Ozaspirocyclic derivatives, preparation methods and uses

Abstract

This invention relates to oxaspirocyclic derivatives, their preparation methods, and their uses. Specifically, this invention provides a compound of general formula (I), its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof, and a method for their preparation, for activating opioid receptor activity, and for their use in the preparation of analgesic drugs.

Description

Technical Field

[0001] This application claims priority to Chinese patent applications 202110895052X and 202110888850X, filed on August 2, 2021. The full text of the aforementioned Chinese patent applications is incorporated herein by reference.

[0002] This invention belongs to the pharmaceutical field, specifically relating to an oxaspirocyclic derivative, its preparation method, and its uses. Prior Technology

[0003] Opium receptors belong to the G protein-coupled receptor (GPCR) family. Currently, nine opium receptors, including μ, δ, κ, and ORL1, have been identified, widely expressed in the central and peripheral nervous systems, neuroendocrine cells, immune cells, and endothelial cells. μ (MOR), δ (DOR), and κ (KOR) opium receptors regulate a range of bodily behaviors through the central nervous system, including pain perception, emotion, stress response, and addictive behavior. Among these, μ, δ, and κ opium receptors are classic opium receptors, sharing a common basic structure: both an extracellular aminoterminal region and an intracellular carboxylterminal region. The agonists of these three subtypes primarily couple with Gi-type G proteins, causing the dissociation of the β and γ subunits from the α subunit of the G protein. The β, γ, and α subunits mediate the activation of multiple intracellular signaling pathways, such as the inhibition of adenylate cyclase activity, and the activation of G protein-coupled receptor kinase (GRK), protein kinase C (PKC), and mitogen-activated protein kinase (MAPK).

[0004] Multiple areas of the cerebral cortex and subcortical regions are involved in the nociceptive response mediated by the pain response (MOR). Some regions exhibit specific functions, primarily modulating sensory (e.g., the nucleus accumbens and amygdala) or emotional (e.g., the anterior cingulate cortex) responses. Studies have shown that activation of the amygdala's MOR mediates the nociceptive response. In the ACC region, activation of the MOR during persistent pain is negatively correlated with pain-specific MPQ affective scores.

[0005] High-precision opioid receptors are present in the ACC region. Opioids are widely used to treat persistent pain and have been suggested to act in the brain. Reports indicate that morphine injection into the ACC region inhibited the emotional response to pain, but no alteration of pain sensation was observed in animals with neurological damage, suggesting that the mechanisms of emotional and sensory pain are different. Later studies confirmed that injection of different doses of the MOR agonist DAMGO into the rostral part of the anterior cingulate cortex can dose-dependently alleviate the emotional response to pain induced by full Freund's adjuvant injection. Other studies have found that activation of MOR in the nucleus accumbens reduces presynaptic glutamate release while simultaneously increasing NMDA receptor activity. NMDA receptors in the basolateral nucleus of the amygdala affect the emotional response to formalin-induced acute and chronic pain. Neurons in the ACC region also have a large number of NMDA receptors, participating in central nervous system learning and memory, as well as pain modulation and other functions.

[0006] The analgesic mechanism of opioids is now clear: during the transmission of pain to the central nervous system, pain stimulation triggers sensory nerve endings and releases glutamate (Glu), which acts on corresponding receptors to complete the transmission of pain impulses to the central nervous system, causing pain. Exogenous opioids or endogenous opioid peptides enhance the effect of opioid receptors on the presynaptic and postsynaptic membranes of sensory nerves. Through G-protein coupling, they inhibit the degradation of ATP by adenylate cyclase to generate cAMP, thereby inhibiting the release of neurotransmitters such as substance P and acetylcholine from the presynaptic membrane. At the same time, they promote K+ efflux and reduce Ca2+ influx, ultimately weakening the pain signal and producing an analgesic effect.

[0007] After years of research, numerous agonists and antagonists of opioid receptors have been discovered. Currently identified agonists include morphine, damine, endorphins, and fentanyl and its derivatives. Naloxone (Nal), CTOP, CTAP, and naltrexone are antagonists of opioid receptors. Naloxone is characterized by its short onset of action, strong antagonistic ability, high lipophilicity, and relatively short duration of action. Naloxone is an effective, broad-spectrum opioid antagonist that competitively acts on opioid receptors (μ, κ, δ in that order), often accompanied by a agonizing effect, i.e., a agonist-antagonist combination. It can alleviate problems such as opioid overdose poisoning and persistent postoperative respiratory depression, and can also be used for differential diagnosis of drug users. Remifentanil possesses analgesic, sedative, and respiratory depressant effects similar to other μ-opioid receptor agonists. It does not exhibit significant binding affinity to non-opioid receptors, and its binding to opioid receptors can be competitively inhibited by naloxone. Its analgesic effect is dose-dependent and exhibits a "ceiling effect," but common adverse effects still exist, such as hypotension, muscle rigidity, bradycardia, nausea, and vomiting. It can easily cause respiratory depression during local anesthesia or when used for postoperative analgesia. Furthermore, long-term use of these opioid drugs can lead to tolerance and side effects such as respiratory depression and constipation.

[0008] Therefore, there is an urgent need to develop novel opioid receptor agonists that can act on the G protein pathway, have fewer side effects, higher activity, and effectively treat diseases mediated by μ-opioid receptor agonists, especially those with significant analgesic effects, to meet the huge market demand. Summary of the Invention

[0009] The object of this invention is to provide a compound of general formula (I), its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof. in: Ring A is a C6-10 aryl or a 5-6 heteroaryl, wherein the 5-6 heteroaryl is a 5-6 heteroaryl containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur atoms; R1 may be the same or different, and R1 and R2 are each independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy, wherein the C1-6 alkyl is optionally further substituted by one or more substituents selected from C3-6 cycloalkyl, C1-6 alkyl, and halogen; preferably hydrogen, halogen, hydroxyl, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy; more preferably hydrogen, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, methoxy, ethoxy, halomethyl, haloethyl, or halomethoxy; further preferably hydrogen, fluorine, chlorine, bromine, methyl, methoxy, or halomethoxy; even more preferably hydrogen, fluorine, chlorine, bromine, methyl, or methoxy. Ring B is phenyl or pyridyl, optionally further substituted by 1-4 R 3 groups; R3 may be the same or different, and each independently represents hydrogen, halogen, hydroxyl, amino, nitro, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; preferably hydrogen, fluorine, chlorine, bromine, or C1-3 alkyl; more preferably hydrogen, fluorine, chlorine, or bromine; X1 is CR aR b or CR aR bCH 2; preferably CH 2, CH(R b) or CH(R b)CH 2; Ra and Rb are each independently hydrogen, halogen, or C1-3 alkyl; Alternatively, Ra or Rb is linked with R2 to form a cyclopentyl or cyclohexyl group, optionally further substituted with one or more substituents selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, halomethyl, haloethyl, halomethoxy, and haloethoxy; preferably, Ra or Rb is linked with R2 to form a cyclopentyl group. n can be 0, 1, 2, or 3.

[0010] For compounds represented by general formula (I), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, ring A is a phenyl group.

[0011] For compounds represented by general formula (I), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, R1 and R2 are each independently hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkoxy; preferably hydrogen, halogen, C1-3 alkyl, or C1-3 haloalkoxy; more preferably hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, or halomethoxy; and even more preferably hydrogen, fluorine, chlorine, bromine, methyl, or fluoromethoxy.

[0012] For compounds represented by general formula (I), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, R1 is independently hydrogen, halogen, or C1-6 alkyl; preferably hydrogen, halogen, or C1-3 alkyl; more preferably hydrogen, fluorine, chlorine, bromine, methyl, ethyl, or propyl; and even more preferably hydrogen, fluorine, chlorine, bromine, or methyl.

[0013] For compounds of general formula (I), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, R1 is hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, or C1-6 haloalkoxy; preferably hydrogen, halogen, C1-3 alkyl, or C1-3 haloalkoxy; more preferably hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, or halomethoxy; even more preferably hydrogen, fluorine, chlorine, methyl, or fluoromethoxy.

[0014] For compounds represented by general formula (I), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, R2 is hydrogen, halogen, C1-3 alkyl, or C1-3 haloalkoxy; preferably hydrogen.

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

[0016] For compounds represented by general formula (I), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, each of R3 is independently hydrogen or a halogen; preferably hydrogen, fluorine, chlorine, or bromine; more preferably hydrogen or fluorine.

[0017] For compounds represented by general formula (I), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, X1 is CR aR b or CR aR bCH 2; Ra and R b are each independently hydrogen, halogen, or C1-3 alkyl, preferably hydrogen.

[0018] For compounds represented by general formula (Ⅰ), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, X1 is CR aR b, preferably CH 2.

[0019] For compounds represented by general formula (I), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, X1 is CR aR b or CR aR bCH 2; Ra or R b is linked with R 2 to form a cyclopentyl or cyclohexyl group, preferably cyclopentyl.

[0020] For compounds represented by general formula (I), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, X1 is CH(Rb) or CH(Rb)CH2; Rb and R2 are linked to form a cyclopentyl or cyclohexyl group, preferably cyclopentyl.

[0021] For compounds of general formula (I), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, n is 0, 1, or 2. For compounds of general formula (I), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, ring B is , or Preferred More preferably or Further optimization .

[0022] A preferred embodiment of the present invention provides a compound of general formula (II), its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof. in: Rings A, R1, R3 and n are as described in general formula (I).

[0023] For compounds represented by general formula (II), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, general formula (II) further has the structure represented by general formula (II-1): in: Rings A, R1, R3 and n are as described in general formula (I).

[0024] For compounds of general formula (ⅠⅠ) or general formula (ⅠⅠ-1), their stereoisomers, their tautomers, or their pharmaceutically acceptable salts, in a further preferred embodiment of the invention, The for , , , , , , , , , , , , , , , , , , or ; Preferred , or ; Wherein: Raa, Rbb, Rcc, Rdd and Ree are each independently a halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy or C1-6 haloalkoxy, wherein the C1-6 alkyl is optionally further substituted by one or more substituents selected from C3-6 cycloalkyl, C1-6 alkyl and halogen; preferably halogen, hydroxyl, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or C1-3 haloalkoxy; more preferably fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, methoxy, ethoxy, halomethyl, haloethyl or halomethoxy; further preferably fluorine, chlorine, bromine, methyl, methoxy or halomethoxy; even more preferably fluorine, chlorine, bromine, methyl or methoxy.

[0025] For compounds of general formula (ⅠⅠ) or general formula (ⅠⅠ-1), their stereoisomers, their tautomers, or their pharmaceutically acceptable salts, in a further preferred embodiment of the invention, The for , or .

[0026] For compounds of general formula (ⅠⅠ) or general formula (ⅠⅠ-1), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, Raa, Rbb, Rcc, Rdd, and Ree are each independently a halogen, C1-6 alkyl, C1-6 alkoxy, or C1-6 haloalkoxy; preferably a halogen, C1-3 alkyl, or C1-3 haloalkoxy; more preferably fluorine, chlorine, bromine, methyl, ethyl, propyl, or halomethoxy; and even more preferably fluorine, chlorine, bromine, methyl, or fluoromethoxy.

[0027] For compounds of general formula (ⅠⅠ) or general formula (ⅠⅠ-1), their stereoisomers, their tautomers or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, Raa is a halogen or C1-6 haloalkoxy; preferably a halogen or C1-3 haloalkoxy; more preferably fluorine, chlorine, bromine or halomethoxy; and even more preferably chlorine or fluoromethoxy.

[0028] For compounds of general formula (ⅠⅠ) or general formula (ⅠⅠ-1), their stereoisomers, their tautomers or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, R dd is a halogen; more preferably fluorine, chlorine or bromine; even more preferably chlorine.

[0029] For compounds of general formula (ⅠⅠ) or general formula (ⅠⅠ-1), their stereoisomers, their tautomers or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, the Ree is a halogen or C1-6 alkyl; preferably a halogen or C1-3 alkyl; more preferably fluorine, chlorine, bromine, methyl, ethyl or propyl; and even more preferably fluorine, chlorine or methyl.

[0030] For compounds of general formula (ⅠⅠ) or general formula (ⅠⅠ-1), their stereoisomers, their tautomers, or their pharmaceutically acceptable salts, in a further preferred embodiment of the invention, The for , , , , or .

[0031] A preferred embodiment of the present invention provides a compound of general formula (ⅠⅠⅠ), its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof. in: Cyclocarbonyl group C is cyclopentyl. R1, R3 and n are as described in general formula (Ⅰ).

[0032] In a further preferred embodiment of the invention, for compounds of general formula (III), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, general formula (III) further has the structure shown in general formula (IV) or general formula (V): or in: R1, R3, and n are as described in general formula (ⅠⅠⅠ); Carbon atoms marked with an asterisk (*) are palmar carbon atoms, existing as a single enantiomer (R) or (S) or in a form rich in a pair of enantiomers; Carbon atoms marked with "#" are palmar carbon atoms, existing as a single enantiomer (R) or (S) or as a form rich in a pair of enantiomers.

[0033] For compounds of general formula (IV) or general formula (V), their stereoisomers, their tautomers, or their pharmaceutically acceptable salts, in a further preferred embodiment of the invention, The for , , , , , , , , , or Preferred , or ; The for , , , , , , , , , or Preferred , or ; Wherein: Raa, Rbb, Rcc and Rdd are each independently a halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy or C1-6 haloalkoxy, wherein the C1-6 alkyl is optionally further substituted by one or more substituents selected from C3-6 cycloalkyl, C1-6 alkyl and halogen; preferably halogen, hydroxyl, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or C1-3 haloalkoxy; more preferably fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, methoxy, ethoxy, halomethyl, haloethyl or halomethoxy; further preferably fluorine, chlorine, bromine, methyl, methoxy or halomethoxy; even more preferably fluorine, chlorine, bromine, methyl or methoxy.

[0034] For compounds of general formula (IV) or general formula (V), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, Raa, Rbb, Rcc, and Rdd are each independently halogenated or C1-6 alkyl; preferably halogenated or C1-3 alkyl; more preferably fluorine, chlorine, bromine, methyl, ethyl, or propyl; and even more preferably fluorine, chlorine, bromine, or methyl.

[0035] For compounds of general formula (Ⅳ) or general formula (Ⅴ), their stereoisomers, their tautomers or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, Raa is a halogen; preferably fluorine, chlorine or bromine; more preferably chlorine or bromine.

[0036] For compounds of general formula (Ⅳ) or general formula (Ⅴ), their stereoisomers, their tautomers or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, the R bb is a halogen; preferably fluorine, chlorine or bromine; more preferably fluorine or chlorine.

[0037] For compounds of general formula (IV) or general formula (V), their stereoisomers, their tautomers or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, R dd is a halogen or C1-6 alkyl; preferably a halogen or C1-3 alkyl; more preferably fluorine, chlorine, bromine, methyl, ethyl or propyl; and even more preferably fluorine, chlorine, bromine or methyl.

[0038] For compounds of general formula (IV), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, the... for , , or .

[0039] For compounds of general formula (V), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, the... for , , , , , or .

[0040] For compounds represented by general formula (Ⅳ), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, general formula (Ⅳ) further has the structure represented by general formula (Ⅳ-1): in: R1, R3, and n are as described in general formula (Ⅳ); Carbon atoms marked with an asterisk (*) are palmar carbon atoms, existing as a single enantiomer (R) or (S) or as a form rich in a pair of enantiomers.

[0041] For compounds represented by general formula (Ⅳ), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, general formula (Ⅳ) further has the structure represented by general formula (Ⅳ-2): in: R1, R3, and n are as described in general formula (Ⅳ); Carbon atoms marked with an asterisk (*) are palmar carbon atoms, existing as a single enantiomer (R) or (S) or as a form rich in a pair of enantiomers.

[0042] For compounds represented by general formula (Ⅳ-1), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, general formula (Ⅳ-1) further has a structure represented by general formula (Ⅳ-1-1) or general formula (Ⅳ-1-2): or in: R1, R3 and n are as described in general formula (Ⅳ-1).

[0043] For compounds represented by general formula (V), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, general formula (V) further has the structure shown in general formula (V-1): in: R1, R3, and n are as described in general formula (V); Carbon atoms marked with an asterisk (*) are palmar carbon atoms, existing as a single enantiomer (R) or (S) or as a form rich in a pair of enantiomers.

[0044] For compounds represented by general formula (V), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, general formula (V) further has the structure shown in general formula (V-2): in: R1, R3, and n are as described in general formula (V); Carbon atoms marked with an asterisk (*) are palmar carbon atoms, existing as a single enantiomer (R) or (S) or as a form rich in a pair of enantiomers.

[0045] For compounds represented by general formula (V-1), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, general formula (V-1) further has the structure represented by general formula (V-1-1) or general formula (V-1-2): or in: R1, R3 and n are as described in general formula (V-1).

[0046] In one embodiment of the present invention, the compound has any of the following structures: ; Preferably, the compound has any of the following structures: ; Preferably, the compound has any of the following structures: .

[0047] A preferred embodiment of the present invention provides a method for preparing the compound represented by the above general formula (I), its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof, comprising: Compounds of general formula (I-A) and general formula (I-B) or their pharmaceutically acceptable salts undergo reductive amination to yield compounds of general formula (I), their stereoisomers, their tautomers, or their pharmaceutically acceptable salts; Wherein: rings A, R1, R2, B, X1 and n are as described in general formula (I).

[0048] A preferred embodiment of the present invention provides a method for preparing compounds represented by the above general formula (ⅠⅠ), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, comprising:

[0049] Method 1: Compounds of general formula (ⅠⅠ-A-1) and compounds of general formula (ⅠⅠ-B-1) or their pharmaceutically acceptable salts undergo reductive amination to yield compounds of general formula (ⅠⅠ), their stereoisomers, their tautomers, or their pharmaceutically acceptable salts;

[0050] Method 2: Compounds of general formula (ⅠⅠ-A-2) and compounds of general formula (ⅠⅠ-B-2) or their pharmaceutically acceptable salts undergo reductive amination to yield compounds of general formula (ⅠⅠ), their stereoisomers, their tautomers, or their pharmaceutically acceptable salts; Wherein: rings A, R1, R3 and n are as described in general formula (ⅠⅠ).

[0051] A preferred embodiment of the present invention provides a method for preparing the compound represented by the above general formula (III), its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof, comprising:

[0052] Method 1: Compounds of general formula (III-A-1) and compounds of general formula (III-B-1) or their pharmaceutically acceptable salts undergo reductive amination to yield compounds of general formula (III), their stereoisomers, their tautomers, or their pharmaceutically acceptable salts;

[0053] Method 2: Compounds of general formula (III-A-2) and compounds of general formula (III-B-2) or their pharmaceutically acceptable salts undergo reductive amination to yield compounds of general formula (III), their stereoisomers, their tautomers, or their pharmaceutically acceptable salts; Wherein: rings C, R1, R3 and n are as described in general formula (III).

[0054] A preferred embodiment of the present invention provides a method for preparing the compound represented by the above general formula (IV), its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof, comprising:

[0055] Method 1: Compounds of general formula (Ⅳ-A-1) and compounds of general formula (Ⅳ-B-1) or their pharmaceutically acceptable salts undergo reductive amination to yield compounds of general formula (Ⅳ), their stereoisomers, their tautomers, or their pharmaceutically acceptable salts;

[0056] Method 2: Compounds of general formula (Ⅳ-A-2) and compounds of general formula (Ⅳ-B-2) or their pharmaceutically acceptable salts undergo reductive amination to yield compounds of general formula (Ⅳ), their stereoisomers, their tautomers, or their pharmaceutically acceptable salts; Where R1, R3 and n are as described in general formula (Ⅳ).

[0057] A preferred embodiment of the present invention provides a method for preparing a compound of the above general formula (V), its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, comprising:

[0058] Method 1: Compounds of general formula (V-A-1) and compounds of general formula (V-B-1) or their pharmaceutically acceptable salts undergo reductive amination to yield compounds of general formula (V), their stereoisomers, their tautomers, or their pharmaceutically acceptable salts;

[0059] Method 2: Compounds of general formula (V-A-2) and compounds of general formula (V-B-2) or their pharmaceutically acceptable salts undergo reductive amination to yield compounds of general formula (V), their stereoisomers, their tautomers, or their pharmaceutically acceptable salts; Where R1, R3 and n are as described in general formula (V).

[0060] The present invention also provides a preferred embodiment relating to a pharmaceutical composition comprising a therapeutically effective amount of the compounds represented by the above general formulas, their stereoisomers, their tautomers or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier, diluent and excipient.

[0061] In some preferred embodiments of the invention, the pharmaceutical composition may be administered in any of the following ways: orally, by spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, non-enteric administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or by means of an external implantable reservoir, wherein oral, intraperitoneal, or intravenous administration is preferred.

[0062] When administered orally, the compounds of this application can be formulated into any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions, or aqueous suspensions. Tablets typically use carriers including lactose and corn starch, and lubricants such as magnesium stearate may also be added. Capsule formulations typically use diluents including lactose and dried corn starch. Aqueous suspension formulations usually involve mixing the active ingredient with suitable emulsifiers and suspending agents. If desired, sweeteners, flavorings, or colorings may also be added to the above oral dosage forms.

[0063] As tablets, including but not limited to lozenges, sublingual tablets, oral patches, chewable tablets, dispersible tablets, effervescent tablets, immediate-release or sustained-release or controlled-release tablets, and enteric-coated tablets.

[0064] When used topically, especially to treat lesions or organs that are easily reached by topical application, such as the eyes, skin, or lower intestinal nerve diseases, the compounds of this application can be formulated into different topical formulations according to different affected areas or organs, as detailed below.

[0065] When applied topically to the eye, the compounds of this application can be formulated as a micronized suspension or solution, using an isotonic sterile saline solution of a specific pH as the carrier, with or without preservatives such as benzyl alkyl chloride. For ophthalmic use, the compounds can also be formulated as an ointment, such as petrolatum.

[0066] When applied topically to the skin, the compounds of this application can be formulated into suitable ointments, lotions, or creams, wherein 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, emulsified wax, and water; carriers that can be used in lotions or creams include, but are not limited to: mineral oil, sorbitan monostearate, Tween 60, hexadecyl ester wax, hexadecene aromatic alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0067] The present invention also provides a preferred embodiment relating to the use of compounds represented by the various general formulas, their stereoisomers, their tautomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof in the preparation of medicaments for the prevention and / or treatment of diseases mediated by μ-opioid receptor agonists.

[0068] The diseases associated with the μ-opioid receptor agonist described above are selected from one or more of pain, immune dysfunction, inflammation, acid reflux, neurological and psychiatric diseases, urinary and reproductive diseases, cardiovascular diseases, and respiratory diseases, with pain being the preferred one.

[0069] The present invention also provides a preferred embodiment relating to the use of compounds represented by the various general formulas, their stereoisomers, their tautomers or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof in the preparation of medicaments for the prevention and / or treatment of pain or pain-related diseases.

[0070] The present invention also relates to a method for treating diseases mediated by μ-opioid receptor agonists, comprising administering to a mammal a therapeutically effective amount of the compound of the present invention, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof.

[0071] In some embodiments of the present invention, the present invention relates to a treatment method such as pain management.

[0072] The diseases associated with μ-opioid receptor agonists described in the above methods are selected from one or more of pain, immune dysfunction, inflammation, acid reflux, neurological and psychiatric diseases, urinary and reproductive diseases, cardiovascular diseases, and respiratory diseases, with pain being the preferred one.

[0073] In some embodiments of the present invention, the pain is selected from one or more of postoperative pain, cancer-related pain, neuropathic pain, traumatic pain, and inflammatory pain.

[0074] In some embodiments of the present invention, the cancer is selected from one or more of breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumors, hemophilia, and leukemia.

[0075] The treatment methods provided herein include administering a therapeutically effective amount of the compound of the present invention to a subject. In one embodiment, the present invention also provides a method for treating diseases mediated by μ-opioid receptor agonists in mammals. This method includes administering a therapeutically effective amount of the compound of the present invention, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof to the mammal. Detailed Description of the Invention

[0076] Unless otherwise stated, the terms used in the specification and the scope of the patent application shall have the following meanings.

[0077] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures and other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention. In some embodiments, the compounds are preferred to be those isomers exhibiting superior biological activity. Purified or partially purified isomers and stereoisomers of the compounds of this invention, or racemic mixtures or diastereomer mixtures, are also included within the scope of this invention. Purification and separation of such substances can be achieved using standard techniques known in the art.

[0078] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0079] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise because the single bonds of double bonds or cyclic carbon atoms cannot rotate freely.

[0080] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more palmar centers and being in a non-mirror relationship with each other.

[0081] Unless otherwise stated, “(D)” or “(+)” indicates right-handed rotation, “(L)” or “(-)” indicates left-handed rotation, and “(DL)” or “(±)” indicates racemic rotation.

[0082] Unless otherwise specified, use wedge-shaped solid line keys ( ) and wedge-shaped dashed key ( ) represents the absolute configuration of a solid center, using a straight solid line key ( ) and straight dashed key ( The relative configuration of the center of a solid is represented by a wavy line. ) indicates a wedge-shaped solid line key ( ) or wedge-shaped dashed key ( ) or use wavy lines ( ) indicates a straight solid line key ( ) and straight dashed key ( ).

[0083] The compounds of this invention can exist in specific forms. Unless otherwise stated, the terms "tautomer" or "tautomer form" refer to isomers of different functional groups in dynamic equilibrium at room temperature, capable of rapid interconversion. If tautomerization is possible (e.g., in solution), chemical equilibrium of the tautomer can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions involving the rearrangement of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0084] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched 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, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, it is an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent can be replaced at any usable connection point. The substituent is preferably one or more of the following groups, independently alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester. The present invention preferably uses methyl, ethyl, isopropyl, tert-butyl, haloalkyl, alkoxy-substituted alkyl, and hydroxyl-substituted alkyl. When the alkyl group is substituted, the substituent is not further substituted.

[0085] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc. The term "alkenyl" refers to an alkyl group as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl groups can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio. When the alkylene group is substituted, the substituent is not further substituted.

[0086] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0087] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 rings sharing a single carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings. Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it consists of 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocycloalkyl groups.

[0088] Non-limiting examples of spirocycloalkyl groups include: It also includes spirocycloalkyl groups that share a spiroatom with a heterocycloalkyl group, non-limiting examples of which include:

[0089] The term "fused-ring alkyl" refers to a 5- to 20-membered polycyclic carbon group in which each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused-ring alkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused-ring alkyl include:

[0090] The term "bridged cycloalkyl" refers to a polycyclic aromatic hydrocarbon group with 5 to 20 members, in which any two rings share two non-directly bonded carbon atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0091] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include indanyl, tetrahydronaphthyl, and benzocycloheptyl. The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate ester. When the cycloalkyl group is substituted, the substituent is not further substituted.

[0092] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated electronic system, preferably 6- to 10-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo3- to 8-membered cycloalkyl and benzo3- to 8-membered heterocyclic groups, preferably benzo3- to 6-membered cycloalkyl and benzo3- to 6-membered heterocyclic groups, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen, oxygen, and sulfur atoms; or may further comprise a three-membered nitrogen-containing fused ring containing a benzene ring.

[0093] The ring connected to the parent structure is an aryl ring, and non-limiting examples include:

[0094] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester. When the aryl group is substituted, the substituent is not further substituted.

[0095] The term "heteroaryl" refers to a heteroaryl system comprising 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 is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thiophene, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably triazolyl, pyrroleyl, thiophene, thiazolyl, and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0096] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group. When the heteroaryl group is substituted by a substituent, the substituent is not further substituted.

[0097] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein alkyl is defined as described above, preferably alkoxy containing 1 to 8 carbon atoms, more preferably alkoxy containing 1 to 6 carbon atoms, and most preferably alkoxy containing 1 to 3 carbon atoms. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester. When the alkoxy group is substituted, the substituent is not further substituted.

[0098] "Halogenated alkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above. Non-limiting examples of halogenated methyl groups include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, etc.; preferably fluoromethyl, difluoromethyl, and trifluoromethyl. Non-limiting examples of haloethyl compounds include: 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2-chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl, etc.; preferably 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, and 2,2-difluoroethyl.

[0099] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above. Non-limiting examples of halomethoxy groups include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, etc.; preferably fluoromethoxy, difluoromethoxy, and trifluoromethoxy. Non-limiting examples of halogenated ethoxy groups include: 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2 -Chloro-2-fluoroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1,2,2-trifluoroethoxy, 2-bromo-1,1,2,2-tetrafluoroethoxy, etc.; preferably 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy.

[0100] "Alkenyl" refers to alkenyl groups, also known as olefin groups. The alkenyl group can be further replaced by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0101] "Alkyne" refers to (CH≡C-), wherein the alkynyl group can be further replaced by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0102] "Hydroxy" refers to the -OH group.

[0103] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0104] "Amino group" refers to -NH2.

[0105] “Cyano” refers to -CN.

[0106] "Nitro" refers to -NO 2.

[0107] "Carboxyl group" refers to -C(O)OH.

[0108] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed. Those skilled in the art will understand that the foregoing terms such as “comprising” encompass the meaning of “consisting of.”

[0109] The term "one or more species" or similar expression "at least one species" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

[0110] When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. In particular, each range of values ​​disclosed herein should be understood as representing each numerical value and range encompassed within a wider range.

[0111] In this article, “Z” and “-Z-” both refer to the same specific group and can be used interchangeably.

[0112] The expression mn used in this article refers to the range from m to n, as well as the subranges and individual point values ​​within it. For example, the expression "C2-C8" or "C2-8" covers the range of 2 to 8 carbon atoms, and should be understood to also cover any subranges and individual point values ​​within it, 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. For example, the expression "C3-C10" or "C3-10" should be understood in a similar way. It can encompass any subrange and point value contained within it, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C10, C7-C9, C7-C8, C8-C9, and C3, C4, C5, C6, C7, C8, C9, C10, etc. Similarly, the expression "C1-C6" or "C1-6" covers a range of 1 to 6 carbon atoms and should be understood to also encompass any subrange and point value within it, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, and C1, C2, C3, C4, C5, C6, etc. For example, the expression "three to ten members" should be understood as encompassing any number of ranges and each point value, such as three to five members, three to six members, three to seven members, three to eight members, four to five members, four to six members, four to seven members, four to eight members, five to seven members, five to eight members, six to seven members, six to eight members, nine to ten members, etc., as well as three, four, five, six, seven, eight, nine, ten members, etc. Other similar expressions in this article should also be understood in a similar manner.

[0113] The different expressions used in this article, such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C", all express the same meaning, that is, X can be any one or more of A, B, and C.

[0114] The terms “optional” or “optionally” mean that an event or condition described below may or may not occur, including both the occurrence and non-occurrence of the event or condition. For example, “optionally (al) alkyl-substituted cycloalkyl” means that an alkyl group may but is not required to be present, and this description includes both cases where the cycloalkyl group is substituted with an alkyl group and cases where the cycloalkyl group is not substituted with an alkyl group.

[0115] The terms "substitution" and "substituted" refer to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a chosen substituent from the indicated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound. When describing the absence of a substituent, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state. When describing the optional substitution of each carbon atom in a group with a heteroatom, the condition is that the substitution does not exceed the normal valence of all atoms in the group in the present case and that a stable compound is formed.

[0116] If a substituent is described as "optionally…substituted," the substituent may be unsubstituted or may be substituted. If an atom or group is described as being optionally substituted by one or more of the substituents in the list, one or more hydrogen atoms on that atom or group may be replaced by independently selected, optional substituents. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted. Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable position of the substituent.

[0117] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0118] When any variable (e.g., R), and labeled variables (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) appear more than once in the composition or structure of a compound, their definition is independent for each occurrence in each case. For example, if a group is substituted by 0, 1, 2, 3, or 4 R substituents, the group can optionally be substituted by up to four R substituents, and the option of each R substituent in each case is independent of each other.

[0119] The term "pharmaceutically acceptable" refers to a substance that, within the bounds of normal medical judgment, is suitable for contact with a patient's tissues without causing undue toxicity, irritation, allergic reactions, etc., has a reasonable benefit-risk ratio, and is effective for its intended use.

[0120] The term "pharmaceutically acceptable salt" refers to the salts of the compounds of this invention, which are safe and effective when used in mammals and have the intended biological activity.

[0121] The term "pharmaceutical composition" refers to a mixture containing one or more compounds described in this invention or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and enabling it to exert its biological activity.

[0122] The term "pharmaceutically acceptable carrier" refers to substances that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0123] The terms "administration" or "giving" refer to methods that enable the delivery of a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral or non-enteric (including intravenous, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), local, and rectal administration. In particular, injection or oral administration.

[0124] As used herein, the term "treatment" includes relieving, reducing, or improving a disease or symptom; preventing other symptoms; improving or preventing underlying metabolic factors of symptoms; inhibiting a disease or symptom, for example, preventing the development of a disease or symptom; reducing a disease or symptom; promoting the remission of a disease or symptom; or stopping the symptoms of a disease or symptom; and extends to include prevention. "Treatment" also includes achieving therapeutic and / or preventive benefits. A therapeutic benefit refers to the eradication or improvement of the condition being treated. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physical symptoms associated with an underlying disease, and an improvement in the patient's condition can be observed even though the patient may still have the underlying disease. A preventive benefit refers to the use of a component by a patient to prevent the risk of a certain disease, or the use by a patient when experiencing one or more physical symptoms of a disease, even though the disease has not yet been diagnosed.

[0125] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that can effectively treat or prevent target disorders, diseases, or symptoms. The term "neuropsychiatric disorders" is a collective term for neurological and psychiatric disorders, encompassing both neurological and / or psychiatric conditions.

[0126] For the purposes of pharmaceuticals, pharmaceutical units, or active ingredients, the terms "effective amount," "therapeutic effective amount," or "preventive effective amount" refer to a sufficient dosage of a drug or agent that provides acceptable side effects while achieving the desired therapeutic effect. The determination of the effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0127] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0128] The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling other skilled in the art to more fully understand the technical solutions, principles, and practical applications of the invention, so that other skilled in the art can modify and implement the invention in many forms to best suit the requirements of a particular application. Beneficial effects

[0129] In vitro receptor function assays have demonstrated that the compounds of this invention have a synergistic effect on MOR receptors, and are effective in preventing and / or treating diseases mediated by μ-opioid receptor synergists, such as pain, immune dysfunction, inflammation, acid reflux, neurological and psychiatric disorders, urinary and reproductive diseases, cardiovascular diseases, and respiratory diseases. The compounds of this invention exhibit high inhibitory activity against cAMP and a high Emax value. Furthermore, the compounds of this invention have a low Emax value against β-arrestin, indicating greater safety and efficacy in clinical use. Compared to the oral drug oxycodone, they offer better analgesic effects, which will significantly improve patient compliance. Simple Explanation of the Diagram

[0130] Figure 1 shows the percentage of analgesic effect in the tail-flick test of mice in Test Example 3. Implementation

[0131] [Detailed Implementation]

[0132] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified, specific conditions in the examples are performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used, unless otherwise specified, are all commercially available conventional products. Unless otherwise specified, all proportions or percentages used herein are by weight. [Example]

[0133] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS).

[0134] NMR chemical shifts (δ) are provided in parts per million (ppm). NMR measurements were performed using an AVANCE III 600 NMR spectrometer with deuterated dimethyl monoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents and tetramethylsilane (TMS) as the internal standard.

[0135] Liquid chromatography-mass spectrometry (LC-MS) determinations were performed using a Shimadzu LCMS2020 mass spectrometer (Japan). HPLC determinations were performed using a Shimadzu LC20A liquid chromatography system (Japan).

[0136] The thin-layer chromatography (TLC) silica gel plates used are from Yantai Jiangyou. The TLC specification is 0.2 mm ± 0.03 mm, and the specification used for separating and purifying products by thin-layer chromatography is 0.4 mm - 0.5 mm. [Intermediate] [1] [2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [-1-] [amine] [1a]

[0137] Synthesis scheme: [step] [A] [:] [1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [Preparation of alcohols]

[0138] 3-Buten-1-ol (10.0 g, 142 mmol) and tetrahydropyranone (7.1 g, 71 mmol) were added to a flask and cooled to 0°C. 75% sulfuric acid (40 mL) was slowly added dropwise to the reaction mixture, and the mixture was gradually brought to room temperature and reacted overnight. Water (100 mL) was added to the reaction system, and the pH was adjusted to 8 with 10% sodium hydroxide solution. The mixture was extracted with ethyl acetate (150 mL × 3). The ethyl acetate layer was washed with water (50 mL × 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and then purified by silicone column chromatography to obtain a pale yellow oily target product (4.8 g, 40% yield).

[0139] 1H NMR (600 MHz, DMSO- d 6): 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). [step] [B] [:] [1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [Preparation of Ketones]

[0140] 1,9-Dioxaspiro[5.5]undecane-4-ol (4.8 g, 28 mmol) was dissolved in dichloromethane (50 mL) in a flask, cooled to 0 °C, and pyridinium chlorochromate (9.0 g, 42 mmol) was slowly added. The mixture was then heated to room temperature and reacted overnight. After filtration under vacuum, the product was concentrated and subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to give a pale yellow oily target product (4.0 g, 85% yield).

[0141] 1H NMR (600 MHz, DMSO- d 6): 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). [step] [C] [:] [(Z)-2-] [Cyano] [-2-(1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [alkylene] [)] [Preparation of methyl acetate] 1,9-dioxaspiro[5.5]undecane-4-one (4.0 g, 23.5 mmol), ammonium acetate (530 mg, 6.8 mmol), acetic acid (270 mg, 4.6 mmol), and 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 under vacuum, concentrated, and then subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to give the target product (5.6 g, 90% yield).

[0142] LC-MS: MS Found: 252[M+H] +.

[0143] 1H NMR (600 MHz, DMSO- d 6): 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). [step] [D] [:] [2-] [Cyano] [-2-(4-(5-(] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Preparation of methyl acetate]

[0144] Dissolve 5-fluoro-2-bromopyridine (5.35 g, 40 mmol) in anhydrous tetrahydrofuran (15 mL) and slowly add it dropwise to isopropyl magnesium chloride solution (20 mL, 40 mmol) at 0 °C. React at room temperature for 3 hours, then add cuprous iodide (0.76 g, 4 mmol) and react for another hour. Dissolve (Z)-2-cyano-2-(1,9-dioxaspiro[5.5]undecane-4-alkylene)acetate (5.0 g, 20 mmol) in tetrahydrofuran (15 mL) and add it dropwise. React at room temperature overnight, then 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 with anhydrous sodium sulfate, filter under vacuum, concentrate, and then column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target product (3.3 g, yield 50%).

[0145] LC-MS: MS Found: 349[M+H] +.

[0146] 1H NMR (600 MHz, CDCl 3) δ8.47 (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). [step] [E] [:] [2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Preparation of acetonitrile]

[0147] 3.0 g (86 mmol) of methyl 2-cyano-2-(4-(5-(fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)acetate was 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 give a pale yellow target product (1.7 g, yield 70%).

[0148] LC-MS: MS Found: 291[M+H] +.

[0149] 1H NMR (600 MHz, CDCl 3): 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). [step] [F] [:] [2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [-1-] [Preparation of Amines]

[0150] 1.5 g (5.2 mmol) of 2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)acetonitrile was dissolved in ethanol (30 mL) and methanol (5 mL). After adding ammonia (2 mL), five spoonfuls of Raney nickel were added. The mixture was stirred overnight at room temperature under hydrogen atmosphere. After the reaction was complete, the mixture was filtered through diatomaceous earth. The filtrate was concentrated to obtain a yellow oily product. [1a](1.3g, yield 85%).

[0151] LC-MS (m / z): 295.1 [M+H] +. [Intermediate] [2] [2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] Acetaldehyde [1b]

[0152] Synthesis scheme:

[0153] 2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)acetonitrile (1.0 g, 3.8 mmol) was added to dry toluene (10 mL), and the mixture was cooled to -78 °C under nitrogen protection. Diisobutylaluminum hydride (7.6 mL, 7.6 mmol) was added dropwise. After the addition was complete, the mixture was stirred at this temperature for 2 hours. After the reaction was completed by LC-MS monitoring, saturated ammonium chloride solution (10 mL) was added to the reaction solution, and the mixture was heated to room temperature and stirred for 1 hour. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The organic phases were washed with water (15 mL), washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the target product. [1b (]0.8g, yield 80%).

[0154] LC-MS (m / z): 294.1 [M+H] +. [Intermediate] [3] [(R)-2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Acetonitrile] [1c]

[0155] Synthesis scheme:

[0156] 100 g of 2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)acetonitrile was separated to obtain two optical isomers:

[0157] Compound (R)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)acetonitrile [1c],0.97 min,45.1 g,ee%=96%,[a]27.3=-6.75 (C=2g / 100mL, MeOH),LC-MS(m / z): 291.2[M+H] +;

[0158] Compound (S)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)acetonitrile, 0.58 min, 46.5 g, ee%=96%, [a]27.3=2.04 (C=2g / 100mL, MeOH). Resolution conditions: Instrument: Waters SFC 150; Column: DAICELCHIRALPAK®AS, 250*40 mm 10 μm; Mobile phase: A: Supercritical CO2, B: MeOH (0.1% Ammonia in MeOH); Gradient: A:B=75:25; Flow rate: 120 mL / min; Back pressure: 100 bar; Column temperature: 25℃; Wavelength: 214 nm; Cycle time: 6 min; Compound to be resolved dissolved in MeOH (1000 mL); Injection: 8 mL. [Example] [1] [(1S)-6-] [fluorine] [-N-(2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [)-2,3-] [Dihydrogen] [-1H-] [Indonesia] [-1-] [amine] [1-1]

[0159] Synthesis scheme:

[0160] 2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)acetaldehyde (100 mg, 0.34 mmol) and (S)-6-fluoro-2,3-dihydro-1H-indene-1-amine (47 mg, 0.34 mmol) were dissolved in methanol (1 mL), acetic acid (0.1 mL) was added, and sodium cyanoborohydride (62 mg, 1.0 mmol) was added. The reaction was carried out at room temperature for 16 hours. The reaction was monitored by LC-MS until complete. The mixture was filtered, concentrated, and purified by preparative HPLC to obtain the target compound. [1-1](25.3 mg, yield 11%).

[0161] LC-MS (m / z): 429.2 [M+H] +.

[0162] 1H NMR (600 MHz, DMSO- d 6) δ9.28 (s, 1H), 8.55 (d, J= 3.0 Hz, 1H), 7.76-7.71 (m, 1H), 7.66-7.63 (m, 1H), 7.47 (d, J= 9.0 Hz, 1H), 7.39-7.29 (m, 1H), 7.24-7.11 (m, 1H), 4.69-4.52 (m, 1H), 3.72-3.70 (m, 1H), 3.64-3.44 (m, 3H), 3.33-3.16 (m, 2H), 2.98 (m, 1H), 2.89-2.70 (m, 2H), 2.58-2.56 (m, 2H), 2.37-2.16 (m, 2H), 2.13-1.79 (m, 3H), 1.66-1.37 (m, 4H), 0.85-0.82 (m, 2H). [Example] [2] [(1S)-4-] [fluorine] [-N-(2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [)-2,3-] [Dihydrogen] [-1H-] [Indonesia] [-1-] [amine] [2-1]

[0163] Synthesis scheme:

[0164] The target compound was prepared by replacing the starting material (S)-6-fluoro-2,3-dihydro-1H-inden-1-amine with (S)-4-fluoro-2,3-dihydro-1H-inden-1-amine using the synthesis method of Example 1. [2-1].

[0165] LC-MS (m / z): 429.2 [M+H] +.

[0166] 1H NMR (600 MHz, DMSO- d 6) 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). [Example] [3] [(1S)-N-(2-(-4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [)-2,3-] [Dihydrogen] [-1H-] [Indonesia] [-1-] [amine] [3-1]

[0167] Synthesis scheme:

[0168] The target compound was prepared by replacing the starting material (S)-6-fluoro-2,3-dihydro-1H-inden-1-amine with (S)-2,3-dihydro-1H-inden-1-amine using the synthesis method of Example 1. [3-1]

[0169] LC-MS (m / z): 411.2 [M+H] +.

[0170] 1H NMR (600 MHz, CDCl 3) 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). [Example] [4] [6-] [chlorine] [-N-(2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [)-2,3-] [Dihydrogen] [-1H-] [Indonesia] [-1-] [amine] [4]

[0171] Synthesis scheme:

[0172] 2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)ethyl-1-amine (150 mg, 0.51 mmol) and 6-chloro-2,3-dihydro-1H-indene-1-one (84.69 mg, 0.51 mmol) were dissolved in tetraisopropoxytitanium (2 mL) and stirred at 80°C for 4 hours. Then, methanol (3 mL) was added for dilution, followed by the addition of sodium borohydride (37.83 mg, 1.0 mmol). The mixture was stirred at room temperature for 0.5–1 hour, and the reaction was quenched with water. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, and the resulting filtrate was washed with saturated brine, dried, concentrated, and purified by reverse-phase C18 column chromatography (water / acetonitrile = 25%) to obtain the target compound. [4](39 mg, yield 17%).

[0173] LC-MS (m / z): 445.2 [M+H] +.

[0174] 1H NMR (600 MHz, DMSO- d 6) δ8.69 (s, 1H), 8.57 (dd, J= 6.6, 3.0 Hz, 1H), 7.77-7.72 (m, 1H), 7.66-7.64 (m, 1H), 7.45 (d, J= 6.0 Hz, 1H), 7.39 (dd, J= 7.8, 1.8 Hz, 1H), 7.34 (dd, J= 7.8, 3.0 Hz, 1H), 4.68-4.59 (m, 1H), 3.72-3.69 (m, 1H), 3.60-3.51 (m, 3H), 3.29-3.20 (m, 2H), 3.00-2.93 (m, 1H), 2.90-2.77 (m, 2H), 2.59-2.52 (m, 1H), 2.37-2.22 (m, 3H), 2.05-1.91 (m, 2H), 1.81-1.70 (m, 1H), 1.62-1.55 (m, 2H), 1.51-1.48 (m, 1H), 1.43-1.40 (m, 1H), 0.85-0.81 (m, 2H). [Example] [5] [(1S)-4-] [chlorine] [-N-(2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [)-2,3-] [Dihydrogen] [-1H-] [Indonesia] [-1-] [amine] [5-1]

[0175] Synthesis scheme:

[0176] The target compound was prepared by replacing the starting material (S)-6-fluoro-2,3-dihydro-1H-inden-1-amine with (S)-4-chloro-2,3-dihydro-1H-inden-1-amine using the synthesis method of Example 1. [5-1]

[0177] LC-MS (m / z): 445.2 [M+H] +.

[0178] 1H NMR (600 MHz, DMSO- d 6) δ8.70 (s, 1H), 8.57 (d, J= 2.4 Hz, 1H), 7.74 (d, J= 6.0 Hz, 1H), 7.68-7.61 (m, 1H), 7.45 (d, J= 7.8 Hz, 1H), 7.38 (dd, J= 7.2, 3.6 Hz, 1H), 7.33-7.29 (m, 1H), 4.88-4.48 (m, 1H), 3.70-3.69 (m, 1H), 3.57-3.54 (m, 4H), 3.27-3.21 (m, 2H), 3.00 (dd, J= 16.2, 8.4 Hz, 1H), 2.87-2.84 (m, 2H), 2.57-2.55 (m, 1H), 2.38-2.35 (m, 2H), 2.07-1.92 (m, 2H), 1.75-1.72 (m, 1H), 1.59-1.55 (m, 2H), 1.48 (dd, J= 13.8, 6.0 Hz, 1H), 1.42-1,40 (m, 1H), 0.84-0.80 (m, 2H). [Example] [6] [(1S)-N-(2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [)-4-] [methyl] [-2,3-] [Dihydrogen] [-1H-] [Indonesia] [-1-] [amine] [6-1]

[0179] Synthesis scheme:

[0180] The target compound was prepared by replacing the starting material (S)-6-fluoro-2,3-dihydro-1H-inden-1-amine with (S)-4-methyl-2,3-dihydro-1H-inden-1-amine using the synthesis method of Example 1. [6-1]

[0181] LC-MS (m / z): 425.2 [M+H] +.

[0182] 1H NMR (600 MHz, DMSO- d 6) δ9.25-8.51 (m, 2H), 7.78-7.68 (m, 1H), 7.66-7.62 (m, 1H), 7.23-7.11 (m, 3H), 4.64-4.61 (m, 1H), 3.70-3.69 (m, 1H), 3.59-3.54 (m, 4H), 3.26-3.22 (m, 2H), 2.92-2.75 (m, 3H), 2.57-2.52 (m, 1H), 2.34-2.28 (m, 2H), 2.22 (s, 3H), 2.04-1.84 (m, 2H), 1.79-1.71 (m, 1H), 1.60-1.55 (m, 2H), 1.50-1.46 (m, 1H), 1.42-1.40 (m, 1H), 0.83-0.80 (m, 2H). [Example] [7] [(1S)-4-] [bromine] [-N-(2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [)-2,3-] [Dihydrogen] [-1H-] [Indonesia] [-1-] [amine] [7-1]

[0183] Synthesis scheme:

[0184] The target compound was prepared by replacing the starting material (S)-6-fluoro-2,3-dihydro-1H-inden-1-amine with (S)-4-bromo-2,3-dihydro-1H-inden-1-amine using the synthetic method of Example 1. [7-1]

[0185] LC-MS (m / z): 489.1 [M+H] +.

[0186] 1H NMR (600 MHz, DMSO- d 6) δ8.70 (s, 1H), 8.57 (d, J= 2.4 Hz, 1H), 7.77-7.72 (m, 1H), 7.66-7.63 (m, 1H), 7.59 (d, J= 7.8 Hz, 1H), 7.41 (dd, J= 7.8, 3.6 Hz, 1H), 7.25-7.21 (m, 1H), 4.76-4.73 (m, 1H), 3.70-3.69 (m, 1H), 3.59-3.54 (m, 4H), 3.26-3.22 (m, 2H), 3.00-2.94 (m, 1H), 2.87-2.81 (m, 2H), 2.57-2.55 (m, 1H), 2.38-2.35 (m, 2H), 2.07-1.92 (m, 2H), 1.75-1.72 (m, 1H), 1.59-1.55 (m, 2H), 1.48 (dd, J= 13.8, 6.0 Hz, 1H), 1.42-1,40 (m, 1H), 0.84-0.80 (m, 2H). [Example] [8] [N-(2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [)-2,3-] [Dihydrogen] [-1H-] [Indonesia] [-2-] [amine] [8]

[0187] Synthesis scheme:

[0188] The target compound was prepared by replacing the starting material 6-chloro-2,3-dihydro-1H-indanone with 1,3-dihydro-2H-indanone using the synthetic method described in Example 4. [8]

[0189] LC-MS(m / z): 411[M+H] +.

[0190] 1H NMR (600 MHz, DMSO- d 6) 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). [Example] [9] [(R)-N-(2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [)-2,3-] [Dihydrogen] [-1H-] [Indonesia] [-2-] [amine] [8-1]

[0191] Synthesis scheme: [step] [A] [:] [(R)-2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [-1-] [Preparation of Amines]

[0192] (R)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)acetonitrile [1c (] 1.5 g, 5.2 mmol) was dissolved in ethanol (30 mL) and methanol (5 mL), and ammonia (2 mL) was added dropwise. Then, 5 spoonfuls of Raney nickel were added, and the mixture was stirred overnight at room temperature under hydrogen atmosphere. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated to give a yellow oily product (R)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxane[5.5]undecane-4-yl)ethyl-1-amine. [1a-1 (] 1.4 g, yield 91%).

[0193] LC-MS (m / z): 295.1 [M+H] +. [step] [B:(R)-N-(2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [)-2,3-] [Dihydrogen] [-1H-] [Indonesia] [-2-] [Preparation of Amines]

[0194] (R)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-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 tetraisopropoxytitanium (2 mL), stirred at 80°C for 4 hours, then diluted with methanol (3 mL), followed by the addition of sodium borohydride (37.83 mg, 1.0 mmol), and stirred at room temperature for 0.5–1 hours. The reaction was then quenched with water. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, and the resulting filtrate was washed with saturated brine, dried, concentrated, and purified by reverse-phase C18 column chromatography (water / acetonitrile = 25%) to obtain the target compound. [8-1](41 mg, yield 19%).

[0195] LC-MS(m / z): 411[M+H] +.

[0196] 1H NMR (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). [Example]

[10] [5-] [fluorine] [-N-(2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [)-2,3-] [Dihydrogen] [-1H-] [Indonesia] [-2-] [amine] [9]

[0197] Synthesis scheme:

[0198] The target compound was prepared by replacing the starting material 6-chloro-2,3-dihydro-1H-indanone with 5-fluoro-1,3-dihydro-2H-indanone using the synthetic method described in Example 4. [9]

[0199] LC-MS (m / z): 429[M+H] +.

[0200] 1H NMR (600 MHz, DMSO- d 6) δ8.57 (d, J= 3.0 Hz, 1H), 7.75 (td, J= 6.0, 3.0 Hz, 1H), 7.64 (dd, J= 9.0, 4.2 Hz, 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). [Example]

[11] [4-] [bromine] [-N-(2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [)-2,3-] [Dihydrogen] [-1H-] [Indonesia] [-2-] [amine]

[10]

[0201] Synthesis scheme:

[0202] The target compound was prepared by replacing the starting material 6-chloro-2,3-dihydro-1H-indanone with 4-bromo-1,3-dihydro-2H-indanone using the synthetic method described in Example 4.

[10]

[0203] LC-MS (m / z): 490 [M+H] +.

[0204] 1H NMR (600 MHz, DMSO- d 6) 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). [Example]

[12] [(S)-4-] [bromine] [-N-(2-((R)-4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [)-2,3-] [Dihydrogen] [-1H-] [Indonesia] [-2-] [amine] [10-1-1] [and] [(R)-4-] [bromine] [-N-(2-((R)-4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [)-2,3-] [Dihydrogen] [-1H-] [Indonesia] [-2-] [amine] [10-1-2]

[0205] Synthesis scheme:

[0206] The target compound was prepared by replacing the starting material 1,3-dihydro-2H-indanone with 4-bromo-1,3-dihydro-2H-indanone using the synthetic method described in Example 9. [10-2].

[0207] Take compounds [10-2] was split, and two optical isomers were obtained after separation:

[0208] (S)-4-bromo-N-(2-((R)-4-(5-fluoropyridin-2-yl)-1,9-dioxane[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine [10-1-1],2.08 min,0.16 g,ee%=96%;

[0209] LC-MS (m / z): 490.5 [M+H] +.

[0210] 1H 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).

[0211] (R)-4-bromo-N-(2-((R)-4-(5-fluoropyridin-2-yl)-1,9-dioxane[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H-indene-2-amine [10-1-2],2.98 min,0.15 g,ee%=96%;

[0212] LC-MS (m / z): 490.5 [M+H] +.

[0213] 1H NMR (400 MHz, DMSO-d 6) 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 = 5.2 Hz, 1H), 1.49 – 1.34 (m, 2H), 0.81 (p, J = 4.7, 3.8 Hz, 2H). Resolution conditions: Instrument: Waters SFC 150; Column: DAICELCHIRALCEL® 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℃; Wavelength: 214 nm; Cycle time: 6 min; Compound to be resolved dissolved in MeOH (40 mL); Injection: 1.8 mL. [Implementation Example]

[13] [N-(3-)] [Chlorobenzyl] [)-2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane-1,4-dioxane] [[5.5]] [Undecane] [-4-] [base] [)] [Ethane] [-1-] [amine]

[11]

[0214] Synthesis scheme:

[0215] The target compound was prepared by replacing the starting material 6-chloro-2,3-dihydro-1H-inden-1-one with 3-chlorobenzaldehyde using the synthetic method of Example 4.

[11]

[0216] LC-MS (m / z): 419.2 [M+H] +.

[0217] 1H NMR (600 MHz, CD 3OD) 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), 4.58-4.54 (m, 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). [Example]

[14] [N-(3-)] [chlorine] [-2-] [Methylbenzyl] [)-2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane-1,4-dioxane] [[5.5]] [Undecane] [-4-] [base] [)] [Ethane] [-1-] [amine]

[12]

[0218] Synthesis scheme:

[0219] The target compound was prepared by replacing the starting material 6-chloro-2,3-dihydro-1H-inden-1-one with 3-chloro-2-methylbenzaldehyde using the synthetic method of Example 4.

[12]

[0220] LC-MS (m / z): 433.2[M+H] +.

[0221] 1H NMR (600 MHz, CD 3OD) δ8.48 (d, J= 2.0 Hz, 1H), 7.64-7.54 (m, 2H), 7.45 (dd, J= 7.7, 1.2 Hz, 1H), 7.31-7.14 (m, 2H), 4.26-4.10 (m, 2H), 4.56-4.52 (m, 1H), 3.83-3.68 (m, 3H), 3.61 (m, 1H), 3.42-3.33 (m, 2H), 3.04 (td, J= 12.6, 4.5 Hz, 1H), 2.63 (m, 2H), 2.52-2.46 (m, 1H), 2.39 (s, 3H), 2.09 (td, J= 12.9, 4.5 Hz, 1H), 1.84 (td, J= 12.8, 4.6 Hz, 1H), 1.76-1.64 (m, 2H), 1.56 (d, J= 13.8 Hz, 1H), 1.46 (d, J= 13.7 Hz, 1H), 1.00-0.87 (m, 2H). [Example]

[15] [(R)-N-(3-)] [chlorine] [-2-] [Methylbenzyl] [)-2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane-1,4-dioxane] [[5.5]] [Undecane] [-4-] [base] [)] [Ethane] [-1-] [amine] [12-1]

[0222] Synthesis scheme:

[0223] The target compound was prepared by replacing the starting material 1,3-dihydro-2H-inden-2-one with 3-chloro-2-methylbenzaldehyde using the synthesis method of Example 9. [12-1] [。]

[0224] LC-MS (m / z): 433.2[M+H] +.

[0225] 1H NMR (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). [Example]

[16] [N-(2,3-)] [Dichlorobenzyl] [)-2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane-1,4-dioxane] [[5.5]] [Undecane] [-4-] [base] [)] [Ethane] [-1-] [amine]

[13]

[0226] Synthesis scheme:

[0227] The target compound was prepared by replacing the starting material 6-chloro-2,3-dihydro-1H-inden-1-one with 2,3-dichlorobenzaldehyde using the synthetic method of Example 4.

[13]

[0228] LC-MS (m / z): 453.2[M+H]+.

[0229] 1H NMR (600 MHz, CD 3OD) 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). [Example]

[17] [(R)-N-(2,3-] [Dichlorobenzyl] [)-2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethane] [-1-] [amine] [13-1]

[0230] The target compound was prepared by replacing the starting material 1,3-dihydro-2H-inden-2-one with 2,3-dichlorobenzaldehyde using the synthesis method of Example 9. [13-1] [。]

[0231] LC-MS (m / z): 454[M+H] +.

[0232] 1H 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, 4.8 Hz, 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). [Implementation Example]

[18] [N-(3-)] [chlorine] [-2-] [Fluorobenzyl] [)-2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane] [[5.5]] [Undecane] [-4-] [base] [)] [Ethane] [-1-] [amine]

[14]

[0233] Synthesis scheme:

[0234] The target compound was prepared by replacing the starting material 6-chloro-2,3-dihydro-1H-inden-1-one with 3-chloro-2-fluorobenzaldehyde using the synthetic method of Example 4.

[14]

[0235] LC-MS (m / z): 438 [M+H] +.

[0236] 1H NMR (600 MHz, DMSO- d 6) δ8.57 (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). [Example]

[19] [N-(2-(4-(] [Pyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [)-2,3-] [Dihydrogen] [-1H-] [Indonesia] [-1-] [amine]

[15]

[0237] Synthesis scheme: [step] [A] [:] [2-] [Cyano] [-2-(4-(] [Pyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] Synthesis of methyl acetate

[0238] 2-Bromopyridine (4.74 g, 30 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and slowly added dropwise to isopropyl magnesium chloride solution (15 mL, 30 mmol) at 0 °C. The reaction was carried out at room temperature for 3 hours. Cuprous iodide (0.57 g, 3 mmol) was added and the reaction was carried out for another hour. Methyl (Z)-2-cyano-2-(1,9-dioxaspiro[5.5]undecane-4-alkylene)acetate (5.0 g, 20 mmol) was dissolved in tetrahydrofuran (15 mL) and added dropwise. 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) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered under vacuum, concentrated, and then subjected to column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the target product (3.3 g, yield 50%).

[0239] LC-MS (m / z): 331[M+H] +. [step] [B] [:] [2-(4-(] [Pyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] Synthesis of acetonitrile

[0240] 3.0 g (9.1 mmol) of methyl 2-cyano-2-(4-(pyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)acetate was 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 the pale yellow target product (1.8 g, yield 73%).

[0241] LC-MS (m / z): 273[M+H] +. [step] [C] [:] [2-(4-(] [Pyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethane] [-1-] [Amine Synthesis]

[0242] Dissolve 1.8 g (6.6 mmol) of 2-(4-(pyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)acetonitrile in 15 mL of tetrahydrofuran. Add 750 mg (19.8 mmol) of lithium aluminum hydride under ice bath and react at room temperature for 2 hours. After the reaction is complete, add 0.75 mL of water, 2 mL of 15% sodium hydroxide solution, 2 mL of water, and 10 mL of ethyl acetate in sequence. Dry under anhydrous sodium sulfate and concentrate under reduced pressure to dryness to obtain the target product (1.5 g, yield 85%) in an oily form.

[0243] LC-MS (m / z): 277[M+H] +. [step] [D] [:] [N-(2-(4-(] [Pyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [)-2,3-] [Dihydrogen] [-1H-] [Indonesia] [-1-] [Amine Synthesis]

[0244] 2-(4-(pyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)ethane-1-amine (100 mg, 0.36 mmol) and 1-indanone (50 mg, 0.36 mmol) were dissolved in tetraisopropyl titanate (1 mL) and reacted at 80 °C for 5 h. After cooling to room temperature, methanol (1 mL) and sodium borohydride (38 mg, 1.0 mmol) were added, and the reaction was allowed to proceed for 1 h. The reaction was monitored by LC-MS until complete. The mixture was filtered, concentrated, and purified by preparative liquid chromatography to obtain the target compound.

[15] (25.3 mg, yield 18%).

[0245] LC-MS (m / z): 393[M+H]+.

[0246] 1H NMR (600 MHz, DMSO- d 6)δ8.59 (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). [Example]

[20] [4-] [chlorine] [-N-(2-(4-(] [Pyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [)-2,3-] [Dihydrogen] [-1H-] [Indonesia] [-1-] [amine]

[16]

[0247] The target compound was prepared by replacing 1-indanone with 4-chloro-1-indanone using the synthetic method described in Example 16.

[16]

[0248] LC-MS (m / z): 428 [M+H] +.

[0249] 1H NMR (600 MHz, DMSO- d 6) δ8.59-8.58 (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). [Example] [twenty one] [4-] [chlorine] [-N-(2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [)-2,3-] [Dihydrogen] [-1H-] [Indonesia] [-2-] [amine]

[17]

[0250] The target compound was prepared by replacing the starting material 6-chloro-2,3-dihydro-1H-indanone with 4-chloro-1,3-dihydro-2H-indanone using the synthetic method described in Example 4.

[17]

[0251] LC-MS(m / z): 447 [M+H] +.

[0252] 1H NMR (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). [Example] [twenty two] [(S)-4-] [chlorine] [-N-(2-((R)-4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [)-2,3-] [Dihydrogen] [-1H-] [Indonesia] [-2-] [amine] [17-1-1] [and] [(R)-4-] [chlorine] [-N-(2-((R)-4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane snail] [[5.5]] [Undecane] [-4-] [base] [)] [Ethyl] [)-2,3-] [Dihydrogen] [-1H-] [Indonesia] [-2-] [amine] [17-1-2]

[0253] Synthesis scheme:

[0254] The target compound was prepared by replacing the starting material 1,3-dihydro-2H-indanone with 4-chloro-1,3-dihydro-2H-indanone using the synthetic method described in Example 9. [17-2].

[0255] Take compounds [17-2] was split, and two optical isomers were obtained after separation:

[0256] (S)-4-chloro-N-(2-((R)-4-(5-fluoropyridin-2-yl)-1,9-dioxane[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H-indene-2-amine [17-1-1], 2.10 min, ee%=97%;

[0257] LC-MS (m / z): 445[M+H] +.

[0258] 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).

[0259] (R)-4-chloro-N-(2-((R)-4-(5-fluoropyridin-2-yl)-1,9-dioxane[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine [17-1-2], 3.1 min, ee%=97%;

[0260] LC-MS (m / z): 445[M+H] +.

[0261] 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).

[0262] Resolution conditions: Instrument: Waters SFC 150; Column: DAICELCHIRALCEL® 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℃; Wavelength: 214 nm; Cycle time: 6 min; Compound to be resolved dissolved in MeOH (40 mL); Injection: 1.8 mL. [Implementation Example] [twenty three] [(R)-N-(2-) [Chlorobenzyl] [)-2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane-1,4-dioxane] [[5.5]] [Undecane] [-4-] [base] [)] [Ethane] [-1-] [amine] [18-1]

[0263] The target compound was prepared by replacing the starting material 1,3-dihydro-2H-inden-2-one with 2-chlorobenzaldehyde using the synthesis method of Example 9. [18-1].

[0264] LC-MS (m / z): 419[M+H] +.

[0265] 1H NMR (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 = 6.0 Hz, 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). [Example] [twenty four] [(R)-N-(2-(] [Difluoromethoxy] [)] [Benzyl] [)-2-(4-(5-] [Fluoropyridine] [-2-] [base] [)-1,9-] [Dioxane-1,4-dioxane] [[5.5]] [Undecane] [-4-] [base] [)] [Ethane] [-1-] [amine] [19-1]

[0266] The target compound was prepared by replacing the starting material 1,3-dihydro-2H-inden-2-one with 2-difluoromethoxybenzaldehyde using the synthesis method of Example 9. [19-1]

[0267] LC-MS (m / z): 451[M+H] +.

[0268] 1H NMR (600 MHz, DMSO) δ 8.53 (d, J= 2.9 Hz, 1H), 7.72 (d, J= 2.9 Hz, 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). [Bioactivity Evaluation]

[0269] The following description, in conjunction with test examples, is used to further illustrate the invention, but it is not intended to limit the scope of the invention. The structure and source of oxycodone in the test examples are shown in Table 1 below: Table 1 Name structural Source Oxycodone Provided by Jiangsu Enhua Pharmaceutical Co., Ltd. [Test Example] [1] 1.1 Experimental Objective

[0270] The purpose of this experiment is to test the activating effect of the compound of the present invention on MOR, and to evaluate the in vitro activity of the compound based on the magnitude of EC50 and Emax. 1.2 The experimental materials are shown below. Table 2 Cell name Growth Culture Medium Frozen culture medium CHO-K1 / OP3 Ham's F-12, 10% FBS, 0.4 mg / ml G418 45% culture medium, 45% FBS, 10% DMSO Table 3 Reagent Name brand Item number Specification cAMP Assay Kit Cisbio 62AM9PEJ 100,000 tests IBMX Sigma I5879 1 g HBSS Gibco 14175103 10×500 mL Forskolin Sigma F6886 50 mg DMSO Sigma D8418 500 mL 1.3 Experimental Procedure

[0271] 1.3.1 Reagent Preparation

[0272] 1.3.1.1 Preparation of experimental buffer solution

[0273] Dilute 5× stimulation buffer to 1× with ddH₂O, and add an appropriate amount of 500 mM IBMX (generally, IBMX stock solution is prepared to 500 mM, i.e., 1000X) to make the final concentration of IBMX 0.5 mM. Mix well and set aside. (It is normal for precipitation to occur after adding IBMX; mix thoroughly to dissolve the precipitate.) It must be prepared and used immediately.

[0274] 1.3.1.2 IBMX was dissolved in DMSO to prepare a 500 mM stock solution, aliquoted into 20 μL / tube, and stored at -80°C to avoid repeated freeze-thaw cycles.

[0275] 1.3.1.3 Forskolin was dissolved in DMSO to prepare a 10 mM stock solution, dispensed into 20 μL / tube, and stored at -20℃ for later use.

[0276] 1.3.1.4 Preparation of cAMP Standards

[0277] Take the cAMP standard from the kit and bring it to room temperature. Add an equal volume of experimental buffer according to the volume marked on the bottle label, vortex to mix, and aliquot into 50 μL / tube and freeze at -20℃ for later use.

[0278] 1.3.1.5 Preparation of test reagent stock solution (20,000 tests package)

[0279] Take one bottle each of cAMP-d2 and Anti-cAMP-Cryptate lyophilized powder, add 5 mL of ddH2O to each, and gently invert to mix. Aliquot into 125, 62.5, and 30 μL containers and store in the dark at -80℃.

[0280] 1.3.2 Test Procedure for Accomplishing Agents

[0281] 1.3.2.1 The positive compound DAMGO and the test compound were serially diluted 4-fold on Bravo using experimental buffer in a compound well plate (Greiner-781280) to obtain 10 concentrations. The initial concentrations were 2 μM (diluted from DMSO stock solution with experimental buffer) and 20 μM (diluted from DMSO stock solution with experimental buffer).

[0282] 1.3.2.2 Thaw the frozen cells in a 37°C water bath. Add the cell suspension to a centrifuge tube containing 10 mL of HBSS buffer and centrifuge at 750 rpm for 5 minutes. Discard the supernatant, resuspend the pellet in an appropriate amount of experimental buffer, and count 20 μL of the pellet using a cell counter. Dilute an appropriate amount of the cell suspension to 0.4 × 10⁶ cells / mL, add 5 μL of the cell suspension to each well of a cell culture dish (cell density of 2000 cells / well), and centrifuge at 1000 rpm for 1 minute. Transfer 5 μL of the diluted compound to a cell culture dish (PerkinElmer-6008280) using Bravo. Transfer 5 μL of 2 μM DAMGO (final concentration 1 μM) to the positive control well and an equal volume of experimental buffer to the negative control well. Centrifuge at 1000 rpm for 1 minute. Seal the cell culture dish and incubate at room temperature for 15 minutes. Forskolin was diluted to 0.2 mM with DMSO, and 25.1 nL was transferred to a cell culture dish using a Tecan-D300e. After centrifugation at 1000 rpm for 1 minute, the dish was sealed and incubated at room temperature for 45 minutes. The final concentration of Forskolin was 1 μM.

[0283] 1.3.2.3 Preparation of cAMP (stock solution concentration of 2848 nM) standard curve: The initial concentration was 1424 nM, and eight 4-fold serial dilutions were performed. 10 μL of each solution was added to the cell culture dish. The final concentration at the starting point was 712 nM.

[0284] 1.3.2.4 Preparation of Detection Reagents: Dilute appropriate amounts of cAMP-d2 stock solution and Anti-cAMP-Cryptate stock solution separately with lysis buffer at a ratio of 1:20. Then, mix the two solutions at a 1:1 ratio by inverting the container, avoiding vortexing. Add 10 μL of the prepared detection reagent to a cell culture dish and centrifuge at 1000 rpm for 1 minute. Incubate the cell culture dish at room temperature in the dark for 1 hour. After centrifuging the cell culture dish at 1000 rpm for 1 minute, read the culture dish using Envision. Excitation light: 340 nm; Emission light: 620 nm and 665 nm.

[0285] 1.3.3 Data Analysis

[0286] Formula for calculating the activation rate of compounds in activator testing: Activity%=100-(Readout-LC) / (HC-LC)*100 HC (High Control): Average readings of the Forskolin well in DMSO + 2.5 μM. LC (Low Control): Average readings of wells containing 1 μM Dopamine and 2.5 μM Forskolin Readout: Compound readings

[0287] 1.3.4 Test Results

[0288] The effect of the compound MOR of the present invention on the change of downstream cAMP level was determined by the above experiments, and the measured EC50 is shown in Table 4 below (the maximum effect of DAMGO is 100%). Table 4. EC50 and Emax values ​​of the MOR receptor-promoting compounds of this invention on cAMP levels. Example number EC 50(nM) Emax Compound 1-1 0.44 103.2% Compound 2-1 23.5 101.4% Compound 3-1 0.79 99.9% Compound 4 2.19 102.8% Compound 5-1 1.33 111% Compound 6-1 1.56 118% Compound 7-1 1.69 116% Compound 8 8.62 72.0% Compound 8-1 4.1 92.8% Compound 10 2.79 80.9% Compound 10-1-1 0.8 104% Compound 11 7.75 100.3% Compound 12 7.63 89.8% Compound 12-1 1.29 93.8% Compound 13 17.3 78.9% Compound 13-1 18.7 78.6% Compound 14 24.2 88.1% Compound 15 30.7 96.9% Compound 16 2.40 101.6% Compound 17 2.14 93.8% Compound 17-1-1 0.64 101.8% oxycodone 64.7 95.2%

[0289] [Conclusion]: The above results show that the compound described in this invention has a strong agonistic activity against MOR; the compound provided by this invention can maintain the analgesic effect while significantly reducing the dosage, thereby reducing side effects during clinical use. Therefore, the compound of this invention has broad prospects for clinical application in analgesia. [Test Example] [2] 2.1 Experimental Objective

[0290] This experiment aimed to test the synergistic effect of the compound on MOR Beta-arrestin, and to evaluate the in vitro activity of the compound based on the values ​​of EC50 and Emax. 2.2 The experimental consumables and instruments are shown below. Table 5 Consumables and Instruments supplier Item number 384-well cell culture tray Corning #3570 384-well Echo compound culture tray Labcyte #LP-0200 384-well compound culture tray PE #6008590 Echo 550 Labcyte / Bravo Agilent / Envision Plate Reader PerkinElmer / 2.3 The experimental reagents are shown below. Table 6 reagents supplier Item number Human Mu opioid β-arrestin U2OS / OPRM1 cell line DiscoveRX #93-0213C3 MEM Gibco #11095-080 FBS Invitrogen #10099-141 0.25% Trpysin / EDTA Invitrogen #25200-072 Hygromycin B Invitrogen #10687-010 GlutaMAX Invitrogen #35050-079 DPBS Invitrogen #14200-075 DAMGO Tocris #1171 Path Hunter Detection Kit DiscoveRX #93-0001L

[0291] Complete cell culture medium: MEM + 10% FBS + 1% PS + 250 μg / mL Hygromycin B + 500 μg / mL G418 + 1X GlutaMAX

[0292] Cell seeding medium: MEM + 10% FBS + 1% PS

[0293] Experimental buffer: 1x DPBS + 0.1% BSA

[0294] Test reagent: Galacton Star : Emerald II : PathHunter Cell Assay Buffer = 1:5:19 2.4 Experimental Methods

[0295] 2.4.1 Compound Preparation

[0296] i) The compound sample was dissolved in DMSO to a storage concentration of 10 mM;

[0297] ii) Sample dilution sequences were prepared on a 384-well LDV disk, with the initial concentration point of each sample being 10 mM (FAC=30 μM), followed by 3.162-fold serial dilutions, for a total of 11 concentration points;

[0298] iii) Use an Echo machine to transfer the sample dilution sequence and HPE, ZPE to the compound culture tray (PE #6008590), with 90 nL transferred per well.

[0299] 2.4.2 Experimental Procedure

[0300] i) MOR beta-arrestin cell line was cultured in complete cell culture medium at 37°C with 5% CO2 up to 70%~90% concentration.

[0301] ii) After digestion, the cells were resuspended in cell seeding medium. 20 μL of MOR beta-arrestin cell suspension was added to each well of the experimental culture dish (Corning #3570), with a cell count of 7500 cells / well. The cells were then incubated at 37°C in a 5% CO2 incubator for 24 h.

[0302] iii) Add 30 μL of experimental buffer to the compound culture dish (PE #6008590) and centrifuge at 1000 rpm for 5 min;

[0303] iv) After 24 h, remove the experimental culture tray, remove the culture medium from the tray, and then use Bravo to transfer 20 μL of the compound from each well of the compound culture tray to the experimental culture tray;

[0304] v) After centrifuging the experimental culture tray at 500 rpm for 30 seconds, place it in a 37℃, 5% CO2 incubator for 90 min;

[0305] vi) Add 10 μL of beta-arrestin detection reagent to each well of the experimental culture dish;

[0306] vii) Read the values ​​on Envision after incubating at room temperature in the dark for 1 hour. 2.5 Experimental Data Processing Methods

[0307] Experimental data were fitted to percentage activation rate and 11-point concentration data using XLFit and parametric nonlinear logic.

[0308] The EC50 value of the compound was calculated using the formula, and the test results are shown in Table 7 (the maximum effect of DAMGO is 100%). Table 7 Results of the activity of the compounds of this invention in activating the Beta-arrestin signaling pathway Example number EC 50(nM) Emax Compound 8 364 2.1% Compound 8-1 >30000 3.0% Compound 10 4801 4.5% Compound 12 >30000 6.3% Compound 13-1 >30000 4.2% Compound 15 1784 7.2%

[0309] [Conclusion]: The above results show that the compound described in this invention has almost no activating effect on the Beta-arrestin signaling pathway; the compound provided by this invention has no obvious side effects and is safer and more effective in clinical use. [Test Example] [3] 3.1 Experimental Objective

[0310] This experiment aims to measure the effect of various compound samples on the pain threshold of mice using the mouse thermal radiation tail flicking method. 3.2 The experimental reagents are shown below. Table 8 Reagent Name supplier Item number Specification Methylcellulose Sigma SLCH2339 250G DMSO Sinopharm Chemical Reagent Co., Ltd. 30072418 500 mL 3.3 Experimental Methods

[0311] 3.3.1 Dosage and route of administration:

[0312] Administered by gavage at a dose of 10 mg / kg;

[0313] 3.3.2 Experimental Procedure

[0314] ICR mice (normal grade, weighing 25-35 g, purchased from Shanghai Silex Laboratory Animal Technology Co., Ltd.) were first fixed in a specially designed plastic tube, with their tails exposed and hanging naturally. Measurements were taken after the animals had calmed down. An 8.75 mm projection lamp (32W, adjustable) was used as the radiant heat source, emitting a beam of light approximately 4 mm in diameter after being focused by a lens. This beam irradiated the skin at the junction of the middle and lower thirds of the tail (the light source and tail skin must be in close contact). An electronic timer connected in parallel with the light source synchronously recorded the irradiation duration; the stopwatch automatically started when irradiation began and automatically stopped when the animal showed a clear escape reaction. The measured time interval was the tail-flick latency. Mice with a tail-flick latency of 2-6 seconds were selected for grouped drug administration experiments. If the animal's analgesic effect lasted longer than 15 seconds, irradiation was stopped, and 15 seconds was used as the upper limit of the tail-flick latency to avoid skin burns from prolonged irradiation. After administering a certain dose of the drug, the mice's pain threshold was measured at different time points. 3.4 Detection Indicators and Statistical Methods:

[0315] Mice were given a certain dose of the drug, and their pain threshold was measured at 0.5 h, 1 h, 2 h, and 3 h (the analgesic effect is shown in Figure 1). The maximum percentage of analgesia after drug administration (%MPE) was calculated using the following formula: %MPE = (pain threshold after drug administration - pain threshold before drug administration) / (15 - pain threshold before drug administration) × 100%. Table 9. Maximum analgesic percentage at different time points after administration of each compound (%MPE, Mean±SEM, n=9-10) Example number 0.5h 1h 2h 3h Compound 8-1 80.64±9.27** 85.69±5.95*** 69.94±10.43***### 87.16±6.80***### Compound 12-1 99.48±0.52*** 86.20±9.32*** 89.98±10.02***### 78.89±10.05***### Oxycodone 37.87±12.44 28.70±9.24 3.63±8.14 -0.23±6.48 Note: Compared with Oxycodone, *p<0.05, **p<0.01, ***p<0.001.

[0316] [Conclusion]: The above results show that, at the same dosage, the compounds of the present invention, especially compounds 8-1 and 12-1, have better efficacy than Oxycodone. Among them, compounds 8-1 and 12-1 have a longer duration of analgesia compared with Oxycodone, and the effect of maintaining analgesia is statistically superior.

[0317] Although specific embodiments of the present invention have been described in detail, based on all the teachings disclosed, those skilled in the art can make various modifications and substitutions to the details of the technical solutions of the present invention, and all such modifications and substitutions are within the scope of protection of the present invention. The full scope of the present invention is provided by the appended claims and any equivalents thereof.

Claims

1. A compound of general formula (I), its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, wherein: Ring A is a C6-10 aryl group; R1 may be the same or different, and R1 and R2 are each independently hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; Ring B is pyridyl, optionally further substituted by one R3; R3 is hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; X1 is CRaRb or CRaRbCH2; Ra and Rb are each independently hydrogen, halogen, or C1-3 alkyl; Alternatively, Ra or Rb may be linked with R2 to form a cyclopentyl or cyclohexyl group; n is 0, 1, or 2.

2. The compound, its stereoisomers, its tautomers, or its pharmaceutically acceptable salts as claimed in claim 1, characterized in that one or more of the following conditions are satisfied: (1) ring A is phenyl; (2) X1 is CRaRb or CRaRbCH2, wherein Ra and Rb are each independently hydrogen; or Ra or Rb is linked with R2 to form a cyclopentyl group; (3) ring B is or; (4) R1 and R2 are each independently hydrogen, halogen, C1-3 alkyl, or C1-3 haloalkoxy; (5) R3 is hydrogen or halogen.

3. The compound, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof as claimed in claim 2, characterized in that one or more of the following conditions are satisfied: (1) X1 is CH2; (2) ring B is ; (3) R1 is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl or halomethoxy; (4) R2 is hydrogen.

4. The compound, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, as claimed in claim 2, characterized in that one or more of the following conditions are satisfied: (1) X1 is CH(Rb) or CH(Rb)CH2, wherein Rb is linked with R2 to form a cyclopentyl group; (2) ring B is or; (3) R1 is independently hydrogen, fluorine, chlorine, bromine, methyl, ethyl or propyl.

5. The compound, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, as claimed in claim 1, characterized in that one or more of the following conditions are satisfied: (1) each of R1 and R2 is independently hydrogen, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or C1-3 haloalkoxy; (2) each of R3 is independently hydrogen, fluorine, chlorine, bromine or C1-3 alkyl; (3) X1 is CH2, CH(Rb) or CH(Rb)CH2; (4) Ra or Rb is linked with R2 to form a cyclopentyl group.

6. The compound, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, characterized in that general formula (I) further has the structure shown in general formula (ⅠⅠ): wherein, Rings A, R1, R3, and n are as described in claim 1.

7. The compound, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, as claimed in claim 6, characterized in that: general formula (I) has the structure shown in general formula (II-1): wherein, Rings A, R1, R3, and n are as described in claim 1.

8. The compound, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, as claimed in claim 6, characterized in that the compound is _____, ... Raa, Rbb, Rcc, Rdd, or Ree are each independently a halogen, a C1-6 alkyl, a C1-6 haloalkyl, a C1-6 alkoxy, or a C1-6 haloalkoxy.

9. The compound, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof as claimed in claim 8, characterized in that Raa, Rbb, Rcc, Rdd and Ree are each independently fluorine, chlorine, bromine, methyl, ethyl, propyl or halomethoxy.

10. The compound, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 6-9, characterized in that the compound is, , , , or .

11. The compound, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, characterized in that general formula (I) further has the structure shown in general formula (III): wherein, Cyclo-C is cyclopentyl, and R1, R3, and n are as described in claim 1.

12. The compound, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, as claimed in claim 11, characterized in that the general formula (III) has the structure shown in general formula (IV-1), general formula (IV-2), general formula (V-1), or general formula (V-2): , , or wherein, R1, R3, and n are as described in claim 1; the carbon atom marked with "*" is a palmar carbon atom, existing in a single enantiomer (R) or (S) form or in a form rich in a pair of enantiomers.

13. The compound, its stereoisomers, its tautomers, or its pharmaceutically acceptable salts as claimed in claim 11, characterized in that the general formula (III) has the structure shown in general formula (IV-1-1), general formula (IV-1-2), general formula (V-1-1), or general formula (V-1-2): , , or wherein, R1, R3, and n are as described in request item 1.

14. The compound, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, as claimed in claim 13, characterized in that: [the compound is] [a specific compound], ... Raa, Rbb, Rcc, and Rdd are each independently a halogen, a C1-6 alkyl, a C1-6 haloalkyl, a C1-6 alkoxy, or a C1-6 haloalkoxy.

15. The compound, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof as claimed in claim 14, characterized in that Raa, Rbb, Rcc and Rdd are each independently fluorine, chlorine, bromine, methyl, ethyl or propyl.

16. The compound, its stereoisomer, its tautomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 11-15, characterized in that it satisfies one of the following conditions: (1) it is , , or; (2) it is , , , , or.

17. The compound, its stereoisomers, its tautomers, or its pharmaceutically acceptable salts as claimed in claim 1, characterized in that the compound has any of the following structures:

18. The compound, its stereoisomers, its tautomers, or its pharmaceutically acceptable salts as claimed in claim 1, characterized in that the compound has any of the following structures:

19. The compound, its stereoisomers, its tautomers, or its pharmaceutically acceptable salts as claimed in claim 17, characterized in that the compound has any of the following structures:

20. A method for preparing a compound of formula (I) as claimed in claim 1, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that it comprises: A compound of general formula (I-A) and a compound of general formula (I-B) or a pharmaceutically acceptable salt thereof undergo a reductive amination reaction to give a compound of general formula (I), its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof; wherein: ring A, R1, R2, ring B, X1, and n are as described in claim 1.

21. A method for preparing a compound of formula (ⅠⅠ) as claimed in claim 6, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that it comprises: Method 1: A compound of general formula (ⅠⅠ-A-1) and a compound of general formula (ⅠⅠ-B-1) or a pharmaceutically acceptable salt thereof undergoes a reductive amination reaction to yield a compound of general formula (ⅠⅠ), its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof; or, Method 2: A compound of general formula (ⅠⅠ-A-2) and a compound of general formula (ⅠⅠ-B-2) or a pharmaceutically acceptable salt thereof undergoes a reductive amination reaction to yield a compound of general formula (ⅠⅠ), its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof; wherein: rings A, R1, R3, and n are as described in claim 6.

22. A method for preparing a compound of formula (III) as claimed in claim 11, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that it comprises: Method 1: A reductive amination reaction is carried out between a compound of formula (III-A-1) and a compound of formula (III-B-1) or a pharmaceutically acceptable salt thereof to give a compound of formula (III), its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof; or, Method 2: A reductive amination reaction is carried out between a compound of formula (III-A-2) and a compound of formula (III-B-2) or a pharmaceutically acceptable salt thereof to give a compound of formula (III), its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof; wherein: ring C, R1, R3, and n are as described in claim 11.

23. A pharmaceutical composition comprising a therapeutically effective amount of any one of claims 1 to 19, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, and excipient.

24. Use of any compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 19, in the preparation of a medicament for the prevention and / or treatment of μ-opioid receptor agonist-mediated diseases, wherein the μ-opioid receptor agonist-mediated diseases are selected from one or more of pain, immune dysfunction, inflammation, acid reflux, neurological and psychiatric diseases, urinary and reproductive diseases, cardiovascular diseases, and respiratory diseases.

25. Use of a compound, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1 to 19, in the preparation of a medicament for the prevention and / or treatment of pain or pain-related diseases, wherein the pain is selected from one or more of postoperative pain, cancer-related pain, neuropathic pain, traumatic pain, and inflammatory pain.

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