Fluorine-containing quinoline formamide compound as well as preparation method and application thereof

Abstract

The invention relates to a fluorine-containing quinoline formamide compound as well as a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. The preparation method of the fluorine-containing quinoline carboxamide compound comprises the following steps: by taking commercially available aryl ketone 1a-1v as a raw material, condensing the aryl ketone 1a-1v with hydroxylamine hydrochloride, and reducing to obtain an intermediate 3a-3v; the method comprises the following steps: by taking commercially available different substituted acetophenone 4a-4e as a raw material, performing oxidation, methylated hydroxylamine hydrochloride condensation, reduction and Boc protection to obtain an intermediate Boc-amino acid methyl ester 8a-8e; the 8a-8e is subjected to LiAlH4 reduction and hydrolysis, and an intermediate 9a-9e is obtained; or carrying out Grignard reaction and hydrolysis to obtain an intermediate 9aa-9ee; the preparation method comprises the following steps: by taking 2-amino-5-fluorobenzoic acid 11 as a raw material, carrying out Skraup quinoline synthesis reaction to obtain an intermediate 6-fluoroquinoline-8-carboxylic acid 12; the target compounds 13a-13af are obtained through a condensation reaction of an intermediate 6-fluoroquinoline-8-carboxylic acid 12, an intermediate 3a-3v, an intermediate 9a-9e and an intermediate 9aa-9ee. The present application provides PDE2 inhibitors for use in AD treatment.

Description

Technical Field

[0001] The present application relates to the technical field of medicinal chemistry, and in particular to a fluoroquinoline carboxamide compound, a preparation method thereof, and an application thereof. Background Art

[0002] Phosphodiesterases (PDEs) regulate cell signaling and synaptic transmission by hydrolyzing the phosphodiester bonds of the second messengers cyclic adenosine monophosphate (cGMP) and / or cyclic guanosine monophosphate (cAMP). PDE inhibitors play an important role in neuroprotection and enhancing neuroplasticity and are important potential targets for anti-AD drugs. PDE2 is highly expressed in the caudate nucleus, nucleus accumbens, cortex, and hippocampus, while its expression levels in most peripheral tissues are relatively low. This tissue distribution makes PDE2 a promising target for AD treatment. Existing PDE2 inhibitors still have problems such as insufficient selectivity and poor drugability. Drug-like PDE2 inhibitors with novel structures, strong inhibitory activity, and high subtype selectivity are urgently needed for the treatment of AD. Summary of the Invention

[0003] In view of this, the present application provides a fluoroquinolinecarboxamide compound, a preparation method and application thereof. Most of the fluoroquinolinecarboxamide compounds have significant PDE2 inhibitory activity, and have good water solubility, blood-brain permeability and metabolic properties. They show good cognitive function improvement and less Aβ protein accumulation in APP / PS1 double transgenic AD model mice, and have certain safety, which can effectively overcome the defects of the above-mentioned existing technologies.

[0004] In a first aspect, an embodiment of the present application provides a fluoroquinolinecarboxamide compound, wherein the compound is a compound of Formula I, a pharmaceutically acceptable salt of the compound of Formula I, an optical isomer of the compound of Formula I, a hydrate of the compound of Formula I, or a solvate of the compound of Formula I, and the structure of Formula I is shown below:

[0005]

[0006] In formula I, R1 is selected from at least one of -Et, -Me, -CH2OMe, -C(Me)2OH, and -CH2OH; R2 is selected from at least one of trifluoromethyl, trifluoromethoxy, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group, an alkoxy group, an alkyl-substituted amino group, a morpholine ring, a piperidine ring, a piperazine ring, and CH2OH; and X1 and X2 are both C or N.

[0007] Preferably, the compound is selected from 6-fluoro-N-(1-(4-(trifluoromethyl)phenyl)propyl)quinoline-8-carboxamide, 6-fluoro-N-(1-(4-(trifluoromethoxy)phenyl)propyl)quinoline-8-carboxamide, 6-fluoro-N-(1-(p-tolyl)propyl)quinoline-8-carboxamide, 6-fluoro-N-(1-(4-methoxyphenyl)propyl)quinoline-8-carboxamide, 6-fluoro-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide, 6-fluoro-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide, 6-fluoro-N-(1-(4-(trifluoromethyl)phenyl)ethyl)quinoline-8-carboxamide, 6-fluoro-N-(1-(3- quinoline-8-carboxamide, 6-fluoro-N-(1-(2-(trifluoromethyl)phenyl)ethyl)quinoline-8-carboxamide, 6-fluoro-N-(1-(3-fluoro-4-(trifluoromethyl)phenyl)ethyl)quinoline-8-carboxamide, N-(1-(4-chlorophenyl)ethyl)-6-fluoroquinoline-8-carboxamide, N-(1-(4-(tert-butyl)phenyl)ethyl)-6-fluoroquinoline-8-carboxamide, N-(1-(4-(dimethylamino)phenyl)ethyl)-6-fluoroquinoline-8-carboxamide, 6-fluoro-N-(1-(4-(hydroxymethyl)phenyl)ethyl)quinoline-8-carboxamide, 6-fluoro-N-(1-(4-morpholinophenyl)ethyl)quinoline-8-carboxamide, 6- fluoro-N-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)quinoline-8-carboxamide, 6-fluoro-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)quinoline-8-carboxamide, 6-fluoro-N-(2-methoxy-1-(4-(trifluoromethyl)phenyl)ethyl)quinoline-8-carboxamide, 6-fluoro-N-(2-methoxy-1-(4-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide, 6-fluoro-N-(2-hydroxy-1-(4-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide, (S)-6-fluoro-N-(2-hydroxy-1-(4-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide, (R)-6-fluoro-N-(2-hydroxy -1-(4-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide, 6-fluoro-N-(2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)quinoline-8-carboxamide, (S)-6-fluoro-N-(2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)quinoline-8-carboxamide, (R)-6-fluoro-N-(2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)quinoline-8-carboxamide, N-(1-(4-chlorophenyl)-2-hydroxy-2-methylpropyl)-6-fluoroquinoline-8-carboxamide, 6-fluoro-N-(2-hydroxy-2-methyl-1-(4-(trifluoromethyl)phenyl)propyl)quinoline-8-carboxamide,(S)-6-Fluoro-N-(2-hydroxy-2-methyl-1-(4-(trifluoromethyl)phenyl)propyl)quinoline-8-carboxamide, (R)-6-Fluoro-N-(2-hydroxy-2-methyl-1-(4-(trifluoromethyl)phenyl)propyl)quinoline-8-carboxamide, 6-Fluoro-N-(2-hydroxy-2-methyl-1-(3-(trifluoromethoxy)phenyl)propyl)quinoline-8-carboxamide, 6-Fluoro-N-(2-hydroxy-2-methyl-1-(2-(trifluoromethoxy)phenyl)propyl)quinoline-8-carboxamide, 6-Fluoro-N-(2-hydroxy-1-(2-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide, 6-Fluoro-N-(2-hydroxy-1-(3-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide Quinoline-8-carboxamide, 6-fluoro-N-(2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)quinoline-8-carboxamide, (S)-6-fluoro-N-(2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)quinoline-8-carboxamide, (R)-6-fluoro-N-(2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)quinoline-8-carboxamide, N-(1-(4-chlorophenyl)-2-hydroxyethyl)-6-fluoroquinoline-8-carboxamide, 6-fluoro-N-(1-(2-(trifluoromethoxy)phenyl)propyl)quinoline-8-carboxamide, 6-fluoro-N-(1-(3-(trifluoromethoxy)phenyl)propyl)quinoline-8-carboxamide, N-(1-(4-chlorophenyl)propyl)-6-fluoroquinoline-8-carboxamide.

[0008] The second aspect of the present invention further provides a method for preparing the above-mentioned fluoroquinolinecarboxamide compound, and the synthesis route is shown in the following formula:

[0009]

[0010] Preferably, the steps include:

[0011] S1. Commercially available aryl ketones 1a-1v were used as starting materials and hydroxylamine hydrochloride as reactant. In the presence of triethylamine and ethanol as solvent, the mixture was refluxed for 6 h and then reduced to obtain intermediates 2a-2v.

[0012] S2 and intermediates 2a to 2v were reacted in an H2 environment with palladium carbon or palladium hydroxide as a catalyst and ethanol as a solvent at room temperature overnight to obtain intermediates 3a to 3v;

[0013] S3, using commercially available substituted acetophenones 4a-4e as raw materials and pyridine as solvent, adding selenium dioxide, reflux reaction for 20 h, and then methylating to obtain intermediates 5a-5e;

[0014] S4. Using intermediates 5a-5e as raw materials, hydroxylamine hydrochloride was added, and ethanol was used as a solvent to reflux for 5 h in the presence of triethylamine to obtain intermediates 6a-6e;

[0015] S5, intermediates 6a-6e are reacted in a H2 environment with palladium carbon or palladium hydroxide as a catalyst and ethanol as a solvent at room temperature overnight to obtain intermediates 7a-7e;

[0016] S6. Using intermediates 7a-7e as raw materials, reacting in the presence of di-tert-butyl dicarbonate and tetrahydrofuran as solvent at room temperature for 48 hours to obtain intermediates Boc-amino acid methyl esters 8a-8e;

[0017] S7. Intermediates 8a-8e are reduced with LiAlH4 and hydrolyzed to give intermediates 9a-9e; or they are hydrolyzed with Grignard reaction to give intermediates 9aa-9ee;

[0018] S8, using 2-amino-5-fluorobenzoic acid 10 as the starting material, the intermediate 6-fluoroquinoline-8-carboxylic acid 11 was obtained by Skraup quinoline synthesis reaction;

[0019] S9. The target compounds 12a to 12af are obtained by condensation reaction of the intermediate 6-fluoroquinoline-8-carboxylic acid 11, the intermediates 3a to 3v, the intermediates 9a to 9e and the intermediates 9aa to 9ee.

[0020] The third aspect of the embodiments of the present application further provides a pharmaceutical composition, which contains the above-mentioned fluoroquinolinecarboxamide compound and optionally a pharmaceutically acceptable additive or excipient.

[0021] The fourth aspect of the present application also provides the use of the above-mentioned fluoroquinolinecarboxamide compounds in the preparation of PDE2 inhibitors.

[0022] The fifth aspect of the present application also provides the use of the above-mentioned fluoroquinolinecarboxamide compounds in the preparation of anti-AD drugs.

[0023] Compared with the prior art, this application has the following beneficial effects:

[0024] The present application provides PDE2 inhibitors with high PDE subtype selectivity, good activity and druggable potential for the treatment of AD. The 6-fluoroquinolinecarboxamide PDE2 inhibitors of the present application mostly have significant PDE2 inhibitory activity and a unique way of binding to the PDE2 protein, with fluorine atoms forming a key hydrogen bond network with the PDE2 protein through water bridges. In addition, most compounds have good water solubility, blood-brain permeability and metabolic properties, and show good cognitive function improvement and Aβ protein accumulation reduction effects in APP / PS1 double transgenic AD model mice, and have certain safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0026] Figure 1 Compound 12a can improve the learning and memory function of APP / PS1 double transgenic AD model mice in a water maze experiment;

[0027] Figure 2 Compound 12a can improve the memory and cognitive function of APP / PS1 model mice in open field test and object recognition test. DETAILED DESCRIPTION

[0028] To make the purpose, technical solutions, and advantages of the embodiments of this application more clear, the technical solutions in the embodiments of this application will be clearly and completely described below in conjunction with the drawings in the embodiments of this application. Obviously, the described embodiments are part of the embodiments of this application, not all of the embodiments. Based on the embodiments in this application, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of this application.

[0029] Unless otherwise specified, the experimental methods used in the examples of this application are all conventional methods.

[0030] In the following examples, unless otherwise specified, all raw materials can be purchased commercially or prepared by conventional methods.

[0031] The term "substituted" in the embodiments of the present application means that one or more hydrogen atoms in a group are independently replaced by a corresponding number of substituent groups.

[0032] In the examples of the present application, the additives or excipients are substances other than the active ingredient that have been reasonably evaluated for safety and are included in the pharmaceutical preparation. Examples include gum arabic, syrup, lanolin, starch, magnesium chloride, cyclodextrin, sebacic acid, dextrin, pharmaceutical calcium sulfate, glycerol, mannitol, sorbitol, inositol, thiols, tromethamine, phenol, m-cresol, benzyl alcohol, parahydroxybenzoates, methylparahydroxybenzoate, tert-butyl alcohol, benzalkonium chloride, chlorobutanol, thimerosal, and the like.

[0033] The derivatives of the compounds of general formula I in the examples of the present application are used as prodrugs, which means that they themselves may have weak activity or even no activity, but after administration, they are converted into corresponding biologically active forms under physiological conditions (for example, by metabolism, solvent decomposition or other means).

[0034] The chemical structures of the examples in this application are 1 H-NMR, 13 The results were confirmed by C-NMR and mass spectrometry. Flash column chromatography was performed on silica gel H (10-40 μM).

[0035] Example 1

[0036] Preparation of 6-fluoro-N-(1-(4-(trifluoromethyl)phenyl)propyl)quinoline-8-carboxamide (12a):

[0037] A mixture of aryl carboxaldehyde (1.0 mmol), hydroxylamine hydrochloride (2.1 mmol) and triethylamine (2.9 mmol) in ethanol (60 mL) was heated at reflux for 6 hours. The residue was purified by flash chromatography to give intermediate 2a. A mixture of 2a (1.0 mmol) and Pd / C (10% wt.) or Pd(OH)2 (20% wt.) in ethanol (15 mL) was hydrogenated under balloon pressure for 24 hours. The mixture was filtered and concentrated in vacuo to give intermediate 3a. To a reaction flask containing 2-amino-5-fluorobenzoic acid (1 mmol) were added 98% concentrated sulfuric acid and a catalytic amount of I2 (5% mol), followed by the slow addition of glycerol (1.2 mmol). The mixture was rapidly stirred and heated to 140°C for 12 h. After the reaction, it was cooled to room temperature, and DCM (5 mL / mmol) and water (5 mL / mmol) were added. The insoluble matter was filtered through celite, and the pH of the filtrate was adjusted to 3-4. Extraction was performed twice. The organic layers were combined, dried over anhydrous magnesium sulfate for 1 h, and concentrated on a rotary evaporator to obtain intermediate 12. HATU (0.1 mmol) and DIPEA (0.2 mmol) were added to a solution of 12 (0.1 mmol) in DMF (5 mL), and the mixture was stirred at room temperature for 1 h. Intermediate 3a (0.1 mmol) was added to the mixture, and stirring was continued for 6 h. The mixture was extracted with EA and concentrated on a rotary evaporator to obtain compound 12a as a white solid in a 75% yield.

[0038] 1 H NMR(400MHz,Chloroform-d)δ11.86(d,J=7.6Hz,1H),8.95(dd,J=4.3,1.9Hz,1H),8.60(dd,J=9.7,3.1Hz,1H),8.26 (dd,J=8.3,1.9Hz,1H),7.62-7.51(m,6H),5.27(q,J=7.2Hz,1H),2.03(pd,J=7.0,2.4Hz,2H),1.05(t,J=7.4Hz,3H). 13C NMR(101MHz,Chloroform-d)δ164.12,160.22(d,J=249.6Hz),148.81(d,J=2.7H z),147.31,142.94,137.43(d,J=5.4Hz),131.77(d,J=7.7Hz),129.87(d,J=9.2H z),129.29(d,J=32.3Hz),127.07,125.60(d,J=3.9Hz),124.10(d,J=27.7Hz),12 2.99,121.85,114.83(d,J=21.7Hz),55.60,29.82,10.70.MS(ESI)m / z:377[M+H] + .HR(ESI)m / z calcd forC 20 H 17 F4N2O[M+H] + :377.1272,found 377.1097.

[0039] Example 2

[0040] Preparation of 6-fluoro-N-(1-(4-(trifluoromethoxy)phenyl)propyl)quinoline-8-carboxamide (12b): Referring to the synthesis method in Example 1, a yellow oil 12b was obtained with a yield of 62%.

[0041] 1 H NMR (400MHz, Chloroform-d) δ11.81(d,J=7.3Hz,1H),8.93(dd,J=4.2,1.6Hz,1H),8.60(dd,J=9.8,3.0Hz,1H),8.25(dd,J=8.4,1.7Hz,1H),7. 55(ddd,J=12.7,8.0,3.6Hz,2H),7.45(d,J=8.6Hz,2H),7.18(d,J=8.1Hz,2H),5.24(q,J=7.2Hz,1H),2.09-1.93(m,2H),1.04(t,J=7.4Hz,3H). 13C NMR(101MHz,Chloroform-d)δ164.04,160.25(d,J=249.5Hz),148.76,148.19,142.96,141.94,137.39,131.88(d,J=7.9Hz),129.87(d,J =8.9Hz),128.10,124.13(d,J=27.7Hz),121.82,121.13,120.50(d,J=256.6Hz),114.77(d,J=21.7Hz),55.20,30.13,10.76.HR(ESI)m / z calcd for C 20 H 15 F4N2O2[MH] - :391.1075,found 391.1083.

[0042] Example 3

[0043] Preparation of 6-fluoro-N-(1-(p-tolyl)propyl)quinoline-8-carboxamide (12c): Referring to the synthesis method in Example 1, a yellow oil 12c was obtained with a yield of 60%.

[0044] 1 H NMR (400MHz, Chloroform-d) δ11.74(d,J=7.9Hz,1H),8.92(dd,J=4.2,1.8Hz,1H),8.62(dd,J=9.8,3.1Hz,1H),8.23(dd,J=8.4,1.8Hz,1H),7.53(ddd ,J=12.6,8.0,3.6Hz,2H),7.33(d,J=8.1Hz,2H),7.15(d,J=7.9Hz,2H),5. 20(q,J=7.2Hz,1H),2.32(s,3H),2.10-1.91(m,2H),1.01(t,J=7.4Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ163.76,160.28(d,J=247.5Hz),148.69(d,J=1.8Hz),143.01,140.06,137.29(d,J=5.6Hz),136.63,132.2 2(d,J=8.5Hz),129.81(d,J=9.3Hz),129.33,126.72,124.09(d,J=27.7Hz),121.72,114.54(d,J=21.7Hz),55.58,30.19,21.22,10.84.

[0045] Example 4

[0046] Preparation of 6-fluoro-N-(1-(4-methoxyphenyl)propyl)quinoline-8-carboxamide (12d): Referring to the synthesis method in Example 1, a yellow oil 12d was obtained with a yield of 65%.

[0047] 1 H NMR (400MHz, Chloroform-d) δ11.72(d,J=7.5Hz,1H),8.91(dd,J=4.2,1.7Hz,1H),8.61(dd,J=9.8,3.0Hz,1H),8.22(dd,J=8.4,1.7Hz,1H),7.52(ddd ,J=12.6,8.0,3.6Hz,2H),7.36(d,J=8.6Hz,2H),6.88(d,J=8.7Hz,2H),5. 19(q,J=7.2Hz,1H),3.78(s,3H),2.10-1.90(m,2H),1.01(t,J=7.4Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ163.71,160.24(d,J=249.3Hz),158.65,148.67,142.97,137.25,135.21,132.19(d,J=8.0Hz),129 .79(d,J=9.4Hz),127.88,124.02(d,J=27.7Hz),121.71,114.53(d,J=21.8Hz),114.02,55.38,55.23,30.14,10.83.HR(ESI)m / z calcd for C 20 H 18 FN2O[MH] - :337.1358,found 337.1366.

[0048] Example 5

[0049] Preparation of 6-fluoro-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide (12e): Referring to the synthesis method in Example 1, a yellow oil 12e was obtained with a yield of 61%.

[0050] 1H NMR (400MHz, Chloroform-d) δ11.77(d,J=6.8Hz,1H),8.89(dd,J=4.2,1.7Hz,1H),8.61(dd,J=9.8,3.0Hz,1H),8.24(dd,J=8.4,1.7Hz,1H),7.57(dd,J=7.6,3. 0Hz, 1H), 7.52 (dd, J=8.4, 4.3Hz, 1H), 7.39 (dd, J=11.4, 7.7Hz, 2H), 7.34 (d, J= 5.0Hz, 1H), 7.11 (d, J = 7.6Hz, 1H), 5.45 (p, J = 7.0Hz, 1H), 1.68 (d, J = 6.9Hz, 3H). 13 C NMR(101MHz,Chloroform-d)δ163.80,160.20(d,J=249.6Hz),149.68,148.78,146.76,142.89,137.37,131.73(d,J=7.9Hz),130.09,129.84( d,J=9.0Hz),124.86,124.06(d,J=27.7Hz),121.85,120.50(d,J=257.2Hz),119.48,118.76,114.83(d,J=21.7Hz),49.39,22.99.HR(ESI)m / z calcd for C 19 H 13 F4N2O2[MH] - :377.0919,found 377.0991.

[0051] Example 6

[0052] Preparation of 6-fluoro-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide (12f): Referring to the synthesis method in Example 1, a white solid 12f was obtained with a yield of 86%.

[0053] 1 H NMR(400MHz,Chloroform-d)δ11.73(d,J=7.5Hz,1H),8.91(dd,J=4.3,1.9Hz,1H),8.62(dd,J=9.8,3.1Hz,1H),8.25(dd,J=8.4, 1.8Hz,1H),7.57(dd,J=7.6,3.1Hz,1H),7.55-7.44(m,4H),7.19(d,J=8.2Hz,2H),5.44(p,J=7.1Hz,1H),1.68(d,J=6.9Hz,3H).13 C NMR (101MHz, Chloroform-d) δ 163.78, 160.29 (d, J = 268.1Hz), 148.81, 148.24, 143.15, 142.95, 137.36, 131.80, 129. 85,127.74,127.68,124.09(d,J=21.2Hz),121.84,121.29,121.23,114.85(d,J=21.7Hz),49.21,23.01.HR(ESI)m / z calcd forC 19 H 13 F4N2O2[MH] - :377.0919,found 377.0926.

[0054] Example 7

[0055] Preparation of 6-fluoro-N-(1-(4-(trifluoromethyl)phenyl)ethyl)quinoline-8-carboxamide (12 g): Referring to the synthesis method in Example 1, 12 g of a white solid was obtained. Yield: 63%.

[0056] 1 H NMR (400MHz, Chloroform-d) δ11.79(d,J=7.3Hz,1H),8.92(dd,J=4.3,1.9Hz,1H),8.61(dd,J=9.8,3. 1Hz,1H),8.25(dd,J=8.4,1.9Hz,1H),7.84-7.38(m,6H),5.47(p,J=7.1Hz,1H),1.70(d,J=6.9Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ163.86(d,J=2.0Hz),160.18(d,J=249.6Hz),148 .81(d,J=2.7Hz),148.45,142.89,137.37(d,J=5.4Hz),131.67(d,J=7.9Hz),12 9.85(d,J=9.3Hz),129.35(d,J=32.4Hz),126.60,125.72(q,J=3.7Hz),124.07( d,J=27.7Hz),122.97,121.84,114.86(d,J=21.6Hz),49.57,22.89.HR(ESI)m / z calcd for C 19 H 13 F4N2O[MH] -:361.0969,found 361.0972.

[0057] Example 8

[0058] Preparation of 6-fluoro-N-(1-(3-(trifluoromethyl)phenyl)ethyl)quinoline-8-carboxamide (12h): Referring to the synthesis method in Example 1, a white solid 12h was obtained with a yield of 68%.

[0059] 1 H NMR(400MHz,Chloroform-d)δ11.82(d,J=7.4Hz,1H),8.89(dd,J=4.4,2.0Hz,1H),8.57(dd,J=9.8,3.1Hz,1H),8.20(dd ,J=8.4,1.9Hz,1H),7.75(s,1H),7.66(d,J=7.5Hz,1H),7.57-7.41(m,4H),5.48(p,J=7.1Hz,1H),1.70(d,J=7.1Hz,3H). 13 CNMR(101MHz,Chloroform-d)δ163.79(d,J=2.0Hz),160.08(d,J=249.2Hz),148.76(d, J=2.6Hz),145.37,142.78,137.29(d,J=5.5Hz),131.61(d,J=7.8Hz),130.96(q,J=32.1 Hz),129.87(d,J=1.5Hz),129.18,124.24(q,J=272.5Hz),124.01,123.95(t,J=3.8Hz) ,123.74,122.85(q,J=3.9Hz),121.83,114.80(d,J=21.5Hz),49.53,23.01.HR(ESI)m / z calcd for C 19 H 13 F4N2O[MH] - :361.0969,found 361.0978.

[0060] Example 9

[0061] Preparation of 6-fluoro-N-(1-(2-(trifluoromethyl)phenyl)ethyl)quinoline-8-carboxamide (12i): Referring to the synthesis method in Example 1, a white oil 12i was obtained with a yield of 61%.

[0062] 1H NMR (400MHz, Chloroform-d) δ11.88(d,J=5.2Hz,1H),8.95(d,J=2.7Hz,1H),8.59(dd,J=9.8,3.0Hz,1H),8.25(d,J=8.4Hz,1H),7.72(d,J=7.9Hz, 1H),7.67(d,J=7.9Hz,1H),7.56(dd,J=7.7,3.1Hz,2H),7.52(d,J=8.6Hz ,1H),7.34(t,J=7.6Hz,1H),5.72(p,J=6.6Hz,1H),1.68(d,J=6.8Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ163.53,160.26(d,J=249.5Hz),148.73,144.2 3,142.95,137.40(d,J=5.3Hz),132.43,131.82(d,J=7.6Hz),129.86(d,J=9. 1Hz),127.54(d,J=30.4Hz),127.09,126.15(d,J=5.9Hz),125.96,124.13(d, J=27.9Hz),123.24,121.80,114.76(d,J=21.7Hz),46.77,23.96.HR(ESI)m / z calcd for C 19 H 13 F4N2O[MH] - :361.0969,found 361.0958.

[0063] Example 10

[0064] Preparation of 6-fluoro-N-(1-(3-fluoro-4-(trifluoromethyl)phenyl)ethyl)quinoline-8-carboxamide (12j): Referring to the synthesis method in Example 1, a white solid 12j was obtained with a yield of 64%.

[0065] 1 H NMR(400MHz,Chloroform-d)δ11.80(d,J=7.2Hz,1H),8.93(dd,J=4.3,2.0Hz,1H),8.59(dd,J=9.7,3.1Hz,1H),8.27( dd,J=8.4,2.0Hz,1H),7.64-7.50(m,3H),7.31(dd,J=17.5,9.9Hz,2H),5.42(q,J=7.1Hz,1H),1.69(d,J=7.0Hz,3H). 13C NMR (101MHz, Chloroform-d) δ 164.03 (d, J = 2.0Hz), 161.40 (d, J = 2.5Hz), 158.90 (d, J = 7.1Hz), 151. 79(d,J=7.1Hz),148.89(d,J=2.7Hz),142.87,137.45(d,J=5.4Hz),131.43(d,J=7.9Hz),129.89(d ,J=9.4Hz),127.70-127.37(m),124.11(d,J=27.7Hz),122.77(q,J=272.1Hz),121.93(d,J=2.6Hz) ,117.27-116.64(m),115.03(d,J=21.5Hz),114.57(d,J=21.1Hz),49.34,22.70.HR(ESI)m / zcalcd for C 19 H 12 F5N2O[MH] - :379.0875,found379.0888.

[0066] Example 11

[0067] Preparation of N-(1-(4-chlorophenyl)ethyl)-6-fluoroquinoline-8-carboxamide (12k): Referring to the synthesis method in Example 1, a white solid 12k was obtained with a yield of 60%.

[0068] 1 H NMR(400MHz,Chloroform-d)δ11.71(d,J=7.4Hz,1H),8.90(dd,J=4.3,1.9Hz,1H),8.61(dd,J=9.8,3.1Hz,1H),8.24(dd,J=8.4,1.8Hz,1H), 7.57(dd,J=7.6,3.1Hz,1H),7.52(dd,J=8.4,4.2Hz,1H),7.44-7.37(m,2H),7.35-7.28(m,2H),5.40(p,J=7.1Hz,1H),1.66(d,J=7.0Hz,3H). 13C NMR(101MHz,Chloroform-d)δ163.66,160.13(d,J=249.6Hz),148.72,142.84,137.31,137.26,132.76,131.76(d,J=7.8H z),129.77(d,J=9.4Hz),128.80,127.69,123.96(d,J=27.8Hz),121.77,114.73(d,J=21.6Hz),49.20,22.84.HR(ESI)m / z calcd for C 18 H 13 ClFN2O[MH] - :327.0706,found 327.0716.

[0069] Example 12

[0070] Preparation of N-(1-(4-(tert-butyl)phenyl)ethyl)-6-fluoroquinoline-8-carboxamide (121): Referring to the synthesis method in Example 1, a white oil 121 was obtained with a yield of 64%.

[0071] 1 H NMR(400MHz,Chloroform-d)δ11.70(d,J=7.5Hz,1H),8.90(dd,J=4.3,1.9Hz,1H),8.64(dd,J=9.8,3.1Hz,1H),8.23(dd,J=8.3,1.8Hz,1H) ,7.55(dd,J=7.6,3.1Hz,1H),7.50(dd,J=8.4,4.2Hz,1H),7.40(q,J=8.2Hz,3H),5.45(p,J=7.1Hz,1H),1.68(d,J=6.9Hz,3H),1.31(s,9H). 13 C NMR(101MHz,Chloroform-d)δ163.50,160.13(d,J=249.2Hz),149.89,148.68,142.85,141.08,137.17(d,J=5.5Hz),132.05(d,J=8.0H z),129.70(d,J=9.3Hz),125.94,125.61,123.89(d,J=27.9Hz),121.68,114.53(d,J=21.8Hz),49.29,34.53,31.45,22.97.HR(ESI)m / z calcd for C 22 H 22 FN2O[MH] -:349.1722,found 349.1709.

[0072] Example 13

[0073] Preparation of N-(1-(4-(dimethylamino)phenyl)ethyl)-6-fluoroquinoline-8-carboxamide (12m): Referring to the synthesis method in Example 1, a yellow oil 12m was obtained with a yield of 52%.

[0074] 1 H NMR (400MHz, Chloroform-d) δ11.60(s,1H),8.86(s,1H),8.63(d,J=9.8Hz,1H),8.20(d,J=8.3Hz,1H),7.53(d,J=7.6Hz,1 H),7.50–7.45(m,1H),7.37(d,J=8.6Hz,2H),6.75(d,J=8.6Hz,2H),5.40–5.29(m,1H),2.93(s,6H),1.66(d,J=6.8Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ 163.44, 160.26 (d, J = 249.3Hz), 150.92, 148.70, 142.98, 137.21, 137.15, 132.29 (d, J = 6. 4Hz), 129.76 (d, J = 9.5Hz), 127.20, 123.99 (d, J = 27.6Hz), 121.66, 114.49 (d, J = 21.3Hz), 113.16, 49.13, 41.01, 22.80.

[0075] Example 14

[0076] Preparation of 6-fluoro-N-(1-(4-(hydroxymethyl)phenyl)ethyl)quinoline-8-carboxamide (12n): Referring to the synthesis method in Example 1, a yellow solid 12n was obtained with a yield of 51%.

[0077] 1H NMR (400MHz, Chloroform-d) δ11.72(s,1H),8.88(dd,J=4.4,1.8Hz,1H),8.60(dd,J=9.8,3.0Hz,1H),8.22(dd,J=8.4,1.6Hz,1H),7.54(dd,J=7.7 ,3.1Hz,1H),7.49(dd,J=8.4,4.3Hz,1H),7.46(d,J=8.1Hz,2H),7.35(d,J=8.1Hz,2H),5.41(p,J=7.0Hz,1H),4.66(s,2H),1.66(d,J=6.9Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ163.66,160.19(d,J=249.4Hz),148.71,143.67,142.88,139.88,137.28(d,J=5.6Hz),131.90(d,J=7 .5Hz),129.78(d,J=9.3Hz),127.47,126.49,124.01(d,J=27.6Hz),121.75,114.67(d,J=21.4Hz),65.18,49.59,23.00.HR(ESI)m / z calcd for C 19 H 16 FN2O2[MH] - :323.1201,found 323.1274.

[0078] Example 15

[0079] Preparation of 6-fluoro-N-(1-(4-morpholinophenyl)ethyl)quinoline-8-carboxamide (12o): Referring to the synthesis method in Example 1, a yellow solid 12o was obtained with a yield of 68%.

[0080] 1H NMR(400MHz,Chloroform-d)δ11.64(d,J=7.4Hz,1H),8.87(dd,J=4.2,1.6Hz,1H) ,8.62(dd,J=9.8,3.0Hz,1H),8.21(dd,J=8.4,1.7Hz,1H),7.54(dd,J=7.7,3.0Hz ,1H),7.49(dd,J=8.4,4.3Hz,1H),7.40(d,J=8.6Hz,2H),6.92(d,J=8.6Hz,2H),5 .39(p,J=7.0Hz,1H),3.89–3.81(m,4H),3.18–3.09(m,4H),1.66(d,J=6.9Hz,3H). 13 CNMR(101MHz,Chloroform-d)δ163.50,160.22(d,J=249.3Hz),148.67,147.99,142.93,137.25,137.20,132.14(d,J=8.0Hz),129.7 7(d,J=9.7Hz),127.22,123.99(d,J=27.8Hz),121.70,116.07,114.56(d,J=21.5Hz),67.00,49.66,49.09,22.79.HR(ESI)m / zcalcd for C 22 H 21 FN3O2[MH] - :378.1623,found 378.1696.

[0081] Example 16

[0082] Preparation of 6-fluoro-N-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)quinoline-8-carboxamide (12p): Referring to the synthesis method in Example 1, a yellow solid 12p was obtained with a yield of 74%.

[0083] 1H NMR(400MHz,Chloroform-d)δ11.86(s,1H),8.92(dd,J=4.2,1.5Hz,1H),8.84(d,J=1.5Hz,1H),8.55(dd,J=9.7,3.0Hz,1H),8.25(dd,J=8.4,1.6Hz,1H), 7.94(dd,J=8.1,2.0Hz,1H),7.64(d,J=8.1Hz,1H),7.58(dd,J=7.6,3.0Hz,1 H),7.53(dd,J=8.4,4.3Hz,1H),5.49(p,J=7.0Hz,1H),1.73(d,J=7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ164.12,160.10(d,J=249.8Hz),148.90(d,J=2.8 Hz), 148.49, 146.92 (q, J = 34.8Hz), 143.09, 142.78, 137.46 (d, J = 5.3Hz), 135. 29,131.24(d,J=7.9Hz),129.86(d,J=9.4Hz),124.03(d,J=27.7Hz),121.93,1 20.44,121.69(q,J=273.9Hz),115.11(d,J=21.7Hz),47.63,22.54.HR(ESI)m / z calcd for C 18 H 12 F4N3O[MH] - :362.0922,found362.0932.

[0084] Example 17

[0085] Preparation of 6-fluoro-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)quinoline-8-carboxamide (12q): Referring to the synthesis method in Example 1, a yellow solid 12q was obtained with a yield of 70%.

[0086] 1H NMR(400MHz,Chloroform-d)δ12.01(s,1H),8.98(dd,J=4.2,1.7Hz,1H),8.89(s,1H),8.60(dd,J=9.8,3.0Hz,1H),8.24(dd,J=8.4,1.7Hz,1H ),7.89(dd,J=8.2,2.1Hz,1H),7.58(d,J=3.0Hz,1H),7.55(d,J=7.0Hz,1H),7.54–7.51(m,1H),5.55(p,J=7.0Hz,1H),1.74(d,J=7.0Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ166.35,164.07,160.18(d,J=249.6Hz),148.95,146.57,142.98,137.24(d,J=5.7Hz),134.09(q,J=3.6Hz),131.74(d, J=8.0Hz),129.81(d,J=9.4Hz),125.10(d,J=3.5Hz),124.01(d,J=27.9Hz) ,122.38,121.87,121.14,114.89(d,J=21.6Hz),51.41,21.77.HR(ESI)m / z calcdfor C 18 H 12 F4N3O[MH] - :362.0922,found 362.0935.

[0087] Example 18

[0088] Preparation of 6-fluoro-N-(2-methoxy-1-(4-(trifluoromethyl)phenyl)ethyl)quinoline-8-carboxamide (12r): Referring to the synthesis method in Example 1, a white solid 12r was obtained with a yield of 85%.

[0089] 1 H NMR(400MHz,Chloroform-d)δ12.11(d,J=7.9Hz,1H),8.96(d,J=4.2Hz,1H),8.64–8.54(m,1 H),8.30–8.18(m,1H),7.69–7.40(m,7H),5.93–4.97(m,6H),3.91–3.80(m,3H),3.46(s,1H). 13C NMR (101MHz, Chloroform-d) δ164.28, 160.16 (d, J = 249.6Hz), 148.88 (d, J = 2. 5Hz),144.67,142.93,137.31(d,J=5.5Hz),131.70(d,J=7.6Hz),129.81(d,J =9.8Hz), 129.44, 127.48 (d, J = 2.8Hz), 125.57 (d, J = 3.7Hz), 124.02 (d, J = 27. 8Hz),122.95,121.88,114.92(d,J=21.5Hz),75.53,59.43,53.75.HR(ESI)m / z calcd forC 20 H 15 F4N2O2[MH] - :391.1075,found 391.1159.

[0090] Example 19

[0091] Preparation of 6-fluoro-N-(2-methoxy-1-(4-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide (12s): Referring to the synthesis method in Example 1, a white solid 12s was obtained with a yield of 67%.

[0092] 1 H NMR(400MHz,Chloroform-d)δ12.05(d,J=7.5Hz,1H),8.95(dd,J=4.3,1.9Hz,1H),8.60(dd,J=9.7,3.1Hz,1H),8.25(dd,J=8.4,1.9Hz,1H), 7.58(dd,J=7.6,3.0Hz,1H),7.55–7.48(m,3H),7.19(d,J=8.2Hz,2H),5.51(dt,J=7.8,4.9Hz,1H),3.83(qd,J=9.8,4.9Hz,2H),3.46(s,3H). 13C NMR(101MHz,Chloroform-d)δ164.19(d,J=2.0Hz),160.16(d,J=249.5Hz),148.85(d,J=2.7Hz),148.46,142.93,139.31,137.30(dd,J=5.5,2.8Hz),131 .78(d,J=8.0Hz),129.80(d,J=9.3Hz),128.54,125.57(q,J=4.1Hz),124.01 (d, J = 27.7Hz), 121.84, 121.09, 114.85 (d, J = 21.6Hz), 75.66, 59.40, 53.30.

[0093] Example 20

[0094] Preparation of 6-fluoro-N-(2-hydroxy-1-(4-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide (12t): At room temperature, 4-(trifluoromethoxy)acetophenone (1mmol), SeO2 (1mmol), and pyridine (5mL / mmol) were mixed and heated to 110°C for 20h. After the reaction, the reaction solution was filtered through celite, the filter cake was washed with DCM, and the filtrate was concentrated on a rotary evaporator. The crude product was dissolved in DMF (5mL / mmol), K2CO3 (2mmol) and CH3I (1.5mmol) were added at 0°C, and the system was transferred to room temperature and reacted for 2h. After the reaction was completed, the reaction solution was quenched by adding 1N HCl solution, extracted with EA, and then washed with saturated NaHCO3, 10% Na2S20 3、The product was washed with saturated NaCl solution, dried over MgSO₄, and purified by column chromatography to obtain intermediate 5a. At room temperature, intermediate 5a (1 mmol) was dissolved in EtOH (5 mL / mmol), hydroxylamine hydrochloride (2 mmol) and TEA (3 mmol) were added, and the mixture was heated to 80°C for 5 h. After completion of the reaction, the mixture was concentrated on a rotary evaporator to obtain intermediate 6a. At room temperature, intermediate 6a was dissolved in EtOH (5 mL / mmol), Pd / C (10%) was added, and the mixture was heated to 80°C under a hydrogen atmosphere and allowed to react overnight. The mixture was filtered through celite, the filtrate was concentrated on a rotary evaporator, and purified by column chromatography to obtain intermediate 7a. At room temperature, intermediate 7a (1 mmol) was dissolved in THF (5 mL / mmol), a solution of Boc₂O (2 mmol) in THF was added, and the mixture was stirred at room temperature for 48 h. After completion of the reaction, the reaction solution was concentrated to obtain intermediate 8a, which was used directly in the next step without purification. A THF solution of intermediate 8a was added to a THF solution of LiAlH4 (4.0 mmol) at 0°C. The mixture was stirred at 0°C for 30 minutes. Anhydrous MgO4, a small amount of water, and EA were added sequentially. The mixture was filtered through celite, and the filtrate was concentrated. The mixture was then dissolved in HCl·dioxane and stirred at room temperature for 5 hours. After the reaction, the solvent was concentrated on a rotary evaporator, a small amount of water was added, and the mixture was extracted with EA and purified by column chromatography to obtain intermediate 9a. Intermediate 12 was obtained by the synthesis method described in Example 1. HATU (0.1 mmol) and DIPEA (0.2 mmol) were added to a solution of intermediate 12 (0.1 mmol) in DMF (5 mL), and the mixture was stirred at room temperature for 1 hour. Intermediate 9a (0.1 mmol) was added to the mixture, and stirring was continued for 6 hours. The mixture was extracted with EA and concentrated on a rotary evaporator to obtain 12t as a white solid in a 65% yield.

[0095] 1 H NMR(400MHz,Chloroform-d)δ12.10(d,J=7.0Hz,1H),8.90(dd,J=4.2,1.7Hz,1H),8.55(dd,J=9.7,3.0Hz,1H),8.23(dd,J=8.4,1.7Hz,1H) ,7.55(dd,J=7.6,3.0Hz,1H),7.52(t,J=4.2Hz,2H),7.50(s,1H),7.21(d,J=8.0Hz,2H),5.48–5.37(m,1H),4.09–3.99(m,2H),3.09(s,1H). 13C NMR(101MHz,Chloroform-d)δ164.95,159.99(d,J=249.9Hz),148.84,148.59,142.65,138.32,137.32,131.24(d,J=7.5Hz),129.67( d,J=9.0Hz),128.40,123.95(d,J=27.7Hz),121.81,121.26,120.45(q,J=257.2Hz),114.93(d,J=21.7Hz),67.01,56.29.HR(ESI)m / z calcd for C 19 H 13 F4N2O3[MH] - :393.0868,found393.0857.

[0096] Example 21

[0097] Preparation of compound (S)-12t: Referring to the synthesis method in Example 20, a white solid (S)-12t was obtained with a yield of 66%.

[0098] 1 H NMR(400MHz,Chloroform-d)δ12.10(d,J=7.0Hz,1H),8.90(dd,J=4.2,1.7Hz,1H),8.55(dd,J=9.7,3.0Hz,1H),8.23(dd,J=8.4,1.7Hz,1H) ,7.55(dd,J=7.6,3.0Hz,1H),7.52(t,J=4.2Hz,2H),7.50(s,1H),7.21(d,J=8.0Hz,2H),5.48–5.37(m,1H),4.09–3.99(m,2H),3.09(s,1H). 13 C NMR(101MHz,Chloroform-d)δ164.95,159.99(d,J=249.9Hz),148.84,148.59,142.65,138.32,137.32,131.24(d,J=7.5Hz),12 9.67 (d, J = 9.0Hz), 128.40, 123.95 (d, J = 27.7Hz), 121.81, 121.26, 120.45 (q, J = 257.2Hz), 114.93 (d, J = 21.7Hz), 67.01, 56.29.

[0099] Example 22

[0100] Preparation of compound (R)-12t: Referring to the synthesis method in Example 20, a white solid (R)-12t was obtained with a yield of 62%.

[0101] 1 H NMR(400MHz,Chloroform-d)δ12.10(d,J=7.0Hz,1H),8.90(dd,J=4.2,1.7Hz,1H),8.55(dd,J=9.7,3.0Hz,1H),8.23(dd,J=8.4,1.7Hz,1H) ,7.55(dd,J=7.6,3.0Hz,1H),7.52(t,J=4.2Hz,2H),7.50(s,1H),7.21(d,J=8.0Hz,2H),5.48–5.37(m,1H),4.09–3.99(m,2H),3.09(s,1H). 13 C NMR(101MHz,Chloroform-d)δ164.95,159.99(d,J=249.9Hz),148.84,148.59,142.65,138.32,137.32,131.24(d,J=7.5Hz),12 9.67 (d, J = 9.0Hz), 128.40, 123.95 (d, J = 27.7Hz), 121.81, 121.26, 120.45 (q, J = 257.2Hz), 114.93 (d, J = 21.7Hz), 67.01, 56.29.

[0102] Example 23

[0103] Preparation of 6-fluoro-N-(2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)quinoline-8-carboxamide (12u): Refer to the synthesis method in Example 20 to obtain Intermediate 8a. To a solution of Intermediate 8a (1 mmol) in THF was added dropwise a solution of MeMgBr (4 mmol) in THF at 0°C. The mixture was warmed to room temperature and stirred for 2 hours. It was then quenched by addition of saturated aqueous NH4Cl solution, filtered through celite, and the filtrate was extracted with EA. The organic layer was concentrated under reduced pressure and then dissolved in HCl·dioxane. The reaction was stirred at room temperature for 5 hours. After completion of the reaction, the solvent was concentrated on a rotary evaporator to obtain Intermediate 9aa. Refer to the synthesis method in Example 1 to obtain Intermediate 12. To a solution of Intermediate 12 (0.1 mmol) in DMF (5 mL) were added HATU (0.1 mmol) and DIPEA (0.2 mmol), and the mixture was stirred at room temperature for 1 hour. Intermediate 9aa (0.1 mmol) was added to the mixture, and stirring was continued for 6 hours. The mixture was extracted with EA and concentrated on a rotary evaporator to obtain a white solid 12u. Yield: 69%.

[0104] 1 H NMR(400MHz,Chloroform-d)δ12.32(d,J=8.2Hz,1H),9.00(dd,J=4.2,1.6Hz,1H),8.57(dd,J=9.7,3.0Hz,1H),8.26(dd,J=8.4,1.6 Hz,1H),7.57(td,J=7.7,3.7Hz,2H),7.52(d,J=8.6Hz,2H),7.18(d,J=8.1Hz,2H),5.24(d,J=8.4Hz,1H),1.42(s,3H),1.24(s,3H). 13 CNMR(101MHz,Chloroform-d)δ148.82,148.52,142.84,138.48,137.28,131.61,129.84, 124.14,123.87,121.77,120.66,114.86,114.64,72.87,62.36,27.69,27.41.HR(ESI)m / z calcd for C 21 H 22 N2O3[MH] - :421.1181,found 421.1212.

[0105] Example 24

[0106] Preparation of N-(1-(4-chlorophenyl)-2-hydroxy-2-methylpropyl)-6-fluoroquinoline-8-carboxamide (12v): Referring to the synthesis method in Example 23, a white solid 12v was obtained with a yield of 68%.

[0107] 1 H NMR(400MHz,Chloroform-d)δ12.28(d,J=8.2Hz,1H),9.10(dd,J=4.2,1.6Hz,1H),8.41(dd,J=9.7,3.0Hz,1H),8.32(d d,J=8.4,1.6Hz,1H),7.50(td,J=7.7,3.7Hz,2H),7.31–7.25(m,4H),5.24(d,J=8.4Hz,1H),1.42(s,3H),1.24(s,3H). 13C NMR(101MHz,Chloroform-d)δ149.02,148.33,142.24,138.31,133.71,130.84,127 .54,124.34,123.17,121.37,120.56,114.46,114.63,72.87,62.36,27.69,27.41.

[0108] Example 25

[0109] Preparation of 6-fluoro-N-(2-hydroxy-2-methyl-1-(4-(trifluoromethyl)phenyl)propyl)quinoline-8-carboxamide (12w): Referring to the synthesis method in Example 23, a white solid 12w was obtained with a yield of 56%.

[0110] 1 H NMR(400MHz,Chloroform-d)δ12.32(d,J=8.2Hz,1H),9.00(dd,J=4.2,1.6Hz,1H),8.57(dd,J=9.7,3.0Hz,1H),8.26(dd,J=8.4,1.6 Hz,1H),7.57(td,J=7.7,3.7Hz,2H),7.52(d,J=8.6Hz,2H),7.18(d,J=8.1Hz,2H),5.24(d,J=8.4Hz,1H),1.42(s,3H),1.24(s,3H). 13 CNMR(101MHz,Chloroform-d)δ148.97,148.29,138.85,136.82,132.15,130.52,13 0.62,123.25,124.80,121.60,121.94,114.47,115.15,72.24,63.11,26.82,28.37.

[0111] Example 26

[0112] Preparation of 6-fluoro-N-(2-hydroxy-2-methyl-1-(3-(trifluoromethoxy)phenyl)propyl)quinoline-8-carboxamide (12x): Referring to the synthesis method in Example 23, a white solid 12x was obtained with a yield of 60%.

[0113] 1H NMR (400MHz, Chloroform-d) δ11.32(d,J=6.8Hz,1H),8.87(dd,J=4.0,1.6Hz,1H),8.24(dt,J=7.9,2.0Hz,1H),7.82(dt,J=8.1,2.3Hz,1H),7.76(d d,J=8.1,2.2Hz,1H),7.61(dd,J=7.9,4.0Hz,1H),7.35(t,J=7.1Hz,1H), 7.16–7.08(m,3H),4.97(dt,J=9.2,0.9Hz,1H),1.37(s,3H),1.32(s,3H).

[0114] Example 27

[0115] Preparation of 6-fluoro-N-(2-hydroxy-2-methyl-1-(2-(trifluoromethoxy)phenyl)propyl)quinoline-8-carboxamide (12y): Referring to the synthesis method in Example 23, a white solid 12y was obtained with a yield of 70%.

[0116] 1 H NMR(400MHz,Chloroform-d)δ11.32(d,J=6.8Hz,1H),8.81(dd,J=4.0,1.6Hz,1H) ,8.20(dt,J=7.9,2.0Hz,1H),7.77(dt,J=8.1,2.3Hz,1H),7.70(dd,J=8.1,2.2Hz, 1H),7.61(dd,J=7.8,4.0Hz,1H),7.31–7.24(m,2H),7.22(dd,J=7.7,1.4Hz,1H),7 .04(td,J=7.3,1.5Hz,1H),5.00(dd,J=9.5,0.9Hz,1H),1.38(s,3H),1.33(s,3H).

[0117] Example 28

[0118] Preparation of 6-fluoro-N-(2-hydroxy-1-(2-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide (12z): Referring to the synthesis method in Example 20, a white solid 12z was obtained with a yield of 55%.

[0119] 1H NMR(400MHz,Chloroform-d)δ12.10(d,J=7.0Hz,1H),8.87(dd,J=4.0,1.7Hz,1H),8.24(dt,J=7 .9,2.0Hz,1H),7.82(dt,J=8.0,2.2Hz,1H),7.76(dd,J=8.1,2.2Hz,1H),7.61(dd,J=7.8,4.0Hz, 1H),7.36(dt,J=8.0,1.1Hz,1H),7.31–7.24(m,1H),7.22(dd,J=7.4,1.4Hz,1H),7.08(ddd,J=8 .5,7.4,1.3Hz,1H),5.04(dtd,J=8.6,4.2,0.9Hz,1H),3.85(dd,J=5.6,4.3Hz,2H),3.24(s,1H).

[0120] Example 29

[0121] Preparation of 6-fluoro-N-(2-hydroxy-1-(3-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide (12aa): Referring to the synthesis method in Example 20, a white solid 12aa was obtained in a yield of 66%.

[0122] 1 H NMR(400MHz,Chloroform-d)δ12.16(d,J=6.9Hz,1H),8.80(dd,J=4.0,1.8Hz,1H),8.21(d t,J=7.9,2.1Hz,1H),7.80(dt,J=8.0,2.3Hz,1H),7.66(dd,J=8.1,2.0Hz,1H),7.60(dd,J =7.8,4.0Hz,1H),7.30(dd,J=7.9,7.2Hz,1H),7.16(q,J=1.1Hz,1H),7.11(ddt,J=8.0,2. 6,1.2Hz,2H),4.95(dtt,J=8.5,4.2,1.0Hz,1H),3.91(dd,J=5.7,4.2Hz,2H),3.44(s,1H).

[0123] Example 30

[0124] Preparation of 6-fluoro-N-(2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)quinoline-8-carboxamide (12ab): Referring to the synthesis method in Example 20, a white solid 12ab was obtained in a yield of 61%.

[0125] 1H NMR(400MHz,Chloroform-d)δ12.18(d,J=7.2Hz,1H),8.81(dd,J=4.0,1.7Hz,1H),8.20(dt,J=7.9,2.0Hz,1H),7.83(dt,J=8.0,2.3Hz,1H),7 .71(dd,J=8.1,2.2Hz,1H),7.60–7.42(m,3H),7.30–7.22(m,2H),4.97(dtt,J=8.4,4.1,1.0Hz,1H),3.88(dd,J=5.4,4.0Hz,2H),3.31(s,1H).

[0126] Example 31

[0127] Preparation of N-(1-(4-chlorophenyl)-2-hydroxyethyl)-6-fluoroquinoline-8-carboxamide (12ac): Referring to the synthesis method in Example 20, a white solid 12ac was obtained in a yield of 68%.

[0128] 1 H NMR(400MHz,Chloroform-d)δ11.85(d,J=7.0Hz,1H),8.77(dd,J=4.0,1.7Hz,1H ),8.18(dt,J=7.9,2.0Hz,1H),7.79(dt,J=8.0,2.2Hz,1H),7.70(dd,J=8.1,2.2 Hz,1H),7.53(dd,J=7.8,4.0Hz,1H),7.33–7.27(m,2H),7.24–7.14(m,2H),4.96 (dtt,J=8.5,4.1,1.0Hz,1H), 3.88(dd,J=5.6,4.2Hz,2H), 3.72(t,J=5.6Hz,1H).

[0129] Example 32

[0130] Preparation of 6-fluoro-N-(1-(2-(trifluoromethoxy)phenyl)propyl)quinoline-8-carboxamide (12ad): Referring to the synthesis method in Example 1, a white solid 12ad was obtained with a yield of 77%.

[0131] 1H NMR(400MHz,Chloroform-d)δ11.65(d,J=7.1Hz,1H),δ8.87(dd,J=4.0,1.6Hz,1H),8.24(d t,J=7.9,2.0Hz,1H),7.82(dt,J=8.0,2.2Hz,1H),7.76(dd,J=8.1,2.2Hz,1H),7.61(dd,J=7 .8,4.0Hz,1H),7.33–7.24(m,2H),7.22(dd,J=7.3,1.5Hz,1H),7.08(td,J=7.6,1.3Hz,1H), 4.99(dtd,J=9.0,5.0,1.0Hz,1H), 1.55(qdd,J=7.3,4.2,1.9Hz,2H), 1.05(t,J=7.2Hz,3H).

[0132] Example 33

[0133] Preparation of 6-fluoro-N-(1-(3-(trifluoromethoxy)phenyl)propyl)quinoline-8-carboxamide (12ae): Referring to the synthesis method in Example 1, a white solid 12ae was obtained with a yield of 67%.

[0134] 1 H NMR(400MHz,Chloroform-d)δ11.77(d,J=7.0Hz,1H),8.90(dd,J=4.1,1.4Hz,1H),8 .30(dt,J=7.8,2.0Hz,1H),7.82(dt,J=8.0,2.2Hz,1H),7.70(dd,J=8.2,2.4Hz,1H), 7.64(dd,J=8.0,4.0Hz,1H),7.26(dd,J=8.1,7.2Hz,1H),7.16–7.09(m,3H),4.96(d tt, J = 8.6, 4.9, 1.0 Hz, 1H), 1.58 ( qdd, J = 7.2, 4.9, 2.4 Hz, 2H), 1.01 ( t, J = 7.1 Hz, 3H).

[0135] Example 34

[0136] Preparation of N-(1-(4-chlorophenyl)propyl)-6-fluoroquinoline-8-carboxamide (12af): Referring to the synthesis method in Example 1, a white solid 12af was obtained with a yield of 79%.

[0137] 1H NMR (400MHz, Chloroform-d) δ11.75(d,J=7.5Hz,1H),8.95(dd,J=4.2,1.7Hz,1H),8.61(dd,J=9.9,3.0Hz,1H),8.26(dd,J=8.6,1.6Hz,1H),7.60(dd, J=7.5,3.0Hz,1H),7.52(dd,J=8.2,4.0Hz,1H),7.44-7.33(m,2H),7.30-7. 35(m,2H),5.40(p,J=7.1Hz,1H),1.92–1.77(m,2H),0.93(t,J=7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ163.61,161.15,147.52,141.53,135.21,135.02,132.75,131.55(d,J=7.0Hz),1 28.89 (d, J = 9.1Hz), 128.81, 126.63, 124.86 (d, J = 23.4Hz), 121.35, 113.83 (d, J = 20.1Hz), 49.11, 25.88, 13.05.

[0138] Example 35

[0139] Preparation of compound (R)-12u: Refer to the synthesis method in Example 23 to obtain white solid (R)-12u with a yield of 66%.

[0140] 1 H NMR(400MHz,Chloroform-d)δ12.32(d,J=8.2Hz,1H),9.00(dd,J=4.2,1.6Hz,1H),8.57(dd,J=9.7,3.0Hz,1H),8.26(dd,J=8.4,1.6 Hz,1H),7.57(td,J=7.7,3.7Hz,2H),7.52(d,J=8.6Hz,2H),7.18(d,J=8.1Hz,2H),5.24(d,J=8.4Hz,1H),1.42(s,3H),1.24(s,3H). 13 CNMR(101MHz,Chloroform-d)δ148.82,148.52,142.84,138.48,137.28,131.61,12 9.84,124.14,123.87,121.77,120.66,114.86,114.64,72.87,62.36,27.69,27.41.

[0141] Example 36

[0142] Preparation of compound (S)-12u: Refer to the synthesis method in Example 23 to obtain a white solid (S)-12u with a yield of 61%.

[0143] 1 H NMR(400MHz,Chloroform-d)δ12.32(d,J=8.2Hz,1H),9.00(dd,J=4.2,1.6Hz,1H),8.57(dd,J=9.7,3.0Hz,1H),8.26(dd,J=8.4,1.6 Hz,1H),7.57(td,J=7.7,3.7Hz,2H),7.52(d,J=8.6Hz,2H),7.18(d,J=8.1Hz,2H),5.24(d,J=8.4Hz,1H),1.42(s,3H),1.24(s,3H). 13 CNMR(101MHz,Chloroform-d)δ148.82,148.52,142.84,138.48,137.28,131.61,12 9.84,124.14,123.87,121.77,120.66,114.86,114.64,72.87,62.36,27.69,27.41.

[0144] Example 37

[0145] Preparation of compound (S)-12w: Refer to the synthesis method in Example 23 to obtain white solid (S)-12w with a yield of 57%.

[0146] 1 H NMR(400MHz,Chloroform-d)δ12.32(d,J=8.2Hz,1H),9.00(dd,J=4.2,1.6Hz,1H),8.57(dd,J=9.7,3.0Hz,1H),8.26(dd,J=8.4,1.6 Hz,1H),7.57(td,J=7.7,3.7Hz,2H),7.52(d,J=8.6Hz,2H),7.18(d,J=8.1Hz,2H),5.24(d,J=8.4Hz,1H),1.42(s,3H),1.24(s,3H). 13CNMR(101MHz,Chloroform-d)δ148.97,148.29,138.85,136.82,132.15,130.52,13 0.62,123.25,124.80,121.60,121.94,114.47,115.15,72.24,63.11,26.82,28.37.

[0147] Example 38

[0148] Preparation of compound (R)-12w: Refer to the synthesis method in Example 23 to obtain white solid (R)-12w with a yield of 59%.

[0149] 1 H NMR (400MHz, Chloroform-d) δ12.32(d,J=8.2Hz,1H),9.00(dd,J=4.2,1.6Hz,1H),8.57(dd,J=9.7,3.0Hz,1H),8.26(dd,J=8.4,1.6 Hz,1H),7.57(td,J=7.7,3.7Hz,2H),7.52(d,J=8.6Hz,2H),7.18(d,J=8.1Hz,2H),5.24(d,J=8.4Hz,1H),1.42(s,3H),1.24(s,3H). 13 CNMR(101MHz,Chloroform-d)δ148.97,148.29,138.85,136.82,132.15,130.52,13 0.62,123.25,124.80,121.60,121.94,114.47,115.15,72.24,63.11,26.82,28.37.

[0150] Example 39

[0151] Preparation of compound (S)-12ab: Referring to the synthesis method in Example 20, a white solid (S)-12ab was obtained with a yield of 59%.

[0152] 1H NMR(400MHz,Chloroform-d)δ12.18(d,J=7.2Hz,1H),8.81(dd,J=4.0,1.7Hz,1H),8.20(dt,J=7.9,2.0Hz,1H),7.83(dt,J=8.0,2.3Hz,1H),7 .71(dd,J=8.1,2.2Hz,1H),7.60–7.42(m,3H),7.30–7.22(m,2H),4.97(dtt,J=8.4,4.1,1.0Hz,1H),3.88(dd,J=5.4,4.0Hz,2H),3.31(s,1H).

[0153] Example 40

[0154] Preparation of compound (R)-12ab: Referring to the synthesis method in Example 20, a white solid (R)-12ab was obtained with a yield of 55%.

[0155] 1 H NMR(400MHz,Chloroform-d)δ12.18(d,J=7.2Hz,1H),8.81(dd,J=4.0,1.7Hz,1H),8.20(dt,J=7.9,2.0Hz,1H),7.83(dt,J=8.0,2.3Hz,1H),7 .71(dd,J=8.1,2.2Hz,1H),7.60–7.42(m,3H),7.30–7.22(m,2H),4.97(dtt,J=8.4,4.1,1.0Hz,1H),3.88(dd,J=5.4,4.0Hz,2H),3.31(s,1H).

[0156] Test example

[0157] The active compounds described in this invention can enter the active pocket of PDE2. The aromatic heterocyclic carboxamide core enters the Q pocket, generating π-π interactions with the hydrophobic clamp formed by Ile826 and Phe862 / Phe830. The F atom on the quinoline ring forms a key hydrogen bond with Gln859 / Thr819 / Gln812 in the Q pocket via an H2O bridge, which is the primary reason for the compound's activity. This provides new insights into the discovery of novel backbone compounds for PDE2 inhibitors.

[0158] Compound Subtype Selectivity: Compound 12a exhibited significant selectivity for other PDE subtypes, with a selectivity factor greater than 100-fold. The data are shown in Table 1.

[0159] Table 1

[0160] PDEs <![CDATA[IC 50 (nM)]]> Selection Index PDE2 <100 - PDE1 >10000 >100 PDE4A >10000 >100 PDE5A >10000 >100 PDE7A >10000 >100 PDE9 >10000 >100 PDE10 >10000 >100

[0161] 2. The selected compounds can improve the learning and memory functions of APP / PS1 double transgenic AD model mice. Water maze experiments confirmed that the compounds can significantly improve the learning and memory behaviors of APP / PS1 AD model mice. Figure 1 shown.

[0162] 3. After 4 weeks of treatment with compound 12a (10 mg / kg or 30.0 mg / kg, ip), APP / PS1 model AD mice showed good performance in the open field test and object recognition test, with increased center residence time and discrimination index. These results indicate that the compound improved AD memory impairment and showed cognitive improvement, as shown in the open field test and object recognition test. Figure 2 shown.

[0163] 4. The relevant data of the compounds of Examples 1-40 are shown in Table 2. Most of the compounds showed significant inhibitory activity against PDE2.

[0164] Table 2

[0165]

[0166]

[0167]

[0168] PDE2 inhibitory activity A:IC 50 <100nm, B:100nm <IC 50 <1μM, C:IC 50 >1μM.

[0169] As shown in Table 2, most compounds showed moderate to excellent inhibitory activity against PDE2.

[0170] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present application, rather than to limit them. Although the present application has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some or all of the technical features therein. These modifications or replacements do not deviate the essence of the corresponding technical solutions from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A fluoroquinolinecarboxamide compound, characterized in that: The compound is a compound of Formula I, a pharmaceutically acceptable salt of the compound of Formula I, an optical isomer of the compound of Formula I, a hydrate of the compound of Formula I, or a solvate of the compound of Formula I. The structure of Formula I is shown below: In formula I, R1 is selected from at least one of -Et, -Me, -CH2OMe, -C(Me)2OH, and -CH2OH; R2 is selected from at least one of trifluoromethyl, trifluoromethoxy, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group, an alkoxy group, an alkyl-substituted amino group, a morpholine ring, a piperidine ring, a piperazine ring, and CH2OH; and X1 and X2 are both C or N.

2. The fluorine-containing quinoline carboxamide compound according to claim 1, characterized in that The compound is selected from 6-fluoro-N-(1-(4-(trifluoromethyl)phenyl)propyl)quinoline-8-carboxamide, 6-fluoro-N-(1-(4-(trifluoromethoxy)phenyl)propyl)quinoline-8-carboxamide, 6-fluoro-N-(1-(p-tolyl)propyl)quinoline-8-carboxamide, 6-fluoro-N-(1-(4-methoxyphenyl)propyl)quinoline-8-carboxamide, 6-fluoro-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide, 6-fluoro-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide, 6-fluoro-N-(1-(4-(trifluoromethyl)phenyl)ethyl)quinoline-8-carboxamide, 6-fluoro-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide, quinoline-8-carboxamide, 6-fluoro-N-(1-(2-(trifluoromethyl)phenyl)ethyl)quinoline-8-carboxamide, 6-fluoro-N-(1-(3-fluoro-4-(trifluoromethyl)phenyl)ethyl)quinoline-8-carboxamide, N-(1-(4-chlorophenyl)ethyl)-6-fluoroquinoline-8-carboxamide, N-(1-(4-(tert-butyl)phenyl)ethyl)-6-fluoroquinoline-8-carboxamide, N-(1-(4-(dimethylamino)phenyl)ethyl)-6-fluoroquinoline-8-carboxamide, 6-fluoro-N-(1-(4-(hydroxymethyl)phenyl)ethyl)quinoline-8-carboxamide, 6-fluoro-N-(1-(4-morpholinophenyl)ethyl)quinoline-8-carboxamide, 6-fluoro- N-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)quinoline-8-carboxamide, 6-fluoro-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)quinoline-8-carboxamide, 6-fluoro-N-(2-methoxy-1-(4-(trifluoromethyl)phenyl)ethyl)quinoline-8-carboxamide, 6-fluoro-N-(2-methoxy-1-(4-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide, 6-fluoro-N-(2-hydroxy-1-(4-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide, (S)-6-fluoro-N-(2-hydroxy-1-(4-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide, (R)-6-fluoro-N-(2-hydroxy- 1-(4-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide, 6-fluoro-N-(2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)quinoline-8-carboxamide, (S)-6-fluoro-N-(2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)quinoline-8-carboxamide, (R)-6-fluoro-N-(2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)quinoline-8-carboxamide, N-(1-(4-chlorophenyl)-2-hydroxy-2-methylpropyl)-6-fluoroquinoline-8-carboxamide, 6-fluoro-N-(2-hydroxy-2-methyl-1-(4-(trifluoromethyl)phenyl)propyl)quinoline-8-carboxamide,(S)-6-Fluoro-N-(2-hydroxy-2-methyl-1-(4-(trifluoromethyl)phenyl)propyl)quinoline-8-carboxamide, (R)-6-Fluoro-N-(2-hydroxy-2-methyl-1-(4-(trifluoromethyl)phenyl)propyl)quinoline-8-carboxamide, 6-Fluoro-N-(2-hydroxy-2-methyl-1-(3-(trifluoromethoxy)phenyl)propyl)quinoline-8-carboxamide, 6-Fluoro-N-(2-hydroxy-2-methyl-1-(2-(trifluoromethoxy)phenyl)propyl)quinoline-8-carboxamide, 6-Fluoro-N-(2-hydroxy-1-(2-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide, 6-Fluoro-N-(2-hydroxy-1-(3-(trifluoromethoxy)phenyl)ethyl)quinoline-8-carboxamide Quinoline-8-carboxamide, 6-fluoro-N-(2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)quinoline-8-carboxamide, (S)-6-fluoro-N-(2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)quinoline-8-carboxamide, (R)-6-fluoro-N-(2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)quinoline-8-carboxamide, N-(1-(4-chlorophenyl)-2-hydroxyethyl)-6-fluoroquinoline-8-carboxamide, 6-fluoro-N-(1-(2-(trifluoromethoxy)phenyl)propyl)quinoline-8-carboxamide, 6-fluoro-N-(1-(3-(trifluoromethoxy)phenyl)propyl)quinoline-8-carboxamide, N-(1-(4-chlorophenyl)propyl)-6-fluoroquinoline-8-carboxamide.

3. A method for preparing the fluorine-containing quinolinecarboxamide compound according to claim 1 or 2, characterized in that: The synthetic route is shown below:

4. The method for preparing the fluoroquinolinecarboxamide compound according to claim 3, wherein The following steps are involved: S1. Commercially available aryl ketones 1a-1v were used as starting materials and hydroxylamine hydrochloride as reactant. In the presence of triethylamine and ethanol as solvent, the mixture was refluxed for 6 h and then reduced to obtain intermediates 2a-2v. S2 and intermediates 2a to 2v were reacted in an H2 environment with palladium carbon or palladium hydroxide as a catalyst and ethanol as a solvent at room temperature overnight to obtain intermediates 3a to 3v; S3, using commercially available substituted acetophenones 4a-4e as raw materials and pyridine as solvent, adding selenium dioxide, reflux reaction for 20 h, and then methylating to obtain intermediates 5a-5e; S4. Using intermediates 5a-5e as raw materials, hydroxylamine hydrochloride was added, and ethanol was used as a solvent to reflux for 5 h in the presence of triethylamine to obtain intermediates 6a-6e; S5, intermediates 6a-6e are reacted in a H2 environment with palladium carbon or palladium hydroxide as a catalyst and ethanol as a solvent at room temperature overnight to obtain intermediates 7a-7e; S6. Using intermediates 7a-7e as raw materials, reacting in the presence of di-tert-butyl dicarbonate and tetrahydrofuran as solvent at room temperature for 48 hours to obtain intermediates Boc-amino acid methyl esters 8a-8e; S7. Intermediates 8a-8e are reduced with LiAlH4 and hydrolyzed to give intermediates 9a-9e; or they are hydrolyzed with Grignard reaction to give intermediates 9aa-9ee; S8, using 2-amino-5-fluorobenzoic acid 10 as the starting material, the intermediate 6-fluoroquinoline-8-carboxylic acid 11 was obtained by Skraup quinoline synthesis reaction; S9. The target compounds 12a to 12af are obtained by condensation reaction of the intermediate 6-fluoroquinoline-8-carboxylic acid 11, the intermediates 3a to 3v, the intermediates 9a to 9e and the intermediates 9aa to 9ee.

5. A pharmaceutical composition, characterized in that The pharmaceutical composition contains the fluoroquinolinecarboxamide compound according to claim 1 or 2 and optionally a pharmaceutically acceptable additive or excipient.

6. Use of the fluoroquinolinecarboxamide compound according to claim 1 or 2 in the preparation of a PDE2 inhibitor.

7. Use of the fluoroquinoline carboxamide compound according to claim 1 or 2 in the preparation of anti-AD drugs.

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