Yohimbine derivatives, methods of making, pharmaceutical compositions, and uses thereof

Abstract

The application discloses a yohimbine derivative, a preparation method, a pharmaceutical composition and an application thereof. The yohimbine derivative has a structure as shown in a formula I. Definitions of the substituents are described in the description and the claims. The yohimbine derivative can be used as an alpha2A-AR antagonist and can be used in the treatment of diabetes and other diseases.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically to a class of α2A-AR antagonists, more specifically to a class of yohimbine derivatives, methods for preparing the same, pharmaceutical compositions comprising the compounds, their use in the preparation of α2A-AR antagonists, and their use in the preparation of drugs for treating diabetes. Background Technology

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

[0003] Studies have shown that a genetic variant of the ADRA2A gene is closely related to type 2 diabetes (T2D): Excessive α2A-AR produced in the pancreatic β-cells of carriers of the risk allele rs553668 inhibits the docking of insulin granules with the plasma membrane, leading to a reduction in the distribution of insulin-containing vesicles on the cell membrane and consequently affecting insulin release levels (Science, 2010, 327, 217-220; N. Engl. J. Med., 2010, 362, 361-362). Subsequent studies have confirmed that the α2A-AR antagonist yohimbine can significantly improve insulin secretion defects associated with the ADRA2A risk variable in patients (Sci. Transl. Med., 2014, 6, 257ra139). Given that reduced pancreatic β-cell secretion is one of the main characteristics of type 2 disease (T2D), blocking α2A-AR signaling may be a novel treatment specifically targeting pancreatic β-cell defects in 40% of T2D patients carrying the rs553668 risk variant.

[0004] Yohimbine is clinically used to treat erectile dysfunction in men. Its pharmacokinetics have been well characterized. Common side effects include dizziness, anxiety, irritability, insomnia, hypertension, and palpitations, mainly caused by 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 unsuitable as a candidate drug for the treatment of type 2 erectile dysfunction (T2D), thus requiring structural modification and optimization.

[0005] Currently, there are few reports on the structural modification of yohimbine, and the main focus is on converting the 16-ester group to an amide to investigate the binding affinity of the derivative to the α2-AR isoform (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 are no reports on the antagonistic activity of novel yohimbine derivatives against α2A-AR and their tissue distribution. Summary of the Invention

[0006] The purpose of this invention is to provide a yohimbine derivative that can be used as an α2A adrenergic receptor (α2A-AR) antagonist.

[0007] In a first aspect, the invention provides a compound of formula (I), a deuterated compound thereof, or a pharmaceutically acceptable salt thereof.

[0008]

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

[0010] R 5 and R 6Each of the following groups, individually hydrogen, substituted or unsubstituted: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocyclic alkyl containing 1-3 heteroatoms, Where R b Selected from: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocyclic alkyl containing 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, where X is O or NR. c ;where R c Selected from: hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl;

[0011] L 1 The following groups are absent, hydrogen-containing, substituted, or unsubstituted: C1-C6 alkylene, C3-C10 cycloalkyl, 4-7 membered heterocyclic alkyl containing 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl. Where R is one of the following groups: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocyclic alkyl containing 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, and X is O or NR. a ;where R a Selected from: hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl;

[0012] R 7 The following groups are absent, hydrogen-containing, substituted, or unsubstituted: C1-C6 alkoxy, C3-C10 cycloalkyl, C6-C10 aryl, 3-7 membered heterocyclic, 5-7 membered heteroaryl. Where R is one of the following groups: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocyclic alkyl containing 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, and X is O or NR. a ;where R a It can be hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl;

[0013] L 1 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;

[0014] The substitution mentioned above refers to the substitution of hydrogen on a group by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 haloalkyl (e.g., trifluoromethyl), alkynyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy (e.g., 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 It can be hydrogen, halogen, cyano, hydroxyl, ethynyl, or C1-C6 alkyl.

[0016] R 2 It can be hydrogen, halogen, cyano, hydroxyl, ethynyl, C1-C4 alkyl, Where R is a substituted or unsubstituted group of the following: C1-C4 alkyl, and X is O, NR. a ;where R a The group 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 or C1-C4 alkyl;

[0017] R 3 Hydrogen, halogen, cyano, hydroxyl, C1-C4 alkyl, Where R is a substituted or unsubstituted group of the following: C1-C4 alkyl, X is O, and wherein the substitution refers to the substitution of a hydrogen atom on the group by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 alkyl, NR. d R e , where R d and R e Each is independently hydrogen or C1-C4 alkyl;

[0018] R 4 It can be hydrogen, halogen, cyano, or hydroxyl.

[0019] In another preferred embodiment, R 1 It consists of hydrogen and fluorine.

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

[0021] In another preferred embodiment, R 3 It can be hydrogen, fluorine, hydroxyl, ethynyl, methyl, or methoxy.

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

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

[0024] R 6 Hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, Where R b The following groups may be substituted or unsubstituted: C1-C4 alkyl, wherein the substitution refers to the substitution of a hydrogen atom 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 can be hydrogen, C1-C3 alkyl, or acetyl.

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

[0027] In another preferred embodiment, L 1 The following groups are absent, hydrogen-containing, substituted, or unsubstituted: C1-C4 alkylene, C3-C8 cycloalkyl, 5-7 membered heterocyclic alkyl containing 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl. Where R is one of the following groups: C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic alkyl containing 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, and X is O or NR. a ;where R a The group is hydrogen, C1-C4 alkyl, or 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, 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.

[0028] In another preferred embodiment, L 1The following groups are absent, hydrogen-containing, substituted, or unsubstituted: C1-C4 alkylene, C3-C6 cycloalkyl, 5-7 membered heterocyclic alkyl containing 1-3 heteroatoms; 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, 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 The following groups are absent, hydrogen-containing, substituted, or unsubstituted: C1-C4 alkoxy, C3-C6 cycloalkyl, C6-C10 aryl, 5-7 membered heterocyclic, 5-7 membered heteroaryl. Where R is one of the following groups: C1-C6 alkyl, C3-C10 cycloalkyl, 4-7 membered heterocyclic alkyl containing 1-3 heteroatoms, C6-C10 aryl, 5-7 membered heteroaryl, and X is O or NR. a ;where R a It can be hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl;

[0030] 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.

[0031] The substitution mentioned refers to the substitution of hydrogen on a group by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C1-C4 haloalkyl (e.g., trifluoromethyl), C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy (e.g., 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 The following groups are absent, hydrogen, substituted or unsubstituted: C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, 5-7 membered heterocyclic, 5-7 membered heteroaryl;

[0033] The substitution mentioned refers to the substitution of a hydrogen atom in a 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 or C1-C4 alkyl;

[0034] R 7 Substituents spaced 0 to 2 atoms above can cyclize into 6-membered aromatic rings and 5 to 7-membered heteroaromatic rings.

[0035] In another preferred embodiment, L 1 and R 7 Form the following formula V:

[0036]

[0037] Where r1 is selected from 1, 2, or 3; r2 is selected from 0, 1, 2, or 3;

[0038] Ring B can be phenyl, 5-6 membered heterocyclic, C3-C6 cycloalkyl, or 5-6 membered heteroaryl.

[0039] Each R f Independently selected from: halogen, hydroxyl, cyano, C1-C4 haloalkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, NR d R e , Where R d and R e Each is independently hydrogen, C1-C4 alkyl; or

[0040] Two adjacent R f Together with the C ring adjacent to ring B, they form a benzene ring and a 5- to 7-membered heteroaryl ring.

[0041] In another preferred embodiment, ring B is a benzene ring, and the substituents thereon are located at L. 1 The alignment.

[0042] In another preferred embodiment, the compound of formula V has the following structure:

[0043]

[0044] Where r1 is selected from 1, 2, or 3; r2 is selected from 0, 1, 2, or 3;

[0045] Z1, Z2, and Z3 are each independently selected from O, S, N, and CH;

[0046] Each R f Independently selected from: halogen, hydroxyl, cyano, C1-C4 haloalkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, NR d R e , Where R d and R e Each is independently hydrogen, C1-C4 alkyl; or

[0047] Two adjacent R f Together with the adjacent C on the ring, it forms a benzene ring and a 5- to 7-membered heteroaryl ring. In another preferred embodiment, r1 is selected from 1 or 2.

[0048] In another preferred embodiment, r2 is selected from 1 or 2.

[0049] In another preferred embodiment, Z1, Z2, and Z3 are each independently selected from O, N, and CH.

[0050] In another preferred embodiment, each R f Independently selected from: fluorine, chlorine, bromine, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, NR d R e , Where R d and R e Each can be independently hydrogen, methyl, or ethyl; or

[0051] Two adjacent R f Together with the adjacent carbon atoms on the ring, they form a benzene ring.

[0052] In another preferred example, -L 1 -R 7 Selected from:

[0053]

[0054] The number of substituents Rf on the benzene ring or benzo[a]ary aromatic ring is 0, 1, 2 or 3, preferably 0, 1 or 2.

[0055] In another preferred example, -L 1 -R 7 Selected from: -CH3,

[0056] In another preferred embodiment, the compound is selected from C1-C35.

[0057] A second aspect of the present invention provides a method for preparing the compound described in the first aspect, so as to... Using the above-mentioned material, the compound is obtained by converting the 16-position carboxyl group into an oxadiazole structure, wherein the definitions of each substituent are as described above.

[0058] In a preferred embodiment, the compound or a pharmaceutically acceptable salt thereof is prepared via the following route:

[0059]

[0060] Compound H1 reacts with compound H2 under condensing agent conditions to give compound H3.

[0061] Compound H3 undergoes intramolecular condensation cyclization under heating conditions to form compound H4;

[0062] When L 1 For methylene, R 7 When the phenyl group is iodine-substituted, the compound of formula H4 undergoes a coupling reaction under palladium catalysis to give L. 1 For methylene, R 7 It is a cyano-substituted phenyl compound;

[0063] When L 1 For methylene, R 7 When the phenyl group is cyano-substituted, the compound is oxidized by hydrogen peroxide under alkaline conditions to yield L. 1 For methylene, R 7 for Substituted phenyl compounds;

[0064] When L 1 For methylene, R 7 When the phenyl group is substituted with a methyl ester, the compound of formula H4 undergoes a hydrolysis reaction to give L. 1 For methylene, R 7 It is a phenyl compound with a carboxyl group substituted;

[0065] The definitions of each substituent are as described above.

[0066] A third aspect of the present invention provides a pharmaceutical composition comprising: a compound of formula (I) as described in the first aspect, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0067] A fourth aspect of the invention provides the use of a compound of formula (I) as described in the first aspect or a pharmaceutical composition as described in the third aspect, (i) for the preparation of an α2A adrenergic receptor (α2A-AR) antagonist; or (ii) for the preparation of a medicament for the treatment of diabetes.

[0068] A fifth aspect of the invention provides a method for treating diabetes, comprising administering to a subject in need a compound described in the first aspect or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in the third aspect.

[0069] The novel oxadiazole yohimbine derivative of the present invention can antagonize α2A adrenergic receptors at micromolar concentrations and has pancreatic targeting characteristics and significantly reduced brain tissue distribution characteristics compared to yohimbine.

[0070] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the various technical features specifically described 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, equivalent, or similar purpose. Due to space limitations, these will not be elaborated upon here. Attached Figure Description

[0071] Figure 1 The tissue concentrations (ng / g or ng / mL) of different compounds in mice after 2 hours of gavage administration of 10 mg / kg are shown.

[0072] Figure 2 The tissue concentrations (ng / g or ng / mL) of compound C27 in mice after gavage administration of 10 mg / kg are shown.

[0073] Figure 3 The baseline blood glucose levels in type 2 diabetic mice after a single intraperitoneal injection of a yohimbine derivative (10 mg / kg) are shown.

[0074] Figure 4 The results of glucose tolerance in type 2 diabetic mice after a single intraperitoneal injection of a yohimbine derivative (10 mg / kg) are shown.

[0075] Figure 5 The results show the insulin sensitivity of type 2 diabetic mice after a single intraperitoneal injection of a yohimbine derivative (10 mg / kg).

[0076] Figure 6 The results of glucose tolerance in type 2 diabetic mice after a single oral administration of a yohimbine derivative (10 mg / kg) are shown.

[0077] Figure 7 The results show the insulin sensitivity of type 2 diabetic mice after a single oral administration of a yohimbine derivative (10 mg / kg).

[0078] Figure 8 The baseline blood glucose levels in type 2 diabetic mice chronically injected with yohimbine derivatives (10 mg / kg, once daily) are shown. Detailed Implementation

[0079] Through extensive and in-depth research, the inventors of this application have, for the first time, developed a class of compounds that maintain good α2A adrenergic receptor antagonistic activity while also possessing pancreatic targeting and low brain permeability. Specifically, these are yohimbine derivatives of the oxadiazole class, characterized by the conversion of the 16-position ester group of yohimbine to an oxadiazole group. This maintains good α2A adrenergic receptor antagonistic activity. Compared to yohimbine, these derivatives exhibit pancreatic targeting and significantly reduced brain tissue distribution, eliminating the central nervous system side effects of yohimbine such as anxiety and hypertension. They can significantly improve glucose metabolism in type 2 diabetic animal models and hold promise as novel drugs for treating diabetes by acting on the α2A adrenergic receptor. Based on this, the present invention was completed.

[0080] the term

[0081] In this document, the alkyl group is preferably an aliphatic alkyl group, which may be a straight-chain alkyl group or a branched alkyl group, and includes, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.; the expression in the form of "C1-C6" is intended to include the corresponding group 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.

[0082] "Alkylene" refers to a straight-chain or branched saturated aliphatic group, i.e., a divalent hydrocarbon group, having a specified number of carbon atoms and being attached to at least two other groups. The two groups attached to the alkylene can be the same or different atoms on the alkylene. For example, a straight-chain alkylene can be -(CH2). n - a divalent group, where 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.

[0083] In this article, the halogens are preferably fluorine, chlorine, bromine or iodine.

[0084] In this document, alkoxy groups refer to -O-(alkyl), where alkyl is defined as described above. "C1-C6 alkoxy" refers to an oxygen-containing alkyl group containing 1-6 carbons, and non-limiting examples include methoxy, ethoxy, propoxy, butoxy, etc.

[0085] In this document, the cycloalkyl group can be a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 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.

[0086] In this document, aryl refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group, and the group has a conjugated π-electron system, such as phenyl and naphthyl. The aryl ring may be fused with a heterocyclic, heteroaryl, or cycloalkyl ring, and non-limiting examples include benzimidazole, benzothiazole, benzoxazole, benziisoxazole, benzopyrazole, quinoline, benzoindole, and benzodihydrofuran.

[0087] In this document, the heterocyclic group refers to an alicyclic heterocyclic system containing 1 to 3 heteroatoms, such as 3 to 7 ring atoms. The heteroatoms in the heterocyclic group include oxygen, sulfur, and nitrogen. The heterocyclic group is preferably 3-membered or 6-membered, such as ethylene oxide, morpholino, piperazine, etc.

[0088] In this document, the term "heteroaryl" refers to a heteroaryl system containing 1 to 4 heteroatoms, such as 5 to 14 ring atoms. The heteroatoms of the heteroaryl include oxygen, sulfur, and nitrogen. The heteroaryl is preferably a 5- or 6-membered compound, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl can be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.

[0089] Unless otherwise indicated, Indicates the connection site.

[0090] In this document, there are no particular limitations on the pharmaceutically acceptable salts, but they preferably include: inorganic acid salts, organic acid salts, alkyl sulfonates, and aryl sulfonates; the inorganic salts include hydrochlorides, hydrobroms, 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.; and the aryl sulfonates include benzene sulfonates, p-toluene sulfonates, etc.

[0091] Preparation method

[0092] The oxadiazole yohimbine derivatives of the present invention can be prepared using the following route. The definitions of each substituent are as described above.

[0093]

[0094] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0095] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0096] In the following preparation examples, NMR was measured using a Bruker Avance III 400 / 500MHz NMR instrument, with NMR calibration as follows: δH 7.26ppm (CDCl3), 2.50ppm (DMSO-d6); mass spectrometry was performed using an Agilent 1200 Quadrupole LC / MS system; reagents were mainly provided by Shanghai Chemical Reagent Company; TLC silica gel plates were manufactured by Shandong Yantai Jiangyou Silica Gel Development Co., Ltd., model HSGF 254; and normal-phase column silica gel used for compound purification was manufactured by the Qingdao Marine Chemical Plant Branch of Shandong, model ZCX-II, 200-300 mesh.

[0097] The Chinese translations of the abbreviations in this article are as follows:

[0098] DMF: N,N-Dimethylformamide; COMU: (1-Cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholino-carbomony hexafluorophosphate; Pd(dba)2: bis(dibenzylideneacetone palladium); dppf: 1,1'-bis(diphenylphosphine)ferrocene;

[0099] Example 1

[0100]

[0101] (1) At room temperature, phenylacetonitrile (1.17 g, 10 mmol) was dissolved in ethanol (20 mL), and water (8 mL), sodium carbonate (848 mg, 8 mmol), and hydroxylamine hydrochloride (695 mg, 10 mmol) were added in sequence. After the addition was completed, the mixture was stirred at room temperature for 24 hours. Most of the solvent was removed by concentration under reduced pressure. The residue was dissolved in ethyl acetate (80 mL), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was used directly for condensation reaction without purification.

[0102] (2) Under ice bath conditions, yohimbine hydrochloride M1 (7.81 g, 20 mmol) was placed in methanol / tetrahydrofuran / water (90 mL / 60 mL / 30 mL), and lithium hydroxide monohydrate (5.04 g, 120 mmol) was added. After stirring under ice bath conditions for half an hour, the mixture was moved to room temperature. LC-MS was monitored until the starting material disappeared. The mixture was concentrated under reduced pressure to remove most of the solvent. The residue was dissolved in water (150 mL). The pH was adjusted with 5% hydrochloric acid under ice bath conditions until a milky white turbidity appeared in the system. The mixture was allowed to stand overnight, filtered, and 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%.

[0103] (3) At room temperature, M2 (340 mg, 1 mmol) was dissolved in DMF (5 mL), 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 complete, the mixture was stirred at room temperature for 20 minutes. Then, the crude product (300 mg, 2 mmol) from operation (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), dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 30:1) to obtain brown foamy solid M3.

[0104] (4) Dissolve the condensation product M3 from operation (3) in 1,4-dioxane (5 mL), then add toluene (10 mL), heat to 100 °C under a nitrogen atmosphere, stop the reaction after 24 hours, concentrate under reduced pressure to remove the solvent, dissolve the residue in dichloromethane / methanol (100 mL / 10 mL), wash with saturated brine (20 mL × 3), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography (dichloromethane / methanol = 30:1) to obtain a light brown foamy solid C1 (46 mg, 0.1 mmol). The molar yield of the two steps (3) and (4) is 10%.

[0105] The other compounds listed in the table below were synthesized using the same method as in Example 1, but with different cyanide bases:

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113] Example 2

[0114]

[0115] (1) At room temperature, 4-iodophenylacetonitrile (2.43 g, 10 mmol) was dissolved in ethanol (20 mL), and water (8 mL), sodium carbonate (848 mg, 8 mmol), and hydroxylamine hydrochloride (695 mg, 10 mmol) were added in sequence. After the addition was completed, the mixture was stirred at room temperature for 24 hours. Most of the solvent was removed by concentration under reduced pressure. The residue was dissolved in ethyl acetate (80 mL), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was used directly for condensation reaction without purification.

[0116] (2) At room temperature, M2 (340 mg, 1 mmol) was dissolved in DMF (5 mL), 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 complete, the mixture was stirred at room temperature for 20 minutes. Then, the crude product (552 mg, 2 mmol) from operation (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), dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 30:1) to obtain brown foamy solid M3.

[0117] (3) Dissolve the condensation product M3 from operation (2) in 1,4-dioxane (5 mL), then add toluene (10 mL), heat to 100 °C under a nitrogen atmosphere, stop the reaction after 24 hours, concentrate under reduced pressure to remove the solvent, dissolve the residue in dichloromethane / methanol (100 mL / 10 mL), wash with saturated brine (20 mL × 3), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography (dichloromethane / methanol = 30:1) to obtain a light brown foamy solid M4 (69 mg, 0.12 mmol). The molar yield of the two steps (2) and (3) is 12%.

[0118] (4) Dissolve M4 (58 mg, 0.1 mmol) in DMF (5 mL), then add 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). Heat to 80 °C under a nitrogen atmosphere. Stop the reaction after 6 hours. Remove the solvent by concentration under reduced pressure. Dissolve the residue in dichloromethane / methanol (100 mL / 10 mL), wash with saturated brine (20 mL × 3), dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography (dichloromethane / methanol = 30:1) to obtain a light brown foamy solid C19 (33 mg, 0.07 mmol), with a molar yield of 70%.

[0119] The other compounds listed in the table below were synthesized using the same method as in Example 2, but with different cyanide bases:

[0120]

[0121] Example 3

[0122]

[0123] Compound C19 (14 mg, 0.03 mmol) was dissolved in EtOH (0.15 mL), and DMSO (0.075 mL) was added under ice bath conditions. Then, 4 M NaOH (0.0073 mL) and 30% H2O2 (0.01 mL) were added. The reaction was carried out under ice bath conditions for 30 minutes, and then moved to room temperature. After 5 hours, the reaction was stopped. 10% Na2S2O3 (0.15 mL) and H2O (2 mL) were added to the reaction system under ice bath conditions. A white solid precipitated out. The solid was filtered under reduced pressure, the filter cake was washed with water, and dried to obtain a white solid C27 (10 mg, 0.02 mmol), with a molar yield of 67%.

[0124]

[0125] Example 4

[0126]

[0127] 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 conditions. Lithium hydroxide monohydrate (42 mg, 1 mmol) was added, and the mixture was stirred under ice bath conditions for half an hour. The mixture was then moved to room temperature, and LC-MS was used to monitor the disappearance of the starting material. The mixture was concentrated under reduced pressure to remove most of the solvent. The residue was then mixed with water (5 mL), and the pH was adjusted to 6 with 5% hydrochloric acid under ice bath conditions. The mixture was allowed to stand, filtered, and the filter cake was washed with water (2 mL). The filter cake was collected and dried to obtain a yellow powder C30 (25 mg, 0.05 mmol), with a molar yield of 50%.

[0128]

[0129] Example 5: α2A-AR Antagonist Test

[0130] 1. Experimental Objective

[0131] The antagonistic activity of yohimbine derivatives against α2A-AR was investigated.

[0132] 2. Experimental Principle

[0133] By establishing a cell line co-transfected with the target receptor and Ga16, the activation of the receptor leads to the activation of Gα16 protein, which in turn activates phospholipase C (PLC) to produce IP3 and DAG. IP3 binds to IP3 receptors on the endoplasmic reticulum and mitochondria, thereby causing intracellular calcium release. Therefore, measuring changes in intracellular calcium can be used as a method to detect the activation state of the target receptor. Fluo-4 / AM is a calcium fluorescent probe indicator used to measure calcium ions. As a nonpolar, lipid-soluble compound, after entering the cell, the AM group dissociates under the action of cellular lipases, releasing Fluo-4. Because Fluo-4 is a polar molecule and does not easily cross the lipid bilayer, it can be retained intracellularly for a long time. Finally, the activation level of Ga protein can be reflected by measuring the excited fluorescence intensity. If the screened compound can stimulate the target receptor, the calcium flux response can be greatly increased; conversely, if the screened compound can antagonize the target receptor, the calcium flux response can be greatly reduced.

[0134] 3. Experimental Samples

[0135] Before the experiment, the test compound was dissolved in DMSO to prepare a stock solution, which was then diluted with culture medium to the required concentration before use.

[0136] 4. Experimental Methods

[0137] Cells stably expressing α2A-AR / Ga16 were seeded in 96-well plates and cultured overnight. The culture medium in the wells containing the cells was aspirated, and freshly prepared dye (40 μL / well) was added. The plates were incubated at 37°C for 40 minutes. The drug to be tested was diluted with calcium buffer and mixed well. The dye was aspirated and discarded, and the plates were washed once with freshly prepared calcium buffer. Then, 50 μL of calcium buffer containing the drug to be tested was added. The plates were then detected using a FlexStation II instrument. Starting at the 15th second, the instrument automatically added 25 μL of calcium buffer containing the known agonist UK14304, and the fluorescence value at 525 nm was read.

[0138] 5. Experimental Results (using the 35 compounds in Table 1 as examples, but not limited to these compounds)

[0139] Table 1 Results of α2A-AR antagonistic activity tests of compounds

[0140]

[0141]

[0142] Note: IC 50 This is to evaluate the antagonistic activity of the sample drug against α2A-AR.

[0143] * indicates 0.5μM≤IC 50 <2μM; ** represents 0.3μM≤IC 50 <0.5μM,

[0144] *** represents 0.1μM≤IC 50 <0.3μM; **** represents IC 50 <0.1μM.

[0145] 6. Results and Discussion

[0146] These compounds were able to compete with the α2A-AR agonist UK14304 in cells expressing α2A-AR and antagonize the α2A-AR agonistic effect of UK14304, IC50 50 See Table 1. The results indicate that these compounds are antagonists of α2A-AR.

[0147] Example 6: Distribution assay of yohimbine derivatives in mouse tissues

[0148] 1. Experimental Objective

[0149] The tissue distribution of yohimbine derivatives in mice was investigated.

[0150] 2. Experimental Design

[0151] Table 2 Dosage regimens for mouse tissue distribution assay Note: All administered compounds were in hydrochloride form and prepared with deionized water; all test animals were male ICR animals.

[0152] Mice were fasted for more than 12 hours but given free access to water.

[0153] Table 3. Experimental protocol for the distribution of compound C27 in mouse tissues.

[0154]

[0155] Note: The solvent ratio was 5% DMSO + 5% solubilol + 90% saline; all experimental animals were male ICR patients.

[0156] Mice were fasted for more than 12 hours but given free access to water.

[0157] 3. Sample collection and measurement

[0158] (1) Mouse tissue distribution test: Animals in each group were euthanized 2 hours after administration, and brain, pancreas, heart, liver and kidney tissues were collected by dissection. After washing with physiological saline, the tissues were frozen and stored at -20℃ for later testing. At the same time, 0.3 mL of whole blood was collected into EDTA-K2 anticoagulant tubes, and plasma was separated by centrifugation at 11000 rpm for 5 min. The plasma was frozen and stored at -20℃ for later testing.

[0159] Blank plasma and tissue were collected from three other animals.

[0160] The concentration of the parent drug in plasma and tissues was determined.

[0161] (2) Tissue distribution test of compound C27 in mice: Mice were euthanized by exsanguination via the abdominal aorta at corresponding time points (0.25, 2, and 8 h) after gavage administration. Brain, heart, liver, lung, pancreas, and kidney tissues were immediately dissected and collected, along with some plasma. Ice water bath was used for the procedure.

[0162] Centrifugation conditions: Centrifuge at 11000 rpm for 5 min to separate plasma (approximately 200 μL).

[0163] After collection, tissues and plasma should be stored at -60°C or below.

[0164] 4. Experimental Results and Discussion

[0165] Figure 1 The tissue concentrations (ng / g or ng / mL) of different compounds in mice after 2 hours of gavage administration at a dose of 10 mg / kg are shown. Figure 1 (Taking four compounds as examples, but not limited to these compounds)

[0166] Figure 2 The tissue concentrations (ng / g or ng / mL) of compound C27 in mice after gavage administration of 10 mg / kg are shown.

[0167] Based on the relative ratio of tissue distribution concentration to blood drug concentration, compounds C1, C6, C13, C19, and C27 all showed reduced brain tissue distribution compared to yohimbine. Among them, compound C19 showed a brain tissue distribution that was about 40 times lower than that of yohimbine, and compound C19 also had good pancreatic distribution. The plasma exposure of compound C27 was comparable to that of yohimbine, but its brain tissue distribution was about 270 times lower than that of yohimbine, and it had pancreatic distribution characteristics comparable to those of compound C19.

[0168] Example 7: Experimental test on the therapeutic effect of yohimbine derivatives on lowering blood glucose in diabetic mice

[0169] 1. Experimental Objective

[0170] To investigate whether the yohimbine derivative C19 can improve glycemic metabolism in type 2 diabetes.

[0171] 2. Experiment Content

[0172] This experiment used a type 2 diabetic mouse model induced by a high-sugar, high-fat diet to conduct tests on the following aspects:

[0173] 1) Effects of a single intraperitoneal administration on basal blood glucose, glucose tolerance, and insulin sensitivity in diabetic mice.

[0174] 2) Effects of a single oral gavage administration on glucose tolerance and insulin sensitivity in diabetic mice.

[0175] 3) Effect of continuous chronic intraperitoneal administration on basal blood glucose in diabetic mice.

[0176] 3. Experimental Methods

[0177] C57BL\6J mice were fed a high-sugar, high-fat diet for 3 months. After the average weight of the mice stabilized above 50g and the average basal blood glucose level stabilized above 12mmol / L, the test experiment was carried out.

[0178] Blood glucose levels were primarily assessed using a glucometer to measure tail vein blood. For testing the effect on basal blood glucose, the study was conducted on mice under normal dietary conditions. Pre-administration basal blood glucose levels were measured, followed by a single intraperitoneal injection or a single gavage administration of yohimbine derivative C19 (10 mg / kg mouse body weight). Venous blood glucose levels were measured sequentially at 15, 30, 60, 90, and 120 minutes after administration. Glucose tolerance in mice was tested after a 16-hour overnight feeding. Thirty minutes after a single intraperitoneal injection or gavage administration of yohimbine derivative C19 (10 mg / kg mouse body weight), glucose (1.5 g / kg) was injected intraperitoneally, and venous blood glucose levels were measured sequentially at 15, 30, 60, 90, and 120 minutes. Insulin sensitivity in mice was assessed after a 6-hour feeding. Thirty minutes after a single intraperitoneal injection or gavage administration of yohimbine derivative C19 (10 mg / kg mouse body weight), insulin (1 UI / kg) was administered intraperitoneally. Venous blood glucose levels were measured at 15, 30, 60, 90, and 120 minutes. For the effect of chronic administration on blood glucose levels, diabetic mice were intraperitoneally injected with yohimbine derivative C19 (10 mg / kg) daily for 12 consecutive days. Basal blood glucose levels were measured daily before drug injection under free-flowing diet. The control group received either saline injection or gavage.

[0179] 4. Experimental Results

[0180] Experimental results are as follows Figure 3-8 As shown. Among them Figure 3 The results showed that a single intraperitoneal injection of yohimbine derivative (10 mg / kg) significantly reduced the basal blood glucose level in type 2 diabetic mice. Figure 4 The results showed that a single intraperitoneal injection of yohimbine derivative (10 mg / kg) significantly improved glucose tolerance in type 2 diabetic mice. Figure 5 The results showed that a single intraperitoneal injection of yohimbine derivative (10 mg / kg) significantly improved insulin sensitivity in type 2 diabetic mice. Figure 6 The results showed that a single oral administration of yohimbine derivative (10 mg / kg) significantly improved glucose tolerance in type 2 diabetic mice. Figure 7 The results showed that a single oral administration of yohimbine derivative (10 mg / kg) significantly improved insulin sensitivity in type 2 diabetic mice. Figure 8 The results showed that chronic injection of yohimbine derivatives (10 mg / kg, once a day) significantly reduced basal blood glucose levels in type 2 diabetic mice.

[0181] 5 Results and Discussion

[0182] This experiment demonstrates that a single injection or gavage administration of the yohimbine derivative C19 of this invention significantly reduces hyperglycemia levels in diabetic mice, improves glucose tolerance, and enhances insulin sensitivity. Chronic administration helps maintain basal blood glucose levels in diabetic mice at levels closer to normal. Therefore, the yohimbine derivative C19 of this invention exhibits a significant effect in improving glycemic metabolism in diabetic mice.

[0183] By structurally modifying yohimbine, a novel derivative was obtained that exhibits enhanced α2A adrenergic receptor antagonistic 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 this invention can significantly improve glucose metabolism in a type 2 diabetic animal model. Chronic administration can stabilize the basal blood glucose level of diabetic mice at a level closer to normal, and it is expected to be used for the treatment of diabetes.

[0184] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, (Ⅰ) In the formula, R 1 R 2 R 3 and R 4 It is hydrogen; R 5 and R 6 It is hydrogen; L 1 It is either absent or a C1-C6 alkylene group; R 7 Selected from: hydrogen, substituted or unsubstituted groups of the following: C1-C6 alkoxy, C3-C10 cycloalkyl, C6-C10 aryl, 3-7 membered heterocyclic, 5-7 membered heteroaryl; wherein, Substituents with 0 to 2 atoms spaced on C6-C10 aryl and 5-7 heteroaryl groups can cyclize to form a 6-membered aromatic ring or a 5-7-membered heteroaryl ring. The substitution refers to the substitution of a hydrogen atom on a group by one or more substituents selected from the group consisting of: halogen, hydroxyl, cyano, C1-C6 haloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, NR. d R e , , , ;where R d and R e Each is independently hydrogen or C1-C6 alkyl.

2. The compound according to claim 1, characterized in that, L 1 It is either absent or a C1-C4 alkylene group.

3. The compound according to claim 1, characterized in that, R 7 Selected from: hydrogen, substituted or unsubstituted of the following groups: C1-C4 alkoxy, C3-C6 cycloalkyl, C6-C10 aryl, 5-7 membered heterocyclic, 5-7 membered heteroaryl; wherein, the substituents on the C6-C10 aryl and 5-7 membered heteroaryl groups with a spacing of 0 to 2 atoms can be cyclized to form a 6-membered aromatic ring or a 5-7 membered heteroaryl ring; The substitution refers to the substitution of a hydrogen atom on a group 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 , , , , where R d and R e Each is independently hydrogen or C1-C4 alkyl.

4. The compound according to claim 1, characterized in that, R 7 Selected from: hydrogen, substituted or unsubstituted of the following groups: C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, 5-7 membered heterocyclic, 5-7 membered heteroaryl; wherein, the substituents on the phenyl and 5-7 membered heteroaryl groups with 0 to 2 atoms in between can be cyclized to form a 6-membered aromatic ring or a 5-7 membered heteroaryl ring; The substitution refers to the substitution of a hydrogen atom on a group by one or more substituents selected from the group consisting of: fluorine, chlorine, bromine, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, C1-C4 alkyl, C1-C4 alkoxy, NR. d R e , , , , where R d and R e Each is independently hydrogen or C1-C4 alkyl.

5. The compound according to claim 1, characterized in that, L 1 and R 7 Form the following formula V: V Where r1 is selected from 1, 2, or 3; r2 is selected from 0, 1, 2, or 3; Ring B can be phenyl, 5-6 membered heterocyclic, C3-C6 cycloalkyl, or 5-6 membered heteroaryl. Each R f Independently selected from: halogen, hydroxyl, cyano, C1-C4 haloalkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, NR d R e , , , , where R d and R e Each is independently hydrogen or C1-C4 alkyl; Or two adjacent R f It forms a benzene ring or a 5-7 membered heteroaryl ring together with the C atom adjacent to the phenyl or 5-6 membered heteroaryl group.

6. The compound according to claim 5, characterized in that, Compound V has the following structure: 、 ； Where r1 is selected from 1, 2, or 3; r2 is selected from 0, 1, 2, or 3; In this context, Z1, Z2, and Z3 are each independently selected from O, S, N, and CH. In this context, Z1, Z2, and Z3 are each independently selected from N and CH; Each R f Independently selected from: halogen, hydroxyl, cyano, C1-C4 haloalkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, NR d R e , , , , where R d and R e Each is independently hydrogen, C1-C4 alkyl; or Two adjacent R f Together with the adjacent C atoms on the ring, they form a benzene ring or a 5- to 7-membered heteroaromatic ring.

7. The compound according to claim 5, characterized in that, Each R f Independently selected from: fluorine, chlorine, bromine, hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, NR d R e , , , , where R d and R e Each independently can be hydrogen, methyl, or ethyl; or Two adjacent R f Together with the adjacent C atoms on the ring, they form a benzene ring.

8. The compound according to claim 5, characterized in that, -L 1 -R 7 Selected from: 。 9. The compound according to claim 1, characterized in that, -L 1 -R 7 Selected from: -CH3, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

10. The compound according to claim 1, characterized in that, The compound is selected from: 。 11. The method for preparing the compound according to claim 1, characterized in that, The preparation method is as follows Using [a specific ingredient] as a starting material, the compound is obtained by converting the 16-position carboxyl group to an oxadiazole structure, comprising the following steps: Compound H1 reacts with compound H2 under condensing agent conditions to yield compound H3. Compound H3 undergoes intramolecular condensation cyclization under heating conditions to form compound I; For compound of formula I, when L 1 For methylene, R 7 When the phenyl group is iodine-substituted, the compound undergoes a coupling reaction under palladium catalysis to give L. 1 For methylene, R 7 Compound I is a cyano-substituted phenyl compound; For compound of formula I, when L 1 For methylene, R 7 When the phenyl group is cyano-substituted, the compound is oxidized by hydrogen peroxide under alkaline conditions to yield L. 1 For methylene, R 7 for Substituted phenyl compounds of formula I; For compound of formula I, when L 1 For methylene, R 7 When the phenyl group is substituted with a methyl ester, the compound undergoes hydrolysis to give L. 1 For methylene, R 7 Compound I is a phenyl group substituted with a carboxyl group.

12. A pharmaceutical composition, characterized in that, Include: The compound of formula (I) as claimed in any one of claims 1-10, or a pharmaceutically acceptable salt thereof; and Pharmaceutically acceptable carrier.

13. Use of the compound of general formula (I) according to any one of claims 1-10 or the pharmaceutical composition according to claim 12, characterized in that, (i) for the preparation of α2A adrenergic receptor (α2A-AR) antagonists; or (ii) for the preparation of drugs for the treatment of diabetes.

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