Oxaspirocyclic derivatives, production methods and uses thereof

Abstract

The present invention relates to oxaspirocyclic derivatives, preparation methods and their uses. Specifically, the present invention provides a compound represented by general formula (I), its stereoisomers, its tautomers or its pharma- ceutically acceptable salts, and its preparation methods for activating opioid-like substance receptor activity, and its use in the manufacture of analgesic drugs. [Formula 1] TIFF2024528181000150.tif35170

Description

Technical Field

[0001] This application claims the priority of Chinese Patent Applications 202110895052X and 202110888850X, the filing date of which is August 2, 2021. The full texts of the above Chinese patent applications are incorporated herein by reference.

[0002] The present invention belongs to the field of medicine, and specifically relates to oxaspirocyclic derivatives, production methods, and their uses.

Background Art

[0003] Opioid receptors belong to one of the members of the G protein-coupled receptor (GPCR) family. Currently, it has been discovered that nine types of opioid receptors, such as μ, δ, κ, and ORL1, are widely expressed in the central and peripheral nerves, as well as in neuroendocrine cells, immune cells, and endothelial cells. The μ (MOR), δ (DOR), and κ (KOR) opioid receptors control a series of physical behaviors, including pain, emotion, stress response, and addictive behavior, via the central nervous system. Among them, the μ, δ, and κ opioid receptors are typical opioid receptors, and the basic structures of these three types of receptors are the same, that is, they simultaneously have an extracellular amino-terminal region and an intracellular carboxyl-terminal region. The agonists of these three isoforms of opioid receptors mainly couple to Gi-type G proteins and dissociate the β subunit and γ subunit of the G protein from the α subunit. The β subunit, γ subunit, and α subunit mediate the activation of multiple intracellular signal transduction pathways, such as the inhibition of adenylate cyclase activity, the activation of G protein-coupled receptor kinase (GRK), protein kinase C (PKC), and mitogen-activated protein kinase (MAPK).

[0004] Multiple regions in the cerebral cortex and subcortex are involved in the anti-nociceptive response mediated by MOR. Some regions exhibit special functions, mainly regulating pain sensation (e.g., the ipsilateral lateral habenula and amygdala) or emotional (e.g., anterior cingulate cortex) responses. Studies have shown that the activation of MOR in the amygdala mediates the anti-nociceptive response. In the ACC region, the activation of MOR during the persistent pain period is negatively correlated with the pain-specific MPQ emotional score.

[0005] High levels of opioid receptors are expressed in the ACC region. Opioid drugs are widely used in the treatment of persistent pain and have been proposed to act in the brain. Reports have shown that injecting morphine into the ACC region suppresses the emotional response to pain, and there is no change in the pain sensation of nerve-injured animals. The results suggest that the emotional and sensory aspects of pain are generated by different mechanisms. Subsequent studies have demonstrated that injecting different doses of the MOR agonist DAMGO into the rostral part of the anterior cingulate cortex can dose-dependently reduce the emotional response to pain induced by injecting complete Freund's adjuvant. Another study found that when MOR is activated in the lateral habenula, reducing presynaptic glutamate release and simultaneously increasing the functional activity of the NMDA receptor suddenly, the NMDA receptor in the basolateral nucleus of the amygdala affects the emotional response to formalin-induced acute and chronic pain, and a large number of NMDA receptors are further distributed in the neurons of the ACC brain region, which is involved in multiple functions such as learning and memory in the central nervous system and pain regulation.

[0006] The analgesic mechanism of opioid drugs is already clear at present. In the process of pain transmission to the central nervous system, pain stimulates sensory nerve endings to release glutamate (Glu), which acts on the corresponding receptors to complete the transmission of pain impulses to the central nervous system and cause pain. Exogenous opioid substances or endogenous opioid peptides activate opioid receptors on the presynaptic and postsynaptic membranes of sensory nerves. Through the G-protein coupling mechanism, they inhibit adenylate cyclase from decomposing ATP to produce cAMP. As a result, they suppress the release of neurotransmitters such as substance P and acetylcholine from the presynaptic membrane of the synapse. At the same time, they + promote the efflux of K 2+ and reduce the influx of Ca

[0007] ultimately attenuate pain signals and produce an analgesic effect.Through years of research, numerous opioid receptor agonists and antagonists have been discovered. Currently discovered opioid receptor agonists include morphine, DAMGO, endomorphin, fentanyl and its derivatives. Naloxone (Naloxone, Nal), CTOP, CTAP, naltrexone, etc. are opioid receptor antagonists. The characteristics of naloxone are its short onset time, strong antagonistic ability, strong lipophilicity, and relatively short drug efficacy duration. Naloxone is an effective and broad-spectrum opioid antagonist that can act by competing with opioid receptors (in order, μ, κ, δ), and always has an agonist effect, that is, an agonist-antagonist binding effect. It can reduce problems such as poisoning caused by overdose of opioid drugs and persistent postoperative respiratory depression, and can further perform differential diagnosis on drug addicts. Remifentanil has effects similar to other μ-opioid receptor agonists such as analgesia, sedation, and respiratory depression, has no obvious binding ability to non-opioid receptors, and at the same time, its binding to opioid receptors can be competitively inhibited by naloxone. Its analgesic effect shows dose-dependence and has a "ceiling effect", but general adverse effects still exist, such as being prone to causing respiratory depression when used in hypotension, muscle rigidity, bradycardia, nausea and vomiting, local anesthesia or postoperative analgesia. Furthermore, these opioid drugs cause side effects such as tolerance and respiratory depression, constipation, etc. after long-term use.

[0008] Therefore, in order to meet the huge market demand, it is urgently required to develop a novel opioid-like substance receptor agonist that acts on the G protein pathway, has fewer side effects, higher activity, can effectively treat related diseases mediated by μ-opioid receptor agonists, and has a particularly significant analgesic effect.

Summary of the Invention

[0009] The object of the present invention is to provide a compound represented by the general formula (I), its stereoisomers, its tautomers or its pharmaceutically acceptable salts,

Chemical Formula

[0010] For the compound represented by the general formula (I), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, in a further preferred embodiment of the present invention, the above ring A is a phenyl group.

[0011] For the compound represented by the general formula (I), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, in a further preferred embodiment of the present invention, the above R 1 and R 2 are each independently hydrogen, halogen, C 1-6 is an alkyl group or C 1-6 is a haloalkoxy group, preferably hydrogen, halogen, C 1-3 is an alkyl group or C 1-3is a haloalkoxy group, more preferably hydrogen, fluorine, chlorine, bromine, a methyl group, an ethyl group, a propyl group or a halomethoxy group, and even more preferably hydrogen, fluorine, chlorine, bromine, a methyl group or a fluoromethoxy group.

[0012] Regarding the compound represented by the general formula (I), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, in a more preferred embodiment of the present invention, the above R 1 is independently hydrogen, halogen or C 1-6 alkyl group, preferably hydrogen, halogen or C 1-3 alkyl group, more preferably hydrogen, fluorine, chlorine, bromine, a methyl group, an ethyl group or a propyl group, and even more preferably hydrogen, fluorine, chlorine, bromine or a methyl group.

[0013] Regarding the compound represented by the general formula (I), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, in a more preferred embodiment of the present invention, the above R 1 is hydrogen, halogen, C 1-6 alkyl group, C 1-6 alkoxy group or C 1-6 haloalkoxy group, preferably hydrogen, halogen, C 1-3 alkyl group or C 1-3 haloalkoxy group, more preferably hydrogen, fluorine, chlorine, bromine, a methyl group, an ethyl group, a propyl group or a halomethoxy group, and even more preferably hydrogen, fluorine, chlorine, a methyl group or a fluoromethoxy group.

[0014] Regarding the compound represented by the general formula (I), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, in a more preferred embodiment of the present invention, the above R 2 is hydrogen, halogen, C 1-3 alkyl group or C 1-3 haloalkoxy group, preferably hydrogen.

[0015] For the compound represented by the general formula (I), its stereoisomers, its tautomers or its pharmaceutically acceptable salts, in a more preferred embodiment of the present invention, the above ring B is a pyridyl group, optionally substituted with one R 3 and further substituted with.

[0016] For the compound represented by the general formula (I), its stereoisomers, its tautomers or its pharmaceutically acceptable salts, in a more preferred embodiment of the present invention, the above R 3 are each independently hydrogen or halogen, preferably hydrogen, fluorine, chlorine or bromine, more preferably hydrogen or fluorine.

[0017] For the compound represented by the general formula (I), its stereoisomers, its tautomers or its pharmaceutically acceptable salts, in a more preferred embodiment of the present invention, the above X1 is CR a R b or CR a R b CH2, and R a and R b are each independently hydrogen, halogen or a C 1-3 alkyl group, preferably hydrogen.

[0018] For the compound represented by the general formula (I), its stereoisomers, its tautomers or its pharmaceutically acceptable salts, in a more preferred embodiment of the present invention, the above X1 is CR a R b and is preferably CH2.

[0019] For the compound represented by the general formula (I), its stereoisomers, its tautomers or its pharmaceutically acceptable salts, in a more preferred embodiment of the present invention, the above X1 is CR a R b or CR a R b CH2, and R a or R b is R 2is linked to form a single cyclopentyl or cyclohexyl group, preferably a cyclopentyl group.

[0020] For the compound represented by the general formula (I), its stereoisomers, its tautomers or its pharmaceutically acceptable salts, in a more preferred embodiment of the present invention, the above X1 is CH(R b ) or CH(R b )CH2, and R b is linked to R 2 to form a single cyclopentyl or cyclohexyl group, preferably a cyclopentyl group.

[0021] For the compound represented by the general formula (I), its stereoisomers, its tautomers or its pharmaceutically acceptable salts, in a more preferred embodiment of the present invention, the above n is 0, 1, or 2. For the compound represented by the general formula (I), its stereoisomers, its tautomers or its pharmaceutically acceptable salts, in a more preferred embodiment of the present invention, the above ring B is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0022] One preferred embodiment of the present invention provides a compound represented by the general formula (II), its stereoisomers, its tautomers or its pharmaceutically acceptable salts,

Chemical formula

[0023] For the compound represented by general formula (II), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, in a more preferred embodiment of the present invention, the above general formula (II) further has a structure represented by general formula (II-1),

Chemical formula

[0024] For the compound represented by general formula (II) or general formula (II-1), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, in a more preferred embodiment of the present invention,

Chemical formula

Chemical formula

Chemical formula

[0025] For the compound represented by the general formula (II) or the general formula (II-1), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, in a more preferred embodiment of the present invention,

Chemical formula

Chemical formula

[0026] For the compound represented by the general formula (II) or the general formula (II-1), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, in a more preferred embodiment of the present invention, the above R aa , R bb , R cc , R dd and R ee are each independently a halogen, C 1-6 alkyl group, C 1-6 alkoxy group or C 1-6 haloalkoxy group, preferably a halogen, C 1-3 alkyl group or C 1-3is a haloalkoxy group, more preferably, fluorine, chlorine, bromine, a methyl group, an ethyl group, a propyl group or a halomethoxy group, and even more preferably, fluorine, chlorine, bromine, a methyl group or a fluoromethoxy group.

[0027] Regarding the compound represented by the general formula (II) or the general formula (II-1), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, in a more preferred embodiment of the present invention, the above R aa is halogen or C 1-6 is a haloalkoxy group, preferably, halogen or C 1-3 is a haloalkoxy group, more preferably, fluorine, chlorine, bromine or a halomethoxy group, and even more preferably, chlorine or a fluoromethoxy group.

[0028] Regarding the compound represented by the general formula (II) or the general formula (II-1), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, in a more preferred embodiment of the present invention, the above R dd is halogen, more preferably, fluorine, chlorine or bromine, and even more preferably chlorine.

[0029] Regarding the compound represented by the general formula (II) or the general formula (II-1), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, in a more preferred embodiment of the present invention, the above R ee is halogen or C 1-6 is an alkyl group, preferably halogen or C 1-3 is an alkyl group, more preferably, fluorine, chlorine, bromine, a methyl group, an ethyl group or a propyl group, and even more preferably fluorine, chlorine or a methyl group.

[0030] Regarding the compound represented by the general formula (II) or the general formula (II-1), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, in a more preferred embodiment of the present invention,

Chemical formula

[0031] One preferred embodiment of the present invention provides a compound represented by general formula (III), its stereoisomers, its tautomers or its pharmaceutically acceptable salts, [Chemical formula] Among them, ring C is a cyclopentyl group, R 1 , R 3 and n are as described in general formula (I).

[0032] Regarding the compound represented by general formula (III), its stereoisomers, its tautomers or its pharmaceutically acceptable salts, in a more preferred embodiment of the present invention, the above general formula (III) further has a structure represented by general formula (IV) or general formula (V), [Chemical formula] Among them, R 1 , R 3 and n are as described in general formula (III), the carbon atom with "*" is an asymmetric carbon atom and exists in the form of (R) or (S) single enantiomer or an enantiomer-rich form, the carbon atom with "#" is an asymmetric carbon atom and exists in the form of (R) or (S) single enantiomer or an enantiomer-rich form.

[0033] Regarding the compound represented by general formula (IV) or general formula (V), its stereoisomers, its tautomers or its pharmaceutically acceptable salts, in a more preferred embodiment of the present invention, [Chemical formula] is, [Chem.] and preferably, [Chem.] is, [Chem.] is, [Chem.] and preferably, [Chem.] is, Among them, R aa , R bb , R cc , and R dd are each independently halogen, a hydroxy group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group or a C 1-6 haloalkoxy group, where the C 1-6 alkyl group is optionally further substituted with one or more substituents selected from the group consisting of a C 3-6 cycloalkyl group, a C 1-6 alkyl group and halogen, preferably halogen, a hydroxy group, a C 1-3 alkyl group, a C 1-3 haloalkyl group, a C 1-3 alkoxy group or a C 1-3 haloalkoxy group, more preferably fluorine, chlorine, bromine, a hydroxy group, a methyl group, an ethyl group, a propyl group, a methoxy group, an ethoxy group, a halomethyl group, a haloethyl group or a halomethoxy group, even more preferably fluorine, chlorine, bromine, a methyl group, a methoxy group or a halomethoxy group, and still more preferably fluorine, chlorine, bromine, a methyl group or a methoxy group.

[0034] For the compound represented by the general formula (IV) or general formula (V), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, in a more preferred embodiment of the present invention, the above R aa , R bb , R cc and R dd are each independently a halogen or a C 1-6 alkyl group, preferably a halogen or a C 1-3 alkyl group, more preferably a fluorine, chlorine, bromine, methyl group, ethyl group or propyl group, and still more preferably a fluorine, chlorine, bromine or methyl group.

[0035] For the compound represented by the general formula (IV) or general formula (V), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, in a more preferred embodiment of the present invention, the above R aa is a halogen, preferably fluorine, chlorine or bromine, and more preferably chlorine or bromine.

[0036] For the compound represented by the general formula (IV) or general formula (V), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, in a more preferred embodiment of the present invention, the above R bb is a halogen, preferably fluorine, chlorine or bromine, and more preferably fluorine or chlorine.

[0037] For the compound represented by the general formula (IV) or general formula (V), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, in a more preferred embodiment of the present invention, the above R dd is a halogen or a C 1-6 alkyl group, preferably a halogen or a C 1-3 alkyl group, more preferably a fluorine, chlorine, bromine, methyl group, ethyl group or propyl group, and still more preferably a fluorine, chlorine, bromine or methyl group.

[0038] Regarding the compound represented by the general formula (IV), its stereoisomers, its tautomers or its pharmaceutically acceptable salts, in a more preferred embodiment of the present invention,

Chemical formula

Chemical formula

[0039] Regarding the compound represented by the general formula (V), its stereoisomers, its tautomers or its pharmaceutically acceptable salts, in a more preferred embodiment of the present invention,

Chemical formula

Chemical formula

[0040] Regarding the compound represented by the general formula (IV), its stereoisomers, its tautomers or its pharmaceutically acceptable salts, in a more preferred embodiment of the present invention, the above general formula (IV) further has a structure represented by the general formula (IV-1),

Chemical formula

[0041] Regarding the compound represented by the general formula (IV), its stereoisomers, its tautomers or its pharmaceutically acceptable salts, in a more preferred embodiment of the present invention, the above general formula (IV) further has a structure represented by the general formula (IV-2), [Chemistry] Among them, R 1 、R 3 and n are as described in general formula (IV), The carbon atom with "*" is an asymmetric carbon atom and exists in the form of (R) or (S) single enantiomer or an enantiomer-rich form.

[0042] Regarding the compound represented by general formula (IV-1), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, in a more preferred embodiment of the present invention, the above general formula (IV-1) further has a structure represented by general formula (IV-1-1) or general formula (IV-1-2), [Chemistry] Among them, R 1 、R 3 and n are as described in general formula (IV-1).

[0043] Regarding the compound represented by general formula (V), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, in a more preferred embodiment of the present invention, the above general formula (V) further has a structure represented by general formula (V-1), [Chemistry] Among them, R 1 、R 3 and n are as described in general formula (V), The carbon atom with "*" is an asymmetric carbon atom and exists in the form of (R) or (S) single enantiomer or an enantiomer-rich form.

[0044] For the compound represented by the general formula (V), its stereoisomers, its tautomers or its pharmaceutically acceptable salts, in a more preferred embodiment of the present invention, the general formula (V) further has a structure represented by the general formula (V-2),

Chemical formula

[0045] For the compound represented by the general formula (V-1), its stereoisomers, its tautomers or its pharmaceutically acceptable salts, in a more preferred embodiment of the present invention, the general formula (V-1) further has a structure represented by the general formula (V-1-1) or the general formula (V-1-2), Among them

Chemical formula

[0046] In an embodiment of the present invention, the above compound is any one of the following structures:

Chemical formula

Chemical formula

Chemical formula

[0047] One preferred embodiment of the present invention provides a method for producing a compound represented by the above general formula (I), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof,

Chemical formula

[0048] One preferred embodiment of the present invention provides a method for producing a compound represented by the above general formula (II), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, Method 1:

Chemical formula

Chemical formula

[0049] One preferred embodiment of the present invention provides a method for producing a compound represented by the above general formula (III), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, Method 1:

Chemical formula

Chemical formula

[0050] One preferred embodiment of the present invention provides a method for producing a compound represented by the above general formula (IV), its stereoisomer, its tautomer or its pharmaceutically acceptable salt, Method 1:

Chemical formula

Chemical formula

[0051] One preferred embodiment of the present invention provides a method for producing a compound represented by the above general formula (V), a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, Method 1:

Chemical formula

Chemical formula

[0052] The present invention further provides a preferred form relating to a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by each of the above general formulas, a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical additive selected from pharmaceutically acceptable carriers, diluents and excipients.

[0053] In some preferred embodiments of the present invention, the pharmaceutical composition can be administered by any of the following routes: oral administration, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as injection or infusion subcutaneously, intravenously, intramuscularly, intraperitoneally, intrathecally, intraventricularly, intrasternal or intracranially, or administration via an implanted reservoir, among which oral, intraperitoneal or intravenous administration is preferred.

[0054] In the case of oral administration, the compounds of the present application may be formulated into any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions or aqueous suspensions. Among these, the carriers used in tablets generally include lactose and corn starch, and lubricants such as magnesium stearate may also be added. The diluents used in capsule formulations generally include lactose and dried corn starch. Aqueous suspension formulations are usually prepared by mixing the active ingredient with suitable emulsifiers and suspending agents. If necessary, sweeteners, fragrances or coloring agents may be added to the above oral dosage forms.

[0055] Tablets include, for example, but are not limited to troches, sublingual tablets, oral patches, chewable tablets, dispersible tablets, effervescent tablets, immediate release or sustained release or controlled release tablets, and enteric-coated tablets.

[0056] In the case of topical administration, especially for the treatment of affected areas or organs where topical application is easily performed, such as the eyes, skin or lower intestinal nerve diseases, the compounds of the present application may be formulated into different topical dosage forms according to different affected areas or organs, and the specific description is as follows.

[0057] When topically administered to the eyes, the compounds of the present application may be prepared in the form of a micronized suspension or solution, and the carrier used is isotonic sterile physiological saline having a certain pH, and preservatives such as benzalkonium chloride may or may not be added thereto. For ophthalmic use, the compound may be formulated in the form of an ointment such as petrolatum.

[0058] When administered topically to the skin, the compounds of the present application may be formulated into appropriate ointments, lotions or creams in which the active ingredient is suspended or dissolved in one or more carriers. Carriers that can be used in ointment formulations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax, and water. Carriers that can be used in lotion or cream formulations include, but are not limited to, mineral oil, sorbitan monostearate, Tween 60, cetyl ester wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0059] The present invention further provides a preferred form relating to the use of the compounds represented by the above general formulas, their stereoisomers, their tautomers or their pharmaceutically acceptable salts, or the above pharmaceutical compositions, in the manufacture of a medicament for preventing and / or treating related diseases mediated by a μ-opioid receptor agonist.

[0060] The related diseases mediated by the μ-opioid receptor agonist described in the above uses are selected from one or more of pain, immune dysfunction, inflammation, gastroesophageal reflux, neurological and psychiatric diseases, urological and genital diseases, cardiovascular diseases and respiratory diseases, preferably pain.

[0061] The present invention further provides a preferred form relating to the use of the compounds represented by the above general formulas, their stereoisomers, their tautomers or their pharmaceutically acceptable salts, or the above pharmaceutical compositions, in the manufacture of a medicament for preventing and / or treating pain or pain-related diseases.

[0062] The present invention further relates to a method for treating related diseases mediated by a μ-opioid receptor agonist, which comprises administering a therapeutically effective amount of the compound of the present invention, its stereoisomer, its tautomer or its pharmaceutically acceptable salt to a mammal.

[0063] In some embodiments of the present invention, the present invention relates to a method for treating pain and the like.

[0064] The related diseases mediated by the μ-opioid receptor agonist described in the above method are selected from one or more of pain, immunodeficiency, inflammation, gastroesophageal reflux, neurological and psychiatric diseases, urogenital diseases, cardiovascular diseases and respiratory diseases, preferably pain.

[0065] In some embodiments of the present invention, the above pain is selected from one or more of postoperative pain, pain caused by cancer, neuropathic pain, traumatic pain, and pain caused by inflammation.

[0066] In some embodiments of the present invention, the above cancer is selected from one or more of breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, hemophilia, and leukemia.

[0067] The treatment method provided herein includes administering a therapeutically effective amount of the compound of the present invention to a subject. In one embodiment, the present invention further provides a method for treating related diseases mediated by μ-opioid receptor agonists in mammals. The method includes administering a therapeutically effective amount of the compound of the present invention, its stereoisomers, its tautomers or its pharmaceutically acceptable salts to the above mammals.

Brief Description of the Drawings

[0068]

Figure 1

Modes for Carrying Out the Invention

[0069] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0070] The compounds of the present invention may exist in the form of specific geometric or stereoisomers. The present invention contemplates that all such compounds include cis and trans isomers, (-)- and (+)- enantiomeric pairs, (R)- and (S)- enantiomers, diastereomers, (D)-isomers, (L)-isomers, as well as their racemic mixtures and other mixtures, such as mixtures enriched in enantiomers or diastereomers, and all of these mixtures are within the scope of the present invention. Substituents such as alkyl groups may have other asymmetric carbon atoms. All of these isomers and their mixtures are included within the scope of the present invention. In certain embodiments, the preferred compounds are isomeric compounds that exhibit superior biological activity. The purified or partially purified isomers and stereoisomers of the compounds of the present invention, or racemic mixtures or diastereomeric mixtures, are all included within the scope of the present invention. The purification and separation of such substances can be achieved by standard techniques known in the art.

[0071] Unless otherwise specified, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0072] Unless otherwise specified, the terms "cis-trans isomer" or "geometric isomer" are due to the fact that the double bond or the single bond of the ring-forming carbon atoms cannot rotate freely.

[0073] Unless otherwise specified, the term "diastereomer" refers to stereoisomers that have two or more chiral centers in a molecule and are non-mirror images of each other.

[0074] Unless otherwise specified, "(D)" or "(+)" indicates dextrorotation, "(L)" or "(-)" indicates levorotation, and "(DL)" or "(±)" indicates racemization.

[0075] Unless otherwise specified,

Chemical formula

[0076] Certain compounds of the present invention may exist. Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to different functional group isomers being in a dynamic equilibrium state at room temperature and being able to rapidly interconvert with each other. When tautomers are possible (e.g., in solution), the chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also called prototropic tautomers) include the interconversions carried out by proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include the interconversions carried out by the reorganization of some bonding electrons. Among them, a specific example of keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0077] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group that is a straight-chain or branched-chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 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, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 3,3-diethylhexyl group, 2,2-diethylhexyl group, and various branched-chain isomers thereof, etc.More preferably, 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, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, etc. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available bonding point. The above substituents are preferably independently one or more groups among alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, alkylamino group, halogen, mercapto group, hydroxy group, nitro group, amino group, cycloalkyl group, heterocyclylalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocyclylalkoxy group, cycloalkylthio group, heterocyclylalkylthio group, oxo group, carboxy group or carboxylic acid ester group. In the present invention, methyl group, ethyl group, isopropyl group, tert-butyl group, haloalkyl group, alkoxy-substituted alkyl group and hydroxy-substituted alkyl group are preferred. When the above alkyl group is substituted with a substituent, the above substituent is not further substituted.

[0078] The term "alkylene group" refers to a group in which one hydrogen atom of an alkyl group is further substituted. For example, "methylene group" refers to -CH2-, "ethylene group" refers to -(CH2)2-, "propylene group" refers to -(CH2)3-, "butylene group" refers to -(CH2)4-, etc.

[0079] The term "alkenyl group" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, vinyl group, 1-propenyl group, 2-propenyl group, 1-, 2- or 3-butenyl group, etc. The alkenyl group may be substituted or unsubstituted. When substituted, the substituents are preferably independently one or more groups selected from alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, alkylamino group, halogen, mercapto group, hydroxy group, nitro group, amino group, cycloalkyl group, heterocyclylalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocyclylalkoxy group, cycloalkylthio group, heterocyclylalkylthio group. When the above-mentioned alkylene group is substituted by a substituent, the said substituent is not further substituted.

[0080] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl group contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclopentenyl group, cyclohexyl group, cyclohexenyl group, cyclohexadienyl group, cycloheptyl group, cycloheptatrienyl group, cyclooctyl group, etc. Polycyclic cycloalkyl groups include spiro ring, fused ring and bridged ring cycloalkyl groups, preferably cyclopropyl group, cyclobutyl group, cyclohexyl group, cyclopentyl group and cycloheptyl group.

[0081] The term "spirocycloalkyl group" refers to a polycyclic group in which two 5- to 20-membered monocyclic rings share one carbon atom (referred to as the spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into a monospirocycloalkyl group, a bisspirocycloalkyl group or a polysspirocycloalkyl group, preferably a monospirocycloalkyl group and a bisspirocycloalkyl group. More preferably, it is a monospirocycloalkyl group of 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member, or 5-member / 6-member.

[0082] Non-limiting examples of the spirocycloalkyl group are

Chem.

[0083] Also included are spirocycloalkyl groups in which a monospirocycloalkyl group and a heterocyclylalkyl group share a spiro atom. Non-limiting examples are

Chem.

[0084] The term "fused cycloalkyl group" refers to a fully carbon polycyclic group that is 5- to 20-membered and in which each ring within the system shares an adjacent pair of carbon atoms with another ring within the system, where one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably a bicyclic alkyl group of 5-member / 5-member or 5-member / 6-member. Non-limiting examples of the fused cycloalkyl group are

Chem.

[0085] The term "bridged cycloalkyl group" refers to a fully carbon polycyclic group having 5 to 20 members and sharing two carbon atoms that are not directly linked to any two rings, which may contain one or more double bonds but no rings having a fully conjugated π electron system. Preferably, it has 6 to 14 members, more preferably 7 to 10 members. It can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of the bridged cycloalkyl group are

Chemical formula

[0086] The above cycloalkyl ring may be condensed with an aryl group, a heteroaryl group or a heterocyclylalkyl ring, among which the ring linked to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl group, tetrahydronaphthyl group, benzocycloheptanyl group, etc. The cycloalkyl group may optionally be substituted or unsubstituted. When substituted, the substituents are preferably independently one or more groups among alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, alkylamino group, halogen, mercapto group, hydroxy group, nitro group, amino group, cycloalkyl group, heterocyclylalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocyclylalkoxy group, cycloalkylthio group, heterocyclylalkylthio group, oxo group, carboxy group or carboxylic acid ester group. When the above cycloalkyl group is substituted with substituents, the above substituents are not further substituted.

[0087] The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic group (i.e., a ring sharing adjacent carbon atom pairs) having a conjugated electron system, preferably 6- to 10-membered, such as a phenyl group or a naphthyl group. More preferably, it is a phenyl group. The above aryl ring may be fused to a heteroaryl group, a heterocyclyl group or a cycloalkyl group ring, including a benzo 3- to 8-membered cycloalkyl group, a benzo 3- to 8-membered heterocyclyl group, preferably including a benzo 3- to 6-membered cycloalkyl group, a benzo 3- to 6-membered heterocyclyl group. Among them, the heterocyclyl group is a heterocyclyl group containing 1 to 3 nitrogen atoms, oxygen atoms, sulfur atoms, or further includes a 3-membered nitrogen-containing fused ring containing a benzene ring.

[0088] Among them, the ring linked to the parent structure is an aryl ring, and its non-limiting examples are

Chemical formula

[0089] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably independently one or more groups among an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an alkylamino group, a halogen, a mercapto group, a hydroxy group, a nitro group, an amino group, a cycloalkyl group, a heterocyclylalkyl group, an aryl group, a heteroaryl group, a cycloalkoxy group, a heterocyclylalkoxy group, a cycloalkylthio group, a heterocyclylalkylthio group, a carboxy group or a carboxylic acid ester group. When the above aryl group is substituted with a substituent, the above substituent is not further substituted.

[0090] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from one or more of oxygen, sulfur, and nitrogen. The heteroaryl group preferably has 5 to 10 members, more preferably 5 or 6 members, such as an imidazolyl group, a furanyl group, a thienyl group, a thiazolyl group, a pyrazolyl group, an oxazolyl group, a pyrrolyl group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a thiadiazole group, a pyrazinyl group, etc., preferably a triazolyl group, a thienyl group, an imidazolyl group, a pyrazolyl group or a pyrimidinyl group, a thiazolyl group, and more preferably a triazolyl group, a pyrrolyl group, a thienyl group, a thiazolyl group, and a pyrimidinyl group. The above heteroaryl ring may be condensed with an aryl group, a heterocyclyl group, or a cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, and non-limiting examples thereof are [Chemical formula] including.

[0091] The heteroaryl group may optionally be substituted or unsubstituted. When substituted, the substituents are preferably independently one or more groups selected from an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an alkylamino group, a halogen, a mercapto group, a hydroxy group, a nitro group, an amino group, a cycloalkyl group, a heterocyclylalkyl group, an aryl group, a heteroaryl group, a cycloalkoxy group, a heterocyclylalkoxy group, a cycloalkylthio group, a heterocyclylalkylthio group, a carboxy group, or a carboxylic acid ester group. When the above heteroaryl group is substituted with a substituent, the above substituent is not further substituted.

[0092] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), wherein the definition of the alkyl group is as described above. Preferably, it is an alkoxy group containing 1 to 8 carbon atoms, more preferably an alkoxy group containing 1 to 6 carbon atoms, and most preferably an alkoxy group containing 1 to 3 carbon atoms. Non-limiting examples of the alkoxy group include methoxy group, ethoxy group, propoxy group, butoxy group, cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group. The alkoxy group may optionally be substituted or unsubstituted. When substituted, the substituent is preferably independently one or more groups selected from alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, alkylamino group, halogen, mercapto group, hydroxy group, nitro group, amino group, cycloalkyl group, heterocyclylalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocyclylalkoxy group, cycloalkylthio group, heterocyclylalkylthio group, carboxy group or carboxylic acid ester group. When the above alkoxy group is substituted with a substituent, the above substituent is not further substituted.

[0093] The term "haloalkyl group" refers to an alkyl group substituted by one or more halogens, wherein the alkyl group is as defined above. Non-limiting examples of halomethyl groups include fluoromethyl group, chloromethyl group, bromomethyl group, iodomethyl group, difluoromethyl group, chlorofluoromethyl group, dichloromethyl group, bromofluoromethyl group, trifluoromethyl group, chlorodifluoromethyl group, dichlorofluoromethyl group, trichloromethyl group, bromodifluoromethyl group, bromochlorofluoromethyl group, dibromofluoromethyl group, etc., preferably fluoromethyl group, difluoromethyl group, trifluoromethyl group. Non-limiting examples of haloethyl groups include 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 2,2-difluoroethyl group, 2-chloro-2-fluoroethyl group, 2,2-dichloroethyl group, 2-bromo-2-fluoroethyl group, 2,2,2-trifluoroethyl group, 2-chloro-2,2-difluoroethyl group, 2,2-dichloro-2-fluoroethyl group, 2,2,2-trichloroethyl group, 2-bromo-2,2-difluoroethyl group, 2-bromo-2-chloro-2-fluoroethyl group, 2-bromo-2,2-dichloroethyl group, 1,1,2,2-tetrafluoroethyl group, pentafluoroethyl group, 1-chloro-1,2,2,2-tetrafluoroethyl group, 2-chloro-1,1,2,2-tetrafluoroethyl group, 1,2-dichloro-1,2,2-trifluoroethyl group, 2-bromo-1,1,2,2-tetrafluoroethyl group, etc., preferably 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, 2,2-difluoroethyl group.

[0094] The "haloalkoxy group" is an alkoxy group substituted by one or more halogens, wherein the alkoxy group is as defined above. Non-limiting examples of haloalkoxy groups include fluoromethoxy group, chloromethoxy group, bromomethoxy group, iodomethoxy group, difluoromethoxy group, chlorofluoromethoxy group, dichloromethoxy group, bromofluoromethoxy group, trifluoromethoxy group, chlorodifluoromethoxy group, dichlorofluoromethoxy group, trichloromethoxy group, bromodifluoromethoxy group, bromochlorofluoromethoxy group, dibromofluoromethoxy group, etc., preferably fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group. Non-limiting examples of haloethoxy groups include 2-fluoroethoxy group, 2-chloroethoxy group, 2-bromoethoxy group, 2,2-difluoroethoxy group, 2-chloro-2-fluoroethoxy group, 2,2-dichloroethoxy group, 2-bromo-2-fluoroethoxy group, 2,2,2-trifluoroethoxy group, 2-chloro-2,2-difluoroethoxy group, 2,2-dichloro-2-fluoroethoxy group, 2,2,2-trichloroethoxy group, 2-bromo-2,2-difluoroethoxy group, 2-bromo-2-chloro-2-fluoroethoxy group, 2-bromo-2,2-dichloroethoxy group, 1,1,2,2-tetrafluoroethoxy group, pentafluoroethoxy group, 1-chloro-1,2,2,2-tetrafluoroethoxy group, 2-chloro-1,1,2,2-tetrafluoroethoxy group, 1,2-dichloro-1,2,2-trifluoroethoxy group, 2-bromo-1,1,2,2-tetrafluoroethoxy group, etc., preferably 2-fluoroethoxy group, 2-chloroethoxy group, 2-bromoethoxy group, 2,2-difluoroethoxy group.

[0095] "Alkenyl group" refers to an alkenyl group, also known as an alkene group, among which the alkenyl group may be further substituted by other related groups, such as an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an alkylamino group, a halogen, a mercapto group, a hydroxy group, a nitro group, an amino group, a cycloalkyl group, a heterocyclylalkyl group, an aryl group, a heteroaryl group, a cycloalkoxy group, a heterocyclylalkoxy group, a cycloalkylthio group, a heterocyclylalkylthio group, a carboxy group or a carboxylic acid ester group.

[0096] "Alkynyl group" refers to (CH≡C-), among which the alkynyl group may be further substituted by other related groups, such as an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an alkylamino group, a halogen, a mercapto group, a hydroxy group, a nitro group, an amino group, a cycloalkyl group, a heterocyclylalkyl group, an aryl group, a heteroaryl group, a cycloalkoxy group, a heterocyclylalkoxy group, a cycloalkylthio group, a heterocyclylalkylthio group, a carboxy group or a carboxylic acid ester group.

[0097] "Hydroxy group" refers to the -OH group.

[0098] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0099] "Amino group" refers to -NH2.

[0100] "Cyano group" refers to -CN.

[0101] "Nitro group" refers to -NO2.

[0102] "Carboxyl group" refers to -C(O)OH.

[0103] The terms "comprising", "including", "having", "containing", or "involving" and other variations thereof in this specification are inclusive or open-ended and do not exclude other elements or method steps not recited. One of ordinary skill in the art should understand that the above terms such as "comprising" include the meaning of "consisting of".

[0104] The term "one or more" or a similar expression "at least one" can mean, for example, one, two, three, four, five, six, seven, eight, nine, ten or more.

[0105] When the lower and upper limits of a numerical range are disclosed, any numerical value within that range and any included range are specifically disclosed. In particular, each possible value range of the values disclosed herein should be understood to mean each value and range that encompasses a broader range.

[0106] In this specification, both "Z" and "-Z-" represent the same specific group and they can be used interchangeably.

[0107] As used herein, the expression m~n refers to the range from m to n, the subscope consisting of each point value therein, and each point value. For example, the expression "C2~C8" or "C2~8" encompasses the range of 2 to 8 carbon atoms, and any subscope and each point value therein, such as C2~C5, C3~C4, C2~C6, C3~C6, C4~C6, C4~C7, C4~C8, C2~C5, etc., and C2, C3, C4, C5, C6, C7, C8, etc. should be understood to be included. For example, the expression "C3~C10" or "C3~10" should also be understood in a similar manner, for example, any subscope and each point value included therein, such as C3~C9, C6~C9, C6~C8, C6~C7, C7~C10, C7~C9, C7~C8, C8~C9, etc., and C3, C4, C5, C6, C7, C8, C9, C10, etc. may be included. Also, for example, the expression "C1~C6" or "C1~6" encompasses the range of 1 to 6 carbon atoms, and any subscope and each point value therein, such as C2~C5, C3~C4, C1~C2, C1~C3, C1~C4, C1~C5, C1~C6, etc., and C1, C2, C3, C4, C5, C6, etc. should be understood to be included. Also, for example, the expression "3-membered to 10-membered" should be understood to include any subscope and each point value therein, such as 3-membered to 5-membered, 3-membered to 6-membered, 3-membered to 7-membered, 3-membered to 8-membered, 4-membered to 5-membered, 4-membered to 6-membered, 4-membered to 7-membered, 4-membered to 8-membered, 5-membered to 7-membered, 5-membered to 8-membered, 6-membered to 7-membered, 6-membered to 8-membered, 9-membered to 10-membered, etc., and 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, etc. Other similar expressions in this specification should also be understood in a similar manner.

[0108] The different terms used herein, such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C", etc., all represent the same meaning, that is, X may be any one or more of A, B, C.

[0109] As used herein, the terms "optionally" or "optionally selected" mean that the event or situation described thereafter may or may not occur, and the description includes both the case where the described event or situation occurs and the case where it does not occur. For example, "a cycloalkyl group optionally substituted with an alkyl group" means that an alkyl group may be present, but not necessarily, and the description includes both the case where the cycloalkyl group is substituted with an alkyl group and the case where the cycloalkyl group is not substituted with an alkyl group.

[0110] As used herein, the terms "substituted" and "substituting" mean that one or more (e.g., 1, 2, 3, or 4) hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the normal valence of the designated atom in its current situation is not exceeded and a stable compound is formed by the above substitution. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound. When a particular substituent is described as being absent, it should be understood that the substituent may be one or more hydrogen atoms, as long as the structure can render the compound stable. When each carbon atom in a group is optionally substituted with a heteroatom, the condition is that the normal valence of all atoms in the group in their current situation is not exceeded and a stable compound is formed.

[0111] When a substituent is described as "optionally... substituted", the substituent may be unsubstituted or substituted. When an atom or group is described as optionally substituted with one or more of a list of substituents, one or more hydrogens on the atom or group may be independently replaced with an optionally selected substituent. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. As used herein, unless otherwise specified, the point of attachment of a substituent may be from any suitable position of the substituent.

[0112] When the bond of a substituent indicates that it penetrates a bond connecting two atoms within a ring, such a substituent may be bonded to any one of the ring-constituting atoms within the ring that can be substituted.

[0113] When any variable (e.g., R) and labeled variables (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) appear one or more times within the composition or structure of a compound, the definitions in each case are independent for each occurrence. For example, when a group is substituted with 0, one, two, three, or four R substituents, the said group may optionally be substituted with at most four R substituents, and the options for each R substituent in each case are all independent of each other.

[0114] The term "pharmaceutically acceptable" substance refers to a substance that, within the scope of normal medical judgment, is suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic reaction, etc., has a reasonable benefit-risk ratio, and can be effectively used for its intended use.

[0115] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, and such a salt has safety and effectiveness when used in the body of a mammal and has the desired biological activity.

[0116] The term "pharmaceutical composition" refers to a mixture containing one or more compounds described in the present invention or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, and also includes other components, such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living body, contribute to the absorption of the active ingredient, and further exert biological activity.

[0117] The term "pharmaceutically acceptable carrier" refers to a substance that has no obvious stimulating effect on an organism and does not impair the biological activity and performance of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, flow promoters, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0118] As used herein, the terms "administer" or "give" refer to a method that enables a compound or composition to be delivered to a desired biological site of action. These methods include, but are not limited to, oral or parenteral (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, etc. In particular, injection or oral administration.

[0119] As used herein, the term "treatment" includes alleviating, reducing, or improving a disease or symptom, preventing other symptoms, improving or preventing the underlying metabolic factors of a symptom, suppressing a disease or symptom, e.g., preventing the progression of a disease or symptom, reducing a disease or symptom, promoting the alleviation of a disease or symptom, or arresting the symptoms of a disease or symptom, and extends to include prevention. "Treatment" further includes achieving a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit refers to the eradication or improvement of the medical condition being treated. Further, a therapeutic benefit is achieved by eradicating or improving one or more physiological symptoms associated with the underlying disease, and an improvement in the patient's disease can be observed even though the patient may still have the underlying disease. A prophylactic benefit refers to the use of a composition by a patient to prevent the risk of a particular disease, or the ingestion by a patient of a composition when the physiological medical condition of one or more diseases appears, even though the disease has not yet been diagnosed.

[0120] The terms "active ingredient", "therapeutic agent", "active substance", or "active agent" refer to a chemical substance that can effectively treat or prevent a target disorder, disease, or medical condition. The term "neuropsychiatric disease" refers to the general term for nervous system diseases and / or mental system diseases, including nervous system diseases and mental system diseases.

[0121] For a drug, drug unit, or active ingredient, the terms "effective amount," "therapeutically effective amount," or "prophylactically effective amount" refer to an amount of the drug or agent sufficient to achieve the desired effect while accompanying acceptable side effects. The effective amount is determined by a person and depends on the individual's age and general condition, as well as on the specific active substance. The suitable effective amount for an individual can be determined by those skilled in the art through routine testing.

[0122] As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) suffering from a disease (e.g., a disease described herein) or normal individuals. The "non-human animals" of the present invention include all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles), and mammals, e.g., non-human primates, domestic animals and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0123] The following detailed description of the invention is intended to illustrate non-limiting embodiments and enables those skilled in the art to more fully understand the technical solution of the invention, its principles, and its actual applications, so that the invention can be modified and implemented in many forms to best suit the requirements of a particular application.

[0124] [Beneficial Effects] In vitro receptor function tests indicate that the compounds of the present invention have an agonist effect on the MOR receptor and are effective in the prevention and / or treatment of related diseases mediated by μ-opioid receptor agonists, such as pain, immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric diseases, urogenital diseases, cardiovascular diseases, and respiratory diseases. The compounds of the present invention have relatively high inhibitory activity against cAMP and relatively high Emax values. Furthermore, the compounds of the present invention have relatively low Emax values against β-arrestin, are safer and more effective in the process of clinical use, and have a more excellent analgesic effect compared to the oral drug oxycodone, suggesting a significant improvement in patient compliance with medication.

[0125] [Specific implementation method] The embodiments of the present invention will be described in detail below with reference to the examples. However, as can be understood by those skilled in the art, the following examples are only for explaining the present invention and should not be regarded as limiting the scope of the present invention. When specific conditions are not specified in the examples, they are carried out under general conditions or conditions recommended by the manufacturer. The reagents or equipment used may be ordinary commercially available products even if the manufacturer is not specified. Unless otherwise specified, the ratios or percentages used in this specification are by weight.

Example

[0126] The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS).

[0127] The NMR chemical shift (δ) is shown in parts per million (ppm). The NMR measurement is carried out using an AVANCE III600 nuclear magnetic device. The measurement solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), and the internal standard is tetramethylsilane (TMS).

[0128] The measurement of liquid chromatography-mass spectrometry (LC-MS) is carried out using a Shimadzu LCMS2020 mass spectrometer in Japan. The HPLC measurement is carried out using a Shimadzu LC20A liquid chromatograph in Japan. The silica gel plate for thin layer chromatography uses a Yantai Jiangyou silica gel plate. The specification used for TLC is 0.2 mm ± 0.03 mm, and the specification used for the separation and purification of products by thin layer chromatography is 0.4 mm - 0.5 mm.

[0129] [Intermediate 1] 2-(4-(5-Fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)ethyl-1-amine 1a [Chemistry]

[0130] Synthesis Scheme: [Chemistry]

[0131] Step A: Preparation of 1,9-dioxaspiro[5.5]undecan-4-ol 3-Buten-1-ol (10.0 g, 142 mmol) and tetrahydropyrone (7.1 g, 71 mmol) were added to a flask, cooled to 0 °C, and 75% sulfuric acid (40 mL) was slowly added dropwise to the reaction solution. After gradually warming to room temperature, the reaction was carried out overnight. Water (100 mL) was added to the reaction system, the pH was adjusted to 8 with 10% sodium hydroxide solution, and the mixture was extracted with ethyl acetate (150 mL × 3). The ethyl acetate layer was washed with water (50 mL × 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and then the target product as a pale yellow oil (4.8 g, yield 40%) was obtained by silica gel column chromatography. 1 HNMR (600 MHz, DMSO-d6): δ4.62 (d, J = 4.5 Hz, 1H),3.78 - 3.73 (m, 1H), 3.67 (m, 1H), 3.62 - 3.58 (m, 1H), 3.55 - 3.47 (m, 4H),1.85 - 1.81 (m, 1H), 1.78 - 1.69 (m, 2H), 1.63 - 1.52 (m, 1H), 1.48 - 1.44 (m, 2H),1.30 - 1.21 (m, 1H), 1.10 (dd, J = 12.6, 10.5 Hz, 1H).

[0132] Step B: Preparation of 1,9-dioxaspiro[5.5]undecan-4-one 1,9-Dioxaspiro[5.5]undecan-4-ol (4.8 g, 28 mmol) was dissolved in dichloromethane (50 mL) in a flask, cooled to 0 °C, pyridinium chlorochromate (9.0 g, 42 mmol) was slowly added, and after warming to room temperature, the reaction was carried out overnight. It was filtered by suction, concentrated, and then the target product as a pale yellow oil (4.0 g, yield 85%) was obtained by column chromatography (petroleum ether:ethyl acetate = 5:1). 1 HNMR (600 MHz, DMSO-d6): δ3.93 (t, J = 6.1 Hz, 2H),3.60 - 3.53 (m, 4H), 2.42 - 2.30 (m, 4H), 1.77 - 1.61 (m, 2H), 1.60 - 1.48 (m, 2H).

[0133] Step C: Preparation of methyl (Z)-2-cyano-2-(1,9-dioxaspiro[5.5]undecane-4-ylidene)acetate 1,9-Dioxaspiro[5.5]undecan-4-one (4.0 g, 23.5 mmol), ammonium acetate (530 mg, 6.8 mmol), acetic acid (270 mg, 4.6 mmol), methyl cyanoacetate (2.6 g, 26.2 mmol) were dissolved in toluene (50 mL) in a flask and refluxed for 8 hours. The organic phase was washed with water (50 mL×3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered by suction, concentrated, and then the target product (5.6 g, yield 90%) was obtained by column chromatography (petroleum ether:ethyl acetate = 5:1). LC-MS: MS Found:252[M + H] + . 1 HNMR (600 MHz, DMSO-d6) : δ4.02 (s, 1H), 3.86 (t, J =5.7 Hz, 1H), 3.78 - 3.76 (m, 3H), 3.57 - 3.54 (m, 4H), 3.08 - 3.06 (m, 2H), 2.75 - 2.63(m, 2H), 1.68 - 1.63 (m, 2H), 1.61 - 1.47 (m, 2H).

[0134] Step D: Preparation of Methyl 2-Cyano-2-(4-(5-(fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)acetate Take 5-Fluoro-2-bromopyridine (5.35 g, 40 mmol), dissolve it in anhydrous tetrahydrofuran (15 mL), slowly add dropwise to an isopropylmagnesium chloride solution (20 mL, 40 mmol) at 0 °C, react at room temperature for 3 hours, add copper(I) iodide (0.76 g, 4 mmol), react for another 1 hour, dissolve Methyl (Z)-2-cyano-2-(1,9-dioxaspiro[5.5]undecane-4-ylidene)acetate (5.0 g, 20 mmol) in tetrahydrofuran (15 mL), add dropwise thereto, react at room temperature overnight, add saturated ammonium chloride solution (20 mL), extract with ethyl acetate (50 mL × 3), wash the organic phase with water (50 mL), wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, perform suction filtration, concentrate, and obtain the target product (3.3 g, yield 50%) by column chromatography (petroleum ether:ethyl acetate = 3:1). LC-MS: MS Found: 349 [M+H] + . 1 H NMR (600 MHz, CDCl3) δ 8.47 (dd, J = 7.0, 2.8 Hz, 1H), 7.64 - 7.27 (m, 2H), 3.91 - 3.63 (m, 8H), 3.46 - 3.33 (m, 2H), 2.94 - 2.58 (m, 2H), 2.15 (dd, J = 4.9, 1.8 Hz, 2H), 1.80 - 1.69 (m, 2H), 1.32 - 1.19 (m, 2H).

[0135] Step E: Preparation of 2-(4-(5-Fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)acetonitrile Methyl 2-cyano-2-(4-(5-(fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)acetate (3.0 g, 86 mmol) was taken and dissolved in ethylene glycol (10 mL), potassium hydroxide (1 g, 17 mmol) was added, and the mixture was reacted at 110 °C for 3 hours. Water (10 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL × 3). The ethyl acetate layer was washed with water (10 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain a pale yellow target product (1.7 g, yield 70%). LC-MS: MS Found:291[M+H] + . 1 HNMR (600 MHz, CDCl3): δ8.47 (d, J = 2.6 Hz, 1H), 7.50-7.34(m, 2H), 4.25-3.81 (m, 2H), 3.78-3.65 (m, 4H), 3.41-3.27 (m, 2H), 2.70-2.59 (m,2H), 1.95-1.83 (m, 2H), 1.70 (m, 2H), 0.97-0.94 (m, 2H).

[0136] Step F: Preparation of 2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl-1-amine 2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)acetonitrile (1.5 g, 5.2 mmol) was dissolved in ethanol (30 mL) and methanol (5 mL). After dropping aqueous ammonia (2 mL), a spatula of Raney nickel was added, and the mixture was stirred overnight at room temperature under hydrogen gas. After the reaction was completed, it was filtered through diatomaceous earth, and the filtrate was concentrated to obtain a yellow oily product 1a (1.3 g, yield 85%). LC-MS(m / z): 295.1[M+H] + .

[0137] [Intermediate 2] 2-(4-(5-Fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)acetaldehyde 1b

Chem.

[0138] Synthesis scheme:

Chem.

[0139] [Intermediate 3] (R)-2-(4-(5-Fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)acetonitrile 1c Synthesis scheme:

Chem.

[0140] [Example 1] (1S)-6-Fluoro-N-(2-(4-(5-Fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-1-amine 1-1

Chemical formula

[0141] Synthesis scheme:

Chemical formula

[0142] [Example 2] (1S)-4-Fluoro-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-1-amine 2-1

Chemical Structure

[0143] Synthesis Scheme: [Chemical formula] Adopt the synthesis method of Example 1, replace the raw material (S)-6-fluoro-2,3-dihydro-1H-inden-1-amine with (S)-4-fluoro-2,3-dihydro-1H-inden-1-amine, and obtain the target compound 2-1. LC-MS (m / z): 429.2 [M+H] + . 1 HNMR (600 MHz, DMSO-d6) δ8.80 (s, 1H), 8.58 - 8.56 (m, 1H), 7.78 - 7.71 (m, 1H), 7.66 - 7.62 (m, 1H), 7.34 - 7.30 (m, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.19 (t, J = 8.4 Hz, 1H), 4.73 - 4.66 (m, 1H), 3.71 - 3.69 (m, 1H), 3.59 - 3.51 (m, 3H), 3.28 - 3.20 (m, 2H), 3.03 - 2.97 (m, 1H), 2.87 - 2.81 (m, 2H), 2.57 - 2.52 (m, 2H), 2.40 - 2.34 (m, 1H), 2.31 - 2.25 (m, 1H), 2.10 - 1.91 (m, 2H), 1.79 - 1.71 (m, 1H), 1.61 - 1.54 (m, 2H), 1.48 (dd, J = 12.0, 6.0 Hz, 1H), 1.42 - 1.40 (m, 1H), 0.84 - 0.81 (m, 2H).

[0144] [Example 3] (1S)-N-(2-(-4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-1-amine 3-1 [Chemical formula]

[0145] Synthesis scheme: [Chemical formula] Adopt the synthesis method of Example 1, replace the raw material (S)-6-fluoro-2,3-dihydro-1H-inden-1-amine with (S)-2,3-dihydro-1H-inden-1-amine, and produce the target compound 3-1 to obtain it. LC-MS (m / z): 411.2 [M+H] + . 1 HNMR (600 MHz, CDCl3) δ8.39 (d, J = 2.4 Hz, 1H), 7.38 - 7.31 (m,2H), 7.23 - 7.10 (m, 4H), 4.65 - 4.62 (m, 1H), 4.17 - 4.01 (m, 1H), 3.83 - 3.59 (m,5H), 3.48 - 3.23 (m, 2H), 2.99 - 2.85 (m, 1H), 2.81 - 2.68 (m, 1H), 2.63 - 2.50 (m,2H), 2.46 (d, J = 13.7 Hz, 1H), 2.31 - 2.21 (m, 1H), 2.17 (m, 1H),1.96 - 1.85 (m, 1H), 1.82 - 1.63 (m, 4H), 1.50 (m, 1H), 0.92 - 0.87 (m, 2H).

[0146] [Example 4] 6-chloro-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-1-amine 4

Chemical formula

[0147] Synthesis scheme:

Chemical formula

[0148] [Example 5] (1S)-4-Chloro-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-1-amine 5-1

Chem.

[0149] Synthesis scheme:

Chem.

[0150] [Example 6] (1S)-N-(2-(4-(5-Fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-4-methyl-2,3-dihydro-1H-inden-1-amine 6-1

Chem.

[0151] Synthesis scheme:

Chem.

[0152] [Example 7] (1S)-4-Bromo-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-1-amine 7-1

Chem.

[0153] Synthesis scheme:

Chem.

[0154] [Example 8] N-(2-(4-(5-Fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine 8

Chem.

[0155] Synthesis scheme: [Chem.] Adopting the synthesis method of Example 4, replacing the raw material 6-chloro-2,3-dihydro-1H-inden-1-one with 1,3-dihydro-2H-inden-2-one, the target compound 8 was obtained by production. LC-MS (m / z): 411 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ8.57 (d, J = 3.0 Hz,1H), 7.78-7.74 (m, 1H), 7.64 (dd, J = 9.0, 4.2 Hz, 1H), 7.23-7.17 (m,4H), 4.54-4.51 (m, 1H), 3.91-3.86 (m, 1H), 3.72-3.70 (m, 1H), 3.62-3.50 (m,3H), 3.27-3.15 (m, 4H), 2.94-2.82 (m, 2H), 2.56-2.53 (m, 2H), 2.29-2.27 (m,1H), 1.96-1.94 (m, 1H), 1.78-1.74 (m, 1H), 1.61-1.39 (m, 5H), 0.81-0.76 (m,2H).

[0156] [Example 9] (R)-N-(2-(4-(5-Fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine 8-1 [Chem.]

[0157] Synthesis scheme: [Chem.]

[0158] Step A: Preparation of (R)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl-1-amine (R)-2-(4-(5-Fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)acetonitrile 1c (1.5 g, 5.2 mmol) was dissolved in ethanol (30 mL) and methanol (5 mL). After dropwise addition of aqueous ammonia (2 mL), five spatulas of Raney nickel were added, and the mixture was stirred overnight at room temperature under hydrogen gas. After completion of the reaction, it was filtered through diatomaceous earth, and the filtrate was concentrated to obtain (R)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl-1-amine 1a-1 (1.4 g, yield 91%) as a yellow oily product. LC-MS (m / z): 295.1 [M+H] + .

[0159] Step B: Preparation of (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine (R)-2-(4-(5-Fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl-1-amine 1a-1 (150 mg, 0.51 mmol) and 1,3-dihydro-2H-inden-2-one (67.32 mg, 0.51 mmol) were dissolved in tetra-isopropyl orthotitanate (2 mL). After stirring at 80 °C for 4 hours, methanol (3 mL) was added for dilution, and then sodium borohydride (37.83 mg, 1.0 mmol) was added. After stirring at room temperature for 0.5 - 1 hour, water was added to quench the reaction. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, and the obtained filtrate was washed with saturated brine, then dried and concentrated, and purified by a reverse-phase C18 column (water / acetonitrile = 25%) to obtain the target compound 8-1 (41 mg, yield 19%). LC-MS (m / z): 411 [M+H] + . 1HNMR (400 MHz, MeOD) δ 8.44 (d, J = 2.4 Hz, 1H), 7.61~7.54(m, 2H), 7.16~7.05 (m, 4H), 3.81~3.75 (m, 2H), 3.73 (dd, J = 11.0, 2.9 Hz, 1H), 3.68~3.60 (m, 1H), 3.45~3.33 (m, 4H), 3.03 (dd, J= 15.7, 7.3 Hz, 2H), 2.68~2.49 (m, 5H), 1.98 (td, J =12.5, 6.0 Hz, 2H), 1.69 (ddt, J = 11.8, 7.6, 2.6 Hz, 3H), 1.59 (d, J = 13.9 Hz,1H), 1.53~1.45 (m, 1H), 0.97 (dd, J = 7.4, 4.4 Hz, 2H).

[0160] [Example 10] 5-Fluoro-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine 9 [Chemical formula]

[0161] Synthesis scheme: [Chemical formula] The synthesis method of Example 4 was adopted, and 6-chloro-2,3-dihydro-1H-inden-1-one as the raw material was replaced with 5-fluoro-1,3-dihydro-2H-inden-2-one to produce the target compound 9. LC-MS(m / z):429[M+H] + . 11H NMR (600 MHz, DMSO-d6) δ8.57 (d, J = 3.0Hz, 1H), 7.75 (td, J = 6.0, 3.0 Hz, 1H), 7.64 (dd, J = 9.0, 4.2Hz, 1H), 7.25-7.23 (m, 1H), 7.08 (d, J = 9.0 Hz, 1H), 7.00 (t, J= 9.6 Hz, 1H), 4.58-4.55 (m, 1H), 3.95-3.91 (m, 1H), 3.72-3.70 (m, 1H),3.60-3.52 (m, 3H), 3.27-3.12 (m, 4H), 2.95-2.82 (m, 3H), 2.55-2.53 (m, 2H),2.28-2.26 (m, 1H), 1.98-1.93 (m, 1H), 1.77-1.73 (m, 1H), 1.61-1.41 (m, 4H),0.82-0.80 (m, 2H).

[0162] [Example 11] 4-Bromo-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine 10 [Chemical formula]

[0163] Synthesis scheme: [Chemical formula] The synthesis method of Example 4 was adopted, and 6-chloro-2,3-dihydro-1H-inden-1-one as the raw material was replaced with 4-bromo-1,3-dihydro-2H-inden-2-one to produce the target compound 10. LC-MS(m / z):490[M+H] + . 11H NMR (600 MHz, DMSO-d6) δ8.57 (d, J = 3.0 Hz,1H), 7.77-7.74 (m, 1H), 7.66-7.63 (m, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.25 (d, J= 7.8 Hz, 1H), 7.17-7.14 (m, 1H), 3.96-3.94 (m, 1H), 4.53-4.49 (m, 1H),3.72-3.70 (m, 1H), 3.60-3.52 (m, 3H), 3.33-3.17 (m, 4H), 3.05-2.84 (m, 3H),2.54-2.52 (m, 2H), 2.34-2.26 (m, 1H), 1.95-1.92 (m, 1H), 1.76-1.74 (m, 1H),1.60-1.40 (m, 4H), 0.82-0.80 (m, 2H).

[0164] [Example 12] (S)-4-Bromo-N-(2-((R)-4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine 10-1-1 and (R)-4-bromo-N-(2-((R)-4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine 10-1-2 [Chemical formula]

[0165] Synthesis scheme: [Chemical formula] The synthesis method of Example 9 was adopted, and the starting material 1,3-dihydro-2H-inden-2-one was replaced with 4-bromo-1,3-dihydro-2H-inden-2-one to produce the target compound 10-2.

[0166] Compound 10-2 was taken and separated, and after separation, two optical isomers were obtained: (S)-4-Bromo-N-(2-((R)-4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine 10-1-1, 2.08 min, 0.16 g, ee% = 96%; LC-MS (m / z): 490.5 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.45 (d, J = 2.9 Hz, 1H), 7.60 (td, J = 8.7, 3.0 Hz, 1H), 7.53 (dd, J = 8.9, 4.4 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 3.60 (ddd, J = 12.1, 5.0, 2.5 Hz, 1H), 3.55~3.42 (m, 3H), 3.24~3.10 (m, 4H), 2.94 (dd, J = 16.1, 7.0 Hz, 1H), 2.83 (dd, J = 16.3, 7.1 Hz, 1H), 2.51 (ddd, J = 15.9, 14.8, 4.0 Hz, 2H), 2.43~2.35 (m, 2H), 2.28 (td, J = 11.0, 5.0 Hz, 1H), 1.82 (td, J = 11.0, 4.7 Hz, 1H), 1.75~1.67 (m, 1H), 1.52~1.43 (m, 3H), 1.39 (d, J = 13.8 Hz, 1H), 1.32 (dt, J = 13.6, 3.6 Hz, 1H), 0.75 (d, J = 4.9 Hz, 2H). (R)-4-Bromo-N-(2-((R)-4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine 10-1-2, 2.98 min, 0.15 g, ee% = 96%; LC-MS (m / z): 490.5 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 2.9 Hz, 1H), 7.67(td, J = 8.8, 3.0 Hz, 1H), 7.60 (dd, J = 8.9, 4.4 Hz, 1H), 7.29 (d, J = 7.8 Hz,1H), 7.13 (d, J = 7.3 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 3.68 (ddd, J = 12.1,4.9, 2.4 Hz, 1H), 3.64~3.46 (m, 3H), 3.32~3.15 (m, 5H), 3.01 (dd, J = 16.0, 7.0 Hz, 1H), 2.89 (dd, J = 16.3,7.0 Hz, 1H), 2.62~2.52 (m, 2H), 2.49~2.43 (m, 1H), 2.36 (td, J = 10.9, 5.0 Hz, 1H), 1.92~1.73 (m, 2H), 1.56 (dq, J = 8.6, 4.1, 3.3 Hz, 2H), 1.52 (d, J = 5.2Hz, 1H), 1.49~1.34 (m, 2H), 0.81 (p, J = 4.7, 3.8 Hz,2H). Separation conditions: Instrument: Waters SFC 150; Column: DAICELCHIRALCEL (R) OZ, 250*25 mm 10 μm; Mobile phase: A: Supercritical CO2, B: MeOH (0.1% Ammonia in MeOH); Gradient: A:B = 50:50; Flow rate: 70 mL / min; Back pressure: 100 bar; Column temperature: 25 °C; Wavelength: 214 nm; Cycle: 6 min; Dissolve the compound to be separated in MeOH (40 mL); Injection: 1.8 mL.

[0167] [Example 13] N-(3-Chlorobenzyl)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxospiro[5.5]undecane-4-yl)ethane-1-amine 11 [Chemical formula]

[0168] Synthesis scheme:

Chem.

[0169] [Example 14] N-(3-chloro-2-methylbenzyl)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxospiro[5.5]undecan-4-yl)ethane-1-amine 12

Chem.

[0170] Synthesis scheme:

Chem.

[0171] [Example 15] (R)-N-(3-chloro-2-methylbenzyl)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxospiro[5.5]undecane-4-yl)ethane-1-amine 12-1

Chemical formula

[0172] Synthesis scheme: The synthesis method of Example 9 was adopted, and 1,3-dihydro-2H-inden-2-one as the raw material was replaced with 3-chloro-2-methylbenzaldehyde to produce the target compound 12-1. LC-MS (m / z): 433.2 [M+H] +. 1 HNMR (400 MHz, Methanol-d4) δ 8.29 (t, J = 1.8 Hz, 1H), 7.45~7.38 (m, 2H), 7.14 (dd, J = 5.6, 3.8 Hz, 1H), 6.99~6.93 (m, 2H), 3.67~3.56 (m, 3H), 3.56~3.46 (m, 3H), 3.28~3.22 (m, 2H), 2.47 (ddd, J = 14.3, 10.0, 2.3 Hz, 2H), 2.38 (td, J = 12.2, 11.7, 5.1 Hz, 1H), 2.19 (s, 3H), 1.92~1.80 (m, 2H), 1.64~1.50 (m, 3H), 1.46 (d, J = 14.1 Hz, 1H), 1.41~1.32 (m, 1H), 0.84 (dd, J = 7.3, 4.5 Hz, 2H).

[0173] [Example 16] N-(2,3-Dichlorobenzyl)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxospiro[5.5]undecan-4-yl)ethane-1-amine 13 [Chemical formula]

[0174] Synthesis scheme: [Chemical formula] Adopt the synthesis method of Example 4, replace the raw material 6-chloro-2,3-dihydro-1H-inden-1-one with 2,3-dichlorobenzaldehyde, and obtain the target compound 13. LC-MS (m / z): 453.2 [M+H] + . 11H NMR (600 MHz, CD3OD) δ8.48 - 8.40 (m, 1H), 7.62 - 7.52 (m, 2H), 7.45 - 7.36 (m, 3H), 7.31 (d, J = 7.4 Hz, 1H), 4.12 - 4.01 (m, 2H), 3.79 - 3.57 (m, 4H), 3.37 - 3.31 (m, 2H), 3.02 - 2.94 (m, 1H), 2.65 - 2.55 (m, 2H), 2.42 (td, J = 12.5, 4.4 Hz, 1H), 2.14 - 2.03 (m, 1H), 1.89 - 1.80 (m, 1H), 1.75 - 1.62 (m, 2H), 1.56 (d, J = 13.9 Hz, 1H), 1.45 (dd, J = 19.9, 8.8 Hz, 1H), 0.96 - 0.87 (m, 2H).

[0175] [Example 17] (R)-N-(2,3-dichlorobenzyl)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethane-1-amine 13-1 [Chemical formula]

[0176] The synthesis method of Example 9 was adopted, and the starting material 1,3-dihydro-2H-inden-2-one was replaced with 2,3-dichlorobenzaldehyde to produce the target compound 13-1. LC-MS(m / z): 454[M+H] + . 11H NMR (600 MHz, Deuterium Oxide) δ 8.37 (d, J = 2.8 Hz, 1H), 7.67(td, J = 8.4, 2.9 Hz, 1H), 7.59 (dd, J = 9.0, 4.3 Hz, 1H), 7.55 (p, J = 4.2 Hz,1H), 7.26~7.21 (m, 2H), 4.24~4.16(m, 2H), 3.74 (dd, J = 12.8, 4.5 Hz, 1H), 3.68 (t, J = 12.4 Hz, 1H), 3.61 (dd,J = 8.6, 2.7 Hz, 2H), 3.28 (tp, J = 11.7, 4.0 Hz, 2H), 2.98 (td, J = 12.6, 4.8Hz, 1H), 2.44 (dd, J = 20.9, 14.6 Hz, 2H), 2.25 (td, J = 12.7, 4.3 Hz, 1H),2.04~1.96 (m, 2H), 1.84 (td, J = 12.9, 4.8 Hz, 1H),1.73~1.59 (m, 3H), 1.44 (d, J = 14.1 Hz, 1H), 0.87 (dd,J = 9.2, 4.6 Hz, 2H).

[0177] [Example 18] N-(3-chloro-2-fluorobenzyl)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethane-1-amine 14 [Chemical Structure]

[0178] Synthesis Scheme: [Chemical Structure] The synthesis method of Example 4 was adopted, and 6-chloro-2,3-dihydro-1H-inden-1-one as the raw material was replaced by 3-chloro-2-fluorobenzaldehyde to produce the target compound 14. LC-MS (m / z): 438 [M+H] + . 1 1H NMR (600 MHz, DMSO-d6) δ 8.57 (d, J = 3.0 Hz, 1H), 7.74 (td, J = 9.0, 3.0 Hz, 1H), 7.67 - 7.62 (m, 2H), 7.43 (t, J = 6.0 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 4.43 - 4.39 (m, 1H), 4.14 - 4.12 (m, 2H), 3.71 - 3.69 (m, 1H), 3.59 - 3.51 (m, 3H), 3.27 - 3.21 (m, 2H), 2.88 - 2.86 (m, 1H), 2.56 - 2.53 (m, 2H), 2.31 - 2.30 (m, 1H), 1.96 - 1.94 (m, 1H), 1.78 - 1.75 (m, 1H), 1.59 - 1.40 (m, 4H), 0.82 - 0.80 (m, 2H).

[0179] [Example 19] N-(2-(4-(Pyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-1-amine 15 [Chemical formula]

[0180] Synthesis scheme: [Chemical formula]

[0181] Step A: Synthesis of methyl 2-cyano-2-(4-(pyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)acetate 2-Bromopyridine (4.74 g, 30 mmol) was taken and dissolved in anhydrous tetrahydrofuran (20 mL). It was slowly added dropwise to an isopropylmagnesium chloride solution (15 mL, 30 mmol) at 0 °C, and reacted at room temperature for 3 hours. Copper(I) iodide (0.57 g, 3 mmol) was added, and the reaction was continued for another 1 hour. Methyl (Z)-2-cyano-2-(1,9-dioxaspiro[5.5]undecane-4-ylidene)acetate (5.0 g, 20 mmol) was dissolved in tetrahydrofuran (15 mL) and added dropwise thereto. The reaction was carried out at room temperature overnight. Saturated ammonium chloride solution (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with water (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered by suction, concentrated, and then purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the target product (3.3 g, yield 50%). LC-MS (m / z): 331 [M+H] + .

[0182] Step B: Synthesis of 2-(4-(pyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)acetonitrile Methyl 2-cyano-2-(4-(pyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)acetate (3.0 g, 9.1 mmol) was taken and dissolved in ethylene glycol (10 mL). Potassium hydroxide (1 g, 17 mmol) was added, and the reaction was carried out at 110 °C for 3 hours. Water (10 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (20 mL × 3). The ethyl acetate layer was washed with water (10 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the target product as a pale yellow solid (1.8 g, yield 73%). LC-MS (m / z): 273 [M+H] + .

[0183] Step C: Synthesis of 2-(4-(pyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethan-1-amine 2-(4-(Pyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)acetonitrile (1.8 g, 6.6 mmol) was taken and dissolved in tetrahydrofuran (15 mL). Lithium aluminum hydride (750 mg, 19.8 mmol) was added under an ice bath, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, water (0.75 mL), 15% sodium hydroxide solution (2 mL), and water (2 mL) were added sequentially. Ethyl acetate (10 mL) was added, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the oily target product (1.5 g, yield 85%). LC-MS (m / z): 277 [M+H] + .

[0184] Step D: Synthesis of N-(2-(4-(pyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-1-amine 2-(4-(Pyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethane-1-amine (100 mg, 0.36 mmol) and 1-indanone (50 mg, 0.36 mmol) were taken and dissolved in titanium tetraisopropoxide (1 mL). The reaction was carried out at 80 °C for 5 hours, cooled to room temperature, methanol (1 mL) was added, sodium borohydride (38 mg, 1.0 mmol) was added, and the reaction was carried out for 1 hour. The completion of the reaction was monitored by LC-MS, filtered, concentrated, and purified by preparative liquid phase to obtain the target compound 15 (25.3 mg, yield 18%). LC-MS (m / z): 393 [M+H] + . 1HNMR (600 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.82 - 7.80 (m, 2H), 7.57 (dd, J = 7.8, 3.0 Hz, 1H), 7.39 - 7.30 (m, 2H), 7.29 (dd, J = 7.2, 4.8 Hz, 1H), 7.25 - 7.23 (m, 1H), 4.65 - 4.61 (m, 1H), 4.48 - 4.45 (m, 1H), 3.77 - 3.64 (m, 1H), 3.64 - 3.44 (m, 3H), 3.32 - 3.13 (m, 2H), 3.01 - 2.97 (m, 1H), 2.94 - 2.76 (m, 2H), 2.62 - 2.54 (m, 2H), 2.34 - 2.25 (m, 2H), 2.05 - 1.91 (m, 2H), 1.80 - 1.74 (m, 1H), 1.62 - 1.41 (m, 4H), 0.88 - 0.75 (m, 2H).

[0185] [Example 20] 4-Chloro-N-(2-(4-(pyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-1-amine 16 [Chemical formula]

[0186] The synthesis method of Example 16 was adopted, and the raw material 1-indanone was replaced with 4-chloro-1-indanone to produce the target compound 16. LC-MS (m / z): 428 [M + H] + . 11H NMR (600 MHz, DMSO-d6) δ 8.59 - 8.58 (m, 1H), 8.04 - 7.73 (m, 1H), 7.56 (dd, J = 7.8, 4.2 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.38 - 7.27 (m, 3H), 4.80 - 4.56 (m, 1H), 4.49 - 4.46 (m, 1H), 3.72 - 3.70 (m, 1H), 3.63 - 3.41 (m, 3H), 3.35 - 3.11 (m, 2H), 3.02 - 2.97 (m, 1H), 2.94 - 2.74 (m, 2H), 2.61 - 2.54 (m, 2H), 2.39 - 2.25 (m, 2H), 2.07 - 1.95 (m, 2H), 1.76 - 1.73 (m, 1H), 1.66 - 1.46 (m, 4H), 0.82 - 0.80 (m, 2H).

[0187] [Example 21] 4-Chloro-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine 17 [Chemical formula]

[0188] The synthetic method of Example 4 was adopted, and the raw material 6-chloro-2,3-dihydro-1H-inden-1-one was replaced with 4-chloro-1,3-dihydro-2H-inden-2-one to produce the target compound 17. LC-MS (m / z): 447 [M + H] + . 1HNMR (600 MHz, MeOD) δ 8.50 (t, J = 3.1 Hz, 1H), 7.63~7.58(m, 2H), 7.21 (ddd, J = 15.5, 7.8, 4.3 Hz, 3H), 4.04~3.95(m, 1H), 3.81~3.70 (m, 3H), 3.66~3.59 (m, 1H), 3.38 (ddt, J = 11.0, 7.2, 2.6 Hz, 4H), 3.10~3.02 (m, 1H), 2.97 (ddd, J = 19.4, 17.4, 5.4 Hz, 2H), 2.64 (dd, J =28.9, 13.9 Hz, 2H), 2.44 (dtd, J = 16.9, 12.5, 4.5 Hz, 1H), 2.10~2.02 (m, 1H), 1.81 (td, J = 12.8, 4.7 Hz, 1H), 1.76~1.66 (m, 2H), 1.57 (d, J = 13.8 Hz, 1H), 1.47 (d, J = 13.8 Hz, 1H),1.31 (dd, J = 15.3, 8.0 Hz, 1H), 0.95 (d, J = 2.5 Hz, 2H).

[0189] [Example 22] (S)-4-chloro-N-(2-((R)-4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine 17-1-1 and (R)-4-chloro-N-(2-((R)-4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine 17-1-2 [Chemical Structure]

[0190] Synthesis Scheme: [Chemical Structure] The synthesis method of Example 9 was adopted, and the raw material 1,3-dihydro-2H-inden-2-one was replaced with 4-chloro-1,3-dihydro-2H-inden-2-one to produce the target compound 17-2.

[0191] Compound 17-2 was taken and separated, and after separation, two optical isomers were obtained: (S)-4-chloro-N-(2-((R)-4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine 17-1-1, 2.10 min, ee% = 97%; LC-MS (m / z): 445 [M+H] + . 1 1H NMR (600 MHz, DMSO) δ 8.56 (s, 1H), 7.74 (d, J = 16.6 Hz,1H), 7.62 (s, 1H), 7.18 (d, J = 36.2 Hz, 4H), 3.83~3.76 (m, 1H), 3.70 (d, J = 11.9 Hz, 1H), 3.60~3.51 (m, 4H), 3.21 (d, J = 11.3 Hz, 1H), 3.12 (dd, J =16.1, 7.8 Hz, 1H), 2.94~2.83 (m, 2H), 2.76 (dd, J= 11.8, 8.6 Hz, 1H), 2.54 (d, J = 13.9 Hz, 2H), 2.21 (dd, J =11.7, 8.1 Hz, 1H), 1.96 (td, J = 12.5, 4.1 Hz, 1H), 1.91 (s, 1H), 1.77(dt, J = 12.3, 6.2 Hz, 1H), 1.64~1.53 (m, 2H),1.48 (d, J = 14.0 Hz, 1H), 1.41 (d, J = 13.5 Hz, 1H), 0.81 (s,2H). (R)-4-chloro-N-(2-((R)-4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecan-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine 17-1-2, 3.1 min, ee% = 97%; LC-MS (m / z): 445 [M+H] + . 1 1H NMR (600 MHz, DMSO) δ 8.55 (s, 1H), 7.71 (td, J = 8.7, 2.5 Hz, 1H), 7.62 (dd, J = 8.8, 4.1 Hz, 1H), 7.19 (dt, J = 16.8, 7.5 Hz, 3H), 3.74~3.66 (m, 2H), 3.61~3.49 (m, 4H), 3.22 (d, J = 6.1 Hz, 1H), 3.15 (dd, J = 16.4, 7.5 Hz, 1H), 3.09 (dd, J = 16.5, 7.6 Hz, 1H), 2.88~2.76 (m, 2H), 2.67 (s, 1H), 2.55 (d, J = 14.3 Hz, 2H), 2.08 (d, J = 14.0 Hz, 1H), 2.08 (d, J = 14.0 Hz, 1H), 1.90 (t, J = 10.4 Hz, 1H), 1.69 (t, J = 10.3 Hz, 1H), 1.62~1.52 (m, 2H), 1.48 (d, J = 13.8 Hz, 1H), 1.40 (d, J = 13.2 Hz, 1H), 0.80 (s, 2H). Separation conditions: Instrument: Waters SFC 150; Column: DAICEL CHIRALCEL (R) OZ, 250*25 mm 10 μm; Mobile phase: A: Supercritical CO2, B: MeOH (0.1% Ammonia in MeOH); Gradient: A:B = 50:50; Flow rate: 70 mL / min; Back pressure: 100 bar; Column temperature: 25 °C; Wavelength: 214 nm; Cycle: 6 min; Dissolve the compound to be separated in MeOH (40 mL); Injection: 1.8 mL.

[0192] [Example 23] (R)-N-(2-Chlorobenzyl)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxospiro[5.5]undecan-4-yl)ethane-1-amine 18-1 [Chemical formula]

[0193] The synthesis method of Example 9 was adopted, and the raw material 1,3-dihydro-2H-inden-2-one was replaced with 2-chlorobenzaldehyde to produce the target compound 18-1. LC-MS (m / z): 419 [M+H] + . 1 HNMR (600 MHz, DMSO) δ 9.30 (d, J = 57.3 Hz, 1H), 8.55 (d, J = 3.0 Hz, 1H), 7.73(td, J = 8.8, 3.0 Hz, 1H), 7.67~7.61 (m, 2H), 7.51 (dd,J = 7.8, 1.2 Hz, 1H), 7.40 (dtd, J = 19.3, 7.4, 1.5 Hz, 2H), 4.12 (t, J = 6.0Hz, 2H), 3.75~3.67 (m, 1H), 3.54 (ddd, J = 15.4, 14.9,7.9 Hz, 3H), 3.30~3.18 (m, 2H), 2.89~2.78 (m, 1H), 2.54 (d, J = 13.2 Hz, 2H), 2.34~2.24 (m, 1H), 2.06 (td, J = 12.8, 4.5 Hz, 1H), 1.88 (td, J = 12.7,4.2 Hz, 1H), 1.62~1.53 (m, 2H), 1.48 (d, J = 13.9 Hz,1H), 1.42 (d, J = 13.5 Hz, 1H), 0.86~0.77 (m, 2H).

[0194] [Example 24] (R)-N-(2-(Difluoromethoxy)benzyl)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxospiro[5.5]undecane-4-yl)ethane-1-amine 19-1 [Chemical formula]

[0195] The synthesis method of Example 9 was adopted, and the raw material 1,3-dihydro-2H-inden-2-one was replaced with 2-difluoromethoxybenzaldehyde to produce the target compound 19-1. LC-MS (m / z): 451 [M+H] + . 1 HNMR (600 MHz, DMSO) δ 8.53 (d, J = 2.9 Hz, 1H), 7.72 (d, J = 2.9Hz, 1H), 7.66~7.57 (m, 2H), 7.44 (s, 1H), 7.38~7.07 (m, 3H), 3.97 (t, J = 5.8 Hz, 2H), 3.76~3.62 (m, 1H), 3.53 (dd, J = 16.1, 3.7 Hz, 3H), 3.22 (dd, J= 10.8, 9.0 Hz, 2H), 2.75 (dd, J = 8.0, 4.0 Hz, 1H), 2.52 (d, J =14.9 Hz, 2H), 2.48 (s, 1H), 2.28~2.15 (m, 1H), 2.11~2.01 (m, 1H), 1.89 (d, J = 4.1 Hz, 1H), 1.55 (ddd, J =13.3, 8.3, 3.7 Hz, 2H), 1.46 (d, J = 13.8 Hz, 2H), 0.80 (s, 2H).

[0196] [Biological Activity Evaluation] Hereinafter, the present invention will be further described in combination with test examples, but these test examples do not limit the scope of the present invention. The structure and source of oxycodone in the test examples are shown in Table 1 below: [Table 1]

[0197] [Test Example 1] 1.1 Experimental Purpose The purpose of this experiment was to test the agonist effect of the compound of the present invention on MOR and evaluate the in vitro activity of the compound according to the magnitudes of EC 50 and Emax.

[0198] 1.2 The experimental materials are shown below [Table 2] [Table 3]

[0199] 1.3 Experimental procedures 1.3.1 Reagent preparation 1.3.1.1 Preparation of experimental buffer The 5×stimulation buffer was diluted to 1× with ddH2O, and an appropriate amount of 500 mM IBMX (generally, the IBMX stock solution is prepared at 500 mM, i.e., 1000X) was added to make the final concentration of IBMX 0.5 mM, and it was uniformly mixed for future use (it is a common phenomenon that precipitation occurs when adding IBMX, and it should be thoroughly and uniformly mixed to dissolve the precipitate). It must be prepared when used.

[0200] 1.3.1.2 IBMX was prepared by dissolving it in a 500 mM stock solution using DMSO, dispensed into 20 μL / tube, and stored frozen at -80°C to avoid repeated freezing and thawing.

[0201] 1.3.1.3 Forskolin was prepared by dissolving it in a 10 mM stock solution using DMSO, dispensed into 20 μL / tube, and stored frozen at -20°C for future use.

[0202] 1.3.1.4 Preparation of cAMP standard The cAMP standard in the reagent kit was taken out and returned to room temperature, an equal volume of experimental buffer was added according to the volume indicated on the bottle label, vortexed to mix uniformly, dispensed into 50 μL / tube, and stored frozen at -20°C for future use.

[0203] 1.3.1.5 Preparation of detection reagent stock solution (packaged for 20000 tests) One vial each of cAMP-d2 and Anti-cAMP-Cryptate lyophilized powder was taken, 5 mL of ddH2O was added to each, and they were gently inverted up and down to mix uniformly. They were dispensed according to specifications such as 125, 62.5, and 30 μL, and stored frozen at -80°C in the dark.

[0204] 1.3.2 Experimental Procedure for Agonist Test 1.3.2.1 For the positive compound DAMGO and the test compound, 4-fold serial dilutions at 10 concentrations were performed on Bravo using the experimental buffer in a compound plate (Greiner-781280), with starting concentrations of 2 μM (diluted from the DMSO stock solution with the experimental buffer) and 20 μM (diluted from the DMSO stock solution with the experimental buffer), respectively.

[0205] 1.3.2.2 The cryopreserved cells were taken and thawed in a 37°C water bath. The cell suspension was added to a centrifuge tube containing 10 mL of HBSS buffer and centrifuged at 750 rpm for 5 minutes. The supernatant was discarded, the precipitate was resuspended in an appropriate amount of experimental buffer, and 20 μL was taken and counted using a cell counter. An appropriate amount of the cell suspension was taken and diluted to 0.4×10 6 cells / mL. 5 μL of the cell suspension was added to each well in the cell plate (cell density was 2000 cells / well), and centrifuged at 1000 rpm for 1 minute. Using Bravo, 5 μL of the diluted compound was transferred to the cell plate (PerkinElmer-6008280), 5 μL of 2 μM DAMGO (final concentration 1 μM) was transferred to the positive control well, and an equal volume of the experimental buffer was transferred to the negative control well, and centrifuged at 1000 rpm for 1 minute. The cell plate was sealed and incubated at room temperature for 15 minutes. Forskolin was diluted to 0.2 mM in DMSO, 25.1 nL was transferred to the cell plate using Tecan-D300e, and after centrifuging at 1000 rpm for 1 minute, the plate was sealed and incubated at room temperature for 45 minutes. The final concentration of Forskolin was 1 μM.

[0206] 1.3.2.3 A cAMP (stock solution concentration: 2848 nM) calibration curve was prepared: The starting concentration was 1424 nM, and serial four-fold dilutions were performed for eight concentrations. 10 μL was taken and added to the cell plate. The final concentration at the starting point was 712 nM.

[0207] 1.3.2.4 Preparation of the detection reagent: Appropriate amounts of cAMP-d2 stock solution and Anti-cAMP-Cryptate stock solution were taken, diluted 1:20 with the dissolution buffer respectively, and then the two solutions were mixed uniformly by inverting up and down at a ratio of 1:1, and vortexing was prohibited. 10 μL of the prepared detection reagent was added to the cell plate and centrifuged at 1000 rpm for 1 minute. The cell plate was incubated at room temperature for 1 hour in the dark. After centrifuging the cell plate at 1000 rpm for 1 minute, plate reading was performed using Envision. The excitation light was 340 nm, and the emission lights were 620 nm and 665 nm.

[0208] 1.3.3 Data analysis The calculation formula for the activation rate of the compound in the agonist test was as follows: Activity% = 100 - (Readout - LC) / (HC - LC) * 100 HC (High Control): The average value of the readout of the DMSO + 2.5 μM Forskolin wells LC (Low Control): The average value of the readout of the 1 μM Dopamine + 2.5 μM Forskolin wells Readout: The compound readout

[0209] 1.3.4 Test results The changes in activating MOR of the compound of the present invention and affecting the downstream cAMP level were measured by the above experiments, and the measured EC 50 is shown in Table 4 below (the maximum effect of DAMGO is 100%).

Table 4

[0210] Conclusion: The above results indicate that the compounds described in the present invention have relatively strong agonist activity against MOR. The compounds provided by the present invention can maintain the analgesic effect while significantly reducing the dosage, thereby reducing the side effects during the clinical use process. Therefore, the compounds of the present invention have broad prospects in the clinical application in the field of analgesia.

[0211] [Test Example 2] 2.1 Experimental Purpose This experiment was to test the agonist effect of the compound on MOR Beta-arrestin and evaluate the in vitro activity of the compound according to the magnitude of EC 50 and Emax.

[0212] 2.2 Experimental Consumables and Equipment are shown below

Table 5

[0213] 2.3 Experimental Reagents are shown below

Table 6

[0214] 2.4 Experimental Method 2.4.1 Preparation of Compounds i) Dissolve the compound sample in DMSO to a storage concentration of 10 mM, ii) Prepare a sample dilution sequence on a 384-well LDV plate. All the initial concentration points of the samples are 10 mM (FAC = 30 uM), with a 3.162-fold gradient dilution, resulting in a total of 11 concentration points. iii) Use the Echo device to transfer the sample dilution sequence, HPE, and ZPE to a compound plate (PE#6008590), transferring 90 nL per well.

[0215] 2.4.2 Experimental Procedures i) Culture the MORbeta-arrestin cell line in complete cell medium at 37 °C and 5% CO2 until 70% - 90% confluence. ii) Digest the cells and resuspend them in cell seeding medium. Add 20 μL of the MOR beta-arrestin cell suspension to each well of the experimental plate (Corning#3570), with 7500 cells per well, and incubate in an incubator at 37 °C and 5% CO2 for 24 h. iii) Add 30 μL of experimental buffer to the compound plate (PE#6008590) and centrifuge at 1000 rpm for 5 min. iv) After 24 h, remove the experimental plate, discard the medium in the plate, and then use Bravo to transfer 20 μL of the compound from each well of the compound plate to the corresponding well of the experimental plate. v) Centrifuge the experimental plate at 500 rpm for 30 sec, then place it in an incubator at 37 °C and 5% CO2 and incubate for 90 min. vi) Add 10 μL of beta-arrestin detection reagent to each well of the experimental plate. vii) Incubate for 1 h at room temperature in the dark and then read with Envision.

[0216] 2.5 Method for Processing Experimental Data The experimental data were fitted to a parametric non-linear logic for percentage activation rate and 11-point concentration data using XLFit. EC of the compound 50The value was calculated by an equation, and the test results are shown in Table 7 (the maximum effect of DAMGO is 100%). [Table 7]

[0217] Conclusion: The above results indicate that the compounds described in the present invention have little activating effect on the Beta-arrestin signaling pathway, that the compounds provided by the present invention have no obvious side effects, and are safer and more effective in the process of clinical use.

[0218] [Test Example 3] 3.1 Experimental Purpose This experiment was to measure the effect of each compound sample on the pain threshold of mice using the mouse thermal radiation tail flick method.

[0219] 3.2 The experimental reagents are shown below [Table 8]

[0220] 3.3 Experimental Method 3.3.1 Dosage and Route: It was force-fed orally at a dose of 10 mg / kg.

[0221] 3.3.2 Experimental Procedure First, ICR mice (general grade, body weight 25 - 35 g, purchased from Shanghai Slack Experimental Animal Technology Co., Ltd.) were fixed in a special plastic cylinder, with their tails exposed and hanging naturally. After the animals calmed down, measurements were taken. The radiant heat source used was an 8.75 mm projection lamp (32 W, adjustable). After being focused by a lens, it emitted a beam with a diameter of approximately 4 mm, irradiating the skin corresponding to the boundary of the middle and lower one-third of the tail (the light source must be in close contact with the tail skin). An electronic timer connected in parallel with the light source was used to synchronously record the irradiation duration. That is, at the same time as the irradiation started, the stopwatch was automatically activated, and when an obvious avoidance reaction appeared in the animal's tail, the timing was automatically stopped. The measured time interval was the latency of the tail flick reaction. Mice with a tail flick latency of 2 - 6 seconds were screened for group administration experiments. When the animal showed an analgesic effect exceeding 15 seconds, the irradiation was stopped, and 15 seconds was set as the upper limit of the tail flick latency to avoid skin burns caused by excessive irradiation. After administering a certain dose of the drug to the mice, the pain threshold of the mice was measured at different times.

[0222] 3.4 Detection indicators and statistical methods: After administering a certain dose of the drug to the mice, the pain threshold of the mice was measured at 0.5 h, 1 h, 2 h, and 3 h (the analgesic effect diagram is shown in Figure 1). The maximum analgesic percentage (%MPE) after drug administration was calculated, and its calculation formula was %MPE = (pain threshold after drug administration - pain threshold before drug administration) / (15 - pain threshold before drug administration) × 100%.

Table 9

[0223] Conclusion: The above results show that at the same dose, the compounds described in the present invention, especially Compound 8 - 1 and Compound 12 - 1, have better drug effects compared to oxycodone. Among them, Compound 8 - 1 and Compound 12 - 1 have a longer analgesic duration and statistically superior analgesic maintenance effect compared to oxycodone.

[0224] Although specific embodiments of the present invention have been described in detail, based on all the disclosed teachings, those skilled in the art can make various modifications and substitutions to the details of the technical solution of the present invention, and all these changes are within the protection scope of the present invention. The full scope of the present invention is defined by the appended claims and any equivalents thereof.

Claims

1. A compound represented by the general formula (I), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein 【Chemical 1】 among them, Ring A is C 6-10 an aryl group or a 5- to 6-membered heteroaryl group, and the 5- to 6-membered heteroaryl group is a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms R 1 are the same as or different from each other, R 1 and R 2 are each independently hydrogen, halogen, hydroxy group, amino group, nitro group, cyano group, C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group or C 1-6 haloalkoxy group, wherein the C 1-6 alkyl group is optionally further substituted with one or more substituents selected from the group consisting of C 3-6 cycloalkyl group, C 1-6 alkyl group and halogen, Ring B is a phenyl group or a pyridyl group, optionally substituted with 1 to 4 R 3 and further substituted with R 3 are the same as or different from each other, and each independently is hydrogen, halogen, a hydroxy group, an amino group, a nitro group, a cyano group, C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group or C 1-6 haloalkoxy group, and X 1 is CR a R b or CR a R b CH 2 and is R a and R b each independently represent hydrogen, halogen or a C 1-3 alkyl group, Alternatively, R a or R b is linked to R 2 to form a single cyclopentyl or cyclohexyl group, optionally further substituted with one or more substituents selected from the group consisting of fluorine, chlorine, bromine, methyl group, ethyl group, propyl group, methoxy group, ethoxy group, halomethyl group, haloethyl group, halomethoxy group and haloethoxy group, n is 0, 1, 2, or 3, the compound, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt.

2. Satisfies any one of the following conditions (1) to (6): (1) The ring A is a phenyl group, (2) The aforementioned X 1 is CR a R b or CR a R b CH 2 and among them, R a and R b are each independently hydrogen, halogen or a C 1-3 alkyl group, or R a or R b is linked to R 2 to form one cyclopentyl group. (3) The ring B is, 【Chemical 2】 and (4) The aforementioned R 1 and R 2 are each independently hydrogen, halogen, C 1-3 alkyl group or C 1-3 haloalkoxy group, and (5) said R 3 is hydrogen, fluorine, chlorine or bromine, (6) The n is 0, 1, or 2, The compound, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt according to claim 1, characterized in that.

3. Satisfies any one of the following conditions (1) to (4): (1) The aforesaid X 1 is CH 2 and (2) The ring B is 【Chemical 3】 and (3) The above R 1 is hydrogen, fluorine, chlorine, bromine, a methyl group, an ethyl group, a propyl group or a halomethoxy group, and (4) The aforementioned R 2 is hydrogen, The compound, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt according to claim 2, characterized in that.

4. Satisfies any one of the following conditions (1) to (3): (1) The aforesaid X 1 is CH(R b ) or CH(R b )CH 2 , wherein, R b is linked to R 2 to form one cyclopentyl group, (2) The ring B is 【Chemical Formula 4】 and (3) said R 1 is hydrogen, fluorine, chlorine, bromine, methyl group, ethyl group or propyl group, The compound, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt according to claim 2, characterized in that.

5. The general formula (I) further has a structure represented by the general formula (II): [Chemical Formula 5] Among them, ring A, R 1 , R 3 and n are as defined in claim 1, The compound, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt according to claim 1, characterized in that.

6. The general formula (I) further has a structure represented by the general formula (II-1): 【Chemical Formula 6】 Among them, the ring A, R1, R3, and n are as described in claim 1, The compound, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt according to claim 1, characterized in that.

7. 【Fig. 7】 is 【Chemical 8】 and among them, R aa 、R bb 、R cc 、R dd or R ee is independently a halogen, a hydroxy group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group or a C 1-6 haloalkoxy group, wherein the C 1-6 alkyl group is optionally further substituted with one or more substituents selected from the group consisting of a C 3-6 cycloalkyl group, a C 1-6 alkyl group or a halogen, The compound, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt according to claim 5, characterized in that.

8. Said R aa , R bb , R cc , R dd and R ee are each independently fluorine, chlorine, bromine, a methyl group, an ethyl group, a propyl group or a fluoromethoxy group, Said R aa is a chlorine or fluoromethoxy group, Said R dd is chlorine, Said R ee is fluorine, chlorine or a methyl group, The compound, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt according to claim 7, characterized in that.

9. 【Fig. 9】 is 【Chemical Formula 10】 and The compound, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt according to claim 5, characterized in that.

10. The general formula (I) has a structure represented by the general formula (III): 【Chemical Formula 11】 Among them, ring C is a cyclopentyl group, and R 1 , R 3 and n are as described in claim 1, The compound, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt according to claim 1, characterized in that.

11. The general formula (III) has a structure represented by the general formula (IV) or the general formula (V): 【Chemical Formula 12】 Among them, the carbon atom with "*" is an asymmetric carbon atom and exists in the form of (R) or (S) single enantiomer or in a form rich in a pair of enantiomers, and the carbon atom with "#" is an asymmetric carbon atom and exists in the form of (R) or (S) single enantiomer or in a form rich in a pair of enantiomers. The compound according to claim 10, its stereoisomer, its tautomer or its pharmaceutically acceptable salt, characterized in that.

12. General formula (III) has a structure represented by general formula (IV-1), general formula (IV-2), general formula (V-1) or general formula (V-2): 【Chemical Formula 13】 Among them, the carbon atom with "*" is an asymmetric carbon atom and exists in the form of (R) or (S) single enantiomer or in a form rich in a pair of enantiomers. The compound according to claim 10, its stereoisomer, its tautomer or its pharmaceutically acceptable salt, characterized in that.

13. General formula (III) has a structure represented by general formula (IV-1-1), general formula (IV-1-2), general formula (V-1-1) or general formula (V-1-2): 【Chemical Formula 14】 The compound according to claim 10, its stereoisomer, its tautomer or its pharmaceutically acceptable salt, characterized in that.

14. 【Fig. 15】 is 【Chemical 16】 and 【Chemical 17】 is 【Chemical Formula 18】 and Among them, R aa , R bb , R cc and R dd are each independently a halogen, a hydroxy group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group or a C 1-6 haloalkoxy group, wherein the C 1-6 alkyl group is optionally further substituted with one or more substituents selected from the group consisting of a C 3-6 cycloalkyl group, a C 1-6 alkyl group or a halogen, The compound according to claim 13, its stereoisomer, its tautomer or its pharmaceutically acceptable salt, characterized in that.

15. Said R aa , R bb , R cc and R dd are each independently fluorine, chlorine, bromine, a methyl group, an ethyl group or a propyl group, Said R aa is fluorine, chlorine or bromine, Said R bb is fluorine, chlorine or bromine, Said R dd is fluorine, chlorine, bromine, a methyl group, an ethyl group or a propyl group, The compound according to claim 14, its stereoisomer, its tautomer or its pharmaceutically acceptable salt, characterized in that.

16. Satisfies any one of the following conditions (1) to (2): （1） 【Chemical 19】 is 【Chemical 20】 and （2） 【Chemical 21】 is 【Chemical 22】 and The compound according to any one of claims 13, its stereoisomer, its tautomer or its pharmaceutically acceptable salt, characterized in that.

17. The said compound is any one of the following structures: 【Chemical 23】 The compound according to claim 1, its stereoisomer, its tautomer or its pharmaceutically acceptable salt, characterized in that.

18. The said compound is any one of the following structures: 【Chemical Formula 24】 The compound according to claim 1, its stereoisomer, its tautomer or its pharmaceutically acceptable salt, characterized in that.

19. The said compound is any one of the following structures: 【Chemical 25】 The compound according to claim 17, its stereoisomer, its tautomer or its pharmaceutically acceptable salt, characterized in that.

20. A process for preparing a compound represented by general formula (I), a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, 【Chemical 26】 wherein the compound of general formula (I-A) and the compound of general formula (I-B) or a pharmaceutically acceptable salt thereof are subjected to a reductive amination reaction to obtain the compound of general formula (I), a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, Among them, ring A, R 1 , R 2 , ring B, X 1 and n are as described in claim 1, characterized by the above.

21. A process for preparing a compound represented by general formula (II), a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof according to claim 5, Method 1: 【Chemical 27】 wherein the compound of general formula (II-A-1) and the compound of general formula (II-B-1) or a pharmaceutically acceptable salt thereof are subjected to a reductive amination reaction to obtain the compound of general formula (II), a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, or Method 2: 【Chemical Formula 28】 wherein the compound of general formula (II-A-2) and the compound of general formula (II-B-2) or a pharmaceutically acceptable salt thereof are subjected to a reductive amination reaction to obtain the compound of general formula (II), a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, Among them, ring A, R 1 , R 3 and n are as described in claim 5, characterized by the above.

22. A process for preparing a compound represented by general formula (III), a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, Method 1: 【Chemical 29】 wherein the compound of general formula (III-A-1) and the compound of general formula (III-B-1) or a pharmaceutically acceptable salt thereof are subjected to a reductive amination reaction to obtain the compound of general formula (III), a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, or Method 2: 【Chemical 30】 wherein the compound of general formula (III-A-2) and the compound of general formula (III-B-2) or a pharmaceutically acceptable salt thereof are subjected to a reductive amination reaction to obtain the compound of general formula (III), a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein ring C is a cyclopentyl group, R 1s are the same as or different from each other, and R 1 and R 2 are each independently hydrogen, halogen, hydroxy group, amino group, nitro group, cyano group, C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group or C 1-6 haloalkoxy group, wherein the C 1-6 alkyl group is optionally further substituted with one or more substituents selected from the group consisting of C 3-6 cycloalkyl group, C 1-6 alkyl group and halogen, R 3s are the same as or different from each other, and each is independently hydrogen, halogen, hydroxy group, amino group, nitro group, cyano group, C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group or C 1-6 haloalkoxy group, n is 0, 1, 2 or 3, characterized in that it is a production method.

23. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 19, its stereoisomer, its tautomer or its pharmaceutically acceptable salt, and at least one pharmaceutical additive selected from pharmaceutically acceptable carriers, diluents and excipients. Pharmaceutical composition.

24. A pharmaceutical composition for preventing and / or treating related diseases mediated by a μ-opioid receptor agonist, comprising the compound according to any one of claims 1 to 19, its stereoisomer, its tautomer or its pharmaceutically acceptable salt, wherein the related diseases mediated by the μ-opioid receptor agonist are selected from one or more of pain, immune dysfunction, inflammation, gastroesophageal reflux, neurological and psychiatric diseases, urogenital diseases, cardiovascular diseases and respiratory diseases. Pharmaceutical composition.

25. A pharmaceutical composition for preventing and / or treating pain or pain-related diseases, comprising the compound according to any one of claims 1 to 19, its stereoisomer, its tautomer or its pharmaceutically acceptable salt, wherein the pain is selected from one or more of postoperative pain, pain caused by cancer, neuropathic pain, traumatic pain, and pain caused by inflammation. Pharmaceutical composition.

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