Quinolinone derivative compound and application thereof

Abstract

The invention discloses a quinolinone derivative and a pharmaceutically acceptable salt of the quinolinone derivative. The quinolinone derivative disclosed by the invention is a compound with phosphodiesterase 3A (PDE3A) inhibition activity, has an important potential treatment value, and is applied to medicines for treating tumors, cardiovascular diseases, cerebrovascular diseases or dementia.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and particularly to the use of a class of substituted quinolinone derivatives or pharmaceutically acceptable salts thereof as phosphodiesterase 3A (PDE3A) inhibitors, especially in the preparation of medicaments for treating tumors, cardiovascular diseases, cerebrovascular diseases or dementia. Background Art

[0002] Cilostazol is a quinolinone-derived compound that can increase the cAMP concentration in platelets and smooth muscle by inhibiting the phosphodiesterase activity in platelets and vascular smooth muscle, thereby exerting antiplatelet and vasodilatory effects. It inhibits the primary and secondary aggregation and release reactions of platelets induced by ADP, adrenaline, collagen and arachidonic acid, and has an obvious antithrombotic effect on models of cerebral circulation and peripheral circulation disorders caused by collagen, ADP, arachidonic acid and sodium laurate. It can be used to treat chronic arterial occlusion caused by atherosclerosis, Takayasu arteritis, thromboangiitis obliterans, diabetes, cerebrovascular diseases or dementia, etc.

[0003] The poor pharmacokinetic properties of cilostazol limit its clinical application: when 50 mg of cilostazol is orally administered to healthy adult men on an empty stomach and after a meal, the Cmax and AUCinf after administration after a meal are 2.3 times and 1.4 times those on an empty stomach, respectively. Cilostazol is mainly metabolized by the cytochrome P450 isozyme CYP3A4 in hepatic microsomes, and secondly by CYP2D6 and CYP2C19, and is metabolized into active metabolites such as OPC-13015 generated by dehydration and OPC-13213 generated by hydroxylation. When severely renal dysfunction patients continuously take 0.1 g of cilostazol orally for 8 days, compared with healthy adults, the Cmax and AUC of cilostazol are reduced by 29% and 39% respectively, while the Cmax and AUC of the active metabolite OPC-13213 are increased by 173% and 209% respectively. Therefore, it is necessary to design a compound that not only satisfies the PDE3A inhibitory activity of cilostazol but also has good pharmacokinetic parameters for treating diseases related to cilostazol. Summary of the Invention

[0004] The object of the present invention is to provide a quinolinone compound or a pharmaceutically acceptable salt thereof, which has PDE3A inhibitory activity and is used for treating diseases such as tumors, cardiovascular diseases, cerebrovascular diseases or dementia.

[0005] To solve the above technical problems, the technical solution provided by the present invention is as follows:

[0006] A class of substituted quinolinone derivatives or pharmaceutically acceptable salts, hydrates or solvates thereof as shown in Formula 1:

[0007]

[0008]

[0009] Wherein, Y is selected from -O-, -NR4- or -S-;

[0010] R4 is selected from hydrogen or C1-C3 alkyl;

[0011] R1, R2 and R3 are each independently selected from hydrogen, halogen, trifluoromethyl or methyl;

[0012] The covalent bond form connecting the carbon atom at the 3-position and the carbon atom at the 4-position is selected from a single bond or a double bond;

[0013] n is selected from the numbers 0 to 3.

[0014] Preferably, wherein, Y is selected from -O- or -NR4-;

[0015] R4 is selected from methyl or ethyl;

[0016] R1, R2 and R3 are each independently selected from hydrogen, fluorine, chlorine, trifluoromethyl or methyl;

[0017] The covalent bond form connecting the carbon atom at the 3-position and the carbon atom at the 4-position is selected from a single bond or a double bond;

[0018] n is selected from the numbers 0 to 2.

[0019] More preferably, wherein, Y is selected from -O- or -NR4-;

[0020] R4 is methyl;

[0021] R1 is selected from hydrogen, fluorine, chlorine, trifluoromethyl or methyl;

[0022] R2 is selected from hydrogen, fluorine or trifluoromethyl;

[0023] R3 is selected from hydrogen or chlorine;

[0024] The covalent bond form connecting the carbon atom at the 3-position and the carbon atom at the 4-position is selected from a single bond or a double bond;

[0025] n is selected from the numbers 0 to 1.

[0026] Most preferably, the compound of formula 1 includes but is not limited to the following specific compound examples:

[0027]

[0028] Compound 1: As shown in S1;

[0029]

[0030] Compound 2: As shown in S2;

[0031]

[0032] Compound 3: as shown in S3;

[0033]

[0034] Compound 4: as shown in S4;

[0035]

[0036] Compound 5: as shown in S5;

[0037]

[0038]

[0039] Compound 6: as shown in S6;

[0040]

[0041] Compound 7: as shown in S7;

[0042]

[0043] Compound 8: as shown in S8;

[0044]

[0045] Compound 9: as shown in S9;

[0046]

[0047] Compound 10: as shown in S10;

[0048]

[0049] Compound 11: as shown in S11;

[0050]

[0051] Compound 12: as shown in S12;

[0052]

[0053] Compound 13: as shown in S13;

[0054]

[0055] Compound 14: as shown in S14;

[0056]

[0057] Compound 15: as shown in S15;

[0058]

[0059] Compound 16: as shown in S16;

[0060]

[0061] Compound 17: as shown in S17;

[0062]

[0063] Compound 18: as shown in S18.

[0064] The compounds provided by the present invention further include pharmaceutically acceptable equivalents of the compound or a mixture of two or more thereof.

[0065] Preferably, the compounds provided by the present invention may include one or a mixture of two or more of pharmaceutically acceptable salts, hydrates, solvates, metabolites, and prodrugs.

[0066] Preferably, the compounds provided by the present invention include acid salts or base salts of the compounds provided by the present invention. The pharmaceutically acceptable salts have the pharmaceutical activity of the compound and meet the requirements both biologically and in practical applications.

[0067] This application provides a quinolinone compound or a pharmaceutically acceptable salt thereof for treating diseases such as tumors, cardiovascular diseases, cerebrovascular diseases, or dementia. Detailed implementation manners

[0068] The present invention discloses quinolinone compounds and their uses, and those skilled in the art can draw on the content of this article and appropriately improve the process parameters to achieve them. The methods and applications of the present invention have been described through preferred embodiments, and relevant personnel can obviously make changes or appropriate alterations and combinations to the methods and applications described herein without departing from the content, spirit, and scope of the present invention to implement and apply the technology of the present invention.

[0069] To enable those skilled in the art to better understand the technical solutions of the present invention, the following specific embodiments are used to further elaborate on the present invention in detail.

[0070] The general formula compounds of the present invention can be synthesized through the following route:

[0071]

[0072] Example 1: Synthesis of Compound S1

[0073]

[0074] Step 1:

[0075] Dissolve 0.44 g (1 eq, 2.92 mmol) of 4-amino-1-methylpiperidine hydrochloride in DCM, add 0.74 g (2.5 eq, 7.3 mmol) of TEA, cool the mixture to 0 °C in an ice bath, and dropwise add 0.67 g (1.5 eq, 4.38 mmol) of acyl chloride. React at room temperature overnight. After completion, wash with 250 mM HCl and saturated NaHCO₃ three times each. Dry and concentrate the organic phase (at 30 °C) to obtain 0.67 g of a white solid with a yield of 100% (theoretical).

[0076] Step 2;

[0077] Dissolve the product of the first step in Tol, cool the mixture to 0 °C in an ice bath, and add 0.85 g (1.4 eq, 4.1 mmol) of PCl₅ portionwise. After addition, stir at room temperature for 2 h, then add 1.17 g (3.5 eq, 10.22 mmol) of TMSN₃ at room temperature and stir for 30 min. Heat the mixture to 80 °C and react for 3 h. After completion, dilute with EA, wash the organic phase with saturated NaHCO₃ three times, dry and concentrate the organic phase (at 30 °C). The yield is 83% with 0.62 g obtained.

[0078] Step 3;

[0079] Take 0.58 g (1.5 eq, 3.63 mmol) of 6-hydroxyquinolinone raw material, add 0.19 g (1.4 eq, 3.39 mmol) of KOH, add 10 ml of isopropanol, heat the mixture to 80 °C, add 0.62 g (1 eq, 2.42 mmol) of the product of the second step, then add 80 mg of KI (0.2 eq, 0.48 mmol), and react at 80 °C for 8 h. Dilute the organic phase with EA and wash with 0.5 N NaOH twice. Dry and concentrate the organic phase (at 30 °C). Purify the crude product by silica gel column chromatography with 200 - 300 mesh (HE:EA = 4:1, start gradient elution until HE:EA = 1:4, collect the product, concentrate, when not completely concentrated, add HE for crystallization, filter by suction to obtain 0.33 g of a white solid with a yield of 30%).

[0080] ESI-MS: 383.2 [M + H]+

[0081] 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 7.82 (d, J = 9.5 Hz, 1H), 7.30–7.15 (m, 2H), 7.12 (dd, J = 8.9, 2.8 Hz, 1H), 6.49 (d, J = 9.5 Hz, 1H), 4.45–4.33 (m, 1H), 4.10–4.03 (m, 2H), 2.96 (m, 2H), 2.87 (m, 2H), 2.22 (s, 3H), 2.13–2.00 (m, 2H), 1.98–1.73 (m, 8H).

[0082] Example 2: Synthesis of Compound S2

[0083]

[0084] First step:

[0085] Dissolve 0.44 g (1 eq, 2.92 mmol) of 4-amino-1-methylpiperidine hydrochloride in 50 mL of DCM, add 0.74 g (2.5 eq, 7.3 mmol) of TEA, cool to 0 °C in an ice bath, and dropwise add 0.67 g (1.5 eq, 4.38 mmol) of acyl chloride. React overnight at room temperature. After completion, wash with 250 mM HCl and saturated NaHCO3 three times each. Dry and concentrate the organic phase (at 30 °C) to obtain 0.67 g of a white solid, with a yield of 100% (theoretical).

[0086] Second step;

[0087] Dissolve the product of the first step in 50 mL of Tol, cool to 0 °C in an ice bath, add 0.85 g (1.4 eq, 4.1 mmol) of PCl5 portionwise. After addition, stir at room temperature for 2 h, then add 1.17 g (3.5 eq, 10.22 mmol) of TMSN3 at room temperature and stir at room temperature for 30 min. Heat to 80 °C and react for 3 h. After completion, dilute with EA. Wash the organic phase with saturated NaHCO3 three times. Dry and concentrate the organic phase (at 30 °C). The yield is 83% (0.62 g).

[0088] Third step;

[0089] Take 0.83 g (1.5 eq, 3.63 mmol) of quinolinone, add 0.52 g (1.4 eq, 3.39 mmol) of DBU, add 10 ml of DMF, heat to 80 °C until clear, add 0.62 g (1 eq) of the second-step product and 80 mg (0.2 eq, 0.48 mmol) of KI, react at 80 °C for 8 h, dilute the organic phase with EA, and wash it twice with 0.5 N NaOH. Dry and concentrate the organic phase (at 30 °C). Purify the crude product by silica gel column chromatography with 200 - 300 mesh (HE:EA = 4:1, start gradient elution until HE:EA = 1:4, collect the product, concentrate. When not completely dried, add HE for crystallization, filter by suction to obtain a white solid) 0.39 g, with a yield of 30%.

[0090] ESI-MS: 453.2 [M+H]+

[0091] 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 7.19 (d, J = 2.7 Hz, 1H), 7.01 (d, J = 2.9 Hz, 1H), 4.45–4.33 (m, 1H), 4.10–4.03 (m, 2H), 2.96 (m, 4H), 2.87 (m, 2H), 2.22 (s, 3H), 2.13–2.00 (m, 4H), 1.98–1.73 (m, 8H).

[0092] Example 3: Synthesis of Compound S3

[0093]

[0094] The first step:

[0095] Dissolve 0.29 g (1 eq, 2.92 mmol) of 4-aminotetrahydropyran in 50 ml of DCM, add 0.74 g (2.5 eq, 7.3 mmol) of TEA, cool to 0 °C in an ice bath, dropwise add 0.67 g (1.5 eq, 4.38 mmol) of acyl chloride, react overnight at room temperature. After completion, wash it three times each with 250 mM HCl and saturated NaHCO3. Dry and concentrate the organic phase (at 30 °C) to obtain a white solid, with a yield of 0.64 g, 100% (theoretical).

[0096] The second step;

[0097] In the first step, the product was dissolved in 50 ml of Tol, cooled to 0 °C in an ice bath, and 0.85 g of PCl5 (1.4 eq, 4.1 mmol) was added portionwise. After the addition, the mixture was stirred at room temperature for 2 h, then 1.17 g of TMSN3 (3.5 eq, 10.22 mmol) was added at room temperature, and the mixture was stirred at room temperature for 30 min and then heated to 80 °C for 3 h. After completion, it was diluted with EA, and the organic phase was washed 3 times with saturated NaHCO3, and the organic phase was dried and concentrated (at 30 °C). 0.59 g was obtained with a yield of 83%.

[0098] The third step;

[0099] 0.59 g (1.5 eq, 3.63 mmol) of quinolinone was taken, 0.19 g of KOH (1.4 eq, 3.39 mmol) was added, 10 ml of isopropanol was added, and the temperature was raised to 80 °C until it was dissolved. 0.59 g (1 eq, 2.42 mmol) of the product from the second step and 80 mg of KI (0.2 eq, 0.48 mmol) were added, and the reaction was carried out at 80 °C for 8 h. The organic phase was diluted with EA and washed 2 times with 0.5 N NaOH. The organic phase was dried and concentrated (at 30 °C). The crude product was purified by silica gel column chromatography with 200 - 300 mesh (HE:EA = 4:1, starting gradient elution until HE:EA = 1:4, collecting the product, concentrating, when not completely concentrated to dryness, adding HE for crystallization, and filtering to obtain a white solid) 0.32 g with a yield of 30%.

[0100] ESI-MS: 372.2 [M + H]+

[0101] 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 6.72 (dt, J = 3.1, 1.9 Hz, 3H), 4.41 (tt, J = 11.5, 4.2 Hz, 1H), 4.18 (ddd, J = 12.3, 4.5, 2.0 Hz, 2H), 4.00 (t, J = 5.9 Hz, 2H), 3.56 (td, J = 12.0, 2.1 Hz, 2H), 2.96 (q, J = 7.4 Hz, 4H), 2.63 (dd, J = 8.5, 6.5 Hz, 2H), 2.40 (dtd, J = 13.2, 11.6, 4.5 Hz, 2H), 2.14–2.02 (m, 2H), 1.96 (ddt, J = 20.3, 9.1, 4.2 Hz, 4H).

[0102] Example 4: Synthesis of Compound S4

[0103]

[0104] The first step:

[0105] Dissolve 0.29 g (1 eq, 2.92 mmol) of 4-aminotetrahydropyran in 50 ml of DCM, add 0.74 g of TEA (2.5 eq, 7.3 mmol), cool the mixture to 0 °C in an ice bath, and dropwise add 0.67 g of acyl chloride (1.5 eq, 4.38 mmol). React at room temperature overnight. After completion, wash with 250 mM HCl and saturated NaHCO₃ three times each. Dry and concentrate the organic phase (at 30 °C) to obtain 0.64 g of a white solid with a yield of 100% (theoretical).

[0106] The second step;

[0107] Dissolve the product of the first step in 50 ml of Tol, cool the mixture to 0 °C in an ice bath, and add 0.85 g of PCl₅ (1.4 eq, 4.1 mmol) portionwise. After addition, stir at room temperature for 2 h, then add 1.17 g of TMSN₃ (3.5 eq, 10.22 mmol) at room temperature and stir for 30 min. Heat the mixture to 80 °C and react for 3 h. After completion, dilute with EA, wash the organic phase with saturated NaHCO₃ three times, dry and concentrate the organic phase (at 30 °C). The yield is 83% for 0.59 g.

[0108] The third step;

[0109] Take 0.83 g (1.5 eq, 3.63 mmol) of quinolinone, add 0.52 g of DBU (1.4 eq, 3.39 mmol), add 10 ml of DMF, heat to 90 °C until clear, add 0.59 g (1 eq) of the product of the second step and 80 mg of KI (0.2 eq, 0.48 mmol), react at 90 °C for 8 h. Dilute the organic phase with EA and wash with 0.5 N NaOH twice. Dry and concentrate the organic phase (at 30 °C). Purify the crude product by silica gel column chromatography (200 - 300 mesh, HE:EA = 4:1, start gradient elution until HE:EA = 1:4, collect the product, concentrate. When not completely concentrated, add HE for crystallization, filter by suction to obtain 0.38 g of a white solid with a yield of 30%).

[0110] ESI-MS: 440.2 [M + H]+

[0111] ¹H NMR (400 MHz, DMSO-d₆) δ 10.09 (s, 1H), 7.17 (s, 1H), 7.08 (s, 1H), 4.77–4.65 (m, 1H), 4.11 (t, J = 5.7 Hz, 1H), 4.03–3.93 (m, 2H), 3.49 (td, J = 11.8, 2.3 Hz, 2H), 2.97 (dt, J = 29.9, 7.3 Hz, 4H), 2.48–2.39 (m, 3H), 2.10–1.76 (m, 8H).

[0112] Example 5: Synthesis of Compound S5

[0113]

[0114] Step 1:

[0115] Dissolve 0.29 g (1 eq, 2.92 mmol) of tetrahydropyranylamine in 50 ml of DCM, add 0.74 g of TEA (2.5 eq, 7.3 mmol), cool the mixture to 0 °C in an ice bath, dropwise add 0.67 g of acyl chloride (1.5 eq, 4.38 mmol), react overnight at room temperature. After completion, wash with 250 mM HCl and saturated NaHCO3 three times each. Dry and concentrate the organic phase (at 30 °C) to obtain 0.64 g of white solid, with a yield of 100% (theoretical).

[0116] Step 2;

[0117] Dissolve the product of the first step in 50 ml of Tol, cool the mixture to 0 °C in an ice bath, add 0.85 g of PCl5 (1.4 eq, 4.1 mmol) in portions. After addition, stir at room temperature for 2 h, then add 1.17 g of TMSN3 (3.5 eq, 10.22 mmol) at room temperature, stir at room temperature for 30 min, and then react at 80 °C for 3 h. After completion, dilute with EA, wash the organic phase with saturated NaHCO3 three times, dry and concentrate the organic phase (at 30 °C). The yield is 83% for 0.59 g.

[0118] Step 3;

[0119] Take 0.83 g (1.5 eq, 3.63 mmol) of quinolinone, add 0.52 g of DBU (1.4 eq, 3.39 mmol), add 10 ml of DMF, heat to 80 °C until clear, add 0.59 g (1 eq) of the product of the second step and 80 mg of KI (0.2 eq, 0.48 mmol), react at 80 °C for 8 h. Dilute the organic phase with EA and wash with 0.5 N NaOH twice. Dry and concentrate the organic phase (at 30 °C). Purify the crude product by silica gel column chromatography with 200 - 300 mesh (HE:EA = 4:1, start gradient elution until HE:EA = 1:4, collect the product, concentrate. When not completely concentrated, add HE for crystallization, filter by suction to obtain 0.38 g of white solid) with a yield of 30%.

[0120] ESI-MS: 440.2 [M + H]+

[0121] 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 7.19 (d, J = 2.7 Hz, 1H), 7.01 (d, J = 2.8 Hz, 1H), 4.72 (tt, J = 11.2, 4.5 Hz, 1H), 4.06 (t, J = 6.0 Hz, 2H), 4.03–3.90 (m, 2H), 3.49 (td, J = 11.7, 2.4 Hz, 2H), 2.97 (dt, J = 31.1, 7.6 Hz, 4H), 2.50–2.45 (m, 2H), 2.09–1.76 (m, 8H).

[0122] Example 6: Synthesis of Compound S6

[0123]

[0124] First step:

[0125] 0.44 g (1 eq, 2.92 mmol) of 4-amino-1-methylpiperidine hydrochloride was dissolved in DCM, 0.74 g (2.5 eq, 7.3 mmol) of TEA was added, the temperature was lowered to 0 °C in an ice bath, 0.61 g (1.5 eq, 4.38 mmol) of acyl chloride was added dropwise, and the reaction was carried out overnight at room temperature. After completion, it was washed 3 times with 250 mM HCl and saturated NaHCO3 respectively. The organic phase was dried and concentrated (30 °C) to obtain 0.64 g of white solid, with a yield of 100% (theoretical).

[0126] Second step;

[0127] The product of the first step was dissolved in Tol, the temperature was lowered to 0 °C in an ice bath, 0.85 g (1.4 eq, 4.1 mmol) of PCl5 was added in batches. After addition, it was stirred at room temperature for 2 h, then 1.17 g (3.5 eq, 10.22 mmol) of TMSN3 was added at room temperature, and it was stirred at room temperature for 30 min, and the temperature was raised to 80 °C for reaction for 3 h. After completion, it was diluted with EA, and the organic phase was washed 3 times with saturated NaHCO3. The organic phase was dried and concentrated (30 °C). The yield was 83% with 0.59 g.

[0128] Third step;

[0129] Take 0.59 g (1.5 eq, 3.63 mmol) of 6-hydroxyquinolinone, add 0.19 g (1.4 eq, 3.39 mmol) of KOH, add 10 ml of isopropanol, heat to 80 °C, add 0.59 g (1 eq, 2.42 mmol) of the product of the second step, then add 80 mg of KI (0.2 eq, 0.48 mmol), react at 80 °C for 8 h, dilute the organic phase with EA, and wash it twice with 0.5 N NaOH. Dry and concentrate the organic phase (30 °C). Purify the crude product by silica gel column chromatography with 200 - 300 mesh (HE:EA = 4:1, start gradient elution until HE:EA = 1:4, collect the product, concentrate, when not completely concentrated to dryness, add HE for crystallization, filter to obtain 0.32 g of white solid) with a yield of 30%.

[0130] ESI-MS: 369.2[M + H]+

[0131] 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 7.82 (d, J = 9.5 Hz, 1H), 7.30–7.15 (m, 2H), 7.12 (dd, J = 8.9, 2.8 Hz, 1H), 6.49 (d, J = 9.5 Hz, 1H), 4.45–4.33 (m, 1H) 4.10–4.03 (m, 2H), 2.96 (m, 2H), 2.22 (s, 3H), 2.13–2.00 (m, 2H), 1.98–1.73 (m, 8H).

[0132] Example 7: Synthesis of Compound S7

[0133]

[0134] First step:

[0135] Dissolve 0.29 g (1 eq, 2.92 mmol) of aminotetrahydropyran in DCM, add 0.74 g (2.5 eq, 7.3 mmol) of TEA, cool to 0 °C in an ice bath, dropwise add 0.61 g (1.5 eq, 4.38 mmol) of acyl chloride, react overnight at room temperature. After completion, wash it three times each with 250 mM HCl and saturated NaHCO3. Dry and concentrate the organic phase (30 °C) to obtain 0.6 g of white solid with a yield of 100% (theoretical).

[0136] Second step;

[0137] In the first step, the product was dissolved in Tol, cooled to 0 °C in an ice bath, and 0.85 g (1.4 eq, 4.1 mmol) of PCl5 was added portionwise. After addition, the mixture was stirred at room temperature for 2 h, then 1.17 g (3.5 eq, 10.22 mmol) of TMSN3 was added at room temperature, and the mixture was stirred at room temperature for 30 min and then heated to 80 °C for reaction for 3 h. After completion, it was diluted with EA, and the organic phase was washed 3 times with saturated NaHCO3, and the organic phase was dried and concentrated (30 °C). 0.56 g was obtained with a yield of 83%.

[0138] The third step;

[0139] Take 0.59 g (1.5 eq, 3.63 mmol) of 6-hydroxyquinolinone, add 0.19 g (1.4 eq, 3.39 mmol) of KOH, add 10 ml of isopropanol, heat to 80 °C, add 0.56 g (1 eq, 2.42 mmol) of the product from the second step, then add 80 mg of KI (0.2 eq, 0.48 mmol), react at 80 °C for 8 h, dilute the organic phase with EA, and wash it 2 times with 0.5 N NaOH. The organic phase was dried and concentrated (30 °C), and the crude product was purified by silica gel column chromatography with 200 - 300 mesh (HE:EA = 4:1, start gradient elution until HE:EA = 1:4, collect the product, concentrate, when not completely concentrated, add HE for crystallization, filter by suction to obtain a white solid) 0.31 g with a yield of 30%.

[0140] ESI-MS: 356.2 [M+H]+

[0141] 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 7.82 (d, J = 9.5 Hz, 1H), 7.30–7.15 (m, 2H), 7.12 (dd, J = 8.9, 2.8 Hz, 1H), 6.49 (d, J = 9.5 Hz, 1H), 4.41 (tt, J = 11.5, 4.2 Hz, 1H), 4.18 (ddd, J = 12.3, 4.5, 2.0 Hz, 2H), 2.96 (q, J = 7.4 Hz, 2H), 2.63 (dd, J = 8.5, 6.5 Hz, 2H), 2.40 (dtd, J = 13.2, 11.6, 4.5 Hz, 2H), 2.14–2.02 (m, 2H), 1.96 (ddt, J = 20.3, 9.1, 4.2 Hz, 4H).

[0142] Example 8: Synthesis of Compound S8

[0143]

[0144] The first step:

[0145] Dissolve 0.29 g (1 eq, 2.92 mmol) of 4-aminotetrahydropyran in 50 ml of DCM. Add 0.74 g of TEA (2.5 eq, 7.3 mmol). Cool the mixture to 0 °C in an ice bath and add dropwise 0.67 g of acyl chloride (1.5 eq, 4.38 mmol). React overnight at room temperature. After completion, wash three times with 250 mM HCl and saturated NaHCO₃ respectively. Dry and concentrate the organic phase (at 30 °C) to obtain 0.64 g of white solid with a yield of 100% (theoretical).

[0146] The second step;

[0147] Dissolve the product of the first step in 50 ml of Tol. Cool the mixture to 0 °C in an ice bath and add 0.85 g of PCl₅ (1.4 eq, 4.1 mmol) in batches. After addition, stir at room temperature for 2 h. Then add 1.17 g of TMSN₃ (3.5 eq, 10.22 mmol) at room temperature and stir for 30 min. Heat the mixture to 80 °C and react for 3 h. After completion, dilute with EA. Wash the organic phase three times with saturated NaHCO₃. Dry and concentrate the organic phase (at 30 °C). The yield is 83% and the product is 0.59 g.

[0148] The third step;

[0149] Take 0.71 g (1.5 eq, 3.63 mmol) of quinolinone, add 0.52 g of DBU (1.4 eq, 3.39 mmol), add 10 ml of DMF, heat to 80 °C until clear. Add 0.59 g (1 eq) of the product of the second step and 80 mg of KI (0.2 eq, 0.48 mmol). React at 80 °C for 8 h. Dilute the organic phase with EA and wash twice with 0.5 N NaOH. Dry and concentrate the organic phase (at 30 °C). Purify the crude product by silica gel column chromatography (200 - 300 mesh, HE:EA = 4:1, start gradient elution until HE:EA = 1:4, collect the product, concentrate. When not completely dried, add HE for crystallization, filter by suction to obtain 0.35 g of white solid with a yield of 30%).

[0150] ESI-MS: 406.2 [M + H]+

[0151] ¹H NMR (400 MHz, DMSO-d₆) δ 11.63 (s, 1H), 7.82 (d, J = 9.5 Hz, 1H), 7.30–7.15 (m, 1H), 6.49 (d, J = 9.5 Hz, 1H), 4.72 (tt, J = 11.2, 4.5 Hz, 1H), 4.06 (t, J = 6.0 Hz, 2H), 3.49 (td, J = 11.7, 2.4 Hz, 2H), 2.97 (dt, J = 31.1, 7.6 Hz, 2H), 2.50–2.45 (m, 2H), 2.09–1.76 (m, 8H).

[0152] Example 9: Synthesis of Compound S9

[0153]

[0154] First Step:

[0155] Dissolve 0.29 g (1 eq, 2.92 mmol) of tetrahydropyranylamine in 50 ml of DCM, add 0.74 g of TEA (2.5 eq, 7.3 mmol), cool to 0 °C in an ice bath, and dropwise add 0.67 g of acyl chloride (1.5 eq, 4.38 mmol). React overnight at room temperature. After completion, wash three times with 250 mM HCl and saturated NaHCO3 respectively. Dry and concentrate the organic phase (at 30 °C) to obtain 0.64 g of white solid, with a yield of 100% (theoretical).

[0156] Second Step;

[0157] Dissolve the product of the first step in 50 ml of Tol, cool to 0 °C in an ice bath, and add 0.85 g of PCl5 (1.4 eq, 4.1 mmol) in batches. After addition, stir at room temperature for 2 h, then add 1.17 g of TMSN3 (3.5 eq, 10.22 mmol) at room temperature, stir at room temperature for 30 min, and then react at 80 °C for 3 h. After completion, dilute with EA, wash the organic phase three times with saturated NaHCO3, dry and concentrate the organic phase (at 30 °C). The yield is 83% for 0.59 g.

[0158] Third Step;

[0159] Take 0.59 g (1.5 eq, 3.63 mmol) of 6-hydroxyquinolinone, add 0.19 g of KOH (1.4 eq, 3.39 mmol), add 10 ml of isopropanol, heat to 80 °C, add 0.59 g (1 eq, 2.42 mmol) of the product of the second step, then add 80 mg of KI (0.2 eq, 0.48 mmol), react at 80 °C for 8 h. Dilute the organic phase with EA and wash twice with 0.5 N NaOH. Dry and concentrate the organic phase (at 30 °C). Purify the crude product by silica gel column chromatography with 200 - 300 mesh (HE:EA = 4:1, start gradient elution until HE:EA = 1:4, collect the product, concentrate, when not completely concentrated, add HE for crystallization, filter by suction to obtain 0.32 g of white solid) with a yield of 30%.

[0160] ESI-MS: 370.2 [M+H]+

[0161] 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 7.82 (d, J = 9.5 Hz, 1H), 7.30–7.15 (m, 2H), 7.12 (dd, J = 8.9, 2.8 Hz, 1H), 6.49 (d, J = 9.5 Hz, 1H), 4.72 (tt, J = 11.2, 4.5 Hz, 1H), 4.06 (t, J = 6.0 Hz, 2H), 3.49 (td, J = 11.7, 2.4 Hz, 2H), 2.97 (dt, J = 31.1, 7.6 Hz, 2H), 2.50–2.45 (m, 2H), 2.09–1.76 (m, 8H).

[0162] Example 10: Synthesis of Compound S10

[0163]

[0164] The first step:

[0165] Dissolve 0.44 g (1 eq, 2.92 mmol) of 4-amino-1-methylpiperidine hydrochloride in 50 mL of DCM, add 0.74 g (2.5 eq, 7.3 mmol) of TEA, cool the mixture to 0 °C in an ice bath, and dropwise add 0.67 g (1.5 eq, 4.38 mmol) of acyl chloride. React at room temperature overnight. After completion, wash with 250 mM HCl and saturated NaHCO3 three times each. Dry and concentrate the organic phase (at 30 °C) to obtain 0.67 g of a white solid with a yield of 100% (theoretical).

[0166] The second step;

[0167] Dissolve the product of the first step in 50 mL of Tol, cool the mixture to 0 °C in an ice bath, and add 0.85 g (1.4 eq, 4.1 mmol) of PCl5 portionwise. After addition, stir at room temperature for 2 h, then add 1.17 g (3.5 eq, 10.22 mmol) of TMSN3 at room temperature and stir at room temperature for 30 min. Heat the mixture to 80 °C and react for 3 h. After completion, dilute with EA, wash the organic phase with saturated NaHCO3 three times, and dry and concentrate the organic phase (at 30 °C). The yield is 83% (0.62 g).

[0168] The third step;

[0169] Take 0.71 g (1.5 eq, 3.63 mmol) of quinolinone, add 0.52 g (1.4 eq, 3.39 mmol) of DBU, add 10 ml of DMF, heat to 80 °C until clear, add 0.62 g (1 eq) of the product of the second step and 80 mg (0.2 eq, 0.48 mmol) of KI, react at 80 °C for 8 h, dilute the organic phase with EA, and wash it twice with 0.5 N NaOH. Dry and concentrate the organic phase (30 °C). Purify the crude product by silica gel column chromatography with 200 - 300 mesh (HE:EA = 4:1, start gradient elution until HE:EA = 1:4, collect the product, concentrate, when not completely dried, add HE for crystallization, filter to obtain a white solid) 0.36 g, 30% yield.

[0170] ESI-MS: 417.2 [M+H]+

[0171] 1H NMR (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), 4.45–4.33 (m, 1H), 4.10–4.03 (m, 2H), 2.96 (m, 2H), 2.87 (m, 2H), 2.22 (s, 3H), 2.13–2.00 (m, 2H), 1.98–1.73 (m, 8H).

[0172] Example 11: Synthesis of Compound S11

[0173]

[0174] The first step:

[0175] Dissolve 0.44 g (1 eq, 2.92 mmol) of 4-amino-1-methylpiperidine hydrochloride in 50 mL of DCM, add 0.74 g (2.5 eq, 7.3 mmol) of TEA, cool to 0 °C in an ice bath, dropwise add 0.67 g (1.5 eq, 4.38 mmol) of acyl chloride, react overnight at room temperature. After completion, wash it three times each with 250 mM HCl and saturated NaHCO3. Dry and concentrate the organic phase (30 °C) to obtain 0.686 g of white solid, 100% yield (theoretical).

[0176] The second step;

[0177] In the first step, the product was dissolved in 50 mL of Tol, cooled to 0 °C in an ice bath, and 0.85 g (1.4 eq, 4.1 mmol) of PCl5 was added portionwise. After addition, the mixture was stirred at room temperature for 2 h, then 1.17 g (3.5 eq, 10.22 mmol) of TMSN3 was added at room temperature, and the mixture was stirred at room temperature for 30 min and then heated to 80 °C for reaction for 3 h. After completion, it was diluted with EA, and the organic phase was washed 3 times with saturated NaHCO3, and the organic phase was dried and concentrated (30 °C). 0.63 g was obtained with a yield of 83%.

[0178] The third step;

[0179] Take 0.65 g (1.5 eq, 3.63 mmol) of quinolinone, add 0.52 g (1.4 eq, 3.39 mmol) of DBU, add 10 mL of DMF, heat to 80 °C until dissolved, add 0.63 g (1 eq) of the product from the second step and 80 mg (0.2 eq, 0.48 mmol) of KI, react at 80 °C for 8 h, dilute the organic phase with EA, and wash it 2 times with 0.5 N NaOH. The organic phase was dried and concentrated (30 °C). The crude product was purified by silica gel column chromatography with 200 - 300 mesh (HE:EA = 4:1, start gradient elution until HE:EA = 1:4, collect the product, concentrate, when not completely concentrated, add HE for crystallization, filter by suction to obtain a white solid) 0.35 g with a yield of 30%.

[0180] ESI-MS: 401.2 [M+H]+

[0181] 1H NMR (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), 4.45–4.33 (m, 1H), 4.10–4.03 (m, 2H), 2.96 (m, 2H), 2.87 (m, 2H), 2.22 (s, 3H), 2.13–2.00 (m, 2H), 1.98–1.73 (m, 8H).

[0182] Example 12: Synthesis of Compound S12

[0183]

[0184] The first step:

[0185] 0.44 g (1 eq, 2.92 mmol) of 4-amino-1-methylpiperidine hydrochloride was dissolved in 50 mL of DCM. 0.74 g (2.5 eq, 7.3 mmol) of TEA was added. The temperature was lowered to 0 °C in an ice bath, and 0.67 g (1.5 eq, 4.38 mmol) of acyl chloride was added dropwise. The reaction was carried out overnight at room temperature. After completion, it was washed three times with 250 mM HCl and saturated NaHCO₃ respectively. The organic phase was dried and concentrated (at 30 °C) to obtain 0.67 g of white solid, with a yield of 100% (theoretical).

[0186] The second step;

[0187] The product of the first step was dissolved in 50 mL of Tol. The temperature was lowered to 0 °C in an ice bath, and 0.85 g (1.4 eq, 4.1 mmol) of PCl₅ was added in batches. After addition, it was stirred at room temperature for 2 h, then 1.17 g (3.5 eq, 10.22 mmol) of TMSN₃ was added at room temperature, and it was stirred at room temperature for 30 min, and then the temperature was raised to 80 °C and reacted for 3 h. After completion, it was diluted with EA. The organic phase was washed three times with saturated NaHCO₃. The organic phase was dried and concentrated (at 30 °C). The yield was 83% with 0.63 g obtained.

[0188] The third step;

[0189] 0.83 g (1.5 eq, 3.63 mmol) of quinolinone was taken, 0.52 g (1.4 eq, 3.39 mmol) of DBU was added, 10 mL of DMF was added, and the temperature was raised to 80 °C until it was clear. 0.63 g (1 eq) of the product of the second step and 80 mg (0.2 eq, 0.48 mmol) of KI were added, and the reaction was carried out at 80 °C for 8 h. The organic phase was diluted with EA and washed twice with 0.5 N NaOH. The organic phase was dried and concentrated (at 30 °C). The crude product was purified by silica gel column chromatography with 200 - 300 mesh (HE:EA = 4:1, starting gradient elution until HE:EA = 1:4, collecting the product, concentrating, when not completely concentrated, adding HE for crystallization, filtering to obtain 0.39 g of white solid) with a yield of 30%.

[0190] ESI-MS: 451.2 [M + H]+

[0191] 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.09 (d, J = 9.9 Hz, 1H), 7.39 (s, 1H), 6.72 (d, J = 9.9 Hz, 1H), 4.45–4.33 (m, 1H), 4.10–4.03 (m, 2H), 2.96 (m, 2H), 2.87 (m, 2H), 2.22 (s, 3H), 2.13–2.00 (m, 2H), 1.98–1.73 (m, 8H).

[0192] Example 13: Synthesis of Compound S13

[0193]

[0194] Step 1:

[0195] Dissolve 0.44 g (1 eq, 2.92 mmol) of 4-amino-1-methylpiperidine hydrochloride in 50 mL of DCM. Add 0.74 g (2.5 eq, 7.3 mmol) of TEA. Cool the mixture to 0 °C in an ice bath and add dropwise 0.67 g (1.5 eq, 4.38 mmol) of acyl chloride. React overnight at room temperature. After completion, wash with 250 mM HCl and saturated NaHCO3 three times each. Dry and concentrate the organic phase (at 30 °C) to obtain 0.686 g of a white solid with a yield of 100% (theoretical).

[0196] Step 2;

[0197] Dissolve the product of the first step in 50 mL of Tol. Cool the mixture to 0 °C in an ice bath and add 0.85 g (1.4 eq, 4.1 mmol) of PCl5 portionwise. After addition, stir at room temperature for 2 h. Then add 1.17 g (3.5 eq, 10.22 mmol) of TMSN3 at room temperature and stir for 30 min. Heat the mixture to 80 °C and react for 3 h. After completion, dilute with EA. Wash the organic phase with saturated NaHCO3 three times. Dry and concentrate the organic phase (at 30 °C). The yield is 83% and the product is 0.63 g.

[0198] Step 3;

[0199] Take 0.71 g (1.5 eq, 3.63 mmol) of quinolinone, add 0.52 g (1.4 eq, 3.39 mmol) of DBU, add 10 mL of DMF, heat to 80 °C until clear. Add 0.63 g (1 eq) of the product of the second step and 80 mg (0.2 eq, 0.48 mmol) of KI. React at 80 °C for 8 h. Dilute the organic phase with EA and wash with 0.5 N NaOH twice. Dry and concentrate the organic phase (at 30 °C). Purify the crude product by silica gel column chromatography (200 - 300 mesh, HE:EA = 4:1, start gradient elution until HE:EA = 1:4, collect the product, concentrate. When not completely concentrated, add HE for crystallization, filter by suction to obtain 0.37 g of a white solid with a yield of 30%).

[0200] ESI-MS: 419.2 [M+H]+

[0201] 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 7.82 (d, J = 9.5 Hz, 1H), 7.30–7.15 (m, 1H), 6.49 (d, J = 9.5 Hz, 1H), 4.45–4.33 (m, 1H), 4.10–4.03 (m, 2H), 2.96 (m, 2H), 2.87 (m, 2H), 2.22 (s, 3H), 2.13–2.00 (m, 2H), 1.98–1.73 (m, 8H).

[0202] Example 14: Synthesis of Compound S14

[0203]

[0204] The first step:

[0205] Dissolve 0.29 g (1 eq, 2.92 mmol) of 4-aminotetrahydropyran in 50 ml of DCM, add 0.74 g of TEA (2.5 eq, 7.3 mmol), cool the mixture to 0 °C in an ice bath, and dropwise add 0.67 g of acyl chloride (1.5 eq, 4.38 mmol). React at room temperature overnight. After completion, wash with 250 mM HCl and saturated NaHCO3 three times each. Dry and concentrate the organic phase (at 30 °C) to obtain 0.64 g of a white solid with a yield of 100% (theoretical).

[0206] The second step;

[0207] Dissolve the product of the first step in 50 ml of Tol, cool the mixture to 0 °C in an ice bath, and add 0.85 g of PCl5 (1.4 eq, 4.1 mmol) in portions. After addition, stir at room temperature for 2 h, then add 1.17 g of TMSN3 (3.5 eq, 10.22 mmol) at room temperature and stir at room temperature for 30 min. Heat the reaction mixture to 80 °C and react for 3 h. After completion, dilute with EA, wash the organic phase with saturated NaHCO3 three times, and dry and concentrate the organic phase (at 30 °C). The yield is 83% (0.59 g).

[0208] The third step;

[0209] Take 0.65 g (1.5 eq, 3.63 mmol) of 6-hydroxyquinolinone, add 0.52 g (1.4 eq, 3.39 mmol) of DBU, add 10 ml of DMF, heat up to 80 °C, add 0.59 g (1 eq, 2.42 mmol) of the product of the second step, then add 80 mg of KI (0.2 eq, 0.48 mmol), react at 80 °C for 8 h, dilute the organic phase with EA, and wash it twice with 0.5 N NaOH. Dry and concentrate the organic phase (30 °C). Purify the crude product by silica gel column chromatography with 200 - 300 mesh (HE:EA = 4:1, start gradient elution until HE:EA = 1:4, collect the product, concentrate, when not completely dried, add HE for crystallization, filter by suction to obtain 0.34 g of white solid) with a yield of 30%.

[0210] ESI-MS: 388.2 [M + H]+

[0211] 1H NMR (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), 4.72 (tt, J = 11.2, 4.5 Hz, 1H), 4.06 (t, J = 6.0 Hz, 2H), 3.49 (td, J = 11.7, 2.4 Hz, 2H), 2.97 (dt, J = 31.1, 7.6 Hz, 2H), 2.50–2.45 (m, 2H), 2.09–1.76 (m, 8H).

[0212] Example 15: Synthesis of Compound S15

[0213]

[0214] First step:

[0215] Dissolve 0.29 g (1 eq, 2.92 mmol) of 4-aminotetrahydropyran in 50 ml of DCM, add 0.74 g (2.5 eq, 7.3 mmol) of TEA, cool down to 0 °C in an ice bath, dropwise add 0.67 g (1.5 eq, 4.38 mmol) of acyl chloride, react overnight at room temperature. After completion, wash it three times each with 250 mM HCl and saturated NaHCO3. Dry and concentrate the organic phase (30 °C) to obtain 0.64 g of white solid with a yield of 100% (theoretical).

[0216] Second step;

[0217] In the first step, the product was dissolved in 50 ml of Tol, cooled to 0 °C in an ice bath, and 0.85 g of PCl5 (1.4 eq, 4.1 mmol) was added portionwise. After the addition, the mixture was stirred at room temperature for 2 h, then 1.17 g of TMSN3 (3.5 eq, 10.22 mmol) was added at room temperature, and the mixture was stirred at room temperature for 30 min and then heated to 80 °C for reaction for 3 h. After completion, it was diluted with EA, and the organic phase was washed 3 times with saturated NaHCO3, and the organic phase was dried and concentrated (at 30 °C). 0.59 g was obtained with a yield of 83%.

[0218] The third step;

[0219] Take 0.71 g (1.5 eq, 3.63 mmol) of 6-hydroxyquinolinone, add 0.52 g (1.4 eq, 3.39 mmol) of DBU, add 10 ml of DMF, heat to 80 °C, add 0.59 g (1 eq, 2.42 mmol) of the product of the second step, then add 80 mg of KI (0.2 eq, 0.48 mmol), react at 80 °C for 8 h, dilute the organic phase with EA, and wash it 2 times with 0.5 N NaOH. The organic phase was dried and concentrated (at 30 °C), and the crude product was purified by silica gel column chromatography with 200 - 300 mesh (HE:EA = 4:1, start gradient elution until HE:EA = 1:4, collect the product, concentrate, when not completely concentrated to dryness, add HE for crystallization, filter by suction to obtain a white solid) 0.35 g with a yield of 30%.

[0220] ESI-MS: 404.1 [M + H]+

[0221] 1H NMR (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), 4.72 (tt, J = 11.2, 4.5 Hz, 1H), 4.06 (t, J = 6.0 Hz, 2H), 3.49 (td, J = 11.7, 2.4 Hz, 2H), 2.97 (dt, J = 31.1, 7.6 Hz, 2H), 2.50–2.45 (m, 2H), 2.09–1.76 (m, 8H)

[0222] Example 16: Synthesis of Compound S16

[0223]

[0224] The first step:

[0225] Dissolve 0.29 g (1 eq, 2.92 mmol) of 4-aminotetrahydropyran in 50 ml of DCM, add 0.74 g of TEA (2.5 eq, 7.3 mmol), cool the mixture to 0 °C in an ice bath, and dropwise add 0.67 g of acyl chloride (1.5 eq, 4.38 mmol). React overnight at room temperature. After completion, wash with 250 mM HCl and saturated NaHCO3 three times each. Dry and concentrate the organic phase (at 30 °C) to obtain 0.64 g of a white solid with a yield of 100% (theoretical).

[0226] The second step;

[0227] Dissolve the product of the first step in 50 ml of Tol, cool the mixture to 0 °C in an ice bath, and add 0.85 g of PCl5 (1.4 eq, 4.1 mmol) in batches. After addition, stir at room temperature for 2 h, then add 1.17 g of TMSN3 (3.5 eq, 10.22 mmol) at room temperature and stir for 30 min. Heat the reaction mixture to 80 °C and react for 3 h. After completion, dilute with EA, wash the organic phase with saturated NaHCO3 three times, dry and concentrate the organic phase (at 30 °C). The yield is 83% and the product is 0.59 g.

[0228] The third step;

[0229] Take 0.83 g (1.5 eq, 3.63 mmol) of 6-hydroxyquinolinone, add 0.52 g of DBU (1.4 eq, 3.39 mmol), add 10 ml of DMF, heat to 80 °C, add 0.59 g (1 eq, 2.42 mmol) of the product of the second step, then add 80 mg of KI (0.2 eq, 0.48 mmol), and react at 80 °C for 8 h. Dilute the organic phase with EA and wash with 0.5 N NaOH twice. Dry and concentrate the organic phase (at 30 °C). Purify the crude product by silica gel column chromatography (200 - 300 mesh, HE:EA = 4:1, start gradient elution until HE:EA = 1:4, collect the product, concentrate. When not completely concentrated, add HE for crystallization, filter by suction to obtain 0.38 g of a white solid with a yield of 30%).

[0230] ESI-MS: 438.1 [M+H]+

[0231] 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.09 (d, J = 9.9 Hz, 1H), 7.39 (s, 1H), 6.72 (d, J = 9.9 Hz, 1H), 4.72 (tt, J = 11.2, 4.5 Hz, 1H), 4.06 (t, J = 6.0 Hz, 2H), 3.49 (td, J = 11.7, 2.4 Hz, 2H), 2.97 (dt, J = 31.1, 7.6 Hz, 2H), 2.50–2.45 (m, 2H), 2.09–1.76 (m, 8H).

[0232] Example 17: Synthesis of Compound S17

[0233]

[0234] First step:

[0235] Dissolve 0.29 g (1 eq, 2.92 mmol) of 4-hydroxypiperidine in 50 ml of DCM, add 0.74 g of TEA (2.5 eq, 7.3 mmol), cool the temperature to 0 °C in an ice bath, dropwise add 0.67 g of acyl chloride (1.5 eq, 4.38 mmol), react overnight at room temperature. After completion, wash with 250 mM HCl and saturated NaHCO3 three times each, dry and concentrate the organic phase (at 30 °C) to obtain 0.64 g of white solid, with a yield of 100% (theoretical).

[0236] Second step;

[0237] Dissolve the product of the first step in 50 ml of Tol, cool the temperature to 0 °C in an ice bath, add 0.85 g of PCl5 (1.4 eq, 4.1 mmol) in batches. After addition, stir at room temperature for 2 h, then add 1.17 g of TMSN3 (3.5 eq, 10.22 mmol) at room temperature, stir at room temperature for 30 min, and react at 80 °C for 3 h. After completion, dilute with EA, wash the organic phase with saturated NaHCO3 three times, dry and concentrate the organic phase (at 30 °C). The yield is 83% for 0.59 g.

[0238] Third step;

[0239] Take 0.63 g (1.5 eq, 3.63 mmol) of 6-hydroxyquinolinone, add 0.19 g of KOH (1.4 eq, 3.39 mmol), add 10 ml of isopropanol, heat to 80 °C, add 0.59 g (1 eq, 2.42 mmol) of the product of the second step, then add 80 mg of KI (0.2 eq, 0.48 mmol), react at 80 °C for 8 h. Dilute the organic phase with EA and wash with 0.5 N NaOH twice. Dry and concentrate the organic phase (at 30 °C). Purify the crude product by silica gel column chromatography with 200 - 300 mesh (HE:EA = 4:1, start gradient elution until HE:EA = 1:4, collect the product, concentrate. When not completely concentrated to dryness, add HE for crystallization, filter by suction to obtain 0.33 g of white solid) with a yield of 30%.

[0240] ESI-MS: 384.2 [M+H]+

[0241] 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.83 (d, J = 9.5 Hz, 1H), 7.09–7.00 (m, 2H), 6.50 (d, J = 9.4 Hz, 1H), 4.72 (tt, J = 11.2, 4.5 Hz, 1H), 4.05 (t, J = 6.0 Hz, 2H), 4.01–3.92 (m, 2H), 3.49 (td, J = 11.7, 2.4 Hz, 2H), 3.02 (t, J = 7.3 Hz, 2H), 2.40 (s, 3H), 2.10–1.78 (m, 8H).

[0242] Example 18: Synthesis of Compound S18

[0243]

[0244] First Step:

[0245] Dissolve 0.44 g (1 eq, 2.92 mmol) of 4-amino-1-methylpiperidine hydrochloride in 50 ml of DCM. Add 0.74 g of TEA (2.5 eq, 7.3 mmol). Cool the mixture to 0 °C in an ice bath and add dropwise 0.67 g of acyl chloride (1.5 eq, 4.38 mmol). React at room temperature overnight. After completion, wash with 250 mM HCl and saturated NaHCO3 three times each. Dry and concentrate the organic phase (at 30 °C) to obtain 0.69 g of a white solid with a yield of 100% (theoretical).

[0246] Second Step;

[0247] Dissolve the product of the first step in 50 ml of Tol. Cool the mixture to 0 °C in an ice bath and add 0.85 g of PCl5 (1.4 eq, 4.1 mmol) in portions. After addition, stir at room temperature for 2 h. Then add 1.17 g of TMSN3 (3.5 eq, 10.22 mmol) at room temperature and stir at room temperature for 30 min. Heat the mixture to 80 °C and react for 3 h. After completion, dilute with EA. Wash the organic phase with saturated NaHCO3 three times. Dry and concentrate the organic phase (at 30 °C). The yield is 83% (0.63 g).

[0248] Third Step;

[0249] Take 0.63 g (1.5 eq, 3.63 mmol) of 6-hydroxyquinolinone, add 0.19 g (1.4 eq, 3.39 mmol) of KOH, add 10 ml of isopropanol, heat to 80 °C, add 0.63 g (1 eq, 2.42 mmol) of the product of the second step, then add 80 mg of KI (0.2 eq, 0.48 mmol), react at 80 °C for 8 h, dilute the organic phase with EA, and wash it twice with 0.5 N NaOH. Dry and concentrate the organic phase (30 °C). Purify the crude product by silica gel column chromatography with 200 - 300 mesh (HE:EA = 4:1, start gradient elution until HE:EA = 1:4, collect the product, concentrate it. When it is not completely dried, add HE for crystallization, filter by suction to obtain 0.35 g of white solid) with a yield of 30%.

[0250] ESI-MS: 397.2 [M+H]+

[0251] 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 7.81 (d, J = 9.5 Hz, 1H), 7.09–7.00 (m, 2H), 6.50 (d, J = 9.4 Hz, 1H), 4.45–4.33 (m, 1H), 4.10–4.03 (m, 2H), 2.96 (m, 2H), 2.87 (m, 2H), 2.40 (s, 3H), 2.22 (s, 3H), 2.13–2.00 (m, 2H), 1.98–1.73 (m, 8H).

[0252] Example 19: Detection of the inhibitory activity of the compound against phosphodiesterase 3A (PDE3A)

[0253] The PDE3A activity was detected using the PDE3A TR-FRET Assay Kit (BPS Catalog# 60706). The PDE3A TR-FRET assay kit is designed to identify PDE3A inhibitors using the TR-FRET (time-resolved fluorescence resonance energy transfer) technique. This assay is based on the FAM-labeled nucleotide monophosphate produced by phosphodiesterase. These phosphate groups bind to the Tb-labeled nanoparticles, resulting in energy transfer from Tb to FAM, and FAM emits a fluorescence signal at 520 nm. The change in fluorescence intensity can be easily measured using a multi-functional microplate reader.

[0254] Experimental procedure:

[0255] 1) Dilute the 20 μM FAM-Cyclic-3',5'-AMP substrate stock solution 100-fold with PDE buffer to make a 200 nM solution. Only perform enough assays; aliquot the remaining stock solution at -20 °C.

[0256] 2) Add 25 μl of FAM-Cyclic-3',5'-AMP (200 nM) to each well labeled "Substrate Control", "Positive Control", and "Test Inhibitor". Add 25 μl of PDE assay buffer to each well designated "Tb Only Control".

[0257] 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".

[0258] 4) Thaw PDE3A on ice. After the first thaw, briefly spin the tube containing the enzyme to resuspend the entire contents of the tube. Aliquot the PDE3A enzyme for single use. Immediately store the remaining undiluted enzyme aliquots at -80 °C.

[0259] 5) Dilute PDE3A to 0.05 ng / μl (1 ng / reaction) in PDE buffer. Add 20 μl of PDE assay buffer to the wells designated "Tb Only Control" and "Substrate Control", and add 20 μl of PDE3A (0.05 ng / μl) to the wells of "Positive Control" to initiate the reaction. For "Test Inhibitor", discard all remaining diluted enzyme after use.

[0260] 6) Incubate for 1 hour at room temperature.

[0261] 7) Prepare the binding dilution buffer by mixing equal volumes of binding buffer A and binding buffer B.

[0262] 8) Mix the binder well and dilute the binder with the binding dilution buffer prepared in step 1 at a ratio of 1:50.

[0263] 9) Add the Tb donor (1:1000 dilution) to the mixture.

[0264] 10) Add 100 μl to each well. Incubate with slow shaking for 1 hour at room temperature.

[0265] 11) Read the fluorescence intensity in a microplate reader with TR-FRET function.

[0266] Calculate the results:

[0267] (1) Fluorescence intensity calculation

[0268]

[0269] Where S520 = sample reading at 520 nm, S490 = sample reading at 490 nm, Tb520 = Tb only reading at 520 nm, and Tb490 = Tb only reading at 490 nm. When calculating the percentage of activity, the FRET value of only the substrate control can be set to zero activity, and the FRET value of the positive control can be set to 100% activity.

[0270] (2) Calculation of enzyme activity inhibition rate

[0271]

[0272] Where FRETs = sample FRET, FRETSub = substrate control only FRET, and FRETP = positive control FRET.

[0273] (3) Calculation of IC50 value:

[0274] Using log[compound concentration] as the abscissa and Inhibition% as the ordinate, in GraphPad Prism 7, fit a non-linear curve: log(inhibitor) vs. response--Variable slope, and calculate the IC50 value.

[0275] The results are shown in the following table. All the synthesized compounds S1 - S18 have PDE3A enzyme inhibitory activity.

[0276] Compound IC50 value Compound IC50 value S1 ++ S10 ++ S2 ++ S11 ++ S3 + S12 +++ S4 +++ S13 ++ S5 + S14 ++ S6 ++ S15 ++ S7 +++ S16 +++ S8 ++ S17 ++++ S9 ++ S18 ++

[0277] Note: ++++ indicates that the IC50 value is less than 0.3 μM; +++ indicates that the IC50 value is between 0.3 μM and 1 μM; ++ indicates that the IC50 value is between 1 μM and 10 μM; + indicates that the IC50 value is greater than 10 μM.

Claims

1. A class of quinolinone compounds represented by formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof: Among them, Y is selected from -O-, -NR4-, or -S-; R4 is selected from hydrogen or C1-C3 alkyl; R1, R2, and R3 are each independently selected from hydrogen, halogen, trifluoromethyl, or methyl; The covalent bond form between the 3-position carbon atom and the 4-position carbon atom is selected from a single bond or a double bond; n is selected from the numbers 0 to 3.

2. Any of the compounds according to claim 1, characterized in that: Among them, Y is selected from -O- or -NR4-; R4 is selected from methyl or ethyl; R1, R2, and R3 are each independently selected from hydrogen, fluorine, chlorine, trifluoromethyl, or methyl; The covalent bond form between the 3-position carbon atom and the 4-position carbon atom is selected from a single bond or a double bond; n is selected from the numbers 0 to 2.

3. Any of the compounds according to claim 1, characterized in that: Among them, Y is selected from -O- or -NR4-; R4 is methyl; R1 is selected from hydrogen, fluorine, chlorine, trifluoromethyl, or methyl; R2 is selected from hydrogen, fluorine, or trifluoromethyl; R3 is selected from hydrogen or chlorine; The covalent bond form between the 3-position carbon atom and the 4-position carbon atom is selected from a single bond or a double bond; n is selected from the numbers 0 to 1.

4. The compound according to claim 1, characterized in that, The compound is a compound selected from the following group or a pharmaceutically acceptable salt thereof: Compound 1: as shown in S1; Compound 2: as shown in S2; Compound 3: as shown in S3; Compound 4: as shown in S4; Compound 5: as shown in S5; Compound 6: as shown in S6; Compound 7: as shown in S7; Compound 8: as shown in S8; Compound 9: as shown in S9; Compound 10: as shown in S10; Compound 11: as shown in S11; Compound 12: as shown in S12; Compound 13: as shown in S13; Compound 14: as shown in S14; Compound 15: as shown in S15; Compound 16: as shown in S16; Compound 17: as shown in S17; Compound 18: as shown in S18.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, characterized in that, The said compound has an application in a drug with phosphodiesterase 3A (PDE3A) inhibitory activity.

6. The application of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the preparation of an anti-tumor, cardiovascular disease, cerebrovascular disease, or dementia drug.

7. A pharmaceutical composition, characterized in that, Comprising the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

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