Quinoline compound and use thereof

Abstract

Disclosed is a quinoline compound and a use thereof. A quinoline derivative of the present invention is a compound having phosphodiesterase 3A (PDE3A) inhibitory activity, has important potential therapeutic value, and is used in the treatment of cerebrovascular diseases or in dementia drugs.

Description

Quinoline compounds and uses thereof

[0001] This application claims priority to the Chinese patent application No. 202410721531.3, filed on June 5, 2024, and entitled "Quinoline compounds and uses thereof", the entire content of which is incorporated herein by reference. TECHNICAL FIELD

[0002] The present application belongs to the field of pharmacy, and relates to a class of quinoline derivatives and a preparation method thereof, applications as phosphodiesterase 3A (PDE3A) inhibitors, and in particular, uses in drugs for treating cerebrovascular diseases or dementia. BACKGROUND

[0003] Cerebral small vessel disease (CSVD) is an important subtype of vascular dementia and the most common cause of clinical vascular dementia. CSVD refers to a series of clinical, imaging and pathological syndromes caused by various causes affecting cerebral small arteries, arterioles, capillaries, venules and small veins, accounting for about 25% of ischemic strokes, and is the main cause of cognitive impairment, emotional disorders, urinary and fecal disorders, and decreased life ability in the elderly. In recent years, the incidence and detection rate of cerebral small vessel disease have shown a gradually increasing trend, but as of now, there is still a lack of effective treatment for cerebral small vessel disease. Most lacunar ischemic strokes are related to cerebral perforator arteriopathy (vascular endothelial dysfunction), and drugs that stabilize vascular endothelial function (such as cilostazol) or can be used to prevent the long-term clinical impact of lacunar ischemic stroke on cognition and function.

[0004] Cilostazol is a quinoline derivative drug that can inhibit the activity of platelets and vascular smooth muscle phosphodiesterase (PDE3), increase intracellular cAMP concentration, and thus play an anti-platelet role and vasodilation effect. In addition, it also inhibits the release of inflammatory mediators, reduces the damage of inflammatory factors to the vascular intima, helps to protect the vascular endothelium and delay the progression of arteriosclerosis, and has the potential to be used for treating various diseases including cerebrovascular diseases or dementia. The present application relates to a class of compounds with high PDE3A inhibitory activity, which can be used for the treatment of related diseases. SUMMARY

[0005] The technical problem solved by the present application is to provide a class of quinoline derivative compounds, which have phosphodiesterase 3A (PDE3A) inhibitory activity and can be used for preparing drugs for treating cerebrovascular diseases or dementia.

[0006] The present application provides a class of compounds as shown in formula I or pharmaceutically acceptable salts, deuterium compounds, solvates, racemic mixtures, enantiomers, diastereomers and tautomers thereof,

[0007] Formula I

[0008] wherein X is selected from -O- or -CH2-;

[0009] R1, R2and R3are each independently selected from hydrogen, halogen, trifluoromethyl, difluoromethyl, C1-C6alkyl, C3-C8cycloalkyl, cyano, nitro, methoxy, hydroxyl or amino;

[0010] R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen or C1-C3alkyl;

[0011] the form of the covalent bond between the carbon atom in position 3 and the carbon atom in position 4 is selected from a single bond or a double bond;

[0012] n is selected from the numbers 0, 1, 2 or 3.

[0013] The present application also provides a class of compounds as illustrated in Formula I or pharmaceutically acceptable salts, deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers and tautomers thereof,

[0014] Formula I

[0015] wherein X is selected from -O- or -CH2-;

[0016] R1, R2and R3are each independently selected from hydrogen, halogen, trifluoromethyl, difluoromethyl, C1-C6alkyl, C3-C8cycloalkyl, cyano, nitro, methoxy, hydroxyl or amino;

[0017] R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen or C1-C3alkyl;

[0018] the form of the covalent bond between the carbon atom in position 3 and the carbon atom in position 4 is selected from a single bond or a double bond;

[0019] n is selected from the numbers 0, 1, 2 or 3.

[0020] with the additional proviso that when X is -CH2-, at least one of R1, R2and R3is not hydrogen;

[0021] with the proviso that when X is -CH2- and the covalent bond between the carbon atom in position 3 and the carbon atom in position 4 is in the form of a double bond, and R2and R3are both hydrogen, then R1is not fluorine;

[0022] with the proviso that when X is -CH2- and the covalent bond between the carbon atom in position 3 and the carbon atom in position 4 is in the form of a double bond, and any two of R1, R2and R3are both hydrogen, then the other non-hydrogen substituent of R1, R2and R3is not trifluoromethyl.

[0023] The present application also provides a class of compounds as illustrated in Formula I, or a pharmaceutically acceptable salt thereof, and / or its deuterium compound, solvate, racemic mixture, enantiomer, diastereoisomer and tautomer,

[0024] Formula I

[0025] wherein,

[0026] X is selected from -O-, -CH2-;

[0027] R1, R2and R3are each independently selected from hydrogen, halogen, trifluoromethyl, difluoromethyl, C1-C6alkyl, C3-C8cycloalkyl, cyano, nitro, methoxy, hydroxyl, amino;

[0028] R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen, C1-C3alkyl;

[0029] the covalent bond between the carbon atom in position 3 and the carbon atom in position 4 is selected from a single bond, or a double bond;

[0030] n is selected from the numbers 0, 1, 2 or 3;

[0031] with the proviso that when X is -CH2-, at least one of R1, R2and R3is not hydrogen;

[0032] with the proviso that when X is -CH2- and the covalent bond between the carbon atom in position 3 and the carbon atom in position 4 is in the form of a single bond, and R2and R3are both hydrogen, then R1is not fluorine;

[0033] with the proviso that when X is -CH2- and the covalent bond between the carbon atom in position 3 and the carbon atom in position 4 is in the form of a single bond, and any two of R1, R2and R3are both hydrogen, then the other non-hydrogen substituent of R1, R2and R3is not trifluoromethyl.

[0034] R1, R2and R3are each independently selected from hydrogen, halogen, trifluoromethyl, difluoromethyl, C1-C6alkyl, C3-C8cycloalkyl, cyano, nitro, methoxy or hydroxy;

[0035] R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen or methyl.

[0036] R1, R2and R3are each independently selected from hydrogen, halogen, trifluoromethyl, difluoromethyl, C1-C3alkyl, cyano, nitro or methoxy;

[0037] R1and R2are each independently selected from hydrogen, halogen, trifluoromethyl, difluoromethyl, C1-C3alkyl, cyano, nitro or methoxy;

[0038] R3is selected from hydrogen, fluorine, chlorine, trifluoromethyl, difluoromethyl or methyl.

[0039] R1and R2are each independently selected from hydrogen, halogen, trifluoromethyl, difluoromethyl, C1-C3alkyl or methoxy;

[0040] R3is selected from hydrogen, fluorine, chlorine or trifluoromethyl;

[0041] n is selected from the numbers 0, 1 or 2.

[0042] R1is selected from hydrogen, fluorine, chlorine, trifluoromethyl or methyl;

[0043] R2is selected from hydrogen, fluorine, chlorine, trifluoromethyl, difluoromethyl or methyl.

[0044] R3is selected from hydrogen, fluorine, chlorine or trifluoromethyl;

[0045] n is selected from the numbers 0, 1 or 2.

[0046] R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 are each independently hydrogen or halogen.

[0047] R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 are each independently hydrogen or fluorine.

[0048] More preferably, the compound is selected from:

[0049] Compound S1, as shown above;

[0050] Compound S2, as shown above;

[0051] Compound S3, as shown above;

[0052] Compound S4, as shown above;

[0053] Compound S5, as shown above;

[0054] Compound S6, as shown above;

[0055] Compound S7, as shown above;

[0056] Compound S8, as shown above;

[0057] Compound S9, as shown above;

[0058] Compound S10, as shown above;

[0059] Compound S11, as shown above;

[0060] Compound S12, as shown above;

[0061] Compound S13, as shown above;

[0062] Compound S14, as shown above;

[0063] Compound S15, as shown above;

[0064] Compound S16, as shown above;

[0065] Compound S17, as shown above;

[0066] Compound S18, as shown above;

[0067] Compound S19, as shown above;

[0068] Compound S20, as shown above;

[0069] Compound S21, as shown above;

[0070] Compound S22, as shown above;

[0071] Compound S23, as shown above;

[0072] Compound S24, as shown above;

[0073] Compound S25, as shown above;

[0074] Compound S26, as shown above;

[0075] Compound S27, as shown above;

[0076] Compound S28, as shown above;

[0077] Compound S29, as shown above;

[0078] Compound S30, as shown above;

[0079] Compound S31, as shown above;

[0080] Compound S32, as shown above;

[0081] Compound S33, as shown above;

[0082] Compound S34, as shown above;

[0083] Compound S35, as shown above.

[0084] The present application provides a compound shown in formula I, or a pharmaceutically acceptable salt thereof, and / or its deuterated compound, solvate, racemic mixture, enantiomer, diastereoisomer and tautomer, having the application in a medicine with phosphodiesterase 3A (PDE3A) inhibitory activity.

[0085] The application provides application of a compound shown in a formula I, or a pharmaceutically acceptable salt thereof, and / or deuterated compounds, solvates, racemic mixtures, enantiomers, diastereoisomers and tautomers thereof in preparation of a drug for cerebrovascular disease or dementia.

[0086] The application provides a pharmaceutical composition comprising the compound shown in the formula I or a pharmaceutically acceptable salt thereof, deuterated compounds, solvates, racemic mixtures, enantiomers, diastereoisomers, tautomers and a pharmaceutically acceptable carrier. Beneficial effects:

[0087] The application provides a quinoline derivative compound, the compound has phosphodiesterase 3A (PDE3A) inhibitory activity, and can be used for preparation of a drug for treating cerebrovascular disease or dementia. DETAILED DESCRIPTION

[0088] The technical solutions in the embodiments of the application will be clearly and completely described below with reference to the embodiments of the application. Obviously, the described embodiments are only part of the embodiments of the application, rather than all the embodiments of the application. Based on the embodiments in the application, all other embodiments obtained by those skilled in the art without creative work fall within the protection scope of the application.

[0089] In the embodiments provided in the application, the yield is rounded to an integer for statistical convenience.

[0090] Preparation of intermediates:

[0091] Intermediate 1:

[0092] First step:

[0093] 2-trifluoromethyl-2-methoxy-aniline (0.5 g, 2.62 mmol) was dissolved in THF (10 ml), and the acetal (0.46 g, 3.14 mmol) was added. After the system was protected by nitrogen, the system was cooled to 0-5 DEG C, and the 1N NaHMDS THF solution (3.2 ml, 3.2 mmol) was added. After the addition was completed, the system was naturally raised to room temperature and reacted for 12 h. After the reaction was completely monitored by LC / MS, the reaction liquid was poured into ice water, and the water phase was extracted with ethyl acetate (EA) for 3 times (20 ml x 3 times), the organic phase was combined, dried and concentrated. Then column chromatography was performed to obtain a light yellow oily substance (0.69 g, yield 87%).

[0094] ESI-MS: 308.1 [M+H] + .

[0095] Second step:

[0096] The intermediate of the first step was suspended in DCM (5 ml), concentrated H2SO4 (1.1 g, 11.4 mmol) was added, and the mixture was stirred at 50 °C for 6 h. After the reaction was completed as monitored by LC / MS, the reaction solution was poured into ice water, and the aqueous phase was extracted with EA (30 ml x 3 times). The combined organic phase was dried and concentrated. Then column chromatography was performed to give a yellow solid (0.39 g, 70% yield).

[0097] ESI-MS: 244.0 [M+H] + .

[0098] Step 3:

[0099] The intermediate of the second step was suspended in DCM (5 ml), and the system was cooled to 0-5 °C. 2N BBr3 solution in DCM (2.4 ml, 4.8 mmol) was added. After the reaction was completed as monitored by LC / MS, the residual BBr3 was removed by concentration under reduced pressure. Then the reaction solution was poured into ice water, and the aqueous phase was extracted with EA (20 ml x 4 times). The combined organic phase was dried and concentrated. Then column chromatography was performed to give a yellow-brown solid (0.3 g, 80% yield).

[0100] ESI-MS: 230.0 [M+H] + .

[0101] Intermediate 2:

[0102] Step 1:

[0103] 3-trifluoromethyl-2-methoxy-aniline (0.5 g, 2.62 mmol) was dissolved in THF (10 ml), and the acetal (0.46 g, 3.14 mmol) was added. After the system was protected by nitrogen, the system was cooled to 0-5 °C, and 1N NaHMDS solution in THF (3.2 ml, 3.2 mmol) was added. After the addition was completed, the system was naturally warmed to room temperature and stirred for 12 h. After the reaction was completed as monitored by LC / MS, the reaction solution was poured into ice water, and the aqueous phase was extracted with EA (20 ml x 3 times). The combined organic phase was dried and concentrated. Then column chromatography was performed to give a yellowish oil (0.69 g, 87% yield).

[0104] ESI-MS: 308.1 [M+H] + .

[0105] Step 2:

[0106] The intermediate of the first step was suspended in DCM (5 ml), concentrated H2SO4 (1.1 g, 11.4 mmol) was added, and the mixture was stirred at 50 °C for 6 h. After the reaction was completed as monitored by LC / MS, the reaction solution was poured into ice water, and the aqueous phase was extracted with EA (30 ml x 3 times). The combined organic phase was dried and concentrated. Then column chromatography was performed to give a yellow solid (0.39 g, 70% yield).

[0107] ESI-MS: 244.0 [M+H] + .

[0108] Step 3:

[0109] The intermediate in the second step was dissolved in DCM (5 ml), the system was cooled to 0-5 degrees, and 2N BBr3 solution in DCM (2.4 ml, 4.8 mmol) was added. After the reaction was completed as monitored by LC / MS, the remaining BBr3 was concentrated under reduced pressure, and the reaction solution was poured into ice water, and the aqueous phase was extracted with EA 4 times (20 ml x 4 times), the combined organic phase was dried and concentrated. Then column chromatography was performed to obtain a yellow-brown solid (0.3 g, 80%).

[0110] ESI-MS: 230.0 [M+H] + .

[0111] Step 4:

[0112] The intermediate in the third step was dissolved in acetic acid (2 ml), and Pa / C (29 mg, 0.0128 mmol) was added, and a hydrogen balloon was connected (replaced 3 times), and the reaction was carried out at room temperature for 12 h. After the reaction was completed as monitored by TLC, the mother liquor was filtered, and the mother liquor was added dropwise into 20 ml of water, and a solid was precipitated, and a yellow solid was obtained by suction filtration (0.26 g, 90%).

[0113] ESI-MS: 232.0 [M+H] + .

[0114] Intermediate 3:

[0115] Referring to the synthesis of intermediate 2, intermediate 3 can be obtained using the corresponding raw materials and appropriate conditions.

[0116] ESI-MS: 232.0 [M+H] + .

[0117] Intermediate 4:

[0118] Referring to the synthesis of intermediate 1, intermediate 4 can be obtained using the corresponding raw materials and appropriate conditions.

[0119] ESI-MS: 196.0 [M+H] + .

[0120] Intermediate 5:

[0121] Referring to the synthesis of intermediate 1, intermediate 5 can be obtained using the corresponding raw materials and appropriate conditions.

[0122] ESI-MS: 180.0 [M+H] + .

[0123] Intermediate 6:

[0124] Following the procedure for synthesis of Intermediate 1, using corresponding starting materials and appropriate conditions, Intermediate 6 was obtained.

[0125] ESI-MS: 198.0 [M+H] + .

[0126] Intermediate 7:

[0127] Following the procedure for synthesis of Intermediate 1, using corresponding starting materials and appropriate conditions, Intermediate 7 was obtained.

[0128] ESI-MS: 229.9 [M+H] + .

[0129] Intermediate 8:

[0130] Following the procedure for synthesis of Intermediate 1, using corresponding starting materials and appropriate conditions, Intermediate 8 was obtained.

[0131] ESI-MS: 196.0 [M+H] + .

[0132] Intermediate 9:

[0133] Step 1:

[0134] 2-methyl-4-methoxy-aniline (0.35 g, 2.62 mmol) was dissolved in acetonitrile (5 ml), K2CO3(0.43 g, 3.14 mmol) was added, then water (10 ml) was added, the system was cooled to 0-5 degrees, cinnamoyl chloride (0.43 g, 2.62 mmol) was dissolved in acetonitrile, then added dropwise to the system, and maintained at 0-5 degrees for 6 h. After the reaction was completed by TLC monitoring, it was filtered, the filter cake was washed with water and dried to obtain a light yellow solid (0.61 g, yield 87%).

[0135] ESI-MS: 268.1 [M+H] + .

[0136] Step 2:

[0137] The first step intermediate was suspended in chlorobenzene (10 ml), AlCl3(0.9 g, 6.84 mmol) was added, and the reaction was refluxed for 6 h. After the reaction was monitored to be complete by LC / MS, the reaction solution was poured into ice water, and filtered, dried, and then slurried with n-hexane (He, 2 ml) to give a yellow-brown solid (0.28 g, yield 70%).

[0138] ESI-MS: 176.0 [M+H] + .

[0139] Intermediate 10:

[0140] Referring to the synthesis of Intermediate 9, Intermediate 10 can be obtained using the corresponding starting materials and appropriate conditions.

[0141] ESI-MS: 190.0 [M+H] + .

[0142] Intermediate 11:

[0143] First step:

[0144] To a solution of 4-bromo-3-fluorophenol (40 g, 98%, 205.24 mmol, 1 eq), K2CO3(57.30 g, 99%, 23.35 mL, 410.47 mmol, 2 eq) in MeCN (400 mL) was cooled to 0-5 degrees, then MOMBr (31.05 g, 95%, 20.28 mL, 236.02 mmol, 1.15 eq) was slowly added. The mixture was stirred at 25 degrees for 16 hours, TLC (Rf = 0.6, PE:EA = 10:1) monitoring the starting material was completely reacted, and a new spot was formed. After the reaction solution was filtered, the crude product was purified by silica gel chromatography to obtain 1-bromo-2-fluoro-4-(methoxymethoxy)benzene (47 g, yield: 97.43%) as colorless oil.

[0145] ESI-MS: 234.9 [M+H] + .

[0146] Second step:

[0147] A solution of 1-bromo-2-fluoro-4-(methoxymethoxy)benzene (10.90 g, 46.37 mmol, 1 eq) in THF (100 mL) was cooled to -78 °C, then LDA (5.96 g, 27.82 mL, 55.65 mmol, 1.2 eq, 2 M) was added. The mixture was stirred at -78 °C for 1 h. Then DMF (4.07 g, 4.30 mL, 55.65 mmol, 1.2 eq) was added. The mixture was stirred at -78 °C for 1 h. TLC (Rf = 0.2, PE:EA = 10:1) monitored the starting material was consumed completely, there was a new spot. To the mixture was added EA (100 mL) and H2O (100 mL), the aqueous phase was extracted with EA (200 mL x 3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The crude was purified by silica gel chromatography DCM:EtOAc = 10:1 to give 3-bromo-2-fluoro-6-(methoxymethoxy)benzaldehyde (10.49 g, yield: 85.99%) as white solid.

[0148] ESI-MS: 262.9 [M+H] + .

[0149] Third step:

[0150] A solution of 3-bromo-2-fluoro-6-(methoxymethoxy)benzaldehyde (10.49 g, 39.88 mmol, 1 eq) in DCM (5 mL) was cooled to 0-5 °C, then DAST (20.30 g, 95%, 17.53 mL, 119.63 mmol, 3 eq) was added. The mixture was stirred at 20 °C for 16 h. TLC (Rf = 0.6, PE:EA = 10:1) monitored the starting material was consumed completely, there was a new spot. The reaction mixture was poured into 300 mL saturated NaHCO3solution. The aqueous phase was extracted with DCM (200 mL x 3). The combined organic layer was washed with brine (200 mL) and dried over Na2SO4, filtered and concentrated. The crude was purified by silica gel chromatography PE:EtOAc = 3:1 to give 1-bromo-3-(difluoromethyl)-2-fluoro-4-(methoxymethoxy)benzene (9.17 g, yield: 80.67%) as colorless oil.

[0151] ESI-MS: 384.9 [M+H] + .

[0152] Fourth step:

[0153] To a solution of 1-bromo-3-(difluoromethyl)-2-fluoro-4- (methoxymethoxy)benzene (9.17 g, 32.17 mmol, 1 eq) in NH4OH (100 mL) was added cuprous oxide (4.48 g, 98%, 731.18 μL, 30.66 mmol, 1 eq). The mixture was stirred at 120 °C under N2for 16 h. LCMS showed the starting material was consumed completely, the main peak was the product. To the mixture was added EA (200 mL) and H2O (200 mL), the aqueous phase was extracted with EA (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography PE:EtOAc = 3:1 to give 3-(difluoromethyl)-2-fluoro-4- (methoxymethoxy)aniline (3.52 g, yield: 49.47%) as yellow oil.

[0154] ESI-MS: 222.0 [M+H] + .

[0155] Step 5:

[0156] To a solution of 3-(difluoromethyl)-2-fluoro-4-(methoxymethoxy)aniline (3.52 g, 15.91 mmol, 1 eq) in THF (50.25 mL, 99.5%) was cooled to 0-5 °C, then NBS (3.12 g, 98%, 1.49 mL, 17.51 mmol, 1.1 eq) in THF (50.25 mL, 99.5%) was added. The mixture was stirred at 25 °C for 16 h, LCMS showed the starting material was consumed completely, the main peak was the product. To the mixture was added EA (100 mL) and H2O (200 mL), the aqueous phase was extracted with EA (80 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography PE:EtOAc = 5:1 to give 6-bromo-3-(difluoromethyl)-2-fluoro-4- (methoxymethoxy)aniline (960 mg, yield: 20.10%) as yellow solid.

[0157] ESI-MS: 299.9 [M+H] + .

[0158] Step 6:

[0159] To a solution of 6-bromo-3-(difluoromethyl)-2-fluoro-4- (methoxymethoxy)aniline (9 g, 29.99 mmol, 1 eq) in DMF (80 mL) was added POT (2.75 g, 99.62%, 9 mmol, 0.3 eq) Pd(OAc)2(687.09 mg, 98%, 3 mmol, 0.1 eq) TEA (9.20 g, 99%, 12.63 mL, 89.98 mmol, 3 eq) methyl acrylate (3.39 g, 99%, 3.51 mL, 38.99 mmol, 1.3 eq). The mixture was stirred at 110 °C under N2for 16 h. LCMS showed the starting material was consumed completely, the main peak was the product, to the mixture was added EA (100 mL) and H2O (100 mL), the aqueous phase was extracted with EA (80 mL x 3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (PE solution 30-50% EA) to give (2E)-3-[2-amino-4-(difluoromethyl)-3-fluoro-5- (methoxymethoxy)phenyl]prop-2-enoic acid methyl ester (7 g, yield: 76.46%) yellow solid.

[0160] ESI-MS: 306.0 [M+H] + .

[0161] Seventh step:

[0162] To a solution of (2E)-3-[2-amino-4-(difluoromethyl)-3-fluoro-5- (methoxymethoxy)phenyl]prop-2-enoic acid methyl ester (7 g, 22.93 mmol, 1 eq) in EtOH (80 mL) was added MeSNa (3.38 g, 95%, 45.86 mmol, 2 eq). The mixture was stirred at 60 °C for 1 h, LCMS showed the starting material was consumed completely, the main peak was the product, the reaction system was concentrated to dryness. The residue was washed with H2O (250 mL) and MTBE (250 mL), the solid was collected by filtration and dried to give 7-(difluoromethyl)-8-fluoro-6- (methoxymethoxy)-1,2-dihydroquinolin-2-one (5 g, yield: 79.81%) yellow solid.

[0163] ESI-MS: 274.0 [M+H] + .

[0164] Eighth step:

[0165] To 7-(difluoromethyl)-8-fluoro-6-(methoxymethoxy)-1,2-dihydroquinolin-2-one (5 g, 18.30 mmol, 1 eq) was added HCl solution (7.29 g, 50 mL, 200 mmol, 10.9284 eq, 4 M in 1,4-dioxane) and stirred at room temperature for 5 h. LCMS showed that the starting material was completely reacted. The reaction solution was filtered, then washed with methyl tert-butyl ether (MTBE, 250 mL) and dried to obtain 7-(difluoromethyl)-8-fluoro-6-hydroxy-1,2-dihydroquinolin-2-one free base salt (3.80 g, yield: 90.61%, purity: 99%) as a white solid.

[0166] ESI-MS: 230.0 [M+H] + .

[0167] Example 1: Synthesis of compound S1

[0168] First step:

[0169] Cyclohexylamine 0.29 g (1 eq, 3 mmol) was dissolved in THF 10 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, lactone 0.3 g (1 eq, 3 mmol) was added, and the reaction was carried out at 60 °C for 5 h. After the reaction was completed, the system was cooled to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 °C), and white oil 0.6 g was obtained with a yield of 100% (theoretical).

[0170] Second step:

[0171] The product of the first step was dissolved in DCE 25 ml, and ice bath was used to cool to 0 °C. 1.2 g of PCl5 (2 eq, 6 mmol) was added in batches, and after the addition was completed, the system was stirred at room temperature for 2 h. Then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, and the system was stirred at room temperature for 30 min. The temperature was raised to 60 °C, and the reaction was carried out for 3 h. After the reaction was completed, EA 120 ml was added for dilution, the organic phase was washed with water 3 times, and the organic phase was dried and concentrated (30 °C). 0.62 g was obtained with a yield of 85%.

[0172] Third step:

[0173] Take quinolinone 0.49 g (1.2 eq, 3.06 mmol), add 0.70 g K2CO3(2 eq, 5.1 mmol), add DMF 5 ml, warm to 80 degrees until clear, add second step product 0.62 g (1 eq, 2.55 mmol) and 92 mg tetrabutylammonium iodide (TBAI, 0.1 eq, 0.25 mmol), 80 degrees for 8 h, add EA to dilute the organic phase and wash with 0.5 N NaOH 2x, dry the organic phase and concentrate (30 degrees), purify the crude product on 200-300 mesh silica gel (HE:EA = 4:1, start gradient elution to HE:EA = 1:4), collect the product, concentrate, while not completely dry, add HE to crystallize, suction filter to get white solid 0.28 g 30% yield.

[0174] ESI-MS: 369.2 [M+H] + .

[0175] 1 HNMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 7.82 (d, J = 9.6 Hz, 1H), 7.27 - 7.18 (m, 2H), 7.12 (dd, J = 8.9, 2.8 Hz, 1H), 6.49 (d, J = 9.7 Hz, 1H), 4.98 (s, 2H), 4.53 (t, J = 9.3 Hz, 1H), 4.22 - 4.09 (m, 2H), 3.90 - 3.76 (m, 2H), 2.03 (m, 2H), 1.80 (m, 4H), 1.64 (m, 1H), 1.41 - 1.26 (m, 3H).

[0176] Example 2: Synthesis of compound S2

[0177] First step:

[0178] Cyclohexylamine 0.29 g (1 eq, 3 mmol) was dissolved in THF 10 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, lactone 0.3 g (1 eq, 3 mmol) was added, 60 degrees for 5 h, after the end of the system was reduced to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees), white oil was obtained, 0.6 g yield 100% (theoretical).

[0179] Second step:

[0180] First step product dissolved in DCE 25 ml, ice bath to 0 degree, 1.2 g PCl5(2 eq, 6 mmol) added in portions, after addition, stirred at room temperature for 2 h, then added TMSN3 1.17 g (3.5 eq, 10.22 mmol) at room temperature, stirred at room temperature for 30 min, heated to 60 degree for 3 h. After completion, diluted with EA 120 ml, organic phase washed with water 3 times, organic phase dried and concentrated (30 degree). 0.62 g yield 85%.

[0181] Third step:

[0182] Quinolinone 0.49 g (1.2 eq 3.06 mmol) taken, 0.70 g K2CO3(2 eq 5.1 mmol) added, DMF 5 ml added, heated to 80 degree till solution clear, second step product 0.62 g (1 eq, 2.55 mmol) and 92 mg TBAI (0.1 eq 0.25 mmol) added, 80 degree for 8 h, organic phase diluted with EA and washed with 0.5 N NaOH 2 times, organic phase dried and concentrated (30 degree), crude purified with 200-300 mesh silica gel (HE:EA = 4: 1, started gradient elution, till HE:EA = 1:4), product collected, concentrated, while concentrating, not completely dry, added HE to crystallize, white solid obtained on suction filtration 0.28 g 30% yield.

[0183] ESI-MS: 371.3 [M+H] + .

[0184] 1 HNMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 6.78 - 6.66 (m, 3H), 4.96 (s, 2H), 4.59 - 4.46 (m, 1H), 4.06 (dd, J = 5.3, 3.4 Hz, 2H), 3.79 (dd, J = 5.3, 3.4 Hz, 2H), 2.85 - 2.76 (m, 2H), 2.42 - 2.36 (m, 2H), 2.03 (d, J = 9.1 Hz, 2H), 1.81 (d, J = 10.4 Hz, 4H), 1.66 (d, J = 12.0 Hz, 1H), 1.37 (q, J = 13.1 Hz, 3H).

[0185] Example 3: Synthesis of compound S3

[0186] First step:

[0187] Cyclohexylamine 0.29 g (1 eq, 3 mmol) was dissolved in THF 10 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, lactone 0.3 g (1 eq, 3 mmol) was added, reaction at 60 degrees for 5 h, after the end of the reaction the system was brought to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees), white oil was obtained, 0.6 g yield 100% (theoretical).

[0188] Second step:

[0189] The product of the first step was dissolved in DCE 25 ml, ice bath to 0 degrees, 1.2 g of PCl5 (2 eq, 6 mmol) was added in portions, after the addition was complete, it was stirred at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, it was stirred at room temperature for 30 min, then it was heated to 60 degrees for 3 h. After the end of the reaction, it was diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees). 0.62 g yield 85%.

[0190] Third step:

[0191] Quinolinone 0.7 g (1.2 eq, 3.06 mmol) was taken, 0.46 g of DBU (1.2 eq, 3.06 mmol) was added, DMF 5 ml was added, it was heated to 80 degrees until it was clear, the product of the second step 0.62 g (1 eq, 2.55 mmol) and 92 mg of TBAI (0.1 eq, 0.25 mmol) were added, it was reacted at 80 degrees for 8 h, the organic phase was diluted with EA and washed with 0.5 N NaOH 2 times, the organic phase was dried and concentrated (30 degrees), the crude product was purified on 200-300 mesh silica gel (HE: EA = 4: 1, start gradient elution, to HE: EA = 1:4), the product was collected, concentrated, when it was not completely concentrated, it was crystallized with HE, suction filtration gave white solid 0.33 g 30% yield.

[0192] ESI-MS: 439.2 [M+H] + .

[0193] 1HNMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.18 (s, 1H), 7.08 (s, 1H), 4.96 (s, 2H), 4.54 - 4.45 (m, 1H), 4.26 - 4.19 (m, 2H), 3.89 - 3.78 (m, 2H), 2.93 (t, J = 7.5 Hz, 2H), 2.45 (dd, J = 8.5, 6.7 Hz, 2H), 1.99 (d, J = 7.2 Hz, 2H), 1.79 (d, J = 10.5 Hz, 4H), 1.64 (d, J = 12.0 Hz, 1H), 1.34 (q, J = 16.0, 14.4 Hz, 3H).

[0194] Example 4: Synthesis of compound S4

[0195] First step:

[0196] Cyclohexylamine 0.29 g (1 eq 3 mmol) was dissolved with THF 10 ml, added N,N- diisopropylethylamine (DIPEA) 0.97 g (2.5 eq, 7.5 mmol), added lactone 0.3 g (1 eq, 3 mmol), reaction at 60 degrees for 5 h, after the end of the system to room temperature, diluted with EA 120 ml, the organic phase washed with water 3 times, the organic phase dried and concentrated (30 degrees), white oil, 0.6 g yield 100% (theoretical).

[0197] Second step:

[0198] The product of the first step was dissolved with DCE 25 ml, ice bath to 0 degrees, added 1.2 g PCl5 (2 eq, 6 mmol) in batches, after adding, stirred at room temperature for 2 h, then added TMSN3 1.17 g (3.5 eq, 10.22 mmol) at room temperature, stirred at room temperature for 30 min, warmed to 60 degrees for 3 h. After the end of the addition, diluted with EA 120 ml, the organic phase washed with water 3 times, the organic phase dried and concentrated (30 degrees). 0.62 g yield 85%.

[0199] Third step:

[0200] Take quinolinone 0.7 g (1.2 eq, 3.06 mmol), add 0.46 g DBU (1.2 eq, 3.06 mmol), add DMF 5 ml, warm to 80 degrees until clear, add second step product 0.62 g (1 eq, 2.55 mmol) and 92 mg TBAI (0.1 eq, 0.25 mmol), 80 degrees for 8 h, organic phase diluted with EA and washed with 0.5 N NaOH 2x, organic phase dried and concentrated (30 degrees), crude purified with 200-300 mesh silica gel (HE:EA = 4:1, start gradient elution to HE:EA = 1:4), product collected, concentrated, while not completely dry, add HE to crystallize, suction filtered to give white solid 0.33 g 30% yield.

[0201] ESI-MS: 439.2 [M+H] + .

[0202] 1 HNMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 7.17 (d, J = 2.8 Hz, 1H), 6.99 (d, J = 2.8 Hz, 1H), 4.97 (s, 2H), 4.52 (tt, J = 11.3, 3.9 Hz, 1H), 4.21 - 4.13 (m, 2H), 3.87 - 3.74 (m, 2H), 2.93 (dd, J = 8.6, 6.1 Hz, 2H), 2.50 - 2.45 (m, 2H), 2.06 - 1.97 (m, 2H), 1.87 - 1.74 (m, 4H), 1.65 (d, J = 12.2 Hz, 1H), 1.43 - 1.23 (m, 3H).

[0203] Example 5: Synthesis of compound S5

[0204] First step:

[0205] Cyclohexylamine 0.29 g (1 eq, 3 mmol) dissolved in THF 10 ml, add DIPEA 0.97 g (2.5 eq, 7.5 mmol), add lactone 0.3 g (1 eq, 3 mmol), 60 degrees for 5 h, after completion the system is brought to room temperature, diluted with EA 120 ml, the organic phase is washed with water 3x, the organic phase is dried and concentrated (30 degrees), to give white oil, 0.6 g yield 100% (theoretical).

[0206] Second step:

[0207] The first step product was dissolved in DCE 25 ml, ice bath to 0°C, 1.2 g of PCl5(2 eq, 6 mmol) was added in portions, after the addition was completed, it was stirred at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, it was stirred at room temperature for 30 min, and then it was heated to 60°C for 3 h. After the end, it was diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30°C). 0.62 g yield 85%.

[0208] Third step:

[0209] Quinolinone 0.53 g (1.2 eq, 3.06 mmol) was taken, 0.70 g of K2CO3(2 eq, 5.1 mmol) was added, DMF 5 ml was added, it was heated to 80°C until it was clear, the second step product 0.62 g (1 eq, 2.55 mmol) and 92 mg of TBAI (0.1 eq, 0.25 mmol) were added, it was reacted at 80°C for 8 h, the organic phase was diluted with EA and washed with 0.5 N NaOH 2 times, the organic phase was dried and concentrated (30°C), the crude was purified with 200-300 mesh silica gel (HE: EA = 4: 1, start gradient elution, to HE: EA = 1:4), the product was collected, concentrated and when it was not completely concentrated, it was crystallized with HE, white solid was obtained by suction filtration. 0.29 g 30% yield.

[0210] ESI-MS: 383.3 [M+H] + .

[0211] 1 HNMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 7.82 (d, J = 9.5 Hz, 1H), 7.08 - 6.98 (m, 2H), 6.50 (d, J = 9.2 Hz, 1H), 4.98 (s, 2H), 4.53 (t, J = 11.0 Hz, 1H), 4.14 (t, J = 4.4 Hz, 2H), 3.83 (t, J = 4.4 Hz, 2H), 2.39 (s, 3H), 2.03 (m, 2H), 1.80 (m, 4H), 1.64 (m, 1H), 1.35 (m, 3H).

[0212] Example 6: Synthesis of compound S6

[0213] First step:

[0214] R, R-ortho-fluorocyclohexylamine hydrochloride 0.45 g (1 eq, 3 mmol) was dissolved in THF 10 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, lactone 0.3 g (1 eq, 3 mmol) was added, reaction at 60 degrees for 5 h, after completion the system was brought to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees), white oil was obtained, 0.65 g, 100% yield (theoretical).

[0215] Second step:

[0216] The product of the first step was dissolved in DCE 25 ml, ice bath to 0 degrees, 1.2 g of PCI5 (2 eq, 6 mmol) was added in portions, after addition, stirring at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, stirring at room temperature for 30 min, warming to 60 degrees for 3 h. After completion, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees). 0.67 g, 85% yield.

[0217] Third step:

[0218] Quinolinone 0.7 g (1.2 eq, 3.06 mmol) was taken, 0.46 g of DBU (1.2 eq, 3.06 mmol) was added, DMF 5 ml was added, warming to 80 degrees until the solution was clear, the product of the second step 0.67 g (1 eq, 2.55 mmol) and 92 mg of TBAI (0.1 eq, 0.25 mmol) were added, reaction at 80 degrees for 8 h, the organic phase was diluted with EA and washed with 0.5 N NaOH 2 times, the organic phase was dried and concentrated (30 degrees), the crude product was purified on 200-300 mesh silica gel (HE: EA = 4: 1, start gradient elution, to HE: EA = 1: 4), the product was collected, concentrated, when not completely concentrated, HE was added to crystallize, suction filtration to obtain white solid 0.35 g, 30% yield.

[0219] ESI-MS: 457.2 [M+H] + .

[0220] 1 HNMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 7.19 (s, 1H), 7.09 (s, 1H), 5.09-4.85 (m, 3H), 4.79-4.68 (m, 1H), 4.22 (m, 2H), 3.91-3.80 (m, 2H), 2.93 (t, J = 7.6 Hz, 2H), 2.45 (dd, J = 8.5, 6.6 Hz, 2H), 2.19 (s, 1H), 2.07 (s, 1H), 1.97-1.49 (m, 6H).

[0221] Example 7: Synthesis of compound S7

[0222] First step:

[0223] R, R-ortho-fluorocyclohexylamine hydrochloride 0.45 g (1 eq, 3 mmol) was dissolved in THF 10 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, lactone 0.3 g (1 eq, 3 mmol) was added, reaction at 60 degrees for 5 h, after the end of the reaction the system was brought to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees), white oil was obtained, 0.65 g yield 100% (theoretical).

[0224] Second step:

[0225] The product of the first step was dissolved in DCE 25 ml, ice bath to 0 degrees, 1.2 g of PCl5 (2 eq, 6 mmol) was added in portions, after the addition was completed, it was stirred at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, it was stirred at room temperature for 30 min, the temperature was raised to 60 degrees and the reaction was carried out for 3 h. After the end of the reaction, EA 120 ml was added for dilution, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees). 0.67 g yield 85%.

[0226] Third step:

[0227] Quinolinone 0.49 g (1.2 eq, 3.06 mmol) was taken, 0.70 g of K2CO3 (2 eq, 5.1 mmol) was added, DMF 5 ml was added, the temperature was raised to 80 degrees until the solution was clear, the product of the second step 0.67 g (1 eq, 2.55 mmol) and 92 mg of TBAI (0.1 eq, 0.25 mmol) were added, the reaction was carried out at 80 degrees for 8 h, the organic phase was diluted with EA and washed with 0.5 N NaOH 2 times, the organic phase was dried and concentrated (30 degrees), the crude product was purified on 200-300 mesh silica gel (HE: EA = 4: 1, start gradient elution, to HE: EA = 1:4), the product was collected, concentrated and, when not completely dried, EA was added to crystallize, and white solid 0.29 g was obtained by suction filtration, 30% yield.

[0228] ESI-MS: 389.2 [M+H ]+ .

[0229] 1HNMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 6.82 - 6.68 (m, 3H), 5.07 - 4.87 (m, 3H), 4.76 (m, 1H), 4.12 - 4.01 (m, 2H), 3.80 (q, J = 4.5 Hz, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.40 (dd, J = 8.5, 6.5 Hz, 2H), 2.16 (m, 2H), 1.92 - 1.31 (m, 6H).

[0230] Example 8: Synthesis of compound S8

[0231] First step:

[0232] Cyclohexylamine 0.29 g (1 eq, 3 mmol) was dissolved in THF 10 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, lactone 0.3 g (1 eq, 3 mmol) was added, reaction at 60 degrees for 5 h, after the end of the reaction the system was brought to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees), white oil was obtained, 0.6 g yield 100% (theoretical).

[0233] Second step:

[0234] The product of the first step was dissolved in DCE 25 ml, ice bath to 0 degrees, 1.2 g of PCl5 (2 eq, 6 mmol) was added in portions, after the addition was completed, stirring at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, stirring at room temperature for 30 min, warming to 60 degrees for 3 h. After the end of the reaction, dilution was carried out with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees). 0.62 g yield 85%.

[0235] Third step:

[0236] Quinolinone 0.7 g (1.2 eq, 3.06 mmol) was taken, 0.46 g of DBU (1.2 eq, 3.06 mmol) was added, DMF 5 ml was added, warming to 80 degrees until the solution was clear, the product of the second step 0.62 g (1 eq, 2.55 mmol) and 92 mg of TBAI (0.1 eq, 0.25 mmol) were added, reaction at 80 degrees for 8 h, the organic phase was diluted with EA and washed with 0.5 N NaOH 2 times, the organic phase was dried and concentrated (30 degrees), the crude product was purified on 200-300 mesh silica gel (HE: EA = 4: 1, start gradient elution, to HE: EA = 1: 4), the product was collected, concentrated, when not completely concentrated, HE was added to crystallize, white solid was obtained by suction filtration, 0.33 g 30% yield.

[0237] ESI-MS: 437.2 [M+H] + .

[0238] 1 HNMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.21 (d, J = 9.0 Hz, 1H), 7.57 (d, J = 2.7 Hz, 1H), 7.41 (d, J = 2.7 Hz, 1H), 7.02 (d, J = 9.0 Hz, 1H), 4.95 (d, J = 7.8 Hz, 2H), 4.64 - 4.44 (m, 3H), 3.90 (t, J = 4.6 Hz, 2H), 1.99 (m, 2H), 1.81 (m, 4H), 1.62 (m, 1H), 1.30 (m, 3H).

[0239] Example 9: Synthesis of compound S9

[0240] First step:

[0241] Cyclohexylamine 0.29 g (1 eq, 3 mmol) was dissolved with THF 10 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, lactone 0.3 g (1 eq, 3 mmol) was added, reaction at 60 degrees for 5h, after the end of the system was reduced to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees), white oil was obtained, 0.6 g yield 100% (theoretical).

[0242] Second step:

[0243] The product of the first step was dissolved with DCE 25 ml, ice bath to 0 degrees, 1.2 g PCl5 (2 eq, 6 mmol) was added in batches, after adding, stirring at room temperature for 2h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, stirring at room temperature for 30 min, warming to 60 degrees for 3h. After the end of the system was reduced to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees). 0.62 g yield 85%.

[0244] Third step:

[0245] Take quinolinone 0.6 g (1.2 eq, 3.06 mmol), add 0.46 g DBU (1.2 eq, 3.06 mmol), add DMF 5 ml, warm to 80 degrees until clear, add second step product 0.62 g (1 eq, 2.55 mmol) and 92 mg TBAI (0.1 eq, 0.25 mmol), 80 degrees for 8 h, add EA to dilute the organic phase and wash with 0.5 N NaOH 2 times, dry the organic phase and concentrate (30 degrees), purify the crude product with 200-300 mesh silica gel (HE:EA = 4:1, start gradient elution to HE:EA = 1:4), collect the product, concentrate, when not completely concentrated dry, add HE to crystallize, suction filter to get white solid 0.31 g 30% yield.

[0246] ESI-MS: 403.2 [M+H] + .

[0247] 1 HNMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.88 (d, J = 9.6 Hz, 1H), 7.35 - 7.24 (m, 2H), 6.60 (d, J = 9.6 Hz, 1H), 4.98 (s, 2H), 4.52 (t, J = 11.6 Hz, 1H), 4.20 (t, J = 4.3 Hz, 2H), 3.84 (t, J = 4.3 Hz, 2H), 2.01 (m, 2H), 1.80 (m, 4H), 1.64 (m, 1H), 1.41 - 1.28 (m, 3H).

[0248] Example 10: Synthesis of compound S10

[0249] First step:

[0250] Cyclohexylamine 0.29 g (1 eq, 3 mmol) was dissolved in THF 10 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, lactone 0.3 g (1 eq, 3 mmol) was added, 60 degrees for 5 h, after the end of the system was reduced to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees), white oil was obtained, 0.6 g yield 100% (theoretical).

[0251] Second step:

[0252] The first step product was dissolved in DCE 25 ml, ice bath to 0°C, 1.2 g of PCl5(2 eq, 6 mmol) was added in portions, after the addition was completed, it was stirred at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, and stirred at room temperature for 30 min, and then the temperature was raised to 60°C for 3 h. After the reaction was completed, EA 120 ml was added for dilution, the organic phase was washed with water 3 times, and the organic phase was dried and concentrated (30°C). The yield was 0.62 g, 85%.

[0253] Third step:

[0254] The quinolinone 0.55 g (1.2 eq, 3.06 mmol) was taken, 0.46 g of DBU (1.2 eq, 3.06 mmol) was added, DMF 5 ml was added, the temperature was raised to 80°C until the solution was clear, the second step product 0.62 g (1 eq, 2.55 mmol) and 92 mg of TBAI (0.1 eq, 0.25 mmol) were added, and the reaction was carried out at 80°C for 8 h. The organic phase was diluted with EA and washed with 0.5N NaOH 2 times, the organic phase was dried and concentrated (30°C), the crude product was purified with 200-300 mesh silica gel (HE: EA = 4: 1, start gradient elution, to HE: EA = 1: 4), the product was collected, concentrated, and when not completely concentrated, HE was added for crystallization, and white solid 0.33 g was obtained by suction filtration, with a yield of 30%.

[0255] ESI-MS: 387.2 [M+H] + .

[0256] 1 HNMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.9 (d, J = 9.6 Hz, 1H), 7.45-7.34 (m, 2H), 6.70 (d, J = 9.6 Hz, 1H), 4.98 (s, 2H), 4.52 (t, J = 11.6 Hz, 1H), 4.20 (t, J = 4.3 Hz, 2H), 3.84 (t, J = 4.3 Hz, 2H), 2.01 (m, 2H), 1.80 (m, 4H), 1.64 (m, 1H), 1.41-1.28 (m, 3H).

[0257] Example 11: Synthesis of compound S11

[0258] First step:

[0259] S, S-ortho-fluorocyclohexylamine hydrochloride 0.45 g (1 eq, 3 mmol) was dissolved in THF 10 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, lactone 0.3 g (1 eq, 3 mmol) was added, reaction at 60 degrees for 5 h, after the end of the reaction the system was brought to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees), white oil was obtained, 0.65 g yield 100% (theoretical).

[0260] Second step:

[0261] The product of the first step was dissolved in DCE 25 ml, ice bath to 0 degrees, 1.2 g of PCl5 (2 eq, 6 mmol) was added in portions, after the addition was complete it was stirred at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, it was stirred at room temperature for 30 min, it was heated to 60 degrees for 3 h. After the end of the reaction, EA 120 ML was added to dilute it, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees). 0.67 g yield 85%.

[0262] Third step:

[0263] Quinolinone 0.6 g (1.2 eq, 3.06 mmol) was taken, 0.46 g of DBU (1.2 eq, 3.06 mmol) was added, DMF 5 ml was added, it was heated to 80 degrees until it was clear, the product of the second step 0.67 g (1 eq, 2.55 mmol) and 92 mg of TBAI (0.1 eq, 0.25 mmol) were added, it was reacted at 80 degrees for 8 h, the organic phase was diluted with EA and washed with 0.5 N NaOH 2 times, the organic phase was dried and concentrated (30 degrees), the crude product was purified on 200-300 mesh silica gel (HE: EA = 4: 1, start gradient elution, to HE: EA = 1: 4, collect the product, concentrate, when not completely concentrated, add HE to crystallize, suction filter to obtain white solid) 0.32 g 30% yield.

[0264] ESI-MS: 421.2 [M+H] + .

[0265] 1 HNMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.89 (d, J = 9.6 Hz, 1H), 7.31 (dd, J = 17.9, 2.7 Hz, 2H), 6.61 (d, J = 9.5 Hz, 1H), 5.08 - 4.85 (m, 4H), 4.82 - 4.70 (m, 1H), 4.20 (t, J = 4.4 Hz, 2H), 3.85 (d, J = 4.5 Hz, 2H), 2.19 (s, 1H), 1.51 - 1.38 (m, 2H).

[0266] Example 12: Synthesis of compound S12

[0267] First step:

[0268] S, S-ortho-fluorocyclohexylamine hydrochloride 0.45 g (1 eq, 3 mmol) was dissolved in THF 10 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, lactone 0.3 g (1 eq, 3 mmol) was added, reaction at 60 degrees for 5 h, after the end of the reaction the system was brought to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees), white oil was obtained, 0.65 g yield 100% (theoretical).

[0269] Second step:

[0270] The product of the first step was dissolved in DCE 25 ml, ice bath to 0 degrees, 1.2 g of PCl5 (2 eq, 6 mmol) was added in portions, after the addition was completed, it was stirred at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, it was stirred at room temperature for 30 min, the temperature was raised to 60 degrees and the reaction was carried out for 3 h. After the end of the reaction, EA 120 ml was added for dilution, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees). 0.67 g yield 85%.

[0271] Third step:

[0272] Quinolinone 0.55 g (1.2 eq, 3.06 mmol) was taken, 0.46 g of DBU (1.2 eq, 3.06 mmol) was added, DMF 5 ml was added, the temperature was raised to 80 degrees until the solution was clear, the product of the second step 0.67 g (1 eq, 2.55 mmol) and 92 mg of TBAI (0.1 eq, 0.25 mmol) were added, the reaction was carried out at 80 degrees for 8 h, the organic phase was diluted with EA and washed with 0.5 N NaOH 2 times, the organic phase was dried and concentrated (30 degrees), the crude product was purified on 200-300 mesh silica gel (HE: EA = 4: 1, start gradient elution, to HE: EA = 1:4), the product was collected, concentrated and, when not completely dried, HE was added to crystallize, white solid was obtained by suction filtration, 0.31 g 30% yield.

[0273] ESI-MS: 405.2 [M+H] + .

[0274] 1HNMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 7.86 (d, J = 9.6 Hz, 1H), 7.16 - 7.07 (m, 2H), 6.57 (d, J = 9.6 Hz, 1H), 4.98 (m, 2H), 4.77 (m, 2H), 4.17 (t, J = 4.2 Hz, 2H), 3.84 (q, J = 3.9 Hz, 2H), 2.19 (m, 2H), 2.10 (m, 2H), 1.75 (m, 4H).

[0275] Example 13: Synthesis of compound S13

[0276] First step:

[0277] Cyclohexylamine 0.29 g (1 eq, 3 mmol) was dissolved in THF 10 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, lactone 0.3 g (1 eq, 3 mmol) was added, reaction at 60 degrees for 5 h, after the end of the reaction the system was brought to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees), white oil was obtained, 0.6 g yield 100% (theoretical).

[0278] Second step:

[0279] The product of the first step was dissolved in DCE 25 ml, ice bath to 0 degrees, 1.2 g of PCl5 (2 eq, 6 mmol) was added in portions, after the addition was completed, stirring at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, stirring at room temperature for 30 min, warming to 60 degrees for 3 h. After the end of the reaction, dilution was carried out with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees). 0.62 g yield 85%.

[0280] Third step:

[0281] Quinolinone 0.6 g (1.2 eq, 3.06 mmol) was taken, 0.46 g of DBU (1.2 eq, 3.06 mmol) was added, DMF 5 ml was added, warming to 80 degrees until the solution was clear, the product of the second step 0.62 g (1 eq, 2.55 mmol) and 92 mg of TBAI (0.1 eq, 0.25 mmol) were added, reaction at 80 degrees for 8 h, the organic phase was diluted with EA and washed with 0.5 N NaOH 2 times, the organic phase was dried and concentrated (30 degrees), the crude product was purified on 200-300 mesh silica gel (HE: EA = 4: 1, start gradient elution, to HE: EA = 1: 4), the product was collected, concentrated, when not completely concentrated, HE was added to crystallize, white solid was obtained by suction filtration, 0.31 g 30% yield.

[0282] ESI-MS: 405.2 [M+H] + .

[0283] 1 HNMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 7.84 (d, J = 9.6 Hz, 1H), 7.35 (dd, J = 8.2, 2.0 Hz, 1H), 6.55 (d, J = 9.5 Hz, 1H), 4.98 (s, 2H), 4.57 - 4.49 (m, 1H), 4.32 - 4.22 (m, 2H), 3.93 - 3.84 (m, 2H), 2.01 (m, 2H), 1.84 - 1.76 (m, 4H), 1.64 (m, 1H), 1.42 - 1.30 (m, 3H).

[0284] Example 14: Synthesis of compound S14

[0285] First step:

[0286] Cyclohexylamine 0.29 g (1 eq, 3 mmol) was dissolved with THF 10 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, lactone 0.3 g (1 eq, 3 mmol) was added, reaction at 60 degrees for 5h, after the end of the system was reduced to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees), white oil was obtained, 0.6 g yield 100% (theoretical).

[0287] Second step:

[0288] The product of the first step was dissolved with DCE 25 ml, ice bath to 0 degrees, 1.2 g PCl5 (2 eq, 6 mmol) was added in batches, after adding, stirring at room temperature for 2h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, stirring at room temperature for 30 min, warming to 60 degrees for 3h. After the end of the system was reduced to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees). 0.62 g yield 85%.

[0289] Third step:

[0290] Take quinolinone 0.7 g (1.2 eq, 3.06 mmol), add 0.46 g DBU (1.2 eq, 3.06 mmol), add DMF 5 ml, warm to 80 degrees until clear, add second step product 0.62 g (1 eq, 2.55 mmol) and 92 mg TBAI (0.1 eq, 0.25 mmol), 80 degrees for 8 h, add EA to the organic phase and dilute, wash with 0.5 N NaOH 2 times, dry the organic phase and concentrate (30 degrees), purify the crude product with 200-300 mesh silica gel (HE:EA = 4:1, start gradient elution to HE:EA = 1:4), collect the product, concentrate, when not completely concentrated dry, add HE to crystallize, suction filter to get white solid 0.33 g 30% yield.

[0291] ESI-MS: 437.2 [M+H] + .

[0292] 1 HNMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H), 8.09 (d, J = 9.8 Hz, 1H), 7.44 (s, 1H), 6.73 (d, J = 9.9 Hz, 1H), 5.01 (s, 2H), 4.61 - 4.52 (m, 1H), 4.33 (d, J = 4.5 Hz, 2H), 3.99 (s, 2H), 1.96 (m, 2H), 1.73 (m, 4H), 1.50 (m, 1H), 1.29 - 1.18 (m, 3H).

[0293] Example 15: Synthesis of compound S15

[0294] First step:

[0295] S, S-ortho-fluorocyclohexylamine hydrochloride 0.45 g (1 eq, 3 mmol) was dissolved with THF 10 ml, added DIPEA 0.97 g (2.5 eq, 7.5 mmol), added lactone 0.3 g (1 eq, 3 mmol), 60 degrees for 5 h, after the end of the system to room temperature, dilute with EA 120 ml, wash the organic phase with water 3 times, dry the organic phase and concentrate (30 degrees) to get white oil, 0.65 g yield 100% (theoretical).

[0296] Second step:

[0297] The first step product was dissolved in DCE 25 ml, ice bath to 0°C, 1.2 g of PCl5(2 eq, 6 mmol) was added in portions, after the addition was completed, it was stirred at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, it was stirred at room temperature for 30 min, and then it was warmed to 60°C for 3 h. After completion, it was diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30°C). The yield was 0.67 g, 85%.

[0298] Third step:

[0299] The quinolinone 0.6 g (1.2 eq, 3.06 mmol) was taken, 0.46 g of DBU (1.2 eq, 3.06 mmol) was added, DMF 5 ml was added, it was warmed to 80°C until it was clear, the second step product 0.67 g (1 eq, 2.55 mmol) and 92 mg of TBAI (0.1 eq, 0.25 mmol) were added, it was reacted at 80°C for 8 h, the organic phase was diluted with EA and washed with 0.5 N NaOH 2 times, the organic phase was dried and concentrated (30°C), the crude product was purified with 200-300 mesh silica gel (HE: EA = 4: 1, start gradient elution, to HE: EA = 1:4), the product was collected, concentrated and, when it was not completely concentrated, it was crystallized with HE, and a white solid 0.32 g was obtained by suction filtration, with a yield of 30%.

[0300] ESI-MS: 423.2 [M+H] + .

[0301] 1 HNMR (400 MHz, DMSO-d6) δ 7.85 (dd, J = 9.6, 1.4 Hz, 1H), 7.36 (dd, J = 8.2, 2.0 Hz, 1H), 6.55 (d, J = 9.6 Hz, 1H), 5.06 - 4.87 (m, 3H), 4.82 - 4.72 (m, 1H), 4.27 (dd, J = 5.1, 3.5 Hz, 2H), 3.89 (q, J = 3.7 Hz, 2H), 2.25 - 2.06 (m, 2H), 1.89 (m, 1H), 1.75 (m, 2H), 1.63 - 1.51 (m, 1H), 1.50 - 1.28 (m, 2H).

[0302] Example 16: Synthesis of compound S16

[0303] First step:

[0304] R, R-ortho-fluorocyclohexylamine hydrochloride 0.45 g (1 eq, 3 mmol) was dissolved in THF 10 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, lactone 0.3 g (1 eq, 3 mmol) was added, reaction at 60 degrees for 5 h, after the end of the reaction the system was brought to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees), white oil was obtained, 0.65 g yield 100% (theoretical).

[0305] Second step

[0306] The product of the first step was dissolved in DCE 25 ml, ice bath to 0 degrees, 1.2 g of PCl5 (2 eq, 6 mmol) was added in portions, after the addition was complete it was stirred at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, it was stirred at room temperature for 30 min, it was brought to 60 degrees for 3 h. After the end of the reaction, it was diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees). 0.67 g yield 85%.

[0307] Third step

[0308] Quinolinone 0.7 g (1.2 eq, 3.06 mmol) was taken, 0.46 g of DBU (1.2 eq, 3.06 mmol) was added, DMF 5 ml was added, it was brought to 80 degrees until it was clear, the product of the second step 0.67 g (1 eq, 2.55 mmol) and 92 mg of TBAI (0.1 eq, 0.25 mmol) were added, it was reacted at 80 degrees for 8 h, the organic phase was diluted with EA and washed with 0.5 N NaOH 2 times, the organic phase was dried and concentrated (30 degrees), the crude product was purified on 200-300 mesh silica gel (HE: EA = 4: 1, start gradient elution, to HE: EA = 1:4), the product was collected, concentrated, when it was not completely concentrated, it was crystallized with HE, it was filtered to give a white solid 0.35 g 30% yield.

[0309] ESI-MS: 457.2 [M+H] + .

[0310] HNMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 9.8 Hz, 1H), 7.44 (s, 1H), 6.73 (d, J = 9.8 Hz, 1H), 5.01 (m, 2H), 4.82 (m, 2H), 4.32 (m, 2H), 4.00 (m, 2H), 2.09 (m, 3H), 1.88 - 1.74 (m, 2H), 1.58 (m, 3H).

[0311] Example 17: Synthesis of compound S17

[0312] First step:

[0313] R, R-ortho-fluorocyclohexylamine hydrochloride 0.45 g (1 eq, 3 mmol) was dissolved in THF 10 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, lactone 0.3 g (1 eq, 3 mmol) was added, reaction at 60 degrees for 5 h, after the end of the reaction the system was brought to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees), white oil was obtained, 0.65 g yield 100% (theoretical).

[0314] Second step:

[0315] The product of the first step was dissolved in DCE 25 ml, ice bath to 0 degrees, 1.2 g of PCl5 (2 eq, 6 mmol) was added in portions, after the addition was complete, it was stirred at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, it was stirred at room temperature for 30 min, the temperature was raised to 60 degrees and it was reacted for 3 h. After the end of the reaction, EA 120 ml was added for dilution, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees). 0.67 g yield 85%.

[0316] Third step:

[0317] Quinolinone 0.49 g (1.2 eq, 3.06 mmol) was taken, 0.70 g of K2CO3 (2 eq, 5.1 mmol) was added, DMF 5 ml was added, the temperature was raised to 80 degrees until the solution was clear, the product of the second step 0.67 g (1 eq, 2.55 mmol) and 92 mg of TBAI (0.1 eq, 0.25 mmol) were added, the reaction was carried out at 80 degrees for 8 h, the organic phase was diluted with EA and washed with 0.5 N NaOH 2 times, the organic phase was dried and concentrated (30 degrees), the crude product was purified on 200-300 mesh silica gel (HE: EA = 4:1, start gradient elution, up to HE: EA = 1:4), the product was collected, concentrated and, when not completely dry, it was recrystallized with HE, white solid was obtained by suction filtration, 0.29 g 30% yield.

[0318] ESI-MS: 387.2 [M+H] + .

[0319] 1HNMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 9.6 Hz, 1H), 7.28 - 7.19 (m, 2H), 7.14 (dd, J = 8.9, 2.8 Hz, 1H), 6.49 (d, J = 9.5 Hz, 1H), 4.99 (m, 3H), 4.79 (m, 1H), 4.20 - 4.13 (m, 2H), 3.85 (m, 2H), 2.24 - 2.06 (m, 2H), 1.94 - 1.83 (m, 1H), 1.74 (m, 2H), 1.58 (m, 1H), 1.49 - 1.34 (m, 2H).

[0320] Example 18: Synthesis of compound S18

[0321] First step:

[0322] Cyclohexylamine 0.29 g (1 eq, 3 mmol) was dissolved with DCM 15 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, the system was cooled to 5 degrees, acyl chloride 0.55 g (1.2 eq, 3.6 mmol) was added, and it was reacted at room temperature for 7 h. After the reaction was completed, it was diluted with DCM 120 ml, the organic phase was washed with water 3 times, and the organic phase was dried and concentrated (30 degrees). White oil was obtained, 0.65 g, yield 100% (theoretical).

[0323] Second step:

[0324] The product of the first step was dissolved with DCE 25 ml, and it was cooled to 0 degrees in an ice bath. PCl5 0.75 g (1.2 eq, 3.6 mmol) was added in portions, and after the addition was completed, it was stirred at room temperature for 2 h. Then, TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, and it was stirred at room temperature for 30 min. The temperature was increased to 60 degrees, and it was reacted for 3 h. After the reaction was completed, it was diluted with EA 120 ml, the organic phase was washed with water 3 times, and the organic phase was dried and concentrated (30 degrees). 0.61 g, yield 85%.

[0325] Third step:

[0326] Take quinolinone 0.6 g (1.2 eq, 3.06 mmol), add 0.46 g DBU (1.2 eq, 3.06 mmol), add DMF 5 ml, warm to 80 degrees until clear, add second step product 0.61 g (1 eq, 2.55 mmol) and 92 mg TBAI (0.1 eq, 0.25 mmol), 80 degrees for 8 h, organic phase diluted with EA and washed with 0.5 N NaOH 2x, organic phase dried and concentrated (30 degrees), crude purified with 200-300 mesh silica gel (HE:EA = 4:1, start gradient elution to HE:EA = 1:4), product collected, concentrated, while not completely dry, add HE to crystallize, suction filtered to give white solid 0.3 g 30% yield.

[0327] ESI-MS: 403.2 [M+H] + .

[0328] 1 HNMR (400 MHz, DMSO-d6) δ 7.87 (dd, J = 9.6, 1.4 Hz, 1H), 7.36 (dd, J = 8.2, 2.0 Hz, 1H), 6.55 (d, J = 9.6 Hz, 1H), 4.41 (m, 1H), 4.21 - 4.13 (m, 2H), 3.00 (m, 2H), 1.97 (m, 2H), 1.93 - 1.72 (m, 8H), 1.68 (m, 1H), 1.43 (m, 2H), 1.27 (m, 1H).

[0329] Example 19: Synthesis of compound S19

[0330] First step:

[0331] Cyclohexylamine 0.29 g (1 eq, 3 mmol) dissolved in DCM 15 ml, add DIPEA 0.97 g (2.5 eq, 7.5 mmol), system cooled to 5 degrees, add acyl chloride 0.55 g (1.2 eq, 3.6 mmol), room temperature for 7 h, after completion diluted with DCM 120 ml, organic phase washed with water 3x, organic phase dried and concentrated (30 degrees), white oil 0.65 g yield 100% (theoretical).

[0332] Second step:

[0333] First step product dissolved in DCE 25 ml, ice bath to 0 degrees, 0.75 g PCl5 (1.2 eq, 3.6 mmol) added in portions, after addition complete, stirred at room temperature for 2 h, then added TMSN3 1.17 g (3.5 eq, 10.22 mmol) at room temperature, stirred at room temperature for 30 min, warmed to 60 degrees for 3 h. After completion, diluted with EA 120 ml, organic phase washed with water 3 times, organic phase dried and concentrated (30 degrees). 0.61 g yield 85%.

[0334] Third step:

[0335] Quinolinone 0.6 g (1.2 eq, 3.06 mmol) added 0.46 g DBU (1.2 eq, 3.06 mmol), added DMF 5 ml, warmed to 80 degrees until clear, added second step product 0.61 g (1 eq, 2.55 mmol) and 92 mg TBAI (0.1 eq, 0.25 mmol), 80 degrees for 8 h, organic phase diluted with EA and washed with 0.5 N NaOH 2 times, organic phase dried and concentrated (30 degrees), crude purified with 200-300 mesh silica gel (HE:EA = 4: 1, start gradient elution, to HE:EA = 1:4), product collected, concentrated, while not completely dry, added HE to crystallize, suction filtered to white solid 0.3 g 30% yield.

[0336] ESI-MS: 401.2 [M+H] + .

[0337] 1 HNMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 9.9 Hz, 0.5H), 7.86 (d, J = 9.6 Hz, 0.05H), 7.48 - 7.44 (m, 1H), 7.37 (s, 0.5H), 7.27 (d, J = 9.1 Hz, 0.5H), 6.63 (d, J = 9.8 Hz, 0.5H), 6.52 (d, J = 9.5 Hz, 0.5H), 4.45 - 4.35 (m, 1H), 4.15 (q, J = 5.5 Hz, 2H), 3.01 (td, J = 7.8, 7.3, 3.2 Hz, 2H), 2.01 - 1.73 (m, 9H), 1.67 (m, 1H), 1.41 (m, 2H), 1.24 (m, 2H).

[0338] Example 20: Synthesis of compound S20

[0339] First step:

[0340] Cyclohexylamine 0.29 g (1 eq, 3 mmol) was dissolved in DCM 15 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, the system was cooled to 5 degrees, acyl chloride 0.55 g (1.2 eq, 3.6 mmol) was added, the reaction was carried out at room temperature for 7 h, after which the system was diluted with DCM 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees), a white oil was obtained, 0.65 g, yield 100% (theoretical).

[0341] Second step:

[0342] The product of the first step was dissolved in DCE 25 ml, it was cooled to 0 degrees in an ice bath, 0.75 g of PCI5 (1.2 eq, 3.6 mmol) was added in portions, after which it was stirred at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, it was stirred at room temperature for 30 min, it was heated to 60 degrees and the reaction was carried out for 3 h. After completion, it was diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees). 0.61 g, yield 85%.

[0343] Third step:

[0344] Quinolinone 0.58 g (1.2 eq, 3.06 mmol) was taken, 0.7 g of K2CO3 (2 eq, 5.1 mmol) was added, DMF 5 ml was added, it was heated to 80 degrees until it was clear, the product of the second step 0.61 g (1 eq, 2.55 mmol) and 92 mg of TBAI (0.1 eq, 0.25 mmol) were added, it was reacted at 80 degrees for 8 h, the organic phase was diluted with EA and washed with 0.5 N NaOH 2 times, the organic phase was dried and concentrated (30 degrees), the crude product was purified on 200-300 mesh silica gel (HE:EA = 4:1, start gradient elution, up to HE:EA = 1:4), the product was collected, concentrated and, when it was not completely dry, it was recrystallized with HE, it was filtered under suction to obtain a white solid 0.3 g, 30% yield.

[0345] ESI-MS: 395.3 [M+H] + .

[0346] 1 HNMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.81 (d, J = 9.5 Hz, 1H), 7.08 (s, 1H), 6.44 (d, J = 9.5 Hz, 1H), 4.41 (m, 1H), 4.04 (t, J = 5.7 Hz, 2H), 3.00 (t, J = 7.2 Hz, 2H), 2.34 (s, 3H), 2.22 (s, 3H), 1.95 - 1.79 (m, 8H), 1.67 (m, 1H), 1.57 (m, 1H), 1.41 (m, 2H), 1.30 (m, 2H).

[0347] Example 21: Synthesis of compound S21

[0348] First step:

[0349] Cyclohexylamine 0.29 g (1 eq, 3 mmol) was dissolved in THF 10 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, lactone 0.3 g (1 eq, 3 mmol) was added, reaction at 60 degrees for 5 h, after the end of the reaction the system was brought to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees), white oil was obtained, 0.6 g yield 100% (theoretical).

[0350] Second step:

[0351] The product of the first step was dissolved in DCE 25 ml, ice bath to 0 degrees, 1.2 g of PCl5 (2 eq, 6 mmol) was added in portions, after the addition was completed, stirring at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, stirring at room temperature for 30 min, warming to 60 degrees for 3 h. After the end of the reaction, dilution was carried out with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees). 0.62 g yield 85%.

[0352] Third step:

[0353] Quinolinone 0.58 g (1.2 eq, 3.06 mmol) was taken, 0.7 g of K2CO3 (2 eq, 5.1 mmol) was added, DMF 5 ml was added, warming to 80 degrees until the solution was clear, the product of the second step 0.62 g (1 eq, 2.55 mmol) and 92 mg of TBAI (0.1 eq, 0.25 mmol) were added, reaction at 80 degrees for 8 h, the organic phase was diluted with EA and washed with 0.5 N NaOH 2 times, the organic phase was dried and concentrated (30 degrees), the crude product was purified on 200-300 mesh silica gel (HE: EA = 4: 1, start gradient elution, to HE: EA = 1:4), the product was collected, concentrated, when not completely concentrated, HE was added to crystallize, and white solid 0.33 g was obtained by suction filtration, 30% yield.

[0354] ESI-MS: 397.3 [M+H] + .

[0355] 1HNMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 7.80 (d, J = 9.5 Hz, 1H), 7.08 (s, 1H), 6.45 (d, J = 9.4 Hz, 1H), 4.99 (s, 2H), 4.18 - 4.10 (m, 2H), 4.53 (m, 1H), 4.18 - 4.10 (m, 2H), 3.92 - 3.85 (m, 2H), 2.33 (s, 3H), 2.20 (s, 3H), 2.01 (m, 2H), 1.79 (m, 4H), 1.29 (m, 4H).

[0356] Example 22: Synthesis of compound S22

[0357] First step:

[0358] Intermediate 1 : 2-(2,6-difluorophenyl)-2-hydroxyacetic acid

[0359] Second step:

[0360] The product of the first step was dissolved in DCE 25 ml, and the solution was cooled to 0°C in an ice bath. 1.2 g of PCl5 (2 eq, 6 mmol) was added in portions. After the addition was complete, the solution was stirred at room temperature for 2 h. Then, TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, and the solution was stirred at room temperature for 30 min. The temperature was then increased to 60°C, and the solution was stirred at this temperature for 3 h. After the reaction was complete, EA 120 ml was added to dilute the solution. The organic phase was washed with water 3 times, and the organic phase was dried and concentrated (30°C). The yield was 0.71 g, 85%.

[0361] Third step:

[0362] Quinolinone 0.6 g (1.2 eq, 3.06 mmol) was added, followed by the addition of DBU 0.46 g (1.2 eq, 3.06 mmol). DMF 5 ml was added, and the solution was heated to 80°C until it became clear. The product of the second step 0.71 g (1 eq, 2.55 mmol) and TBAI 92 mg (0.1 eq, 0.25 mmol) were added, and the solution was stirred at 80°C for 8 h. The organic phase was diluted with EA and washed with 0.5 N NaOH 2 times. The organic phase was dried and concentrated (30°C). The crude product was purified using 200-300 mesh silica gel (HE:EA = 4:1, starting gradient elution, up to HE:EA = 1:4). The product was collected and concentrated. When the product was not completely dried, it was recrystallized using HE. The white solid was obtained by suction filtration. The yield was 0.34 g, 30%.

[0363] ESI-MS: 441.2 [M+H] + .

[0364] 1 HNMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 7.84 (d, J = 9.6 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 6.54 (d, J = 9.6 Hz, 1H), 5.02 (s, 2H), 4.74 (t, J = 11.9 Hz, 1H), 4.26 (t, J = 4.3 Hz, 2H), 3.89 (dd, J = 5.4, 3.1 Hz, 2H), 2.15 - 1.95 (m, 4H), 1.89 (m, 2H), 1.57 - 1.43 (m, 2H).

[0365] Example 23: Synthesis of compound S23

[0366] First step:

[0367] Intermediate 1.1 g (1 eq, 3 mmol) was dissolved in THF 10 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, then lactone 0.3 g (1 eq, 3 mmol) was added, and the reaction was carried out at 60°C for 5 h. After the reaction was completed, the system was cooled to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, and the organic phase was dried and concentrated (30°C). White oil was obtained, 0.71 g, yield 100% (theoretical).

[0368] Second step:

[0369] The product of the first step was dissolved in DCE 25 ml, and 1.2 g of PCl5 (2 eq, 6 mmol) was added in batches in an ice bath to 0°C. After the addition was complete, it was stirred at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, and stirred at room temperature for 30 min, then the temperature was raised to 60°C and the reaction was carried out for 3 h. After the reaction was completed, EA 120 ml was added for dilution, the organic phase was washed with water 3 times, and the organic phase was dried and concentrated (30°C). 0.71 g, yield 85%.

[0370] Third step:

[0371] Take quinolinone 0.6 g (1.2 eq, 3.06 mmol), add 0.46 g DBU (1.2 eq, 3.06 mmol), add DMF 5 ml, warm to 80 degrees until clear, add second step product 0.71 g (1 eq, 2.55 mmol) and 92 mg TBAI (0.1 eq, 0.25 mmol), 80 degrees for 8 h, add EA to dilute the organic phase and wash with 0.5 N NaOH 2x, dry the organic phase and concentrate (30 degrees), purify the crude product on 200-300 mesh silica gel (HE:EA = 4:1, start gradient elution to HE:EA = 1:4), collect the product, concentrate, while not completely dry, add HE to crystallize, suction filter to get white solid 0.33 g 30% yield.

[0372] ESI-MS: 439.2 [M+H] + .

[0373] 1 HNMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 7.87 (d, J = 9.5 Hz, 1H), 7.28 (dd, J = 15.8, 2.7 Hz, 2H), 6.60 (d, J = 9.4 Hz, 1H), 5.02 (d, J = 4.0 Hz, 2H), 4.75 (m, 1H), 4.19 (t, J = 4.3 Hz, 2H), 3.85 (d, J = 3.9 Hz, 2H), 2.01 (m, 2H), 1.91 (m, 2H), 1.81 - 1.73 (m, 2H), 1.55 - 1.45 (m, 2H).

[0374] Example 24: Synthesis of compound S24

[0375] First step:

[0376] R, R-ortho-fluorocyclohexylamine hydrochloride 0.45 g (1 eq, 3 mmol) was dissolved in THF 10 ml, added DIPEA 0.97 g (2.5 eq, 7.5 mmol), added lactone 0.3 g (1 eq, 3 mmol), 60 degrees for 5 h, after completion the system was brought to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3x, the organic phase was dried and concentrated (30 degrees), white oil was obtained, 0.65 g yield 100% (theoretical).

[0377] Second step:

[0378] The first step product was dissolved in DCE 25 ml, ice bath to 0°C, 1.2 g of PCl5(2 eq, 6 mmol) was added in portions, after the addition was completed, it was stirred at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, it was stirred at room temperature for 30 min, and then it was warmed to 60°C for 3 h. After completion, it was diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30°C). The yield was 0.67 g, 85%.

[0379] Third step:

[0380] The quinolinone 0.6 g (1.2 eq, 3.06 mmol) was taken, 0.46 g of DBU (1.2 eq, 3.06 mmol) was added, DMF 5 ml was added, it was warmed to 80°C until it was clear, the second step product 0.67 g (1 eq, 2.55 mmol) and 92 mg of TBAI (0.1 eq, 0.25 mmol) were added, it was reacted at 80°C for 8 h, the organic phase was diluted with EA and washed with 0.5 N NaOH 2 times, the organic phase was dried and concentrated (30°C), the crude product was purified with 200-300 mesh silica gel (HE: EA = 4: 1, start gradient elution, to HE: EA = 1:4), the product was collected, concentrated and, when it was not completely concentrated, it was crystallized with HE, and a white solid 0.32 g was obtained by suction filtration, with a yield of 30%.

[0381] ESI-MS: 423.2 [M+H] + .

[0382] 1 HNMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 7.85 (d, J = 9.7 Hz, 1H), 7.36 (dd, J = 8.2, 2.1 Hz, 1H), 6.55 (d, J = 9.6 Hz, 1H), 5.07 - 4.86 (m, 3H), 4.82 - 4.72 (m, 1H), 4.27 (dd, J = 5.3, 3.8 Hz, 2H), 3.94 - 3.82 (m, 2H), 2.25 - 2.06 (m, 2H), 1.89 (m, 1H), 1.73 (m, 2H), 1.65 - 1.53 (m, 1H), 1.44 (m, 2H).

[0383] Example 25: Synthesis of compound S25

[0384] First step:

[0385] R, R-ortho-fluorocyclohexylamine hydrochloride 0.45 g (1 eq, 3 mmol) was dissolved in THF 10 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, lactone 0.3 g (1 eq, 3 mmol) was added, reaction at 60 degrees for 5 h, after completion the system was brought to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees), white oil was obtained, 0.65 g, 100% yield (theoretical).

[0386] Second step:

[0387] The first step product was dissolved in DCE 25 ml, ice bath to 0 degrees, 1.2 g PCl5 (2 eq, 6 mmol) was added in portions, after addition, stirring at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, stirring at room temperature for 30 min, warming to 60 degrees for 3 h. After completion, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees). 0.67 g, 85% yield.

[0388] Third step:

[0389] Quinolinone 0.58 g (1.2 eq, 3.06 mmol) was taken, 0.7 g K2CO3 (2 eq, 5.1 mmol) was added, DMF 5 ml was added, warming to 80 degrees until the solution was clear, the second step product 0.67 g (1 eq, 2.55 mmol) and 92 mg TBAI (0.1 eq, 0.25 mmol) were added, reaction at 80 degrees for 8 h, the organic phase was diluted with EA and washed with 0.5 N NaOH 2 times, the organic phase was dried and concentrated (30 degrees), the crude product was purified with 200-300 mesh silica gel (HE: EA = 4: 1, start gradient elution, to HE: EA = 1: 4), the product was collected, concentrated, when not completely concentrated, HE was added to crystallize, suction filtration to obtain white solid 0.32 g, 30% yield.

[0390] ESI-MS: 415.3 [M+H] + .

[0391] 1HNMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 7.80 (d, J = 9.5 Hz, 1H), 7.09 (s, 1H), 6.48 - 6.41 (m, 1H), 5.07 - 4.86 (m, 3H), 4.82 - 4.72 (m, 1H), 4.27 (dd, J = 5.3, 3.8 Hz, 2H), 3.94 - 3.82 (m, 2H), 2.44 (s, 3H), 2.31 (s, 3H), 2.25 - 2.06 (m, 2H), 1.89 (m, 1H), 1.73 (m, 2H), 1.65 - 1.53 (m, 1H), 1.44 (m, 2H).

[0392] Example 26: Synthesis of compound S26

[0393] First step:

[0394] R meso difluorocyclohexylamine hydrochloride 0.51 g (1 eq, 3 mmol) was dissolved in DCM 15 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, the system was cooled to 5 degrees, acyl chloride 0.55 g (1.2 eq, 3.6 mmol) was added, and it was left to react at room temperature for 7 h. After the end, it was diluted with DCM 120 ml, the organic phase was washed with water 3 times, and the organic phase was dried and concentrated (30 degrees). A white oil was obtained, 0.76 g, 100% yield (theoretical).

[0395] Second step:

[0396] The product of the first step was dissolved in DCE 25 ml, and it was cooled to 0 degrees in an ice bath. PCl5 0.75 g (1.2 eq, 3.6 mmol) was added in portions, after the addition was complete, it was left to stir at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, it was left to stir at room temperature for 30 min, and it was left to react at 60 degrees for 3 h. After the end, it was diluted with EA 120 ml, the organic phase was washed with water 3 times, and the organic phase was dried and concentrated (30 degrees). 0.71 g, 85% yield.

[0397] Third step:

[0398] Take quinolinone 0.6 g (1.2 eq, 3.06 mmol), add 0.46 g DBU (1.2 eq, 3.06 mmol), add DMF 5 ml, warm to 80 degrees until clear, add second step product 0.61 g (1 eq, 2.55 mmol) and 92 mg TBAI (0.1 eq, 0.25 mmol), 80 degrees for 8 h, organic phase diluted with EA and washed with 0.5 N NaOH 2x, organic phase dried and concentrated (30 degrees), crude purified with 200-300 mesh silica gel (HE:EA = 4:1, start gradient elution to HE:EA = 1:4), product collected, concentrated, while not completely dry, add HE to crystallize, suction filtered to give white solid 0.34 g 30% yield.

[0399] ESI-MS: 439.2 [M+H] + .

[0400] 1 HNMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 7.86 (d, J = 9.8 Hz, 1H), 7.35 (dd, J = 8.2, 2.1 Hz, 1H), 6.55 (d, J = 9.5 Hz, 1H), 4.59 (m, 1H), 4.21 - 4.14 (m, 2H), 3.06 - 2.99 (m, 2H), 2.42 (m, 2H), 2.13 - 1.99 (m, 3H), 1.97 - 1.87 (m, 6H), 1.63 (m, 1H).

[0401] Example 27: Synthesis of compound S27

[0402] First step:

[0403] S intermediate difluorocyclohexylamine hydrochloride 0.51 g (1 eq, 3 mmol) dissolved in DCM 15 ml, add DIPEA 0.97 g (2.5 eq, 7.5 mmol), system cooled to 5 degrees, add acyl chloride 0.55 g (1.2 eq, 3.6 mmol), room temperature for 7 h, after completion diluted with DCM 120 ml, organic phase washed with water 3x, organic phase dried and concentrated (30 degrees) to give white oil, 0.76 g yield 100% (theoretical).

[0404] Second step:

[0405] The first step product was dissolved in DCE 25 ml, ice bath to 0°C, 0.75 g of PCl5(1.2 eq, 3.6 mmol) was added in portions, after the addition was complete, it was stirred at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, it was stirred at room temperature for 30 min, and then it was warmed to 60°C for 3 h. After the end, it was diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30°C). 0.71 g yield 85%.

[0406] Third step:

[0407] The quinolinone 0.6 g (1.2 eq, 3.06 mmol) was taken, 0.46 g of DBU (1.2 eq, 3.06 mmol) was added, DMF 5 ml was added, it was warmed to 80°C until it was clear, the second step product 0.61 g (1 eq, 2.55 mmol) and 92 mg of TBAI (0.1 eq, 0.25 mmol) were added, it was reacted at 80°C for 8 h, the organic phase was diluted with EA and washed with 0.5 N NaOH 2 times, the organic phase was dried and concentrated (30°C), the crude was purified with 200-300 mesh silica gel (HE: EA = 4: 1, starting gradient elution, up to HE: EA = 1:4), the product was collected, concentrated and, when it was not completely concentrated, it was crystallized with HE, and a white solid was obtained by suction filtration 0.34 g 30% yield.

[0408] ESI-MS: 439.2 [M+H] + .

[0409] 1 HNMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 7.86 (d, J = 9.8 Hz, 1H), 7.35 (dd, J = 8.2, 2.1 Hz, 1H), 6.55 (d, J = 9.5 Hz, 1H), 4.57 (m, 1H), 4.21 - 4.14 (m, 2H), 3.06 - 2.99 (m, 2H), 2.42 (m, 2H), 2.13 - 1.99 (m, 3H), 1.97 - 1.87 (m, 6H), 1.63 (m, 1H).

[0410] Example 28: Synthesis of compound S28

[0411] First step:

[0412] Cyclopentylamine 0.25 g (1 eq, 3 mmol) was dissolved in THF 10 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, lactone 0.3 g (1 eq, 3 mmol) was added, reaction at 60 degrees for 5 h, after completion the system was brought to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees), white oil was obtained, 0.56 g yield 100% (theoretical).

[0413] Second step:

[0414] The product of the first step was dissolved in DCE 25 ml, ice bath to 0 degrees, 1.2 g of PCl5 (2 eq, 6 mmol) was added in portions, after addition room temperature was stirred for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, stirred for 30 min at room temperature, the temperature was raised to 60 degrees and the reaction was carried out for 3 h. After completion, EA 120 ml was added for dilution, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees). 0.58 g yield 85%.

[0415] Third step:

[0416] Quinolinone 0.49 g (1.2 eq, 3.06 mmol) was taken, 0.70 g of K2CO3 (2 eq, 5.1 mmol) was added, DMF 5 ml was added, the temperature was raised to 80 degrees until the solution was clear, the product of the second step 0.58 g (1 eq, 2.55 mmol) and 92 mg of TBAI (0.1 eq, 0.25 mmol) were added, the reaction was carried out at 80 degrees for 8 h, the organic phase was diluted with EA and washed with 0.5 N NaOH 2 times, the organic phase was dried and concentrated (30 degrees), the crude product was purified on 200-300 mesh silica gel (HE: EA = 4: 1, start gradient elution, to HE: EA = 1: 4), the product was collected, concentrated and when not completely concentrated, HE was added for crystallization, white solid was obtained by suction filtration, 0.27 g 30% yield.

[0417] ESI-MS: 355.2 [M+H] + .

[0418] 1 HNMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 7.82 (d, J = 9.6 Hz, 1H), 7.27 - 7.18 (m, 2H), 7.12 (dd, J = 8.9, 2.8 Hz, 1H), 6.49 (d, J = 9.7 Hz, 1H), 4.98 (s, 2H), 4.53 (t, J = 9.3 Hz, 1H), 4.22 - 4.09 (m, 2H), 3.90 - 3.76 (m, 2H), 2.03 (m, 2H), 1.80 (m, 2H), 1.64 (m, 1H), 1.41 - 1.26 (m, 3H).

[0419] Example 29: Synthesis of compound S29

[0420] First step:

[0421] Cyclopentylamine 0.25 g (1 eq, 3 mmol) was dissolved in THF 10 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, lactone 0.3 g (1 eq, 3 mmol) was added, reaction at 60 degrees for 5 h, after the end of the reaction the system was brought to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees), white oil was obtained, 0.56 g yield 100% (theoretical).

[0422] Second step:

[0423] The product of the first step was dissolved in DCE 25 ml, ice bath to 0 degrees, 1.2 g of PCl5 (2 eq, 6 mmol) was added in portions, after the addition was completed, it was stirred at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, it was stirred at room temperature for 30 min, the temperature was raised to 60 degrees and the reaction was carried out for 3 h. After the end of the reaction, EA 120 ml was added for dilution, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees). 0.58 g yield 85%.

[0424] Third step:

[0425] Quinolinone 0.55 g (1.2 eq, 3.06 mmol) was taken, 0.46 g of DBU (1.2 eq, 3.06 mmol) was added, DMF 5 ml was added, the temperature was raised to 80 degrees until the solution was clear, the product of the second step 0.58 g (1 eq, 2.55 mmol) and 92 mg of TBAI (0.1 eq, 0.25 mmol) were added, the reaction was carried out at 80 degrees for 8 h, the organic phase was diluted with EA and washed with 0.5 N NaOH 2 times, the organic phase was dried and concentrated (30 degrees), the crude product was purified on 200-300 mesh silica gel (HE: EA = 4: 1, start gradient elution, to HE: EA = 1:4), the product was collected, concentrated, when not completely concentrated, HE was added to crystallize, and white solid 0.28 g was obtained by suction filtration, 30% yield.

[0426] ESI-MS: 373.2 [M+H] + .

[0427] 1HNMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.9 (d, J = 9.6 Hz, 1H), 7.45 - 7.34 (m, 2H), 6.70 (d, J = 9.6 Hz, 1H), 4.98 (s, 2H), 4.52 (t, J = 11.6 Hz, 1H), 4.20 (t, J = 4.3 Hz, 2H), 3.84 (t, J = 4.3 Hz, 2H), 2.01 (m, 2H), 1.80 (m, 2H), 1.64 (m, 1H), 1.41 - 1.28 (m, 3H).

[0428] Example 30: Synthesis of compound S30

[0429] First step:

[0430] Cycloheptanamine 0.34g (1 eq, 3mmol), dissolved with DCM 15ml, added DIPEA 0.97g (2.5eq, 7.5mmol), the system was cooled to 5 degrees, added acyl chloride 0.55g (1.2eq, 3.6mmol), reacted at room temperature for 7h, after the end of the reaction, diluted with DCM 120ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees), white oil was obtained, 0.69g yield 100% (theoretical).

[0431] Second step:

[0432] The product of the first step was dissolved with DCE 25ml, ice bath to 0 degrees, added 0.75g PCl5 (1.2eq, 3.6mmol) in batches, after the addition was completed, stirred at room temperature for 2h, then added TMSN3 1.17g (3.5eq, 10.22mmol) at room temperature, stirred at room temperature for 30min, heated to 60 degrees for 3h. After the end of the reaction, diluted with EA 120ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees). 0.65g yield 85%.

[0433] Third step:

[0434] Take quinolinone 0.6 g (1.2 eq, 3.06 mmol), add 0.46 g DBU (1.2 eq, 3.06 mmol), add DMF 5 ml, warm to 80 degrees until clear, add second step product 0.65 g (1 eq, 2.55 mmol) and 92 mg TBAI (0.1 eq, 0.25 mmol), 80 degrees for 8 h, organic phase diluted with EA and washed with 0.5 N NaOH 2x, organic phase dried and concentrated (30 degrees), crude purified with 200-300 mesh silica gel (HE:EA = 4:1, start gradient elution to HE:EA = 1:4), product collected, concentrated, while not completely dry, add HE to crystallize, suction filtered to give white solid 0.32 g 30% yield.

[0435] ESI-MS: 417.2 [M+H] + .

[0436] 1 HNMR (400 MHz, Chloroform-d) δ 8.92 (s, 1H), 7.64 (s, 1H), 7.18 (s, 1H), 6.92 (s, 1H), 6.67 (s, 1H), 4.34 (m, 1H), 4.04 (m, 2H), 2.91 (d, J = 7.3 Hz, 2H), 2.15 (m, 2H), 2.10 - 1.97 (m, 4H), 1.90 (m, 4H), 1.68 (m, 4H), 1.51 (m, 2H).

[0437] Example 31: Synthesis of compound S31

[0438] First step:

[0439] Cycloheptanamine 0.34 g (1 eq, 3 mmol) dissolved in DCM 15 ml, add DIPEA 0.97 g (2.5 eq, 7.5 mmol), system cooled to 5 degrees, add acyl chloride 0.55 g (1.2 eq, 3.6 mmol), room temperature for 7 h, after completion diluted with DCM 120 ml, organic phase washed with water 3x, organic phase dried and concentrated (30 degrees) to give white oil, 0.69 g yield 100% (theoretical).

[0440] Second step:

[0441] The first step product was dissolved in DCE 25 ml, ice bath to 0°C, 0.75 g of PCl5(1.2 eq, 3.6 mmol) was added in portions, after the addition was complete, it was stirred at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, it was stirred at room temperature for 30 min, and then it was warmed to 60°C for 3 h. After the end, it was diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30°C). 0.65 g yield 85%.

[0442] Third step:

[0443] The quinolinone 0.6 g (1.2 eq, 3.06 mmol) was taken, 0.46 g of DBU (1.2 eq, 3.06 mmol) was added, DMF 5 ml was added, it was warmed to 80°C until it was clear, the second step product 0.65 g (1 eq, 2.55 mmol) and 92 mg of TBAI (0.1 eq, 0.25 mmol) were added, it was reacted at 80°C for 8 h, the organic phase was diluted with EA and washed with 0.5 N NaOH 2 times, the organic phase was dried and concentrated (30°C), the crude was purified with 200-300 mesh silica gel (HE:EA = 4:1, starting gradient elution, up to HE:EA = 1:4), the product was collected, concentrated and, when it was not completely concentrated, it was crystallized with HE, and a white solid was obtained by suction filtration 0.31 g 30% yield.

[0444] ESI-MS: 415.2 [M+H] + .

[0445] 1 HNMR (400 MHz, Chloroform-d) δ 8.92 (s, 1H), 7.65 (d, J = 11.6 Hz, 1H), 7.18 (s, 1H), 6.92 (s, 1H), 6.68 (d, J = 11.8 Hz, 1H), 4.34 (m, 1H), 4.04 (m, 2H), 2.91 (d, J = 7.3 Hz, 2H), 2.15 (m, 2H), 2.10 - 1.97 (m, 4H), 1.90 (m, 4H), 1.68 (s, 4H), 1.51 (m, 2H).

[0446] Example 32: Synthesis of compound S32

[0447] First step:

[0448] R-methyldifluorocyclohexylamine hydrochloride 0.51 g (1 eq, 3 mmol) was dissolved in DCM 15 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, the system was cooled to 5 degrees, acyl chloride 0.55 g (1.2 eq, 3.6 mmol) was added, it was left to react at room temperature for 7 h, after which it was diluted with DCM 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees), obtaining a white oil, 0.76 g, 100% yield (theoretical).

[0449] Second step:

[0450] The product of the first step was dissolved in DCE 25 ml, it was cooled to 0 degrees in an ice bath, 0.75 g of PCI5 (1.2 eq, 3.6 mmol) was added in portions, after which it was left to stir at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, it was left to stir at room temperature for 30 min, it was heated to 60 degrees and left to react for 3 h. After which it was diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees). 0.71 g, 85% yield.

[0451] Third step:

[0452] Quinolinone 0.7 g (1.2 eq, 3.06 mmol) was taken, 0.46 g of DBU (1.2 eq, 3.06 mmol) was added, DMF 5 ml was added, it was left to dissolve clear at 80 degrees, the product of the second step 0.61 g (1 eq, 2.55 mmol) and 92 mg of TBAI (0.1 eq, 0.25 mmol) were added, it was left to react at 80 degrees for 8 h, the organic phase was diluted with EA and washed with 0.5 N NaOH 2 times, the organic phase was dried and concentrated (30 degrees), the crude product was purified on 200-300 mesh silica gel (HE:EA = 4:1, starting gradient elution, up to HE:EA = 1:4), the product was collected, concentrated and, when not completely dry, it was recrystallized with HE, obtaining a white solid 0.36 g, 30% yield.

[0453] ESI-MS: 471.2 [M+H] + .

[0454] 1 HNMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 7.90 (d, J = 9.7 Hz, 1H), 7.40 (s, 0.5H), 7.29 (d, J = 13.3 Hz, 1H), 7.14 (s, 0.5H), 6.67 (d, J = 9.6 Hz, 1H), 4.58 (m, 1H), 4.16 (d, J = 5.7 Hz, 2H), 3.01 (t, J = 6.8 Hz, 2H), 2.15 - 1.83 (m, 9H), 1.80 - 1.72 (m, 1H), 1.61 (m, 2H).

[0455] Example 33: Synthesis of compound S33

[0456] First step:

[0457] Cyclohexylamine 0.29 g (1 eq, 3 mmol) was dissolved in DCM 15 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, the system was cooled to 5 degrees, acyl chloride 0.55 g (1.2 eq, 3.6 mmol) was added, the reaction was carried out at room temperature for 7 h, after the end, it was diluted with DCM 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees), white oil was obtained, 0.65 g, 100% yield (theoretical).

[0458] Second step:

[0459] The product of the first step was dissolved in DCE 25 ml, ice bath to 0 degrees, 0.75 g PCl5 (1.2 eq, 3.6 mmol) was added in batches, after the addition was completed, it was stirred at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, it was stirred at room temperature for 30 min, the temperature was raised to 60 degrees and the reaction was carried out for 3 h. After the end, it was diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees). 0.61 g, 85% yield.

[0460] Third step:

[0461] Quinolinone 0.7 g (1.2 eq, 3.06 mmol) was taken, 0.46 g DBU (1.2 eq, 3.06 mmol) was added, DMF 5 ml was added, the temperature was raised to 80 degrees until the solution was clear, the product of the second step 0.61 g (1 eq, 2.55 mmol) and 92 mg TBAI (0.1 eq, 0.25 mmol) were added, the reaction was carried out at 80 degrees for 8 h, the organic phase was diluted with EA and washed with 0.5 N NaOH 2 times, the organic phase was dried and concentrated (30 degrees), the crude product was purified with 200-300 mesh silica gel (HE:EA=4:1, gradient elution was started, to HE:EA=1:4), the product was collected, concentrated, when not completely concentrated, HE was added for crystallization, white solid was obtained by suction filtration, 0.33 g, 30% yield.

[0462] ESI-MS: 435.2 [M+H] + .

[0463] 1HNMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 7.90 (d, J = 9.6 Hz, 1H), 7.40 (s, 0.5H), 7.29 (d, J = 12.1 Hz, 1H), 7.14 (s, 0.5H), 6.67 (d, J = 9.5 Hz, 1H), 4.41 (m, 1H), 4.15 (m, 2H), 3.03 - 2.95 (m, 2H), 2.00 - 1.72 (m, 10H), 1.67 (m, 1H), 1.42 (m, 3H).

[0464] Example 34: Synthesis of compound S34

[0465] First step:

[0466] Difluorocyclohexylamine hydrochloride 0.51 g (1 eq, 3 mmol) was dissolved in DCM 15 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, the system was cooled to 5 degrees, acyl chloride 0.55 g (1.2 eq, 3.6 mmol) was added, and it was left to react at room temperature for 7 h. After this time, it was diluted with DCM 120 ml, the organic phase was washed with water 3 times, and the organic phase was dried and concentrated (30 degrees). A white oil was obtained with a yield of 100% (theoretical) 0.65 g.

[0467] Second step:

[0468] The product of the first step was dissolved in DCE 25 ml, it was cooled to 0 degrees in an ice bath, and PCl5 0.75 g (1.2 eq, 3.6 mmol) was added in portions. After the addition was complete, it was left to stir at room temperature for 2 h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, it was left to stir at room temperature for 30 min, and it was left to react at 60 degrees for 3 h. After this time, it was diluted with EA 120 ml, the organic phase was washed with water 3 times, and the organic phase was dried and concentrated (30 degrees). A yield of 85% was obtained 0.61 g.

[0469] Third step:

[0470] Quinolinone 0.7 g (1.2 eq, 3.06 mmol) was taken, DBU 0.46 g (1.2 eq, 3.06 mmol) was added, DMF 5 ml was added, it was left to dissolve, it was left to dissolve at 80 degrees, the product of the second step 0.61 g (1 eq, 2.55 mmol) and TBAI 92 mg (0.1 eq, 0.25 mmol) were added, it was left to react at 80 degrees for 8 h, the organic phase was diluted with EA and washed with 0.5 N NaOH 2 times, the organic phase was dried and concentrated (30 degrees). The crude product was purified on silica gel 200-300 mesh (HE:EA = 4:1, start gradient elution, up to HE:EA = 1:4), the product was collected, concentrated, and, while it was not completely dry, it was recrystallized with HE, and it was filtered to obtain a white solid 0.36 g with a yield of 30%.

[0471] ESI-MS: 471.2 [M+H] + .

[0472] 1 HNMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 7.90 (d, J = 9.7 Hz, 1H), 7.41 (s, 0.5H), 7.29 (d, J = 8.7 Hz, 1H), 7.15 (s, 0.5H), 6.67 (d, J = 9.6 Hz, 1H), 4.71 (s, 1H), 4.16 (t, J = 5.6 Hz, 2H), 3.00 (t, J = 7.0 Hz, 2H), 2.16 (m, 3H), 2.08 (m, 5H), 1.90 (m, 4H).

[0473] Example 35: Synthesis of compound S35

[0474] First step:

[0475] Cyclohexylamine 0.29 g (1 eq, 3 mmol) was dissolved with THF 10 ml, DIPEA 0.97 g (2.5 eq, 7.5 mmol) was added, lactone 0.3 g (1 eq, 3 mmol) was added, reaction at 60 degrees for 5h, after the end of the system was reduced to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees), white oil was obtained, 0.6 g yield 100% (theoretical).

[0476] Second step:

[0477] The product of the first step was dissolved with DCE 25 ml, ice bath to 0 degrees, 1.2 g PCl5 (2 eq, 6 mmol) was added in batches, after adding, stirring at room temperature for 2h, then TMSN3 1.17 g (3.5 eq, 10.22 mmol) was added at room temperature, stirring at room temperature for 30 min, warming to 60 degrees for 3h. After the end of the system was reduced to room temperature, diluted with EA 120 ml, the organic phase was washed with water 3 times, the organic phase was dried and concentrated (30 degrees). 0.62 g yield 85%.

[0478] Third step:

[0479] Take quinolinone 0.7 g (1.2 eq, 3.06 mmol), add 0.46 g DBU (1.2 eq, 3.06 mmol), add DMF 5 ml, warm to 80 degrees until clear, add second step product 0.62 g (1 eq, 2.55 mmol) and 92 mg TBAI (0.1 eq, 0.25 mmol), 80 degrees for 8 h, organic phase diluted with EA and washed with 0.5 N NaOH 2x, organic phase dried and concentrated (30 degrees), crude purified with 200-300 mesh silica gel (HE:EA = 4:1, start gradient elution to HE:EA = 1:4), collect product, concentrate, while not completely dry, add HE to crystallize, suction filtered to give white solid 0.34 g 30% yield.

[0480] ESI-MS: 437.2 [M+H] + .

[0481] 1 HNMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 7.88 (d, J = 9.6 Hz, 1H), 7.37 (s, 0.5H), 7.32 (s, 1H), 7.23 (s, 0.5H), 6.67 (d, J = 10.0 Hz, 1H), 4.93 (m, 2H), 4.51 (m, 1H), 4.28 (m, 2H), 3.89 (m, 2H), 2.06 - 1.94 (m, 2H), 1.81 (m, 4H), 1.61 (m, 1H), 1.52 - 1.36 (m, 3H).

[0482] Example 36: Assay of compounds for phosphodiesterase 3A (PDE3A) inhibitory activity

[0483] PDE3A activity assay was detected using PDE3A TR-FRET Assay Kit (BPS Catalog # 60706), which is designed to identify PDE3A inhibitors using TR-FRET (time-resolved fluorescence resonance energy transfer) technology. The assay is based on the FAM-labeled nucleotide monophosphates produced by phosphodiesterases. These phosphate groups bind to Tb-labeled nanoparticles, resulting in energy transfer from Tb to FAM, which emits a fluorescent signal at 520 nm. Changes in fluorescence intensity can be easily measured using a multifunctional microplate reader.

[0484] Experimental procedure:

[0485] 1) Dilute 20 mM FAM-Cyclic-3', 5'-AMP substrate stock 100-fold with PDE buffer to make a 200 nM solution. Only enough for the assay should be prepared; the remaining stock solution is aliquoted and stored at -20 °C.

[0486] 2) Add 25 μL FAM-Cyclic-3',5'-AMP (200 nM) to each well labeled "Substrate Control", "Positive Control", and "Test Inhibitor". Add 25 μL PDE Assay Buffer to each well designated "Tb Only Control".

[0487] 3) Add 5 μL of inhibitor solution to each well designated "Test Inhibitor". Add 5 μL of the same solution without inhibitor (inhibitor buffer) to "Tb Only Control", "Substrate Control", and "Positive Control".

[0488] 4) Thaw PDE3A on ice. After the first thaw, briefly spin the tube containing the enzyme to restore the entire contents of the tube. Aliquot the PDE3A enzyme for single use. Immediately store the remaining undiluted enzyme aliquots at -80 °C.

[0489] 5) Dilute PDE3A to 0.05 ng / μL (1 ng / reaction) in PDE Buffer. Add 20 μL PDE Assay Buffer to wells designated "Tb Only Control" and "Substrate Control", and 20 μL PDE3A (0.05 ng / μL) to the well for "Positive Control" to initiate the reaction. "Test Inhibitor", use all remaining diluted enzyme and discard.

[0490] 6) Incubate at room temperature for 1 hour.

[0491] 7) Prepare Binding Dilution Buffer by mixing equal volumes of Binding Buffer A and Binding Buffer B.

[0492] 8) Mix the Adhesive thoroughly and dilute the Adhesive with the Binding Dilution Buffer prepared in Step 1 at a ratio of 1 :50.

[0493] 9) Add Tb Donor (1 : 1000 dilution) to the mixture.

[0494] 10) Add 100 μL to each well. Incubate at room temperature for 1 hour with slow shaking.

[0495] 11) Read the fluorescence intensity in a microtiter plate reader with TR-FRET capability.

[0496] Calculate Results:

[0497] (1) Fluorescence Intensity Calculation

[0498] Where S520 = sample 520 nm reading, S490 = sample 490 nm reading, Tb520 = Tb only 520 nm reading, Tb490 = Tb only 490 nm reading. When calculating percent activity, the FRET value of the substrate only control can be set to zero activity and the FRET value of the positive control can be set to 100% activity.

[0499] (2) Enzyme activity inhibition rate calculation

[0500] Where FRETs = sample FRET, FRETSub = substrate only control FRET, FRETP = positive control FRET.

[0501] (3) IC50 value calculation:

[0502] In GraphPad Prism 7, with log[concentration of compound] as the x-axis and Inhibition % as the y-axis, a non-linear curve was fitted: log(inhibitor) vs. response - Variable slope, and the IC50 value was calculated.

[0503] The results are shown in Table 1, from which it can be seen that the synthesized compounds S1-S35 have PDE3A enzyme inhibitory activity.

[0504] Table 1 IC50 value calculation results of compounds S1-S35 Note: ++++ indicates that the IC50 value is less than 200 nM; +++ indicates that the IC50 value is between 200 nM and 1000 nM; ++ indicates that the IC50 value is between 1000 nM and 2000 nM; + indicates that the IC50 value is greater than 2000 nM.

[0505] It is apparent to those skilled in the art that the present application is not limited to the details of the foregoing exemplary embodiments, but can be implemented in other particular forms without departing from the spirit or essential characteristics of the present application. Therefore, the embodiments should be considered in all respects as illustrative and not restrictive, and the scope of the present application should be defined by the appended claims rather than the above description, and it is intended to include all changes falling within the meaning and range of equivalents of the claims. Any mark in the claims should not be considered as limiting the claims involved.

Claims

1. A class of compounds as shown in Formula I or pharmaceutically acceptable salts, deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, characterized in that, wherein X is selected from -O- or -CH2-; R1, R2and R3are each independently selected from hydrogen, halogen, trifluoromethyl, difluoromethyl, C1-C6alkyl, C3-C8cycloalkyl, cyano, nitro, methoxy, hydroxy or amino; R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen or Ci-C3alkyl; the form of the covalent bond between the carbon atom in position 3 and the carbon atom in position 4 is selected from a single bond or a double bond; n is selected from the numbers 0, 1, 2 or 3.

2. A class of compounds of Formula I or pharmaceutically acceptable salts, deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, characterized in that, wherein X is selected from -O- or -CH2-; R1, R2and R3are each independently selected from hydrogen, halogen, trifluoromethyl, difluoromethyl, C1-C6alkyl, C3-C8cycloalkyl, cyano, nitro, methoxy, hydroxy or amino; R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen or Ci-C3alkyl; the form of the covalent bond between the carbon atom in position 3 and the carbon atom in position 4 is selected from a single bond or a double bond; n is selected from the numbers 0, 1, 2 or 3; with the additional proviso that when X is -CH2-, at least one of R1, R2and R3is not hydrogen; with the additional proviso that when X is -CH2-, the form of the covalent bond between the carbon atom in position 3 and the carbon atom in position 4 is a single bond, and R2and R3are both hydrogen, R1is not fluorine; with the additional proviso that when X is -CH2-, the form of the covalent bond between the carbon atom in position 3 and the carbon atom in position 4 is a single bond, and any two of R1, R2and R3are both hydrogen, the other non-hydrogen substituent of R1, R2and R3is not trifluoromethyl.

3. A class of compounds represented by Formula I or pharmaceutically acceptable salts, deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, characterized in that, wherein X is selected from -O- or -CH2-; R1, R2and R3are each independently selected from hydrogen, halogen, trifluoromethyl, difluoromethyl, C1-C6alkyl, C3-C8cycloalkyl, cyano, nitro, methoxy, hydroxy or amino; R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen or Ci-C3alkyl; the form of the covalent bond between the carbon atom in position 3 and the carbon atom in position 4 is selected from a single bond or a double bond; n is selected from the numbers 0, 1, 2 or 3; with the additional proviso that when X is -CH2-, at least one of R1, R2and R3is not hydrogen; with the additional proviso that when X is -CH2-, the form of the covalent bond between the carbon atom in position 3 and the carbon atom in position 4 is a single bond, and R2and R3are both hydrogen, R1is not fluorine; with the additional proviso that when X is -CH2-, the form of the covalent bond between the carbon atom in position 3 and the carbon atom in position 4 is a single bond, and any two of R1, R2and R3are both hydrogen, the other non-hydrogen substituent of R1, R2and R3is not trifluoromethyl.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, a deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and tautomer thereof, wherein R1, R2and R3are each independently selected from hydrogen, halogen, trifluoromethyl, difluoromethyl, C1-C6alkyl, C3-C8cycloalkyl, cyano, nitro, methoxy or hydroxy.

5. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, a deuterated compound, solvate, racemic mixture, enantiomer, diastereomer and tautomer thereof, wherein R1, R2and R3are each independently selected from hydrogen, halogen, trifluoromethyl, difluoromethyl, C1-C3alkyl, cyano, nitro, methoxy. R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 are each independently hydrogen, halogen or methyl. ​ ​ 6. The compound according to any one of claims 1 to 3, or pharmaceutically acceptable salts, deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, wherein, R1and R2are each independently selected from hydrogen, halogen, trifluoromethyl, difluoromethyl, C1-C3 alkyl, cyano, nitro, or methoxy; R3is selected from hydrogen, fluorine, chlorine, trifluoromethyl, difluoromethyl, or methyl; and n is selected from the numbers 0, 1, or 2. R1and R2are each independently selected from hydrogen, halogen, trifluoromethyl, difluoromethyl, C1-C3 alkyl, or methoxy; R3is selected from hydrogen, fluorine, chlorine, or trifluoromethyl; and n is selected from the numbers 0, 1, or 2. R1is selected from hydrogen, fluorine, chlorine, trifluoromethyl, or methyl; R2is selected from hydrogen, fluorine, chlorine, trifluoromethyl, difluoromethyl, or methyl; R3is selected from hydrogen, fluorine, chlorine, or trifluoromethyl; and n is selected from the numbers 0, 1, or 2. Compound S35, as shown above. Use of the compound in the manufacture of a medicament having phosphodiesterase 3A inhibitory activity. Use of the compound in the manufacture of a medicament for cerebrovascular disease or dementia.

14. Use of the compound according to any one of claims 1 to 11, or pharmaceutically acceptable salts, deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, in the manufacture of a medicament having phosphodiesterase 3A inhibitory activity.

15. Use of the compound according to any one of claims 1 to 11, or pharmaceutically acceptable salts, deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, and tautomers thereof, in the manufacture of a medicament for cerebrovascular disease or dementia. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, or pharmaceutically acceptable salts, deuterated compounds, solvates, racemic mixtures, enantiomers, diastereomers, tautomers, and pharmaceutically acceptable carriers thereof. ​ ​ ​ 9. The compound or pharmaceutically acceptable salt, deuterated compound, solvate, racemic mixture, enantiomer, diastereomer, and tautomer thereof of any one of claims 1-3, wherein R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 are each independently hydrogen or halogen.

10. The compound or pharmaceutically acceptable salt, deuterated compound, solvate, racemic mixture, enantiomer, diastereomer, and tautomer thereof of any one of claims 1-3, wherein R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 and R 13 are each independently hydrogen or fluoro.

11. The compound or pharmaceutically acceptable salt, deuterated compound, solvate, racemic mixture, enantiomer, diastereomer, and tautomer thereof of any one of claims 1-3, wherein The compound is selected from: Compound S1, as shown above; Compound S2, as shown above; Compound S3, as shown above; Compound S4, as shown above; Compound S5, as shown above; Compound S6, as shown above: Compound S7, as shown above: Compound S8, as shown above: Compound S9, as shown above: Compound S10, as shown above: Compound S11, as shown above: Compound S12, as shown above: Compound S13, as shown above: Compound S14, as shown above: Compound S15, as shown above: Compound S16, as shown above: Compound S17, as shown above: Compound S18, as shown above: Compound S19, as shown above: Compound S20, as shown above: Compound S21, as shown above: Compound S22, as shown above: Compound S23, as shown above: Compound S24, as shown above: Compound S25, as shown above: Compound S26, as shown above: Compound S27, as shown above: Compound S28, as shown above: Compound S29, as shown above: Compound S30, as shown above: Compound S31, as shown above: Compound S32, as shown above: Compound S33, as shown above: Compound S34, as shown above: ​ 12. The compound or pharmaceutically acceptable salt, deuterated compound, solvate, racemic mixture, enantiomer, diastereomer, and tautomer thereof of any one of claims 1-11, wherein ​ 13. The compound or pharmaceutically acceptable salt, deuterated compound, solvate, racemic mixture, enantiomer, diastereomer, and tautomer thereof of any one of claims 1-11, wherein ​ ​ ​ 16. A pharmaceutical composition, characterized by, ​

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