Application of N-(3-hydroxy-6-oxo-6H-benzo [c] chromene-8-yl) acetamide hydroxyl etherified derivative in preparation of medicine for treating PDE2 mediated diseases

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to application of an N-(3-hydroxy-6-oxo-6H-benzo [c] chromene-8-yl) acetamide hydroxyl etherified derivative to preparation of a medicine for treating PDE2 mediated diseases. The N-(3-hydroxy-6-oxo-6H-benzo [c] chromene-8-yl) acetamide etherified derivative is as shown in the specification. According to the invention, 2-bromo-5-aminobenzoic acid is used as a raw material, and a final product is obtained through acetylation, cyclization and etherification. By adjusting the dosage of the catalyst and improving the purification method, the purposes of improving the product purity and the reaction yield are achieved. Meanwhile, through biological activity detection, the compound obtained by the invention has excellent PDE2 inhibitory activity. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to an N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)acetamide hydroxyetherification derivative as an inhibitor of phosphodiesterase 2 (PDE2), and a preparation method and application thereof. Background Art

[0002] Phosphodiesterase II (PDE2) belongs to the dual-substrate specific enzyme, which can catalyze the hydrolysis of cAMP and cGMP simultaneously. It is encoded by the single gene PDE2A and can be expressed as three subtypes, namely PDE2A1, PDE2A2 and PDE2A3, with a molecular weight of about 105 kDa. A large number of experimental results show that PDE2 hydrolyzes intracellular cAMP or cGMP, and then terminates the corresponding physiological effects.

[0003] For a long time, PDE2 has been regarded as an important target for the treatment of various diseases. In the field of neurological diseases, numerous studies have focused on the potential of PDE2 inhibitors to improve nerve function and relieve neurodegenerative diseases. In terms of cardiovascular diseases, regulating PDE2 activity to improve myocardial function and regulate vascular status has also become a research hotspot. It is worth mentioning that recently, some studies have proposed that PDE2 inhibitors are expected to open up a new path for the treatment of Candida infections. Therefore, PDE2 inhibitors show great therapeutic potential in the treatment of neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease), mental disorders (such as depression, schizophrenia), cognitive dysfunction, cardiovascular diseases (such as heart failure, pulmonary hypertension) and inflammation-related diseases, etc., and are a hot spot in the field of drug research and development.

[0004] In recent years, scientific research personnel have been committed to developing highly efficient and highly selective PDE2 inhibitors. Chinese Patent Application CN202411672257.1 discloses a class of 3,8-dihydroxy-6H-benzo[c]chromen-6-one 8-position hydroxyetherification derivatives as PDE2 inhibitors. This patent reports that these derivatives have good PDE2 inhibitory activity. However, although the prior art has made certain progress in the research and development of benz[c]chromen-6-one PDE2 inhibitors, there is still room for improvement in the inhibitory activity, selectivity, pharmacokinetic properties or side effects of existing compounds. In particular, for compounds with a benz[c]chromen-6-one core structure, the influence law of the type and combination of substituents at different positions on the PDE2 inhibitory activity still needs to be further explored. For the modification of other positions of this skeleton, especially replacing the 8-position hydroxy group with other functional groups and performing etherification modification on the 3-position hydroxy group, the influence on the PDE2 inhibitory activity is still unclear. There is an urgent need to develop PDE2 inhibitors with novel structures and better activities to meet the needs of clinical treatment. Summary of the Invention

[0005] The present invention aims to solve the technical problem that the activity of benz[c]chromen-6-one-based PDE2 inhibitors in the prior art needs to be further improved. The present invention provides a class of novel 3-hydroxy etherified derivatives of N-(3-hydroxy-6-oxo-6H-benz[c]chromen-8-yl)acetamide. By structurally modifying specific positions of the parent nucleus, its inhibitory activity against PDE2 is explored, with the expectation of obtaining candidate compounds with better activity and potential drug-likeness. At the same time, the present invention also provides a preparation method for such compounds, which is scientific, reasonable, simple and feasible.

[0006] In order to achieve the object of the present invention, the technical solutions adopted by the present invention are as follows:

[0007] The N-(3-hydroxy-6-oxo-6H-benz[c]chromen-8-yl)acetamide compounds as PDE2 inhibitors described in the present invention have the general formula as formula (Ⅰ):

[0008]

[0009] Wherein, R is C1-C6 alkyl, C1-C6 cycloalkyl, aryl or substituted aryl, heteroatom-containing alkyl, oxygen-containing heterocyclic group.

[0010] Further, the alkyl is straight-chain alkyl, branched-chain alkyl; the aryl is phenyl, benzyl; the substituents of the substituted aryl are halogen, alkyl, haloalkyl, alkoxy; the heteroatom-containing alkyl is methylthioethyl, methoxyethyl; the oxygen-containing heterocyclic group is tetrahydrofuranyl.

[0011] The preparation method of the N-(3-hydroxy-6-oxo-6H-benz[c]chromen-8-yl)acetamide derivatives as PDE2 inhibitors described in the present invention comprises the following steps:

[0012]

[0013] Preferably, the steps are as follows:

[0014] (1) Acetylation: Add 2-bromo-5-aminobenzoic acid to water, stir evenly and place it in a cold trap at 0 °C. Slowly dropwise add the prepared sodium hydroxide aqueous solution until the solution becomes clear, and then dropwise add acetic anhydride. At this time, white solid precipitates. Then, restore to room temperature, react for 4 h and then filter by suction. The obtained filter residue is recrystallized with ethanol to obtain 2-bromo-5-acetamidobenzoic acid monohydrate.

[0015] (2) Cyclization: Add the product obtained in step (1), resorcinol, and NaOH to water, heat to 50 °C and react for 1 h, then dropwise add 3% aqueous CuSO4 solution, and continue to reflux for 30 min. After the reaction is completed, cool, and filter by suction to filter out the precipitate. The precipitate is washed repeatedly with 1M HCl and dried in an oven. Recrystallize from methanol to obtain the product.

[0016] (3) Etherification: Dissolve the product obtained in step (2) in DMF, then add K2CO3 and the halide, react at 80 °C overnight. After the reaction is completed, pour it into ice water, stir well and oscillate, then let it stand to precipitate, filter by suction. The filter residue is dried in the oven, dissolved in DMF by heating to 100 °C, and solid is precipitated by adding water in the reverse direction, filter by suction. Add 100 mL of water to the filter residue, heat to 80 °C, and stir well. Repeat twice to remove the residual DMF. After the filter residue is filtered by suction, it is dried to obtain the product.

[0017] In step (1), the molar ratio of the raw material 2-bromo-5-amino-benzoic acid, acetic anhydride and sodium hydroxide is 2:3:2.

[0018] In step (2), the molar ratio of the product of step (1), resorcinol and NaOH is 1:3:3.

[0019] In step (2), the molar ratio of the product of step (1) to copper sulfate in the 3% aqueous CuSO4 solution as the catalyst is 4.75:1.

[0020] In step (3), the molar ratio of the product of step (2), anhydrous potassium carbonate and the halide is 1:1.1:1.1.

[0021] The reagents and raw materials used in the synthesis steps of the present invention are all commercially available.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] The present invention provides a novel inhibitor compound of PDE2, mainly including 33 compounds of a series of N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)acetamide hydroxy etherification derivatives, which have good PDE2 inhibitory activity. These compounds have the potential to treat central nervous system diseases, such as memory defects, cognitive impairment, anxiety and depression, etc., and can be used as active ingredients to prepare drugs that inhibit the activity of PDE2.

[0024] In addition, a corresponding synthesis method is given for the provided compound structure. The synthesis method is simple and has a high yield. Among them, in the cyclization step, when the reaction temperature is stabilized at 80°C, the reaction time is effectively shortened to 1h. In terms of catalytic conditions, copper sulfate plays a catalytic role in the system. When a large amount of copper sulfate solution is added, the copper ions will be freed and attached to the surface of the product, making the derivative reddish and affecting the purity and physicochemical properties. The copper sulfate solution was adjusted for the reaction at 1%, 2%, 3%, 4%, and 5%, respectively. It was found that 3% had the best reaction properties and the highest purity.

[0025] In terms of post-treatment methods, the post-etherification post-treatment was optimized. Originally, after the reaction was completed, water was added to precipitate the product, which was then filtered and washed, and the filter residue was recrystallized with methanol. In actual operation, the solubility of the product in methanol after etherification was very low, and a large amount of methanol was consumed; also due to the solubility, column chromatography also required the consumption of a large amount of solvent, both of which were not in line with the concept of green chemistry. After TLC and NMR analysis, it was determined that the impurity was the unreacted raw material - 8-acetylamino urolithin A. Finally, through literature search and experience accumulation, it was chosen to use hot DMSO to dissolve the filter residue and control the amount of water added (experimentally, twice the volume of DMSO was optimal) for reverse precipitation to obtain the product. In subsequent structural analysis, a relatively obvious DMSO peak was found in the NMR hydrogen spectrum, which was presumably residual during reverse precipitation. Finally, hot water beating was used to remove it. DETAILED DESCRIPTION

[0026] The technical solutions of the present invention will be described in detail below with reference to the following examples. The following examples are provided to illustrate, but not to limit, the synthesis methods of the compounds of Formula I. In one embodiment, the N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)acetamide compounds include the following compounds:

[0027]

[0028]

[0029] Example 1

[0030] 2-Bromo-5-aminobenzoic acid (14 mmol) was added to 250 mL of water, stirred evenly, and placed in a cold trap at 0°C. 5 M aqueous sodium hydroxide solution (2.8 mL) was slowly added dropwise until the solution clarified. Acetic anhydride (21 mmol) was then added dropwise, at which point a white solid precipitated. The mixture was then returned to room temperature and filtered after reacting for 4 h. The resulting residue was recrystallized from ethanol to obtain 2-bromo-5-acetamidobenzoic acid monohydrate (yield: 92%), mp 178.6-181.3°C. 11H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.03 (dd, J = 2.2, 0.9 Hz, 1H), 7.67–7.57 (m, 2H), 2.05 (s, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 169.23, 167.59, 139.21, 134.59, 134.01, 123.06, 121.16, 113.20, 24.50.

[0031] Example 2

[0032] The product obtained in Example 1 (4.46 mmol), resorcinol (13.38 mmol) and NaOH (13.38 mmol) were added with 20 mL of water, heated to 50 °C, reacted for 1 h, and an aqueous CuSO4 solution (3%, 5 mL) was added dropwise, and the mixture was refluxed for another 30 min. After the reaction was completed, it was cooled and the precipitate was filtered by suction. The precipitate was washed repeatedly with 1M HCl and dried in an oven. Recrystallization from methanol gave white crystals of N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)acetamide, yield: 76%, m.p. 234.8 - 236.9 °C. 1 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 10.28 (s, 1H), 8.51 (s, 1H), 8.21 (d, J = 8.6 Hz, 1H), 8.11 - 8.04 (m, 1H), 8.00 (d, J = 8.6 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 2.11 (s, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 168.76, 160.57, 160.44, 151.40, 139.05, 129.60, 125.99, 124.07, 122.71, 119.63, 118.03, 112.22, 110.70, 101.34, 24.06.

[0033] Example 3

[0034]

[0035] Weigh the product obtained in Example 2 (3.72 mmol, 1 g), dissolve it in DMF (20 mL), add anhydrous K2CO3 (4.10 mmol, 0.57 g), stir for 10 min, and then dropwise add the halide iodomethane (4.10 mmol, 0.58 g). React at 80 °C for 8 h. After the reaction is completed, pour it into 100 mL of ice water, stir and shake well, then let it stand to precipitate, filter by suction. The filter residue is dried in an oven, dissolved in DMF (10 mL) by heating to 100 °C, and then add twice the volume of water (20 mL) to reverse precipitate the solid. Filter by suction again. Add 100 mL of water to the filter residue, heat to 80 °C, and stir well. Repeat this twice to remove the residual DMF. After filtering the filter residue by suction, dry it to obtain the product N-(3-methoxy-6-oxo-6H-benzo[c]chromen-8-yl)acetamide (Compound UD1).

[0036] UD1: White solid (69% yield), m.p. 299.6 - 300.2 °C, 1 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.49 (d, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.10 (d, J = 9.4 Hz, 1H), 7.99 (dd, 1H), 6.95 (d, J = 4.5 Hz, 1H), 6.93 (dd, 1H), 3.84 (s, 3H), 2.11 (s, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 168.73, 160.54, 160.41, 151.37, 139.02, 129.57, 125.96, 124.04, 122.68, 119.60, 118.00, 112.19, 110.67, 101.32, 55.66, 24.03.

[0037] Example 4

[0038]

[0039] Compared with Examples 1 - 3, Example 4 is different in that: the halide in Example 3 is replaced with bromoethane, and other operations are the same as those in Examples 1 - 3, to obtain a solid product UD2 with a yield of 67%.

[0040] UD2: White solid (67% yield), m.p. 262.4 - 263.6 °C, 1HNMR(400MHz, DMSO-d6) δ 10.35 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.99 (dd, J = 8.8, 2.3 Hz, 1H), 6.93 (d, J = 2.5 Hz, 1H), 6.91 (dd, 1H), 4.09 (q, J = 6.9 Hz, 2H), 2.11 (s, 3H), 1.36 (t, J = 6.9 Hz, 3H). 13 C NMR(101MHz, DMSO-d6) δ 168.73, 160.43, 159.81, 151.35, 138.99, 129.61, 125.96, 124.03, 122.67, 119.59, 118.00, 112.48, 110.55, 101.69, 63.69, 24.03, 14.45.

[0041] Example 5

[0042]

[0043] Compared with Examples 1 - 3, Example 5 is different in that: the halide in Example 3 is replaced with n-propyl bromide, and other operations are the same as those in Examples 1 - 3, obtaining a solid product UD3 with a yield of 70%.

[0044] UD3: White solid (70% yield), m.p. 256.2 - 257.6 °C, 1 H NMR(400MHz, DMSO-d6) δ 10.34 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 8.00 (dd, J = 8.8, 2.4 Hz, 1H), 6.93 (d, J = 8.7 Hz, 2H), 3.99 (t, J = 6.5 Hz, 2H), 2.11 (s, 3H), 1.75 (h, J = 7.1 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H). 13 C NMR(101MHz, DMSO-d6) δ 168.73, 160.44, 159.98, 151.37, 139.00, 129.63, 126.00, 124.04, 122.68, 119.60, 118.04, 112.53, 110.57, 101.75, 69.48, 24.03, 21.87, 10.31.

[0045] Example 6

[0046]

[0047] Example 6 is different from Examples 1-3 in that the halide in Example 3 is replaced with 1-bromobutane, and other operations are the same as those in Examples 1-3, obtaining a solid product UD4 with a yield of 77%.

[0048] UD4: White solid (77% yield), m.p. 232.0-233.8 °C, 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.50 (d, J = 2.3 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.10 (d, J = 9.2 Hz, 1H), 8.00 (dd, J = 8.8, 2.3 Hz, 1H), 6.94 (d, J = 2.6 Hz, 1H), 6.91 (dd, J = 1.9, 1.2 Hz, 1H), 4.02 (t, J = 6.5 Hz, 2H), 2.11 (s, 3H), 1.71 (m, J = 6.7 Hz, 2H), 1.44 (m, J = 7.4 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 168.72, 160.43, 159.99, 151.36, 139.00, 129.63, 125.99, 124.03, 122.67, 119.59, 118.03, 112.53, 110.56, 101.74, 67.73, 30.56, 24.02, 18.67, 13.66.

[0049] Example 7

[0050]

[0051] Example 7 is different from Examples 1-3 in that the halide in Example 3 is replaced with 1-bromopentane, and other operations are the same as those in Examples 1-3, obtaining a solid product UD5 with a yield of 68%.

[0052] UD5: White solid (68% yield), m.p. 222.6-224.2 °C, 11H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.50 (d, J = 2.3 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 8.00 (dd, J = 8.8, 2.4 Hz, 1H), 6.93 (d, J = 7.6 Hz, 2H), 4.01 (t, J = 6.5 Hz, 2H), 2.11 (s, 3H), 1.73 (p, J = 6.6 Hz, 2H), 1.46 - 1.28 (m, 4H), 0.90 (t, J = 6.9 Hz, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 168.70, 160.43, 159.99, 151.37, 139.01, 129.63, 125.98, 124.03, 122.68, 119.60, 118.03, 112.53, 110.56, 101.74, 68.01, 28.21, 27.63, 24.03, 21.88, 13.89.

[0053] Example 8

[0054]

[0055] Compared with Examples 1 - 3, Example 8 is different in that: the halide in Example 3 is replaced with 1-bromohexane, and other operations are the same as those in Examples 1 - 3, obtaining a solid product UD6 with a yield of 84%.

[0056] UD6: white solid (84% yield), m.p. 216.0 - 217.7 °C, 1 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 8.01 (dd, J = 6.9, 1.6 Hz, 1H), 6.94 (d, J = 2.5 Hz, 1H), 6.91 (dd, J = 2.1, 1.1 Hz, 1H), 4.01 (t, J = 6.5 Hz, 2H), 2.11 (s, 3H), 1.71 (p, J = 6.7 Hz, 2H), 1.41 (p, J = 6.8 Hz, 2H), 1.31 (dd, J = 7.3, 3.6 Hz, 4H), 0.92 - 0.84 (m, 3H). 1313C NMR (101 MHz, DMSO-d6) δ 168.70, 160.44, 159.98, 151.37, 139.02, 129.63, 125.98, 124.03, 122.68, 119.60, 118.03, 112.53, 110.56, 101.73, 68.03, 30.99, 28.48, 25.13, 24.03, 22.07, 13.90.

[0057] Example 9

[0058]

[0059] Compared with Examples 1 - 3, Example 9 is different in that: the halide in Example 3 is replaced with 2 - bromopropane, and other operations are the same as those in Examples 1 - 3, obtaining a solid product UD7 with a yield of 78%.

[0060] UD7: White solid (78% yield), m.p. 247.6 - 250.0 °C, 1 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.52 (d, J = 2.3 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 8.01 (dd, J = 8.8, 2.4 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 8.5, 2.6 Hz, 1H), 4.75 (m, J = 6.0 Hz, 1H), 2.12 (s, 3H), 1.31 (d, J = 5.9 Hz, 6H). 13 13C NMR (101 MHz, DMSO-d6) δ 168.73, 160.47, 158.80, 151.46, 138.99, 129.66, 126.01, 124.14, 122.69, 119.61, 118.04, 113.33, 110.46, 102.72, 69.83, 24.04, 21.64.

[0061] Example 10

[0062]

[0063] Compared with Examples 1 - 3, Example 10 is different in that: the halide in Example 3 is replaced with 1 - bromo - 2 - methylpropane, and other operations are the same as those in Examples 1 - 3, obtaining a solid product UD8 with a yield of 76%.

[0064] UD8: White solid (76% yield), m.p. 237.6 - 240.2 °C, 1HNMR(400MHz, DMSO-d6) δ 10.35 (s, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.01 (dd, J = 8.8, 2.4 Hz, 1H), 6.97 (d, J = 2.5 Hz, 1H), 6.94 - 6.87 (m, 1H), 3.83 (d, J = 6.5 Hz, 2H), 2.11 (s, 3H), 2.04 (dt, J = 13.3, 6.6 Hz, 1H), 1.00 (d, J = 6.7 Hz, 6H). 13 C NMR(101MHz, DMSO-d6) δ 168.72, 160.45, 160.06, 151.37, 139.02, 129.63, 125.99, 124.06, 122.71, 119.61, 118.02, 112.57, 110.59, 101.81, 74.14, 27.59, 24.04, 18.96.

[0065] Example 11

[0066]

[0067] Compared with Examples 1 - 3, Example 11 is different in that the halide in Example 3 is replaced with 2 - bromobutane, and other operations are the same as those in Examples 1 - 3, obtaining a solid product UD9 with a yield of 81%.

[0068] UD9: White solid (81% yield), m.p. 208.4 - 210.2 °C, 1 H NMR(400MHz, DMSO-d6) δ 10.36 (s, 1H), 8.52 (d, J = 2.2 Hz, 1H), 8.23 (d, J = 8.7 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 8.02 (dd, J = 8.5, 2.5 Hz, 1H), 6.97 (d, J = 1.9 Hz, 1H), 6.94 (dd, J = 2.4, 0.8 Hz, 1H), 4.54 (h, J = 5.9 Hz, 1H), 2.12 (s, 3H), 1.66 (dh, J = 27.7, 6.9 Hz, 2H), 1.27 (d, J = 5.9 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H). 13CNMR(101MHz, DMSO-d6) δ 169.19, 160.94, 159.63, 151.96, 139.49, 130.15, 126.51, 124.62, 123.15, 120.10, 118.56, 113.83, 110.97, 103.25, 75.18, 28.88, 24.51, 19.35, 9.91.

[0069] Example 12

[0070]

[0071] Compared with Examples 1-3, Example 12 is different in that the halide in Example 3 is replaced with 1-bromo-3-methylbutane, and other operations are the same as those in Examples 1-3, obtaining a solid product UD10 with a yield of 82%.

[0072] UD10: White solid (82% yield), m.p. 210.0 - 212.4 °C, 1 H NMR(400MHz, DMSO-d6) δ 10.35(s, 1H), 8.50(d, J = 2.2Hz, 1H), 8.20(d, J = 8.8Hz, 1H), 8.10(d, J = 9.3Hz, 1H), 8.00(dd, J = 8.8, 2.4Hz, 1H), 6.94(d, J = 0.9Hz, 1H), 6.92(dd, J = 2.6, 0.5Hz, 1H), 4.05(t, J = 6.7Hz, 2H), 2.10(s, 3H), 1.84 - 1.71(m, J = 6.7Hz, 1H), 1.62(q, J = 6.7Hz, 2H), 0.94(d, J = 6.6Hz, 6H). 13 CNMR(101MHz, DMSO-d6) δ 168.72, 160.44, 159.97, 151.36, 139.00, 129.63, 125.97, 124.02, 122.68, 119.59, 118.01, 112.57, 110.55, 101.74, 66.50, 37.21, 24.54, 24.03, 22.38.

[0073] Example 13

[0074]

[0075] Compared with Examples 1-3, Example 13 is different in that the halide in Example 3 is replaced with 2-bromopentane, and other operations are the same as those in Examples 1-3, obtaining a solid product UD11 with a yield of 81%.

[0076] UD11: White solid (81% yield), m.p. 206.9 - 209.2 °C, 1 1H NMR (400 MHz, DMSO - d6) δ 10.36 (s, 1H), 8.51 (d, J = 4.0 Hz, 1H), 8.22 (d, J = 8.7 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.01 (dd, J = 4.7, 1.1 Hz, 1H), 6.94 (d, J = 11.1 Hz, 2H), 4.58 (dt, J = 6.9, 3.2 Hz, 1H), 2.10 (s, 3H), 1.70 - 1.61 (m, 1H), 1.57 - 1.49 (m, 1H), 1.44 - 1.32 (m, 2H), 1.29 - 1.21 (m, 3H), 0.90 (t, J = 7.0 Hz, 3H). 13 13C NMR (101 MHz, DMSO - d6) δ 168.69, 160.44, 159.15, 151.47, 138.98, 129.67, 126.04, 124.16, 122.69, 119.61, 118.06, 113.33, 110.47, 102.70, 73.34, 37.80, 24.01, 19.35, 18.05, 13.82.

[0077] Example 14

[0078]

[0079] Compared with Examples 1 - 3, Example 14 is different in that: the halide in Example 3 is replaced with 3 - bromopentane, and other operations are the same as in Examples 1 - 3, obtaining a solid product UD12 with a yield of 76%.

[0080] UD12: White solid (76% yield), m.p. 183.5 - 186.2, 1 1H NMR (400 MHz, DMSO - d6) δ 10.36 (s, 1H), 8.51 (d, J = 8.1 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.5 Hz, 1H), 8.00 (dd, J = 11.8, 2.4 Hz, 1H), 7.06 - 6.68 (m, 2H), 4.37 (s, 1H), 2.10 (dt, J = 4.8, 2.4 Hz, 2H), 1.64 (dt, J = 8.4, 4.9 Hz, 2H), 1.47 - 1.04 (m, 1H), 0.91 (t, J = 7.1 Hz, 6H). 1313C NMR (101 MHz, DMSO-d6) δ 168.75, 160.48, 159.71, 151.47, 138.98, 129.69, 126.05, 124.18, 122.69, 119.61, 118.07, 113.39, 110.48, 102.79, 79.52, 25.43, 24.02, 9.27.

[0081] Example 15

[0082]

[0083] Compared with Examples 1 - 3, Example 15 is different in that: the halide in Example 3 is replaced with bromomethylcyclopropane, and other operations are the same as those in Examples 1 - 3, obtaining a solid product UD13 with a yield of 85%.

[0084] UD13: White solid (85% yield), m.p. 247.6 - 249.5 °C, 1 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.99 (dd, J = 8.6, 2.3 Hz, 1H), 6.93 (dd, J = 8.6, 2.6 Hz, 1H), 6.90 (d, J = 2.5 Hz, 1H), 3.88 (d, J = 7.0 Hz, 2H), 2.10 (s, 3H), 1.24 (tq, J = 12.7, 7.3, 6.1 Hz, 1H), 0.60 (q, J = 5.3 Hz, 2H), 0.35 (q, J = 5.3 Hz, 2H). 13 13C NMR (101 MHz, DMSO-d6) δ 168.73, 160.44, 159.91, 151.33, 138.98, 129.62, 125.97, 124.02, 122.68, 119.57, 118.00, 112.53, 110.52, 101.77, 72.62, 24.03, 9.95, 3.14.

[0085] Example 16

[0086]

[0087] Compared with Examples 1 - 3, Example 16 is different in that: the halide in Example 3 is replaced with bromomethylcyclobutane, and other operations are the same as those in Examples 1 - 3, obtaining a solid product UD14 with a yield of 75%.

[0088] UD14: White solid (75% yield), m.p. 254.2 - 255.6 °C, 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.98 (dd, J = 8.7, 2.4 Hz, 1H), 6.92 (d, J = 2.6 Hz, 1H), 6.89 (dd, J = 2.1, 0.5 Hz, 1H), 3.99 (d, J = 6.7 Hz, 2H), 2.72 (hept, J = 7.3 Hz, 1H), 2.10 (s, 3H), 2.07 (dt, J = 9.2, 4.9 Hz, 2H), 1.87 (ddd, J = 32.9, 14.7, 8.3 Hz, 4H). 13 C NMR (101 MHz, DMSO-d6) δ 168.71, 160.42, 160.05, 151.31, 138.99, 129.59, 125.94, 123.98, 122.65, 119.56, 117.98, 112.51, 110.55, 101.74, 71.91, 33.77, 24.32, 24.02, 18.08.

[0089] Example 17

[0090]

[0091] Compared with Examples 1 - 3, Example 17 is different in that: the halide in Example 3 is replaced by bromomethylcyclopentane, and other operations are the same as those in Examples 1 - 3, obtaining a solid product UD15 with a yield of 80%.

[0092] UD15: White solid (80% yield), m.p. 250.4 - 251.6 °C, 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 6.96 - 6.71 (m, 2H), 3.89 (d, J = 6.9 Hz, 2H), 2.30 (hept, J = 7.3 Hz, 1H), 2.10 (s, 3H), 1.78 (dt, J = 13.4, 6.4 Hz, 2H), 1.67 - 1.46 (m, 4H), 1.33 (dq, J = 13.3, 6.8 Hz, 2H). 1313C NMR (101 MHz, DMSO-d6) δ 168.72, 160.44, 160.08, 151.34, 138.99, 129.62, 125.97, 124.00, 122.67, 119.57, 118.01, 112.54, 110.54, 101.74, 72.07, 38.36, 28.93, 24.91, 24.02.

[0093] Example 18

[0094]

[0095] The difference between Example 18 and Examples 1 - 3 lies in that: the halide in Example 3 was replaced with bromomethylcyclohexane, and other operations were the same as in Examples 1 - 3, obtaining a solid product UD16 with a yield of 72%.

[0096] UD16: White solid (72% yield), m.p. 268.3 - 269.6 °C, 1 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.50 (d, J = 2.4 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H), 8.01 (dd, J = 8.5, 0.7 Hz, 1H), 6.94 (d, J = 2.1 Hz, 1H), 6.91 (dd, J = 3.5, 0.8 Hz, 1H), 3.83 (d, J = 6.2 Hz, 2H), 2.11 (s, 3H), 1.81 (d, J = 12.9 Hz, 2H), 1.69 (dd, J = 24.9, 11.7 Hz, 4H), 1.21 (dp, J = 24.5, 12.7 Hz, 4H), 1.04 (q, J = 11.7 Hz, 2H). 13 13C NMR (101 MHz, DMSO-d6) δ 168.70, 160.44, 160.10, 151.36, 139.01, 129.64, 125.98, 124.03, 122.69, 119.59, 118.02, 112.53, 110.55, 101.77, 73.14, 36.92, 29.14, 25.99, 25.21, 24.04.

[0097] Example 19

[0098]

[0099] Example 19 is different from Examples 1-3 in that: the halide in Example 3 is replaced with 2-fluorobenzyl bromide, the amount of DMF used to dissolve the filter residue is increased to 20 mL, and at the same time the amount of water added for reverse precipitation is increased to 40 mL. Other operations are the same as those in Examples 1-3, obtaining the solid product UD17 with a yield of 73%.

[0100] UD17: White solid (73% yield), m.p. 301.8 - 303.9 °C, 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.53 (d, J = 2.5 Hz, 1H), 8.27 (d, J = 8.6 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 8.02 (dd, J = 8.7, 2.4 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.46 (q, J = 7.1 Hz, 1H), 7.28 (q, J = 8.6, 7.3 Hz, 2H), 7.13 (d, J = 2.6 Hz, 1H), 7.07 (dd, J = 8.7, 2.7 Hz, 1H), 5.25 (s, 2H), 2.11 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 168.79, 161.72, 160.42, 159.34, 151.35, 139.16, 130.97, 129.54, 126.03, 124.61, 124.23, 123.24, 122.86, 119.77, 118.06, 115.47, 112.75, 111.14, 102.28, 64.08, 24.05.

[0101] Example 20

[0102]

[0103] Example 20 is different from Examples 1-3 in that: the halide in Example 3 is replaced with 3-fluorobenzyl bromide, the amount of DMF used to dissolve the filter residue is increased to 20 mL, and at the same time the amount of water added for reverse precipitation is increased to 40 mL. Other operations are the same as those in Examples 1-3, obtaining the solid product UD18 with a yield of 79%.

[0104] UD18: White solid (79% yield), m.p. 290.5 - 294.6 °C, 11H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.52 (s, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.16 (d, J = 8.7 Hz, 1H), 8.01 (d, J = 8.7 Hz, 1H), 7.47 (q, J = 7.2 Hz, 1H), 7.33 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 8.6 Hz, 1H), 7.06 (d, J = 9.3 Hz, 2H), 5.23 (s, 2H), 2.11 (s, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 168.76, 163.40, 160.39, 159.32, 151.31, 139.42, 139.15, 130.55, 129.52, 126.00, 124.20, 123.67, 122.83, 119.75, 118.04, 114.76, 114.37, 112.85, 111.10, 102.38, 68.78, 24.05.

[0105] Example 21

[0106]

[0107] Compared with Examples 1 - 3, Example 21 is different in that: the halide in Example 3 is replaced with 4-fluorobenzyl bromide, the amount of DMF used to dissolve the filter residue is increased to 20 mL, and at the same time, the amount of water added for reverse precipitation is increased to 40 mL. Other operations are the same as those in Examples 1 - 3, and a solid product UD19 is obtained with a yield of 80%.

[0108] UD19: White solid (80% yield), m.p. 291.6 - 293.4 °C, 1 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.22 (d, J = 8.7 Hz, 1H), 8.13 (d, J = 8.7 Hz, 1H), 8.00 (dd, J = 8.7, 2.3 Hz, 1H), 7.57 - 7.49 (m, 2H), 7.23 (t, J = 8.8 Hz, 2H), 7.07 - 6.98 (m, 2H), 5.17 (s, 2H), 2.09 (s, 3H). 1313C NMR (101 MHz, DMSO-d6) δ 168.76, 160.43, 159.62, 151.33, 139.10, 137.30, 133.42, 129.60, 129.04, 127.97, 126.03, 124.13, 122.81, 119.70, 118.05, 112.94, 110.87, 102.33, 69.61, 24.05, 20.77.

[0109] Example 22

[0110]

[0111] Compared with Examples 1 - 3, Example 22 is different in that: the halide in Example 3 is replaced with 3-methylbenzyl bromide, the amount of DMF used to dissolve the filter residue is increased to 20 mL, and at the same time, the amount of water added for reverse precipitation is increased to 40 mL. Other operations are the same as those in Examples 1 - 3, obtaining the solid product UD20 with a yield of 79%.

[0112] UD20: white solid (79% yield), m.p. 293.7 - 296.4 °C, 1 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H), 8.01 (dd, J = 8.7, 2.3 Hz, 1H), 7.28 (dt, J = 9.1, 4.7 Hz, 3H), 7.16 (d, J = 7.1 Hz, 1H), 7.03 (d, J = 8.7 Hz, 2H), 5.15 (s, 2H), 2.33 (s, 3H), 2.11 (s, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 169.24, 160.91, 160.13, 151.83, 139.60, 138.16, 136.87, 130.08, 129.14, 128.88, 126.53, 125.43, 124.65, 123.30, 120.21, 118.56, 113.39, 111.41, 102.81, 70.24, 24.53, 21.46.

[0113] Example 23

[0114]

[0115] Example 23 is different from Examples 1-3 in that: the halide in Example 3 is replaced with 4-methylbenzyl bromide, the amount of DMF used to dissolve the filter residue is increased to 20 mL, and at the same time, the amount of water added for reverse precipitation is increased to 40 mL. Other operations are the same as those in Examples 1-3, and the solid product UD21 is obtained with a yield of 69%.

[0116] UD21: white solid (69% yield), m.p. 291.7-294.2 °C, 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 8.00 (dd, J = 8.7, 2.3 Hz, 1H), 7.37 (d, J = 7.6 Hz, 2H), 7.21 (d, J = 7.6 Hz, 2H), 7.02 (d, J = 8.9 Hz, 2H), 5.14 (s, 2H), 3.46 (s, 27H), 2.31 (s, 3H), 2.11 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 169.23, 160.90, 160.09, 151.79, 139.57, 137.77, 133.90, 130.06, 129.51, 128.43, 126.49, 124.59, 123.25, 120.17, 118.53, 113.39, 111.35, 102.79, 70.09, 24.53, 21.25.

[0117] Example 24

[0118]

[0119] Example 24 is different from Examples 1-3 in that: the halide in Example 3 is replaced with 2-chlorobenzyl bromide, the amount of DMF used to dissolve the filter residue is increased to 20 mL, and at the same time, the amount of water added for reverse precipitation is increased to 40 mL. Other operations are the same as those in Examples 1-3, and the solid product UD22 is obtained with a yield of 73%.

[0120] UD22: white solid (73% yield), m.p. 291.4-294.6 °C, 11H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.52 (d, J = 2.4 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 8.02 (dd, J = 8.5, 1.8 Hz, 1H), 7.68 - 7.61 (m, 1H), 7.58 - 7.51 (m, 1H), 7.46 - 7.38 (m, 2H), 7.11 (d, J = 2.4 Hz, 1H), 7.07 (dd, J = 8.7, 2.5 Hz, 1H), 5.26 (s, 2H), 2.11 (s, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 168.75, 160.39, 159.40, 151.34, 139.18, 133.75, 132.84, 130.44, 130.13, 129.51, 129.47, 127.42, 126.01, 124.24, 122.84, 119.78, 118.06, 112.71, 111.22, 102.34, 67.41, 24.06.

[0121] Example 25

[0122]

[0123] Compared with Examples 1 - 3, Example 25 is different in that: the halide in Example 3 is replaced with 3-chlorobenzyl bromide, the amount of DMF used to dissolve the filter residue is increased to 20 mL, and at the same time, the amount of water added for reverse precipitation is increased to 40 mL. Other operations are the same as those in Examples 1 - 3, and the solid product UD23 is obtained with a yield of 72%.

[0124] UD23: white solid (72% yield), m.p. 290.2 - 293.5 °C, 1 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 8.6 Hz, 1H), 8.02 (dd, J = 8.8, 2.3 Hz, 1H), 7.56 (d, J = 2.1 Hz, 1H), 7.49 - 7.38 (m, 3H), 7.05 (d, J = 8.3 Hz, 2H), 5.22 (s, 2H), 2.11 (s, 3H). 1313C NMR (101 MHz, DMSO-d6) δ 168.74, 160.38, 159.29, 151.31, 139.16, 139.07, 133.15, 130.42, 129.50, 127.92, 127.43, 126.31, 125.98, 124.19, 122.81, 119.75, 118.04, 112.83, 111.12, 102.37, 68.70, 24.05.

[0125] Example 26

[0126]

[0127] The difference between Example 26 and Examples 1-3 is that: the halide in Example 3 was replaced with 4-chlorobenzyl bromide, the amount of DMF used to dissolve the filter residue was increased to 20 mL, and at the same time the amount of water added for reverse precipitation was increased to 40 mL. Other operations were the same as in Examples 1-3, and the solid product UD24 was obtained with a yield of 64%.

[0128] UD24: White solid (64% yield), m.p. 326.3 - 328.1 °C, 1 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.51 (d, J = 2.6 Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 8.01 (dd, J = 7.7, 1.1 Hz, 1H), 7.49 (q, J = 8.2 Hz, 4H), 7.03 (d, J = 11.2 Hz, 2H), 5.20 (s, 2H), 2.11 (s, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 169.24, 160.88, 159.88, 151.81, 139.64, 136.03, 133.08, 130.12, 130.02, 128.98, 126.53, 124.68, 123.31, 120.24, 118.59, 113.39, 111.57, 102.94, 69.32, 24.53.

[0129] Example 27

[0130]

[0131] The difference between Example 27 and Examples 1-3 is that: the halide in Example 3 was replaced with 3-(trifluoromethyl)benzyl bromide, the amount of DMF used to dissolve the filter residue was increased to 20 mL, and at the same time the amount of water added for reverse precipitation was increased to 40 mL. Other operations were the same as in Examples 1-3, and the solid product UD25 was obtained with a yield of 77%.

[0132] UD25: White solid (77% yield), m.p. 245.9 - 247.2 °C, 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.52 (d, J = 2.3 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 8.02 (dd, J = 8.8, 2.3 Hz, 1H), 7.87 (d, J = 2.1 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 7.7 Hz, 1H), 7.13 - 7.05 (m, 2H), 5.32 (s, 2H), 2.11 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 168.76, 160.39, 159.30, 151.33, 139.18, 138.03, 131.83, 129.65, 129.50, 129.04, 126.00, 125.51, 124.74, 124.24, 122.86, 119.78, 118.05, 112.84, 111.18, 102.40, 68.75, 24.05.

[0133] Example 28

[0134]

[0135] Compared with Examples 1 - 3, Example 28 is different in that: the halide in Example 3 is replaced with 4-(trifluoromethyl)benzyl bromide, the amount of DMF used to dissolve the filter residue is increased to 20 mL, and at the same time the amount of water added for reverse precipitation is increased to 40 mL. Other operations are the same as those in Examples 1 - 3, and the solid product UD26 is obtained with a yield of 74%.

[0136] UD26: White solid (74% yield), m.p. 319.3 - 322.6 °C, 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.52 (d, J = 3.9 Hz, 1H), 8.24 (d, J = 8.7 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H), 8.02 (dd, J = 8.0, 1.3 Hz, 1H), 7.79 (d, J = 7.8 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 10.2 Hz, 2H), 5.33 (s, 2H), 2.11 (s, 3H). 1313C NMR (101 MHz, DMSO-d6) δ 168.75, 160.37, 159.23, 157.83, 154.12, 151.31, 141.39, 139.17, 129.47, 128.26, 128.11, 125.98, 125.38, 124.24, 122.83, 119.76, 118.03, 112.83, 111.17, 102.40, 68.70, 24.04.

[0137] Example 29

[0138]

[0139] Compared with Examples 1-3, Example 29 is different in that: the halide in Example 3 is replaced with 4-bromobenzyl bromide, the amount of DMF used to dissolve the filter residue is increased to 20 mL, and at the same time, the amount of water added for reverse precipitation is increased to 40 mL. Other operations are the same as those in Examples 1-3, and the solid product UD27 is obtained with a yield of 83%.

[0140] UD27: White solid (83% yield), m.p. 332.6 - 335.4 °C, 1 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.52 (d, J = 2.3 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 8.02 (dd, J = 8.8, 2.4 Hz, 1H), 7.62 (d, J = 1.9 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.07 (d, J = 2.5 Hz, 1H), 7.05 (dd, J = 8.7, 2.6 Hz, 1H), 5.20 (s, 2H), 2.10 (s, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 169.25, 160.89, 159.86, 151.82, 139.65, 136.46, 131.91, 130.44, 130.03, 126.53, 124.70, 123.34, 121.63, 120.25, 118.56, 113.40, 111.57, 102.91, 69.34, 24.54.

[0141] Example 30

[0142]

[0143] Example 30 is different from Examples 1-3 in that: the halide in Example 3 is replaced with 4-tert-butylbenzyl bromide, the amount of DMF used to dissolve the filter residue is increased to 20 mL, and at the same time, the amount of water added for reverse precipitation is increased to 40 mL. Other operations are the same as those in Examples 1-3, and the solid product UD28 is obtained with a yield of 80%.

[0144] UD28: White solid (80% yield), m.p. 291.9 - 294.5 °C, 1 HNMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.52 (d, J = 2.3 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 8.02 (dd, J = 8.8, 2.3 Hz, 1H), 7.41 (d, J = 1.8 Hz, 4H), 7.04 (dd, J = 12.7, 3.9 Hz, 2H), 5.16 (s, 2H), 2.11 (s, 3H), 1.28 (s, 9H). 13 C NMR (101 MHz, DMSO-d6) δ 168.75, 160.43, 159.67, 151.35, 150.50, 139.11, 133.47, 129.60, 127.78, 126.04, 125.23, 124.16, 122.80, 119.71, 118.07, 112.89, 110.89, 102.31, 69.52, 34.29, 31.08, 24.05.<s

[0145] Example 31

[0146]

[0147] Example 31 is different from Examples 1-3 in that: the halide in Example 3 is replaced with 3,5-dimethoxybenzyl bromide, the amount of DMF used to dissolve the filter residue is increased to 20 mL, and at the same time, the amount of water added for reverse precipitation is increased to 40 mL. Other operations are the same as those in Examples 1-3, and the solid product UD29 is obtained with a yield of 67%.

[0148] UD29: White solid (67% yield), m.p. 280.0 - 282.4 °C, 11H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.51 (d, J = 2.9 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 9.5 Hz, 1H), 8.02 (dd, J = 8.5, 2.3 Hz, 1H), 7.07 - 7.02 (m, 2H), 6.64 (d, J = 2.5 Hz, 2H), 6.49 - 6.44 (m, 1H), 5.14 (s, 2H), 3.76 (s, 6H), 2.11 (s, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 168.75, 160.55, 160.41, 159.48, 151.31, 139.12, 138.83, 129.55, 125.99, 124.14, 122.79, 119.73, 118.04, 112.88, 110.98, 105.51, 102.36, 99.49, 69.52, 55.17, 24.05.

[0149] Example 32

[0150]

[0151] Compared with Examples 1 - 3, Example 32 is different in that: the halide in Example 3 is replaced with 2-chloroethyl methyl sulfide, and other operations are the same as those in Examples 1 - 3, obtaining a solid product UD30 with a yield of 73%.

[0152] UD30: White solid (73% yield), m.p. 235.8 - 238.6 °C, 1 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.49 (d, J = 2.1 Hz, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 8.00 (dd, J = 8.8, 1.8 Hz, 1H), 6.98 - 6.91 (m, 2H), 4.22 (t, J = 6.6 Hz, 2H), 2.88 (t, J = 6.6 Hz, 2H), 2.19 (s, 3H), 2.12 (s, 3H). 13 13C NMR (101 MHz, DMSO-d6) δ 168.70, 160.38, 159.45, 151.30, 139.06, 129.51, 125.92, 124.06, 122.69, 119.64, 117.99, 112.50, 110.83, 101.90, 67.41, 32.00, 24.04, 15.21.

[0153] Example 33

[0154]

[0155] Example 33 is different from Examples 1 - 3 in that the halide in Example 3 is replaced with 2 - chloroethyl methyl ether, and other operations are the same as those in Examples 1 - 3, obtaining a solid product UD31 with a yield of 76%.

[0156] UD31: White solid (76% yield), m.p. 230.6 - 234.2 °C, 1 H NMR (400 MHz, DMSO - d6) δ 10.34 (s, 1H), 8.50 (d, J = 3.3 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 9.1 Hz, 1H), 8.00 (dd, J = 7.9, 3.3 Hz, 1H), 6.98 - 6.92 (m, 2H), 4.18 (t, J = 4.3 Hz, 2H), 3.72 - 3.67 (m, 2H), 3.34 (s, 3H), 2.11 (s, 3H). 13 C NMR (101 MHz, DMSO - d6) δ 168.73, 160.42, 159.73, 151.34, 139.03, 129.57, 125.95, 124.06, 122.69, 119.64, 118.01, 112.54, 110.74, 101.82, 70.17, 67.44, 58.15, 24.04.

[0157] Example 34

[0158]

[0159] Example 34 is different from Examples 1 - 3 in that the halide in Example 3 is replaced with 2 - bromomethyl tetrahydrofuran, and other operations are the same as those in Examples 1 - 3, obtaining a solid product UD32 with a yield of 77%.

[0160] UD32: White solid (77% yield), m.p. 233.6 - 235.8 °C, 11H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.13 (d, J = 9.1 Hz, 1H), 8.01 (dd, J = 8.9, 2.3 Hz, 1H), 7.00 - 6.93 (m, 2H), 4.17 (td, J = 6.8, 3.5 Hz, 1H), 4.06 (dd, J = 10.3, 3.7 Hz, 1H), 4.00 (dd, J = 10.3, 6.5 Hz, 1H), 3.80 (q, J = 7.2 Hz, 1H), 3.70 (q, J = 7.2 Hz, 1H), 2.11 (s, 3H), 2.06 - 1.97 (m, 1H), 1.87 (qt, J = 12.3, 6.5 Hz, 2H), 1.68 (dq, J = 14.7, 7.3 Hz, 1H). 13 13C NMR (101 MHz, DMSO-d6) δ 169.21, 160.91, 160.36, 151.83, 139.55, 130.08, 126.48, 124.57, 123.24, 120.15, 118.52, 113.09, 111.25, 102.39, 76.79, 71.07, 67.96, 28.05, 25.66, 24.53.

[0161] Example 35

[0162]

[0163] The difference between Example 35 and Examples 1 - 3 is that: the halide in Example 3 was replaced with 2-(bromomethyl)tetrahydropyran, and other operations were the same as those in Examples 1 - 3, obtaining a solid product UD33 with a yield of 76%.

[0164] UD33: White solid (76% yield), m.p. 279.6 - 282.3 °C, 1 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.50 (d, J = 3.1 Hz, 1H), 8.22 (d, J = 8.7 Hz, 1H), 8.11 (d, J = 8.9 Hz, 1H), 8.01 (dd, J = 8.1, 1.9 Hz, 1H), 6.97 - 6.91 (m, 2H), 3.93 - 3.86 (m, 4H), 3.32 (d, J = 11.8 Hz, 2H), 2.11 (s, 3H), 2.01 (dt, J = 12.0, 6.2 Hz, 1H), 1.68 (d, J = 12.9 Hz, 2H), 1.34 (qd, J = 12.3, 4.3 Hz, 2H). 13CNMR (101 MHz, DMSO-d6) δ 168.71, 160.42, 159.94, 151.36, 139.04, 129.61, 125.98, 124.06, 122.72, 119.63, 118.03, 112.54, 110.67, 101.83, 72.44, 66.57, 34.28, 29.12, 24.04.

[0165] Effect example: The obtained product UD1-33 was studied for its phosphodiesterase inhibitory activity

[0166] Experimental method: The inhibitor to be tested was dissolved in DMSO to form a 1 μM dilution; BAY 60-7550 was taken out of the -20 °C refrigerator and diluted with DMSO to form a 10 mM solution, and then further diluted with 1×Reaction Buffer (RA) to form seven gradient solutions of 50 nM, 25 nM, 12.5 nM, 6.25 nM, 3.12 nM, 1.56 nM, and 0.78 nM; PDE2 protein with a fixed concentration was taken from -80 °C and dissolved into a protein dilution of 2.44 mg / mL; cAMP was diluted with RA to form a 1 μM solution.

[0167] Select a range on a 384-well white plate, then pipette 1 μL of the diluted inhibitor to be tested and 1.5 μL of the PDE2 protein dilution into the 284-well white plate. Each group was set with three parallel wells, where for Min, each well contained 2.5 μL of RA without adding protein; for Max, each well contained 1 μL of RA and 1.5 μL of protein; for the positive control, each well contained 1 μL of BAY 60-7550 and 1.5 μL of protein; for the compound, 1 μL was added to each well. Then cover the white plate with a sealing film and centrifuge at 1000 rpm for 1 min. After centrifugation, place the white plate in a thermostatic oscillator and react at 25 °C and 300 rpm for 30 min. After the reaction, add 2.5 μL of the cAMP solution to each well, centrifuge at 1000 rpm for 1 min, and then react at 25 °C and 300 rpm for 20 min. At the same time, take out Termination buffer (T) and Detection buffer (D) from the refrigerator. After the reaction, add 2.5 μL of T to each well, centrifuge under the same conditions, then add 2.5 μL of D to each well, centrifuge, and react under the same conditions for 20 min. After the reaction, add Kinase Reagent buffer (KR) in the dark, cover with tin foil, centrifuge under the same conditions and then react for 10 min. During the reaction, turn on the multi-functional microplate reader to read the values, select the program, select the area, and after the reaction, place the white plate in the detection area of the instrument, run the program, and obtain the results.

[0168] Only replace the inhibitor diluent with BAY 60-7550 diluent at each concentration gradient, add reagents in sequence according to the above experimental procedure, and use a microplate reader to read the data and calculate its IC 50 .

[0169] The IC 50 values of the 33 synthesized compounds were further measured. The potential compounds were diluted to 7 final concentrations of 200 μM, 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, and 3.125 μM with 1×Reaction buffer. The specific experimental steps refer to the IC 50 determination method of BAY60-7550 above.

[0170] Table 1

[0171]

[0172]

[0173] From the specific IC 50 value data in the above table, it can be seen that the compounds of the general formula N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)acetamide show excellent inhibitory effects on PDE2 and have the potential to treat central nervous system diseases such as memory defects, cognitive impairment, anxiety, and depression. They can be used as active ingredients to prepare drugs that inhibit the activity of PDE2. Except for compounds UD4, UD5, UD11, UD13, UD18, and UD28, the IC 50 values of this series of compounds are all <50, and the IC 50 values of UD23 and UD29 have reached the nanomolar level breakthrough. Although the present invention is illustrated by specific embodiments before, it should not be construed as being limited thereto; rather, the present invention covers the general aspects disclosed before. Various modifications can be made and various embodiments can be implemented without departing from the spirit and scope of the present invention.

[0174] As mentioned above, the above are only the preferred specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and its concept of the present invention, makes equivalent substitutions or changes, and should be covered by the protection scope of the present invention.

Claims

1. Use of a class of N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)acetamide 3-O-etherified derivatives in the preparation of a medicament for treating or preventing PDE2-mediated diseases, characterized in that: The structural formula of the N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)acetamide 3-O-etherified derivative is as follows: Among them, R is a C1-C6 alkyl group, a C1-C6 cycloalkyl group, an aromatic group or a substituted aromatic group, a heteroatom-containing alkyl group, or an oxygen-containing heterocyclic group.

2. The use according to claim 1, characterized in that: The N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)acetamide 3-O-etherified derivative is one of the following structural formulas:

3. The use according to claim 2, wherein: The N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)acetamide 3-O-etherified derivative is one of the following structural formulas:

4. The use according to any one of claims 1 to 3, characterized in that: The diseases mediated by PDE2 are selected from neurodegenerative diseases, cognitive dysfunction, cardiovascular diseases or mental disorders.

5. A pharmaceutical preparation, characterized in that: It contains the N-(3-hydroxy-6-oxo-6H-benzo[c]chromen-8-yl)acetamide 3-O-etherified derivative described in claim 1, and one or more pharmaceutically acceptable carriers or excipients.

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