Yohimbine derivative, and preparation method therefor and pharmaceutical composition and use thereof

Abstract

A yohimbine derivative, and a preparation method therefor and a pharmaceutical composition and use thereof. The biological structure of the yohimbine derivative is as shown by formula (I), wherein the definitions of the substituents in the formula are as stated in the description and claims. The yohimbine derivative is used as an α2A-AR antagonist, and can be used for treating diseases such as diabetes.

Description

Yohimbe derivatives and preparation methods, pharmaceutical compositions and uses thereof Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to a class of α2A-AR antagonists, more specifically, to a class of yohimbine derivatives, and a preparation method thereof, as well as a pharmaceutical composition containing the compound, the use of the compound in the preparation of α2A-AR antagonists, and the use of the compound in the preparation of medicaments for treating diabetes. Background Art

[0002] The alpha2-adrenergic receptor (α2-AR) belongs to the G protein-coupled receptor (GPCR) superfamily and is crucial for regulating catecholamine signaling. Pharmacologically, α2-ARs are further divided into three subtypes: α2A-AR, α2B-AR, and α2C-AR. α2A-ARs are widely distributed in the central nervous system (CNS) and peripheral tissues, with the former predominating and accounting for approximately 90% of α2-ARs in the CNS. α2A-ARs inhibit neuronal excitation and the release of norepinephrine and other neurotransmitters, mediating a range of important physiological responses and pharmacological effects. Multiple polymorphisms in the gene encoding α2A-AR, ADRA2A, have been identified that can differentially increase α2A-AR expression, reduce antidepressant responses, and alter memory and behavior.

[0003] Studies have shown that a genetic variant in the ADRA2A gene is closely associated with type 2 diabetes (T2D): Carriers of the risk allele rs553668 produce excessive amounts of α2A-AR in pancreatic β cells, which inhibits the docking of insulin granules to the plasma membrane, leading to a decrease in the arrangement of insulin-containing vesicles on the cell membrane and, in turn, affecting insulin release (Science, 2010, 327, 217-220; N. Engl. J. Med., 2010, 362, 361-362). Subsequent studies have confirmed that the α2A-AR antagonist yohimbine significantly improves the insulin secretion defects associated with the ADRA2A risk variant in patients (Sci. Transl. Med., 2014, 6, 257ra139). Given that reduced pancreatic β-cell secretory capacity is one of the main characteristics of T2D, blocking α2A-AR signaling may be a new therapeutic approach specifically targeting the pancreatic β-cell defect in the 40% of T2D patients carrying the rs553668 risk variant.

[0004] Yohimbine is clinically used to treat erectile dysfunction in men, and its pharmacokinetics are well characterized. Common side effects include dizziness, anxiety, irritability, insomnia, hypertension, and palpitations, primarily due to presynaptic α2A-AR blockade and sympathetic nerve activation in the CNS (EFSA.J., 2013, 11, 3302). Although yohimbine is effective in correcting insulin secretion defects, its common central nervous system side effects make it an unsuitable candidate for the treatment of T2D, necessitating structural modification and optimization.

[0005] Currently, there are few reports on the structural modification of yohimbine. The main focus is on converting the ester group at position 16 into an amide and examining the binding affinity of the derivatives for the α2-AR subtype (J.Pharmacol.Exp.Ther., 2002, 303, 979-984; Bioorg.Med.Chem.Lett., 2005, 15, 2758-2760; J.Pharmacol.Exp.Ther., 2006, 319, 739-748). To date, there have been no reports on the antagonistic activity and tissue distribution of new yohimbine derivatives against α2A-AR.

[0006] Summary of the Invention

[0007] The object of the present invention is to provide a yohimbine derivative useful as an α2A adrenergic receptor (α2A-AR) antagonist.

[0008] In a first aspect of the present invention, there is provided a compound represented by formula (I), a deuterated compound thereof or a pharmaceutically acceptable salt thereof,

[0009] Where R 1 、R 2 、R 3 and R 4 Each is independently hydrogen, halogen, cyano, hydroxyl, ethynyl, substituted or unsubstituted C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl containing 1 to 3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, Wherein R is the following groups: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl containing 1 to 3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, X is O or NR a ; where R a Selected from: hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl;

[0010] R 5 and R 6Each is independently hydrogen, substituted or unsubstituted: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl containing 1 to 3 heteroatoms, where R b Selected from: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl containing 1 to 3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, X is O or NR c ; where R c Selected from: hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl;

[0011] L 1 is absent, hydrogen, substituted or unsubstituted: C1-C6 alkylene, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl containing 1 to 3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, Wherein R is the following groups: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl containing 1 to 3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, X is O or NR a ; where R a Selected from: hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl;

[0012] R 7 is absent, hydrogen, substituted or unsubstituted: C1-C6 alkoxy, C3-C10 cycloalkyl, C6-C10 aryl, 3-7 membered heterocyclyl, 5-7 membered heteroaryl, Wherein R is the following groups: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl containing 1 to 3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, X is O or NR a ; where R a is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl;

[0013] L 1 、R 7 The substituents separated by 0 to 2 atoms can be cyclized to form a 3 to 7-membered alkyl ring, a 4 to 7-membered heteroalkyl ring, a 6-membered aromatic ring, or a 5 to 7-membered heteroaromatic ring;

[0014] The above substitution means that the hydrogen on the group is replaced by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, C1-C6 haloalkyl (such as trifluoromethyl), alkynyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy (such as trifluoromethoxy), NR d R e 、 where R d and R e Each is independently hydrogen or C1-C6 alkyl.

[0015] In another preferred embodiment, R 1 is hydrogen, halogen, cyano, hydroxy, ethynyl, or C1-C6 alkyl;

[0016] R 2 is hydrogen, halogen, cyano, hydroxy, ethynyl, C1-C4 alkyl, Wherein R is a substituted or unsubstituted group: C1-C4 alkyl, X is O, NR a ; where R a is hydrogen, C1-C4 alkyl, wherein the substitution refers to the substitution of hydrogen on the group by one or more substituents selected from the group consisting of halogen, hydroxyl, C1-C4 alkyl, NR d R e , where R d and R e Each is independently hydrogen, C1-C4 alkyl;

[0017] R 3 is hydrogen, halogen, cyano, hydroxyl, C1-C4 alkyl, Wherein R is a substituted or unsubstituted group: C1-C4 alkyl, X is O, wherein the substitution means that the hydrogen on the group is replaced by one or more substituents selected from the following groups: halogen, hydroxyl, cyano, C1-C6 alkyl, NR d R e , where R d and R e Each is independently hydrogen, C1-C4 alkyl;

[0018] R 4 It is hydrogen, halogen, cyano, and hydroxyl.

[0019] In another preferred embodiment, R 1 For hydrogen and fluorine.

[0020] In another preferred embodiment, R 2 It is hydrogen, fluorine, chlorine, bromine, cyano, hydroxy, ethynyl, methyl, or methoxy.

[0021] In another preferred embodiment, R 3 It is hydrogen, fluorine, hydroxy, ethynyl, methyl, or methoxy.

[0022] In another preferred embodiment, R 4 For hydrogen.

[0023] In another preferred embodiment, R 5 is hydrogen, C1-C4 alkyl, where R bThe following groups are substituted or unsubstituted: C1-C4 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, 5-7 membered heteroaryl, wherein the substitution refers to the replacement of hydrogen on the group by one or more substituents selected from the following groups: halogen, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, NR d R e , where R d and R e Each is independently hydrogen, C1-C4 alkyl;

[0024] R 6 is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, where R b is a substituted or unsubstituted group: C1-C4 alkyl, wherein the substitution refers to the replacement of hydrogen on the group by one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, trifluoromethyl, NR d R e , where R d and R e Each is independently hydrogen or C1-C4 alkyl.

[0025] In another preferred embodiment, R 5 It is hydrogen, C1-C3 alkyl, or acetyl.

[0026] In another preferred embodiment, R 6 It is hydrogen, C1-C3 alkyl, or acetyl.

[0027] In another preferred embodiment, L 1 is absent, hydrogen, substituted or unsubstituted: C1-C4 alkylene, C3-C8 cycloalkyl, 5-7 membered heterocycloalkyl containing 1 to 3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, Wherein R is the following groups: C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocycloalkyl containing 1 to 3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, X is O or NR a ; where R a is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, wherein the substitution refers to the substitution of hydrogen on the group by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, NR d R e , where R d and R e Each is independently hydrogen or C1-C4 alkyl.

[0028] In another preferred embodiment, L 1is absent, hydrogen, substituted or unsubstituted: C1-C4 alkylene, C3-C6 cycloalkyl, 5-7 membered heterocycloalkyl containing 1 to 3 heteroatoms; wherein the substitution means that the hydrogen on the group is replaced by one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, NR d R e , where R d and R e Each is independently hydrogen or C1-C4 alkyl.

[0029] In another preferred embodiment, R 7 is absent, hydrogen, substituted or unsubstituted: C1-C4 alkoxy, C3-C6 cycloalkyl, C6-C10 aryl, 5-7 membered heterocyclyl, 5-7 membered heteroaryl, Wherein R is the following groups: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl containing 1 to 3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, X is O or NR a ; where R a is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl;

[0030] R 7 The substituents separated by 0 to 2 atoms can be cyclized to form a 3- to 7-membered alkyl ring, a 4- to 7-membered heteroalkyl ring, a 6-membered aromatic ring, or a 5- to 7-membered heteroaromatic ring.

[0031] Wherein the substitution refers to the substitution of hydrogen on the group by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, C1-C4 haloalkyl (such as trifluoromethyl), C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy (such as trifluoromethoxy), NR d R e 、 where R d and R e Each is independently hydrogen or C1-C4 alkyl.

[0032] In another preferred embodiment, R 7 is absent, hydrogen, or substituted or unsubstituted: C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, 5-7 membered heterocyclyl, 5-7 membered heteroaryl;

[0033] Wherein the substitution refers to the substitution of hydrogen on the group by one or more substituents selected from the group consisting of fluorine, chlorine, bromine, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkynyl, C1-C4 alkyl, C1-C4 alkoxy, where R d and R eEach is independently hydrogen, C1-C4 alkyl;

[0034] R 7 The substituents separated by 0 to 2 atoms can be cyclized to form a 6-membered aromatic ring or a 5- to 7-membered heteroaromatic ring.

[0035] In another preferred embodiment, L 1 and R 7 The following formula V is formed:

[0036] wherein r1 is selected from 1, 2 or 3; r2 is selected from 0, 1, 2 or 3;

[0037] Ring B is phenyl, 5-6 membered heterocyclyl, C3-C6 cycloalkyl, or 5-6 membered heteroaryl;

[0038] Each R f Independently selected from: halogen, hydroxy, cyano, C1-C4 haloalkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, NR d R e 、 where R d and R e are each independently hydrogen, C1-C4 alkyl; or

[0039] Two adjacent R f Together with the adjacent C on ring B, it forms a benzene ring or a 5- to 7-membered heteroaromatic ring.

[0040] In another preferred embodiment, ring B is a benzene ring, and the substituent thereon is located at L 1 counterpoint.

[0041] In another preferred embodiment, the compound of formula V has the following structure:

[0042] wherein r1 is selected from 1, 2 or 3; r2 is selected from 0, 1, 2 or 3;

[0043] Z1, Z2, and Z3 are each independently selected from O, S, N, and CH;

[0044] Each R f Independently selected from: halogen, hydroxy, cyano, C1-C4 haloalkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, NR d R e 、 where R d and R e are each independently hydrogen, C1-C4 alkyl; or

[0045] Two adjacent R fTogether with the adjacent C on the ring, it forms a benzene ring or a 5- to 7-membered heteroaromatic ring. In another preferred embodiment, r1 is selected from 1 or 2.

[0046] In another preferred embodiment, r2 is selected from 1 or 2.

[0047] In another preferred embodiment, Z1, Z2, and Z3 are each independently selected from O, N, and CH.

[0048] In another preferred embodiment, each R f Independently selected from: fluorine, chlorine, bromine, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, NR d R e 、 where R d and R e are each independently hydrogen, methyl, ethyl; or

[0049] Two adjacent R f Together with the adjacent C on the ring, it forms a benzene ring.

[0050] In another preferred embodiment, -L 1 -R 7 Selected from:

[0051] The number of substituents Rf on the benzene ring or benzoheteroaromatic ring is 0, 1, 2 or 3, preferably 0, 1 or 2.

[0052] [Corrected 19.05.2025 according to Rule 26] In another preferred embodiment, -L 1 -R 7 Selected from: -CH3,

[0053] [Corrected 19.05.2025 according to Rule 26] In another preferred embodiment, the compound is selected from C1-C35.

[0054] [Corrected 19.05.2025 according to Rule 26] The second aspect of the present invention provides a method for preparing the compound described in the first aspect, As a raw material, the compound is obtained by converting the 16-carboxyl group into an oxadiazole structure, wherein the definition of each substituent is as described above.

[0055] [Corrected 19.05.2025 according to Rule 26] In a preferred embodiment, the compound or a pharmaceutically acceptable salt thereof is prepared by the following route:

[0056] [Corrected 19.05.2025 according to Rule 26] The compound of formula H1 is reacted with the compound of formula H2 in the presence of a condensing agent to obtain a compound of formula H3;

[0057] [Corrected 19.05.2025 in accordance with Rule 26] The compound of formula H3 undergoes intramolecular condensation cyclization under heating conditions to form the compound of formula H4;

[0058] [Corrected 19.05.2025 according to Rule 26] When L 1 When R7 is a phenyl group substituted with iodine, the compound of formula H4 is subjected to a coupling reaction under palladium catalysis to obtain L 1 is a methylene group, and R7 is a phenyl compound substituted with a cyano group;

[0059] [Corrected 19.05.2025 according to Rule 26] When L 1 When R7 is a phenyl group substituted with a cyano group, the compound is oxidized by hydrogen peroxide under alkaline conditions to obtain L 1 is methylene, R7 is Substituted phenyl compounds;

[0060] When L 1 is methylene, R 7 When the phenyl group is substituted by methyl ester, the compound of formula H4 is hydrolyzed to obtain L 1 is methylene, R 7 A phenyl compound substituted with a carboxyl group;

[0061] The definitions of the substituents are as described above.

[0062] The third aspect of the present invention provides a pharmaceutical composition comprising: the compound represented by the general formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0063] The fourth aspect of the present invention provides the use of the compound represented by general formula (I) described in the first aspect or the pharmaceutical composition described in the third aspect, (i) for preparing an α2A adrenergic receptor (α2A-AR) antagonist; or (ii) for preparing a drug for treating diabetes.

[0064] The fifth aspect of the present invention provides a method for treating diabetes, comprising administering the compound or pharmaceutically acceptable salt thereof according to the first aspect, or the pharmaceutical composition according to the third aspect to a subject in need thereof.

[0065] The novel oxadiazole yohimbine derivative of the present invention can antagonize α2A adrenaline receptor at a micromolar concentration, and has the characteristics of pancreas targeting and significantly lower brain tissue distribution characteristics compared with yohimbine.

[0066] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equal, or similar purpose. Due to space limitations, they will not be detailed here. BRIEF DESCRIPTION OF THE DRAWINGS

[0067] FIG1 shows the tissue concentrations (ng / g or ng / mL) of different compounds in mice 2 hours after oral administration of 10 mg / kg.

[0068] FIG2 shows the tissue concentrations (ng / g or ng / mL) of compound C27 in mice after oral administration of 10 mg / kg at 0.25, 2, and 8 hours.

[0069] FIG3 shows the basal blood glucose levels in type 2 diabetic mice after a single intraperitoneal injection of yohimbine derivatives (10 mg / kg).

[0070] FIG4 shows the glucose tolerance results of type 2 diabetic mice after a single intraperitoneal injection of yohimbine derivatives (10 mg / kg).

[0071] FIG5 shows the results of insulin sensitivity in type 2 diabetic mice after a single intraperitoneal injection of yohimbine derivatives (10 mg / kg).

[0072] FIG6 shows the glucose tolerance results of type 2 diabetic mice after a single oral administration of yohimbine derivatives (10 mg / kg).

[0073] FIG7 shows the results of insulin sensitivity in type 2 diabetic mice after a single oral administration of yohimbine derivatives (10 mg / kg).

[0074] FIG8 shows the basal blood glucose levels in type 2 diabetic mice chronically injected with yohimbine derivatives (10 mg / kg, once a day). DETAILED DESCRIPTION

[0075] After extensive and in-depth research, the inventors of this application have developed for the first time a class of compounds that maintain excellent α2A adrenergic receptor antagonist activity while also possessing pancreatic targeting and low brain penetrance. Specifically, these compounds are oxadiazole yohimbine derivatives. Their key feature is the conversion of the 16-position ester group of yohimbine into an oxadiazole group, maintaining excellent α2A adrenergic receptor antagonist activity. Compared to yohimbine, these derivatives exhibit pancreatic targeting and significantly reduced brain tissue distribution, eliminating yohimbine's central nervous system side effects, such as anxiety and hypertension. They can significantly improve blood glucose metabolism in animal models of type 2 diabetes, and are expected to become novel α2A adrenergic receptor-directed drugs for the treatment of diabetes. This is the basis for the completion of the present invention.

[0076] the term

[0077] Herein, the alkyl group is preferably an aliphatic alkyl group, which can be a linear alkyl group or a branched alkyl group, including but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.; expressions such as "C1-C6" are intended to include corresponding groups having 1, 2, 3, 4, 5 or 6 carbon atoms, for example, "C1-C6 alkyl" refers to an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0078] "Alkylene" refers to a straight or branched chain saturated aliphatic group, i.e., a divalent hydrocarbon group, having the specified number of carbon atoms and linking at least two other groups. The two groups linked to the alkylene group can be linked to the same or different atoms on the alkylene group. For example, a straight chain alkylene group can be -(CH2) n -, wherein n is 1, 2, 3, 4, 5, or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene.

[0079] Herein, the halogen preferably refers to fluorine, chlorine, bromine or iodine.

[0080] Herein, the alkoxy group refers to -O-(alkyl), wherein alkyl is defined as above. "C1-C6 alkoxy" refers to an oxygen-containing alkyl group containing 1-6 carbon atoms, non-limiting examples of which include methoxy, ethoxy, propoxy, butoxy, and the like.

[0081] Herein, the cycloalkyl group may be a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused ring, and bridged ring cycloalkyl groups.

[0082] As used herein, the term "aryl" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, such as phenyl and naphthyl. The aryl ring may be fused to a heterocyclic, heteroaryl, or cycloalkyl ring, non-limiting examples of which include benzimidazole, benzothiazole, benzoxazole, benzisoxazole, benzopyrazole, quinoline, benzindole, and benzodihydrofuran.

[0083] As used herein, the term "heterocyclic group" refers to an aliphatic heterocyclic ring system containing 1 to 3 heteroatoms, such as 3 to 7 ring atoms. The heteroatoms of a heterocyclic group include oxygen, sulfur, and nitrogen. Preferably, the heterocyclic group is 3-membered or 6-membered, such as oxiranyl, morpholinyl, piperazinyl, and the like.

[0084] As used herein, the term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, such as 5 to 14 ring atoms. Heteroatoms in heteroaryl groups include oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl group may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring.

[0085] Unless otherwise specified in the present invention, Indicates the attachment site.

[0086] Herein, the pharmaceutically acceptable salts are not particularly limited, and preferably include: inorganic acid salts, organic acid salts, alkyl sulfonates and aryl sulfonates; the inorganic salts include hydrochlorides, hydrobromides, nitrates, sulfates, phosphates, etc.; the organic salts include formates, acetates, propionates, benzoates, maleates, fumarates, succinates, tartrates, citrates, etc.; the alkyl sulfonates include methyl sulfonates, ethyl sulfonates, etc.; the aryl sulfonates include benzene sulfonates, p-toluene sulfonates, etc.

[0087] Preparation method

[0088] The oxadiazole yohimbine derivatives of the present invention can be prepared by the following route: The definitions of the substituents are the same as those described above.

[0089] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0090] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0091] In the following preparation examples, NMR was measured using a Bruker Avance III 400 / 500 MHz NMR instrument, with NMR calibration: δH 7.26 ppm (CDCl 3 ), 2.50 ppm (DMSO-d 6 ); mass spectrometry was measured using an Agilent 1200 Quadrupole LC / MS liquid chromatography-mass spectrometer; reagents were primarily provided by Shanghai Chemical Reagent Company; TLC thin-layer chromatography silica gel plates were produced by Shandong Yantai Jiangyou Silica Gel Development Co., Ltd., model HSGF 254; and normal-phase column chromatography silica gel used for compound purification was produced by Shandong Qingdao Ocean Chemical Plant Branch, model zcx-II, 200-300 mesh.

[0092] The Chinese equivalents of the abbreviations in this article are as follows:

[0093] DMF: N,N-dimethylformamide; COMU: (1-cyano-2-ethoxy-2-oxyethyleneaminooxy)dimethylamino-morpholinyl-carbonium hexafluorophosphate; Pd(dba)2: bis(dibenzylideneacetonepalladium); dppf: 1,1'-bis(diphenylphosphino)ferrocene;

[0094] Example 1

[0095] (1) Benzyl cyanide (1.17 g, 10 mmol) was dissolved in ethanol (20 mL) at room temperature. Water (8 mL), sodium carbonate (848 mg, 8 mmol), and hydroxylamine hydrochloride (695 mg, 10 mmol) were added in sequence. The mixture was stirred at room temperature for 24 hours and concentrated under reduced pressure to remove most of the solvent. The residue was dissolved in ethyl acetate (80 mL) and washed with saturated brine (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was used directly in the condensation reaction without purification.

[0096] (2) Yohimbine hydrochloride M1 (7.81 g, 20 mmol) was placed in methanol / tetrahydrofuran / water (90 mL / 60 mL / 30 mL) under ice bath, and lithium hydroxide monohydrate (5.04 g, 120 mmol) was added. The mixture was stirred under ice bath for half an hour and then moved to room temperature. LC-MS monitoring was performed until the starting material disappeared. Most of the solvent was removed by concentration under reduced pressure. The residue was dissolved in water (150 mL). The pH was adjusted with 5% hydrochloric acid under ice bath until milky white turbidity appeared in the system. The mixture was allowed to stand overnight and filtered. The filter cake was washed with water (100 mL). The filter cake was collected and dried to obtain white powder M2 (5.9 g, 17.3 mmol) with a molar yield of 86%.

[0097] (3) M2 (340 mg, 1 mmol) was dissolved in DMF (5 mL) at room temperature, and triethylamine (304 mg, 3 mmol) was added. After stirring for 5 minutes, COMU (428 mg, 1 mmol) was slowly added. After the addition was completed, the mixture was stirred at room temperature for 20 minutes. The crude product (300 mg, 2 mmol) obtained in step (1) was added. After stirring at room temperature for 24 hours, the reaction solution was concentrated under reduced pressure to remove the solvent. The residue was dissolved in dichloromethane / methanol (100 mL / 10 mL), washed with saturated brine (20 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 30:1) to obtain M3 as a brown foamy solid.

[0098] (4) The condensation product M3 in operation (3) was dissolved in 1,4-dioxane (5 mL), and toluene (10 mL) was added. The mixture was heated to 100° C. under a nitrogen atmosphere. The reaction was stopped after 24 hours, and the solvent was removed by concentration under reduced pressure. The residue was dissolved in dichloromethane / methanol (100 mL / 10 mL), washed with saturated brine (20 mL×3), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 30:1) to obtain a light brown foamy solid C1 (46 mg, 0.1 mmol). The molar yield of operations (3) and (4) was 10%.

[0099] The other compounds in the following table were synthesized using the same method as in Example 1 with different cyanide substrates:

[0100] Example 2

[0101] (1) 4-Iodobenzeneacetonitrile (2.43 g, 10 mmol) was dissolved in ethanol (20 mL) at room temperature. Water (8 mL), sodium carbonate (848 mg, 8 mmol), and hydroxylamine hydrochloride (695 mg, 10 mmol) were added in sequence. The mixture was stirred at room temperature for 24 hours and concentrated under reduced pressure to remove most of the solvent. The residue was dissolved in ethyl acetate (80 mL) and washed with saturated brine (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was used directly in the condensation reaction without purification.

[0102] (2) M2 (340 mg, 1 mmol) was dissolved in DMF (5 mL) at room temperature, and triethylamine (304 mg, 3 mmol) was added. After stirring for 5 minutes, COMU (428 mg, 1 mmol) was slowly added. After the addition was completed, the mixture was stirred at room temperature for 20 minutes. The crude product (552 mg, 2 mmol) obtained in step (1) was added. After stirring at room temperature for 24 hours, the reaction solution was concentrated under reduced pressure to remove the solvent. The residue was dissolved in dichloromethane / methanol (100 mL / 10 mL), washed with saturated brine (20 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 30:1) to obtain a brown foamy solid M3.

[0103] (3) The condensation product M3 in operation (2) was dissolved in 1,4-dioxane (5 mL), and toluene (10 mL) was added. The mixture was heated to 100° C. under a nitrogen atmosphere. The reaction was stopped after 24 hours. The solvent was removed by concentration under reduced pressure. The residue was dissolved in dichloromethane / methanol (100 mL / 10 mL), washed with saturated brine (20 mL×3), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 30:1) to obtain a light brown foamy solid M4 (69 mg, 0.12 mmol). The molar yield of operations (2) and (3) was 12%.

[0104] (4) M4 (58 mg, 0.1 mmol) was dissolved in DMF (5 mL), and Pd(dba)2 (5.7 mg, 0.01 mmol), dppf (5.5 mg, 0.01 mmol), and Zn(CN)2 (11.7 mg, 0.1 mmol) were added. The mixture was heated to 80 °C under nitrogen atmosphere. The reaction was stopped after 6 hours. The solvent was removed by concentration under reduced pressure. The residue was dissolved in dichloromethane / methanol (100 mL / 10 mL), washed with saturated brine (20 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 30:1) to obtain C19 (33 mg, 0.07 mmol) as a light brown foamy solid with a molar yield of 70%.

[0105] The same method as in Example 2 was used to synthesize other compounds in the following table using different cyanide substrates:

[0106] Example 3

[0107] Compound C19 (14 mg, 0.03 mmol) was dissolved in EtOH (0.15 mL), and DMSO (0.075 mL) was added under ice bath, followed by 4 M NaOH (0.0073 mL) and 30% H2O2 (0.01 mL). The mixture was reacted under ice bath for 30 minutes and then brought to room temperature. The reaction was stopped after 5 hours. 10% Na2S2O3 (0.15 mL) was added to the reaction system under ice bath, followed by H2O (2 mL). A white solid precipitated and was filtered under reduced pressure. The filter cake was washed with water and dried to obtain C27 (10 mg, 0.02 mmol) as a white solid with a molar yield of 67%.

[0108] Example 4

[0109] Compound C29 (50 mg, 0.1 mmol) was placed in methanol / tetrahydrofuran / water (2.1 mL / 0.3 mL / 0.6 mL) under ice bath, and lithium hydroxide monohydrate (42 mg, 1 mmol) was added. After stirring under ice bath for half an hour, the mixture was brought to room temperature. LC-MS monitoring was performed until the starting material disappeared. Most of the solvent was removed by concentration under reduced pressure, and water (5 mL) was added to the residue. The pH was adjusted to 6 with 5% hydrochloric acid under ice bath. The mixture was allowed to stand and filtered. The filter cake was washed with water (2 mL). The filter cake was collected and dried to obtain yellow powder C30 (25 mg, 0.05 mmol) with a molar yield of 50%.

[0110] Example 5 α2A-AR antagonist test

[0111] 1. Purpose of the experiment

[0112] The antagonistic activity of yohimbine derivatives on α2A-AR was investigated.

[0113] 2. Experimental Principle

[0114] By establishing a cell line co-transfected with the target receptor and Ga16, receptor activation triggers the activation of the Ga16 protein, which in turn activates phospholipase C (PLC) to produce IP3 and DAG. IP3 then binds to IP3 receptors on the endoplasmic reticulum and mitochondria, triggering the release of intracellular calcium. Therefore, measuring changes in intracellular calcium can be used to monitor the activation status of the target receptor. Fluo-4 / AM is a fluorescent calcium probe indicator used to measure calcium ions. As a non-polar, lipid-soluble compound, upon entry into cells, the AM group dissociates under the action of cellular lipolytic enzymes, releasing Fluo-4. Because Fluo-4 is a polar molecule that does not readily cross the lipid bilayer, it remains intracellular for extended periods. Ultimately, the level of Ga protein activation can be measured by measuring the excited fluorescence intensity. If the screened compound agonizes the target receptor, the calcium flux response will be significantly increased; conversely, if the screened compound antagonizes the target receptor, the calcium flux response will be significantly reduced.

[0115] 3. Experimental samples

[0116] Before the test, the test compound was dissolved in DMSO to prepare a stock solution, which was then diluted with culture medium to the desired concentration.

[0117] 4. Experimental Methods

[0118] Cells stably expressing α2A-AR / Ga16 were seeded in 96-well plates and cultured overnight. The culture medium in the wells containing cells was aspirated, and freshly prepared dye (40 μL / well) was added. The cells were incubated in a 37°C incubator for 40 minutes. The drug to be tested was diluted with calcium buffer and mixed thoroughly. The dye was aspirated and discarded, and the plates were washed once with freshly prepared calcium buffer, followed by replacement with 50 μL of calcium buffer containing the drug to be tested. The plates were tested using a FlexStation II instrument. Starting at the 15th second, 25 μL of calcium buffer containing the known agonist UK14304 was automatically added, and the fluorescence value was finally read at 525 nm.

[0119] 5. Experimental results (taking the 35 compounds in Table 1 as an example, but not limited to these compounds)

[0120] Table 1 Test results of α2A-AR antagonistic activity of compounds

[0121] Note: IC 50 This is an evaluation of the sample drug's antagonistic activity against α2A-AR.

[0122] *Indicates 0.5 μM ≤ IC 50 <2μM; ** represents 0.3μM ≤ IC 50 <0.5 μM,

[0123] *** represents 0.1μM ≤ IC 50 <0.3 μM; **** represents IC 50 <0.1 μM.

[0124] 6. Results and Discussion

[0125] These compounds can compete with the α2A-AR agonist UK14304 in cells expressing α2A-AR and antagonize the agonistic effect of UK14304 on α2A-AR. 50 See Table 1. The results showed that these compounds are antagonists of α2A-AR.

[0126] Example 6 Tissue distribution test of yohimbine derivatives in mice

[0127] 1. Purpose of the experiment

[0128] To investigate the tissue distribution of yohimbine derivatives in mice.

[0129] 2. Experimental Design

[0130] Table 2 Dosage regimen for mouse tissue distribution test

[0131] Note: All administered compounds were in the form of hydrochloride and prepared with deionized water; all experimental animals were ICR males.

[0132] Mice were fasted for more than 12 h and had free access to water.

[0133] Table 3 Compound C27 mouse tissue distribution test plan

[0134] Note: The solvent ratio is 5% DMSO + 5% solutol + 90% saline; all experimental animals are ICR males

[0135] Mice were fasted for more than 12 h and had free access to water.

[0136] 3. Sample Collection and Measurement

[0137] (1) Tissue distribution test in mice: The animals in each group were anesthetized and killed 2 hours after administration. The brain, pancreas, heart, liver, and kidney tissues were collected by dissection, washed with physiological saline, and frozen in a -20°C refrigerator for testing. At the same time, 0.3 mL of whole blood was collected and placed in an EDTA-K2 anticoagulant tube. The plasma was separated by centrifugation at 11,000 rpm for 5 minutes and then frozen in a -20°C refrigerator for testing.

[0138] Blank plasma and tissues were collected from another 3 animals.

[0139] Determine the concentration of unchanged drug in plasma and tissues.

[0140] (2) Tissue distribution study of compound C27 in mice: At corresponding time points (0.25, 2, and 8 h) after oral administration, mice were sacrificed by exsanguination via the abdominal aorta. Brain, heart, liver, lung, pancreas, and kidney tissues were immediately collected by autopsy, and plasma was collected. The operation was performed in an ice-water bath.

[0141] Centrifugation conditions: 11000 rpm for 5 min to separate plasma (about 200 μL).

[0142] After collection, tissues and plasma were stored below -60°C.

[0143] 4. Experimental Results and Discussion

[0144] Figure 1 shows the tissue concentrations (ng / g or ng / mL) of different compounds in mice 2 hours after oral administration at 10 mg / kg. (The four compounds in Figure 1 are used as examples, but are not limited to these compounds)

[0145] FIG2 shows the tissue concentrations (ng / g or ng / mL) of compound C27 in mice after oral administration of 10 mg / kg at 0.25, 2, and 8 hours.

[0146] Calculated by the relative ratio of tissue distribution concentration to blood concentration, compounds C1, C6, C13, C19, and C27 all showed lower brain tissue distribution than yohimbine, among which the brain tissue distribution of compound C19 was approximately forty times lower than that of yohimbine, and compound C19 also had good pancreatic distribution; the plasma exposure of compound C27 was equivalent to that of yohimbine, but its brain tissue distribution was approximately two hundred and seventy times lower than that of yohimbine, and it had pancreatic distribution characteristics comparable to those of compound C19.

[0147] Example 7 Experimental test on the therapeutic effect of yohimbine derivatives on lowering blood sugar in diabetic mice

[0148] 1. Purpose of the experiment

[0149] To examine whether the yohimbine derivative C19 can improve blood sugar metabolism in type 2 diabetes

[0150] 2. Experimental content

[0151] This experiment used a high-sugar, high-fat diet-induced type 2 diabetes mouse model and mainly conducted the following tests:

[0152] 1) Effect of a single intraperitoneal administration on basal blood glucose, glucose tolerance and insulin sensitivity in diabetic mice.

[0153] 2) Effect of single oral administration on glucose tolerance and insulin sensitivity in diabetic mice.

[0154] 3) Effect of continuous chronic intraperitoneal administration on basal blood glucose in diabetic mice.

[0155] 3. Experimental Methods

[0156] C57BL\6J mice were fed with a high-sugar and high-fat diet for 3 consecutive months. The test experiment was conducted after the average weight of the mice stabilized at above 50g and the average basal blood glucose value stabilized at above 12mmol / L.

[0157] Blood glucose levels are mainly measured by measuring tail vein blood using a blood glucose meter. For the test of the effect of basal blood glucose, the mice are fed a normal diet. The basal blood glucose value is first measured before administration, and then a single intraperitoneal injection or a single oral gavage of the yohimbine derivative C19 (10 mg / kg mouse body weight) is given, and the venous blood glucose level is measured 15, 30, 60, 90, and 120 minutes after administration. The mouse glucose tolerance test is performed after the mice have eaten for 16 hours overnight. 30 minutes after a single intraperitoneal injection or a single oral gavage of the yohimbine derivative C19 (10 mg / kg mouse body weight), glucose (1.5 g / kg) is injected intraperitoneally, and the venous blood glucose level is measured 15, 30, 60, 90, and 120 minutes later. The mouse insulin sensitivity is tested after the mice have eaten for 6 hours. Thirty minutes after a single intraperitoneal injection or oral gavage of the yohimbine derivative C19 (10 mg / kg mouse body weight), insulin (1 UI / kg) was administered intraperitoneally. Venous blood glucose levels were measured 15, 30, 60, 90, and 120 minutes later. For experiments examining the effects of chronic administration on blood glucose levels, diabetic mice were intraperitoneally injected with the yohimbine derivative C19 (10 mg / kg) daily for 12 consecutive days. Baseline blood glucose levels were measured daily on a free-flowing diet before drug injection. A control group received saline injection or oral gavage.

[0158] 4. Experimental Results

[0159] The experimental results are shown in Figures 3-8. The results of Figure 3 show that a single intraperitoneal injection of a yohimbine derivative (10 mg / kg) significantly reduces the basal blood glucose level of type 2 diabetic mice. The results of Figure 4 show that a single intraperitoneal injection of a yohimbine derivative (10 mg / kg) significantly improves the glucose tolerance of type 2 diabetic mice. The results of Figure 5 show that a single intraperitoneal injection of a yohimbine derivative (10 mg / kg) significantly improves the insulin sensitivity of type 2 diabetic mice. The results of Figure 6 show that a single oral administration of a yohimbine derivative (10 mg / kg) significantly improves the glucose tolerance of type 2 diabetic mice. The results of Figure 7 show that a single oral administration of a yohimbine derivative (10 mg / kg) significantly improves the insulin sensitivity of type 2 diabetic mice. The results of Figure 8 show that chronic injection of a yohimbine derivative (10 mg / kg, once a day) significantly reduces the basal blood glucose level of type 2 diabetic mice.

[0160] 5 Results and Discussion

[0161] This experiment demonstrates that a single injection or oral administration of the yohimbine derivative C19 of the present invention significantly reduces hyperglycemia in diabetic mice, improves glucose tolerance, and enhances insulin sensitivity. Chronic administration can also maintain basal blood glucose levels in diabetic mice at levels closer to normal. Therefore, the yohimbine derivative C19 of the present invention has a significant effect on improving blood glucose metabolism in diabetes.

[0162] By structurally modifying yohimbine, a new derivative was obtained with enhanced α2A adrenergic receptor antagonist activity, pancreatic targeting and reduced brain tissue distribution. The lower brain tissue distribution eliminates the central side effects of yohimbine, such as anxiety and increased blood pressure. The compound of the present invention can significantly improve blood glucose metabolism in animal models of type 2 diabetes. Chronic administration can stabilize the basal blood glucose levels of diabetic mice at a level closer to normal, and is expected to be used in the treatment of diabetes.

[0163] All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound represented by the general formula (I), its deuterated compound or a pharmaceutically acceptable salt thereof, In the formula, R 1 , R 2 , R 3 and R 4 are each independently hydrogen, halogen, cyano, hydroxy, ethynyl, a substituted or unsubstituted group selected from the following: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl containing 1 to 3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, wherein R is a group selected from the following: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl containing 1 to 3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, X is O or NR a ; wherein R a is selected from: hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl; R 5 and R 6 are each independently hydrogen, a substituted or unsubstituted group selected from the following: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl containing 1 to 3 heteroatoms, wherein R b is selected from: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl containing 1 to 3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, X is O or NR c ; wherein R c is selected from: hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl; L 1 is absent, hydrogen, a substituted or unsubstituted group selected from the following: C1-C6 alkylene, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl containing 1 to 3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, wherein R is a group selected from the following: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl containing 1 to 3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, X is O or NR a ; wherein R a is selected from: hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl; R 7 is absent, hydrogen, a substituted or unsubstituted group selected from the following: C1-C6 alkoxy, C3-C10 cycloalkyl, C6-C10 aryl, 3-7 membered heterocyclic group, 5-7 membered heteroaryl, wherein R is one of the following groups: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heteroalkyl ring containing 1 to 3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, and X is O or NR a ; wherein R a is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl; L 1 and R 7 substituents spaced 0 to 2 atoms apart on it can cyclize to form 3-7 membered alkyl rings, 4-7 membered heteroalkyl rings, 6 membered aromatic rings, 5-7 membered heteroaromatic rings; the above-mentioned substitution means that the hydrogen on the group is substituted by one or more substituents selected from the following group: halogen, hydroxyl, cyano, C1-C6 haloalkyl, alkynyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, NR d R e and wherein R d and R e are each independently hydrogen, C1-C6 alkyl.

2. The compound according to claim 1, characterized in that, R 1 is hydrogen, halogen, cyano, hydroxyl, ethynyl, C1-C6 alkyl; R 2 is hydrogen, halogen, cyano, hydroxyl, ethynyl, C1-C4 alkyl, wherein R is a substituted or unsubstituted group selected from the following: C1-C4 alkyl, and X is O, NR a ; wherein R a is hydrogen, C1-C4 alkyl, and the substitution means that the hydrogen on the group is substituted by one or more substituents selected from the following group: halogen, hydroxyl, C1-C4 alkyl, NR d R e wherein R d and R e are each independently hydrogen, C1-C4 alkyl; R 3 is hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, wherein R is a substituted or unsubstituted group selected from the following: C1-C4 alkyl, X is O, and the substitution means that the hydrogen on the group is substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 alkyl, NR d R e , wherein R d and R e are each independently hydrogen, C1-C4 alkyl; R 4 is hydrogen, halogen, cyano, or hydroxy.

3. The compound according to claim 1, characterized in that, R 5 is hydrogen, C1-C4 alkyl, wherein R b is a substituted or unsubstituted group selected from the following: C1-C4 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, 5-7 membered heteroaryl, wherein said substitution means that the hydrogen on the group is substituted by one or more substituents selected from the group consisting of: halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, NR d R e wherein R d and R e are each independently hydrogen, C1-C4 alkyl; R 6 is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, wherein R b is a substituted or unsubstituted group selected from the group consisting of: C1-C4 alkyl, wherein said substitution means that one or more substituents selected from the following group replace the hydrogen on the group: halogen, hydroxyl, cyano, trifluoromethyl, NR d R e wherein R d and R e are each independently hydrogen, C1-C4 alkyl.

4. The compound according to claim 1, characterized in that, L 1 is absent, hydrogen, a substituted or unsubstituted group selected from the following: C1-C4 alkylene, C3-C8 cycloalkyl, 5-7 membered heteroalkyl containing 1 to 3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, where R is a group selected from the following: C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heteroalkyl containing 1 to 3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, and X is O or NR a ; where R a is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and the substitution means that the hydrogen on the group is substituted by one or more substituents selected from the group consisting of: halogen, hydroxy, cyano, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, NR d R e where R d and R e are each independently hydrogen, C1-C4 alkyl.

5. The compound according to claim 1, characterized in that, R 7 is absent, hydrogen, a substituted or unsubstituted group selected from the following: C1-C4 alkoxy, C3-C6 cycloalkyl, C6-C10 aryl, 5-7 membered heterocycloalkyl, 5-7 membered heteroaryl, wherein R is a group selected from the following: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocycloalkyl containing 1 to 3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, and X is O or NR a ; wherein R a is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl; R 7 Substituents spaced 0 to 2 atoms above can cyclize into 3- to 7-membered alkyl rings, 4- to 7-membered heteroalkyl rings, 6-membered aromatic rings, and 5- to 7-membered heteroaromatic rings. wherein the substitution means that the hydrogen on the group is substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C1-C4 haloalkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, NR d R e , wherein R d and R e are each independently hydrogen, C1-C4 alkyl; Another preferred, R 7 is absent, hydrogen, a substituted or unsubstituted group selected from the following: C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, 5-7 membered heterocyclic group, 5-7 membered heteroaryl; wherein the substitution means that the hydrogen on the group is substituted by one or more substituents selected from the following group: fluorine, chlorine, bromine, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkynyl, C1-C4 alkyl, C1-C4 alkoxy, NR d R e , wherein R d and R e are each independently hydrogen, C1-C4 alkyl; R 7 Substituents spaced 0 to 2 atoms above can cyclize into a 6-membered aromatic ring or a 5- to 7-membered heteroaromatic ring.

6. The compound according to claim 1, wherein L 1 and R 7 form the following formula V: wherein r1 is selected from 1, 2 or 3; r2 is selected from 0, 1, 2 or 3; Ring B is phenyl, 5- or 6-membered heterocyclic group, C3-C6 cycloalkyl, 5- or 6-membered heteroaryl; Each R f is independently selected from: halogen, hydroxy, cyano, C1-C4 haloalkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, NR d R e , wherein R d and R e are each independently hydrogen, C1-C4 alkyl; or two adjacent Rs f together with adjacent Cs on ring B form a benzene ring, a 5- to 7-membered heteroaromatic ring.

7. The compound according to claim 1, wherein The compound is selected from:

8. The method for preparing the compound according to claim 1, wherein The preparation method uses as a raw material, and obtains the compound by converting the 16-bit carboxyl group into an oxadiazole structure. In the formula, the definitions of each substituent are as described in claim 1.

9. A pharmaceutical composition, wherein comprising: a compound represented by the general formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

10. The use of the compound represented by the general formula (I) according to claim 1 or the pharmaceutical composition according to claim 9, wherein (i) for preparing an α2A adrenergic receptor (α2A-AR) antagonist; or (ii) for preparing a medicament for treating diabetes.

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