Yohimbine derivatives, their preparation, pharmaceutical compositions and uses

Abstract

The structure of the yohimbine derivative is as shown in Formula I, and the definitions of each substituent in the formula are as described in the specification and claims. The yohimbine derivative can be used as an α2A-AR antagonist to treat diseases such as diabetes.

Description

[Technical Field]

[0001] The present invention relates to the field of biomedicine, in particular to alpha2A-AR antagonists, in particular to yohimbine derivatives and methods for their preparation, as well as the use of pharmaceutical compositions comprising said compounds in the preparation of alpha2A-AR antagonists and in the preparation of drugs for treating diabetes. [Background technology]

[0002] Alpha2-adrenergic receptors (α2-ARs) belong to the G protein-coupled receptor (GPCR) superfamily and are crucial for regulating catecholamine signaling. Pharmacologically, α2-ARs are classified into three subtypes: α2A-ARs, α2B-ARs, and α2C-ARs. α2A-ARs are widely distributed in the central nervous system (CNS) and peripheral tissues, and the former is predominant, accounting for approximately 90% of α2-ARs in the CNS. α2A-ARs can inhibit neuronal excitation and the release of norepinephrine and other neurotransmitters, mediating a range of important physiological responses and pharmacological effects. Multiple polymorphisms have been identified in the gene ADRA2A, which encodes the α2A-AR, and they differentially increase α2A-AR expression, reduce antidepressant responses, and alter memory and behavior.

[0003] Studies have shown that genetic variants in the ADRA2A gene are closely associated with type 2 diabetes (T2D). Excessive α2A-AR production in the pancreatic beta cells of carriers of the risk allele rs553668 inhibits insulin granule docking with the plasma membrane, resulting in reduced placement of insulin-containing vesicles on the plasma membrane and 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 the insulin secretion defect associated with the ADRA2A risk variable in patients (Sci. Transl. Med., 2014, 6, 257ra139). Because reduced pancreatic beta-cell secretory capacity is one of the major features of T2D, blocking α2A-AR signaling may represent a novel therapeutic avenue specifically targeting the pancreatic beta-cell defects present in the 40% of T2D patients who carry the rs553668 risk variant.

[0004] Yohimbine is clinically used to treat male erectile dysfunction, and its pharmacokinetics have been well characterized. Common side effects include dizziness, anxiety, irritability, insomnia, hypertension, and palpitations, which are primarily caused by presynaptic α2A-AR blockade and sympathetic activation in the CNS (EFSA.J.,2013,11,3302). Although yohimbine is effective in correcting insulin secretion defects, its frequent central side effects make it unsuitable as a candidate drug for the treatment of T2D. Therefore, structural modification and optimization are necessary.

[0005] Currently, there are few reports on the structural modification of yohimbine, and most of them focus on converting the ester group at position 16 to an amide and examining the binding affinity of the derivatives to 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 relevant reports on the antagonistic activity and tissue distribution of novel yohimbine derivatives against the α2A-AR. Summary of the Invention [Problem to be solved by the invention]

[0006] It is an object of the present invention to provide yohimbine derivatives for use as α2A adrenergic receptor (α2A-AR) antagonists. [Means for solving the problem]

[0007] A first aspect of the present invention provides a compound represented by formula (I), a deuterated compound thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, R 1 , R 2 , R 3 and R 4 are each independently hydrogen, halogen, a cyano group, a hydroxy group, an ethynyl group, or a substituted or unsubstituted group selected from the following: a C1-C6 alkyl group, a C3-C10 cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms, a C6-C10 aryl group, and a 5- to 7-membered heteroaryl group; [ka] wherein R is one of the following groups: a C1-C6 alkyl group, a C3-C10 cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms, a C6-C10 aryl group, or a 5- to 7-membered heteroaryl group; and X is O or NRa where R a is selected from hydrogen, a C1-C6 alkyl group, and a C3-C10 cycloalkyl group; R 5 and R 6 are each independently hydrogen, a substituted or unsubstituted group selected from the following: a C1-C6 alkyl group, a C3-C10 cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms, [ka] where R b is selected from a C1-C6 alkyl group, a C3-C10 cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms, a C6-C10 aryl group, and a 5- to 7-membered heteroaryl group; and X is O or NR c where R c is selected from hydrogen, a C1-C6 alkyl group, and a C3-C10 cycloalkyl group; L 1 is absent, hydrogen, or a substituted or unsubstituted group selected from the following: a C1-C6 alkylene group, a C3-C10 cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms, a C6-C10 aryl group, a 5- to 7-membered heteroaryl group, [ka] wherein R is one of the following groups: a C1-C6 alkyl group, a C3-C10 cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms, a C6-C10 aryl group, or a 5- to 7-membered heteroaryl group; and X is O or NR a where R a is selected from hydrogen, a C1-C6 alkyl group, and a C3-C10 cycloalkyl group;

[0008] R 7 is absent, hydrogen, or a substituted or unsubstituted group selected from the following: a C1-C6 alkoxy group, a C3-C10 cycloalkyl group, a C6-C10 aryl group, a 3- to 7-membered heterocyclic group, a 5- to 7-membered heteroaryl group, [ka] wherein R is one of the following groups: a C1-C6 alkyl group, a C3-C10 cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms, a C6-C10 aryl group, or a 5- to 7-membered heteroaryl group; and X is O or NR a where R a is hydrogen, a C1-C6 alkyl group, or a C3-C10 cycloalkyl group; L 1 , R 7 The substituents spaced 0 to 2 atoms above can be cyclized to 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; The above-mentioned substitution means that the hydrogen on the group is replaced with a halogen, a hydroxy group, a cyano group, a C1-C6 halogenated alkyl group (e.g., a trifluoromethyl group), an alkynyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group (e.g., a trifluoromethoxy group), NR d R e , [ka] where R d and R e are each independently hydrogen or a C1-C6 alkyl group.

[0009] In another preferred embodiment, R 1 is hydrogen, halogen, cyano group, hydroxy group, ethynyl group, C1-C6 alkyl group, R 2 represents hydrogen, halogen, cyano group, hydroxy group, ethynyl group, C1-C4 alkyl group, [ka] where R is a substituted or unsubstituted group: a C1-C4 alkyl group; and X is O, NR a where R ais hydrogen, a C1-C4 alkyl group, and the substitution means that the hydrogen on the group is replaced with a halogen, a hydroxy group, a C1-C4 alkyl group, NR d R e where R d and R e are each independently hydrogen or a C1-C4 alkyl group; R 3 represents hydrogen, halogen, cyano group, hydroxy group, C1-C4 alkyl group, [ka] wherein R is a substituted or unsubstituted group: a C1-C4 alkyl group; X is O, where the substitution means that a hydrogen on the group is replaced with a halogen, a hydroxy group, a cyano group, a C1-C6 alkyl group, NR d R e where R d and R e are each independently hydrogen or a C1-C4 alkyl group; R 4 is hydrogen, halogen, cyano group, or hydroxy group. In another preferred embodiment, R 1 are hydrogen and fluorine. In another preferred embodiment, R 2 is hydrogen, fluorine, chlorine, bromine, cyano group, hydroxy group, ethynyl group, methyl group, or methoxy group. In another preferred embodiment, R 3 is hydrogen, fluorine, a hydroxy group, an ethynyl group, a methyl group, or a methoxy group. In another preferred embodiment, R 4 is hydrogen.

[0010] In another preferred embodiment, R 5 represents hydrogen, a C1-C4 alkyl group, [ka] where R b is a substituted or unsubstituted group: a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a C6-C10 aryl group, or a 5- to 7-membered heteroaryl group, where the substitution means that a hydrogen atom on the group is replaced with a halogen atom, a hydroxy group, a C1-C4 alkyl group, a C1-C4 alkoxy group, or an NR d R e where R d and R e are each independently hydrogen or a C1-C4 alkyl group; R 6 represents hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, [ka] where R b is a substituted or unsubstituted group: a C1-C4 alkyl group, where the substitution means that a hydrogen on the group is replaced with a halogen, a hydroxy group, a cyano group, a trifluoromethyl group, NR d R e where R d and R e are each independently hydrogen or a C1-C4 alkyl group.

[0011] In another preferred embodiment, R 5 is hydrogen, a C1-C3 alkyl group, or an acetyl group. In another preferred embodiment, R 6 is hydrogen, a C1-C3 alkyl group, or an acetyl group. In another preferred embodiment, L 1 is absent, hydrogen, or a substituted or unsubstituted group selected from the following: a C1-C4 alkylene group, a C3-C8 cycloalkyl group, a 5- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms, a C6-C10 aryl group, a 5- to 7-membered heteroaryl group, [ka] wherein R is one of the following groups: a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms, a C6-C10 aryl group, or a 5- to 7-membered heteroaryl group; and X is O or NR a where R a is hydrogen, a C1-C4 alkyl group, or a C3-C6 cycloalkyl group, and the substitution means that the hydrogen on the group is replaced with a halogen, a hydroxy group, a cyano group, a trifluoromethyl group, a C1-C4 alkyl group, a C1-C4 alkoxy group, or NR d R e where R d and R e are each independently hydrogen or a C1-C4 alkyl group.

[0012] In another preferred embodiment, L 1 is absent, hydrogen, or a substituted or unsubstituted group: a C1-C4 alkylene group, a C3-C6 cycloalkyl group, or a 5- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms, where the substitution means that the hydrogen on the group is replaced with a halogen, a hydroxy group, a cyano group, a trifluoromethyl group, a C1-C4 alkyl group, a C1-C4 alkoxy group, or NR d R e where R d and R e are each independently hydrogen or a C1-C4 alkyl group.

[0013] In another preferred embodiment, R 7 is absent, hydrogen, or a substituted or unsubstituted group selected from the following: a C1-C4 alkoxy group, a C3-C6 cycloalkyl group, a C6-C10 aryl group, a 5- to 7-membered heterocyclic group, a 5- to 7-membered heteroaryl group, [ka] wherein R is one of the following groups: a C1-C6 alkyl group, a C3-C10 cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms, a C6-C10 aryl group, or a 5- to 7-membered heteroaryl group; and X is O or NR a where R a is hydrogen, a C1-C6 alkyl group, or a C3-C10 cycloalkyl group; R 7 The substituents spaced 0 to 2 atoms above can be cyclized to 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; Here, the substitution means that the hydrogen on the group is replaced with a halogen, a hydroxy group, a cyano group, a C1-C4 halogenated alkyl group (e.g., a trifluoromethyl group), a C1-C4 alkyl group, a C1-C4 alkoxy group, a C1-C4 halogenated alkoxy group (e.g., a trifluoromethoxy group), NR d R e , [ka] where R d and R e are each independently hydrogen or a C1-C4 alkyl group.

[0014] In another preferred embodiment, R 7 is absent, hydrogen, or a substituted or unsubstituted group selected from the group consisting of a C1-C4 alkoxy group, a C3-C6 cycloalkyl group, a phenyl group, a 5- to 7-membered heterocyclic group, and a 5- to 7-membered heteroaryl group; Here, the substitution means that hydrogen on the group is replaced with fluorine, chlorine, bromine, a hydroxy group, a cyano group, a trifluoromethyl group, a trifluoromethoxy group, an alkynyl group, a C1-C4 alkyl group, a C1-C4 alkoxy group, [ka] where R d and R eare each independently hydrogen or a C1-C4 alkyl group; R 7 The substituents spaced 0 to 2 atoms above can be cyclized to a 6-membered aromatic ring, a 5- to 7-membered heteroaromatic ring.

[0015] In another preferred embodiment, L 1 and R 7 forms the following equation V: [ka] wherein r1 is selected from 1, 2, or 3, and r2 is selected from 0, 1, 2, or 3; Ring B is a phenyl group, a 5- to 6-membered heterocyclic group, a C3-C6 cycloalkyl group, or a 5- to 6-membered heteroaryl group; Each R f is a halogen, a hydroxy group, a cyano group, a C1-C4 halogenated alkyl group, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C1-C4 halogenated alkoxy group, NR d R e , [ka] are independently selected from, where R d and R e are each independently hydrogen, a C1-C4 alkyl group, or Two adjacent R f together with the adjacent C on ring B to form a benzene ring, a 5- to 7-membered heteroaromatic ring. In another preferred embodiment, ring B is a benzene ring, and its substituents are L 1 It is positioned in para position relative to the

[0016] In another preferred embodiment, the compound of formula V has the structure: [ka] wherein r1 is selected from 1, 2, or 3, and r2 is selected from 0, 1, 2, or 3; Z1, Z2, and Z3 are each independently selected from O, S, N, and CH; Each R f is a halogen, a hydroxy group, a cyano group, a C1-C4 halogenated alkyl group, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C1-C4 halogenated alkoxy group, NR d R e , [ka] are independently selected from, where R d and R e are each independently hydrogen, a C1-C4 alkyl group, or Two adjacent R f together with the adjacent C on the ring to form a benzene ring or a 5- to 7-membered heteroaromatic ring.

[0017] In another preferred example, r1 is selected from 1 or 2. In another preferred embodiment, r2 is selected from 1 or 2. In another preferred example, Z1, Z2, and Z3 are each independently selected from O, N, and CH. In another preferred embodiment, each R f represents fluorine, chlorine, bromine, hydroxyl group, cyano group, trifluoromethyl group, trifluoromethoxy group, methyl group, ethyl group, methoxy group, ethoxy group, NR d R e , [ka] are independently selected from, where R d and R e are each independently a hydrogen atom, a methyl group, or an ethyl group; Two adjacent R f together with the adjacent C on the ring to form a benzene ring.

[0018] In another preferred embodiment, -L 1 -R 7 is selected from the following: [ka]

[0019] The number of substituents Rf on the benzene ring or benzoheteroaromatic ring is 0, 1, 2 or 3, preferably 0, 1 or 2. In another preferred embodiment, -L 1 -R 7 is -CH3, [ka] is selected from.

[0020] In another preferred example, the compound is selected from C1 to C35. A second aspect of the invention provides a method for preparing a compound according to the first aspect, comprising the steps of: [ka] is used as a raw material, and the carboxy group at position 16 is converted to an oxadiazole structure to obtain the compound, wherein the definitions of the respective substituents are as described above.

[0021] In a preferred embodiment, the compound or a pharmaceutically acceptable salt thereof is prepared by the following route: [ka] The compound of formula H1 is reacted with a compound of formula H2 under condensing agent conditions to give a compound of formula H3; The compound of formula H3 undergoes intramolecular cyclocondensation under heating conditions to form a compound of formula H4, L 1 is a methylene group, and R 7 is an iodine-substituted phenyl group, a compound of formula H4 can be subjected to a coupling reaction under palladium metal catalysis to give L 1 is a methylene group, and R 7 is a phenyl group substituted with a cyano group, L 1 is a methylene group, and R7 When L is a phenyl group substituted with a cyano group, the compound can be oxidized with hydrogen peroxide under basic conditions to give L 1 is a methylene group, and R 7 but [ka] to obtain a compound which is a phenyl group substituted with L 1 is a methylene group, and R 7 is a phenyl group substituted with a methyl ester, the compound of formula H4 is hydrolyzed to give L 1 is a methylene group, and R 7 is a phenyl group substituted with a carboxy group, The definition of each substituent is as described above.

[0022] A third aspect of the present invention provides a pharmaceutical composition, comprising a compound represented by general formula (I) according to the first aspect, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A fourth aspect of the present invention provides the use of a compound of general formula (I) according to the first aspect or a pharmaceutical composition according to the third aspect (i) for the preparation of an α2A-adrenergic receptor (α2A-AR) antagonist, or (ii) for the preparation of a medicament for treating diabetes. A fifth aspect of the present invention provides a method of treating diabetes, comprising administering to a subject in need thereof a compound according to the first aspect or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect. The novel oxadiazole yohimbine derivatives of the present invention are capable of antagonizing α2A adrenergic receptors at micromolar concentrations and have pancreatic targeting characteristics and significantly reduced brain tissue distribution properties compared to yohimbine. [Effects of the Invention]

[0023] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions. Each feature disclosed in this specification can be replaced with any alternative feature providing the same, equivalent, or similar purpose. Due to space limitations, they will not be repeated here. [Brief explanation of the drawings]

[0024] [Figure 1] Tissue concentrations (ng / g or ng / mL) of various compounds are shown 2 hours after oral gavage in mice at 10 mg / kg. [Figure 2] Tissue concentrations (ng / g or ng / mL) are shown at 0.25, 2, and 8 hours after oral gavage of 10 mg / kg of compound C27 in mice. [Figure 3] 1 shows the basal blood glucose levels of type 2 diabetic mice after a single intraperitoneal injection of a yohimbine derivative (10 mg / kg). [Figure 4] 1 shows the glucose tolerance results of type 2 diabetic mice given a single intraperitoneal injection of a yohimbine derivative (10 mg / kg).

[0025] [Figure 5] 1 shows the insulin sensitivity results of type 2 diabetic mice given a single intraperitoneal injection of a yohimbine derivative (10 mg / kg). [Figure 6] 1 shows the results of glucose tolerance in type 2 diabetic mice given a single oral gavage of a yohimbine derivative (10 mg / kg). [Figure 7] 1 shows the results of insulin sensitivity in type 2 diabetic mice given a single oral gavage of a yohimbine derivative (10 mg / kg). [Figure 8] 1 shows the basal blood glucose levels of type 2 diabetic mice chronically injected with a yohimbine derivative (10 mg / kg, once daily). DETAILED DESCRIPTION OF THE INVENTION

[0026] After extensive and thorough research, the inventors of the present application have for the first time developed a compound that maintains good α2A adrenergic receptor antagonistic activity while having both pancreas targeting and low brain permeability, specifically an oxadiazole yohimbine derivative, its main feature is that the 16-position ester group of yohimbine is converted to an oxadiazole group, so that it can maintain good α2A adrenergic receptor antagonistic activity.Compared with yohimbine, this type of derivative has pancreas targeting properties and significantly reduced brain tissue distribution properties compared to yohimbine, eliminating the central side effects of yohimbine such as anxiety and hypertension, and can significantly improve blood glucose metabolism in animal models of type 2 diabetes, and is expected to become a new drug for treating diabetes that acts on α2A adrenergic receptors.Based on this, the present invention has been completed.

[0027] term In this specification, the alkyl group is preferably an aliphatic alkyl group, which may be a straight-chain alkyl group or a branched-chain alkyl group, including, but not limited to, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a t-butyl group, etc., and the expression in the form "C1-C6" includes corresponding groups having 1, 2, 3, 4, 5 or 6 carbon atoms, for example, "C1-C6 alkyl group" refers to an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0028] An "alkylene group" refers to a straight-chain 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 atom or different atoms on the alkylene group. For example, a straight-chain alkylene group can be a divalent group of -(CH)-, 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.

[0029] In this specification, the halogen preferably refers to fluorine, chlorine, bromine or iodine. As used herein, the alkoxy group refers to -O-(alkyl), where alkyl is as defined above. A "C1-C6 alkoxy group" refers to an oxygen-containing alkyl group containing 1 to 6 carbon atoms, non-limiting examples of which include methoxy, ethoxy, propoxy, butoxy, etc.

[0030] In this specification, the cycloalkyl group can be a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl group contains 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., and polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0031] In this specification, the aryl group refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group, and the group has a conjugated π-electron system, such as a phenyl group and a naphthyl group. The aryl ring can be fused with a heterocyclic group, a heteroaryl group, or a cycloalkyl ring, and non-limiting examples include benzimidazole, benzothiazole, benzoxazole, benzisoxazole, benzopyrazole, quinoline, benzoindole, and benzodihydrofuran.

[0032] As used herein, the term "heterocyclic group" refers to an aliphatic heterocyclic system containing 1 to 3 heteroatoms, for example, 3 to 7 ring atoms. Heteroatoms in heterocyclic groups include oxygen, sulfur, and nitrogen. The heterocyclic group is preferably a 3- or 6-membered ring, such as an ethylene oxide group, a morpholinyl group, or a piperazinyl group. As used herein, the term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms, e.g., 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, and tetrazolyl. The heteroaryl group can be fused to an aryl, heterocyclic, or cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring.

[0033] Unless otherwise specified in the present invention, [ka] represents the linking site. In this specification, the pharmaceutically acceptable salt is not particularly limited and preferably includes inorganic acid salts, organic acid salts, alkylsulfonates, and arylsulfonates, the inorganic salts including hydrochloride, hydrobromide, nitrate, sulfate, phosphate, etc., the organic salts including formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, etc., the alkylsulfonates including methylsulfonate, ethylsulfonate, etc., and the arylsulfonates including benzenesulfonate, p-toluenesulfonate, etc.

[0034] Preparation method The oxadiazole-based yohimbine derivatives of the present invention can be prepared by the following route: The definitions of each substituent are the same as above. [ka]

[0035] Hereinafter, the present invention will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. In the following examples, experimental methods without specific conditions are usually in accordance with conventional conditions or conditions suggested by manufacturers. Unless otherwise specified, percentages and parts are calculated by weight percentages and parts by weight. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by 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 implementation methods and materials described herein are used for illustrative purposes only.

[0036] 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 (CDCl3), 2.50 ppm (DMSO-d6). Mass spectra were measured using an Agilent 1200 Quadrupole LC / MS instrument. Reagents were mainly provided by Shanghai Chemical Reagent Company. TLC thin-layer chromatography silica gel plates were manufactured by Shandong Yantai Jiangyou Silica Gel Development Co., Ltd., model HSGF 254. Normal-phase column chromatography silica gel used for compound purification was manufactured by Shandong Qingdao Ocean Chemical Plant Branch, model ZCX-II, with a mesh size of 200-300.

[0037] The abbreviations used in this specification are as follows: DMF: N,N-dimethylformamide, COMU: (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate, Pd(dba)2: bis(dibenzylideneacetone palladium), dppf: 1,1'-bis(diphenylphosphino)ferrocene

[0038] Example 1 [ka] (1) At room temperature, benzyl cyanide (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 successively. 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) 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 further purification.

[0039] (2) In an ice bath, yohimbine hydrochloride M1 (7.81 g, 20 mmol) was placed in methanol / tetrahydrofuran / water (90 mL / 60 mL / 30 mL), lithium hydroxide monohydrate (5.04 g, 120 mmol) was added, and the mixture was stirred in an ice bath for 30 minutes, then cooled to room temperature. The disappearance of the raw materials was monitored by LC-MS, and most of the solvent was removed by concentration under reduced pressure. The residue was dissolved in water (150 mL), and the pH was adjusted with 5% hydrochloric acid in an ice bath until a milky white turbidity appeared in the system. The mixture was left overnight, filtered, and the filter cake was washed with water (100 mL). The filter cake was collected and dried to give a white powder M2 (5.9 g, 17.3 mmol). The molar yield was 86%.

[0040] (3) At room temperature, M2 (340 mg, 1 mmol) was dissolved in DMF (5 mL), triethylamine (304 mg, 3 mmol) was added, and 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. The crude product from step (1) (300 mg, 2 mmol) was added, and after stirring at room temperature for 24 hours, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was dissolved in dichloromethane / methanol (100 mL / 10 mL) and washed with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 30:1) to give a brown foamy solid M3.

[0041] (4) The condensation product M3 from operation (3) was dissolved in 1,4-dioxane (5 mL), toluene (10 mL) was added, and the mixture was heated to 100°C under a nitrogen gas protective atmosphere. After 24 hours, the reaction was stopped, 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 x 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 the two steps, operations (3) and (4), was 10%. Using the same method as in Example 1, but with different cyano substrates, the other compounds in the table below are synthesized.

[0042] [Table A-1] [Table A-2] [Table A-3] [Table A-4] [Table A-5] [Table A-6] [Table A-7]

[0043] Example 2 [ka] (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 sequentially. 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) 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 further purification. (2) At room temperature, M2 (340 mg, 1 mmol) was dissolved in DMF (5 mL), triethylamine (304 mg, 3 mmol) was added, and 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. The crude product from step (1) (552 mg, 2 mmol) was added, and after stirring at room temperature for 24 hours, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was dissolved in dichloromethane / methanol (100 mL / 10 mL) and washed with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 30:1) to give a brown foamy solid M3.

[0044] (3) The condensation product M3 from operation (2) was dissolved in 1,4-dioxane (5 mL), toluene (10 mL) was added, and the mixture was heated to 100°C under a nitrogen gas protective atmosphere. After 24 hours, the reaction was stopped, 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 x 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 the two steps, operations (2) and (3), was 12%. (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 a nitrogen gas protective atmosphere. After 6 h, the reaction was stopped, and the solvent was removed by concentration under reduced pressure. The residue was dissolved in dichloromethane / methanol (100 mL / 10 mL) and washed with saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 30:1) to give C19 (33 mg, 0.07 mmol) as a light brown foamy solid. The molar yield was 70%. Using the same method as in Example 2, but with different cyano substrates, the other compounds in the table below are synthesized.

[0045] [Table B]

[0046] Example 3 [ka] Compound C19 (14 mg, 0.03 mmol) was dissolved in EtOH (0.15 mL), and DMSO (0.075 mL) was added under ice bath. 4 M NaOH (0.0073 mL) and 30% HO (0.01 mL) were added. The mixture was reacted under ice bath for 30 minutes, then cooled to room temperature. After 5 hours, the reaction was stopped. 10% NaSO (0.15 mL) was added to the reaction mixture under ice bath, and HO (2 mL) was added. A white solid precipitated, which was suction filtered under reduced pressure. The filter cake was washed with water and dried to obtain white solid C27 (10 mg, 0.02 mmol). The molar yield was 67%.

[0047] [Table C]

[0048] Example 4 [ka] 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, lithium hydroxide monohydrate (42 mg, 1 mmol) was added, and the mixture was stirred under ice bath for 30 minutes, then cooled to room temperature. The disappearance of the raw materials was monitored by LC-MS. Most of the solvent was removed by concentration under reduced pressure. Water (5 mL) was added to the residue, and the pH was adjusted to 6 with 5% hydrochloric acid under ice bath. The mixture was then allowed to stand, filtered, and the filter cake was washed with water (2 mL). The filter cake was collected and dried to give yellow powder C30 (25 mg, 0.05 mmol). The molar yield was 50%.

[0049] [Table D]

[0050] Example 5. α2A-AR Antagonist Testing 1. Purpose of the experiment To investigate the antagonistic activity of yohimbine derivatives against α2A-AR. 2. Experimental Principle By establishing a cell line co-transfected with target receptors and Ga16, receptor activation triggers activation of the Gα16 protein, which then activates phospholipase C (PLC) to produce IP3 and DAG. IP3 binds to IP3 receptors in the endoplasmic reticulum and mitochondria, thereby triggering the release of intracellular calcium. Therefore, measuring changes in intracellular calcium can be used to detect the activation state of target receptors. Fluo-4 / AM is a calcium fluorescent probe indicator used to measure calcium ions. As a non-polar lipid-soluble compound, upon entry into cells, the AM group is dissociated by the action of cellular lipolytic enzymes, releasing Fluo-4. Because Fluo-4 is a polar molecule that cannot easily cross lipid bilayers, it can be stored intracellularly for long periods of time. Finally, the activation level of Ga proteins can be reflected by measuring the excited fluorescence intensity. If the screened compound stimulates the target receptor, the calcium flux response can be significantly increased. Conversely, if the screened compound antagonizes the target receptor, the calcium flux response can be significantly decreased.

[0051] 3. Experimental Sample Prior to testing, test compounds are dissolved in DMSO to prepare stock solutions, which are diluted to the required concentration with culture medium at the time of use. 4. Experimental Method Cells stably expressing α2A-AR / Gal6 were seeded into a 96-well plate and cultured overnight. The culture medium in the wells containing the cells was aspirated, and freshly prepared dye (40 μL / well) was added. The wells were incubated at 37°C for 40 minutes. The test drug was diluted with calcium buffer and mixed uniformly. The dye was aspirated and discarded. After washing once with freshly prepared calcium buffer, the wells were replaced with 50 μL of calcium buffer containing the test drug. The wells were then detected using a FlexStation II instrument. At 15 seconds, the instrument automatically added 25 μL of calcium buffer containing the known agonist UK14304. Finally, the fluorescence value at 525 nm was read. 5. Experimental Results (The 35 compounds in Table 1 are used as examples, but are not limited to these compounds)

[0052] [Table 1-1] [Table 1-2]

[0053] 6. Results and Discussion These compounds can compete with the α2A-AR agonist UK14304 in cells expressing the α2A-AR and antagonize the agonist effect of UK14304 on the α2A-AR, demonstrating IC 50 are shown in Table 1. The results indicate that these compounds are antagonists of the α2A-AR.

[0054] Example 6. Tissue distribution test of yohimbine derivatives in mice 1. Purpose of the experiment To investigate the tissue distribution of yohimbine derivatives in mice. 2. Experimental Design

[0055] [Table 2]

[0056] [Table 3]

[0057] 3. Sample collection and measurement (1) Mouse tissue distribution test: Animals in each group were anesthetized 2 hours after administration, then sacrificed and dissected. Brain, pancreas, heart, liver, and kidney tissues were collected and washed with saline, then frozen and stored in a refrigerator at -20°C for testing. At the same time, 0.3 mL of whole blood was collected, placed in an EDTA-K2 anticoagulant test tube, and centrifuged at 11,000 rpm for 5 minutes to separate the plasma, which was then frozen and stored in a refrigerator at -20°C for testing. Blank plasma and tissues are collected from three additional animals. The concentration of unchanged drug in plasma and tissues is measured. (2) Tissue distribution test of compound C27 in mice: After oral gavage, the mice were killed by bleeding from the abdominal aorta at the corresponding time points (0.25, 2, and 8 hours) and immediately dissected to collect the brain, heart, liver, lung, pancreas, and kidney tissues, and a portion of the plasma was collected in an ice-water bath. Centrifugation conditions: Centrifuge at 11,000 rpm for 5 minutes to separate plasma (approximately 200 μL). After collection, tissues and plasma are stored at -60°C or below.

[0058] 4. Experimental Results and Discussion Figure 1 shows the tissue concentrations (ng / g or ng / mL) of various compounds 2 hours after oral gavage in mice at 10 mg / kg (using the four compounds in Figure 1 as examples, but not limited to these compounds). FIG. 2 shows the tissue concentrations (ng / g or ng / mL) of compound C27 at 0.25, 2, and 8 hours after oral gavage of 10 mg / kg to mice. Calculations based on the relative ratio of tissue distribution concentration to blood drug concentration revealed that compounds C1, C6, C13, C19, and C27 all exhibited lower brain tissue distribution than yohimbine, with the brain tissue distribution of compound C19 being approximately 40-fold lower than that of yohimbine and compound C19 having good pancreatic distribution. The plasma exposure of compound C27 was comparable to that of yohimbine, but its brain tissue distribution was approximately 270-fold lower than that of yohimbine, demonstrating comparable pancreatic distribution characteristics to compound C19.

[0059] Example 7. Taste experiment on the therapeutic effect of yohimbine derivatives on lowering blood glucose levels in diabetic mice 1. Purpose of the experiment To test whether the yohimbine derivative C19 can improve the blood glucose metabolic effects of type 2 diabetes. 2. Experimental content In this experiment, a high-carbohydrate, high-fat diet-induced type 2 diabetes mouse model will be used, and the following tests will be mainly performed. 1) Effects of a single intraperitoneal administration on basal blood glucose, glucose tolerance, and insulin sensitivity in diabetic mice. 2) The effect of a single oral gavage on glucose tolerance and insulin sensitivity in diabetic mice. 3) Effect of continuous chronic intraperitoneal administration on basal blood glucose in diabetic mice. 3. Experimental Method C57BL_6J mice will be fed a high-carbohydrate, high-fat diet for three consecutive months, and test experiments will be conducted once the average mouse weight has stabilized at 50g or more and the average basal blood glucose level has stabilized at 12mmol / L or more.

[0060] Blood glucose levels are typically measured by measuring tail vein blood using a blood glucose meter. Tests of the effects on basal blood glucose are performed under normal eating and drinking conditions. First, basal blood glucose levels are measured before administration. Next, yohimbine derivative C19 (10 mg / kg body weight) is administered intraperitoneally or orally once, and venous blood glucose levels are measured sequentially 15, 30, 60, 90, and 120 minutes after administration. After 16 hours of overnight feeding, the mice are tested for glucose tolerance. Yohimbine derivative C19 (10 mg / kg body weight) is administered intraperitoneally or orally once, and 30 minutes later, glucose (1.5 g / kg) is injected intraperitoneally. Venous blood glucose levels are measured sequentially 15, 30, 60, 90, and 120 minutes after administration. Insulin sensitivity is measured 6 hours after the mice have been allowed to eat and drink. Yohimbine derivative C19 (10 mg / kg mouse body weight) was administered intraperitoneally or orally once. Thirty minutes after administration, insulin (1 UI / kg) was administered intraperitoneally, and intravenous blood glucose levels were measured 15, 30, 60, 90, and 120 minutes later. To test the effects of chronic administration on blood glucose levels, diabetic mice were intraperitoneally injected with yohimbine derivative C19 (10 mg / kg) daily for 12 consecutive days, and basal blood glucose levels were measured daily in mice fed ad libitum before drug injection. Control groups were injected with saline or orally administered.

[0061] 4. Experimental Results The experimental results are shown in Figures 3 to 8. Figure 3 shows that a single intraperitoneal injection of a yohimbine derivative (10 mg / kg) significantly reduced the basal blood glucose levels of type 2 diabetic mice. Figure 4 shows that a single intraperitoneal injection of a yohimbine derivative (10 mg / kg) significantly improved glucose tolerance in type 2 diabetic mice. Figure 5 shows that a single intraperitoneal injection of a yohimbine derivative (10 mg / kg) significantly improved insulin sensitivity in type 2 diabetic mice. Figure 6 shows that a single oral gavage administration of a yohimbine derivative (10 mg / kg) significantly improved glucose tolerance in type 2 diabetic mice. Figure 7 shows that a single oral gavage administration of a yohimbine derivative (10 mg / kg) significantly improved insulin sensitivity in type 2 diabetic mice. Figure 8 shows that chronic injection of a yohimbine derivative (10 mg / kg, once daily) significantly reduced the basal blood glucose levels of type 2 diabetic mice.

[0062] 5. Results and Discussion This experiment shows that a single injection or oral gavage of the yohimbine derivative C19 of the present invention can significantly reduce hyperglycemia in diabetic mice, improve glucose tolerance, and increase insulin sensitivity. Chronic administration can stably maintain the basal blood glucose level of diabetic mice at a level close to normal. Therefore, the yohimbine derivative C19 of the present invention has a clear effect of improving diabetic blood glucose metabolism.

[0063] By modifying the structure of yohimbine, novel derivatives were obtained that have enhanced α2A adrenergic receptor antagonist activity and are characterized by pancreatic targeting and reduced brain tissue distribution. The lower brain tissue distribution eliminates yohimbine's central side effects, such as anxiety and elevated blood pressure. The compounds of the present invention can significantly improve blood glucose metabolism in animal models of type 2 diabetes, and chronic administration can stably maintain the basal blood glucose levels of diabetic mice at near-normal levels, making them promising for use in diabetes treatment. All documents mentioned in this application are incorporated by reference in this application as if each document were incorporated by reference individually. Furthermore, after reading the above teachings of the present invention, those skilled in the art will be able to make various changes or modifications to the present invention, and these equivalents will also fall within the scope defined by the appended claims of this application.

Claims

1. A compound represented by general formula (I), a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 In the formula: R １ , R ２ , R ３ and R ４ each independently represents a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, an ethynyl group, or a substituted or unsubstituted group selected from the following: a C1-C6 alkyl group, a C3-C10 cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms, a C6-C10 aryl group, and a 5- to 7-membered heteroaryl group; 【Chemistry 2】 wherein R is a C1-C6 alkyl group, a C3-C10 cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms, a C6-C10 aryl group, or a 5- to 7-membered heteroaryl group; and X is O or NR ａ where R ａ is selected from hydrogen, a C1-C6 alkyl group, and a C3-C10 cycloalkyl group; R ５ and R ６ are each independently hydrogen, a substituted or unsubstituted group selected from the following: a C1-C6 alkyl group, a C3-C10 cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms, 【Transformation 3】 where R ｂ is selected from a C1-C6 alkyl group, a C3-C10 cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms, a C6-C10 aryl group, and a 5- to 7-membered heteroaryl group; and X is O or NR ｃ where R ｃ is selected from hydrogen, a C1-C6 alkyl group, and a C3-C10 cycloalkyl group; L １ is absent, hydrogen, or a substituted or unsubstituted group selected from the following: a C1-C6 alkylene group, a C3-C10 cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms, a C6-C10 aryl group, and a 5- to 7-membered heteroaryl group; 【Chemistry 4】 wherein R is a C1-C6 alkyl group, a C3-C10 cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms, a C6-C10 aryl group, or a 5- to 7-membered heteroaryl group; and X is O or NR ａ where R ａ is selected from hydrogen, a C1-C6 alkyl group, and a C3-C10 cycloalkyl group; R ７ is absent, hydrogen, or a substituted or unsubstituted group selected from the following: a C1-C6 alkoxy group, a C3-C10 cycloalkyl group, a C6-C10 aryl group, a 3- to 7-membered heterocyclic group, a 5- to 7-membered heteroaryl group, 【Transformation 5】 wherein R is a C1-C6 alkyl group, a C3-C10 cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms, a C6-C10 aryl group, or a 5- to 7-membered heteroaryl group; and X is O or NR ａ where R ａ is hydrogen, a C1-C6 alkyl group, or a C3-C10 cycloalkyl group; L １ , R ７ the substituents spaced 0 to 2 atoms above can be cyclized into 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; The above-mentioned substitution means that the hydrogen on the group is replaced with a halogen, a hydroxy group, a cyano group, a C1-C6 halogenated alkyl group, an alkynyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, an NR ｄ R ｅ , 【Transformation 6】 where R ｄ and R ｅ are each independently hydrogen or a C1-C6 alkyl group, a compound represented by general formula (I), a deuterated compound thereof, or a pharmaceutically acceptable salt thereof.

2. R １ is hydrogen, halogen, cyano, hydroxy, ethynyl, or C1-C6 alkyl; R ２ is hydrogen, halogen, cyano group, hydroxy group, ethynyl group, C1-C4 alkyl group, or 【Transformation 7】 where R is a substituted or unsubstituted group: a C1-C4 alkyl group; and X is O or NR ａ where R ａ is hydrogen or a C1-C4 alkyl group, and the substitution means that the hydrogen on the group is replaced with a halogen, a hydroxy group, a C1-C4 alkyl group, and NR ｄ R ｅ where R ｄ and R ｅ are each independently hydrogen or a C1-C4 alkyl group; R ３ is hydrogen, halogen, cyano group, hydroxy group, C1-C4 alkyl group, or 【Transformation 8】 wherein R is a substituted or unsubstituted group: a C1-C4 alkyl group; X is O, where the substitution means that a hydrogen on the group is replaced with a halogen, a hydroxy group, a cyano group, a C1-C6 alkyl group, and NR ｄ R ｅ where R ｄ and R ｅ are each independently hydrogen or a C1-C4 alkyl group; R ４ is hydrogen, halogen, a cyano group, or a hydroxy group; The compound of claim 1.

3. R ５ is hydrogen, a C1-C4 alkyl group, or 【Chemistry 9】 where R ｂ is a substituted or unsubstituted group: a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a C6-C10 aryl group, or a 5- to 7-membered heteroaryl group, where the substitution means that a hydrogen on the group is replaced with a halogen, a hydroxy group, a C1-C4 alkyl group, a C1-C4 alkoxy group, and NR ｄ R ｅ where R ｄ and R ｅ are each independently hydrogen or a C1-C4 alkyl group; R ６ is hydrogen, a C1-C4 alkyl group, a C3-C6 cycloalkyl group, or 【Chemistry 10】 where R ｂ is a substituted or unsubstituted group: a C1-C4 alkyl group, where the substitution means that a hydrogen on the group is replaced with a halogen, a hydroxy group, a cyano group, a trifluoromethyl group, and an NR ｄ R ｅ where R ｄ and R ｅ are each independently hydrogen or a C1-C4 alkyl group; The compound of claim 1.

4. L １ is absent, hydrogen, or a substituted or unsubstituted group selected from the following: a C1-C4 alkylene group, a C3-C8 cycloalkyl group, a 5- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms, a C6-C10 aryl group, and a 5- to 7-membered heteroaryl group; 【Chemistry 11】 wherein R is a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms, a C6-C10 aryl group, or a 5- to 7-membered heteroaryl group; and X is O or NR ａ where R ａ is hydrogen, a C1-C4 alkyl group, or a C3-C6 cycloalkyl group, and the substitution means that the hydrogen on the group is replaced with a halogen, a hydroxy group, a cyano group, a trifluoromethyl group, a C1-C4 alkyl group, a C1-C4 alkoxy group, and NR ｄ R ｅ where R ｄ and R ｅ are each independently hydrogen or a C1-C4 alkyl group; The compound of claim 1.

5. R ７ is absent, hydrogen, or a substituted or unsubstituted group selected from the following: a C1-C4 alkoxy group, a C3-C6 cycloalkyl group, a C6-C10 aryl group, a 5- to 7-membered heterocyclic group, or a 5- to 7-membered heteroaryl group; 【Chemistry 12】 wherein R is a C1-C6 alkyl group, a C3-C10 cycloalkyl group, a 4- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms, a C6-C10 aryl group, or a 5- to 7-membered heteroaryl group; and X is O or NR ａ where R ａ is hydrogen, a C1-C6 alkyl group, or a C3-C10 cycloalkyl group; R ７ the substituents spaced 0 to 2 atoms above can be cyclized into 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; Here, the substitution means that the hydrogen on the group is replaced with a halogen, a hydroxy group, a cyano group, a C1-C4 halogenated alkyl group, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C1-C4 halogenated alkoxy group, or an NR ｄ R ｅ , 【Chemistry 13】 where R ｄ and R ｅ are each independently hydrogen or a C1-C4 alkyl group; Preferably, R ７ is absent, hydrogen, or a substituted or unsubstituted group selected from the following: a C1-C4 alkoxy group, a C3-C6 cycloalkyl group, a phenyl group, a 5- to 7-membered heterocyclic group, or a 5- to 7-membered heteroaryl group; Here, the substitution means that hydrogen on the group is replaced with fluorine, chlorine, bromine, a hydroxy group, a cyano group, a trifluoromethyl group, a trifluoromethoxy group, an alkynyl group, a C1-C4 alkyl group, a C1-C4 alkoxy group, an NR ｄ R ｅ , 【Chemistry 14】 where R ｄ and R ｅ are each independently hydrogen or a C1-C4 alkyl group; R ７ The substituents spaced 0 to 2 atoms above can be cyclized into a 6-membered aromatic ring or a 5- to 7-membered heteroaromatic ring; The compound of claim 1.

6. L １ and R ７ forms the following formula V: 【Chemistry 15】 Here, r １ is selected from 1, 2 or 3; r ２ is selected from 0, 1, 2 or 3; Ring B is a phenyl group, a 5- to 6-membered heterocyclic group, a C3-C6 cycloalkyl group, or a 5- to 6-membered heteroaryl group; Each R ｆ represents a halogen, a hydroxy group, a cyano group, a C1-C4 halogenated alkyl group, a C1-C4 alkyl group, a C1-C4 alkoxy group, a C1-C4 halogenated alkoxy group, NR ｄ R ｅ , 【Chemistry 16】 where R ｄ and R ｅ are each independently hydrogen, a C1-C4 alkyl group, or two adjacent R ｆ is combined with the adjacent C on ring B to form a benzene ring or a 5- to 7-membered heteroaromatic ring, The compound of claim 1.

7. The compound is selected from the following: The compound of claim 1. 【Chemistry 17】 [Chemistry 18]

8. A process for preparing the compound of claim 1, comprising: The preparation method comprises: 【Chemistry 19】 The compound is obtained by converting the carboxy group at position 16 into an oxadiazole structure, and the definitions of each substituent in the formula are as defined in claim 1.

9. A compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, and A pharmaceutical composition comprising a pharmaceutically acceptable carrier.

10. Use of a compound of general formula (I) as defined in claim 1 or a pharmaceutical composition as defined in claim 9 for (i) the preparation of an α2A-adrenergic receptor (α2A-AR) antagonist, or (ii) the preparation of a medicament for treating diabetes.

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