Cyclopentyladenosine derivatives and their pharmaceutical uses

Abstract

The present disclosure relates to cyclopentyladenosine derivatives and their pharmaceutical uses. Specifically, the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 ~R 8 is as defined in the specification. 【Chemical 1】 JPEG2025520300000035.jpg5968

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine and relates to cyclopentyladenosine derivatives and their pharmaceutical uses.

Background Art

[0002] Chronic pain can be classified into nociceptive pain (somatic and visceral) and non-nociceptive pain (neuropathic and psychogenic) according to physiological mechanisms, and the clinical symptoms include tissue-damaging pain and neuropathic pain. Adenosine is an adenine nucleotide precursor and metabolite, and its receptors include A1, A2A, A2B and A3 receptors. Among them, the A1 receptor plays a major role in the pain transmission process. By activating the G protein-coupled receptor (GPCR), it regulates the transmembrane flux of intracellular cations, affects the excitability of neurons and the release of neurotransmitters, and exerts effects such as analgesia and anti-inflammation.

[0003] Patent US6110902A discloses the related suggestion of the adenosine A1 receptor agonist CCPA (2-chloro-N-cyclopentyladenosine) for the treatment of chronic pain. However, in chronic pain, although the A1 receptor agonist shows good clinical effects, its cardiovascular side effects and the characteristics of a narrow therapeutic range limit its use. Therefore, developing an adenosine A1 receptor agonist with a relatively wide therapeutic range and a low risk of cardiovascular diseases is a technical problem that needs to be urgently solved at present.

Summary of the Invention

[0004] The present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

Chemical formula

[0005] In some embodiments, it is a compound represented by formula (I) described in the present disclosure or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 Are both hydrogen.

[0006] In some embodiments, it is a compound described in the present disclosure 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,

Chemical formula

[0007] In some embodiments, it is a compound represented by formula (I) or formula (I-1) described in the present disclosure or a pharmaceutically acceptable salt thereof, wherein R 4 Is halogen, preferably fluorine, chlorine, bromine, most preferably chlorine.

[0008] In some embodiments, it is a compound described in the present disclosure 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-2) or a pharmaceutically acceptable salt thereof,

Chemical formula

[0009] In some embodiments, a compound represented by formula (I), formula (I-1) or formula (I-2) described in the present disclosure, or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen.

[0010] In some embodiments, a compound represented by formula (I), formula (I-1) or formula (I-2) described in the present disclosure, or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.

[0011] In some embodiments, a compound described in the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the compound described in formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by formula (I-3) or a pharmaceutically acceptable salt thereof,

Chemical formula

[0012] In some embodiments, a compound represented by formula (I), formula (I-1), formula (I-2) or formula (I-3) described in the present disclosure, or a pharmaceutically acceptable salt thereof, wherein R 7 , R 8 are both hydrogen.

[0013] In some embodiments, a compound described in the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the compound described in formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by formula (I-4) or a pharmaceutically acceptable salt thereof,

Chemical formula

[0014] In some embodiments, it is a compound represented by formula (I), formula (I-1), formula (I-2), formula (I-3) or formula (I-4) described in the present disclosure, or a pharmaceutically acceptable salt thereof, among which R 1 is -(CO)-C 1-5 alkyl group, -(CO)-C 10-20 alkyl group, -(CO)-5- to 6-membered cycloalkyl group, -(CO)-5- to 6-membered heterocyclyl group, -(CO)-phenyl group, -(CO)-5- to 6-membered heteroaryl group,

Chemical formula

[0015] In some embodiments, it is a compound represented by formula (I), formula (I-1), formula (I-2), formula (I-3) or formula (I-4) described in the present disclosure, or a pharmaceutically acceptable salt thereof, among which R 1 is -(CO)-methyl group, -(CO)-ethyl group, -(CO)-propyl group, -(CO)-butyl group, -(CO)-pentyl group, -(CO)-C 14an alkyl group, a -(CO)-phenyl group, a -(CO)-cyclopropane, a -(CO)-cyclobutane, a -(CO)-cyclopentane, a -(CO)-cyclohexane, a -(CO)-pyrrolidine, a -(CO)-piperidine, a -(CO)-piperazine, a -(CO)-morpholine, a -(CO)-thiomorpholine, a -(CO)-pyrrole, a -(CO)-furan, a -(CO)-thiophene, a -(CO)-pyridine, a -(CO)-thiazole, a -(CO)-oxazole, a -(CO)-imidazole, a -(CO)-triazole, a -(CO)-tetrazole, [Chemical formula] selected from the above R 1 is optionally substituted with one or more substituents selected from halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 alkyl group, a C 1-6 alkoxy group, and the above substituents are preferably fluorine, chlorine, bromine, a hydroxy group, an amino group, an oxo group, a methyl group.

[0016] In some embodiments, it is a compound represented by formula (I), formula (I-1), formula (I-2), formula (I-3) or formula (I-4) described in the present disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 is a -(CO)-C 10 alkyl group, a -(CO)-C 11 alkyl group, a -(CO)-C 12 alkyl group, a -(CO)-C 13 alkyl group, a -(CO)-C 14 alkyl group, a -(CO)-C 15 alkyl group, a -(CO)-C 16 alkyl group, a -(CO)-C 17 alkyl group, a -(CO)-C 18 alkyl group selected from, and further, the above R 1 is optionally substituted with one or more substituents selected from halogen, a hydroxy group, an amino group, a cyano group, an oxo group, a C 1-6 alkyl group, a C 1-6Substituted with one or more substituents selected from alkoxy groups, and the substituents are preferably fluorine, chlorine, bromine, hydroxy group, amino group, oxo group, methyl group.

[0017] In some embodiments, it is a compound represented by formula (I), formula (I-1), formula (I-2), formula (I-3) or formula (I-4) described in the present disclosure or a pharmaceutically acceptable salt thereof, wherein R 1 is -(CO)-C 12 alkyl group, -(CO)-C 13 alkyl group, -(CO)-C 14 alkyl group, -(CO)-C 15 alkyl group, -(CO)-C 16 alkyl group, and further, the above R 1 is optionally substituted with one or more substituents selected from halogen, hydroxy group, amino group, cyano group, oxo group, C 1-6 alkyl group, C 1-6 alkoxy group, and the substituents are preferably fluorine, chlorine, bromine, hydroxy group, amino group, oxo group, methyl group.

[0018] In some embodiments, specific compounds of the present disclosure include, but are not limited to, the following.

[0019]

Table 1-1

Table 1-2

Table 1-3

[0020] The present disclosure further provides isotope substitution products of the above compounds or pharmaceutically acceptable salts thereof. In some embodiments, the isotope substitution products are deuterides.

[0021] The present disclosure further provides a pharmaceutical composition comprising at least one therapeutically effective amount of the compounds shown in Formula (I), Formula (I-1), Formula (I-2), Formula (I-3), Formula (I-4) and Table A, or pharmaceutically acceptable salts thereof, or isotope-substituted forms thereof, and a pharmaceutically acceptable excipient.

[0022] In some embodiments, the unit dose of the pharmaceutical composition is from 0.001 mg to 1000 mg.

[0023] In certain embodiments, based on the total weight of the composition, the pharmaceutical composition comprises from 0.01% to 99.99% of the compound or a pharmaceutically acceptable salt thereof or an isotope-substituted form thereof. In certain embodiments, the pharmaceutical composition comprises from 0.1% to 99.9% of the compound or a pharmaceutically acceptable salt thereof or an isotope-substituted form thereof. In certain embodiments, the pharmaceutical composition comprises from 0.5% to 99.5% of the compound or a pharmaceutically acceptable salt thereof or an isotope-substituted form thereof. In certain embodiments, the pharmaceutical composition comprises from 1% to 99% of the compound or a pharmaceutically acceptable salt thereof or an isotope-substituted form thereof. In certain embodiments, the pharmaceutical composition comprises from 2% to 98% of the compound or a pharmaceutically acceptable salt thereof or an isotope-substituted form thereof.

[0024] In certain embodiments, based on the total weight of the composition, the pharmaceutical composition comprises from 0.01% to 99.99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises from 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises from 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises from 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises from 2% to 98% of a pharmaceutically acceptable excipient.

[0025] The compounds or pharmaceutically acceptable salts thereof or isotope-substituted forms thereof provided by the present disclosure, or the above pharmaceutical composition, can be used to improve all forms of acute and chronic pain, particularly pain caused by cancer, neuropathic pain, postoperative pain, neuralgia and neural pain.

[0026] The compounds provided by the present disclosure, or pharmaceutically acceptable salts thereof, or isotope-substituted forms thereof, or the above pharmaceutical compositions may also be used for treating specific pain syndromes including pain associated with soft tissue diseases and peripheral injuries (e.g., acute wounds, osteoarthritis, rheumatoid arthritis, burns, episiotomy), spinal pain, musculoskeletal pain, upper limb pain, limb pain, myofascial pain syndrome, headache, deep and visceral pain syndromes (e.g., angina pectoris, muscle pain, eye pain, orofacial pain, abdominal pain, gynecological pain and labor pain), pain associated with nerve and root injuries (e.g., peripheral neuropathy or infections, pain due to amputation of hands or feet, peripheral neuropathy, spasm and atypical facial pain, meningitis), cancer pain (especially pain associated with bone and soft tissue cancer and metastasis), and central nervous system pain (e.g., central pain caused by spinal cord or brainstem injury).

[0027] The present disclosure further provides a method for treating or preventing chronic pain, which is carried out by administering to a patient a therapeutically effective amount of the compound represented by the above formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-4) or shown in Table A, or a pharmaceutically acceptable salt thereof, or an isotope-substituted form thereof, or the above pharmaceutical composition.

[0028] The present disclosure further provides the use of the compound represented by the above formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-4) or shown in Table A, or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a medicament for treating or preventing chronic pain. In some embodiments, chronic pain includes, but is not limited to, nociceptive pain, neuropathic pain, headache, migraine, tension headache, cluster headache, chronic tension headache, inflammatory pain, neck and shoulder pain, lumbar and lower limb pain, neuralgia, eye pain, toothache.

[0029] The pharmaceutically acceptable salts of the compounds described in the present disclosure may be selected from inorganic salts or organic salts.

[0030] The compounds according to the present disclosure may be in the form of specific geometric or stereoisomers. The present disclosure includes cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomer- or diastereomer-enriched mixtures, and it is intended that all such compounds are included within the scope of the present disclosure. Substituents such as alkyl groups may have other asymmetric carbon atoms. All such isomers and mixtures thereof are included within the scope of the present disclosure. Compounds containing asymmetric carbon atoms according to the present disclosure can be isolated in optically pure form or in racemic form. The optically pure form may be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.

[0031] Optically active (R)- and (S)-isomers and D- and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. To obtain one enantiomer of a certain compound of the present disclosure, it can be prepared by asymmetric synthesis or by induction with a chiral auxiliary, among which the resulting mixture of diastereomers is isolated and the pure enantiomer required is provided by assisting the cleavage of the group. Alternatively, when the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxy group), a diastereomeric salt is formed with a suitable optically active acid or base, and diastereomeric resolution is carried out by conventional methods well known in the art, and then recovered to obtain a pure enantiomer. It should be noted that the isolation of enantiomers and diastereomers is generally accomplished by using chromatography, and the above chromatography employs a chiral stationary phase and is optionally combined with a chemical induction method (e.g., generating a carbamate from an amine).

[0032] JPEG2025520300000013.jpg40150

[0033] JPEG2025520300000014.jpg21147

[0034] Also, the compounds and intermediates of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The terms "tautomer" or "tautomeric form" refer to structural isomers of different energies that are interconvertible by a low energy barrier. For example, proton tautomers (also called proton-transfer tautomers) include, for example, interconversion by protolysis such as keto-enol and imine-enamine isomerization. An example of a lactam-lactim equilibrium is between A and B as follows.

[0035]

Chemical Structure

[0036] The present disclosure further includes some compounds of the present disclosure that are isotope-labeled in which one or more atoms are replaced with atoms having an atomic weight or mass number different from the atomic weight or mass number normally found in nature, which are the same as those described herein. 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, for example, 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 and the like.

[0037] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position is to be understood as having a deuterium abundance that is at least 1000 times higher than the natural abundance of deuterium (which is 0.015%), i.e., deuterium with at least 10% incorporated. For a compound in an example to have a deuterium abundance higher than the natural abundance of deuterium, it may be deuterium with an abundance of at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times or more of the natural abundance of deuterium. The present disclosure further includes compounds of formula (I) in various deuterated forms. Each available hydrogen atom linked to a carbon atom may independently be replaced by a deuterium atom. Those skilled in the art can synthesize compounds of formula (I) in deuterated forms with reference to relevant literature. When preparing compounds of formula (I) in deuterated forms, commercially available deuterated starting materials may be used, or they may be synthesized with deuterating reagents by ordinary techniques. Deuterating reagents include, but are not limited to, deuterated borane, borane trihydride tetrahydrofuran solution, lithium aluminum deuterohydride, iodoethane-d and iodomethane-d, etc.

[0038] "Optionally" or "optionally" means that the event or situation described thereafter may or may not occur, and this description includes both the case where the event or situation occurs and the case where it does not occur. For example, "C alkyl group optionally substituted with a halogen or a cyano group" means that a halogen or a cyano group may or may not be present, and this description includes both the case where the alkyl group is substituted with a halogen or a cyano group and the case where the alkyl group is not substituted with a halogen or a cyano group. 1-6 Unless otherwise stated, the terms used in the specification and the claims have the following meanings.

[0039] Term Explanation Unless otherwise stated, the terms used in the specification and the claims have the following meanings.

[0040] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group containing straight-chain and branched-chain groups of 1 to 20 carbon atoms. It is an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, and various branched-chain isomers thereof. The alkyl group may or may not be substituted. When substituted, the substituent may be substituted at any available linkage point, preferably independently halogen, hydroxy group, oxo, amino group, C 1-6 alkyl group, C 1-6 alkoxy group, 3- to 6-membered cycloalkyl group, 3- to 6-membered heterocyclyl group, 6- to 10 aryl group or 5- to 10 heteroaryl group, and the above alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group is optionally substituted with one or more halogen, hydroxy group, amino group, cyano group, C 1-6 alkyl group or C 1-6 is substituted with an alkoxy group.

[0041] The term "cycloalkyl group" or "carbocyclic ring" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the cycloalkyl group ring contains 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclopentenyl group, cyclohexyl group, cyclohexenyl group, cyclohexadienyl group, etc., and polycyclic cycloalkyl groups include spiro ring, fused ring and bridged ring cycloalkyl groups. The cycloalkyl group may or may not be substituted. When substituted, the substituent may be substituted at any available linkage point, preferably independently halogen, hydroxy group, oxo, amino group, cyano group, C 1-6 alkyl group, C 1-6One or more groups selected from an alkoxy group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclyl group, a 6- to 10-membered aryl group, or a 5- to 10-membered heteroaryl group, wherein the above alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally substituted with one or more halogen, hydroxy group, amino group, cyano group, C 1-6 alkyl group or C 1-6 is substituted with an alkoxy group.

[0042] The term "heterocyclyl group" or "heterocycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, wherein one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, and the above sulfur may optionally be substituted with an oxo group (i.e., form a sulfoxide or sulfone), but does not contain a ring moiety of -O-O-, -O-S-, or -S-S-, 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, among which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms, more preferably contains 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) ring atoms, among which 1 to 3 (e.g., 1, 2, and 3) are heteroatoms, still more preferably contains 3 to 6 ring atoms, among which 1 to 3 are heteroatoms, and most preferably contains 5 or 6 ring atoms, among which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl group, piperidinyl group, piperazinyl group, N-alkylpiperazinyl group, N-alkylpiperidinyl group, morpholinyl group, thiomorpholinyl group, etc. Polycyclic heterocyclyl groups include spiro ring, fused ring, and bridged ring heterocyclyl groups.

[0043] The heterocyclyl group may or may not be optionally substituted. When substituted, the substituents are preferably independently halogen, hydroxy group, oxo, amino group, cyano group, C 1-6 alkyl group, C 1-6One or more groups selected from an alkoxy group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclyl group, a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, wherein the above alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group is optionally substituted with one or more halogen, hydroxy group, amino group, cyano group, C 1-6 alkyl group or C 1-6 substituted with an alkoxy group.

[0044] The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycycles are rings sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, for example, phenyl group and naphthyl group.

[0045] The aryl group may or may not be optionally substituted. When substituted, the substituents are preferably independently halogen, hydroxy group, oxo, nitro group, cyano group, amino group, C 1-6 alkyl group, C 1-6 one or more groups selected from an alkoxy group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclyl group, wherein the above alkyl group, alkoxy group, cycloalkyl group or heterocyclyl group is substituted with one or more groups selected from halogen, hydroxy group, amino group, C 1-6 alkyl group or C 1-6 substituted with an alkoxy group.

[0046] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 (for example, 1, 2, 3 and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5- to 10-membered (for example, 5, 6, 7, 8, 9 or 10-membered), more preferably 5-membered or 6-membered, for example, furanyl group, thienyl group, pyridyl group, pyrrolyl group, N-alkylpyrrolyl group, imidazolyl group, triazolyl group, tetrazolyl group and the like.

[0047] The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably independently a halogen, a hydroxy group, oxo, a nitro group, a cyano group, an amino group, C 1-6 alkyl group, C 1-6 alkoxy group, a 3- to 6-membered cycloalkyl group, or one or more groups selected from 3- to 6-membered heterocyclyl groups. The alkyl group, alkoxy group, cycloalkyl group or heterocyclyl group described above is substituted with one or more groups selected from a halogen, a hydroxy group, an amino group, C 1-6 alkyl group or C 1-6 alkoxy group.

[0048] The term "alkoxy group" refers to -O-(alkyl group), where the definition of the alkyl group is as described above. Non-limiting examples of alkoxy groups include methoxy group, ethoxy group, propoxy group, butoxy group, cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably independently a halogen, a hydroxy group, oxo, a nitro group, a cyano group, an amino group, C 1-6 alkyl group, C 1-6 alkoxy group, a 3- to 6-membered cycloalkyl group, or one or more groups selected from 3- to 6-membered heterocyclyl groups. The alkyl group, alkoxy group, cycloalkyl group or heterocyclyl group described above is substituted with one or more groups selected from a halogen, a hydroxy group, an amino group, C 1-6 alkyl group or C 1-6 alkoxy group.

[0049] The term "alkylene group" represents the moiety remaining after removing two hydrogen atoms from an alkane molecule and includes linear and branched subunits of 1 to 20 carbon atoms. Non-limiting examples of alkylene groups containing 1 to 6 carbon atoms include methylene group (-CH2-), ethylidene group (e.g., -CH2CH2- or -CH(CH3)-). Unless otherwise specified, the alkylene group may be substituted or unsubstituted.

[0050] The term "heteroalkylene group" refers to the substitution of one or more of the -CH2- in the alkylene group with a heteroatom selected from N, O, and S, wherein the alkylene group is as defined above, and the heteroalkylene group may or may not be substituted. The term "hydroxy group" refers to the -OH group.

[0051] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0052] The term "cyano group" refers to -CN.

[0053] The term "amino group" refers to -NH2.

[0054] The term "nitro group" refers to -NO2.

[0055] The term "oxo" refers to the =O substituent.

[0056] "Substituted" means that one or more hydrogen atoms of the group, preferably 5 or fewer, more preferably 1 to 3 hydrogen atoms, are independently substituted with a corresponding number of substituents. Of course, the substituents are located only at their chemically possible sites, and those skilled in the art can determine possible or impossible substitutions without much effort (by experiment or theory).

[0057] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs with other chemical components, and other components such as physiologically pharmaceutically acceptable carriers and excipients. The pharmaceutical composition is for promoting administration to a living body, contributing to the absorption of the active ingredient, and further exerting biological activity.

[0058] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent approved by the United States Food and Drug Administration for use in humans or domestic animals.

[0059] The term "pharmaceutically acceptable" means that these compounds, materials, compositions and / or dosage forms are within the scope of reasonable medical judgment, without excessive toxicity, irritation, allergic reaction or other problems or complications, applicable to contact with the patient's tissues, having a reasonable benefit-risk ratio, and effective for the desired use.

[0060] As used herein, "effective amount" or "effective therapeutic amount" includes an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical disorder. An effective amount further refers to an amount sufficient to permit or facilitate diagnosis. The effective amount used for a particular patient or veterinary subject can vary depending on factors such as the disorder to be treated, the overall health of the patient, the method of administration, route and dosage, and the severity of side effects. The effective amount may be the maximum dose or dosing schedule at which significant side effects or toxic effects are avoided.

[0061] For a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a sufficient dosage of the drug or agent that is non-toxic while achieving the desired effect. The effective amount is determined by a person and depends on the age and general condition of the recipient, as well as the specific active substance. The suitable effective amount for an individual can be determined by those skilled in the art through routine testing.

[0062] As used herein, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise, and vice versa.

[0063] The compounds described in the present disclosure can be prepared by the following general reaction schemes or similar methods. However, the conditions of the methods, such as reactants, solvents, bases, amounts of compounds used, reaction temperature, reaction time required, etc., are not limited to the descriptions in the prior art. The compounds according to the present disclosure can also be conveniently manufactured 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.

Embodiments for Carrying out the Invention

[0064] Hereinafter, the present disclosure will be further described in conjunction with examples, but these examples do not limit the scope of the present disclosure.

[0065] In the examples in the present disclosure, experimental methods for which specific conditions are not specified generally follow normal conditions or the conditions recommended by the raw material or commercial manufacturer. Reagents for which specific sources are not specified are ordinary commercially available reagents.

[0066] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is shown in units of 10 -6 (ppm). For NMR measurement, a nuclear magnetic resonance apparatus Bruker AVANCE-400 is used, and the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (Methanol-d4), and the internal standard is tetramethylsilane (TMS).

[0067] For HPLC measurement, an Agilent1100 high-performance liquid chromatograph, a GAS15B DAD ultraviolet detector, and a Water Vbridge C18 150×4.6mm 5μm column were used.

[0068] For MS measurement, an Agilent 6120 triple quadrupole mass spectrometer, a G1315D DAD detector, a Waters Xbridge C18 4.6×50mm, 5μm column were used, scanned in positive / negative ion mode, and the mass scanning range was 80 - 1200.

[0069] As the silica gel plate for thin-layer chromatography, a Yantai Huanghai HSGF254 silica gel plate was used. The specification for the silica gel plate used in thin-layer chromatography (TLC) was 0.2mm ± 0.03mm, and the specification for the separation and purification of products by thin-layer chromatography was 0.4mm - 0.5mm.

[0070] For the flash column purification system, Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage) was used.

[0071] For normal-phase column chromatography, generally, silica gel of 200 - 300 mesh or 300 - 400 mesh from Yantai Huanghai was used as the carrier, or a pre-packed ultra-high purity normal-phase silica gel column (40 - 63μm, 60g, 24g, 40g, 120g or other specifications) from Changzhou Santai was used.

[0072] The known starting materials in this disclosure may be synthesized by methods known in this field or according thereto, or may be purchased from companies such as Shanghai Titan Scientific, ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Bide Pharmatech.

[0073] Unless otherwise specified in the examples, all reactions can be carried out in a nitrogen gas atmosphere.

[0074] The nitrogen gas atmosphere means that a nitrogen gas balloon with a volume of about 1L is connected to the reaction flask.

[0075] The hydrogen atmosphere refers to that a hydrogen balloon with a volume of about 1 L is connected to the reaction flask.

[0076] Hydrogen gas is produced by a QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instruments Co., Ltd.

[0077] The nitrogen gas atmosphere or hydrogen atmosphere usually involves repeating evacuation, introduction of nitrogen gas or hydrogen gas three times.

[0078] In the examples, unless otherwise specified, the solution refers to an aqueous solution.

[0079] In the examples, unless otherwise specified, the reaction temperature is room temperature of 20 °C to 30 °C.

[0080] In monitoring the progress of the reaction in the examples, thin-layer chromatography (TLC) is employed. For the developing solvent used in the reaction, the eluent system of column chromatography for purifying the compound, and the developing solvent system of thin-layer chromatography, the volume ratio of the solvents is adjusted according to the polarity of the compound, and it may also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

[0081] Examples Example 1 Methyl ((2R,3S,4R,5R)-5-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl) pentadecanoate (Compound 1)

Chemical formula

[0082] Step 2) Preparation of ((3aR,4R,6R,6aR)-6-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (1-d) 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 sequentially added to a 100 mL three-necked flask, replaced with nitrogen gas three times, heated under reflux for 1 h. When it was detected that the reaction was completed, the heating was stopped, the reaction solution was cooled to room temperature (20 °C), the reaction solution was concentrated under reduced pressure to obtain an oily substance, dichloromethane (150 mL) was added, and it was washed successively with saturated sodium bicarbonate (60 mL × 2) and saturated brine (50 mL), dried over anhydrous sodium sulfate (5 g), filtered, concentrated to obtain 4.0 g of a crude yellow solid product, and directly proceeded to the next step. The yield was 96.6%. MS-ESI: 410.2 [M+H] + 。 1 H NMR (400 MHz, CD3OD) δ 8.22 (s, 1 H), 6.09 (d, J = 3.6 Hz, 1 H), 5.23 (dd, J = 6.0 Hz, J = 3.2 Hz, 1 H), 5.01 (dd, J = 6.4 Hz, J = 2.4 Hz, 1 H), 4.53 - 4.49 (m, 1 H), 4.34 (dd, J = 6.0 Hz, J = 4.0 Hz, 1 H), 3.78 (dd, J = 12.0 Hz, J = 4.0 Hz, 1 H), 3.71 (dd, J = 12.0 Hz, J = 4.0 Hz, 1 H), 2.16 - 2.04 (m, 2 H), 1.83 - 1.76 (m, 2 H), 1.72 - 1.56 (m, 7 H), 1.37 (s, 3 H).

[0083] Step 3) Preparation of methyl ((3aR,4R,6R,6aR)-6-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pentadecanoate (1-e) Add DCM (6 mL), 1-d (600 mg, 1.46 mmol), DCC (453 mg, 2.2 mmol) and DMAP (18 mg, 0.146 mmol) successively to a 25 mL single-neck flask, replace with nitrogen gas three times, stir at room temperature (19 - 26 °C) for 5 h. When it was detected that the reaction was complete, stop the reaction, filter, wash the filter cake twice with dichloromethane, 20 mL each time. Concentrate the filtrate under reduced pressure to obtain an oily substance, and obtain a white solid (896 mg) by column chromatography (EA / PE = 0 - 1 / 1), yield: 96%. 1 H NMR (400 MHz, CD3OD) δ 8.13 (s, 1 H), 6.13 (d, J = 2.0 Hz, 1 H), 5.48 - 5.44 (m, 1 H), 5.43 (s, 1 H), 5.08 - 5.05 (m, 1 H), 4.53 - 4.48 (m, 1 H), 4.45 - 4.42 (m, 1 H), 4.27 - 4.25 (m, 2 H), 2.23 - 2.18 (m, 2 H), 2.11 - 2.04 (m, 2 H), 1.82 - 1.78 (m, 2 H), 1.72 - 1.58 (m, 6 H), 1.50 - 1.47 (m, 2 H), 1.39 (s, 3 H), 1.35 - 1.23 (m, 20 H), 0.89 (t, J = 6.8 Hz, 3 H).

[0084] Step 4) Preparation of Methyl (2R,3S,4R,5R)-5-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)pentadecanoate (Compound 1) To a 50 mL three-necked flask, dichloromethane (6 mL) and 1-e (600 mg, 0.946 mmol) were added in sequence. The flask was purged with nitrogen gas three times, and the internal temperature was cooled to 5 °C in an ice-water bath. TFA (6 mL) was added dropwise while maintaining the internal temperature below 5 °C. The addition was completed in about 5 min. The ice-water bath was removed, and the mixture was stirred at room temperature for 3 h. When the completion of the reaction was detected, the reaction was stopped, and the reaction mixture was concentrated under reduced pressure to obtain an oily substance. 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 oily substance. A white solid (289 mg) was obtained by column chromatography (MeOH / DCM = 0% - 10%), and the yield was 51%. MS-ESI: 594.3[M+H] + 。 1 H NMR (400 MHz, CDCI3) δ 7.87 (s, 1 H), 6.01 (d, J = 3.2 Hz, 1 H), 5.90 (d, J = 5.2 Hz, 1 H), 5.43 (s, 1 H), 4.58 - 4.57 (m, 1 H), 4.54 (t, J = 5.2 Hz, 1 H), 4.52 - 4.47 (m, 1 H), 4.46 - 4.37 (m, 2 H), 4.28 (dd, J = 12.4 Hz, J = 4.0 Hz, 1 H), 3.26 (d, J = 1.6 Hz, 1 H), 2.28 - 2.20 (m, 2 H), 2.18 - 2.10 (m, 2 H), 1.57 - 1.43 (m, 2 H), 1.51 - 1.48 (m, 4 H), 1.31 - 1.22 (m, 22 H), 0.87 (t, J = 6.8 Hz, 3 H).

[0085] Example 2 Methyl ((2R,3S,4R,5R)-5-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)benzoate (Compound 2)

Chemical Structure

[0086] Preparation of methyl ((2R,3S,4R,5R)-5-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)benzoate (Compound 2) 2-a (610 mg, 1.1 mmol, 1.0 eq) was dissolved in DCM (3 mL), then TFA (3 mL) was added. Under nitrogen gas protection, it was stirred for 2 - 3 h. When the reaction was shown to be complete by the center console, the reaction solution was concentrated under reduced pressure to remove the solvent. The residue was added to DCM (30 mL) and dissolved, then washed with saturated sodium bicarbonate (40 mL), concentrated under reduced pressure, and the residue was purified by column chromatography (EA:PE=0% - 75%) to obtain Compound 2 (130 mg) with a yield of 23.11%. MS-ESI: 474.1 [M+H] + 。 11H NMR (400 M, CDCl3): δ 7.86 - 7.84 (m, 3H), 7.52 (t, J = 7.6 Hz, 1H), 7.38 - 7.26 (m, 2H), 6.10 - 6.08 (bs, 1H), 5.91 (d, J = 7.6 Hz, 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).

[0087] Example 3 ((2R,3S,4R,5R)-5-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate (Compound 3)

Chemical Structure

[0088] 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) Under nitrogen gas protection, 3-a (610 mg, 1.1 mmol, 1.0 eq) was dissolved in DCM (3 mL), then TFA (3 mL) was added, and the mixture was stirred for 2 - 3 h. When the reaction was shown to be complete by the center console, the reaction solution was concentrated under reduced pressure to remove the solvent. The residue was added to DCM (30 mL) and dissolved, then washed with saturated sodium bicarbonate (40 mL), concentrated under reduced pressure, and the residue was purified by column chromatography (EA:PE = 0% - 75%) to obtain Compound 3 (291 mg) with a yield of 23.11%. MS-ESI: 440.2 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 7.89 (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).

[0089] Example 4: Methyl ((2R,3S,4R,5R)-5-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)L-valinate (Compound 4)

Chemical formula

[0090] 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 (Compound 4) To a 50 mL three-necked flask, add TFA (6 mL) and 1-d (600 mg, 0.946 mmol) in sequence. Replace the gas with nitrogen gas three times, and stir at room temperature (19 - 26 °C) for 2 h. When it is detected that the reaction is complete, concentrate the reaction under reduced pressure to obtain an oily substance. Add saturated sodium bicarbonate (60 mL), extract with dichloromethane (60 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate (5 g), filter, concentrate, and obtain an oily substance. Obtain a white solid (206 mg) by column chromatography (MeOH / DCM = 0% - 10%), with a yield of 44.6%. MS-ESI: 469.2 [M+1] + 。 11H NMR (400 MHz, CD3OD) δ 8.16 (s, 1 H), 5.92 (d, J = 4.4 Hz, 1 H), 4.78 (t, J = 4.8 Hz, 1 H), 4.51 - 4.46 (m, 1 H), 4.44 - 4.38 (m, 3 H), 4.27 - 4.23 (m, 1 H), 2.10 - 2.05 (m, 2 H), 1.97 - 1.92 (m, 1 H), 1.82 - 1.76 (m, 2 H), 1.73 - 1.35 (m, 4 H), 0.91 (d, J = 7.2 Hz, 3 H), 0.87 (d, J = 6.8 Hz, 3 H).

[0091] Biological evaluation Test Example 1 1. Experimental materials [Table 2]

[0092] Experimental animals: SPF-grade male Sprague-Dawley (SD) rats, weighing 180 ± 30 g, were obtained from Shanghai Xipu'er-Bikai Experimental Animal Co., Ltd.

[0093] Experimental samples: Compounds 1, 2, 3 and CCPA were used to prepare the corresponding pharmaceutical compositions according to the following prescribed amounts and methods.

[0094] [Table 3]

[0095] Preparation method: Weigh the prescribed amounts of Compounds 1, 2, 3 and CCPA respectively, add them to an appropriate amount of tert-butyl alcohol / water mixed solution, stir to dissolve, and then further add the prescribed dimyristoyl phosphatidylcholine (DMPC) and cholesterol, and continue to stir to dissolve.

[0096] The above solution was made up to 25 - 40 mL, filled into vials respectively, placed in a freeze dryer for freeze drying, and prepared for use. When in use, it was prepared with physiological saline to 1 mg / mL, 2 mg / mL, 4 mg / mL and 8 mg / mL for use.

[0097] 2. Experimental methods 2.1 Animals and administration SD rats aged 6 - 8 weeks and weighing 150 g - 200 g were selected and divided into a control group, a model control group and an administration group. For the CFA inflammatory pain model, 100 μL of complete Freund's adjuvant was injected into the left plantar surface of the rats in the model control group and the administration group, and the model was established 24 h later.

[0098] It was injected into the left Zusanli point, and the injection volume was 100 μL. The specific administration information is shown in Table 2.

[0099]

Table 4

[0100] Note: The control group was injected with 100 μL of physiological saline into the plantar surface, and the model control group was injected with 100 μL of physiological saline into the Zusanli point after successful modeling.

[0101] 2.2 Evaluation indicators and data The pain threshold was measured using a VonFrey electronic pain sensation measuring device, and mechanical pain was used as the evaluation index. The basic pain threshold was observed from the day before model construction until the 14th day after model construction.

[0102] Using the software Graph Pad Prism 8.3.0, the pain thresholds of animals in different groups before and after administration were plotted. Based on the dose - response curve 48 h after administration, fittings were performed respectively to obtain EC 50 and EC 90 were obtained.

[0103]

Table 5

[0104] Conclusion: According to the biological activity data, Compound 1 modified by a "fatty alkanoyl group" at the 5'-position had significantly reduced EC 50 and EC 90 values, which were nearly 4-fold and 6-fold improved compared to CCPA, respectively. Moreover, compared to Compound 2, EC 50 and EC 90 increased by nearly 3-fold. Different from the prior art (or common knowledge), the activity of the aliphatic compound was equal to or worse than that of the compound activity.

Claims

1. A compound represented by formula (I) or a medicinal salt thereof, 【Chemistry 1】 Eventually, R １ , R ２ , R ３ They are the same or different, and each is independently hydrogen, 【Chemistry 2】 ,-(CO)-C １～２０ Alkyl alkyl group, -(CO)-C １～２０ Selected from alkoxy groups, -(CO)-5-6 membered cycloalkyl groups, -(CO)-5-6 membered heterocyclyl groups, -(CO)-6 membered aryl groups, and -(CO)-5-6 membered heteroaryl groups, the alkyl groups, alkoxy groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may optionally be halogens, hydroxyl groups, oxo groups, amino groups, cyano groups, and C １－６ alkyl group, C １－６ Substituted with one or more substituents selected from alkoxy groups, Y is selected from an alkylene group or a heteroalkylene group, and the alkylene group or heteroalkylene group is optionally substituted with one or more substituents selected from halogen, hydroxy group, oxo group, amino group, cyano group, C １－６ alkyl group, C １－６ alkoxy group, R ａ , R ｂ , R ｃ They are the same or different, and each is independently C １－６ It is an alkyl group, Furthermore, R １ , R ２ , R ３ It cannot be hydrogen at the same time. R ４ These are halogens, hydroxyl groups, amino groups, cyano groups, and C １－６ alkyl group, C １－６ Selected from alkoxy groups, the alkyl group and alkoxy group can optionally be halogen, hydroxyl group, amino group, cyano group, or C １－６ alkyl group, C １－６ Substituted with one or more substituents selected from alkoxy groups, R ５ , R ６ , R ７ , R ８ They are the same or different, and each is independently a hydrogen, halogen, hydroxyl group, amino group, cyano group, and C １－６ alkyl group, C １－６ Selected from alkoxy groups, the alkyl group and alkoxy group can optionally be halogen, hydroxyl group, amino group, cyano group, or C １－６ alkyl group, C １－６ Substituted with one or more substituents selected from alkoxy groups, n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8. A compound or a medicinal salt thereof.

2. R ２ , R ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein all of the elements are hydrogen.

3. The compound represented by formula (I) or its medicinal salt is the compound represented by formula (I-1) or its medicinal salt, 【Transformation 3】 Eventually, R １ , R ４ , R ５ , R ６ , R ７ , R ８ and n are as defined in claim 1, The compound according to claim 1 or a medicinal salt thereof.

4. R ４ The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein is a halogen, preferably fluorine, chlorine, bromine, most preferably chlorine.

5. The compound represented by formula (I) or its medicinal salt is the compound represented by formula (I-2) or its medicinal salt, 【Chemistry 4】 Eventually, R １ , R ５ , R ６ , R ７ , R ８ and n are as defined in claim 1, The compound according to claim 1 or a medicinal salt thereof.

6. R ５ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

7. R ６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

8. The compound represented by formula (I) or its medicinal salt is the compound represented by formula (I-3) or its medicinal salt, 【Transformation 5】 Eventually, R １ , R ７ , R ８ This is as defined in claim 1, The compound according to claim 1 or a medicinal salt thereof.

9. R ７ , R ８ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein all of the elements are hydrogen.

10. The compound represented by formula (I) or its medicinal salt is the compound represented by formula (I-4) or its medicinal salt, 【Transformation 6】 Eventually, R １ This is as defined in claim 1, The compound according to claim 1 or a medicinal salt thereof.

11. R １ is -(CO)-C １－５ Alkyl alkyl group, -(CO)-C １０－２０ Alkyl groups, -(CO)-5-6 membered cycloalkyl groups, -(CO)-5-6 membered heterocyclyl groups, -(CO)-phenyl groups, -(CO)-5-6 membered heteroaryl groups, 【Transformation 7】 Selected from, Y is C １－６ It is an alkylene group, R ａ , R ｂ , R ｃ They are the same or different, and each is independently C １－６ It is an alkyl group, The aforementioned alkylene group, alkyl group, cycloalkyl group, heterocyclyl group, phenyl group, heteroaryl group can be selectively a halogen, hydroxyl group, amino group, cyano group, oxo group, or C １－６ alkyl group, C １－６ It is substituted with one or more substituents selected from alkoxy groups, the substituents being preferably fluorine, chlorine, bromine, a hydroxyl group, an amino group, an oxo group, or a methyl group. The compound according to claim 1 or a medicinal salt thereof.

12. R １ -(CO)-methyl group, -(CO)-ethyl group, -(CO)-propyl group, -(CO)-butyl group, -(CO)-pentyl group, -(CO)-C １４ Alkyl groups, -(CO)-phenyl groups, -(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, 【Transformation 8】 Selected from, The aforementioned R １ It can optionally include halogens, hydroxyl groups, amino groups, cyano groups, oxo groups, and C. １－６ alkyl group, C １－６ It is substituted with one or more substituents selected from alkoxy groups, the substituents being preferably fluorine, chlorine, bromine, a hydroxyl group, an amino group, an oxo group, or a methyl group. The compound according to claim 11 or a medicinal salt thereof.

13. A compound according to claim 1, or a medicinal salt thereof, which is one of the compounds selected from the table below. Table 1-1 Table 1-2 Table 1-3 。

14. Preferably, the isotope substitution is a deuteride, wherein the compound according to claim 13 or an isotope substitution of the pharmaceutically acceptable salt thereof.

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

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

17. A method for treating or preventing chronic pain, comprising administering the pharmaceutical composition described in claim 15 to a patient.

18. Use of a compound according to any one of claims 1 to 13 or an isotope substitution according to claim 14 in the preparation of a drug for treating or preventing chronic pain.

19. Use of the pharmaceutical composition according to claim 15 in the preparation of a drug for treating or preventing chronic pain.

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