Cyclopentyl adenosine derivative and pharmaceutical application thereof

Abstract

The invention relates to a cyclopentyl adenosine derivative and a pharmaceutical application thereof. Specifically, the present disclosure provides a compound represented by formula (I) or a pharmaceutical salt thereof, in which R1-R8 are as defined in the specification. # imgabs0 #

Description

A cyclopentyl adenosine derivative and its pharmaceutical use Technical Field

[0001] The present invention belongs to the field of medicine and relates to a cyclopentyl adenosine derivative and its pharmaceutical use. Background Art

[0002] Chronic pain can be divided into nociceptive pain (somatic and visceral) and non-nociceptive pain (neurological and psychiatric) according to physiological mechanisms. Clinical manifestations include tissue damage pain and neurogenic pain. Adenosine is a precursor and metabolite of adenine nucleotides, including A l , A2A, A2B and A3 receptors, of which A l Receptors play a major role in the process of pain transmission. They regulate the transmembrane flow of intracellular cations by activating G protein-coupled receptors (GPCRs), affecting the excitability of neurons and the release of neurotransmitters, and exerting analgesic and anti-inflammatory effects.

[0003] Patent US6110902A discloses adenosine A l The relevant implications of the receptor agonist CCPA (2-chloro-N-cyclopentyl adenosine) for the treatment of chronic pain. l Adenosine A receptor agonists have shown good clinical effects, but their cardiovascular side effects and narrow therapeutic window limit their application. Therefore, it is necessary to develop a drug with a larger therapeutic window and a lower risk of cardiovascular disease. l Receptor agonists are a technical problem that needs to be solved urgently.

[0004] Summary of the Invention

[0005] The present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0006] in,

[0007] R 1 、R 2 、R 3 the same or different, each independently selected from hydrogen, -(CO)-C 1～20 Alkyl, -(CO)-C 1～20 Alkoxy, -(CO)-5-6 membered cycloalkyl, -(CO)-5-6 membered heterocyclic group, -(CO)-6 membered aryl, -(CO)-5-6 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally substituted by one or more selected from halogen, hydroxyl, oxo, amino, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent,

[0008] Y is selected from alkylene or heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted by one or more groups selected from halogen, hydroxy, oxo, amino, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent,

[0009] R a 、R b 、R c The same or different, each independently C 1-6 alkyl,

[0010] And, R 1 、R 2 、R 3 It cannot be hydrogen at the same time;

[0011] R 4 Selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the alkyl, alkoxy is optionally substituted by one or more selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0012] R 5 、R 6 、R 7 、R 8 The same or different, each independently selected from hydrogen, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the alkyl, alkoxy is optionally substituted by one or more selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0013] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8.

[0014] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present disclosure, wherein R 2 、R 3 All are hydrogen.

[0015] In some embodiments, the compound or pharmaceutically acceptable salt thereof described in the present disclosure, wherein the compound or pharmaceutically acceptable salt thereof described in formula (I) is a compound or pharmaceutically acceptable salt thereof represented by formula (I-1)

[0016] where R 1 、R 4 、R 5 、R6 、R 7 、R 8 and n are as defined in formula (I).

[0017] In some embodiments, the compound of formula (I) or formula (I-1) or a pharmaceutically acceptable salt thereof according to the present disclosure, wherein R 4 is halogen, preferably fluorine, chlorine, bromine, most preferably chlorine.

[0018] In some embodiments, the compound or pharmaceutically acceptable salt thereof described in the present disclosure, wherein the compound or pharmaceutically acceptable salt thereof described in formula (I) is a compound or pharmaceutically acceptable salt thereof represented by formula (I-2)

[0019] where R 1 、R 5 、R 6 、R 7 、R 8 and n are as defined in formula (I).

[0020] In some embodiments, the compound of formula (I), formula (I-1) or formula (I-2) or a pharmaceutically acceptable salt thereof, wherein R 5 For hydrogen.

[0021] In some embodiments, the compound of formula (I), formula (I-1) or formula (I-2) or a pharmaceutically acceptable salt thereof, wherein R 6 For hydrogen.

[0022] In some embodiments, the compound or pharmaceutically acceptable salt thereof disclosed herein, wherein the compound or pharmaceutically acceptable salt thereof of formula (I) is a compound or pharmaceutically acceptable salt thereof represented by formula (I-3)

[0023] where R 1 、R 7 、R 8 As defined in formula (I).

[0024] In some embodiments, the compounds of formula (I), formula (I-1), formula (I-2) or formula (I-3) or pharmaceutically acceptable salts thereof, wherein R 7 、R 8 All are hydrogen.

[0025] In some embodiments, the compound or pharmaceutically acceptable salt thereof described in the present disclosure, wherein the compound or pharmaceutically acceptable salt thereof described in formula (I) is a compound or pharmaceutically acceptable salt thereof represented by formula (I-4)

[0026] where R 1As defined in formula (I).

[0027] In some embodiments, the compounds of formula (I), formula (I-1), formula (I-2), formula (I-3) or formula (I-4) or pharmaceutically acceptable salts thereof, wherein R 1 Selected from -(CO)-C 1-5 Alkyl, -(CO)-C 10-20 alkyl, -(CO)-5- to 6-membered cycloalkyl, -(CO)-5- to 6-membered heterocyclic group, -(CO)-phenyl, -(CO)-5- to 6-membered heteroaryl,

[0028] Y is C 1-6 Alkylene,

[0029] R a 、R b 、R c The same or different, each independently C 1-6 alkyl

[0030] The alkylene, alkyl, cycloalkyl, heterocyclic, phenyl, heteroaryl are optionally substituted by one or more selected from halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted by a substituent, and the substituent is preferably fluorine, chlorine, bromine, hydroxyl, amino, oxo, or methyl.

[0031] In some embodiments, the compounds of formula (I), formula (I-1), formula (I-2), formula (I-3) or formula (I-4) or pharmaceutically acceptable salts thereof, wherein R 1 Selected from -(CO)-methyl, -(CO)-ethyl, -(CO)-propyl, -(CO)-butyl, -(CO)-pentyl, -(CO)-C 14 Alkyl, -(CO)-phenyl, -(CO)-cyclopropane, -(CO)-cyclobutane, -(CO)-cyclopentane, -(CO)-cyclohexane, -(CO)-pyrrolidine, -(CO)-piperidine, -(CO)-piperazine, -(CO)-morpholine, -(CO)-thiomorpholine, -(CO)-pyrrole, -(CO)-furan, -(CO)-thiophene, -(CO)-pyridine, -(CO)-thiazole, -(CO)-oxazole, -(CO)-imidazole, -(CO)-triazole, -(CO)-tetrazole,

[0032] The R 1 Optionally, one or more selected from halogen, hydroxy, amino, cyano, oxo, C 1-6 Alkyl, C 1-6The alkoxy group is substituted by a substituent, and the substituent is preferably fluorine, chlorine, bromine, hydroxyl, amino, oxo, or methyl.

[0033] In some embodiments, the compounds of formula (I), formula (I-1), formula (I-2), formula (I-3) or formula (I-4) or pharmaceutically acceptable salts thereof, wherein R 1 Selected from -(CO)-C 10 Alkyl, -(CO)-C 11 Alkyl, -(CO)-C 12 Alkyl, -(CO)-C 13 Alkyl, -(CO)-C 14 Alkyl, -(CO)-C 15 Alkyl, -(CO)-C 16 Alkyl, -(CO)-C 17 Alkyl, -(CO)-C 18 Alkyl, further, the R 1 Optionally, one or more selected from halogen, hydroxy, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted by a substituent, and the substituent is preferably fluorine, chlorine, bromine, hydroxyl, amino, oxo, or methyl.

[0034] In some embodiments, the compounds of formula (I), formula (I-1), formula (I-2), formula (I-3) or formula (I-4) or pharmaceutically acceptable salts thereof, wherein R 1 Selected from -(CO)-C 12 Alkyl, -(CO)-C 13 Alkyl, -(CO)-C 14 Alkyl, -(CO)-C 15 Alkyl, -(CO)-C 16 Alkyl, further, the R 1 Optionally, one or more selected from halogen, hydroxy, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted by a substituent, and the substituent is preferably fluorine, chlorine, bromine, hydroxyl, amino, oxo, or methyl.

[0035] In some embodiments, specific compounds of the present disclosure include, but are not limited to,

[0036] Table A

[0037] The present disclosure also provides isotopic substitutions of the aforementioned compounds or pharmaceutically acceptable salts thereof. In some embodiments, the isotopic substitutions are deuterated.

[0038] The present disclosure also provides a pharmaceutical composition comprising at least one therapeutically effective amount of the compound shown in the aforementioned formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-4) and Table A, or a pharmaceutically acceptable salt thereof, or an isotope substitute thereof, and a pharmaceutically acceptable excipient.

[0039] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0040] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.

[0041] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.

[0042] The compounds provided by the present disclosure, or their pharmaceutically acceptable salts or isotopic substitutes, or the aforementioned pharmaceutical compositions, can be used to improve all forms of acute and chronic pain, especially cancer-induced pain, neurogenic pain, postoperative pain, neuropathic pain, and neuralgia.

[0043] The compounds provided by the present disclosure, or their pharmaceutically acceptable salts, or their isotopic substitutes, or the aforementioned pharmaceutical compositions, can also be used to treat specific pain syndromes, including pain associated with soft tissue diseases and peripheral injuries (e.g., acute trauma, osteoarthritis, rheumatoid arthritis, burns, episiotomy), spinal pain, musculoskeletal pain, upper limb pain, limb pain, myofascial pain syndrome, headache, deep and visceral pain syndrome (e.g., cardiac pain, muscle pain, eye pain, oral and facial pain, abdominal pain, gynecological pain, and labor pain), pain associated with nerve and root damage (e.g., peripheral nerve disease or infection, pain caused by amputation, peripheral neuropathy, tics and atypical facial pain, arachnoiditis), cancer pain (especially pain involving bone and soft tissue cancer and metastasis), and central nervous system pain (e.g., central pain caused by spinal cord or brainstem injury).

[0044] The present disclosure also provides a method for treating or preventing chronic pain, which comprises administering to the patient a therapeutically effective amount of a compound as shown in the aforementioned formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-4) or Table A, or a pharmaceutically acceptable salt or isotope thereof, or the aforementioned pharmaceutical composition.

[0045] The present disclosure also provides the use of the compounds of the aforementioned formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-4) or Table A, or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions in the preparation of medicaments for treating or preventing chronic pain. In some embodiments, chronic pain includes, but is not limited to, tissue injury pain, neurogenic pain, headache, migraine, tension headache, cluster headache, chronic tension-type headache, inflammatory pain, neck and shoulder pain, low back and leg pain, neuropathic pain, eye pain, and toothache.

[0046] The pharmaceutically acceptable salts of the compounds described in the present disclosure may be selected from inorganic salts or organic salts.

[0047] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0048] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0049] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or or include both and Two configurations.

[0050] In the chemical structures of the compounds disclosed herein, the bond The configuration is not specified, that is, it can be Z configuration or E configuration, or contain both configurations.

[0051] In addition, the compounds and intermediates of the present disclosure can also exist in different tautomeric forms, and all such forms are included in the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. An example of a lactam-lactim equilibrium is between A and B as shown below.

[0052] All compounds in this disclosure can be drawn as either Form A or Form B. All tautomeric forms are within the scope of this disclosure. The naming of the compounds does not exclude any tautomers.

[0053] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H.3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0054] Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have at least 1000 times the abundance of deuterium greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). In the example, the compound has a natural abundance greater than deuterium that can be at least 1000 times the abundance of deuterium, at least 2000 times the abundance of deuterium, at least 3000 times the abundance of deuterium, at least 4000 times the abundance of deuterium, at least 5000 times the abundance of deuterium, at least 6000 times the abundance of deuterium or more abundant deuterium. The disclosure also includes various deuterated forms of formula (I) compounds. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of formula (I) compounds with reference to relevant literature. Commercially available deuterated starting materials may be used in the preparation of deuterated forms of the compounds of formula (I), or they may be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0055] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally substituted C 1-6 The term "alkyl" means that halogen or cyano may but need not be present, and the description includes both the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano.

[0056] Terminology

[0057] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0058] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched chain isomers thereof. Alkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, oxo, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclyl, 6 to 10 membered aryl or 5 to 10 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 Alkoxy substituted.

[0059] The term "cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls. Cycloalkyls may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, oxo, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclyl, 6 to 10 membered aryl or 5 to 10 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 Alkoxy substituted.

[0060] The term "heterocyclyl" or "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, wherein the sulfur may be optionally oxoed (i.e., forming a sulfoxide or sulfone), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3 and 4) are heteroatoms; more preferably, it contains 3 to 8 (e.g., 3, 4, 5, 6, 7 and 8) ring atoms, of which 1 to 3 (e.g., 1, 2 and 3) are heteroatoms; more preferably, it contains 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; and most preferably, it contains 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, N-alkylpiperidinyl, morpholinyl, thiomorpholinyl, etc. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

[0061] The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclyl, 6 to 10 membered aryl or 5 to 10 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 Alkoxy substituted.

[0062] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring which shares adjacent pairs of carbon atoms) group having a conjugated pi electron system, preferably 6- to 10-membered, such as phenyl and naphthyl.

[0063] Aryl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is substituted by one or more selected from halogen, hydroxyl, amino, C 1-6 Alkyl or C 1-6 Alkoxy substitution.

[0064] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5-membered or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, imidazolyl, triazolyl, tetrazolyl, and the like.

[0065] Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is substituted by one or more selected from halogen, hydroxyl, amino, C 1-6 Alkyl or C 1-6 Alkoxy substitution.

[0066] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is substituted by one or more selected from halogen, hydroxyl, amino, C 1-6 Alkyl or C 1-6 Alkoxy substitution.

[0067] The term "alkylene" refers to the portion remaining after removing two hydrogen atoms from an alkane molecule, including straight and branched chain subgroups having 1 to 20 carbon atoms. Non-limiting examples of alkylene groups having 1 to 6 carbon atoms include methylene (-CH2-) and ethylene (e.g., -CH2CH2- or -CH(CH3)-). Unless otherwise specified, alkylene groups may be substituted or unsubstituted.

[0068] The term "heteroalkylene" refers to an alkylene group in which one or more -CH2- groups are replaced by a heteroatom selected from N, O and S; wherein the alkylene group is as defined above; the heteroalkylene group may be substituted or unsubstituted. The term "hydroxy" refers to an -OH group.

[0069] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0070] The term "cyano" refers to -CN.

[0071] The term "amino" refers to -NH2.

[0072] The term "nitro" refers to -NO2.

[0073] The term "oxo" refers to a =0 substituent.

[0074] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) whether substitution is possible or not without undue effort.

[0075] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0076] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or domestic animals.

[0077] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0078] As used herein, an "effective amount" or "therapeutically effective amount" encompasses an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also refers to an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[0079] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active agent. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0080] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0081] The compounds disclosed herein can be prepared according to the following general reaction scheme or similar methods. However, the process conditions, such as reactants, solvents, bases, amounts of the compounds used, reaction temperature, reaction time, etc., are not limited to those described in the prior art. The compounds disclosed herein can also be conveniently prepared by optionally combining various synthetic methods described herein or known in the art, and such combinations are readily available to those skilled in the art. DETAILED DESCRIPTION

[0082] The present disclosure is further described below with reference to examples, but these examples are not intended to limit the scope of the present disclosure.

[0083] Experimental methods in the examples of this disclosure that do not specify specific conditions are generally based on conventional conditions or the conditions recommended by the raw material or product manufacturers. Reagents without specific sources are conventional reagents purchased from the market.

[0084] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (Methanol-d4). The internal standard was tetramethylsilane (TMS).

[0085] HPLC determination used Agilent1100 high pressure liquid chromatograph, GAS15B DAD UV detector, Water Vbridge C18 150*4.6mm 5um chromatographic column.

[0086] MS was determined using an Agilent 6120 triple quadrupole mass spectrometer, a G1315D DAD detector, and a Waters Xbridge C18 4.6*50mm, 5um column. The samples were scanned in positive / negative ion mode with a mass scan range of 80-1200.

[0087] The thin layer chromatography silica gel plate used was Yantai Huanghai HSGF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) was 0.2 mm ± 0.03 mm. The specification used for thin layer chromatography separation and purification products was 0.4 mm - 0.5 mm.

[0088] The flash column purification system used was Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).

[0089] Forward column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh or 300-400 mesh silica gel as the carrier, or uses Changzhou Santai pre-packed ultra-pure normal phase silica gel column (40-63μm, 60g, 24g, 40g, 120g or other specifications).

[0090] The known starting materials in the present disclosure can be synthesized by methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Bid Pharmaceuticals, etc.

[0091] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0092] Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a capacity of about 1L.

[0093] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0094] Hydrogen was produced by a QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instrument Co., Ltd.

[0095] The nitrogen atmosphere or hydrogen atmosphere is usually evacuated and filled with nitrogen or hydrogen, and the operation is repeated three times.

[0096] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0097] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0098] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the column chromatography eluent system used to purify the compound, and the developing solvent system for thin layer chromatography, the volume ratio of the solvent were adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could be added for adjustment.

[0099] Example

[0100] Example 1 Methyl ((2R,3S,4R,5R)-5-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)pentadecanoate (Compound 1)

[0101] Step 1) Preparation of (2R,3R,4S,5R)-2-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (1-c)

[0102] 1-a (6.0 g, 13.4 mmol), ethanol (40 mL), 1-b (1.370 g, 16.1 mmol), and TEA (2.2 mL, 16.1 mmol) were added to a 250 mL three-necked flask in sequence, and stirring was started. The atmosphere was replaced with nitrogen three times. The system was heated to reflux (internal temperature 70 ° C) for 2 hours. After the reaction of the raw materials was completed, the reaction was stopped, the internal temperature was cooled to 20 ° C, and the oil was concentrated under reduced pressure to obtain an oil. Methanol (120 mL) and potassium carbonate were added in sequence. (12.9 g, 93.4 mmol), stirred at room temperature for 3 h; the reaction was stopped, and the mixture was concentrated under reduced pressure to obtain an oil. Water (50 mL), saturated ammonium chloride (150 mL), and dichloromethane were added in sequence, and extracted three times with 60 mL each time. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate (5 g), filtered, and concentrated to obtain an oil. Column chromatography (MeOH / DCM = 0-10%) gave a yellow solid (4.750 g), yield: 95.9%.

[0103] MS-ESI:370.1[M+H] + .

[0104] 1 H NMR (400MHz, CD3OD) δ8.22(s,1H),5.89(d,J=6.0Hz,1H),4.66(t,J=5.2Hz,1H),4.53-4.49(m,1H),4.31(t,J=3.2Hz,1H),4.15-4.13( m,1H),3.88(dd,J=12.4Hz,J=2.4Hz,1H),4.74(dd,J=12.4Hz,J=4.0Hz,1H),2.11-2.05(m,2H),1.82-1.76(m,2H),1.73-1.58(m,4H).

[0105] Step 2) Preparation of ((3aR,4R,6R,6aR)-6-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]diol-4-yl)methanol (1-d)

[0106] To a 100 mL three-necked flask, 1-c (4.0 g, 10.8 mmol), acetone (40 mL), 2,2-dimethoxypropane (5.637 g, 54.2 mmol), and PTSA (0.372 g, 2.16 mmol) were added sequentially. The atmosphere was replaced with nitrogen three times. The mixture was heated under reflux for 1 h. Upon completion of the reaction, heating was discontinued and the reaction mixture was cooled to room temperature (20°C). The reaction mixture was concentrated under reduced pressure to obtain an oil. Dichloromethane (150 mL) was added and the mixture was washed sequentially with saturated sodium bicarbonate (60 mL x 2) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate (5 g), filtered, and concentrated to obtain 4.0 g of a crude yellow solid, which was used directly in the next step. Yield: 96.6%.

[0107] MS-ESI:410.2[M+H] + .

[0108] 1 H NMR (400MHz, CD3OD) δ8.22(s,1H),6.09(d,J=3.6Hz,1H),5.23(dd,J=6.0Hz,J= 3.2Hz,1H),5.01(dd,J=6.4Hz,J=2.4Hz,1H),4.53-4.49(m,1H),4.34(dd,J=6. 0Hz, J=4.0Hz, 1H), 3.78 (dd, J=12.0Hz, J=4.0Hz, 1H), 3.71 (dd, J=12.0Hz, J=4. 0Hz,1H),2.16-2.04(m,2H),1.83-1.76(m,2H),1.72-1.56(m,7H),1.37(s,3H).

[0109] Step 3) Preparation of methyl ((3aR,4R,6R,6aR)-6-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]diol-4-yl)pentadecanoate (1-e)

[0110] To a 25 mL single-necked flask, DCM (6 mL), 1-d (600 mg, 1.46 mmol), DCC (453 mg, 2.2 mmol), and DMAP (18 mg, 0.146 mmol) were added sequentially, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at room temperature (19-26°C) for 5 h. After the reaction was detected to be complete, the reaction was stopped and filtered. The filter cake was washed with dichloromethane twice with 20 mL each time. The filtrate was concentrated under reduced pressure to obtain an oil, which was purified by column chromatography (EA / PE = 0-1 / 1) to give a white solid (896 mg) in a yield of 96%.

[0111] 1H NMR (400MHz, CD3OD) δ8.13 (s, 1H), 6.13 (d, J = 2.0Hz, 1H), 5.48-5.44 (m, 1H), 5. 43(s,1H),5.08-5.05(m,1H),4.53-4.48(m,1H),4.45-4.42(m,1H),4.27-4.25( m,2H),2.23-2.18(m,2H),2.11-2.04(m,2H),1.82-1.78(m,2H),1.72-1.58(m, 6H), 1.50-1.47 (m, 2H), 1.39 (s, 3H), 1.35-1.23 (m, 20H), 0.89 (t, J = 6.8Hz, 3H).

[0112] Step 4 Preparation of ((2R,3S,4R,5R)-5-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)pentadecanoic acid methyl ester (Compound 1)

[0113] In a 50 mL three-necked flask, dichloromethane (6 mL) and 1-e (600 mg, 0.946 mmol) were added in sequence, the atmosphere was replaced with nitrogen three times, and the internal temperature was cooled to 5°C in an ice-water bath; TFA (6 mL) was added dropwise with the internal temperature not exceeding 5°C for about 5 min, the ice-water bath was removed, and the mixture was stirred at room temperature for 3 h; the reaction was detected to be complete, the reaction was stopped, and the reaction mixture was concentrated under reduced pressure to obtain an oil, saturated brine (60 mL) was added, and the mixture was extracted with dichloromethane (60 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate (5 g), filtered, and concentrated to obtain an oil, which was purified by column chromatography (MeOH / DCM=0% to 10%) to give a white solid (289 mg) in a yield of 51%.

[0114] MS-ESI:594.3[M+H] + .

[0115] 1H NMR (400MHz, CDCI3) δ7.87(s,1H),6.01(d,J=3.2Hz,1H),5.90(d,J=5.2Hz,1H),5.43(s ,1H),4.58-4.57(m,1H),4.54(t,J=5.2Hz,1H),4.52-4.47(m,1H),4.46-4.37(m,2H),4 .28(dd,J=12.4Hz,J=4.0Hz,1H),3.26(d,J=1.6Hz,1H),2.28-2.20(m,2H),2.18-2.10( m,2H),1.57-1.43(m,2H),1.51-1.48(m,4H),1.31-1.22(m,22H),0.87(t,J=6.8Hz,3H).

[0116] Example 2 Methyl ((2R,3S,4R,5R)-5-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)benzoate (Compound 2)

[0117] Step 1 Preparation of methyl ((3aR,4R,6R,6aR)-6-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]diol-4-yl)benzoate (2-a)

[0118] Under nitrogen protection, 1-d (550 mg, 1.34 mmol, 1.0 eq) was added to DCM (25 ml) and stirred to dissolve. Benzoic acid (196 mg, 1.74 mmol, 1.3 eq), DMAP (16.5 mg, 0.134 mmol, 0.1 eq) and DCC (418 mg, 2.01 mmol, 1.5 eq) were added in sequence. The reaction was allowed to proceed for 3-4 h. The central control panel indicated that the reaction was complete. The product was directly concentrated under reduced pressure and purified by reverse column chromatography (ACN:H2O (1% TFA) = 0-95%) to give 2-a (610 mg) in a yield of 88%.

[0119] MS-ESI:514.2[M+H] + .

[0120] Step 2 Preparation of methyl ((2R,3S,4R,5R)-5-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)benzoate (Compound 2)

[0121] 2-a (610 mg, 1.1 mmol, 1.0 eq) was dissolved in DCM (3 ml), and then TFA (3 ml) was added. The mixture was stirred under nitrogen for 2-3 h. The reaction was completed in the intermediate control. The reaction solution was concentrated under reduced pressure to remove the solvent. The residue was dissolved in DCM (30 ml) and washed with saturated sodium bicarbonate (40 ml). The residue was concentrated under reduced pressure and purified by column chromatography (EA:PE = 0-75%) to give compound 2 (130 mg) in a yield of 23.11%.

[0122] MS-ESI:474.1[M+H] + .

[0123] 1 H NMR (400M, CDCl3): δ7.86-7.84(m,3H),7.52(t,J=7.6Hz,1H),7.38-7.26(m,2H),6.10-6.08(bs,1H),5.91(d,J=7.6Hz,1H),5 .48(s,1H),4.72-4.47(m,6H),3.26-3.23(m,1H),2.22-2.17(m,2H),1.77-1.72(m,2H),1.55-1.53(m,2H),1.33-1.31(m,1H).

[0124] Example 3 Methyl ((2R,3S,4R,5R)-5-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)isobutyrate (Compound 3)

[0125] Step 1 Preparation of methyl ((3aR,4R,6R,6aR)-6-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]diol-4-yl)isobutyrate (3-a)

[0126] Under nitrogen protection, 1-d (550 mg, 1.34 mmol, 1.0 eq) was added to DCM (25 ml) and stirred, and then isobutyric acid (154 mg, 1.74 mmol, 1.3 eq), DMAP (16.5 mg, 0.134 mmol, 0.1 eq) and DCC (418 mg, 2.01 mmol, 1.5 eq) were added in sequence. The reaction was allowed to proceed for 3-4 h. The central control panel indicated that the reaction was complete. After direct concentration under reduced pressure, the product was purified by reverse column chromatography (ACN:H2O (1% TFA) = 0-95%) to give 3-a (613 mg) in a yield of 95%.

[0127] MS-ESI:480.2[M+H] + .

[0128] Step 2 Preparation of methyl ((2R,3S,4R,5R)-5-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)isobutyrate (Compound 3)

[0129] Under nitrogen protection, 3-a (610 mg, 1.1 mmol, 1.0 eq) was dissolved in DCM (3 ml), and then TFA (3 ml) was added and stirred for 2-3 h. The reaction was complete when the central control system showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to remove the solvent. The residue was dissolved in DCM (30 ml) and washed with saturated sodium bicarbonate (40 ml). The residue was concentrated under reduced pressure and purified by column chromatography (EA:PE = 0-75%) to give compound 3 (291 mg) in a yield of 23.11%.

[0130] MS-ESI:440.2[M+H] + .

[0131] 1 H NMR (400MHz, CDCl3) δ7.89 (s, 1H), 6.10 (bs, 1H), 5.92 (d, J = 4.8Hz, 1H), 5.54 (bs, 1H), 4.58-4.108 (m, 6H), 3 .38(bs,1H),2.55-2.48(m,1H),2.17-2.10(m,2H),1.80-1.66(m,7H),1.57-1.53(m,2H),1.13-0.96(m,3H).

[0132] Example 4 ((2R,3S,4R,5R)-5-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)L-valine methyl ester (Compound 4)

[0133] Step 1) Preparation of ((3aR,4R,6R,6aR)-6-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]diol-4-yl)L-valine (4-a)

[0134] In a 25 mL single-necked flask, DCM (10 mL), 1-d (500 mg, 1.22 mmol), Boc-D-valine (345 mg, 1.59 mmol), DCC (377 mg, 1.83 mmol) and DMAP (15 mg, 0.122 mmol) were added in sequence, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at room temperature (19-26°C) for 5 h. After the reaction was detected to be complete, the reaction was stopped, filtered, and the filter cake was washed with dichloromethane twice, each time with 20 mL. The filtrate was concentrated under reduced pressure to obtain an oily substance, which was purified by column chromatography (EA / PE = 0:1-1:1) to obtain a white solid (718 mg) with a yield of 96%.

[0135] MS-ESI:609.3[M+1] + .

[0136] Step 2 Preparation of ((2R,3S,4R,5R)-5-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)L-valine methyl ester (Compound 4)

[0137] To a 50 mL three-necked flask were added TFA (6 mL) and 1-d (600 mg, 0.946 mmol), and the atmosphere was replaced with nitrogen three times; the mixture was stirred at room temperature (19-26° C.) for 2 h; after the reaction was detected to be complete, the reaction mixture was concentrated under reduced pressure to obtain an oil, to which saturated sodium bicarbonate (60 mL) was added, and the mixture was extracted with dichloromethane (60 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate (5 g), filtered, and concentrated to obtain an oil, which was purified by column chromatography (MeOH / DCM=0%-10%) to give a white solid (206 mg) in a yield of 44.6%.

[0138] MS-ESI:469.2[M+1] + .

[0139] 1 H NMR (400MHz, CD3OD) δ8.16 (s, 1H), 5.92 (d, J = 4.4Hz, 1H), 4.78 (t, J = 4.8Hz, 1H), 4.51-4.46 (m, 1H), 4.44-4.38 (m, 3H), 4.27-4.23 (m,1H),2.10-2.05(m,2H),1.97-1.92(m,1H),1.82-1.76(m,2H),1.73-1.35(m,4H),0.91(d,J=7.2Hz,3H),0.87(d,J=6.8Hz,3H).

[0140] Biological evaluation

[0141] Test Example 1

[0142] 1. Experimental Materials

[0143] Experimental animals: SPF male Sprague-Dawley (SD) rats, weighing 180±30 g, were obtained from Shanghai Xipu-Bikai Laboratory Animal Co., Ltd.

[0144] Experimental samples: Compounds 1, 2, 3 and CCPA were used to prepare corresponding pharmaceutical compositions according to the following dosage and method.

[0145] Table 1 Prescription of pharmaceutical composition

[0146] Preparation method: Weigh the prescribed amount of compounds 1, 2, 3 and CCPA respectively, add them to an appropriate amount of tert-butanol / water mixed solution, stir to dissolve, then add the prescribed amount of dimyristoylphosphatidylcholine (DMPC) and cholesterol, and continue stirring to dissolve.

[0147] The above solution was diluted to 25-40 ml, filled into vials, and lyophilized in a freeze dryer for later use. When used, the solution was prepared with normal saline to 1 mg / ml, 2 mg / ml, 4 mg / ml, and 8 mg / ml.

[0148] 2. Experimental methods

[0149] 2.1 Animals and Dosing

[0150] 6-8 weeks old SD rats weighing 150g-200g were divided into control group, model control group and drug administration group. The CFA inflammatory pain model was established by injecting 100μL complete Freund's adjuvant into the left foot of the rats in the model control group and drug administration group 24 hours later.

[0151] Injection was performed at the Zusanli point on the left side with an injection volume of 100 μL. Specific dosing information is shown in Table 2.

[0152] Table 2 Dosage information

[0153] Note: The control group received 100 μL of normal saline injected into the sole of the foot; the model control group received 100 μL of normal saline injected into Zusanli after successful modeling.

[0154] 2.2 Evaluation indicators and data

[0155] Pain threshold was measured using a VonFrey electronic analgesia instrument, with mechanical pain as the evaluation index. The basal pain threshold was observed from 1 day before modeling to 14 days after modeling.

[0156] Graph Pad Prism 8.3.0 software was used to plot the pain thresholds of animals in different groups before and after administration. Based on the dose-response curves 48 hours after administration, EC 50 and EC 90 .

[0157] Table 3 Activity data of prescription samples

[0158] Conclusion: The biological activity data showed that compound 1, after modification with a fatty alkanoyl group at the 5' position, had an EC 50 and EC 90 The values ​​of EC were significantly reduced, which were increased by nearly 4 times and 6 times respectively compared with CCPA. 50 and EC 90 There was also a nearly 3-fold improvement, which was different from the known, fatty compounds whose activity was comparable or worse than that of the compounds.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in, R 1 、R 2 、R 3 the same or different, each independently selected from hydrogen, -(CO)-C 1～20 Alkyl, -(CO)-C 1～20 Alkoxy, -(CO)-5-6 membered cycloalkyl, -(CO)-5-6 membered heterocyclic group, -(CO)-6 membered aryl, -(CO)-5-6 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally substituted by one or more selected from halogen, hydroxyl, oxo, amino, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent, Y is selected from alkylene or heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted by one or more groups selected from halogen, hydroxy, oxo, amino, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent, R a 、R b 、R c The same or different, each independently C 1-6 alkyl, And, R 1 、R 2 、R 3 It cannot be hydrogen at the same time; R 4 Selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the alkyl, alkoxy is optionally substituted by one or more selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; R 5 、R 6 、R 7 、R 8 The same or different, each independently selected from hydrogen, halogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, the alkyl, alkoxy is optionally substituted by one or more selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 、R 3 All are hydrogen.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof, where R 1 、R 4 、R 5 、R 6 、R 7 、R 8 and n as defined in claim 1.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 4 is halogen, preferably fluorine, chlorine, bromine, most preferably chlorine.

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the compound represented by formula (I) or pharmaceutically acceptable salt thereof is a compound represented by formula (I-2) or pharmaceutically acceptable salt thereof, where R 1 、R 5 、R 6 、R 7 、R 8 and n as defined in claim 1.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 5 For hydrogen.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 6 For hydrogen.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein the compound represented by formula (I) or pharmaceutically acceptable salt thereof is a compound represented by formula (I-3) or pharmaceutically acceptable salt thereof, where R 1 、R 7 、R 8 As defined in claim 1.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 7 、R 8 All are hydrogen.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein the compound represented by formula (I) or pharmaceutically acceptable salt thereof is a compound represented by formula (I-4) or pharmaceutically acceptable salt thereof, where R 1 As defined in claim 1.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from -(CO)-C 1-5 Alkyl, -(CO)-C 10-20 alkyl, -(CO)-5- to 6-membered cycloalkyl, -(CO)-5- to 6-membered heterocyclic group, -(CO)-phenyl, -(CO)-5- to 6-membered heteroaryl, Y is C 1-6 Alkylene, R a 、R b 、R c The same or different, each independently C 1-6 alkyl The alkylene, alkyl, cycloalkyl, heterocyclic, phenyl, heteroaryl are optionally substituted by one or more selected from halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted by a substituent, and the substituent is preferably fluorine, chlorine, bromine, hydroxyl, amino, oxo, or methyl.

12. The compound according to any one of claims 11 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from -(CO)-methyl, -(CO)-ethyl, -(CO)-propyl, -(CO)-butyl, -(CO)-pentyl, -(CO)-C 14 Alkyl, -(CO)-phenyl, -(CO)-cyclopropane, -(CO)-cyclobutane, -(CO)-cyclopentane, -(CO)-cyclohexane, -(CO)-pyrrolidine, -(CO)-piperidine, -(CO)-piperazine, -(CO)-morpholine, -(CO)-thiomorpholine, -(CO)-pyrrole, -(CO)-furan, -(CO)-thiophene, -(CO)-pyridine, -(CO)-thiazole, -(CO)-oxazole, -(CO)-imidazole, -(CO)-triazole, -(CO)-tetrazole, The R 1 Optionally, one or more selected from halogen, hydroxy, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted by a substituent, and the substituent is preferably fluorine, chlorine, bromine, hydroxyl, amino, oxo, or methyl.

13. A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, which is selected from any one of the compounds in the following table, 14. An isotope substituted compound or a pharmaceutically acceptable salt thereof according to any one of claims 13, wherein the isotope substituted compound is preferably a deuterated compound.

15. A pharmaceutical composition comprising at least one therapeutically effective amount of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or the isotope-substituted compound according to claim 14, and a pharmaceutically acceptable excipient.

16. A method for treating or preventing chronic pain, comprising administering to the patient a therapeutically effective amount of the compound according to any one of claims 1 to 13, or the isotope substitute according to claim 14, or the pharmaceutical composition according to claim 15.

17. Use of the compound according to any one of claims 1 to 13, or the isotope-substituted compound according to claim 14, or the pharmaceutical composition according to claim 15 in the preparation of a drug for treating or preventing chronic pain.

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