Melatonin receptor stimulant as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a melatonin receptor stimulant as well as a preparation method and application thereof. The compound shown in the formula I has obvious agonistic activity on the melatonin receptor, can be used as a melatonin receptor agonist, is used for preventing and / or treating various neurodegenerative diseases mediated by the melatonin receptor, and has a wide application prospect. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a melatonin receptor agonist, a preparation method thereof, and uses thereof. Background Art

[0002] Melatonin, also known as N-acetyl-5-methoxytryptamine, is an indoleamine neurohormone that exists ubiquitously in living organisms and is mainly secreted by the pineal gland in the human body. It regulates various important physiological functions such as circadian rhythm, sleep, endocrine, immunity, and anti-aging.

[0003] Melatonin is an endogenous agonist of two G protein-coupled receptors (MT1 and MT2), showing high affinity at nanomolar concentrations. Another binding site with lower affinity, MT3, has been identified as quinone reductase 2. MT1 and MT2 receptors produce biological effects through a series of cascade signal transduction actions such as regulating intracellular calcium levels, nitric oxide (NO) release, and cyclic guanosine monophosphate (cGMP) levels, and simultaneously coupling the MEK / ERK signal transduction pathway [2]. In the central nervous system, the functional distinction between MT1 and MT2 receptors has only been partially elucidated. Activation of the MT1 receptor can inhibit the firing of neurons in the suprachiasmatic nucleus (SCN) and promote cardiovascular constriction; while activation of the MT2 receptor can regulate the circadian rhythm and dilate coronary artery blood vessels; the exact biological relationship between the MT3 binding site and melatonin remains unclear, but it has been proven to be involved in the acute inflammatory response in rats and the regulation of intraocular pressure in rabbits.

[0004] Although MT1 and MT2 in the human body are highly homologous, there are significant differences in their distribution and signal pathways in the human body. The physiological functions of MT1 and MT2 also show significant differences: MT1 mainly plays a regulatory role during the rapid eye movement (REM) phase of sleep, while MT2 is mainly responsible for increasing non-REM sleep. However, currently available melatonin drugs on the market lack selectivity between MT1 and MT2 and cannot achieve precise treatment of related diseases. MT1 receptor subtype mRNA expression exists in human peripheral blood granulocytes, while MT2 receptor subtype mRNA expression does not. Therefore, MT subtype-selective drugs contribute to the precise treatment of diseases, improve treatment targeting, reduce drug adverse reactions, and improve drug safety.

[0005] Neurodegenerative diseases (degenerative diseases of the central nervous system, neurodegenerative disease, ND) are a disease state in which neurons in the brain and spinal cord are lost. The brain and spinal cord are composed of neurons. Neurodegenerative diseases are caused by the loss of neurons or their myelin sheaths, and deteriorate over time, leading to dysfunction. Such diseases mainly include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and neuronal degeneration caused by cerebral ischemia and hypoxia, etc.

[0006] Multiple studies have shown that compared with their peers, the melatonin level in the cerebrospinal fluid (CSF) of Alzheimer's disease patients decreases. After Parkinson's syndrome patients are given levodopa (L-Dopa), the peak time of the nocturnal melatonin level is advanced, and at the same time, the melatonin level in the daytime serum increases. This finding suggests that the neuroprotective effect of melatonin may be closely related to the disease progression process. The occurrence of Huntington's Disease (HD) is most closely related to mitochondria. Melatonin can prevent lipid peroxidation in rat brain tissue and also prevent the death of nerve cells in the hippocampal region.

[0007] The pathogenesis of neurodegenerative diseases is complex, involving multiple pathological processes such as inflammation, oxidative stress, and neuronal damage. Currently, there is no effective treatment for neurodegenerative diseases, and the lesions are irreversible. Only the disease progression can be delayed through symptom relief or disease management. Moreover, the early symptoms of some neurodegenerative diseases are not obvious, which is likely to lead to missed treatment opportunities. Therefore, finding melatonin receptor agonists is of great significance for the treatment of neurodegenerative diseases. Summary of the Invention

[0008] In view of the problems of the prior art, the present invention provides a melatonin receptor agonist, its preparation method, and its use.

[0009] A compound represented by Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystal form thereof:

[0010]

[0011] Wherein, R 1 is selected from hydrogen, halogen;

[0012] Ring A is selected from 3- to 10-membered heteroalkyl, 3- to 10-membered heteroaryl;

[0013] L 1 selected from substituted or unsubstituted C 1 -C 5 alkylene, wherein the substituent is selected from halogen, hydroxy, C 1 -C 10 alkyl, cyano, amino, C 3 -C 10 cycloalkyl;

[0014] L 2 selected from amide bond;

[0015] L 3 selected from C 1 -C 5 alkyl, C 3 -C 10 cycloalkyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl;

[0016] R 2 selected from hydrogen, substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, wherein the substituent is selected from halogen, hydroxy, cyano, amino, C 3 -C 10 cycloalkyl.

[0017] Preferably, the compound of formula I has the structure as described in formula II below:

[0018]

[0019] wherein, R 1 is selected from hydrogen, halogen;

[0020] L 3 is selected from C 1 ~C 5 alkyl, C 3 ~C 10 cycloalkyl.

[0021] Preferably, the R 1 is selected from hydrogen, fluorine; L 3 is selected from C 2 alkyl, C 3 cycloalkyl. Preferably, the L 3 is selected from C 2 alkyl.

[0022] Preferably, the compound of formula I has the structure as described in formula III below:

[0023]

[0024] Among them, R 1 is selected from hydrogen, halogen;

[0025] L 3 is selected from C 1 ~C 5 alkyl.

[0026] Preferably, the R 1 is selected from hydrogen, fluorine; L 3 is selected from C 3 alkyl.

[0027] Preferably, the R 1 is selected from fluorine.

[0028] Preferably, the compound shown in formula I is one of the following structures:

[0029] The present invention also provides a preparation method of the above compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystal form thereof, comprising the following steps:

[0030]

[0031] Step 1, reacting compound a with acrylonitrile to obtain compound b;

[0032] Step 2, hydrolyzing and cyclizing compound b to obtain compound c;

[0033] Step 3, reacting diethyl cyanomethylphosphonate with a strong base to prepare an intermediate;

[0034] Step 4, subjecting compound c to a condensation reaction with the intermediate to obtain compound d;

[0035] Step 5, performing one of the following operations: a. subjecting compound d to a reduction reaction to obtain compound e; and then reacting compound e with a carboxylic acid to obtain the compound shown in formula II;

[0036] Or, b. subjecting compound d to hydrolysis and reduction reactions to obtain compound f; and then reacting compound f with an amine compound to obtain the compound shown in formula III.

[0037] Preferably, in step 1, the reaction is carried out under the action of a basic catalyst, and the catalyst is selected from at least one of sodium methoxide, n-butyllithium, and potassium tert-butoxide;

[0038] And / or, in step 2, the hydrolysis is carried out under the action of an acid, and the acid is selected from at least one of hydrochloric acid, sulfuric acid, and phosphoric acid; the cyclization reaction is carried out under the action of a catalyst, and the catalyst is selected from polyphosphoric acid;

[0039] And / or, in step 3, the solvent for the reaction is selected from ethanol, and the strong base is selected from potassium tert-butoxide;

[0040] And / or, in step 4, the temperature of the reaction is 20 - 25 °C, and the reaction time is 1 - 5 h;

[0041] And / or, in step 5a, the solvent for the reduction reaction is selected from methanol; the reduction reaction is carried out under the action of a catalyst and a reducing agent, the catalyst is selected from palladium on carbon catalyst, and the reducing agent is selected from hydrogen; and / or, the carboxylic acid is selected from at least one of propionic acid and cyclopropanecarboxylic acid; the solvent for the reaction is selected from pyridine; the reaction is carried out under the action of a dehydrating agent, and the dehydrating agent is selected from N,N'-dicyclohexylcarbodiimide;

[0042] And / or, in step 5b, the hydrolysis is carried out under the action of an acid, the acid is selected from at least one of hydrochloric acid, sulfuric acid, and phosphoric acid; the reduction reaction is carried out under the action of a catalyst and a reducing agent, the catalyst is selected from palladium on carbon catalyst, and the reducing agent is selected from hydrogen; the amine compound is selected from propylamine, the solvent for the reaction is selected from pyridine; the reaction is carried out under the action of a condensing agent, and the condensing agent is selected from N,N'-dicyclohexylcarbodiimide.

[0043] The present invention also provides the use of the above compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystal form thereof in the preparation of a melatonin receptor agonist.

[0044] Preferably, the melatonin receptor agonist is a drug for treating neurodegenerative diseases.

[0045] The present invention provides a pharmaceutical composition which is prepared by using the above compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystal form thereof as an active ingredient and adding pharmaceutically acceptable excipients.

[0046] The compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) naming system.

[0047] Definition of terms used in the present invention: Unless otherwise specified, the initial definitions provided for groups or terms herein apply to such groups or terms throughout the specification; for terms not specifically defined herein, meanings that can be given to them by those skilled in the art should be provided according to the disclosure and context.

[0048] The minimum and maximum carbon atom contents in hydrocarbon groups are indicated by prefixes. For example, the prefix C a -C bAn alkyl group denotes any alkyl group containing from “a” to “b” carbon atoms. Thus, for example, “C 1 -C 6 alkyl” refers to an alkyl group containing 1 to 6 carbon atoms.

[0049] “Alkyl” refers to a saturated hydrocarbon chain having a specified number of member atoms. For example, C 1 -C 6 alkyl refers to an alkyl group having 1 to 6 member atoms, such as 1 to 4 member atoms. The alkyl group may be straight-chain or branched-chain. Representative branched-chain alkyl groups have one, two, or three branches. The alkyl group may optionally be substituted with one or more substituents as defined herein. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. The alkyl group may also be part of other groups, such as C 1 -C 6 alkoxy.

[0050] “Cycloalkyl” refers to a saturated or partially saturated cyclic group having 3 to 14 carbon atoms, no ring heteroatoms, and having a single ring or multiple rings (including fused, bridged, and spiro ring systems). For polycyclic systems having aromatic and non-aromatic rings without ring heteroatoms, the term “cycloalkyl” applies when the point of attachment is at a non-aromatic carbon atom (e.g., 5,6,7,8-tetrahydronaphthalen-5-yl). The term “cycloalkyl” includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl.

[0051] “Halogen” is fluorine, chlorine, bromine, or iodine.

[0052] The “amide bond” structure is “-CONH-”, which is a covalent bond formed by the combination of an acyl group (-CO-) and an amino group (-NH-).

[0053] The term “pharmaceutically acceptable” means that a carrier, vehicle, diluent, excipient, and / or the salt formed is generally chemically or physically compatible with the other components that make up a pharmaceutical dosage form and is physiologically compatible with the receptor.

[0054] The terms "salt" and "pharmaceutically acceptable salt" refer to acid addition and / or base salts formed from the above compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (inner salts), and also including quaternary ammonium salts, such as alkylammonium salts. These salts can be directly obtained during the final isolation and purification of the compound. They can also be obtained by appropriately (e.g., equimolarly) mixing the above compound or its stereoisomer with a certain amount of acid or base. These salts may form precipitates in solution and be collected by filtration, or recovered after evaporation of the solvent, or prepared by lyophilization after reaction in an aqueous medium. The salts described in the present invention can be hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, fumarate, maleate, tartrate or trifluoroacetate of the compound.

[0055] In certain embodiments, one or more compounds of the present invention can be used in combination with each other. Optionally, the compounds of the present invention can be combined with any other active agent for the preparation of a drug or pharmaceutical composition for regulating cell function or treating a disease. If a group of compounds is used, these compounds can be administered to a subject simultaneously, separately or sequentially.

[0056] The present invention provides new compounds of formula I, which exhibit good melatonin receptor agonist activity, providing a new drug option for preventing and / or treating various neurodegenerative diseases mediated by melatonin receptors, and having broad application prospects.

[0057] Obviously, based on the above content of the present invention, according to the common general knowledge and conventional means in the art, without departing from the above basic technical idea of the present invention, various other forms of modification, substitution or variation can be made.

[0058] The above content of the present invention will be further described in detail below by specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. Detailed Description of the Invention

[0059] In the following examples and experimental examples, the reagents and raw materials not specifically described are commercially available products.

[0060] Example 1 Preparation of Chroman Compounds

[0061] The structures of the chroman compounds are shown as follows:

[0062]

[0063] The specific synthesis route is as follows:

[0064]

[0065] The preparation method is as follows:

[0066] (1) Weigh 1.12 g of 4-fluorophenol, add 10 ml of acrylonitrile, stir evenly, and then add 0.81 g of sodium methoxide in portions under ice bath. After slowly warming to room temperature under inert gas protection and heating under reflux for 5 h, acrylonitrile is removed by reduced pressure concentration. Then add 30 ml of water, and extract with ethyl acetate (3×20 mL). Combine the organic layers, wash with water (1×30 mL), wash with saturated brine (1×30 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then perform column chromatography (gradient elution with PE:EA = 20:1 - 10:1) to obtain 1.33 g of off-white solid 3-(4-fluorophenoxy)propionitrile, with a yield of 80.6%. 1 H-NMR(400MHz,CDCl 3 / TMS)δ:2.82(t,J=8.4Hz,2H,CH 2 ),4.31(t,J=8.8Hz,2H,CH 2 ),7.18(m,2H,ArH),7.51(m,2H,ArH).

[0067] (2) Weigh 1.65 g of 3-(4-fluorophenoxy)propionitrile, add 10 ml of 6M hydrochloric acid, reflux for 5 h, then concentrate and dry under reduced pressure to obtain a pale yellow solid. Add 5 g of polyphosphoric acid (PPA) to this solid, stir at room temperature for 10 h, then add 30 ml of ice water, and extract with ethyl acetate (3×20 mL). Combine the organic layers, wash with water (2×30 mL), wash with saturated brine (1×30 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then perform column chromatography (gradient elution with PE:EA = 20:1 - 10:1) to obtain 1.30 g of yellow solid 6-fluorochroman-4-one, with a yield of 78.3%. 1 H-NMR(400MHz,CDCl 3 / TMS)δ:2.91(t,J=8.8Hz,2H,CH 2 ),4.16(t,J=8.8Hz,2H,CH 2 ),7.05(m,1H,ArH),7.34(m,1H,ArH),7.56(m,1H,ArH).

[0068] (3) Weigh 2.12 g of diethyl cyanomethylphosphonate, add 30 mL of ethanol, transfer the reaction to an ice-salt bath to cool down. At 0 °C, slowly add 1.68 g of potassium tert-butoxide while controlling the temperature. After adding potassium tert-butoxide completely, keep the temperature at 0 °C and react for half an hour. Finally, add 1.66 g of 6-fluorochroman-4-one, warm up to room temperature and react for 3 hours until the reaction is completed. Add 50 mL of ice water to the reaction solution, extract with ethyl acetate (3×30 mL), combine the organic layers, wash with water (2×30 mL), wash with saturated brine (1×30 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then perform column chromatography (gradient elution with PE:EA = 20:1 - 10:1) to obtain 1.77 g of yellow solid 2-(6-fluorochroman-4-ylidene)acetonitrile, with a yield of 93.6%. 1 H-NMR(400MHz,CDCl 3 / TMS)δ:2.41(t,J=8.8Hz,2H,CH 2 ),4.01(t,J=8.4Hz,2H,CH 2 ),5.44(s,1H,CH),6.89(m,1H,ArH),6.96(m,1H,ArH),7.11(m,1H,ArH)。

[0069] (4) Place 1.89 g of 2-(6-fluorochroman-4-ylidene)acetonitrile in a reaction flask, add anhydrous methanol (20 mL), then add 10% Pd-C (50 mg), evacuate the air, stir at room temperature under a hydrogen atmosphere for 5 h. After the reaction is complete, filter by suction, concentrate the filtrate under reduced pressure, and then perform column chromatography (PE:EA = 10:1 - 5:1, gradient elution with 0.1% TEA) to obtain 1.88 g of white solid 6-fluorochroman-4-yl ethylamine, with a yield of 96.4%.

[0070] 1 H-NMR(400MHz,CDCl 3 / TMS)δ:δ:1.82(m,3H,CH 2 ,CH 2 ),2.10(m,1H,CH 2 ),2.60(m,3H,CH,CH 2 ),3.98(m,2H,CH 2 ),6.89(m,1H,ArH),6.96(m,1H,ArH),7.11(m,1H,ArH),8.5(brs,2H,NH 2 )。

[0071] (5) 1.95 g of 6-fluorochroman-4-yl-ethylamine and 0.82 g of propionic acid were added to 20 ml of anhydrous pyridine, and then 3.0 g of N,N'-dicyclohexylcarbodiimide (DCC) was added. After stirring at room temperature for 5 h, pyridine was removed by concentration under reduced pressure as much as possible. The mixture was extracted with ethyl acetate (3×20 mL), the organic layers were combined, washed with water (1×30 mL), washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (gradient elution with PE:EA = 20:1 - 10:1) to obtain a chroman compound as a white solid, 2.45 g, with a yield of 97.6%. 1 H-NMR(400MHz,CDCl 3 / TMS)δ:0.98(t,J=8.8Hz,3H,CH 3 ),1.81-1.85(m,3H,CH 2 ,CH 2 ),2.10(m,1H,CH 2 ),2.60(m,3H,CH,CH 2 ),3.18(m,2H,CH 2 ),3.98(m,2H,CH 2 ),6.89(m,1H,ArH),6.96(m,1H,ArH),7.11(m,1H,ArH),7.73(s,1H,NH)。

[0072] Example 2 Preparation of chroman compounds

[0073] The structure of the chroman compound is as follows:

[0074]

[0075] The preparation method is as follows:

[0076] (1) Weigh 1.12 g of phenol, add 10 ml of acrylonitrile, stir evenly, and add 0.81 g of sodium methoxide in portions under an ice bath. After slowly warming to room temperature under inert gas protection and refluxing for 5 h, acrylonitrile was removed by concentration under reduced pressure, then 30 ml of water was added, and the mixture was extracted with ethyl acetate (3×20 mL). The organic layers were combined, washed with water (1×30 mL), washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (gradient elution with PE:EA = 20:1 - 10:1) to obtain 1.33 g of phenoxypropionitrile as a white solid, with a yield of 80.6%. 1 H-NMR(400MHz,CDCl 3 / TMS)δ:2.82(t,J=8.4Hz,2H,CH 2 ),4.31(t,J=8.4Hz,2H,CH2 ), 6.93 (m, 3H, ArH), 7.28 (m, 2H, ArH).

[0077] (2) Weigh 1.65 g of phenoxyacetonitrile, add 10 mL of 6 M hydrochloric acid, reflux for 5 h, then concentrate under reduced pressure and dry to obtain a pale yellow solid. Add 5 g of PPA to this solid, stir at room temperature for 10 h, then add 30 mL of ice water, extract with ethyl acetate (3 × 20 mL), combine the organic layers, wash with water (2 × 30 mL), wash with saturated brine (1 × 30 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then perform column chromatography (gradient elution with PE:EA = 20:1 - 10:1) to obtain 1.30 g of yellow solid chroman-4-one, with a yield of 78.3%. 1 H-NMR (400 MHz, CDCl 3 / TMS) δ: 2.91 (t, J = 8.8 Hz, 2H, CH 2 ), 4.16 (t, J = 8.8 Hz, 2H, CH 2 ), 6.94 (t, J = 8.0 Hz, 1H, ArH), 6.92 (d, J = 8.0 Hz, 1H, ArH), 7.40 (d, J = 8.0 Hz, 1H, ArH), 7.512 (t, J = 8.0 Hz, 1H, ArH).

[0078] (3) Weigh 2.12 g of diethyl cyanomethylphosphonate, add 30 mL of ethanol, transfer the reaction to an ice-salt bath to cool down. At 0 °C, slowly add 1.68 g of potassium tert-butoxide while controlling the temperature. After adding potassium tert-butoxide, maintain the temperature at 0 °C and react for half an hour. Finally, add 1.66 g of chroman-4-one, warm up to room temperature and react for 3 hours until the reaction is complete. Add 50 mL of ice water to the reaction solution, extract with ethyl acetate (3 × 30 mL), combine the organic layers, wash with water (2 × 30 mL), wash with saturated brine (1 × 30 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then perform column chromatography (gradient elution with PE:EA = 20:1 - 10:1) to obtain 1.77 g of yellow solid, with a yield of 93.6%. 1 H-NMR (400 MHz, CDCl 3 / TMS) δ: 2.38 (t, J = 8.8 Hz, 2H, CH 2 ), 4.01 (t, J = 8.4 Hz, 2H, CH 2 ), 5.44 (s, 1H, CH), 7.02 - 7.05 (m, 2H, ArH), 7.23 (d, J = 8.0 Hz, 1H, ArH), 7.32 (t, J = 8.0 Hz, 1H, ArH).

[0079] (4) Place 1.89 g of the yellow solid obtained in step (3) in a reaction flask, add anhydrous methanol (20 mL), then add 10% Pd-C (50 mg), evacuate the air, stir at room temperature for 5 h under a hydrogen atmosphere. After the reaction is complete, perform suction filtration. The filtrate is concentrated under reduced pressure and then subjected to column chromatography (PE:EA = 10:1 - 5:1, gradient elution with 0.1% TEA) to obtain 1.88 g of the white solid chroman-4-yl-ethylamine, with a yield of 96.4%. 1 H-NMR(400MHz,CDCl 3 / TMS)δ:1.80-1.85(m,3H,CH 2 ,CH 2 ),2.10-2.20(m,1H,CH 2 ),2.55-2.63(m,3H,CH,CH 2 ),3.95(m,2H,CH 2 ),7.02-7.05(m,2H,ArH),7.23(d,J=8.0Hz,1H,ArH),7.32(t,J=8.0Hz,1H,ArH),8.5(brs,2H,NH 2 )。

[0080] (5) Add 1.95 g of chroman-4-yl-ethylamine and 0.82 g of propionic acid to 20 ml of anhydrous pyridine, then add 3.0 g of DCC. Stir at room temperature for 5 h and then concentrate under reduced pressure to remove pyridine as much as possible. Extract with ethyl acetate (3×20 mL), combine the organic layers, wash with water (1×30 mL), wash with saturated brine (1×30 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure and then perform column chromatography (gradient elution with PE:EA = 20:1 - 10:1) to obtain the chroman compound, which is a off-white solid of 2.45 g, with a yield of 97.6%. 1 H-NMR(400MHz,CDCl 3 / TMS)δ:0.98(t,J=8.8Hz,3H,CH 3 ),1.80-1.85(m,3H,CH 2 ,CH 2 ),2.10-2.20(m,1H,CH 2 ),2.31(q,J=8.8Hz,2H,CH 2 ),2.58(m,1H,CH),3.18(t,J=8.8Hz,2H,CH 2 ),3.98(m,2H,CH 2), 6.82 - 6.91 (m, 2H, ArH), 7.33 (d, J = 8.0 Hz, 1H, ArH), 7.51 (t, J = 8.0 Hz, 1H, ArH), 7.73 (s, 1H, NH).

[0081] Example 3 Preparation of Chroman Compounds

[0082] The structures of the chroman compounds are as follows:

[0083]

[0084] The preparation method is as follows:

[0085] (1) Weigh 1.12 g of 4-fluorophenol, add 10 ml of acrylonitrile. After stirring evenly, add 0.81 g of sodium methoxide in portions under ice bath. Slowly warm to room temperature under inert gas protection and then reflux for 5 h. After concentrating under reduced pressure to remove acrylonitrile, add 30 ml of water and extract with ethyl acetate (3 × 20 mL). Combine the organic layers, wash with water (1 × 30 mL), wash with saturated brine (1 × 30 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure and then perform column chromatography (gradient elution with PE:EA = 20:1 - 10:1) to obtain 1.33 g of off-white solid 3-(4-fluorophenoxy)propanenitrile, with a yield of 80.6%. 1 H-NMR (400 MHz, CDCl 3 / TMS) δ: 2.82 (t, J = 8.4 Hz, 2H, CH 2 ), 4.31 (t, J = 8.8 Hz, 2H, CH 2 ), 7.18 (m, 2H, ArH), 7.51 (m, 2H, ArH).

[0086] (2) Weigh 1.65 g of 3-(4-fluorophenoxy)propanenitrile, add 10 ml of 6M hydrochloric acid. After refluxing for 5 h, concentrate and dry under reduced pressure to obtain a pale yellow solid. Add 5 g of PPA to this solid, stir at room temperature for 10 h, then add 30 ml of ice water and extract with ethyl acetate (3 × 20 mL). Combine the organic layers, wash with water (2 × 30 mL), wash with saturated brine (1 × 30 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure and then perform column chromatography (gradient elution with PE:EA = 20:1 - 10:1) to obtain 1.30 g of yellow solid 6-fluorochroman-4-one, with a yield of 78.3%. 1 H-NMR (400 MHz, CDCl 3 / TMS) δ: 2.91 (t, J = 8.8 Hz, 2H, CH 2 ), 4.16 (t, J = 8.8 Hz, 2H, CH 2), 7.05 (m, 1H, ArH), 7.34 (m, 1H, ArH), 7.56 (m, 1H, ArH).

[0087] (3) Weigh 2.12 g of diethyl cyanomethylphosphonate, add 30 mL of ethanol, transfer the reaction to an ice-salt bath to cool down. At 0 °C, slowly add 1.68 g of potassium tert-butoxide while controlling the temperature. After adding potassium tert-butoxide, maintain the temperature at 0 °C and react for half an hour. Finally, add 1.66 g of 6-fluorochroman-4-one, warm up to room temperature and react for 3 hours until the reaction is complete. Add 50 ml of ice water to the reaction solution, extract with ethyl acetate (3×30 mL), combine the organic layers, wash with water (2×30 mL), wash with saturated brine (1×30 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then perform column chromatography (gradient elution with PE:EA = 20:1 - 10:1) to obtain 1.77 g of yellow solid 2-(6-fluorochroman-4-ylidene)acetonitrile, with a yield of 93.6%. 1 H-NMR (400 MHz, CDCl 3 / TMS) δ: 2.41 (t, J = 8.8 Hz, 2H, CH 2 ), 4.01 (t, J = 8.4 Hz, 2H, CH 2 ), 5.44 (s, 1H, CH), 6.89 (m, 1H, ArH), 6.96 (m, 1H, ArH), 7.11 (m, 1H, ArH).

[0088] (4) Place 1.89 g of 2-(6-fluorochroman-4-ylidene)acetonitrile in a reaction flask, add anhydrous methanol (20 mL), and then add 10% Pd-C (50 mg). Evacuate the air, stir at room temperature under a hydrogen atmosphere for 5 h. After the reaction is complete, filter by suction. Concentrate the filtrate under reduced pressure and then perform column chromatography (PE:EA = 10:1 - 5:1, gradient elution with 0.1% TEA) to obtain 1.88 g of white solid 6-fluorochroman-4-yl-ethylamine, with a yield of 96.4%.

[0089] 1 H-NMR (400 MHz, CDCl 3 / TMS) δ: 1.81 - 1.85 (m, 3H, CH 2 , CH 2 ), 2.10 (m, 1H, CH 2 ), 2.60 (m, 3H, CH, CH 2 ), 3.98 (m, 2H, CH 2 ), 6.89 (m, 1H, ArH), 6.96 (m, 1H, ArH), 7.11 (m, 1H, ArH), 8.5 (brs, 2H, NH 2 ).

[0090] (5) 1.95 g of 6-fluorochroman-4-yl-ethylamine and 0.82 g of cyclopropanecarboxylic acid were added to 20 ml of anhydrous pyridine, and then 3.0 g of DCC was added. After stirring at room temperature for 5 h, pyridine was removed by concentration under reduced pressure as much as possible. The mixture was extracted with ethyl acetate (3×20 mL). The organic layers were combined, washed with water (1×30 mL), washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (gradient elution with PE:EA = 20:1 - 10:1) to obtain a chroman compound as a slightly white solid, 2.45 g, with a yield of 97.6%. 1 H-NMR(400MHz,CDCl 3 / TMS)δ: 1.81 - 1.99 (m, 4H, CH 2 ), 1.80 - 1.84 (m, 3H, CH 2 , CH 2 ), 2.10 (m, 1H, CH 2 ), 2.58 (m, 1H, CH,), 2.72 (m, 1H, CH), 2.20 (t, J = 8.8 Hz, 2H, CH 2 ), 3.98 (m, 2H, CH 2 ), 6.89 (m, 1H, ArH), 7.01 (m, 1H, ArH), 7.10 (m, 1H, ArH), 7.73 (s, 1H, NH).

[0091] Example 4 Preparation of chroman compounds

[0092] The structure of the chroman compound is shown below:

[0093]

[0094] The specific synthesis route is as follows:

[0095]

[0096] Its preparation method is as follows:

[0097] (1) Weigh 1.12 g of 4-fluorophenol, add 10 ml of acrylonitrile, stir evenly, and add 0.81 g of sodium methoxide portionwise in an ice bath. After slowly warming to room temperature under inert gas protection and refluxing for 5 h, acrylonitrile was removed by concentration under reduced pressure, then 30 ml of water was added, and the mixture was extracted with ethyl acetate (3×20 mL). The organic layers were combined, washed with water (1×30 mL), washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (gradient elution with PE:EA = 20:1 - 10:1) to obtain 1.33 g of 3-(4-fluorophenoxy)propanenitrile as a slightly white solid, with a yield of 80.6%. 1 H-NMR(400MHz,CDCl3 / TMS) δ: 2.82 (t, J = 8.4 Hz, 2H, CH 2 ), 4.31 (t, J = 8.8 Hz, 2H, CH 2 ), 7.18 (m, 2H, ArH), 7.51 (m, 2H, ArH).

[0098] (2) Weigh 1.65 g of 3-(4-fluorophenoxy) propionitrile, add 10 ml of 6 M hydrochloric acid, reflux for 5 h, then concentrate under reduced pressure and dry to obtain a pale yellow solid. Add 5 g of PPA to this solid, stir at room temperature for 10 h, then add 30 ml of ice water, extract with ethyl acetate (3 × 20 mL), combine the organic layers, wash with water (2 × 30 mL), wash with saturated brine (1 × 30 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and perform column chromatography (gradient elution with PE:EA = 20:1 - 10:1) to obtain 1.30 g of yellow solid 6-fluorochroman-4-one, with a yield of 78.3%. 1 H-NMR (400 MHz, CDCl 3 / TMS) δ: 2.91 (t, J = 8.8 Hz, 2H, CH 2 ), 4.16 (t, J = 8.8 Hz, 2H, CH 2 ), 7.05 (m, 1H, ArH), 7.34 (m, 1H, ArH), 7.56 (m, 1H, ArH).

[0099] (3) Weigh 2.12 g of diethyl cyanomethylphosphonate, add 30 mL of ethanol, transfer the reaction to an ice-salt bath to cool down. At 0 °C, slowly add 1.68 g of potassium tert-butoxide while controlling the temperature. After adding potassium tert-butoxide, keep the temperature at 0 °C and react for half an hour. Finally, add 1.66 g of 6-fluorochroman-4-one, warm up to room temperature and react for 3 hours until the reaction is complete. Add 50 ml of ice water to the reaction solution, extract with ethyl acetate (3 × 30 mL), combine the organic layers, wash with water (2 × 30 mL), wash with saturated brine (1 × 30 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and perform column chromatography (gradient elution with PE:EA = 20:1 - 10:1) to obtain 1.77 g of yellow solid 2-(6-fluorochroman-4-ylidene) acetonitrile, with a yield of 93.6%. 1 H-NMR (400 MHz, CDCl 3 / TMS) δ: 2.41 (t, J = 8.8 Hz, 2H, CH 2 ), 4.01 (t, J = 8.4 Hz, 2H, CH 2 ), 5.44 (s, 1H, CH), 6.89 (m, 1H, ArH), 6.96 (m, 1H, ArH), 7.11 (m, 1H, ArH).

[0100] (4) Weigh 2.03 g of 2-(6-fluorochroman-4-ylidene)acetonitrile, add 20 ml of 6 M hydrochloric acid, reflux for 5 h, concentrate under reduced pressure and dry to obtain a pale yellow solid. Then add 20 ml of isopropanol, add 10% Pd-C (100 mg), evacuate the air, stir at room temperature for 5 h under a hydrogen atmosphere. After the reaction is complete, filter by suction, concentrate the filtrate under reduced pressure and perform column chromatography (PE:EA = 10:1 - 5:1, gradient elution with 0.1% glacial acetic acid) to obtain 1.79 g of white solid 2-(6-fluorochroman-4-yl)acetic acid, and the two-step yield is 79.9%. 1 H-NMR(400MHz,CDCl 3 / TMS)δ:1.85-2.10(m,2H,CH 2 ),2.36-2.57(m,2H,CH 2 ),2.99(m,1H,CH),3.97(m,2H,CH 2 ),6.93(m,1H,ArH),7.02(m,1H,ArH),7.11(m,1H,ArH),11.4(brs,1H,COOH)。

[0101] (5) Weigh 2.10 g of 2-(6-fluorochroman-4-yl)acetic acid and 0.65 g of propylamine, add 20 ml of pyridine, then add 3.0 g of N,N'-dicyclohexylcarbodiimide (DCC), stir at room temperature for 5 h, concentrate under reduced pressure to remove pyridine, extract with ethyl acetate (3×20 mL), combine the organic layers, wash with water (1×30 mL), wash with saturated brine (1×30 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure and perform column chromatography (gradient elution with PE:EA = 20:1 - 10:1) to obtain a benzodihydropyran compound, which is 2.31 g of an off-white solid, and the yield is 92.0%. 1 H-NMR(400MHz,CDCl 3 / TMS)δ:0.88(t,J=8.8Hz,3H,CH 3 ),1.55(m,2H,CH 2 ),1.80-2.10(m,2H,CH 2 ),2.35-2.51(m,2H,CH 2 ),2.99(m,1H,CH),3.42(t,J=8.8Hz,2H,CH 2 ),3.98(m,2H,CH 2 ),6.94(m,1H,ArH),7.02(m,1H,ArH),7.11(m,1H,ArH),7.81(s,1H,NH)。

[0102] Preparation of Chroman Compounds - Example 5

[0103] The structure of chroman compounds is shown as follows:

[0104]

[0105] The preparation method is as follows:

[0106] (1) Weigh 1.12 g of phenol, add 10 ml of acrylonitrile. After stirring evenly, add 0.81 g of sodium methoxide portionwise in an ice bath. Slowly warm to room temperature under inert gas protection and then reflux for 5 h. After concentrating under reduced pressure to remove acrylonitrile, add 30 ml of water, and extract with ethyl acetate (3×20 mL). Combine the organic layers, wash with water (1×30 mL), wash with saturated brine (1×30 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then perform column chromatography (gradient elution with PE:EA = 20:1 - 10:1) to obtain 1.33 g of off - white solid phenoxypropionitrile, with a yield of 80.6%. 1 H - NMR(400MHz,CDCl 3 / TMS)δ:2.82(t,J = 8.4Hz,2H,CH 2 ),4.31(t,J = 8.4Hz,2H,CH 2 ),6.93(m,3H,ArH),7.28(m,2H,ArH).

[0107] (2) Weigh 1.65 g of phenoxypropionitrile, add 10 ml of 6M hydrochloric acid, reflux for 5 h, concentrate and dry under reduced pressure to obtain a pale yellow solid. Add 5 g of PPA to this solid, stir at room temperature for 10 h, then add 30 ml of ice - water, extract with ethyl acetate (3×20 mL). Combine the organic layers, wash with water (2×30 mL), wash with saturated brine (1×30 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then perform column chromatography (gradient elution with PE:EA = 20:1 - 10:1) to obtain 1.30 g of yellow solid chroman - 4 - one, with a yield of 78.3%. 1 H - NMR(400MHz,CDCl 3 / TMS)δ:2.91(t,J = 8.8Hz,2H,CH 2 ),4.16(t,J = 8.8Hz,2H,CH 2 ),6.94(t,J = 8.0Hz,1H,ArH),6.92(d,J = 8.0Hz,1H,ArH),7.40(d,J = 8.0Hz,1H,ArH),7.512(t,J = 8.0Hz,1H,ArH).

[0108] (3) Weigh 2.12 g of diethyl cyanomethylphosphonate, add 30 mL of ethanol, transfer the reaction to an ice-salt bath to cool down. When the temperature reaches 0 °C, slowly add 1.68 g of potassium tert-butoxide while controlling the temperature. After adding potassium tert-butoxide, maintain the temperature at 0 °C and react for half an hour. Finally, add 1.66 g of chroman-4-one, warm up to room temperature and react for 3 hours until the reaction is complete. Add 50 mL of ice water to the reaction solution, extract with ethyl acetate (3×30 mL), combine the organic layers, wash with water (2×30 mL), wash with saturated brine (1×30 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then perform column chromatography (gradient elution with PE:EA = 20:1 - 10:1) to obtain 1.77 g of a yellow solid with a yield of 93.6%. 1 H-NMR(400MHz,CDCl 3 / TMS)δ:2.38(t,J=8.8Hz,2H,CH 2 ),4.01(t,J=8.4Hz,2H,CH 2 ),5.44(s,1H,CH),7.02-7.05(m,2H,ArH),7.23(d,J=8.0Hz,1H,ArH),7.32(t,J=8.0Hz,1H,ArH).

[0109] (4) Weigh 1.71 g of 2-(chroman-4-ylidene)acetonitrile, add 20 mL of 6M hydrochloric acid, reflux for 5 h, concentrate and dry under reduced pressure to obtain a pale yellow solid. Then add 20 mL of isopropanol, add 10% Pd-C (100 mg), evacuate the air, stir at room temperature under a hydrogen atmosphere for 5 h. After the reaction is complete, filter by suction, concentrate the filtrate under reduced pressure, and perform column chromatography (gradient elution with PE:EA = 10:1 - 5:1, 0.1% glacial acetic acid) to obtain 1.55 g of white solid 2-(chroman-4-yl)acetic acid with a two-step yield of 80.7%. 1 H-NMR(400MHz,CDCl 3 / TMS)δ:1.84-2.12(m,2H,CH 2 ),2.38-2.65(m,2H,CH 2 ),3.01(m,1H,CH),3.98(m,2H,CH 2 ),6.85-6.90(m,2H,ArH),7.31(d,J=8.0Hz,1H,ArH),7.52(t,J=8.0Hz,1H,ArH), 12.7(brs,1H,COOH).

[0110] (5) Weigh 1.92 g of 2-(chroman-4-yl)-acetic acid and 0.65 g of propylamine, add 20 ml of pyridine, then add 3.0 g of N,N'-dicyclohexylcarbodiimide (DCC), stir at room temperature for 5 h, then concentrate under reduced pressure to remove pyridine as much as possible. Extract with ethyl acetate (3×20 mL), combine the organic layers, wash with water (1×30 mL), wash with saturated brine (1×30 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and perform column chromatography (gradient elution with PE:EA = 20:1 - 10:1) to obtain the chroman compound, which is a white solid of 2.18 g with a yield of 93.6%. 1 H-NMR(400MHz,CDCl 3 / TMS)δ:0.87(t,J=8.8Hz,3H,CH 3 ),1.54(m,2H,CH 2 ),1.82-2.13(m,2H,CH 2 ),2.31-2.49(m,2H,CH 2 ),2.98(m,1H,CH),3.42(t,J=8.8Hz,2H,CH 2 ),3.98(m,2H,CH 2 ),6.85-6.90(m,2H,ArH),7.33(d,J=8.0Hz,1H,ArH),7.52(t,J=8.0Hz,1H,ArH),7.81(s,1H,NH).

[0111] The technical solution of the present invention will be further described through experiments below.

[0112] Experimental Example 1 Screening of the Biological Activity of Chroman Compounds

[0113] I. Experimental Method

[0114] The MT1 and MT2 cell lines correspond to human renal epithelial cells MT1-HEK293 and MT2-HEK293, respectively.

[0115] Using Dulbecco's modified Eagle medium, seed the cells at a density of 4×10 4 per well in a 96-well plate coated with Matrigel matrix, and place it in CO 2Cultivate for 24 h in a 37 °C constant temperature incubator with a concentration of 5%. Aspirate the supernatant, then discard the original medium, and add 100 μL / well of the commercially available HDB calcium flux kit staining solution freshly prepared, and incubate at 37 °C in the dark for 60 min. The test compound and the positive drug are respectively dissolved in 10 μL of dimethyl sulfoxide (DMSO) and 990 μL of HBSS buffer (the concentration of all samples is 1.00 mmol / L), and 100 μL / well is taken from each well in a 96-well transparent bottom plate coated with Matrigel. Prepare the samples to be tested: Prepare the samples to be tested at a concentration of 1.00 mmol / L, and place the test samples in another transparent bottom plate. The above two 96-well plates are simultaneously placed in a Flex Station3 bench-top multi-functional microplate reader. Read the absorbance value at room temperature using a Flexstation 3 bench-top multi-mode microplate reader, with the wavelength (excitation: 485 nm; emission: 525 nm; emission cut-off: 515 nm). The antagonistic activity expressed as X±SD (n = 3) is obtained by comparing with the highest antagonistic activity obtained with the highest concentration of melatonin, and it is set to 100%. The experimental data is read by a Flex Station3 bench-top multi-functional microplate reader, and the EC 50 value is calculated using Graph Pad Prism5 software; the agonist rate = (Δδa / Δδc)×100% (a: test sample; c: positive control), and the positive control is melatonin (1.00 mmol / L).

[0116] II. Experimental Results

[0117] The results are shown in Table 1. The chroman compounds prepared in Examples 1 and 2 have significant agonist activities on the melatonin receptor MT2, which are 151±3.88% and 197±6.41% respectively; the chroman compound prepared in Example 4 has significant agonist activities on both the melatonin receptor MT1 (117±5.21%) and MT2 (134±4.78%). The results show that the chroman compounds prepared in the present invention have significant agonist activities on the melatonin receptor and can be used for preventing or / and treating various neurodegenerative diseases mediated by melatonin receptors.

[0118] Table 1

[0119]

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystalline form thereof: in, R1 is selected from hydrogen, halogen; Ring A is selected from 3-10 membered heterocycloalkyl, 3-10 membered heteroaryl; L1 is selected from substituted or unsubstituted C1-C5 alkylene, wherein the substituent is selected from halogen, hydroxyl, C1-C 10 Alkyl, cyano, amino, C3-C 10 Cycloalkyl; L2 is selected from an amide bond; L3 is selected from C1-C5 alkyl, C3-C 10 Cycloalkyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl; R2 is selected from hydrogen, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, wherein the substituent is selected from halogen, hydroxy, cyano, amino, C3-C 10 Cycloalkyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystalline form thereof, characterized in that: The compound shown in Formula I has the structure described in Formula II below: Wherein, R1 is selected from hydrogen and halogen; L3 is selected from C1-C5 alkyl, C3-C 10 Cycloalkyl.

3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystalline form thereof, characterized in that: The R1 is selected from hydrogen and fluorine; L3 is selected from C2 alkyl and C3 cycloalkyl.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystalline form thereof, characterized in that: The compound shown in Formula I has the structure described in Formula III below: Wherein, R1 is selected from hydrogen and halogen; L3 is selected from C1-C5 alkyl.

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystalline form thereof, characterized in that: The R1 is selected from hydrogen and fluorine; L3 is selected from C3 alkyl.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystalline form thereof, characterized in that: The compound shown in formula I is one of the following structures:

7. A method for preparing the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystalline form thereof, characterized in that: The steps include: Step 1, reacting compound a with acrylonitrile to obtain compound b; Step 2, subjecting compound b to hydrolysis and cyclization to obtain compound c; Step 3, reacting diethyl cyanomethylphosphonate with a strong base to prepare an intermediate; Step 4, condensing compound c with the intermediate to obtain compound d; Step 5 is performed by one of the following operations: a. subjecting compound d to a reduction reaction to obtain compound e; and then reacting compound e with a carboxylic acid to obtain a compound represented by formula II; Or, b. Compound d is subjected to hydrolysis and reduction reaction to obtain compound f; and compound f is reacted with an amine compound to obtain a compound represented by formula III.

8. Use of the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystalline form thereof in the preparation of a melatonin receptor agonist.

9. The use according to claim 8, characterized in that: The melatonin receptor agonist is a drug used to treat neurodegenerative diseases.

10. A pharmaceutical composition, characterized in that: The invention is prepared by using the compound described in any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated compound thereof, or a solvate thereof, or a crystal form thereof as an active ingredient, and adding pharmaceutically acceptable excipients.

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