Substituted cyanoquinolinone compound and preparation method and application thereof

Abstract

The application belongs to the technical field of biological medicine, and particularly relates to a substituted cyano quinolinone compound and a preparation method and application thereof. The substituted cyano quinolinone compound has a significant inhibitory effect on phosphodiesterase type I, has a significant therapeutic effect on animal models of phosphodiesterase related diseases, lung fibrosis, intestinal inflammation and the like, and can be developed into a new target candidate drug for inflammatory diseases such as lung fibrosis and intestinal inflammation. Moreover, the preparation method of the substituted cyano quinolinone compound is simple, the reaction condition is mild, and is very suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology. More specifically, it relates to a substituted cyanoquinolinone compound, its preparation method, and its application. Background Technology

[0002] Phosphodiesterases (PDEs) are a family of superenzymes in the body that degrade the second messengers cAMP (cyclic adenosine monophosphate) and cGMP (cyclic guanosine monophosphate). These two nucleotides, cAMP and cGMP, activate protein kinases A and G, thereby mediating downstream signaling pathways that control important physiological processes in the body. Therefore, PDE inhibitors can regulate various important physiological processes in the body by modulating cAMP and cGMP concentrations.

[0003] PDE1 is a subfamily of the PDE superenzyme family capable of simultaneously hydrolyzing cAMP and cGMP, comprising three subtypes: PDE1A, PDE1B, and PDE1C. PDE1A is primarily expressed in the whole brain and rodent heart; PDE1B is primarily expressed in brain tissue; and PDE1C is primarily expressed in heart tissue and vascular smooth muscle, mainly composed of calcium... 2+ The calmodulin-binding domain specifically regulates and mediates calcium and cyclic nucleotide signaling pathways. Previous studies have shown that changes in PDE1-regulated signaling pathways are associated with the central nervous system and can be used to regulate mental disorders, movement disorders, cognitive function, and Alzheimer's disease. Other studies have indicated that PDE1 is related to heart failure and can be used to regulate heart failure, cardiac remodeling, and dysfunction. Still other studies have shown that PDE1 is associated with the lungs, kidneys, hematology, gastrointestinal tract, liver, fertility, cancer, and metabolic disorders (Samidurai, A.; Xi, L.; Das, A.; Iness, AN; Vigneshwar, NG; Li, P.; et al. Role of phosphodiesterase 1 in the pathophysiology of diseases and potential therapeutic opportunities. Pharmacol. Therapeut. 2021, 226, 107858.). However, research on PDE1 remains limited, there are few PDE1 inhibitors, and no PDE1 inhibitors are currently marketed as drugs. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to overcome the shortcomings and deficiencies of the limited types of existing PDE1 inhibitors and to provide a substituted cyanoquinolone compound.

[0005] The purpose of this invention is to provide a method for preparing the substituted cyanoquinoline ketone compounds.

[0006] Another object of the present invention is to provide the use of the substituted cyanoquinolone compounds in the preparation of phosphodiesterase-related disease drugs.

[0007] Another object of the present invention is to provide the use of the substituted cyanoquinolinone compounds in the preparation of phosphodiesterase inhibitors.

[0008] Another object of the present invention is to provide a phosphodiesterase inhibitor.

[0009] The above-mentioned objective of this invention is achieved through the following technical solution:

[0010] A substituted cyanoquinolinone compound having the structure of formula (I):

[0011]

[0012] Where R1 is C 1～8 Alkyl or substituted C 1～8 Alkyl, the substituted C 1～8 The alkyl substituent is phenyl or substituted phenyl, C 3～8 Cycloalkyl or heterocyclic groups containing one or more of N, O, and S;

[0013] R2 is a phenyl or substituted phenyl group, a heterocyclic group containing one or more of N, O, and S, an amino group or a substituted amino group, or C. 3～8 cycloalkyl, C 1～8 Alkyl, indane, or substituted indane;

[0014] R3 is hydrogen, amino group or substituted amino group, piperazine group or pyridine-substituted piperazine group;

[0015] The substituent of the substituted amine group is C. 1～5 Alkyl or substituted C 1～5 Alkyl, the substituted C 1～5 The alkyl substituent is phenyl or substituted phenyl, pyridyl, halopyridyl, benzodioxazolyl, tetrahydropyranyl, piperidine or substituted piperidine, C 1～5 Alkyl-substituted amino groups, C 3～8 Cycloalkyl, morpholino, or substituted morpholino, tetrahydrofurano; the substituent of the substituted piperidinyl or substituted morpholino is C. 2～4 Alkyl group, C 1～5 Alkyl, pyridyl, halophenyl;

[0016] The substituent of the substituted phenyl group is C. 1～5 Alkyl groups, halogens; the substituents of the substituted indene are methyl ester groups.

[0017] Preferably, R1 is C 1～5 Alkyl or substituted C 1～5 Alkyl, the substituted C 1～5 The alkyl substituents are phenyl, halophenyl, C 3～6 cycloalkyl or pyridinyl;

[0018] R2 is a phenyl or substituted phenyl group, an amino group or a substituted amino group, C 3～6 Cycloalkyl, morpholino, C 1～5 Alkyl, indane, or substituted indane;

[0019] R3 is hydrogen, amino group or substituted amino group, piperazine group or pyridine-substituted piperazine group;

[0020] The substituent of the substituted amine group is C. 1～5 Alkyl or substituted C 1～5 Alkyl, the substituted C 1～5 The alkyl substituent is phenyl or substituted phenyl, pyridyl, halopyridyl, benzodioxazolyl, tetrahydropyranyl, piperidine or substituted piperidine, C 1～5 Alkyl-substituted amino groups, C 3～8 Cycloalkyl, morpholino, or substituted morpholino, tetrahydrofurano; the substituent of the substituted piperidinyl or substituted morpholino is C. 2～4 Alkyl group, C 1～5 Alkyl, pyridyl, halophenyl;

[0021] The substituent of the substituted phenyl group is C. 1～3 Alkyl groups, halogens; the substituents of the substituted indene are methyl ester groups.

[0022] More preferably, R1 is selected from any of the following structures:

[0023]

[0024] R2 is selected from any of the following structures:

[0025]

[0026] R3 is hydrogen or any of the following structures:

[0027]

[0028] Furthermore, the substituted cyanoquinolinone compounds may also be pharmaceutically acceptable salts or solvates thereof.

[0029] In addition, the present invention also provides a method for preparing the substituted cyanoquinoline ketone compound, specifically comprising the following steps:

[0030] S1. The amino-substituted bromobenzonitrile was heated to reflux with R2MgBr. After the reaction was completed, hydrochloric acid was added in an ice bath. The reaction was completed and then post-treated to obtain compound (II).

[0031] S2. The compound of formula (II) obtained in step S1 is mixed with phosphorus pentachloride and cyanoacetic acid to carry out a cyclization reaction, and then processed to obtain compound of formula (III).

[0032] S3. React the compound of formula (III) obtained in step S2 with R1Br and a basic reagent until complete, and then perform post-treatment to obtain compound of formula (IV).

[0033] S4. The compound of formula (IV) obtained in step S3 is reacted with R3NH2 via a Buchwald-Hartwig arylation reaction to obtain the compound of formula (I). The structural formulas of compounds (I) to (IV) are as follows:

[0034]

[0035] Furthermore, in step S1, the temperature of the heating reflux is 50-150°C; the heating reflux time is 6-12 hours.

[0036] Furthermore, in step S1, the reaction time after adding hydrochloric acid is 1-6 hours.

[0037] Preferably, in step S1, the post-processing includes the following steps: concentration under reduced pressure to remove solvent, adjusting pH to neutral, extraction with ethyl acetate, collecting and drying the organic layer, concentration under reduced pressure to remove solvent, drying, and purification by column chromatography to obtain the final product.

[0038] Furthermore, in step S2, the cyclization reaction is carried out at a temperature of 60–80°C for 0.5–4 hours.

[0039] Preferably, in step S2, the post-processing includes the following steps: diluting the reaction system with water, extracting with DCM, collecting and drying the organic phase, concentrating under reduced pressure to remove the solvent, redissolving the DCM, adding NaOH and stirring, and slurrying with EA to obtain the final product.

[0040] Furthermore, in step S3, the reaction is carried out at room temperature (15-35°C) for 4-10 hours.

[0041] Preferably, in step S3, the post-processing includes the following steps: diluting the reaction system with water, extracting with EA, collecting the organic phase, drying it, concentrating it under reduced pressure to remove the solvent, and purifying it by column chromatography to obtain the final product.

[0042] Furthermore, in step S4, the reaction temperature is 90–150°C, and the reaction time is 6–10 h.

[0043] Preferably, in step S4, the post-processing includes the following steps: removing the catalyst by diatomaceous earth filtration, collecting the organic phase, removing the solvent by vacuum concentration, and purifying by column chromatography to obtain the final product.

[0044] Preferably, an organic solvent needs to be added during the reaction process in steps S1 to S4. The organic solvent is selected from one or more of tetrahydrofuran (THF), dichloromethane, N,N-dimethylformamide (DMF), toluene, and diethyl ether.

[0045] The present invention has demonstrated through experiments that the substituted cyanoquinolone compounds have a significant inhibitory effect on phosphodiesterase type I, and can significantly improve the pathological condition of bleomycin-induced pulmonary fibrosis in rats and improve the pathological changes of dextran sulfate sodium-induced enteritis in rats.

[0046] Therefore, the present invention also claims protection for the use of the substituted cyanoquinolone compounds in the preparation of phosphodiesterase-related disease drugs.

[0047] Preferably, the phosphodiesterase-related diseases include pulmonary fibrosis, enteritis, heart failure, schizophrenia, vascular dementia, neurodegenerative diseases (such as Alzheimer's disease), and pulmonary hypertension.

[0048] Additionally, the present invention also claims the use of the substituted cyanoquinolone compounds in the preparation of phosphodiesterase inhibitors.

[0049] Furthermore, the present invention also provides a phosphodiesterase inhibitor, wherein the substituted cyanoquinoline ketone compound is used as the main active ingredient.

[0050] Furthermore, the phosphodiesterase is PDE1. Currently, PDE1 inhibitors are mainly used for central nervous system diseases and rarely for peripheral diseases. This invention is the first to experimentally demonstrate that it has a good effect on improving peripheral diseases such as pulmonary fibrosis and enteritis.

[0051] The present invention has the following beneficial effects:

[0052] The substituted cyanoquinolone compounds of this invention exhibit significant inhibitory effects on phosphodiesterase type I and demonstrate significant therapeutic effects on phosphodiesterase-related diseases, as well as on animal models of pulmonary fibrosis and enteritis. They can be developed into novel drug candidates for treating inflammatory diseases such as pulmonary fibrosis and enteritis. Furthermore, the preparation method of the substituted cyanoquinolone compounds of this invention is simple, with mild reaction conditions, making it highly suitable for large-scale industrial production. Attached Figure Description

[0053] Figure 1 This is a statistical chart of the respiratory function index test results in Example 4.

[0054] Figure 2 This is a Western blot image and statistical data graph of α-SMA expression in rat lung tissue in Example 4.

[0055] Figure 3 This is a pathological section of rat enteritis induced by sodium dextran sulfate in Example 5. Detailed Implementation

[0056] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in this technical field.

[0057] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0058] Example 1: Preparation of Compound 8

[0059] The preparation of compound 8 specifically includes the following steps:

[0060] S1. Preparation of compound 8a: 2-amino-4-bromobenzonitrile (648 mg, 3 mmol) was dissolved in 10 mL of THF and stirred in an ice bath. 9 mL of a 1 mol / L THF solution of p-tolyl magnesium bromide was added dropwise. After the addition was complete, the mixture was refluxed at 70 °C for 10 h. The next day, 10 mL of 4 mol / L hydrochloric acid was slowly added dropwise to the reaction system under ice bath conditions. The reaction was allowed to proceed for 6 h. After the reaction was completed by TLC, the solvent was removed by rotary evaporation under reduced pressure. The pH of the solution was adjusted to neutral by adding water. The mixture was extracted three times with ethyl acetate, and the organic layer was collected. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. After drying, the mixture was purified by column chromatography to obtain a yellow oil (600 mg, 75%), which is compound 8a.

[0061]

[0062] Preparation of S2 and compound 8b: Phosphorus pentachloride (434 mg, 2.08 mmol) and cyanoacetic acid (180 mg, 2.1 mmol) were dissolved in 20 mL of dichloromethane. A DCM solution of compound 8a (600 mg, 2.08 mmol) obtained in step S1 was added dropwise at 60 °C. The reaction was allowed to proceed for 0.5 h. The reaction system was diluted with water and extracted twice with DCM. The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The solution was redissolved with DCM, and NaOH (100 mg, 2.5 mmol) was added and stirred for 1 h. The mixture was then slurried with EA to obtain a white solid (459 mg, 65%), which is compound 8b.

[0063]

[0064] Preparation of S3 and compound 8c: Compound 8b (212 mg, 0.625 mmol) obtained in step S2, benzyl bromide (117 mg, 0.69 mmol) and potassium carbonate (104 mg, 0.75 mmol) were dissolved in 10 mL of DMF and stirred at room temperature for 4 h. After the reaction was completed, 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%), which is compound 8c.

[0065]

[0066] Preparation of S4 and Compound 8: Compound 8c (90 mg, 0.21 mmol) obtained in step S3, n-butylamine (18 mg, 0.25 mmol), Pd2(dba)3 (10 mg, 0.0105 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (BINAP, 13 mg, 0.021 mmol) and NaOBu-t (36 mg, 0.315 mmol) were dissolved in toluene (10 mL). The reaction was carried out at 95 °C for 9 h under argon protection. The reaction was monitored by TLC. After the reaction was completed, the catalyst was removed by diatomaceous earth filtration, the organic phase was collected, the solvent was removed by rotary evaporation under reduced pressure, and the product was purified by column chromatography to obtain a yellow solid (39 mg, 44%), which is compound 8.

[0067]

[0068] Example 2: Preparation of substituted cyanoquinolinone compounds

[0069] Following the preparation method of compound 8 in Example 1, compounds 1-7 and 9-47 were prepared using different raw materials based on their structures. The structures of compounds 1-47 are as follows:

[0070] Table 1 Structures of compounds 1–47

[0071]

[0072]

[0073]

[0074]

[0075] The NMR data are as follows:

[0076] Compound 1: 1H NMR (400MHz, CDCl3) 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, CDCl3)δ160.07,159.12,140.40,140.37,135.44,133.77,130.63,129.95,129.65,129.00, 128.79,127.74,126.85,123.00,119.91,115.64,115.06,106.57,46.81,21.50.HRMS(ESI-TOF)m / z[M+H] + calcd for C 24 H 18 N2O 351.1492, found 351.1486.

[0077] Compound 2: 1 H NMR (400MHz, CDCl3) 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, CDCl3) 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 N2OCl 385.1102; found 385.1102.

[0078] Compound 3: 1H NMR (400MHz, CDCl3) 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,DMSO-d6)δ163.21,160.94,140.42,136.84,133.92,129.13,127.63,126.9 7,122.77,117.49,116.92,116.70,91.82,66.98,53.07,45.59.HRMS(ESI-TOF)m / z[M+H] + calcd for C 21 H 19 N3O2 346.1550; found 346.1562.

[0079] Compound 4: 1 H NMR (400MHz, CDCl3) 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 N3O 360.2070; found 360.2082.

[0080] Compound 5: 11H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.2 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.35–7.28 (m, 3H), 7.27 (s, 2H), 7.25 (s, 1H), 7.18 (t, J = 7.6 Hz, 1H), 5.51 (s, 2H), 3.70 (q, J = 7.1 Hz, 4H), 1.26 (t, J = 7.1 Hz, 6H). 13 13C NMR (101 MHz, DMSO-d6) δ 164.24, 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 N3O 332.1757; found 332.1771.

[0081] Compound 6: 1 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.4 Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.51–7.39 (m, 4H), 7.36 (dd, J = 10.5, 3.9 Hz, 2H), 7.33–7.29 (m, 4H), 7.19 (t, J = 7.7 Hz, 1H), 5.58 (dd, J = 57.5, 15.6 Hz, 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, 4.8 Hz, 1H). 13 13C NMR (126 MHz, CDCl3) δ 173.35, 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, 116.24, 115.38, 107.64, 64.73, 53.32, 47.44, 38.01, 31.55. HRMS (ESI-TOF) m / z [M+H] + calcd for C28 H 22 N2O3 435.1703; found 435.1700.

[0082] Compound 7: 1 H NMR (400 MHz, CDCl3) δ 7.45–7.31 (m, 5H), 7.28 (d, J = 7.0 Hz, 4H), 7.24 (s, 1H), 7.11 (t, J = 7.4 Hz, 1H), 6.93–6.86 (m, 2H), 5.59 (dd, J = 40.6, 15.6 Hz, 2H), 5.38 (t, J = 9.4 Hz, 1H), 3.27 (t, J = 8.3 Hz, 2H), 2.79 (dd, J = 17.5, 10.7 Hz, 1H), 2.50 (td, J = 20.4, 10.2 Hz, 1H). 13 C NMR (126 MHz, CDCl3) δ 161.30, 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 N2O 377.1648; found 377.1653.

[0083] Compound 8: 1 H NMR (500 MHz, CDCl3) δ 7.37–7.29 (m, 8H), 7.28 (d, J = 1.9 Hz, 1H), 7.15 (d, J = 9.0 Hz, 1H), 6.34 (dd, J = 9.0, 2.1 Hz, 1H), 6.27 (d, J = 2.1 Hz, 1H), 5.55 (s, 2H), 4.40 (t, J = 5.4 Hz, 1H), 3.05 (dd, J = 12.8, 7.0 Hz, 2H), 2.45 (s, 3H), 1.48 (dt, J = 14.9, 7.3 Hz, 2H), 1.34 (dq, J = 14.5, 7.3 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H). 13C NMR (126MHz, DMSO-d6) δ160.31,158.95,154.15,143.22,139.51,136.79,132.18,129.66,129.16,129.07, 127.66,127.12,117.43,109.88,96.63,45.91,42.24,30.58,21.41,20.07,14.07.HRMS(ESI-TOF)m / z[M+H] + calcd for C 28 H 27 N3O 422.2227, found 422.2227.

[0084] Compound 9: 1 H NMR(400MHz,DMSO-d6)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, CDCl3) δ160.34,159.26,151.67,143.07,142.85,139.71,135.57,131.49,130.94,129.38,128.97,128.79,128.74,1 27.57,127.41,126.74,125.60,116.39,111.47,111.32,99.35,96.59,53.41,46.67,26.93,24.55,21.43.HRMS(ESI-TOF)m / z[M+H] + calcd for C 32 H 27 N3O470.2227, found470.2224.

[0085] Compound 10: 11H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 4.2 Hz, 1H), 7.80 (t, J = 6.0 Hz, 1H), 7.64 (td, J = 7.7, 1.6 Hz, 1H), 7.37 (dd, J = 19.5, 8.0 Hz, 4H), 7.25 (ddd, J = 17.5, 10.4, 7.2 Hz, 6H), 7.15 (d, J = 7.8 Hz, 1H), 6.97 (d, J = 9.0 Hz, 1H), 6.64 (d, J = 9.1 Hz, 1H), 6.47 (s, 1H), 5.40 (s, 2H), 4.42 (d, J = 6.0 Hz, 2H), 2.42 (s, 3H). 13 13C NMR (126 MHz, DMSO-d6) δ 166.55, 160.14, 159.18, 158.29, 155.37, 153.99, 150.70, 149.53, 148.93, 143.27, 139.57, 139.53, 138.11, 137.32, 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 N4O 457.2023, found 457.2030.

[0086] Compound 11: 1 1H NMR (500 MHz, DMSO-d6) δ 8.48 (d, J = 4.1 Hz, 1H), 7.71 (d, J = 7.0 Hz, 1H), 7.63 (t, J = 7.3 Hz, 1H), 7.38 (d, J = 7.9 Hz, 2H), 7.31 (dd, J = 16.8, 7.6 Hz, 4H), 7.25 (d, J = 6.9 Hz, 1H), 7.23–7.17 (m, 4H), 6.94 (d, J = 9.1 Hz, 1H), 6.63 (d, J = 7.5 Hz, 1H), 6.36 (s, 1H), 5.43 (d, J = 14.7 Hz, 1H), 5.23 (d, J = 5.2 Hz, 1H), 4.75–4.53 (m, 1H), 2.42 (s, 3H), 1.43 (d, J = 6.7 Hz, 3H). 13C NMR (126MHz, DMSO-d6) δ162.99,160.09,159.06,153.29,149.52,143.04,139.52,137.47,136.32,132.07,129.65,129.1 0,129.04,127.61,127.13,122.79,120.37,117.24,110.26,97.37,54.00,46.00,22.24,21.41.HRMS(ESI-TOF)m / z[M+H] + calcd for C 31 H 26 N4O 471.2179, found 471.2162.

[0087] Compound 12: 1 H NMR(500MHz, CDCl3) δ8.46(d,J=4.7Hz,1H),7.56(td,J=7.7,1.6Hz,1H),7.38(d,J=7.7 Hz,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, CDCl3) 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 .41,127.56,126.85,122.13,121.85,120.80,120.33,116.53,115.43,110.59,106.40,54.89,46.66,22.92,21.54.HRMS(ESI-TOF)m / z[M+H] + calcd for C 31 H 26 N4O 471.2179, found 471.2158.

[0088] Compound 13: 11H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 4.2 Hz, 1H), 7.64 (dd, J = 15.7, 6.9 Hz, 3H), 7.39 (t, J = 7.3 Hz, 2H), 7.35–7.28 (m, 6H), 7.25–7.20 (m, 1H), 7.09–7.02 (m, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 7.7 Hz, 1H), 5.72 (s, 2H), 4.83 (d, J = 6.5 Hz, 1H), 4.31 (t, J = 6.7 Hz, 1H), 2.45 (s, 3H), 1.73 (d, J = 6.8 Hz, 3H). 13 13C NMR (126 MHz, CDCl3) δ 163.62, 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 N4O 471.2179, found 471.2157.

[0089] Compound 14: 1 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 4.8 Hz, 1H), 7.69 (td, J = 7.7, 1.7 Hz, 1H), 7.38–7.32 (m, 3H), 7.30 (s, 1H), 7.28–7.18 (m, 3H), 6.51 (dd, J = 8.9, 2.1 Hz, 1H), 6.45 (d, J = 1.9 Hz, 1H), 5.46 (d, J = 5.7 Hz, 1H), 4.89–4.69 (m, 1H), 4.18–4.07 (m, 2H), 2.46 (s, 3H), 1.65 (d, J = 6.7 Hz, 3H), 1.34–1.26 (m, 1H), 0.94–0.84 (m, 2H), 0.50–0.44 (m, 2H). 13C NMR(101MHz,DMSO-d6)δ163.68,159.79,158.67,153.28,149.60,142.89,139.44,137.67,132.07,130.66,129.63,12 9.01,122.77,120.34,117.22,110.17,97.61,54.49,46.25,26.81,22.49,21.39,9.48,4.22.HRMS(ESI-TOF)m / z[M+H] + calcd for C 28 H 26 N4O435.2179, found 435.2179.

[0090] Compound 15: 1 H NMR (400MHz, CDCl3) 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, CDCl3) 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.HRMS(ESI-TOF)m / z[M+H] + calcd for C 30 H 30 N4O 463.2492, found 463.2474.

[0091] Compound 16: 11H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 4.8 Hz, 1H), 7.70 (td, J = 7.7, 1.7 Hz, 1H), 7.34 (dd, J = 7.8, 4.8 Hz, 4H), 7.25 (dd, J = 7.6, 5.0 Hz, 2H), 7.18 (d, J = 9.0 Hz, 1H), 6.50 (dd, J = 9.0, 2.1 Hz, 1H), 6.30 (d, J = 2.0 Hz, 1H), 5.44 (d, J = 5.8 Hz, 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 = 7.1 Hz, 3H). 13 13C NMR (126 MHz, CDCl3) δ 162.23, 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 N4O 451.2492, found 451.2505.

[0092] Compound 17: 1 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 6.0 Hz, 2H), 8.52 (d, J = 4.8 Hz, 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, 2.0 Hz, 1H), 6.08 (d, J = 1.9 Hz, 1H), 5.46 (d, J = 6.0 Hz, 1H), 5.37 (s, 1H), 4.74–4.44 (m, 1H), 2.47 (s, 3H), 1.50 (d, J = 6.7 Hz, 3H). 13C NMR (126MHz, DMSO-d6) 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 N5O472.2132, found 472.2123.

[0093] Compound 18: 1 H NMR (400MHz, CDCl3) 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),7.1 6(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, CDCl3) δ161.38,160.26,159.44,151.57,149.32,142.86,139.82,137.92,137.08,134.77,131.40,131.25,130.23,129.41,12 8.75,127.75,126.81,124.96,122.63,120.31,116.22,111.59,111.29,99.34,95.92,54.03,46.23,22.48,21.43.HRMS(ESI-TOF)m / z[M+H] + calcd for C 31 H 25 N4OCl 505.1790, found 505.1777.

[0094] Compound 19: 11H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 3.9 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.34 (dt, J = 13.5, 6.8 Hz, 5H), 7.19 (dd, J = 8.2, 5.0 Hz, 3H), 7.05 (d, J = 7.4 Hz, 1H), 6.96 (dd, J = 14.3, 8.8 Hz, 2H), 6.48 (d, J = 8.8 Hz, 1H), 6.23 (s, 1H), 5.50 (d, J = 5.6 Hz, 2H), 5.32 (s, 1H), 4.62–4.49 (m, 1H), 2.47 (s, 3H), 1.49 (d, J = 6.7 Hz, 3H). 13 13C NMR (126 MHz, CDCl3) δ 161.42, 160.26, 159.44, 151.57, 149.31, 142.85, 139.83, 138.36, 138.31, 137.17, 131.37, 131.25, 130.52, 130.45, 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. HRMS (ESI-TOF) m / z [M + H]+ calcd for C 31 1 25 1H

[0095] Compound 20: 1 1H NMR (500 MHz, CDCl3) δ 8.56 (d, J = 4.6 Hz, 1H), 7.69 (d, J = 9.1 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 7.4 Hz, 2H), 7.24–7.13 (m, 5H), 6.52 (d, J = 9.1 Hz, 1H), 6.27 (s, 1H), 5.55 (s, 1H), 5.40 (d, J = 6.5 Hz, 1H), 5.20 (s, 1H), 4.52 (dd, J = 13.2, 6.7 Hz, 1H), 3.81–3.72 (m, 1H), 2.19–2.01 (m, 6H), 1.91–1.75 (m, 2H), 1.45 (d, J = 6.7 Hz, 3H). 13CNMR(126MHz,DMSO-d6)δ164.20,163.10,160.56,152.95,149.50,142.61,137.47,136.36,129.08,127.55,126.99,12 2.78,120.32,117.38,109.60,96.26,55.34,54.02,45.98,41.13,33.07,33.02,27.36,22.30.HRMS(ESI-TOF)m / z[M+H] + calcd for C 29 H 28 N4O449.2336, found449.2332.

[0096] Compound 21: 1 H NMR (400MHz, CDCl3) δ8.58(d,J=3.8Hz,1H),8.05(d,J=8.9Hz,1H),7.63(t,J=7.4Hz,1 H),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-d6) 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 N4O 421.2023, found 421.2013.

[0097] Compound 22: 11H NMR (500 MHz, CDCl3) δ 8.56 (d, J = 4.1 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.60 (t, J = 7.1 Hz, 1H), 7.33–7.27 (m, 2H), 7.24–7.12 (m, 5H), 6.54 (d, J = 9.1 Hz, 1H), 6.27 (s, 1H), 5.55 (s, 1H), 5.43 (d, J = 6.2 Hz, 1H), 5.20 (s, 1H), 4.67–4.45 (m, 1H), 3.74 (s, 1H), 1.56 (d, J = 10.1 Hz, 6H), 1.45 (d, J = 6.7 Hz, 3H). 13 13C NMR (126 MHz, DMSO-d6) δ 165.57, 163.09, 160.62, 152.96, 149.46, 142.94, 137.39, 136.44, 129.04, 128.39, 127.52, 127.05, 120.37, 117.45, 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 N4O 423.2179, found 423.2175.

[0098] Compound 23: 1 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.68 (s, 1H), 7.30 (s, 2H), 7.27–7.14 (m, 5H), 6.55 (d, J = 8.6 Hz, 1H), 6.26 (s, 1H), 5.50 (s, 2H), 5.37 (s, 1H), 4.59 (d, J = 5.7 Hz, 1H), 1.78 (s, 9H), 1.50 (d, J = 6.0 Hz, 3H). 13 13C NMR (126 MHz, CDCl3) δ 166.05, 161.66, 161.31, 149.98, 149.01, 142.57, 137.47, 135.76, 131.17, 128.84, 127.34, 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 C28 H 28 N4O 437.2336, found 437.2318.

[0099] Compound 24: 1 H NMR (400MHz, CDCl3) 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),4.88–4.6 7(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-d6)δ163.76,163.29,160.43,152.85,149.55,142.57,137.49,128.22,122.67,120.25,117.29,111.48,1 09.62,96.80,96.04,54.56,46.30,41.35,37.93,32.93,30.31,30.10,27.22,24.78,22.54.HRMS(ESI-TOF)m / z[M+H]+calcd for C 28 H 32 N4O 441.2649, found 441.2639.

[0100] Compound 25: 11H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 2.7 Hz, 1H), 7.75 (d, J = 9.1 Hz, 1H), 7.46–7.39 (m, 1H), 7.35 (dd, J = 8.6, 4.4 Hz, 1H), 6.62 (dd, J = 9.1, 2.2 Hz, 1H), 6.41 (d, J = 2.1 Hz, 1H), 5.58 (t, J = 5.1 Hz, 1H), 4.57 (d, J = 5.2 Hz, 2H), 4.19 (d, J = 7.1 Hz, 2H), 3.76 (dt, J = 18.4, 9.4 Hz, 1H), 2.22 (dd, J = 15.0, 7.5 Hz, 1H), 2.18–2.03 (m, 6H), 1.83 (d, J = 6.4 Hz, 2H), 1.71 (s, 2H), 1.62 (d, J = 6.5 Hz, 2H), 1.52–1.44 (m, 2H), 1.44–1.33 (m, 2H). 13 13C NMR (126 MHz, CDCl3) δ 163.19, 160.56, 159.85, 157.82, 152.61, 151.35, 142.65, 137.67, 137.48, 128.19, 123.94, 123.79, 122.42, 122.38, 116.58, 110.66, 110.2, 99.89, 96.13, 47.89, 46.79, 42.49, 38.33, 33.12, 30.47, 27.43, 24.81. HRMS (ESI-TOF) m / z [M + H] + calcd for C 27 H 29 FN4O 445.2398, found 445.2389.

[0101] Compound 26: 1 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 2.7 Hz, 1H), 7.77 (d, J = 9.1 Hz, 1H), 7.45 (td, J = 8.3, 2.8 Hz, 1H), 7.38 (dd, J = 8.7, 4.4 Hz, 1H), 6.65 (dd, J = 9.1, 2.1 Hz, 1H), 6.39 (d, J = 2.0 Hz, 1H), 5.65 (s, 1H), 4.59 (d, J = 5.2 Hz, 2H), 4.25–4.09 (m, 2H), 3.76 (dd, J = 18.8, 9.5 Hz, 1H), 2.28–1.99 (m, 6H), 1.84 (s, 2H), 1.68 (td, J = 15.2, 7.6 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H).13 13C NMR (126 MHz, DMSO-d6) δ 163.56, 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 FN4O 417.2085, found 417.2088.

[0102] Compound 27: 1 1H NMR (500 MHz, DMSO-d6) δ 8.54 (d, J = 2.7 Hz, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.80 (s, 1H), 7.70 (td, J = 8.7, 2.8 Hz, 1H), 7.44 (dd, J = 8.6, 4.5 Hz, 1H), 6.74 (d, J = 9.2 Hz, 1H), 6.55 (s, 1H), 4.58 (d, J = 5.9 Hz, 2H), 4.02 (d, J = 6.8 Hz, 2H), 3.74 (d, J = 9.0 Hz, 1H), 2.00 (d, J = 6.9 Hz, 6H), 1.76 (s, 2H), 0.93 (s, 1H), 0.36 (d, J = 6.2 Hz, 4H). 13 13C NMR (126 MHz, DMSO-d6) δ 163.65, 160.27, 159.76, 157.75, 155.29, 155.26, 153.51, 142.64, 137.52, 137.34, 128.47, 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 FN4O 405.2085, found 405.2087.

[0103] Compound 28: 11H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 2.6 Hz, 1H), 7.77 (d, J = 9.0 Hz, 1H), 7.45 (td, J = 8.3, 2.9 Hz, 1H), 7.37 (dd, J = 8.7, 4.2 Hz, 1H), 6.65 (d, J = 9.0 Hz, 1H), 6.40 (s, 1H), 5.63 (s, 1H), 4.59 (d, J = 5.2 Hz, 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 = 8.3 Hz, 2H), 1.39 (d, J = 3.7 Hz, 4H), 0.95 (t, J = 6.9 Hz, 3H). 13 13C NMR (126 MHz, DMSO-d6) δ 163.39, 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 FN4O 433.2398, found 433.2401.

[0104] Compound 29: 1 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 4.0 Hz, 1H), 7.70 (d, J = 9.1 Hz, 1H), 7.60 (t, J = 7.1 Hz, 1H), 7.18 (dd, J = 16.7, 8.6 Hz, 5H), 7.07 (s, 1H), 6.56 (d, J = 8.9 Hz, 1H), 6.17 (s, 1H), 5.52 (d, J = 5.8 Hz, 2H), 5.22 (s, 1H), 4.65–4.41 (m, 1H), 3.76 (dd, J = 18.4, 9.1 Hz, 1H), 2.24–2.04 (m, 6H), 1.83 (s, 2H), 1.47 (d, J = 6.6 Hz, 3H). 1313C NMR (126 MHz, CDCl3) δ 164.25, 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 ClN4O4 83.1946, found 483.1952.

[0105] Compound 30: 1 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 4.2 Hz, 1H), 7.82 (d, J = 9.3 Hz, 1H), 7.60 (d, J = 6.7 Hz, 2H), 7.30 (dd, J = 13.7, 7.3 Hz, 1H), 7.21–7.14 (m, 2H), 7.04 (t, J = 7.5 Hz, 1H), 6.94 (dd, J = 19.9, 8.7 Hz, 2H), 6.71 (d, J = 8.5 Hz, 1H), 6.24 (s, 1H), 5.30 (d, J = 17.1 Hz, 2H), 4.86–4.52 (m, 1H), 3.76 (dd, J = 17.8, 8.7 Hz, 1H), 2.03 (d, J = 5.2 Hz, 6H), 1.76 (s, 2H), 1.44 (d, J = 6.8 Hz, 3H). 13 13C NMR (126 MHz, DMSO-d6) δ 164.45, 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, 113.82, 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 FN4O + 467.2242, found 467.2245.

[0106] Compound 31: 1 H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 9.1 Hz, 1H), 7.28 (d, J = 6.8 Hz, 1H), 7.23 (d, J = 6.9 Hz, 2H), 7.15 (d, J = 7.0 Hz, 2H), 6.71 (dd, J = 24.7, 9.0 Hz, 3H), 6.51 (d, J = 9.1 Hz, 1H), 6.28 (s, 1H), 5.95 (s, 2H), 5.38 (s, 2H), 4.82 (s, 1H), 4.17 (d, J = 5.2 Hz, 2H), 3.90–3.69 (m, 1H), 2.12 (dd, J = 20.2, 6.4 Hz, 6H), 1.83 (d, J = 4.4 Hz, 2H). 13 C NMR (126 MHz, DMSO-d6) δ 164.14, 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 N3O3 478.2125, found 478.2131.

[0107] Compound 32: 1 H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.7 Hz, 1H), 7.31 (d, J = 7.2 Hz, 3H), 7.25–7.19 (m, 2H), 6.45 (d, J = 9.4 Hz, 1H), 6.24 (s, 1H), 5.50 (s, 2H), 4.50 (s, 1H), 3.93 (d, J = 8.1 Hz, 2H), 3.85–3.69 (m, 1H), 3.25 (t, J = 11.6 Hz, 2H), 2.96 (s, 2H), 2.34–1.95 (m, 6H), 1.84 (s, 2H), 1.52 (d, J = 13.5 Hz, 4H). 13C NMR (126MHz, CDCl3) 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 N3O2 442.2489, found 442.2479.

[0108] Compound 33: 1 H NMR(400MHz,DMSO-d6)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-d6) δ164.06,163.87,160.76,154.02,142.82,139.93,131.23,128.42,122.87,117.37,114.52,

[0109] 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] + calcd for C 28 H 30 FN3O2

[0110] 460.2395, found 460.2387.

[0111] Compound 34: 11H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 9.0 Hz, 1H), 7.26 (dd, J = 15.4, 9.8 Hz, 3H), 7.16 (t, J = 8.7 Hz, 2H), 6.65 (d, J = 8.7 Hz, 1H), 6.23 (s, 1H), 5.45 (s, 2H), 3.79 (d, J = 8.1 Hz, 2H), 3.17–3.03 (m, 2H), 2.96 (s, 2H), 2.06 (s, 6H), 1.78 (s, 2H), 1.45 (d, J = 11.0 Hz, 3H), 1.08 (d, J = 9.7 Hz, 2H). 13 13C NMR (126 MHz, DMSO-d6) δ 163.97, 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 FN3O2 460.2395, found 460.2392.

[0112] Compound 35: 1 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.9 Hz, 1H), 7.32 (d, J = 7.1 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.97 (dd, J = 17.1, 9.1 Hz, 2H), 6.50 (d, J = 8.5 Hz, 1H), 6.19 (s, 1H), 5.50 (s, 2H), 4.63 (d, J = 13.3 Hz, 1H), 3.89–3.66 (m, 2H), 3.02 (d, J = 5.6 Hz, 2H), 2.95 (d, J = 12.5 Hz, 1H), 2.42 (t, J = 12.2 Hz, 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). 1313C NMR (126 MHz, DMSO-d6) δ 168.33, 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 FN4O2 501.2660, found 501.2665.

[0113] Compound 36: 1 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 9.3 Hz, 1H), 7.39 (dd, J = 14.2, 7.7 Hz, 1H), 7.26 (s, 1H), 7.11 (dd, J = 18.8, 9.5 Hz, 2H), 7.04 (d, J = 7.6 Hz, 1H), 6.66 (d, J = 8.8 Hz, 1H), 6.23 (s, 1H), 5.48 (s, 2H), 3.79 (dd, J = 16.0, 11.2 Hz, 1H), 3.14 (d, J = 12.2 Hz, 2H), 2.98 (t, J = 5.8 Hz, 2H), 2.57 (d, J = 12.1 Hz, 2H), 2.04 (d, J = 16.4 Hz, 6H), 1.78 (s, 2H), 1.64 (d, J = 12.9 Hz, 2H), 1.46 (s, 1H), 1.16 (dd, J = 22.5, 11.4 Hz, 3H). 13 13C NMR (126 MHz, DMSO-d6) δ 164.25, 163.75, 161.81, 160.75, 153.82, 142.72, 139.95, 131.32, 131.26, 128.55, 122.94, 117.50, 114.56, 114.40, 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 FN4O4 59.2555, found 459.2559.

[0114] Compound 37: 1 H NMR(500MHz,CDCl3)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 C NMR(126MHz,DMSO-d6)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 FN4O 459.2555,found 459.2548.

[0115] Compound 38: 1 H NMR(500MHz,CDCl3)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). 1313C NMR (126 MHz, CDCl3) δ 164.15, 162.18, 160.77, 152.46, 142.70, 138.79, 138.73, 130.45, 130.39, 128.07, 122.46, 122.44, 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 FN4O 461.2711, found 461.2725.

[0116] Compound 39: 1 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 9.3 Hz, 1H), 7.38 (dd, J = 14.2, 7.8 Hz, 1H), 7.26 (d, J = 5.4 Hz, 1H), 7.11 (dd, J = 17.4, 9.0 Hz, 2H), 7.02 (d, J = 7.6 Hz, 1H), 6.66 (d, J = 8.1 Hz, 1H), 6.22 (s, 1H), 5.48 (s, 2H), 3.79 (dd, J = 18.2, 9.1 Hz, 1H), 2.95 (d, J = 5.3 Hz, 2H), 2.79 (d, J = 10.9 Hz, 2H), 2.21 (s, 3H), 2.03 (d, J = 20.9 Hz, 6H), 1.87–1.71 (m, 3H), 1.55 (d, J = 11.3 Hz, 2H), 1.18–1.05 (m, 2H). 13 13C NMR (126 MHz, DMSO-d6) δ 164.15, 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 FN4O 473.2711, found 473.2718.

[0117] Compound 40: 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 9.2 Hz, 1H), 7.37 (dd, J = 14.3, 7.3 Hz, 1H), 7.19 (s, 1H), 7.10 (dd, J = 15.3, 8.9 Hz, 2H), 7.00 (d, J = 7.5 Hz, 1H), 6.63 (d, J = 9.3 Hz, 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 = 9.6 Hz, 4H), 1.04 (s, 3H), 0.85 (s, 1H), 0.76 (d, J = 10.7 Hz, 2H). 13 C NMR (126 MHz, DMSO-d6) δ 164.10, 160.84, 154.16, 142.83, 139.85, 122.78, 114.34, 113.93, 109.28, 102.10, 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 FN3O 458.2602, found 458.2609.

[0118] Compound 41: 1 H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 9.3 Hz, 1H), 7.37 (dd, J = 14.2, 7.8 Hz, 1H), 7.08 (dt, J = 25.5, 9.1 Hz, 4H), 6.66 (d, J = 8.2 Hz, 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, 6.4 Hz, 2H), 2.37–2.21 (m, 6H), 2.03 (d, J = 18.7 Hz, 6H), 1.78 (s, 2H). 1313C NMR (126 MHz, DMSO-d6) δ 164.25, 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 FN4O2 475.2504, found 475.2512.

[0119] Compound 42: 1 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.9 Hz, 1H), 7.28 (d, J = 12.0 Hz, 1H), 7.05 (d, J = 7.3 Hz, 1H), 6.94 (d, J = 7.6 Hz, 2H), 6.51 (d, J = 8.8 Hz, 1H), 6.25 (s, 1H), 5.47 (s, 2H), 4.84 (s, 1H), 3.76 (ddd, J = 55.2, 25.9, 11.0 Hz, 4H), 3.10 (dd, J = 14.2, 6.1 Hz, 2H), 2.66 (d, J = 11.0 Hz, 2H), 2.29 (s, 3H), 2.13 (dd, J = 21.0, 7.3 Hz, 6H), 1.95–1.69 (m, 4H). 13 13C NMR (126 MHz, DMSO-d6) δ 164.23, 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] + calcd for C 28 H 31 FN4O2 475.2504, found 475.2508.

[0120] Compound 43: 11H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 9.2 Hz, 1H), 7.39–7.26 (m, 2H), 7.16 (t, J = 8.7 Hz, 2H), 6.68 (d, J = 9.0 Hz, 1H), 6.36 (s, 1H), 5.43 (dd, J = 26.7, 15.7 Hz, 2H), 3.85–3.76 (m, 1H), 3.73 (d, J = 11.1 Hz, 1H), 3.40 (d, J = 10.7 Hz, 3H), 3.15 (d, J = 5.7 Hz, 2H), 2.58 (dd, J = 20.6, 11.5 Hz, 2H), 2.15 (s, 3H), 2.12–1.89 (m, 6H), 1.78 (s, 2H), 1.65 (t, J = 10.5 Hz, 1H). 13 13C NMR (126 MHz, DMSO-d6) δ 164.03, 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-TOF) m / z [M+H] + calcd for C 28 H 31 FN4O2 475.2504, found 475.2510.

[0121] Compound 44:<000024​​13C NMR (126 MHz, DMSO-d6) δ 164.51, 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 FN4O 473.2711, found 473.2720.

[0122] Compound 45: 1 1H NMR (500 MHz, DMSO-d6) δ 7.83 (d, J = 9.4 Hz, 1H), 7.37 (dd, J = 14.1, 8.0 Hz, 1H), 7.22 (t, J = 5.9 Hz, 1H), 7.15–7.08 (m, 2H), 7.02 (d, J = 7.7 Hz, 1H), 6.68 (dd, J = 9.2, 2.0 Hz, 1H), 6.33 (s, 1H), 5.45 (d, J = 36.1 Hz, 2H), 3.83–3.77 (m, 1H), 3.68 (dd, J = 14.4, 6.9 Hz, 2H), 3.08 (dd, J = 13.7, 6.9 Hz, 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, 12.2 Hz, 4H). 13 13C NMR (126 MHz, DMSO-d6) δ 164.29, 163.77, 161.83, 160.75, 154.00, 142.59, 139.82, 131.24, 131.18, 128.53, 123.00, 117.53, 114.55, 114.38, 114.22, 114.04, 109.38, 95.66, 77.02, 67.55, 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 FN3O2 446.2238, found 446.2241.

[0123] Compound 46: 1 H NMR(400MHz,CDCl3)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-d6)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 N5O 490.2601,found 490.2578.

[0124] Compound 47: 1 H NMR(400MHz,CDCl3)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). 13CNMR(126MHz,DMSO-d6)δ164.15,160.74,152.69,142.77,140.52,136.84,129.08,127.50,126.92,125.31,122.99,120.29,1 17.49,116.44,109.47,95.92,55.39,51.41,48.99,45.82,41.13,33.08,29.80,27.38,24.01.HRMS(ESI-TOF)m / z[M+H]+calcd for C 33 H 33 N4OF 521.2711, found 521.2695.

[0125] Example 3: Inhibitory activity of substituted cyanoquinolinone compounds against PDE1C

[0126] The inhibitory activity of compounds 1–47 against phosphodiesterase type 1 was determined: the IC50 values ​​of the compounds for PDE1C inhibition were tested. 50 The results are shown in Table 2.

[0127] Table 2 shows the inhibitory effects of compounds on phosphodiesterase type 1.

[0128]

[0129]

[0130] As shown in the table, most of the compounds exhibited some inhibitory effect on phosphodiesterase type 1 (PDE1C), with compounds 11, 20, 24, 25, and 29 showing particularly significant inhibitory effects. 50 Below 20 nM.

[0131] Example 4: Effects of substituted cyanoquinolinone compounds on bleomycin-induced pulmonary fibrosis

[0132] This embodiment uses compound 25 as an example for animal experiments; the effects of other compounds are similar. The specific experimental methods are as follows:

[0133] SPF-grade male SD rats (200±20)g were randomly divided into 4 groups: control group (Con), model group (Mod), pirfenidone (150mg / kg) positive control group (PFD), and compound 25 (5mg / kg) group (3f). The modeling method was as follows: bleomycin solution (BLM, 5mg / kg) was administered intratracheally, while the control group rats received an equal volume of physiological saline intratracheally. The following day after modeling, the rats were administered the drug, while the control and model groups received an equal volume of physiological saline. After 28 days of continuous administration, the respiratory function indicators of relaxation time (RT) and airway stenosis index (Penh) were measured in each group. The test results are as follows: Figure 1 As shown.

[0134] As shown in the figure, all indicators in the model group were statistically significant compared with those in the control group, indicating that the model was successfully established. After 28 days of treatment with PFD (150 mg / kg) or compound 25 (5 mg / kg), all these parameters recovered to some extent, indicating that both PFD and compound 25 can regulate and improve respiratory dysfunction caused by BLM.

[0135] The expression level of the myofibroblast marker protein α-SMA in rat lung tissue was measured. The results are shown in [link to results]. Figure 2 As shown in the figure, after bleomycin induction, the level of α-SMA, a marker protein of myofibroblasts, was significantly increased in the lung tissue of rats in the model group. After treatment with compound 25 and pirfenidone, the expression of α-SMA was significantly decreased. This indicates that treatment with compound 25 can significantly improve BLM-induced pulmonary fibrosis.

[0136] The above results indicate that substituted cyanoquinolinone compound 25 has a significant ameliorative effect on BLM-induced pulmonary fibrosis.

[0137] Example 5: Effects of substituted cyanoquinolinone compounds on DSS-induced enteritis induced by dextran sulfate sodium.

[0138] This embodiment uses compound 25 as an example for animal experiments; the effects of other compounds are similar. The specific experimental methods are as follows:

[0139] Forty mice were randomly divided into four groups: a control group, a DSS-induced model group, a 25 mg / kg (5.0 mg / kg, twice daily, ip) group, and a positive control group (DIP, 25 mg / kg, twice daily, ip for two weeks), with ten mice in each group. The model was established by allowing free access to 3% DSS (MW36000-50000, batch number: A0418C; Melomboplast, Dalian, China) for 7 consecutive days (day 1 to day 8) in autoclaved drinking water (w / v). The DSS solution was changed every 2–3 days. The control group had free access to water. During modeling and drug treatment, mice were examined daily in the morning, and fecal samples were collected. Weight loss, fecal consistency, and blood were assessed. An occult blood test (OB reagent, Baso) was used to measure blood in the feces, and a weight loss score relative to day 1 was calculated.

[0140] Mice were anesthetized with sodium pentobarbital (45 mg / kg, Sigma) and euthanized on the morning of day 8. The abdomen was longitudinally incised to expose the gastrointestinal tract. The entire colon, from the cecum to the rectum, was removed, and its length was recorded and photographed using calipers. Approximately 1 cm of the distal colon was cut and placed overnight in 4% paraformaldehyde at room temperature, then embedded in paraffin. Paraffin-embedded tissue sections with a thickness of 5 μm were placed on glass slides. The paraffin was dewaxed and eluted using a gradient, and stained with hematoxylin and eosin (H&E). Pathological changes of colonic inflammation were observed under a microscope (20× objective, Life Technologies, EVOS FL Auto).

[0141] See results Figure 3 As shown in the figure, the terminal colon in the model group was shortened, and hematoxylin and eosin (H&E) staining revealed significant pathological damage, including lymphocyte infiltration in the lamina propria of the colonic mucosa, local intestinal epithelial defects, fibrous tissue hyperplasia in the lamina propria of the mucosa, and dilatation of intestinal glands. Compound 25 (5.0 mg / kg, twice daily, i.p.) significantly increased colon length and pathological condition.

[0142] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A substituted cyanoquinolinone compound or a pharmaceutically acceptable salt thereof, characterized in that, The substituted cyanoquinolinone compounds have the structure of formula (I): Where R1 is C 1~5 Alkyl or substituted C 1~5 Alkyl, the substituted C 1~5 The alkyl substituent is phenyl, halophenyl, or C. 3~6 cycloalkyl; R2 is a substituted phenyl group, C 3~6 cycloalkyl or C 1~5 alkyl; R3 is a substituted amino group or a pyridine-substituted piperazine group; In R3, the substituent of the substituted amino group is a substituted C. 1~5 Alkyl, the substituted C 1~5 The alkyl substituents are phenyl, pyridyl, halopyridyl, benzodioxazolyl, tetrahydropyranyl, piperidine or substituted piperidine, C 1~5 Alkyl-substituted amino groups, C 3~8 Cycloalkyl or substituted morpholino; the substituent of the substituted piperidinyl group is a halophenyl group; the substituent of the substituted morpholino group is C 1~5 alkyl; The substituent of the substituted phenyl group is C. 1~3 Alkyl or halogen.

2. The substituted cyanoquinoline ketone compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R1 is selected from any of the following structures: ； R2 is selected from any of the following structures: ； R3 is hydrogen or any of the following structures: 。 3. The substituted cyanoquinoline ketone compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The substituted cyanoquinolinone compounds have any of the following structures: 。 4. A method for preparing the substituted cyanoquinolinone compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that, Specifically, the following steps are included: S1. The amino-substituted bromobenzonitrile was heated to reflux with R2MgBr. After the reaction was completed, hydrochloric acid was added in an ice bath. The reaction was completed and then post-treated to obtain compound (II). S2. The compound of formula (II) obtained in step S1 is mixed with phosphorus pentachloride and cyanoacetic acid to carry out a cyclization reaction, and then processed to obtain compound of formula (III); S3. React the compound of formula (III) obtained in step S2 with R1Br and a basic reagent until complete, and then perform post-treatment to obtain compound of formula (IV). S4. The compound of formula (IV) obtained in step S3 is reacted with R3NH2 via a Buchwald-Hartwig arylation reaction to obtain the compound of formula (I). The structural formulas of compounds (I) to (IV) are as follows: 。 5. The use of any of the substituted cyanoquinolinone compounds of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for phosphodiesterase-related diseases; wherein the phosphodiesterase is PDE1; and the phosphodiesterase-related diseases are selected from pulmonary fibrosis or enteritis.

6. The use of any of the substituted cyanoquinolinone compounds of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of a phosphodiesterase inhibitor; wherein the phosphodiesterase is PDE1.

7. A phosphodiesterase inhibitor, characterized in that, The phosphodiesterase inhibitor uses any of the substituted cyanoquinolinone compounds of claims 1 to 3 or their pharmaceutically acceptable salts as the main active ingredient; the phosphodiesterase is PDE1.

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