CN103265480B - Quinolyl dione analog derivative and its production and use - Google Patents

Abstract

The invention provides a quinolinedione derivative and a pharmaceutically acceptable salt thereof, the compound includes optical isomers, tautomers and stereoisomers and pharmaceutically acceptable salts thereof under applicable conditions. Accepted salts, solvates, hydrates or crystalline forms. The compound provided by the invention is an active ligand of the novel cannabinoid type II receptor CB2, and can be used to prepare medicines for preventing and alleviating diseases mediated by the CB2 receptor. The medicine is an agonist, a partial agonist of the cannabinoid CB2 receptor agents, inverse agonists, or antagonists. Its general structural formula B is as follows .

Description

Quinolinedione derivatives and their preparation methods and uses

technical field

The invention belongs to the technical field of medicine, and relates to a class of quinolinedione CB2 active ligands and a preparation method of pharmaceutically acceptable salts, solvates or hydrates thereof; the invention also relates to such compounds and their preparation under applicable conditions. Optical isomers, tautomers and stereoisomers and pharmaceutically acceptable salts, solvates, hydrates or crystal forms thereof are used for the treatment of diseases mediated by cannabinoid type II receptor CB2 application in medicine.

Background technique

As early as several centuries ago, people have realized that plant cannabis has medicinal effects such as pain relief, anti-vomiting, anti-convulsion, and anti-inflammation. Cannabinoids are also one of the earliest addictive substances recognized by humans. The main active substance of plant cannabis is Δ ⁹ -tetrahydrocannabinol (Δ ⁹ -THC), which mainly acts on cannabinoid receptors in the human body. Studies have proved that there are at least two subtypes of cannabinoid receptors: CB1 receptors and CB2 receptors, both of which belong to the rhodopsin-like family of G protein-coupled receptors (GPCRs) and have a 7-segment α-helix transmembrane structure , its complete amino acid sequence has 44% homology, and the relatively conserved transmembrane region amino acid sequence has 68% homology (Pertwee, R. G. Pharmacology of Cannabinoid CB1 and CB2 Receptors. Pharmacol. Ther. 1997, 74, 129 -180). The CB1 receptor is one of the most widely distributed CPCRs found in the central nervous system, and is related to the regulation of cannabinoids on memory, cognition, and motor control; the CB2 receptor is mainly expressed in the peripheral immune system, such as the spleen marginal area, immune Cells, tonsils, etc., are related to immune regulation (Di Marzo, V.; et al. The endocannabinoid system and its therapeutic exploitation. Nat. Rev. Drug Discov. 2004, 3, 771-784). Cannabinoid receptors belong to the Gi/o type of G protein-coupled receptors through which multiple intracellular signal transduction pathways can be activated. CB2 receptors can inhibit the production of cAMP, regulate phosphatidylinositol-3 kinase (PI3K) and ceramide metabolism by inhibiting adenylate cyclase and activating mitogen-activated protein kinase (MAP kinase) channels.

The basic structure of traditional cannabinoid ligands can be divided into the following five categories: 1) Classic cannabinoid compounds represented by Δ ⁹ -THC, which are cannabinoids extracted from natural plants or in natural products 2) Non-classic cannabinoid compounds represented by CP55940, most of which are derivatives of classic cannabinoids; 3) Ananamide represented 4) Aminoalkylindole compounds represented by WIN55212-2; 5) Diarylpyrazole compounds represented by SR141716A and SR144528. With the increasing application of new technologies such as high-throughput screening and virtual screening in the field of medicinal chemistry, more and more novel cannabinoid ligands have been reported, showing rich diversity in chemical structure.

Modern research has shown that cannabinoid receptors are related to various diseases in the human body. CB1 antagonists can be used in the development of new drugs such as weight loss and smoking cessation, while CB2 ligands can be used in the treatment of immune system diseases and inflammation, pain, acute and chronic liver diseases, osteoporosis, atherosclerosis and other diseases. Since CB1 is mainly located in the central nervous system, its ligands are likely to cause related side effects. For example, the CB1 inhibitor rimonabant, which was introduced to the market as a weight-loss drug, was quickly removed from the shelves due to possible side effects such as depression and anxiety shortly after its launch in Europe. Compared with this, the CB2 receptor, which is mainly distributed in the peripheral system, has become a more promising drug target because of its high safety. At present, the CB2 agonist GW842166X reported by GSK has completed three clinical phase II studies as an analgesic drug, but the drug effect is not satisfactory (Giblin, G. M. P.; et al. Discovery of 2-[(2,4-Dichlorophenyl) amino]-N-[(tetrahydro-2H-pyran-4-yl)methyl]-4-(trifluoromethyl)-5-pyrimidinecarboxamide, a Selective CB2 Receptor Agonist for the Treatment of Inflammatory Pain. J. Med. Chem. 2007, 50, 2597-2600); the CB2 agonist S-777469 as a candidate drug for the treatment of atopic dermatitis has also completed the clinical phase II study (Odan, M., et al., Discovery of S-777469: an orally available CB2 agonist as an antipruritic agent. Bioorg. Med. Chem. Lett. , 2012, 22, 2803-2806). At present, the research on CB2 selective ligands is mostly concentrated in the preclinical stage and clinical research stage, and there is no marketed drug yet. Therefore, the discovery of highly active and highly selective CB2 ligands is of great significance for drug development.

Contents of the invention

The first object of the present invention is to provide quinolinedione derivatives and pharmaceutically acceptable salts, solvates, hydrates or crystal forms thereof, including optical isomers and tautomers under applicable conditions and stereoisomers, which are a class of quinolinedione cannabinoid type II receptor CB2 active ligands, and their general structural formula is shown in B:

in,

A ₁ , A ₂ , A ₃ and A ₄ are each independently carbon or nitrogen;

R1 is absent when _A1 is nitrogen, _R2 is _absent when _A2 is nitrogen, _R3 is _absent when A3 is nitrogen, and _R4 is absent when A4 is nitrogen _;

R ₁ , R ₂ , R ₃ , and R ₄ are each independently selected from a hydrogen atom, a C ₁ -C ₁₂ linear or branched hydrocarbon group or alkoxy group substituted or unsubstituted by one or more halogen atoms, a single or Di C ₁ -C ₃ alkylamino, mono or di C ₁ -C ₃ alkyl amido, C ₁ -C ₃ alkylsulfonyl, C ₁ -C ₃ alkoxycarbonyl, hydroxyl, carboxyl, halogen, amino Among the sulfonyl, amino, nitro and cyano groups;

R ₅ is selected from a hydrogen atom, a C ₁ -C ₁₂ linear or branched hydrocarbon group or alkoxy group substituted or unsubstituted by one or more halogen atoms, a hydrocarbon group or alkoxy group with a C ₃ -C ₁₂ ring , C ₃ -C ₁₂ cycloalkyl or aryl or heteroaryl or heterocyclic substituted C ₁ -C ₄ alkyl, C ₆ -C ₁₂ aryl, heteroaryl or heterocyclic;

R ₆ is selected from C ₁ -C ₁₂ linear or branched hydrocarbon groups or alkoxy groups, hydrocarbon groups or alkoxy groups with C ₃ -C ₁₂ rings, C ₃ -C ₁₂ cycloalkyl or aryl or heteroaryl or heterocyclic substituted C ₁ -C ₄ alkyl, adamantyl, C ₆ -C ₁₂ aryl, heteroaryl or heterocyclic;

The aryl group, heteroaryl group or heterocyclic group is optionally replaced by a C ₁ -C ₈ linear or branched hydrocarbon group or alkoxy group, a mono or di C ₁ -C ₃ alkylamino, a mono or di C ₁ -C ₃ alkylamido, C ₁ -C ₃ alkylsulfonyl, C ₁ -C ₃ alkoxycarbonyl, hydroxyl, carboxyl, halogen, trifluoromethyl, trifluoromethoxy, aminosulfonyl, amino , nitro and cyano substitutions;

The heteroaryl group is a 5-10 membered aromatic group containing 1-3 identical or different heteroatoms selected from N, O and S;

The heterocyclic group is a 4-10 membered non-aromatic group containing 1-3 same or different heteroatoms selected from N, O and S.

In another preferred example, A ₁ , A ₂ , A ₃ , and A ₄ are carbon, and R ₁ , R ₂ , R ₃ , and R ₄ are each independently hydrogen, chlorine, bromine, trifluoromethyl, trifluoromethyl Oxygen, C ₁ -C ₃ alkoxy or C ₁ -C ₄ alkyl;

R ₅ is a C ₁ -C ₈ straight chain or branched chain alkyl group or a hydrocarbon group with a C ₃ -C ₁₂ ring;

R ₆ is a C ₁ -C ₈ straight chain or branched chain alkyl, a hydrocarbon group with a C ₃ -C ₈ ring, a C ₃ -C ₈ ring hydrocarbon group or a C ₁ - substituted by an aryl or heteroaryl or heterocyclic group C ₄ alkyl, adamantyl or heterocyclyl.

Specific compounds preferred in the present invention include:

1) 1-n-Butyl-3-((cyclohexylamino)enyl)quinoline-2,4(1H,3H)-dione

2) 1-n-Butyl-3-((p-tolylamino)alkenyl)quinoline-2,4(1H,3H)-dione

3) 1-n-Butyl-3-((p-methylbenzylamino)alkenyl)quinoline-2,4(1H,3H)-dione

4) 1-n-Butyl-3-((cyclohexylamino)alkenyl)-6-methylquinoline-2,4(1H,3H)-dione

5) 1-n-Butyl-3-((1-adamantylamino)alkenyl)-6-methylquinoline-2,4(1H,3H)-dione

6) 1-n-Butyl-3-((p-methylbenzylamino)alkenyl)-6-methylquinoline-2,4(1H,3H)-dione

7) 1-n-Butyl-3-((cyclohexylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione

8) 1-n-Butyl-3-((cyclohexylamino)alkenyl)-6-methoxyquinoline-2,4(1H,3H)-dione

9) 1-n-Butyl-3-((1-adamantylamino)alkenyl)-6-methoxyquinoline-2,4(1H,3H)-dione

10) 3-((cyclohexylamino)alkenyl)-6-methoxy-1-n-pentylquinoline-2,4(1H,3H)-dione

11) 3-((cyclohexylamino)alkenyl)-1-n-hexyl-6-methoxyquinoline-2,4(1H,3H)-dione

12) 1-n-Butyl-6,8-dichloro-3-((cyclohexylamino)enyl)quinoline-2,4(1H,3H)-dione

13) 1-n-Butyl-3-((n-butylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione

14) 1-n-Butyl-3-((tert-butylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione

15) 1-n-Butyl-3-((cyclopentylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione

16) 1-n-Butyl-3-((1-adamantylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione

17) 1-n-Butyl-3-((cyclopropylmethylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione

18) 1-n-Butyl-3-((cyclohexylmethylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione

19) 1-n-Butyl-8-methyl-3-((piperidin-1-amino)enyl)quinoline-2,4(1H,3H)-dione

20) 1-n-Butyl-8-methyl-3-((morpholino)alkenyl)quinoline-2,4(1H,3H)-dione

21) 3-((Cyclohexylamino)alkenyl)-1-n-pentylquinoline-2,4(1H,3H)-dione

22) 3-((1-adamantylamino)alkenyl)-6-methoxy-1-n-pentylquinoline-2,4(1H,3H)-dione

23) 6-tert-butyl-3-((cyclohexylamino)alkenyl)-1-n-pentylquinoline-2,4(1H,3H)-dione

24) 6-Chloro-3-((cyclohexylamino)alkenyl)-1-n-pentylquinoline-2,4(1H,3H)-dione

25) 6-Chloro-3-((1-adamantylamino)alkenyl)-1-n-pentylquinoline-2,4(1H,3H)-dione

26) 6-Bromo-3-((cyclohexylamino)alkenyl)-1-n-pentylquinoline-2,4(1H,3H)-dione

27) 3-((Cyclohexylamino)alkenyl)-8-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione

28) 3-((1-adamantylamino)alkenyl)-8-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione

29) 3-((Cyclohexylamino)alkenyl)-8-ethyl-1-n-pentylquinoline-2,4(1H,3H)-dione

30) 3-((cyclohexylamino)alkenyl)-8-methoxy-1-n-pentylquinoline-2,4(1H,3H)-dione

31) 3-((1-adamantylamino)alkenyl)-8-methoxy-1-n-pentylquinoline-2,4(1H,3H)-dione

32) 8-Chloro-3-((cyclohexylamino)alkenyl)-1-n-pentylquinoline-2,4(1H,3H)-dione

33) 3-((Cyclohexylamino)alkenyl)-5-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione

34) 3-((Cyclohexylamino)alkenyl)-7-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione

35) 6-Chloro-3-((cyclohexylamino)alkenyl)-8-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione

36) 3-((Cyclohexylamino)alkenyl)-6-methoxy-8-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione

37) 3-((1-adamantylamino)alkenyl)-6-methoxy-8-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione

38) 3-((Cyclohexylamino)alkenyl)-1-ethyl-8-methylquinoline-2,4(1H,3H)-dione

39) 3-((Cyclohexylamino)alkenyl)-1-n-pentyl-1,8-naphthyridine-2,4(1H,3H)-dione

40) 3-((cyclohexylmethylamino)alkenyl)-6-methoxy-1-n-pentylquinoline-2,4(1H,3H)-dione

41) 3-((cyclohexylmethylamino)alkenyl)-6-methoxy-8-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione

42) 1-n-Butyl-8-methyl-3-((n-propylamino)enyl)quinoline-2,4(1H,3H)-dione

43) 1-n-Butyl-3-((isopropylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione

44) 1-n-Butyl-8-chloro-3-((cyclohexylamino)enyl)quinoline-2,4(1H,3H)-dione

45) 1-n-Butyl-7-chloro-3-((cyclohexylamino)enyl)quinoline-2,4(1H,3H)-dione

46) 3-((Cyclohexylamino)alkenyl)-1-cyclopropylmethyl-8-methylquinoline-2,4(1H,3H)-dione

47) 1-n-Butyl-3-((cyclobutylmethylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione

48) 1-n-Butyl-3-((isobutylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione

49) 3-((tert-butylamino)alkenyl)-1-cyclopropylmethyl-8-methylquinoline-2,4(1H,3H)-dione

50) 3-((Cyclohexylamino)alkenyl)-7-methoxy-1-n-pentylquinoline-2,4(1H,3H)-dione

51) 3-((Cyclohexylamino)alkenyl)-5-methoxy-1-n-pentylquinoline-2,4(1H,3H)-dione

52) 1-n-Butyl-3-((cyclohexylamino)alkenyl)-8-ethylquinoline-2,4(1H,3H)-dione

53) 3-((Cyclohexylamino)alkenyl)-1-n-pentyl-6-trifluoromethylquinoline-2,4(1H,3H)-dione

54) 7-Chloro-3-((cyclohexylamino)alkenyl)-1-n-pentylquinoline-2,4(1H,3H)-dione

55) 3-((Cyclohexylamino)alkenyl)-6-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione

56) 3-((cyclohexylamino)alkenyl)-1-n-pentyl-6-trifluoromethoxyquinoline-2,4(1H,3H)-dione

57) 1-n-Butyl-3-((cyclopropylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione

58) 1-n-Butyl-8-methyl-3-((tetrahydro-2H-pyran-4-methyleneamino)enyl)quinoline-2,4(1H,3H)-dione

59) 1-n-Butyl-3-((cyclohexylamino)alkenyl)-8-methoxyquinoline-2,4(1H,3H)-dione

60) 3-((Cyclohexylamino)alkenyl)-8-methyl-1-propylquinoline-2,4(1H,3H)-dione

61) 3-((tert-butylamino)alkenyl)-8-methyl-1-propylquinoline-2,4(1H,3H)-dione

62) 1-n-Butyl-3-((cyclohexylamino)alkenyl)-5-methylquinoline-2,4(1H,3H)-dione

63) 1-n-Butyl-3-((cyclohexylamino)alkenyl)-7-methylquinoline-2,4(1H,3H)-dione

64) 1-n-Butyl-3-((cyclohexylmethylamino)alkenyl)-5-methylquinoline-2,4(1H,3H)-dione

65) 1-n-Butyl-3-((cyclohexylmethylamino)alkenyl)-7-methylquinoline-2,4(1H,3H)-dione

66) 3-((cyclohexylamino)alkenyl)-6,8-dimethoxy-1-n-pentylquinoline-2,4(1H,3H)-dione

67) 3-((Cyclohexylmethylamino)alkenyl)-6,8-dimethoxy-1-n-pentylquinoline-2,4(1H,3H)-dione

68) 1-n-Butyl-3-((cyclohexylamino)alkenyl)-6-fluoroquinoline-2,4(1H,3H)-dione

69) 1-n-Butyl-3-((tert-butylamino)alkenyl)-6-fluoroquinoline-2,4(1H,3H)-dione

70) 7-((cyclohexylmethylamino)alkenyl)-5-n-pentylpyrido[2,3- b ]pyrazine-6,8(5H,7H)-dione

Optical isomers, tautomers and stereoisomers of the specific compounds mentioned above and their pharmaceutically acceptable salts, solvates, hydrates or crystal forms thereof under applicable conditions.

The pharmaceutically acceptable salt is selected from hydrochloride, hydrobromide, sulfate, sulfuric acid salt, phosphate, dihydrogen phosphate, methanesulfonate, monomethyl sulfate, cis-butene Dialate, fumarate, succinate, ascorbate, nicotinate, lactate, tartrate, acetate, oxalate, malonate, glycolate, naphthalene-2 - sulfonates, gluconates, citrates, isethionates, p-toluenesulfonates, 3,5-dimethylbenzylsulfonates, or quaternary ammonium salts with haloalkanes, Wherein said haloalkane is fluorine, chlorine, bromine or iodoalkane.

The second object of the present invention is to provide a preparation method of quinolinedione derivatives and pharmaceutically acceptable salts, solvates or hydrates thereof, which is achieved by the following steps:

(1) Compound (I) reacts with halogenated hydrocarbon (II) under basic conditions at a reaction temperature of 0-100°C to obtain compound (III);

Wherein, described alkali is organic base or inorganic base, selects sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, sodium hydride, triethylamine, diisopropylethylamine (DIEA) , 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine or 4-dimethylaminopyridine (DMAP);

(2) Compound (III) reacts with cyanoacetic acid or cyanoacetyl chloride at room temperature to obtain compound (IV);

(3) Under room temperature conditions, compound (IV) is catalyzed by a catalyst in an organic solvent to close the ring to obtain compound (V);

Among them, the organic solvent is N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, the catalyst is phosphorus oxychloride, thionyl chloride, oxalyl chloride, trifluoromethanesulfonate anhydride or trifluoromethanesulfonic acid;

(4) Under acidic or alkaline conditions, compound (V) reacts with amine compound (VI) to obtain compound (B);

Wherein acidic condition is room temperature or reflux reaction in acetic acid solvent; Basic condition is in water, methanol or ethanol solvent, selects sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methylate or sodium ethylate to react, reaction temperature 25-100°C;

(5) Dissolve compound B in anhydrous methanol, add an appropriate amount of acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, maleic acid, fumaric acid, etc. under ice bath, and spin Dry solvent to obtain its pharmaceutically acceptable acid addition salt; or dissolve compound B in absolute ethanol, add equivalent sodium hydroxide, potassium iodide and halogenated hydrocarbons such as methyl iodide, heat and reflux overnight, and the crude product is reconstituted with acetone Crystallization and purification to obtain a pharmaceutically acceptable quaternary ammonium salt of Compound B;

(6) Dissolving compound B in an aqueous acid solution, adding a non-acidic organic solvent to the system, and obtaining a solvate or hydrate of compound B by crystallization; wherein the suitable acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, citric acid , acetic acid, potassium acid, perchloric acid, hydrobromic acid, nitric acid, formic acid, tartaric acid, benzoic acid, phenylacetic acid, maleic acid, oxalic acid, trifluoroacetic acid, non-acidic organic solvents selected from ethanol, methanol, acetonitrile, ethyl acetate Esters, tetrahydrofuran, diethyl ether, petroleum ether, isopropanol, n-butanol, N,N-dimethylformamide.

The third object of the present invention is to provide quinolinedione derivatives and optical isomers, tautomers and stereoisomers under applicable conditions and their pharmaceutically acceptable salts, solvates, hydrated The use of substances or crystal forms in the preparation of medicines for preventing and alleviating diseases mediated by CB2 receptors, said medicines are agonists, partial agonists, inverse agonists or antagonists of cannabinoid CB2 receptors, said Diseases include cancer, inflammation, acquired immunodeficiency syndrome, autoimmune disease, rheumatic disease, allergy, pain, acute and chronic liver disease, osteoporosis, atherosclerosis regulated by CB2 receptor agonists and partial agonists , multiple sclerosis, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, Huntington's disease and inflammation regulated by CB2 receptor inverse agonists and antagonists, immune system diseases, neurodegenerative diseases and Osteoporosis.

The fourth object of the present invention is to provide a quinolinedione derivative and its optical isomers, tautomers and stereoisomers under applicable conditions and their pharmaceutically acceptable salts and solvates , hydrate or crystal pharmaceutical composition, and may further include excipients, diluents and carriers. The compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, polyethylene glycol, propylene glycol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention. The pharmaceutical composition of the present invention may include one or more compounds of the present invention, and a typical formulation is by mixing the compound of the present invention and its pharmaceutically acceptable salt, solvate or hydrate with a carrier, excipient or diluent Prepare. Commonly used carriers, excipients or diluents include substances such as carbohydrates, cellulose and its derivatives, gelatin, oils, polyols, water and the like. The dosage form of the medicine is selected from solid preparation or liquid preparation, such as tablet, capsule, powder, granule, solution, syrup, suspension or aerosol.

The present invention provides a method for regulating the activity of the cannabinoid CB2 receptor, the method comprising contacting the compound represented by the structure B with the cannabinoid CB2 receptor, the compound is an agonist, a partial agonist, an inverse agonist of the cannabinoid CB2 receptor agent or antagonist.

The compound of the present invention is the active ligand of the novel cannabinoid type II receptor CB2, the compound and its optical isomers, tautomers and stereoisomers under applicable conditions and pharmaceutically acceptable salts thereof , solvate, hydrate or crystal form can be used to prepare medicines for treating, preventing and inhibiting diseases mediated by CB2 receptors.

Description of drawings

Figure 1 In vitro activity test results of some compounds.

Figure 2 shows the results of the in vivo efficacy experiment of compound CHG07 on the experimental autoimmune encephalomyelitis (EAE) model in mice, where Figure A shows the in vivo efficacy experiment of compound CHG07 on the experimental autoimmune encephalomyelitis model As a result, Panel B shows the cell statistics of the leukocytes infiltrating the spinal cord, and Panel C shows the statistics of the area of demyelination.

Detailed ways

The present invention will be further described in conjunction with examples, but not limit the present invention in any way.

Example 1: 1-n-Butyl-3-((cyclohexylamino)enyl)quinoline-2,4(1H,3H)-dione (CHG01)

a) Preparation of N-n-butylaniline 1a

Dissolve aniline (20.00 mmol, 1.86 g) in 50 mL of acetonitrile, add n-bromobutane (10.00 mmol, 1.37 g) and potassium carbonate (50.00 mmol, 6.91 g), and heat to reflux overnight. Cool to room temperature, filter, take the filtrate and distill under reduced pressure to obtain the crude product, the crude product is separated and purified by column chromatography, the elution condition is petroleum ether:ethyl acetate=20:1～10:1, and 1a is obtained as a yellow liquid 613.2mg , yield 41.1%.

b) Preparation of N-n-butyl-2-cyano-N-phenylacetamide 1b

Dissolve cyanoacetic acid (2.50mmol, 212.8mg) in 2mL DMF, ice bath, add 4-dimethylaminopyridine (DMAP) (1.00mmol, 122.2mg), 1-ethyl-(3-dimethylamino Propyl) carbodiimide hydrochloride (3.75mmol, 718.9mg), react at room temperature for 1 hour, dissolve 1a (3.00mmol, 447.6mg) in 1mL DMF, add dropwise, and react at room temperature for 24 hours. After the reaction, wash with water, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous magnesium sulfate, and distill under reduced pressure to obtain a crude product. Separation and purification by column chromatography, the elution condition is petroleum ether: ethyl acetate = 6:1 ~ 2:1, 1b was obtained as light yellow liquid 192.0mg, yield 35.5%.

¹ H NMR (CDCl ₃ , 500Hz): δ 7.49 (t, 2H, J=7.5Hz), 7.44 (t, 1H, J=7.5Hz), 7.21 (d, 2H, J=7.0Hz), 3.75 (t , 2H, J=7.5Hz), 3.19 (s, 2H), 1.50 (m, 2H), 1.32 (m, 2H), 0.90 (t, 3H, J=7.5Hz).

c) Preparation of 1-n-butyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde 1c

Take 1b (0.50mmol, 108.2mg) and dissolve it in 0.5mL DMF, put in an ice bath, add trifluoromethanesulfonic anhydride (1.50mmol, 423.3mg) dropwise, and react overnight at room temperature. After the reaction, 5 mL of ice water was added, filtered and washed with water to obtain 98.7 mg of 1c as a yellow solid with a yield of 80.5% and a melting point of 77.6-78.4°C.

¹ H NMR (CDCl ₃ , 500Hz): δ 14.62 (s, 1H), 10.27 (s, 1H), 8.18 (d, 1H, J=8.0Hz), 7.71 (t, 1H, J=7.5Hz), 7.32 (d, 1H, J=8.5Hz), 7.27 (t, 1H, J=7.5Hz), 4.23 (t, 2H, J=7.5Hz), 1.71 (m, 2H), 1.49 (m, 2H), 1.01 (t, 3H, J=7.5Hz).

d) Preparation of 1-n-butyl-3-((cyclohexylamino)enyl)quinoline-2,4(1H,3H)-dione (CHG01)

Take 1c (0.10mmol, 24.5mg) and dissolve it in 2mL of acetic acid, add cyclohexylamine (0.12mmol, 11mg), and reflux overnight. After the reaction, the solvent acetic acid was distilled off under reduced pressure, washed with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to obtain a crude product. Separation and purification by column chromatography, the elution condition is petroleum ether: ethyl acetate = 2:1, CHG01 was obtained as yellow liquid 29.0 mg, yield 88.8%.

¹ H NMR (CDCl ₃ , 500Hz): δ12.29 (s, 1H), 8.53 (d, 1H, J=14.0Hz), 8.20 (q, 1H, J=8.0Hz), 7.49 (q, 1H, J =7.0Hz), 7.12 (m, 2H), 4.10 (t, 2H, J=7.5Hz), 3.37 (m, 1H), 1.97 (m, 2H), 1.77 (m, 2H), 1.62 (m, 3H ), 1.40 (m, 6H), 1.21 (m, 1H), 0.93 (t, 3H, J=7.0Hz).

Example 2: 1-n-Butyl-3-((p-tolylamino)alkenyl)quinoline-2,4(1H,3H)-dione (CHG02)

The preparation of compound CHG02 was the same as that of compound CHG01 in Example 1, except that p-toluidine (0.12 mmol, 12.9 mg) was used instead of cyclohexylamine to obtain CHG02 as a yellow solid of 30.7 mg with a yield of 91.8% and a melting point of 130.4 -131.2°C.

¹ H NMR (CDCl3, 500Hz): δ14.03 (d, 1H, J=13.5Hz), 9.00 (d, 1H, J=13.5Hz), 8.28 (m, 1H), 7.58 (t, 1H, J= 7Hz), 7.21 (m, 6H), 4.18 (t, 2H, J=7.5Hz), 2.36 (s, 3H), 1.71 (m, 2H), 1.49 (m, 2H), 1.00 (t, 3H, J =7.5Hz).

Example 3: 1-n-Butyl-3-((p-methylbenzylamino)enyl)quinoline-2,4(1H,3H)-dione (CHG03)

The preparation of compound CHG03 was the same as that of compound CHG01 in Example 1, except that p-methylbenzylamine (0.12 mmol, 14.5 mg) was used instead of cyclohexylamine to obtain 33.1 mg of CHG03 as a yellow solid with a yield of 95.0%, melting point 141.9-143.3°C.

¹ H NMR (CDCl3, 500Hz): δ12.44 (s, 1H), 8.59 (d, 1H, J=13.5Hz), 8.23 (m, 1H), 7.55 (m, 1H), 7.17 (m, 6H) , 4.63 (d, 2H, J=6.0Hz), 4.15 (t, 3H, J=7.5Hz), 2.35 (s, 3H), 1.68 (m, 2H), 1.46 (m, 2H), 0.99 (t, 3H, J=7.5Hz).

Example 4: 1-n-Butyl-3-((cyclohexylamino)alkenyl)-6-methylquinoline-2,4(1H,3H)-dione (CHG04)

a) Preparation of 4-methyl-N-n-butylaniline 2a

Compound 2a was prepared in the same manner as compound 1a in Example 1, except that 4-methylaniline (20.00 mmol, 2.14 g) was used instead of aniline to obtain 587.9 mg of 2a as a yellow liquid with a yield of 36.0%.

b) Preparation of N-n-butyl-2-cyano-N-(4-methylphenyl)acetamide 2b

The preparation of compound 2b was the same as that of compound 1b in Example 1, except that 2a (3.00 mmol, 489.9 mg) was used instead of 1a to obtain 186.0 mg of 2b as a light yellow liquid with a yield of 32.3%.

c) Preparation of 1-n-butyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde 2c

The preparation of compound 2c was the same as the preparation method of compound 1c in Example 1, except that 2b (0.50 mmol, 115.2 mg) was used instead of 1 b to obtain 112.3 mg of 2c as a light yellow solid with a yield of 86.6% and a melting point of 110.2-110.8 °C .

d) Preparation of 1-n-butyl-3-((cyclohexylamino)enyl)-6-methylquinoline-2,4(1H,3H)-dione (CHG04)

The preparation of compound CHG04 was the same as that of compound CHG01 in Example 1, except that 2c (0.10 mmol, 25.9 mg) was used instead of 1c to obtain 30.4 mg of CHG04 as a yellow liquid with a yield of 89.4%.

¹ H NMR (CDCl3, 500Hz): δ12.34 (s, 1H), 8.56 (d, 1H, J=14.0Hz), 8.02 (d, 1H, J=46.0Hz), 7.33 (m, 1H), 7.07 (d, 1H, J=8.5Hz), 4.11 (t, 3H, J=7.5Hz), 3.43 (m, 1H), 2.36 (s, 3H), 2.01 (m, 2H), 1.80 (m, 2H) , 1.64 (m, 3H), 1.43 (m, 6H), 1.25 (m, 1H), 0.95 (t, 3H, J=7.5Hz).

Example 5: 1-n-Butyl-3-((1-adamantylamino)alkenyl)-6-methylquinoline-2,4(1H,3H)-dione (CHG05)

Compound CHG05 was prepared in the same manner as compound CHG04 in Example 4, except that cyclohexylamine was replaced by 1-adamantylamine (0.12 mmol, 18.1 mg). CHG05 was obtained as a yellow liquid, 38.6 mg, with a yield of 98.3%.

¹ H NMR (CDCl3, 500Hz): δ12.57 (d, 1H, J=14.0Hz), 8.62 (dd, 1H, J=14.0Hz, J=23.0Hz), 8.02 (d, 1H, J=46.0Hz ), 7.32 (m, 1H), 7.07 (d, 1H, J=8.5Hz), 4.11 (t, 2H, J=7.5Hz), 2.36 (s, 3H), 2.19 (s, 3H), 1.92 (s , 6H), 1.72 (d, 3H, J=12.5Hz), 1.65 (m, 5H), 1.44 (m, 2H), 0.95 (t, 3H, J=7.5Hz).

Example 6: 1-n-Butyl-3-((p-methylbenzylamino)alkenyl)-6-methylquinoline-2,4(1H,3H)-dione (CHG06)

The preparation of compound CHG06 was the same as that of compound CHG04 in Example 4, except that p-methylbenzylamine (0.12 mmol, 14.5 mg) was used instead of cyclohexylamine to obtain 32.7 mg of CHG06 as a yellow solid with a yield of 90.2%, melting point 146.2-147.5°C.

¹ H NMR (CDCl3, 500Hz): δ12.44 (s, 1H), 8.58 (d, 1H, J=14.0Hz), 8.03 (dd, 1H, J=2.0Hz, J=54.0Hz), 7.36 (m , 1H), 7.18 (t, 4H, J=9.0Hz), 7.08 (d, 1H, J=8.5Hz), 4.63 (d, 2H, J=6.0Hz), 4.13 (t, 2H, J=7.5Hz ), 2.37 (s, 3H), 2.34 (s, 3H), 1.67 (m, 2H), 1.45 (m, 2H), 0.98 (t, 3H, J=7.5Hz).

Example 7: 1-n-Butyl-3-((cyclohexylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione (CHG07)

a) Preparation of 2-methyl-N-n-butylaniline 3a

The preparation of compound 3a was the same as that of compound 1a in Example 1, except that 2-methylaniline (20.00 mmol, 2.14 g) was used instead of aniline to obtain 460.5 mg of 3a as a yellow liquid with a yield of 28.2%.

b) Preparation of N-n-butyl-2-cyano-N-(2-methylphenyl)acetamide 3b

The preparation of compound 3b was the same as that of compound 1b in Example 1, except that 3a (2.70 mmol, 440.9 mg) was used instead of 1a to obtain 181.4 mg of 3b as a light yellow liquid with a yield of 35.0%.

c) Preparation of 1-n-butyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde 3c

The preparation of compound 3c was the same as that of compound 1c in Example 1, except that 3b (0.50mmol, 115.2mg) was used instead of 1b to obtain 93.1mg of 3c as a light yellow solid with a yield of 71.8% and a melting point of 67.2-68.6°C .

d) Preparation of 1-n-butyl-3-((cyclohexylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione (CHG07)

The preparation of compound CHG07 was the same as that of compound CHG01 in Example 1, except that 3c (0.10 mmol, 25.9 mg) was used instead of 1c to obtain 31.1 mg of CHG07 as a light yellow liquid with a yield of 91.4%.

¹ H NMR (CDCl3, 500Hz): δ12.16 (s, 1H), 8.51 (d, 1H, J=14.0Hz), 8.10 (dd, 1H, J=7.0Hz, J=38.5Hz), 7.31 (t , 1H, J=6.5Hz), 7.06 (t, 1H, J=7.5Hz), 4.28 (t, 2H, J=7.5Hz), 3.40 (m, 1H), 2.53 (s, 3H), 2.020 (m , 2H), 1.81 (m, 2H), 1.63 (m, 1H), 1.50 (m, 4H), 1.37 (m, 2H), 1.22 (m, 3H), 0.83 (t, 3H, J=7.5Hz) .

Example 8: 1-n-Butyl-3-((cyclohexylamino)alkenyl)-6-methoxyquinoline-2,4(1H,3H)-dione (CHG08)

a) Preparation of 4-methoxy-N-n-butylaniline 4a

The preparation of compound 4a was the same as that of compound 1a in Example 1, except that 4-methoxyaniline (20.00 mmol, 2.46 g) was used instead of aniline to obtain 1102.7 mg of 4a as a yellow liquid with a yield of 61.5%.

b) Preparation of N-n-butyl-2-cyano-N-(4-methoxyphenyl)acetamide 4b

The preparation of compound 4b was the same as that of compound 1b in Example 1, except that 4a (3.00 mmol, 537.9 mg) was used instead of 1a to obtain 232.8 mg of 4b as a yellow liquid with a yield of 37.8%.

c) Preparation of 1-n-butyl-4-hydroxy-6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde 4c

The preparation of compound 4c was the same as that of compound 1c in Example 1, except that 4b (0.50 mmol, 123.2 mg) was used instead of 1 b to obtain 111.9 mg of 4c as a yellow solid with a yield of 81.3% and a melting point of 130.8-132.5°C.

d) Preparation of 1-n-butyl-3-((cyclohexylamino)alkenyl)-6-methoxyquinoline-2,4(1H,3H)-dione (CHG08)

The preparation of compound CHG08 was the same as that of compound CHG01 in Example 1, except that 4c (0.10 mmol, 27.5 mg) was used instead of 1c to obtain 29.1 mg of CHG08 as a yellow liquid with a yield of 81.5%.

¹ H NMR (CDCl3, 500Hz): δ12.32 (s, 1H), 8.57 (d, 1H, J=14.5Hz), 7.68 (dd, 1H, J=2.5Hz, J=44.5Hz), 7.12 (m , 2H), 4.10 (t, 2H, J=7.5Hz), 3.83 (s, 3H), 3.41 (m, 1H), 2.00 (m, 2H), 1.79 (m, 2H), 1.63 (m, 3H) , 1.41 (m, 6H), 1.25 (m, 1H), 0.94 (t, 3H, J=7.5H).

Example 9: 1-n-Butyl-3-((1-adamantylamino)alkenyl)-6-methoxyquinoline-2,4(1H,3H)-dione (CHG09)

The preparation of compound CHG09 was the same as that of compound CHG08 in Example 8, except that 1-adamantanamine (0.12 mmol, 18.1 mg) was used instead of cyclohexylamine to obtain CHG09 as a yellow solid of 36.8 mg with a yield of 90.1%. The melting point is 51.4-53.0°C.

¹ H NMR (CDCl3, 500Hz): δ12.58 (d, 1H, J=14.0Hz), 8.64 (dd, 1H, J=14.5Hz, J=18Hz), 7.70 (dd, 1H, J=2.5Hz, J=46.0Hz), 7.12 (m, 2H), 4.12 (t, 2H, J=7.5Hz), 3.85 (s, 3H), 2.20 (s, 3H), 1.93 (s, 6H), 1.75 (d, 3H, J=12.5Hz), 1.66 (m, 5H), 1.44 (m, 2H), 0.96 (t, 3H, J=7.5Hz).

Example 10: 3-((cyclohexylamino)alkenyl)-6-methoxy-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG10)

a) Preparation of 4-methoxy-N-n-pentylaniline 5a

Compound 5a was prepared in the same way as Compound 1a in Example 1, except that 4-methoxyaniline (20.00mmol, 2.46g) was used instead of aniline, and bromo-n-pentane (10.00mmol, 1.51g) was used instead Bromo-n-butane gave 1202.3 mg of 5a as a yellow liquid with a yield of 62.2%.

b) Preparation of 2-cyano-N-(4-methoxyphenyl)-N-pentylacetamide 5b

The preparation of compound 5b was the same as that of compound 1b in Example 1, except that 5a (3.00 mmol, 579.9 mg) was used instead of 1a to obtain 237.5 mg of 5b as a yellow liquid with a yield of 36.5%.

c) Preparation of 4-hydroxy-6-methoxy-2-oxo-1-n-pentyl-1,2-dihydroquinoline-3-carbaldehyde 5c

The preparation of compound 5c was the same as that of compound 1c in Example 1, except that 5b (0.50 mmol, 130.2 mg) was used instead of 1b to obtain 118.2 mg of 5c as a yellow solid with a yield of 81.7% and a melting point of 106.4-107.8 °C.

d) Preparation of 3-((cyclohexylamino)alkenyl)-6-methoxy-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG10)

The preparation of compound CHG10 was the same as that of compound CHG01 in Example 1, except that 5c (0.10 mmol, 28.9 mg) was used instead of 1c to obtain 34.6 mg of CHG10 as a yellow liquid with a yield of 93.4%.

¹ H NMR (CDCl3, 500Hz): δ12.33 (s, 1H), 8.59 (t, 1H, J=15.0Hz), 7.70 (dd, 1H, J=2.5Hz, J=43.0Hz), 7.12 (m , 2H), 4.10 (t, 2H, J=7.5Hz), 3.85 (s, 3H), 3.42 (m, 1H), 2.02 (m, 2H), 1.81 (m, 2H), 1.76 (m, 3H) , 1.50 (m, 2H), 1.38 (m, 6H), 1.25 (m, 1H), 0.90 (t, 3H, J=7.0Hz).

Example 11: 3-((cyclohexylamino)alkenyl)-1-n-hexyl-6-methoxyquinoline-2,4(1H,3H)-dione (CHG11)

a) Preparation of N-n-hexyl-4-methoxyaniline 6a

Compound 6a was prepared in the same manner as Compound 1a in Example 1, except that 4-methoxyaniline (20.00mmol, 2.46g) was used instead of aniline, and bromo-n-hexane (10.00mmol, 1.65g) was used instead of bromine Substitute n-butane to obtain 1316.4 mg of 6a as a yellow liquid, with a yield of 63.5%.

b) Preparation of 2-cyano-N-n-hexyl-N-(4-methoxyphenyl)acetamide 6b

Compound 6b was prepared in the same manner as compound 1b in Example 1, except that 6a (3.00 mmol, 621.9 mg) was used instead of 1a to obtain 258.6 mg of 6b as a yellow liquid with a yield of 37.7%.

c) Preparation of 1-n-hexyl-4-hydroxy-6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde 6c

The preparation of compound 6c was the same as that of compound 1c in Example 1, except that 6b (0.50 mmol, 137.2 mg) was used instead of 1 b to obtain 134.1 mg of 6c as a yellow solid with a yield of 88.4% and a melting point of 84.0-85.2 °C.

d) Preparation of 3-((cyclohexylamino)alkenyl)-1-n-hexyl-6-methoxyquinoline-2,4(1H,3H)-dione (CHG11)

The preparation of compound CHG11 was the same as that of compound CHG01 in Example 1, except that 6c (0.10 mmol, 30.3 mg) was used instead of 1c to obtain 25.2 mg of CHG11 as a yellow liquid with a yield of 65.6%.

¹ H NMR (CDCl3, 500Hz): δ12.34 (s, 1H), 8.60 (t, 1H, J=14.0Hz), 7.71 (dd, 1H, J=3.0Hz, J=43.5Hz), 7.13 (m , 2H), 4.11 (t, 2H, J=7.5Hz), 3.86 (s, 3H), 3.42 (m, 1H), 2.02 (m, 2H), 1.82 (m, 2H), 1.66 (m, 3H) , 1.49 (m, 2H), 1.41 (m, 4H), 1.33 (m, 5H), 0.88 (t, 3H, J=7.0Hz).

Example 12: 1-n-Butyl-6,8-dichloro-3-((cyclohexylamino)enyl)quinoline-2,4(1H,3H)-dione (CHG12)

a) Preparation of N-n-butyl-2,4-dichloroaniline 7a

Compound 7a was prepared in the same manner as Compound 1a in Example 1, except that 2,4-dichloroaniline (0.20mol, 32.4g) was used instead of aniline to obtain 2.02g of yellow liquid with a yield of 9.3%.

b) Preparation of N-n-butyl-2-cyano-N-(2,4-dichlorophenyl)acetamide 7b

The preparation method of compound 7b was the same as that of compound 1b in Example 1, except that compound 7a (9.00 mmol, 1.96 g) was used instead of compound 1a to obtain 183.9 mg of yellow liquid with a yield of 8.6%.

c) Preparation of 1-n-butyl-6,8-dichloro-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde 7c

Take 7b (0.50mmol, 142.6mg) dissolved in 0.5mL DMF, ice bath, add trifluoromethanesulfonic anhydride (1.50mmol, 423.3mg) dropwise, react overnight at room temperature. After the reaction, 5 mL of ice water was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to obtain a crude product. After separation and purification by column chromatography, the elution condition was dichloromethane:methanol=50:1, and 7c was obtained as reddish-brown liquid 101.3mg, yield 64.5%.

d) Preparation of 1-n-butyl-6,8-dichloro-3-((cyclohexylamino)enyl)quinoline-2,4(1H,3H)-dione (CHG12)

The preparation of compound CHG12 was the same as that of compound CHG01 in Example 1, except that 7c (0.10 mmol, 31.4 mg) was used instead of 1c to obtain 14.2 mg of CHG12 as a yellow solid with a yield of 35.8% and a melting point of 86.0-86.7°C.

¹ H NMR (CDCl3, 500Hz): δ7.58 (d, 1H, J=2.5Hz), 7.40 (dd, 1H, J=2.5Hz, J=8.5Hz), 7.27 (d, 1H, J=3.0Hz ), 4.06 (t, 2H, J=7.5Hz), 3.34 (m, 1H), 1.94 (m, 2H), 1.73(m, 2H), 1.58 (m, 3H), 1.35 (m, 6H), 1.17 (m, 1H), 0.89 (t, 3H, J=7.5Hz).

Example 13: 1-n-Butyl-3-((n-Butylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione (CHG13)

The preparation of compound CHG13 was the same as that of compound CHG07 in Example 7, except that n-butylamine (0.12 mmol, 8.8 mg) was used instead of cyclohexylamine, and CHG13 was obtained as light yellow solid 28.7 mg, yield 91.4%, melting point 65.8-66.8°C.

¹ H NMR (CDCl3, 500Hz): δ12.07 (s, 1H), 8.46 (d, 1H, J=14.0Hz), 8.10 (dd, 1H, J=8.0Hz, J=37.5Hz), 7.32 (t , 1H, J=7.0Hz), 7.07 (m, 1H), 4.29 (t, 2H, J=7.5Hz), 3.50 (q, 2H, J=6.5Hz), 2.54 (s, 3H), 1.68 (m , 2H), 1.53 (m, 2H), 1.43 (m, 2H), 1.23 (m, 2H), 0.95 (t, 3H, J=7.5Hz), 0.85 (t, 3H, J=7.5Hz).

Example 14: 1-n-Butyl-3-((tert-butylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione (CHG14)

The preparation of compound CHG14 was the same as that of compound CHG07 in Example 7, except that tert-butylamine (0.12 mmol, 8.8 mg) was used instead of cyclohexylamine to obtain 25.0 mg of CHG14 as a yellow liquid with a yield of 79.5%.

¹ H NMR (CDCl3, 500Hz): δ12.51 (d, 1H, J=12.5Hz), 8.60 (d, 1H, J=14.0Hz), 8.11 (dd, 1H, J=8.0Hz, J=40.5Hz ), 7.33 (t, 1H, J=6.5Hz), 7.07 (m, 1H), 4.28 (t, 2H, J=7.5Hz), 2.55 (s, 3H), 1.54 (m, 2H), 1.45 (s , 9H), 1.24 (m, 2H), 0.86 (t, 3H, J=7.5Hz).

Example 15: 1-n-Butyl-3-((cyclopentylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione (CHG15)

The preparation of compound CHG15 was the same as that of compound CHG07 in Example 7, except that cyclopentylamine (0.12 mmol, 10.2 mg) was used instead of cyclohexylamine to obtain 27.9 mg of CHG15 as a light yellow liquid with a yield of 85.4%.

¹ H NMR (CDCl3, 500Hz): δ12.18 (s, 1H), 8.51 (d, 1H, J=14.0Hz), 8.10 (dd, 1H, J=8.0Hz, J=42.5Hz), 7.32 (t , 1H, J=7.0Hz), 7.07 (t, 1H, J=7.5Hz), 4.29 (t, 2H, J=7.5Hz), 3.94 (m, 1H), 2.54 (s, 3H), 2.08 (m , 2H), 1.81 (m, 2H), 1.70 (m, 4H), 1.52 (m, 2H), 1.22 (m, 2H), 0.84 (t, 3H, J=7.5Hz).

Example 16: 1-n-Butyl-3-((1-adamantylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione (CHG16)

The preparation method of compound CHG16 is the same as that of compound CHG07 in Example 7, except that 1-adamantanamine (0.12 mmol, 18.1 mg) is used instead of cyclohexylamine to obtain 37.2 mg of CHG16 as a light yellow liquid with a yield of 94.8%. .

¹ H NMR (CDCl3, 500Hz): δ12.41 (d, 1H, J=14.0Hz), 8.57 (dd, 1H, J=14.0Hz, J=6.0Hz), 8.10 (dd, 1H, J=8.0Hz , J=40.5Hz), 7.30 (t, 1H, J=7.0Hz), 7.06 (t, 1H, J=7.5Hz), 4.27 (t, 2H, J=7.5Hz), 2.53 (s, 3H), 2.19 (s, 3H), 1.92 (s, 6H), 1.73 (d, 3H, J=12.5Hz), 1.66 (d, 5H, J=12.0Hz), 1.53 (m, 2H), 1.23 (m, 2H ), 0.84 (t, 3H, J=7.5Hz).

Example 17: 1-n-Butyl-3-((cyclopropylmethylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione (CHG17)

The preparation of compound CHG17 was the same as that of compound CHG07 in Example 7, except that cyclopropylmethylamine (0.12 mmol, 8.5 mg) was used instead of cyclohexylamine to obtain CHG17 as a light yellow solid of 28.5 mg with a yield of 91.2%. The melting point is 111.1-112.0°C.

¹ H NMR (CDCl3, 500Hz): δ12.13 (s, 1H), 8.53 (d, 1H, J=14.0Hz), 8.13 (dd, 1H, J=7.5Hz, J=33.0Hz), 7.35 (t , 1H, J=6.5Hz), 7.10 (t, 1H, J=7.5Hz), 4.31 (t, 2H, J=7.0Hz), 3.37 (t, 2H, J=6.0Hz), 2.56 (s, 3H ), 1.55 (m, 2H), 1.25 (m, 2H), 1.13 (m, 1H), 0.86 (t, 3H, J=7.5Hz), 0.68 (m, 2H), 0.34 (m, 2H).

Example 18: 1-n-Butyl-3-((cyclohexylmethylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione (CHG18)

The preparation of compound CHG18 was the same as that of compound CHG07 in Example 7, except that cyclohexylmethylamine (0.12 mmol, 13.6 mg) was used instead of cyclohexylamine to obtain 30.2 mg of CHG18 as a yellow solid with a yield of 85.3%, melting point 96.6-98.1°C.

¹ H NMR (CDCl3, 500Hz): δ12.11 (s, 1H), 8.41 (d, 1H, J=14.0Hz), 8.10 (dd, 1H, J=8.0Hz, J=34.0Hz), 7.32 (t , 1H, J=6.0Hz), 7.07 (t, 1H, J=7.0Hz), 4.29 (t, 2H, J=7.5Hz), 3.32 (t, 2H, J=6.5Hz), 2.54 (s, 3H ), 1.76 (t, 4H, J=7.0Hz), 1.66 (d, 1H, J=13.0Hz), 1.61 (s, 1H), 1.53 (m, 2H), 1.21 (m, 5H), 1.01 (m , 2H), 0.84 (t, 3H, J=7.5Hz).

Example 19: 1-n-Butyl-8-methyl-3-((piperidin-1-amino)enyl)quinoline-2,4(1H,3H)-dione (CHG19)

The preparation of compound CHG19 was the same as that of compound CHG07 in Example 7, except that 1-aminopiperidine (0.12 mmol, 12.0 mg) was used instead of cyclohexylamine to obtain CHG19 as a yellow solid of 18.4 mg with a yield of 53.8%. The melting point is 72.3-73.9°C.

¹ H NMR (CDCl3, 500Hz): δ13.24 (d, 1H, J=7.5Hz), 8.50 (d, 1H, J=7.0Hz), 8.09 (dd, 1H, J=8.0Hz, J=47.5Hz ), 7.33 (t, 1H, J=6.0Hz), 7.10 (t, 1H, J=7.5Hz), 4.35 (t, 2H, J=7.5Hz), 2.98 (t, 4H, J=5.5Hz), 2.59 (s, 3H), 1.73 (m, 4H), 1.56 (m, 2H), 1.49 (m, 2H), 1.25 (m, 2H), 0.87 (t, 3H, J=7.5Hz).

Example 20: 1-n-Butyl-8-methyl-3-((morpholinylamino)alkenyl)quinoline-2,4(1H,3H)-dione (CHG20)

The preparation of compound CHG20 was the same as that of compound CHG07 in Example 7, except that 4-aminomorpholine (0.12 mmol, 12.3 mg) was used instead of cyclohexylamine to obtain CHG20 as a yellow solid 26.1 mg with a yield of 76.1%. The melting point is 88.9-90.0°C.

¹ H NMR (CDCl3, 500Hz): δ13.35 (s, 1H), 8.44 (d, 1H, J=2.0Hz), 8.07 (dd, 1H, J=7.5Hz, J=58.0Hz), 7.33 (d , 1H, J=7.0Hz), 7.11 (t, 1H, J=7.5Hz), 4.37 (t, 2H, J=7.5Hz), 3.85 (t, 4H, J=5.0Hz), 3.07 (t, 4H , J=5.0Hz), 2.62 (s, 3H), 1.57 (m, 2H), 1.25 (m, 2H), 0.87 (t, 3H, J=7.5Hz).

Example 21: 3-((Cyclohexylamino)alkenyl)-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG21)

a) Preparation of N-n-pentylaniline 8a

The preparation of compound 8a is the same as that of compound 1a in Example 1, except that n-pentane bromide (10.00 mmol, 1.51 g) is used instead of n-butane bromide to obtain 893.25 mg of 8a as a yellow liquid, with a yield of 54.7 %.

b) Preparation of 2-cyano-N-n-pentyl-N-phenylacetamide 8b

The preparation of compound 8b was the same as that of compound 1b in Example 1, except that compound 8a (3.00 mmol, 489.9 mg) was used instead of compound 1a to obtain 176.8 mg of 8b as a light yellow liquid with a yield of 30.7%.

c) Preparation of 4-hydroxy-2-oxo-1-n-pentyl-1,2-dihydroquinoline-3-carbaldehyde 8c

The preparation of compound 8c was the same as that of compound 1c in Example 1, except that 1b was replaced by 8b (0.50mmol, 115.2mg), and 8c was obtained as light yellow solid 102.7mg, yield 79.2%, melting point 95.4-96.2°C .

d) Preparation of 3-((cyclohexylamino)alkenyl)-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG21)

The preparation of compound CHG21 was the same as that of compound CHG01 in Example 1, except that 1c was replaced by 8c (0.10 mmol, 25.9 mg), to obtain 31.7 mg of CHG21 as a light yellow liquid with a yield of 93.2%.

¹ H NMR (CDCl3, 500Hz): δ12.31 (s, 1H), 8.56 (d, 1H, J=13.5Hz), 8.24 (dd, 1H, J=8.0Hz, J=45.5Hz), 7.53 (m , 1H), 7.15 (m, 2H), 4.13 (t, 2H, J=7.5Hz), 3.42 (m, 1H), 2.01 (m, 2H), 1.81 (m, 2H), 1.67 (m, 3H) , 1.49 (m, 2H), 1.38 (m, 6H), 1.26 (m, 1H), 0.91 (t, 3H, J=7.0Hz).

Example 22: 3-((1-adamantylamino)alkenyl)-6-methoxy-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG22)

The preparation of compound CHG22 was the same as that of compound CHG10 in Example 10, except that 1-adamantanamine (0.12 mmol, 18.1 mg) was used instead of cyclohexylamine to obtain 39.7 mg of CHG22 as a light yellow liquid with a yield of 94.0%. .

¹ H NMR (CDCl3, 500Hz): δ12.60 (d, 1H, J=14.0Hz), 8.67 (d, 1H, J=14.5Hz), 7.74 (dd, 1H, J=2.5Hz, J=45.5Hz ), 7.14 (m, 2H), 4.13 (t, 2H, J=7.5Hz), 3.88 (s, 3H), 2.22 (s, 3H), 1.96 (s, 6H), 1.76 (d, 3H, J= 12.5Hz), 1.69 (d, 5H, J=13.0Hz), 1.40 (m, 4H), 0.92 (t, 3H).

Example 23: 6-tert-butyl-3-((cyclohexylamino)alkenyl)-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG23)

a) Preparation of 4-tert-butyl-N-n-pentylaniline 9a

The preparation of compound 9a was the same as that of compound 1a in Example 1, except that 4-tert-butylaniline (20.00mmol, 2.98g) was used instead of aniline, and bromo-n-pentane (10.00mmol, 1.51g) was used instead Bromo-n-butane gave 844.7 mg of 9a as a yellow liquid with a yield of 38.5%.

b) Preparation of N-(4-tert-butylphenyl)-2-cyano-N-n-pentylacetamide 9b

The preparation of compound 9b was the same as that of compound 1b in Example 1, except that compound 9a (3.00 mmol, 658.2 mg) was used instead of compound 1a to obtain 203.3 mg of 9b as a yellow solid with a yield of 28.4% and a melting point of 92.9-94.0 ℃.

c) Preparation of 6-tert-butyl-4-hydroxy-2-oxo-1-n-butyl-1,2-dihydroquinoline-3-carbaldehyde 9c

Compound 9c was prepared in the same manner as compound 1c in Example 1, except that 9b (0.50 mmol, 143.2 mg) was used instead of 1b to obtain 154.7 mg of 9c as a brown solid with a yield of 98.1% and a melting point of 61.6-62.4°C.

d) Preparation of 6-tert-butyl-3-((cyclohexylamino)alkenyl)-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG23)

The preparation of compound CHG23 was the same as that of compound CHG01 in Example 1, except that 9c (0.10 mmol, 31.5 mg) was used instead of 1c to obtain 37.9 mg of CHG23 as a yellow liquid with a yield of 95.5%.

¹ H NMR (CDCl3, 500Hz): δ12.35 (s, 1H), 8.60 (t, 1H, J=17.0Hz), 8.27 (dd, 1H, J=2.0Hz, J=37.0Hz), 7.61 (dd , 1H, J=2.5Hz, J=8.0Hz), 7.15 (d, 1H, J=9.0Hz), 4.14 (t, 2H, J=7.5Hz), 3.43 (m, 1H), 2.03 (m, 2H ), 1.83 (m, 2H), 1.68 (m, 3H), 1.51 (m, 2H), 1.40 (m, 15H), 1.26 (m, 2H), 0.92 (t, 3H, J=7.5Hz).

Example 24: 6-Chloro-3-((cyclohexylamino)alkenyl)-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG24)

a) Preparation of 4-chloro-N-n-pentylaniline 10a

Compound 10a was prepared in the same manner as Compound 1a in Example 1, except that 4-chloroaniline (20.00mmol, 2.55g) was used instead of aniline, and bromo-n-pentane (10.00mmol, 1.51g) was used instead of bromo With n-butane, 10a was obtained as 597.1 mg of orange-yellow liquid, with a yield of 30.2%.

b) Preparation of N-(4-chlorophenyl)-2-cyano-N-n-pentylacetamide 10b

The preparation of compound 10b was the same as that of compound 1b in Example 1, except that compound 10a (3.00 mmol, 593.1 mg) was used instead of compound 1a to obtain 247.6 mg of 10b as a yellow liquid with a yield of 37.4%.

c) Preparation of 6-chloro-4-hydroxy-2-oxo-1-n-butyl-1,2-dihydroquinoline-3-carbaldehyde 10c

Compound 10c was prepared in the same manner as compound 1c in Example 1, except that 10b (0.50 mmol, 132.4 mg) was used instead of 1b to obtain 109.8 mg of 10c as a yellow solid with a yield of 74.8% and a melting point of 107.2-108.6 °C.

d) Preparation of 6-chloro-3-((cyclohexylamino)enyl)-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG24)

The preparation of compound CHG24 was the same as that of compound CHG01 in Example 1, except that 10c (0.10 mmol, 29.4 mg) was used instead of 1c to obtain 26.5 mg of CHG24 as a yellow liquid with a yield of 70.7%.

¹ H NMR (CDCl3, 500Hz): δ12.30 (s, 1H), 8.57 (d, 1H, J=14.0Hz), 8.19 (dd, 1H, J=2.5Hz, J=44.5Hz), 7.47 (m , 1H), 7.12 (dd, 1H, J=2.5Hz, J=9.0Hz), 4.11 (t, 2H, J=7.5Hz), 3.45 (m, 1H), 2.04 (m, 2H), 1.84 (m , 2H), 1.67 (m, 3H), 1.53 (m, 2H), 1.41 (m, 6H), 1.28 (m, 1H), 0.92 (t, 3H, J=7.0Hz).

Example 25: 6-Chloro-3-((1-adamantylamino)alkenyl)-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG25)

The preparation of compound CHG25 was the same as that of compound CHG24 in Example 24, except that 1-adamantanamine (0.12 mmol, 18.1 mg) was used instead of cyclohexylamine to obtain CHG25 as a yellow solid of 29.8 mg with a yield of 69.7%. The melting point is 73.8-75.2°C.

¹ H NMR (CDCl3, 500Hz): δ12.52 (d, 1H, J=14.5Hz), 8.63 (dd, 1H, J=15Hz, J=22.5Hz), 8.19 (dd, 1H, J=2.5Hz, J=46.5Hz), 7.47 (m, 1H), 7.11 (d, 1H, J=8.5Hz), 4.10 (t, 2H, J=7.5Hz), 2.22 (s, 3H), 1.94 (s, 6H) , 1.76 (d, 4H, J=12.5Hz), 1.67 (d, 4H, J=13.5Hz), 1.39 (m, 4H), 0.91 (t, 3H, J=7.0Hz).

Example 26: 6-Bromo-3-((cyclohexylamino)alkenyl)-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG26)

a) Preparation of 4-bromo-N-n-pentylaniline 11a

Compound 11a was prepared in the same manner as Compound 1a in Example 1, except that 4-bromoaniline (20.00mmol, 3.44g) was used instead of aniline, and bromo-n-pentane (10.00mmol, 1.51g) was used instead of bromo With n-butane, 741.1 mg of 11a was obtained as a yellow liquid, with a yield of 30.6%.

b) Preparation of N-(4-bromophenyl)-2-cyano-N-n-pentylacetamide 11b

The preparation of compound 11b was the same as that of compound 1b in Example 1, except that compound 11a (3.00 mmol, 726.6 mg) was used instead of compound 1a to obtain 211.0 mg of 11b as a yellow liquid with a yield of 27.3%.

c) Preparation of 6-bromo-4-hydroxy-2-oxo-1-n-butyl-1,2-dihydroquinoline-3-carbaldehyde 11c

The preparation of compound 11c was the same as that of compound 1c in Example 1, except that 11b (0.50 mmol, 154.6 mg) was used instead of 1b to obtain 11c as a tan solid 152.9 mg, yield 90.4%, melting point 109.4-110.8 °C .

d) Preparation of 6-bromo-3-((cyclohexylamino)alkenyl)-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG26)

The preparation of compound CHG26 was the same as that of compound CHG01 in Example 1, except that 11c (0.10 mmol, 33.8 mg) was used instead of 1c to obtain 41.3 mg of CHG26 as a yellow liquid with a yield of 98.4%.

¹ H NMR (CDCl3, 500Hz): δ12.29 (s, 1H), 8.56 (dd, 1H, J=14.5Hz, J=23.0Hz), 8.32 (d, 1H, J=44.5Hz), 7.59 (t , 1H, J=8.5Hz), 7.04 (d, 1H, J=9.0Hz), 4.08 (t, 2H, J=7.0Hz), 3.43 (m, 1H), 2.01 (m, 2H), 1.82 (m , 2H), 1.64 (m, 3H), 1.50 (m, 2H), 1.37 (m, 6H), 1.25 (m, 1H), 0.89 (t, 3H, J=7.0Hz).

Example 27: 3-((Cyclohexylamino)alkenyl)-8-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG27)

a) Preparation of 2-methyl-N-n-pentylaniline 12a

Compound 12a was prepared in the same manner as Compound 1a in Example 1, except that 2-methylaniline (20.00mmol, 2.14g) was used instead of aniline, and bromo-n-pentane (10.00mmol, 1.51g) was used instead of bromine Substitute n-butane to obtain 765.9 mg of 12a as a yellow liquid, with a yield of 43.2%.

b) Preparation of 2-cyano-N-n-pentyl-N-(2-methylphenyl)acetamide 12b

The preparation of compound 12b was the same as that of compound 1b in Example 1, except that compound 12a (3.00 mmol, 531.9 mg) was used instead of compound 1a to obtain 205.2 mg of 12b as a light yellow liquid with a yield of 33.6%.

c) Preparation of 4-hydroxy-8-methyl-2-oxo-1-n-pentyl-1,2-dihydroquinoline-3-carbaldehyde 12c

Compound 12c was prepared in the same manner as compound 1c in Example 1, except that 12b (0.50 mmol, 122.2 mg) was used instead of 1b to obtain 113.7 mg of 12c as a brown solid with a yield of 83.2% and a melting point of 57.3-58.7°C.

d) Preparation of 3-((cyclohexylamino)alkenyl)-8-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG27)

The preparation of compound CHG27 was the same as that of compound CHG01 in Example 1, except that 12c (0.10 mmol, 27.3 mg) was used instead of 1c to obtain 25.2 mg of CHG27 as a light yellow liquid with a yield of 71.2%.

¹ H NMR (CDCl3, 500Hz): δ12.17 (s, 1H), 8.52 (d, 1H, J=14.0Hz), 8.11 (dd, 1H, J=7.5Hz, J=38.5Hz), 7.32 (t , 1H, J=6.5Hz), 7.08 (t, 1H, J=7.5Hz), 4.28 (t, 2H, J=7.5Hz), 3.41 (m, 1H), 2.55 (s, 3H), 2.02 (m , 2H), 1.82 (m, 2H), 1.64 (m, 1H), 1.51 (m, 4H), 1.49 (m, 2H), 1.22 (m, 5H), 0.81 (t, 3H, J=7.5Hz) .

Example 28: 3-((1-adamantylamino)alkenyl)-8-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG28)

Compound CHG28 was prepared in the same way as compound CHG27 in Example 27, except that cyclohexylamine was replaced by 1-adamantylamine (0.12 mmol, 18.1 mg). CHG28 was obtained as a yellow liquid, 25.6 mg, with a yield of 63.0%.

¹ H NMR (CDCl3, 500Hz): δ12.42 (d, 1H, J=13.5Hz), 8.58 (dd, 1H, J=5.5Hz, J=9.0Hz), 8.11 (dd, 1H, J=7.5Hz , J=40.5Hz), 7.32 (t, 1H, J=4.0Hz, J=7.0Hz), 7.07 (t, 1H, J=7.5Hz), 4.27 (t, 2H, J=7.5Hz), 2.55 ( s, 3H), 2.20 (s, 3H), 1.94 (s, 6H), 1.75 (d, 3H, J=12.5Hz), 1.67 (d, 3H, J=12.5Hz), 1.57 (m, 2H), 1.23 (m, 4H), 0.82 (t, 3H, J=7.0Hz).

Example 29: 3-((Cyclohexylamino)alkenyl)-8-ethyl-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG29)

a) Preparation of 2-ethyl-N-n-pentylaniline 13a

Compound 13a was prepared in the same manner as Compound 1a in Example 1, except that 2-ethylaniline (20.00mmol, 2.42g) was used instead of aniline, and bromo-n-pentane (10.00mmol, 1.51g) was used instead of bromine On behalf of n-butane, 13a was obtained as 669.6 mg of light yellow liquid, with a yield of 35.0%.

b) Preparation of 2-cyano-N-(2-ethylphenyl)-N-pentylacetamide 13b

The preparation of compound 13b was the same as that of compound 1b in Example 1, except that compound 13a (3.00 mmol, 573.9 mg) was used instead of compound 1a to obtain 197.7 mg of 13b as a light yellow liquid with a yield of 30.6%.

c) Preparation of 8-ethyl-4-hydroxy-2-oxo-1-n-pentyl-1,2-dihydroquinoline-3-carbaldehyde 13c

The preparation of compound 13c was the same as that of compound 7c in Example 12, except that 13b (0.50 mmol, 129.2 mg) was used instead of 7b to obtain 120.8 mg of 13c as a brownish-red liquid with a yield of 84.1%.

d) Preparation of 3-((cyclohexylamino)alkenyl)-8-ethyl-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG29)

The preparation of compound CHG29 was the same as that of compound CHG01 in Example 1, except that 13c (0.10 mmol, 28.7 mg) was used instead of 1c to obtain 34.4 mg of CHG29 as a yellow liquid with a yield of 93.4%.

¹ H NMR (CDCl3, 500Hz): δ12.13 (s, 1H), 8.51 (d, 1H, J=14.0Hz), 8.09 (dd, 1H, J=7.5Hz, J=37.5Hz), 7.37 (t , 1H, J=6.5Hz), 7.11 (t, 1H, J=7.5Hz), 4.20 (t, 2H, J=7.0Hz), 3.40 (m, 1H), 2.83 (q, 2H, J=7.5Hz ), 2.01 (m, 2H), 1.81 (m, 2H), 1.63 (m, 1H), 1.51 (m, 4H), 1.38 (m, 2H), 1.22 (m, 6H), 1.15 (m, 2H) , 0.79 (t, 3H, J=7.5Hz).

Example 30: 3-((Cyclohexylamino)alkenyl)-8-methoxy-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG30)

a) Preparation of 2-methoxy-N-n-pentylaniline 14a

Compound 14a was prepared in the same manner as Compound 1a in Example 1, except that 2-methoxyaniline (20.00mmol, 2.46g) was used instead of aniline, and bromo-n-pentane (10.00mmol, 1.51g) was used instead Bromo-n-butane gave 1442.0mg of 14a as a yellow liquid with a yield of 74.6%.

b) Preparation of 2-cyano-N-(2-methoxyphenyl)-N-pentylacetamide 14b

Compound 14b was prepared in the same manner as compound 1b in Example 1, except that compound 14a (3.00 mmol, 579.9 mg) was used instead of compound 1a to obtain 175.7 mg of 14b as a yellow liquid with a yield of 27.0%.

c) Preparation of 4-hydroxy-8-methoxy-2-oxo-1-n-pentyl-1,2-dihydroquinoline-3-carbaldehyde 14c

Compound 14c was prepared in the same manner as compound 1c in Example 1, except that 14b (0.50 mmol, 130.2 mg) was used instead of 1b to obtain 135.8 mg of 14c as a yellow solid with a yield of 93.9% and a melting point of 102.2-103.6 °C.

d) Preparation of 3-((cyclohexylamino)alkenyl)-8-methoxy-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG30)

The preparation of compound CHG30 was the same as that of compound CHG01 in Example 1, except that 14c (0.10 mmol, 28.9 mg) was used instead of 1c to obtain 36.9 mg of CHG30 as a yellow liquid with a yield of 99.5%.

¹ H NMR (CDCl3, 500Hz): δ12.31 (s, 1H), 8.58 (q, 1H, J=14.0Hz), 7.89 (dd, 1H, J=5.0Hz, J=44.0Hz), 7.09 (t , 2H, J=3.5Hz), 4.35 (t, 2H, J=7.5Hz), 3.87 (s, 3H), 3.40 (m, 1H), 2.01 (m, 2H), 1.81 (m, 2H), 1.71 (m, 2H), 1.63 (m, 1H), 1.49 (m, 2H), 1.35 (m, 6H), 1.24 (m, 1H), 0.89 (t, 3H, J=6.5Hz).

Example 31: 3-((1-adamantylamino)alkenyl)-8-methoxy-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG31)

The preparation of compound CHG31 was the same as that of compound CHG30 in Example 30, except that 1-adamantanamine (0.12 mmol, 18.1 mg) was used instead of cyclohexylamine to obtain CHG31 as a yellow solid of 28.9 mg with a yield of 68.3%. The melting point is 108.9-110.1°C.

¹ H NMR (CDCl3, 500Hz): δ12.55 (d, 1H, J=13.5Hz), 8.64 (dd, 1H, J=7.0Hz, J=14.5Hz), 7.92 (dd, 1H, J=4.5Hz , J=49.0Hz), 7.11 (m, 2H), 4.36 (t, 2H, J=7.5Hz), 3.89 (s, 3H), 2.21 (s, 3H), 1.95 (s, 6H), 1.72 (m , 8H), 1.35 (m, 4H), 0.91 (t, 3H, J=7.0Hz).

Example 32: 8-Chloro-3-((cyclohexylamino)alkenyl)-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG32)

a) Preparation of 2-chloro-N-n-pentylaniline 15a

Compound 15a was prepared in the same manner as Compound 1a in Example 1, except that 2-chloroaniline (40.00mmol, 5.1g) was used instead of aniline, and bromo-n-pentane (20.00mmol, 3.02g) was used instead of bromo With n-butane, 15a was obtained as 664.2 mg of yellow liquid, with a yield of 16.8%.

b) Preparation of N-(2-chlorophenyl)-2-cyano-N-n-pentylacetamide 15b

The preparation of compound 15b was the same as that of compound 1b in Example 1, except that compound 15a (3.00 mmol, 593.1 mg) was used instead of compound 1a to obtain 118.5 mg of 15b as a yellow liquid with a yield of 17.9%.

c) Preparation of 8-chloro-4-hydroxy-2-oxo-1-n-pentyl-1,2-dihydroquinoline-3-carbaldehyde 15c

Compound 15c was prepared in the same manner as compound 7c in Example 12, except that 15b (0.50 mmol, 132.4 mg) was used instead of 7b to obtain 102.2 mg of brownish-red liquid of 15c, with a yield of 69.6%.

d) Preparation of 8-chloro-3-((cyclohexylamino)enyl)-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG32)

The preparation of compound CHG32 was the same as that of compound CHG01 in Example 1, except that 15c (0.10 mmol, 29.4 mg) was used instead of 1c to obtain 4.8 mg of CHG32 as a brownish-yellow liquid with a yield of 12.9%.

¹ H NMR (CDCl3, 500Hz): δ12.19 (s, 1H), 8.54 (d, 1H, J=14.0Hz), 8.20 (dd, 1H, J=8.0Hz, J=40.0Hz), 7.56 (t , 1H, J=7.0Hz), 7.08 (t, 1H, J=7.0Hz), 4.47 (t, 2H, J=8.0Hz), 3.44 (m, 1H), 2.03 (m, 2H), 1.83 (m , 2H), 1.76 (m, 1H), 1.66 (m, 4H), 1.50 (m, 2H), 1.30 (m, 5H), 0.88 (t, 3H, J=7.5Hz).

Example 33: 3-((Cyclohexylamino)alkenyl)-5-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG33)

a) Preparation of 3-methyl-N-n-pentylaniline 16a

Compound 16a was prepared in the same manner as Compound 1a in Example 1, except that 3-methylaniline (20.00mmol, 2.14g) was used instead of aniline, and bromo-n-pentane (10.00mmol, 1.51g) was used instead of bromine On behalf of n-butane, 16a was obtained as yellow liquid 700.3 mg, yield 39.5%.

b) Preparation of 2-cyano-N-n-pentyl-N-(3-methylphenyl)acetamide 16b

Compound 16b was prepared in the same manner as compound 1b in Example 1, except that compound 16a (3.00 mmol, 531.9 mg) was used instead of compound 1a to obtain 192.4 mg of 16b as a light yellow liquid with a yield of 31.5%.

c) 4-Hydroxy-5-methyl-2-oxo-1-n-pentyl-1,2-dihydroquinoline-3-carbaldehyde 16c, 4-Hydroxy-7-methyl-2-oxo- Preparation of 1-n-pentyl-1,2-dihydroquinoline-3-carbaldehyde 16c'

Compounds 16c and 16c' were prepared in the same way as compound 7c in Example 12, except that 16b (0.50 mmol, 122.2 mg) was used instead of 7b to obtain 90.3 mg of 16c with a yield of 66.1%; 45.1 mg of 16c' , yield 33.0%.

d) Preparation of 3-((cyclohexylamino)alkenyl)-5-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG33)

The preparation of compound CHG33 was the same as that of compound CHG01 in Example 1, except that 16c (0.05 mmol, 13.7 mg) was used instead of 1c to obtain 10.4 mg of CHG33 as a yellow liquid with a yield of 58.9%.

¹ H NMR (CDCl3, 500Hz): δ12.17 (s, 1H), 8.53 (dd, 1H, J=5.0Hz, J=14.0Hz), 7.35 (t, 1H, J=7.5Hz), 7.07 (d , 1H, J=8.5Hz), 6.89 (t, 1H, J=9.5Hz), 4.13 (t, 2H, J=7.5Hz), 3.36 (m, 1H), 2.86 (s, 3H), 2.02 (m , 2H), 1.82 (m, 2H), 1.68 (m, 3H), 1.50 (m, 2H), 1.37 (m, 6H), 1.23 (m, 1H), 0.91 (t, 3H, J=7.0Hz) .

Example 34: 3-((Cyclohexylamino)alkenyl)-7-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG34)

The preparation of compound CHG34 was the same as that of compound CHG01 in Example 1, except that 16c' (0.05 mmol, 13.7 mg) was used instead of 1c to obtain 16.9 mg of CHG34 as a yellow liquid with a yield of 95.2%.

¹ H NMR (CDCl3, 500Hz): δ12.29 (s, 1H), 8.57 (q, 1H, J=7.0Hz), 8.12 (dd, 1H, J=8.0Hz, J=45.0Hz), 6.97 (d , 1H, J=7.5Hz), 6.96 (s, 1H), 4.12 (t, 2H, J=8.0Hz), 3.41 (m, 1H), 2.45 (s, 3H), 2.02 (m, 2H), 1.83 (m, 2H), 1.68 (m, 3H), 1.50 (m, 2H), 1.41 (m, 6H), 1.26 (m, 1H), 0.92 (t, 3H, J=7.0Hz).

Example 35: 6-Chloro-3-((cyclohexylamino)alkenyl)-8-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG35)

a) Preparation of 4-chloro-2methyl-N-n-pentylaniline 17a

Compound 17a was prepared in the same manner as Compound 1a in Example 1, except that 4-chloro-2-methylaniline (20.00mmol, 2.83g) was used instead of aniline, and bromo-n-pentane (10.00mmol, 1.51g ) instead of n-butane bromide to obtain 624.5 mg of yellow liquid with a yield of 29.5%.

b) Preparation of N-(4-chloro-2methylphenyl)-2-cyano-N-n-pentylacetamide 17b

The preparation method of compound 17b was the same as that of compound 1b in Example 1, except that compound 17a (3.00 mmol, 635.1 mg) was used instead of compound 1a to obtain 151.9 mg of yellow liquid with a yield of 21.8%.

c) Preparation of 6-chloro-4-hydroxy-8-methyl-2-oxo-1-n-pentyl-1,2-dihydroquinoline-3-carbaldehyde 17c

The preparation of compound 17c was the same as that of compound 7c in Example 12, except that 17b (0.50 mmol, 139.4 mg) was used instead of 7b to obtain 107.1 mg of brownish red liquid of 17c, with a yield of 69.6%.

d) Preparation of 6-chloro-3-((cyclohexylamino)enyl)-8-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG35)

The preparation of compound CHG35 was the same as that of compound CHG01 in Example 1, except that 17c (0.10 mmol, 30.8 mg) was used instead of 1c to obtain 24.4 mg of CHG35 as a brownish-red liquid with a yield of 62.7%.

¹ H NMR (CDCl3, 500Hz): δ12.16 (s, 1H), 8.53 (d, 1H, J=3.0Hz), 8.07 (dd, 1H, J=2.5Hz, J=40.0Hz), 7.29 (d , 1H, J=4.0Hz), 4.26 (t, 2H, J=7.5Hz), 3.44 (m, 2H), 2.53 (s, 3H), 2.02 (m, 2H), 1.83 (m, 2H), 1.65 (m, 1H), 1.52 (m, 4H), 1.38 (m, 2H), 1.25 (m, 5H), 0.82 (t, 3H, J=7.0Hz).

Example 36: 3-((Cyclohexylamino)alkenyl)-6-methoxy-8-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG36)

a) Preparation of 4-methoxy-2methyl-N-n-pentylaniline 18a

Compound 18a was prepared in the same manner as Compound 1a in Example 1, except that 4-methoxy-2-methylaniline (20.00mmol, 2.74g) was used instead of aniline, and n-pentane bromide (10.00mmol, 1.51g) instead of n-butane bromide to obtain 984.7mg of yellow liquid with a yield of 47.5%.

b) Preparation of 2-cyano-N-(4-methoxy-2methylphenyl)-N-n-pentylacetamide 18b

The preparation method of compound 18b was the same as that of compound 1b in Example 1, except that compound 18a (3.00 mmol, 621.9 mg) was used instead of compound 1a to obtain 219.5 mg of yellow liquid with a yield of 32.0%.

c) Preparation of 4-hydroxy-6-methoxy-8-methyl-2-oxo-1-n-pentyl-1,2-dihydroquinoline-3-carbaldehyde 18c

The preparation of compound 18c was the same as that of compound 1c in Example 1, except that 18b (0.50 mmol, 137.2 mg) was used instead of 1b to obtain 111.0 mg of 18c as a tan solid with a yield of 73.2% and a melting point of 77.8-78.6°C .

d) Preparation of 3-((cyclohexylamino)alkenyl)-6-methoxy-8-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG36)

The preparation of compound CHG36 was the same as that of compound CHG01 in Example 1, except that 18c (0.10 mmol, 30.3 mg) was used instead of 1c to obtain 35.3 mg of CHG36 as a brownish-yellow liquid with a yield of 91.7%.

¹ H NMR (CDCl3, 500Hz): δ12.17 (s, 1H), 8.54 (d, 1H, J=5.5Hz), 7.59 (dd, 1H, J=3.5Hz, J=38.0Hz), 6.93 (d , 1H, J=3.5Hz), 4.27 (t, 2H, J=7.5Hz), 3.84 (s, 3H), 3.41 (m, 1H), 2.51 (s, 3H), 2.01 (m, 2H), 1.82 (m, 2H), 1.64 (m, 1H), 1.49 (m, 4H), 1.40 (m, 2H), 1.21 (m, 5H), 0.81 (t, 3H, J=7.5Hz).

Example 37: 3-((1-Adamantylamino)alkenyl)-6-methoxy-8-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione ( CHG37)

Compound CHG37 was prepared in the same manner as compound CHG36 in Example 36, except that cyclohexylamine was replaced by 1-adamantylamine (0.12 mmol, 18.1 mg). CHG37 was obtained as a yellow liquid, 29.7 mg, with a yield of 68.1%.

¹ H NMR (CDCl3, 500Hz): δ12.44 (d, 1H, J=13.5Hz), 8.59 (d, 1H, J=14.0Hz), 7.60 (dd, 1H, J=3.0Hz, J=38.0Hz ), 6.93 (s, 1H), 4.24 (t, 2H, J=7.5Hz), 3.84 (s, 3H), 2.52 (s, 3H), 2.20 (s, 3H), 1.94 (s, 6H), 1.74 (d, 3H, J=12.5Hz), 1.67 (d, 3H, J=12.5Hz), 1.54 (m, 2H), 1.21 (m, 4H), 0.82 (t, 3H, J=7.0Hz).

Example 38: 3-((Cyclohexylamino)alkenyl)-1-ethyl-8-methylquinoline-2,4(1H,3H)-dione (CHG38)

a) Preparation of N-ethyl-2-methylaniline 19a

Compound 19a was prepared in the same manner as Compound 1a in Example 1, except that 2-methylaniline (20.00 mmol, 2.14 g) was used instead of aniline, and bromoethane (10.00 mmol, 1.09 g) was used instead of bromo-n- Butane, 670.6 mg of yellow liquid was obtained, the yield was 49.6%.

b) Preparation of 2-cyano-N-ethyl-N-(2-methylphenyl)acetamide 19b

Compound 19b was prepared in the same manner as Compound 1b in Example 1, except that Compound 19a (3.00 mmol, 405.6 mg) was used instead of Compound 1a to obtain 139.1 mg of a yellow liquid with a yield of 27.5%.

c) Preparation of 1-ethyl-4-hydroxy-8-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde 19c

Compound 19c was prepared in the same manner as compound 1c in Example 1, except that 19b (0.50 mmol, 101.1 mg) was used instead of 1b to obtain 85.9 mg of 19c as a yellow solid with a yield of 74.3% and a melting point of 105.4-106.5°C.

d) Preparation of 3-((cyclohexylamino)alkenyl)-1-ethyl-8-methylquinoline-2,4(1H,3H)-dione (CHG38)

The preparation of compound CHG38 was the same as that of compound CHG01 in Example 1, except that 19c (0.10 mmol, 23.1 mg) was used instead of 1c to obtain 26.1 mg of CHG38 as a light yellow liquid with a yield of 83.6%.

¹ H NMR (CDCl3, 500Hz): δ12.19 (s, 1H), 8.52 (dd, 1H, J=4.5Hz, J=8.0Hz), 8.11 (dd, 1H, J=7.5Hz, J=40.5Hz ), 7.33 (t, 1H, J=6.5Hz), 7.07 (t, 1H, J=7.5Hz), 4.03 (q, 2H, J=7.0Hz), 3.40 (m, 1H), 2.57 (s, 3H ), 2.01 (m, 2H), 1.81 (m, 2H), 1.64 (m, 1H), 1.49 (m, 2H), 1.37 (m, 2H), 1.24 (m, 4H).

Example 39: 3-((Cyclohexylamino)alkenyl)-1-n-pentyl-1,8-naphthyridine-2,4(1H,3H)-dione (CHG39)

a) Preparation of N-n-pentyl-2-aminopyridine 20a

Dissolve 2-aminopyridine (20.00mmol, 1.88g) in 5mL DMF, ice bath, 60% sodium hydride (28.00mmol, 1.12g) in 10mL DMF to obtain a suspension, drop slowly, and react at room temperature for 1 hour, Add n-pentane bromide (10.00 mmol, 1.51 g) and react overnight at 80°C. Cool to room temperature, add 10 mL of ice water to quench the reaction, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous magnesium sulfate, and distill off the solvent ethyl acetate under reduced pressure. Separation and purification by column chromatography, the elution condition is petroleum ether: ethyl acetate = 6:1 ~ 3:1, 835.8 mg of yellow solid was obtained, the yield was 50.9%, and the melting point was 42.9-44.6°C.

b) Preparation of 2-cyano-N-n-pentyl-N-(2-pyridyl)acetamide 20b

The preparation method of compound 20b was the same as that of compound 1b in Example 1, except that compound 20a (3.00 mmol, 492.6 mg) was used instead of compound 1a to obtain 135.9 mg of yellow liquid with a yield of 23.5%.

c) Preparation of 4-hydroxy-2-oxo-1-n-pentyl-1,2-dihydro-1,8-naphthalene-3-carbaldehyde 20c

The preparation of compound 20c is the same as that of compound 7c in Example 12, except that 20b (0.50 mmol, 115.6 mg) is used instead of 7b, and the elution condition is dichloromethane:methanol=5:1, and 17c is dark red Liquid 31.6mg, yield 24.3%.

d) Preparation of 3-((cyclohexylamino)alkenyl)-1-n-pentyl-1,8-naphthyridine-2,4(1H,3H)-dione (CHG39)

The preparation of compound CHG39 was the same as that of compound CHG01 in Example 1, except that 20c (0.10 mmol, 26.0 mg) was used instead of 1c to obtain 4.3 mg of CHG39 as a brownish-red solid with a yield of 12.7% and a melting point of 139.8-140.9°C .

¹ H NMR (CDCl3, 500Hz): δ9.23 (d, 1H, J=6.0Hz), 8.67 (s, 1H), 8.57 (t, 1H, J=8.0Hz), 7.92 (d, 1H, J=8.0Hz), 7.92 (d, 1H, J= 8.0Hz), 7.61 (t, 1H, J=7.0Hz), 4.33 (t, 2H, J=8.0Hz), 3.70 (m, 1H), 2.13 (m, 2H), 1.91 (m, 2H), 1.75 (m, 2H), 1.58 (m, 2H), 1.44 (m, 6H), 1.32 (m, 2H), 0.93 (t, 3H, J=7.0Hz).

Example 40: 3-((Cyclohexylmethylamino)alkenyl)-6-methoxy-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG40)

The preparation of compound CHG40 was the same as that of compound CHG10 in Example 10, except that cyclohexylmethylamine (0.12 mmol, 13.6 mg) was used instead of cyclohexylamine to obtain 33.4 mg of CHG40 as a yellow solid with a yield of 86.8%, melting point 85.3-86.7°C.

¹ H NMR (CDCl3, 500Hz): δ12.27 (s, 1H), 8.51 (t, 1H, J=12.5Hz), 7.73 (dd, 1H, J=2.5Hz, J=41.0Hz), 7.15 (m , 2H), 4.12 (t, 2H, J=7.5Hz), 3.87 (s, 3H), 3.36 (t, 2H, J=6.5Hz), 1.78 (m, 4H), 1.68 (m, 3H), 1.62 (m, 1H), 1.40 (m, 4H), 1.21 (m, 3H), 1.02 (m, 2H), 0.92 (t, 3H, J=7.0Hz).

Example 41: 3-((Cyclohexylmethylamino)alkenyl)-6-methoxy-8-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG41 )

The preparation of compound CHG41 was the same as that of compound CHG36 in Example 36, except that cyclohexylmethylamine (0.12 mmol, 13.6 mg) was used instead of cyclohexylamine to obtain 33.8 mg of CHG41 as a yellow solid with a yield of 84.7%, melting point 114.0-115.4°C.

¹ H NMR (CDCl3, 500Hz): δ12.12 (s, 1H), 8.44 (dd, 1H, J=6.5Hz, J=7.5Hz), 7.61 (dd, 1H, J=3.0Hz, J=35.0Hz ), 6.96 (t, 1H, J=8.0Hz), 4.27 (t, 2H, J=7.0Hz), 3.86 (s, 3H), 3.35 (t, 2H, J=6.5Hz), 2.53 (s, 3H ), 1.78 (m, 4H), 1.66 (m, 2H), 1.54 (m, 2H), 1.21 (m, 7H), 1.00 (m, 2H), 0.83 (t, 3H, J=7.0Hz).

Example 42: 1-n-Butyl-8-methyl-3-((n-propylamino)enyl)quinoline-2,4(1H,3H)-dione (CHG42)

The preparation of compound CHG42 was the same as that of compound CHG07 in Example 7, except that n-propylamine (0.12 mmol, 7.1 mg) was used instead of cyclohexylamine to obtain CHG42 as a yellow solid 27.6 mg with a yield of 92.0% and a melting point of 82.5- 83.6°C.

¹ H NMR (CDCl3, 500Hz): δ12.09 (s, 1H), 8.49 (dd, 1H, J=14.0Hz, J=3.0Hz), 8.12 (m, 1H), 7.35 (t, 1H, J= 6.0Hz, J=7.5Hz), 7.10 (t, 1H, J=7.5Hz), 4.13 (t, 2H, J=7.5Hz), 3.48 (dd, 2H, J=6.5Hz), 2.56 (s, 3H ), 1.75 (m, 2H), 1.54 (m, 2H), 1.24 (m, 2H), 1.02 (t, 3H, J=7.5Hz), 0.86 (t, 3H, J=7.5Hz).

Example 43: 1-n-Butyl-3-((isopropylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione (CHG43)

The preparation of compound CHG43 was the same as that of compound CHG07 in Example 7, except that isopropylamine (0.12 mmol, 7.1 mg) was used instead of cyclohexylamine to obtain CHG43 as a yellow solid of 26.1 mg with a yield of 87.0%. The melting point is 65.5-66.5°C.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.14 (s, 1H), 8.54 (d, 1H, J=14.0Hz), 8.12 (m, 1H), 7.34 (t, 1H, J=7.0Hz), 7.10 (t, 1H, J=7.5Hz), 4.31 (t, 2H, J=7.5Hz), 3.78 (m, 1H), 2.56 (s, 3H), 1.54 (m, 2H), 1.40 (d, 6H , J=6.5Hz), 1.25 (m, 2H), 0.86 (t, 3H, J=7.5Hz).

Example 44: 1-n-Butyl-8-chloro-3-((cyclohexylamino)enyl)quinoline-2,4(1H,3H)-dione (CHG44)

a) Preparation of N-n-butyl-2-chloro-aniline 21a

Compound 21a was prepared in the same manner as compound 1a in Example 1, except that 2-chloroaniline (40.00 mmol, 5.1 g) was used instead of aniline to obtain 775.1 mg of 21a as a yellow liquid with a yield of 21.1%.

b) Preparation of N-n-butyl-N-(2-chlorophenyl)-2-cyanoacetamide 21b

The preparation of compound 21b was the same as that of compound 1b in Example 1, except that compound 21a (4.00 mmol, 734.7 mg) was used instead of compound 1a to obtain 154.6 mg of 21b as a yellow liquid with a yield of 18.5%.

c) Preparation of 1-n-butyl-8-chloro-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde 21c

Compound 21c was prepared in the same manner as compound 7c in Example 12, except that 21b (0.60 mmol, 150.4 mg) was used instead of 7b to obtain 35.2 mg of 21c as a brownish-red liquid with a yield of 21.0%.

d) Preparation of 1-n-butyl-8-chloro-3-((cyclohexylamino)enyl)quinoline-2,4(1H,3H)-dione (CHG44)

The preparation of compound CHG44 was the same as that of compound CHG01 in Example 1, except that 21c (0.10 mmol, 28.0 mg) was used instead of 1c to obtain 2.3 mg of CHG44 as a yellow liquid with a yield of 6.3%.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.20 (s, 1H), 8.55 (d, 1H, J=14.0Hz), 8.21 (m, 1H), 7.58 (t, 1H, J=7.5Hz), 7.10 (t, 1H, J=7.5Hz), 4.50 (t, 2H, J=7.5Hz), 3.45 (m, 1H), 2.04 (m, 2H), 1.85 (m, 2H), 1.75 (m, 1H ), 1.68 (m, 1H), 1.51 (m, 2H), 1.42 (m, 2H), 1.33 (m, 3H), 1.25 (m, 1H), 0.92 (t, 3H, J=7.5Hz).

Example 45: 1-n-Butyl-7-chloro-3-((cyclohexylamino)enyl)quinoline-2,4(1H,3H)-dione (CHG45)

a) Preparation of N-n-butyl-3-chloro-aniline 22a

Compound 22a was prepared in the same manner as compound 1a in Example 1, except that 3-chloroaniline (20.00 mmol, 2.55 g) was used instead of aniline to obtain 635.5 mg of 22a as a yellow liquid with a yield of 34.6%.

b) Preparation of N-n-butyl-N-(3-chlorophenyl)-2-cyanoacetamide 22b

The preparation of compound 22b was the same as that of compound 1b in Example 1, except that compound 22a (3.00 mmol, 551.0 mg) was used instead of compound 1a to obtain 178.6 mg of 22b as a yellow solid with a yield of 28.5% and a melting point of 51.3-52.8 ℃.

c) Preparation of 1-n-butyl-7-chloro-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde 22c

Compound 22c was prepared in the same way as compound 7c in Example 12, except that 22b (0.50 mmol, 125.4 mg) was used instead of 7b to obtain 115.8 mg of 22c as a dark red liquid with a yield of 82.8%.

d) Preparation of 1-n-butyl-7-chloro-3-((cyclohexylamino)enyl)quinoline-2,4(1H,3H)-dione (CHG45)

The preparation of compound CHG45 was the same as that of compound CHG01 in Example 1, except that 22c (0.10 mmol, 28.0 mg) was used instead of 1c to obtain 28.5 mg of CHG45 as a yellow liquid with a yield of 79.1%.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.26 (d, 1H, J=14.0Hz), 8.56 (m, 1H), 7.34 (m, 1H), 7.15 (m, 2H), 4.10 (m, 2H ), 3.40 (m, 1H), 2.03 (m, 2H), 1.84 (m, 2H), 1.67 (m, 3H), 1.43(m, 6H), 1.240 (m, 1H), 0.98 (t, 3H, J=7.5Hz).

Example 46: 3-((Cyclohexylamino)alkenyl)-1-cyclopropylmethyl-8-methylquinoline-2,4(1H,3H)-dione (CHG46)

a) Preparation of N-cyclopropylmethyl-2-methylaniline 23a

Compound 23a was prepared in the same manner as Compound 1a in Example 1, except that 2-methylaniline (20.00mmol, 2.14g) was used instead of aniline, and cyclopropyl bromide (10.00mmol, 1350mg) was used instead of bromo-n- Butane, 23a was obtained as yellow liquid 840.1mg, yield 52.1%.

b) Preparation of 2-cyano-N-cyclopropylmethyl-N-(2-methylphenyl)acetamide 23b

The preparation of compound 23b was the same as that of compound 1b in Example 1, except that compound 23a (3.00 mmol, 483.7 mg) was used instead of compound 1a to obtain 182.1 mg of 23b as a yellowish solid with a yield of 31.9% and a melting point of 103.6- 104.4°C.

c) Preparation of 1-cyclopropylmethyl-4-hydroxy-8-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde 23c

Compound 23c was prepared in the same manner as compound 1c in Example 1, except that 23b (0.50 mmol, 114.1 mg) was used instead of 1b to obtain 103.9 mg of 23c as a yellow solid with a yield of 80.8% and a melting point of 96.0-96.5°C.

d) Preparation of 3-((cyclohexylamino)alkenyl)-1-cyclopropylmethyl-8-methylquinoline-2,4(1H,3H)-dione (CHG46)

The preparation of compound CHG46 was the same as that of compound CHG01 in Example 1, except that 23c (0.10 mmol, 25.7 mg) was used instead of 1c to obtain 30.9 mg of CHG46 as a yellow liquid with a yield of 91.3%.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.17 (s, 1H), 8.53 (dd, 1H, J=5.5Hz, J=14.0Hz), 8.12 (m, 1H), 7.34 (m, 1H), 7.10 (t, 1H, J=7.5Hz), 4.26 (d, 2H, J=6.5Hz), 3.43 (m, 1H), 2.60 (s, 3H), 2.03 (m, 2H), 1.84 (m, 2H ), 1.65 (m, 1H), 1.51 (m, 2H), 1.40 (m, 2H), 1.27 (m, 1H), 0.98 (m, 1H), 0.35 (m, 2H), 0.21 (m, 2H) .

Example 47: 1-n-Butyl-3-((cyclobutylmethylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione (CHG47)

The preparation of compound CHG47 was the same as that of compound CHG07 in Example 7, except that cyclobutylmethylamine (0.12 mmol, 10.2 mg) was used instead of cyclohexylamine to obtain CHG47 as a yellow solid 30.9 mg, with a yield of 94.6%. , melting point 84.5-85.1 ℃.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.07 (s, 1H), 8.46 (d, 1H, J=14.0Hz), 8.11 (dd, 1H, J=8.0Hz, J=37.5Hz), 7.33 ( t, 1H, J=6.5Hz), 7.08 (m, 1H), 4.30 (t, 2H, J=7.0Hz), 3.50 (t, 2H, J=6.5Hz), 2.64 (m, 1H), 2.55 ( s, 3H), 2.12 (m, 2H), 1.93 (m, 2H), 1.78 (m, 2H), 1.53 (m, 2H), 1.23 (m, 2H), 0.85 (t, 3H, J=7.0Hz ).

Example 48: 1-n-Butyl-3-((isobutylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione (CHG48)

The preparation of compound CHG48 was the same as that of compound CHG07 in Example 7, except that isobutylamine (0.12 mmol, 8.8 mg) was used instead of cyclohexylamine to obtain CHG48 as a yellow solid of 29.7 mg with a yield of 94.6% and a melting point of 69.8 -71.0°C.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.14 (s, 1H), 8.44 (d, 1H, J=14.0Hz), 8.12 (m, 1H), 7.34 (t, 1H, J=6.0Hz), 7.09 (t, 1H, J=7.5Hz), 4.30 (t, 2H, J=7.5Hz), 3.32 (t, 2H, J=6.5Hz), 2.55 (s, 3H), 1.95 (m, 1H), 1.53 (m, 2H), 1.24 (m, 2H), 1.01 (d, 6H, J=6.5Hz), 0.85 (t, 3H, J=7.5Hz).

Example 49: 3-((tert-Butylamino)alkenyl)-1-cyclopropylmethyl-8-methylquinoline-2,4(1H,3H)-dione (CHG49)

Compound CHG49 was prepared in the same manner as compound CHG46 in Example 46, except that tert-butylamine (0.12 mmol, 8.8 mg) was used instead of cyclohexylamine to obtain 30.5 mg of CHG49 as a yellow liquid with a yield of 97.5%.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.54 (s, 1H), 8.61 (dd, 1H, J=8.0Hz, J=6.5Hz), 8.14 (dd, 1H, J=7.5Hz, J=39.5 Hz), 7.34 (d, 1H, J=7.0Hz), 7.11 (m, 1H), 4.26 (d, 2H, J=6.5Hz), 2.61 (s, 3H), 1.47 (s, 9H), 1.00 ( m, 1H), 0.35 (m, 2H), 0.23 (dd, 2H, J=4.5Hz, J=6.0Hz).

Example 50: 3-((Cyclohexylamino)alkenyl)-7-methoxy-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG50)

a) Preparation of 3-methoxy-N-n-pentylaniline 24a

Compound 24a was prepared in the same manner as Compound 1a in Example 1, except that m-aminoanisole (20.00 mmol, 2.46 g) was used instead of aniline, and bromo-n-pentane (10.00 mmol, 1.51 g) was used instead of bromine Substitute n-butane to obtain 885.3 mg of 24a as a yellow liquid, with a yield of 45.8%.

b) Preparation of 2-cyano-N-(3-methoxyphenyl)-N-pentylacetamide 24b

The preparation of compound 24b was the same as that of compound 1b in Example 1, except that compound 24a (3.00 mmol, 579.9 mg) was used instead of compound 1a to obtain 195.2 mg of 24b as a yellow liquid with a yield of 30.0%.

c) 4-Hydroxy-7-methoxy-2-oxo-1-n-pentyl-1,2-dihydroquinoline-3-carbaldehyde 24c and 4-hydroxy-5-methoxy-2-oxo Preparation of Dai-1-n-pentyl-1,2-dihydroquinoline-3-carbaldehyde 24c'

Compounds 24c and 24c' were prepared in the same way as compound 7c in Example 12, except that 24b (0.50 mmol, 130.2 mg) was used instead of 7b to obtain 101.0 mg of 24c, with a yield of 69.8%, and 28.2 mg of 24c' , yield 19.5%.

d) Preparation of 3-((cyclohexylamino)alkenyl)-7-methoxy-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG50)

The preparation of compound CHG50 was the same as that of compound CHG01 in Example 1, except that 24c (0.10 mmol, 28.9 mg) was used instead of 1c to obtain 28.9 mg of CHG50 as a yellow liquid with a yield of 78.1%.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.22 (s, 1H), 8.56 (dd, 1H, J=14.0Hz, J=15.0Hz), 8.18 (m, 1H), 6.74 (t, 1H, J =8.5Hz), 6.64 (s, 1H), 4.10 (t, 2H, J=7.5Hz), 3.90 (s, 3H), 3.41 (m, 1H), 2.02 (m, 2H), 1.83 (m, 2H ), 1.71 (m, 3H), 1.43 (m, 8H), 1.28 (m, 1H), 0.93 (t, 3H, J=6.5Hz).

Example 51: 3-((Cyclohexylamino)alkenyl)-5-methoxy-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG51)

The preparation of compound CHG51 was the same as that of compound CHG01 in Example 1, except that 24c' (0.08 mmol, 23.1 mg) was used instead of 1c to obtain 23.1 mg of CHG51 as a yellow liquid with a yield of 78.0%.

¹ H NMR (CDCl ₃ , 500 Hz): δ 8.53 (d, 1H, J=14.0Hz), 8.11 (s, 1H), 7.45 (t, 1H, J=8.5Hz), 6.83 (d, 1H, J =8.5Hz), 6.68 (d, 1H, J=8.5Hz), 4.13 (t, 2H, J=6.5Hz), 4.00 (s, 3H), 3.35 (m, 1H), 2.01 (m, 2H), 1.83 (m, 2H), 1.64 (m, 2H), 1.39 (m, 8H), 1.26 (m, 1H), 0.92 (t, 3H, J=7.0Hz).

Example 52: 1-n-Butyl-3-((cyclohexylamino)enyl)-8-ethylquinoline-2,4(1H,3H)-dione (CHG52)

a) Preparation of N-n-butyl-2-ethylaniline 25a

Compound 25a was prepared in the same manner as compound 1a in Example 1, except that 2-ethylaniline (20.00 mmol, 2.42 g) was used instead of aniline to obtain 670.2 mg of 25a as a yellow liquid with a yield of 37.8%.

b) Preparation of N-n-butyl-2-cyano-N-(2-ethylphenyl)acetamide 25b

The preparation of compound 25b was the same as that of compound 1b in Example 1, except that compound 25a (3.00 mmol, 531.9 mg) was used instead of compound 1a to obtain 164.3 mg of 25b as a yellow liquid with a yield of 26.9%.

c) Preparation of 1-n-butyl-8-ethyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde 25c

Compound 25c was prepared in the same manner as compound 1c in Example 1, except that 25b (0.50 mmol, 122.2 mg) was used instead of 1b to obtain 124.0 mg of 25c as a yellow solid with a yield of 90.7% and a melting point of 49.1-49.8°C.

d) Preparation of 1-n-butyl-3-((cyclohexylamino)enyl)-8-ethylquinoline-2,4(1H,3H)-dione (CHG52)

The preparation of compound CHG52 was the same as that of compound CHG01 in Example 1, except that 25c (0.10 mmol, 27.3 mg) was used instead of 1c to obtain 33.3 mg of CHG52 as a yellow liquid with a yield of 93.8%.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.14 (s, 1H), 8.52 (d, 1H, J=14.0Hz), 8.11 (m, 1H), 7.38 (t, 1H, J=7.0Hz), 7.12 (t, 1H, J=8.0Hz), 4.23 (t, 2H, J=7.0Hz), 3.41 (m, 1H), 2.84 (dd, 2H, J=7.5Hz), 2.02 (m, 2H), 1.82 (m, 2H), 1.64 (m, 1H), 1.49 (m, 4H), 1.39 (m, 2H), 1.22 (m, 6H), 0.83 (t, 3H, J=7.5Hz).

Example 53: 3-((Cyclohexylamino)alkenyl)-1-n-pentyl-6-trifluoromethylquinoline-2,4(1H,3H)-dione (CHG53)

a) Preparation of N-n-pentyl-4-trifluoromethylaniline 26a

The preparation of compound 26a was the same as that of compound 20a in Example 39, except that 4-trifluoromethylaniline (40.00 mmol, 6.44 g) was used instead of 2-aminopyridine to obtain 545.8 mg of 26a as a yellow liquid, with a yield of 11.8%.

b) Preparation of 2-cyano-N-n-pentyl-N-(4-trifluoromethylphenyl)acetamide 26b

The preparation of compound 26b was the same as that of compound 1b in Example 1, except that compound 26a (2.10 mmol, 485.6 mg) was used instead of compound 1a to obtain 123.2 mg of 26b as a yellow liquid with a yield of 23.6%.

c) Preparation of 4-hydroxy-2-oxo-1-n-pentyl-6-trifluoromethyl-1,2-dihydroquinoline-3-carbaldehyde 26c

The preparation of compound 26c was the same as that of compound 7c in Example 12, except that 26b (0.40 mmol, 119.3 mg) was used instead of 7b to obtain 126.1 mg of 26c as a brownish-red liquid with a yield of 96.3%.

d) Preparation of 3-((cyclohexylamino)alkenyl)-1-n-pentyl-6-trifluoromethylquinoline-2,4(1H,3H)-dione (CHG53)

The preparation of compound CHG53 was the same as that of compound CHG01 in Example 1, except that 26c (0.10 mmol, 32.7 mg) was used instead of 1c to obtain 15.9 mg of CHG53 as a yellow solid with a yield of 39.0% and a melting point of 100.7-102.4°C.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.34 (s, 1H), 8.56 (m, 2H), 7.75 (m, 1H), 7.26 (d, 1H), 4.15 (t, 2H, J=7.5Hz ), 3.47 (m, 1H), 2.03 (m, 2H), 1.84 (m, 2H), 1.68 (m, 3H), 1.53 (m, 2H), 1.41 (m, 6H), 1.30 (m, 1H) , 0.92 (t, 3H, J=7.0Hz).

Example 54: 7-Chloro-3-((cyclohexylamino)alkenyl)-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG54)

a) Preparation of 3-chloro-N-n-pentylaniline 27a

Compound 27a was prepared in the same manner as compound 1a in Example 1, except that 3-chloroaniline (40.00mmol, 5.10g) was used instead of aniline, and bromo-n-pentane (20.00mmol, 3.02g) was used instead of bromo With n-butane, 549.6 mg of 27a was obtained as a yellow liquid, with a yield of 13.9%.

b) Preparation of N-(3-chlorophenyl)-2-cyano-N-n-pentylacetamide 27b

The preparation of compound 27b was the same as that of compound 1b in Example 1, except that compound 27a (2.70 mmol, 533.8 mg) was used instead of compound 1a to obtain 176.9 mg of 27b as a yellow solid with a yield of 29.7% and a melting point of 96.9-97.8 ℃.

c) Preparation of 7-chloro-4-hydroxy-2-oxo-1-n-pentyl-1,2-dihydroquinoline-3-carbaldehyde 27c

Compound 27c was prepared in the same manner as compound 7c in Example 12, except that 27b (0.50 mmol, 132.4 mg) was used instead of 7b to obtain 132.6 mg of 27c as a brownish-yellow liquid with a yield of 90.3%.

d) Preparation of 7-chloro-3-((cyclohexylamino)enyl)-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG54)

The preparation of compound CHG54 was the same as that of compound CHG01 in Example 1, except that 27c (0.10 mmol, 29.4 mg) was used instead of 1c to obtain 32.5 mg of CHG54 as a yellow liquid with a yield of 86.7%.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.12 (s, 1H), 8.53 (m, 1H), 7.33 (t, 1H, J=8.0Hz), 7.11 (m, 2H), 4.08 (t, 2H , J=7.0Hz), 3.37 (m, 1H), 2.00 (m, 2H), 1.81 (m, 2H), 1.63 (m, 3H), 1.47 (m, 2H), 1.35 (m, 6H), 1.22 (m, 1H), 0.89 (t, 3H, J=6.5Hz).

Example 55: 3-((Cyclohexylamino)alkenyl)-6-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG55)

a) Preparation of 4-methyl-N-n-pentylaniline 28a

Compound 28a was prepared in the same manner as Compound 1a in Example 1, except that 4-methylaniline (20.00mmol, 2.14g) was used instead of aniline, and bromo-n-pentane (10.00mmol, 1.51g) was used instead of bromine Substitute n-butane to obtain 976.9 mg of 28a as a yellow liquid, with a yield of 55.1%.

b) Preparation of 2-cyano-N-n-pentyl-N-(p-tolyl)acetamide 28b

The preparation of compound 28b was the same as that of compound 1b in Example 1, except that compound 28a (3.00 mmol, 531.9 mg) was used instead of compound 1a to obtain 174.1 mg of 28b as a yellow liquid with a yield of 28.5%.

c) Preparation of 4-hydroxy-6-methyl-2-oxo-1-n-pentyl-1,2-dihydroquinoline-3-carbaldehyde 28c

The preparation of compound 28c was the same as that of compound 1c in Example 1, except that 28b (0.50 mmol, 122.2 mg) was used instead of 1b to obtain 130.9 mg of 28c as a light yellow solid with a yield of 95.8% and a melting point of 85.3-86.3°C .

d) Preparation of 3-((cyclohexylamino)alkenyl)-6-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG55)

The preparation of compound CHG55 was the same as that of compound CHG01 in Example 1, except that 28c (0.10 mmol, 27.3 mg) was used instead of 1c to obtain 35.0 mg of CHG55 as a yellow liquid with a yield of 98.7%.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.35 (s, 1H), 8.58 (dd, 1H, J=14.0Hz, J=6.5Hz), 8.04 (d, 1H, J=35.0Hz), 7.36 ( t, 1H, J=6.0Hz, J=8.5Hz), 7.08 (d, 1H, J=8.5Hz), 4.12 (t, 2H, J=7.5Hz), 3.42 (m, 1H), 2.38 (s, 3H), 2.02 (m, 2H), 1.83 (m, 2H), 1.66 (m, 3H), 1.50 (m, 2H), 1.40 (m, 6H), 1.27 (m, 1H), 0.91 (t, 3H , J=7.0Hz).

Example 56: 3-((Cyclohexylamino)alkenyl)-1-n-pentyl-6-trifluoromethoxyquinoline-2,4(1H,3H)-dione (CHG56)

a) Preparation of N-n-pentyl-4-trifluoromethoxyaniline 29a

Compound 29a was prepared in the same manner as Compound 1a in Example 1, except that 4-trifluoromethoxyaniline (40.00mmol, 7.08g) was used instead of aniline, and bromo-n-pentane (20.00mmol, 3.02g ) instead of n-butane bromide to obtain 914.9 mg of 29a as a yellow liquid, with a yield of 18.5%.

b) Preparation of 2-cyano-N-n-pentyl-N-(4-trifluoromethoxyphenyl)acetamide 29b

Compound 29b was prepared in the same manner as compound 1b in Example 1, except that compound 29a (3.60 mmol, 890.1 mg) was used instead of compound 1a to obtain 109.4 mg of 29b as a yellow liquid with a yield of 11.6%.

c) Preparation of 4-hydroxy-2-oxo-1-n-pentyl-6-trifluoromethoxy-1,2-dihydroquinoline-3-carbaldehyde 29c

Compound 29c was prepared in the same manner as compound 7c in Example 12, except that 29b (0.30 mmol, 94.3 mg) was used instead of 7b to obtain 37.4 mg of 29c as a brownish-yellow liquid with a yield of 36.3%.

d) Preparation of 3-((cyclohexylamino)alkenyl)-1-n-pentyl-6-trifluoromethoxyquinoline-2,4(1H,3H)-dione (CHG56)

The preparation of compound CHG56 was the same as that of compound CHG01 in Example 1, except that 29c (0.10 mmol, 34.3 mg) was used instead of 1c to obtain 25.8 mg of CHG56 as a yellow liquid with a yield of 60.8%.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.31 (s, 1H), 8.60 (dd, 1H, J=14.0Hz, J=2.5Hz), 8.10 (dd, 1H, J=41.0Hz, J=2.5 Hz), 7.40 (m, 1H), 7.20 (dd, 1H, J=9.0Hz, J=2.5Hz), 4.14 (t, 2H, J=7.5Hz), 3.47 (m, 1H), 2.04 (m, 2H), 1.85 (m, 2H), 1.69 (m, 3H), 1.53 (m, 2H), 1.41 (m, 6H), 1.30 (m, 1H), 0.93 (t, 3H, J=7.0Hz). Example 57: 1-n-Butyl-3-((cyclopropylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione (CHG57)

The preparation of compound CHG57 was the same as that of compound CHG07 in Example 7, except that cyclopropylamine (0.12 mmol, 6.9 mg) was used instead of cyclohexylamine to obtain 25.9 mg of CHG57 as a yellow liquid with a yield of 86.7%.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.15 (d, 1H, J=12.0Hz), 8.58 (d, 1H, J=13.5Hz), 8.11 (m, 1H), 7.34 (t, 1H, J =7.0Hz), 7.09 (m, 1H), 4.30 (t, 2H, J=7.5Hz), 3.04 (m, 1H), 2.55 (s, 3H), 1.54 (m, 2H), 1.24 (m, 2H ), 0.92 (m, 4H), 0.86 (t, 3H, J=7.5Hz).

Example 58: 1-n-Butyl-8-methyl-3-((tetrahydro-2H-pyran-4-methyleneamino)enyl)quinoline-2,4(1H,3H)-dione (CHG58)

The preparation of compound CHG58 was the same as that of compound CHG07 in Example 7, except that 4-aminomethyltetrahydropyran (0.12 mmol, 13.8 mg) was used instead of cyclohexylamine to obtain 13.8 mg of CHG58 as a yellow liquid. The rate is 38.6%.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.17 (s, 1H), 8.44 (dd, 1H, J=14.0Hz, J=4.0Hz), 8.12 (m, 1H), 7.35 (t, 1H, J =6.0Hz), 7.11 (m, 1H), 4.31 (t, 2H, J=7.5Hz), 4.01 (dd, 2H, J=7.0Hz, J=4.0Hz), 3.38 (m, 4H), 2.56 ( s, 3H), 1.90 (m, 1H), 1.71 (m, 2H), 1.54 (m, 2H), 1.40 (m, 2H), 1.25 (m, 2H), 0.86 (t, 3H, J=7.5Hz ).

Example 59: 1-n-Butyl-3-((cyclohexylamino)alkenyl)-8-methoxyquinoline-2,4(1H,3H)-dione (CHG59)

a) Preparation of N-n-butyl-2-methoxyaniline 30a

Compound 30a was prepared in the same manner as compound 1a in Example 1, except that 2-methoxyaniline (20.00 mmol, 2.46 g) was used instead of aniline to obtain 754.7 mg of 30a as a yellow liquid with a yield of 42.1%.

b) Preparation of N-n-butyl-2-cyano-N-(2-methoxyphenyl)acetamide 30b

The preparation of compound 30b was the same as that of compound 1b in Example 1, except that compound 30a (3.00 mmol, 537.8 mg) was used instead of compound 1a to obtain 180.4 mg of 30b as a yellow liquid with a yield of 29.3%.

c) Preparation of 1-n-butyl-4-hydroxy-8-methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde 30c

The preparation of compound 30c was the same as that of compound 1c in Example 1, except that 30b (0.50 mmol, 123.2 mg) was used instead of 1b to obtain 114.7 mg of 30c as a light yellow solid with a yield of 83.3% and a melting point of 89.5-90.6°C .

d) Preparation of 1-n-butyl-3-((cyclohexylamino)alkenyl)-8-methoxyquinoline-2,4(1H,3H)-dione (CHG59)

The preparation of compound CHG59 was the same as that of compound CHG01 in Example 1, except that 30c (0.10 mmol, 27.5 mg) was used instead of 1c to obtain 33.6 mg of CHG59 as a yellow liquid with a yield of 94.3%.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.31 (s, 1H), 8.56 (dd, 1H, J=14.0Hz, J=4.0Hz), 7.90 (m, 1H), 7.10 (m, 2H), 4.38 (t, 2H, J=7.5Hz), 3.87 (s, 3H), 3.41 (m, 1H), 2.02 (m, 2H), 1.82 (m, 2H), 1.70 (m, 3H), 1.50 (m , 2H), 1.38 (m, 4H), 1.27 (m, 1H), 0.94 (t, 3H, J=7.5Hz).

Example 60: 3-((Cyclohexylamino)alkenyl)-8-methyl-1-propylquinoline-2,4(1H,3H)-dione (CHG60)

a) Preparation of 2-methyl-N-propylaniline 31a

Compound 31a was prepared in the same manner as Compound 1a in Example 1, except that 2-methylaniline (20.00mmol, 2.14g) was used instead of aniline, and 1-bromopropane (10.00mmol, 1.23g) was used instead of bromo With n-butane, 31a was obtained as 455.2 mg of yellow liquid, with a yield of 30.5%.

b) Preparation of 2-cyano-N-propyl-N-(2-methylphenyl)acetamide 31b

The preparation of compound 31b was the same as that of compound 1b in Example 1, except that compound 31a (3.00 mmol, 447.7 mg) was used instead of compound 1a to obtain 141.1 mg of 31b as a yellow liquid with a yield of 26.1%.

c) Preparation of 4-hydroxy-8-methyl-2-oxo-1-propyl-1,2-dihydroquinoline-3-carbaldehyde 31c

The preparation of compound 31c was the same as that of compound 1c in Example 1, except that 31b (0.50mmol, 108.1mg) was used instead of 1b to obtain 105.1mg of 31c as a light yellow solid with a yield of 85.7% and a melting point of 71.9-73.2°C .

d) Preparation of 3-((cyclohexylamino)alkenyl)-8-methyl-1-propylquinoline-2,4(1H,3H)-dione (CHG60)

The preparation of compound CHG60 was the same as that of compound CHG01 in Example 1, except that 31c (0.10 mmol, 24.5 mg) was used instead of 1c to obtain 30.7 mg of CHG60 as a yellow liquid with a yield of 94.2%.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.19 (s, 1H), 8.53 (dd, 1H, J=14.0Hz, J=3.5Hz), 8.12 (m, 1H), 7.33 (t, 1H, J =7.5Hz), 7.08 (t, 1H, J=7.5Hz), 4.26 (t, 2H, J=7.5Hz), 3.42 (m, 1H), 2.55 (s, 3H), 2.02 (m, 2H), 1.83 (m, 2H), 1.64 (m, 1H), 1.57 (m, 2H), 1.49 (m, 2H), 1.39 (m, 2H), 1.27 (m, 1H), 0.81 (t, 3H, J= 7.5Hz).

Example 61: 3-((tert-Butylamino)alkenyl)-8-methyl-1-propylquinoline-2,4(1H,3H)-dione (CHG61)

Compound CHG61 was prepared in the same manner as compound CHG60 in Example 60, except that tert-butylamine (0.12 mmol, 8.8 mg) was used instead of cyclohexylamine to obtain 28.5 mg of CHG61 as a yellow liquid with a yield of 94.9%.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.53 (d, 1H, J=12.0Hz), 8.61 (dd, 1H, J=14.5Hz, J=5.0Hz), 8.11 (dd, 1H, J=41.5 Hz, J=5.0Hz), 7.33 (t, 1H, J=7.0Hz), 7.08 (t, 1H, J=7.5Hz), 4.25 (t, 2H, J=7.5Hz), 2.56 (s, 3H) , 1.61 (m, 2H), 1.45 (s, 9H), 0.83 (t, 3H, J=7.5Hz).

Example 62: 1-n-Butyl-3-((cyclohexylamino)alkenyl)-5-methylquinoline-2,4(1H,3H)-dione (CHG62)

a) Preparation of N-n-butyl-3-methylaniline 32a

The preparation of compound 32a was the same as that of compound 1a in Example 1, except that 3-methylaniline (20.00 mmol, 2.14 g) was used instead of aniline to obtain 666.1 mg of 32a as a yellow liquid with a yield of 40.8%.

b) Preparation of N-n-butyl-2-cyano-N-(3-methylphenyl)acetamide 32b

The preparation of compound 32b was the same as that of compound 1b in Example 1, except that compound 32a (3.00 mmol, 489.8 mg) was used instead of compound 1a to obtain 162.4 mg of 32b as a yellow liquid with a yield of 28.2%.

c) 1-n-butyl-4-hydroxy-5-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde 32c, 1-n-butyl-4-hydroxy-7-methyl - Preparation of 2-oxo-1,2-dihydroquinoline-3-carbaldehyde 32c'

The preparation of compounds 32c and 32c' was the same as that of compound 7c in Example 12, except that 32b (0.50 mmol, 115.2 mg) was used instead of 7b to obtain 75.8 mg of 32c, with a yield of 58.5%; 32c' was 38.0 mg , yield 29.3%.

d) Preparation of 1-n-butyl-3-((cyclohexylamino)enyl)-5-methylquinoline-2,4(1H,3H)-dione (CHG62)

The preparation of compound CHG62 was the same as that of compound CHG01 in Example 1, except that 32c (0.10 mmol, 25.9 mg) was used instead of 1c to obtain 32.6 mg of CHG62 as a yellow liquid with a yield of 95.8%.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.18 (s, 1H), 8.54 (dd, 1H, J=14.0Hz, J=5.0Hz), 7.36 (dd, 1H, J=7.0Hz, J=7.5 Hz), 7.07 (d, 1H, J=8.5Hz), 6.90 (t, 1H, J=10.0Hz, J=7.5Hz), 4.15 (t, 2H, J=7.5Hz), 3.36 (m, 1H) , 2.86 (s, 3H), 2.02 (m, 2H), 1.83 (m, 2H), 1.67 (m, 3H), 1.48 (m, 4H), 1.37 (m, 2H), 1.23 (m, 1H), 0.98 (t, 3H, J=7.5Hz).

Example 63: 1-n-Butyl-3-((cyclohexylamino)enyl)-7-methylquinoline-2,4(1H,3H)-dione (CHG63)

The preparation of compound CHG63 was the same as that of compound CHG01 in Example 1, except that 32c' (0.05 mmol, 13.0 mg) was used instead of 1c to obtain 16.3 mg of CHG63 as a yellow liquid with a yield of 96.0%.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.30 (s, 1H), 8.58 (dd, 1H, J=14.0Hz, J=7.5Hz), 8.13 (dd, 1H, J=46.0Hz, J=8.0 Hz), 6.99 (d, 2H, J=5.0Hz), 4.15 (t, 2H, J=7.5Hz), 3.41 (m, 1H), 2.46 (s, 3H), 2.02 (m, 2H), 1.83 ( m, 2H), 1.68 (m, 3H), 1.45 (m, 6H), 1.29 (m, 1H), 1.00 (t, 3H, J=8.0Hz).

Example 64: 1-n-Butyl-3-((cyclohexylmethylamino)enyl)-5-methylquinoline-2,4(1H,3H)-dione (CHG64)

Compound CHG64 was prepared in the same manner as compound CHG62 in Example 62, except that cyclohexylmethylamine (0.12 mmol, 13.6 mg) was used instead of cyclohexylamine to obtain 32.4 mg of CHG64 as a yellow liquid with a yield of 91.5%.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.15 (s, 1H), 8.43 (dd, 1H, J=14.0Hz, J=5.0Hz), 7.37 (m, 1H), 7.08 (d, 1H, J =8.5Hz), 6.91 (t, 1H, J=9.0Hz, J=7.5Hz), 4.15 (t, 2H, J=7.5Hz), 3.30 (t, 2H, J=6.5Hz), 2.86 (s, 3H), 1.79 (m, 4H), 1.68 (m, 3H), 1.62 (m, 1H), 1.45 (m, 2H), 1.21 (m, 3H), 0.97 (m, 5H).

Example 65: 1-n-Butyl-3-((cyclohexylmethylamino)enyl)-7-methylquinoline-2,4(1H,3H)-dione (CHG65)

Compound CHG65 was prepared in the same manner as compound CHG63 in Example 63, except that cyclohexylmethylamine (0.06 mmol, 6.8 mg) was used instead of cyclohexylamine to obtain 16.4 mg of CHG65 as a yellow liquid with a yield of 92.3%.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.23 (s, 1H), 8.47 (dd, 1H, J=13.5Hz, J=5.5Hz), 8.13 (dd, 1H, J=42.0Hz, J=8.5 Hz), 6.99 (d, 2H, J=4.5Hz), 4.14 (t, 2H, J=7.5Hz), 3.34 (t, 2H, J=6.5Hz), 2.46 (s, 3H), 1.77 (m, 4H), 1.69 (m, 3H), 1.62 (m, 1H), 1.48 (m, 2H), 1.21 (m, 3H), 1.01 (m, 5H).

Example 66: 3-((Cyclohexylamino)alkenyl)-6,8-dimethoxy-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG66)

a) Preparation of 2,4-dimethoxy-N-n-pentylaniline 33a

Compound 33a was prepared in the same manner as Compound 1a in Example 1, except that 2,4-dimethoxyaniline (20.00mmol, 3.06g) was used instead of aniline, and bromo-n-pentane (10.00mmol, 1.51 g) Instead of n-butane bromide, 1063.0 mg of 33a was obtained as a yellow liquid with a yield of 47.6%.

b) Preparation of 2-cyano-N-(2,4-dimethoxyphenyl)-N-pentylacetamide 33b

The preparation of compound 33b was the same as that of compound 1b in Example 1, except that compound 33a (3.00 mmol, 669.9 mg) was used instead of compound 1a to obtain 222.9 mg of 33b as a yellow liquid with a yield of 30.7%.

c) Preparation of 4-hydroxy-6,8-dimethoxy-2-oxo-1-n-pentyl-1,2-dihydroquinoline-3-carbaldehyde 33c

Compound 33c was prepared in the same manner as compound 1c in Example 1, except that 33b (0.50 mmol, 145.2 mg) was used instead of 1b to obtain 125.2 mg of 33c as a yellow solid with a yield of 78.4%.

d) Preparation of 3-((cyclohexylamino)alkenyl)-6,8-dimethoxy-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG66)

The preparation of compound CHG66 was the same as that of compound CHG01 in Example 1, except that 33c (0.10 mmol, 31.9 mg) was used instead of 1c to obtain 29.2 mg of CHG66 as a yellow liquid with a yield of 73.0%.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.33 (s, 1H), 8.58 (dd, 1H, J=14.0Hz, J=5.0Hz), 7.34 (dd, 1H, J=42.0Hz, J=3.0 Hz), 6.71 (d, 1H, J=3.0Hz), 4.34 (t,2H, J=7.5Hz), 3.86 (s, 3H), 3.85 (s, 3H), 3.42 (m, 1H), 2.03 ( m, 2H), 1.83 (m, 2H), 1.69 (m, 3H), 1.50 (m, 2H), 1.33 (m, 7H), 0.89 (t, 3H, J=7.0Hz).

Example 67: 3-((Cyclohexylmethylamino)alkenyl)-6,8-dimethoxy-1-n-pentylquinoline-2,4(1H,3H)-dione (CHG67)

Compound CHG67 was prepared in the same manner as compound CHG66 in Example 66, except that cyclohexylmethylamine (0.12 mmol, 13.6 mg) was used instead of cyclohexylamine to obtain 31.5 mg of CHG67 as a yellow liquid with a yield of 76.0%.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.25 (s, 1H), 8.48 (dd, 1H, J=14.0Hz, J=7.0Hz), 7.38 (dd, 1H, J=40.0Hz, J=3.0 Hz), 6.71 (d, 1H, J=3.0Hz), 4.34 (t, 2H, J=7.5Hz), 3.87 (s, 3H), 3.86(s, 3H), 3.34 (t, 2H, J=6.5 Hz), 1.76 (m, 4H), 1.69 (m, 3H), 1.62 (m, 1H), 1.33 (m, 4H), 1.22 (m, 3H), 1.02 (m, 2H), 0.90 (t, 3H , J=7.0Hz).

Example 68: 1-n-Butyl-3-((cyclohexylamino)enyl)-6-fluoroquinoline-2,4(1H,3H)-dione (CHG68)

a) Preparation of N-n-butyl-4-fluoroaniline 34a

Compound 34a was prepared in the same manner as compound 1a in Example 1, except that 4-fluoroaniline (20.00 mmol, 2.22 g) was used instead of aniline to obtain 729.1 mg of 34a as a yellow liquid, with a yield of 43.6%.

b) Preparation of N-n-butyl-2-cyano-N-(4-fluorophenyl)acetamide 34b

The preparation of compound 34b was the same as that of compound 1b in Example 1, except that compound 34a (3.00 mmol, 501.7 mg) was used instead of compound 1a to obtain 206.2 mg of 34b as a yellow liquid with a yield of 35.2%.

c) Preparation of 1-n-butyl-6-fluoro-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde 34c

Compound 34c was prepared in the same manner as compound 1c in Example 1, except that 34b (0.50 mmol, 117.1 mg) was used instead of 1b to obtain 112.4 mg of 34c as a light yellow solid with a yield of 85.4%.

d) Preparation of 1-n-butyl-3-((cyclohexylamino)alkenyl)-6-fluoroquinoline-2,4(1H,3H)-dione (CHG68)

The preparation of compound CHG68 was the same as that of compound CHG01 in Example 1, except that 34c (0.10 mmol, 26.3 mg) was used instead of 1c to obtain 32.6 mg of CHG68 as a light yellow solid with a yield of 94.7% and a melting point of 105.4-106.5°C .

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.29 (s, 1H), 8.58 (dd, 1H, J=14.0Hz, J=2.0Hz), 7.90 (m, 1H), 7.25 (m, 1H), 7.15 (dd, 1H, J=9.5Hz, J=4.0Hz), 4.13 (t, 2H, J=7.5Hz), 3.44 (m, 1H), 2.02 (m, 2H), 1.84 (m, 2H), 1.62 (m, 3H), 1.46 (m, 6H), 1.28 (m, 1H), 0.98 (t, 3H, J=7.5Hz).

Example 69: 1-n-Butyl-3-((tert-butylamino)alkenyl)-6-fluoroquinoline-2,4(1H,3H)-dione (CHG69)

The preparation of compound CHG69 was the same as that of compound CHG68 in Example 68, except that tert-butylamine (0.12 mmol, 8.8 mg) was used instead of cyclohexylamine to obtain 31.3 mg of CHG69 as a light yellow solid with a yield of 98.2% and a melting point of 90.6- 91.9°C.

¹ H NMR (CDCl ₃ , 500 Hz): δ 12.62 (s, 1H), 8.67 (m, 1H), 7.90 (m, 1H), 7.25 (t, 1H, J=7.5Hz), 7.15 (dd, 1H , J=3.0Hz, J=6.0Hz), 4.13 (t, 2H, J=7.5Hz), 1.66 (m, 2H), 1.46 (m, 11H), 0.98 (t, 3H, J=6.5Hz).

Example 70: 7-((Cyclohexylmethylamino)alkenyl)-5-n-pentylpyrido[2,3- b ]pyrazine-6,8(5H,7H)-dione (CHG70)

a) Preparation of N-n-pentyl-2-aminopyrazine 35a

The preparation of compound 35a was the same as that of compound 20a in Example 39, except that 2-aminopyrazine (20.00mmol, 1.90g) was used instead of 2-aminopyridine to obtain 753.5mg of 35a as a yellow liquid, with a yield of 45.6% .

b) Preparation of 2-cyano-N-n-pentyl-N-(2-pyrazinyl)acetamide 35b

The preparation of compound 35b was the same as that of compound 1b in Example 1, except that compound 35a (3.00 mmol, 495.7 mg) was used instead of compound 1a to obtain 102.2 mg of 35b as a yellow liquid with a yield of 20.7%.

c) Preparation of 8-hydroxy-6-oxo-5-n-pentyl-5,6-dihydropyrido[2,3- b ]pyrazine-7-carbaldehyde 35c

Compound 35c was prepared in the same manner as compound 7c in Example 12, except that 35b (0.50 mmol, 116.1 mg) was used instead of 7b to obtain 90.5 mg of 35c as a brown liquid with a yield of 69.3%.

d) Preparation of 7-((cyclohexylmethylamino)alkenyl)-5-n-pentylpyrido[2,3- b ]pyrazine-6,8(5H,7H)-dione (CHG70)

The preparation of compound CHG70 was the same as that of compound CHG01 in Example 1, except that 35c (0.10 mmol, 26.1 mg) was used instead of 1c to obtain 3.3 mg of CHG70 as a brown liquid with a yield of 9.5%.

ESI-MS: m/z 329.19 [M+1] ⁺

Example 71: Preparation of hydrochloride CHG07A, quaternary ammonium salt CHG07B and monohydrate CHG07C of compound CHG07

a) Preparation of the hydrochloride CHG07A of compound CHG07

Dissolve 0.1 mmol of compound CHG07 in 2 mL of anhydrous methanol, slowly add 2N HCl solution dropwise under ice bath to pH = 2, and spin down the solvent under reduced pressure to obtain the hydrochloride CHG07A of CHG07 as a white solid 32.0 mg, yield 84.9% .

ESI-MS: m/z 341.22 [M ⁺ ]

b) Preparation of quaternary ammonium salt CHG07B of compound CHG07

Dissolve 0.1 mmol of compound CHG07 in 5 mL of absolute ethanol, add equivalents of sodium hydroxide, potassium iodide and methyl iodide, heat to reflux overnight, spin the solvent under reduced pressure, and purify the crude product by recrystallization from acetone to obtain the quaternary ammonium compound CHG07 Salt CHG07B was white solid 18.5 mg, yield 37.3%.

ESI-MS: m/z 369.25 [M ⁺ ]

c) Preparation of monohydrate CHG07C of compound CHG07

Dissolve 0.1 mmol of compound CHG07 in 1N HCl solution, slowly add petroleum ether dropwise with stirring until the solution becomes cloudy, leave it at room temperature until no crystals are precipitated, and filter to obtain the monohydrate CHG07C of compound CHG07.

Elem. Anal.: C, 70.36%; H, 8.44%; N, 7.81%; O, 13.39%.

According to the similar method described in this example, it can be used to prepare pharmaceutically acceptable salts, solvates, hydrates or crystal forms of compound A of the present invention, including hydrochloride, hydrobromide, sulfate, hydrogen sulfide, Phosphate, Dihydrogen Phosphate, Methanesulfonate, Monomethyl Sulfate, Maleate, Fumarate, Succinate, Ascorbate, Nicotinate, Lactate, Tartrate, acetate, oxalate, malonate, glycolate, naphthalene-2-sulfonate, gluconate, citrate, isethionate, p-toluenesulfonate, 3,5-Dimethylbenzylsulfonate, or a quaternary ammonium salt formed with a haloalkane, wherein the haloalkane is fluorine, chlorine, bromine or iodoalkane.

Example 72: Pharmaceutical composition

Compound CHG07A 20g

Starch 140g

Microcrystalline Cellulose 60g

According to the conventional operation method, after the above-mentioned 3 kinds of substances are mixed physically, they are packed into gelatin capsules to obtain 1000 capsules.

Example 73: Pharmaceutical composition

Compound CHG07A 50g

Starch 400g

Microcrystalline Cellulose 200g

According to the conventional operation method, after the above-mentioned 3 kinds of substances are mixed physically, they are packed into gelatin capsules to obtain 1000 capsules.

Example 74: Example of Pharmacological Test——Calcium current assay

Activation of cannabinoid receptors leads to inhibition of intracellular calcium flow. However, after the G protein Gɑ16 was transferred, it showed the activation of intracellular calcium flow, and other physiological functions were not affected. By establishing cell lines co-transfected with CB1 and Gɑ16, CB2 and Gɑ16, the receptors are activated to activate the Gɑ16 protein, and then activate phospholipase C (PLC) to produce IP3 and DAG, and IP3 can bind to the endoplasmic reticulum in the cell Binding to the IP3 receptor, thereby causing the release of intracellular calcium. Therefore, measuring the change of intracellular calcium can be used as a method to detect the activation state of CB1 and CB2. Fluo-4/AM is a calcium fluorescent probe indicator used to measure calcium ions. As a non-polar fat-soluble compound, after entering the cell, under the action of cell lipolytic enzymes, the AM group dissociates and releases Fluo -4; Since Fluo-4 is a polar molecule, it is not easy to pass through the lipid bilayer membrane, so it can keep Fluo-4 in the cell for a long time. Finally, the activated level of Gɑ protein can be reflected by measuring the amount of excited photons. Based on this principle, a calcium flux screening model was established.

Experimental method: Cells were simultaneously transfected with human cannabinoid receptors (hCB1, hCB2) and Gɑ16, and stable transfected cell lines CHO-hCB1-Gɑ16 and CHO-hCB2-Gɑ16 were established by antibiotic selection. 24 hours before the test, an appropriate concentration of CHO/CB2-Gɑ16 or CHO/CB1-Gɑ16 (about 20,000 cells/well) was planted in a 96-well cell plate, so that the number of cells per well during the test was about 40,000-60,000 cells/well. After culturing overnight, the culture medium was removed after the cells adhered to the wall, and incubated with 2 μmol/L fluo-4 AM dye in a 37°C incubator for 50 minutes at constant temperature. After aspirating excess dye, cells were washed once with Hanks'Balanced Salt Solution (HBSS) buffer. In the antagonistic mode, cells were incubated with HBSS buffer containing positive control or test compound or negative control containing DMSO for 10 minutes at room temperature, and 25 μL agonist was automatically added to the reaction system by the FlexStation detector to detect intracellular calcium ion flux in real time Changes in fluorescence intensity of the dye caused by the change. In the activation mode, the cells are incubated with HBSS buffer at room temperature for 10 minutes, and the HBSS buffer containing positive control or test compound or negative control DMSO is automatically added to the reaction system by the FlexStation detector to detect the change of intracellular calcium ion flow in real time The resulting change in the fluorescence intensity of the dye. The inhibitory rate or relative agonistic ratio value of the test compound can be obtained.

Inhibition rate = (peak calcium current of negative control - peak calcium current of test compound)/(peak calcium current of negative control - peak calcium current of positive control) × 100%.

Relative activation ratio = (peak calcium current of the compound to be tested - peak calcium current of the negative control)/(peak calcium current of the positive control - peak calcium current of the negative control) × 100%.

The half inhibitory concentration IC ₅₀ or the half effective dose EC ₅₀ of the compound was determined by the above method, which was mainly obtained by making the response rate and dose curve, and a total of 10μM, 1μM, 100nM, 10nM, 1nM, 100pM, 10pM, and 0 were selected. For each dose concentration, the calcium flow detection was carried out according to the above-mentioned experimental procedure, and each concentration was measured in parallel three times, that is, an 8-gradient 3-multiple well plate was used. Data were analyzed with GraphPad Prism software. The dose-dependent curve of the test compound was fitted by nonlinear regression method and IC ₅₀ or EC ₅₀ was calculated.

The activity data in Table 1 and Table 2 show that the compounds of the present invention generally exhibit higher calcium flux activity and good selectivity to the human cannabinoid receptor CB2, and accompanying drawing 1 shows the dose dependence of the in vitro pharmacological tests of some compounds Graph. At the same time, the differences in the R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ groups of the compounds of the present invention have an important impact on the activity of the compounds, and the differences in the substituents can cause the compounds to exhibit agonist activity or inverse agonist activity. . In general, the compounds of the present invention are specific agonists or inverse agonists of the cannabinoid receptor CB2.

Example 75: In vivo drug efficacy experiment of compound CHG07 on mouse experimental autoimmune encephalomyelitis model

Female C57BL/6 mice were subcutaneously injected with 200 μg MOG35-55 (MEVGWYRSPFSRVVHLYRNGK, purchased from Jill Biochemical) supplemented with 5 mg/ml heat-inactivated Mycobacterium tuberculosis (H37Ra strain, purchased from Difco Laboratories) complete Freund's adjuvant. The day of immunization was defined as day 0. On day 0 and day 2, 200 ng of pertussis toxin (Calbiochem) was intraperitoneally injected into each mouse. The mice were scored every day, and the scoring was based on the "5-point system" as follows: 0 points, no clinical symptoms; 1 point, tail paralysis; 2 points, mild hind limb paralysis (unilateral or bilateral hind limb weakness, incomplete paralysis); 3 points, paraplegia (complete paralysis of bilateral hind limbs); 4 points, paraplegia with forelimb weakness or paralysis; 5 points, dying state or death.

EAE administration group: CHG-07 (1/3/10 mg/kg) was given by intragastric administration from the 3rd day after immunization until the end of the experiment. The solvent for dissolving CHG07 was phosphate buffered saline (PBS) containing 0.4% dimethyl sulfoxide.

EAE control group: from the 3rd day after immunization, the solvent control (vehicle), ie, phosphate buffer containing 0.4% dimethyl sulfoxide, was given by intragastric administration.

Histopathological analysis: The diseased mice in the EAE administration group and the EAE control group were anesthetized and fixed by perfusion with PBS and 4% paraformaldehyde. The removed spinal cord tissue samples were fixed overnight in 4% paraformaldehyde. The fixed spinal cord tissue samples were dehydrated with alcohol, embedded in paraffin, stained with hematoxylin and eosin (H&E) to analyze the infiltration of inflammatory cells, and stained with fast blue to analyze the demyelination of the spinal cord. Image pro software was used to analyze the inflammatory cell infiltration of the slices and the degree of demyelination of the spinal cord.

Data processing: The data were analyzed and processed with GraphPad Prism software. Statistical differences among EAE mouse treatment groups were analyzed by two-way ANOVA test. Other data analysis (such as pathological statistical analysis) was analyzed with Stilton's t test. p < 0.05 was considered statistically significant.

Figure 2 shows the results of the in vivo efficacy experiment of the compound CHG07 on the experimental autoimmune encephalomyelitis (EAE) model in mice. Figure A shows the clinical score data of experimental animals in each group. Compared with the vehicle group, the EAE symptoms of the experimental animals under the three doses were all alleviated to varying degrees, and CHG07 dose-dependently relieved the clinical score of EAE. At the same time, no experimental animals were killed during the experiment, which also shows that the compound CHG07 has relatively good safety. Figure B shows that the pathological section of the spinal cord 21 days after immunization shows that compared with the large number of leukocytes infiltrating the spinal cord in the vehicle group, the administration of CHG07 10 mg/kg can significantly reduce the infiltration of leukocytes into the spinal cord; Figure C shows that the EAE in the vehicle group is small Extensive demyelination occurred in the white matter of rat spinal cord, but after administration of CHG07 10mg/kg, the demyelination was significantly reduced.

Claims (3)

1. A quinolinedione derivative and a pharmaceutically acceptable salt thereof, characterized in that it is selected from the following quinolinedione derivatives: (1) 1-n-Butyl-3-((cyclohexylamino)alkenyl)quinoline-2,4(1H,3H)-dione (6) 1-n-Butyl-3-((cyclohexylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione (7) 1-n-Butyl-3-((cyclohexylamino)alkenyl)-6-methoxyquinoline-2,4(1H,3H)-dione (8) 1-n-Butyl-3-((1-adamantylamino)alkenyl)-6-methoxyquinoline-2,4(1H,3H)-dione (9) 3-((cyclohexylamino)alkenyl)-6-methoxy-1-n-pentylquinoline-2,4(1H,3H)-dione (10) 1-n-butyl-3-((n-butylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione (11) 1-n-Butyl-3-((tert-butylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione (12) 1-n-Butyl-3-((cyclopentylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione (13) 1-n-Butyl-3-((1-adamantylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione (14) 1-n-Butyl-3-((cyclopropylmethylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione (15) 1-n-Butyl-3-((cyclohexylmethylamino)alkenyl)-8-methylquinoline-2,4(1H,3H)-dione (16) 1-n-Butyl-8-methyl-3-((piperidin-1-amino)enyl)quinoline-2,4(1H,3H)-dione (17) 1-n-Butyl-8-methyl-3-((morpholinylamino)alkenyl)quinoline-2,4(1H,3H)-dione (18) 3-((Cyclohexylamino)alkenyl)-1-n-pentylquinoline-2,4(1H,3H)-dione (19) 3-((1-adamantylamino)alkenyl)-6-methoxy-1-n-pentylquinoline-2,4(1H,3H)-dione (20) 6-Chloro-3-((cyclohexylamino)alkenyl)-1-n-pentylquinoline-2,4(1H,3H)-dione (21) 6-Chloro-3-((1-adamantylamino)alkenyl)-1-n-pentylquinoline-2,4(1H,3H)-dione (22) 6-Bromo-3-((cyclohexylamino)alkenyl)-1-n-pentylquinoline-2,4(1H,3H)-dione (23) 3-((Cyclohexylamino)alkenyl)-8-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione (24) 3-((1-adamantylamino)alkenyl)-8-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione (25) 3-((Cyclohexylamino)alkenyl)-8-ethyl-1-n-pentylquinoline-2,4(1H,3H)-dione (26) 3-((Cyclohexylamino)alkenyl)-8-methoxy-1-n-pentylquinoline-2,4(1H,3H)-dione (27) 3-((1-adamantylamino)alkenyl)-8-methoxy-1-n-pentylquinoline-2,4(1H,3H)-dione (28) 8-Chloro-3-((cyclohexylamino)alkenyl)-1-n-pentylquinoline-2,4(1H,3H)-dione (29) 3-((Cyclohexylamino)alkenyl)-5-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione (30) 3-((Cyclohexylamino)alkenyl)-7-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione (31) 6-Chloro-3-((cyclohexylamino)alkenyl)-8-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione (32) 3-((Cyclohexylamino)alkenyl)-6-methoxy-8-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione (33) 3-((1-adamantylamino)alkenyl)-6-methoxy-8-methyl-1-n-pentylquinoline-2,4(1H,3H)-dione (34) 3-((Cyclohexylamino)alkenyl)-1-ethyl-8-methylquinoline-2,4(1H,3H)-dione (35) 3-((Cyclohexylamino)alkenyl)-1-n-pentyl-1,8-naphthyridine-2,4(1H,3H)-dione and the pharmaceutically acceptable salts of the specific compounds above. 2. A kind of quinolinedione derivatives and pharmaceutically acceptable salts thereof according to claim 1 are used in the medicine for preparing prevention and treatment and alleviating diseases mediated by CB2 receptors, and the medicine is marijuana Agonists, partial agonists, inverse agonists or antagonists of CB2 receptors, the diseases are cancer, inflammation, acquired immunodeficiency syndrome, autoimmune diseases modulated by CB2 receptor agonists and partial agonists diseases, rheumatic diseases, allergies, pain, acute and chronic liver disease, osteoporosis, atherosclerosis, multiple sclerosis, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, Huntington's disease and by CB2 Receptor inverse agonists and antagonists modulate inflammation, immune system disorders, neurodegenerative diseases, and osteoporosis. 3. The use according to claim 2, characterized in that the dosage form of the medicine is solid preparation or liquid preparation.