2-substituted-1H-benzimidazole compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a 2-substituted-1H-benzimidazole compound 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 technical field of medicine, and particularly relates to a 2-substituted-1H-benzimidazole compound, 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. In the human body, it is mainly secreted by the pineal gland, and 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 distinction of the functions of MT1 and MT2 receptors has only been partially elucidated. Activation of the MT1 receptor can inhibit the discharge of neurons in the suprachiasmatic nucleus (SCN) and promote cardiovascular contraction; 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 of rats and the regulation of intraocular pressure in rabbits.

[0004] Although MT1 and MT2 in the human body are highly homologous, their distributions and signal pathways in the human body are significantly different. The physiological functions of MT1 and MT2 also show significant differences: MT1 mainly plays a regulatory role in the rapid eye movement (REM) phase of sleep, while MT2 is mainly responsible for increasing non-REM sleep. However, the melatonin drugs currently 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 exist. 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 serum during the day increases. This finding suggests that the neuroprotective effect of melatonin may be closely related to the progression of the disease. The occurrence of Huntington's Disease (HD) is most closely related to mitochondria. Melatonin can prevent lipid peroxidation in the rat brain tissue and can also prevent the death of nerve cells in the hippocampal region.

[0007] The pathogenesis of neurodegenerative diseases is complex and involves multiple pathological processes such as inflammation, oxidative stress, and neuronal damage. At present, there is no effective treatment method for neurodegenerative diseases, and the lesions are irreversible. Only the progression of the disease can be delayed through symptom relief or disease management, and 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] Aiming at the problems of the prior art, the present invention provides a 2-substituted-1H-benzimidazole compound, its preparation method and use.

[0009] The compound shown in Formula I, or its pharmaceutically acceptable salt, or its stereoisomer, or its deuterated compound, or its solvate, or its crystal form:

[0010]

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

[0012] R 2 is selected from C 1 ~C5 alkyl, C 3 ~C 10 cycloalkyl;

[0013] L 1 selected from substituted or unsubstituted C 1 -C 5 alkylene, wherein the substituent is selected from halogen, hydroxyl, 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, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl.

[0016] Preferably, the compound represented by formula I has the structure represented by the following formula II:

[0017]

[0018] wherein, R 2 selected from C 1 ~C 5 alkyl, C 3 ~C 10 cycloalkyl;

[0019] L 3 selected from C 1 ~C 5 alkyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl.

[0020] Preferably, the said R 2 selected from C 1 ~C 2 alkyl, C 3 cycloalkyl;

[0021] L 3 selected from C 2 ~C 3 alkyl, methylcyclopropyl, methylcyclobutyl.

[0022] Preferably, the compound represented by formula I has the structure represented by the following formula III:

[0023]

[0024] wherein, R 2 selected from C 1~C 5 alkyl, C 3 ~C 10 cycloalkyl;

[0025] L 3 selected from C 1 ~C 5 alkyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl.

[0026] Preferably, the R 2 is selected from C 2 alkyl, C 3 cycloalkyl; L 3 is selected from C 2 alkyl.

[0027] Preferably, the R 2 is selected from C 2 alkyl.

[0028] Preferably, the compound represented by Formula I is one of the following structures:

[0029]

[0030] The present invention also provides a method for preparing 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:

[0031]

[0032] Step 1, reacting compound a with a carboxylic acid to obtain compound b;

[0033] Step 2, reacting compound b with chloroacetonitrile to obtain compound c;

[0034] Step 3, performing one of the following operations: A. Hydrolyzing compound c to obtain compound d; reacting compound d with an amine compound to obtain the compound represented by Formula II;

[0035] Or, B. Reducing compound c to obtain intermediate e; performing an amidation reaction of intermediate e with a carboxylic acid to obtain the compound represented by Formula III.

[0036] Preferably, in Step 1, the carboxylic acid is selected from at least one of acetic acid, propionic acid, and cyclopropylformic acid; the reaction is carried out under the action of an acid, and the acid is selected from hydrochloric acid;

[0037] And / or, in Step 2, the solvent for the reaction is selected from pyridine, and the reaction is carried out under the action of a base, and the base is selected from lithium hydroxide monohydrate;

[0038] And / or, in A of Step 3, 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 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; the amine compound is selected from at least one of ethylamine, propylamine, cyclopropylmethylamine, and cyclobutylmethylamine;

[0039] And / or, in B of Step 3, the solvent for the 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-carbon catalyst, and the reducing agent is selected from hydrogen; the carboxylic acid is selected from propionic acid; the solvent for the reaction is selected from pyridine, and the reaction is carried out under the action of a dehydrating agent, and the dehydrating agent is selected from N,N'-dicyclohexylcarbodiimide.

[0040] 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.

[0041] Preferably, the melatonin receptor agonist is a drug for treating neurodegenerative diseases.

[0042] The present invention also provides a pharmaceutical composition which is prepared by adding a pharmaceutically acceptable excipient 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.

[0043] 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) nomenclature system.

[0044] Regarding the definition of the terms used in the present invention: Unless otherwise specified, the initial definitions provided for the groups or terms herein apply to the entire specification for such groups or terms; for terms not specifically defined herein, meanings that can be given to them by those skilled in the art should be given according to the disclosure and context.

[0045] The minimum and maximum carbon atom contents in the hydrocarbon group are represented by a prefix. For example, the prefix C a -C b alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Thus, for example, "C 1 -C 6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms.

[0046] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. For example, C 1 -C 6An alkyl group refers to an alkyl group having 1 to 6 member atoms, for example 1 to 4 member atoms. The alkyl group can be straight-chain or branched-chain. Representative branched-chain alkyl groups have one, two or three branches. The alkyl group can be optionally 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 can also be part of other groups, such other groups being for example C 1 -C 6 alkoxy.

[0047] "Cycloalkyl" refers to a saturated or partially saturated cyclic group having 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged and spiro ring systems). For a polycyclic system having aromatic and non-aromatic rings without ring heteroatoms, the term "cycloalkyl" is applicable 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.

[0048] "Halogen" is fluorine, chlorine, bromine or iodine.

[0049] 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-).

[0050] 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 constituting a pharmaceutical dosage form and is physiologically compatible with the receptor.

[0051] The terms "salt" and "pharmaceutically acceptable salt" refer to the acid addition and / or base salts formed by the above compounds or their stereoisomers with inorganic and / or organic acids and bases, also including zwitterionic salts (inner salts), and also including quaternary ammonium salts, such as alkylammonium salts. These salts can be directly obtained in the final separation and purification of the compound. They can also be obtained by appropriately (e.g., equimolarly) mixing the above compounds, or their stereoisomers, with a certain amount of acid or base. These salts may form a precipitate 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 the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.

[0052] 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 also be combined with any other active reagent for preparing a drug or a pharmaceutical composition for regulating cell function or treating diseases. If a group of compounds is used, these compounds can be administered to a subject simultaneously, separately, or in sequence.

[0053] The present invention provides novel compounds represented by 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.

[0054] 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 modifications, substitutions, or changes can be made.

[0055] The following is a further detailed description of the above content of the present invention through 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. Specific Embodiments

[0056] In the following examples and experimental examples, the reagents and raw materials not specifically described are all commercially available products.

[0057] Example 1 Preparation of 2-Substituted-1H-Benzimidazole Compounds

[0058] The structures of 2-substituted-1H-benzimidazole compounds are shown as follows:

[0059]

[0060] The specific synthetic route is as follows:

[0061]

[0062] The preparation method is as follows:

[0063] (1) Weigh 1.08 g of o-phenylenediamine, add 1 ml of glacial acetic acid, and then add 30 ml of 6 M hydrochloric acid. Stir and reflux the reaction under inert gas protection for 24 h. After the reaction is complete, let it stand overnight at room temperature, and a large amount of solid will precipitate. Filter by suction, wash the filter cake with a small amount of water, dry it to constant weight, and extract it with acetone (3×15 mL) to obtain 1.32 g of light blue solid 2-methylbenzimidazole hydrochloride, with a yield of 84.5%. 1 H-NMR(400MHz,DMSO-d6 / TMS)δ:2.76(s,3H,CH 3), 7.18 (d, J = 8.0 Hz, 2H, ArH), 7.52 (d, J = 8.8 Hz, 2H, ArH), 15.2 (brs, 2H, HCl, NH).

[0064] (2) Weigh 1.68 g of 2-methylbenzimidazole hydrochloride, add 1.00 g of lithium hydroxide monohydrate and 10 ml of chloroacetonitrile, then keep it at 50 °C for 10 h. Concentrate under reduced pressure to remove chloroacetonitrile 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 = 10:1 - 5:1) to obtain 1.51 g of off-white solid (2-methylbenzimidazol-1-yl)acetonitrile, with a yield of 88.3%. 1 1H-NMR (400 MHz, DMSO-d6 / TMS) δ: 2.55 (s, 3H, CH 3 ), 4.85 (s, 2H, CH 2 ), 7.18 (t, J = 8.8 Hz, 1H, ArH), 7.27 (t, J = 8.0 Hz, 1H, ArH), 7.52 (d, J = 8.8 Hz, 1H, ArH), 7.64 (d, J = 8.0 Hz, 1H, ArH).

[0065] (3) Place (1.71 g of (2-methylbenzimidazol-1-yl)acetonitrile) in a reaction flask, add 20 ml of 6 M hydrochloric acid, reflux for 5 h, then concentrate under reduced pressure and perform column chromatography (PE:EA = 10:1 - 5:1, gradient elution with 0.1% acetic acid) to obtain 1.62 g of white solid (2-methyl-benzimidazol-1-yl)acetic acid, with a yield of 85.3%.

[0066] 1 1H-NMR (400 MHz, CDCl 3 3 / TMS) δ: 2.53 (s, 3H, CH 3 ), 4.65 (s, 2H, CH 2 ),

[0067] 7.17 - 7.20 (m, 2H, ArH), 7.53 (m, 1H, ArH), 7.63 (m, 1H, ArH), 12.1 (brs, 1H, COOH).

[0068] (4) 1.90 g of (2-methyl-benzoimidazol-1-yl)acetic acid and 0.71 g of ethylamine 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 2-substituted-1H-benzoimidazole compound, which was a slightly white solid of 2.08 g with a yield of 90.0%. 1 H-NMR(400MHz,CDCl 3 / TMS)δ:0.98(t,J=8.8Hz,3H,CH 3 ),2.52(s,3H,CH 3 ),3.11(q,J=8.8Hz,2H,CH 2 ),4.61(t,J=8.8Hz,2H,CH 2 ),7.17-7.20(m,2H,ArH),7.53(m,1H,ArH),7.63(m,1H,ArH),8.01(brs,1H,NH)。

[0069] Example 2 Preparation of 2-substituted-1H-benzoimidazole compounds

[0070] The structure of the 2-substituted-1H-benzoimidazole compound is shown below:

[0071]

[0072] The preparation method thereof is as follows:

[0073] (1) 1.08 g of o-phenylenediamine was weighed, 1 ml of propionic acid was added, and then 30 ml of 6M hydrochloric acid was added. The mixture was stirred and refluxed under inert gas protection for 24 h. After the reaction was complete, it was allowed to stand overnight at room temperature, and a large amount of solid precipitated. It was filtered by suction, and the filter cake was washed with a small amount of water and dried to constant weight. After extraction with acetone (3×15 mL), 1.32 g of light blue solid 2-ethylbenzoimidazole hydrochloride was obtained with a yield of 84.5%. 1 H-NMR(400MHz,DMSO-d6 / TMS)δ:1.28(t,J=8.8Hz,3H,CH 3 ),2.97(q,J=8.8Hz,2H,CH 2 ),7.18(d,J=8.0Hz,2H,ArH),7.46(d,J=8.0Hz,2H,ArH),15.2(brs,2H,HCl,NH)。

[0074] (2) Weigh 1.68 g of 2-ethylbenzimidazole hydrochloride, add 1.00 g of lithium hydroxide monohydrate and 10 mL of chloroacetonitrile, keep warm at 50 °C for 10 h, concentrate under reduced pressure to remove chloroacetonitrile 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 = 10:1 - 5:1) to obtain 1.51 g of off-white solid (2-ethylbenzimidazol-1-yl)acetonitrile, with a yield of 88.3%. 1 H-NMR(400MHz,CDCl3 / TMS)δ:1.28(t,J=8.8Hz,3H,CH 3 ),2.97(q,J=8.8Hz,2H,CH 2 ),4.85(s,2H,CH 2 ),4.83(s,2H,CH 2 ),7.18(m,1H,ArH),7.27(m,1H,ArH),7.53(m,1H,ArH),7.64(m,1H,ArH).

[0075] (3) Place (1.85 g of (2-ethylbenzimidazol-1-yl)acetonitrile) in a reaction flask, add anhydrous methanol (10 mL), then add 10% Pd-C (50 mg), exhaust 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 then perform column chromatography (PE:EA = 10:1 - 5:1, gradient elution with 0.1% TEA) to obtain 1.81 g of white solid 2-(2-ethyl-1H-benzimidazol-1-yl)ethylamine, with a yield of 95.8%. 1 H-NMR(400MHz,CDCl3 / TMS)δ:1.28(t,J=8.8Hz,3H,CH 3 ),1.61(brs,2H,NH 2 ),2.81(q,J=8.8Hz,2H,CH 2 ),3.13(t,J=8.8Hz,2H,CH 2 ),4.56(t,J=8.8Hz,2H,CH 2 ),7.17 - 7.20(m,2H,ArH),7.51 - 7.53(m,2H,ArH).

[0076] (4) 1.89 g of 2-(2-ethyl-1H-benzoimidazol-1-yl)ethylamine and 0.82 g of propionic acid were added to 20 ml of anhydrous pyridine, then 3.0 g of DCC was added. After stirring at room temperature for 5 h, the pyridine was removed by concentration under reduced pressure as much as possible. The residue 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 purified by column chromatography (gradient elution with PE:EA = 20:1 - 10:1) to obtain the 2-substituted-1H-benzoimidazole compound as a light white solid (2.17 g, yield 88.6%). 1 1H-NMR (400 MHz, CDCl3 / TMS) δ: 0.98 (t, J = 8.0 Hz, 3H, CH 3 ), 1.28 (t, J = 8.4 Hz, 3H, CH 3 ), 2.25 (q, J = 8.8 Hz, 2H, CH 2 ), 2.81 (q, J = 8.8 Hz, 2H, CH 2 ), 3.68 (t, J = 8.8 Hz, 2H, CH 2 ), 4.56 (t, J = 8.8 Hz, 2H, CH 2 ), 7.17 - 7.20 (m, 2H, ArH), 7.51 - 7.53 (m, 2H, ArH), 8.01 (s, 1H, NH).

[0077] Example 3 Preparation of 2-substituted-1H-benzoimidazole compounds

[0078] The structure of the 2-substituted-1H-benzoimidazole compound is as follows:

[0079]

[0080] The preparation method is as follows:

[0081] (1) 1.08 g of o-phenylenediamine was weighed, 1 ml of propionic acid was added, and then 30 ml of 6 M hydrochloric acid was added. The mixture was stirred and refluxed under inert gas protection for 24 h. After the reaction was complete, it was allowed to stand overnight at room temperature, and a large amount of solid precipitated. The solid was filtered by suction, the filter cake was washed with a small amount of water, dried to constant weight, and extracted with acetone (3×15 mL) to obtain 1.32 g of light blue solid 2-ethylbenzimidazole hydrochloride, with a yield of 84.5%. 1 1H-NMR (400 MHz, DMSO-d6 / TMS) δ: 1.28 (t, J = 8.8 Hz, 3H, CH 3 ), 2.97 (q, J = 8.8 Hz, 2H, CH 2), 7.18 (d, J = 8.0 Hz, 2H, ArH), 7.46 (d, J = 8.0 Hz, 2H, ArH), 15.2 (brs, 2H, HCl, NH).

[0082] (2) Weigh 1.68 g of 2-ethylbenzimidazole hydrochloride, add 1.00 g of lithium hydroxide monohydrate and 10 ml of chloroacetonitrile, then keep it at 50 °C for 10 h. Concentrate under reduced pressure to remove chloroacetonitrile 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 = 10:1 - 5:1) to obtain 1.51 g of off-white solid (2-ethylbenzimidazol-1-yl)acetonitrile, with a yield of 88.3%. 1 1H-NMR (400 MHz, CDCl3 / TMS) δ: 1.28 (t, J = 8.8 Hz, 3H, CH 3 ), 2.97 (q, J = 8.8 Hz, 2H, CH 2 ), 4.85 (s, 2H, CH 2 ), 4.83 (s, 2H, CH 2 ), 7.18 (m, 1H, ArH), 7.27 (m, 1H, ArH), 7.53 (m, 1H, ArH), 7.64 (m, 1H, ArH).

[0083] (3) Place (2-ethylbenzimidazol-1-yl)acetonitrile (1.85 g) in a reaction flask, add 20 ml of 6 M hydrochloric acid, reflux for 5 h, then concentrate under reduced pressure and perform column chromatography (PE:EA = 10:1 - 5:1, gradient elution with 0.1% glacial acetic acid) to obtain 1.62 g of white solid (2-ethyl-benzimidazol-1-yl)acetic acid, with a yield of 85.3%. 1 1H-NMR (400 MHz, CDCl3 / TMS) δ: 1.28 (t, J = 8.8 Hz, 3H, CH 3 ), 2.81 (q, J = 8.8 Hz, 2H, CH 2 ), 4.67 (s, 2H, CH 2 ), 4.56 (t, J = 8.8 Hz, 2H, CH 2 ), 7.17 - 7.25 (m, 2H, ArH), 7.51 - 7.53 (m, 2H, ArH).

[0084] (4) 2.04 g of 2-(2-ethyl-1H-benzoimidazol-1-yl)acetic acid and 0.71 g of propylamine were added to 20 ml of anhydrous pyridine, 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 the 2-substituted-1H-benzoimidazole compound, which was a light white solid of 2.24 g with a yield of 91.4%. 1 H-NMR(400MHz,CDCl3 / TMS)δ:0.87(t,J=8.0Hz,3H,CH 3 ),1.28(t,J=8.4Hz,3H,CH 3 ),1.54(m,2H,CH 2 ),2.79(q,J=8.8Hz,2H,CH 2 ),3.42(t,J=8.8Hz,2H,CH 2 ),4.62(s,2H,CH 2 ),7.17 - 7.20(m,2H,ArH),7.51 - 7.53(m,2H,ArH),8.01(s,1H,NH)。

[0085] Example 4 Preparation of 2-substituted-1H-benzoimidazole compounds

[0086] The structure of the 2-substituted-1H-benzoimidazole compound is as follows:

[0087]

[0088] The preparation method thereof is as follows:

[0089] 1) Weigh 1.08 g of o-phenylenediamine, add 1 ml of glacial acetic acid, and then add 30 ml of 6M hydrochloric acid. Stir and reflux the reaction under inert gas protection for 24 h. After the reaction is complete, let it stand at room temperature overnight, and a large amount of solid will precipitate. Filter by suction, wash the filter cake with a small amount of water, dry it to constant weight, and extract with acetone (3×15 mL) to obtain 1.32 g of light blue solid 2-methylbenzoimidazole hydrochloride with a yield of 84.5%. 1 H-NMR(400MHz,DMSO-d6 / TMS)δ:2.76(s,3H,CH 3 ),7.18(d,J=8.0Hz,2H,ArH),7.52(d,J=8.8Hz,2H,ArH),15.2(brs,2H,HCl,NH)。

[0090] (2) Weigh 1.68 g of 2-methylbenzimidazole hydrochloride, add 1.00 g of lithium hydroxide monohydrate and 10 mL of chloroacetonitrile, then keep it at 50 °C for 10 h. Concentrate under reduced pressure to remove chloroacetonitrile 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 = 10:1 - 5:1) to obtain 1.51 g of off-white solid (2-methylbenzimidazol-1-yl)acetonitrile, with a yield of 88.3%. 1 H-NMR(400MHz,DMSO-d6 / TMS)δ:2.55(s,3H,CH 3 ),4.85(s,2H,CH 2 ),7.18(t,J=8.8Hz,1H,ArH),7.27(t,J=8.0Hz,1H,ArH),7.52(d,J=8.8Hz,1H,ArH),7.64(d,J=8.0Hz,1H,ArH).

[0091] (3) Place (1.71 g of (2-methylbenzimidazol-1-yl)acetonitrile) in a reaction flask, add 20 mL of 6M hydrochloric acid, reflux for 5 h, then concentrate under reduced pressure and perform column chromatography (PE:EA = 10:1 - 5:1, gradient elution with 0.1% acetic acid) to obtain 1.62 g of white solid (2-methyl-benzimidazol-1-yl)acetic acid, with a yield of 85.3%.

[0092] 1 H-NMR(400MHz,CDCl 3 / TMS)δ:2.53(s,3H,CH 3 ),4.65(s,2H,CH 2 ),

[0093] 7.17 - 7.20(m,2H,ArH),7.53(m,1H,ArH),7.63(m,1H,ArH),10.1(brs,1H,COOH).

[0094] (4) Add 1.90 g of (2-methyl-benzimidazol-1-yl)acetic acid and 0.71 g of propylamine to 20 mL of anhydrous pyridine, then add 3.0 g of DCC, stir at room temperature for 5 h, 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 a 2-substituted-1H-benzimidazole compound, which is 2.08 g of off-white solid, with a yield of 90.0%. 1H-NMR (400 MHz, CDCl3 / TMS) δ: 0.88 (t, J = 8.4 Hz, 3H, CH 3 ), 1.53 (m, 2H, CH 2 ), 2.53 (s, 3H, CH 3 ), 3.42 (t, J = 8.4 Hz, 2H, CH 2 ), 4.63 (s, 2H, CH 2 ), 7.17 - 7.20 (m, 2H, ArH), 7.53 (m, 1H, ArH), 7.63 (m, 1H, ArH), 8.01 (s, 1H, NH).

[0095] Preparation of 52-Substituted-1H-Benzimidazole Compounds

[0096] The structure of 2-Substituted-1H-benzimidazole compounds is shown as follows:

[0097]

[0098] The preparation method is as follows:

[0099] (1) Weigh 1.08 g of o-phenylenediamine, add 1 ml of glacial acetic acid, and then add 30 ml of 6 M hydrochloric acid. Stir and reflux the reaction under inert gas protection for 24 h. After the reaction is complete, let it stand at room temperature overnight. A large amount of solid will precipitate. Filter by suction, wash the filter cake with a small amount of water, dry it to constant weight, and extract it with acetone (3×15 mL) to obtain 1.32 g of light blue solid 2-methylbenzimidazole hydrochloride, with a yield of 84.5%. 1 H-NMR (400 MHz, DMSO-d6 / TMS) δ: 2.76 (s, 3H, CH 3 ), 7.18 (d, J = 8.0 Hz, 2H, ArH), 7.52 (d, J = 8.8 Hz, 2H, ArH), 15.2 (brs, 2H, HCl, NH).

[0100] (2) Weigh 1.68 g of 2-methylbenzimidazole hydrochloride, add 1.00 g of lithium hydroxide monohydrate and 10 ml of chloroacetonitrile, keep it at 50 °C for 10 h, concentrate under reduced pressure to remove chloroacetonitrile as much as possible, extract it with ethyl acetate (3×20 mL), combine the organic layers, wash with water (1×30 mL), wash with saturated brine (1×30 mL), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and then perform column chromatography (gradient elution with PE:EA = 10:1 - 5:1) to obtain 1.51 g of off-white solid (2-methylbenzimidazol-1-yl)acetonitrile, with a yield of 88.3%. 1 H-NMR (400 MHz, DMSO-d6 / TMS) δ: 2.55 (s, 3H, CH 3 ), 4.85 (s, 2H, CH2 ), 7.18 (t, J = 8.8 Hz, 1H, ArH), 7.27 (t, J = 8.0 Hz, 1H, ArH), 7.52 (d, J = 8.8 Hz, 1H, ArH), 7.64 (d, J = 8.0 Hz, 1H, ArH).

[0101] (3) Place (2-methylbenzimidazol-1-yl)acetonitrile (1.71 g) in a reaction flask, add 20 ml of 6 M hydrochloric acid, reflux for 5 h, then concentrate under reduced pressure and perform column chromatography (PE:EA = 10:1 - 5:1, gradient elution with 0.1% glacial acetic acid) to obtain 1.62 g of white solid (2-methyl-benzimidazol-1-yl)acetic acid, with a yield of 85.3%.

[0102] 1 H-NMR (400 MHz, CDCl 3 / TMS) δ: 2.53 (s, 3H, CH 3 ), 4.65 (s, 2H, CH 2 ),

[0103] 7.17 - 7.20 (m, 2H, ArH), 7.53 (m, 1H, ArH), 7.63 (m, 1H, ArH), 10.1 (brs, 1H, COOH).

[0104] (4) Add 1.90 g of (2-methyl-benzimidazol-1-yl)acetic acid and 0.85 g of cyclopropylmethylamine to 20 ml of anhydrous pyridine, then add 3.0 g of DCC, stir at room temperature for 5 h, 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 2.20 g of a 2-substituted-1H-benzimidazole compound, which is an off-white solid, with a yield of 90.9%. 1 H-NMR (400 MHz, CDCl 3 / TMS) δ: 0.15 - 0.45 (m, 4H, CH 2 ), 1.01 (m, 1H, CH), 2.53 (s, 3H, CH 3 ), 3.12 (d, J = 8.8 Hz, 2H, CH 2 ), 4.62 (s, 2H, CH 2 ), 7.17 - 7.20 (m, 2H, ArH), 7.53 (m, 1H, ArH), 7.63 (m, 1H, ArH), 8.01 (s, 1H, NH).

[0105] Preparation of 2-Substituted-1H-Benzimidazole Compounds

[0106] The structure of 2-substituted-1H-benzimidazole compounds is shown as follows:

[0107]

[0108] The preparation method is as follows:

[0109] (1) Weigh 1.08 g of o-phenylenediamine, add 1 ml of glacial acetic acid, and then add 30 ml of 6 M hydrochloric acid. Stir and reflux the reaction under inert gas protection for 24 h. After the reaction is complete, let it stand overnight at room temperature. A large amount of solid will precipitate. Filter by suction, wash the filter cake with a small amount of water, dry it to constant weight, and extract with acetone (3×15 mL) to obtain 1.32 g of light blue solid 2-methylbenzimidazole hydrochloride, with a yield of 84.5%. 1 H-NMR(400MHz,DMSO-d6 / TMS)δ:2.76(s,3H,CH 3 ),7.18(d,J=8.0Hz,2H,ArH),7.52(d,J=8.8Hz,2H,ArH),15.2(brs,2H,HCl,NH).

[0110] (2) Weigh 1.68 g of 2-methylbenzimidazole hydrochloride, add 1.00 g of lithium hydroxide monohydrate and 10 ml of chloroacetonitrile, keep it at 50 °C for 10 h, concentrate under reduced pressure to remove chloroacetonitrile 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 = 10:1 - 5:1) to obtain 1.51 g of off-white solid (2-methylbenzimidazol-1-yl)acetonitrile, with a yield of 88.3%. 1 H-NMR(400MHz,DMSO-d6 / TMS)δ:2.55(s,3H,CH 3 ),4.85(s,2H,CH 2 ),7.18(t,J=8.8Hz,1H,ArH),7.27(t,J=8.0Hz,1H,ArH),7.52(d,J=8.8Hz,1H,ArH),7.64(d,J=8.0Hz,1H,ArH).

[0111] (3) Place (2-methylbenzimidazol-1-yl)acetonitrile (1.71 g) in a reaction flask, add 20 ml of 6 M hydrochloric acid, reflux for 5 h, concentrate under reduced pressure, and then perform column chromatography (PE:EA = 10:1 - 5:1, gradient elution with 0.1% acetic acid) to obtain 1.62 g of white solid (2-methyl-benzimidazol-1-yl)acetic acid, with a yield of 85.3%.

[0112] 1 H-NMR (400 MHz, CDCl 3 / TMS) δ: 2.53 (s, 3H, CH 3 ), 4.65 (s, 2H, CH 2 ),

[0113] 7.17 - 7.20 (m, 2H, ArH), 7.53 (m, 1H, ArH), 7.63 (m, 1H, ArH), 10.1 (brs, 1H, COOH).

[0114] (4) 1.90 g of (2-methyl-benzoimidazol-1-yl)acetic acid and 1.02 g of cyclobutylmethylamine were added to 20 ml of anhydrous pyridine, 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), 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 2-substituted-1H-benzimidazole compound, which was a white solid, 2.27 g, with a yield of 88.3%. 1 H-NMR (400 MHz, CDCl 3 / TMS) δ: 1.21 - 2.2 (m, 6H, CH 2 ), 2.33 (m, 1H, CH), 2.49 (d, J =

[0115] 7.2 Hz, 2H, CH 2 ), 2.53 (s, 3H, CH 3 ), 4.62 (s, 2H, CH 2 ), 7.17 - 7.20 (m, 2H, ArH), 7.53 (m, 1H, ArH), 7.63 (m, 1H, ArH), 8.01 (s, 1H, NH).

[0116] Example 7 Preparation of 2-substituted-1H-benzimidazole compounds

[0117] The structure of the 2-substituted-1H-benzimidazole compound is as follows:

[0118]

[0119] The preparation method is as follows:

[0120] (1) Weigh 1.08 g of o-phenylenediamine. After adding 1.0 mL of cyclopropylformic acid, add 30 mL of 6 M hydrochloric acid. Stir and reflux the reaction under inert gas protection for 24 h. After the reaction is complete, let it stand at room temperature overnight. A large amount of solid will precipitate. Filter by suction. Wash the filter cake with a small amount of water and dry it to constant weight. After extraction with acetone (3×15 mL), 1.12 g of light blue solid 2-cyclopropylbenzimidazole hydrochloride is obtained, with a yield of 71.0%. 1 H-NMR(400MHz,CDCl 3 / TMS)δ:0.98-1.25(m,4H,CH 2 ),2.22(m,1H,CH),7.16(d,J=8.0Hz,2H,ArH),7.52(d,J=8.4Hz,2H,ArH),12.2(brs,2H,HCl,NH).

[0121] (2) Weigh 1.68 g of 2-cyclopropylbenzimidazole hydrochloride. Add 1.00 g of lithium hydroxide monohydrate and 10 mL of chloroacetonitrile. Keep the temperature at 50 °C for 10 h. Concentrate under reduced pressure to remove chloroacetonitrile 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 = 10:1 - 5:1) to obtain 1.32 g of off-white solid (2-cyclopropylbenzimidazol-1-yl)acetonitrile, with a yield of 67.0%. 1 H-NMR(400MHz,CDCl 3 / TMS)δ:0.98-1.25(m,4H,CH 2 ),2.22(m,1H,CH),4.85(s,2H,CH 2 ),7.17-7.20(m,2H,ArH),7.53(m,1H,ArH),7.63(m,1H,ArH).

[0122] (3) Place (2-cyclopropylbenzimidazol-1-yl)acetonitrile (1.71 g) in a reaction flask. Add 20 mL of 6 M hydrochloric acid. After refluxing for 5 h, concentrate under reduced pressure and then perform column chromatography (PE:EA = 10:1 - 5:1, gradient elution with 0.1% acetic acid) to obtain 1.52 g of white solid (2-cyclopropyl-benzimidazol-1-yl)acetic acid, with a yield of 70.4%. 1 H-NMR(400MHz,CDCl 3 / TMS)δ:0.98-1.25(m,4H,CH 2 ),2.22(m,1H,CH),4.65(s,2H,CH 2), 7.17 - 7.20 (m, 2H, ArH), 7.53 (m, 1H, ArH), 7.63 (m, 1H, ArH), 12.1 (brs, 1H, COOH).

[0123] (4) 2.16 g of (2 - cyclopropyl - benzimidazol - 1 - yl) acetic acid and 0.71 g of propylamine were added to 20 ml of anhydrous pyridine, then 3.0 g of DCC was added. After stirring at room temperature for 5 h, pyridine was removed as much as possible by concentration under reduced pressure. 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 purified by column chromatography (gradient elution with PE:EA = 20:1 - 10:1) to obtain 2 - substituted - 1H - benzimidazole compound, which was a light - white solid of 2.27 g, with a yield of 88.3%. 1 H - NMR (400 MHz, CDCl3 / TMS) δ: 0.86 (t, J = 8.4 Hz, 3H, CH 3 ), 0.98 - 1.25 (m, 4H, CH 2 ), 1.53 (m, 2H, CH 2 ), 2.22 (m, 1H, CH), 3.42 (t, J = 8.4 Hz, 2H, CH 2 ), 4.63 (s, 2H, CH 2 ), 7.17 - 7.20 (m, 2H, ArH), 7.53 (m, 1H, ArH), 7.63 (m, 1H, ArH), 8.01 (s, 1H, NH).

[0124] Example 8 Preparation of 2 - substituted - 1H - benzimidazole compounds

[0125] The structure of 2 - substituted - 1H - benzimidazole compounds is shown as follows:

[0126]

[0127] The preparation method is as follows:

[0128] (1) 1.08 g of o - phenylenediamine was weighed, 1.0 ml of cyclopropylformic acid was added, and then 30 ml of 6M hydrochloric acid was added. The mixture was stirred and refluxed under inert gas protection for 24 h. After the reaction was complete, it was allowed to stand overnight at room temperature, and a large amount of solid precipitated. It was filtered by suction, the filter cake was washed with a small amount of water, dried to constant weight, and extracted with acetone (3 × 15 mL) to obtain 1.12 g of light - blue solid 2 - cyclopropylbenzimidazole hydrochloride, with a yield of 71.0%. 1 H - NMR (400 MHz, CDCl 3 / TMS) δ: 0.98 - 1.25 (m, 4H, CH 2), 2.22 (m, 1H, CH), 7.16 (d, J = 8.0 Hz, 2H, ArH), 7.52 (d, J = 8.4 Hz, 2H, ArH), 12.2 (brs, 2H, HCl, NH).

[0129] (2) Weigh 1.68 g of 2-cyclopropylbenzimidazole hydrochloride, add 1.00 g of lithium hydroxide monohydrate and 10 mL of chloroacetonitrile, keep at 50 °C for 10 h, concentrate under reduced pressure to remove chloroacetonitrile 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 = 10:1 - 5:1) to obtain 1.32 g of off-white solid (2-cyclopropylbenzimidazol-1-yl)acetonitrile, with a yield of 67.0%. 1 H-NMR (400 MHz, CDCl 3 / TMS) δ: 0.98 - 1.25 (m, 4H, CH 2 ), 2.22 (m, 1H, CH), 4.85 (s, 2H, CH 2 ), 7.17 - 7.20 (m, 2H, ArH), 7.53 (m, 1H, ArH), 7.63 (m, 1H, ArH).

[0130] (3) Place (2-cyclopropylbenzimidazol-1-yl)acetonitrile (1.97 g) in a reaction flask, add anhydrous methanol (10 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 1.97 g of white solid 2-(2-cyclopropyl-1H-benzimidazol-1-yl)ethylamine, with a yield of 98.0%. 1 H-NMR (400 MHz, CDCl 3 / TMS) δ: 0.98 - 1.25 (m, 4H, CH 2 ), 1.50 (brs, 2H, NH 2 ), 2.22 (m, 1H, CH), 3.13 (t, J = 8.4 Hz, 2H, CH 2 ), 4.57 (t, J = 8.4 Hz, 2H, CH 2 ), 7.17 - 7.20 (m, 2H, ArH), 7.53 (m, 1H, ArH), 7.63 (m, 1H, ArH).

[0131] (4) 2.01 g of 2-(2-cyclopropyl-1H-benzoimidazol-1-yl)ethylamine and 0.89 g of propionic 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 as much as possible by concentration under reduced pressure. 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 2-substituted-1H-benzoimidazole compounds as a white solid, 1.88 g, with a yield of 73.2%. 1 H-NMR(400MHz,CDCl 3 / TMS)δ:0.98 - 1.25(m,7H,CH 2 ,CH 3 ),2.10 - 2.31(m,3H,CH,CH 2 ),3.13(t,J=8.4Hz,2H,CH 2 ),4.57(t,J=8.4Hz,2H,CH 2 ),7.17 - 7.20(m,2H,ArH),7.53(m,1H,ArH),7.63(m,1H,ArH). 8.01(s,1H,NH).

[0132] The technical solution of the present invention will be further described through experiments below.

[0133] Experimental Example 1 Screening of the biological activity of 2-substituted-1H-benzoimidazole compounds

[0134] I. Experimental method

[0135] The MT1 and MT2 cell lines correspond to human renal epithelial cells MT1-HEK293 and MT2-HEK293, respectively.

[0136] Using Dulbecco's modified Eagle medium, the cells were seeded at a density of 4×10 4 per well in a 96-well plate coated with Matrigel matrix, and incubated 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 culture medium, and add 100 μL / well of the commercially available HDB calcium flow 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 with 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 are 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).

[0137] II. Experimental Results

[0138] The results are shown in Table 1. The 2-substituted-1H-benzimidazole compound prepared in Example 2 has significant agonist activity against the melatonin receptor MT1, which is 131±1.86%. The results show that the 2-substituted-1H-benzimidazole compound prepared in the present invention has significant agonist activity against the melatonin receptor and can be used for preventing or / and treating various neurodegenerative diseases mediated by melatonin receptors.

[0139] Table 1

[0140]

[0141]

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; R2 is selected from C1-C5 alkyl, C3-C 10 Cycloalkyl; 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, methylcyclopropane, methylcyclobutane, methylcyclopentane and methylcyclohexane.

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, R2 is selected from C1-C5 alkyl, C3-C 10 Cycloalkyl; L3 is selected from C1-C5 alkyl, methylcyclopropane, methylcyclobutane, methylcyclopentane and methylcyclohexane.

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 R2 is selected from C1-C2 alkyl and C3 cycloalkyl; L3 is selected from C2-C3 alkyl, methylcyclopropane and methylcyclobutane.

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, R2 is selected from C1-C5 alkyl, C3-C 10 Cycloalkyl; L3 is selected from C1-C5 alkyl, methylcyclopropane, methylcyclobutane, methylcyclopentane and methylcyclohexane.

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 R2 is selected from a C2 alkyl group and a C3 cycloalkyl group; and L3 is selected from a C2 alkyl group.

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 carboxylic acid to obtain compound b; Step 2, reacting compound b with chloroacetonitrile to obtain compound c; Step 3 is performed by one of the following operations: A. hydrolyzing compound c to obtain compound d; reacting compound d with an amine compound to obtain a compound represented by formula II; Or, B. subjecting compound c to a reduction reaction to obtain an intermediate product e; subjecting the intermediate product e to an amidation reaction with carboxylic acid 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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