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CN118946565A - Substituted condensed ring cannabinoid receptor compounds and their applications - Google Patents

Substituted condensed ring cannabinoid receptor compounds and their applications Download PDF

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CN118946565A
CN118946565A CN202380030151.9A CN202380030151A CN118946565A CN 118946565 A CN118946565 A CN 118946565A CN 202380030151 A CN202380030151 A CN 202380030151A CN 118946565 A CN118946565 A CN 118946565A
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马彦彬
金磊
王思勤
张宏学
陆爱军
沈淳
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Changchun Genescience Pharmaceutical Co Ltd
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
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Abstract

本发明提供了式I所示大麻素受体化合物，该化合物对人CB2受体具有良好的结合能力，且显示出对CB2受体良好的激动活性和高度选择性，从而能够在治疗炎症疾病、自身免疫病等症的基础上降低神经系统方面的副作用。 The present invention provides a cannabinoid receptor compound as shown in formula I, which has good binding ability to human CB2 receptors and shows good agonist activity and high selectivity to CB2 receptors, thereby being able to reduce side effects on the nervous system on the basis of treating inflammatory diseases, autoimmune diseases and the like.

Description

Substituted fused ring cannabinoid receptor compounds and uses thereof
The application claims priority from the prior application filed by the national intellectual property agency of China on 7.21.2022, with patent application number 20221086884. X and entitled "substituted fused ring cannabinoid receptor Compounds and uses thereof". The entirety of this prior application is incorporated by reference into the present application.
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a substituted condensed ring cannabinoid receptor compound, and a preparation method and application thereof.
Background
Cannabinoid receptors CB1 and CB2 are key components of the endogenous cannabinoid system and are also the primary targets for D9-tetrahydrocannabinol (D9-THC). D9-THC is a psychoactive chemical substance extracted from cannabis (J Clin invest.1973Oct;52 (10): 2411-7) with a wide range of therapeutic applications. Lipid activation by Tetrahydrocannabinol (THC), cannabinoid receptor 1 (CB 1), is involved in mental activity, neuromodulation and analgesic effects. Cannabidiol (CBD) has received a great deal of attention for its pharmacological effects or efficacy in neuroprotection, analgesia, anti-inflammatory, antioxidant, antiepileptic, etc. The effects of the endogenous cannabinoid receptor system are mainly highly expressed in the central nervous system, adipocytes, hepatocytes (hepatocytes) and musculoskeletal tissues, and endogenous cannabinoid agonists include: cannabinoids (anandamide, AEA) and 2-arachidyl glycerol (2-arachidonoyl glycerol, 2-AG). CB1 and CB2 play an important role in a variety of physiological processes, including appetite, pain sensation, memory and immunomodulation (Manuel Guzm an, NAT REV CANCER,2003Oct;3 (10): 745-55.). These two cannabinoid receptors share 44% overall sequence homology and 68% sequence similarity in the transmembrane region (Munro et al, 1993). However, their tissue distribution is different, playing a different role in the endogenous cannabinoid system, with CB1 and CB2 being expressed mainly in the central nervous system and immune system, respectively. First, the development of therapeutic applications is limited by the selectivity for a single target, due to the high similarity of the two sequences. CB2 is associated with anti-inflammatory and immunomodulatory effects, with no psychoactive effects. CB2 is expressed in somatic cells that control immune function and possibly in the Central Nervous System (CNS). In addition, studies have shown that secondary metabolites of phytonutrients in vegetable foods can enhance CB2 receptor activity and promote healthy inflammatory responses. In addition, CB2 selective agonists are also a hotspot in the field as highly potential candidates for the treatment of inflammatory and neuropathic pain without CB1 mental activity.
The project is mainly developed by developing CB2 small molecule agonists in the early stage. The mechanism of anti-inflammatory action of CB2 agonists includes: reducing chemoattractant production, reducing PGE and other Pro-inflammatory eicosanoids, reducing endothelial cell activation, inflammatory cell adhesion, rolling and migration between endothelial cells, reducing Pro-inflammatory cytokine reactive oxygen species and increasing Pro-resolving lipid mediators. CB2 agonist anti-fibrosis mechanisms 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 tissue, phagocytizing bacteria and cellular debris, and cytokinesis. Compared with the small molecular compound with the same target point known in the prior art, the development of a novel small molecular agonist drug with higher CB2 selectivity, the improvement of the bioavailability thereof and the urgent need in the field still exist. In terms of drug development, lupus erythematosus (SLE), diffuse skin thickening, autoimmune diseases, colitis or inflammatory bowel disease, allergic dermatitis, pain, arthritis, etc. are all indications that can be developed in the future for this target.
Disclosure of Invention
In order to solve the technical problems, the invention provides a compound shown in the following formula I, racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable salt or prodrug thereof,
Wherein a 1 is selected from the following groups, unsubstituted or optionally substituted with one, two or more Ra: 3-20 membered heterocyclyl, 5-20 membered heteroaryl and 3-20 membered heterocyclyl;
Ra is selected from C 1-12 alkyl, C 1-12 alkoxy, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, OH, HO-C 1-12 alkyl, CN, -C (O) C 1-12 alkyl, -S (O) 2C1-12 alkyl, -S (=o) C 1-12 alkyl, -S (C 1-12 alkyl) 2、-C(O)NHC1-12 alkyl, -C (O) N (C 1-12 alkyl) 2、-C(O)NH2、-N(C1-12 alkyl) 2, =o;
x 1、X2、X3、X4、X5、X6, which are identical or different, are C, CH, or N independently of one another, with the proviso that X 3、X4、X5 is not simultaneously N, or X 4、X5、X6 is not simultaneously N;
R 1 is selected from halogen, C 1-12 alkyl, C 1-12 alkoxy, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, and C 3-20 cycloalkyl;
A 2 is selected from C 6-20 aryl or 5-20 membered heteroaryl, unsubstituted or optionally substituted with 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, nitro;
A 3 is selected from C 3-20 cycloalkyl or 3-20 membered heterocyclyl, unsubstituted or optionally substituted with one, two or more Rc;
Rc is selected from halogen, C 1-12 alkyl, halogenated C 1-12 alkyl, NH 2、-NHC(O)C1-12 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, unsubstituted or optionally substituted with one, two or more Ra: 3-12 membered heterocyclyl, 5-12 membered heteroaryl and 3-12 membered heterocyclyl;
Ra is selected from C 1-6 alkyl, halo C 1-6 alkyl, HO-C 1-6 alkyl, CN, -C (O) C 1-6 alkyl, -S (O) 2C1-6 alkyl, -C (O) NHC 1-6 alkyl, -C (O) NH 2、-N(C1-6 alkyl) 2, =o;
R 1 is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, and C 3-12 cycloalkyl;
A 2 is selected from C 6-12 aryl or 5-12 membered heteroaryl, unsubstituted or optionally substituted with 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, unsubstituted or optionally substituted with 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)C1-6 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 may be selected from the following structures:
In one embodiment of the invention, a 1 is selected from the following groups, unsubstituted or optionally substituted with one, two or more Ra: 3-12 membered N-containing heterocyclyl, 5-12 membered N-containing heteroaryl and 3-12 membered N-containing heterocyclyl.
In one embodiment of the invention, a 1 is selected from the following groups, unsubstituted or optionally substituted with one, two or more Ra: piperazinyl, piperidinyl, hexahydropyrazino [2,1-c ] [1,4] oxazin-8 (1H) -yl, 1, 4-diazepinyl, 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 azetidinyl.
In one embodiment of the invention Ra is selected from methyl, ethyl, isopropyl, 2-difluoroethyl, 2-trifluoroethyl, 2-hydroxyethyl, CN, acetyl, methanesulfonyl, methylaminocarbonyl, dimethylamino, carbamoyl or oxo.
In one embodiment of the invention A 1 is selected from the group consisting of 4-methylpiperazinyl, 4-ethylpiperazinyl, 4- (2, 2-trifluoroethyl) piperazinyl, 4-hydroxyethylpiperazinyl, 3-cyano-4-methylpiperazinyl, 4-isopropylpiperazinyl, 4-acetylpiperazinyl, 4-methylsulfonylpiperazinyl, 4-methylcarbamoylpiperazinyl, 4- (2, 2-difluoroethyl) piperazinyl,4-Methanesulfonyl group piperidinyl group,4-Carbamoyl piperazinyl,
R 1 is selected from methyl, trifluoromethyl, cyclopropyl;
A 2 is selected from phenyl or pyridinyl, optionally substituted with 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, unsubstituted or optionally substituted with one, two or more Rc:
the Rc is preferably the following group: F. methyl, trifluoromethyl, NH 2, carbamoyl, acetamido, methylamino, CN, hydroxymethyl, hydroxyethyl, methyl ester, OH.
In one embodiment of the invention, the compound of formula I has a structure selected from the group consisting of:
Wherein L 1 and L 2 are independently of each other-CH 2-、-CH2-CH2 -or-CH 2 -O-; preferably, L 1 is-CH 2 -and L 2 is-CH 2-O-,A1、R1、A2 and Rc have the meanings defined herein.
In one embodiment of the invention, the compound of formula I has a structure selected from the group consisting of:
Wherein a 1、R1、A2 and Rc have the meanings defined herein.
In one embodiment of the invention, the compound of formula I has a structure selected from the group consisting of:
Wherein a 1、R1、A2 and Rc have the meanings defined herein.
In some preferred embodiments of the present invention, the compound of formula I is selected from the group consisting of compounds of the following structures:
The invention also provides a preparation method of the compound shown in the formula I or the formulas I-1 to I-10, which comprises the following steps:
Method a.
Reacting the compound Ia with a compound HA 1 to obtain a compound shown in a formula I; or alternatively
Method b.
Reacting a compound Ib with a compound R 1 -ZnBr to obtain a compound shown in a formula I, wherein R 1 is C 3-20 cycloalkyl; or alternatively
Method c.
Reacting the compound Ic with a compound Id to obtain a compound shown as a formula I-3;
wherein ,A1、A2、A3、R1、X1、X2、X3、X4、X5、X6 has the definition as described above.
The invention also provides a pharmaceutical composition comprising at least one of a compound shown in formula I, a racemate, a stereoisomer, a tautomer, an isotope label, a solvate, a polymorph, a pharmaceutically acceptable salt or a prodrug thereof.
According to an embodiment of the invention, the pharmaceutical composition is for use in the prevention or treatment of a cannabinoid receptor mediated disease or disorder, preferably a cannabinoid receptor 2 (CB 2) mediated disease or disorder.
According to embodiments of the present invention, the cannabinoid receptor mediated diseases or disorders 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 invention, the pharmaceutical composition further comprises one, two or more pharmaceutically acceptable excipients.
According to an embodiment of the invention, the pharmaceutically acceptable excipients are selected from one, two or more of physiologically or pharmaceutically acceptable carriers, diluents, vehicles and/or excipients.
According to embodiments of the present invention, suitable routes of administration for the pharmaceutical composition include, but are not limited to, oral, rectal, topical, buccal, parenteral, intramuscular, intradermal, intravenous and transdermal administration.
According to an embodiment of the present invention, the pharmaceutical composition is for oral administration, and the pharmaceutical composition may be a tablet, a pill, a lozenge, a sugar-coated agent, a capsule, an oral liquid, or the like.
According to an embodiment of the present invention, the pharmaceutical composition for topical administration may be an ointment, cream, paste, tincture, plaster, gel, film coating agent, paint, aerosol, spray, foam, microspongate, or the like.
The invention provides the use of a compound of formula i, a racemate, a stereoisomer, a tautomer, an isotopic label, a solvate, a polymorph, a pharmaceutically acceptable salt or a prodrug thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment or prophylaxis of a cannabinoid receptor mediated disease or condition.
The present invention also provides a method of treating or preventing a cannabinoid receptor mediated condition or disease comprising administering to a subject in need thereof a prophylactically or therapeutically effective amount of a compound of formula i, racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt or prodrug thereof, of the invention, or a pharmaceutical composition of the invention.
According to an embodiment of the invention, the cannabinoid receptor mediated disease or disorder is selected from lupus erythematosus (SLE), diffuse skin thickening, autoimmune diseases, colitis, inflammatory bowel disease, allergic dermatitis, pain and/or arthritis.
In all methods of administration of the compounds of formula I of the present invention, the daily dosage is from 0.01 to 200mg/kg body weight.
According to embodiments of the present invention, the dosing regimen may be adjusted to provide the best desired response. For example, a single oral administration may be administered, several divided doses may be administered over time, or the doses may be proportionally reduced or increased as indicated by the urgent need for the treatment situation. It is noted that the dosage value may vary with 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, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions.
Advantageous effects
The compound of the invention has good binding capacity and selectivity to human CB2 receptor, and shows good agonistic activity and high selectivity to CB2 receptor, thereby being capable of reducing side effects in the aspect of nervous system on the basis of treating inflammation diseases, autoimmune diseases and other diseases. In addition, the compound of the invention has the advantages of short synthetic route, convenient operation in the preparation process and simple post-treatment of the product.
Definition and description
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.
The substituents listed in the present invention are at the attachment site.
"More" means three or more.
The term "halogen" includes F, cl, br or I.
In the general structure, C (O) represents carbonyl, i.eS (O) 2 represents a sulfonyl group, e.g., -S (O) 2 R represents a structural formulaThe dotted line in the general structure indicates that the chemical bond at the corresponding position may be a single bond or a double bond.
The term "comprising" is an open-ended expression, i.e. including what is indicated by the invention, but not excluding other aspects.
The numerical ranges recited in the specification and claims are equivalent to at least each specific integer number recited therein unless otherwise stated. For example, the numerical range "1-20" corresponds to the numerical range "1-10" in which each of the integer numbers 1,2, 3,4,5,6, 7, 8,9, 10, and the numerical range "11-20" in which each of the integer numbers 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 is recited. Other numerical ranges should be similarly understood and interpreted.
The term "C 1-12 alkyl" is understood to mean a straight or branched saturated monovalent hydrocarbon radical having from 1 to 12 carbon atoms. For example, "C 1-6 alkyl" means straight and branched 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-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, or the like, or an isomer thereof.
The term "C 3-20 cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic or polycyclic hydrocarbon ring (also known as a thick cyclic hydrocarbon ring) having from 3 to 20 carbon atoms. Bicyclic or polycyclic cycloalkyl includes fused-ring cycloalkyl, bridged-ring cycloalkyl, spirocycloalkyl; by fused ring is meant a fused ring structure formed by two or more cyclic structures sharing two adjacent ring atoms with each other (i.e., sharing a bond). The bridged ring refers to a condensed ring structure formed by two or more ring-mounted structures sharing two non-adjacent ring atoms with each other. The spiro ring refers to a condensed ring structure formed by two or more cyclic structures sharing one ring atom with each other. For example, the C 3-20 cycloalkyl group may be a C 3-8 monocyclic cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or a C 7-12 bicyclic cycloalkyl group, such as decalin ring; c 7-12 bridged cycloalkyl radicals, such as norbornane, adamantane, bicyclo [2, 2] octane, are also possible.
The term "3-20 membered heterocyclyl" means a saturated or unsaturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1 to 5 heteroatoms independently selected from N, O and S, preferably a "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated or unsaturated monovalent monocyclic or bicyclic hydrocarbon ring comprising 1 to 5, preferably 1 to 3 heteroatoms selected from N, O and S. The heterocyclic group may be attached to the remainder of the molecule through any one of the carbon or nitrogen atoms, if present. In particular, the heterocyclic groups may include, but are not limited to: 4-membered rings such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6 membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring such as diazepinyl, diazepinyl. Optionally, the heterocyclyl may be a fused ring, bridged ring or spiro ring. The heterocyclic group may be bicyclic, such as, but not limited to, hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl. The nitrogen atom-containing ring 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-dihydro-oxazolyl or 4H- [1,4] thiazinyl, 5H,6H,8H- [1,2,4] triazolo [4,3-a ] pyrazinyl, or it may be benzo-fused, such as, but not limited to, dihydro-isoquinolinyl, 1, 3-benzoxazolyl, 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 mono-, bi-or tricyclic hydrocarbon ring ("C 6-14 aryl") having a monovalent aromatic or partially aromatic nature of 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, in particular a ring having 6 carbon atoms ("C 6 aryl"), for example phenyl; or biphenyl, or a ring having 9 carbon atoms ("C 9 aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl"), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl"), such as anthracenyl. When the C 6-20 aryl group is substituted, it may be mono-substituted or poly-substituted. The substitution site is not limited, and may be, for example, ortho, para or meta substitution.
The term "5-20 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: it has 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, in addition, can be benzo-fused in each case. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and their benzo derivatives, such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and their benzo derivatives, such as quinolinyl, quinazolinyl, isoquinolinyl, and the like; or an axcinyl group, an indolizinyl group, a purinyl group, etc., and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.
The definition of the term "C 1-12 alkyl" above applies to other C 1-12 alkyl-containing groups as well, such as C 1-12 alkoxy and the like.
Similarly, C 6-20 aryl, 5-20 membered heteroaryl, C 3-20 cycloalkyl have the same definition throughout.
Detailed Description
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
Example 1: preparation of 8- (2-chlorophenyl) -9- { 3-fluoro-bicyclo [1.1.1] pentan-1-yl } -2-methyl-6- (4-methylpiperazin-1-yl) purine (Compound 1)
Step 1: synthesis of Compound 6-chloro-N- { 3-fluoro-bicyclo [1.1.1] pentan-1-yl } -2-methyl-5-nitropyrimidin-4-amine (2)
To a solution of 2-methyl-4, 6-dichloro-5-nitropyrimidine (604.74 mg,2.90mmol,2.00 eq.) in isopropanol (10 mL) was added 3-fluorobicyclo [1.1.1] pentane-1-amine hydrochloride (200.00 mg,1.45mmol,1.00 eq.) and N, N-diisopropylethylamine (375.77 mg,2.90mmol,2.00 eq.) at room temperature. After the addition was completed, the system was stirred at room temperature for 1 hour. The reaction was monitored to completion, the reaction was diluted with water (1X 40 mL), extracted with ethyl acetate (2X 40 mL), the organic phases combined, backwashed with saturated brine (1X 40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 6-chloro-N- { 3-fluoro-bicyclo [1.1.1] pentan-1-yl } -2-methyl-5-nitropyrimidin-4-amine (360.40 mg, 90.93%). LCMS (ES, m/z): 272.95[ M+H ] +.
Step 2: synthesis of 6-chloro-N4- { 3-fluoro-bicyclo [1.1.1] pentan-1-yl } -2-methylpyrimidine-4, 5-diamine (3)
To a solution of 6-chloro-N- { 3-fluoro-bicyclo [1.1.1] pentan-1-yl } -2-methyl-5-nitropyrimidin-4-amine (340.00 mg,1.25mmol,1.00 eq.) in anhydrous methanol (10 mL) was added reduced iron powder (278.55 mg,5.00mmol,4.00 eq.) and glacial acetic acid (1 mL,17.45 mmol) at room temperature. After the addition was completed, the system was stirred at room temperature for 2 hours. The reaction was completely monitored for liquid quality and the reaction mixture was basified with saturated aqueous sodium bicarbonate to pH 8. The reaction mixture was diluted with water (10 mL) and then 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 resulting residue was purified by silica gel column chromatography to give 6-chloro-N4- { 3-fluoro-bicyclo [1.1.1] pent-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-fluoro-bicyclo [1.1.1] pentan-1-yl } -2-methylpurine (4)
To a solution of 6-chloro-N4- { 3-fluoro-bicyclo [1.1.1] pentan-1-yl } -2-methylpyrimidine-4, 5-diamine (260.00 mg,1.07mmol,1.00 eq.) in1, 4-dioxane (10 mL) was added o-chlorobenzaldehyde (241.35 uL,2.14mmol,2.00 eq.) and ferric trichloride (78.00 mg,0.32mmol,0.30 eq.) at room temperature under nitrogen. The reaction was warmed to 55℃and stirred overnight. The reaction was monitored to completion, the reaction solution was filtered, the filter cake was washed with dichloromethane (3X 10 mL) and the resulting residue was concentrated under reduced pressure to give crude 6-chloro-8- (2-chlorophenyl) -9- { 3-fluoro-bicyclo [1.1.1] pentan-1-yl } -2-methyl-7, 8-dihydropyridine. The crude product was dissolved in dichloromethane (6 mL) and then 2, 3-dichloro-5, 6-dicyanobenzoquinone (243.02 mg,1.07mmol,1.00 eq.) was added under ice-bath. The reaction mixture was warmed to room temperature and stirred for 2 hours. The liquid monitoring reaction is complete. The reaction was quenched with 1M sodium hydroxide solution, then diluted with water (20 mL), extracted with dichloromethane (2X 20 mL), the combined organic phases were backwashed with saturated brine (1X 30 mL), dried over anhydrous sulfuric acid, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 6-chloro-8- (2-chlorophenyl) -9- { 3-fluoro-bicyclo [1.1.1] pent-1-yl } -2-methylpurine (285.00 mg, 73.29%). LCMS (ES, m/z): 362.95[ M+H ] +.
Step 4: synthesis of Compound 8- (2-chlorophenyl) -9- { 3-fluoro-bicyclo [1.1.1] pentan-1-yl } -2-methyl-6- (4-methylpiperazin-1-yl) purine (Compound 1)
To a solution of 6-chloro-8- (2-chlorophenyl) -9- { 3-fluoro-bicyclo [1.1.1] pentan-1-yl } -2-methylpurine (100.00 mg,0.28mmol,1.00 eq.) in 1, 4-dioxane (5 mL) was added N-methylpiperazine (30.54 uL,0.28mmol,1.00 eq.) and N, N-diisopropylethylamine (143.87 uL,0.84mmol,3.00 eq.) at room temperature. The reaction mixture was heated to 100℃and stirred for 1 hour. The reaction was monitored to completion by liquid chromatography, the reaction was cooled to room temperature, diluted with water (1×20 ml), extracted with ethyl acetate (2×30 ml), the organic phases combined, backwashed with saturated brine (1×40 ml), dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure and the crude product purified by preparative HPLC using the following conditions: the specification of the chromatographic Column is XBridge Prep OBD C Column,30x150mm and 5 μm; mobile phase A is water (10 mmol/L ammonium bicarbonate), mobile phase B is acetonitrile flow rate 60mL/min; elution gradient 45% b to 70% b,8 min); the detection wavelength is UV 254nm/220nm. To obtain the compound 8- (2-chlorophenyl) -9- { 3-fluoro-bicyclo [1.1.1] pentane-1-yl } -2-methyl-6- (4-methylpiperazin-1-yl) purine (25.80mg,21.84％).1H NMR(400MHz,DMSO-d6)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 similar conditions as in example 1, the compounds in table 1 below were prepared. The structural characterization data for these compounds are also shown in table 1.
TABLE 1
Example 2: preparation of 8- (2-chlorophenyl) -2-cyclopropyl-9- { 3-fluoro-bicyclo [1.1.1] pentan-1-yl } -6- (4-methylpiperazin-1-yl) purine (Compound 61)
Step 1-4: synthesis of Compound 2-chloro-8- (2-chlorophenyl) -9- { 3-fluoro-bicyclo [1.1.1] pentan-1-yl } -6- (4-methylpiperazin-1-yl) purine (8)
Using a method similar to example 1 (starting material was changed to 2,4, 6-trichloro-5-nitropyrimidine and 3-fluoro-bicyclo [1.1.1] pentane-1-amine hydrochloride), the compound 2-chloro-8- (2-chlorophenyl) -9- { 3-fluoro-bicyclo [1.1.1] pentane-1-yl } -6- (4-methylpiperazin-1-yl) purine (1.20 g, 89.49%). LCMS (ES, m/z): 447.30[ M+H ] +.
Step 5: synthesis of Compound 8- (2-chlorophenyl) -2-cyclopropyl-9- { 3-fluoro-bicyclo [1.1.1] pentan-1-yl } -6- (4-methylpiperazin-1-yl) purine (Compound 61)
To a solution of 2-chloro-8- (2-chlorophenyl) -9- { 3-fluoro-bicyclo [1.1.1] pentan-1-yl } -6- (4-methylpiperazin-1-yl) purine (500.00 mg,1.12mmol,1.00 eq.) in 1, 4-dioxane (10 mL) was added 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (53.28 mg,0.11mmol,0.10 eq.) 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,0.11mmol,0.10 eq.) at room temperature followed by dropwise addition of a solution of zinc cyclopropylbromide in 0.5M tetrahydrofuran (6.70 mL,3.36mmol,3.00 eq.). The temperature was raised to 100℃and the reaction was stirred for 1 hour. The liquid monitoring reaction is complete. The reaction was cooled to room temperature, filtered, the filter cake washed with dichloromethane (3 x 10 ml) and the filtrate concentrated under reduced pressure. Dilute with water (100 mL) and extract with dichloromethane (3 x 100 mL). The organic phases were combined, backwashed with saturated sodium chloride solution (1 x 100 ml), 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: the chromatographic Column specification is XBridge Prep OBD C Column,30 x 150mm,5 μm; mobile phase A is water (10 mmol/L ammonium bicarbonate), mobile phase B is acetonitrile; the flow rate is 60mL/min; elution gradient 45% b to 90% b, 90% b over 8 min; the detection wavelength is UV 254nm/220nm; retention time (min): 7.7. To obtain the compound 8- (2-chlorophenyl) -2-cyclopropyl-9- { 3-fluoro-bicyclo [1.1.1] pentane-1-yl } -6- (4-methylpiperazine-1-yl) purine (143.00mg,28.02％).1H NMR(400MHz,DMSO-d6)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: preparation of 1- (1- { bicyclo [1.1.1] pentan-1-yl } -2- (2-chlorophenyl) -6-methylimidazo [4,5-c ] pyridin-4-yl) -4-methylpiperazine (compound 62)
Using a method similar to example 1 (starting material replaced with 2, 4-dichloro-6-methyl-3-nitropyridine and bicyclo [1.1.1] pentachlorobenzene-1-amine), compound 1- (1- { bicyclo [1.1.1] pentan-1-yl } -2- (2-chlorophenyl) -6-methylimidazo [4,5-c ] pyridin-4-yl) -4-methylpiperazine (26.50 mg, 22.23%) was obtained. 1 H NMR (400 MHz, 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 similar conditions as in example 3, the compounds in table 2 below were prepared. The structural characterization data for these compounds are also shown in table 2.
TABLE 2
Example 4: preparation of 1- (3- { bicyclo [1.1.1] pentan-1-yl } -2- (2-chlorophenyl) -5-methylimidazo [4,5-b ] pyridin-7-yl) -4-methylpiperazine (compound 65)
Step 1: synthesis of Compound 1- (2-chloro-6-methyl-3-nitropyridin-4-yl) -4-methylpiperazine (14)
By a method similar to step four of example 1 (starting material was changed to 2, 4-dichloro-6-methyl-3-nitropyridin) compound 1- (2-chloro-6-methyl-3-nitropyridin-4-yl) -4-methylpiperazine (700.00 mg, 53.53%). LCMS (ES, m/z): 271.00[ M+H ] +.
The next three steps were carried out in a similar manner to the steps one, two and three of example 1 (starting material was changed to 1- (2-chloro-6-methyl-3-nitropyridin-4-yl) -4-methylpiperazine and bicyclo [1.1.1] pentachlorobenzene-1-amine) to give the 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 (400 MHz, 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 assay
The affinity of the compounds of the invention for the human CB2 receptor was tested using a radioisotope labelled ligand receptor binding assay. mu.L of assay buffer (25mM Hepes,10mM MgCl 2,1mM CaCl2, 0.5% BSA, pH 7.4) was added to the 96-well deep-well assay plate, followed by 5. Mu.L of 100 Xcompound to the corresponding well and shaking at 600rpm for 5 min. Add 300. Mu.L of a mixture of CHO-CB2 cell membrane and assay buffer (0.2. Mu.L of membrane and 299.8. Mu.L of assay buffer) to each well and shake at 600rpm for 5 min. 100. Mu.L of 5X isotope [ 3 H ] -CP 55940 was added to each well, centrifuged at 1000rpm for 1min, and mixed well by shaking at 600rpm for 5min, and the plates were incubated at 30℃for 1.5 hours. The UNIFILTER-96GF/C plates, to which 0.5% PEI solution was added and incubated at 4℃for 1 hour, were washed 2 times with 50mL of wash solution (50 mM Tris-HCl,2.5mM EDTA,5mM MgCl 2, 0.5mg/mL BSA, pH 7.4). The reaction system in the 96-well deep-well assay plate was transferred to UNIFILTER-96GF/C plate and washed 4 times with wash solution, 900. Mu.L of wash solution per well. The washed UNIFILTER-96GF/C plate was placed in an oven at 55℃and dried for 10 minutes. 40. Mu.L of ULTIMA GOLD scintillation fluid was added to each well and the dried UNIFILTER-96GF/C plates and data collected using Microbeta 2. The whole reaction system was 500. Mu.L, and the final concentration of [ 3 H ] -CP 55940 was 0.5nM, and the final concentration of DMSO was 1%.
A compound dose-response curve is generated using the XLfit or GRAPHPAD PRISM software nonlinear four parameter equation and its corresponding Ki values are calculated.
The compounds of the present invention have good binding capacity to human CB2 receptor, and the binding data of some compounds are shown in table 3 below.
TABLE 3 Table 3
Test example 2 CB1 and CB2cAMP production 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 complete medium of F12K, 10% fetal bovine serum, 1% penicillin-streptomycin and 600. Mu.g/ml hygromycin at 37℃in a 5% CO 2 cell incubator. On the day of the experiment, cells were digested and resuspended in HBSS in experimental buffer containing 20mM HEPES, 0.1% bsa and 500 μm IBMX, followed by seeding into 384 well cell culture plates. The seeding density of human and mouse CB1/2 cells was 8000 cells per well, the seeding density of rat CB1/2 cells was 2000 cells per well, and the seeding volume was 15. Mu.L. The agonistic activity of the above compounds on human CB1 and CB2 receptors was then examined using a cAMP production assay.
Human CB2 agonist assay
To the above cell experiment plate, 2.5. Mu.L of 8X concentration SR144528 working solution was added, and after incubation at 37℃for 10 minutes, 2.5. Mu.L of 8X concentration mixture of compound and Forskolin was added, and incubation at 37℃for 30 minutes. After the reaction was completed, 10. Mu.L of Eu-CAMP TRACER and 10. Mu.L of Ulight-anti-cAMP detection reagent were added to the experimental plate, and after incubation at room temperature for 1 hour, data were collected using an Envision HTRF functional module. The whole reaction system was 20. Mu.L, the final DMSO concentration was 0.2%, the final Forskolin concentration was 2. Mu.M, and the final SR144528 concentration was 80nM.
A compound dose-response curve was generated using the nonlinear four-parameter equation of XLfit or GRAPHPAD PRISM software and its corresponding EC 50 was calculated.
The compounds of the present invention show good human CB2 agonistic activity, and the human CB2 agonistic activity of a part of the compounds is shown in table 4 below.
TABLE 4 Table 4
Human CB1 agonist assay
To the above cell assay plate, 2.5. Mu.L of 8X concentration compound working solution was added, and after incubation at 37℃for 10 minutes, 2.5. Mu.L of 8X concentration Forskolin solution was added, and incubation at 37℃for 30 minutes. After the reaction was completed, 10. Mu.L of Eu-CAMP TRACER and 10. Mu.L of Ulight-anti-cAMP detection reagent were added to the experimental plate, and after incubation at room temperature for 1 hour, data were collected using an Envision HTRF functional module. The whole reaction system was 20. Mu.L, the final DMSO concentration was 0.2% and the final Forskolin concentration was 1. Mu.M.
A compound dose-response curve was generated using the nonlinear four-parameter equation of XLfit or GRAPHPAD PRISM software and its corresponding EC 50 was calculated.
The compounds of the present invention show good selectivity for human CB1 agonism, and the agonism activity of some of the compounds human CB1 is shown in table 5 below.
TABLE 5
As a control, test results as in table 6 were obtained using the following compounds.
TABLE 6
By comparing the human CB2 ligand binding activity and the human CB2 agonistic activity data of the compound of the present invention with those of the control compound LY-2828360, it is known that the compound of the present invention has better biological activity for CB2 receptor, and at the same time, the compound of the present invention has good selectivity for CB2 receptor.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (16)

  1. A compound of formula (I), racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts or prodrugs thereof,
    Wherein a 1 is selected from the following groups, unsubstituted or optionally substituted with one, two or more Ra: 3-20 membered heterocyclyl, 5-20 membered heteroaryl and 3-20 membered heterocyclyl;
    Ra is selected from C 1-12 alkyl, C 1-12 alkoxy, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, OH, HO-C 1-12 alkyl, CN, -C (O) C 1-12 alkyl, -S (O) 2C1-12 alkyl, -S (=o) C 1-12 alkyl, -S (C 1-12 alkyl) 2、-C(O)NHC1-12 alkyl, -C (O) N (C 1-12 alkyl) 2、-C(O)NH2、-N(C1-12 alkyl) 2, =o;
    x 1、X2、X3、X4、X5、X6, which are identical or different, are C, CH, or N independently of one another, with the proviso that X 3、X4、X5 is not simultaneously N, or X 4、X5、X6 is not simultaneously N;
    R 1 is selected from halogen, C 1-12 alkyl, C 1-12 alkoxy, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, and C 3-20 cycloalkyl;
    A 2 is selected from C 6-20 aryl or 5-20 membered heteroaryl, unsubstituted or optionally substituted with 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, nitro;
    A 3 is selected from C 3-20 cycloalkyl or 3-20 membered heterocyclyl, unsubstituted or optionally substituted with one, two or more Rc;
    Rc is selected from halogen, C 1-12 alkyl, halogenated C 1-12 alkyl, NH 2、-NHC(O)C1-12 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 of formula I, racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt or prodrug thereof of claim 1,
    A 1 is selected from the following groups, unsubstituted or optionally substituted with one, two or more Ra: 3-12 membered heterocyclyl, 5-12 membered heteroaryl and 3-12 membered heterocyclyl;
    Ra is selected from C 1-6 alkyl, halo C 1-6 alkyl, HO-C 1-6 alkyl, CN, -C (O) C 1-6 alkyl, -S (O) 2C1-6 alkyl, -C (O) NHC 1-6 alkyl, -C (O) NH 2、-N(C1-6 alkyl) 2, =o;
    R 1 is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, and C 3-12 cycloalkyl;
    A 2 is selected from C 6-12 aryl or 5-12 membered heteroaryl, unsubstituted or optionally substituted with 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, unsubstituted or optionally substituted with 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)C1-6 alkyl, -NHC 1-6 alkyl, CN, -COOC 1-6 alkyl, HO-C 1-6 alkyl, OH, C 1-6 alkoxy.
  3. A compound of formula i, a racemate, a stereoisomer, a tautomer, an isotopic label, a solvate, a polymorph, a pharmaceutically acceptable salt or a prodrug thereof, according to claim 1 or 2, wherein formula i is selected from the following structures:
  4. A compound of formula i, as claimed in any one of claims 1 to 3, racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt or prodrug thereof, wherein a 1 is selected from the following groups, unsubstituted or optionally substituted by one, two or more Ra: 3-12 membered N-containing heterocyclyl, 5-12 membered N-containing heteroaryl and 3-12 membered N-containing heterocyclyl;
    Preferably, a 1 is selected from the following groups, unsubstituted or optionally substituted with one, two or more Ra: piperazinyl, piperidinyl, hexahydropyrazino [2,1-c ] [1,4] oxazin-8 (1H) -yl, 1, 4-diazepinyl, 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 azetidinyl.
  5. A compound of formula i, as defined in any one of claims 1 to 4, racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt or prodrug thereof, wherein Ra is selected from methyl, ethyl, isopropyl, 2-difluoroethyl, 2-trifluoroethyl, 2-hydroxyethyl, CN, acetyl, methanesulfonyl, methylaminocarbonyl, dimethylamino, carbamoyl or oxo.
  6. A compound of formula i, racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts or prodrugs thereof according to any one of claims 1 to 5, wherein a 1 is selected from 4-methylpiperazinyl, 4-ethylpiperazinyl, 4- (2, 2-trifluoroethyl) piperazinyl, 4-hydroxyethylpiperazinyl, 3-cyano-4-methylpiperazinyl, 4-isopropylpiperazinyl, 4-acetylpiperazinyl, 4-methanesulfonylpiperazinyl, 4-methylcarbamoyl piperazinyl, 4- (2, 2-difluoroethyl) piperazinyl,4-Methanesulfonyl group piperidinyl group,4-Carbamoyl piperazinyl,
  7. A compound of formula i, as defined in any one of claims 1 to 6, racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt or prodrug thereof, wherein R 1 is selected from methyl, trifluoromethyl, cyclopropyl.
  8. A compound of formula i, a racemate, a stereoisomer, a tautomer, an isotopic label, a solvate, a polymorph, a pharmaceutically acceptable salt or a prodrug thereof according to any one of claims 1 to 7, wherein a 2 is selected from phenyl or pyridinyl, optionally substituted by one, two or more Rb.
  9. A compound of formula i, racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt or prodrug thereof according to any one of claims 1 to 8, wherein Rb is the following group: F. cl, CF 3, CN, methoxy, methyl, OH.
  10. A compound of formula i, a racemate, a stereoisomer, a tautomer, an isotopic label, a solvate, a polymorph, a pharmaceutically acceptable salt or a prodrug thereof according to any one of claims 1 to 9, wherein a 3 is selected from the following groups, unsubstituted or optionally substituted with one, two or more Rc:
  11. A compound of formula i, a racemate, a stereoisomer, a tautomer, an isotopic label, a solvate, a polymorph, a pharmaceutically acceptable salt or a prodrug thereof according to any one of claims 1 to 10, wherein Rc is the following group: F. methyl, trifluoromethyl, NH 2, carbamoyl, acetamido, methylamino, CN, hydroxymethyl, hydroxyethyl, methyl ester, OH.
  12. A compound of formula I, a racemate, a stereoisomer, a tautomer, an isotopic label, a solvate, a polymorph, a pharmaceutically acceptable salt or a prodrug thereof, according to any one of claims 1 to 10, wherein the compound of formula I has a structure selected from the group consisting of I-8, I-9 or I-10:
    Wherein L 1 and L 2 are independently of each other-CH 2-、-CH2-CH2 -or-CH 2 -O-; preferably, L 1 is-CH 2 -and L 2 is-CH 2 -O-.
  13. A compound of formula i according to any one of claims 1 to 10 having a structure selected from the group consisting of:
  14. A pharmaceutical composition comprising at least one of a compound of formula i, a racemate, a stereoisomer, a tautomer, an isotopic label, a solvate, a polymorph, a pharmaceutically acceptable salt or a prodrug thereof, according to any one of claims 1 to 13;
    preferably, the pharmaceutical composition further comprises one, two or more pharmaceutically acceptable excipients.
  15. The pharmaceutical composition according to claim 14, for use in the prevention or treatment of a cannabinoid receptor mediated disease or disorder, preferably a cannabinoid receptor 2 (CB 2) mediated disease or disorder;
    preferably, the cannabinoid receptor mediated disease or disorder is selected from: lupus Erythematosus (SLE), diffuse skin thickening, autoimmune diseases, colitis, inflammatory bowel disease, allergic dermatitis, pain, and/or arthritis.
  16. Use of a compound of formula i, a racemate, a stereoisomer, a tautomer, an isotopic label, a solvate, a polymorph, a pharmaceutically acceptable salt or a prodrug thereof, according to any one of claims 1 to 13, or a pharmaceutical composition according to claim 14 or 15, for the manufacture of a medicament for the treatment or prophylaxis of a cannabinoid receptor mediated disease or condition.
CN202380030151.9A 2022-07-21 2023-07-18 Substituted condensed ring cannabinoid receptor compounds and their applications Pending CN118946565A (en)

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