Substituted indanyl imidazole compounds, their preparation methods and uses

Abstract

The present invention relates to a compound represented by formula I, its pharmaceutically acceptable salts, isotopically labeled compounds, racemates, enantiomers, solvates, hydrates, crystal forms, or co-crystals, and also relates to pharmaceutical combinations containing the compound, and further relates to a method for preparing the compound and its use in the preparation of drugs. The compound can be used as an α2A-AR agonist, especially as a sedative and analgesic drug.

Description

Technical Field

[0001] The present invention relates to a substituted indanyl imidazole compound, its pharmaceutically acceptable salt, isotope-labeled compound, racemate, enantiomer, solvate, hydrate, crystal form or cocrystal, and also relates to a pharmaceutical combination containing the compound, and also relates to a preparation method of the compound and its application in the preparation of drugs. The compound can be used as an α 2A -AR agonist, especially as a sedative and analgesic drug. Background Art

[0002] α 2A -adrenergic receptor (α 2A -AR) is mainly located presynaptically and participates in various physiological or pharmacological effects in the body by regulating neurotransmitter release on adrenergic and noradrenergic neurons in the central nervous system through feedback. Its agonists have been used for decades to treat hypertension, attention deficit / hyperactivity disorder, various pains and panic disorders, as well as opioid, benzodiazepine class and alcohol withdrawal symptoms.

[0003] Numerous behavioral studies have shown that α 2A -AR agonists can significantly reduce mechanical hypersensitivity to pain caused by tissue and nerve damage, as well as allergic reactions to pain caused by thermal stimulation. Clinical studies have shown that α2-AR agonists can also have good effects on chronic pathological pain that is ineffective for traditional opioid analgesics.

[0004] Dexmedetomidine (DMED) was approved by the FDA at the end of 1999 and is used as a short-term drug for analgesia and sedation in the intensive care unit, and can also be used to assist anesthesia to reduce withdrawal symptoms caused by opioid receptor agonists. However, studies have shown that as the intravenous bolus or rapid infusion dose increases, the drug will lose its selectivity for α2-AR, activate postsynaptic α1-AR in the periphery, and cause side effects such as bradycardia or even asystole, tachycardia, hypertension, and hypotension. Therefore, there is an urgent clinical need to develop a new generation of highly efficient and highly selective α 2A -AR agonists for sedative and analgesic drugs. Summary of the Invention

[0005] The present invention provides a substituted indanyl imidazole derivative, which can be used as an α 2A -AR agonist, effectively activate α 2A -AR, inhibit the content of intracellular cAMP, and thus produce good sedative and analgesic effects.

[0006] In the first aspect of the present invention, there are provided a compound represented by Formula I, its pharmaceutically acceptable salt, isotope-labeled compound, racemate, enantiomer, solvate, hydrate, crystal form or cocrystal,

[0007]

[0008] Wherein:

[0009] X is -CH2- or -CH=CH-;

[0010] Y is -(CH2) n -, where n is 0, 1 or 2;

[0011] R1, R2, R3, R4, R5 and R6 are each independently selected from H, D, F, Cl, Br, I, -OH, -NH2, -NO2, -CN, C 1-10 alkyl, deuterated C 1-10 alkyl, C 1-10 alkoxy, C 1-10 alkylamino, -C(=O)NH-C 1-10 alkyl, -NHC(=O)-C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkylamino, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkylamino and 4-10 membered heterocycloalkyl substituted by a carbonyl group;

[0012] is a single bond or a double bond.

[0013] In certain embodiments, the compound according to the first aspect of the present invention has the structure shown in Formula I-1,

[0014]

[0015] wherein the definitions of R1, R2, R3, R4, R5, R6 and Y are as described in any embodiment of the present invention.

[0016] In certain embodiments, the compound according to the first aspect of the present invention has the structure shown in Formula I-2,

[0017]

[0018] Wherein the definitions of R1, R2, R3 and R4 are as described in any embodiment of the present invention.

[0019] In certain embodiments, the compound according to the first aspect of the present invention has the structure shown in Formula I-3,

[0020]

[0021] wherein the definitions of R1, R2, R3 and R4 are as described in any embodiment of the present invention.

[0022] In certain embodiments, in Formula I, Formula I-1, Formula I-2, or Formula I-3: R1, R2, R3, and R4 are each independently selected from H, D, F, Cl, Br, I, -OH, -NH2, -NO2, -CN, and C 1-6 alkyl groups.

[0023] In certain embodiments, in Formula I, Formula I-1, Formula I-2, or Formula I-3: R1, R2, R3, and R4 are each independently selected from H, D, F, Cl, Br, I, and C 1-4 alkyl groups.

[0024] In certain embodiments, in Formula I, Formula I-1, Formula I-2, or Formula I-3: R1, R2, R3, and R4 are each independently selected from H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, and n-butyl.

[0025] In certain embodiments, in Formula I, Formula I-1, Formula I-2, or Formula I-3: R1, R2, R3, and R4 are each independently selected from H, D, F, Cl, Br, I, and methyl.

[0026] In certain embodiments, in Formula I, Formula I-1, Formula I-2, or Formula I-3: R1, R2, R3, and R4 are each independently selected from H, F, Cl, Br, I, and methyl.

[0027] In certain embodiments, in Formula I, Formula I-1, Formula I-2, or Formula I-3: R1 is H, F, Cl, Br, or methyl.

[0028] In certain embodiments, in Formula I, Formula I-1, Formula I-2, or Formula I-3: R2 is H or F;

[0029] In certain embodiments, in Formula I, Formula I-1, Formula I-2, or Formula I-3: R3 is H, F, or Cl;

[0030] In certain embodiments, in Formula I, Formula I-1, Formula I-2, or Formula I-3: R4 is H, F, or Cl.

[0031] In certain embodiments, in Formula I or Formula I-1: R5, R6 are each independently selected from H, D, F, Cl, Br, I, -OH, -NH2, -NO2, -CN, and C 1-6 alkyl groups.

[0032] In certain embodiments, in Formula I or Formula I-1: R5, R6 are each independently selected from H, D, F, Cl, Br, I, and C 1-4 alkyl groups.

[0033] In certain embodiments, in Formula I or Formula I-1: R5 and R6 are each independently selected from H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, and n-butyl.

[0034] In certain embodiments, in Formula I or Formula I-1: R5 and R6 are each independently selected from H, D, F, Cl, Br, and I.

[0035] In certain embodiments, in Formula I or Formula I-1: R5 and R6 are each independently selected from H, F, Cl, Br, and I.

[0036] In certain embodiments, in Formula I or Formula I-1: R5 and R6 are each independently H.

[0037] In certain embodiments, the compounds according to the first aspect of the present invention are selected from the following:

[0038]

[0039]

[0040] The second aspect of the present invention provides a pharmaceutical composition comprising the compound according to the first aspect of the present invention, its pharmaceutically acceptable salt, isotopically labeled compound, racemate, enantiomer, solvate, hydrate, crystal form or cocrystal, and one or more pharmaceutically acceptable carriers or excipients.

[0041] The third aspect of the present invention provides a combination drug, which comprises the compound according to the first aspect of the present invention, its pharmaceutically acceptable salt, isotopically labeled compound, racemate, enantiomer, solvate, hydrate, crystal form or cocrystal, and at least one additional drug. In certain embodiments, the additional drug is a chemotherapeutic agent or an immunomodulator (such as an immune checkpoint inhibitor, a tyrosine kinase inhibitor, a proteasome inhibitor, an antibiotic, an alkylating agent, an antimetabolite, a hormone drug, an immunostimulatory agent, an interferon-like agent, and a mixed agent).

[0042] The fourth aspect of the present invention provides the use of the compound according to the first aspect of the present invention, its pharmaceutically acceptable salt, isotopically labeled compound, racemate, enantiomer, solvate, hydrate, crystal form or cocrystal, or the pharmaceutical composition according to the second aspect of the present invention, or the combination drug according to the third aspect of the present invention in the preparation of a drug for treating and / or preventing a disease or disorder.

[0043] In certain embodiments, the disease or disorder is related to α 2A -AR.

[0044] In certain embodiments, the disease or disorder is selected from cancer, pain, neurological diseases, and immune system diseases.

[0045] In certain embodiments, the disease or disorder is selected from hypertension, attention deficit / hyperactivity disorder, pain, panic disorder, opioid withdrawal symptoms, benzodiazepine withdrawal symptoms, alcohol withdrawal symptoms, and neurological diseases.

[0046] In certain embodiments, the neurological disease is selected from depression, anxiety, bipolar disorder, Alzheimer's disease, and Parkinson's disease.

[0047] The compounds of formula I of the present invention can be synthesized from commercially available starting materials by known methods. Exemplary preparation methods of the compounds of formula I may include (but are not limited to) the procedures described below. During the specific operation process, the steps in the method can be expanded or combined as needed.

[0048] The compounds of formula I can be synthesized according to the following route:

[0049] 1) Using 4-iodoimidazole as a starting material to react with triphenylmethyl chloride to form a triphenylmethyl (Trt)-protected compound 2;

[0050] 2) Exchanging the Grignard reagent of compound 2 with isopropylmagnesium chloride-lithium chloride, and then reacting with an indanone substituted with R (such as a benzene ring) to form compound 3;

[0051] 3) Dehydrating the alcohol hydroxyl group of compound 3 with Burgess reagent to obtain an alkene 4;

[0052] 4) Due to the large steric hindrance of the triphenylmethyl substituent, the protecting group is replaced with tert-butoxycarbonyl (Boc) in the subsequent reaction to obtain compound 6. Compound 6 reacts with diethylzinc and diiodomethane through Simmons-Smith cyclopropanation reaction to obtain compound 7, and then the protecting group is removed to generate the target compound 8; or

[0053] Compound 5 is reduced with hydrogen over palladium on carbon to obtain the target compound 9.

[0054]

[0055] Term Definitions

[0056] The various terms and phrases used in the present invention have the general meanings well-known to those skilled in the art. Even so, the present invention still wishes to provide a more detailed description and explanation of these terms and phrases herein. If the terms and phrases mentioned are inconsistent with the well-known meanings, the meanings expressed in the present invention shall prevail. The following are the definitions of various terms used in the present invention, and these definitions apply to the terms used throughout the specification of this application, unless otherwise specified in specific cases.

[0057] In the present invention, the term "alkyl" refers to a hydrocarbon group selected from saturated straight-chain and branched-chain hydrocarbon groups. Examples of alkanes include methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), and 1,1-dimethylethyl or tert-butyl ("t-Bu"). Other examples of alkyl groups include 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups.

[0058] In the present invention, the term "cycloalkyl" refers to a hydrocarbon group selected from saturated and partially unsaturated cycloaliphatic groups, which include monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, and the cycloalkyl may have 3-10 carbon atoms. For example, the cycloalkyl may be a monocyclic group having 3-10 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Examples of bicyclic cycloalkyl groups include bicyclic or bridged bicyclic structures composed of 7-12 ring atoms arranged in [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems or selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. The ring may be saturated or have at least one double bond (i.e., partially unsaturated), but not completely conjugated and not aromatic (as defined as aromatic herein).

[0059] In the present invention, the term "heterocycloalkyl" refers to a cycloalkyl as defined above in which at least one ring member is replaced by a heteroatom (such as heteroatoms O, S, N, etc.).

[0060] The compounds of the present invention may exist in tautomeric forms, and the present invention also encompasses such forms.

[0061] The present invention encompasses all possible crystalline forms or polymorphs of the compounds, which may be a single polymorph or a mixture of any proportion of more than one polymorph.

[0062] The compounds of the present invention may exist in the form of solvates (such as hydrates), wherein the compounds of the present application contain a solvent, such as water, methanol or ethanol, as a structural element of the crystal lattice of the compound. The amount of the solvent may be present in a stoichiometric or non-stoichiometric ratio.

[0063] In the present invention, the term "isotopically labeled compound" means that one or more atoms in the compound are replaced with atoms having the same number of atoms but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of isotopes suitable for incorporation into the compounds of the present invention include, but are not limited to, hydrogen isotopes such as 2 H, 3 H; carbon isotopes such as 11 C, 13 C and 14 C; chlorine isotopes such as 36 Cl; fluorine isotopes such as 18 F; iodine isotopes such as 123 I and 125 I; nitrogen isotopes such as 13 N and 15 N; oxygen isotopes such as 15 O, 17 O and 18 O; and sulfur isotopes such as 35 S.

[0064] In the present invention, the term "pharmaceutically acceptable" or "medicinally acceptable" which may be used interchangeably therewith, for example, when describing "pharmaceutically acceptable salts", means that the salt is not only physiologically acceptable to the subject, but also a synthetic substance having a use value in pharmacy, such as a salt formed as an intermediate during chiral resolution. Although such an intermediate salt cannot be directly administered to the subject, the salt can play a role in obtaining the end product of the present invention.

[0065] The compounds represented by formula (I) of the present invention may also be in the form of their salts, generally salts formed with organic or inorganic bases or acids. Pharmaceutically acceptable salts of the compounds of the present invention are preferred. Pharmaceutically acceptable salts of the compounds of the present invention may be salts formed by the substances of the present invention with inorganic acids, carboxylic acids or sulfonic acids. Particularly preferred are salts formed with, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid, citric acid, pamoic acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, tannic acid. Other acids, such as oxalic acid, although not pharmaceutically acceptable per se, can be used to prepare salts used as intermediates to obtain the compounds of the present invention and their pharmaceutically acceptable salts.

[0066] In the present invention, the term "pharmaceutically acceptable carrier and / or excipient" refers to a carrier and / or excipient that is pharmacologically and / or physiologically compatible with the subject and the active ingredient, which is well-known in the art (see, for example, Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995). Pharmaceutically acceptable carriers and / or excipients include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, beeswax, lanolin.

[0067] In the present invention, the term "pharmaceutical composition", which may also refer to "composition", can be used to achieve treatment and / or prevention of the diseases or disorders described in the present invention in a subject, particularly a mammal.

[0068] In the present invention, the purpose of "treatment" is to relieve, reduce, improve or eliminate the targeted disease state or disorder. If a subject has received a therapeutically effective amount of the compound, its pharmaceutically acceptable salt, isotopically labeled compound, racemate, enantiomer, solvate, hydrate, crystal form or co-crystal according to the methods described herein, and one or more indications and symptoms of the subject show an observable and / or detectable reduction or improvement, then the subject has been successfully "treated". It should also be understood that the treatment of the disease state or disorder not only includes complete treatment, but also includes cases where complete treatment is not achieved, but some biologically or medically relevant results are obtained.

[0069] In the present invention, the purpose of "prevention" is to avoid, reduce, prevent or delay the occurrence of a disease or disease-related symptoms, and such disease or disease-related symptoms have not yet occurred before the administration of the relevant drug. "Prevention" does not necessarily require completely preventing the occurrence of the disease or disease-related symptoms. For example, after the administration of the relevant drug, if the risk of a subject developing a specific disease or disease-related symptoms can be reduced, or the severity of the subsequent related symptoms can be attenuated, it can be considered that the occurrence or development of the disease has been "prevented".

[0070] The compound of the present invention as an active ingredient can have systemic and / or local effects, and therefore, it can be administered by suitable routes, such as oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, topical administration or in the form of implants.

[0071] The compound of the present invention as an active ingredient can also be administered in dosage forms suitable for these administration routes.

[0072] For oral administration, there are known dosage forms that can rapidly and / or in a modified manner deliver the active ingredient, such as tablets (uncoated tablets or coated tablets, such as tablets with enteric coating or film coating), capsules, dragees, granules, pills, powders, emulsions, suspensions and aerosols.

[0073] Parenteral administration may avoid the absorption step (intravenous, intra-arterial, intracardiac, intraspinal or intralumbar administration) or involve absorption (intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal administration). Dosage forms suitable for parenteral administration include preparations in the form of solutions, suspensions, emulsions, lyophilized products and sterile powders for injection and infusion.

[0074] Suitable for other administration routes are: for example, drugs for inhalation (especially powder inhalation, spraying), nasal drops / solutions, sprays; tablets or capsules for lingual, sublingual or buccal administration, suppositories, preparations for ears and eyes, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, emulsions, pastes, powders or implants, such as stent models.

[0075] The compound of the present invention can be converted into the said dosage forms by known methods.

[0076] The compound of the present invention or a pharmaceutical composition or combination product containing it can be administered in unit dosage form. Among them, the said pharmaceutical composition and combination product can contain 0.01 mg to 1000 mg of the compound of the present invention, its tautomer, its polymorph, its solvate, its prodrug, its isotope-labeled compound, or its pharmaceutically acceptable salt.

[0077] It must be recognized that the optimal dosage and interval of the compound of the present invention are determined by the properties of the compound and external conditions such as the form, route and site of administration and the specific mammal being treated, and this optimal dosage can be determined by conventional techniques. It must also be recognized that the optimal course of treatment, that is, the daily dose of the compound within a specified time, can be determined by methods well known in the art.

[0078] The actual dosage levels of the active ingredients in the pharmaceutical compositions and combination drugs of the present invention can be varied so that the amount of the active compound obtained can effectively achieve the desired therapeutic response for a specific patient, composition, and mode of administration. The dosage levels must be selected according to the activity of the specific compound, the route of administration, the severity of the condition being treated, and the condition and medical history of the patient to be treated. However, it is common practice in the art to start with a low dose of the compound at the level required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is obtained. Generally speaking, the dosage of the compound described in the present invention for mammals, especially humans, can range from 0.001 - 1000 mg / kg body weight / day.

[0079] Beneficial effects

[0080] The compound provided by the present invention can be used as an α 2A -AR agonist, effectively activating α 2A -AR and inhibiting the content of intracellular cAMP, thereby producing good sedative and analgesic effects. Description of the drawings

[0081] Figure 1 Shows the enantiomeric resolution chromatogram of the compound S-7-45, where: (A) is the liquid phase separation diagram of the racemate; (B) is the liquid chromatogram of the resolved compound S-7-45-1; (C) is the liquid chromatogram of the resolved compound S-7-45-2; (D) is the liquid chromatographic purity detection diagram of S-7-45-1; (E) is the liquid chromatographic purity detection diagram of S-7-45-2; (F) is the theoretical prediction and experimental ECD spectra of the compounds S-7-45-1 and S-7-45-2. Detailed implementation manners

[0082] The embodiments of the present invention will be described in detail below in conjunction with the examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. For those not specified in the examples, the conventional conditions or the conditions recommended by the manufacturer are followed. Those reagents or instruments not specified by the manufacturer can be obtained through commercial purchases as conventional products.

[0083] Example 1: Synthesis of 5-(5-methyl-6,6a-dihydro-1aH-cyclopropa[1,2-a]indene-1a-yl)-1H-imidazole (S-7-18)

[0084]

[0085] [1-1] Synthesis of 4-iodo-3-(triphenylmethyl)imidazole (Intermediate 2)

[0086] Weigh 1.90 g (10 mmol) of 4-iodoimidazole, add it to 20 mL of acetonitrile and stir to dissolve. Add 1.40 g (10 mmol) of K2CO3 powder and 2.80 g (10 mmol) of (chlorodiphenylmethyl)benzene, and react at room temperature for 2 h. After detecting by TLC that the reaction no longer proceeds, filter, and rotary evaporate the reaction solution. Purify by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 3.01 g of intermediate 2, a slightly yellowish white solid, with a yield of 69.0%. The mass spectrometry molecular weight only shows the ion peak of the Trt protecting group; 1 H NMR (600 MHz, DMSO-d6) δ (ppm) 7.43 (t, J = 1.8 Hz, 1H), 7.42 (d, J = 2.2 Hz, 3H), 7.41 (d, J = 1.7 Hz, 2H), 7.40 (t, J = 1.5 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.38 (d, J = 1.4 Hz, 1H), 7.36 (d, J = 1.5 Hz, 1H), 7.09 (d, J = 1.7 Hz, 3H), 7.08 (t, J = 1.4 Hz, 3H), 7.05 (d, J = 1.5 Hz, 1H).

[0087] [1-2] Synthesis of 4-methyl-1-[1-(triphenylmethyl)imidazol-5-yl]-2,3-dihydro-1H-inden-1-ol (intermediate 3)

[0088] Weigh 2.18 g (5 mmol) of intermediate 2, add it to a 50 mL two-necked round-bottom flask, protect with nitrogen, and place it in a -20 °C low-temperature reactor. Add 10 mL of ultra-dry tetrahydrofuran and 5 mL of a 1 M solution of isopropylmagnesium chloride-lithium chloride complex in tetrahydrofuran to the flask, and stir for 1 h. Use a syringe to add 0.73 g (5 mmol) of 4-methyl-2,3-dihydro-1H-inden-1-one (dissolved in 10 mL of ultra-dry tetrahydrofuran) to the flask, and slowly warm up to -5 °C, and continue to stir for 3 h. After detecting by TLC that the reaction no longer proceeds, add 5 mL of saturated NH4Cl solution to the flask to quench, place it in a separatory funnel, and take the upper organic layer and rotary evaporate. Purify by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 1.82 g of intermediate 3, a white solid, with a yield of 79.8%. The mass spectrometry molecular weight only shows the ion peak of the Trt protecting group; 11H NMR (600 MHz, DMSO-d6) δ (ppm) 7.21 (d, J = 1.5 Hz, 1H), 7.14 - 7.06 (m, 13H), 7.02 (t, J = 7.4 Hz, 1H), 6.99 (d, J = 5.8 Hz, 2H), 6.89 (d, J = 1.6 Hz, 1H), 6.82 (d, J = 1.5 Hz, 1H), 6.75 (d, J = 7.3 Hz, 1H), 5.27 (s, 1H), 2.91 (dt, J = 15.1, 7.4 Hz, 1H), 2.80 (m, 1H), 2.68 (m, 1H), 2.22 (s, 3H), 2.14 (m, 1H).

[0089] [1 - 3] Synthesis of 5-(4-methyl-3H-indenyl)-1H-imidazole (Intermediate 5)

[0090] Weigh 1.82 g of Intermediate 3 (4 mmol), add 10 mL of dichloromethane, add 2.38 g (10 mmol) of Burgess reagent, and stir at room temperature for 2 h. After TLC detection shows that the reaction no longer proceeds, spin-dry the reaction solution and extract it 3 times with water and ethyl acetate. After combining the organic phases and spin-drying, add 5 mL of trifluoroacetic acid and stir for 1 h. After TLC detection shows that the Trt protecting group has been removed, add 10 mL of water and 20 mL of ethyl acetate, and adjust the pH to neutral with K2CO3 powder. Extract 3 times with 15 mL of ethyl acetate, combine the organic phases and spin-dry, and purify by silica gel column chromatography (dichloromethane:methanol:ammonia water = 10:1:0.5) to obtain 0.71 g of Intermediate 5, a yellow solid, with a yield of 90.6%. ESI-MS m / z: 197.11 [M + H] + ; 1 1H NMR (600 MHz, DMSO-d6) δ (ppm) 12.30 (s, 1H), 7.90 - 7.65 (m, 2H), 7.57 (s, 1H), 7.25 (t, J = 7.5 Hz, 1H), 7.06 (d, J = 7.4 Hz, 1H), 6.81 (t, J = 2.3 Hz, 1H), 2.36 (s, 3H).

[0091] [1 - 4] Synthesis of 5-(5-methyl-6,6a-dihydro-1aH-cyclopropa[1,2-a]inden-1a-yl)-1H-imidazole (S-7-18)

[0092] Weigh 0.60 g of Intermediate 5 (3 mmol), add 20 mL of dichloromethane and 1.31 g (6 mmol) of Boc anhydride to a round-bottom flask, stir until dissolved, and add 2 mL of N,N-dimethyl ethylamine to the reaction system. After TLC detection shows that the reaction is complete, extract with 10 mL of water. After spin-drying the organic phase, dry it in a blast drying oven to obtain Intermediate 6.

[0093] Add 50 mL of ultradry dichloromethane to a 250 mL two-necked round-bottom flask protected by argon, and place it in a low-temperature reactor at -50 °C. Add 50 mL of 1 M diethylzinc toluene solution, and slowly add 10 mL of diiodomethane dropwise using a separatory funnel. Stir vigorously for 1 h. Dissolve intermediate 6 in 20 mL of ultradry dichloromethane, slowly add it to the reaction system, and slowly warm up to -20 °C, and react overnight. After the reaction is completed, carefully pour out the upper clear liquid, spin-dry it, add 10 mL of trifluoroacetic acid, and stir at room temperature for 1 h. After the reaction is completed, dilute with water and adjust the pH to neutral with K2CO3 powder. Extract with ethyl acetate three times, combine the organic phases, spin-dry them, and purify by silica gel column chromatography (dichloromethane:methanol:ammonia water = 10:1:0.5) to obtain compound 8, namely S-7-18, 101 mg, yellow solid, yield 16.0%. ESI-MS m / z: 211.1231 [M+H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.57 (d, J = 1.2 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.98 - 6.89 (m, 2H), 3.12 (dd, J = 17.0, 6.7 Hz, 1H), 2.84 (d, J = 17.0 Hz, 1H), 2.18 (s, 3H), 2.00 (m, 1H), 1.72 (dd, J = 8.2, 3.9 Hz, 1H), 0.41 (t, J = 4.2 Hz, 1H). 13 13C NMR (151 MHz, DMSO) δ (ppm) 147.33, 140.87, 135.19, 134.72, 126.93, 126.56, 121.31, 33.99, 25.98, 23.61, 19.01.

[0094] Example 2: Synthesis of 5-(5-fluoro-6,6a-dihydro-1aH-cyclopropa[1,2-a]indene-1a-yl)-1H-imidazole (S-7-19)

[0095] Referring to the method of compound S-7-18 in Example 1, replace 4-methyl-2,3-dihydro-1H-indene-1-one in step [1-2] with 4-fluoro-2,3-dihydro-1H-indene-1-one to prepare compound S-7-19, obtaining 121 mg of yellow solid, yield 20.0%. ESI-MS m / z: 215.0979 [M+H] + ; 11H NMR (600 MHz, DMSO-d6) δ (ppm) 11.97 (s, 1H), 7.57 (s, 1H), 7.23 - 7.12 (m, 2H), 7.00 (s, 1H), 6.93 (t, J = 8.7 Hz, 1H), 3.21 (dd, J = 17.1, 6.7 Hz, 1H), 2.95 (d, J = 17.1 Hz, 1H), 2.07 (td, J = 7.5, 4.8 Hz, 1H), 1.75 (dd, J = 8.3, 4.2 Hz, 1H), 0.49 (t, J = 4.4 Hz, 1H). 13 13C NMR (151 MHz, DMSO) δ (ppm) 160.62, 159.00, 151.60, 128.86, 128.81, 127.51, 127.39, 120.17, 112.85, 112.72, 40.42, 40.28, 40.14, 40.00, 39.86, 39.72, 39.59, 31.23, 26.43, 23.70, 0.58.

[0096] Example 3: Synthesis of 5-(1,2-dihydrocyclopenta[3,2,1-ij]naphthalen-1-yl)-1H-imidazole (S-7-21)

[0097] Referring to the method of compound S-7-18 in Example 1, replace 4-methyl-2,3-dihydro-1H-inden-1-one in step [1-2] with 1-acenaphthenone to prepare compound S-7-21, obtaining 135 mg of a yellow solid with a yield of 12.3%. ESI-MS m / z: 221.1077 [M + H] + ; 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.71 - 7.62 (m, 3H), 7.50 (m, 2H), 7.36 (d, J = 6.8 Hz, 1H), 7.27 (dd, J = 6.9, 1.4 Hz, 1H), 6.92 (s, 1H), 4.92 (dd, J = 8.6, 4.4 Hz, 1H), 3.82 (dd, J = 17.3, 8.5 Hz, 1H), 3.51 (dd, J = 17.4, 4.4 Hz, 1H). 13 13C NMR (151 MHz, DMSO) δ (ppm) 148.31, 144.60, 138.25, 135.76, 131.52, 128.48, 128.42, 123.00, 122.67, 120.17, 119.69, 41.88, 38.60.

[0098] Example 4: Synthesis of 5-(4-fluoro-3H-indenyl)-1H-imidazole (S-7-22)

[0099] Referring to the preparation method of Intermediate 5 in Example 1, replace 4-methyl-2,3-dihydro-1H-inden-1-one in Step [1-2] with 4-fluoro-2,3-dihydro-1H-inden-1-one to prepare Compound S-7-22, obtaining 80 mg of a yellow solid with a yield of 70.2%. ESI-MS m / z: 201.0824 [M+H] + ; 1 H NMR (600 MHz, DMSO-d6) δ (ppm) 12.29 (s, 1H), 7.93 - 7.80 (m, 1H), 7.77 (s, 1H), 7.64 (d, J = 22.5 Hz, 1H), 7.39 (td, J = 7.9, 5.3 Hz, 1H), 7.13 - 7.00 (m, 1H), 6.84 (d, J = 2.3 Hz, 1H), 3.56 (d, J = 2.4 Hz, 2H). 13 C NMR (151 MHz, DMSO) δ (ppm) 159.42, 157.81, 136.24, 135.60, 129.81, 129.68, 129.12, 129.07, 128.27, 118.24, 112.09, 111.95, 34.44.

[0100] Example 5: Synthesis of 5-(4-fluoro-2,3-dihydro-1H-indenyl)-1H-imidazole (S-7-23)

[0101] Weigh 0.10 g (0.5 mmol) of Compound S-7-22 in a round-bottom flask, add 10 mL of anhydrous ethanol and stir to dissolve. Then add 50.23 mg of palladium-carbon, and react with hydrogen for 5 h. Filter, and rotary evaporate the filtrate to obtain Compound S-7-23, 90 mg of a white powder with a yield of 89.0%. ESI-MS m / z: 203.0980 [M+H] + ; 1 HNMR (400 MHz, DMSO-d6) δ (ppm) 7.58 (d, J = 1.1 Hz, 1H), 7.18 (td, J = 7.8, 5.4 Hz, 1H), 7.03 - 6.91 (m, 2H), 6.84 (s, 1H), 4.38 (t, J = 8.1 Hz, 1H), 3.04 (m, 1H), 2.90 (dt, J = 16.0, 8.1 Hz, 1H), 2.46 (td, J = 8.1, 4.1 Hz, 1H), 2.23 (m, 1H). 13CNMR(151MHz, DMSO) δ(ppm) 159.96, 158.34, 150.62, 150.58, 135.60, 129.49, 129.37, 128.81, 128.76, 120.92, 120.90, 113.32, 113.19, 43.82, 33.19, 27.38.

[0102] Example 6: Synthesis of 5-(5-Fluoro-2,3-dihydro-1H-indenyl)-1H-imidazole (S-7-24)

[0103] Referring to the preparation method of Intermediate 5 in Example 1, replace 4-Methyl-2,3-dihydro-1H-inden-1-one in Step [1-2] with 5-Fluoro-2,3-dihydro-1H-inden-1-one to prepare 5-(5-Fluoro-3H-indenyl)-1H-imidazole.

[0104] Referring to the preparation method of Compound S-7-23 in Example 5, replace Compound S-7-22 with 5-(5-Fluoro-3H-indenyl)-1H-imidazole to prepare Compound S-7-24, obtaining 93 mg of a yellow solid with a yield of 71.5%. ESI-MS m / z: 203.0982 [M+H] + ; 1 H NMR(600MHz, DMSO-d6) δ(ppm) 7.66(s, 1H), 7.11 - 7.05(m, 2H), 6.91(m, 1H), 6.83(s, 1H), 4.28(t, J = 8.0Hz, 1H), 2.96(m, 1H), 2.87(m, 1H), 2.43(m, 1H), 2.18(m, 1H). 13 C NMR(151MHz, DMSO) δ(ppm) 162.73, 161.13, 146.33, 146.28, 142.24, 142.22, 135.43, 125.99, 125.93, 113.33, 113.19, 111.69, 111.54, 42.51, 33.70, 31.60, 31.59.

[0105] Example 7: Synthesis of 5-(4-Fluoro-6,6a-dihydro-1aH-cyclopropa[1,2-a]inden-1a-yl)-1H-imidazole (S-7-25)

[0106] Referring to the method of compound S-7-18 in Example 1, replace 4-methyl-2,3-dihydro-1H-inden-1-one in step [1-2] with 5-fluoro-2,3-dihydro-1H-inden-1-one to prepare compound S-7-25, obtaining 83 mg of a yellow solid with a yield of 12.3%. ESI-MS m / z: 215.0981 [M+H] + ; 1 H NMR (600 MHz, DMSO-d6) δ (ppm) 11.90 (s, 1H), 7.55 (s, 1H), 7.30 (t, J = 6.8 Hz, 1H), 7.01 (dd, J = 9.4, 2.5 Hz, 1H), 6.97 (s, 1H), 6.92 (m, 1H), 3.24 (dd, J = 17.3, 6.7 Hz, 1H), 2.90 (d, J = 17.4 Hz, 1H), 2.01 (m, 1H), 1.69 (dd, J = 8.3, 4.1 Hz, 1H), 0.42 (t, J = 4.4 Hz, 1H). 13 C NMR (151 MHz, DMSO) δ (ppm) 162.18, 160.59, 144.64, 144.58, 143.64, 135.32, 124.98, 124.92, 113.04, 112.93, 112.89, 112.79, 35.08, 35.06, 26.36, 23.59.

[0107] Example 8: Synthesis of 5-(6-fluoro-2,3-dihydro-1H-indenyl)-1H-imidazole (S-7-27)

[0108] Referring to the preparation method of compound S-7-23 in Example 5, replace compound S-7-22 with 5-(6-fluoro-3H-indenyl)-1H-imidazole to prepare compound S-7-27, obtaining 83 mg of a yellow solid with a yield of 82.4%. ESI-MS m / z: 203.0980 [M+H] + ; 1 H NMR (600 MHz, DMSO-d6) δ (ppm) 7.66 (dd, J = 5.3, 2.8 Hz, 1H), 7.25 (dd, J = 8.2, 5.4 Hz, 1H), 6.95 (td, J = 9.0, 2.5 Hz, 1H), 6.89 - 6.83 (m, 2H), 4.31 (t, J = 8.1 Hz, 1H), 2.93 (m, 1H), 2.84 (m, 1H), 2.43 (m, 1H), 2.20 (m, 1H). 1313C NMR (151 MHz, DMSO) δ (ppm) 162.58, 160.99, 149.00, 148.95, 139.52, 139.51, 135.53, 125.96, 125.91, 115.75, 113.65, 113.50, 111.65, 111.50, 43.50, 33.67, 30.82.

[0109] Example 9: Synthesis of 5-(3-fluoro-6,6a-dihydro-1aH-cyclopropa[1,2-a]indene-1a-yl)-1H-imidazole (S-7-28)

[0110] Referring to the method of compound S-7-18 in Example 1, replacing 4-methyl-2,3-dihydro-1H-inden-1-one in step [1-2] with 6-fluoro-2,3-dihydro-1H-inden-1-one to prepare compound S-7-28, 123 mg of yellow solid was obtained, with a yield of 12.9%. ESI-MS m / z: 215.0980 [M+H] + ; 1 1H NMR (600 MHz, DMSO-d6) δ (ppm) 11.94 (s, 1H), 7.56 (d, J = 1.2 Hz, 1H), 7.18 (dd, J = 8.3, 5.4 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 7.01 (s, 1H), 6.91 (m, 1H), 3.19 (m, 1H), 2.88 (d, J = 16.8 Hz, 1H), 2.06 (m, 1H), 1.72 (dd, J = 8.2, 4.1 Hz, 1H), 0.46 (t, J = 4.4 Hz, 1H). 13 13C NMR (151 MHz, DMSO) δ (ppm) 162.45, 160.86, 150.27, 150.22, 137.64, 137.62, 135.37, 127.05, 126.99, 112.85, 112.70, 111.15, 111.00, 34.31, 26.94, 23.90.

[0111] Example 10: Synthesis of 5-(7-fluoro-2,3-dihydro-1H-indenyl)-1H-imidazole (S-7-30)

[0112] Referring to the preparation method of compound S-7-23 in Example 5, replacing compound S-7-22 with 5-(7-fluoro-3H-indenyl)-1H-imidazole to prepare compound S-7-30, 112 mg of yellow solid was obtained, with a yield of 72.4%. ESI-MS m / z: 203.23 [M+H] + ; 11H NMR (600 MHz, DMSO-d6) δ (ppm) 11.86 (s, 1H), 7.51 (d, J = 1.3 Hz, 1H), 7.21 (td, J = 7.8, 5.2 Hz, 1H), 7.09 (d, J = 7.4 Hz, 1H), 6.90 (t, J = 8.9 Hz, 1H), 6.62 (s, 1H), 4.49 (dd, J = 8.5, 4.3 Hz, 1H), 3.04 (dt, J = 16.0, 8.0 Hz, 1H), 2.87 (m, 1H), 2.40 (dq, J = 12.5, 8.3 Hz, 1H), 2.17 (m, 1H). 13 13C NMR (151 MHz, DMSO) δ (ppm) 160.37, 158.74, 148.13, 148.10, 135.26, 132.06, 131.95, 129.36, 129.32, 120.94, 120.92, 113.49, 113.35, 33.92, 31.86.

[0113] Example 11: Synthesis of 5-(2-fluoro-6,6a-dihydro-1aH-cyclopropa[1,2-a]indene-1a-yl)-1H-imidazole (S-7-31)

[0114] Referring to the method of compound S-7-18 in Example 1, replace 4-methyl-2,3-dihydro-1H-indene-1-one in step [1-2] with 7-fluoro-2,3-dihydro-1H-indene-1-one to prepare compound S-7-31, obtaining 112 mg of a yellow solid with a yield of 11.8%. ESI-MS m / z: 215.0979 [M+H] + ; 1 1H NMR (600 MHz, DMSO-d6) δ (ppm) 7.55 (s, 1H), 7.16 (td, J = 7.8, 5.0 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 6.90 (dd, J = 10.3, 8.1 Hz, 2H), 2.94 (d, J = 17.3 Hz, 1H), 1.86 (d, J = 3.3 Hz, 2H), 0.55 (s, 1H). 13 13C NMR (151 MHz, DMSO) δ (ppm) 160.34, 158.70, 146.32, 128.46, 128.41, 121.95, 121.93, 113.88, 113.74, 35.31, 26.97, 22.34.

[0115] Example 12: Synthesis of 5-(4,7-difluoro-2,3-dihydro-1H-indenyl)-1H-imidazole (S-7-33)

[0116] Referring to the preparation method of compound S-7-23 in Example 5, replace compound S-7-22 with 5-(4,7-difluoro-3H-indenyl)-1H-imidazole to prepare compound S-7-33, obtaining 60 mg of a yellow solid with a yield of 82.3%. ESI-MS m / z: 221.0886 [M+H] + ; 1 H NMR (600 MHz, DMSO-d6) δ (ppm) 11.87 (s, 1H), 7.04 (td, J = 8.5, 3.8 Hz, 1H), 6.96 (td, J = 8.7, 3.9 Hz, 1H), 6.69 (s, 1H), 4.53 (dd, J = 8.6, 4.2 Hz, 1H), 3.04 (dt, J = 16.1, 8.0 Hz, 1H), 2.91 (ddd, J = 16.1, 8.7, 4.5 Hz, 1H), 2.48 - 2.41 (m, 1H), 2.22 (m, 1H). 13 C NMR (151 MHz, DMSO) δ (ppm) 156.20, 155.90, 154.61, 154.30, 154.27, 135.41, 135.19, 133.00, 132.96, 132.86, 132.82, 115.46, 115.40, 115.38, 115.33, 115.31, 115.25, 115.23, 115.18, 41.35, 33.93, 28.13.

[0117] Example 13: Synthesis of 5-(2,5-difluoro-6,6a-dihydro-1aH-cyclopropa[1,2-a]inden-1a-yl)-1H-imidazole (S-7-34)

[0118] Referring to the method of compound S-7-18 in Example 1, replace 4-methyl-2,3-dihydro-1H-inden-1-one in step [1-2] with 4,7-difluoro-2,3-dihydro-1H-inden-1-one to prepare compound S-7-34, obtaining 89 mg of a yellow solid with a yield of 13.3%. ESI-MS m / z: 233.0882 [M+H] + ; 1 H NMR (600 MHz, DMSO-d6) δ (ppm) 11.98 (s, 1H), 7.54 (s, 1H), 6.99 (t, J = 4.4 Hz, 2H), 6.94 (d, J = 15.2 Hz, 1H), 3.27 (d, J = 6.4 Hz, 1H), 2.96 (d, J = 17.4 Hz, 1H), 1.98 - 1.81 (m, 2H), 0.65 (t, J = 4.3 Hz, 1H). 1313C NMR(151MHz, DMSO) δ(ppm) 156.39, 156.27, 154.68, 115.89, 115.68, 114.67, 114.51, 114.46, 31.69, 27.38, 22.20.

[0119] Example 14: Synthesis of 5-(3,5-difluoro-6,6a-dihydro-1aH-cyclopropa[1,2-a]indene-1a-yl)-1H-imidazole (S-7-39)

[0120] Referring to the method of compound S-7-18 in Example 1, replace 4-methyl-2,3-dihydro-1H-indene-1-one in step [1-2] with 4,6-difluoro-2,3-dihydro-1H-indene-1-one to prepare compound S-7-39, obtaining 122 mg of a yellow solid with a yield of 11.3%. ESI-MS m / z: 233.0887 [M+H] + ; 1 1H NMR(600MHz, DMSO-d6) δ(ppm) 11.94(s, 1H), 7.57(d, J = 1.2Hz, 1H), 7.03(s, 2H), 6.94(td, J = 9.5, 2.1Hz, 1H), 3.17(dd, J = 17.1, 6.6Hz, 1H), 2.93(d, J = 16.9Hz, 1H), 2.17 - 2.06(m, 1H), 1.75(dd, J = 8.2, 4.2Hz, 1H), 0.55(t, J = 4.3Hz, 1H). 13 13C NMR(151MHz, DMSO) δ(ppm) 162.88, 162.81, 161.27, 161.20, 160.01, 159.92, 158.37, 158.28, 152.80, 135.49, 123.39, 123.37, 123.27, 123.25, 107.77, 107.62, 101.49, 101.32, 101.15, 30.78, 26.94, 23.95.

[0121] Example 15: Synthesis of 5-(3-chloro-5-fluoro-6,6a-dihydro-1aH-cyclopropa[1,2-a]indene-1a-yl)-1H-imidazole (S-7-40)

[0122] Referring to the method of compound S-7-18 in Example 1, replace 4-methyl-2,3-dihydro-1H-indene-1-one in step [1-2] with 6-chloro-4-fluoro-2,3-dihydro-1H-indene-1-one to prepare compound S-7-40, obtaining 70 mg of a yellow solid with a yield of 14.2%. ESI-MS m / z: 249.0590 [M+H]+ ; 1 1H NMR (600 MHz, DMSO-d6) δ (ppm) 11.93 (s, 1H), 7.58 (s, 1H), 7.27 - 6.99 (m, 3H), 3.18 (dd, J = 17.2, 6.6 Hz, 1H), 2.94 (d, J = 17.3 Hz, 1H), 2.22 - 2.05 (m, 1H), 1.73 (dd, J = 8.0, 4.1 Hz, 1H), 0.54 (t, J = 4.5 Hz, 1H). 13 13C NMR (151 MHz, DMSO) δ (ppm) 160.19, 158.54, 153.28, 135.57, 132.11, 132.05, 126.77, 126.65, 120.56, 113.59, 113.43, 31.03, 26.67, 23.81.

[0123] Example 16: Synthesis of 5-(3-chloro-6,6a-dihydro-1aH-cyclopropa[1,2-a]indene-1a-yl)-1H-imidazole (S-7-41)

[0124] Referring to the method of compound S-7-18 in Example 1, replace 4-methyl-2,3-dihydro-1H-inden-1-one in step [1-2] with 6-chloro-2,3-dihydro-1H-inden-1-one to prepare compound S-7-41, obtaining 98 mg of yellow solid with a yield of 18.5%. ESI-MS m / z: 231.0683 [M+H] + ; 1 1H NMR (600 MHz, DMSO-d6) δ (ppm) 8.42 (s, 1H), 7.40 (d, J = 1.3 Hz, 1H), 7.28 - 7.16 (m, 3H), 3.24 (dd, J = 17.2, 6.7 Hz, 1H), 2.94 (d, J = 17.3 Hz, 1H), 2.18 (ddd, J = 8.3, 6.6, 4.7 Hz, 1H), 1.78 (dd, J = 8.4, 4.6 Hz, 1H), 0.58 (t, J = 4.7 Hz, 1H). 13 13C NMR (151 MHz, DMSO) δ (ppm) 148.83, 140.90, 135.45, 131.26, 127.72, 126.63, 123.63, 34.47, 30.82, 26.66, 23.14.

[0125] Example 17: Synthesis of 5-(5-chloro-6,6a-dihydro-1aH-cyclopropa[1,2-a]indene-1a-yl)-1H-imidazole (S-7-45)

[0126] Referring to the method of compound S-7-18 in Example 1, replace 4-methyl-2,3-dihydro-1H-inden-1-one in step [1-2] with 4-chloro-2,3-dihydro-1H-inden-1-one to prepare compound S-7-45, obtaining 108 mg of a yellow solid with a yield of 19.1%. ESI-MS m / z: 231.07 [M+H] + ; 1 H NMR (600 MHz, DMSO-d6) δ (ppm) 12.01 (s, 1H), 7.64 - 7.54 (m, 1H), 7.26 (q, J = 4.4 Hz, 1H), 7.18 (d, J = 3.8 Hz, 2H), 7.01 (d, J = 4.0 Hz, 1H), 3.21 (dd, J = 17.4, 6.7 Hz, 1H), 2.94 (d, J = 17.4 Hz, 1H), 2.09 - 2.00 (m, 1H), 1.75 (dd, J = 8.2, 4.2 Hz, 1H), 0.51 (t, J = 4.5 Hz, 1H).

[0127] Example 18: Synthesis of 5-(5-bromo-6,6a-dihydro-1aH-cyclopropa[1,2-a]inden-1a-yl)-1H-imidazole (S-7-46)

[0128] Referring to the method of compound S-7-18 in Example 1, replace 4-methyl-2,3-dihydro-1H-inden-1-one in step [1-2] with 4-bromo-2,3-dihydro-1H-inden-1-one to prepare compound S-7-46, obtaining 104 mg of a yellow solid with a yield of 15.7%. ESI-MS m / z: 275.0179 [M+H] + ; 1 H NMR (600 MHz, DMSO-d6) δ (ppm) 11.93 (s, 1H), 7.55 (d, J = 1.1 Hz, 1H), 7.31 (t, J = 8.4 Hz, 2H), 7.10 (t, J = 7.7 Hz, 1H), 6.99 (s, 1H), 3.17 (dd, J = 17.4, 6.7 Hz, 1H), 2.90 (d, J = 17.4 Hz, 1H), 2.14 - 1.96 (m, 1H), 1.74 (dd, J = 8.3, 4.2 Hz, 1H), 0.51 (t, J = 4.4 Hz, 1H). 13 C NMR (151 MHz, DMSO) δ (ppm) 150.11, 142.12, 135.41, 128.99, 128.85, 123.33, 120.16, 36.97, 25.50, 23.53.

[0129] Example 19: Synthesis of 5-(5-bromo-2-chloro-6,6a-dihydro-1aH-cyclopropa[1,2-a]inden-1a-yl)-1H-imidazole (S-7-47)

[0130] Referring to the method of compound S-7-18 in Example 1, replace 4-methyl-2,3-dihydro-1H-inden-1-one in step [1-2] with 4-bromo-7-chloro-2,3-dihydro-1H-inden-1-one to prepare compound S-7-47, obtaining 93 mg of yellow solid with a yield of 13.6%. ESI-MS m / z: 310.9763 [M+H] + ; 1 H NMR (600 MHz, DMSO-d6) δ (ppm) 11.89 (s, 1H), 7.50 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.95 - 6.77 (m, 1H), 3.26 (dd, J = 17.7, 6.8 Hz, 1H), 2.90 (d, J = 17.8 Hz, 1H), 1.90 (dd, J = 8.4, 4.7 Hz, 1H), 1.79 (s, 1H), 0.65 (t, J = 4.8 Hz, 1H). 13 C NMR (151 MHz, DMSO) δ (ppm) 146.38, 145.03, 135.11, 130.83, 130.04, 129.72, 118.40, 37.22, 33.79, 26.20, 20.99.

[0131] Example 20: Synthesis of 5-(5-chloro-3-fluoro-6,6a-dihydro-1aH-cyclopropa[1,2-a]inden-1a-yl)-1H-imidazole (S-7-48)

[0132] Referring to the method of compound S-7-18 in Example 1, replace 4-methyl-2,3-dihydro-1H-inden-1-one in step [1-2] with 4-chloro-6-fluoro-2,3-dihydro-1H-inden-1-one to prepare compound S-7-48, obtaining 95 mg of yellow solid with a yield of 14.2%. ESI-MS m / z: 249.0590 [M+H] + ; 11H NMR (600 MHz, DMSO-d6) δ (ppm) 11.98 (s, 1H), 7.58 (s, 1H), 7.15 (dd, J = 9.0, 2.3 Hz, 1H), 7.10 (d, J = 8.9 Hz, 1H), 7.03 (s, 1H), 3.22 - 3.12 (m, 1H), 2.90 (d, J = 17.3 Hz, 1H), 2.19 - 2.00 (m, 1H), 1.75 (dd, J = 8.3, 4.3 Hz, 1H), 0.57 (t, J = 4.5 Hz, 1H). 13 13C NMR (151 MHz, DMSO) δ (ppm) 162.60, 160.98, 151.86, 151.80, 136.00, 135.98, 135.50, 130.80, 130.72, 113.39, 113.21, 110.58, 110.42, 34.19, 34.07, 26.51, 23.82.

[0133] Example 21: Synthesis of 5-(5-bromo-3-fluoro-6,6a-dihydro-1aH-cyclopropa[1,2-a]indene-1a-yl)-1H-imidazole (S-7-49)

[0134] Referring to the method of compound S-7-18 in Example 1, replace 4-methyl-2,3-dihydro-1H-inden-1-one in step [1-2] with 4-bromo-6-fluoro-2,3-dihydro-1H-inden-1-one to prepare compound S-7-49, obtaining 90 mg of a yellow solid with a yield of 11.4%. ESI-MS m / z: 293.0085 [M+H] + ; 1 1H NMR (600 MHz, DMSO-d6) δ (ppm) 12.11 - 11.83 (m, 1H), 7.57 (d, J = 1.1 Hz, 1H), 7.27 (dd, J = 8.7, 2.3 Hz, 1H), 7.13 (s, 1H), 7.03 (s, 1H), 3.13 (m, 1H), 2.87 (d, J = 17.2 Hz, 1H), 2.19 - 2.04 (m, 1H), 1.75 (dd, J = 8.2, 4.3 Hz, 1H), 0.57 (t, J = 4.5 Hz, 1H). 13 13C NMR (151 MHz, DMSO) δ (ppm) 160.32, 158.70, 149.55, 149.49, 136.02, 136.01, 133.40, 117.66, 117.58, 113.99, 113.82, 108.89, 108.73, 34.13, 32.22, 24.25, 21.67.

[0135] Example 22: Resolution of the enantiomers of compound S-7-45 (Preparation of S-7-45-1 and S-7-45-2)

[0136] The enantiomers were resolved using a chiral preparative column, and the chromatographic conditions were as follows: the chromatographic column was Daicel CHIRALPAK AY-3 (0.46 cm I.D. × 15 cm L); the mobile phase was acetonitrile and diethylamine (volume ratio 100:0.1); the flow rate was 1.0 mL / min; the column temperature was 35 °C; the injection volume was 50 μL; the detection wavelength was UV 254 nm; the eluents with retention times of 5.252 min (S-7-45-1) and 5.968 min (S-7-45-2) were collected respectively. As Figure 1 shown, the optical purity (ee value) of each isomer after resolution was greater than 95% ( Figure 1 A-C). By liquid phase detection, the purity of compound S-7-45-1 was 96.6%, and the purity of compound S-7-45-2 was 99.2% ( Figure 1 D, E).

[0137] Compound S-7-45-1 (1aSR), light yellow powder, and its stereoconfiguration was determined by circular dichroism (ECD) (as shown in Figure 1 F, compound 1aSR). ESI-MS m / z: 231.0685 [M+H] + ; 1 1H NMR (600 MHz, DMSO-d6) δ (ppm) 11.94 (s, 1H), 7.56 (s, 1H), 7.26 (d, J = 4.5 Hz, 1H), 7.22 - 7.11 (m, 2H), 6.99 (s, 1H), 3.21 (dd, J = 17.4, 6.7 Hz, 1H), 2.94 (d, J = 17.4 Hz, 1H), 2.09 - 1.99 (m, 1H), 1.75 (dd, J = 8.2, 4.2 Hz, 1H), 0.50 (t, J = 4.4 Hz, 1H). 13 13C NMR (151 MHz, DMSO) δ (ppm) 150.28, 140.02, 135.40, 130.61, 128.66, 126.03, 122.83, 34.82, 25.75, 23.57.

[0138] Compound S-7-45-2 (1aRS), light yellow powder, and its stereoconfiguration was determined by ECD (as shown in Figure 1 F, compound 1aRS). ESI-MS m / z: 231.0685 [M+H] + ; 11H NMR (600 MHz, DMSO-d6) δ (ppm) 11.90 (s, 1H), 7.55 (d, J = 1.1 Hz, 1H), 7.31 (s, 1H), 7.17 (d, J = 4.3 Hz, 2H), 7.01 (s, 1H), 3.21 (dd, J = 17.4, 6.7 Hz, 1H), 2.94 (d, J = 17.4 Hz, 1H), 2.08 - 1.96 (m, 1H), 1.75 (s, 1H), 0.50 (s, 1H).

[0139] [Biological Activity Test Example 1]

[0140] Using the intracellular PKA redistribution assay, with dexmedetomidine as a control, the compound of the present invention was tested for its ability to activate α 2A -AR EC 50 . The experimental methods and results are as follows:

[0141] 1. Materials and Reagents

[0142] Table 1 Materials and Reagents for the PKA Redistribution Model Experiment

[0143] Materials and Reagents Source <![CDATA[CHO-PKAcat-α 2A -AR cells]]> Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences DMED Jinan Dexinjia Biotechnology Co., Ltd. Atipamezole Suzhou Bohong Chemical Technology Co., Ltd. F12 Basal Medium HyClone, USA Forskolin Wuhan Sevier Biotechnology Co., Ltd. PBS Buffer Beijing Ruixin Nuo Biotechnology Co., Ltd.

[0144] 2. Operating Procedures

[0145] When the CHO-PKAcat-α 2A -AR cell density reached 90%, it was seeded in a 96-well plate and washed with F12 medium. The cells were pre-treated with Forskolin (10 μM) and then incubated with the test compound for 15 minutes. Then, they were fixed with 4% formaldehyde for 20 min and washed twice with PBS. The formation of fluorescent granules in the cytoplasm was measured using a Cellomics Array Scan VTI Reader and the Spot DetectorV3 BioApplication in high-throughput screening assays.

[0146] The activity of the test compound in activating α 2A -AR was calculated using the following formula:

[0147] Activity (%) = (Fluorescent granule formation index at each concentration of the test compound - Negative control granule formation index) / (Positive control granule formation index - Negative control granule formation index) × 100%

[0148] The positive control was incubation with the positive drug dexmedetomidine (DMED) for 15 minutes under the condition of pre-treatment with Forskolin (10 μM). The negative control was incubation with 0.25% DMSO and Forskolin (10 μM) for 15 minutes.

[0149] 3. Experimental Results

[0150] Table 2 Activation of α 2A -AR EC 50 Value

[0151] Number <![CDATA[α 2A -AR EC 50 (nM)]]> Number <![CDATA[α 2A -AR EC 50 (nM)]]> Positive Drug DMED 3.4 S-7-18 0.1 S-7-19 0.7 S-7-21 13.7 S-7-45-1 35.0 S-7-28 0.5 S-7-45-2 0.09 S-7-46 0.1 S-7-48 0.3 S-7-47 10.2 S-7-34 7.7 S-7-49 0.1

[0152] The results of the activation of α 2A -AR by the compounds of the present invention and the positive reference compound DMED are shown in Table 2. The experimental results show that, compared with the positive control drug DMED, the compounds of the present invention have a significant activation effect on α 2A -AR. Among them, the EC 2A of S-7-18, S-7-19, S-7-45-2, S-7-46, S-7-48 and S-7-49 on α 50 -AR are 0.1 nM, 0.7 nM, 0.09 nM, 0.1 nM, 0.3 nM and 0.1 nM respectively, which are significantly better than DMED.

[0153] [Biological Activity Test Example 2]

[0154] Using a radioactive ligand binding assay, with dexmedetomidine as a control, the affinity of the compounds of the present invention for α 2A -AR was tested. The experimental methods and results are as follows:

[0155] 1. Materials and Reagents

[0156] Table 3 Materials and Reagents Used in the Radioactive Ligand Binding Experiment

[0157]

[0158] 2. Operating Method

[0159] (1) Solution Preparation

[0160] Test buffer: 50 mM Tris-HCl pH 7.4, 1 mM EDTA.

[0161] Elution buffer: 50 mM Tris-HCl pH 7.4, stored at 4°C.

[0162] 0.5% PEI solution: 0.5 mL of PEI was added to 100 mL of double-distilled water and stored at 4°C.

[0163] (2) Agonist Activity Test

[0164] ① Add 5 μL of the test compound solution containing 1% DMSO and 95 μL of the test buffer to a 96-well plate.

[0165] ② Add 2 μL of protein and 298 μL of test buffer to each well.

[0166] ③ Add 100 μL of [3H]-Rauwolscine (final concentration 2.5 nM) to the system and incubate at 27 °C for 1 h.

[0167] ④ Pre-incubate the UNIFILTER-96GF / B filter plate with 0.5% PEI solution for 1 h.

[0168] ⑤ Wash each well of the UNIFILTER-96GF / B filter plate twice with 1 mL of elution buffer, transfer the protein mixture to the UNIFILTER-96GF / B filter plate, and wash 4 times.

[0169] ⑥ Incubate at 55 °C for 10 min.

[0170] ⑦ Add 40 μL of ULTIMAGOLD scintillation fluid to each well and read the CPM using Microbeta.

[0171] (3) Data analysis

[0172] ① The % inhibitory activity is calculated using the following formula:

[0173] % Activity = (Signal cmpd - Signal Ave_VC ) / (Signal Ave_PC - Signal Ave_VC ) × 100

[0174] ② The IC 50 of the compound and the dose-effect curve:

[0175] Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 - X) * HillSlope))

[0176] X: log of agonist concentration; Y: % Activity.

[0177] 3. Experimental results

[0178] Table 4 The IC 2A of the affinity between the compounds of the present invention and α 50

[0179]

[0180] The affinity results of the compounds of the present invention and the positive reference compound DMED for α 2A -AR are shown in Table 4. The experimental results indicate that the activity results measured by the radioactive ligand binding experiment and the intracellular PKA redistribution experiment are basically consistent. The affinities and activation potencies of compounds S-7-19, S-7-45-2, S-7-18, and S-7-46 are significantly better than those of the positive drug DMED.

[0181] [Biological Activity Test Example 3]

[0182] Using the mouse righting reflex model, with dexmedetomidine as a control, the in vivo pharmacodynamics of the compounds of the present invention were tested respectively. The experimental methods and results are as follows:

[0183] 1. Materials and Reagents

[0184] Table 5 Experimental Materials and Reagents Used in the Mouse Righting Reflex Model

[0185] Materials and Reagents Source C57BL / 6 Mice (SPF Grade, Male, Initial Body Weight 18 - 22 g) Beijing Sibefu Experimental Animal Technology Co., Ltd.

[0186] 2. Operating Method

[0187] There were 10 mice in each of the DMED group and the test compound group. Different concentrations of the test compounds were intraperitoneally injected, and the injection dose was 0.1 mL / kg. After administration, the disappearance rate of the righting reflex of the mice in each group was recorded.

[0188] Judgment criteria for the disappearance of the mouse righting reflex: Ensure that the experimental environment is quiet to avoid causing unnecessary stress or fear to the mice. Put the tested mice after administration into a plastic box and gently turn them over so that their backs are facing down. Observe whether the mice can right themselves within a few seconds. Under normal circumstances, the mice should be able to quickly turn over and return to a standing or walking position. If the mice stay on their backs for more than 1 minute, it is determined that the righting reflex has disappeared. Observe and record the number of mice with the disappearance of the righting reflex in each group, and calculate the disappearance rate of the righting reflex of each test drug at different doses.

[0189] 3. Experimental Results

[0190] The activity evaluation results of compounds S-7-18, S-7-19, and S-7-28, etc. in the mouse righting reflex model are as follows:

[0191] Table 6 ED of the Compounds of the Present Invention Inducing the Disappearance of the Mouse Righting Reflex 50 Value

[0192] Compound <![CDATA[ED 50 (mg / kg) <!-- 18 -->]]> Positive Drug DMED 0.15 S-7-18 1.00 S-7-19 0.39 S-7-28 >1.00 S-7-45-2 0.07 S-7-46 0.5-1 S-7-47 >1.00 S-7-48 0.5-1 S-7-49 >1.00

[0193] The in vivo pharmacodynamic results of the compounds of the present invention and the positive reference compound DMED are shown in Table 6. The experimental results indicate that the in vivo pharmacodynamics of compound S-7-45-2 are significantly better than those of the positive drug DMED.

[0194] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. It should be noted that for those of ordinary skill in the art, without departing from the technical principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein: The compound has a structure shown in Formula I-3, wherein R1, R2, R3 and R4 are each independently selected from H, D, F, Cl, Br, I and C 1-6 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R1, R2, R3 and R4 are each independently selected from H, D, F, Cl, Br, I and C 1-4 alkyl.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein: R1, R2, R3 and R4 are each independently selected from H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, n-butyl.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein: R1, R2, R3 and R4 are each independently selected from H, D, F, Cl, Br, I and methyl.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein: R1, R2, R3 and R4 are each independently selected from H, F, Cl, Br, I and methyl.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein: R1 is H, F, Cl, Br or methyl; R2 is H or F; R3 is H, F or Cl; R4 is H, F or Cl.

7. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: and .

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

9. Use of the compound according to any one of claims 1 to 7 or its pharmaceutically acceptable salt or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and / or preventing a disease or condition, wherein the disease or condition is related to α 2A -AR-related diseases.

10. The use according to claim 9, wherein the disease or condition is selected from cancer, pain, nervous system disease, and immune system disease.

11. The use of claim 9, wherein the disease or condition is selected from hypertension, attention deficit / hyperactivity disorder, pain, panic disorder, opioid withdrawal symptoms, benzodiazepine withdrawal symptoms, alcohol withdrawal symptoms, and nervous system diseases.

12. The use according to claim 11, wherein the nervous system disease is selected from depression, anxiety, bipolar disorder, Alzheimer's disease, and Parkinson's disease.

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