,J=9.0,2.1Hz,1H),6.27(d,J=2.1Hz,1H),5.55(s,2H),4.40(t,J=5.4Hz,1H),3.05(dd,J=12.8, 7.0Hz, 2H), 2.45(s, 3H), 1.48(dt, J=14.9, 7.3Hz, 2H), 1.34(dq, J=14.5, 7.3Hz, 2H), 0.91(t, J=7.3Hz, 3H). ¹³ C NMR (126MHz, DMSO-d ₆ ) δ160.31, 158.95, 154.15, 143.22, 139.51, 136.79, 132.18, 129.66, 129.16, 129.07, 127.66, 127.12, 117.43, 109.8 8,96.63,45.91,42.24,30.58, 21.41,20.07,14.07.HRMS(ESI-TOF)m/z[M+H] ⁺ calcd for C ₂₈ H ₂₇ N ₃ O 422.2227,found 422.2227.

Compound 9: ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.65(d, J=7.0Hz, 1H), 7.38(d, J=7.9Hz, 2H), 7.34–7.28(m, 5H), 7.24 (dd, J=11.7,4.7Hz,4H),7.19(dd,J=11.0,5.0Hz,3H),6.93(d,J=9.1Hz,1H),6.59(d,J=8.6Hz,1H) ,6.30(s,1H),5.41(d,J=16.5Hz,1H),5.25(d,J=11.3Hz,1H),4.68–4.44(m,1H),2.41(s,3H),1.39( d, J＝6.7Hz, 3H). ¹³ C NMR (126MHz, CDCl ₃ ) δ160.34, 159.26, 151.67, 143.07, 142.85, 139.71, 135.57, 131.49, 130.94, 129.38, 128.97, 128.79, 128.74 ,127.57,127.41,126.74 ,125.60,116.39,111.47,111.32,99.35,96.59,53.41,46.67,26.93,24.55,21.43.HRMS(ESI-TOF)m/z[M+H] ⁺ calcd for C ₃₂ H ₂₇ N ₃ O470.2227, found470.2224.

Compound 10: ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.49(d, J=4.2Hz, 1H), 7.80(t, J=6.0Hz, 1H), 7.64(td, J=7.7, 1.6Hz ,1H),7.37(dd,J=19.5,8.0Hz,4H),7.25(ddd,J=17.5,10.4,7.2Hz,6H),7.15(d,J=7.8Hz,1H),6.97(d, J＝9.0Hz, 1H), 6.64(d, J＝9.1Hz, 1H), 6.47(s, 1H), 5.40(s, 2H), 4.42(d, J＝6.0Hz, 2H), 2.42(s, 3H). ¹³ C NMR (126MHz, DMSO-d ₆ ) δ166.55, 160.14, 159.18, 158.29, 155.37, 153.99, 150.70, 149.53, 148.93, 143.27, 139.57, 139.53, 138.11, 137.3 2,136.48,136.42,132.16,131.38, 129.67, 129.16, 129.06, 127.67, 127.62, 127.21, 127.07, 126.93, 122.82, 122.36, 121.60, 117.35, 112.30, 110.07, 97.03, 96.90, 48.19, 46.04 ,21.40.HRMS(ESI-TOF)m/z[M+ H] ⁺ calcd for C ₃₀ H ₂₄ N ₄ O 457.2023,found 457.2030.

Compound 11: ¹ H NMR (500MHz, DMSO-d ₆ ) δ8.48(d, J=4.1Hz, 1H), 7.71(d, J=7.0Hz, 1H), 7.63(t, J=7.3Hz, 1H ),7.38(d,J=7.9Hz,2H),7.31(dd,J=16.8,7.6Hz,4H),7.25(d,J=6.9Hz,1H),7.23–7.17(m,4H),6.94 (d,J=9.1Hz,1H),6.63(d,J=7.5Hz,1H),6.36(s,1H),5.43(d,J=14.7Hz,1H),5.23(d,J=5.2Hz ,1H),4.75–4.53(m,1H),2.42(s,3H),1.43(d,J＝6.7Hz,3H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ162.99,160.09,159.06,153.29 . 00,22.24,21.41.HRMS(ESI-TOF)m/z [M+H] ⁺ calcd for C ₃₁ H ₂₆ N ₄ O 471.2179, found 471.2162.

Compound 12: ¹ H NMR (500MHz, CDCl ₃ ) δ8.46(d, J=4.7Hz, 1H), 7.56(td, J=7.7, 1.6Hz, 1H), 7.38(d, J=7.7Hz, 1H ),7.34–7.29(m,3H),7.29–7.24(m,2H),7.23(d,J＝8.3Hz,2H),7.19–7.08(m,3H),7.00(d,J＝7.8Hz, 1H), 6.90(dd, J=9.1, 2.7Hz, 1H), 6.38(d, J=2.6Hz, 1H), 5.54(d, J=11.1Hz, 2H), 4.50(d, J=5.5Hz, 1H), 4.41–4.25(m, 1H), 2.49(s, 3H), 1.45(d, J=6.7Hz, 3H). ¹³ C NMR(126MHz, CDCl ₃ ) δ162.71, 159.22, 158.58, 149.44, 142.72, 139.82, 136.83, 135.83, 132.83, 130.98, 129.62, 129.44, 128.89, 128.61, 128.41, 127.56, 126.85, 122.13, 121.85, 120.80, 120.33, 116.53, 11 5.43, 110.59, 106.40, 54.89, 46.66, 22.92, 21.54. HRMS ( ESI-TOF) m/z[M+H] ⁺ calcd for C ₃₁ H ₂₆ N ₄ O 471.2179,found 471.2158.

Compound 13: ¹ H NMR (400MHz, CDCl ₃ ) δ8.63(d, J=4.2Hz, 1H), 7.64(dd, J=15.7, 6.9Hz, 3H), 7.39(t, J=7.3Hz, 2H ),7.35–7.28(m,6H),7.25–7.20(m,1H),7.09–7.02(m,1H),6.81(d,J＝8.4Hz,1H),6.54(d,J＝7.7Hz, 1H), 5.72(s, 2H), 4.83(d, J=6.5Hz, 1H), 4.31(t, J=6.7Hz, 1H), 2.45(s, 3H), 1.73(d, J=6.8Hz, 3H). ¹³ C NMR (126MHz, CDCl ₃ ) δ163.62, 158.71, 157.78, 149.13, 142.21, 139.65, 137.23, 136.88, 136.06, 131.66, 129.34, 129.23, 129.17, 128.65, 127.98, 127.67, 126.04, 123.33, 122.20, 119.91,115.21,113.88,109.68,97.95,68.71,54.69,31.45,23.22,21.44. HRMS(ESI-TOF)m/z[M+H] ⁺ calcd for C ₃₁ H ₂₆ N ₄ O 471.2179,found 471.2157.

Compound 14: ¹ H NMR (400MHz, CDCl ₃ ) δ8.63 (d, J = 4.8Hz, 1H), 7.69 (td, J = 7.7, 1.7Hz, 1H), 7.38-7.32 (m, 3H), 7.30 (s,1H),7.28–7.18(m,3H),6.51(dd,J=8.9,2.1Hz,1H),6.45(d,J=1.9Hz,1H),5.46(d,J=5.7Hz, 1H),4.89–4.69(m,1H),4.18–4.07(m,2H),2.46(s,3H),1.65(d,J＝6.7Hz,3H),1.34–1.26(m,1H),0.94 –0.84(m,2H),0.50–0.44(m,2H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ163.68,159.79,158.67,153.28,149.60,142.89,139.44,137.67,132.07,130.66,129 .63, 129.01,122.77,120.34,117.22,110.17,97.61,54.49,46.25,26.81,22.49,21.39,9.48,4.22. HRMS(ESI-TOF)m/z[M+H] ⁺ calcd for C ₂₈ H ₂₆ N ₄ O435 .2179,found 435.2179.

Compound 15: ¹ H NMR (400MHz, CDCl ₃ ) δ8.62(d, J=4.8Hz, 1H), 7.74(s, 1H), 7.38(d, J=7.6Hz, 1H), 7.31(d, J =8.1Hz, 4H), 7.24(s, 1H), 7.16(d, J=8.9Hz, 1H), 6.49(dd, J=8.9, 1.9Hz, 1H), 6.33(s, 1H), 4.79(d ,J=6.5Hz,1H),4.27–4.03(m,2H),2.43(s,3H),2.20–2.08(m,1H),1.71(s,2H),1.66(d,J=6.7Hz, 3H),1.60(s,4H),1.49(s,2H). ¹³ C NMR(126MHz,CDCl ₃ )δ162.20,160.24,158.62,151.31,149.53,142.83,139.59,137.24,131.56,131.09,129.34 ,128.75, 128.71,122.56,120.16,116.41,111.46,111.08,99.90,95.93,54.61,46.80,38.21,30.47,30.30,24.81,22.94,21.41 ^. calcd for C ₃₀ H ₃₀ N ₄ O 463.2492, found 463.2474.

Compound 16: ¹ H NMR (400MHz, CDCl ₃ ) δ8.63(d, J=4.8Hz, 1H), 7.70(td, J=7.7, 1.7Hz, 1H), 7.34(dd, J=7.8, 4.8Hz ,4H),7.25(dd,J=7.6,5.0Hz,2H),7.18(d,J=9.0Hz,1H),6.50(dd,J=9.0,2.1Hz,1H),6.30(d,J= 2.0Hz,1H),5.44(d,J=5.8Hz,1H),4.91–4.73(m,1H),4.35–4.03(m,2H),2.45(s,3H),1.65(d,J=6.7 Hz,3H),1.43–1.33(m,6H),0.96(t,J=7.1Hz,3H). ¹³ C NMR(126MHz,CDCl ₃ )δ162.23,159.82,158.66,151.59,149.46,142.66,139.58,137.27 ,131.57,131.08,129.34,128.72,128.69,122.60,120.21,116.39,111.41,111.17,99.60,95.44,54.60,43.03,29.12,26.59,22.85,22.47,21 .40,14.05.HRMS(ESI-TOF)m/z [M+H] ⁺ calcd for C ₂₉ H ₃₀ N ₄ O 451.2492, found 451.2505.

Compound 17: ¹ H NMR (400MHz, CDCl ₃ ) δ8.55(d, J=6.0Hz, 2H), 8.52(d, J=4.8Hz, 1H), 7.81-7.52(m, 1H), 7.39-7.30 (m,5H),7.24–7.12(m,5H),6.49(dd,J=9.0,2.0Hz,1H),6.08(d,J=1.9Hz,1H),5.46(d,J=6.0Hz, 1H),5.37(s,1H),4.74–4.44(m,1H),2.47(s,3H),1.50(d,J＝6.7Hz,3H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ162 .91, 160.02, 159.28, 153.39, 150.25, 149.45, 145.35, 139.56, 137.31, 132.05, 129.66, 129.03, 122.73, 121.98, 120.24, 117.16, 110.25, 97.30 ,53.92,45.26,31.42,26.81,22.21,21.41. HRMS (ESI -TOF)m/z[M+H] ⁺ calcd for C ₃₀ H ₂₅ N ₅ O472.2132,found 472.2123.

Compound 18: ¹ H NMR (400MHz, CDCl ₃ ) δ8.55(d, J=4.1Hz, 1H), 7.64(t, J=7.5Hz, 1H), 7.35(dd, J=14.1, 7.9Hz, 5H ),7.26(s,2H),7.20(d,J=8.5Hz,3H),7.16(s,1H),6.48(d,J=8.9Hz,1H),6.22(s,1H),5.53(d , J＝6.0Hz, 2H), 5.32(s, 1H), 4.66–4.47(m, 1H), 2.47(s, 3H), 1.50(d, J＝6.6Hz, 3H). ¹³ C NMR (126MHz, CDCl ₃ )δ161.38, 160.26, 159.44, 151.57, 149.32, 142.86, 139.82, 137.92, 137.08, 134.77, 131.40, 131.25, 130.23, 129.41, 128.75, 127.75, 12 6.81, 124.96, 122.63, 120.31, 116.22, 111.59, 111.29, 99.34 ,95.92,54.03,46.23,22.48,21.43.HRMS(ESI-TOF)m/z[M+H] ⁺ calcd for C ₃₁ H ₂₅ N ₄ OCl 505.1790,found505.1777.

Compound 19: ¹ H NMR (400MHz, CDCl ₃ ) δ8.55(d, J=3.9Hz, 1H), 7.63(t, J=7.6Hz, 1H), 7.34(dt, J=13.5, 6.8Hz, 5H ),7.19(dd, J=8.2,5.0Hz,3H),7.05(d,J=7.4Hz,1H),6.96(dd,J=14.3,8.8Hz,2H),6.48(d,J=8.8Hz ,1H),6.23(s,1H),5.50(d,J=5.6Hz,2H),5.32(s,1H),4.62–4.49(m,1H),2.47(s,3H),1.49(d, J＝6.7Hz, 3H). ¹³ C NMR (126MHz, CDCl ₃ ) δ161.42, 160.26, 159.44, 151.57, 149.31, 142.85, 139.83, 138.36, 138.31, 137.17, 131.37, 131.25, 130.52, 1 30.45, 129.43, 128.75, 122.66 , _{122.35,120.29,116.23,114.37,113.80,113.62,111.55,111.31,99.34,95.97,54.04,46.20,22.54,21.45 . 25} N ₄ OF 489.2085,found 489.2079.

Compound 20: ¹ H NMR (500MHz, CDCl ₃ ) δ8.56(d, J=4.6Hz, 1H), 7.69(d, J=9.1Hz, 1H), 7.60(t, J=7.6Hz, 1H), 7.30(t, J=7.4Hz, 2H), 7.24–7.13(m, 5H), 6.52(d, J=9.1Hz, 1H), 6.27(s, 1H), 5.55(s, 1H), 5.40(d ,J=6.5Hz,1H),5.20(s,1H),4.52(dd,J=13.2,6.7Hz,1H),3.81–3.72(m,1H),2.19–2.01(m,6H),1.91– 1.75(m,2H),1.45(d,J=6.7Hz,3H) ^.13 CNMR(126MHz,DMSO-d ₆ )δ164.20,163.10,160.56,152.95,149.50,142.61,137.47,136.36,129.08,127.55,1 26.99 ,122.78,120.32,117.38,109.60,96.26,55.34,54.02,45.98,41.13,33.07,33.02,27.36,22.30. HRMS(ESI-TOF)m/z[M+H] ⁺ calcd for C ₂₉ H ₂₈ N ₄ O449.2336,found449.2332.

Compound 21: ¹ H NMR (400MHz, CDCl ₃ ) δ8.58(d, J=3.8Hz, 1H), 8.05(d, J=8.9Hz, 1H), 7.63(t, J=7.4Hz, 1H), 7.31(s, 2H), 7.26(d, J=6.1Hz, 1H), 7.23–7.16(m, 3H), 6.86(d, J=8.0Hz, 1H), 6.59(d, J=9.2Hz, 1H ),6.25(s,1H),5.55(d,J=14.3Hz,1H),5.45(s,1H),5.23(s,1H),4.68–4.48(m,1H),3.75(dd,J= 14.0,7.0Hz,1H),1.49(d,J＝6.7Hz,3H),1.37–1.26(m,4H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ163.17,160.45,159.48,157.78,152.97, 149.52, 142.23, 137.46, 136.42, 129.83, 129.05, 127.54, 127.04, 122.76, 120.35, 119.25, 116.92, 115.69, 111.51, 98.62, 54.02, 45.84, 22.32 ,13.23,8.30,8.27.HRMS(ESI-TOF)m/ z[M+H] ⁺ calcd for C ₂₇ H ₂₄ N ₄ O 421.2023,found 421.2013.

Compound 22: ¹ H NMR (500MHz, CDCl ₃ ) δ8.56(d, J=4.1Hz, 1H), 7.78(d, J=9.0Hz, 1H), 7.60(t, J=7.1Hz, 1H), 7.33–7.27(m,2H),7.24–7.12(m,5H),6.54(d,J=9.1Hz,1H),6.27(s,1H),5.55(s,1H),5.43(d,J= 6.2Hz, 1H), 5.20(s, 1H), 4.67–4.45(m, 1H), 3.74(s, 1H), 1.56(d, J=10.1Hz, 6H), 1.45(d, J=6.7Hz, 3H). ¹³ C NMR (126MHz, DMSO-d ₆ ) δ165.57, 163.09, 160.62, 152.96, 149.46, 142.94, 137.39, 136.44, 129.04, 128.39, 127.52, 127.05, 120.37, 117.4 5,111.61,109.02,96.32,54.12, 46.09,22.20,21.07.HRMS(ESI-TOF)m/z[M+H] ⁺ calcd for C ₂₇ H ₂₆ N ₄ O 423.2179,found 423.2175.

Compound 23: ¹ H NMR (400MHz, CDCl ₃ ) δ8.58(s, 1H), 8.05(d, J=9.1Hz, 1H), 7.68(s, 1H), 7.30(s, 2H), 7.27–7.14 (m,5H),6.55(d,J=8.6Hz,1H),6.26(s,1H),5.50(s,2H),5.37(s,1H),4.59(d,J=5.7Hz,1H) ,1.78(s,9H),1.50(d,J=6.0Hz,3H). ¹³ C NMR(126MHz,CDCl ₃ )δ166.05,161.66,161.31,149.98,149.01,142.57,137.47,135.76,131.17,128.84,12 7.34 ,126.72,122.64,120.55,117.75,110.27,110.05,99.11,96.54,53.82,47.22,38.62,33.18,22.53. HRMS(ESI-TOF)m/z[M+H] ⁺ calcd for C ₂₈ H ₂₈ N ₄ O 437.2336,found 437.2318.

Compound 24: ¹ H NMR (400MHz, CDCl ₃ ) δ8.63 (d, J = 4.7Hz, 1H), 7.70 (dd, J = 14.0, 8.3Hz, 2H), 7.35 (d, J = 7.8Hz, 1H ),7.26–7.21(m,1H),6.61(dd,J＝9.1,1.8Hz,1H),6.30(s,1H),5.36(d,J＝5.6Hz,1H),4.88–4.67(m, 1H), 4.11(dt, J＝21.1, 13.6Hz, 2H), 3.88–3.59(m, 1H), 2.21–1.98(m, 6H), 1.83(s, 2H), 1.70(d, J＝4.2Hz , 2H), 1.65(s, 3H), 1.59(dd, J＝12.1, 7.2Hz, 2H), 1.47(s, 1H), 1.40–1.25(m, 4H). ¹³ C NMR (126MHz, DMSO-d ₆ ) δ163.76, 163.29, 160.43, 152.85, 149.55, 142.57, 137.49, 128.22, 122.67, 120.25, 117.29, 111.48, 109.62, 96.80, 96.04, 54.56, 46.30, 41 .35, 37.93, 32.93, 30.31, 30.10, 27.22, 24.78, 22.54.HRMS(ESI-TOF)m/z[M+H]+calcd for C ₂₈ H ₃₂ N ₄ O 441.2649,found 441.2639.

Compound 25: ¹ H NMR (400MHz, CDCl ₃ ) δ8.48(d, J=2.7Hz, 1H), 7.75(d, J=9.1Hz, 1H), 7.46–7.39(m, 1H), 7.35(dd ,J=8.6,4.4Hz,1H),6.62(dd,J=9.1,2.2Hz,1H),6.41(d,J=2.1Hz,1H),5.58(t,J=5.1Hz,1H),4.57 (d, J = 5.2Hz, 2H), 4.19 (d, J = 7.1Hz, 2H), 3.76 (dt, J = 18.4, 9.4Hz, 1H), 2.22 (dd, J = 15.0, 7.5Hz, 1H) ,2.18–2.03(m,6H),1.83(d,J＝6.4Hz,2H),1.71(s,2H),1.62(d,J＝6.5Hz,2H),1.52–1.44(m,2H), 1.44–1.33(m,2H) ^.13 CNMR(126MHz,CDCl ₃ )δ163.19,160.56,159.85,157.82,152.61,151.35,142.65,137.67,137.48,128.19,123.94,123.79,12 2.42, 122.38, 116.58, 110.66, 110.22 _{, 99.89,96.13,47.89,46.79,42.49,38.33,33.12,30.47,27.43,24.81} ^. _{_}

Compound 26: ¹ H NMR (400MHz, CDCl ₃ ) δ8.50(d, J=2.7Hz, 1H), 7.77(d, J=9.1Hz, 1H), 7.45(td, J=8.3, 2.8Hz, 1H ),7.38(dd,J=8.7,4.4Hz,1H),6.65(dd,J=9.1,2.1Hz,1H),6.39(d,J=2.0Hz,1H),5.65(s,1H),4.59 (d,J=5.2Hz,2H),4.25–4.09(m,2H),3.76(dd,J=18.8,9.5Hz,1H),2.28–1.99(m,6H),1.84(s,2H), 1.68(td, J=15.2,7.6Hz,2H),1.02(t,J=7.4Hz,3H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ163.56,159.91,159.76,157.75,155.32,155.29,153.48 ,142.37,137.50,137.32,128.45,124.43,124.28,123.27,123.23,117.36,109.63,96.56,47.74,47.63,43.97,41.09,32.98,27.34,20.00,11 .51.HRMS(ESI-TOF)m/z[M +H] ⁺ calcd for C ₂₅ H ₂₅ FN ₄ O 417.2085,found 417.2088.

Compound 27: ¹ H NMR (500MHz, DMSO-d ₆ ) δ8.54(d, J=2.7Hz, 1H), 7.85(d, J=9.2Hz, 1H), 7.80(s, 1H), 7.70(td ,J=8.7,2.8Hz,1H),7.44(dd,J=8.6,4.5Hz,1H),6.74(d,J=9.2Hz,1H),6.55(s,1H),4.58(d,J= 5.9Hz, 2H), 4.02(d, J=6.8Hz, 2H), 3.74(d, J=9.0Hz, 1H), 2.00(d, J=6.9Hz, 6H), 1.76(s, 2H), 0.93 (S, 1H), 0.36 (d, j = 6.2Hz, 4H). ¹³ C NMR (126MHz, DMSO-D ₆ ) Δ163.65,160.27,1576,1575,155.26,153.51,142.64.52,137.34,1288 .47 ,124.42,124.27,123.27,123.23,117.38,109.63,96.67,47.72,46.13,41.12,32.98,27.35,9.57,4.16. HRMS(ESI-TOF)m/z[M+H] ⁺ calcd for C ₂₄ H ₂₅ FN ₄ O405.2085,found 405.2087.

Compound 28: ¹ H NMR (400MHz, CDCl ₃ ) δ8.50(d, J=2.6Hz, 1H), 7.77(d, J=9.0Hz, 1H), 7.45(td, J=8.3, 2.9Hz, 1H ),7.37(dd,J=8.7,4.2Hz,1H),6.65(d,J=9.0Hz,1H),6.40(s,1H),5.63(s,1H),4.59(d,J=5.2Hz ,2H),4.26–4.04(m,2H),3.89–3.66(m,1H),2.41–2.02(m,6H),1.84(s,2H),1.64(d,J＝8.3Hz,2H), 1.39(d, J=3.7Hz, 4H), 0.95(t, J=6.9Hz, 3H). ¹³ C NMR (126MHz, DMSO-d ₆ ) δ163.39, 159.91, 157.77, 155.28, 153.52, 142.47, 137.47, 137.28 ,128.42,124.36,124.21,123.07,117.25,111.21,109.75,96.77,95.20,47.84,47.73,42.49,41.30,41.13,32.96,28.92,27.33,27.26,26.51 , 22.29, 22.23, 14.24, 14.17. HRMS (ESI -TOF)m/z[M+H] ⁺ calcd for C ₂₆ H ₂₉ FN ₄ O 433.2398,found 433.2401.

Compound 29: ¹ H NMR (400MHz, CDCl ₃ ) δ8.53(d, J=4.0Hz, 1H), 7.70(d, J=9.1Hz, 1H), 7.60(t, J=7.1Hz, 1H), 7.18(dd,J=16.7,8.6Hz,5H),7.07(s,1H),6.56(d,J=8.9Hz,1H),6.17(s,1H),5.52(d,J=5.8Hz,2H ),5.22(s,1H),4.65–4.41(m,1H),3.76(dd,J＝18.4,9.1Hz,1H),2.24–2.04(m,6H),1.83(s,2H),1.47( d, J＝6.6Hz, 3H). ¹³ C NMR (126MHz, CDCl ₃ ) δ164.25, 161.50, 160.65, 151.13, 149.29, 142.56, 137.95, 137.13, 134.70, 130.19, 128.11, 127.67, 126.69 ,124.86,122.63,120.32 ,116.47,111.22,98.90,96.43,54.01,46.24,42.53,33.21,27.44,22.52.HRMS(ESI-TOF)m/z[M+H] ⁺ calcd for C ₂₉ H ₂₇ ClN ₄ O483.1946,found 483.1952 .

Compound 30: ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.45(d, J=4.2Hz, 1H), 7.82(d, J=9.3Hz, 1H), 7.60(d, J=6.7Hz, 2H ),7.30(dd,J=13.7,7.3Hz,1H),7.21–7.14(m,2H),7.04(t,J=7.5Hz,1H),6.94(dd,J=19.9,8.7Hz,2H) ,6.71(d,J=8.5Hz,1H),6.24(s,1H),5.30(d,J=17.1Hz,2H),4.86–4.52(m,1H),3.76(dd,J=17.8,8.7 Hz, 1H), 2.03(d, J=5.2Hz, 6H), 1.76(s, 2H), 1.44(d, J=6.8Hz, 3H). ¹³ C NMR(126MHz, DMSO-d ₆ ) δ164.45, 163.67 ,163.04,161.73,160.57,152.98,149.39,142.53,139.26,139.20,137.41,131.12,131.05,128.43,122.76,120.21,117.35,114.55,114.38,1 13.82, 113.64, 109.62, 96.17, 55.28, 53.94, 45.65, 33.08 ,33.04,27.37,22.29.HRMS(ESI-TOF)m/z[M+H] ⁺ calcd for C ₂₉ H ₂₇ FN ₄ O ⁺ 467.2242,found467.2245.

Compound 31: ¹ H NMR (400MHz, CDCl ₃ ) δ7.71(d, J=9.1Hz, 1H), 7.28(d, J=6.8Hz, 1H), 7.23(d, J=6.9Hz, 2H), 7.15(d, J=7.0Hz, 2H), 6.71(dd, J=24.7, 9.0Hz, 3H), 6.51(d, J=9.1Hz, 1H), 6.28(s, 1H), 5.95(s, 2H ),5.38(s,2H),4.82(s,1H),4.17(d,J=5.2Hz,2H),3.90–3.69(m,1H),2.12(dd,J=20.2,6.4Hz,6H) ,1.83(d,J=4.4Hz,2H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ164.14,160.61,153.60,147.83,146.63,142.74,136.49,132.76,129.03,128.49,127.52,126. 99,120.59, 117.44,109.59,108.56,107.89,101.32,96.17,45.99,45.90,41.20,33.08,27.39.HRMS(ESI-TOF)m/z[M+H] ⁺ calcd for C ₃₀ H ₂₇ N ₃ O ₃ 478.2125,found 478.2131.

Compound 32: ¹ H NMR (400MHz, CDCl ₃ ) δ7.70(d, J=8.7Hz, 1H), 7.31(d, J=7.2Hz, 3H), 7.25–7.19(m, 2H), 6.45(d ,J=9.4Hz,1H),6.24(s,1H),5.50(s,2H),4.50(s,1H),3.93(d,J=8.1Hz,2H),3.85–3.69(m,1H) ¹³ C NMR(126MHz, CDCl ₃ )δ163.92, 160.74, 151.93, 142.86, 136.08, 128.95, 128.11, 127.48, 126.48, 116.48, 110.25, 100.21, 99.20, 95.91, 67.42, 49.14 ,46.86,42.58,34.38,33.20,30.68,27.45 .HRMS(ESI-TOF)m/z[M+H] ⁺ calcdfor C ₂₈ H ₃₁ N ₃ O ₂ 442.2489,found 442.2479.

Compound 33: ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.82(d, J=9.4Hz, 1H), 7.37(dd, J=14.3, 7.7Hz, 1H), 7.24(s, 1H), 7.11 (dd,J=15.2,9.0Hz,2H),7.01(d,J=7.7Hz,1H),6.64(d,J=8.7Hz,1H),6.21(s,1H),5.48(s,2H) ,3.78(d,J=11.4Hz,2H),3.08(t,J=11.1Hz,2H),2.96(s,2H),2.03(d,J=19.4Hz,6H),1.78(s,2H) ,1.43(d,J=11.9Hz,3H),1.07(d,J=9.6Hz,2H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ164.06,163.87,160.76,154.02,142.82,139.93,131.23, 128.42, 122.87, 117.37, 114.52,

114.36,113.99,113.82,109.38,95.87,95.04,67.09,48.40,45.63,41.45,34.36,33.04,30.80,30.73,27.38,27.29.HRMS(ESI-TOF)m/z[M+H] ⁺ calc d for C ₂₈ H ₃₀ FN ₃ O ₂

460.2395,found 460.2387.

Compound 34: ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.82(d, J=9.0Hz, 1H), 7.26(dd, J=15.4, 9.8Hz, 3H), 7.16(t, J=8.7Hz ,2H),6.65(d,J=8.7Hz,1H),6.23(s,1H),5.45(s,2H),3.79(d,J=8.1Hz,2H),3.17–3.03(m,2H) , 2.96(s, 2H), 2.06(s, 6H), 1.78(s, 2H), 1.45(d, J=11.0Hz, 3H), 1.08(d, J=9.7Hz, 2H). ¹³ C NMR( 126MHz,DMSO-d ₆ )δ163.97,160.75,154.01,142.82,133.02,131.95,128.99,128.93,128.39,116.00,115.83,109.38,95.88,67.12,48.39,45.37 ,41.43,34.36,33.03,30.82,27.29.HRMS (ESI-TOF)m/z[M+H] ⁺ calcd for C ₂₈ H ₃₀ FN ₃ O ₂ 460.2395,found 460.2392.

Compound 35: ¹ H NMR (400MHz, CDCl ₃ ) δ7.75(d, J=8.9Hz, 1H), 7.32(d, J=7.1Hz, 1H), 7.06(d, J=7.8Hz, 1H), 6.97(dd,J=17.1,9.1Hz,2H),6.50(d,J=8.5Hz,1H),6.19(s,1H),5.50(s,2H),4.63(d,J=13.3Hz,1H ),3.89–3.66(m,2H),3.02(d,J=5.6Hz,2H),2.95(d,J=12.5Hz,1H),2.42(t,J=12.2Hz,1H),2.19(s ,4H),2.10(s,5H),1.87(s,2H),1.67(s,3H),1.08(s,2H),0.90(s,1H). ¹³ C NMR(126MHz,DMSO-d ₆ ) δ168.33, 164.19, 161.84, 160.77, 153.90, 139.92, 138.63, 131.30, 128.47, 122.81, 117.53, 114.58, 114.41, 114.02, 113.85, 109.26, 95.62, 47 .72,45.97,45.50,41.18,41.03,35.27,33.08,30.37, 29.59,27.40,21.75.HRMS(ESI-TOF)m/z[M+H] ⁺ calcd for C ₃₀ H ₃₃ FN ₄ O ₂ 501.2660,found 501.2665.

Compound 36: ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.84(d, J=9.3Hz, 1H), 7.39(dd, J=14.2, 7.7Hz, 1H), 7.26(s, 1H), 7.11 (dd,J=18.8,9.5Hz,2H),7.04(d,J=7.6Hz,1H),6.66(d,J=8.8Hz,1H),6.23(s,1H),5.48(s,2H) ,3.79(dd,J=16.0,11.2Hz,1H),3.14(d,J=12.2Hz,2H),2.98(t,J=5.8Hz,2H),2.57(d,J=12.1Hz,2H) ,2.04(d,J=16.4Hz,6H),1.78(s,2H),1.64(d,J=12.9Hz,2H),1.46(s,1H),1.16(dd,J=22.5,11.4Hz, 3H). ¹³ C NMR (126MHz, DMSO-d ₆ ) δ164.25, 163.75, 161.81, 160.75, 153.82, 142.72, 139.95, 131.32, 131.26, 128.55, 122.94, 117.50, 114.56, 114.4 0,114.09,113.92,109.33,95.77, 47.59,45.50,43.87,41.19,33.37,33.09,27.49,27.41.HRMS(ESI-TOF)m/z[M+H] ⁺ calcd for C ₂₈ H ₃₁ FN ₄ O459.2555,found459.2559.

Compound 37: ¹ H NMR (500MHz, CDCl ₃ ) δ7.73(d, J=9.1Hz, 1H), 7.27–7.21(m, 2H), 7.03(t, J=8.6Hz, 2H), 6.49(d ,J=9.0Hz,1H),6.22(s,1H),5.48(s,2H),4.58(s,1H),3.93–3.71(m,1H),3.12(d,J=11.8Hz,2H) ,2.99(t,J=6.3Hz,2H),2.55(t,J=12.2Hz,2H),2.14(d,J=33.3Hz,6H),1.86(s,2H),1.54(m,2H) ,1.25–1.13(m,2H),0.89(d,J＝6.6Hz,1H). ¹³ CNMR(126MHz,DMSO-d ₆ )δ164.07,162.69,160.77,153.94,142.77,133.00,128.99,128.43,117.55, 116.06,115.89,109.21,95.52,48.43,45.56,45.26,41.16,35.12, 33.06,30.29,27.39.hrms (ESI-TOF) M/Z [m + H] ⁺ Calcd for C ₂₈ H ₃₁ FN _459.255 5, found 459.2548.

Compound 38: ¹ H NMR (500MHz, CDCl ₃ ) δ7.71(d, J=9.1Hz, 1H), 7.32–7.27(m, 1H), 7.06(d, J=7.6Hz, 1H), 6.94(t ,J=8.0Hz,2H),6.50(d,J=9.0Hz,1H),6.19(s,1H),5.48(s,2H),5.20(s,1H),3.88–3.69(m,1H) ,3.03(d,J=4.6Hz,2H),2.63(t,J=5.4Hz,2H),2.52(dd,J=13.6,6.7Hz,4H),2.28–2.05(m,6H),1.84( s,2H),0.99(t,J=7.0Hz,6H). ¹³ C NMR(126MHz,CDCl ₃ )δ164.15,162.18,160.77,152.46,142.70,138.79,138.73,130.45,130.39,128.07,122.46,1 22.44, 116.63,114.48,114.31,113.91,113.73,110.77,110.03,98.37,95.68,50.76,46.50,46.22,42.49,40.18,33.20,27.45,11.61.HRMS(ESI-TOF)m/z [M+H] ⁺ calcd for C ₂₈ H ₃₃ FN ₄ O 461.2711, found 461.2725.

Compound 39: ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.83(d, J=9.3Hz, 1H), 7.38(dd, J=14.2, 7.8Hz, 1H), 7.26(d, J=5.4Hz ,1H),7.11(dd,J=17.4,9.0Hz,2H),7.02(d,J=7.6Hz,1H),6.66(d,J=8.1Hz,1H),6.22(s,1H),5.48 (s,2H),3.79(dd,J=18.2,9.1Hz,1H),2.95(d,J=5.3Hz,2H),2.79(d,J=10.9Hz,2H),2.21(s,3H) , 2.03(d, J＝20.9Hz, 6H), 1.87–1.71(m, 3H), 1.55(d, J＝11.3Hz, 2H), 1.18–1.05(m, 2H). ¹³ C NMR (126MHz, DMSO -d ₆ )δ164.15,163.79,161.84,160.76,153.92,142.76,139.95,131.27,131.20,128.45,122.82,117.54,114.60,114.43,114.03,113.86,109 .23,95.59,55.00,47.98,45.99,45.50,41.18, 34.08, 33.07, 29.55, 27.40. HRMS (ESI-TOF) m/z[M+H] ⁺ calcd for C ₂₉ H ₃₃ FN ₄ O 473.2711, found 473.2718.

Compound 40: ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.81(d, J=9.2Hz, 1H), 7.37(dd, J=14.3, 7.3Hz, 1H), 7.19(s, 1H), 7.10 (dd,J=15.3,8.9Hz,2H),7.00(d,J=7.5Hz,1H),6.63(d,J=9.3Hz,1H),6.18(s,1H),5.46(s,2H) ,3.89–3.71(m,1H),2.89(s,2H),2.06(s,6H),1.78(s,2H),1.56(d,J＝9.6Hz,4H),1.04(s,3H), 0.85 (s, 1H), 0.76 (D, J = 10.7Hz, 2H). ¹³ C NMR (126MHz, DMSO-D ₆ ) Δ164.10, 1160.84,154.16,142.83,139.85,114.34,113.28.28,102.10.10 ,, 95.55,49.07,48.90,45.67,41.41,37.12,33.04,31.59,30.79,27.28,26.37,25.68. HRMS(ESI-TOF)m/z[M+H] ⁺ calcd for C ₂₉ H ₃₂ FN ₃ O 458.2602, found458.2609.

Compound 41: ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.84(d, J=9.3Hz, 1H), 7.37(dd, J=14.2, 7.8Hz, 1H), 7.08(dt, J=25.5, 9.1Hz, 4H), 6.66(d, J=8.2Hz, 1H), 6.27(s, 1H), 5.47(s, 2H), 3.90–3.72(m, 1H), 3.63–3.49(m, 4H), 3.18(dd, J＝12.4, 6.4Hz, 2H), 2.37–2.21(m, 6H), 2.03(d, J＝18.7Hz, 6H), 1.78(s, 2H). ¹³ C NMR (126MHz, DMSO- d ₆ )δ164.25,163.79,161.85,160.71,153.71,142.72,139.87,139.81,131.27,131.21,128.53,122.92,117.49,114.56,114.39,114.17,113. 99,109.38,95.77,66.55,56.84,53.70,45.47,41.16 ,33.08,27.40.HRMS(ESI-TOF)m/z[M+H] ⁺ calcd for C ₂₈ H ₃₁ FN ₄ O ₂ 475.2504,found 475.2512.

Compound 42: ¹ H NMR (400MHz, CDCl ₃ ) δ7.72(d, J=8.9Hz, 1H), 7.28(d, J=12.0Hz, 1H), 7.05(d, J=7.3Hz, 1H), 6.94(d,J=7.6Hz,2H),6.51(d,J=8.8Hz,1H),6.25(s,1H),5.47(s,2H),4.84(s,1H),3.76(ddd,J =55.2,25.9,11.0Hz,4H),3.10(dd,J=14.2,6.1Hz,2H),2.66(d,J=11.0Hz,2H),2.29(s,3H),2.13(dd,J= 21.0,7.3Hz,6H),1.95–1.69(m,4H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ164.23,163.78,161.83,160.72,153.92,142.65,139.81,131.19,128.49,122.98, 117.45, 114.61,114.44,114.15,113.98,109.44,95.90,73.91,66.15,58.08,54.78,46.27,45.59,45.35,41.20,33.08,27.40.HRMS(ESI-TOF)m/z[M+H] ⁺ cal cd for C ₂₈ H ₃₁ FN ₄ O ₂ 475.2504, found 475.2508.

Compound 43: ¹ H NMR (400MHz, DMSO-d ₆ )δ7.84(d, J=9.2Hz, 1H), 7.39–7.26(m, 2H), 7.16(t, J=8.7Hz, 2H), 6.68 (d,J=9.0Hz,1H),6.36(s,1H),5.43(dd,J=26.7,15.7Hz,2H),3.85–3.76(m,1H),3.73(d,J=11.1Hz, 1H), 3.40(d, J=10.7Hz, 3H), 3.15(d, J=5.7Hz, 2H), 2.58(dd, J=20.6, 11.5Hz, 2H), 2.15(s, 3H), 2.12– 1.89(m,6H),1.78(s,2H),1.65(t,J=10.5Hz,1H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ164.03,160.70,153.95,142.73,132.99,129.22,129.15 ,128.44,117.31,115.99,115.82,109.57,96.16,95.48,74.02,66.22,58.17,54.86,46.26,45.50,45.39,41.43,39.41,33.04,27.29.HRMS(ESI-TO F)m/z[M+H ] ⁺ calcd for C ₂₈ H ₃₁ FN ₄ O ₂ 475.2504,found 475.2510.

Compound 44: ¹ H NMR (400MHz, CDCl ₃ ) δ7.73(d, J=9.0Hz, 1H), 7.30(d, J=11.3Hz, 1H), 7.08(d, J=7.4Hz, 1H), 6.96(t, J=8.5Hz, 2H), 6.54(d, J=8.6Hz, 1H), 6.22(s, 1H), 5.50(s, 2H), 5.37(s, 1H), 3.94–3.72(m ,1H),3.11(d,J=4.8Hz,1H),2.57(s,2H),2.40(s,3H),2.15(d,J=29.2Hz,6H),1.86(s,2H),1.60 (s,4H),1.48(s,2H),1.29(d,J=11.1Hz,2H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ164.51,163.70,161.76,160.60,153.04,142.56,139.77, 131.24,131.17,128.74,123.18,117.31,114.61,114.44,114.33,114.15,109.92,96.58,54.26,52.58,45.28,41.19,37.02,33.12,27.41,22. 70,21.68.HRMS(ESI-TOF)m/z[ M+H] ⁺ calcd for C ₂₉ H ₃₃ FN ₄ O 473.2711, found 473.2720.

Compound 45: ¹ H NMR (500MHz, DMSO-d ₆ ) δ7.83(d, J=9.4Hz, 1H), 7.37(dd, J=14.1, 8.0Hz, 1H), 7.22(t, J=5.9Hz ,1H),7.15–7.08(m,2H),7.02(d,J＝7.7Hz,1H),6.68(dd,J＝9.2,2.0Hz,1H),6.33(s,1H),5.45(d, J＝36.1Hz, 2H), 3.83–3.77(m, 1H), 3.68(dd, J＝14.4, 6.9Hz, 2H), 3.08(dd, J＝13.7, 6.9Hz, 2H), 2.72–2.58(m ,1H),2.41–2.34(m,2H),2.13–1.94(m,6H),1.77(dd,J＝20.0,12.2Hz,4H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ164.29,163.77 . 55, 46.83, 45.44, 41.11, 33.09, 29.09, 27.41, 25.54 .HRMS(ESI-TOF)m/z[M+H] ⁺ calcd for C ₂₇ H ₂₈ FN ₃ O ₂ 446.2238,found 446.2241.

Compound 46: ¹ H NMR (400MHz, CDCl ₃ ) δ8.23(d, J=3.6Hz, 1H), 7.82(d, J=9.4Hz, 1H), 7.57-7.50(m, 1H), 7.39-7.29 (m,4H),7.28–7.25(m,1H),6.81(dd,J＝9.4,2.3Hz,1H),6.74–6.63(m,2H),6.57(d,J＝2.3Hz,1H), 5.55(s,2H),3.82(dd,J＝18.6,9.2Hz,1H),3.68(dd,J＝6.3,4.2Hz,4H),3.50–3.35(m,4H),2.32–2.03(m, 6H),1.95–1.75(m,2H). ¹³ C NMR(126MHz,DMSO-d ₆ )δ164.34,160.58,159.01,153.84,148.04,142.03,138.13,136.95,129.23,128.58,127.76,127 .37, 113.70, 111.06 ,107.54,98.67,86.04,46.31,45.30,44.19,41.19,33.16,27.44.HRMS(ESI-TOF)m/z[M+H]+calcd for C ₃₁ H ₃₁ N ₅ O 490.2601,found 490.2578.

Compound 47: ¹ H NMR (400MHz, CDCl ₃ ) δ7.73(d, J=9.1Hz, 1H), 7.40(d, J=4.5Hz, 1H), 7.30(s, 2H), 7.24–7.17(m ,1H),7.14–6.89(m,5H),6.52(d,J=9.1Hz,1H),6.36(s,1H),5.73(s,1H),5.30(d,J=16.0Hz,1H) ,5.01(d,J=7.8Hz,1H),3.91–3.73(m,1H),3.62(s,1H),3.19(d,J=11.4Hz,1H),3.14–2.93(m,3H), 2.16(d,J=28.5Hz,6H),1.86(s,2H),1.66(d,J=9.2Hz,3H),0.97–0.80(m,1H). ¹³ CNMR(126MHz,DMSO-d ₆ ) δ164.15,160.74,152.69,142.77,140.52,136.84,129.08,127.50,126.92,125.31,122.99,120.29,117.49,116.44,109.47,95.92,55.39,51. 41, 48.99, 45.82, 41.13, 33.08, 29.80, 27.38, 24.01. HRMS(ESI-TOF)m/z[M+H]+calcd for C ₃₃ H ₃₃ N ₄ OF 521.2711,found 521.2695.

The inhibitory activity of embodiment 3 substituted cyanoquinolinones to PDE1C

The inhibitory activity of the obtained compounds 1-47 on phosphodiesterase type 1 was determined: the IC ₅₀ of the tested compounds on PDE1C inhibition, the results are shown in Table 2.

The inhibitory effect of table 2 compound on phosphodiesterase type 1

It can be seen from the table that most of the compounds showed certain inhibitory effect on phosphodiesterase type 1, and compounds 11, 20, 24, 25, and 29 had particularly obvious inhibitory effects on phosphodiesterase type 1, and the IC for PDE1C ₅₀ below 20nM.

Example 4 Effects of substituted cyanoquinolinones on bleomycin-induced pulmonary fibrosis

In this embodiment, compound 25 was taken as an example to carry out animal experiments, and the effects of other compounds were similar to it. The specific experimental method is as follows:

SPF male SD rats (200 ± 20) g were randomly divided into 4 groups: control group (Con), model group (Mod), pirfenidone (150 mg/kg) positive control group (PFD), compound 25 ( 5 mg/kg) group (3f). The modeling method is as follows: intratracheal instillation with bleomycin solution (BLM, 5mg/kg), intratracheal injection of the same amount of normal saline in the control group rats; The same amount of normal saline was administered, and the respiratory function indexes of relaxation time (RT) and airway stenosis index (Penh) of each group were measured after continuous administration for 28 days. The test results are shown in Figure 1.

It can be seen from the figure that, compared with the control group, the indicators of the model group were statistically significant, suggesting that the model was successfully established; after 28 days of treatment with PFD (150mg/kg) or compound 25 (5mg/kg), all these parameters were obtained. A certain recovery, indicating that both PFD and compound 25 can regulate and improve the respiratory dysfunction caused by BLM.

The expression level of the myofibroblast marker protein α-SMA in rat lung tissue was determined, and the results are shown in FIG. 2 . It can be seen from the figure that after bleomycin induction, the level of myofibroblast marker protein α-SMA in the lung tissue of rats in the model group was significantly increased, and after compound 25 and pirfenidone treatment, the expression of α-SMA was significantly reduced. It shows that compound 25 can significantly improve BLM-induced pulmonary fibrosis after treatment.

The above results indicated that the substituted cyanoquinolinone compound 25 had a significant improvement effect on BLM-induced pulmonary fibrosis.

Example 5 Effect of substituted cyanoquinolinones on dextran sodium sulfate DSS-induced enteritis

In this embodiment, compound 25 was taken as an example to carry out animal experiments, and the effects of other compounds were similar to it. The specific experimental method is as follows:

Forty mice were randomly divided into 4 groups: control group, DSS-induced model group, 25 (5.0mg/kg, twice a day, ip) group and positive control group (DIP, 25mg/kg, two weeks a day, ip ), 10 in each group. The drug was prepared by ad libitum drinking of 3% DSS (MW36000-50000, batch number: A0418C; Merumbio, China, Dalian) in autoclaved drinking water (w/v) for 7 consecutive days (day 1 to day 8). Model. The DSS solution was changed every 2-3 days, and the control group drank water freely. During modeling and drug treatment, mice were examined every morning while feces were obtained. Assess for weight loss, stool consistency, and blood. An occult blood test (OB reagent, Baso) was used to measure blood in the stool and to calculate a body weight score for weight loss relative to day 1.

Mice were anesthetized with sodium pentobarbital (45 mg/kg, Sigma) and euthanized on the morning of day 8. The abdomen was cut longitudinally to expose the gastrointestinal tract. The entire colon from the cecum to the rectum was excised, and the length of the colon was recorded with a caliper and photographed. Approximately 1 cm of the distal colon was dissected and left overnight in 4% paraformaldehyde at room temperature before embedding in paraffin. Paraffin-embedded tissue sections with a thickness of 5 μm were placed on glass slides. Paraffin was deparaffinized and eluted through a gradient and stained with hematoxylin and eosin (H&E). The pathological changes of colonic inflammation were observed with a microscope (20× objective lens, Life Technologies, EVOS FL Auto).

The results are shown in Figure 3. It can be seen from the figure that the end of the colon in the model group was shortened, and hematoxylin-eosin (H&E) staining showed obvious pathological damage, including lymphocyte infiltration in the lamina propria of the colonic mucosa, local intestinal epithelial defects, and fibrous tissue in the lamina propria Hyperplasia, intestinal gland dilation. Compound 25 (5.0 mg/kg, twice a day, ip) significantly increased colon length and pathological conditions.

The above-mentioned embodiment is a preferred embodiment of the present invention, but the embodiment of the present invention is not limited by the above-mentioned embodiment, and any other changes, modifications, substitutions, combinations, Simplifications should be equivalent replacement methods, and all are included in the protection scope of the present invention.

Claims (10)

1. a substituted cyanoquinolinone compound, characterized in that, the substituted cyanoquinolinone compound has a formula (I) structure: Wherein, R ₁ is C _1-8 alkyl or substituted C _{1-8 alkyl, and the substituent of said substituted C 1-8 alkyl} is phenyl or substituted phenyl, C _3-8 cycloalkyl or N-containing , O, S one or more heterocyclic groups; _R2 is phenyl or substituted phenyl, heterocyclic group containing one or more of N, O, S, amino or substituted amino, C _3~8 cycloalkyl, C _1~8 alkyl, indene full or substituted indane; R ₃ is hydrogen, amino or substituted amino, piperazinyl or pyridine substituted piperazinyl; The substituent of the substituted amino group is C _1-5 alkyl or substituted C _1-5 alkyl, the substituent of the substituted C _1-5 alkyl is phenyl or substituted phenyl, pyridyl, halogenated pyridine Base, benzobisoxazolyl, tetrahydropyranyl, piperidine or substituted piperidinyl, C _1~5 alkyl substituted amino, C _3~8 cycloalkyl, morpholinyl or substituted morpholinyl, Tetrahydrofuryl; the substituent of the substituted piperidinyl or substituted morpholinyl is C _2-4 alkanonyl, C _1-5 alkyl, pyridyl, halogenated phenyl; The substituent of the substituted phenyl is C _1-5 alkyl, halogen; the substituent of the substituted indane is methylcarboxylate. 2. The substituted cyanoquinolinone compound according to claim 1, characterized in that, the R ₁ is a C _1～5 alkyl or a substituted C _1～5 alkyl, and the substituted C _1～5 alkyl is The substituents are phenyl, halophenyl, C _3~6 cycloalkyl or pyridyl; _R2 is phenyl or substituted phenyl, amino or substituted amino, C _3-6 cycloalkyl, morpholinyl, C _1-5 alkyl, indane or substituted indane; R ₃ is hydrogen, amino or substituted amino, piperazinyl or pyridine substituted piperazinyl; The substituent of the substituted amino group is C _1-5 alkyl or substituted C _1-5 alkyl, the substituent of the substituted C _1-5 alkyl is phenyl or substituted phenyl, pyridyl, halogenated pyridine Base, benzobisoxazolyl, tetrahydropyranyl, piperidine or substituted piperidinyl, C _1~5 alkyl substituted amino, C _3~8 cycloalkyl, morpholinyl or substituted morpholinyl, Tetrahydrofuryl; the substituent of the substituted piperidinyl or substituted morpholinyl is C _2-4 alkanonyl, C _1-5 alkyl, pyridyl, halogenated phenyl; The substituent of the substituted phenyl is C _1-3 alkyl, halogen; the substituent of the substituted indane is methylcarboxylate. 3. substituted cyanoquinolinones compound according to claim 2, is characterized in that, described _R is selected from any of the following structures: The _R2 is selected from any of the following structures: The R ₃ is hydrogen or any of the following structures: 4. The substituted cyanoquinolinone compound according to any one of claims 1-3, characterized in that the substituted cyanoquinolinone compound can also be a pharmaceutically acceptable salt or solvate thereof. 5. the preparation method of the arbitrary described substituted cyanoquinolinone compound of claim 1～3, it is characterized in that, specifically comprises the following steps: S1. Heat the amino-substituted bromoxynil and R ₂ MgBr to reflux, add hydrochloric acid in an ice bath after the reaction is complete, and perform post-treatment to obtain the compound of formula (II); S2. Mixing the compound of formula (II) obtained in step S1 with phosphorus pentachloride and cyanoacetic acid for ring-forming reaction, and post-processing to obtain the compound of formula (III); S3. Completely react the compound of formula (III) obtained in step S2 with R ₁ Br and an alkaline reagent, and post-process to obtain the compound of formula (IV); S4. The compound of formula (IV) obtained in step S3 is reacted with R ₃ NH ₂ through Buchwald-Hartwig aryl amination reaction to obtain the compound of formula (I). The structural formulas of the compounds of formulas (I)-(IV) are as follows: 6. The application of the substituted cyanoquinolinone compound according to any one of claims 1 to 4 in the preparation of drugs for phosphodiesterase-related diseases. 7. The application according to claim 6, wherein the phosphodiesterase-related diseases include pulmonary fibrosis, enteritis, heart failure, schizophrenia, vascular dementia, neurodegenerative diseases, and pulmonary hypertension. 8. The application of the substituted cyanoquinolinone compound according to any one of claims 1 to 4 in the preparation of phosphodiesterase inhibitors. 9. A phosphodiesterase inhibitor, characterized in that the phosphodiesterase inhibitor uses the substituted cyanoquinolinone compound according to any one of claims 1-4 as the main functional ingredient. 10. The phosphodiesterase inhibitor according to claim 9, wherein the phosphodiesterase is PDE1.