PDE5 inhibitors and uses thereof

Abstract

The invention relates to the technical field of biological medicine, in particular to a PDE5 inhibitor, a stereoisomer or pharmaceutically acceptable salt thereof and application of the PDE5 inhibitor. The compound disclosed by the invention has good activity and relatively good safety. The compound has the potential of being developed into drugs.

Description

Technical Field

[0001] The present invention relates to the field of biological medicine technology, and specifically relates to PDE5 inhibitors and their uses. Background Art

[0002] Erectile dysfunction is a common disease among middle-aged and elderly men. Statistical data shows that there are about 30 million patients in the United States, and the number of patients worldwide can reach 150 million. In the next few years, the number of patients will double. With the accelerating pace of global aging, the number of patients is increasing year by year, making the demand for good therapeutic drugs to improve the quality of life of patients increasingly urgent.

[0003] Phosphodiesterases (PDEs) are a family of nucleotide metabolic enzymes widely distributed in different tissues of organisms. They hydrolyze cyclic adenosine monophosphate or cyclic guanosine monophosphate to generate the corresponding inactive 5-nucleotides, thereby reducing the activity of intracellular second messengers. The balance between the actions of nucleotide cyclases and phosphodiesterases determines the concentrations of the second messengers cAMP and cGMP, thereby affecting various metabolic functions of organisms. To date, phosphodiesterases have been reported to have at least 11 structurally related but functionally distinct gene families (PDE1 - PDE11), and each family includes multiple subfamilies. All phosphodiesterases contain a conserved C-terminal catalytic site of approximately 270 amino acids, and their regulatory sites are located at the N-terminal. All phosphodiesterases contain a conserved carboxyl terminus with multiple isoenzymes as functionally specific variants, which participate in different signal transduction pathways, thereby regulating specific physiological and pathological processes, including ED, asthma, depression, visual degeneration, and congestive heart failure, etc.

[0004] In recent years, phosphodiesterases have attracted extensive attention as new therapeutic targets and become a new research hotspot. However, among the numerous phosphodiesterase families, phosphodiesterase type V (abbreviated as PDE5), as a promising target in biology, its mechanism of action has been highly regarded by scientists. Currently, PDE5 inhibitors are widely used as first-line therapeutic drugs for patients. However, the existing therapeutic drugs have not achieved the therapeutic goal and have certain adverse reactions. Therefore, the development of new selective PDE5 inhibitors with strong efficacy, rapid onset, and the ability to improve adverse reactions has important research significance and economic value.

[0005] Among the phosphodiesterase type V inhibitors that have been marketed globally, such as sildenafil, vardenafil, and tadalafil, the therapeutic effects are similar, and all can enable the above patients to achieve erections. However, the differences in their structures determine certain differences in their inhibitory effects and tissue selectivity. Research has shown that the higher the selectivity for PDE1, the higher the incidence of adverse reactions such as flushing and fever; the higher the selectivity for PDE6, the higher the incidence of visual impairment; and the higher the selectivity for PDE11, the higher the incidence of adverse reactions such as back pain and muscle pain.

[0006] The selectivity of sildenafil and vardenafil for PDE1 and PDE6 is higher than that of tadalafil, while the selectivity of tadalafil for PDE11 is higher than that of sildenafil and vardenafil. Sildenafil has been clinically used for many years. Its relatively serious adverse reactions include a decrease in lying blood pressure and cardiac output, an increased probability of cardiac abnormalities, such as symptoms like angina, dizziness, and nausea, and it may cause sudden cardiac death. Additionally, it may also cause visual impairment. In May 2005, the FDA reported that tadalafil was associated with vision loss due to ischemic optic neuropathy in some patients, and this drug may also cause sudden hearing loss. In October 2007, the FDA reported that vardenafil may also cause deafness. Additionally, it is indicated that patients taking nitrate drugs should not take vardenafil because the combination of such drugs with vardenafil may cause potentially life-threatening hypotension. Therefore, based on the clinical observation data on the safety of long-term medication and medication for high-risk populations, further improvement is still needed, and rational and cautious use of these drugs still needs to be emphasized.

[0007] Avanafil (trade name Stendra), chemical name (S)–4–(3–chloro–4–methoxybenzylamino)–2–(2–hydroxymethyl–1–pyrrolidinyl)–N–(2–pyrimidinylmethyl)–5–pyrimidinecarboxamide, is a phosphodiesterase type V (PDE5) inhibitor and is a product licensed by the US company Vivus from the Japanese company Mitsubishi Tanabe Pharma Corporation. Vivus announced the FDA approval of avanafil for marketing in the United States on April 27, 2012, for the treatment of male ED (Erectile Dysfunction).

[0008] Avanafil is a more potent and selective inhibitor than sildenafil. Preclinical studies have shown that the side effect of blood pressure reduction when avanafil is combined with organic nitrates is significantly lower than that of the corresponding sildenafil. This compound has a very weak affinity for other phosphodiesterases, and these results indicate that the cardiovascular side effects of this compound should be weaker than those of sildenafil. In addition, avanafil has a very weak inhibitory effect on PDE6, so it is very likely that it does not have the side effect of visual impairment that other marketed drugs have. Clinical trials have shown that when patients take avanafil or sildenafil, the duration of erection hardness in 60% of cases is significantly better than that of the placebo. The peak time of the therapeutic dose of this compound at 50 mg or 100 mg is 20 - 40 minutes after administration, and the duration is similar to that of sildenafil, but at a dose of 200 mg, the time is significantly longer than that of sildenafil, while the peak response time of sildenafil appears after 60 - 120 minutes. Therefore, it takes effect faster than sildenafil, has better tolerance, and no patients withdrew from the trial due to adverse reactions. The most common adverse reaction is only flushing, and the side effects and safety are satisfactory.

[0009] In summary, avanafil can become a new generation of therapeutic drug with higher selectivity, faster onset, and fewer side effects, and has good market prospects. Given that there are few marketed drugs and inhibitors under research currently, and they have obvious side effects, it is of great significance to further develop more ideal inhibitors. And based on the structural analogs of avanafil, they will also be potential active drug molecules. Therefore, the development of such novel PDE5 inhibitor compounds is of great significance. Summary of the Invention

[0010] The object of the present invention is to provide a PDE5 inhibitor, its stereoisomer or its pharmaceutically acceptable salt and their uses. Experiments of the present invention have shown that the said compound has good prevention and treatment activities and good safety.

[0011] The first object of the present invention is to provide a PDE5 inhibitor, its stereoisomer or its pharmaceutically acceptable salt, and the said inhibitor is a 6 - chloro - pyrimidine derivative, and the structural formula is as follows:

[0012]

[0013] wherein R1 is selected from pyrimidinyl or substituted pyrimidinyl, pyridinyl or substituted pyridinyl, phenyl or substituted phenyl, morpholinyl or substituted morpholinyl,

[0014] The said substituted pyrimidinyl is a C 1～6 alkyl - substituted pyrimidinyl, the said substituted pyridinyl is a C 1～6 alkyl - substituted pyridinyl, the said substituted phenyl is a C 1～6 alkyl - substituted phenyl or the C 1～6 alkyl - substituted phenyl is further substituted by C1～6 Alkoxy-substituted, and the substituted morpholinyl is C 1～6 alkyl-substituted morpholinyl;

[0015] R2 is selected from pyrrolidinyl or substituted pyrrolidinyl, morpholinyl or substituted morpholinyl, amino or substituted amino, dihydroisoquinolinyl or substituted dihydroisoquinolinyl, dihydropyrrolopyridinyl or substituted dihydropyrrolopyridinyl,

[0016] The substituted pyrrolidinyl is C 1～6 alkyl-substituted pyrrolidinyl or the C 1～6 alkyl of the alkyl-substituted pyrrolidinyl 1～6 alkyl is further substituted by a hydroxyl group, and the substituted morpholinyl is C 1～6 alkyl-substituted morpholinyl, and the substituted amino is C 1～6 alkyl-substituted amino or the C 1～6 alkyl of the alkyl-substituted amino 1～6 alkyl is further substituted by a hydroxyl group, C 1～6 alkoxy, and the substituted dihydroisoquinolinyl is C 1～6 alkyl-substituted dihydroisoquinolinyl or the C 1～6 alkyl of the alkyl-substituted dihydroisoquinolinyl 1～6 alkyl is further substituted by a hydroxyl group, and the substituted dihydropyrrolopyridinyl is C 1～6 alkyl-substituted dihydropyrrolopyridinyl.

[0017] Preferably, the PDE5 inhibitor, its stereoisomer or its pharmaceutically acceptable salt, wherein R1 is selected from substituted pyrimidinyl, substituted pyridinyl, substituted phenyl, substituted morpholinyl,

[0018] The substituted pyrimidinyl is C 1～3 alkyl-substituted pyrimidinyl, the substituted pyridinyl is C 1～3 alkyl-substituted pyridinyl, the substituted phenyl is C 1～3 alkyl-substituted phenyl or the C 1～3 alkyl of the alkyl-substituted phenyl is further substituted by C 1～3 alkoxy, and the substituted morpholinyl is C 1～3 alkyl-substituted morpholinyl;

[0019] R2 is selected from pyrrolidinyl or substituted pyrrolidinyl, morpholinyl, substituted amino, substituted dihydroisoquinolinyl, dihydropyrrolopyridinyl,

[0020] The substituted pyrrolidinyl is C 1～3 alkyl-substituted pyrrolidinyl or the C 1～3 alkyl of the alkyl-substituted pyrrolidinyl 1～3 alkyl is further substituted by a hydroxyl group, and the substituted amino is C 1～3 alkyl-substituted amino or the C1～3 The C of the alkyl-substituted amino 1～3 The alkyl is further substituted by a hydroxyl group, C 1～3 alkoxy group, and the substituted dihydroisoquinolinyl group is C 1～3 alkyl-substituted dihydroisoquinolinyl group or the C 1～3 alkyl-substituted dihydroisoquinolinyl group of the C 1～3 alkyl is further substituted by a hydroxyl group.

[0021] Preferably, the PDE5 inhibitor, its stereoisomer or its pharmaceutically acceptable salt has the following structural formula:

[0022]

[0023] where ○ represents that the ring is saturated or unsaturated,

[0024] wherein R1 is selected from pyrimidinyl or substituted pyrimidinyl, pyridyl or substituted pyridyl, phenyl or substituted phenyl, morpholinyl or substituted morpholinyl,

[0025] The substituted pyrimidinyl group is C 1～6 alkyl-substituted pyrimidinyl group, the substituted pyridyl group is C 1～6 alkyl-substituted pyridyl group, the substituted phenyl group is C 1～6 alkyl-substituted phenyl group or the C 1～6 alkyl-substituted phenyl group is further substituted by C 1～6 alkoxy group, and the substituted morpholinyl group is C 1～6 alkyl-substituted morpholinyl group;

[0026] R2 is selected from pyrrolidinyl or substituted pyrrolidinyl, morpholinyl or substituted morpholinyl, amino or substituted amino, dihydroisoquinolinyl or substituted dihydroisoquinolinyl, dihydropyrrolopyridinyl or substituted dihydropyrrolopyridinyl,

[0027] The substituted pyrrolidinyl group is C 1～6 alkyl-substituted pyrrolidinyl group or the C 1～6 alkyl-substituted pyrrolidinyl group of the C 1～6 alkyl is further substituted by a hydroxyl group, the substituted morpholinyl group is C 1～6 alkyl-substituted morpholinyl group, the substituted amino group is C 1～6 alkyl-substituted amino group or the C 1～6 alkyl-substituted amino group of the C 1～6 alkyl is further substituted by a hydroxyl group, C 1～6 alkoxy group, and the substituted dihydroisoquinolinyl group is C 1～6 alkyl-substituted dihydroisoquinolinyl group or the C 1～6 alkyl-substituted dihydroisoquinolinyl group of the C 1～6 alkyl is further substituted by a hydroxyl group, and the substituted dihydropyrrolopyridinyl group is C1～6 Alkyl substituted dihydropyrrolopyridinyl.

[0028] Preferably, the PDE5 inhibitor, its stereoisomer or its pharmaceutically acceptable salt, wherein R1 is selected from substituted pyrimidinyl, substituted pyridinyl, substituted phenyl, substituted morpholinyl,

[0029] The substituted pyrimidinyl group is C 1～3 Alkyl substituted pyrimidinyl, the substituted pyridinyl is C 1～3 Alkyl substituted pyridyl, the substituted phenyl is C 1～3 Alkyl substituted phenyl or the C 1～3 The alkyl-substituted phenyl group is further replaced by C 1～3 Alkoxy substituted, the substituted morpholinyl is C 1～3 Alkyl substituted morpholinyl;

[0030] R2 is selected from pyrrolidinyl or substituted pyrrolidinyl, morpholinyl, substituted amino, substituted dihydroisoquinolinyl, dihydropyrrolopyridinyl,

[0031] The substituted pyrrolidinyl group is C 1～3 Alkyl-substituted pyrrolidinyl or the C 1～3 Alkyl substituted pyrrolidinyl C 1～3 The alkyl group is further substituted with a hydroxyl group, wherein the substituted amino group is C 1～3 Alkyl substituted amino or the C 1～3 Alkyl substituted amino C 1～3 The alkyl group is further replaced by hydroxyl, C 1～3 Alkoxy substituted, the substituted dihydroisoquinolinyl is C 1～3 Alkyl substituted dihydroisoquinolinyl or said C 1～3 Alkyl-substituted dihydroisoquinolinyl C 1～3 The alkyl group is further substituted with a hydroxy group.

[0032] Preferably, the PDE5 inhibitor, its stereoisomer or a pharmaceutically acceptable salt thereof, is a pyrimidopyridone derivative, and has the following structural formula:

[0033]

[0034] Preferably, the PDE5 inhibitor, its stereoisomer or a pharmaceutically acceptable salt thereof, is a pyrimidodihydropyridone derivative, and has the following structural formula:

[0035]

[0036] Preferably, the PDE5 inhibitor, its stereoisomer or a pharmaceutically acceptable salt thereof, the inhibitor is a thioamide derivative, and has the following structural formula:

[0037]

[0038] Wherein R1 is selected from pyrimidinyl or substituted pyrimidinyl, pyridinyl or substituted pyridinyl, phenyl or substituted phenyl, morpholinyl or substituted morpholinyl,

[0039] The substituted pyrimidinyl is a C 1～6 alkyl-substituted pyrimidinyl, the substituted pyridinyl is a C 1～6 alkyl-substituted pyridinyl, the substituted phenyl is a C 1～6 alkyl-substituted phenyl or the C 1～6 alkyl-substituted phenyl is further substituted by a C 1～6 alkoxy group, the substituted morpholinyl is a C 1～6 alkyl-substituted morpholinyl;

[0040] R2 is selected from pyrrolidinyl or substituted pyrrolidinyl, morpholinyl or substituted morpholinyl, amino or substituted amino, dihydroisoquinolinyl or substituted dihydroisoquinolinyl, dihydropyrrolopyridinyl or substituted dihydropyrrolopyridinyl,

[0041] The substituted pyrrolidinyl is a C 1～6 alkyl-substituted pyrrolidinyl or the C 1～6 alkyl of the alkyl-substituted pyrrolidinyl is further substituted by a hydroxyl group, the substituted morpholinyl is a C 1～6 alkyl-substituted morpholinyl, the substituted amino is a C 1～6 alkyl-substituted amino or the C 1～6 alkyl of the alkyl-substituted amino is further substituted by a hydroxyl group and a C 1～6 alkoxy group, the substituted dihydroisoquinolinyl is a C 1～6 alkyl-substituted dihydroisoquinolinyl or the C 1～6 alkyl of the alkyl-substituted dihydroisoquinolinyl is further substituted by a hydroxyl group, the substituted dihydropyrrolopyridinyl is a C 1～6 alkyl-substituted dihydropyrrolopyridinyl. 1～6 1～6 1～6 Preferably, the PDE5 inhibitor, its stereoisomer or its pharmaceutically acceptable salt, wherein R1 is selected from substituted pyrimidinyl, substituted pyridinyl, substituted phenyl, substituted morpholinyl, 1～6 alkyl-substituted dihydropyrrolopyridinyl.

[0042] The substituted pyrimidinyl is a C

[0043] The substituted pyrimidinyl is a C 1～3 alkyl-substituted pyrimidinyl, the substituted pyridinyl is a C 1～3 alkyl-substituted pyridinyl, the substituted phenyl is a C 1～3 alkyl-substituted phenyl or the C 1～3 alkyl-substituted phenyl is further substituted by a C 1～3Alkoxy substitution, and the substituted morpholinyl is a C 1～3 alkyl-substituted morpholinyl;

[0044] R2 is selected from pyrrolidinyl or substituted pyrrolidinyl, morpholinyl, substituted amino, substituted dihydroisoquinolinyl, dihydropyrrolopyridinyl,

[0045] The substituted pyrrolidinyl is a C 1～3 alkyl-substituted pyrrolidinyl or the C 1～3 alkyl of the alkyl-substituted pyrrolidinyl is further substituted by a hydroxyl group, and the substituted amino is a C 1～3 alkyl-substituted amino or the C 1～3 alkyl of the alkyl-substituted amino is further substituted by a hydroxyl group and a C 1～3 alkoxy group, and the substituted dihydroisoquinolinyl is a C 1～3 alkyl-substituted dihydroisoquinolinyl or the C 1～3 alkyl of the alkyl-substituted dihydroisoquinolinyl is further substituted by a hydroxyl group. 1～3 alkyl of the alkyl-substituted dihydroisoquinolinyl is further substituted by a hydroxyl group. 1～3 alkyl of the alkyl-substituted dihydroisoquinolinyl is further substituted by a hydroxyl group. 1～3 alkyl of the alkyl-substituted dihydroisoquinolinyl is further substituted by a hydroxyl group.

[0046] Preferably, for the PDE5 inhibitor, its stereoisomer or its pharmaceutically acceptable salt, R1 is -(CH2) n -R 11 wherein: R

[0047] is selected from pyrimidinyl, pyridinyl, phenyl or morpholinyl, and the pyrimidinyl, pyridinyl, phenyl or morpholinyl is substituted by 0, 1 or 2 C 11 alkoxy groups; 1～6 alkoxy groups;

[0048] n = 1 to 6.

[0049] Preferably, for the PDE5 inhibitor, its stereoisomer or its pharmaceutically acceptable salt, R1 is selected from

[0050] R2 is selected from

[0051] Preferably, the use of the PDE5 inhibitor, its stereoisomer or its pharmaceutically acceptable salt in the preparation of a PDE5 inhibitor drug.

[0052] The third object of the present invention is to provide a composition comprising a therapeutically effective amount of the PDE5 inhibitor, its stereoisomer or its pharmaceutically acceptable salt and other pharmaceutically acceptable excipients.

[0053] The dosage form of the composition may include oral dosage forms and injection dosage forms, and can be prepared into tablets, capsules or injections by conventional methods.

[0054] 1. 6-Chloro derivatives (I-1 to I-20)

[0055] 1) Synthetic route

[0056]

[0057] 2) List of target compounds

[0058]

[0059]

[0060] 2. Pyrimido[4,5 - b]pyridinone derivatives (II-1 to II-17)

[0061] 1) Synthetic route

[0062]

[0063] 2) List of target compounds

[0064]

[0065]

[0066] 3. Pyrimido[4,5 - b]dihydropyridinone derivatives (III-1 to III-12)

[0067] 1) Synthetic route

[0068]

[0069] 2) List of target compounds

[0070]

[0071]

[0072] 4. Thioamide derivatives (IV-1 to IV-13)

[0073] 1) Synthetic route

[0074]

[0075] 2) List of target compounds

[0076]

[0077]

[0078] The beneficial effects of the present invention are as follows: 1. The compounds of the present invention show relatively high inhibitory activity against PDE5. Therefore, these compounds have the potential to be used in the preparation of therapeutic drugs for diseases related to PDE5 inhibitor activity.

[0079] 2. The compounds of the present invention have better drug-likeness compared to the positive control. Therefore, the compounds of the present invention are expected to have good development prospects. Detailed implementation manners

[0080] The present invention will be further described in detail below in conjunction with the embodiments, but is not limited thereto.

[0081] Example 1:

[0082] Synthesis steps and structural characterization of 6-chloro derivatives (I-1 to I-20)

[0083] Synthesis of ethyl 4-chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (2)

[0084] At room temperature, 500 mg of raw material 1 (1.88 mmol) was dissolved in 4 mL of anhydrous DMF in a 50 mL round-bottom single-necked flask. Separately, 389 mg of benzylamine hydrochloride (1.88 mmol, 1 eq.) was dissolved in 3 mL of anhydrous DMF, 518 μL (3.76 mmol, 2 eq.) of triethylamine was added, and after sonication for 10 min, it was slowly added dropwise to the reaction flask. The reaction solution was stirred at room temperature for 3.5 h. TLC (PE:EA = 10:1) showed that the raw material had basically reacted completely. The reaction solution was poured into 150 mL of water, extracted with EA (40 mL × 4), the organic layers were combined, dried by evaporation to obtain a crude product, and purified by silica gel column chromatography (PE:A = 20:1 to 10:1) to obtain 684 mg of a pure colorless oily substance, with a yield of 91.1%.

[0085] 1 H NMR (400 MHz, CDCl3) δ 8.69 (t, J = 5.7 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.17 (dd, J = 8.4, 2.1 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 4.63 (d, J = 5.6 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 2.48 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H).

[0086] 1313C NMR (101 MHz, CDCl3) δ 173.87, 166.60, 161.50, 159.97, 154.44, 131.12, 129.62, 126.97, 122.62, 112.20, 99.64, 61.78, 56.22, 44.36, 14.28, 14.09.

[0087] Synthesis of 4-chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-carboxylic acid (3)

[0088] At room temperature, 684 mg of intermediate 2 (1.706 mmol) was dissolved in a mixed solvent of 7 mL of THF and 7 mL of water in a 50 mL round-bottom flask, 90 mg of LiOH (2.047 mmol, 1.2 eq.) was added, and the temperature was raised to 60 °C. After reacting for 6 h, TLC showed that the raw materials had basically reacted completely. 1 N dilute hydrochloric acid was slowly added dropwise until a large amount of white flocculent precipitate was formed, allowed to stand for 1 h, filtered by suction, the filter cake was washed with a mixed solution of PE:EA = 20:1, and dried by suction to obtain 586 mg of white powder product 3, with a yield of 96.4%.

[0089] 1 1H NMR (400 MHz, Acetone) δ 7.45 (d, J = 2.1 Hz, 1H), 7.33 (dd, J = 8.5, 2.1 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 4.73 (s, 2H), 3.88 (s, 3H), 2.49 (s, 3H).

[0090] 13 13C NMR (101 MHz, Acetone) δ 205.27, 173.34, 166.86, 161.46, 159.34, 154.29, 132.06, 129.35, 127.38, 121.73, 112.47, 100.06, 55.61, 43.69, 13.32.

[0091] General method for the synthesis of 4-chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-carboxamide (4)

[0092] Taking 4-chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-N-(pyrimidin-2-ylmethyl)-5-carboxylic acid (4a) as an example: At room temperature, 102 mg of intermediate 3 (0.273 mmol) was added to a 25 mL single-necked round-bottom flask, and then 2 mL of SOCl2 was added. After reacting for 10 min, the temperature was raised to reflux. The reaction solution gradually changed from white turbidity to yellow transparent and clear. After refluxing for 5 h, the reaction solution was rotary evaporated to obtain a yellowish-green oily substance. Under room temperature and argon protection, the acyl chloride intermediate from the previous step was dissolved in 3 mL of anhydrous DCM, and aminomethylpyrimidine hydrochloride (0.273 mmol, 1 eq.) and 113 μL of triethylamine (0.819 mmol, 3 eq.) were added successively, and the mixture was stirred overnight at 25 - 30 °C. The reaction solution was concentrated, and column chromatography (1.5% MeOH / DCM) gave a white powder, and the combined yield of the two steps was 46%.

[0093] 1 H NMR (400 MHz, CDCl3) δ 8.91 (t, J = 5.8 Hz, 1H), 8.68 (d, J = 4.9 Hz, 2H), 8.07 (d, J = 4.9 Hz, 2H), 7.33 (d, J = 2.1 Hz, 1H), 7.23 (s, 1H), 7.18 (dd, J = 8.4, 2.2 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.86 (d, J = 4.7 Hz, 2H), 4.62 (d, J = 5.7 Hz, 2H), 3.88 (s, 3H), 2.48 (s, 3H).

[0094] 13 C NMR (101 MHz, CDCl3) δ 172.69, 165.22, 165.10, 161.19, 157.26, 155.77, 154.35, 131.38, 129.66, 127.03, 122.53, 119.68, 112.18, 103.29, 56.23, 45.85, 44.30, 14.23, 14.23.

[0095] General method for the synthesis of target products I-1 to I-20

[0096] At room temperature, intermediate 4 (0.624 mmol) was added to a 100 mL single-necked round-bottom flask and dissolved in 5 mL of chloroform. Under argon protection, 161 mg of m-chloroperbenzoic acid (mCPBA) (0.935 mmol, 1.5 eq.) was added. After stirring at room temperature for 2 h, TLC showed that 4 had completely reacted, forming two spots of sulfoxide and sulfone. 2 mL of saturated NaHCO3 was slowly added dropwise to quench the reaction, and then 100 mL of water was added. The mixture was extracted with DCM (30 mL × 3). The organic layers were combined and concentrated, and directly used for the next step.

[0097] Dissolve the intermediate from the previous step in 5 mL of anhydrous DCM, under argon protection, add R 2 the corresponding secondary amine (0.624 mmol, 1 eq.) and 130 μL of triethylamine (0.935 mmol, 1.5 eq.), stir at room temperature for 12 h. Concentrate the reaction solution, and perform column chromatography (5% MeOH / DCM) to obtain the target products I-1 to I-20.

[0098] (S)-4-chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-(2-hydroxymethylpyrrolidin-1)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide (I-1)

[0099] Yellow foamy solid, yield 54.2%.

[0100] 1 H NMR (400 MHz, CDCl3) δ 9.14 (d, J = 6.0 Hz, 1H), 8.70 (d, J = 4.9 Hz, 2H), 8.10 (t, J = 4.4 Hz, 1H), 7.35 (d, J = 2.1 Hz, 1H), 7.22 (t, J = 4.9 Hz, 1H), 7.18 (dd, J = 8.5, 2.1 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 4.84 (d, J = 4.5 Hz, 2H), 4.54 (d, J = 5.7 Hz, 2H), 4.40 (d, J = 14.7 Hz, 1H), 4.24 (s, 1H), 3.87 (s, 3H), 3.79–3.60 (m, 3H), 3.58–3.38 (m, 1H), 2.11 (d, J = 7.7 Hz, 1H), 1.90 (dt, J = 14.6, 6.7 Hz, 2H), 1.67 (s, 1H).

[0101] 13 C NMR (101 MHz, CDCl3) δ 166.03, 165.74, 162.77, 158.41, 157.36, 156.29, 154.26, 132.38, 129.91, 127.07, 122.46, 119.71, 112.26, 97.96, 68.21, 61.39, 56.36, 48.50, 46.08, 44.24, 30.04, 23.90.

[0102] ESI-MS (m / z): 518.2 (M + H) + , 540.2 (M + Na) + .

[0103] 4-Chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-(N-methyl-2-hydroxyethylamino)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide (I-2)

[0104] Pale yellow massive solid, yield 58.6%.

[0105] 1 H NMR (400 MHz, CDCl3) δ 9.14 (t, J = 5.7 Hz, 1H), 8.71 (d, J = 4.5 Hz, 2H), 8.11 (s, 1H), 7.33 (d, J = 2.1 Hz, 1H), 7.23 (d, J = 4.8 Hz, 1H), 7.17 (dd, J = 8.4, 2.2 Hz, 1H), 4.84 (d, J = 4.4 Hz, 2H), 4.52 (s, 2H), 3.87 (s, 3H), 3.82 (s, 2H), 3.70 (s, 2H), 3.18 (s, 3H).

[0106] 13 C NMR (101 MHz, CDCl3) δ 166.04, 165.68, 162.65, 159.91, 157.27, 154.12, 132.05, 129.54, 126.80, 122.36, 119.61, 112.13, 97.75, 56.23, 52.25, 45.95, 44.23, 36.46, 29.71.

[0107] ESI-MS (m / z): 492.0 (M + H) + .

[0108] 4-Chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-morpholinyl-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide (I-3)

[0109] Milky white massive solid, yield 56.6%.

[0110] 11H NMR (400 MHz, CDCl3) δ 9.10 (t, J = 5.7 Hz, 1H), 8.70 (d, J = 4.9 Hz, 2H), 8.11 (t, J = 4.5 Hz, 1H), 7.33 (d, J = 2.2 Hz, 1H), 7.22 (td, J = 4.9, 0.8 Hz, 1H), 7.16 (dd, J = 8.4, 2.2 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.84 (d, J = 4.5 Hz, 2H), 4.52 (d, J = 5.7 Hz, 2H), 3.87 (s, 3H), 3.78 (dd, J = 5.6, 3.7 Hz, 4H), 3.70 (dd, J = 5.6, 3.8 Hz, 4H).

[0111] 13 13C NMR (101 MHz, CDCl3) δ 166.05, 165.70, 162.87, 158.66, 157.41, 157.25, 154.10, 132.24, 129.63, 126.83, 122.33, 119.58, 112.09, 97.81, 66.73, 56.23, 53.43, 45.96, 44.20, 44.14.

[0112] ESI-MS (m / z): 504.0 (M+H) + .

[0113] 4-Chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-(N-methyl-N-methoxyethylamino)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide (I-4)

[0114] Off-white solid mass, yield 57.2%.

[0115] 1 1H NMR (400 MHz, CDCl3) δ 9.08 (t, J = 5.8 Hz, 1H), 8.71 (d, J = 4.9 Hz, 2H), 8.12 (s, 1H), 7.37–7.28 (m, 1H), 7.21 (t, J = 4.9 Hz, 1H), 7.15 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.84 (d, J = 4.6 Hz, 2H), 4.52 (s, 2H), 3.87 (s, 3H), 3.78–3.51 (m, 3H), 3.45–3.23 (m, 4H), 3.18 (s, 3H).

[0116] 1313C NMR (101 MHz, CDCl3) δ 166.35, 165.81, 162.73, 159.04, 157.24, 153.98, 132.61, 129.19, 126.48, 122.30, 119.55, 112.06, 96.97, 70.58, 58.85, 56.24, 56.19, 49.31, 45.97, 44.05, 36.56.

[0117] ESI-MS (m / z): 506.1.2 (M + H) + , 528.1 (M + Na) + .

[0118] 4-Chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-pyrrolidinyl-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide (I-5)

[0119] White block solid, yield 62.5%.

[0120] 1 1H NMR (400 MHz, CDCl3) δ 9.05 (t, J = 5.9 Hz, 1H), 8.70 (d, J = 4.9 Hz, 2H), 8.10 (t, J = 4.6 Hz, 1H), 7.36 (d, J = 2.2 Hz, 1H), 7.25–7.15 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H), 4.84 (d, J = 4.6 Hz, 2H), 4.54 (d, J = 5.8 Hz, 2H), 3.87 (s, 3H), 3.54 (d, J = 25.1 Hz, 4H), 1.99–1.88 (m, 4H).

[0121] 13 13C NMR (101 MHz, CDCl3) δ 166.46, 165.84, 162.65, 157.51, 157.23, 156.98, 153.97, 132.72, 129.85, 127.01, 122.16, 119.53, 112.00, 97.02, 56.21, 46.80, 46.60, 45.99, 43.98, 25.42, 25.28.

[0122] ESI-MS (m / z): 488.0 (M + H) + .

[0123] (S)-4-Chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-(2-hydroxymethylpyrrolidin-1-yl)-N-(pyridin-2-ylmethyl)pyrimidine-5-carboxamide (I-6)

[0124] White foamy solid, yield 49.2%.

[0125] 1 H NMR (400 MHz, CDCl3) δ 9.02 (t, J = 5.7 Hz, 1H), 8.53–8.46 (m, 1H), 7.98 (t, J = 5.0 Hz, 1H), 7.66 (td, J = 7.7, 1.8 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.31–7.24 (m, 1H), 7.17 (dd, J = 8.2, 2.0 Hz, 2H), 6.85 (d, J = 8.4 Hz, 1H), 4.69 (d, J = 5.0 Hz, 2H), 4.53 (d, J = 5.8 Hz, 2H), 4.20 (d, J = 9.0 Hz, 1H), 3.86 (s, 3H), 3.76–3.59 (m, 3H), 3.49 (dt, J = 12.0, 6.5 Hz, 1H), 2.13–2.01 (m, 1H), 1.87 (dp, J = 19.3, 6.2 Hz, 2H), 1.68 (dq, J = 10.3, 6.1 Hz, 1H).

[0126] 13 C NMR (101 MHz, CDCl3) δ 165.95, 162.48, 158.23, 156.06, 155.94, 154.08, 149.07, 136.82, 132.22, 129.72, 126.95, 122.39, 121.73, 112.09, 97.98, 67.70, 61.10, 56.19, 48.33, 44.99, 29.78, 23.71.

[0127] ESI-MS (m / z): 517.1 (M + H) + .

[0128] 4-Chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-(N-methyl-2-hydroxyethylamino)-N-(pyridin-2-ylmethyl)pyrimidine-5-carboxamide (I-7)

[0129] White massive solid, yield 56.1%.

[0130] 11H NMR (400 MHz, CDCl3) δ 9.05 (t, J = 5.7 Hz, 1H), 8.52 (ddd, J = 4.9, 1.7, 0.9 Hz, 1H), 7.95 (t, J = 5.0 Hz, 1H), 7.66 (td, J = 7.7, 1.8 Hz, 1H), 7.35–7.25 (m, 2H), 7.23–7.13 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H), 4.70 (d, J = 5.0 Hz, 2H), 4.54–4.49 (m, 2H), 3.86 (s, 3H), 3.79 (s, 3H), 3.72–3.67 (m, 3H), 3.16 (s, 3H).

[0131] 13 13C NMR (101 MHz, CDCl3) δ 166.11, 162.59, 159.88, 156.11, 154.09, 149.12, 136.83, 132.10, 129.49, 126.76, 122.40, 122.34, 121.77, 112.11, 97.73, 62.11, 56.25, 56.18, 52.24, 45.03, 44.21, 36.45.

[0132] ESI-MS (m / z): 491.0 (M+H) + , 513.0 (M+Na) + .

[0133] 4-Chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-morpholinyl-N-(pyridin-2-ylmethyl)pyrimidine-5-carboxamide (I-8)

[0134] White block solid, yield 59.5%.

[0135] 1 1H NMR (400 MHz, CDCl3) δ 9.03 (t, J = 5.7 Hz, 1H), 8.53 (dt, J = 4.9, 1.3 Hz, 1H), 7.97 (t, J = 4.9 Hz, 1H), 7.67 (td, J = 7.7, 1.8 Hz, 1H), 7.35–7.26 (m, 2H), 7.23–7.12 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H), 4.71 (d, J = 5.0 Hz, 2H), 4.51 (d, J = 5.7 Hz, 2H), 3.87 (s, 3H), 3.76 (q, J = 4.3 Hz, 4H), 3.69 (dd, J = 5.5, 3.8 Hz, 4H).

[0136] 1313C NMR (101 MHz, CDCl3) δ 166.12, 162.82, 158.65, 157.29, 156.12, 154.10, 149.14, 136.81, 132.22, 129.62, 129.60, 126.84, 126.82, 122.39, 122.32, 121.77, 112.11, 112.07, 97.84, 66.73, 56.26, 56.18, 45.05, 44.19, 44.14.

[0137] ESI-MS (m / z): 503.0 (M+H) + , 525.1 (M+Na) + .

[0138] 4-Chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-(N-methyl-N-methoxyethylamino)-N-(pyridin-2-ylmethyl)pyrimidine-5-carboxamide (I-9)

[0139] Milky white lumpy solid, yield 63.3%.

[0140] 1 1H NMR (400 MHz, CDCl3) δ 9.01 (t, J = 5.8 Hz, 1H), 8.56–8.50 (m, 1H), 7.94 (t, J = 4.9 Hz, 1H), 7.67 (td, J = 7.9, 1.8 Hz, 1H), 7.30 (d, J = 7.8 Hz, 2H), 7.19 (dd, J = 7.5, 4.9 Hz, 1H), 7.15 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.71 (d, J = 5.0 Hz, 2H), 4.52 (s, 2H), 3.86 (s, 3H), 3.71 (d, J = 37.8 Hz, 3H), 3.30 (d, J = 32.9 Hz, 4H), 3.17 (s, 3H).

[0141] 13 13C NMR (151 MHz, CDCl3) δ 166.43, 162.66, 159.03, 156.33, 153.99, 149.15, 136.78, 132.59, 129.18, 126.46, 122.35, 121.75, 112.08, 97.19, 70.57, 58.84, 56.22, 49.31, 45.08, 44.06, 36.58.

[0142] ESI-MS (m / z): 505.0 (M+H) + , 527.0 (M+Na) + .

[0143] 4-Chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-pyrrolidinyl-N-(pyridin-2-ylmethyl)pyrimidine-5-carboxamide (I-10)

[0144] White lumpy solid, yield 68.9%.

[0145] 1 H NMR (600 MHz, CDCl3) δ 8.98 (t, J = 5.8 Hz, 1H), 8.53 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 7.91 (t, J = 5.0 Hz, 1H), 7.66 (td, J = 7.7, 1.8 Hz, 1H), 7.36 (d, J = 2.2 Hz, 1H), 7.29 (dt, J = 7.8, 1.0 Hz, 1H), 7.18 (ddd, J = 8.3, 3.8, 1.5 Hz, 2H), 6.85 (d, J = 8.4 Hz, 1H), 4.71 (d, J = 5.0 Hz, 2H), 4.53 (d, J = 5.8 Hz, 2H), 3.86 (s, 3H), 3.53 (d, J = 36.7 Hz, 4H), 1.96–1.88 (m, 4H).

[0146] 13 C NMR (101 MHz, CDCl3) δ 166.55, 162.60, 157.52, 156.87, 156.37, 153.96, 149.12, 136.80, 132.70, 129.83, 127.00, 122.33, 122.16, 121.74, 111.99, 97.01, 56.20, 46.81, 46.58, 45.09, 43.98, 25.42, 25.26.

[0147] ESI-MS (m / z): 487.0 (M+H) + .

[0148] (S)-4-Chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-(2-hydroxymethylpyrrolidin-1-yl)-N-(4-methoxybenzyl)pyrimidine-5-carboxamide (I-11)

[0149] Pale yellow foamy solid, yield 51.2%.

[0150] 11H NMR (400 MHz, CDCl3) δ 9.04 (t, J = 5.7 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.24 (s, 1H), 7.18 (dd, J = 8.4, 2.2 Hz, 1H), 6.98 (s, 1H), 6.87 (dd, J = 8.7, 2.4 Hz, 3H), 4.54 (d, J = 6.0 Hz, 2H), 4.50 (d, J = 5.5 Hz, 2H), 4.36 (s, 1H), 4.20 (d, J = 8.3 Hz, 1H), 3.88 (s, 3H), 3.82–3.77 (m, 3H), 3.73–3.44 (m, 3H), 3.49 (dt, J = 12.1, 6.7 Hz, 1H), 2.10 (dt, J = 15.1, 7.7 Hz, 1H), 1.93–1.79 (m, 2H), 1.68 (s, 1H).

[0151] 13 13C NMR (101 MHz, CDCl3) δ 165.78, 162.64, 159.09, 158.19, 155.64, 154.13, 132.17, 129.63, 129.01, 126.95, 122.30, 114.19, 112.11, 97.65, 67.96, 61.18, 56.22, 55.31, 48.37, 44.10, 43.56, 29.84, 26.92, 23.73.

[0152] ESI-MS (m / z): 546.1 (M + H) + , 568.1 (M + Na) + .

[0153] 4-Chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-(N-methyl-2-hydroxyethylamino)-N-(4-methoxybenzyl)pyrimidine-5-carboxamide (I-12)

[0154] Off-white foamy solid, yield 56.5%.

[0155] 1 1H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 7.34 (d, J = 2.1 Hz, 1H), 7.17 (dd, J = 8.3, 2.2 Hz, 1H), 6.99 (s, 1H), 6.92–6.84 (m, 3H), 4.51 (d, J = 5.4 Hz, 4H), 3.88 (s, 3H), 3.80 (s, 5H), 3.70 (s, 2H), 3.16 (s, 3H).

[0156] 1313C NMR (151 MHz, CDCl3) δ 165.92, 162.71, 159.84, 159.10, 154.14, 131.97, 130.25, 129.70, 129.51, 129.00, 126.69, 122.41, 114.20, 112.14, 97.46, 56.23, 55.31, 44.24, 43.55, 36.43, 29.70.

[0157] ESI-MS (m / z): 520.0 (M+H) + .

[0158] 4-Chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-morpholinyl-N-(4-methoxybenzyl)pyrimidine-5-carboxamide (I-13)

[0159] Off-white lumpy solid, yield 57.6%.

[0160] 1 1H NMR (600 MHz, CDCl3) δ 9.01 (t, J = 5.8 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1zH), 7.25 (d, J = 8.2 Hz, 2H), 7.16 (dd, J = 8.4, 2.2 Hz, 1H), 7.01 (t, J = 5.5 Hz, 1H), 6.91–6.84 (m, 3H), 4.51 (dd, J = 5.6, 2.2 Hz, 4H), 3.88 (s, 3H), 3.80 (s, 3H), 3.76 (t, J = 4.8 Hz, 4H), 3.68 (t, J = 4.8 Hz, 4H).

[0161] 13 13C NMR (151 MHz, CDCl3) δ 165.92, 162.90, 159.08, 158.55, 156.93, 154.12, 132.17, 129.72, 129.62, 129.00, 126.82, 122.35, 114.17, 112.09, 97.56, 66.70, 56.22, 55.31, 44.18, 44.14, 43.53.

[0162] ESI-MS (m / z): 532.0 (M+H) + .

[0163] 4-Chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-(N-methyl-N-methoxyethylamino)-N-(4-methoxybenzyl)pyrimidine-5-carboxamide (I-14)

[0164] Off-white block solid, yield 55.3%.

[0165] 1 H NMR (400 MHz, CDCl3) δ 9.01 (t, J = 5.8 Hz, 1H), 7.32–7.22 (m, 3H), 7.16 (s, 1H), 7.02 (t, J = 5.5 Hz, 1H), 6.92–6.83 (m, 3H), 4.51 (d, J = 5.5 Hz, 4H), 3.87 (s, 3H), 3.80 (s, 3H), 3.70 (d, J = 33.0 Hz, 2H), 3.56 (d, J = 5.6 Hz, 1H), 3.43–3.30 (m, 2H), 3.26 (s, 2H), 3.16 (s, 3H).

[0166] 13 C NMR (101 MHz, CDCl3) δ 166.22, 162.73, 159.04, 156.72, 154.01, 132.55, 129.85, 129.17, 128.98, 126.47, 122.33, 114.16, 112.08, 96.97, 70.57, 58.84, 56.22, 55.31, 49.30, 44.06, 43.50, 36.56, 26.93.

[0167] ESI-MS (m / z): 534.0 (M + H) + .

[0168] 4-Chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-pyrrolidinyl-N-(4-methoxybenzyl)pyrimidine-5-carboxamide (I-15)

[0169] Brown block solid, yield 64.2%.

[0170] 1 H NMR (400 MHz, CDCl3) δ 8.98 (t, J = 5.9 Hz, 1H), 7.39 (d, J = 2.2 Hz, 1H), 7.32–7.24 (m, 2H), 7.21 (dd, J = 8.4, 2.2 Hz, 1H), 7.02 (t, J = 5.4 Hz, 1H), 6.94–6.85 (m, 3H), 4.54 (dd, J = 10.9, 5.6 Hz, 4H), 3.89 (s, 3H), 3.82 (s, 3H), 3.55 (dd, J = 14.9, 7.0 Hz, 4H), 2.00–1.89 (m, 4H).

[0171] 1313C NMR (101 MHz, CDCl3) δ 166.35, 162.67, 159.02, 157.45, 156.53, 154.00, 132.67, 129.89, 129.84, 128.98, 127.01, 122.20, 114.15, 112.03, 96.82, 56.21, 55.30, 46.82, 46.58, 43.99, 43.50, 25.40, 25.25.

[0172] ESI-MS (m / z): 516.1 (M+H) + .

[0173] (S)-4-Chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-(2-hydroxymethylpyrrolidin-1)-N-(pyridin-3-ylmethyl)pyrimidine-5-carboxamide (I-16)

[0174] Red-brown massive solid, yield 45.8%.

[0175] 1 1H NMR (400 MHz, CDCl3) δ 9.00–8.94 (m, 1H), 8.61–8.51 (m, 1H), 8.55–8.49 (m, 1H), 7.68 (dt, J = 7.8, 1.9 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.32–7.24 (m, 2H), 7.18 (dd, J = 8.4, 2.2 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 4.57 (dd, J = 20.6, 5.8 Hz, 4H), 4.21 (d, J = 10.5 Hz, 1H), 3.88 (s, 3H), 3.77–3.59 (m, 3H), 3.50 (dt, J = 12.3, 6.6 Hz, 1H), 2.09 (td, J = 13.7, 13.2, 6.6 Hz, 1H), 1.88 (ddt, J = 26.3, 13.1, 6.5 Hz, 2H), 1.69 (h, J = 6.2 Hz, 1H).

[0176] 13 13C NMR (151 MHz, CDCl3) δ 166.18, 162.57, 158.16, 155.81, 154.15, 149.04, 148.86, 135.35, 133.58, 132.06, 129.76, 126.95, 123.63, 122.30, 112.12, 97.33, 67.65, 61.11, 56.21, 48.37, 44.11, 41.41, 29.73, 23.69.

[0177] ESI-MS (m / z): 517.0 (M+H) + .

[0178] 4-Chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-(N-methyl-2-hydroxyethylamino)-N-(pyridin-3-ylmethyl)pyrimidine-5-carboxamide (I-17)

[0179] Yellow-brown massive solid, yield 54.1%.

[0180] 1 H NMR (400 MHz, CDCl3) δ 9.01 (d, J = 5.8 Hz, 1H), 8.62–8.57 (m, 2H), 8.53 (d, J = 4.8 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.34 (s, 1H), 7.32–7.23 (m, 2H), 7.17 (dd, J = 8.4, 2.2 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 4.60 (d, J = 5.8 Hz, 2H), 4.53 (s, 2H), 3.89 (s, 3H), 3.81 (d, J = 7.7 Hz, 2H), 3.76–3.67 (m, 2H), 3.17 (s, 3H).

[0181] 13 C NMR (101 MHz, CDCl3) δ 166.33, 162.64, 159.75, 154.14, 149.04, 148.87, 135.37, 133.61, 131.97, 129.49, 126.77, 123.65, 122.37, 112.17, 112.11, 97.00, 61.40, 56.27, 56.16, 52.14, 44.22, 41.43, 41.40, 41.37, 36.44.

[0182] ESI-MS (m / z): 491.0 (M+H) + .

[0183] 4-Chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-morpholinyl-N-(pyridin-3-ylmethyl)pyrimidine-5-carboxamide (I-18)

[0184] Yellow massive solid, yield 57.6%.

[0185] 11H NMR (400 MHz, CDCl3) δ 8.99 (t, J = 5.6 Hz, 1H), 8.59 (dd, J = 2.3, 0.8 Hz, 1H), 8.52 (dd, J = 4.8, 1.7 Hz, 1H), 7.70–7.63 (m, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.29–7.23 (m, 1H), 7.22 (s, 1H), 7.14 (dd, J = 8.4, 2.2 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.59 (d, J = 5.8 Hz, 2H), 4.50 (d, J = 5.7 Hz, 2H), 3.87 (s, 3H), 3.76 (dd, J = 5.5, 3.7 Hz, 4H), 3.67 (dd, J = 5.6, 3.8 Hz, 4H).

[0186] 13 13C NMR (101 MHz, CDCl3) δ 166.29, 162.96, 158.56, 157.09, 154.22, 149.14, 148.94, 135.27, 133.56, 132.10, 129.59, 126.76, 123.55, 122.47, 112.23, 97.14, 66.65, 56.27, 56.18, 44.22, 44.17, 41.41, 29.29.

[0187] ESI-MS (m / z): 503.0 (M+H) + .

[0188] 4-Chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-(N-methyl-N-methoxyethylamino)-N-(pyridin-3-ylmethyl)pyrimidine-5-carboxamide (I-19)

[0189] Light red block solid, yield 54.2%.

[0190] 11H NMR (400 MHz, CDCl3) δ 9.00 (t, J = 5.8 Hz, 1H), 8.60 (d, J = 2.3 Hz, 1H), 8.52 (dd, J = 4.8, 1.6 Hz, 1H), 7.67 (dt, J = 7.9, 2.0 Hz, 1H), 7.36–7.24 (m, 2H), 7.24–7.19 (m, 1H), 7.15 (s, 1H), 6.86 (d, J = 8.3 Hz, 1H), 4.59 (d, J = 5.8 Hz, 2H), 4.51 (s, 2H), 3.87 (s, 3H), 3.74 (s, 1H), 3.65 (s, 1H), 3.56 (s, 1H), 3.40 (s, 1H), 3.33 (s, 1H), 3.26 (s, 2H), 3.15 (d, J = 7.6 Hz, 3H).

[0191] 13 13C NMR (101 MHz, CDCl3) δ 166.59, 162.71, 158.91, 156.90, 154.02, 149.08, 148.88, 135.35, 133.70, 132.41, 123.64, 122.33, 112.16, 112.07, 96.59, 70.51, 58.85, 56.21, 49.32, 44.09, 41.39, 29.28.

[0192] ESI-MS (m / z): 505.0 (M+H) + .

[0193] 4-Chloro-6-((3-chloro-4-methoxybenzyl)amino)-2-pyrrolidinyl-N-(pyridin-3-ylmethyl)pyrimidine-5-carboxamide (I-20)

[0194] Yellow solid block, yield 63.4%.

[0195] 11H NMR (400 MHz, CDCl3) δ 8.92 (t, J = 5.8 Hz, 1H), 8.58 (d, J = 2.3 Hz, 1H), 8.51 (dd, J = 4.8, 1.6 Hz, 1H), 7.66 (dt, J = 7.9, 2.0 Hz, 1H), 7.34 (d, J = 2.1 Hz, 1H), 7.26 (dd, J = 7.6, 5.1 Hz, 1H), 7.19 (s, 1H), 7.16 (dd, J = 8.4, 2.2 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 4.57 (d, J = 5.8 Hz, 2H), 4.51 (d, J = 5.8 Hz, 2H), 3.85 (s, 3H), 3.54 (d, J = 5.2 Hz, 4H), 1.94–1.85 (m, 4H).

[0196] 13 13C NMR (101 MHz, CDCl3) δ 166.71, 162.64, 157.40, 156.66, 154.01, 149.07, 148.84, 135.35, 133.73, 132.53, 129.83, 127.00, 123.62, 122.18, 112.01, 96.35, 56.20, 46.85, 46.60, 44.01, 41.38, 25.39, 25.23.

[0197] ESI-MS (m / z): 487.0 (M+H) + , 509.1 (M+Na) + .

[0198] Example 2:

[0199] Synthesis steps and structural characterization of pyrimidinopyridone derivatives (II-1 to II-17)

[0200] Synthesis of ethyl 4-((3-chloro-4-methoxybenzyl)amino)-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (6)

[0201] At room temperature, 500 mg of raw material 5 (2.03 mmol, 1 eq.) was dissolved in 4 mL of anhydrous DMF in a 50 mL single-necked round-bottom flask. Separately, 420 mg of 3-chloro-4-methoxybenzylamine hydrochloride (2.03 mmol, 1 eq.) was dissolved in 3 mL of anhydrous DMF, 560 μL (4.06 mmol, 2 eq.) of triethylamine was added, and after ultrasonic treatment for 10 min, it was slowly added dropwise to the reaction flask. The reaction solution was stirred at room temperature for 6 h and monitored by TLC (PE:EA = 10:1) until the raw material was basically completely reacted. The reaction solution was poured into 150 mL of water, extracted with EA (40 mL × 4), the organic layers were combined, dried by evaporation to obtain a crude product, and purified by silica gel column chromatography (PE:EA = 20:1 - 10:1) to obtain 684 mg of a pure product as a colorless oily substance, with a yield of 85%.

[0202] 1 H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 7.33 (d, J = 2.2 Hz, 1H), 7.17 (dd, J = 8.4, 2.2 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.64 (d, J = 5.7 Hz, 2H), 4.33 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 2.59 (s, 3H), 2.47 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H).

[0203] 13 C NMR (101 MHz, CDCl3) δ 173.49, 168.70, 168.55, 161.19, 154.25, 131.94, 129.56, 126.90, 122.51, 112.15, 100.16, 61.10, 56.23, 43.89, 26.73, 14.26, 14.14.

[0204] ESI-MS (m / z): 382.0 (M + H) + .

[0205] (E)-Ethyl 4-((3-chloro-4-methoxybenzyl)amino)-6-(2-(dimethylamino)vinyl)-2-(methylthio)pyrimidine-5-carboxylate (7) synthesis

[0206] A 50 mL single-necked reaction flask was selected, and 200 mg of intermediate 6 (0.52 mmol, 1 eq.) was dissolved in 10 mL of anhydrous DMF. Separately, 120 μL of DMF-DMA (1.04 mmol, 2 eq.) was added. The reaction flask was placed in an oil bath at 130 °C and reacted under argon protection, monitored by TLC (PE:EA = 5:1), and the reaction was stopped after 4 h. The reaction solution was dried by evaporation to obtain 7, which was directly used in the next step without purification.

[0207] General Synthetic Method for 4-((3-Chloro-4-methoxybenzyl)amino)-2-(methylthio)-6-substituted-pyrido[4,3-d]pyrimidin-5(6H)-one (8)

[0208] Taking 4-((3-Chloro-4-methoxybenzyl)amino)-2-(methylthio)-6-(pyrimidin-2-ylmethyl)-pyrido[4,3-d]pyrimidin-5(6H)-one (8a) as an example, at room temperature, 250 mg of the crude product of intermediate 7 was dissolved in anhydrous DMF (8 mL), 109 mg (0.75 mmol, 1.5 eq.) of 2-aminomethylpyrimidine hydrochloride and 70 μL of triethylamine (0.75 mmol, 1.5 eq.) were added, and the mixture was stirred until completely dissolved. After 2 h, it was transferred to an oil bath and heated to 105 °C for further reaction, monitored by TLC (PE:EA = 5:1). After the reaction was completed, the reaction solution was cooled to room temperature, poured into a separatory funnel, 150 mL of water was added, and it was extracted with DCM (5 mL × 3). The organic phase was concentrated and separated by silica gel column (PE:EA = 5:1) to obtain a pale yellow solid with a yield of 78.4%.

[0209] 1 H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 8.69 (d, J = 4.9 Hz, 2H), 7.43 (d, J = 7.5 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.21 (t, J = 4.9 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.44 (d, J = 7.5 Hz, 1H), 5.29 (s, 2H), 4.66 (d, J = 5.8 Hz, 2H), 3.86 (s, 3H), 2.52 (s, 3H).

[0210] 13 C NMR (101 MHz, CDCl3) δ 175.31, 165.12, 162.92, 160.64, 159.82, 157.58, 154.28, 139.75, 131.57, 129.85, 127.23, 122.46, 119.96, 112.12, 106.77, 100.89, 56.22, 54.21, 43.51, 14.21.

[0211] General Synthetic Method for Target Products II-1 to II-17

[0212] At room temperature, in a 25 mL round-bottom flask, add intermediate 8 (0.44 mmol), dissolve it in 5 mL of anhydrous chloroform, add 176 mg of 85% mCPBA (0.66 mmol, 1.5 eq.), and stir the reaction at room temperature. After reacting for 2 h, wash it successively with saturated aqueous NaHCO3 solution (10 mL × 3) and distilled water (30 mL × 3). Add anhydrous sodium sulfate to dry the organic phase, filter, and rotary evaporate under reduced pressure to obtain a yellow oil, which is directly used in the next step.

[0213] At room temperature, in a 25 mL round-bottom flask, add the mixture of sulfone and sulfoxide obtained in the previous step (1 eq.), anhydrous chloroform (10 mL), 2 the corresponding secondary amine (0.60 mmol, 1.5 eq.), and 60 μL of triethylamine (0.60 mmol, 1.5 eq.). After stirring at room temperature for 6 h, add distilled water to wash the organic layer (30 mL × 3). Dry the organic layer with anhydrous sodium sulfate, filter, rotary evaporate under reduced pressure to obtain a yellow oil, purify it by silica gel column (DCM:MeOH = 20:1), and rotary evaporate under reduced pressure to obtain the target product.

[0214] (S)-4-((3-Chloro-4-methoxybenzyl)amino)-2-(2-hydroxymethylpyrrolidin-1)-6-(pyrimidin-2-ylmethyl)-pyrido[4,3-d]pyrimidin-5(6H)-one (II-1)

[0215] Off-white block solid, yield 57.4%.

[0216] 1 1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 8.68 (d, J = 4.9 Hz, 2H), 7.37 (d, J = 2.2 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 7.23–7.15 (m, 2H), 6.84 (d, J = 8.4 Hz, 1H), 6.26 (d, J = 7.5 Hz, 1H), 5.26 (d, J = 5.8 Hz, 2H), 4.59 (d, J = 5.9 Hz, 2H), 4.32 (d, J = 7.8 Hz, 1H), 3.86 (s, 3H), 3.83 (dd, J = 9.3, 4.8 Hz, 1H), 3.73 (dd, J = 11.0, 2.2 Hz, 1H), 3.65 (dd, J = 11.0, 9.0 Hz, 1H), 3.55 (dt, J = 12.2, 6.6 Hz, 1H), 2.12 (dt, J = 14.6, 7.4 Hz, 1H), 1.88 (dh, J = 19.2, 6.3 Hz, 2H), 1.63 (dd, J = 12.9, 6.4 Hz, 1H).

[0217] 1313C NMR (101 MHz, CDCl3) δ 165.50, 162.55, 161.86, 157.54, 154.10, 139.44, 132.27, 129.96, 127.17, 122.28, 119.84, 112.07, 105.79, 98.54, 68.62, 61.17, 56.21, 53.93, 53.41, 48.50, 43.37, 29.97, 23.88.

[0218] ESI-MS (m / z): 508.2 (M+H) + .

[0219] (S)-4-((3-chloro-4-methoxybenzyl)amino)-2-(3-hydroxymethyl-3,4-dihydroisoquinolin-2(1H))-6-(pyrimidin-2-ylmethyl)-pyrido[4,3-d]pyrimidin-5(6H)-one (II-2)

[0220] Yellow foamy solid, yield 54.6%.

[0221] 1 1H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 8.68 (d, J = 4.9 Hz, 2H), 7.40 (d, J = 2.2 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.19 (qq, J = 8.3, 4.7, 3.4 Hz, 6H), 6.86 (d, J = 8.5 Hz, 1H), 6.32 (s, 1H), 5.26 (d, J = 4.8 Hz, 2H), 5.12 (d, J = 16.1 Hz, 1H), 4.99 (s, 1H), 4.63 (d, J = 5.8 Hz, 2H), 4.57–4.42 (m, 1H), 3.87 (s, 3H), 3.74–3.62 (m, 1H), 3.55 (ddd, J = 10.0, 7.4, 4.6 Hz, 1H), 3.06 (dd, J = 15.5, 6.0 Hz, 1H), 2.79 (dd, J = 15.6, 4.8 Hz, 1H).

[0222] 13 13C NMR (101 MHz, CDCl3) δ 165.47, 162.58, 161.88, 157.55, 154.13, 139.41, 132.14, 129.69, 127.86, 127.05, 126.97, 126.51, 126.27, 122.35, 119.87, 112.14, 98.03, 56.24, 53.98, 53.45, 44.82, 43.64.

[0223] ESI-MS (m / z): 570.1 (M+H) + .

[0224] 4-((3-chloro-4-methoxybenzyl)amino)-2-(N-methyl-2-hydroxyethylamino)-6-(pyrimidin-2-ylmethyl)pyrido[4,3-d]pyrimidin-5(6H)-one (II-3)

[0225] Off-white block solid, yield 56.8%.

[0226] 1 H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 8.69 (d, J = 4.9 Hz, 2H), 7.36 (d, J = 2.2 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.24–7.15 (m, 2H), 6.84 (d, J = 8.4 Hz, 1H), 6.29 (s, 1H), 5.26 (s, 2H), 4.58 (d, J = 5.9 Hz, 2H), 3.86 (s, 5H), 3.78 (s, 2H), 3.22 (s, 2H).

[0227] 13 C NMR (101 MHz, CDCl3) δ 165.48, 162.95, 161.78, 160.50, 157.57, 154.09, 138.75, 129.79, 127.08, 122.28, 119.88, 112.03, 97.49, 94.36, 56.21, 53.98, 53.46, 43.48, 36.61, 35.55.

[0228] ESI-MS (m / z): 482.2 (M+H) + .

[0229] 4-((3-chloro-4-methoxybenzyl)amino)-2-morpholinyl-6-(pyrimidin-2-ylmethyl)pyrido[4,3-d]pyrimidin-5(6H)-one (II-4)

[0230] Off-white block solid, yield 74.5%.

[0231] 11H NMR (400 MHz, CDCl3) δ 9.67 (t, J = 5.9 Hz, 1H), 8.70 (d, J = 4.9 Hz, 2H), 7.37 (d, J = 2.2 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.24–7.15 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H), 6.29 (d, J = 7.5 Hz, 1H), 5.28 (s, 2H), 4.58 (d, J = 5.8 Hz, 2H), 3.88 (s, 7H), 3.73 (t, J = 4.8 Hz, 4H).

[0232] 13 13C NMR (101 MHz, CDCl3) δ 165.61, 162.70, 162.17, 161.92, 161.51, 157.54, 154.04, 139.01, 132.36, 129.82, 127.05, 122.25, 119.83, 112.00, 106.96, 97.79, 66.95, 56.21, 53.95, 44.22, 43.36, 29.70, 29.37.

[0233] ESI-MS (m / z): 494.1 (M + H) + .

[0234] 4-((3-Chloro-4-methoxybenzyl)amino)-2-(N-methyl-N-methoxyethylamino)-6-(pyrimidin-2-ylmethyl)pyrido[4,3-d]pyrimidin-5(6H)-one (II-5)

[0235] Pale yellow solid in block, yield 76.5%.

[0236] 1 1H NMR (400 MHz, CDCl3) δ 9.61 (s, 1H), 8.69 (d, J = 4.9 Hz, 2H), 7.34 (s, 1H), 7.29 (d, J = 7.5 Hz, 1H), 7.18 (q, J = 7.8, 6.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 1H), 6.29 (d, J = 7.5 Hz, 1H), 5.26 (s, 2H), 4.57 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 3.82–3.69 (m, 3H), 3.47 (s, 1H), 3.30 (s, 3H), 3.23 (s, 3H).

[0237] 1313C NMR (101 MHz, CDCl3) δ 165.75, 162.84, 161.95, 157.53, 153.93, 138.71, 132.71, 129.54, 126.86, 122.24, 119.79, 111.98, 107.19, 97.39, 70.96, 58.85, 56.21, 53.93, 49.15, 43.28, 36.47, 29.71.

[0238] ESI-MS (m / z): 496 (M+H) + .

[0239] 4-((3-Chloro-4-methoxybenzyl)amino)-2-pyrrolidinyl-6-(pyrimidin-2-ylmethyl)-pyrido[4,3-d]pyrimidin-5(6H)-one (II-6)

[0240] Brown solid mass, yield 68.4%.

[0241] 1 1H NMR (400 MHz, CDCl3) δ 9.62 (t, J = 6.0 Hz, 1H), 8.69 (d, J = 4.9 Hz, 2H), 7.39 (d, J = 2.1 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.20 (dt, J = 9.8, 3.6 Hz, 2H), 6.83 (d, J = 8.4 Hz, 1H), 6.30 (d, J = 7.5 Hz, 1H), 5.25 (s, 2H), 4.58 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 3.60 (s, 4H), 2.00–1.90 (m, 4H).

[0242] 13 13C NMR (101 MHz, CDCl3) δ 165.78, 162.90, 161.97, 161.91, 160.38, 157.53, 153.93, 138.66, 132.82, 130.05, 127.23, 122.12, 119.78, 111.94, 107.03, 97.42, 56.20, 53.94, 46.86, 46.46, 43.22, 29.71, 25.48.

[0243] ESI-MS (m / z): 478.1 (M+H) + .

[0244] (S)-4-((3-Chloro-4-methoxybenzyl)amino)-2-(2-hydroxymethylpyrrolidin-1-yl)-6-(pyridin-2-ylmethyl)-pyrido[4,3-d]pyrimidin-5(6H)-one (II-7)

[0245] Yellow foamy solid, yield 56.9%.

[0246] 1 H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 8.53 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 7.63 (td, J = 7.7, 1.8 Hz, 1H), 7.37 (s, 1H), 7.36 (d, J = 5.5 Hz, 2H), 7.28–7.13 (m, 3H), 6.84 (d, J = 8.4 Hz, 1H), 6.20 (d, J = 7.5 Hz, 1H), 5.12 (d, J = 5.1 Hz, 2H), 4.60 (d, J = 6.0 Hz, 2H), 4.29 (s, 1H), 3.85 (s, 3H), 3.83–3.76 (m, 1H), 3.70 (d, J = 2.3 Hz, 1H), 3.67–3.60 (m, 2H), 3.53 (dt, J = 12.3, 6.6 Hz, 1H), 2.16–2.05 (m, 1H), 1.95–1.76 (m, 2H), 1.66–1.54 (m, 1H).

[0247] 13 C NMR (101 MHz, CDCl3) δ 162.39, 161.86, 160.98, 160.43, 155.95, 154.07, 149.64, 139.09, 137.05, 132.28, 129.92, 127.16, 122.83, 122.22, 122.12, 112.04, 97.53, 68.58, 68.05, 61.11, 56.19, 53.14, 48.50, 43.34, 29.95, 23.89.

[0248] ESI-MS (m / z): 507.2 (M + H) + .

[0249] (S)-4-((3-Chloro-4-methoxybenzyl)amino)-2-(3-hydroxymethyl-3,4-dihydroisoquinolin-2(1H))-6-(pyridin-2-ylmethyl)-pyrido[4,3-d]pyrimidin-5(6H)-one (II-8)

[0250] Light yellow massive solid, yield 46.8%.

[0251] 11H NMR (400 MHz, CDCl3) δ 9.81 (t, J = 5.9 Hz, 1H), 8.55 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 7.65 (td, J = 7.7, 1.8 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.23 (s, 1H), 7.23–7.14 (m, 5H), 6.88 (d, J = 8.4 Hz, 1H), 6.29 (d, J = 7.1 Hz, 1H), 5.15 (d, J = 2.4 Hz, 2H), 5.07 (s, 2H), 4.66 (q, J = 9.9, 8.0 Hz, 2H), 4.50 (d, J = 15.6 Hz, 1H), 3.88 (s, 3H), 3.70 (s, 1H), 3.55 (t, J = 9.9 Hz, 1H), 3.06 (dd, J = 15.5, 6.0 Hz, 1H), 2.79 (dd, J = 15.4, 4.8 Hz, 1H).

[0252] 13 13C NMR (101 MHz, CDCl3) δ 162.44, 162.32, 161.91, 155.96, 154.15, 149.68, 139.03, 137.05, 134.35, 132.17, 129.67, 127.85, 126.94, 126.51, 126.27, 122.85, 122.39, 122.15, 112.16, 105.93, 98.01, 56.24, 53.19, 44.80, 43.64, 31.54.

[0253] ESI-MS (m / z): 569.2 (M+H) + .

[0254] 4-((3-Chloro-4-methoxybenzyl)amino)-2-(N-methyl-2-hydroxyethylamino)-6-(pyridin-2-ylmethyl)pyrido[4,3-d]pyrimidin-5(6H)-one (II-9)

[0255] Light yellow block solid, yield 49.4%.

[0256] 11H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 8.55 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 7.65 (td, J = 7.7, 1.8 Hz, 1H), 7.42–7.35 (m, 2H), 7.25–7.22 (m, 1H), 7.22–7.16 (m, 2H), 6.86 (d, J = 8.4 Hz, 1H), 6.28 (d, 1H), 5.14 (s, 2H), 4.60 (d, 2H), 3.87 (s, 3H), 3.84 (d, J = 6.2 Hz, 2H), 3.80–3.75 (m, 2H), 3.22 (s, 3H).

[0257] 13 13C NMR (101 MHz, CDCl3) δ 162.38, 161.83, 161.05, 155.94, 154.14, 149.68, 139.07, 137.04, 132.20, 129.76, 127.03, 122.84, 122.35, 122.14, 112.09, 97.53, 62.79, 56.21, 53.16, 43.50, 33.88.

[0258] ESI-MS (m / z): 481.0 (M + H) + .

[0259] 4-((3-Chloro-4-methoxybenzyl)amino)-2-morpholin-6-(pyridin-2-ylmethyl)pyrido[4,3-d]pyrimidin-5(6H)-one (II-10)

[0260] Off-white solid mass, yield 53.6%.

[0261] 1 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 8.58–8.52 (m, 1H), 7.65 (td, J = 7.7, 1.8 Hz, 1H), 7.37 (d, J = 2.2 Hz, 2H), 7.24 (d, J = 7.8 Hz, 1H), 7.22–7.17 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H), 6.25 (d, 1H), 5.15 (s, 2H), 4.59 (d, J = 5.8 Hz, 2H), 3.87 (s, 7H), 3.72 (t, J = 4.7 Hz, 4H).

[0262] 1313C NMR (101 MHz, CDCl3) δ 162.62, 161.79, 160.96, 155.96, 154.10, 149.66, 138.37, 137.06, 129.80, 127.02, 122.83, 122.31, 122.14, 112.04, 107.13, 97.73, 66.93, 56.22, 53.18, 44.23, 43.39.

[0263] ESI-MS (m / z): 493.2 (M+H) + .

[0264] (S)-4-((3-chloro-4-methoxybenzyl)amino)-2-(2-hydroxymethylpyrrolidin-1)-6-(2-morpholinoethyl)-pyrido[4,3-d]pyrimidin-5(6H)-one (II-11)

[0265] Yellowish-brown foamy solid, yield 43.5%.

[0266] 1 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.21 (td, J = 11.7, 10.0, 4.3 Hz, 2H), 6.87 (d, J = 8.4 Hz, 1H), 6.23 (s, 1H), 4.63 (d, J = 5.9 Hz, 2H), 4.33 (s, 1H), 3.95 (t, J = 5.9 Hz, 2H), 3.88 (s, 3H), 3.83 (s, 1H), 3.76–3.70 (m, 1H), 3.66 (q, J = 4.8 Hz, 5H), 2.63 (t, J = 6.3 Hz, 2H), 2.49 (t, J = 4.7 Hz, 4H), 2.12 (s, 1H), 1.89 (dt, J = 12.0, 6.2 Hz, 2H), 1.65 (t, J = 6.8 Hz, 1H).

[0267] 13 13C NMR (101 MHz, CDCl3) δ 162.38, 161.88, 160.81, 154.12, 150.72, 139.12, 132.30, 129.93, 127.13, 122.31, 112.07, 105.20, 97.49, 68.62, 66.97, 61.15, 57.20, 56.22, 53.78, 48.52, 45.88, 43.36, 29.99, 23.90.

[0268] ESI-MS (m / z): 529.2 (M+H) + .

[0269] (S)-4-((3-chloro-4-methoxybenzyl)amino)-2-(3-hydroxymethyl-3,4-dihydroisoquinolin-2(1H))-6-(2-morpholinoethyl)-pyrido[4,3-d]pyrimidin-5(6H)-one (II-12)

[0270] Brown foamy solid, yield 41.5%.

[0271] 1 H NMR (400 MHz, CDCl3) δ 9.88 (t, J = 5.8 Hz, 1H), 7.43 (d, J = 2.2 Hz, 1H), 7.21 (dtd, J = 15.2, 9.1, 7.7, 3.5 Hz, 6H), 6.89 (d, J = 8.4 Hz, 1H), 6.27 (s, 1H), 5.12 (d, J = 16.0 Hz, 1H), 4.98 (s, 1H), 4.68 (d, J = 5.8 Hz, 2H), 4.49 (s, 1H), 3.96 (t, J = 6.3 Hz, 2H), 3.89 (s, 3H), 3.67 (t, J = 4.7 Hz, 5H), 3.60–3.50 (m, 1H), 3.06 (dd, J = 15.5, 6.0 Hz, 1H), 2.79 (dd, J = 15.5, 4.8 Hz, 1H), 2.64 (t, J = 6.4 Hz, 2H), 2.49 (t, J = 4.6 Hz, 4H).

[0272] 13 C NMR (101 MHz, CDCl3) δ 162.37, 161.86, 161.46, 154.17, 139.19, 132.12, 129.66, 127.91, 127.10, 126.93, 126.54, 126.27, 122.41, 112.15, 97.65, 66.98, 57.18, 56.25, 53.78, 45.92, 44.81, 43.65.

[0273] ESI-MS (m / z): 591.0 (M+H) + .

[0274] 4-((3-chloro-4-methoxybenzyl)amino)-2-(N-methyl-2-hydroxyethylamino)-6-(2-morpholinoethyl)-pyrido[4,3-d]pyrimidin-5(6H)-one (II-13)

[0275] Light yellow foamy solid, yield 43.2%.

[0276] 11H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 7.41 (d, J = 2.2 Hz, 1H), 7.24 (dd, J = 8.2, 2.6 Hz, 2H), 6.89 (d, J = 8.4 Hz, 1H), 6.27 (d, 1H), 4.67–4.61 (m, 2H), 3.98 (t, J = 6.4 Hz, 2H), 3.90 (s, 3H), 3.88 (s, 4H), 3.80 (d, J = 5.2 Hz, 2H), 3.70 (t, J = 4.7 Hz, 4H), 3.24 (s, 3H), 2.66 (t, J = 6.4 Hz, 2H), 2.52 (t, J = 4.7 Hz, 4H).

[0277] 13 13C NMR (101 MHz, CDCl3) δ 162.31, 161.80, 161.37, 154.15, 138.90, 132.05, 129.74, 127.03, 122.36, 119.79, 112.08, 105.10, 97.19, 66.93, 57.17, 56.22, 53.75, 45.85, 43.50, 36.81.

[0278] ESI-MS (m / z): 503.2 (M+H) + .

[0279] (S)-4-((3-Chloro-4-methoxybenzyl)amino)-2-(2-hydroxymethylpyrrolidin-1)-6-(4-methoxybenzyl)-pyrido[4,3-d]pyrimidin-5(6H)-one (II-14)

[0280] Yellow solid in block, yield 52.3%.

[0281] 11H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.23 (dd, J = 8.4, 2.2 Hz, 1H), 7.21–7.15 (m, 3H), 6.91–6.83 (m, 3H), 6.22 (s, 1H), 4.98 (s, 2H), 4.63 (d, J = 6.0 Hz, 2H), 4.33 (s, 1H), 3.88 (s, 3H), 3.80 (s, 1H), 3.78 (s, 3H), 3.72 (dd, J = 11.0, 2.5 Hz, 1H), 3.64 (dd, J = 11.1, 9.0 Hz, 1H), 3.55 (dt, J = 12.0, 6.5 Hz, 1H), 2.13 (dq, J = 14.6, 7.3 Hz, 1H), 1.88 (dtd, J = 25.4, 12.5, 6.5 Hz, 2H), 1.64 (s, 1H).

[0282] 13 13C NMR (151 MHz, CDCl3) δ 162.43, 161.83, 159.39, 154.12, 138.26, 132.24, 129.96, 129.14, 128.38, 127.15, 122.29, 114.35, 112.08, 105.78, 97.59, 68.49, 61.11, 56.22, 55.31, 50.78, 48.54, 43.41, 29.92, 29.71, 23.84.

[0283] ESI-MS (m / z): 536.2 (M+H) + .

[0284] (S)-4-((3-chloro-4-methoxybenzyl)amino)-2-(3-hydroxymethyl-3,4-dihydroisoquinolin-2(1H))-6-(4-methoxybenzyl)-pyrido[4,3-d]pyrimidin-5(6H)-one (II-15)

[0285] Brown block solid, yield 42.4%.

[0286] 11H NMR (400 MHz, CDCl3) δ 9.62 (s, 1H), 8.10 (d, J = 5.1 Hz, 1H), 7.49–7.39 (m, 1H), 7.31–7.14 (m, 6H), 6.95–6.83 (m, 3H), 5.03 (d, J = 11.0 Hz, 4H), 4.82–4.49 (m, 3H), 3.89 (d, J = 2.5 Hz, 3H), 3.79 (d, J = 2.0 Hz, 3H), 3.74–3.46 (m, 2H), 3.08 (dd, J = 15.6, 5.6 Hz, 1H), 2.90–2.80 (m, 1H).

[0287] 13 13C NMR (151 MHz, CDCl3) δ 162.90, 161.75, 159.72, 154.30, 129.70, 129.68, 129.52, 129.30, 126.98, 126.54, 126.32, 122.53, 114.65, 114.52, 112.32, 112.26, 104.38, 96.70, 56.26, 55.35, 55.32, 51.71, 44.56, 43.69, 30.89, 29.69, 29.29.

[0288] ESI-MS (m / z): 598.3 (M + H) + .

[0289] 4-((3-Chloro-4-methoxybenzyl)amino)-2-(N-methyl-2-hydroxyethylamino)-6-(pyridin-2-ylmethyl)pyrido[4,3-d]pyrimidin-5(6H)-one (II-16)

[0290] Off-white block solid, yield 50.4%.

[0291] 1 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 7.39 (d, J = 2.2 Hz, 1H), 7.22 (dd, J = 8.4, 2.2 Hz, 1H), 7.19 (dd, J = 8.2, 3.1 Hz, 3H), 6.91–6.82 (m, 3H), 6.21 (s, 1H), 4.98 (s, 2H), 4.65–4.59 (m, 2H), 3.88 (s, 3H), 3.84 (d, J = 4.4 Hz, 2H), 3.78 (s, 3H), 3.76 (d, J = 4.9 Hz, 2H), 3.22 (s, 3H).

[0292] 1313C NMR (151 MHz, CDCl3) δ 162.52, 161.90, 159.38, 154.13, 138.10, 132.12, 129.77, 129.14, 128.44, 127.03, 122.35, 114.35, 112.11, 106.09, 97.62, 56.22, 55.31, 53.13, 50.72, 43.51, 36.85, 29.71.

[0293] ESI-MS (m / z): 510.4 (M+H) + .

[0294] 4-((3-Chloro-4-methoxybenzyl)amino)-2-morpholino-6-(pyridin-2-ylmethyl)pyrido[4,3-d]pyrimidin-5(6H)-one (II-17)

[0295] Off-white block solid, yield 56.4%.

[0296] 1 1H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 7.39 (d, J = 2.2 Hz, 1H), 7.24–7.16 (m, 4H), 6.93–6.82 (m, 3H), 6.21 (s, 1H), 4.99 (s, 2H), 4.61 (d, J = 5.8 Hz, 2H), 3.88 (s, 7H), 3.78 (s, 3H), 3.72 (t, J = 4.8 Hz, 4H).

[0297] 13 13C NMR (101 MHz, CDCl3) δ 162.16, 161.64, 159.36, 154.12, 151.85, 149.21, 145.15, 138.07, 129.81, 129.24, 129.15, 127.02, 122.33, 114.33, 112.06, 106.45, 96.66, 66.92, 63.69, 55.32, 50.66, 44.25, 43.42.

[0298] ESI-MS (m / z): 522.0 (M+H) + .

[0299] Example 3:

[0300] Synthesis steps and structural characterization of pyrimidinedihydropyridone derivatives (III-1~III-12)

[0301] Synthesis of ethyl 3-substituted aminopropionate (10)

[0302] Taking ethyl 3-((pyrimidin-2-ylmethyl)amino)propionate (10a) as an example, at room temperature, 2 g of the raw material 2-(aminomethyl)pyrimidine (13.79 mmol, 1 eq.) was added to a 100 mL single-necked round-bottom flask and dissolved in 25 mL of methanol. Under argon protection, 1.7 g of the raw material ethyl acrylate 9 (16.55 mmol, 1.2 eq.) and 2.34 mL of triethylamine (16.55 mmol, 1.2 eq.) were added, and the reaction was stirred at room temperature for 2 h, monitored by TLC (DCM:MeOH = 9:1). After the reaction was completed, distilled water (30 mL × 3) was added to wash the organic layer, anhydrous sodium sulfate was added for drying, filtered, rotary evaporated under reduced pressure, and purified by silica gel column to obtain 2.6 g of a yellow solid with a yield of 88%.

[0303] 1 H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 4.9 Hz, 2H), 7.15 (t, J = 4.9 Hz, 1H), 4.16 (s, 2H), 4.03 (q, J = 7.2 Hz, 2H), 3.10 (t, J = 6.9 Hz, 2H), 2.75 (t, J = 6.9 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H).

[0304] ESI-MS (m / z): 210.0 (M+H) + .

[0305] Synthesis of ethyl 3-(2-cyano-N-substituted acetamido)propionate (11)

[0306] Taking ethyl 3-(2-cyano-N-(pyrimidin-2-ylmethyl)acetamido)propionate (11a) as an example, at room temperature, 1 g of the intermediate 10a (4.78 mmol, 1 eq.) was added to a 50 mL single-necked round-bottom flask and dissolved in 10 mL of methanol. Under argon protection, 500 mg of cyanoacetic acid (5.74 mmol, 1.2 eq.), 1 g of EDC hydrochloride (5.74 mmol, 1.2 eq.) were added, and the reaction was stirred at room temperature, monitored by TLC (DCM:MeOH = 20:1). After the reaction was completed, 10 mL of DCM was added, washed with distilled water (30 mL × 3), anhydrous sodium sulfate was added for drying, filtered, rotary evaporated under reduced pressure, and purified by silica gel column to obtain 1.06 g of a yellow solid with a yield of 82%.

[0307] 11H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 4.9 Hz, 2H), 7.20 (t, J = 4.9 Hz, 1H), 4.78 (s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 3.80–3.69 (m, 3H), 2.66 (dt, J = 13.0, 6.4 Hz, 2H), 1.26 (dt, J = 16.2, 7.1 Hz, 3H).

[0308] 13 13C NMR (101 MHz, CDCl3) δ 171.80, 165.43, 163.24, 157.70, 120.32, 114.11, 60.70, 55.53, 51.35, 44.70, 32.69, 25.47, 14.15.

[0309] Note: This compound has isomerism, E:Z = 2:1. The data of 1H NMR and 13C NMR listed are for the Z-configured component.

[0310] ESI-MS (m / z): 277.1 (M+H) + , 299.1 (M+Na) + .

[0311] Synthesis of 4-hydroxy-2-oxo-1-substituted-1,2,5,6-tetrahydropyridine-3-carbonitrile (12)

[0312] Taking 4-hydroxy-2-oxo-1-(pyrimidin-2-ylmethyl)-1,2,5,6-tetrahydropyridine-3-carbonitrile (12a) as an example, at room temperature, 1 g of intermediate 11a (3.6 mmol, 1 eq.) was added to a 50 mL single-necked round-bottom flask and dissolved in 10 mL of methanol. 536 μL of DBU (3.6 mmol, 1 eq.) was added, and the mixture was stirred at room temperature under argon protection, monitored by TLC (DCM:MeOH = 9:1). After the reaction was completed, the reaction solution was directly concentrated and purified by silica gel column chromatography to obtain 1.1 g of a brown-yellow solid (DBU salt) with a yield of 80%.

[0313] 11H NMR (400 MHz, D2O) δ 8.69 (dd, J = 5.0, 1.5 Hz, 2H), 7.40 (td, J = 5.1, 1.5 Hz, 1H), 4.74 (s, 2H), 3.47 (dq, J = 8.1, 6.5, 5.9 Hz, 4H), 3.39 (dt, J = 4.8, 1.6 Hz, 1H), 3.25 (t, J = 5.9 Hz, 1H), 2.59–2.52 (m, 1H), 2.45 (td, J = 7.1, 1.5 Hz, 2H), 1.94 (pd, J = 6.0, 1.5 Hz, 1H), 1.71–1.56 (m, 3H).

[0314] 13 13C NMR (101 MHz, D2O) δ 194.08, 170.91, 166.47, 158.49, 121.05, 118.64, 77.64, 54.94, 53.08, 49.00, 45.76, 38.76, 34.50, 33.60, 29.22, 27.38, 26.99, 26.64, 24.09, 19.71.

[0315] ESI-MS (m / z): 229.0 (M + ).

[0316] Synthesis of 4-methoxy-2-oxo-1-substituted-1,2,5,6-tetrahydropyridine-3-carbonitrile (13)

[0317] Taking 4-methoxy-2-oxo-1-(pyrimidin-2-ylmethyl)-1,2,5,6-tetrahydropyridine-3-carbonitrile (13a) as an example, at room temperature, a 50 mL round-bottom flask was charged with 500 mg of intermediate 12a (1.31 mmol, 1 eq.), dissolved in 8 mL of anhydrous DMF, and sonicated with shaking to dissolve completely. The air in the flask was displaced with argon, and this was repeated 3 times, and then protected with an argon balloon. 123 μL of dimethyl sulfate (1.31 mmol, 1 eq.) was injected into the reaction flask using a syringe, and then the reaction flask was heated in an oil bath at 60 °C. The reaction was monitored by TLC (DCM:MeOH = 20:1). After the reaction was completed, 10 mL of DCM was added, and it was washed with saturated NaCl (50 mL × 3). The organic layer was rotary evaporated under reduced pressure to obtain 192 mg of the target product, with a yield of 62%.

[0318] 1 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 4.9 Hz, 2H), 7.18 (t, J = 4.9 Hz, 1H), 4.88 (s, 2H), 4.17 (s, 3H), 3.65 (t, J = 6.9 Hz, 2H), 2.78 (t, J = 6.9 Hz, 2H).

[0319] 13 C NMR (101 MHz, CDCl3) δ 177.80, 165.86, 162.50, 157.35, 119.63, 114.03, 86.76, 58.26, 52.42, 44.12, 27.42.

[0320] ESI-MS (m / z): 245.0 (M+H) + , 267.0 (M+Na) + .

[0321] Synthesis of 4-amino-2-methylthio-6-substituted-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (14)

[0322] Taking 4-amino-2-methylthio-6-(pyrimidin-2-ylmethyl)-7,8-dihydropyrrolo[4,3-d]pyrimidin-5(6H)-one (14a) as an example, at room temperature, a 50 mL round-bottom flask was charged with 200 mg of intermediate 13a (0.82 mmol, 1 eq.), dissolved in 5 mL of anhydrous methanol, and 231 mg of S-methylisothiourea sulfate (1.23 mmol, 1.5 eq.) and 185 μL of DBU (1.23 mmol, 1.5 eq.) were added. The reaction was carried out under argon protection at room temperature and monitored by TLC (DCM:MeOH = 20:1). After the reaction was completed, 10 mL of DCM was added, and it was washed with distilled water (30 mL × 3). The organic layer was rotary evaporated under reduced pressure and purified by silica gel column chromatography to obtain 210 mg of a brown solid with a yield of 85%.

[0323] 1 H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 4.9 Hz, 2H), 8.63 (s, 1H), 7.20 (t, J = 4.9 Hz, 1H), 5.53 (s, 1H), 4.94 (s, 2H), 3.72 (t, J = 6.9 Hz, 2H), 3.00 (t, J = 6.9 Hz, 2H), 2.51 (s, 3H).

[0324] 13 C NMR (101 MHz, CDCl3) δ 174.14, 166.84, 166.39, 165.76, 161.54, 157.45, 119.55, 99.94, 52.88, 45.57, 30.60, 30.54, 14.02.

[0325] ESI-MS (m / z): 303.1 (M+H) + .

[0326] Synthesis of 4-((3-chloro-4-methoxybenzyl)amino)-2-methylthio-6-substituted-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (15)

[0327] Taking 4-((3-chloro-4-methoxybenzyl)amino)-2-methylthio-6-(pyrimidin-2-ylmethyl)-7,8-dihydropyrrolo[4,3-d]pyrimidin-5(6H)-one (15a) as an example, at room temperature, a 50 mL round-bottom flask was charged with 200 mg of intermediate 14a (0.66 mmol, 1 eq.), dissolved in 8 mL of anhydrous DMF, and 24 mg of sodium hydride (0.99 mmol, 1.5 eq.) was rapidly added under argon protection. After the reaction flask was stirred in an ice bath for 30 min, 232 mg of 4-bromomethyl-2-chloro-1-methoxybenzene (0.99 mmol, 1.5 eq.) was added, and the reaction was carried out at room temperature, monitored by TLC (DCM:MeOH = 20:1). After the reaction was completed, 10 mL of DCM was added, washed with saturated NaCl (30 mL × 3), the organic layer was evaporated under reduced pressure, and purified by silica gel column chromatography to obtain 196 mg of a pale yellow solid, with a yield of 65%.

[0328] 1 H NMR (400 MHz, CDCl3) δ 9.49 (t, J = 5.9 Hz, 1H), 8.71 (d, J = 4.9 Hz, 2H), 7.34 (d, J = 2.2 Hz, 1H), 7.23–7.17 (m, 2H), 6.86 (d, J = 8.3 Hz, 1H), 4.92 (s, 2H), 4.64 (d, J = 5.9 Hz, 2H), 3.88 (s, 3H), 3.73 (t, J = 7.0 Hz, 2H), 2.99 (t, J = 6.9 Hz, 2H), 2.50 (s, 3H).

[0329] 13 C NMR (101 MHz, CDCl3) δ 174.19, 166.37, 166.24, 166.23, 159.86, 157.32, 154.17, 131.99, 129.66, 127.02, 122.39, 119.56, 112.12, 112.09, 99.68, 56.21, 53.44, 52.89, 45.71, 43.36, 30.49, 14.19.

[0330] ESI-MS (m / z): 457.1 (M + H) + , 479.2 (M + Na) + .

[0331] General method for the synthesis of target products III-1 to III-12

[0332] At room temperature, in a 25 mL round-bottom flask, add intermediate 15a (0.44 mmol, 1 eq.), dissolve it in 5 mL of anhydrous chloroform, add 176 mg of 85% mCPBA (0.66 mmol, 1.5 eq.), and react at room temperature for 2 h. The reaction solution is washed successively with saturated aqueous sodium bicarbonate (10 mL × 3) and distilled water (30 mL × 3). The organic phase is dried over anhydrous sodium sulfate, filtered, and rotary evaporated under reduced pressure to obtain a yellow oil, which is directly used in the next step.

[0333] At room temperature, in a 25 mL round-bottom flask, add the mixture of sulfone and sulfoxide obtained in the previous step (1 eq.), anhydrous chloroform (10 mL), R 2 the corresponding secondary amine (0.60 mmol, 1.5 eq.), and triethylamine (60 μL, 0.60 mmol, 1.5 eq.). Stir at room temperature and monitor by TLC. After the reaction is completed, wash with distilled water (30 mL × 3), dry over anhydrous sodium sulfate, filter, and rotary evaporate under reduced pressure to obtain a yellow oil, which is purified by silica gel column (DCM:MeOH = 20:1) to obtain the target product.

[0334] (S)-4-((3-chloro-4-methoxybenzyl)amino)-2-(2-hydroxymethylpyrrolidin-1-yl)-6-(pyrimidin-2-ylmethyl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (III-1)

[0335] A pale yellow foamy solid with a yield of 56.3%.

[0336] 1 H NMR (400 MHz, CDCl3) δ 9.43 (s, 1H), 8.68 (d, J = 4.9 Hz, 2H), 7.35 (d, J = 2.1 Hz, 1H), 7.21–7.13 (m, 2H), 6.83 (d, J = 8.4 Hz, 1H), 4.88 (s, 2H), 4.55 (d, J = 6.0 Hz, 2H), 4.26 (s, 1H), 3.86 (s, 3H), 3.80 (d, J = 11.7 Hz, 1H), 3.69 (d, J = 2.4 Hz, 1H), 3.68–3.58 (m, 3H), 3.51 (dt, J = 12.0, 6.6 Hz, 1H), 2.87 (t, J = 6.8 Hz, 2H), 2.17–2.05 (m, 1H), 1.87 (dh, J = 25.4, 6.4 Hz, 2H), 1.63 (dt, J = 12.9, 7.2 Hz, 1H).

[0337] 1313C NMR (101 MHz, CDCl3) δ 166.77, 166.56, 161.20, 157.40, 154.00, 132.71, 129.85, 127.05, 122.21, 119.44, 112.03, 95.41, 68.59, 61.22, 56.21, 53.43, 52.77, 48.50, 45.57, 43.22, 30.40, 30.02, 29.69, 23.84.

[0338] ESI-MS (m / z): 510.2 (M+H) + , 532.2 (M+Na) + .

[0339] (S)-4-((3-chloro-4-methoxybenzyl)amino)-2-(3-hydroxymethyl-3,4-dihydroisoquinolin-2(1H))-6-(pyrimidin-2-ylmethyl)-7,8-dihydropyrrolo[4,3-d]pyrimidin-5(6H)-one (III-2)

[0340] Yellowish brown solid mass, yield 42.8%.

[0341] 1 1H NMR (400 MHz, CDCl3) δ 9.47 (s, 1H), 8.69 (d, J = 4.9 Hz, 2H), 7.39 (d, J = 2.2 Hz, 1H), 7.24–7.13 (m, 6H), 6.86 (d, J = 8.4 Hz, 1H), 5.07 (s, 2H), 4.90 (s, 2H), 4.58 (p, J = 5.8 Hz, 2H), 4.47 (d, J = 15.0 Hz, 1H), 3.87 (s, 3H), 3.67 (t, J = 7.0 Hz, 3H), 3.53 (t, J = 9.8 Hz, 1H), 3.05 (dd, J = 15.5, 6.0 Hz, 1H), 2.92 (s, 2H), 2.79 (dd, J = 15.5, 4.6 Hz, 1H).

[0342] 13 13C NMR (101 MHz, CDCl3) δ 166.72, 166.51, 161.11, 157.42, 154.04, 134.22, 132.56, 129.57, 127.90, 127.08, 126.83, 126.54, 126.28, 122.32, 119.47, 112.12, 95.93, 56.24, 53.44, 52.81, 45.65, 44.79, 43.52, 31.52, 29.71.

[0343] ESI-MS (m / z): 572.1 (M+H) + .

[0344] 4-((3-Chloro-4-methoxybenzyl)amino)-2-(N-methyl-2-hydroxyethylamino)-6-(pyrimidin-2-ylmethyl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (III-3)

[0345] Light yellow oil, yield 58.4%.

[0346] 1 H NMR (400 MHz, CDCl3) δ 9.42 (s, 1), 8.69 (d, J = 4.9 Hz, 2H), 7.34 (d, J = 2.2 Hz, 1H), 7.21–7.13 (m, 2H), 6.84 (d, J = 8.4 Hz, 1H), 4.89 (s, 2H), 4.53 (s, 2H), 3.86 (s, 3H), 3.83 (d, J = 4.5 Hz, 2H), 3.73 (s, 2H), 3.65 (t, J = 7.0 Hz, 2H), 3.18 (s, 3H), 2.87 (d, J = 8.6 Hz, 2H).

[0347] 13 C NMR (101 MHz, CDCl3) δ 166.78, 166.60, 161.16, 157.41, 153.98, 132.54, 129.65, 126.92, 122.24, 119.45, 112.03, 95.34, 58.42, 56.21, 52.78, 45.64, 43.33, 29.70, 18.44.

[0348] ESI-MS (m / z): 484.2 (M+H) + .

[0349] 4-((3-Chloro-4-methoxybenzyl)amino)-2-morpholinyl-6-(pyrimidin-2-ylmethyl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (III-4)

[0350] Milky white powdery solid, yield 62.4%.

[0351] 11H NMR (400 MHz, CDCl3) δ 9.32 (t, J = 5.9 Hz, 1H), 8.68 (d, J = 4.9 Hz, 2H), 7.33 (d, J = 2.1 Hz, 1H), 7.20–7.11 (m, 2H), 6.82 (d, J = 8.4 Hz, 1H), 4.89 (s, 2H), 4.52 (d, J = 5.9 Hz, 2H), 3.82 (t, J = 4.8 Hz, 3H), 3.70 (t, J = 4.8 Hz, 4H), 3.65 (t, J = 6.9 Hz, 4H), 2.86 (t, J = 6.9 Hz, 2H).

[0352] 13 13C NMR (101 MHz, CDCl3) δ 167.98, 166.89, 166.73, 161.44, 160.83, 157.39, 153.95, 132.82, 129.71, 126.93, 122.21, 119.42, 112.01, 95.41, 66.88, 56.21, 52.81, 45.78, 44.15, 43.21, 31.22.

[0353] ESI-MS (m / z): 496.0 (M+H) + .

[0354] 4-((3-Chloro-4-methoxybenzyl)amino)-2-pyrrolidinyl-6-(pyrimidin-2-ylmethyl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (III-5)

[0355] Pale yellow foamy solid, yield 30.4%.

[0356] 1 1H NMR (600 MHz, CDCl3) δ 9.31 (s, 1H), 8.69 (d, J = 4.9 Hz, 2H), 7.19 (ddd, J = 16.4, 7.8, 3.5 Hz, 1H), 7.11 (d, J = 9.4 Hz, 1H), 6.82 (dd, J = 8.4, 5.7 Hz, 2H), 4.90 (s, 2H), 4.55 (d, J = 5.9 Hz, 2H), 3.86 (s, 3H), 3.65 (t, J = 6.9 Hz, 2H), 3.60–3.52 (m, 4H), 2.90 (dt, J = 14.3, 6.5 Hz, 2H), 1.93 (dq, J = 9.3, 5.8, 4.6 Hz, 4H).

[0357] ESI-MS (m / z): 480.1 (M+H) + .

[0358] (S)-4-((3-chloro-4-methoxybenzyl)amino)-2-(2-hydroxymethylpyrrolidin-1-yl)-6-(pyridin-2-ylmethyl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (III-6)

[0359] Light yellow foamy solid, yield 52.4%.

[0360] 1 H NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 8.51 (ddd, J = 5.0, 1.8, 0.9 Hz, 1H), 7.62 (td, J = 7.7, 1.8 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.22–7.11 (m, 2H), 6.83 (d, J = 8.5 Hz, 1H), 4.73 (s, 2H), 4.55 (d, J = 6.0 Hz, 2H), 4.30–4.17 (m, 1H), 3.86–3.44 (m, 9H), 2.77 (t, J = 6.9 Hz, 2H), 2.09 (dq, J = 14.8, 7.4 Hz, 1H), 1.84 (dtd, J = 25.7, 12.7, 6.6 Hz, 2H), 1.61 (tq, J = 12.5, 6.3, 5.2 Hz, 1H).

[0361] 13 C NMR (101 MHz, CDCl3) δ 166.38, 166.30, 161.20, 160.19, 157.46, 154.02, 149.41, 136.86, 132.69, 129.84, 127.03, 122.36, 122.24, 121.81, 112.06, 95.26, 68.58, 61.19, 56.21, 51.99, 48.49, 44.79, 43.23, 30.46, 30.00, 23.84.

[0362] ESI-MS (m / z): 509.1 (M+H) + .

[0363] (S)-4-((3-chloro-4-methoxybenzyl)amino)-2-(3-hydroxymethyl-3,4-dihydroisoquinolin-2(1H))-6-(pyridin-2-ylmethyl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (III-7)

[0364] Light green oil, yield 57.8%.

[0365] 11H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 8.55 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 7.66 (td, J = 7.7, 1.8 Hz, 1H), 7.41 (d, J = 2.2 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.25–7.09 (m, 6H), 6.88 (d, J = 8.4 Hz, 1H), 5.08 (s, 1H), 4.94 (s, 1H), 4.78 (d, J = 3.1 Hz, 2H), 4.61 (d, J = 5.9 Hz, 1H), 4.47 (d, J = 17.6 Hz, 1H), 3.88 (s, 3H), 3.60–3.47 (m, 3H), 3.05 (dd, J = 15.5, 6.0 Hz, 1H), 2.87 (d, J = 18.7 Hz, 3H), 2.79 (dd, J = 15.5, 4.4 Hz, 1H).

[0366] 13 13C NMR (101 MHz, CDCl3) δ 166.21, 163.29, 161.12, 157.42, 154.08, 149.39, 149.24, 136.93, 132.54, 129.56, 127.92, 127.08, 126.82, 126.54, 126.28, 122.69, 122.41, 122.36, 121.87, 112.15, 95.77, 56.24, 53.44, 52.00, 44.86, 43.54, 29.70, 14.21.

[0367] ESI-MS (m / z): 571.1 (M+H) + .

[0368] 4-((3-Chloro-4-methoxybenzyl)amino)-2-(N-methyl-2-hydroxyethylamino)-6-(pyridin-2-ylmethyl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (III-8)

[0369] Yellow solid in block, yield 63.6%.

[0370] 11H NMR (400 MHz, CDCl3) δ 9.44 (s, 1H), 8.54 (ddd, J = 4.9, 1.9, 0.9 Hz, 1H), 7.66 (td, J = 7.7, 1.8 Hz, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.23–7.15 (m, 2H), 6.86 (d, J = 8.4 Hz, 1H), 4.77 (s, 2H), 4.56 (s, 2H), 3.87 (s, 3H), 3.84 (s, 2H), 3.72 (t, J = 6.4 Hz, 2H), 3.55 (t, J = 6.9 Hz, 2H), 3.19 (s, 3H), 2.80 (s, 2H).

[0371] 13 13C NMR (101 MHz, CDCl3) δ 166.32, 161.91, 161.14, 157.44, 154.03, 149.30, 137.01, 132.50, 129.93, 129.64, 129.53, 126.91, 122.43, 122.29, 121.90, 112.07, 95.20, 56.21, 51.92, 44.84, 43.36, 36.78, 30.75.

[0372] ESI-MS (m / z): 480 (M + H) + .

[0373] (S)-4-((3-Chloro-4-methoxybenzyl)amino)-2-(2-hydroxymethylpyrrolidin-1-yl)-6-(4-methoxybenzyl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (III-9)

[0374] Green oil, yield 53.5%.

[0375] 11H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 7.39 (d, J = 2.2 Hz, 1H), 7.20 (dq, J = 9.8, 2.6 Hz, 3H), 6.90–6.81 (m, 3H), 4.64–4.50 (m, 4H), 4.25 (s, 1H), 3.88 (s, 3H), 3.79 (s, 4H), 3.70 (dd, J = 11.1, 2.2 Hz, 1H), 3.66–3.48 (m, 1H), 3.42–3.31 (m, 2H), 2.72 (t, J = 7.0 Hz, 2H), 2.10 (p, J = 7.3 Hz, 1H), 1.87 (ddq, J = 25.6, 12.7, 6.6 Hz, 2H), 1.63 (p, J = 6.5, 6.0 Hz, 1H).

[0376] 13 13C NMR (151 MHz, CDCl3) δ 166.13, 161.23, 159.07, 154.09, 132.72, 129.86, 129.39, 129.20, 127.02, 122.33, 114.12, 112.14, 95.41, 68.52, 61.19, 56.23, 55.29, 53.40, 49.10, 48.50, 43.55, 43.27, 30.33, 29.99, 23.81.

[0377] ESI-MS (m / z): 538.2 (M+H) + .

[0378] (S)-4-((3-Chloro-4-methoxybenzyl)amino)-2-(3-hydroxymethyl-3,4-dihydroisoquinolin-2(1H))-6-(4-methoxybenzyl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (III-10)

[0379] Yellow oil, yield 41.7%.

[0380] 11H NMR (400 MHz, CDCl3) δ 9.53 (d, J = 6.8 Hz, 1H), 7.43 (d, J = 2.2 Hz, 1H), 7.28–7.12 (m, 7H), 6.92–6.82 (m, 3H), 5.06 (d, J = 15.8 Hz, 1H), 4.91 (s, 1H), 4.58 (d, J = 6.1 Hz, 4H), 4.47 (d, J = 16.1 Hz, 1H), 3.89 (s, 3H), 3.79 (s, 3H), 3.63 (t, J = 7.4 Hz, 1H), 3.52 (dd, J = 10.7, 8.9 Hz, 1H), 3.37 (t, J = 6.9 Hz, 2H), 3.11–2.99 (m, 1H), 2.80 (d, J = 4.7 Hz, 1H), 2.78–2.69 (m, 2H).

[0381] 13 13C NMR (151 MHz, CDCl3) δ 166.17, 161.70, 161.22, 159.06, 154.09, 132.69, 129.57, 129.41, 129.33, 129.20, 127.89, 127.04, 126.80, 126.52, 126.28, 122.41, 114.11, 112.22, 95.85, 56.25, 55.29, 49.09, 45.83, 44.74, 43.64, 43.53, 30.89, 29.69, 29.29.

[0382] ESI-MS (m / z): 600.2 (M+H) + .

[0383] 4-((3-Chloro-4-methoxybenzyl)amino)-2-(N-methyl-2-hydroxyethylamino)-6-(4-methoxybenzyl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (III-11)

[0384] Pale yellow oil, yield 54.7%.

[0385] 1 1H NMR (400 MHz, CDCl3) δ 9.51 (s, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.25–7.16 (m, 3H), 6.91–6.82 (m, 3H), 4.58 (s, 4H), 3.88 (s, 3H), 3.79 (s, 5H), 3.72 (d, J = 5.0 Hz, 2H), 3.36 (t, J = 7.0 Hz, 2H), 3.18 (s, 3H), 2.72 (s, 2H).

[0386] 13 C NMR (151 MHz, CDCl3) δ 165.82, 161.21, 159.05, 154.07, 153.07, 149.42, 132.78, 129.66, 129.43, 129.20, 126.89, 122.37, 114.11, 112.14, 95.33, 56.23, 55.29, 49.08, 43.60, 43.38, 36.22, 30.41.

[0387] ESI-MS (m / z): 512.0 (M + H) + .

[0388] 4-((3-Chloro-4-methoxybenzyl)amino)-2-morpholinyl-6-(4-methoxybenzyl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (III-12)

[0389] Pale yellow lumps, yield 57.8%.

[0390] 1 H NMR (400 MHz, CDCl3) δ 9.43 (t, J = 5.9 Hz, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.24–7.17 (m, 3H), 6.89–6.81 (m, 3H), 4.60–4.53 (m, 4H), 3.87 (s, 3H), 3.85–3.80 (m, 4H), 3.79 (s, 3H), 3.70 (dd, J = 5.6, 4.0 Hz, 4H), 3.37 (t, J = 6.9 Hz, 2H), 2.72 (t, J = 6.9 Hz, 2H).

[0391] 13 C NMR (151 MHz, CDCl3) δ 167.50, 166.33, 161.47, 160.80, 159.03, 154.04, 132.86, 129.72, 129.54, 129.22, 126.91, 122.33, 114.09, 112.12, 95.41, 66.87, 56.24, 55.29, 53.42, 49.09, 44.19, 43.76, 43.27, 31.15.

[0392] ESI-MS (m / z): 524.0 (M + H) + .

[0393] Example 4:

[0394] Synthesis steps and structural characterization of thioamide derivatives (IV-1 to IV-13)

[0395] Synthesis of Ethyl 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (17)

[0396] At room temperature, 500 mg of starting material 16 (1.88 mmol, 1 eq.) was dissolved in 4 mL of anhydrous DMF in a 50 mL single-necked round-bottom flask. Separately, 389 mg of benzylamine hydrochloride (1.88 mmol, 1 eq.) was dissolved in 3 mL of anhydrous DMF, 518 μL (3.76 mmol, 2 eq.) of triethylamine was added, and after sonication for 10 min, it was slowly added dropwise to the reaction flask. The reaction solution was stirred at room temperature for 3.5 h, and TLC (PE:EA = 10:1) showed that the starting material had reacted completely. The reaction solution was poured into 150 mL of water, extracted with EA (40 mL × 4), the organic layers were combined, concentrated in vacuo to obtain a crude product, and purified by silica gel column chromatography (PE:EA = 20:1 - 10:1) to obtain 684 mg of a pure colorless oily product, with a yield of 91.1%.

[0397] Synthesis of 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-carboxylic acid (18)

[0398] At room temperature, 684 mg of intermediate 17 (1.706 mmol, 1 eq.) was dissolved in a mixed solvent of 7 mL of THF and 7 mL of water in a 50 mL round-bottom flask, 90 mg of LiOH (2.047 mmol, 1.2 eq.) was added, and the temperature was raised to 60 °C. After reacting for 3 h, TLC showed that the starting material had reacted completely. 1N dilute hydrochloric acid was slowly added dropwise until a large amount of white flocculent precipitate was formed, allowed to stand for 1 h, filtered by suction, and the filter cake was washed with a mixed solution of PE:EA = 20:1, and dried by suction to obtain 586 mg of white powder product 18, with a yield of 96.4%.

[0399] Synthesis of 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)-N-substituted-pyrimidine-5-carboxamide (19)

[0400] Taking the synthesis of 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide (19a) as an example, at room temperature, 784 mg of compound 18 (2.312 mmol, 1 eq.) and 15 mL of DCM were added to a 50 mL round-bottom flask, then 683.15 mg of EDC hydrochloride (3.468 mmol, 1.5 eq.) was added, and the mixture was stirred for 5 min. After the solution became clear, 402 mg of aminomethylpyrimidine hydrochloride (2.774 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 3 h. The reaction was monitored by TCL until completion. 50 mL of saturated ammonium chloride solution was added to wash the reaction solution, the organic layer was collected, distilled under reduced pressure, and purified by silica gel column to obtain 845 mg of the product, with a yield of 85%.

[0401] Synthesis of 4-((3-chloro-4-methoxybenzyl)amino)-2-substituted-N-substituted-pyrimidine-5-carboxamide (20)

[0402] Taking the synthesis of (S)-4-((3-chloro-4-methoxybenzyl)amino)-2-(2-hydroxymethylpyrrolidin-1)-N-(pyrimidin-2-ylmethyl)-pyrimidine-5-carboxamide (20a) as an example, at room temperature, 430 mg of intermediate 19a (1 mmol, 1 eq.) was added to a 100 mL single-necked round-bottom flask and dissolved in 5 mL of chloroform. Under argon protection, 258 mg of mCPBA (1.5 mmol, 1.5 eq.) was added. After stirring at room temperature for 2 h, TLC showed that all of 19a had reacted, forming two spots of sulfoxide and sulfone. 2 mL of saturated NaHCO3 was slowly added dropwise to quench the reaction, and then 100 mL of water was added. The mixture was extracted with DCM (30 mL×3). The organic layers were combined and concentrated, and directly used for the next step.

[0403] The intermediate from the previous step was dissolved in 5 mL of anhydrous DCM. Under argon protection, 90 μL of L-prolinol (1 mmol, 1 eq.) and 208 μL of triethylamine (1.5 mmol, 1.5 eq.) were added. The mixture was stirred at room temperature for 12 h. The reaction solution was concentrated, and column chromatography (MeOH / DCM = 5%) gave 150 mg of the white powder product 20a with a yield of 48%.

[0404] 1 H NMR (400 MHz, CDCl3) δ 9.04 (t, J = 5.8 Hz, 1H), 8.71 (d, J = 4.9 Hz, 2H), 8.41 (s, 1H), 7.36 (s, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.23 (t, J = 4.9 Hz, 1H), 7.17 (dd, J = 8.4, 2.2 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.78 (d, J = 4.4 Hz, 2H), 4.54 (d, J = 5.8 Hz, 2H), 3.86 (s, 3H), 3.84 (s, 4H), 3.71 (dd, J = 5.6, 3.9 Hz, 4H).

[0405] 13 C NMR (101 MHz, CDCl3) δ 167.36, 165.80, 161.41, 161.37, 157.22, 155.76, 154.03, 132.54, 129.67, 126.87, 122.27, 119.63, 112.04, 99.15, 66.82, 56.21, 45.07, 44.21, 43.23.

[0406] General method for the synthesis of target products IV-1 to IV-13

[0407] At room temperature, add intermediate 20 (1 mmol) and 808 mg of Lawesson's reagent (2 mmol) into a 100 mL single-necked round-bottom flask. Add 18 mL of anhydrous toluene and 2 mL of anhydrous acetonitrile. React at 120 °C for 12 h under argon protection, and monitor by TLC (DCM:acetone = 8:2). After the reaction is completed, cool the solution, wash it with saturated NaHCO3 solution (50 mL × 3), collect the organic layer, and obtain the crude product as a black solid by distillation under reduced pressure. Purify it by silica gel column chromatography (DCM:acetone = 9:1) to obtain the target product.

[0408] 4-((3-Chloro-4-methoxybenzyl)amino)-2-morpholinyl-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carbothioamide (IV-1)

[0409] Brown blocky solid, yield 45.5%.

[0410] 1 H NMR (400 MHz, CDCl3) δ 9.46 (t, J = 5.8 Hz, 1H), 8.90 (t, J = 4.2 Hz, 1H), 8.73 (d, J = 4.9 Hz, 2H), 8.35 (s, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.29–7.25 (m, 1H), 7.22 (dd, J = 8.4, 2.2 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 5.11 (d, J = 4.1 Hz, 2H), 4.59 (d, J = 5.7 Hz, 2H), 3.88 (s, 3H), 3.85–3.77 (m, 4H), 3.72 (dd, J = 5.6, 3.9 Hz, 4H).

[0411] 13 C NMR (101 MHz, CDCl3) δ 192.09, 164.42, 160.43, 160.32, 157.32, 154.04, 153.50, 132.31, 129.57, 126.78, 122.29, 119.93, 112.10, 108.46, 66.80, 56.22, 50.35, 44.27, 43.67, 29.70.

[0412] ESI-MS (m / z): 486.3 (M+H) + .

[0413] 4-((3-Chloro-4-methoxybenzyl)amino)-2-((N-methyl-N-methoxyethyl)amino)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carbothioamide (IV-2)

[0414] Reddish-brown foamy solid, yield 43.5%.

[0415] 1 H NMR (400 MHz, CDCl3) δ 9.54 (t, J = 5.6 Hz, 1H), 8.99 (s, 1H), 8.73 (d, J = 4.9 Hz, 2H), 8.41 (s, 1H), 7.36 (s, 1H), 7.29–7.19 (m, 2H), 6.88 (d, J = 8.4 Hz, 1H), 5.11 (d, J = 4.1 Hz, 2H), 4.60 (d, J = 5.6 Hz, 2H), 3.88 (s, 3H), 3.81–3.61 (m, 2H), 3.45 (s, 2H), 3.30 (s, 3H), 3.20 (s, 3H).

[0416] 13 C NMR (101 MHz, CDCl3) δ 191.93, 164.51, 160.10, 157.33, 153.99, 152.38, 132.40, 129.11, 126.63, 122.31, 119.89, 112.11, 70.77, 60.41, 58.94, 56.22, 50.36, 43.67, 36.73, 21.06, 14.21.

[0417] ESI-MS (m / z): 488.0 (M + H) + .

[0418] 4-((3-Chloro-4-methoxybenzyl)amino)-2-pyrrolidinyl-N-(pyrimidin-2-ylmethyl)-pyrimidine-5-carbothioamide (IV-3)

[0419] Brown massive solid, yield 46.5%.

[0420] 1 H NMR (400 MHz, CDCl3) δ 9.61 (d, J = 7.0 Hz, 1H), 9.11 (s, 1H), 8.71 (d, J = 4.9 Hz, 2H), 8.45 (s, 1H), 7.40 (d, J = 2.1 Hz, 1H), 7.28–7.20 (m, 2H), 6.88 (d, J = 8.4 Hz, 1H), 5.10 (d, J = 3.8 Hz, 2H), 4.61 (d, J = 5.6 Hz, 2H), 3.88 (s, 3H), 3.59 (d, J = 21.1 Hz, 4H), 2.08–1.87 (m, 4H).

[0421] 1313C NMR (101 MHz, CDCl3) δ 191.56, 164.46, 159.95, 157.32, 154.05, 132.13, 129.80, 126.98, 122.22, 119.86, 113.83, 113.65, 112.08, 107.91, 56.21, 50.35, 47.27, 46.68, 43.71, 25.64, 25.12.

[0422] ESI-MS (m / z): 470.0 (M+H) + .

[0423] 4-((3-Chloro-4-methoxybenzyl)amino)-2-morpholinyl-N-(pyridin-2-ylmethyl)-pyrimidine-5-carbothioamide (IV-4)

[0424] Green block solid, yield 42.6%.

[0425] 1 1H NMR (400 MHz, CDCl3) δ 9.45 (t, J = 5.7 Hz, 1H), 9.24–9.18 (m, 1H), 8.51 (ddd, J = 5.0, 1.7, 0.9 Hz, 1H), 8.32 (s, 1H), 7.71 (td, J = 7.7, 1.7 Hz, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.31 (dt, J = 7.9, 1.0 Hz, 1H), 7.25–7.19 (m, 2H), 6.87 (d, J = 8.4 Hz, 1H), 4.97 (d, J = 4.1 Hz, 2H), 4.59 (d, J = 5.7 Hz, 2H), 3.88 (s, 3H), 3.81 (dd, J = 5.6, 3.9 Hz, 4H), 3.71 (dd, J = 5.7, 3.9 Hz, 4H).

[0426] 13 13C NMR (101 MHz, CDCl3) δ 191.74, 160.46, 160.33, 154.00, 153.94, 153.60, 148.78, 137.02, 132.39, 129.56, 126.76, 122.80, 122.27, 122.12, 112.08, 108.45, 66.82, 56.22, 49.28, 44.26, 43.64.

[0427] ESI-MS (m / z): 485.0 (M+H) + .

[0428] 4-((3-chloro-4-methoxybenzyl)amino)-2-((N-methyl-N-methoxyethyl)amino)-N-(pyridin-2-ylmethyl)pyrimidine-5-carbothioamide (IV-5)

[0429] Black lumpy solid, yield 46.7%.

[0430] 1 H NMR (400 MHz, CDCl3) δ 9.52 (t, J = 5.7 Hz, 1H), 9.26 (s, 1H), 8.51 (d, J = 4.9 Hz, 1H), 8.38 (s, 1H), 7.70 (td, J = 7.7, 1.7 Hz, 1H), 7.35 (s, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.26–7.19 (m, 2H), 6.87 (d, J = 8.4 Hz, 1H), 4.97 (d, J = 4.0 Hz, 2H), 4.59 (d, J = 5.5 Hz, 2H), 3.87 (s, 3H), 3.80–3.43 (m, 4H), 3.29 (s, 3H), 3.19 (s, 3H).

[0431] 13 C NMR (101 MHz, CDCl3) δ 191.68, 160.10, 154.11, 153.93, 153.12, 148.80, 136.99, 132.56, 129.30, 126.58, 122.75, 122.27, 122.17, 112.08, 107.86, 70.79, 58.92, 56.20, 49.30, 43.61, 36.68.

[0432] ESI-MS (m / z): 487.1 (M + H) + .

[0433] 4-((3-chloro-4-methoxybenzyl)amino)-2-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(pyridin-2-ylmethyl)pyrimidine-5-carbothioamide (IV-6)

[0434] Brown solid, yield 20.4%.

[0435] 11H NMR (400 MHz, CDCl3) δ 11.92 (s, 1H), 10.70 (s, 1H), 9.67 (s, 1H), 8.70 (s, 1H), 8.43 (s, 1H), 8.25 (s, 1H), 7.63 (s, 3H), 7.37 (d, J = 10.1 Hz, 1H), 7.10 (s, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.62 (s, 1H), 5.17 (d, J = 15.7 Hz, 4H), 4.67 (s, 2H), 4.10 (s, 1H), 3.86 (s, 3H).

[0436] ESI-MS (m / z): 518.1 (M + H) + .

[0437] 4 - ((3-chloro-4-methoxybenzyl)amino)-2-pyrrolidinyl-N-(pyridin-2-ylmethyl)-pyrimidine-5-carbothioamide (IV-7)

[0438] Grey block solid, yield 45.3%.

[0439] 1 1H NMR (400 MHz, CDCl3) δ 9.53 (t, J = 5.8 Hz, 1H), 9.26 (s, 1H), 8.53–8.47 (m, 1H), 8.36 (s, 1H), 7.70 (tt, J = 7.7, 1.4 Hz, 1H), 7.41 (d, J = 2.1 Hz, 1H), 7.33–7.19 (m, 3H), 6.87 (d, J = 8.4 Hz, 1H), 4.97 (d, J = 3.8 Hz, 2H), 4.61 (d, J = 5.8 Hz, 2H), 3.87 (d, J = 1.0 Hz, 3H), 3.59 (s, 4H), 1.96 (d, J = 5.1 Hz, 4H).

[0440] 13 13C NMR (101 MHz, CDCl3) δ 191.78, 160.16, 158.79, 154.15, 153.90, 153.23, 148.77, 136.96, 132.75, 129.77, 126.93, 122.72, 122.14, 122.11, 112.02, 107.71, 56.20, 49.26, 46.97, 46.43, 43.50, 25.60, 25.26.

[0441] ESI-MS (m / z): 469.0 (M + H) + .

[0442] 4-((3-chloro-4-methoxybenzyl)amino)-2-morpholinyl-N-(4-methoxybenzyl)-pyrimidine-5-carbothioamide (IV-8)

[0443] Yellowish green foamy solid, yield 43.6%.

[0444] 1 H NMR (400 MHz, CDCl3) δ 9.28 (t, J = 5.7 Hz, 1H), 8.01 (s, 1H), 7.44 (t, J = 4.9 Hz, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.30–7.25 (m, 2H), 7.21 (dd, J = 8.5, 2.2 Hz, 1H), 6.88 (dd, J = 8.6, 3.3 Hz, 3H), 4.80 (d, J = 4.8 Hz, 2H), 4.56 (d, J = 5.6 Hz, 2H), 3.87 (s, 3H), 3.80 (s, 3H), 3.75 (t, J = 4.7 Hz, 4H), 3.66 (t, J = 4.7 Hz, 4H).

[0445] 13 C NMR (101 MHz, CDCl3) δ 192.41, 160.39, 160.26, 159.56, 154.04, 152.88, 132.24, 129.74, 129.56, 128.11, 126.79, 122.27, 114.42, 112.09, 108.62, 66.75, 56.21, 55.36, 49.29, 44.22, 43.66.

[0446] ESI-MS (m / z): 514.0 (M+H) + .

[0447] 4-((3-chloro-4-methoxybenzyl)amino)-2-((N-methyl-N-methoxyethyl)amino)-N-(4-methoxybenzyl)-pyrimidine-5-carbothioamide (IV-9)

[0448] Brownish yellow foamy solid, yield 41.5%.

[0449] 11H NMR (600 MHz, CDCl3) δ 9.31 (t, J = 5.8 Hz, 1H), 8.05 (s, 1H), 7.41 (s, 1H), 7.35 (s, 1H), 7.30–7.24 (m, 2H), 7.22 (s, 1H), 6.88 (dd, J = 8.5, 5.2 Hz, 3H), 4.80 (d, J = 4.9 Hz, 2H), 4.58 (s, 2H), 3.88 (s, 3H), 3.80 (s, 3H), 3.78–3.59 (m, 2H), 3.46 (d, J = 70.7 Hz, 2H), 3.27 (s, 3H), 3.15 (s, 3H).

[0450] 13 13C NMR (101 MHz, CDCl3) δ 192.52, 160.57, 160.13, 159.54, 153.96, 152.75, 132.55, 129.72, 129.36, 128.23, 126.63, 122.29, 114.41, 112.09, 108.05, 70.78, 58.88, 56.21, 55.36, 49.23, 43.58, 36.53.

[0451] ESI-MS (m / z): 516.0 (M + H) + .

[0452] 4-((3-Chloro-4-methoxybenzyl)amino)-2-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1)-N-(4-methoxybenzyl)-pyrimidine-5-carbothioamide (IV-10)

[0453] Tan-yellow foamy solid, yield 47.9%.

[0454] 1 1H NMR (400 MHz, CDCl3) δ 9.31 (t, J = 5.9 Hz, 1H), 8.03 (s, 1H), 7.49 (t, J = 5.0 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.30–7.21 (m, 3H), 6.87 (d, J = 9.0 Hz, 3H), 4.80 (d, J = 4.9 Hz, 2H), 4.59 (d, J = 5.8 Hz, 2H), 3.87 (s, 3H), 3.80 (s, 3H), 3.49 (d, J = 6.4 Hz, 4H), 1.98–1.87 (m, 4H).

[0455] 1313C NMR (101 MHz, CDCl3) δ 192.60, 160.11, 159.49, 158.99, 153.93, 152.84, 132.68, 129.78, 129.68, 128.32, 126.96, 122.15, 114.37, 112.03, 107.98, 56.20, 55.35, 49.18, 46.91, 46.35, 43.50, 25.52, 25.25.

[0456] ESI-MS (m / z): 498.0 (M+H) + .

[0457] 4-((3-Chloro-4-methoxybenzyl)amino)-2-morpholinyl-N-(pyridin-3-ylmethyl)pyrimidine-5-carbothioamide (IV-11)

[0458] Brown foamy solid, yield 45.9%.

[0459] 1 1H NMR (600 MHz, CDCl3) δ 9.44 (s, 1H), 8.74–8.39 (m, 2H), 8.25–8.21 (m, 1H), 7.75–7.72 (m, 1H), 7.34 (d, J = 2.1 Hz, 1H), 7.19 (dd, J = 8.4, 2.2 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 4.92 (s, 2H), 4.54 (d, J = 5.5 Hz, 2H), 3.88 (s, 3H), 3.76–3.66 (m, 4H), 3.66–3.62 (m, 4H).

[0460] 13 13C NMR (151 MHz, D2O_salt) δ 189.76, 157.45, 151.70, 146.88, 146.13, 134.07, 129.84, 128.89, 127.04, 124.27, 121.31, 119.86, 110.58, 109.66, 105.86, 63.98, 55.88, 53.69, 52.81, 43.79, 41.95, 41.41.

[0461] ESI-MS (m / z): 485.1 (M+H) + .

[0462] 4-((3-Chloro-4-methoxybenzyl)amino)-2-((N-methyl-N-methoxyethyl)amino)-N-(pyridin-3-ylmethyl)pyrimidine-5-carbothioamide (IV-12)

[0463] Reddish-brown foamy solid, yield 41.2%.

[0464] 1 H NMR (400 MHz, CDCl3) δ 9.38 (d, J = 5.8 Hz, 1H), 8.16 (m, 3H), 7.74 (s, 1H), 7.37–7.32 (m, 1H), 7.20 (d, J = 8.3 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 4.97 (s, 2H), 4.57 (s, 2H), 3.87 (s, 3H), 3.69 (s, 2H), 3.42 (s, 2H), 3.27 (s, 3H), 3.14 (s, 3H).

[0465] 13 C NMR (101 MHz, CDCl3) δ 192.88, 160.02, 154.04, 151.55, 148.99, 140.41, 135.74, 132.09, 129.28, 126.65, 122.31, 112.12, 107.96, 70.63, 58.90, 56.21, 49.54, 46.67, 43.74, 36.78, 29.33, 27.22.

[0466] ESI-MS (m / z): 487.0 (M + H) + .

[0467] 4-((3-Chloro-4-methoxybenzyl)amino)-2-pyrrolidinyl-N-(pyridin-3-ylmethyl)-pyrimidine-5-carbothioamide (IV-13)

[0468] Brown massive solid, yield 39.8%.

[0469] 1 H NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 8.63 (s, 1H), 8.49 (s, 1H), 8.19 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.22 (dd, J = 8.4, 2.2 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 4.95–4.89 (m, 2H), 4.57 (d, J = 5.7 Hz, 2H), 3.88 (s, 3H), 3.49 (s, 4H), 1.92 (d, J = 6.2 Hz, 4H).

[0470] 1313C NMR(101MHz,CDCl3)δ192.88,160.02,154.04,151.70,148.84,140.26,136.19,132.09,129.28,126.65,122.31,112.12,107.81,70.63,58.90,56.21,49.38,46.15,43.74,36.78,29.33,27.22.

[0471] ESI-MS(m / z):469.0(M + H) + .

[0472] Example 5: Activity Test

[0473] 1. Test Principle

[0474] This test uses a commercial PDE5 analysis kit (BPS Bioscience) to determine the PDE5 inhibitory activity of the test compound by fluorescence polarization technology. The test principle is as follows.

[0475]

[0476] PDE5 enzyme catalyzes the hydrolysis of the phosphodiester bond in FAM-labeled cyclic guanosine monophosphate (FAM-cGMP) to generate FAM-labeled guanosine monophosphate

[0477] (FAM-GMP). After adding nanobeads that can bind to GMP, further formation of FAM-GMP-nanobead conjugate occurs. Compared with FAM in FAM-cGMP, FAM on the conjugate rotates more slowly due to steric hindrance, and the polarized light emitted becomes stronger. PDE5 inhibitors can inhibit the occurrence of the above process, so the PDE5 inhibitory activity of the test compound can be evaluated by measuring the intensity of polarized light.

[0478] 2. Test Procedures

[0479] 2.1 Solution Preparation

[0480] (1) Take a certain amount of the test compound and dissolve it ultrasonically in DMSO to prepare a mother solution of the test compound with a concentration of 10 -2 M. Dilute the mother solution with an aqueous solution containing 5% DMSO to prepare 7 - 8 groups of test compound solutions with different concentrations.

[0481] (2) Dilute the thawed FAM-cGMP solution to 200 nM with PDE Assay Buffer in the kit.

[0482] (3) Dilute the thawed PDE5 solution to 10 pg / μL with PDE Assay Buffer in the kit.

[0483] 2.2 Sample addition and reaction

[0484] (1) Set up a blank group, a substrate control group, an enzyme control group, and an experimental group, with 3 replicates for each:

[0485] ① Blank group: contains only the solvent

[0486] ② Substrate control group: contains the substrate FAM-cGMP

[0487] ③ Enzyme control group: contains FAM-cGMP and PDE5 enzyme, equivalent to a test compound concentration of 0

[0488] ④ Experimental group: contains FAM-cGMP, PDE5 enzyme, and different concentrations of the test compound

[0489] (2) The sample addition volume per well of the 384-well plate is shown in Table 1.

[0490] Table 1 Sample addition volume of each component per well (unit: μL)

[0491]

[0492] (3) After adding samples to each well of the 384-well plate, centrifuge at 4500 rpm for 1 min at room temperature, and then place it at 20 °C for reaction for 1 h.

[0493] (4) Add 50 μL of the nanobead solution to each well, and slowly shake (70 rpm) in a shaker at 20 °C for 20 min.

[0494] 2.3 Detection and data analysis

[0495] (1) Use a Synergy H4 microplate reader (Agilent) to detect the fluorescence polarization value of each well, set the excitation wavelength to 485 nm, the emission wavelength to 528 nm, the gain value to 100, the dichroic mirror to 510 nm at the top, and the detection height to 7 mm.

[0496] (2) After subtracting the blank group value from the original value of each well reading, use GraphPad Prism software to fit the dose-effect curve and calculate the half-maximal inhibitory concentration (IC50).

[0497] (3) Each test compound is independently repeated and tested twice according to the above steps. According to the data of the first test of each test compound, the concentration gradient is adjusted as necessary during the second test.

[0498] 3. Test results

[0499] This test investigated the PDE5 inhibitory activities of a total of 10 avanafil derivatives, YB-I-1 to YB-I-10, with avanafil

[0500] (Avanafil, Shanghai Bide Pharmaceutical Technology Co., Ltd., purity 98%) and Sildenafil (Shanghai Bide Pharmaceutical Technology Co., Ltd., purity 98%) were used as positive controls, and each test compound was tested twice. YB-I-1IC 50 value was less than 10 nM, and the IC 50 values of each test compound all showed good performance.

[0501] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the inventive concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention.

Claims

1. A PDE5 inhibitor, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that, The inhibitor is a 6-chloropyrimidine derivative, and its structural formula is as follows: wherein R1 is selected from pyrimidinyl or substituted pyrimidinyl, pyridinyl or substituted pyridinyl, phenyl or substituted phenyl, morpholinyl or substituted morpholinyl, The substituted pyrimidinyl is a C 1～6 alkyl-substituted pyrimidinyl, the substituted pyridinyl is a C 1～6 alkyl-substituted pyridinyl, the substituted phenyl is a C 1～6 alkyl-substituted phenyl or the C 1～6 alkyl-substituted phenyl is further substituted by a C 1～6 alkoxy group, the substituted morpholinyl is a C 1～6 alkyl-substituted morpholinyl; R2 is selected from pyrrolidinyl or substituted pyrrolidinyl, morpholinyl or substituted morpholinyl, amino or substituted amino, dihydroisoquinolinyl or substituted dihydroisoquinolinyl, dihydropyrrolopyridinyl or substituted dihydropyrrolopyridinyl, The substituted pyrrolidinyl is C 1～6 alkyl-substituted pyrrolidinyl or the C 1～6 alkyl of the alkyl-substituted pyrrolidinyl is further substituted by a hydroxyl group, the substituted morpholinyl is C 1～6 alkyl-substituted morpholinyl, the substituted amino group is C 1～6 alkyl-substituted amino group or the C 1～6 alkyl of the alkyl-substituted amino group is further substituted by a hydroxyl group or a C 1～6 alkoxy group, the substituted dihydroisoquinolinyl is C 1～6 alkyl-substituted dihydroisoquinolinyl or the C 1～6 alkyl of the alkyl-substituted dihydroisoquinolinyl is further substituted by a hydroxyl group, the substituted dihydropyrrolopyridinyl is C 1～6 alkyl-substituted dihydropyrrolopyridinyl. 1～6 alkyl of the alkyl-substituted dihydropyrrolopyridinyl is further substituted by a hydroxyl group, the substituted dihydropyrrolopyridinyl is C 1～6 alkyl-substituted dihydropyrrolopyridinyl. 1～6 alkyl-substituted dihydropyrrolopyridinyl.

2. The PDE5 inhibitor, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, characterized in that, wherein R1 is selected from substituted pyrimidinyl, substituted pyridinyl, substituted phenyl, substituted morpholinyl, The substituted pyrimidinyl is C 1～3 alkyl-substituted pyrimidinyl, the substituted pyridinyl is C 1～3 alkyl-substituted pyridinyl, the substituted phenyl is C 1～3 alkyl-substituted phenyl or the C 1～3 alkyl-substituted phenyl is further substituted by C 1～3 alkoxy, the substituted morpholinyl is C 1～3 alkyl-substituted morpholinyl; R2 is selected from pyrrolidinyl or substituted pyrrolidinyl, morpholinyl, substituted amino, substituted dihydroisoquinolinyl, dihydropyrrolopyridinyl, The substituted pyrrolidinyl group is C 1～3 Alkyl-substituted pyrrolidinyl or the C 1～3 Alkyl substituted pyrrolidinyl C 1～3 The alkyl group is further substituted with a hydroxyl group, wherein the substituted amino group is C 1～3 Alkyl substituted amino or the C 1～3 Alkyl substituted amino C 1～3 The alkyl group is further replaced by hydroxyl, C 1～3 Alkoxy substituted, the substituted dihydroisoquinolinyl is C 1～3 Alkyl substituted dihydroisoquinolinyl or said C 1～3 Alkyl-substituted dihydroisoquinolinyl C 1～3 The alkyl group is further substituted with a hydroxy group.

3. A PDE5 inhibitor, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that, The structural formula of the inhibitor is as follows: wherein ○ represents that the ring is saturated or unsaturated, wherein R1 is selected from pyrimidinyl or substituted pyrimidinyl, pyridinyl or substituted pyridinyl, phenyl or substituted phenyl, morpholinyl or substituted morpholinyl, The substituted pyrimidinyl is C 1～6 alkyl-substituted pyrimidinyl, and the substituted pyridinyl is C 1～6 alkyl-substituted pyridinyl, and the substituted phenyl is C 1～6 alkyl-substituted phenyl or the C 1～6 alkyl-substituted phenyl is further substituted by C 1～6 alkoxy, and the substituted morpholinyl is C 1～6 alkyl-substituted morpholinyl; R2 is selected from pyrrolidinyl or substituted pyrrolidinyl, morpholinyl or substituted morpholinyl, amino or substituted amino, dihydroisoquinolinyl or substituted dihydroisoquinolinyl, dihydropyrrolopyridinyl or substituted dihydropyrrolopyridinyl, The substituted pyrrolidinyl is C 1～6 alkyl-substituted pyrrolidinyl or the C 1～6 alkyl of the alkyl-substituted pyrrolidinyl is further substituted by a hydroxyl group, the substituted morpholinyl is C 1～6 alkyl-substituted morpholinyl, the substituted amino group is C 1～6 alkyl-substituted amino group or the C 1～6 alkyl of the alkyl-substituted amino group is further substituted by a hydroxyl group, C 1～6 alkoxy group, the substituted dihydroisoquinolinyl is C 1～6 alkyl-substituted dihydroisoquinolinyl or the C 1～6 alkyl of the alkyl-substituted dihydroisoquinolinyl is further substituted by a hydroxyl group, the substituted dihydropyrrolopyridinyl is C 1～6 alkyl-substituted dihydropyrrolopyridinyl. 1～6 alkyl of the alkyl-substituted dihydropyrrolopyridinyl is further substituted by a hydroxyl group, the substituted dihydropyrrolopyridinyl is C 1～6 alkyl-substituted dihydropyrrolopyridinyl. 1～6 alkyl-substituted dihydropyrrolopyridinyl.

4. The PDE5 inhibitor, its stereoisomer or its pharmaceutically acceptable salt according to claim 3, characterized in that, wherein R1 is selected from substituted pyrimidinyl, substituted pyridinyl, substituted phenyl, substituted morpholinyl, The substituted pyrimidinyl is C 1～3 alkyl-substituted pyrimidinyl, and the substituted pyridinyl is C 1～3 alkyl-substituted pyridinyl, and the substituted phenyl is C 1～3 alkyl-substituted phenyl or the C 1～3 alkyl-substituted phenyl is further substituted by C 1～3 alkoxy, and the substituted morpholinyl is C 1～3 alkyl-substituted morpholinyl; R2 is selected from pyrrolidinyl or substituted pyrrolidinyl, morpholinyl, substituted amino, substituted dihydroisoquinolinyl, dihydropyrrolopyridinyl, The substituted pyrrolidinyl is C 1～3 alkyl-substituted pyrrolidinyl or the C 1～3 alkyl of the alkyl-substituted pyrrolidinyl 1～3 alkyl is further substituted by a hydroxyl group, and the substituted amino group is C 1～3 alkyl-substituted amino or the C 1～3 alkyl of the alkyl-substituted amino 1～3 alkyl is further substituted by a hydroxyl group and C 1～3 alkoxy, and the substituted dihydroisoquinolinyl is C 1～3 alkyl-substituted dihydroisoquinolinyl or the C 1～3 alkyl of the alkyl-substituted dihydroisoquinolinyl 1～3 alkyl is further substituted by a hydroxyl group.

5. A PDE5 inhibitor, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 3-4, characterized in that The inhibitor is a pyrimidinopyridinone derivative, and its structural formula is as follows:

6. A PDE5 inhibitor according to any one of claims 3-4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that, The inhibitor is a pyrimidinodihydropyridone derivative, and its structural formula is as follows:

7. A PDE5 inhibitor, its stereoisomer or its pharmaceutically acceptable salt, characterized in that, The inhibitor is a thioamide derivative, and its structural formula is as follows: wherein R1 is selected from pyrimidinyl or substituted pyrimidinyl, pyridinyl or substituted pyridinyl, phenyl or substituted phenyl, morpholinyl or substituted morpholinyl, The substituted pyrimidinyl is C 1～6 alkyl-substituted pyrimidinyl, and the substituted pyridinyl is C 1～6 alkyl-substituted pyridinyl, and the substituted phenyl is C 1～6 alkyl-substituted phenyl or the C 1～6 alkyl-substituted phenyl is further substituted by C 1～6 alkoxy, and the substituted morpholinyl is C 1～6 alkyl-substituted morpholinyl; R2 is selected from pyrrolidinyl or substituted pyrrolidinyl, morpholinyl or substituted morpholinyl, amino or substituted amino, dihydroisoquinolinyl or substituted dihydroisoquinolinyl, dihydropyrrolopyridinyl or substituted dihydropyrrolopyridinyl, The substituted pyrrolidinyl is C 1～6 alkyl-substituted pyrrolidinyl or the C 1～6 alkyl of the alkyl-substituted pyrrolidinyl is further substituted by a hydroxyl group, the substituted morpholinyl is C 1～6 alkyl-substituted morpholinyl, the substituted amino group is C 1～6 alkyl-substituted amino group or the C 1～6 alkyl of the alkyl-substituted amino group is further substituted by a hydroxyl group or a C 1～6 alkoxy group, the substituted dihydroisoquinolinyl is C 1～6 alkyl-substituted dihydroisoquinolinyl or the C 1～6 alkyl of the alkyl-substituted dihydroisoquinolinyl is further substituted by a hydroxyl group, the substituted dihydropyrrolopyridinyl is C 1～6 alkyl-substituted dihydropyrrolopyridinyl. 1～6 The C 1～6 alkyl of the alkyl-substituted dihydropyrrolopyridinyl is further substituted by a hydroxyl group, the substituted dihydropyrrolopyridinyl is C 1～6 alkyl-substituted dihydropyrrolopyridinyl.

8. The PDE5 inhibitor, its stereoisomer or its pharmaceutically acceptable salt according to claim 7, characterized in that, wherein R1 is selected from substituted pyrimidinyl, substituted pyridinyl, substituted phenyl, substituted morpholinyl, The substituted pyrimidinyl is C 1～3 alkyl-substituted pyrimidinyl, and the substituted pyridinyl is C 1～3 alkyl-substituted pyridinyl, and the substituted phenyl is C 1～3 alkyl-substituted phenyl or the C 1～3 alkyl-substituted phenyl is further substituted by C 1～3 alkoxy, and the substituted morpholinyl is C 1～3 alkyl-substituted morpholinyl; R2 is selected from pyrrolidinyl or substituted pyrrolidinyl, morpholinyl, substituted amino, substituted dihydroisoquinolinyl, dihydropyrrolopyridinyl, The substituted pyrrolidinyl is C 1～3 alkyl-substituted pyrrolidinyl or the C 1～3 alkyl of the alkyl-substituted pyrrolidinyl 1～3 alkyl is further substituted by a hydroxyl group, and the substituted amino is C 1～3 alkyl-substituted amino or the C 1～3 alkyl of the alkyl-substituted amino 1～3 alkyl is further substituted by a hydroxyl group and a C 1～3 alkoxy group, and the substituted dihydroisoquinolinyl is C 1～3 alkyl-substituted dihydroisoquinolinyl or the C 1～3 alkyl of the alkyl-substituted dihydroisoquinolinyl 1～3 alkyl is further substituted by a hydroxyl group.

9. The PDE5 inhibitor, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1, 2, 3, 4, 7 and 8, characterized in that, R1 is -(CH2) n -R 11 , Wherein: R 11 is selected from pyrimidinyl, pyridinyl, phenyl or morpholinyl, and the pyrimidinyl, pyridinyl, phenyl or morpholinyl is substituted with 0, 1 or 2 C 1～6 alkoxy groups; n＝1～6。 10. The PDE5 inhibitor, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1, 2, 3, 4, 7, and 8, characterized in that, R1 is selected from R2 is selected from 11. Use of a PDE5 inhibitor, its stereoisomer or its pharmaceutically acceptable salt in the preparation of a PDE5 inhibitor drug.

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