WO2024017227A1 - Substituted fused ring cannabinoid receptor compound and use thereof - Google Patents

Abstract

Provided is a cannabinoid receptor compound as represented by formula I. The compound has a good ability to bind to the human CB2 receptor, and exhibits good agonistic activity and high selectivity on the CB2 receptor. Consequently, said compound can treat an inflammatory disease, an autoimmune disease, etc. while reducing neurological side effects.

Description

Substituted fused ring cannabinoid receptor compounds and their applications

This application claims the priority of the earlier application submitted to the State Intellectual Property Office of China on July 21, 2022, with the patent application number 202210864884.X and the invention title "Substituted fused ring cannabinoid receptor compounds and their applications". The entirety of this prior application is incorporated by reference into this application.

Technical field

The invention belongs to the field of medical technology, and specifically relates to substituted fused ring cannabinoid receptor compounds and their preparation methods and applications.

Background technique

Cannabinoid receptors CB1 and CB2 are key components of the endocannabinoid system and the primary target of D9-tetrahydrocannabinol (D9-THC). D9-THC is a psychoactive chemical extracted from cannabis with a wide range of uses for treating diseases (J Clin Invest. 1973 Oct; 52(10):2411-7). Activated by the lipid tetrahydrocannabinol (THC), cannabinoid receptor 1 (CB1) is associated with psychoactive, neuromodulatory, and analgesic effects. Cannabidiol (CBD) has received widespread attention due to its pharmacological effects or effects such as neuroprotection, analgesia, anti-inflammatory, antioxidant, and anti-epilepsy. The effects of the endocannabinoid receptor system are mainly highly expressed in the central nervous system, adipocytes, liver cells (liver cells) and musculoskeletal tissues. Endocannabinoid agonists include: anandamide (AEA) and 2-arachidonoyl glycerol (2-AG). CB1 and CB2 play important roles in a variety of physiological processes, including appetite, pain perception, memory, and immune regulation (Manuel Guzmán, Nat Rev Cancer, 2003 Oct; 3(10):745-55.). The two cannabinoid receptors share 44% total sequence homology and 68% sequence similarity in the transmembrane region (Munro et al., 1993). However, they have different tissue distribution and play different functions in the endocannabinoid system, with CB1 and CB2 being mainly expressed in the central nervous system and immune system, respectively. First, due to their high sequence similarity, the development of therapeutic applications is limited by selectivity for a single target. CB2 is associated with anti-inflammatory and immunomodulatory effects and has no psychoactive effects. CB2 is expressed in somatic cells and (possibly) the central nervous system (CNS) that control immune function. Additionally, research shows that secondary metabolites of phytonutrients found in plant foods can enhance CB2 receptor activity and promote a healthy inflammatory response. also, CB2 selective agonists are also hot topics in the field as high potential drug candidates for the treatment of inflammatory and neuropathic pain without CB1 psychoactivity.

The early stage of this project focuses on the development of CB2 small molecule agonists. The anti-inflammatory mechanisms of CB2 agonists include: reducing the production of chemoattractants, reducing the production of PGE and other pro-inflammatory eicosanoids, reducing endothelial cell activation, inflammatory cell adhesion, rolling and migration between endothelial cells, and reducing pro-inflammatory cells Factors reactive oxygen species and increases pro-resolving lipid mediators. The anti-fibrotic mechanisms of CB2 agonists include: reducing TGFB production, reducing fibroblast accumulation and proliferation, reducing collagen production, smooth muscle proliferation and migration; increasing the recruitment of non-inflammatory macrophages into tissues to phagocytose bacteria and cell debris, Macrophage efferocytosis. Compared with the known small molecule compounds with the same target in the prior art, there is still an urgent need in this field to develop new small molecule agonist drugs with higher CB2 selectivity and improve their bioavailability. In terms of drug development, lupus erythematosus (SLE), diffuse skin thickening, autoimmune diseases, colitis or inflammatory bowel disease, atopic dermatitis, pain, arthritis, etc. are all adaptations that can be developed for this target in the future. disease.

Contents of the invention

In order to improve the above technical problems, the present invention provides compounds represented by the following formula I, their racemates, stereoisomers, tautomers, isotope labels, solvates, polymorphs, and pharmaceutically acceptable salts or its prodrug,

Among them, A ₁ is selected from the following groups that are unsubstituted or optionally substituted by one, two or more Ra: 3-20-membered heterocyclyl, 5-20-membered heteroaryl, 5-20-membered heteroaryl 3-20 membered heterocyclic group;

Ra is selected from C _1-12 alkyl, C _1-12 alkoxy, halo C _1-12 alkyl, halo C _1-12 alkoxy, OH, HO-C _1-12 alkyl, CN, -C(O)C _1-12 alkyl, -S(O) ₂ C _1-12 alkyl, -S(=O)C _1-12 alkyl, -S(C _1-12 alkyl) ₂ , -C(O)NHC _1-12 alkyl, -C(O)N(C _1-12 alkyl) ₂ , -C(O)NH ₂ , -N(C _1-12 alkyl) ₂ , =O ;

X ₁ , X ₂ , X _{3 ,} X ₄ , X ₅ , _and X ₆ are the same or different and are independently C, _CH , or _N , provided that , X ₅ and X ₆ are not N at the same time;

R ₁ is selected from halogen, C _1-12 alkyl, C _1-12 alkoxy, halogenated C _1-12 alkyl, halogenated C _1-12 alkoxy, C _3-20 cycloalkyl;

A ₂ is selected from C _6-20 aryl or 5-20 membered heteroaryl that is unsubstituted or optionally substituted by one, two or more Rb;

Rb is selected from halogen, halogenated C _1-12 alkyl, C _1-12 alkyl, C _1-12 alkoxy, halogenated C _1-12 alkoxy, CN, OH, NH ₂ and nitro;

A ₃ is selected from C _3-20 cycloalkyl or 3-20 membered heterocyclyl that is unsubstituted or optionally substituted by one, two or more Rc;

Rc is selected from halogen, C _1-12 alkyl, halogenated C _1-12 alkyl, NH ₂ , -NHC(O)C _1-12 alkyl, -NHC _1-12 alkyl, CN, nitro, - COOC _1-12 alkyl, HO-C _1-12 alkyl, OH, C _1-12 alkoxy, halogenated C _1-12 alkoxy.

In one embodiment of the invention, A ₁ is selected from the following groups that are unsubstituted or optionally substituted by one, two or more Ra: 3-12 membered heterocyclyl, 5-12 membered heteroaryl , 5-12 membered heteroaryl and 3-12 membered heterocyclyl;

Ra is selected from C _1-6 alkyl, halogenated C _1-6 alkyl, HO-C _1-6 alkyl, CN, -C(O)C _1-6 alkyl, -S(O) ₂ C _{1 -6} alkyl, -C(O)NHC _1-6 alkyl, -C(O)NH ₂ , -N(C _1-6 alkyl) ₂ , =O;

R ₁ is selected from C _1-6 alkyl, halogenated C _1-6 alkyl, C _3-12 cycloalkyl;

A ₂ is selected from C ₆ - ₁₂ aryl or 5-12 membered heteroaryl that is unsubstituted or optionally substituted by one, two or more Rb;

Rb is selected from halogen (especially F, Cl), halogenated C _1-6 alkyl, CN, C _1-6 alkoxy, C _1-6 alkyl, OH;

A ₃ is selected from C _3-12 cycloalkyl or 3-12 membered heterocyclyl that is unsubstituted or optionally substituted by one, two or more Rc; and/or

Rc is selected from halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, NH ₂ , -NHC(O)C _1-6 alkyl, -NHC _1-6 alkyl, CN, -COOC _{1- 6} alkyl, HO-C _1-6 alkyl, OH, C _1-6 alkoxy.

In one embodiment of the invention, Formula I can be selected from the following structures:

In one embodiment of the invention, A ₁ is selected from the following groups that are unsubstituted or optionally substituted by one, two or more Ra: 3-12 membered N-containing heterocyclyl, 5-12 membered N-containing heterocyclyl N heteroaryl, 5-12 membered N-containing heteroaryl and 3-12 membered N-containing heterocyclic group.

In one embodiment of the invention, A ₁ is selected from the following groups that are unsubstituted or optionally substituted by one, two or more Ra: piperazinyl, piperidinyl, hexahydropyrazino[2 ,1-c][1,4]oxazin-8(1H)-yl, 1,4-diazepanyl, octahydropyrido[1,2-a]pyrazinyl, 5H,6H ,8H-[1,2,4]triazolo[4,3-a]pyrazinyl, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl or azetidine base.

In one embodiment of the invention, Ra is selected from methyl, ethyl, isopropyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, CN, Acetyl, methanesulfonyl, methylaminocarbonyl, dimethylamino, carbamoyl or oxo.

In one embodiment of the invention, A ₁ is selected from 4-methylpiperazinyl, 4-ethylpiperazinyl, 4-(2,2,2-trifluoroethyl)piperazinyl, 4-hydroxy Ethylpiperazinyl, 3-cyano-4-methylpiperazinyl, 4-isopropylpiperazinyl, 4-acetylpiperazinyl, 4-methanesulfonylpiperazinyl, 4-methylaminomethyl Acylpiperazinyl, 4-(2,2-difluoroethyl)piperazinyl, 4-methanesulfonylpiperidinyl, 4-carbamoylpiperazinyl,

R ₁ is selected from methyl, trifluoromethyl, and cyclopropyl;

A ₂ is selected from phenyl or pyridyl which is unsubstituted or optionally substituted by one, two or more Rb;

Rb is preferably the following group: F, Cl, CF ₃ , CN, methoxy, methyl, OH;

A ₃ is selected from the following groups that are unsubstituted or optionally substituted by one, two or more Rc:

The Rc is preferably the following group: F, methyl, trifluoromethyl, NH ₂ , carbamoyl, acetamido, methylamino, CN, hydroxymethyl, hydroxyethyl, methylesteryl, OH.

In one embodiment of the present invention, the compound represented by formula I has a structure selected from the following:

Wherein, L ₁ and L ₂ are -CH ₂ -, -CH ₂ -CH ₂ - or -CH ₂ -O- independently of each other; preferably, L ₁ is -CH ₂ - and L ₂ is -CH ₂ -O -, A ₁ , R ₁ , A ₂ and Rc have the meanings defined herein.

In one embodiment of the present invention, the compound represented by formula I has a structure selected from the following:

Wherein, A ₁ , R ₁ , A ₂ and Rc have the meanings defined herein.

In one embodiment of the present invention, the compound represented by formula I has a structure selected from the following:

Wherein, A ₁ , R ₁ , A ₂ and Rc have the meanings defined herein.

In some preferred embodiments of the present invention, the compound represented by formula I is selected from compounds with the following structure:

The present invention also provides a method for preparing the compounds represented by the above formula I or formulas I-1 to I-10, which includes the following steps:

Method a.

Compound Ia reacts with compound HA ₁ to obtain a compound of formula I; or,

Method b.

Compound Ib reacts with compound R ₁ -ZnBr to obtain a compound of formula I, provided that R ₁ is a C _3-20 cycloalkyl group; or,

Method c.

Compound Ic reacts with compound Id to obtain the compound represented by formula I-3;

Among them, A ₁ , A ₂ , A ₃ , R ₁ , X ₁ , X ₂ , X ₃ , X ₄ , X ₅ and X ₆ have the above definitions.

The present invention also provides a pharmaceutical composition, which includes the compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable At least one of the salts or prodrugs thereof is accepted.

According to an embodiment of the present invention, the pharmaceutical composition is used to prevent or treat cannabinoid receptor-mediated diseases or conditions, preferably cannabinoid receptor 2 (CB2)-mediated diseases or conditions.

According to embodiments of the present invention, the cannabinoid receptor-mediated diseases or conditions include, but are not limited to: lupus erythematosus (SLE), diffuse skin thickening, autoimmune diseases, colitis, inflammatory bowel disease, allergic Dermatitis, pain and/or arthritis.

According to an embodiment of the present invention, the pharmaceutical composition further includes one, two or more pharmaceutically acceptable excipients.

According to an embodiment of the present invention, the pharmaceutically acceptable auxiliary material is selected from one, two or more types of physiologically or pharmaceutically acceptable carriers, diluents, vehicles and/or excipients.

According to embodiments of the present invention, suitable routes of administration of the pharmaceutical composition include, but are not limited to, oral, rectal, topical, buccal, parenteral, intramuscular, intradermal, intravenous and transdermal administration.

According to embodiments of the present invention, the pharmaceutical composition is for oral administration, and the pharmaceutical composition can be tablets, pills, lozenges, sugar-coated agents, capsules, oral liquids, etc.

According to an embodiment of the present invention, the pharmaceutical composition is for topical administration, and the pharmaceutical composition can be an ointment, cream, paste, tincture, plaster, gel, film, or liniment. , aerosols, sprays, foams, micro sponges, etc.

The present invention provides the compound represented by the above formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable salt or its prodrug, Or the use of the pharmaceutical composition in the preparation of a medicament for the treatment or prevention of cannabinoid receptor-mediated diseases or conditions.

The present invention also provides a method for treating or preventing symptoms or diseases mediated by cannabinoid receptors, which includes administering to an individual in need a preventive or therapeutically effective amount of the compound represented by Formula I of the present invention, or its racemate. , stereoisomers, tautomers, isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts or prodrugs thereof, or the pharmaceutical composition of the present invention.

According to an embodiment of the invention, the cannabinoid receptor mediated disease or disorder is selected from the group consisting of lupus erythematosus (SLE), diffuse skin thickening, autoimmune disease, colitis, inflammatory bowel disease, atopic dermatitis, pain and/or arthritis.

In all administration methods of the compound represented by formula I of the present invention, the daily dosage is 0.01 to 200 mg/kg body weight.

According to embodiments of the invention, dosing regimens may be adjusted to provide the optimal desired response. For example, a single oral dose may be administered, several divided doses may be administered over time, or the dosage may be proportionally reduced or increased as the exigencies of the therapeutic situation indicate. It is noted that dosage values may vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that, for any particular individual, specific dosage regimens should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions.

beneficial effects

The compound of the present invention has good binding ability and selectivity for human CB2 receptors, and shows good agonistic activity and high selectivity for CB2 receptors, so that it can reduce the risk of inflammatory diseases, autoimmune diseases and other diseases on the basis of treating inflammatory diseases, autoimmune diseases and other diseases. Nervous system side effects. Moreover, the compound of the present invention also has the advantages of short synthetic route, convenient preparation process and simple product post-processing.

Definition and Description

Unless otherwise defined, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.

Among the substituents listed in the present invention, the * position is the connection site.

"More" means three or more.

The term "halogen" includes F, Cl, Br or I.

In the general structure, C(O) represents a carbonyl group, that is S(O) ₂ represents a sulfonyl group. For example, the structural formula represented by -S(O) ₂ R is The dotted lines in the general structure indicate that the chemical bond at the corresponding position can be a single bond or a double bond.

The term "comprising" is an open-ended expression, that is, it includes the contents specified in the present invention, but does not exclude other aspects.

Unless otherwise stated, the numerical ranges stated in the specification and claims are equivalent to recording at least each specific integer value therein. For example, the numerical range "1-20" is equivalent to recording each integer value in the numerical range "1-10", that is, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and the numerical range Each integer value in "11-20" is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. Other numerical ranges should be similarly understood and interpreted.

The term "C _1-12 alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1 to 12 carbon atoms. For example, "C _1-6 alkyl" refers to straight and branched chain alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-Methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers.

The term "C _3-20 cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic or polycyclic hydrocarbon ring (also called fused hydrocarbon ring) having 3 to 20 carbon atoms. Bicyclic or polycyclic cycloalkyl groups include pendant cycloalkyl, bridged cycloalkyl, and spirocycloalkyl; the pendant ring refers to two or more cyclic structures sharing two adjacent ring atoms. A fused ring structure formed by sharing one bond. The bridged ring refers to a fused ring structure formed by two or more ring structures sharing two non-adjacent ring atoms with each other. The spiro ring refers to a fused ring structure formed by two or more ring structures sharing one ring atom with each other. For example, the C _3-20 cycloalkyl group can be a C _3-8 monocyclic cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or C _{7 -12-} branched cycloalkyl group, such as decalin ring; it can also be C _7-12 bridged cycloalkyl group, such as norbornane, adamantane, and bicyclo[2,2,2]octane.

The term "3-20 membered heterocyclyl" means a saturated or unsaturated monovalent monocyclic or bicyclic hydrocarbon ring, which contains 1-5 heteroatoms independently selected from N, O and S, preferably "3-10 membered Heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated or unsaturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3 heteroatoms selected from N, O and S. The heterocyclyl group may be attached to the remainder of the molecule through any of the carbon atoms or nitrogen atom, if present. In particular, the heterocyclyl group may include, but is not limited to: 4-membered rings, such as azetidinyl, oxetanyl; 5-membered rings, such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl Or trithialkyl; or 7-membered ring, such as diazacycloheptyl, diazacycloheptenyl. Optionally, the heterocyclyl group may be a fused ring, a bridged ring, or a spiro ring. The heterocyclyl group may be bicyclic, such as but not limited to hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl. The ring containing nitrogen atoms may be partially unsaturated, i.e. it may contain one, two or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3, 4]thiadiazinyl, 4,5-dihydroxazolyl or 4H-[1,4]thiazinyl, 5H,6H,8H-[1,2,4]triazolo[4,3-a]pyrazinyl, alternatively, it can be benzo-fused, e.g. However, it is not limited to dihydroisoquinolyl, 1,3-benzoxazolyl, and 1,3-benzodioxolyl.

The term "C _6-20 aryl" is understood to mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably "C _6-14 aryl". The term "C _6-14 aryl" is understood to mean preferably a monovalent or partially aromatic monocyclic, bicyclic or Tricyclic hydrocarbon rings ("C _6-14 aryl"), especially rings with 6 carbon atoms ("C ₆ aryl"), such as phenyl; or biphenyl, or with 9 carbon atoms a ring ("C ₉ aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C ₁₀ aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, Either a ring with 13 carbon atoms ("C ₁₃ aryl"), such as fluorenyl, or a ring with 14 carbon atoms ("C ₁₄ aryl"), such as anthracenyl. When the C _6-20 aryl group is substituted, it may be mono- or poly-substituted. Moreover, there is no restriction on the substitution position, for example, it may be ortho, para or meta substitution.

The term "5-20 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 independently selected from N, O and S heteroatoms, such as "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and it contains 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, additionally in each case The following can be benzo-fused. In particular, the heteroaryl group is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl Diazolyl, thi-4H-pyrazolyl, etc. and their benzo derivatives, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzene Triazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinoline base, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolinyl, purinyl, etc. and their benzo derivatives; or cinolinyl, phthalazinyl, quinazolinyl, quinoxalyl Phinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.

The above definition of the term "C _1-12 alkyl" is also applicable to other groups containing C _1-12 alkyl, such as C _1-12 alkoxy, etc.

Similarly, C _6-20 aryl, 5-20 membered heteroaryl, and C _3-20 cycloalkyl have the same definitions throughout the text.

Detailed ways

The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following examples are only illustrative and explain the present invention and should not be construed as limiting the scope of the present invention. All technologies implemented based on the above contents of the present invention are covered by the scope of protection intended by the present invention.

Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

Example 1: 8-(2-chlorophenyl)-9-{3-fluorobicyclo[1.1.1]pentan-1-yl}-2-methyl-6-(4-methylpiperazine-1 Preparation of -base)purine (compound 1)

Step 1: Synthesis of compound 6-chloro-N-{3-fluorobicyclo[1.1.1]pentan-1-yl}-2-methyl-5-nitropyrimidine-4-amine (2)

To a solution of 2-methyl-4,6-dichloro-5-nitropyrimidine (604.74 mg, 2.90 mmol, 2.00 equiv) in isopropanol (10 mL) at room temperature was added 3-fluorobicyclo[1.1. 1] Pentan-1-amine hydrochloride (200.00 mg, 1.45 mmol, 1.00 equivalent), N,N-diisopropylethylamine (375.77 mg, 2.90 mmol, 2.00 equivalent). After the addition was completed, the system continued to stir at room temperature for 1 hour. Liquid quality monitoring showed that the reaction was complete. The reaction solution was diluted with water (1x 40mL) and extracted with ethyl acetate (2 x 40mL). The organic phases were combined, backwashed with saturated brine (1 x 40mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 6-chloro-N-{3-fluorobicyclo[1.1.1]pentan-1-yl}-2-methyl-5-nitropyrimidine-4-amine ( 360.40mg, 90.93%). LCMS(ES,m/z):272.95[M+H] ⁺ .

Step 2: Synthesis of compound 6-chloro-N4-{3-fluorobicyclo[1.1.1]pentan-1-yl}-2-methylpyrimidine-4,5-diamine (3)

To 6-chloro-N-{3-fluorobicyclo[1.1.1]pentan-1-yl}-2-methyl-5-nitropyrimidin-4-amine (340.00 mg, 1.25 mmol, Add reduced iron powder (278.55 mg, 5.00 mmol, 4.00 equivalent) and glacial acetic acid (1 mL, 17.45 mmol) to a solution of 1.00 equivalents) in anhydrous methanol (10 mL). After the addition was completed, the system was continued to stir at room temperature for 2 hours. Liquid quality monitoring showed that the reaction was complete, and the reaction mixture was alkalized to pH 8 with saturated sodium bicarbonate aqueous solution. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 6-chloro-N4-{3-fluorobicyclo[1.1.1]pentan-1-yl}-2-methylpyrimidine-4,5-diamine (286.00 mg, 94.51%). LCMS(ES,m/z):243.00[M+H] ⁺ .

Step 3: Synthesis of compound 6-chloro-8-(2-chlorophenyl)-9-{3-fluorobicyclo[1.1.1]pentan-1-yl}-2-methylpurine (4)

Under nitrogen protection, add 6-chloro-N4-{3-fluorobicyclo[1.1.1]pentan-1-yl}-2-methylpyrimidine-4,5-diamine (260.00mg, 1.07mmol, 1.00 Equivalent) of 1,4-dioxane (10 mL) solution, add o-chlorobenzaldehyde (241.35 uL, 2.14 mmol, 2.00 equivalent) and ferric chloride (78.00 mg, 0.32 mmol, 0.30 equivalent). The reaction solution was heated to 55°C and stirred overnight. The liquid quality monitoring showed that the reaction was complete, the reaction solution was filtered, the filter cake was washed with dichloromethane (3 x 10mL), and the resulting residue was concentrated under reduced pressure to obtain 6-chloro-8-(2-chlorophenyl)-9-{3-fluoro Bicyclo[1.1.1]pentan-1-yl}-2-methyl-7,8-dihydropurine crude product. The above crude product was dissolved in dichloromethane (6 mL), and then 2,3-dichloro-5,6-dicyanobenzoquinone (243.02 mg, 1.07 mmol, 1.00 equivalent) was added under an ice bath. The reaction solution was warmed to room temperature, and stirring was continued for 2 hours. The liquid quality monitoring response was complete. The reaction solution was quenched with 1M sodium hydroxide solution, then diluted with water (20mL), and extracted with dichloromethane (2 x 20mL). The organic phases were combined, backwashed with saturated brine (1 x 30mL), and dried with anhydrous sulfuric acid. , filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 6-chloro-8-(2-chlorophenyl)-9-{3-fluorobicyclo[1.1.1]pentan-1-yl}-2-methylpurine ( 285.00 mg, 73.29%). LCMS(ES,m/z):362.95[M+H] ⁺ .

Step 4: Compound 8-(2-chlorophenyl)-9-{3-fluorobicyclo[1.1.1]pentan-1-yl}-2-methyl-6-(4-methylpiperazine-1 -Synthesis of purine (compound 1)

To 6-chloro-8-(2-chlorophenyl)-9-{3-fluorobicyclo[1.1.1]pentan-1-yl}-2-methylpurine (100.00 mg, 0.28 mmol, 1.00 equiv) of 1,4-dioxane (5 mL) was added to a solution of N-methylpiperazine (30.54uL, 0.28mmol, 1.00 equivalent), N,N-diisopropylethylamine (143.87uL, 0.84mmol, 3.00 equivalent). The temperature of the reaction solution was raised to 100°C, and stirring was continued for 1 hour. Liquid quality monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water (1 x 20mL), extracted with ethyl acetate (2 x 30mL), combined the organic phases, backwashed with saturated brine (1 x 40mL), and anhydrous sodium sulfate. Dry, filter, and concentrate the filtrate under reduced pressure. The crude product is purified by preparative HPLC under the following conditions: chromatography column specifications: XBridge Prep OBD C18 Column, 30x150mm, 5μm; mobile phase A: water (10mmol/L ammonium bicarbonate), flowing Phase B: acetonitrile flow rate: 60mL/min; elution gradient: 45% B to 70% B, within 8 minutes); detection wavelength: UV 254nm/220nm. Obtain compound 8-(2-chlorophenyl)-9-{3-fluorobicyclo[1.1.1]pentan-1-yl}-2-methyl-6-(4-methylpiperazin-1-yl) )Purine (25.80mg, 21.84%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.70-7.61 (m, 3H), 7.58-7.43 (m, 1H), 4.16 (s, 4H) 2.46 (d, J = 3.1Hz, 9H), 2.40 (t,J＝5.1Hz,4H),2.20(s,3H).LCMS(ES,m/z):427.10[M+H] ⁺ .

Using conditions similar to those in Example 1, the compounds in Table 1 below were prepared. The structural characterization data of these compounds are listed in Table 1.

Table 1

Example 2: 8-(2-chlorophenyl)-2-cyclopropyl-9-{3-fluorobicyclo[1.1.1]pentan-1-yl}-6-(4-methylpiperazine- Preparation of 1-yl)purine (compound 61)

Step 1-4: Compound 2-chloro-8-(2-chlorophenyl)-9-{3-fluorobicyclo[1.1.1]pentan-1-yl}-6-(4-methylpiperazine- Synthesis of 1-yl)purine(8)

A compound was obtained using a method similar to Example 1 (the starting raw materials were replaced with 2,4,6-trichloro-5-nitropyrimidine and 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride). 2-Chloro-8-(2-chlorophenyl)-9-{3-fluorobicyclo[1.1.1]pentan-1-yl}-6-(4-methylpiperazin-1-yl)purine( 1.20g, 89.49%). LCMS(ES,m/z):447.30[M+H] ⁺ .

Step 5: Compound 8-(2-chlorophenyl)-2-cyclopropyl-9-{3-fluorobicyclo[1.1.1]pentan-1-yl}-6-(4-methylpiperazine- Synthesis of 1-yl)purine (compound 61)

Nitrogen protection, at room temperature to 2-chloro-8-(2-chlorophenyl)-9-{3-fluorobicyclo[1.1.1]pentan-1-yl}-6-(4-methylpiperazine- To a solution of 1-yl)purine (500.00 mg, 1.12 mmol, 1.00 equivalent) in 1,4-dioxane (10 mL) was added 2-dicyclohexylphosphine-2',4',6'-triisopropyl Biphenyl (53.28 mg, 0.11 mmol, 0.10 equivalent) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) ( 2'-Amino-1,1'-biphenyl-2-yl)palladium (II) (94.61 mg, 0.11 mmol, 0.10 equivalent), followed by dropwise addition of a 0.5 M solution of cyclopropylzinc bromide in tetrahydrofuran (6.70 mL ,3.36mmol, 3.00 equivalent). The temperature was raised to 100°C and the reaction was stirred for 1 hour. The liquid quality monitoring response was complete. The reaction was cooled to room temperature, filtered, the filter cake was washed with dichloromethane (3 x 10 mL), and the filtrate was concentrated under reduced pressure. Dilute with water (100mL) and extract with dichloromethane (3 x 100mL). The organic phases were combined, backwashed with saturated sodium chloride solution (1 x 100mL), and dried over anhydrous sodium sulfate. After the resulting mixture was filtered, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: chromatography column specifications: XBridge Prep OBD C18 Column, 30*150mm, 5μm; mobile phase A: water (10mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60mL/min; elution gradient: 45% B to 90% B, within 8 minutes, 90% B; detection wavelength: UV 254nm/220nm; retention time (minutes): 7.7. Obtain compound 8-(2-chlorophenyl)-2-cyclopropyl-9-{3-fluorobicyclo[1.1.1]pentan-1-yl}-6-(4-methylpiperazine-1- base) purine (143.00mg, 28.02%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.69-7.64(m,2H),7.64-7.59(m,1H),7.58-7.48(m,1H),4.14(s,4H),2.45(d ,J＝2.1Hz,6H),2.39(t,J＝5.1Hz,4H),2.20(s,3H),2.07-1.97(m,1H),1.02-0.89(m,4H).LCMS(ES, m/z):452.95[M+H] ⁺ .

Example 3: 1-(1-{bicyclo[1.1.1]pentan-1-yl}-2-(2-chlorophenyl)-6-methylimidazo[4,5-c]pyridine-4 Preparation of -yl)-4-methylpiperazine (compound 62)

Compound 1- was obtained using a method similar to Example 1 (the starting raw materials were replaced with 2,4-dichloro-6-methyl-3-nitropyridine and bicyclo[1.1.1]pentachlorobenzene-1-amine). (1-{Bicyclo[1.1.1]pentan-1-yl}-2-(2-chlorophenyl)-6-methylimidazo[4,5-c]pyridin-4-yl)-4- Methylpiperazine (26.50mg, 22.23%). ¹ H NMR (400MHz, deuterated methanol) δ7.52-7.47(m,2H),7.46-7.42(m,1H),7.41-7.35(m,1H),6.86(d,J＝0.8Hz,1H) ,3.91(s,4H),2.51(t,J＝4.7Hz,4H),2.37(t,J＝1.1Hz,4H),2.24(d,J＝1.3Hz,3H),2.09(d,J＝ 1.7Hz,6H).LCMS(ES,m/z):409.05[M+H] ⁺ .

Using conditions similar to those in Example 3, the compounds in Table 2 below were prepared. The structural characterization data of these compounds are listed in Table 2.

Table 2

Example 4: 1-(3-{bicyclo[1.1.1]pentan-1-yl}-2-(2-chlorophenyl)-5-methylimidazo[4,5-b]pyridine-7 Preparation of -yl)-4-methylpiperazine (compound 65)

Step 1: Synthesis of compound 1-(2-chloro-6-methyl-3-nitropyridin-4-yl)-4-methylpiperazine (14)

Compound 1-(2-chloro-6-methyl-3-nitropyridine was obtained using a method similar to step 4 of Example 1 (the starting material was replaced with 2,4-dichloro-6-methyl-3-nitropyridine) Nitropyridin-4-yl)-4-methylpiperazine (700.00 mg, 53.53%). LCMS(ES,m/z):271.00[M+H] ⁺ .

The subsequent three steps are carried out using methods similar to steps one, two and three of Example 1 (the starting raw material is replaced with 1-(2-chloro -6-methyl-3-nitropyridin-4-yl)-4-methylpiperazine and bicyclo[1.1.1]pentachlorobenzene-1-amine) to obtain compound 1-(3-{bicyclo[1.1. 1]pentan-1-yl}-2-(2-chlorophenyl)-5-methylimidazo[4,5-b]pyridin-7-yl)-4-methylpiperazine (10.60 mg, 6.79%). ¹ H NMR (400MHz, deuterated methanol) δ7.52-7.41(m,3H),7.40-7.35(m,1H),6.43(s,1H),3.64(s,4H),2.56(t,J＝ 5.1Hz, 4H), 2.43 (s, 3H), 2.33 (s, 1H), 2.26 (s, 3H), 2.14 (d, J = 4.1Hz, 6H). LCMS (ES, m/z): 408.05[ M+H] ⁺ .

Biological test evaluation

Test Example 1 Human CB2 ligand receptor binding test

A radioisotope-labeled ligand receptor binding assay is used to detect the affinity of the compounds of the present invention for human CB2 receptors. Add 95 μL of experimental buffer (25mM Hepes, 10mM MgCl ₂ , 1mM CaCl ₂ , 0.5% BSA, pH 7.4) to the 96-well deep well experimental plate, then add 5 μL of 100X compound to the corresponding well, and shake at 600 rpm for 5 minutes to mix. Add 300 μL of a mixture of CHO-CB2 cell membrane and experimental buffer (0.2 μL membrane and 299.8 μL experimental buffer) to each experimental well, and mix well by shaking at 600 rpm for 5 minutes. Add 100 μL of 5X concentration isotope [ ³ H]-CP 55940 to each experimental well, centrifuge at 1000 rpm for 1 min, shake at 600 rpm for 5 min to mix, and then incubate the experimental plate at 30°C for 1.5 hours. The UNIFILTER-96GF/C plate added with 0.5% PEI solution and incubated for 1 hour at 4°C was washed twice with washing solution (50mM Tris-HCl, 2.5mM EDTA, 5mM MgCl ₂ , 0.5mg/ml BSA, pH 7.4). 50mL wash solution each time. Transfer the reaction system in the 96-well deep-well experimental plate to the UNIFILTER-96GF/C plate, wash it 4 times with washing solution, 900 μL of washing solution per well. Place the cleaned UNIFILTER-96GF/C board in a 55°C oven and dry for 10 minutes. Add 40 μL of ULTIMA GOLD scintillation fluid to each well into the dried UNIFILTER-96GF/C plate, and use Microbeta2 to collect data. The entire reaction system is 500 μL, the final concentration of [ ³ H]-CP 55940 is 0.5 nM, and the final concentration of DMSO is 1%.

Use the nonlinear four-parameter equation of XLfit or GraphPad Prism software to generate the dose-effect curve of the compound and calculate its corresponding Ki value.

The compounds of the present invention have good binding ability to human CB2 receptors, and the binding data of some compounds are shown in Table 3 below.

table 3

Test Example 2 CB1 and CB2 cAMP generation function test

Flp-In-CHO-human CB1/2, Flp-In-CHO-mouse CB1/2 and Flp-In-CHO-rat CB1/2 cells were cultured in F12K, 10% fetal bovine serum, 1% penicillin-streptococci The cells were cultured in a complete medium containing 600 μg/ml hygromycin and 600 μg/ml hygromycin in a 37°C, 5% _CO2 cell culture incubator. On the day of the experiment, the cells were digested and resuspended in HBSS experimental buffer containing 20mM HEPES, 0.1% BSA and 500μM IBMX, and then seeded into a 384-well cell culture plate. The seeding density of human and mouse CB1/2 cells is 8000 cells per well, and the seeding density of rat CB1/2 cells is 2000 cells per well, and the seeding volume is 15 μL. Subsequently, a cAMP production assay was used to detect the agonistic activity of the above compounds on human CB1 and CB2 receptors.

Human CB2 Agonist Trial

Add 2.5 μL of 8X concentration of SR144528 working solution to the above cell experiment plate, incubate at 37°C for 10 minutes, then add 2.5 μL of a mixture of 8X concentration of compound and Forskolin, and incubate at 37°C for 30 minutes. After the reaction is completed, add 10 μL Eu-cAMP tracer and 10 μL Ulight-anti-cAMP detection reagent to the experimental plate. After incubating at room temperature for 1 hour, use the Envision HTRF function module to collect data. The entire reaction system is 20 μL, the final concentration of DMSO is 0.2%, the final concentration of Forskolin is 2 μM, and the final concentration of SR144528 is 80 nM.

Use the nonlinear four-parameter equation of XLfit or GraphPad Prism software to generate the dose-effect curve of the compound and calculate its corresponding EC ₅₀ .

The compounds of the present invention show good human CB2 agonistic activity, and the human CB2 agonistic activity of some compounds is shown in Table 4 below.

Table 4

Human CB1 Agonist Trial

Add 2.5 μL of 8X concentration compound working solution to the above cell experiment plate, incubate at 37°C for 10 minutes, then add 2.5 μL of 8X concentration Forskolin solution, and incubate at 37°C for 30 minutes. After the reaction is completed, add 10 μL Eu-cAMP tracer and 10 μL Ulight-anti-cAMP detection reagent to the experimental plate. After incubating at room temperature for 1 hour, use the Envision HTRF function module to collect data. The entire reaction system is 20 μL, the final concentration of DMSO is 0.2%, and the final concentration of Forskolin is 1 μM.

Use the nonlinear four-parameter equation of XLfit or GraphPad Prism software to generate the dose-effect curve of the compound and calculate its corresponding EC ₅₀ .

The compounds of the present invention show good selectivity for human CB1 agonism. The agonistic activities of some compounds on human CB1 are shown in Table 5 below.

table 5

As controls, the following compounds were used to obtain test results as shown in Table 6.

Table 6

By comparing the human CB2 ligand binding activity and human CB2 agonistic activity data of the compound of the present invention and the control compound LY-2828360, it can be seen that the compound of the present invention has better biological activity for CB2 receptors, and at the same time, the compound of the present invention has better biological activity for CB2 receptors. The body has good selectivity.

The embodiments of the present invention have been described above. However, the present invention is not limited to the above-described embodiment. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims (16)

1. The compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable salt or its prodrug,
   

   Among them, A ₁ is selected from the following groups that are unsubstituted or optionally substituted by one, two or more Ra: 3-20-membered heterocyclyl, 5-20-membered heteroaryl, 5-20-membered heteroaryl 3-20 membered heterocyclic group;

   Ra is selected from C _1-12 alkyl, C _1-12 alkoxy, halo C _1-12 alkyl, halo C _1-12 alkoxy, OH, HO-C _1-12 alkyl, CN, -C(O)C _1-12 alkyl, -S(O) ₂ C _1-12 alkyl, -S(=O)C _1-12 alkyl, -S(C _1-12 alkyl) ₂ , -C(O)NHC _1-12 alkyl, -C(O)N(C _1-12 alkyl) ₂ , -C(O)NH ₂ , -N(C _1-12 alkyl) ₂ , =O ;

   X ₁ , X ₂ , X _{3 ,} X ₄ , X ₅ , _and X ₆ are the same or different, and are independently C, CH _, or _N , provided that , X ₅ and X ₆ are not N at the same time;

   R ₁ is selected from halogen, C _1-12 alkyl, C _1-12 alkoxy, halogenated C _1-12 alkyl, halogenated C _1-12 alkoxy, C _3-20 cycloalkyl;

   A ₂ is selected from C _6-20 aryl or 5-20 membered heteroaryl that is unsubstituted or optionally substituted by one, two or more Rb;

   Rb is selected from halogen, halogenated C _1-12 alkyl, C _1-12 alkyl, C _1-12 alkoxy, halogenated C _1-12 alkoxy, CN, OH, NH ₂ and nitro;

   A ₃ is selected from C _3-20 cycloalkyl or 3-20 membered heterocyclyl that is unsubstituted or optionally substituted by one, two or more Rc;

   Rc is selected from halogen, C _1-12 alkyl, halogenated C _1-12 alkyl, NH ₂ , -NHC(O)C _1-12 alkyl, -NHC _1-12 alkyl, CN, nitro, - COOC _1-12 alkyl, HO-C _1-12 alkyl, OH, C _1-12 alkoxy, halogenated C _1-12 alkoxy.
2. The compound represented by formula I according to claim 1, its racemate, stereoisomer, tautomer Conforms, isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts or prodrugs thereof, wherein,

   A ₁ is selected from the following groups that are unsubstituted or optionally substituted by one, two or more Ra: 3-12 membered heterocyclyl, 5-12 membered heteroaryl, 5-12 membered heteroaryl 3-12 membered heterocyclyl;

   Ra is selected from C _1-6 alkyl, halogenated C _1-6 alkyl, HO-C _1-6 alkyl, CN, -C(O)C _1-6 alkyl, -S(O) ₂ C _{1 -6} alkyl, -C(O)NHC _1-6 alkyl, -C(O)NH ₂ , -N(C _1-6 alkyl) ₂ , =O;

   R ₁ is selected from C _1-6 alkyl, halogenated C _1-6 alkyl, C _3-12 cycloalkyl;

   A ₂ is selected from C _6-12 aryl or 5-12 membered heteroaryl that is unsubstituted or optionally substituted by one, two or more Rb;

   Rb is selected from halogen (especially F, Cl), halogenated C _1-6 alkyl, CN, C _1-6 alkoxy, C _1-6 alkyl, OH;

   A ₃ is selected from C _3-12 cycloalkyl or 3-12 membered heterocyclyl that is unsubstituted or optionally substituted by one, two or more Rc; and/or

   Rc is selected from halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, NH ₂ , -NHC(O)C _1-6 alkyl, -NHC _1-6 alkyl, CN, -COOC _{1- 6} alkyl, HO-C _1-6 alkyl, OH, C _1-6 alkoxy.
3. The compound represented by formula I according to claim 1 or 2, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable salt or Its prodrug, wherein formula I is selected from the following structures:
   
4. The compound represented by formula I according to any one of claims 1 to 3, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable Accepted salts or prodrugs thereof, wherein A ₁ is selected from the following groups that are unsubstituted or optionally substituted by one, two or more Ra: 3-12-membered N-containing heterocyclyl, 5-12-membered N-containing heteroaryl, 5-12-membered N-containing heteroaryl and 3-12-membered N-containing heterocyclic group;

   Preferably, A ₁ is selected from the following groups that are unsubstituted or optionally substituted by one, two or more Ra: piperazinyl, piperidinyl, hexahydropyrazino[2,1-c][ 1,4]oxazin-8(1H)-yl, 1,4-diazepanyl, octahydropyrido[1,2-a]pyrazinyl, 5H,6H,8H-[1, 2,4]triazolo[4,3-a]pyrazinyl, hexahydropyrro[1,2-a]pyrazin-2(1H)-yl or azetidinyl.
5. The compound represented by formula I according to any one of claims 1 to 4, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable Accepted salts or prodrugs thereof, wherein Ra is selected from methyl, ethyl, isopropyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, CN , acetyl, methanesulfonyl, methylaminocarbonyl, dimethylamino, carbamoyl or oxo.
6. The compound represented by formula I according to any one of claims 1 to 5, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable Accepted salts or prodrugs thereof, wherein A ₁ is selected from 4-methylpiperazinyl, 4-ethylpiperazinyl, 4-(2,2,2-trifluoroethyl)piperazinyl, 4- Hydroxyethylpiperazinyl, 3-cyano-4-methylpiperazinyl, 4-isopropylpiperazinyl, 4-acetylpiperazinyl, 4-methanesulfonylpiperazinyl, 4-methylamino Formylpiperazinyl, 4-(2,2-difluoroethyl)piperazinyl, 4-methanesulfonylpiperidinyl, 4-carbamoylpiperazinyl,
7. The compound represented by formula I according to any one of claims 1 to 6, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable Acceptable salts or prodrugs thereof, wherein R ₁ is selected from methyl, trifluoromethyl, and cyclopropyl.
8. The compound represented by formula I according to any one of claims 1 to 7, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable Acceptable salts or prodrugs thereof, wherein _A2 is selected from phenyl or pyridyl which is unsubstituted or optionally substituted by one, two or more Rb.
9. The compound represented by formula I according to any one of claims 1 to 8, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable Accepted salts or prodrugs thereof, wherein Rb is the following group: F, Cl, CF ₃ , CN, methoxy, methyl, OH.
10. The compound represented by formula I according to any one of claims 1 to 9, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable Acceptable salts or prodrugs thereof, wherein A ₃ is selected from the following groups that are unsubstituted or optionally substituted by one, two or more Rc:
11. The compound represented by formula I according to any one of claims 1 to 10, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable accepted Salt or its prodrug, wherein Rc is the following group: F, methyl, trifluoromethyl, NH ₂ , carbamoyl, acetamido, methylamino, CN, hydroxymethyl, hydroxyethyl, methyl ester group ,OH.
12. The compound represented by formula I according to any one of claims 1 to 10, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable Acceptable salts or prodrugs thereof, wherein the compound represented by formula I has a structure selected from I-8, I-9 or I-10:
    

    Wherein, L ₁ and L ₂ are -CH ₂ -, -CH ₂ -CH ₂ - or -CH ₂ -O- independently of each other; preferably, L ₁ is -CH ₂ - and L ₂ is -CH ₂ -O -.
13. The compound of formula I according to any one of claims 1 to 10, which has a structure selected from the following:
    
    
    
    
    
    
    
    
14. Pharmaceutical composition, which contains the compound represented by formula I according to any one of claims 1 to 13, its racemate, stereoisomer, tautomer, isotope label, solvate, and polymorph. , at least one of pharmaceutically acceptable salts or prodrugs thereof;

    Preferably, the pharmaceutical composition further includes one, two or more pharmaceutically acceptable excipients.
15. The pharmaceutical composition according to claim 14, characterized in that the pharmaceutical composition is used to prevent or treat cannabinoid receptor-mediated diseases or conditions, preferably cannabinoid receptor 2 (CB2)-mediated diseases. or disease;

    Preferably, the cannabinoid receptor mediated disease or disorder is selected from: lupus erythematosus (SLE), diffuse skin thickening, autoimmune disease, colitis, inflammatory bowel disease, atopic dermatitis, pain and/or Or arthritis.
16. The compound represented by formula I according to any one of claims 1 to 13, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable The use of a salt or a prodrug thereof, or a pharmaceutical composition according to claim 14 or 15 in the preparation of a medicament for the treatment or prevention of cannabinoid receptor-mediated diseases or conditions.