Deuterated nop and opioid receptor dual-target agonists and uses thereof

Abstract

The present application relates to a deuterated dual NOP and opioid receptor agonist and uses thereof. Disclosed are compounds of formula (II) or pharmaceutically acceptable salts thereof and pharmaceutical compositions thereof, and uses thereof in the manufacture of medicaments for the treatment / prevention of diseases mediated by NOP and opioid receptors, wherein each group in (II) is as defined in the specification. (II)

Description

Technical Field

[0001] This invention relates to a deuterated NOP and opioid receptor dual-target agonist or a pharmaceutically acceptable salt thereof, and its use in the preparation of medicaments for treating NOP and opioid receptor-mediated diseases. Background Technology

[0002] Pain is an unpleasant sensory and emotional experience caused by strong stimuli that damage (or potentially damage) tissue. Based on its course, pain can be divided into acute pain and chronic pain. Acute pain typically lasts less than one month, while pain that persists for more than one month is called chronic pain. In the United States and Europe, approximately one-fifth of the population suffers from chronic pain, and globally, the prevalence of chronic pain is approximately 12%–30%. Postoperative pain refers to acute pain that occurs immediately after surgery. It is nociceptive pain and is the most common and urgent type of acute pain in clinical practice. Almost all patients experience acute postoperative pain. In China, 75% of surgical patients experience significant postoperative pain. In the United States, approximately 46 million inpatients and 53 million outpatients undergo surgery annually, and 80% of these patients experience postoperative pain. Up to 45% of emergency room patients report moderate to severe pain. Severe postoperative pain can affect the function of various systems throughout the body, causing serious complications and even endangering life.

[0003] Currently, there are three main categories of drugs used clinically for pain management: First, nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen. These are numerous and their mechanism of action primarily involves inhibiting cyclooxygenase (COX), blocking the conversion of arachidonic acid into prostaglandin (PG), thereby exerting anti-inflammatory and analgesic effects. Clinically, they are mainly used to treat mild pain, such as pain caused by rheumatism, arthritis, and acute injuries, and can also be used as a combination therapy for moderate to severe pain. Second, opioids, such as morphine, oxycodone, and fentanyl, are mainly used to treat chronic and moderate to severe pain. Third, adjunctive pain management drugs, such as neurotrophic drugs, anticonvulsant drugs (e.g., carbamazepine and oxcarbazepine), and antidepressants (e.g., prozac and duloxetine), can assist analgesics in reducing pain. Due to the limitations of their mechanisms of action, the clinical application of these drugs is greatly restricted. For example, while centrally acting opioids have good analgesic effects, they also have serious side effects such as respiratory depression, constipation, nausea, vomiting, hallucinations, dizziness, and sedation. They are also accompanied by adverse reactions such as drug tolerance, physical dependence, addiction, and drug-induced hyperalgesia. Nonsteroidal anti-inflammatory drugs (NSAIDs), while lacking the side effects of opioids, have insufficient analgesic efficacy and also pose adverse reactions such as gastrointestinal bleeding and cardiovascular risks. Therefore, there is an urgent need for safer and more effective analgesics on the market.

[0004] Opioid receptors include the classical mu(μ) opioid receptor (MOR), kappa(κ) opioid receptor (KOR), and delta(δ) opioid receptor (DOR), as well as the atypical norepinephrine receptor (NOPR; also known as orphanonephrine receptor or opioid receptor-like receptor 1, ORL-1). The endogenous ligands corresponding to MOR, KOR, and DOR have been identified as endorphins, dynorphins, and enkephalins, respectively. The endogenous ligand for NOPR is norepinephrine (also known as orphanonephrine FQ (OFQ)). Studies have found that NOPR agonism provides good analgesic efficacy and can alleviate adverse reactions associated with MOR agonism. Therefore, dual-target agonists of NOPR and MOR have the potential to become novel analgesics.

[0005] Currently, Tris Pharma's drug Cebranopadol has entered Phase III clinical trials. The earliest research on Cebranopadol appeared in patent WO2004043967A1, filed in November 2003, which has since expired. However, there are currently no reports on deuterated Cebranopadol drugs; therefore, research on deuterated compounds of Cebranopadol and its derivatives has significant clinical implications. Summary of the Invention

[0006] This invention provides a compound of general formula (I) or (II) or a pharmaceutically acceptable salt thereof, which is a deuterated NOP and opioid receptor agonist with excellent effects such as high activity, high stability, excellent physicochemical properties, easy formulation, excellent pharmacokinetic properties, high bioavailability, good safety, low toxicity and side effects, and stable metabolism.

[0007] This invention relates to a compound of formula (I), (II), (IA), (IB), (II-A), (II-B) or a pharmaceutically acceptable salt thereof.

[0008] (I) (II)

[0009] (IA) (II-A)

[0010] (IB) (II-B)

[0011] in,

[0012] R is selected from H or CH3;

[0013] In some implementations, R is selected from H;

[0014] In some implementations, R is selected from CH3;

[0015] In formula (I), at least one hydrogen atom is replaced by deuterium;

[0016] R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 Each is independently selected from H and deuterium;

[0017] In some implementation schemes, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15R 16 R 17 R 18 R 19 R 20 R 21 Selected from H;

[0018] In some implementation schemes, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 At least one of them is selected from deuterium;

[0019] In some implementation schemes, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 At least two of them are selected from deuterium;

[0020] In some implementation schemes, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 At least three of them are selected from deuterium;

[0021] In some implementation schemes, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R16 R 17 R 18 R 19 R 20 R 21 At least four of them are selected from deuterium;

[0022] In some implementation schemes, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 At least five of them are selected from deuterium;

[0023] In some implementation schemes, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 At least seven of them are selected from deuterium;

[0024] In some implementation schemes, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 At least eight of them are selected from deuterium;

[0025] In some implementation schemes, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 At least nine of them are selected from deuterium;

[0026] In some implementation schemes, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 At least ten of them are selected from deuterium;

[0027] In some implementation schemes, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 At least eleven of them are selected from deuterium;

[0028] In some implementation schemes, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 At least twelve of them are selected from deuterium;

[0029] In some implementation schemes, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 At least thirteen of them are selected from deuterium;

[0030] In some implementation schemes, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 At least fifteen of them are selected from deuterium;

[0031] In some implementation schemes, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 At least sixteen of them are selected from deuterium;

[0032] In some implementation schemes, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 At least seventeen of them are selected from deuterium;

[0033] In some implementation schemes, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 At least twenty of them are selected from deuterium;

[0034] In some implementation schemes, R1, R2, and R3 are selected from deuterium;

[0035] In some implementation schemes, R5 and R6 are selected from deuterium;

[0036] In some implementation schemes, R7 and R8 are selected from deuterium;

[0037] In some implementation schemes, R5, R6, R7, and R8 are selected from deuterium;

[0038] In some implementation schemes, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 Selected from deuterium;

[0039] In some implementation schemes, R 17 R 18 R 19 R 20 R 21 Selected from deuterium;

[0040] In some implementation schemes, R 17 Selected from deuterium;

[0041] In some implementation schemes, R 18 Selected from deuterium;

[0042] In some implementation schemes, R 19 Selected from deuterium;

[0043] In some implementation schemes, R 18 R 20 Selected from deuterium;

[0044] In some implementation schemes, R 17 R 21Selected from deuterium;

[0045] In some implementation schemes, R5, R6, R 19 Selected from deuterium;

[0046] In some implementation schemes, R5, R6, R7, R8, R 19 Selected from deuterium;

[0047] In some implementation schemes, R5, R6, R 18 R 20 Selected from deuterium;

[0048] In some implementation schemes, R1, R2, R3, R5, and R6 are selected from deuterium;

[0049] In some implementation schemes, R1, R2, R3, R5, R6, R7, and R8 are selected from deuterium;

[0050] In some implementation schemes, R5, R6, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 Selected from deuterium;

[0051] In some implementation schemes, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 Selected from deuterium;

[0052] In some implementation schemes, R5, R6, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 19 Selected from deuterium;

[0053] In some implementation schemes, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 19 Selected from deuterium;

[0054] In some implementation schemes, R5, R6, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 18 R 20 Selected from deuterium;

[0055] In some implementation schemes, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 18 R 20 Selected from deuterium;

[0056] In some implementation schemes, R1, R2, R3, R 17 R 18 R 19 R 20 R 21 Selected from deuterium;

[0057] In some implementation schemes, R1, R2, R3, R 19 Selected from deuterium;

[0058] In some implementation schemes, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 19 Selected from deuterium;

[0059] In some implementation schemes, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 Selected from deuterium;

[0060] In some implementation schemes, R5, R6, R9, R 10 R 11 R 12 R13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 Selected from deuterium;

[0061] In some implementation schemes, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 Selected from deuterium;

[0062] In some implementation schemes, R1, R2, R3, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 Selected from deuterium;

[0063] In some implementation schemes, R1, R2, R3, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 Selected from deuterium;

[0064] R 22 Selected from CH3 and CD3;

[0065] In some implementation schemes, R 22 Selected from CH3;

[0066] In some implementation schemes, R 22 Selected from CD3;

[0067] R 23 Selected from H, deuterium, CH3, and CD3;

[0068] In some implementation schemes, R 23 Selected from D;

[0069] In some implementation schemes, R 23 Selected from H and CH3;

[0070] In some implementation schemes, R 23 Selected from H;

[0071] In some implementation schemes, R 23 Selected from CH3;

[0072] In some implementation schemes, R 23 Selected from CD3;

[0073] In some implementation schemes, R 22 R 23 Selected from CD3;

[0074] The conditions are: R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 At least one of them is selected from deuterium or CD3.

[0075] The first technical solution of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0076]

[0077] (I)

[0078] Wherein, R is selected from H or CH3; at least one hydrogen atom in formula (I) is deuterated.

[0079] The second technical solution of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, said compound having the structure of formula (II).

[0080]

[0081] (II)

[0082] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 Each is independently selected from H and deuterium;

[0083] R 22 Selected from CH3 and CD3;

[0084] R 23 Selected from H, deuterium, CH3, and CD3;

[0085] The conditions are: R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 At least one of them is selected from deuterium or CD3.

[0086] The third technical solution of the present invention is a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R 22 R 23 At least one of them is selected from CD3;

[0087] The definitions of other functional groups are consistent with any of the technical solutions mentioned above.

[0088] The fourth technical solution of the present invention is a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18R 19 R 20 R 21 At least one of them is selected from deuterium;

[0089] The definitions of other functional groups are consistent with any of the technical solutions mentioned above.

[0090] The fifth technical solution of the present invention is a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R 22 R 23 The text is selected from CD3.

[0091] As a more specific embodiment of the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the structures in Table 1:

[0092] Table 1

[0093]

[0094] The present invention also provides a pharmaceutical composition or pharmaceutical formulation comprising the compound described in any of the foregoing embodiments or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

[0095] Furthermore, the compositions or pharmaceutical preparations of the present invention contain 1-1500 mg of the compound described in any of the foregoing schemes or its pharmaceutically acceptable salt and carrier and / or excipient.

[0096] Furthermore, the present invention also provides the use of the compounds described in any of the foregoing embodiments, their stereoisomers or pharmaceutically acceptable salts, in the preparation of medicaments for the treatment / prevention of NOP and opioid receptor-mediated diseases.

[0097] Furthermore, the NOP and opioid receptor-mediated diseases are pain, preferably cancer pain, chronic low back pain, knee osteoarthritis, diabetic peripheral neuropathy, and postoperative pain.

[0098] The present invention also provides a method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof described in any of the foregoing embodiments, preferably 1-1500 mg, wherein the disease is preferably pain. In some embodiments, the mammals described in the present invention include humans.

[0099] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the compound disclosed in this application will alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of the compound disclosed in this application required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1- 20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5 -150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-25 0mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg;50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg. ;

[0100] This invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical composition may be in unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as a "dosage strength"). In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1500 mg, 5-1500 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 25-500 mg, 40-200 mg, 50-100 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 17 mg, etc. The compounds of the present invention or pharmaceutically acceptable salts thereof, in the amounts of 0 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, and 1500 mg.

[0101] A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient, the therapeutically effective amount preferably being 1-1500 mg, wherein the disease is preferably pain.

[0102] A method for treating a disease in a mammal, the method comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof, along with a pharmaceutically acceptable carrier and / or excipient, to a subject at a daily dose of 1-1500 mg / day, said daily dose being a single dose or divided doses. In some embodiments, the daily dose includes, but is not limited to, 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, 10 ... 0 mg / day, 200-1000 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day. In some embodiments, the daily dose includes, but is not limited to, 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, and 1500 mg / day.

[0103] This invention relates to a kit that may comprise a single-dose or multi-dose composition containing a compound of the present invention or a pharmaceutically acceptable salt thereof, wherein the amount of the compound of the present invention or a pharmaceutically acceptable salt thereof is the same as the amount in the aforementioned pharmaceutical composition.

[0104] In this invention, the amount of the compound of the invention or its pharmaceutically acceptable salt is converted in each case as a free base.

[0105] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0106] Synthetic route

[0107] Those skilled in the art can prepare the compounds of this invention using known organic synthesis techniques, with starting materials being commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are obtained from legitimate commercial sources, and suppliers include: Titan Technology, Energie Chemicals, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology, among others.

[0108] Indexes of known chemical substances prepared by the American Chemical Society's Chemical Abstracts Service can selectively identify specific and similar reactants. These indexes are available in most public and university libraries, as well as online. Known but not commercially available chemicals in the catalogue can optionally be prepared by custom chemical synthesis plants, many of which offer custom synthesis services to standard chemical supply plants (such as those listed above).

[0109] the term

[0110] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of any conflict, the definitions provided herein shall prevail. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

[0111] The term "deuteration" refers to the substitution of one or more hydrogen atoms in a compound or group by deuterium. Deuteration can be monosubstituted, disubstituted, polysubstituted, or total substituted.

[0112] 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.

[0113] 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.

[0114] The term "deuterium" or "D" is a stable, non-radioactive isotope of hydrogen with a mass of protium ( ). 1 It has about twice the mass of H and is the most common hydrogen isotope.

[0115] In the compounds of this invention, when a position is specifically designated as deuterium or D, that position should be understood as having a deuterium abundance at least 1000 times greater than the native abundance (which is 0.015%) (i.e., at least 15% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 1000 times greater than the native abundance of deuterium (i.e., at least 15% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 2000 times greater than the native abundance of deuterium (i.e., at least 30% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3000 times greater than the native abundance of deuterium (i.e., at least 45% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3340 times greater than the natural deuterium abundance (i.e., at least 50.1% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3500 times greater than the natural deuterium abundance (i.e., at least 52.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4000 times greater than the natural deuterium abundance (i.e., at least 60% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4500 times greater than the natural deuterium abundance (i.e., at least 67.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5000 times greater than the natural deuterium abundance (i.e., at least 75% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5500 times greater than the natural deuterium abundance (i.e., at least 82.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6000 times greater than the natural deuterium abundance (i.e., at least 90% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6333.3 times greater than the natural deuterium abundance (i.e., at least 95% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6466.7 times greater than the natural deuterium abundance (i.e., at least 97% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6600 times greater than the natural deuterium abundance (i.e., at least 99% deuterium doping). In some implementations, the abundance of deuterium in each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium doping).

[0116] 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.

[0117] 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.

[0118] The term "pharmaceutical composition" refers to a composition containing one or more compounds described in this invention, or their physiologically / pharmaceutically acceptable salts or prodrugs, as well as other components such as physiologically / pharmaceutically 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.

[0119] The term "carrier" refers to a system that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the given compound, and can alter the way a drug enters the body and its distribution in the body, control the rate of drug release, and deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0120] The term "excipient" refers to an agent that is not itself a therapeutic agent but is used as a diluent, excipient, binder, and / or medium to be added to a pharmaceutical composition to improve its disposal or storage properties or to allow or facilitate the formation of a unit dosage form of the compound or pharmaceutical composition for administration. As is known to those skilled in the art, pharmaceutical excipients can provide a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweeteners. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and croscarmellose (e.g., sodium croscarmellose); (4) tragacanth gum powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter. (9) Oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) Diols, such as propylene glycol; (11) Polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) Esters, such as ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers, such as magnesium hydroxide and aluminum hydroxide; (15) Alginate; (16) Atherless water; (17) Isotonic saline; (18) Ringer's solution; (19) Ethanol; (20) pH buffer solution; (21) Polyesters, polycarbonates and / or polyanhydrides; and (22) Other non-toxic compatible substances used in pharmaceutical preparations.

[0121] 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, intravascular injection or infusion), local administration, and rectal administration.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.).

[0126] The term "room temperature" refers to a temperature ranging from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature ranging from 15°C to 30°C; in other embodiments, "room temperature" refers to a temperature ranging from 18°C ​​to 25°C.

[0127] "Equivalent" or its abbreviation "eq" is the equivalent amount of other raw materials required based on the equivalence relationship of a chemical reaction, using the basic raw materials used in each step as a reference (1 equivalent).

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

[0129] The present invention will be described in detail below through embodiments. Unless otherwise specified, experimental methods under conventional conditions were used in the embodiments. The embodiments are provided to better illustrate the present invention, but should not be construed as limiting the invention to the examples given. Non-essential improvements and adjustments made to the implementation schemes by those skilled in the art based on the above description are still within the scope of protection of the present invention.

[0130] Unless otherwise specified, the raw materials were purchased from companies such as Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology.

[0131] The structure of the compounds was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using Bruker Avance III 400 and Bruker Avance 300 NMR spectrometers in the following solvents: deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), and deuterated methanol (CD₃OD). Tetramethylsilane (TMS) was used as the internal standard.

[0132] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0133] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM).

[0134] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used for TLC have a diameter of 0.15 mm to 0.20 mm, and the diameter of the plates used for TLC separation and purification is 0.4 mm to 0.5 mm.

[0135] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0136] Retention time was determined by HPLC analysis. HPLC analysis method: Instrument: Shimadzu LC-20AT; Column: Yuexu, Column model: Ultimate C18 4.6*50mm, 3μm. Chromatographic conditions: Detection wavelength 254nm / 210nm; Flow rate: 1.0 ml / min; Column temperature: 35℃; Injection volume: 2μl; Acquisition time: 10min; Mobile phase A was 0.05% TFA solution, and mobile phase B was acetonitrile. Gradient elution program: Mobile phase A (95%) to mobile phase B (95%).

[0137] Example 1:

[0138]

[0139] Step 1: Compound 1a (5.0 g, 32.01 mmol) was added to a reaction flask and dissolved in methanol (5 ml). Deuterated dimethylamine hydrochloride (8.41 g, 96.03 mmol) was added, and the mixture was stirred for 10 min. Then, 1b (40% deuterated dimethylamine hydrochloride aqueous solution, 50 ml) and potassium cyanide (8.34 g, 128.04 mmol) were added, and the mixture was reacted at room temperature for 72 hours. After the reaction was completed by TLC monitoring, the mixture was diluted with water (200 mL), extracted twice with ethyl acetate (200 ml * 2), the organic phases were combined and dried, and concentrated under reduced pressure to obtain compound 1c (5.9 g, 85.20%).

[0140] LC-MS(ESI): m / z=217.2[M+H] + .

[0141] Step 2: Compound 1c (5.9 g, 27.30 mmol) was dissolved in THF (60 mL), and 1d (phenylmagnesium chloride, 136.5 mL, 273.0 mmol) was added at 0 °C. The mixture was then allowed to react at room temperature for 16 hours. After the reaction was completed by TLC monitoring, saturated ammonium chloride solution was added to quench the reaction, followed by dilution with water (200 mL). The mixture was extracted twice with ethyl acetate (200 mL * 2), the organic phases were combined and dried, and concentrated under reduced pressure to obtain compound 1e (5.3 g, 72.67%).

[0142] LC-MS(ESI): m / z=268.2[M+H] + .

[0143] Step 3: Compound 1e (5.3 g, 19.82 mmol) was added to a reaction flask and dissolved in THF:H2O = 1:1 (100 mL). Concentrated hydrochloric acid (5 mL) was added, and the reaction was carried out at 90 °C for 16 hours. After the reaction was completed by TLC monitoring, water (100 mL) was added for dilution, and the mixture was extracted once with DCM (100 mL). The aqueous phase was collected, and the pH of the aqueous phase was adjusted to 10. The mixture was extracted twice with ethyl acetate (100 mL * 2). The organic phases were combined, dried, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 1f (1.8 g, 40.66%).

[0144] LC-MS(ESI): m / z=224.1[M+H] + .

[0145] Step 4: 5-Fluorordol (180 mg, 1.00 mmol) and compound 1f (245 mg, 1.10 mmol) were added to a reaction flask, dissolved in DCM (10 mL), and TMSOTf (267 mg, 1.20 mmol) was slowly added at 40 °C. The reaction was continued for 24 hours. After the reaction was completed by TLC monitoring, the compounds were purified by reversed-phase column chromatography to obtain compound 1-1 (80 mg, 22%) and compound 1-2 (20 mg, 5.48%).

[0146] Compound 1-1, HPLC retention time 4.167 min, 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s,1H), 7.39 - 7.33 (m, 4H), 7.32 - 7.23 (m, 2H), 7.11 - 7.10 (m, 1H), 6.88 -6.82 (m, 1H), 3.90 - 3.86 (m, 2H), 2.66 – 2.61 (m, 2H), 2.56 – 2.51 (m, 2H), 2.31 – 2.21 (m, 2H), 1.82 – 1.71 (m, 4H).

[0147] LC-MS(ESI): m / z=385.3[M+H] + .

[0148] Compounds 1-2, HPLC retention time 3.853 min, 1H NMR (400 MHz, DMSO-d6) δ 10.58 (s,1H), 7.48 – 7.41 (m, 4H), 7.36 – 7.30 (m, 1H), 7.17 – 7.07 (m, 2H), 6.83 –6.76 (m, 1H), 3.96 – 3.90 (m, 2H), 2.66 – 2.61 (m, 2H), 2.49-2.43 (m, 2H)2.05 – 1.88 (m, 2H), 1.85 – 1.77 (m, 2H), 1.64 – 1.54 (m, 2H).

[0149] LC-MS(ESI): m / z=385.3[M+H] + .

[0150] Example 2:

[0151]

[0152] Step 1: Compound 1a (10.0 g, 64.03 mmol) was added to a reaction flask and dissolved in DCM. Then, 2a (9.87 g) and tetraethyl titanate (15.48 g) were added, and the mixture was reacted at room temperature for 16 hours. After the reaction was completed by TLC monitoring, the reaction mixture was poured into 1 L of water, stirred for 10 minutes, extracted twice with DCM, the organic phases were combined and dried, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 2b (6.3 g, yield: 37.95%).

[0153] LC-MS(ESI): m / z=260.2[M+H] + .

[0154] Step 2: Compound 2b (6.0 g, 23.13 mmol) was added to the reaction flask, dissolved in THF, cooled to 0°C, and phenylmagnesium chloride (23.13 ml, 46.26 mmol) was added dropwise. After the addition was complete, the mixture was slowly brought to room temperature and reacted for 4 hours. After the reaction was completed by TLC monitoring, the reaction was quenched with saturated ammonium chloride solution, extracted twice with ethyl acetate, the organic phases were combined and dried, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 2c (2.5 g, yield: 32.05%).

[0155] 1H NMR (400 MHz, DMSO-d6) δ 7.54 – 7.49 (m, 2H), 7.34 – 7.28 (m, 2H), 7.24 – 7.18 (m, 1H), 5.24 (s, 1H), 3.91 – 3.81 (m, 4H), 2.25 – 2.07 (m, 4H), 1.88 – 1.72 (m, 2H), 1.54 – 1.40 (m, 2H), 1.08 (s, 9H).

[0156] Step 3: Compound 2c (2.5 g, 7.41 mmol) was added to a reaction flask, dissolved in DMF, cooled to 0°C, and then NaH (445 mg, 11.12 mmol) was added. The mixture was stirred at this temperature for 30 minutes, followed by the addition of deuterated iodomethane (1.2 g). The reaction was then brought to room temperature and allowed to proceed for 16 hours. After the reaction was completed by TLC monitoring, the mixture was quenched with saturated ammonium chloride solution, extracted twice with ethyl acetate, and the organic phases were combined, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 2d (950 mg, yield: 36.26%).

[0157] LC-MS (ESI): m / z = 355.2 [M+H] + .

[0158] Step 4: Compound 2d (950 mg, 2.68 mmol) was added to a reaction flask, dissolved in DCM (40 ml), and dioxane hydrochloride solution (2 ml) was added. The reaction was carried out at room temperature for 2 hours. After the reaction was completed by TLC monitoring, saturated sodium bicarbonate solution (40 ml) was added to separate the organic phase. The aqueous phase was extracted again with DCM. The organic phases were combined, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 2e (460 mg, yield: 68.55%).

[0159] LC-MS(ESI): m / z=251.2[M+H] + .

[0160] Step 5: Compound 2e (460 mg, 1.83 mmol) was added to a reaction flask, dissolved in THF, and then mixed with formaldehyde aqueous solution (2.3 ml) and sodium cyanoborohydride (172 mg, 2.75 mmol). The mixture was reacted at room temperature for 16 hours. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 2f (300 mg, yield: 62.01%).

[0161] LC-MS(ESI): m / z=265.3[M+H] + .

[0162] Step 6: Compound 2f (300 mg, 1.13 mmol) was added to a reaction flask, dissolved in DCM (10 ml), and dioxane hydrochloride solution (10 ml) was added. The mixture was reacted at room temperature for 30 minutes. After the reaction was completed by TLC monitoring, saturated sodium bicarbonate solution (40 ml) was added to separate the organic phase. The aqueous phase was extracted twice more with DCM. The organic phases were combined, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 2 g (170 mg, yield: 68.27%).

[0163] LC-MS(ESI): m / z=221.2[M+H] + .

[0164] Step 7: Compound 2 g (170 mg, 0.77 mmol) and 5-fluorotryptol (138 mg, 0.77 mmol) were added to a reaction flask, dissolved in DCM, and TMSOTf (205 mg, 0.92 mmol) was added. The mixture was reacted at 40 °C for 16 hours. After the reaction was completed by TLC monitoring, saturated sodium bicarbonate solution (40 ml) was added, the organic phase was separated, and the aqueous phase was extracted twice with DCM. The organic phases were combined, dried, concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography to give compound 2 (84 mg, yield: 28.59%).

[0165] LC-MS(ESI): m / z=382.3[M+H] + .

[0166] 1 H NMR (400 MHz, DMSO- d6) δ 10.96 (s, 1H), 7.40 – 7.34 (m, 4H), 7.33– 7.23 (m, 2H), 7.15 – 7.10 (m, 1H), 6.89 – 6.82 (m, 1H), 3.91 – 3.85 (m,2H), 2.67 – 2.61 (m, 2H), 2.57 – 2.51 (m, 2H), 2.31 – 2.20 (m, 2H), 2.04 (s,3H), 1.82 – 1.70 (m, 4H).

[0167] Biological testing

[0168] 1. Assay for the agonistic activity of the orphanone receptor (NOPR)

[0169] CHO cells overexpressing the orphanone receptor (NOPR) (constructed in the laboratory of Beijing Aisiyipu Biotechnology Co., Ltd.) were cultured in F-12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B. Cells were cultured in an incubator at 37ºC and 5% CO2. On the day of the experiment, 1× Stimulation Buffer was prepared according to the LANCE Ultra cAMP kit (Revity, TRF0264) instructions. The test sample stock solution was diluted with DMSO (9-10 concentration points), and then 10 nL / well was transferred to the corresponding well using ECHO. For cell treatment, the old medium was removed and the cells were rinsed once with PBS, then 1 mL of 0.25%-Trypsin-EDTA solution was added, and the cells were incubated at 37ºC for approximately 2 minutes. When the cells detached from the bottom of the dish, approximately 5 mL of preheated 37ºC complete medium was added. Gently pipette the cell suspension to separate aggregated cells, then transfer them to sterile centrifuge tubes and collect the cells by centrifugation at 1000 rpm for 5 minutes. Resuspend the cells in 1× Stimulation Buffer, count them, and adjust the cell density to 1×10⁻⁶. 5 Cells / mL were seeded at 10 μL / well in a 384-well plate containing the test sample, centrifuged, and incubated at 37ºC for 10 min. Then, 10 nL / well of Forskolin (2 mM) solution was transferred to the corresponding well using ECHO, centrifuged, and incubated at 37ºC for 30 min. Eu-cAMP was diluted 50-fold with detection buffer, and 4 μL was added to the corresponding well. Ultra-anti-cAMP was diluted 150-fold with detection buffer, and 4 μL was added to the corresponding well. After centrifugation, the cells / well was incubated at room temperature for 1 hour. After incubation, the readings at 665 nm and 620 nm were detected using a microplate reader at a wavelength of 330 nm excitation. The final concentration of DMSO was 0.1%. The ratio and activation rate were calculated using the following formula: Ratio = Signal 665 / Signal 620 =10000, Activation Rate (%) = (Ratio) 受试物 Ratio 阴性对照 ) / (Ratio 阳性对照 Ratio 阴性对照 100. EC was fitted using GraphPad Prism software. 50 value.

[0170] Experimental results: NOPR EC for some specific compounds 50(nM) and NOPR Emax% @10μM are shown in Table 1. For EC 50 A represents EC 50 ≤10 nM, B means 10 nM < EC 50 ≤100nM, C represents EC 50 >100nM; For Emax% @10μM, A means Emax%>90%, B means 60%<Emax%≤90%, and C means Emax%≤60%.

[0171] Table 1

[0172] Compound numbering <![CDATA[NOPR EC 50 (nM)]]> 1-1 A 2 A

[0173] Conclusion: The compounds of the present invention, such as the compounds in the examples, have excellent agonistic activity towards NOPR.

[0174] 2. Assay for the agonistic activity of mu-opioid receptors (MOR)

[0175] CHO cells overexpressing the mu opioid receptor (constructed in the laboratory of Beijing Aisiyipu Biotechnology Co., Ltd.) were cultured in F-12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B. Cells were cultured in an incubator at 37ºC and 5% CO2. On the day of the experiment, 1× Stimulation Buffer was prepared according to the LANCE Ultra cAMP kit (Revity, TRF0264) instructions. The test sample stock solution was diluted with DMSO (9-10 concentration points), and then 10 nL / well was transferred to the corresponding experimental well using ECHO. For cell treatment, the old medium was removed and the cells were rinsed once with PBS, then 1 mL of 0.25%-Trypsin-EDTA solution was added, and the cells were incubated at 37ºC for approximately 2 minutes. When the cells detached from the bottom of the dish, approximately 5 mL of preheated 37ºC complete medium was added. Gently pipette the cell suspension to separate aggregated cells, then transfer them to sterile centrifuge tubes and collect the cells by centrifugation at 1000 rpm for 5 minutes. Resuspend the cells in 1× Stimulation Buffer, count them, and adjust the cell density to 2.2×10⁻⁶. 5Cells / mL were seeded at 10 μL / well in a 384-well plate containing the test sample, centrifuged, and incubated at 37ºC for 10 min. Then, 10 nL / well of Forskolin (6 mM) solution was transferred to the corresponding well using ECHO, centrifuged, and incubated at 37ºC for 30 min. Eu-cAMP was diluted 50-fold with detection buffer, and 4 μL was added to the corresponding well. Ultra-anti-cAMP was diluted 150-fold with detection buffer, and 4 μL was added to the corresponding well. After centrifugation, the cells / well was incubated at room temperature for 1 hour. After incubation, the readings at 665 nm and 620 nm were detected using a microplate reader at a wavelength of 330 nm excitation. The final concentration of DMSO was 0.1%. The Ratio and activation rate were calculated using the following formula: Ratio = Signal 665 / Signal 620 =10000, Activation Rate (%) = (Ratio) 受试物 Ratio 阴性对照 ) / (Ratio 阳性对照 Ratio 阴性对照 100. EC was fitted using GraphPad Prism software. 50 value.

[0176] Experimental results: MOR EC of some specific compounds 50 (nM) and MOR Emax% @10μM are shown in Table 2. For EC 50 A represents EC 50 ≤10 nM, B means 10 nM < EC 50 ≤100nM, C represents EC 50 >100nM; For Emax% @10μM, A means Emax%>90%, B means 60%<Emax%≤90%, and C means Emax%≤60%.

[0177] Table 2

[0178] Compound numbering <![CDATA[MOR EC 50 (nM)]]> 1-1 A 2 A

[0179] Conclusion: The compounds of the present invention, such as the compounds in the examples, have excellent agonistic activity for MOR.

[0180] 3. Kappa opioid receptor (KOR) agonistic activity assay

[0181] CHO cells overexpressing the kappa opioid receptor (constructed in the laboratory of Beijing Aisiyipu Biotechnology Co., Ltd.) were cultured in F-12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B. Cells were cultured in an incubator at 37ºC and 5% CO2. On the day of the experiment, 1× Stimulation Buffer was prepared according to the LANCE Ultra cAMP kit (Revvity, TRF0264) instructions. The test sample stock solution was diluted with DMSO (9-10 concentration points), and then 10 nL / well was transferred to the corresponding experimental well using ECHO. For cell treatment, the old medium was removed and the cells were rinsed once with PBS, then 1 mL of 0.25%-Trypsin-EDTA solution was added, and the cells were incubated at 37ºC for approximately 2 minutes. When the cells detached from the bottom of the dish, approximately 5 mL of preheated 37ºC complete medium was added. Gently pipette the cell suspension to separate aggregated cells, then transfer them to sterile centrifuge tubes and collect the cells by centrifugation at 1000 rpm for 5 minutes. Resuspend the cells in 1× Stimulation Buffer, count them, and adjust the cell density to 2×10⁶ cells / mL. 5 Cells / mL were seeded at 10 μL / well in a 384-well plate containing the test sample, centrifuged, and incubated at 37ºC for 10 min. Then, 10 nL / well of Forskolin (1 mM) solution was transferred to the corresponding well using ECHO, centrifuged, and incubated at 37ºC for 30 min. Eu-cAMP was diluted 50-fold with detection buffer, and 4 μL was added to the corresponding well. Ultra-anti-cAMP was diluted 150-fold with detection buffer, and 4 μL was added to the corresponding well. After centrifugation, the cells / well was incubated at room temperature for 1 hour. After incubation, the readings at 665 nm and 620 nm were detected using a microplate reader at a wavelength of 330 nm excitation. The final concentration of DMSO was 0.1%. The ratio and activation rate were calculated using the following formula: Ratio = Signal 665 / Signal 620 =10000, Activation Rate (%) = (Ratio) 受试物 Ratio 阴性对照 ) / (Ratio 阳性对照 Ratio 阴性对照 100. EC was fitted using GraphPad Prism software. 50 value.

[0182] Experimental results: KOR EC of some specific compounds 50(nM) and KOR Emax% @10μM are shown in Table 3. For EC 50 A represents EC 50 ≤10 nM, B means 10 nM < EC 50 ≤100nM, C represents EC 50 >100nM; For Emax% @10μM, A means Emax%>90%, B means 60%<Emax%≤90%, and C means Emax%≤60%.

[0183] Table 3

[0184] Compound numbering <![CDATA[KOR EC 50 (nM)]]> 1-1 A

[0185] Conclusion: The compounds of the present invention, such as the compounds in the examples, have excellent agonistic activity toward KOR.

[0186] 4. Assay for the agonistic activity of delta-opioid receptors (DOR)

[0187] CHO cells overexpressing delta-opioid receptors (constructed in the laboratory of Beijing Aisiyipu Biotechnology Co., Ltd.) were cultured in F-12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B. Cells were cultured in an incubator at 37ºC and 5% CO2. On the day of the experiment, 1× Stimulation Buffer was prepared according to the LANCE Ultra cAMP kit (Revity, TRF0264) instructions. The test sample stock solution was diluted with DMSO (9-10 concentration points), and then 10 nL / well was transferred to the corresponding experimental well using ECHO. For cell treatment, the old medium was removed and the cells were rinsed once with PBS, then 1 mL of 0.25%-Trypsin-EDTA solution was added, and the cells were incubated at 37ºC for approximately 2 minutes. When the cells detached from the bottom of the dish, approximately 5 mL of preheated 37ºC complete medium was added. Gently pipette the cell suspension to separate aggregated cells, then transfer them to sterile centrifuge tubes and collect the cells by centrifugation at 1000 rpm for 5 minutes. Resuspend the cells in 1× Stimulation Buffer, count them, and adjust the cell density to 2×10⁶ cells / mL. 5Cells / mL, seeded at 10 μL / well in a 384-well plate containing the test sample, centrifuged, and incubated at 37ºC for 10 min. Then, 10 nL / well of Forskolin (0.5 mM) solution was transferred to the corresponding well using ECHO, centrifuged, and incubated at 37ºC for 30 min. Eu-cAMP was diluted 50-fold with detection buffer, and 4 μL was added to the corresponding well. Ultra-anti-cAMP was diluted 150-fold with detection buffer, and 4 μL was added to the corresponding well. After centrifugation, the cells / mL were incubated at room temperature for 1 hour. After incubation, the readings at 665 nm and 620 nm were detected using a microplate reader at a wavelength of 330 nm excitation. The final concentration of DMSO was 0.1%. The Ratio and activation rate were calculated using the following formula: Ratio = Signal 665 / Signal 620 =10000, Activation Rate (%) = (Ratio) 受试物 Ratio 阴性对照 ) / (Ratio 阳性对照 Ratio 阴性对照 100. EC was fitted using GraphPad Prism software. 50 value.

[0188] Experimental results: DOR EC of some specific compounds 50 (nM) and DOR Emax% @10μM are shown in Table 4. For EC 50 A represents EC 50 ≤10 nM, B means 10 nM < EC 50 ≤100nM, C represents EC 50 >100nM; For Emax% @10μM, A means Emax%>90%, B means 60%<Emax%≤90%, and C means Emax%≤60%.

[0189] Table 4

[0190] Compound numbering <![CDATA[DOR EC 50 (nM)]]> 1-1 A

[0191] Conclusion: The compounds of the present invention, such as the compounds in the examples, have excellent agonistic activity toward DOR.

[0192] 5. In vitro plasma stability test

[0193] A prepared compound solution is added to a certain amount of biological matrix to prepare stability samples at two concentration levels (low-concentration quality control sample and high-concentration quality control sample), with three copies of each concentration level. Under the required experimental conditions, the peak area ratio of the sample after a certain period of time / the peak area ratio of the sample at point 0 is multiplied by 100% to obtain the stability test result of the compound.

[0194] Conclusion: The compounds of this invention exhibit good in vitro plasma stability.

[0195] 6. Rat pharmacokinetic test

[0196] Experimental animals: Male SD rats, approximately 180-220 g in size, 6-8 weeks old, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0197] Experimental design: On the day of the experiment, SD rats were randomly divided into groups according to their body weight. They were fasted for 12-14 hours before drug administration but allowed free access to water, and were fed 4 hours after drug administration.

[0198] Before and after administration of isoflurane anesthesia, 0.10 mL of blood was drawn via the orbital cavity and placed in an EDTAK2 centrifuge tube. The centrifuge was then incubated at 5000 rpm for 4 hours. o Centrifuge at 1°C for 10 min and collect plasma. Store all samples at -80°C before analysis. o C. Quantitative analysis of the sample was performed using LC-MS / MS.

[0199] Conclusion: The compounds of this invention exhibit good pharmacokinetic properties in rats.

[0200] 7. Mouse pharmacokinetics test

[0201] Experimental animals: Male C57 mice, 22-25 g, purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0202] Experimental design: On the day of the experiment, ICR mice were randomly divided into groups according to body weight. They were fasted for 12-14 hours before administration but allowed free access to water, and were fed 4 hours after administration.

[0203] Before and after administration of isoflurane anesthesia, 0.04 mL of blood was drawn via the orbital cavity and placed in an EDTAK2 centrifuge tube. The centrifuge was then incubated at 5000 rpm for 4 hours. o Centrifuge at 1°C for 10 min and collect plasma. Store all samples at -80°C before analysis. o C. Quantitative analysis of the sample was performed using LC-MS / MS.

[0204] Conclusion: The compounds of this invention exhibit good pharmacokinetic properties in mice.

[0205] 8. Pharmacokinetics of Beagle Dogs

[0206] Experimental animals: Male beagle dogs, weighing approximately 8-11 kg, purchased from Beijing Mars Biotechnology Co., Ltd.

[0207] Experimental method: On the day of the experiment, beagles were randomly divided into groups according to their body weight. They were fasted for 12-14 hours before administration but allowed free access to water. They were fed 4 hours after administration.

[0208] Blood samples of 1 mL were collected via jugular or limb veins before and after drug administration and placed in EDTAK2 centrifuge tubes. The plasma was collected by centrifugation at 5000 rpm and 4 °C for 10 min. All samples were stored at -80 °C before analysis and quantitative analysis was performed using LC-MS / MS.

[0209] Conclusion: The compound of this invention exhibits good pharmacokinetic properties compared to guinea pigs.

[0210] 9. Pharmacokinetics in monkeys

[0211] Experimental animals: Male cynomolgus monkeys, 3-5 kg, 2.5-5 years old, purchased from Hainan Xinzhengyuan Biotechnology Co., Ltd.

[0212] Experimental method: On the day of the experiment, monkeys were randomly divided into groups according to their body weight. They were fasted for 14-18 hours before administration but allowed free access to water, and were fed 4 hours after administration.

[0213] Blood samples of 1.0 mL were collected via venous sampling from each limb before and after administration and placed in EDTAK2 centrifuge tubes. The centrifuge volume was 5000 rpm, 4 mL. o Centrifuge at 1°C for 10 min and collect plasma. Store all samples at -80°C before analysis. o C. Quantitative analysis of the sample was performed using LC-MS / MS.

[0214] Conclusion: The compounds of this invention exhibit good pharmacokinetic properties in monkeys.

[0215] 10. hERG potassium ion channel function test

[0216] Experimental platform: Electrophysiological manual patch-clamp system

[0217] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channels

[0218] Experimental Methods: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents at room temperature using whole-cell patch-clamp technique. Glass microelectrodes were fabricated from glass electrode blanks (BF150-86-10, Sutter) using a stretching device. The tip resistance after perfusion with electrode fluid was approximately 2-5 MΩ. The glass microelectrodes were inserted into the amplifier probe to connect to the patch-clamp amplifier. Clamp voltage and data recording were controlled and recorded using pClamp 10 software via computer, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After obtaining whole-cell recordings, the cells were clamped at -80 mV to induce hERG potassium current (Ik). hERG The step voltage was applied from -80 mV to +20 mV over 2 s, then repolarized to -50 mV for 1 s before returning to -80 mV. This voltage stimulation was applied every 10 s, and the drug administration process began after the hERG potassium current stabilized (at least 1 minute). Each test concentration of the compound was administered for at least 1 minute, and at least 2 cells (n≥2) were tested for each concentration.

[0219] Data processing: Data analysis and processing were performed using pClamp 10, GraphPad Prism 5, and Excel software. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula:

[0220] Inhibition % = [1 – (I / Io)]×100%

[0221] Where Inhibition % represents the percentage of inhibition of hERG potassium current by the compound, and I and Io represent the amplitude of hERG potassium current before and after drug administration, respectively.

[0222] Compound IC 50 The following equations were fitted and calculated using GraphPad Prism 5 software:

[0223] Y=Bottom + (Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0224] Where X is the Log value of the detected concentration of the test sample, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0225] Conclusion: The compounds of this invention do not inhibit the hERG potassium channel current.

[0226] 11. CYP450 enzyme inhibition test

[0227] The aim of this study was to evaluate the effects of test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro assay system. Specific probe substrates for CYP450 isoenzymes were co-incubated with human liver microsomes and different concentrations of the test substances. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS) after sample processing, and the changes in CYP enzyme activity were measured. The IC50 values ​​were calculated. 50 The value is used to evaluate the inhibitory potential of the test substance against each CYP enzyme subtype.

[0228] Conclusion: The compounds of this invention do not inhibit the five isoenzymes of human liver microsomal cytochrome P450 (CYP).

[0229] 12. Liver microsomal stability test

[0230] This experiment used liver microsomes from five genera—human, canine, rat, and mouse—as in vitro models to evaluate the metabolic stability of the test substance.

[0231] At 37°C, 1 µM of the test substance was co-incubated with microsomal protein and coenzyme NADPH. The reaction was terminated by adding ice-cold acetonitrile containing an internal standard after certain time intervals (5, 10, 20, 30, 60 min). The concentration of the test substance in the sample was detected by LC-MS / MS. T1 / 2 was calculated using the ln value of the drug residue in the incubation system and the incubation time. The intrinsic clearance rate (CL) of liver microsomes was further calculated. int(mic) and hepatic intrinsic clearance rate CL int(Liver) .

[0232] 13. Caco-2 Permeability Test

[0233] The experiment used monolayers of Caco-2 cells, incubated in triple parallel in 96-well Transwell plates. A transport buffer solution (HBSS, 10 mM HEPES, pH 7.4±0.05) containing either the compound of the present invention (2 μM) or the control compounds digoxin (10 μM), naldolol (2 μM), and metoprolol (2 μM) was added to the dosing well on the apical or basal side. A transport buffer solution containing DMSO was added to the corresponding receiving well. After incubation at 37±1°C for 2 hours, the cell plate was removed, and appropriate amounts of sample were transferred from both the apical and basal sides to new 96-well plates. Acetonitrile containing an internal standard was then added to precipitate the protein. The samples were analyzed using LC MS / MS to determine the concentrations of the compound of the present invention and the control compounds. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to the basal side of the monolayer cells, and from the basal side to the apical side, thereby calculating the efflux rate. Leakage of fluorescein was used to evaluate the integrity of the monolayer cells after 2 hours of incubation.

[0234] 14. Mouse hot plate test

[0235] Female C57 / BL6J mice (6-8 weeks old) purchased from Vital River Laboratory Animal Technology Co., Ltd. were acclimatized in an SPF-grade animal facility for approximately one week before the experiment began. The hot plate apparatus (UGO BASILE SRL) was turned on, and the temperature was set to 56°C. After the temperature stabilized, the mouse was gently lifted by the base of its tail with the right thumb and forefinger, while the body was supported by the left palm. The mouse was quickly and smoothly placed in the center of the hot plate, and the mouse's pain response was observed, such as licking / biting its hind paws, rapid paw lifting or shaking, and jumping (limbs leaving the plate). Animals with a response latency of 8-25 seconds were selected for the study. The animals were divided into a solvent control group (Vehicle) and a test substance test group. The solvent or test substance was administered via tail vein injection. The mouse's pain response latency was tested again at a preset time point after administration. The maximum possible percentage of efficacy (%MPE) was then calculated using the following formula: (Post-administration latency − Pre-administration latency) / (30 − Pre-administration latency) 100. GraphPad Prism software was used to perform statistical analysis on the data to compare differences between groups and evaluate the analgesic effect of the test drug.

[0236] Conclusion: In the mouse hot plate test, the compounds of the present invention, such as the compounds in the examples, dose-dependently inhibited the pain response in the animals, demonstrating good analgesic efficacy.

[0237] 15. Mouse hot tail flicking test

[0238] Male ICR mice (6-8 weeks old) purchased from Vital River Laboratory Animal Technology Co., Ltd. were acclimatized in an SPF-grade animal facility for approximately one week before being placed on the YLS-12A mouse tail photoanalgia testing platform. After setting the power, the run button was pressed and the experiment was awaited. The animal was placed in the photoanalgia's dedicated restraint, ensuring its tail was aligned with the sensor and the heat transfer plate. The start button was pressed, and timing began. When the animal moved its tail away from the sensor due to heat pain, both infrared radiation and the timer stopped simultaneously. The tail-flick latency was recorded. Mice with a latency of less than 7 seconds were selected and randomly divided into a solvent control group (Vehicle) and a test substance group. The solvent or test substance was administered via tail vein injection, and the tail-flick latency was measured again at a preset time point after administration. The maximum possible percentage of efficacy (%MPE) was then calculated using the following formula: (Post-administration latency − Pre-administration latency) / (16.01 − Pre-administration latency) 100. GraphPad Prism software was used to perform statistical analysis on the data to compare differences between groups and evaluate the analgesic effect of the test drug.

[0239] Conclusion: In the mouse hot tail-flick experiment, the compounds of the present invention, such as the compounds in the examples, dose-dependently prolonged the tail-flick latency in animals and had good analgesic efficacy.

[0240] 16. Rat paw incision-induced mechanical pain sensitization model

[0241] Male SD rats (6-8 weeks old) purchased from Viton Lever Laboratories underwent environmental acclimatization training for approximately one week before the Von Frey test, allowing the rats to become fully familiar with the testing environment and the operator. The specific procedures and protocols for this experiment are as follows:

[0242] (1) Preparation for adaptive training: Place the rats in a transparent plexiglass test cage in advance and allow them to adapt for 20-30 minutes.

[0243] (2) Adaptive training: Using calibrated Von Frey fiber kits (0.6~26.0 g), a medium-strength Von Frey fiber (e.g., 8.0 g) was selected to begin stimulation. If the rat exhibited a rapid withdrawal response to the stimulation, it was marked as a positive response. If no positive response was observed, a larger adjacent stimulus was given; if a positive response was observed, a smaller stimulus was given, and so on. After the first negative and positive straddling occurred, four more consecutive measurements were taken. A positive response was recorded as X, and a negative response as O. The interval between two stimuli was at least 5 seconds to eliminate the previous stimulus, and the bending angle of the Von Frey fiber was controlled between 15 and 30 degrees. Finally, starting from the last negative response before the first positive straddling, a total of 6-digit measurement values ​​were obtained, and the 50% withdrawal threshold of the rat was calculated. The training was conducted continuously for 3 days.

[0244] (3) Preparation for foot incision surgery: After cleaning the scalpel, forceps, scissors, suture needles and other instruments, sterilize them by high pressure steam sterilization to ensure a sterile operating environment.

[0245] (4) Anesthesia and positioning: Rats were anesthetized with isoflurane inhalation. After complete anesthesia (loss of righting reflex and spontaneous movement), they were fixed in a prone position on a temperature-controlled operating table. The left hind limb was fully abducted and fixed to expose the surgical area on the sole of the foot. The skin on the sole of the left hind foot was strictly disinfected with povidone-iodine solution.

[0246] (5) Surgical incision preparation: Using a No. 11 scalpel blade, make a longitudinal skin incision about 1 cm long on the bottom of the left hind foot, about 0.5 cm from the heel, towards the toes. Use forceps to lift the plantar muscle underneath and separate it through the longitudinal incision (without damaging the origin, insertion and attachment points of the plantar muscle). Gently press the incision to stop bleeding and remove any blood accumulation in the surgical area.

[0247] (6) Postoperative care: The muscles and skin were sutured with 4-0 absorbable sutures to ensure good closure of the incision, with no obvious bleeding or tissue exposure. After the operation, the rats were put back into the cage and raised separately.

[0248] (7) Baseline mechanical pain threshold test: The baseline test is performed about 2 hours after the operation to determine the mechanical withdrawal threshold of the non-incision area (such as the sole of the foot) on the operated side. The specific operation procedure is the same as the adaptation training phase.

[0249] (8) Grouping and administration: Based on the 50% PWT calculated 2 hours after surgery, animals weighing 1-4 g were selected for enrollment. The rats were evenly distributed into the solvent control group (Vehicle) and the test substance test group. The solvent or test substance was administered via tail vein injection, and then the 50% PWT was measured at different time points.

[0250] (9) Statistical analysis: GraphPad Prism software was used to perform statistical analysis on the data to compare differences between groups and evaluate the analgesic effect of the test substance.

[0251] Conclusion: In a rat model of mechanical pain sensitization induced by plantar lesion, the compounds of the present invention, such as those in the examples, dose-dependently increased the mechanical pain threshold of the animals, indicating that the test substances have good analgesic efficacy.

[0252] 17. Mouse respiratory depression experiment

[0253] Female C57 / BL6J mice (6-8 weeks old) purchased from Vital River Laboratory Animal Technology Co., Ltd. were acclimatized in an SPF-grade animal facility for approximately one week before the experiment began. The FinePointe Whole Body Volume Sampling System (WBP system) was calibrated and validated, and the measured parameters (such as respiratory rate, tidal volume, etc.) were set up for use. After administering the appropriate dose of solvent or test substance to each group of animals, they were placed in the measurement container, and data collection began. The measurement period included both the acclimatization and measurement periods. After the measurement, the data for each indicator of the animals during that time period were obtained using the instrument software. The mean values ​​were calculated to obtain the average respiratory rate, average tidal volume, and other data for that time period. GraphPad Prism software was used for statistical analysis of the data to compare differences between groups and assess the effect of the test substance on mouse respiration.

[0254] 18. Rat rotarod test

[0255] Male SD rats (4-6 weeks old) purchased from Vital River Laboratory Animal Technology Co., Ltd. were acclimatized in an SPF-grade animal facility for 3-5 days. Before drug administration testing, the rats underwent rotarod acclimatization training. Rats were placed on a 6 cm diameter rotarod at a rotation speed of 15 rpm / min. Each training round lasted 120 seconds, with 4 rounds per day for 3 consecutive days. The rotarod was set every other day according to the acclimatization training program, with 120 seconds used as the cutoff value for the animal's latency on the rotarod. Animals with a latency of 120 seconds in all four rounds were selected for drug administration. The latency on the rotarod was measured after drug administration. Three consecutive tests were conducted, and the average value was obtained. The maximum possible percentage of efficacy (%MPE) was then calculated using the following formula: (Liquefied group latency on the rotarod - Drug administration group latency on the rotarod) / Liquefied group latency on the rotarod ≈ 100. GraphPad Prism software was used for statistical analysis of the data to compare differences between groups and assess the effect of the test substance on the rat's motor ability.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, (I) in, R is selected from H or CH3; at least one hydrogen atom in formula (I) is deuterated.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (II), (II) in, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 Each is independently selected from H and deuterium; R 22 Selected from CH3 and CD3; R 23 Selected from H, deuterium, CH3, and CD3; The conditions are: R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 At least one of them is selected from deuterium or CD3.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein, R 22 R 23 At least one of them is selected from CD3.

4. The compound according to claim 2 or 3, or a pharmaceutically acceptable salt thereof, wherein, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 At least one of them is selected from deuterium.

5. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following structures.

6. A pharmaceutical composition or pharmaceutical preparation comprising the compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient.

7. The pharmaceutical composition or pharmaceutical preparation according to claim 6, comprising 1-1500 mg of the compound according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof and a carrier and / or excipient.

8. Use of the compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, or the composition of claims 6-7, in the preparation of a medicament for the treatment / prevention of NOP and opioid receptor-mediated diseases.

9. The use as claimed in claim 8, wherein the NOP and opioid receptor-mediated diseases are selected from pain.

10. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, preferably 1-1500 mg, wherein the disease is preferably pain.

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