Oxaspiro derivatives, methods of preparation and uses thereof

Abstract

Oxaspirocyclic derivatives, methods of preparation and uses thereof. Specifically, provided is a compound as shown in general formula (I), a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, a preparation method thereof, uses for activating opioid receptor activity, and uses in preparing analgesic drugs.

Description

[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. Technical Field

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

[0003] Opioid receptors belong to the G protein-coupled receptor (GPCR) family. Currently, nine opioid receptors, including μ, δ, κ, and ORL1, have been identified and are widely expressed in the central and peripheral nervous systems, as well as neuroendocrine cells, immune cells, and endothelial cells. μ (MOR), δ (DOR), and κ (KOR) opioid 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 opioid receptors are classic opioid receptors, sharing a common basic structure: both an extracellular N-terminal region and an intracellular spindle-terminal region. Agonists of these three opioid receptor subtypes primarily couple to 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 in the cerebral cortex and subcortical regions are involved in the nociceptive response mediated by the nociceptive response (MOR). Some areas 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 levels of opioid receptors are expressed in the ACC region. Opioids are widely used to treat persistent pain and have been suggested to act in the brain. Reports have shown that morphine injection into the ACC region inhibits the emotional response to pain, without altering pain sensation 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 opioid substances or endogenous opioid peptides stimulate opioid receptors on the presynaptic and postsynaptic membranes of sensory nerves. Through the G-protein coupling mechanism, 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, while promoting the release of K+. + Outflow, reduce Ca 2+ The influx of fluids eventually weakens the pain signals, producing an analgesic effect.

[0007] After years of research, numerous opioid receptor agonists and antagonists have been discovered. Currently identified opioid receptor agonists include morphine, damine, endorphins, and fentanyl and its derivatives. Naloxone (Nal), CTOP, CTAP, and naltrexone are opioid receptor antagonists. 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 agonistic effects, i.e., an agonist-antagonist binding effect. It can alleviate problems such as opioid overdose poisoning and persistent postoperative respiratory depression, and can also be used for differential diagnosis of drug addicts. Remifentanil possesses analgesic, sedative, and respiratory depressant effects similar to other μ-opioid receptor agonists. It does not bind significantly to non-opioid receptors, and its binding to opioid receptors can be competitively inhibited by naloxone. Its analgesic effect is dose-dependent and has 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 opioids 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 μ-opioid receptor agonist-mediated diseases, 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.

[0010]

[0011] in:

[0012] Ring A is C 6-10 Aryl or 5-6 heteroaryl, wherein the 5-6 heteroaryl is a 5-6 heteroaryl containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur atoms;

[0013] R 1 Same or different, R 1 and R 2 Each can be independently represented by hydrogen, halogen, hydroxyl, amino, nitro, cyano, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, wherein the C 1-6Alkyl groups may optionally be further selected from C10. 3-6 cycloalkyl, C 1-6 The alkyl group is substituted with one or more substituents of halogen; preferably hydrogen, halogen, hydroxyl, or C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy group; more preferably hydrogen, fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, methoxy, ethoxy, halomethyl, haloethyl or halomethoxy group; further preferably hydrogen, fluorine, chlorine, bromine, methyl, methoxy or halomethoxy group; even more preferably hydrogen, fluorine, chlorine, bromine, methyl or methoxy group;

[0014] Ring B is phenyl or pyridyl, optionally further surrounded by 1-4 R groups. 3 Replaced;

[0015] R 3 Whether the groups are the same or different, each can be independently identified as hydrogen, halogen, hydroxyl, amino, nitro, cyano, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy group; preferably hydrogen, fluorine, chlorine, bromine or C 1-3 Alkyl; more preferably hydrogen, fluorine, chlorine or bromine;

[0016] X1 is CR a R b or CR a R b CH2; preferably CH2, CH(R) b ) or CH(R b CH2;

[0017] R a and R b Each is independently hydrogen, halogen, or C 1-3 alkyl;

[0018] Or, R a Or R b With R 2 The link forms a cyclopentyl or cyclohexyl group, optionally further substituted by one or more substituents selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, halomethyl, haloethyl, halomethoxy, and haloethoxy; preferably R a Or R b With R 2 The link forms a cyclopentyl group;

[0019] n can be 0, 1, 2, or 3.

[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, ring A is a phenyl group.

[0021] For compounds represented by general formula (I), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, the R... 1 and R 2 Each is independently hydrogen, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkoxy groups; preferably hydrogen, halogen, or C. 1-3 Alkyl or C 1-3 Halogenated alkoxy group; more preferably hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl or halogenated methoxy group; even more preferably hydrogen, fluorine, chlorine, bromine, methyl or fluoromethoxy group.

[0022] For compounds represented by general formula (I), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, the R... 1 Independently hydrogen, halogen or C 1-6 Alkyl; preferably hydrogen, halogen or C 1-3 Alkyl; more preferably hydrogen, fluorine, chlorine, bromine, methyl, ethyl or propyl; even more preferably hydrogen, fluorine, chlorine, bromine or methyl.

[0023] For compounds represented by general formula (I), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, the R... 1 For hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; preferably hydrogen, halogen, or C. 1-3 Alkyl or C 1-3 Halogenated alkoxy group; more preferably hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl or halogenated methoxy group; even more preferably hydrogen, fluorine, chlorine, methyl or fluoromethoxy group.

[0024] For compounds represented by general formula (I), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, the R... 2 For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkoxy group; preferably hydrogen.

[0025] 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 a pyridinyl group, optionally further surrounded by an R group. 3 What it replaced.

[0026] For compounds represented by general formula (I), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, the R... 3 Each is independently hydrogen or halogen; preferably hydrogen, fluorine, chlorine or bromine; more preferably hydrogen or fluorine.

[0027] For compounds of general formula (I), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, X1 is a CR a R b or CR a R b CH2; R a and R b Each is independently hydrogen, halogen, or C 1-3 Alkyl group, preferably hydrogen.

[0028] For compounds of general formula (I), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, X1 is a CR a R b CH2 is preferred.

[0029] For compounds of general formula (I), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention, X1 is a CR a R b or CR a R b CH2; R a Or R b With R 2 The linker forms a cyclopentyl or cyclohexyl group, preferably a cyclopentyl group.

[0030] 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(R) b ) or CH(R b CH2; R b With R 2 The linker forms a cyclopentyl or cyclohexyl group, preferably a cyclopentyl group.

[0031] 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,

[0032] The ring B is Preferred More Further optimization

[0033] A preferred embodiment of the present invention provides a compound of general formula (II), its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof.

[0034]

[0035] in:

[0036] Rings A and R 1 R 3 And n is as described in general formula (I).

[0037] 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):

[0038]

[0039] in:

[0040] Rings A and R 1 R 3 And n is as described in general formula (I).

[0041] 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,

[0042] The for

[0043] Preferred

[0044] Where: R aa R bb R cc R dd and R ee Each is independently a halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, wherein the C 1-6 Alkyl groups may optionally be further selected from C10. 3-6cycloalkyl, C 1-6 The alkyl group is substituted with one or more substituents of the halogen; preferably halogen, hydroxyl, or C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy; 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.

[0045] 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,

[0046] The for

[0047] 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 R aa R bb R cc R dd and R ee Each independently constitutes a halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; preferably halogens, C 1-3 Alkyl or C 1-3 Halogenated alkoxy; more preferably fluorine, chlorine, bromine, methyl, ethyl, propyl or halogenated methoxy; even more preferably fluorine, chlorine, bromine, methyl or fluoromethoxy.

[0048] 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 R aa Halogen or C 1-6 Halogenated alkoxy groups; preferably halogenated or C 1-3 Halogenated alkoxy; more preferably fluorine, chlorine, bromine or halogenated methoxy; even more preferably chlorine or fluorinated methoxy.

[0049] 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 R dd It is a halogen; more preferably fluorine, chlorine or bromine; chlorine is even more preferred.

[0050] 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 R ee Halogen or C 1-6 Alkyl; preferably halogen or C 1-3 Alkyl; more preferably fluorine, chlorine, bromine, methyl, ethyl or propyl; even more preferably fluorine, chlorine or methyl.

[0051] 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,

[0052] The for

[0053] A preferred embodiment of the present invention provides a compound of general formula (III), its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof.

[0054]

[0055] in:

[0056] Cyclocarbonyl group C is cyclopentyl.

[0057] R 1 R 3 And n is as described in general formula (I).

[0058] In a further preferred embodiment of the invention, for compounds of general formula (III), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, said general formula (III) further has the structure shown in general formula (IV) or general formula (V):

[0059]

[0060] in:

[0061] R 1 R 3 and n as described in general formula (III);

[0062] Carbon atoms marked with "*" are chiral carbon atoms, existing as a single enantiomer (R) or (S) or in a form rich in a pair of enantiomers;

[0063] Carbon atoms marked with "#" are chiral carbon atoms, existing as a single enantiomer (R) or (S) or in a form rich in a pair of enantiomers.

[0064] 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,

[0065] The for Preferred

[0066] The for Preferred

[0067] Where: R aa R bb R cc and R dd Each is independently a halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, wherein the C 1-6 Alkyl groups may optionally be further selected from C10. 3-6 cycloalkyl, C 1-6 The alkyl group is substituted with one or more substituents of the halogen; preferably halogen, hydroxyl, or C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy; 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.

[0068] For compounds represented by 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 R... aa R bb R cc and R dd Each is independently halogen or C 1-6 Alkyl; preferably halogen or C 1-3 Alkyl; more preferably fluorine, chlorine, bromine, methyl, ethyl or propyl; even more preferably fluorine, chlorine, bromine or methyl.

[0069] For compounds represented by 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 R... aa It is a halogen; preferably fluorine, chlorine or bromine; more preferably chlorine or bromine.

[0070] For compounds represented by 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 R... bb It is a halogen; preferably fluorine, chlorine or bromine; more preferably fluorine or chlorine.

[0071] For compounds represented by 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 R... dd Halogen or C 1-6 Alkyl; preferably halogen or C 1-3 Alkyl; more preferably fluorine, chlorine, bromine, methyl, ethyl or propyl; even more preferably fluorine, chlorine, bromine or methyl.

[0072] In a further preferred embodiment of the invention, for compounds of general formula (IV), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof,

[0073] The for

[0074] For compounds of general formula (V), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, in a further preferred embodiment of the invention...

[0075] The for

[0076] 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):

[0077]

[0078] in:

[0079] R 1 R 3 and n as described in general formula (IV);

[0080] Carbon atoms marked with an asterisk (*) are chiral carbon atoms, existing as a single enantiomer (R) or (S) or as a form rich in a pair of enantiomers.

[0081] 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):

[0082]

[0083] in:

[0084] R 1 R 3 and n as described in general formula (IV);

[0085] Carbon atoms marked with an asterisk (*) are chiral carbon atoms, existing as a single enantiomer (R) or (S) or as a form rich in a pair of enantiomers.

[0086] 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):

[0087]

[0088] in:

[0089] R 1 R 3 And n is as described in general formula (IV-1).

[0090] 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 represented by general formula (V-1):

[0091]

[0092] in:

[0093] R 1 R 3 and n are as described in general formula (V);

[0094] Carbon atoms marked with an asterisk (*) are chiral carbon atoms, existing as a single enantiomer (R) or (S) or as a form rich in a pair of enantiomers.

[0095] 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 represented by general formula (V-2):

[0096]

[0097] in:

[0098] R 1 R 3 and n are as described in general formula (V);

[0099] Carbon atoms marked with an asterisk (*) are chiral carbon atoms, existing as a single enantiomer (R) or (S) or as a form rich in a pair of enantiomers.

[0100] 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 a structure represented by general formula (V-1-1) or general formula (V-1-2):

[0101]

[0102] in:

[0103] R 1 R 3 And n is as described in general formula (V-1).

[0104] In one embodiment of the present invention, the compound has any of the following structures:

[0105]

[0106] Preferably, the compound has any of the following structures:

[0107]

[0108] Preferably, the compound has any of the following structures:

[0109]

[0110] A preferred embodiment of the present invention provides a method for preparing a compound of the above general formula (I), its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, comprising:

[0111]

[0112] Compounds of general formula (IA) and compounds of general formula (IB) or their pharmaceutically acceptable salts undergo reductive amination to yield compounds of general formula (I), their stereoisomers, their tautomers, or their pharmaceutically acceptable salts.

[0113] Among them: rings A and R 1 R2 Ring B, X1, and n are as described in general formula (I).

[0114] A preferred embodiment of the present invention provides a method for preparing the compound represented by the above general formula (II), its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof, comprising:

[0115] Method 1:

[0116]

[0117] Compounds of general formula (II-A-1) and compounds of general formula (II-B-1) or their pharmaceutically acceptable salts undergo reductive amination to give compounds of general formula (II), their stereoisomers, their tautomers or their pharmaceutically acceptable salts;

[0118] Method 2:

[0119]

[0120] Compounds of general formula (II-A-2) and compounds of general formula (II-B-2) or their pharmaceutically acceptable salts undergo reductive amination to give compounds of general formula (II), their stereoisomers, their tautomers or their pharmaceutically acceptable salts;

[0121] Among them: rings A and R 1 R 3 And n is as described in general formula (II).

[0122] 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:

[0123] Method 1:

[0124]

[0125] Compounds of general formula (III-A-1) and compounds of general formula (III-B-1) or their pharmaceutically acceptable salts undergo reductive amination to give compounds of general formula (III), their stereoisomers, their tautomers or their pharmaceutically acceptable salts;

[0126] Method 2:

[0127]

[0128] Compounds of general formula (III-A-2) and compounds of general formula (III-B-2) or their pharmaceutically acceptable salts undergo reductive amination to give compounds of general formula (III), their stereoisomers, their tautomers or their pharmaceutically acceptable salts;

[0129] Among them: rings C and R 1 R 3 And n is as described in general formula (III).

[0130] 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:

[0131] Method 1:

[0132]

[0133] Compounds of general formula (IV-A-1) and compounds of general formula (IV-B-1) or their pharmaceutically acceptable salts undergo reductive amination to give compounds of general formula (IV), their stereoisomers, their tautomers or their pharmaceutically acceptable salts.

[0134] Method 2:

[0135]

[0136] Compounds of general formula (IV-A-2) and compounds of general formula (IV-B-2) or their pharmaceutically acceptable salts undergo reductive amination to give compounds of general formula (IV), their stereoisomers, their tautomers or their pharmaceutically acceptable salts.

[0137] Where: R 1 R 3 And n is as described in general formula (IV).

[0138] A preferred embodiment of the present invention provides a method for preparing compounds of the above general formula (V), their stereoisomers, their tautomers, or pharmaceutically acceptable salts thereof, comprising:

[0139] Method 1:

[0140]

[0141] A compound of general formula (VA-1) and a compound of general formula (VB-1) or a pharmaceutically acceptable salt thereof undergo a reductive amination reaction to give a compound of general formula (V), its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof.

[0142] Method 2:

[0143]

[0144] A compound of general formula (VA-2) and a compound of general formula (VB-2) or a pharmaceutically acceptable salt thereof undergo a reductive amination reaction to give a compound of general formula (V), its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof;

[0145] Where: R 1 R 3 And n is as described in general formula (V).

[0146] The present invention also provides a preferred embodiment of 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 excipient selected from a carrier, diluent and excipient.

[0147] 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 implantation device, wherein oral, intraperitoneal, or intravenous administration is preferred.

[0148] 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.

[0149] 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.

[0150] When used topically, especially for treating affected areas or organs that are easily accessible through topical application, such as the eyes, skin, or lower ileus, the compounds of this application can be formulated into different topical formulations depending on the affected area or organ, as detailed below.

[0151] 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.

[0152] 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 may be used in ointment formulations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsified waxes, and water; carriers that may 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.

[0153] 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 μ-opioid receptor agonist-mediated diseases.

[0154] The μ-opioid receptor agonist-mediated diseases described above are selected from one or more of pain, immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric diseases, urinary and reproductive diseases, cardiovascular diseases, and respiratory diseases, with pain being the preferred one.

[0155] 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.

[0156] The present invention also relates to a method for treating μ-opioid receptor agonist-mediated diseases, 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.

[0157] In some embodiments of the invention, the invention relates to treatment methods such as pain management.

[0158] The μ-opioid receptor agonist-mediated diseases described in the above methods are selected from one or more of pain, immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric diseases, urinary and reproductive diseases, cardiovascular diseases, and respiratory diseases, with pain being the preferred one.

[0159] 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.

[0160] 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.

[0161] 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 μ-opioid receptor agonist-mediated diseases 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 said mammal.

[0162] Detailed Description of the Invention

[0163] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0164] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as 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 preferred compounds are 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.

[0165] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0166] 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.

[0167] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and being in a non-mirror relationship with each other.

[0168] Unless otherwise stated, "(D)" or "(+)" indicates right-handed rotation, "(L)" or "(-)" indicates left-handed rotation, and "(DL)" or "(±)" indicates racemic rotation.

[0169] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key and straight dashed key

[0170] 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 rapidly interconverting. If tautomerization is possible (e.g., in solution), chemical equilibrium of the tautomer can be achieved. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve 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.

[0171] 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. The alkyl group 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, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate. 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.

[0172] 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, which are 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.

[0173] 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.

[0174] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 quintile rings sharing a single carbon atom (called a spiro atom). It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 quintiles, more preferably 7 to 10 quintiles. Spirocycloalkyl groups are classified into 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, they are 4-quintile, 4-quintile, 4-quintile, 5-quintile, or 5-quintile / 6-quintile monospirocycloalkyl groups.

[0175] Non-limiting examples of spirocycloalkyl groups include:

[0176]

[0177] It also includes spirocyclic alkyl groups that share a spiro atom with a heterocyclic alkyl group, and non-limiting examples include:

[0178]

[0179] 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 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-membered, more preferably 7- to 10-membered. 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:

[0180]

[0181] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group 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 is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of 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:

[0182]

[0183] 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, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally 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, oxo, carboxyl, or carboxylate ester. When the cycloalkyl group is substituted, the substituent is not further substituted.

[0184] 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 include a three-membered nitrogen-containing fused ring containing a benzene ring.

[0185] The ring connected to the parent structure is an aryl ring, and non-limiting examples include:

[0186]

[0187] 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.

[0188] 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-membered, more preferably 5- or 6-membered, 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:

[0189]

[0190] The heteroaryl group can 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, carboxyl, or carboxylic acid ester group. When the heteroaryl group is substituted by a substituent, the substituent is not further substituted.

[0191] 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 carboxylate ester. When the alkoxy group is substituted, the substituent is not further substituted.

[0192] "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.

[0193] "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- 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, and 2,2-difluoroethoxy.

[0194] "Alkenyl" refers to alkenyl groups, also known as olefin groups, which 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.

[0195] "Alynyl" 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.

[0196] "Hydroxy" refers to the -OH group.

[0197] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0198] "Amino" refers to -NH2.

[0199] “Cyano” refers to -CN.

[0200] "Nitro" refers to -NO2.

[0201] "Carboxyl group" refers to -C(O)OH.

[0202] 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 term “comprising” encompasses the meaning of “consisting of.”

[0203] 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.

[0204] 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.

[0205] In this article, "Z" and "-Z-" both refer to the same specific group and can be used interchangeably.

[0206] The expression mn used in this article refers to the range from m to n, as well as the subranges consisting of the individual point values ​​and the individual point values ​​themselves. 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 each point value 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, encompassing any subrange and point value included within it, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C10, C7-C9, C7-C8, C8-C9, etc., as well as C3, C4, C5, C6, C7, C8, C9, C10, etc. Similarly, the expression "C1-C6" or "C1-6" covers a range of 1-6 carbon atoms and should be understood to also encompass any subrange and each point value within it, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, etc., as well as C1, C2, C3, C4, C5, C6, etc. For example, the expression "three to ten yuan" should be understood as encompassing any subrange and each point value within it, such as three to five yuan, three to six yuan, three to seven yuan, three to eight yuan, four to five yuan, four to six yuan, four to seven yuan, four to eight yuan, five to seven yuan, five to eight yuan, six to seven yuan, six to eight yuan, nine to ten yuan, etc., as well as three, four, five, six, seven, eight, nine, ten yuan, etc. Other similar expressions in this article should also be understood in a similar manner.

[0207] 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.

[0208] 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 cases where the cycloalkyl group is substituted with an alkyl group and cases where the cycloalkyl group is not substituted with an alkyl group.

[0209] 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.

[0210] 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 at any suitable position of the substituent.

[0211] 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.

[0212] 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 may optionally be substituted by up to four R substituents, and the options for each R substituent in each case are independent of each other.

[0213] 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.

[0214] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention that is safe and effective when used in mammals and has the intended biological activity.

[0215] 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.

[0216] 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.

[0217] 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 parenteral administration (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, and intravascular injection or infusion), local administration, and rectal administration. In particular, injection or oral administration.

[0218] 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 causing the symptom of a disease or symptom to cease; 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 composition 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.

[0219] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that can effectively treat or prevent a target disorder, disease, or symptom. The term "neuropsychiatric disorders" is a collective term for neurological and psychiatric disorders, encompassing both neurological and / or psychiatric conditions.

[0220] 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 quantity 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.

[0221] 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.).

[0222] 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.

[0223] Beneficial effects

[0224] In vitro receptor function assays have demonstrated that the compounds exhibit agonistic activity against the MOP receptor, which is beneficial for the prevention and / or treatment of μ-opioid receptor agonist-mediated diseases, such as pain, immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric disorders, urinary and reproductive disorders, 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, suggesting greater safety and efficacy in clinical use. Compared to the oral drug oxycodone, they offer better analgesic effects, significantly improving patient compliance. Attached Figure Description

[0225] Figure 1 This is a graph showing the percentage of analgesic effect in the tail-flick test of mice in Test Example 3. Detailed Implementation

[0226] 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.

[0227] Example

[0228] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS).

[0229] NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using an AVANCE III 600 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents and tetramethylsilane (TMS) as the internal standard.

[0230] The determinations were performed using liquid chromatography-mass spectrometry (LC-MS) on a Shimadzu LCMS2020 mass spectrometer (Japan). The determinations were performed using a Shimadzu LC20A liquid chromatograph (Japan).

[0231] The silica gel plates used for thin-layer chromatography are from Yantai Jiangyou. The TLC specification is 0.2mm±0.03mm, and the specification used for thin-layer chromatography separation and purification products is 0.4mm-0.5mm.

[0232] Intermediate 1

[0233] 2-(4-(5-fluoropyridin-2-yl)-1,9-dioxane[5.5]undecane-4-yl)ethyl-1-amine 1a

[0234]

[0235] Synthesis scheme:

[0236]

[0237] Step A: Preparation of 1,9-dioxaspiro[5.5]undecane-4-ol

[0238] 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 silica gel column chromatography to obtain a pale yellow oily target product (4.8 g, yield 40%).

[0239] 1H NMR (600MHz, DMSO-d6): δ4.62 (d, J=4.5Hz, 1H), 3.78-3.73 (m, 1H), 3.67 (m, 1H), 3.62-3.58 (m, 1H), 3.55-3.47 (m, 4H), 1.8 5-1.81 (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, 10.5Hz, 1H).

[0240] Step B: Preparation of 1,9-dioxaspiro[5.5]undecane-4-one

[0241] 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. The product was filtered, concentrated, and subjected to column chromatography (petroleum ether:ethyl acetate = 5:1) to give a pale yellow oily target product (4.0 g, yield 85%).

[0242] 1 H NMR (600MHz, DMSO-d6): δ3.93 (t, J=6.1Hz, 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).

[0243] Step C: Preparation of (z)-2-cyano-2-(1,9-dioxaspiro[5.5]undecane-4-alkylene)acetic acid methyl ester

[0244] 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, concentrated, and then subjected to column chromatography (petroleum ether:ethyl acetate = 5:1) to give the target product (5.6 g, 90% yield).

[0245] LC-MS: MS Found: 252 [M+H] + .

[0246] 1H NMR (600MHz, DMSO-d6): δ4.02 (s, 1H), 3.86 (t, J=5.7Hz, 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).

[0247] Step D: Preparation of methyl 2-cyano-2-(4-(5-(fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)acetate

[0248] 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, add cuprous iodide (0.76 g, 4 mmol), and react for another 1 hour. Dissolve (z)-2-cyano-2-(1,9-dioxaspiro[5.5]undecane-4-alkylene)acetate (5.0 g, 20 mmol) in tetrahydrofuran (15 mL), add it dropwise, and react at room temperature overnight. Add saturated ammonium chloride solution (20 mL), extract with ethyl acetate (50 mL × 3), wash the organic phase with water (50 mL), wash with saturated brine (50 mL), dry with anhydrous sodium sulfate, filter, concentrate, and then column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target product (3.3 g, yield 50%).

[0249] LC-MS: MS Found: 349 [M+H] + .

[0250] 1 H NMR (600MHz, CDCl3) δ8.47 (dd, J=7.0, 2.8Hz, 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, 1.8Hz, 2H), 1.80-1.69 (m, 2H), 1.32-1.19 (m, 2H).

[0251] Step E: Preparation of 2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)acetonitrile

[0252] 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 obtain the pale yellow target product (1.7 g, yield 70%).

[0253] LC-MS: MS Found: 291 [M+H] + .

[0254] 1 H NMR (600MHz, CDCl3): δ8.47 (d, J=2.6Hz, 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).

[0255] Step F: Preparation of 2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)ethyl-1-amine

[0256] 2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)acetonitrile (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 1a (1.3 g, yield 85%).

[0257] LC-MS (m / z): 295.1 [M+H] + .

[0258] Intermediate 2

[0259] 2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)acetaldehyde 1b

[0260]

[0261] Synthesis scheme:

[0262]

[0263] 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), cooled to -78 °C under nitrogen protection, and 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 (0.8 g, yield 80%).

[0264] LC-MS (m / z): 294.1 [M+H] + .

[0265] Intermediate 3

[0266] (R)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)acetonitrile 1c

[0267] Synthesis scheme:

[0268]

[0269] 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:

[0270] 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 = 2 g / 100 mL, MeOH), LC-MS (m / z): 291.2 [M+H] + ;

[0271] 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 = 2 g / 100 mL, MeOH).

[0272] Split conditions: Instrument: Waters SFC 150; Column: 250*40mm 10μm; Mobile phase: A: Supercritical CO2, B: MeOH (0.1% Ammoniain MeOH); Gradient: A∶B=75∶25; Flow rate: 120mL / min; Back pressure: 100bar; Column temperature: 25℃; Wavelength: 214nm; Cycle time: 6min; Compound to be resolved dissolved in MeOH (1000mL); Injection: 8mL.

[0273] Example 1

[0274] (1S)-6-fluoro-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxane[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H-indene-1-amine 1-1

[0275]

[0276] Synthesis scheme:

[0277]

[0278] 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 it was complete. The mixture was filtered, concentrated, and purified by preparative HPLC to obtain the target compound 1-1 (25.3 mg, yield 11%).

[0279] LC-MS (m / z): 429.2 [M+H] + .

[0280] 1H NMR (600MHz, DMSO-d6) δ9.28 (s, 1H), 8.55 (d, J=3.0Hz, 1H), 7.76-7.71 (m, 1H), 7.66-7.63 ( m, 1H), 7.47 (d, J=9.0Hz, 1H), 7.39-7.29 (m, 1H), 7.24-7.11 (m, 1H), 4.69-4.52 (m, 1H), 3.7 2-3.70 (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).

[0281] Example 2

[0282] (1S)-4-fluoro-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxane[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H-indene-1-amine 2-1

[0283]

[0284] Synthesis scheme:

[0285]

[0286] Using the synthesis method of Example 1, the target compound 2-1 was prepared by replacing the starting material (S)-6-fluoro-2,3-dihydro-1H-indene-1-amine with (S)-4-fluoro-2,3-dihydro-1H-indene-1-amine.

[0287] LC-MS (m / z): 429.2 [M+H] + .

[0288] 1H NMR (600MHz, DMSO-d6) δ8.80 (s, 1H), 8.58-8.56 (m, 1H), 7.78-7.71 (m, 1H), 7.66-7.62 (m, 1H), 7.34-7.30 (m, 1H), 7.25 (d, J=7.8Hz, 1H), 7.19 (t, J=8.4Hz, 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, 6.0Hz, 1H), 1.42-1,40 (m, 1H), 0.84-0.81 (m, 2H).

[0289] Example 3

[0290] (1S)-N-(2-(-4-(5-fluoropyridin-2-yl)-1,9-dioxane[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H-indene-1-amine 3-1

[0291]

[0292] Synthesis scheme:

[0293]

[0294] The target compound 3-1 was prepared by replacing the starting material (S)-6-fluoro-2,3-dihydro-1H-indene-1-amine with (S)-2,3-dihydro-1H-indene-1-amine using the synthesis method of Example 1.

[0295] LC-MS (m / z): 411.2 [M+H] + .

[0296] 1H NMR (600MHz, CDCl3) δ8.39 (d, J=2.4Hz, 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=13.7Hz, 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).

[0297] Example 4

[0298] 6-Chloro-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxane[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H-inden-1-amine 4

[0299]

[0300] Synthesis scheme:

[0301]

[0302] 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 (water / acetonitrile = 25%) to obtain target compound 4 (39 mg, yield 17%).

[0303] LC-MS (m / z): 445.2 [M+H] + .

[0304] 1H NMR (600MHz, DMSO-d6) δ8.69 (s, 1H), 8.57 (dd, J=6.6, 3.0Hz, 1H), 7.77-7.72 (m, 1H), 7.66-7.64 (m, 1H), 7.45 (d, J=6.0Hz, 1H), 7.39 (dd, J=7.8, 1.8Hz, 1H), 7.34 (dd, J=7.8, 3.0Hz, 1H), 4.68-4.59 (m, 1H), 3.72-3.69 (m, 1H), 3.6 0-3.51(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).

[0305] Example 5

[0306] (1S)-4-chloro-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxane[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H-indene-1-amine 5-1

[0307]

[0308] Synthesis scheme:

[0309]

[0310] Using the synthesis method of Example 1, the target compound 5-1 was prepared by replacing the starting material (S)-6-fluoro-2,3-dihydro-1H-indene-1-amine with (S)-4-chloro-2,3-dihydro-1H-indene-1-amine.

[0311] LC-MS (m / z): 445.2 [M+H] + .

[0312] 1H NMR (600MHz, DMSO-d6) δ8.70 (s, 1H), 8.57 (d, J = 2.4Hz, 1H), 7.74 (d, J = 6.0Hz, 1H), 7.68-7.61 (m, 1H), 7.45 (d, J = 7. 8Hz, 1H), 7.38 (dd, J=7.2, 3.6Hz, 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, 8.4Hz, 1H), 2.87-2.84 (m, 2H), 2.57-2.55 (m, 1H), 2.38-2.35 (m, 2H), 2.07-1.9 2(m, 2H), 1.75-1.72(m, 1H), 1.59-1.55(m, 2H), 1.48(dd, J=13.8, 6.0Hz, 1H), 1.42-1,40(m, 1H), 0.84-0.80(m, 2H).

[0313] Example 6

[0314] (1S)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxanespiro[5.S]undecane-4-yl)ethyl)-4-methyl-2,3-dihydro-1H-inden-1-amine 6-1

[0315]

[0316] Synthesis scheme:

[0317]

[0318] Using the synthesis method of Example 1, the target compound 6-1 was prepared by replacing the starting material (S)-6-fluoro-2,3-dihydro-1H-indene-1-amine with (S)-4-methyl-2,3-dihydro-1H-indene-1-amine.

[0319] LC-MS (m / z): 425.2 [M+H] + .

[0320] 1H NMR (600MHz, DMSO-d6) 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), 2.9 2-2.75(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).

[0321] Example 7

[0322] (1S)-4-bromo-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxane[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H-indene-1-amine 7-1

[0323]

[0324] Synthesis scheme:

[0325]

[0326] Using the synthesis method of Example 1, the target compound 7-1 was prepared by replacing the starting material (S)-6-fluoro-2,3-dihydro-1H-indene-1-amine with (S)-4-bromo-2,3-dihydro-1H-indene-1-amine.

[0327] LC-MS (m / z): 489.1 [M+H] + .

[0328] 1H NMR (600MHz, DMSO-d6) δ8.70 (s, 1H), 8.57 (d, J=2.4Hz, 1H), 7.77-7.72 (m, 1H), 7.66-7.63 (m, 1H), 7.59 (d, J=7. 8Hz, 1H), 7.41 (dd, J=7.8, 3.6Hz, 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, 6.0Hz, 1H), 1.42-1,40 (m, 1H), 0.84-0.80 (m, 2H).

[0329] Example 8

[0330] N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxane[5.5]undecane-4-yl)ethyl)-2,3-di-hydro-1H-inden-2-amine 8

[0331]

[0332] Synthesis scheme:

[0333]

[0334] Using the synthesis method of Example 4, the target compound 8 was prepared by replacing the starting material 6-chloro-2,3-dihydro-1H-indanone with 1,3-dihydro-2H-indanone.

[0335] LC-MS (m / z): 411 [M+H] + .

[0336] 1H NMR (600MHz, DMSO-d6) δ8.57 (d, J=3.0Hz, 1H), 7.78-7.74 (m, 1H), 7.64 (dd, J=9.0, 4. 2Hz, 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), 2.29-2.2 7(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).

[0337] Example 9

[0338] (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxane[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H-indene-2-amine 8-1

[0339]

[0340] Synthesis scheme:

[0341]

[0342] Step A: Preparation of (R)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)ethyl-1-amine

[0343] (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 water (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 obtain a yellow oily product (R)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)ethyl-1-amine 1a-1 (1.4 g, yield 91%).

[0344] LC-MS (m / z): 295.1 [M+H] + .

[0345] Step B: Preparation of (R)-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine

[0346] (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-indene-2-one (67.32 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 hours, and then 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 (water / acetonitrile = 25%) to obtain the target compound 8-1 (41 mg, yield 19%).

[0347] LC-MS (m / z): 411 [M+H] + .

[0348] 1 H NMR (400MHz, MeOD) δ8.44 (d, J=2.4Hz, 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, 2.9Hz, 1H), 3.68-3.60(m, 1H), 3.45-3.33(m, 4H), 3.03(dd , J=15.7, 7.3Hz, 2H), 2.68-2.49 (m, 5H), 1.98 (td, J=12.5, 6.0Hz, 2H), 1.69 (ddt, J=11.8 , 7.6, 2.6Hz, 3H), 1.59 (d, J=13.9Hz, 1H), 1.53-1.45 (m, 1H), 0.97 (dd, J=7.4, 4.4Hz, 2H).

[0349] Example 10

[0350] 5-Fluoro-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxane[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H-inden-2-amine 9

[0351]

[0352] Synthesis scheme:

[0353]

[0354] Using the synthesis method of Example 4, the target compound 9 was prepared by replacing the raw material 6-chloro-2,3-dihydro-1H-indanone with 5-fluoro-1,3-dihydro-2H-indanone.

[0355] LC-MS (m / z): 429 [M+H] + .

[0356] 1 H NMR (600MHz, DMSO-d6) δ8.57 (d, J=3.0Hz, 1H), 7.75 (td, J=6.0, 3.0Hz, 1H), 7.64 (dd, J=9.0, 4.2Hz, 1H), 7.25-7.23 (m, 1H), 7.08 (d, J=9.0Hz, 1H), 7.00 (t, J=9.6Hz, 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).

[0357] Example 11

[0358] 4-Bromo-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxane[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H-indene-2-amine 10

[0359]

[0360] Synthesis scheme:

[0361]

[0362] The target compound 10 was prepared by replacing the raw material 6-chloro-2,3-dihydro-1H-indanone with 4-bromo-1,3-dihydro-2H-indanone using the synthesis method of Example 4.

[0363] LC-MS (m / z): 490 [M+H] + .

[0364] 1H NMR (600MHz, DMSO-d6) δ8.57 (d, J=3.0Hz, 1H), 7.77-7.74 (m, 1H), 7.66-7.63 (m, 1H), 7.41 (d, J =7.8Hz, 1H), 7.25 (d, J = 7.8Hz, 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).

[0365] Example 12

[0366] (S)-4-bromo-N-(2-((R)-4-(5-fluoropyridin-2-yl)-1,9-dioxanespiro[5.5]undecane-4-yl)ethyl)-2,3-diyl-1H-indene-2-amine 10-1-1 and (R)-4-bromo-N-(2-((R)-4-(5-fluoropyridin-2-yl)-1,9-dioxanespiro[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H-indene-2-amine 10-1-2

[0367]

[0368] Synthesis scheme:

[0369]

[0370] Using the synthesis method of Example 9, the target compound 10-2 was prepared by replacing the starting material 1,3-dihydro-2H-indanone with 4-bromo-1,3-dihydro-2H-indanone.

[0371] Compound 10⁻² was separated to yield two optical isomers:

[0372] (S)-4-bromo-N-(2-(R)-4-(5-fluoropyridin-2-yl)-1,9-dioxanespiro[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H-indene-2-amine 10-1-1, 2.08 min, 0.16 g, ee% = 96%;

[0373] LC-MS (m / z): 490.5 [M+H] + .

[0374] 1 H NMR (400MHz, DMSO) δ8.45 (d, J=2.9Hz, 1H), 7.60 (td, J=8.7, 3.0Hz, 1H), 7.53 (dd, J=8.9, 4.4Hz, 1H), 7.22 (d, J=7.9Hz, 1H), 7.07 (d, J =7.4Hz, 1H), 6.97 (t, J = 7.6Hz, 1H), 3.60 (ddd, J = 12.1, 5.0, 2.5Hz, 1H), 3.55-3.42 (m, 3H), 3.24-3.10 (m, 4H), 2.94 (dd, J = 16.1, 7.0Hz , 1H), 2.83 (dd, J=16.3, 7.1Hz, 1H), 2.51 (ddd, J=15.9, 14.8, 4.0Hz, 2H), 2.43-2.35 (m, 2H), 2.28 (td, J=11.0, 5.0Hz, 1H), 1.82 (td, J =11.0, 4.7Hz, 1H), 1.75-1.67 (m, 1H), 1.52-1.43 (m, 3H), 1.39 (d, J = 13.8Hz, 1H), 1.32 (dt, J = 13.6, 3.6Hz, 1H), 0.75 (d, J = 4.9Hz, 2H).

[0375] (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%;

[0376] LC-MS (m / z): 490.5 [M+H] + .

[0377] 1H NMR (400MHz, DMSO-d6) δ8.52 (d, J=2.9Hz, 1H), 7.67 (td, J=8.8, 3.0Hz, 1H), 7.60 (dd, J=8.9, 4.4Hz, 1H), 7.29 (d, J=7.8Hz, 1 H), 7.13 (d, J=7.3Hz, 1H), 7.04 (t, J=7.6Hz, 1H), 3.68 (ddd, J=12.1, 4.9, 2.4Hz, 1H), 3.64-3.46 (m, 3H), 3.32-3.15 (m, 5H), 3 .01 (dd, J=16.0, 7.0Hz, 1H), 2.89 (dd, J=16.3, 7.0Hz, 1H), 2.62-2.52 (m, 2H), 2.49-2.43 (m, 1H), 2.36 (td, J=10.9, 5.0Hz, 1H ), 1.92-1.73 (m, 2H), 1.56 (dq, J=8.6, 4.1, 3.3Hz, 2H), 1.52 (d, J=5.2Hz, 1H), 1.49-1.34 (m, 2H), 0.81 (p, J=4.7, 3.8Hz, 2H).

[0378] Split conditions: Instrument: Waters SFC 150; Column: 250*25mm 10μm; Mobile phase: A: Supercritical CO2, B: MeOH (0.1% Ammoniain MeOH); Gradient: A∶B=50∶50; Flow rate: 70mL / min; Back pressure: 100bar; Column temperature: 25℃; Wavelength: 214nm; Cycle time: 6min; Compound to be resolved dissolved in MeOH (40mL); Injection: 1.8mL.

[0379] Example 13

[0380] N-(3-chlorobenzyl)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxospiro[5.5]undecane-4-yl)ethane-1-amine 11

[0381]

[0382] Synthesis scheme:

[0383]

[0384] Using the synthesis method of Example 4, the target compound 11 was prepared by replacing the raw material 6-chloro-2,3-dihydro-1H-inden-1-one with 3-chlorobenzaldehyde.

[0385] LC-MS (m / z): 419.2 [M+H] + .

[0386] 1 H NMR (600MHz, CD3OD) δ8.48-8.40 (m, 1H), 7.62-7.52 (m, 2H), 7.45-7.36 (m, 3H), 7.31 (d, J=7.4 Hz, 1H), 4.58-4.54 (m, 1H), 4.12-4.01 (m, 2H), 3.79-3.57 (m, 4H), 3.37-3.31 (m, 2H), 3.02-2.9 4(m, 1H), 2.65-2.55(m, 2H), 2.42(td, J=12.5, 4.4Hz, 1H), 2.14-2.03(m, 1H), 1.89-1.80(m, 1H ), 1.75-1.62 (m, 2H), 1.56 (d, J=13.9Hz, 1H), 1.45 (dd, J=19.9, 8.8Hz, 1H), 0.96-0.87 (m, 2H).

[0387] Example 14

[0388] N-(3-chloro-2-methylbenzyl)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxospiro[5.5]undecane-4-yl)ethane-1-amine 12

[0389]

[0390] Synthesis scheme:

[0391]

[0392] The target compound 12 was prepared by replacing the raw material 6-chloro-2,3-dihydro-1H-inden-1-one with 3-chloro-2-methylbenzaldehyde using the synthesis method of Example 4.

[0393] LC-MS (m / z): 433.2 [M+H] + .

[0394] 1H NMR (600MHz, CD3OD) δ8.48 (d, J=2.0Hz, 1H), 7.64-7.54 (m, 2H), 7.45 (dd, J=7.7, 1.2Hz, 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, 4.5Hz, 1H), 2.63 (m, 2H), 2.52-2.46 (m, 1H), 2.39 (s, 3H), 2.09 (td, J=12.9, 4.5Hz, 1H), 1.84 (td, J=12.8, 4.6Hz, 1H), 1.76-1.64 (m, 2H), 1.56 (d, J=13.8Hz, 1H), 1.46 (d, J=13.7Hz, 1H), 1.00-0.87 (m, 2H).

[0395] Example 15

[0396] (R)-N-(3-chloro-2-methylbenzyl)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxospiro[5.5]undecane-4-yl)ethane-1-amine 12-1

[0397]

[0398] Synthesis scheme:

[0399] The target compound 12-1 was prepared by replacing the raw material 1,3-dihydro-2H-inden-2-one with 3-chloro-2-methylbenzaldehyde using the synthesis method of Example 9.

[0400] LC-MS (m / z): 433.2 [M+H] + .

[0401] 1H NMR(400MHz,Methanol-d4)δ8.29(t,J=1.8Hz,1H),7.45-7.38(m,2H),7.14(dd,J=5.6,3.8H z,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=14.3,10.0,2.3Hz,2H),2.38(td,J=12.2,11.7,5.1Hz,1H),2.19(s,3H),1.92-1.80(m,2H ),1.64-1.50(m,3H),1.46(d,J=14.1Hz,1H),1.41-1.32(m,1H),0.84(dd,J=7.3,4.5Hz,2H).

[0402] Example 16

[0403] N-(2,3-dichlorobenzyl)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxospiro[5.5]undecane-4-yl)ethane-1-amine 13

[0404]

[0405] Synthesis scheme:

[0406]

[0407] Using the synthesis method of Example 4, the target compound 13 was prepared by replacing the raw material 6-chloro-2,3-dihydro-1H-inden-1-one with 2,3-dichlorobenzaldehyde.

[0408] LC-MS (m / z): 453.2 [M+H] + .

[0409] 1H NMR (600MHz, CD3OD) δ8.48-8.40 (m, 1H), 7.62-7.52 (m, 2H), 7.45-7.36 (m, 3H), 7.31 (d, J =7.4Hz, 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, 4.4Hz, 1H), 2.14-2.03(m, 1H), 1.89-1.80(m, 1H), 1. 75-1.62 (m, 2H), 1.56 (d, J=13.9Hz, 1H), 1.45 (dd, J=19.9, 8.8Hz, 1H), 0.96-0.87 (m, 2H).

[0410] Example 17

[0411] (R)-N-(2,3-dichlorobenzyl)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxanespiro[5.5]undecane-4-yl)ethane-1-amine 13-1

[0412]

[0413] The target compound 13-1 was prepared by replacing the raw material 1,3-dihydro-2H-inden-2-one with 2,3-dichlorobenzaldehyde using the synthesis method of Example 9.

[0414] LC-MS (m / z): 454 [M+H] + .

[0415] 1H NMR (600MHz, Deuterium Oxide) δ8.37 (d, J=2.8Hz, 1H), 7.67 (td, J=8.4, 2.9Hz, 1H), 7.59 (dd, J=9.0, 4.3Hz, 1H), 7.55 (p, J=4.2Hz, 1H), 7.26-7 .21 (m, 2H), 4.24-4.16 (m, 2H), 3.74 (dd, J=12.8, 4.5Hz, 1H), 3.68 (t, J=12.4Hz, 1H), 3.61 (dd, J=8.6, 2.7Hz, 2H), 3.28 (tp, J=11.7, 4.0Hz, 2H), 2.98 (td, J=12.6, 4.8Hz, 1H), 2.44 (dd, J=20.9, 14.6Hz, 2H), 2.25 (td, J=12.7, 4.3Hz, 1H), 2. 04-1.96 (m, 2H), 1.84 (td, J=12.9, 4.8Hz, 1H), 1.73-1.59 (m, 3H), 1.44 (d, J=14.1Hz, 1H), 0.87 (dd, J=9.2, 4.6Hz, 2H).

[0416] Example 18

[0417] N-(3-chloro-2-fluorobenzyl)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxane[5.5]undecane-4-yl)ethane-1-amine 14

[0418]

[0419] Synthesis scheme:

[0420]

[0421] The target compound 14 was prepared by replacing the raw material 6-chloro-2,3-dihydro-1H-inden-1-one with 3-chloro-2-fluorobenzaldehyde using the synthesis method of Example 4.

[0422] LC-MS (m / z): 438 [M+H] + .

[0423] 1H NMR (600MHz, DMSO-d6) δ8.57 (d, J=3.0Hz, 1H), 7.74 (td, J=9.0, 3.0Hz, 1H), 7.67-7.62 (m, 2H ), 7.43 (t, J=6.0Hz, 1H), 7.28 (t, J=7.8Hz, 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).

[0424] Example 19

[0425] N-(2-(4-(pyridin-2-yl)-1,9-dioxane[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H-inden-1-amine 15

[0426]

[0427] Synthesis scheme:

[0428]

[0429] Step A: Synthesis of methyl 2-cyano-2-(4-(pyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)acetate

[0430] Dissolve 2-bromopyridine (4.74 g, 30 mmol) in anhydrous tetrahydrofuran (20 mL) and slowly add it dropwise to isopropyl magnesium chloride solution (15 mL, 30 mmol) at 0 °C. React at room temperature for 3 hours. Add cuprous iodide (0.57 g, 3 mmol) and react for another 1 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. Add saturated ammonium chloride solution (50 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, concentrate, and then column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the target product (3.3 g, yield 50%).

[0431] LC-MS (m / z): 331 [M+H] + .

[0432] Step B: Synthesis of 2-(4-(pyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)acetonitrile

[0433] 3.0 g (9.1 mmol) of methyl 2-cyano-2-(4-(pyridinyl)-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%).

[0434] LC-MS (m / z): 273 [M+H] + .

[0435] Step C: Synthesis of 2-(4-(pyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)ethane-1-amine

[0436] 1.8 g (6.6 mmol) of 2-(4-(pyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)acetonitrile was dissolved in 15 mL of tetrahydrofuran. Lithium aluminum hydride (750 mg, 19.8 mmol) was added under ice bath conditions, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, 0.75 mL of water, 2 mL of 15% sodium hydroxide solution, and 2 mL of water were added sequentially. Ethyl acetate (10 mL) was then added, and the mixture was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to dryness to obtain the target product (1.5 g, 85% yield) in an oily form. LC-MS (m / z): 277 [M+H] + .

[0437] Step D: Synthesis of N-(2-(4-(pyridin-2-yl)-1,9-dioxaspiro[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H-inden-1-amine)

[0438] 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 carried out for 1 h. The reaction was monitored by LC-MS until it was complete. The mixture was filtered, concentrated, and purified by preparative liquid chromatography to obtain the target compound 15 (25.3 mg, yield 18%).

[0439] LC-MS (m / z): 393 [M+H] + .

[0440] 1 H NMR (600MHz, DMSO-d6) δ8.59 (s, 1H), 7.82-7.80 (m, 2H), 7.57 (dd, J=7.8, 3.0Hz, 1H), 7.39-7.30 (m, 2H), 7.29 (dd, J=7.2, 4.8Hz, 1H), 7.25-7.23 (m, 1H), 4.65-4.61 (m, 1H), 4.48-4.45 (m, 1H), 3.77-3.6 4(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).

[0441] Example 20

[0442] 4-Chloro-N-(2-(4-(pyridin-2-yl)-1,9-dioxane[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H-indene-1-amine 16

[0443]

[0444] The target compound 16 was prepared by replacing the starting material 1-indanone with 4-chloro-1-indanone using the synthesis method of Example 16.

[0445] LC-MS (m / z): 428 [M+H] + .

[0446] 1H NMR (600MHz, DMSO-d6) δ8.59-8.58 (m, 1H), 8.04-7.73 (m, 1H), 7.56 (dd, J=7.8, 4.2Hz, 1H), 7.4 4(d, J=7.2Hz, 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).

[0447] Example 21

[0448] 4-Chloro-N-(2-(4-(5-fluoropyridin-2-yl)-1,9-dioxane[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H[-inden-2-amine 17

[0449]

[0450] Using the synthesis method of Example 4, the target compound 17 was prepared by replacing the starting material 6-chloro-2,3-dihydro-1H-indanone with 4-chloro-1,3-dihydro-2H-indanone.

[0451] LC-MS (m / z): 447 [M+H] + .

[0452] 1H NMR (600MHz, MeOD) δ8.50 (t, J=3.1Hz, 1H), 7.63-7.58 (m, 2H), 7.21 (ddd, J=15.5, 7.8, 4.3Hz, 3H), 4.04-3.95 (m, 1H), 3.8 1-3.70 (m, 3H), 3.66-3.59 (m, 1H), 3.38 (ddt, J=11.0, 7.2, 2.6Hz, 4H), 3.10-3.02 (m, 1H), 2.97 (ddd, J=19.4, 17.4, 5.4Hz , 2H), 2.64 (dd, J=28.9, 13.9Hz, 2H), 2.44 (dtd, J=16.9, 12.5, 4.5Hz, 1H), 2.10-2.02 (m, 1H), 1.81 (td, J=12.8, 4.7Hz, 1H ), 1.76-1.66 (m, 2H), 1.57 (d, J = 13.8Hz, 1H), 1.47 (d, J = 13.8Hz, 1H), 1.31 (dd, J = 15.3, 8.0Hz, 1H), 0.95 (d, J = 2.5Hz, 2H).

[0453] Example 22

[0454] (S)-4-chloro-N-(2-((R)-4-(5-fluoropyridin-2-yl)-1,9-dioxanespiro[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H-indene-2-amine 17-1-1 and (R)-4-chloro-N-(2-((R)-4-(5-fluoropyridin-2-yl)-1,9-dioxanespiro[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H-indene-2-amine 17-1-2

[0455]

[0456] Synthesis scheme:

[0457]

[0458] Using the synthesis method of Example 9, the target compound 17-2 was prepared by replacing the starting material 1,3-dihydro-2H-indanone with 4-chloro-1,3-dihydro-2H-indanone.

[0459] Compound 17-2 was separated to obtain two optical isomers:

[0460] (S)4-chloro-N-(2-((R)-4-(5-fluoropyridinyl)-1,9-dioxane[5.5]undecane-4-yl)ethyl)-2,3-dihydro-1H-indene-2-amine 17-1-1, 2.10 min, ee% = 97%;

[0461] LC-MS (m / z): 445 [M+H] + .

[0462] 1 H NMR (600MHz, DMSO) δ8.56 (s, 1H), 7.74 (d, J=16.6Hz, 1H), 7.62 (s, 1H), 7.18 (d, J=36.2Hz, 4H), 3.83-3.76 (m, 1H), 3. 70 (d, J=11.9Hz, 1H), 3.60-3.51 (m, 4H), 3.21 (d, J=11.3Hz, 1H), 3.12 (dd, J=16.1, 7.8Hz, 1H), 2.94-2.83 (m, 2H), 2.7 6 (dd, J=11.8, 8.6Hz, 1H), 2.54 (d, J=13.9Hz, 2H), 2.21 (dd, J=11.7, 8.1Hz, 1H), 1.96 (td, J=12.5, 4.1Hz, 1H), 1.91 ( s, 1H), 1.77 (dt, J=12.3, 6.2Hz, 1H), 1.64-1.53 ​​(m, 2H), 1.48 (d, J=14.0Hz, 1H), 1.41 (d, J=13.5Hz, 1H), 0.81 (s, 2H).

[0463] (R)-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 17-1-2,3.1 min, ee% = 97%;

[0464] LC-MS (m / z): 445 [M+H] + .

[0465] 1H NMR (600MHz, DMSO) δ8.55 (s, 1H), 7.71 (td, J=8.7, 2.5Hz, 1H), 7.62 (dd, J=8.8, 4.1Hz, 1H), 7.19 (dt, J=16.8, 7.5Hz, 3H ), 3.74-3.66 (m, 2H), 3.61-3.49 (m, 4H), 3.22 (d, J = 6.1Hz, 1H), 3.15 (dd, J = 16.4, 7.5Hz, 1H), 3.09 (dd, J = 16.5, 7.6Hz, 1H), 2.88-2.76 (m, 2H), 2.67 (s, 1H), 2.55 (d, J=14.3Hz, 2H), 2.08 (d, J=14.0Hz, 1H), 2.08 (d, J=14.0Hz, 1H), 1.90 (t, J =10.4Hz, 1H), 1.69 (t, J = 10.3Hz, 1H), 1.62-1.52 (m, 2H), 1.48 (d, J = 13.8Hz, 1H), 1.40 (d, J = 13.2Hz, 1H), 0.80 (s, 2H).

[0466] Split conditions: Instrument: Waters SFC 150; Column: 250*25mm 10μm; Mobile phase: A: Supercritical CO2, B: MeOH (0.1% Ammonia in MeOH); Gradient: A∶B=50∶50; Flow rate: 70mL / min; Back pressure: 100bar; Column temperature: 25℃; Wavelength: 214nm; Cycle: 6min; Compound to be resolved dissolved in MeOH (40mL): Injection: 1.8mL.

[0467] Example 23

[0468] (R)-N-(2-chlorobenzyl)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxospiro[5.5]undecane-4-yl)ethane-1-amine 18-1

[0469]

[0470] The target compound 18-1 was prepared by replacing the raw material 1,3-dihydro-2H-inden-2-one with 2-chlorobenzaldehyde using the synthesis method of Example 9.

[0471] LC-MS (m / z): 419 [M+H] + .

[0472] 1H NMR (600MHz, DMSO) δ9.30 (d, J=57.3Hz, 1H), 8.55 (d, J=3.0Hz, 1H), 7.73 (td, J=8.8, 3.0Hz, 1H), 7.67-7.61 (m, 2H), 7.51 ( dd, J=7.8, 1.2Hz, 1H), 7.40 (dtd, J=19.3, 7.4, 1.5Hz, 2H), 4.12 (t, J=6.0Hz, 2H), 3.75-3.67 (m, 1H), 3.54 (ddd, J=15.4, 14 .9, 7.9Hz, 3H), 3.30-3.18(m, 2H), 2.89-2.78(m, 1H), 2.54(d, J=13.2Hz, 2H), 2.34-2.24(m, 1H), 2.06(td, J=12.8, 4.5Hz , 1H), 1.88 (td, J=12.7, 4.2Hz, 1H), 1.62-1.53 ​​(m, 2H), 1.48 (d, J=13.9Hz, 1H), 1.42 (d, J=13.5Hz, 1H), 0.86-0.77 (m, 2H).

[0473] Example 24

[0474] (R)-N-(2-(difluoromethoxy)benzyl)-2-(4-(5-fluoropyridin-2-yl)-1,9-dioxospiro[5.5]undecane-4-yl)ethane-1-amine 19-1

[0475]

[0476] The target compound 19-1 was prepared by replacing the raw material 1,3-dihydro-2H-inden-2-one with 2-difluoromethoxybenzaldehyde using the synthesis method of Example 9.

[0477] LC-MS (m / z): 451 [M+H] + .

[0478] 1H NMR (600MHz, DMSO) δ8.53 (d, J=2.9Hz, 1H), 7.72 (d, J=2.9Hz, 1H), 7.66-7.57 (m, 2H), 7.44 (s, 1H), 7.38- 7.07 (m, 3H), 3.97 (t, J=5.8Hz, 2H), 3.76-3.62 (m, 1H), 3.53 (dd, J=16.1, 3.7Hz, 3H), 3.22 (dd, J=10.8, 9. 0Hz, 2H), 2.75 (dd, J=8.0, 4.0Hz, 1H), 2.52 (d, J=14.9Hz, 2H), 2.48 (s, 1H), 2.28-2.15 (m, 1H), 2.11-2.0 1 (m, 1H), 1.89 (d, J=4.1Hz, 1H), 1.55 (ddd, J=13.3, 8.3, 3.7Hz, 2H), 1.46 (d, J=13.8Hz, 2H), 0.80 (s, 2H).

[0479] Bioactivity evaluation

[0480] The following description, in conjunction with test examples, is used to further explain the present invention, but these are 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:

[0481] Table 1

[0482]

[0483] Test Example 1

[0484] 1.1 Experimental Objective

[0485] The purpose of this experiment is to test the agonistic effect of the compound of this invention on MOR, according to EC. 50 The size of Emax is used to evaluate the in vitro activity of the compound.

[0486] 1.2 The experimental materials are shown below.

[0487] Table 2

[0488]

[0489] Table 3

[0490] Reagent Name brand Item number Specification cAMP Assay Kit Cisbio 62AM9PEJ 100,000 tests IBMX Sigma 15879 1g HBSS Gibco 14175103 10×500mL Forskolin Sigma F6886 50mg DMSO Sigma D8418 500mL

[0491] 1.3 Experimental Procedure

[0492] 1.3.1 Reagent Preparation

[0493] 1.3.1.1 Preparation of experimental buffer solution

[0494] Dilute 5× stimulation buffer to 1× with ddH2O, and add an appropriate amount of 500mM IBMX (generally, IBMX stock solution is prepared to 500mM, i.e., 1000X) to make the final concentration of IBMX 0.5mM. 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.

[0495] 1.3.1.2 IBMX was dissolved in DMSO to prepare a 500mM stock solution, dispensed into 20μL / tube, and stored at -80℃ to avoid repeated freeze-thaw cycles.

[0496] 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°C for later use.

[0497] 1.3.1.4 Preparation of cAMP Standards

[0498] Bring the cAMP standard from the kit to room temperature, add an equal volume of experimental buffer according to the volume marked on the bottle label, vortex to mix, aliquot into 50 μL / tube and freeze at -20℃ for later use.

[0499] 1.3.1.5 Preparation of test reagent stock solution (20,000 tests package)

[0500] 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 sizes and store in the dark at -80°C.

[0501] 1.3.2 Agonist Test Experimental Procedure

[0502] 1.3.2.1 The positive compound DAMGO and the test compound were serially diluted 4-fold on a Bravo plate (Greiner-781280) using experimental buffer 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).

[0503] 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 resuspended cell using a cell counter. Dilute an appropriate amount of the cell suspension to 0.4 × 10⁻⁶. 6Cells / mL: Add 5 μL of cell suspension (cell density 2000 cells / well) to each well of the cell plate and centrifuge at 1000 rpm for 1 minute. Transfer 5 μL of the diluted compound to the cell plate (PerkinElmer-6008280) using Bravo. Transfer 5 μL of 2 μM DAMO (final concentration 1 μM) to the positive control well and transfer an equal volume of experimental buffer to the negative control well. Centrifuge at 1000 rpm for 1 minute. Block the cell plate and incubate at room temperature for 15 minutes. Dilute Forskolin to 0.2 mM with DMSO, transfer 25.1 nL to the cell plate using Tecan-D300e, centrifuge at 1000 rpm for 1 minute, and then seal the plate and incubate at room temperature for 45 minutes. The final concentration of Forskolin is 1 μM.

[0504] 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 plate. The final concentration at the starting point was 712 nM.

[0505] 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 plate, avoiding vortexing. Add 10 μL of the prepared detection reagent to a cell plate and centrifuge at 1000 rpm for 1 minute. Incubate the cell plate at room temperature in the dark for 1 hour. After centrifuging the cell plate at 1000 rpm for 1 minute, read the plate using Envision. Excitation light is 340 nm, and emission light is 620 nm and 665 nm.

[0506] 1.3.3 Data Analysis

[0507] Formula for calculating compound activation rate in agonist testing:

[0508] Activity%=100-(Readout-LC) / (HC-LC)*100

[0509] HC (High Control): Average readings from the DMSO + 2.5μM Forskolin well.

[0510] LC (Low Control): Average readings from wells containing 1 μM Dopamine and 2.5 μM Forskolin

[0511] Readout: Compound readout

[0512] 1.3.4 Test Results

[0513] The effect of the compound of this invention on the downstream cAMP level by stimulating MOR was determined through the above experiments, and the measured EC 50 See Table 4 below (DAMGO's maximum effect is 100%).

[0514] Table 4. Effects of the compounds of this invention on cAMP levels by activating MOR receptors (ECG) 50 and Emax

[0515]

[0516]

[0517] Conclusion: The above results show that the compound of the present invention has strong agonistic activity against MOR; the compound provided by the present invention can maintain the analgesic effect while significantly reducing the dosage, thereby reducing side effects during clinical use. Therefore, the compound of the present invention has broad prospects for clinical application in analgesia.

[0518] Test Example 2

[0519] 2.1 Experimental Objective

[0520] This experiment was conducted to test the agonistic effect of the compound on MOR Beta-arrestin, according to EC... 50 The size of Emax is used to evaluate the in vitro activity of the compound.

[0521] 2.2 The experimental consumables and instruments are shown below.

[0522] Table 5

[0523]

[0524]

[0525] 2.3 The experimental reagents are shown below.

[0526] Table 6

[0527]

[0528] Complete cell culture medium: MEM + 10% FBS + 1% PS + 250ug / mL Hygromycin B + 500ug / mL G418 + 1X GlutaMAX

[0529] Cell seeding medium: MEM + 10% FBS + 1% PS

[0530] Experimental buffer: 1x DPBS + 0.1% BSA

[0531] Test reagent: Galacton Star∶Emerald II∶PathHunter Cell Assay Buffer=1∶5∶19)

[0532] 2.4 Experimental Methods

[0533] 2.4.1 Compound Preparation

[0534] i) The compound sample was dissolved in DMSO to a storage concentration of 10 mM;

[0535] ii) Prepare sample dilution sequences on 384-well LDV plates. The first concentration point of each sample is 10 mM (FAC = 30 μM), and the samples are serially diluted 3.162 times, for a total of 11 concentration points.

[0536] iii) Use an Echo machine to transfer the sample dilution sequence and HPE, ZPE to the compound plate (PE#6008590), 90 nL per well.

[0537] 2.4.2 Experimental Procedure

[0538] i) MOR beta-arrestin cell line was cultured in complete cell culture medium at 37°C with 5% CO2 until 70%–90% confluence.

[0539] ii) Digest and resuspend the cells in cell seeding medium, add 20 μL of MOR beta-arrestin cell suspension to each well of the experimental plate (Corning#3570), with 7500 cells per well, and then incubate at 37°C in a 5% CO2 incubator for 24 h.

[0540] iii) Add 30 μL of experimental buffer to the compound plate (PE#6008590) and centrifuge at 1000 rpm for 5 min;

[0541] iv) After 24 hours, remove the experimental plate, remove the culture medium from the plate, and then use Bravo to transfer 20 μL of the compound from each well of the compound plate to the experimental plate.

[0542] v) After centrifuging the experimental plate at 500 rpm for 30 seconds, incubate it in a 37°C, 5% CO2 incubator for 90 min.

[0543] vi) Add 10 μL of beta-arrestin detection reagent to each well of the experimental plate;

[0544] vii) After incubating at room temperature in the dark for 1 hour, take readings on Envision.

[0545] 2.5 Experimental Data Processing Methods

[0546] Experimental data were fitted to the percentage activation rate and 11-point concentration data using XLFit to the nonlinear logic parameters.

[0547] The formula calculates the EC of the compound. 50 The test results are shown in Table 7 (the maximum effect of DAMGO is 100%).

[0548] Table 7 Results of the activity of the compounds of this invention in activating the Beta-arrestin signaling pathway

[0549] Example number <![CDATA[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％

[0550] 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.

[0551] Test Example 3

[0552] 3.1 Experimental Objective

[0553] 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.

[0554] 3.2 The experimental reagents are shown below.

[0555] Table 8

[0556]

[0557]

[0558] 3.3 Experimental Methods

[0559] 3.3.1 Dosage and route of administration:

[0560] Administered by gavage at a dose of 10 mg / kg;

[0561] 3.3.2 Experimental Procedure

[0562] ICR mice (common grade, weighing 25-35g, purchased from Shanghai Silex Laboratory Animal Technology Co., Ltd.) were first secured in a specially designed plastic tube, with their tails exposed and hanging naturally. Measurements were taken after the animals had calmed down. An 8.75mm projection lamp (32W, adjustable) was used as the radiant heat source, emitting a beam of light approximately 4mm 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 exhibited a clear tail-flicking response. The measured time interval was the tail-flicking latency. Mice with a tail-flicking 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, with 15 seconds serving as the upper limit for the tail-flicking 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.

[0563] 3.4 Detection Indicators and Statistical Methods:

[0564] Mice were given a certain dose of the drug, and their pain threshold was measured at 0.5h, 1h, 2h, and 3h (analgesic effect graph shown). Figure 1 (As shown). The maximum percentage of analgesia (%MPE) after drug administration is calculated using the following formula: %MPE = (pain threshold after drug administration - pain threshold before drug administration) / (15 - pain threshold before drug administration) × 100%.

[0565] Table 9. Maximum analgesic percentage (%MPE, Mean±SEM, n=9-10) at different time points after administration of each compound.

[0566] 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

[0567] Note: Compared with Oxycodone, *p<0.05, **p<0.01, ***p<0.001.

[0568] 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.

[0569] Although specific embodiments of the present invention have been described in detail, those skilled in the art can make various modifications and substitutions to the details of the technical solutions of the present invention based on all the teachings disclosed, and all such modifications and substitutions are within the scope of protection of the present invention. The full scope of the present invention is given 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, ； in: Ring A is C 6-10 Aryl; R 1 Same or different, R 1 R 2 Each is independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; Ring B is pyridyl, optionally further coupled with one R 3 Replaced; R 3 Whether the elements are the same or different, they are independently hydrogen, halogen, or carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; X1 is CR a R b or CR a R b CH2; R a R b Each is independently hydrogen, halogen, or C 1-3 alkyl; Or, R a Or R b With R 2 The link forms 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 must be met: (1) Ring A is a phenyl group; (2) X1 is CR a R b or CR a R b CH2, where R a and R b Each is independently hydrogen; or R a Or R b With R 2 The link forms a cyclopentyl group; (3) The ring B is or ; (4) The R 1 and R 2 Each is independently hydrogen, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkoxy groups; (5) The R 3 It is hydrogen or halogen.

3. The compound of claim 2, its stereoisomers, its tautomers, or its pharmaceutically acceptable salts, characterized in that, One or more of the following conditions must be met: (1) The ring B is ; (2) The R 1 and R 2 Each is independently hydrogen, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkoxy groups; (3) The R 3 It can be hydrogen, fluorine, chlorine, or bromine.

4. The compound of claim 3, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, One or two of the following conditions must be met: (1) The R 1 and R 2 Each can be independently hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, or halomethoxy. (2) The R 3 It is either hydrogen or fluorine.

5. The compound of claim 1, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, One or more of the following conditions must be met: (1) X1 is CR a R b ; (2) The ring B is ; (3) The R 1 For hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; (4) The R 2 It is hydrogen.

6. The compound of claim 5, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, One or two of the following conditions must be met: (1) X1 is CH2; (2) The R 1 It can be hydrogen, fluorine, chlorine, methyl, or fluoromethoxy.

7. The compound of claim 1, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, One or more of the following conditions must be met: (1) X1 is CH(R) b ) or CH(R b CH2, where R b With R 2 The link forms a cyclopentyl or cyclohexyl group; (2) The ring B is or ; (3) The R 1 Independently hydrogen, halogen or C 1-6 alkyl.

8. The compound of claim 7, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, One or more of the following conditions must be met: (1) X1 is CH(R) b ) or CH(R b CH2, where R b With R 2 The link forms a cyclopentyl group; (2) The R 1 Independently hydrogen, halogen or C 1-3 alkyl.

9. The compound of claim 8, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The R 1 It can be hydrogen, fluorine, chlorine, bromine, methyl, ethyl, or propyl.

10. The compound of claim 9, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The R 1 It can be hydrogen, fluorine, chlorine, bromine, or methyl independently.

11. The compound of claim 1, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, One or more of the following conditions must be met: (1) The R 1 and R 2 Each is independently hydrogen, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups; (2) The R 3 Each is independently hydrogen, fluorine, chlorine, bromine, or C. 1-3 alkyl; (3) X1 is CH2, CH(R) b ) or CH(R b CH2; (4) R a Or R b With R 2 The link forms a cyclopentyl group.

12. The compound of claim 11, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The R 1 and R 2 Each can be independently hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, halomethyl, haloethyl, or halomethoxy.

13. The compound of claim 12, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The R 1 and R 2 Each can be independently hydrogen, fluorine, chlorine, bromine, methyl, methoxy, or halomethoxy.

14. The compound of claim 13, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The R 1 and R 2 Each can be independently hydrogen, fluorine, chlorine, bromine, methyl, or methoxy.

15. The compound of claim 1, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, Formula (I) has the structure shown in formula (ⅠⅠ): ； Among them, rings A and R 1 R 3 And n as described in claim 1.

16. The compound of claim 15, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, General formula (Ⅰ) has the structure shown in general formula (ⅠⅠ-1): ； Among them, rings A and R 1 R 3 And n as described in claim 1.

17. The compound of claim 15, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The for , , , , , , , , , , , , , , or ; in: R aa R bb R cc R dd Or R ee Each independently constitutes a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

18. The compound of claim 17, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, R aa R bb R cc R dd Or R ee Each independently constitutes a halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups.

19. The compound of claim 18, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, R aa R bb R cc R dd Or R ee Each of them independently can be fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, halomethyl, haloethyl, or halomethoxy.

20. The compound of claim 19, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, R aa R bb R cc R dd Or R ee Each can be independently fluorine, chlorine, bromine, methyl, methoxy, or halomethoxy.

21. The compound of claim 20, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, R aa R bb R cc R dd Or R ee Each can be independently fluorine, chlorine, bromine, methyl, or methoxy.

22. The compound of claim 17, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The for or .

23. The compound of claim 17, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The R aa R bb R cc R dd and R ee Each independently constitutes a halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

24. The compound of claim 23, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The R aa R bb R cc R dd and R ee Each independently constitutes a halogen, C 1-3 Alkyl or C 1-3 Halogenated alkoxy groups.

25. The compound of claim 24, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The R aa R bb R cc R dd and R ee Each can be independently fluorine, chlorine, bromine, methyl, ethyl, propyl, or halomethoxy.

26. The compound of claim 25, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The R aa R bb R cc R dd and R ee Each can be independently fluorine, chlorine, bromine, methyl, or fluoromethoxy.

27. The compound of claim 23, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The R aa Halogen or C 1-6 Halogenated alkoxy groups; The R dd It is a halogen; The R ee Halogen or C 1-6 alkyl.

28. The compound of claim 27, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The R aa Halogen or C 1-3 Halogenated alkoxy groups; Or, the R dd It is fluorine, chlorine, or bromine; Or, the R ee Halogen or C 1-3 alkyl.

29. The compound of claim 28, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The R aa It is fluorine, chlorine, bromine, or a halomethoxy group; Or, the R dd It is chlorine; Or, the R ee It can be fluorine, chlorine, bromine, methyl, ethyl, or propyl.

30. The compound of claim 29, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The R aa It is chlorinated or fluoromethoxy; Or, the R ee It can be fluorine, chlorine, or methyl.

31. The compound of claim 17, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The for , or .

32. The compound of claim 31, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The for , , , , or .

33. The compound of claim 1, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, Formula (I) has the structure shown in Formula (III): ； Wherein, ring C is cyclopentyl, R 1 R 3 And n as described in claim 1.

34. The compound of claim 33, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The general formula (III) has the structure shown in general formula (IV) or general formula (V): or ； Among them, R 1 R 3 and n as described in claim 1; with " "The carbon atom is a chiral carbon atom, existing in a single enantiomer (R) or (S) form or rich in a pair of enantiomers; the carbon atom marked with "#" is a chiral carbon atom, existing in a single enantiomer (R) or (S) form or rich in a pair of enantiomers." 35. The compound of claim 34, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, Formula (III) has the structure shown in formula (IV-1), formula (IV-2), formula (V-1), or formula (V-2): , , or ; Among them, R 1 R 3 and n as described in claim 1; with " "The carbon atom is a chiral carbon atom, existing as a single enantiomer (R) or (S) or in a form rich in a pair of enantiomers." 36. The compound of claim 35, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, Formula (III) has the structure shown in formula (Ⅳ-1-1), formula (Ⅳ-1-2), formula (Ⅴ-1-1), or formula (Ⅴ-1-2): , , or ; Among them, R 1 R 3 And n as described in claim 1.

37. The compound of claim 33, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The for , , , , , , , , , or ; The for , , , , , , , , , or ; Where: R aa R bb R cc and R dd Each independently constitutes a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups.

38. The compound of claim 37, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, R aa R bb R cc and R dd Each independently constitutes a halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups.

39. The compound of claim 38, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, R aa R bb R cc and R dd Each of them independently can be fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, halomethyl, haloethyl, or halomethoxy.

40. The compound of claim 39, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, R aa R bb R cc and R dd Each can be independently fluorine, chlorine, bromine, methyl, methoxy, or halomethoxy.

41. The compound of claim 40, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, R aa R bb R cc and R dd Each can be independently fluorine, chlorine, bromine, methyl, or methoxy.

42. The compound of claim 37, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The for , or ; The for , or .

43. The compound of claim 37, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The R aa R bb R cc and R dd Each is independently a halogen or C 1-6 alkyl.

44. The compound of claim 43, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The R aa R bb R cc and R dd Each is independently a halogen or C 1-3 alkyl.

45. The compound of claim 44, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The R aa R bb R cc and R dd Each can be fluorine, chlorine, bromine, methyl, ethyl, or propyl.

46. ​​The compound of claim 45, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The R aa R bb R cc and R dd Each can be fluorine, chlorine, bromine, or methyl.

47. The compound of claim 43, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The R aa It is a halogen; The R bb It is a halogen; The R dd Halogen or C 1-6 alkyl.

48. The compound of claim 47, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The R aa It is fluorine, chlorine, or bromine; Or, the R bb It is fluorine, chlorine, or bromine; Or, the R dd Halogen or C 1-3 alkyl.

49. The compound of claim 48, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The R aa It is chlorine or bromine; Or, the R bb It is either fluorine or chlorine; Or, the R dd It can be fluorine, chlorine, bromine, methyl, ethyl, or propyl.

50. The compound of claim 49, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, The R dd It can be fluorine, chlorine, bromine, or methyl.

51. The compound, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof, as described in any one of claims 33-50, characterized in that, One of the following conditions must be met: (1) The above for , , or ; (2) The above for , , , , , or .

52. The compound, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof as claimed in claim 1, characterized in that, The compound has any of the following structures: 。 53. The compound, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof as described in claim 52, characterized in that, The compound has any of the following structures: 。 54. The compound, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof as described in claim 52, characterized in that, The compound has any of the following structures: 。 55. 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, include: 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. Among them: rings A and R 1 R 2 Ring B, X1, and n are as described in claim 1.

56. A method for preparing a compound of general formula (ⅠⅠ) as described in claim 15, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, include: 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. 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; Among them: rings A and R 1 R 3 And n as described in claim 15.

57. A method for preparing a compound of formula (III) as described in claim 33, its stereoisomers, its tautomers, or a pharmaceutically acceptable salt thereof, characterized in that, include: 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 give compounds of general formula (III), their stereoisomers, their tautomers or their pharmaceutically acceptable salts; 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 give compounds of general formula (III), their stereoisomers, their tautomers or their pharmaceutically acceptable salts; Among them: rings C and R 1 R 3 And n as described in claim 33.

58. A pharmaceutical composition comprising a therapeutically effective amount of the compound as described in any one of claims 1 to 54, its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

59. Use of the compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 54, or the pharmaceutical composition as described in claim 58, in the preparation of a medicament for the prevention and / or treatment of μ-opioid receptor agonist-mediated diseases.

60. In the use described in claim 59, the μ-opioid receptor agonist-mediated related diseases are selected from one or more of pain, immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric diseases, urinary and reproductive diseases, cardiovascular diseases, and respiratory diseases.

61. In the use described in claim 60, the related disease mediated by the μ-opioid receptor agonist is pain.

62. Use of the compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 54, or the pharmaceutical composition as described in claim 58, in the preparation of a medicament for the prevention and / or treatment of pain or pain-related diseases.

63. In the use described in claim 62, 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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