Uridine phosphate amine compound, preparation method therefor, pharmaceutical composition thereof, and use thereof

Abstract

A uridine phosphate amine compound, a preparation method therefor, a pharmaceutical composition thereof, and a use thereof. The structure of the uridine phosphate amine compound is as shown in formula I. The uridine phosphate amine compound can effectively deliver active uridine 5'-monophosphate into the body, greatly improving the in vivo concentration of uridine monophosphate and in particular effectively raising the concentration of uridine monophosphate in the brain, thereby enhancing therapeutic efficacy against brain-related diseases.

Description

Uridine phosphate amine compounds, preparation methods, pharmaceutical compositions and uses thereof Technical Field

[0001] The present invention relates to uridine phosphate amine compounds, preparation methods thereof, pharmaceutical compositions thereof and medical uses thereof. The uridine phosphate amine compounds can better introduce active uridine 5'-monophosphate into the body, greatly increasing the uridine 5'-monophosphate concentration in the body, and in particular can effectively increase the uridine 5'-monophosphate concentration in the brain, thereby improving the therapeutic effect of brain-related diseases. Background Art

[0002] Normally, uridine is the primary pyrimidine nucleoside form absorbed by the brain and used in the synthesis of nucleic acids and cell membranes (Curr. Top. Med. Chem. 2011, 11, 1058). Furthermore, uridine is a bioactive molecule in the brain, playing an important role in central nervous system functions such as memory and neuroplasticity. Uridine levels in the brains of patients with Alzheimer's disease, cognitive impairment, or Parkinson's disease are significantly lower than those of normal individuals (Alzheimer's & Dementia: Siagnosis, Assessment & Disease Monitoring 2017, 1; Neurol. Ther. 2021, 10, 43). Uridine is also a fundamental raw material for cell membrane synthesis. Supplementing uridine in vivo, particularly in the brain, can increase the formation of synaptic networks in the brain (Nutr. Rev. 2010, 68:S88-101), effectively alleviating the progression of neurodegenerative diseases such as Alzheimer's disease, cognitive impairment, and Parkinson's disease, or improving their therapeutic efficacy.

[0003] Experiments (Cell Discovery 2022, 8:6, 1-22) show that uridine injection or oral gavage increased uridine levels in mice's plasma, muscles, and brains. It also promoted the repair of five tissue and organ injuries, including muscle regeneration, cardiovascular disease, hair regeneration, and liver fibrosis. For example, mice with muscle damage improved limb grip strength, mice with hair damage regenerated hair, mice with myocardial infarction experienced increased cardiac contractility, and mice with liver fibrosis were alleviated. Directly feeding uridine to elderly mice for two months significantly improved their systemic motor function. It has also been found that cells or tissues with higher uridine levels have greater regenerative capacity. Uridine is also known to enhance brain plasticity by creating and reorganizing synaptic connections, enhancing the brain's ability to adapt, remember, and learn. Aging diseases often reduce the number of synapses, or nerve cell connections, through which neurotransmitters transmit information to the brain and body. Therefore, increasing uridine levels in tissues, particularly the brain, may help slow the aging process. Uridine is a precursor for the synthesis of phospholipids and cell membranes. Supplementing uridine in the body, including in the brain, can increase brain citicoline (CDP-choline) levels, promoting recovery from impaired consciousness after brain trauma or surgery. Elevated uridine levels can increase synaptic formation in brain neurons (Nutrition Reviews 2010, 68, Suppl. 2, S88-S-101), which can help improve memory, optimize mitochondrial function, enhance mood, and protect nerves.

[0004] Low uridine levels are also a key characteristic of patients with Alzheimer's disease and dementia (Alzheimer's Dement. 2020, 12, e12120). Animal studies have also shown that the combination of uridine and DHA has a restorative effect on Parkinson's disease (Neurosci. Res. 2008, 62, 206). Therefore, supplementing patients with Alzheimer's disease or Parkinson's disease with uridine, or supplementing them with DHA simultaneously, or supplementing them with choline derivatives, may improve the therapeutic effect. Increasing these substances in the body, especially in the brain, may help slow or reverse the progression of Alzheimer's and Parkinson's disease. Studies have shown that uridine supplementation can increase dopamine release (Bipolar Disorders. 2010, 12, 825; J. Mol. Neurosci. 2005, 27, 137), effectively alleviating symptoms of depression. In an open-label, six-week clinical trial of uridine for the treatment of manic-depressive psychosis in adolescents, uridine was shown to alleviate depressive symptoms (J. Child and Adolescent Psychopharmacology. 2011, 21, 171). Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), currently has no effective drug treatment. Mouse studies showed that uridine administration significantly prolonged survival in G93A mice in a dose-dependent manner, while also improving behavioral and neuropathological phenotypes. Uridine increased the survival rate of G93A mice by 17.4%, improved weight loss, enhanced motor performance, reduced atrophy of the lumbar spine and ventral horn, alleviated neuronal cell death in the lumbar ventral horn, and reduced reactive astrogliosis. These data suggest that increasing uridine may be effective in treating ALS (Amyotrophic Lateral Sclerosis. 2010, 11, 520).

[0005] Supplementing uridine can repair cells and tissues, improve memory and cognitive function, and is beneficial for the treatment of Alzheimer's disease, the improvement of cognitive dysfunction and the treatment of depression. It may also have a certain effect on the treatment of ALS patients.

[0006] It is well known that uridine must be converted into uridine triphosphate (UTP) to exert its physiological effects. During this process, uridine is first converted into uridine monophosphate (UMP) under the catalysis of uridine-cytidine kinase (UCK) (Molecular Pharmacology, 59, 1181). UMP is converted into uridine diphosphate (UDP) under the catalysis of nucleoside monophosphate kinases (NMPs). UDP is then converted into uridine triphosphate (UTP) under the catalysis of nucleoside diphosphate kinases (NDPKs). UTP is converted into cytidine triphosphate (CTP) under the catalysis of cytidine triphosphate synthase. CTP is converted into the key active ingredient phosphatidylcholine (Phosphatidylcholine, Brain Research Reviews 2006, 52, 389) through a series of processes. Phosphatidylcholine can promote the repair and regeneration of cells or tissues, and promote the repair and regeneration of neurons and synapses. In this conversion process, the reaction of uridine to uridine monophosphate is not easy to proceed, and the monophosphorylation of uridine is the rate-limiting reaction.

[0007] The bioavailability of uridine in mice is only 7% (Cancer Chemother. Pharmacol. 1986, 17, 236). The oral bioavailability in humans is between 5.8% and 9.9% (J. National Cancer Institute. 1991, 83, 437). Uridine triacetate can significantly increase the bioavailability of uridine, increasing uridine levels in the circulation by 4-6 times (Hosp. Pharm. 2016, 51, 484). However, the absolute exposure to uridine monophosphate remains very low. Therefore, it is essential to develop a substance and method that can effectively and directly deliver uridine monophosphate to the body, especially the brain. Summary of the Invention

[0008] After extensive research, the inventors designed and synthesized uridine phosphate amine compounds, which significantly increase the exposure of uridine monophosphate in plasma and in the brain. This will improve the repair and regeneration of brain cells, brain tissue, cranial nerves, and synapses, and more effectively improve the treatment of uridine deficiency-related diseases, such as better delaying the progression of Alzheimer's disease, cognitive dysfunction, Alzheimer's disease, and Parkinson's disease, and better improve the symptoms of depression and the treatment of diseases such as amyotrophic lateral sclerosis (ALS).

[0009] In view of this, the present invention provides a pharmaceutical composition comprising one or more compounds of the following formula I or pharmaceutically acceptable salts thereof, or deuterated compounds thereof, and pharmaceutically acceptable excipients:

[0010] in,

[0011] R 1 and R 2 Independently selected from H, R 4 C(O)-、R 4 OC(O)- or R 4 NHC(O)-, or R 1 and R 2 Connected together to form -C(O)- or -C(S)-;

[0012] Optionally, R 1 and R 2 Each independently selected from H or R 4 C(O)-;

[0013] R 4 Selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, substituted or unsubstituted C 6-10 Aryl, or substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S;

[0014] Optionally, R 4 is selected from H, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, (CH3CH2)2-CH2-, tert-butylmethyl, 2-ethylbutyl, cyclopropyl, cyclopropyl-methyl, cyclopentyl, benzyl, phenyl, or naphthyl;

[0015] R 3 Selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl-C 1-6 Alkyl, 3-7 membered non-aromatic heterocyclic group containing 1-3 heteroatoms selected from N, O, S, substituted or unsubstituted C 6-10 Aryl, or substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S;

[0016] Optionally, R 3 is selected from H, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, (CH3CH2)2-CH2-, tert-butylmethyl, 2-ethylbutyl, cyclopropyl, cyclopropyl-methyl, cyclopentyl, benzyl, phenyl, or naphthyl;

[0017] R' is selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, substituted or unsubstituted C 6-10 Aryl, or substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S;

[0018] Alternatively, R' is selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, tert-butylmethyl, (2-ethyl)butyl, benzyl, or phenyl; Alternatively, R' is H;

[0019] R" and R"' are each independently selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, substituted or unsubstituted C 6-10 Aryl, or substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S;

[0020] Alternatively, R" and R'" are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, tert-butylmethyl, (2-ethyl)butyl, benzyl, or phenyl; Alternatively, R" and R'" are each independently selected from H, or methyl, ethyl, n-propyl, isopropyl, isopropylmethyl;

[0021] Ar is selected from substituted or unsubstituted C 6-10 Aryl, or a substituted or unsubstituted 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S, optionally, Ar is selected from phenyl or naphthyl;

[0022] The substituents in the substituted aryl and substituted heteroaryl are each independently selected from C 1-6 Alkyl, C 3-7 Cycloalkyl, halogen, halogenated C 1-6 Alkyl, CN, NHR', OR', SR', two adjacent substituents can form a 5-7 membered cycloalkyl or a 5-7 membered heterocycloalkyl containing N, O, or S; optionally, the substituents are each independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, phenyl, F, Cl, Br, I, CN, -NH2, -NHCH3, OMe, OEt, SMe, SEt or -CF3.

[0023] Optionally, in the pharmaceutical composition, the compound of formula I or its pharmaceutically acceptable salt, or its deuterated compound is a compound of formula II or its pharmaceutically acceptable salt, or its deuterated compound:

[0024] Among them, R', R", R'', R 3 and Ar are as defined above.

[0025] Optionally, in the pharmaceutical composition, the compound of formula I or its pharmaceutically acceptable salt, or its deuterated compound is a compound of the following formula III or the following formula III' or its pharmaceutically acceptable salt, or its deuterated compound:

[0026] Among them, R”, R1 、R 2 、R 3 and Ar are as defined above.

[0027] Optionally, in the pharmaceutical composition, the compound of formula I or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof is a compound of the following formula IV or the following formula IV' or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof:

[0028] Among them, R 3 and Ar are as defined above.

[0029] Optionally, in the pharmaceutical composition, the compound of formula I or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof is a compound of the following formula V or the following formula V' or the following formula V" or the following formula V'" or the following formula V'" or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof:

[0030] R”、R 1 、R 2 、R 3 and Ar are as defined above.

[0031] Optionally, in the pharmaceutical composition, the compound of formula I or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof is a compound of the following formula VI or the following formula VI' or the following formula VI" or the following formula VI'' or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof:

[0032] R 3 and Ar are as defined above.

[0033] Optionally, in the pharmaceutical composition, the compound of formula I or its pharmaceutically acceptable salt, or its deuterated compound, is selected from:

[0034] The compounds of formula I or pharmaceutically acceptable salts thereof, or deuterated compounds thereof described in the present invention include their tautomers, mesomers, racemates, enantiomers, diastereomers, or various mixtures thereof.

[0035] Optionally, the pharmaceutically acceptable salt is a salt formed by a compound of formula I and an acid, wherein the acid includes an inorganic acid or an organic acid; optionally, the inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or carbonic acid; optionally, the organic acid includes formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, phthalic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid.

[0036] The pharmaceutically acceptable salts can be prepared by conventional methods in the art.

[0037] The dosage form of the pharmaceutical composition is not limited, including but not limited to solid preparations or liquid preparations. The solid preparations include but are not limited to tablets, capsules, granular preparations, powder preparations or lyophilized preparations.

[0038] The pharmaceutical composition can be used to increase uridine monophosphate levels in the body (including increasing brain uridine monophosphate levels) or increase dopamine release. Alternatively, the pharmaceutical composition is used to treat neurodegenerative diseases, Alzheimer's disease, cognitive impairment, Parkinson's disease, depression, amyotrophic lateral sclerosis, or to slow the progression of these diseases.

[0039] On the other hand, the present invention also provides the use of the above-mentioned compound of formula I, or its pharmaceutically acceptable salt, or its deuterated compound, or the above-mentioned pharmaceutical composition in the preparation of a drug for increasing the level of uridine monophosphate in the body (including increasing the level of uridine monophosphate in the brain) or increasing dopamine release.

[0040] On the other hand, the present invention provides the use of the above-mentioned compound of formula I, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicament for treating neurodegenerative diseases, senile dementia, Alzheimer's disease, cognitive impairment, Parkinson's disease, depression, amyotrophic lateral sclerosis, or delaying the progression thereof.

[0041] On the other hand, the present invention also provides a method for increasing uridine monophosphate levels in the body (including increasing brain uridine monophosphate levels) or increasing dopamine release, comprising administering to a subject in need thereof an effective amount of the above-mentioned compound of Formula I, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or the above-mentioned pharmaceutical composition.

[0042] On the other hand, the present invention also provides a method for treating neurodegenerative diseases, senile dementia, Alzheimer's disease, cognitive impairment, Parkinson's disease, depression, amyotrophic lateral sclerosis, or delaying their progression, comprising administering to a subject in need thereof an effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or the pharmaceutical composition described above.

[0043] On the other hand, the present invention also provides the use of the above-mentioned compound of formula I, or its pharmaceutically acceptable salt, or its deuterated compound, or the above-mentioned pharmaceutical composition for increasing the level of uridine monophosphate in the body (including increasing the level of uridine monophosphate in the brain) or increasing dopamine release.

[0044] On the other hand, the present invention provides the use of the above-mentioned compound of formula I, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or the above-mentioned pharmaceutical composition for treating neurodegenerative diseases, senile dementia, Alzheimer's disease, cognitive impairment diseases, Parkinson's disease, depression, amyotrophic lateral sclerosis, or delaying the progression thereof.

[0045] On the other hand, the present invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or the pharmaceutical composition described above, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or the pharmaceutical composition described above is used to increase the level of uridine monophosphate in the body (including increasing the level of uridine monophosphate in the brain) or increase dopamine release.

[0046] On the other hand, the present invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or the above-mentioned pharmaceutical composition, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or the above-mentioned pharmaceutical composition is used to treat neurodegenerative diseases, senile dementia, Alzheimer's disease, cognitive impairment diseases, Parkinson's disease, depression, amyotrophic lateral sclerosis, or delay their progression.

[0047] The compound of formula I, or its pharmaceutically acceptable salt, or its deuterated compound, or the pharmaceutical composition can be used alone or in combination with other drugs, for example, in combination with DHA unsaturated fatty acids and / or in combination with choline or its analogs.

[0048] On the other hand, the present invention also provides the above-mentioned compound of formula I, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, which does not include the following compounds:

[0049] Alternatively, in the compound of formula I of the present invention, or its pharmaceutically acceptable salt, or its deuterated compound, when R 3 C 1-6 When alkyl, the C 1-6 Alkyl is selected from ethyl, n-propyl, n-butyl, isobutyl, (CH3CH2)2-CH2-, tert-butylmethyl, 2-ethylbutyl;

[0050] Alternatively, in the compound of formula I of the present invention, or its pharmaceutically acceptable salt, or its deuterated compound, when R 3is methyl, isopropyl, and Ar is substituted or unsubstituted C 6-10 When the C 6-10 Aryl is naphthyl; or, when R 3 When it is methyl or isopropyl, R 1 and R 2 R 4 C(O)-.

[0051] The present invention also provides a method for preparing the compound of formula I, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, which comprises the following reaction scheme:

[0052] The preparation of the compound of formula Ib comprises: dissolving compound Ia, compound 7 and magnesium chloride in a solvent (preferably tetrahydrofuran), adding N,N-diisopropylethylamine (DIPEA), reacting (preferably stirring the reaction at 50-60°C), quenching with water (preferably at 0°C), extracting with ethyl acetate (EA), washing the organic layer with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating to remove the solvent, and purifying by silica gel column chromatography to obtain the compound of formula Ib.

[0053] The preparation of the compound of formula II comprises: dissolving compound Ib in a solvent (preferably methanol), adding water, adding trifluoroacetic acid (TFA) dropwise (preferably at 0°C), warming to room temperature for reaction, concentrating to remove the solvent, and purifying by silica gel column chromatography to obtain the compound of formula II.

[0054] In the compound of formula I, R 1 and R 2 When Ac is present, the preparation steps include: dissolving the compound of formula II in a solvent (preferably tetrahydrofuran), adding triethylamine and acetic anhydride, and reacting at room temperature. The mixture is quenched with water (preferably at 0°C), extracted with ethyl acetate (EA), and the EA layer is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and purified by silica gel column chromatography to obtain the compound of formula I. DETAILED DESCRIPTION

[0055] The following is a detailed description of the specific embodiments of the present invention. It should be understood that the specific embodiments described herein are only used to illustrate the present invention and are not intended to limit the present invention.

[0056] Similar methods can be used to prepare other derivatives of the present invention.

[0057] Preparation of compounds

[0058] Preparation Example 1 Preparation of Compound I-1a:

[0059] Compound 3

[0060] Compound 1 (25.0 g, 290.3 mmol), compound 2 (65.9 g, 348.3 mmol), EDCI (72.3 g, 377.3 mmol), and DMAP (53.2 g, 435.4 mmol) were dissolved in acetonitrile (500 mL). The mixture was stirred at room temperature for 16 h. After concentration to remove the solvent, the residue was dissolved in ethyl acetate (EA), washed once with 1 M hydrochloric acid, saturated sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and dried in vacuo to obtain compound 3 (74.7 g, 99%).

[0061] Compound 4

[0062] Compound 3 (74.7 g, 290.3 mmol) was dissolved in dichloromethane (200 mL), 4M HCl in Dioxane (363 mL, 1451 mmol) was added, and the mixture was stirred at room temperature for 2 h. The solvent was removed by concentration and vacuum drying to obtain compound 4 (56.2 g), which was used directly in the next step without purification.

[0063] Compound 5

[0064] Compound 4 (56.2 g, 290.3 mmol) and phenyl dichlorophosphate (61.2 g, 290.3 mmol) were dissolved in dichloromethane (500 mL). A solution of triethylamine (638.7 mmol, 64.5 g) in dichloromethane (50 mL) was added dropwise to the reaction mixture at 0°C and stirred for one hour. p-Nitrophenol (40.4 g, 290.3 mmol) was then added, followed by a solution of triethylamine (319.3 mmol, 32.3 g) in dichloromethane (50 mL) at 0°C. The mixture was warmed to room temperature and stirred for two hours. Methyl tert-butyl ether (500 mL) was added, and the solid was removed by filtration. The filtrate was washed twice with 10% sodium hydroxide solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to remove the solvent. Purification by silica gel column chromatography afforded a yellow oil (80 g). Chiral separation (SFC) afforded the S-configured compound 5 (15 g).

[0065] 1 H NMR (400MHz, MeOD) δ8.18(d,J=9.0Hz,2H),7.38(d,J=9.0Hz,2H),7.28(t,J=8.0Hz,2H),7.16-7.11(m ,3H),5.01-4.98(m,1H),3.94-3.86(m,1H),1.76-1.45(m,8H),1.22(d,J=7.0Hz,3H); m / z(ESI)[M+H] + =435.

[0066] Compound 7

[0067] Compound 6 (100 g, 409.5 mmol), 2,2-dimethoxypropane (47 g, 450.5 mmol), and p-toluenesulfonic acid monohydrate (7.8 g, 41.0 mmol) were dissolved in acetone (500 mL) and refluxed under nitrogen for 3 h. The mixture was cooled to room temperature and concentrated to remove the solvent. Aqueous sodium bicarbonate solution was added with stirring, filtered, washed with water, and the filter cake was dried to obtain a white solid 7 (98 g, 84%).

[0068] 1 H NMR (400MHz, DMSO) δ11.39(s,1H),7.80(d,J=8.1Hz,1H),5.84(d,J=2.7Hz,1H),5.64(d,J=8.0Hz,1H),5.09(t,J=5.1Hz,1H),4.90(d d,J=6.4,2.7Hz,1H),4.75(dd,J=6.4,3.6Hz,1H),4.07(q,J=4.4Hz,1H),3.81–3.50(m,2H),1.49(s,3H),1.29(s,3H).m / z(ESI)[MH] - =283.1.

[0069] Compound 8

[0070] Compound 5 (9.0 g, 20.7 mmol), 7 (7.1 g, 24.9 mmol) and magnesium chloride (3.0 g, 31.1 mmol) were dissolved in tetrahydrofuran (200 mL), and DIPEA (8.6 mL, 51.8 mmol) was added. The reaction was stirred at 50 ° C for 16 h, quenched by adding water at 0 ° C, and extracted with EA. The EA layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and purified by silica gel column chromatography to obtain white solid compound 8 (4.0 g, 33%).

[0071] 1 H NMR(400MHz, CDCl3)δ8.71(br s,1H),7.33-7.30(m,3H),7.21-7.14(m,3H),5.72(s,1H),5.66(d,J=8.0Hz,1H),5.19(s,1H),4.88(s, 2H),4.37-4.28(m,3H),4.00-3.82(m,2H),1.87-1.60(m,8H),1.57(s,3H),1.35(s,6H); m / z(ESI)[M+H] +=580.

[0072] Compound I-1a

[0073] Compound 8 (4.2 g, 7.2 mmol) was dissolved in methanol (8 mL), and water (10 mL) was added. Trifluoroacetic acid (TFA, 10 mL) was added at 0°C and allowed to react at room temperature for 16 h. The solvent was removed by concentration, and toluene was co-evaporated twice. The product was purified by silica gel column chromatography to afford compound I-1a (1.4 g, 36%) as a white foamy solid.

[0074] 1 HNMR(400MHz,DMSO)δ11.36(s,1H),7.58(d,J=8.1Hz,1H),7.38(t,J=8.0Hz,2H ),7.23-7.17(m,3H),6.05(dd,J=10.3,12.9Hz,1H),5.76(d,J=5.4Hz,1H),5.5 3(dd,J=2.2,8.0Hz,1H),5.06-5.01(m,1H),4.22-4.17(m,1H),4.13-3.95(m,4 H),3.84-3.74(m,1H),1.81-1.49(m,8H),1.22(d,J=7.0Hz,3H); m / z(ESI)[M+H] + =540.

[0075] Preparation Example 2 Preparation of Compound I-2a:

[0076] Compound 11

[0077] Compound 10 (25 g, 283.61 mmol), compound 2 (64.4 g, 340.33 mmol), EDCI (70.7 g, 368.69 mmol), and DMAP (52 g, 425.42 mmol) were dissolved in acetonitrile (500 mL) and reacted at room temperature for 16 h under nitrogen protection. The acetonitrile was removed by concentration, and EA (500 mL) was added. The mixture was washed with 1N HCl solution, saturated sodium bicarbonate aqueous solution, and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a colorless viscous oil 11 (73.5 g), which was used directly in the next step without purification.

[0078] 1H NMR (400MHz, CDCl3) δ5.04(s,1H),4.41–4.27(m,1H),3.88(d,J=10.5Hz,1H),3.77(d,J=10.5Hz,1H),1.44(s,9H),1.39(d,J=7.2Hz,3H),0.93(s,9H).

[0079] Compound 12

[0080] Compound 11 (73.5 g, 283.61 mmol) was dissolved in DCM (200 mL), and 4N HCl in Dioxane (355 mL) was added. The mixture was reacted at room temperature for 5 h under nitrogen protection. The solvent was removed by concentration, and ether was added with stirring. The mixture was filtered and dried in vacuo to obtain Compound 12 (48.43 g, 87.5%) as a white solid.

[0081] 1 H NMR (400MHz, DMSO) δ8.62 (s, 3H), 4.10 (s, 1H), 3.94 (d, J = 10.4Hz, 1H), 3.81 (d, J = 10.4Hz, 1H), 1.46 (d, J = 7.2Hz, 3H), 0.93 (s, 9H).

[0082] Compound 13

[0083] Compound 12 (48.43 g, 247.48 mmol) and phenyl dichlorophosphate (52.2 g, 247.48 mmol) were dissolved in DCM (500 mL). Under nitrogen protection, a solution of triethylamine (75.7 mL, 544.46 mmol) in DCM (100 mL) was added dropwise to the reaction system at 0°C. The reaction was carried out at 0°C for 1 h, and then p-nitrophenol (34.4 g, 247.48 mmol) was added. A solution of triethylamine (37.8 mL, 272.23 mmol) in DCM (50 mL) was added dropwise to the reaction system at 0°C. After the addition was complete, the temperature was raised to room temperature and the reaction was carried out for 2 h. MTBE (500 mL) was added and filtered. The filtrate was concentrated, and MTBE (500 mL) was added. The filtrate was filtered and concentrated to remove the solvent. The product was purified by silica gel column chromatography. The obtained product was separated by chiral separation (FSC) to obtain the (S)-configuration product 13 (15 g).

[0084] 1HNMR(400MHz,MeOD)δ8.32–8.23(m,2H),7.52–7.44(m,2H),7.42–7.34(m,2H),7.24(ddd,J=12.6,5.8,1 .0Hz,3H),4.10(dq,J=9.8,7.2Hz,1H),3.78(q,J=10.5Hz,2H),1.35(dd,J=7.2,1.0Hz,3H),0.92(s,9H). 31 P NMR(162MHz,MeOD)δ-1.49.m / z(ESI)[M+H] + =437.1.

[0085] Compound 14

[0086] Compound 13 (10 g, 22.91 mmol), compound 7 (7.8 g, 27.49 mmol), anhydrous magnesium chloride (3.3 g, 34.37 mmol), and DIPEA (10.2 mL, 57.28 mmol) were dissolved in THF (70 mL). The mixture was reacted at 60°C for 16 h under nitrogen protection. The mixture was cooled to room temperature, EA was added, and the mixture was extracted with water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to remove the solvent. The mixture was purified by silica gel column chromatography to obtain a foamy solid 14 (12.4 g, 91%).

[0087] 1 H NMR(400MHz, CDCl3)δ8.16(s,1H),7.35–7.28(m,3H),7.24–7.10(m,3H),5. 72(s,1H),5.66(dd,J=8.1,2.1Hz,1H),4.85(s,2H),4.43–4.23(m,3H),4.0 4(dd,J=15.4,8.1Hz,1H),3.88(d,J=10.4Hz,1H),3.76(t,J=8.6Hz,2H),1. 56(s,3H),1.41(d,J=7.0Hz,3H),1.35(s,3H),0.93(s,9H).m / z(ESI)[M+H] + =582.2.

[0088] Compound I-2a

[0089] Compound 14 (12.4 g, 21.0 mmol) was dissolved in MeOH (15 mL), and water (20 mL) was added. TFA (20 mL) was added dropwise at 0°C. After the addition was complete, the temperature was raised to room temperature and reacted for 5 h. The solvent was removed and concentrated, and the mixture was purified by silica gel column chromatography to obtain a white foamy solid I-2a (6.4 g, 59%).

[0090] 1 H NMR (400MHz, DMSO) δ11.38(d,J=1.8Hz,1H),7.59(d,J=8.1Hz,1H),7.38(t,J=7.9Hz,2H ),7.26–4.15(m,3H),6.11(dd,J=12.8,10.2Hz,1H),5.78(d,J=5.4Hz,1H),5.53(dd,J=8 .1,2.1Hz,1H),4.26–4.15(m,1H),4.15–4.07(m,1H),4.05–3.95(m,3H),3.95–3.86(m, 1H), 3.80 (d, J = 10.4Hz, 1H), 3.69 (d, J = 10.4Hz, 1H), 1.28 (d, J = 7.1Hz, 3H), 0.89 (s, 9H). 31 PNMR(162MHz,DMSO)δ3.82.m / z(ESI)[M+H] + =542.2.

[0091] Preparation Example 3 Preparation of Compound I-9a:

[0092] Compound 18

[0093] Compound 16 (40.0 g, 238.6 mmol) and phenyl dichlorophosphate (50.3 g, 238.6 mmol) were dissolved in dichloromethane (350 mL). A solution of triethylamine (53.0 g, 524.9 mmol) in dichloromethane (100 mL) was added dropwise to the reaction mixture at 0°C and stirred for one hour. Compound 17 (43.9 g, 238.6 mmol) was then added dropwise to the reaction mixture. A solution of triethylamine (26.5 g, 262.45 mmol) in dichloromethane (50 mL) was then added dropwise to the reaction mixture at 0°C. The mixture was warmed to room temperature and stirred for two hours. Water (100 mL) was added, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and recrystallized from isopropyl ether and n-hexane to obtain white S-configuration compound 18 (18.8 g).

[0094] 1H NMR(400MHz, CDCl3)δ7.38(t,J=8.0Hz,2H),7.28-7.21(m,3H),5.11-5.01(m,1H) ,4.22-4.01(m,2H),1.47(d,J=7.0Hz,3H),1.27(t,J=5.9Hz,6H); m / z(ESI)[M+H] + =554.

[0095] Compound 19

[0096] Compound 18 (18.8 g, 41.6 mmol), compound 7 (14.2 g, 49.9 mmol) and magnesium chloride (5.94 g, 62.3 mmol) were dissolved in tetrahydrofuran (300 mL), and finally DIPEA (17.2 mL, 103.9 mmol) was added. The reaction was stirred at 50 ° C for 16 h, quenched by adding water at 0 ° C, and extracted with EA. The EA layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to remove the solvent. After purification by silica gel column chromatography, compound 19 (14.5 g, 63%) was obtained as a white solid.

[0097] 1 H NMR (400MHz, CDCl3) δ7.33(t,J=8.0Hz,3H),7.22-7.15(m,3H),5.71(d,J=2.2Hz,1H),5.69(d,J=8.0Hz,1H),5.06-4.97(m,1H),4.91 -4.85(m,2H),4.40-4.28(m,3H),4.08-3.90(m,2H),1.58(s,3H),1.36(d,J=8.0Hz,6H),1.24(dd,J=2.0,6.2Hz,6H); m / z(ESI)[M+H] + =454.

[0098] Compound I-9a

[0099] Compound 19 (14.5 g, 26.3 mmol) was dissolved in methanol (24 mL), and water (30 mL) was added. Trifluoroacetic acid (30 mL) was added at 0°C and allowed to react at room temperature for 16 h. The solvent was concentrated and toluene was co-evaporated twice. The product was purified by silica gel column chromatography to obtain compound I-9a (5.2 g, 39%) as a white foamy solid.

[0100] 1HNMR (400MHz, DMSO) δ11.38 (s, 1H), 7.58 (d, J = 8.1Hz, 1H), 7.38 (t, J = 8.0Hz, 2H), 7.24-7.16 (m, 3H), 6.06 (t, J = 11.6Hz, 1H), 5.76 (d, J = 5. 4Hz,1H),5.53(dd,J=2.2,8.0Hz,1H),4.91-4.82(m,1H),4.23-3.77(m,5H),1.23(d,J=7.0Hz,3H),1.16(d,J=6.2Hz,6H); m / z(ESI)[M+H] + =514.

[0101] Preparation Example 4 Preparation of Compound I-24a:

[0102] Compound 20 (513 mg, 1.0 mmol) was dissolved in tetrahydrofuran (5 mL), and triethylamine (505 mg, 5 mmol) and acetic anhydride (510 mg, 5 mmol) were added. The mixture was allowed to react at room temperature for 16 h. The mixture was quenched with water at 0°C and extracted with EA. The EA layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to remove the solvent. The mixture was purified by silica gel column chromatography to afford compound I-24a (595 mg, 99%) as a white foamy solid.

[0103] 1 H NMR (400MHz, CDCl3) δ8.64 (s, 1H), 7.38-7.34 (m, 3H), 7.28-7.19 (m, 3H), 6.14 (d, J = 6.8Hz, 1H),5.56(dd,J=2.2,8.0Hz,1H),5.44(dd,J=3.2,5.8Hz,1H),5.18(t,J=6.2Hz,1H),5.10- 5.00(m,1H),4.44-4.29(m,3H),4.07-3.97(m,1H),3.84(t,J=10.5Hz,1H),2.16(s,1H),2. 10(s,1H),1.67(s,2H),1.42(d,J=7.0Hz,3H),1.26(dd,J=3.4,6.2Hz,6H); m / z(ESI)[M+H] + =598.

[0104] Preparation Example 5 Preparation of D-amino acid compound I-31a and other derivatives:

[0105] The D-amino acid compound I-31a was prepared from the D-amino acid intermediate using the method for preparing compound I-9a. m / z (ESI) [M+H]+ = 514. Different D-amino acid derivatives were prepared using different D-amino acid intermediates.

[0106] Preparation Example 6 Preparation of deuterated uridine compound I-32a and other derivatives:

[0107] The method for preparing compound I-9a was applied to prepare deuterated uridine compound I-32a using deuterated uridine as raw material, m / z (ESI) [M+H] + = 516. Different deuterated uridine derivatives were prepared using different amino acid intermediates.

[0108] Preparation Example 7 Preparation of 5'-deuterated uridine compound I-33a and other derivatives:

[0109] The method for preparing compound I-9a was used to prepare 5'-deuterated uridine compound I-33a, m / z (ESI) [M+H] + = 516. Different 5'-deuterated uridine derivatives were prepared using different amino acid intermediates.

[0110] Using similar methods as above, the following compounds were prepared:

[0111] Animal testing

[0112] Example 1 Testing the Content of Uridine and Uridine Monophosphate (UMP) in Plasma and Brain of Mice

[0113] The test method is as follows:

[0114] 1. Test sample preparation: Accurately weigh an appropriate amount of the test compound (see Table 1 below) and mix with an appropriate volume of solvent (5% DMSO / 10% solutol / 85% (0.5% sodium carboxymethyl cellulose) to obtain a clear solution or uniform suspension.

[0115] 2. Administration: The animals will be administered within 4 hours after preparation of the formulation. The formulation will be administered via oral gavage according to standard operating procedures (SOP). Mice will be given vehicle or test article (test compound dose 1 mmol / kg mouse body weight).

[0116] 3. Blood collection: Blood was collected from the jugular vein of each animal at each time point (approximately 0.2 ml at each time point). All blood samples were transferred to pre-cooled commercial EDTA-K2 tubes and placed on wet ice.

[0117] 4. Plasma processing: Blood samples were centrifuged at approximately 4°C (3200 rpm, 10 minutes). Plasma was collected separately and transferred to pre-labeled PP tubes on wet ice, then immediately precipitated with acetonitrile (ACN) (6IS) (plasma:ACN ratio of 1:4). Centrifuged again (10 minutes, 12,000 rpm) and the supernatant was obtained. It was quickly frozen on dry ice and kept at -70 ± 10°C until LC / MS / MS analysis.

[0118] 5. Brain Tissue Processing: Brain tissue was collected at each time point, washed twice with pre-chilled deionized water, and dried using filter paper. Immediately homogenize the brain tissue with 10 volumes of a methanol-water solution (1:2, v / v). Immediately remove an appropriate amount of the homogenate (e.g., 200 μL), pellet the sample on wet ice, centrifuge, and collect the supernatant. Store at -70 ± 10°C until LC-MS / MS analysis.

[0119] Mice were gavaged with either vehicle (5% DMSO / 10% solutol / 85% (0.5% sodium carboxymethyl cellulose)) or the test article (all at a dose of 1 mmol / kg). Brain tissue samples were obtained at 0, 0.5, 1, 2, 4, 6, 8, and 12 h. The concentrations of uridine and uridylic acid in brain tissue were determined by LC-MS / MS as described above.

[0120] The results are shown in Tables 1 and 2 respectively.

[0121] Table 1. Contents of uridine and uridine monophosphate in plasma after oral administration of vehicle or test sample

[0122] The test results in Table 1 show that the AUC of uridine in the vehicle group is 315 times that of uridine monophosphate, indicating that uridine cannot be effectively phosphated into active uridine monophosphate. Although the use of uridine triethyl ester can increase the content of uridine in the body to a certain extent, the amount of uridine monophosphate increased is limited, only 1.52 times that of the vehicle group. However, the Formula I compound of the present invention increases the exposure of uridine monophosphate in plasma by more than 6.9 times that of the vehicle group. Therefore, the Formula I compound of the present invention is a better uridine monophosphate supplement and can better play the role of supplementing uridine monophosphate.

[0123] Table 2. Uracillin content in the brain of mice after oral administration of vehicle or test sample

[0124] The test results in Table 2 show that the compound of formula I of the present invention significantly increases the exposure of uridine monophosphate in the mouse brain, which also proves that the compound of formula I provided by the present invention is a better uridine monophosphate supplement.

[0125] The above description is merely an exemplary embodiment of the present invention and is not intended to limit the scope of the present invention. Equivalent changes, modifications, and combinations made by those skilled in the art without departing from the concept and principle of the present invention, including any deuterated compounds, should all fall within the scope of the present invention.

Claims

1. A pharmaceutical composition comprising one or more compounds of the following formula I or pharmaceutically acceptable salts thereof, or deuterated compounds thereof, and pharmaceutically acceptable excipients: in, R 1 and R 2 Independently selected from H, R 4 C(O)-、R 4 OC(O)- or R 4 NHC(O)-, or R 1 and R 2 Connected together to form -C(O)- or -C(S)-; Optionally, R 1 and R 2 Each independently selected from H or R 4 C(O)-; R 4 Selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, substituted or unsubstituted C 6-10 Aryl, or substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S; Optionally, R 4 is selected from H, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, (CH3CH2)2-CH2-, tert-butylmethyl, 2-ethylbutyl, cyclopropyl, cyclopropyl-methyl, cyclopentyl, benzyl, phenyl, or naphthyl; R 3 Selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl-C 1-6 Alkyl, 3-7 membered non-aromatic heterocyclic group containing 1-3 heteroatoms selected from N, O, S, substituted or unsubstituted C 6-10 Aryl, or substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S; Optionally, R 3 is selected from H, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, (CH3CH2)2-CH2-, tert-butylmethyl, 2-ethylbutyl, cyclopropyl, cyclopropyl-methyl, cyclopentyl, benzyl, phenyl, or naphthyl; R' is selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, substituted or unsubstituted C 6-10 Aryl, or substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S; Alternatively, R' is selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, tert-butylmethyl, (2-ethyl)butyl, benzyl, or phenyl; Alternatively, R' is H; R" and R"' are each independently selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, substituted or unsubstituted C 6-10 Aryl, or substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S; Alternatively, R" and R'" are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, tert-butylmethyl, (2-ethyl)butyl, benzyl, or phenyl; Alternatively, R" and R'" are each independently selected from H, or methyl, ethyl, n-propyl, isopropyl, isopropylmethyl; Alternatively, R" is selected from methyl, isopropyl, or isopropylmethyl; Ar is selected from substituted or unsubstituted C 6-10 Aryl, or a substituted or unsubstituted 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S, optionally, Ar is selected from phenyl or naphthyl; The substituents in the substituted aryl and substituted heteroaryl are each independently selected from C 1-6 Alkyl, C 3-7 Cycloalkyl, halogen, halogenated C 1-6 Alkyl, CN, NHR', OR', SR', two adjacent substituents can form a 5-7 membered cycloalkyl or a 5-7 membered heterocyclic group containing N, O, or S; optionally, the substituents are each independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, phenyl, F, Cl, Br, I, CN, -NH2, -NHCH3, OMe, OEt, SMe, SEt or -CF3.

2. The pharmaceutical composition according to claim 1, characterized in that The compound of formula I or its pharmaceutically acceptable salt, or its deuterated compound is a compound of formula II or its pharmaceutically acceptable salt, or its deuterated compound: Among them, R', R", R'', R 3 and Ar is as defined in claim 1; Optionally, the compound of formula I or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof is a compound of formula III or III' or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof: Among them, R”, R 1 、R 2 、R 3 and Ar is as defined in claim 1; Optionally, the compound of formula I or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof is a compound of formula IV or IV' or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof: Among them, R 3 and Ar is as defined in claim 1; Optionally, the compound of formula I or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof is a compound of the following formula V or the following formula V' or the following formula V" or the following formula V'" or the following formula V'" or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof: Among them, R”, R 1 、R 2 、R 3 and Ar is as defined in claim 1; Optionally, the compound of formula I or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof is a compound of formula VI or formula VI' or formula VI" or formula VI'' or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof: R 3 and Ar are as defined in claim 1.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that The compound of formula I or its pharmaceutically acceptable salt, or its deuterated compound, is selected from:

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The pharmaceutically acceptable salt is a salt formed by a compound of formula I and an acid, wherein the acid includes an inorganic acid or an organic acid; optionally, the inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or carbonic acid; optionally, the organic acid includes formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, phthalic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid; Optionally, the dosage form of the pharmaceutical composition includes a solid preparation or a liquid preparation, and the solid preparation includes a tablet, a capsule, a granule preparation, a powder preparation or a lyophilized preparation.

5. Use of the pharmaceutical composition according to any one of claims 1 to 4 or the compound of formula I according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof in the preparation of a medicament for increasing uridine monophosphate levels in the body (including increasing brain uridine monophosphate levels) or increasing dopamine release.

6. Use of the pharmaceutical composition according to any one of claims 1 to 4 or the compound of formula I according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof in the preparation of a medicament for treating neurodegenerative diseases, senile dementia, Alzheimer's disease, cognitive impairment, Parkinson's disease, depression, amyotrophic lateral sclerosis, or delaying the progression thereof.

7. A compound of formula I, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, in, R 1 and R 2 Independently selected from H, R 4 C(O)-、R 4 OC(O)- or R 4 NHC(O)-, or R 1 and R 2 Connected together to form -C(O)- or -C(S)-; Optionally, R 1 and R 2 Each independently selected from H or R 4 C(O)-; R 4 Selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, substituted or unsubstituted C 6-10 Aryl, or substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S; Optionally, R 4 is selected from H, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, (CH3CH2)2-CH2-, tert-butylmethyl, 2-ethylbutyl, cyclopropyl, cyclopropyl-methyl, cyclopentyl, benzyl, phenyl, or naphthyl; R 3 Selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl-C 1-6 Alkyl, 3-7 membered non-aromatic heterocyclic group containing 1-3 heteroatoms selected from N, O, S, substituted or unsubstituted C 6-10 Aryl, or substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S; Optionally, R 3 is selected from H, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, (CH3CH2)2-CH2-, tert-butylmethyl, 2-ethylbutyl, cyclopropyl, cyclopropyl-methyl, cyclopentyl, benzyl, phenyl, or naphthyl; R' is selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, substituted or unsubstituted C 6-10 Aryl, or substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S; Alternatively, R' is selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, tert-butylmethyl, (2-ethyl)butyl, benzyl, or phenyl; Alternatively, R' is H; R" and R"' are each independently selected from H, C 1-6 Alkyl, C 3-7 Cycloalkyl, substituted or unsubstituted C 6-10 Aryl, or substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S; Alternatively, R" and R'" are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, tert-butylmethyl, (2-ethyl)butyl, benzyl, or phenyl; Alternatively, R" and R'" are each independently selected from H, or methyl, ethyl, n-propyl, isopropyl, isopropylmethyl; Alternatively, R" is selected from methyl, isopropyl, or isopropylmethyl; Ar is selected from substituted or unsubstituted C 6-10 Aryl, or a substituted or unsubstituted 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, and S, optionally, Ar is selected from phenyl or naphthyl; The substituents in the substituted aryl and substituted heteroaryl are each independently selected from C 1-6 Alkyl, C 3-7 Cycloalkyl, halogen, halogenated C 1-6 Alkyl, CN, NHR', OR', SR', two adjacent substituents can form a 5-7 membered cycloalkyl or a 5-7 membered heterocycloalkyl containing N, O, or S; alternatively, the substituents are each independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, phenyl, F, Cl, Br, I, CN, -NH2, -NHCH3, OMe, OEt, SMe, SEt or -CF3; The following compounds are not included:

8. The compound of formula I or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof according to claim 7, characterized in that: When R 3 C 1-6 When alkyl, the C 1-6 Alkyl is selected from ethyl, n-propyl, n-butyl, isobutyl, (CH3CH2)2-CH2-, tert-butylmethyl, 2-ethylbutyl; Optionally, when R 3 is methyl, isopropyl, and Ar is substituted or unsubstituted C 6-10 When the C 6-10 Aryl is naphthyl; or, when R 3 When it is methyl or isopropyl, R 1 and R 2 R 4 C(O)-.

9. The compound of formula I according to claim 7 or 8, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, characterized in that: It is a compound of the following formula II or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof: Among them, R', R", R'', R 3 and Ar is as defined in claim 7 or 8; Optionally, the compound of formula I or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof is a compound of formula III or III' or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof: Among them, R”, R 1 、R 2 、R 3 and Ar is as defined in claim 7 or 8; Optionally, the compound of formula I or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof is a compound of formula IV or IV' or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof: Among them, R 3 and Ar is as defined in claim 7 or 8; Optionally, the compound of formula I or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof is a compound of the following formula V or the following formula V' or the following formula V" or the following formula V'" or the following formula V'" or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof: Among them, R”, R 1 、R 2 、R 3 and Ar is as defined in claim 7 or 8; Optionally, the compound of formula I or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof is a compound of formula VI or formula VI' or formula VI" or formula VI'' or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof: R 3 and Ar are as defined in claim 7 or 8.

10. The following compound of formula I or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof:

11. The compound of formula I according to any one of claims 7 to 10, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, characterized in that: The pharmaceutically acceptable salt is a salt formed by a compound of formula I and an acid, wherein the acid includes an inorganic acid or an organic acid; optionally, the inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or carbonic acid; optionally, the organic acid includes formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, phthalic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid.

12. A method for preparing a compound of formula I according to any one of claims 7 to 11, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, comprising the following reaction scheme: The preparation of the compound of formula Ib comprises: Compound Ia, compound 7 and magnesium chloride are dissolved in a solvent (preferably tetrahydrofuran), N,N-diisopropylethylamine (DIPEA) is added, and the reaction is carried out (preferably with stirring at 50-60°C), quenched with water (preferably at 0°C), extracted with ethyl acetate (EA), and the organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and purified by silica gel column chromatography to obtain a compound of formula Ib; The preparation of the compound of formula II comprises: dissolving compound Ib in a solvent (preferably methanol), adding water, adding trifluoroacetic acid (TFA) dropwise (preferably at 0° C.), warming to room temperature for reaction, concentrating to remove the solvent, and purifying by silica gel column chromatography to obtain the compound of formula II; In the compound of formula I, R 1 and R 2 When it is Ac, the preparation steps include: dissolving the compound of formula II in a solvent (preferably tetrahydrofuran), adding triethylamine and acetic anhydride, reacting at room temperature, quenching with water (preferably at 0°C), extracting with ethyl acetate (EA), washing the EA layer with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating to remove the solvent, and purifying by silica gel column chromatography to obtain the compound of formula I.

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