Deuterated fused ring compound, and preparation method therefor and use thereof

Abstract

Provided in the present invention is a deuterated fused ring compound. In particular, the present invention relates to a compound represented by general formula (II), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof. The present invention also relates to a pharmaceutical composition containing the compound, a preparation method therefor, and a method and use thereof for treating pain, especially pain related to opioid receptor activation. Substituents in general formula (II) are as defined in the description.

Description

A deuterated fused-ring compound, its preparation method and uses

[0001] This application claims priority to Chinese patent application CN202411624054.5 filed on November 14, 2024; Chinese patent application CN202510566922.7 filed on April 30, 2025; Chinese patent application CN202510782119.7 filed on June 12, 2025; Chinese patent application CN202510938927.8 filed on July 8, 2025; and Chinese patent application CN202511118818.8 filed on August 15, 2025, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of medicinal chemistry, specifically relating to a deuterated fused-ring compound and its preparation method, a pharmaceutical composition containing the compound, and its methods and uses in treating pain, especially pain associated with opioid receptor activation. Background Technology

[0003] International patent application WO2004043967A1 discloses a class of fused-ring compounds, including Cebranopadol. These compounds reportedly possess multiple mechanisms of action, activating opioid receptors (especially μ-opioid receptors, i.e., MOR) and / or orphanone receptors (nociceptin / orphanin FQ, i.e., NOP), thereby producing a broad-spectrum analgesic effect. Specifically, activation of opioid receptors effectively inhibits pain transmission, resulting in significant analgesia; activation of orphanone helps reduce addiction and tolerance.

[0004] Compared to traditional opioids, cerebranopadol is believed to have advantages in treating acute and chronic pain, such as cancer pain and neuropathic pain, especially in patients who are resistant to or do not respond well to opioids. Currently, cerebranopadol is still in Phase III clinical trials. Although it has good analgesic effects, some metabolites produced during its metabolism may cause adverse reactions such as nausea, vomiting, dizziness, and drowsiness, especially in sensitive patients. Therefore, further improving the analgesic activity and metabolic properties of cerebranopadol, such as achieving a better safety window and improved brain penetration, prolonging its half-life, reducing dosing frequency, and minimizing adverse reactions, has become a technically significant clinical challenge in this field. Summary of the Invention

[0005] This invention provides a deuterated fused-ring compound with improved analgesic activity, metabolic stability, and pharmacokinetic properties. This compound enhances analgesia by reducing the in vivo metabolic rate and prolonging the effective concentration time, exhibiting a superior safety window and brain penetration, while reducing the toxic side effects of metabolites, thereby improving patient tolerance. This compound is suitable for the long-term management of chronic pain such as cancer pain, neuropathic pain, osteoarthritis pain, fibromyalgia, and chronic low back pain, and is expected to significantly improve patients' quality of life and medication adherence.

[0006] This invention relates to a compound of formula (II), its stereoisomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of its stereoisomers.

[0007] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 11 R 12 R 13 R 21 R 22 R 23 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 Each is independently selected from H and D; and at least one of them is D.

[0008] In some embodiments, the compound represented by formula (II) is as shown in formula (II-A):

[0009] This invention relates to a compound of formula (II-1), its stereoisomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of its stereoisomers.

[0010] Among them, R6, R7, R8, R9, R 11 R 12 R 13 R 21 R 22 R 23 R 31 R 32 R 33 R 34 R 35R 36 R 37 R 38 R 41 R 42 R 43 and R 44 Each is independently selected from H and D.

[0011] In some implementation schemes, R6, R7, R8, R9, R 11 R 12 R 13 R 21 R 22 R 23 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 All are H.

[0012] In some embodiments, the compound represented by formula (II-1) is as shown in formula (II-1A):

[0013] On the other hand, the present invention relates to a compound represented by formula (II-2), its stereoisomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of its stereoisomers.

[0014] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 21 R 22 R 23 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 Each is independently selected from H and D.

[0015] In some implementation schemes, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 21 R 22 R23 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 All are H.

[0016] In some embodiments, the compound represented by formula (II-2) is as shown in formula (II-2A):

[0017] In some embodiments, the present invention relates to a compound of formula (II-2-1), its stereoisomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of its stereoisomers.

[0018] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 21 R 22 R 23 R 41 R 42 R 43 and R 44 Each is independently selected from H and D.

[0019] In some implementation schemes, R 21 R 22 and R 23 All are D, R1, R2, R3, R4, R5, R6, R7, R8, R 41 R 42 R 43 and R 44 Each is independently selected from H and D. In some implementations, R 21 R 22 R 23 R1, R2, R3, R4, and R5 are all D, R6, R7, R8, and R... 41 R 42 R 43 and R 44 Each is independently selected from H and D. In some implementations, R 21 R 22 R 23 R1, R2, R3, R4, R5, R 41 and R 42 All are D, R6, R7, R8, R 43 and R44 Each is independently selected from H and D. In some implementations, R 21 R 22 R 23 R1, R2, R3, R4, R5, R 43 and R 44 All are D, R6, R7, R8, R 41 and R 42 Each is independently selected from H and D. In some implementations, R 21 R 22 R 23 R1, R2, R3, R4, R5, R 41 R 42 R 43 and R 44 All are D, while R6, R7, and R8 are each independently selected from H and D. In some embodiments, R1, R2, R3, R4, R5, R6, R7, R8, R 21 R 22 R 23 R 41 R 42 R 43 and R 44 All are D.

[0020] In some implementations, R1, R2, R3, R4, and R5 are all D, and R6, R7, R8, and R... 21 R 22 R 23 R 41 R 42 R 43 and R 44 Each is independently selected from H and D. In some implementations, R1, R2, R3, R4, R5, R 41 and R 42 All are D, R6, R7, R8, R 21 R 22 R 23 R 43 and R 44 Each is independently selected from H and D. In some implementations, R1, R2, R3, R4, R5, R 43 and R 44 All are D, R6, R7, R8, R 21 R 22 R 23 R 41 and R 42 Each is independently selected from H and D. In some implementations, R1, R2, R3, R4, R5, R 41 R 42 R43 and R 44 All are D, R6, R7, R8, R 21 R 22 and R 23 Each is independently selected from H and D. In some implementations, R1, R2, R3, R4, R5, R6, R7, R8, R 41 R 42 R 43 and R 44 Both are D, R 21 R 22 and R 23 Each is independently selected from H and D.

[0021] In some implementation schemes, R 41 R 42 R 43 and R 44 All are D, R1, R2, R3, R4, R5, R6, R7, R8, R 21 R 22 and R 23 Each is independently selected from H and D. In some implementations, R 41 R 42 All are D, R1, R2, R3, R4, R5, R6, R7, R8, R 21 R 22 R 23 R 43 and R 44 Each is independently selected from H and D. In some implementations, R 43 R 44 All are D, R1, R2, R3, R4, R5, R6, R7, R8, R 21 R 22 R 23 R 41 and R 42 Each is independently selected from H and D.

[0022] In some implementations, R6, R7, and R8 are all D, and R1, R2, R3, R4, R5, and R... 21 R 22 R 23 R 41 R 42 R 43 and R 44 Each is independently selected from H and D.

[0023] In some implementation schemes, R1, R2, R3, R4, R5, R6, R7, R8, R 21 R 22 R23 R 41 R 42 R 43 and R 44 All are H. In some implementations, R 21 R 22 and R 23 All are D, R1, R2, R3, R4, R5, R6, R7, R8, R 41 R 42 R 43 and R 44 All are H. In some embodiments, the compound represented by formula (II-2-1) is as shown in formula (II-2A-1):

[0024] On the other hand, the present invention relates to a compound represented by formula (II-3), its stereoisomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of its stereoisomers.

[0025] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 Each is independently selected from H and D.

[0026] In some implementation schemes, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 All are H.

[0027] In some embodiments, the compound represented by formula (II-3) is as shown in formula (II-3A):

[0028] On the other hand, the present invention relates to a compound of formula (II-4), its stereoisomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of its stereoisomers.

[0029] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 11 R 12 R 13 R 21 R 22 R 23 R 31 R 32 R 33 R 34 R 35 R 36 R 37 and R 38 Each is independently selected from H and D.

[0030] In some implementation schemes, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 11 R 12 R 13 R 21 R 22 R 23 R 31 R 32 R 33 R 34 R 35 R 36 R 37 and R 38 All are H.

[0031] In some embodiments, the compound represented by formula (II-4) is as shown in formula (II-4A):

[0032] On the other hand, the present invention relates to a compound of formula (II-5), its stereoisomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of its stereoisomers.

[0033] Among them, R1, R2, R3, R4, R5, R9, R 11 R 12 R 13 R 21 R 22 R 23 R 31 R 32 R 33 R 34 R35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 Each is independently selected from H and D.

[0034] In some implementation schemes, R1, R2, R3, R4, R5, R9, R 11 R 12 R 13 R 21 R 22 R 23 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 All are H.

[0035] In some embodiments, the compound represented by formula (II-5) is as shown in formula (II-5A):

[0036] On the other hand, the present invention relates to a compound of formula (II-6), its stereoisomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of its stereoisomers.

[0037] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 11 R 12 R 13 R 21 R 22 R 23 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 Each is independently selected from H and D.

[0038] In some implementation schemes, R1, R2, R3, R4, R5, R6, R7, R8, R 11 R 12 R 13 R 21 R 22 R 23 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 All are H.

[0039] In some embodiments, the compound represented by formula (II-6) is as shown in formula (II-6A):

[0040] On the other hand, the present invention relates to a compound of formula (II-7), its stereoisomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of its stereoisomers.

[0041] Among them, R1, R2, R3, R4, R5, R 11 R 12 R 13 R 21 R 22 R 23 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 Each is independently selected from H and D.

[0042] In some implementation schemes, R1, R2, R3, R4, R5, R 11 R 12 R 13 R 21 R 22 R 23 R 31 R 32 R 33 R 34R 35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 All are H.

[0043] In some embodiments, the compound represented by formula (II-7) is as shown in formula (II-7A):

[0044] On the other hand, the present invention relates to a compound of formula (II-8), its stereoisomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of its stereoisomers.

[0045] Among them, R1, R2, R3, R4, R5, R 11 R 12 R 13 R 21 R 22 R 23 R 31 R 32 R 33 R 34 R 35 R 36 R 37 and R 38 Each is independently selected from H and D.

[0046] In some implementation schemes, R1, R2, R3, R4, R5, R 11 R 12 R 13 R 21 R 22 R 23 R 31 R 32 R 33 R 34 R 35 R 36 R 37 and R 38 All are H.

[0047] In some embodiments, the compound represented by formula (II-8) is as shown in formula (II-8A).

[0048] On the other hand, the present invention relates to a compound of formula (III-1), its stereoisomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of its stereoisomers.

[0049] R1, R2, R3, R4 and R5 are each independently selected from hydrogen and deuterium; and at least one of R1, R2, R3, R4 and R5 is a deuterium atom.

[0050] In some embodiments, one of R1, R2, R3, R4, and R5 is selected from deuterium. In some embodiments, two of R1, R2, R3, R4, and R5 are selected from deuterium. In some embodiments, three of R1, R2, R3, R4, and R5 are selected from deuterium. In some embodiments, four of R1, R2, R3, R4, and R5 are selected from deuterium. In some embodiments, all of R1, R2, R3, R4, and R5 are deuterium.

[0051] In some embodiments, the compound represented by formula (III-1) is as shown in formula (III-1A).

[0052] On the other hand, the present invention relates to a compound of formula (III-2), its stereoisomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of its stereoisomers.

[0053] Among them, R 11 R 12 and R 13 Each is independently selected from hydrogen and deuterium; and R 11 R 12 and R 13 At least one of them is a deuterium atom.

[0054] In some implementation schemes, R 11 R 12 and R 13 One of them is selected from deuterium. In some implementations, R 11 R 12 and R 13 Two of them are selected from deuterium. In some implementations, R 11 R 12 and R 13 All are deuterium.

[0055] In some embodiments, the compound represented by formula (III-2) is as shown in formula (III-2A).

[0056] On the other hand, the present invention relates to a compound represented by formula (III-3), its stereoisomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of its stereoisomers.

[0057] Among them, R 11 R 12 R 13 R 21 R 22 and R 23 Each is independently selected from hydrogen and deuterium; and R 11 R 12 R 13 R 21 R 22 and R 23 At least one of them is deuterium.

[0058] In some implementation schemes, R 11 R 12 R 13 R 21 R 22 and R 23 One of them is selected from deuterium; R 11 R 12 R 13 R 21 R 22 and R 23 Two of them are selected from deuterium; R 11 R 12 R 13 R 21 R 22 and R 23 Three of them are selected from deuterium; R 11 R 12 R 13 R 21 R 22 and R 23 Four of them are selected from deuterium; R 11 R 12 R 13 R 21 R 22 and R 23 Five of them are selected from deuterium; or R 11 R 12 R 13 R 21 R 22 and R 23 All are deuterium. In some implementations, R 11 R 12 and R 13 Both are D, and R 21 R 22 and R 23 All are H.

[0059] In some embodiments, the compound represented by formula (III-3) is as shown in formula (III-3A).

[0060] On the other hand, the present invention relates to a compound represented by formula (III-4), its stereoisomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of its stereoisomers.

[0061] Among them, R 41 R 42 R 43 and R 44 Each is independently selected from hydrogen and deuterium; and R 41 R 42 R 43 and R 44 At least one of them is deuterium.

[0062] In some implementation schemes, R 41 R 42 R 43 and R 44 One of them is selected from deuterium. In some implementations, R 41 R 42 R 43 and R 44 Two of them are selected from deuterium. In some implementations, R 41 R 42 R 43 and R 44 Three of them are selected from deuterium. In some implementations, R 41 R 42 R 43 and R 44 All four of them are deuterium.

[0063] In some embodiments, the compound represented by formula (III-4) is as shown in formula (III-4A).

[0064] On the other hand, the present invention relates to a compound of formula (III-5), its stereoisomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of its stereoisomers.

[0065] R6, R7, and R8 are each independently selected from hydrogen and deuterium; and at least one of R6, R7, and R8 is deuterium.

[0066] In some embodiments, one of R6, R7, and R8 is selected from deuterium. In some embodiments, R6, R7, and R8... 84 Two of the elements are selected from deuterium. In some implementations, all three of R6, R7, and R8 are deuterium.

[0067] In some embodiments, the compound represented by formula (III-5) is as shown in formula (III-5A).

[0068] On the other hand, the present invention relates to a compound represented by formula (III-6), its stereoisomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of its stereoisomers.

[0069] R9 is selected from hydrogen and deuterium.

[0070] In some embodiments, the compound represented by formula (III-6) is as shown in formula (III-6A).

[0071] On the other hand, the present invention relates to a compound of formula (III-7), its stereoisomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of its stereoisomers.

[0072] Among them, R6, R7, R8 and R9 are each independently selected from hydrogen and deuterium; and at least one of R6, R7, R8 and R9 is a deuterium atom.

[0073] In some embodiments, one of R6, R7, R8, and R9 is selected from deuterium. In some embodiments, two of R6, R7, R8, and R9 are selected from deuterium. In some embodiments, three of R6, R7, R8, and R9 are selected from deuterium. In some embodiments, all four of R6, R7, R8, and R9 are deuterium.

[0074] In some embodiments, the compound represented by formula (III-7) is as shown in formula (III-7A).

[0075] On the other hand, the present invention relates to a compound represented by formula (III-8), its stereoisomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of its stereoisomers.

[0076] Among them, R 41 R 42 R 43 R 44 R6, R7, R8, and R9 are each independently selected from hydrogen and deuterium; and R 41 R 42 R 43 R 44 At least one of R6, R7, R8, and R9 is a deuterium atom;

[0077] In some embodiments, the compound represented by formula (III-8) is as shown in formula (III-8A).

[0078] It should be understood that the above-mentioned formula (II) can be further shown as formulas (II-1), (II-2), (II-2-1), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (III), (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), (III-8), etc.

[0079] In some embodiments, the compounds described above in this invention are specifically selected from:

[0080] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of formula (II) as described in the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0081] On the other hand, the present invention provides a method for preparing a compound of formula (II), its stereoisomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of its stereoisomers, comprising the following scheme and steps:

[0082] Option A:

[0083] Compound (II-A) and compound (II-B) are reacted via an electrophilic substitution reaction to yield compound (II-C);

[0084] Compound (II-C) and compound (II-D) undergo an addition-elimination-cyclization reaction to yield compound (II-E);

[0085] Compound (II-E) is reduced to give compound (II-F);

[0086] Compounds of formula (II-F) and (compounds) and compounds Compound (II) is obtained by nucleophilic substitution reaction; wherein LG1 and LG2 are leaving groups, such as halogens (e.g., -Cl, -Br or -I); preferably, LG1 and LG2 are -Cl;

[0087] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11R 12 R 13 R 21 R 22 R 23 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 The definition is the same as before.

[0088] Option B:

[0089] Compound (II-A) and compound (II-B) are reacted via an electrophilic substitution reaction to yield compound (II-C);

[0090] Compound (II-C) and compound (II-D) undergo an addition-elimination-cyclization reaction to yield compound (II-E), which is then subjected to an amino protection reaction to yield compound (II-E'). In compound (II-E'), Poc is an amino protecting group, which includes, but is not limited to, Boc (tert-butyloxycarbonyl), Cbz (benzyloxycarbonyl), Fmoc (fluorenylmethoxycarbonyl), SEM (2-(trimethylsilyl)ethoxycarbonyl), Alloc (allyloxycarbonyl), Ts (p-toluenesulfonyl), and Tr (triphenylmethyl). Preferably, the amino protecting group is Boc (tert-butyloxycarbonyl) or SEM (2-(trimethylsilyl)ethoxycarbonyl).

[0091] Compound (II-E') is reduced to give compound (II-F');

[0092] Compounds of formula (II-F') and (compounds) and compounds The compound of formula (II-G') is obtained by nucleophilic substitution reaction; wherein LG1 and LG2 are leaving groups, such as halogens (e.g., -Cl, -Br or -I); preferably, LG1 and LG2 are -Cl;

[0093] Compound (II-G') is deprotected to obtain compound (II), in which R9 is -H in compound (II) of scheme B;

[0094] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11R 12 R 13 R 21 R 22 R 23 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 The definition is the same as before.

[0095] Option C:

[0096] Compound (II-H) is hydrolyzed by reacting it with compound (II-I) using a Grignard reagent to yield compound (II-J);

[0097] Compounds of formula (II-J) and (II-D) are cyclized via addition-elimination reactions to give compound (II);

[0098] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 21 R 22 R 23 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 The definition is the same as before.

[0099] On the other hand, the present invention provides the use of compounds of formula (II) described above, their stereoisomers, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of their stereoisomers; or pharmaceutical compositions containing them in the preparation of medicaments for treating pain disorders or disorders associated with opioid receptor activation. In some embodiments, the pain disorders or disorders include, but are not limited to, cancer pain, chronic pain, neuropathic pain, osteoarthritis pain, fibromyalgia, and low back pain.

[0100] On the other hand, the present invention provides a method for treating a subject suffering from a disease or disorder of pain associated with opioid receptor activation, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (II) described above, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition containing the thereof. In some embodiments, the disease or disorder of pain associated with opioid receptor activation includes, but is not limited to, cancer pain, chronic pain, neuropathic pain, osteoarthritis pain, fibromyalgia, and low back pain.

[0101] Beneficial technical effects

[0102] The inventors have surprisingly discovered that by deuterating Cebranopadol, particularly by deuterating a specific amount at a specific site, compounds with excellent analgesic activity, safety, and pharmacokinetic characteristics such as a safe window and brain penetration can be obtained. Compared to Cebranopadol, the compounds of this invention exhibit at least comparable or even superior agonistic activity against MOR and NOP receptors, and superior binding activity against MOR and / or κ-opioid receptors (i.e., KOR). They possess stronger pharmacodynamic activity, longer duration of action, and are expected to have superior analgesic effects. Furthermore, the compounds of this invention demonstrate higher safety in terms of acute toxicity, a larger safe window, and effectively prolonged half-life in terms of pharmacokinetics, resulting in superior brain penetration. In summary, the compounds of this invention are expected to significantly improve patients' quality of life and medication adherence, providing pain patients with a more effective, longer-acting, and safer option.

[0103] Terminology Definition

[0104] Unless otherwise stated, the following terms have the meanings described below. Other terms are defined elsewhere throughout this specification.

[0105] The term "D" or "deuterium" refers to the 2H-isotope of atomic hydrogen. The natural abundance of both isotopes of hydrogen is approximately 99.98% protium (¹H) and 0.02% deuterium (²H). Therefore, an arbitrary hydrogen atom in a molecule synthesized using conventional reagents has an average of approximately 0.02% deuterium at each hydrogen atom position. Thus, those skilled in the art will understand that when referring to chemical structures with CD bonds or "D" atoms as described herein, this means that the said positions of the molecule are enriched with a natural deuterium abundance exceeding 0.02%. Therefore, an atom marked "D" indicates that the position contains at least 0.1%, 1%, 10%, or a higher proportion of deuterium, preferably at least 6.3%, at least 12.5%, at least 18.8%, at least 25.0%, at least 31.3%, at least 37.5%, at least 43.8%, at least 50.0%, at least 56.3%, at least 62.5%, at least 68.8%, at least 75.0%, at least 81.3%, at least 87.5%, at least 93.8%, 100.0%, or any two of the aforementioned values ​​of deuterium.

[0106] In this invention, isotopic abundance is typically defined as the ratio of the number of atoms substituted by an isotope to the total number of atoms that can be substituted. This calculation is a simple percentage: Abundance = (Number of deuterium atoms) / (Total number of hydrogen atoms before deuteration) × 100%. For example, if there are 19 hydrogen atom positions replacing 1 deuterium atom, the abundance calculation formula is: 1 / 19 ≈ 5.3%. This abundance calculation method is used to describe the degree to which deuterium replaces the original hydrogen atoms, so as to clearly indicate the proportion of different deuteration sites.

[0107] In the embodiments of the present invention, hydrogen isotopes directly bonded to C or N atoms in the compound structure are all considered to be "H" unless specifically specified as "H" or "D". For example, in the structure of Example 1, In this compound, apart from the five specifically designated "D" atoms, all other atoms directly bonded to either C or N atoms are "H".

[0108] The compounds disclosed in this invention may contain one or more chiral carbon atoms and thus may exist in different isomeric forms, such as enantiomers, diastereomers, or mixtures thereof (e.g., racemic mixtures or diastereomer mixtures). The asymmetric center may be any isomer having (R)-, (S)-, or (R,S)- configurations. This invention includes all optical isomers and mixtures thereof (e.g., racemic mixtures or diastereomer mixtures). Therefore, the compounds of this invention may be racemic mixtures or exist primarily in pure or substantially pure isomeric forms, for example, with an enantiomer / diastereomer (“ee”) ratio greater than 70%, preferably greater than 80%, more preferably greater than 90%, and most preferably greater than 95%. The purification of these isomers and the separation of mixtures thereof can be achieved by standard techniques known in the art, such as column chromatography, preparative TLC, preparative HPLC, simulated moving bed chromatography, etc.

[0109] "Subjects" preferably refers to humans, but also includes other mammals such as equines, pigs, bovines, felines, and canines.

[0110] "Treatment" or "management" includes the management of a disease state in a mammal and includes the following: (a) preventing the occurrence of the disease state in a mammal, especially in a mammal that is susceptible to the disease state but has not yet been diagnosed with the disease; (b) suppressing the disease state, such as preventing its development; and / or (c) alleviating the disease state, such as causing the disease state to regress until a desired endpoint is reached. Treatment also includes alleviating the symptoms of the disease (e.g., reducing pain or discomfort), which may directly or indirectly affect the disease (e.g., affecting its etiology, transmission, expression, etc.).

[0111] This invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salt" refers to a derivative of the compounds described herein, wherein the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral acid or organic acid salts of basic residues (such as amines); basic or organic salts of acidic residues (such as carboxylic acids); etc. Pharmaceutically acceptable salts of this invention include, for example, non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of this invention can be synthesized from parent compounds containing basic or acidic moieties using conventional chemical methods. Typically, the salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof; typically, a non-aqueous medium such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (ACN) is preferred. The list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), which are incorporated herein by reference in their entirety.

[0112] The term “pharmaceutically acceptable” is used herein to refer to compounds, substances, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0113] "Pharmaceutically acceptable carrier" or "pharmaceutical acceptable excipient" refers to a non-toxic, biologically tolerable, and otherwise biologically suitable substance, such as an inert substance, that is added to or otherwise used as a medium, carrier, or diluent to facilitate the administration of a drug to a subject. Examples of carriers or excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0114] "Pharmaceutical composition" refers to one or more compounds described in this invention, or a mixture of their stereoisomers, tautomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents. "Pharmaceutical composition" may be in a form suitable for oral administration (e.g., tablets, lozenges, hard or soft capsules, aqueous or oil suspensions, emulsions, dispersible powders or granules, syrups or elixirs), may be for injection (e.g., aqueous or oil suspensions, or emulsions), may be for topical application (e.g., creams, ointments, gels, or aqueous or oil solutions or suspensions), may be for inhalation (e.g., fine powders or liquid aerosols), may be administered by blowing (e.g., fine powders), or may be administered parenterally (e.g., sterile aqueous-oil solutions for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration, or as suppositories for rectal administration).

[0115] A medically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof means an amount sufficient to effectively treat the pain conditions mentioned herein, slow their progression, and / or alleviate symptoms associated with the condition. The amount of active ingredient required to produce a single dosage form in combination with one or more excipients varies depending on the individual being treated and the specific route of administration. For example, formulations for oral administration to humans typically contain, for example, 0.1 mg to 1000 mg of the compound of the present invention or a pharmaceutically acceptable salt thereof, and a suitable and appropriate amount of excipients, the amount of which may vary from about 5% to about 98% of the total weight of the composition. The dosage of the compound of the present invention for therapeutic or preventative purposes varies according to well-known medical principles, depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0116] The compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising such compounds, may be administered to a subject by any convenient method of administration, whether systemic / peripheral or local (i.e., at the site of desired action). Methods of administration include, but are not limited to: oral (e.g., by ingestion); sublingual; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or blowing therapy, such as by aerosols, e.g., through the mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by a pessary); parenteral, such as by injection; and by implantation in a reservoir or pouch, such as subcutaneously or intramuscularly.

[0117] The method typically involves administering a therapeutically effective amount of the compound of the invention to a subject. The therapeutically effective amount of the combination of target compounds may vary depending on the intended application (in vitro or in vivo) or the subject being treated and the nature of the disease, such as the subject's weight and age, the severity of the disease, the route of administration, etc., which can be readily determined by those skilled in the art. The term also applies to doses that will induce a specific response in target cells, such as reduced proliferation or downregulation of target proteins. The specific dose will vary depending on the specific compound selected, the administration regimen followed, whether it is administered in combination with other compounds, the time of administration, the tissue to which it is administered, and the physical delivery system on which it is carried.

[0118] Unless otherwise stated herein or clearly contradicted by the context, all methods described herein may be performed in any suitable order. The use of any and all examples or exemplary language (such as “such as”) provided herein is intended only to better illustrate the invention and does not constitute a limitation on the scope of the otherwise claimed invention. Detailed Implementation

[0119] The compounds of this invention can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein. Examples outlining specific synthetic routes and the following general schemes are intended to provide guidance to ordinary synthetic chemists, who will easily understand that solvents, concentrations, reagents, protecting groups, the order of synthetic steps, time, temperature, etc., can be modified as needed within the skill and judgment of a person of ordinary skill.

[0120] In this invention, "room temperature" and "rt" generally refer to temperature in the art, such as reaction temperature, which refers to the temperature of the surrounding environment during the reaction operation, for example, about 20°C to about 30°C.

[0121] Example

[0122] The following examples will better illustrate the invention. Unless otherwise expressly stated, all parts and percentages are by weight, and all temperatures are in degrees Celsius. The examples use abbreviations in the following table:

[0123] Example 1

[0124] (1r,4r)-6'-fluoro-N,N-dimethyl-4-(phenyl-d5)-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine

[0125] AgNO2 (9.29 g, 0.058 mol, 2 eq.) was added fractionally to a solution of deuterated benzyl bromide (5 g, 0.029 mol, 1 eq.) in Et₂O (300 mL). The reaction mixture was stirred overnight at 35 °C, poured into water (500 mL), and extracted three times with EA (3 × 200 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 1-1 (1.2 g, yield 29.7%).

[0126] Cs₂CO₃ (5.7 g, 17.5 mmol, 2 eq.), KI (436 mg, 2.63 mmol, 0.3 eq.), and 1,5-dichloropentan-3-one (1.4 g, 8.75 mmol, 1 eq.) were added to a DMF (20 mL) solution of compound 1-1 (1.2 g, 8.75 mmol, 1 eq.). The reaction mixture was reacted under a nitrogen atmosphere at 50 °C for 3 h. Water (100 mL) was then added, and the mixture was extracted three times with EA (3 × 100 mL). The organic phase was concentrated, and the residue was purified by silica gel column chromatography to give compound 1-2 (220 mg, yield 10.5%).

[0127] 5-Fluorordol (294 mg, 1 mmol, 1 eq.) and TFA (225 mg, 1.2 mmol, 1, 2 eq.) were added to a DCM (6 mL) solution of compounds 1-2 (220 mg, 1 mmol, 1 eq.). The reactants were reacted at 50 °C for 12 h, then concentrated, and the residue was purified by silica gel column chromatography to give compounds 1-3 (80 mg, yield 25.4%).

[0128] To a MeOH solution of compounds 1-3 (80 mg, 0.208 mmol, 1 eq.) in 10 mL of water, Zn (547 mg, 8.32 mmol, 40 eq.) was added, followed by dropwise addition of HCOOH (382 mg, 8.32 mmol, 40 eq.). The reaction mixture was reacted overnight at 50 °C and then concentrated under reduced pressure to give crude products of compounds 1-4 (70 mg). These crude products did not require further purification and could be used directly in the next reaction step.

[0129] To a MeOH solution (3 mL) containing 70 mg of the crude products of compounds 1-4, 0.1 mL of formaldehyde solution (10%), 0.02 mL of glacial acetic acid, and NaBH3CN (37 mg, 0.593 mmol, 3 eq.) were added. The reaction mixture was reacted at room temperature for 2 h, quenched with water (10 mL), and extracted three times with DCM (3 × 10 mL). The organic phase was concentrated, and the residue was purified by silica gel column chromatography to give compound 1 (32 mg, yield 42.4%). Compound 1 was further purified by silica gel column chromatography (dichloromethane:methanol = 20:1), collecting the weaker polar fraction to give compound 1-A. MS (ESI, m / z): 384.2 (M+H) + .

[0130] 1 H NMR (400MHz, CDCl3) δ10.91(s,1H),7.46(dd,J=8.8,4.5Hz,1H),7.11(dd,J=9.6,2.5Hz,1H),6.91(td,J=9.1,2.5 Hz,1H),3.94(t,J=5.3Hz,2H),2.97–2.85(m,2H),2.82–2.67(m,10H),2.48–2.36(m,2H),2.14(d,J=14.9Hz,2H).

[0131] Example 2

[0132] (1r,4r)-6'-fluoro-N-methyl-N-(methyl-d3)-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine

[0133] Following a similar method to that used in Example 1 to prepare compound 1-1, compound 2-1 (3.0 g, yield 30.8%) was synthesized using benzyl bromide (12 g, 0.071 mol, 1 eq) and AgNO2 (21.8 g, 0.14 mol, 2 eq) as reactants.

[0134] Following a similar method to that used for compounds 1-2 in Example 1, compound 2-2 (640 mg, yield 13.9%) was synthesized using compound 2-1 (3 g, 0.021 mol, 1 eq) and 1,5-dichloropentan-3-one (3.23 g, 0.021 mol, 1 eq) as reactants.

[0135] Following a similar method to that used for compounds 1-3 in Example 1, compounds 2-2 (640 mg, 2.9 mmol, 1 eq) and 5-fluorotryptol (520 mg, 2.9 mmol, 1 eq) were reacted to synthesize compounds 2-3 (145 mg, 13.1% yield).

[0136] At 0 °C, NaH (15 mg, 0.57 mmol, 1.5 eq.) and SEMCl (100 mg, 0.57 mmol, 1.5 eq.) were added sequentially to a DMF solution (10 mL) of compound 2-3 (145 mg, 0.38 mmol, 1 eq.). The reaction mixture was stirred at room temperature for 8 hours and then concentrated. The resulting residue was purified by silica gel column chromatography to give compound 2-4 (145 mg, yield 73.6%).

[0137] Zn (728 mg, 11.2 mmol, 40 eq) was added to a MeOH (10 mL) solution of compounds 2-4 (145 mg, 0.28 mmol, 1 eq.), followed by the dropwise addition of HCOOH (380 mg, 11.2 mmol, 40 eq). After reacting overnight at 50 °C, the resulting mixture was filtered and concentrated to give a crude product of compounds 2-5 (130 mg). This crude product did not require further purification and could be used directly in the next reaction.

[0138] CD3I (70 mg, 0.44 mmol, 1 eq) and potassium carbonate (60 mg, 0.44 mmol, 2 eq) were added sequentially to a DMF (5 mL) solution of compound 2-5 (130 mg, 0.22 mmol, 1 eq). The reaction mixture was reacted at 40 °C for 8 h, quenched with water (20 mL), and extracted three times (3 × 20 mL) with DCM. The organic phase was concentrated, and the residue was purified by silica gel column chromatography to give compound 2-6 (45 mg, 42% yield).

[0139] To a DMF (3 mL) solution of compound 2-6 (45 mg, 0.092 mmol, 1 eq), 0.1 mL of formaldehyde solution (10%), 0.02 mL of glacial acetic acid, and NaBH3CN (30 mg, 0.46 mmol, 5 eq) were added sequentially. The reaction mixture was reacted at room temperature for 2 h, then quenched with water and extracted with DCM. The organic phase was concentrated, and the residue was purified by silica gel column chromatography to give compound 2-7 (40 mg, 86% yield).

[0140] A solution of trifluoroacetic acid (1 mL) was added to a solution of compound 2-7 (40 mg, 0.079 mmol, 1 eq) in DCM (5 mL). After stirring at room temperature for 2 h, ammonia was added. The reaction mixture was stirred overnight at room temperature and extracted three times with DCM (3 × 15 mL). The organic phase was concentrated, and the residue was purified by silica gel column chromatography to give compound 2 (26 mg, yield 78%). Compound 2 was further purified by silica gel column chromatography (dichloromethane:methanol = 20:1), and the weaker polar fraction was collected to give compound 2-A. MS (ESI, m / z): 382.2 (M+H) + .

[0141] 1 H NMR (400MHz, CDCl3) δ10.93(s,1H),7.67–7.52(m,5H),7.47(dd,J=8.8,4.5Hz,1H),7.11(dd,J=9.6,2.5Hz,1H),6.91(td,J=9.2,2 .6Hz,1H),3.93(t,J=5.3Hz,2H),2.88(t,J=13.7Hz,2H),2.81–2.56(m,7H),2.40(td,J=14.6,3.9Hz,2H),2.13(d,J=14.9Hz,2H).

[0142] Example 3

[0143] (1r,4r)-6'-fluoro-N,N-bis(methyl-d3)-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine

[0144] Following a similar method to that used in the preparation of compounds 2-6 in Example 2, compounds 2-5 (55 mg, 0.107 mmol, 1 eq) were reacted with deuterated iodomethane (35 mg, 0.22 mmol, 2 eq) to give compound 3-1 (55 mg, 80% yield).

[0145] Trifluoroacetic acid (1 mL) was added to a DCM (5 mL) solution of compound 3-1 (55 mg, 0.107 mmol, 1 eq). After stirring at room temperature for 2 h, ammonia was added. The reaction mixture was allowed to react overnight at room temperature, and extracted three times with DCM (3 × 15 mL). The organic phase was concentrated, and the residue was purified by silica gel column chromatography to give compound 3 (32 mg, 78% yield). Compound 3 was further purified by silica gel column chromatography (dichloromethane:methanol = 20:1), and the weaker polar fraction was collected to give compound 3-A.

[0146] MS(ESI, m / z): 385.2(M+H) + .

[0147] 1 H NMR (400MHz, CDCl3) δ10.71(s,1H),7.77–7.50(m,5H),7.46(dd,J=8.8,4.4Hz,1H),7.11(dd,J=9.7,2.5Hz,1H),6.91(ddd,J=9.5,8. 8, 2.5Hz, 1H), 3.94 (t, J = 5.3Hz, 2H), 2.90 (t, J = 14.4Hz, 2H), 2.83–2.60 (m, 4H), 2.41 (td, J = 14.5, 3.9Hz, 2H), 2.14 (d, J = 14.9Hz, 2H).

[0148] Example 4

[0149] (1r,4r)-6'-fluoro-N,N-bis(methyl-d3)-4-phenyl-4',9'-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine

[0150] At room temperature, 1-fluoro-4-nitrobenzene-2,3,5,6-d4 (10 g, 0.069 mol) was dissolved in methanol (200 mL), and Pd / C (0.2 g) was added. The reaction was terminated at room temperature under a hydrogen atmosphere for 16 hours. After the reaction was completed, the mixture was filtered, and the filtrate was evaporated to dryness to give compound 4-1 (9 g, unpurified, yield 102.03%).

[0151] At 0°C, 21 mL of 35% sodium nitrite solution was added to a 6N hydrochloric acid solution of compound 4-1 (9 g, 0.078 mol), and the mixture was stirred at this temperature for 0.5 hours. Then, a 2M stannous chloride / 6N hydrochloric acid solution was added, and the reaction mixture was stirred at this temperature for 3 hours. A solid precipitated out; this was then filtered, and the solid was dried to give compound 4-2 (11 g, yield 97.31%).

[0152] Compound 4-2 (1000 mg, 7.68 mmol) was dissolved in 4% sulfuric acid (10 mL) and DMAc (10 mL) at room temperature and heated to 100 °C. 2,3-Dihydrofuran (807.76 mg, 7.5 mmol) was added dropwise to the reaction mixture, and the reaction was maintained at this temperature for 3 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were backwashed with water and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated to dryness, and purified by column chromatography (petroleum ether / ethyl acetate = 6 / 4) to give compound 4-3 (300 mg, yield 20.36%).

[0153] 1,4-Dioxaspiro[4.5]decane-8-one (5.5 g, 0.0352 mol) was dissolved in MeOH / H2O (2 / 1, 150 mL) at room temperature. Bis(methyl-d3)amine hydrochloride (9.25 g, 0.1056 mol) and potassium cyanide (5.73 g, 0.088 mol) were added, and the reaction was terminated after 16 hours at room temperature. After the reaction was complete, the mixture was extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 4-4 (4.83 g, yield 57.10%), a colorless oil.

[0154] Compound 4-4 (2.55 g, 0.0118 mol) was dissolved in 50 mL of THF at 0 °C. A tetrahydrofuran solution of magnesium phenyl bromide (35.4 mL, 1 mol / L) was added, and the reaction was terminated at room temperature for 16 hours. After the reaction was completed, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound 4-5 (1.48 g, yield 42.37%) as a pale yellow solid.

[0155] At 0 °C, 20 mL of 7.5 M hydrochloric acid solution was added to compound 4-5 (1.48 g, 0.0055 mol), and the reaction was terminated at room temperature for 16 hours. After the reaction was completed, the pH was adjusted to 7-8 with 6 M NaOH solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound 4-6 (0.79 g, yield 58.18%).

[0156] Compound 4-6 (150 mg, 0.6716 mmol) was dissolved in DCM (5 mL) under nitrogen protection at -50 °C. Compound 4-3 (122 mg, 0.6716 mmol) and TMSOTf (179 mg, 0.80592 mmol) were added to the solution. The reaction mixture was gradually brought to room temperature and reacted for 16 hours. After the reaction, the pH was adjusted to 7-8 with 6 M NaOH solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound 4 (102.05 mg, yield 38.58%). Compound 4 was further purified by silica gel column chromatography (dichloromethane:methanol = 20:1), and the weaker polar fraction was collected to give compound 4-A.

[0157] MS(ESI, m / z): 388.2(M+H) + .

[0158] 1 HNMR(400MHz,DMSO)δ10.97(s,1H),7.37(d,J=4.0Hz,4H),7.29–7.23(m,1H),3.88(t,J=5 .2Hz,2H),2.64(t,J=5.2Hz,2H),2.57–2.52(m,2H),2.30–2.22(m,2H),1.80–1.72(m,4H).

[0159] Example 5

[0160] (1r,4r)-6'-fluoro-N-methyl-N-(methyl-d3)-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine-5',7',8'-d3

[0161] At 0 °C, 60% NaH (9.08 g, 0.227 mol) was slowly added to a DMF solution (150 mL) of tert-butyl methylcarbamate (15 g, 0.114 mol), and the mixture was stirred for 0.5 h. Then, a CD3I solution (24.68 g, 0.17 mol) was added, and the reaction mixture was stirred at room temperature for 12 h. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 5-1 (12 g, yield 63.79%).

[0162] Compound 5-1 (12 g, 0.08 mol) was dissolved in 4 M HCl EtOAc (100 mL) at 0 °C, and the reaction was terminated at room temperature for 16 hours. After the reaction was completed, the solution was concentrated to give compound 5-2 (6 g, yield 79.48%).

[0163] 1,4-Dioxolane[4.5]dec-8-one (2.7 g, 17.28 mmol) was dissolved in MeOH / H2O (2 / 1, 60 mL) at room temperature. Compound 5-2 (5.85 g, 69.15 mmol) and potassium cyanide (2.25 g, 34.58 mmol) were added to the solution, and the reaction was terminated at room temperature for 16 hours. After the reaction was completed, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 5-3 (3 g, yield 73.22%).

[0164] Compound 5-3 (3 g, 14.06 mmol) was dissolved in 30 mL of THF at 0 °C. A tetrahydrofuran solution of magnesium phenyl bromide (42.2 mL, 1 mol / L) was added, and the reaction was terminated at room temperature for 16 hours. After the reaction was completed, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give compound 5-4 (1.5 g, yield 36.3%).

[0165] At 0 °C, 20 mL of 7.5 M hydrochloric acid solution was added to compound 5-4 (1.5 g, 5.67 mmol), and the reaction was terminated at room temperature for 16 hours. After the reaction was completed, the pH was adjusted to 7-8 with 8 M NaOH solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give compound 5-5 (0.7 g, yield 50.4%).

[0166] Compound 5-5 (217.65 mg, 0.99 mmol) was dissolved in DCM (5 mL) under nitrogen protection at -50 °C. Compound 4-3 (200 mg, 1.09 mmol) and TMSOTf (365.93 mg, 1.65 mmol) were added to the solution. The reaction mixture was gradually brought to room temperature and reacted for 16 hours. After the reaction, the pH was adjusted to 7-8 with 1 M NaOH solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound 5 (88.58 mg, yield 18.89%). Compound 5 was further purified by silica gel column chromatography (dichloromethane:methanol = 20:1), and the weaker polar fraction was collected to give compound 5-A.

[0167] MS(ESI, m / z): 385.2(M+H) + .

[0168] 1 H NMR (400MHz, DMSO) δ10.96 (s, 1H), 7.37 (d, J = 4.3Hz, 4H), 7.26 (dd, J = 8.4, 4.1Hz, 1H), 3.88 (t, J = 5.4Hz, 2 H), 2.64 (t, J = 5.4Hz, 2H), 2.55-2.54 (m, 2H), 2.26 (t, J = 13.8Hz, 2H), 2.04 (s, 3H), 1.76 (t, J = 12.5Hz, 4H).

[0169] Example 6

[0170] (1r,4r)-6'-fluoro-N-methyl-N-(methyl-d3)-4-(phenyl-d5)-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine

[0171] At room temperature, Mg (2.48 g, 102 mmol) and one I2 particle were dissolved in THF (10 mL). 41 mL of a THF solution of 1-bromobenzene-2,3,4,5,6-d5 (8.26 g, 51 mmol) was added, and the reaction was terminated at 70 °C for 2 hours. After the reaction was complete, the temperature was lowered to room temperature. Under nitrogen protection at 0 °C, the reaction mixture was added dropwise to a THF solution of compound 5-3 (2.2 g, 10.2 mmol) in 20 mL, and the reaction was carried out at room temperature for 18 hours. After the reaction was complete, the reaction was quenched with NH4Cl aqueous solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give compound 6-1 (1.08 g, yield 37%).

[0172] Compound 6-1 (1.08 g, 4.0 mmol) was dissolved in 20 mL of MeOH at 0 °C, and concentrated hydrochloric acid (20 mL) was added. The reaction was terminated at room temperature for 16 hours. After the reaction was completed, the pH was adjusted to 9 with 6 M NaOH solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give compound 6-2 (0.48 g, yield 50%).

[0173] Compound 6-2 (150 mg, 0.67 mmol) and 5-fluorotryptol (119 mg, 0.67 mmol) were added to a three-necked flask, purged with nitrogen, and then DCM (7 mL) was added. The mixture was cooled to -60 °C, and TMSOTf (222 mg, 1.0 mmol) was added. The reaction mixture was gradually brought to room temperature and reacted for 16 hours. After the reaction, the pH was adjusted to 7-8 with 6 M NaOH solution, and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound 6 (142.16 mg, 54% yield). Compound 6 was further purified by silica gel column chromatography (dichloromethane:methanol = 20:1), and the weaker polar fraction was collected to give compound 6-A.

[0174] MS(ESI, m / z): 387.3(M+H) + .

[0175] 1HNMR (400MHz, DMSO) δ10.98 (s, 1H), 7.35-7.26 (m, 1H), 7.18-7.08 (m, 1H), 6.92-6.81 (m, 1H), 3.87 (t, J = 5. 2Hz,2H),2.64(t,J=5.2Hz,2H),2.59-2.51(m,2H),2.35-2.17(m,2H),2.03(s,3H),1.76(t,J=12.0Hz,4H).

[0176] Example 7

[0177] (1r,4r)-6'-fluoro-N,N-bis(methyl-d3)-4-(phenyl-d5)-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine

[0178] At room temperature, Mg (2.48 g, 102 mmol) and one I2 particle were dissolved in THF (10 mL). 41 mL of a THF solution of 1-bromobenzene-2,3,4,5,6-d5 (8.26 g, 51 mmol) was added, and the reaction was terminated at 70 °C for 2 hours. After the reaction was complete, the temperature was lowered to room temperature. Under nitrogen protection at 0 °C, the reaction mixture was added dropwise to a THF solution of compound 4-4 (2.2 g, 10.2 mmol) in 20 mL, and the reaction was carried out at room temperature for 18 hours. After the reaction was complete, the reaction was quenched with NH4Cl aqueous solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give compound 7-1 (1.03 g, yield 35%).

[0179] Compound 7-1 (1.03 g, 3.8 mmol) was dissolved in 20 mL of MeOH at 0 °C, and concentrated hydrochloric acid (20 mL) was added. The reaction was terminated at room temperature for 16 hours. After the reaction was completed, the pH was adjusted to 9 with 6 M NaOH solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give compound 7-2 (0.49 g, yield 53%).

[0180] Compound 7-2 (150 mg, 0.66 mmol) and 5-fluorotryptol (118 mg, 0.66 mmol) were added to a three-necked flask, purged with nitrogen, and then DCM (7 mL) was added. The mixture was cooled to -60 °C, and TMSOTf (219 mg, 0.99 mmol) was added. The reaction mixture was gradually brought to room temperature and reacted for 16 hours. After the reaction, the pH was adjusted to 7-8 with 6 M NaOH solution, and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound 7 (150.90 mg, yield 58%). Compound 7 was further purified by silica gel column chromatography (dichloromethane:methanol = 20:1), and the weaker polar fraction was collected to give compound 7-A.

[0181] MS(ESI, m / z): 390.3(M+H) + .

[0182] 1 HNMR(400MHz,DMSO)δ10.98(s,1H),7.33-7.26(m,1H),7.19-7.08(m,1H),6.91-6.81(m,1H),3.88(t ,J=5.2Hz,2H),2.64(t,J=5.2Hz,2H),2.59-2.51(m,2H),2.34-2.18(m,2H),1.76(t,J=12.0Hz,4H).

[0183] Example 8

[0184] (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine-5',7',8'-d3

[0185] Under nitrogen protection, compounds 4-3 (240 mg, 1.3 mmol) and 4-(dimethylamino)-4-phenylcyclohexane-1-one (240 mg, 1.1 mmol) were dissolved in 5 mL of dichloromethane and cooled to 0 °C. TMSOTf (245 mg, 1.1 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with sodium bicarbonate aqueous solution, extracted with DCM, dried the organic layer, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 8 (60 mg, yield 14%). Compound 8 was further purified by silica gel column chromatography (dichloromethane:methanol = 20:1), and the weaker polar fraction was collected to obtain compound 8-A.

[0186] MS(ESI, m / z): 382.2(M+H)+ .

[0187] 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),7.37(d,J=4.2Hz,4H),7.26(dt,J=8.4,4.0Hz,1H),3.88(t,J=5.6 Hz, 2H), 2.64 (t, J = 5.2 Hz, 2H), 2.55 (s, 2H), 2.26 (t, J = 13.6 Hz, 2H), 2.04 (s, 6H), 1.76 (t, J = 12.2 Hz, 4H).

[0188] Example 9

[0189] (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine-3',3'-d2

[0190] Acetyl chloride (1.63 g) was added to a solution of 5-fluoroindole-3-acetic acid (2.0 g, 10.4 mmol) in MeOH (30 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum, and the residue dissolved in EtOAc. The residue was washed with aqueous Na₂CO₃ solution and brine, and then dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (eluent:PE:EtOAc = 7:3) to give compound 9-1 (2.10 g, yield 92.31%).

[0191] Compound 9-1 (500 mg, 2.41 mmol) was dissolved in tetrahydrofuran (10 mL), and LiAlD4 (203 mg, 4.83 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, 0.3 mL of water was slowly added under ice bath conditions, followed by 0.3 mL of 15% sodium hydroxide solution. After adding 1 mL of water, the mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was collected and concentrated under reduced pressure, and purified by silica gel column chromatography to give compound 9-2 (410 mg, 94% yield).

[0192] Under argon protection, compound 9-2 (182 mg, 1 mmol) and 4-(dimethylamino)-4-phenylcyclohexane-1-one (229 mg, 1.05 mmol) were added to anhydrous dichloromethane (7 mL). The mixture was cooled to -30 °C, and trimethylsilyl trifluoromethanesulfonate (335 mg, 1.50 mmol) was rapidly added. The mixture was slowly heated to room temperature and stirred at room temperature for 16 hours. For post-treatment, 1 N sodium hydroxide solution (10 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The organic phase was separated, and the remaining aqueous phase was extracted with dichloromethane (3 × 20 mL). The combined organic phases were washed with water and dried over sodium sulfate. The crude product was purified by silica gel column chromatography to give compound 9 (120 mg, yield 31.5%). Compound 9 was further purified by silica gel column chromatography (dichloromethane:methanol = 20:1), and the weaker polar fraction was collected to give compound 9-A.

[0193] MS(ESI, m / z): 381.2(M+H) + .

[0194] 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),7.37(d,J=3.5Hz,4H),7.29(td,J=9.8,9.2,4.4Hz,2H),7.13(d,J=8. 7Hz,1H),6.89-6.83(m,1H),2.66-2.54(m,4H),2.26(t,J=13.5Hz,2H),2.05(s,6H),1.76(t,J=12.8Hz,4H).

[0195] 19 FNMR (376MHz, DMSO-d6) δ = -125.59 (s, 1F).

[0196] Example 10

[0197] (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine-4',4'-d2

[0198] 2-(5-fluoro-1H-indol-3-yl)methyl acetate (200 mg, 0.97 mmol) was dissolved in CDCl3 (5 mL), and 1,5,7-triazabicyclo[4.4.0]decen-5-ene (13 mg, 0.10 mmol) was added. The mixture was stirred at room temperature for 12 hours. The solvent was evaporated to dryness and then redissolved in CDCl3 (5 mL), and stirred for 5 hours. After the reaction was complete, the solvent was evaporated to dryness and purified by silica gel column chromatography to give compound 10-1 (190 mg, 94% yield).

[0199] Compound 10⁻¹ (190 mg, 0.90 mmol) was dissolved in tetrahydrofuran (3 mL), and LiAlH₄ (70 mg, 1.79 mmol) was added at 0°C, followed by stirring at room temperature for 2 hours. After the reaction was complete, 0.3 mL of water was slowly added under ice bath conditions, followed by 0.3 mL of 15% sodium hydroxide solution, and then 1 mL of water was added. The mixture was then filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was collected and concentrated under reduced pressure, and purified by silica gel column chromatography to give compound 10⁻² (140 mg, 86% yield).

[0200] Compound 10-2 (140 mg, 0.77 mmol) and 4-(dimethylamino)-4-phenylcyclohexane-1-one (168 mg, 0.77 mmol) were dissolved in dichloromethane (6 mL). TMSOTf (180 mg, 0.81 mmol) was rapidly added under nitrogen protection, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, a 15% aqueous sodium hydroxide solution was slowly added to the reaction mixture, causing precipitation. The mixture was filtered, and the filter cake was washed with water. The filter cake was dried to give compound 10 (150 mg, 51% yield). Compound 10 was further purified by silica gel column chromatography (dichloromethane:methanol = 20:1), collecting the weaker polar fraction to give compound 10-A.

[0201] MS(ESI, m / z): 381.2(M+H) + .

[0202] 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),7.37(d,J=4.3Hz,4H),7.30(dd,J=8.8,4.7Hz,1H),7.28–7.23(m,1H),7.13(dd,J=9 .9,2.6Hz,1H),6.85(td,J=9.2,2.6Hz,1H),3.86(s,2H),2.55(s,2H),2.31–2.21(m,2H),2.05(s,6H),1.81–1.71(m,4H).

[0203] 19FNMR (376MHz, DMSO-d6) δ = -125.59 (s, 1F).

[0204] Example 11

[0205] (1r,4r)-6'-fluoro-N-methyl-N-(methyl-d3)-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine-3',3'-d2

[0206] Under nitrogen protection at -60°C, compounds 9-2 (200 mg, 1.1 mmol) and 5-5 (243.17 mg, 1.1 mmol) were dissolved in 10 mL of DCM. TMSOTf (367.96 mg, 1.66 mmol) was added dropwise, and the reaction mixture was gradually brought to room temperature and reacted for 16 hours. After the reaction, the pH was adjusted to 7-8 with 1 M NaOH solution, followed by extraction with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound 11 (201.53 mg, yield 45.23%). Compound 11 was further purified by silica gel column chromatography (DCM / MeOH = 97:3), and the weaker polar fraction was collected to give compound 11-A.

[0207] LCMS:[M+H] + =384.2.

[0208] 1 H NMR (400MHz, DMSO) δ10.97(s,1H),7.37(d,J=4.2Hz,4H),7.28(ddd,J=18.4,8.5,4.3Hz,2H),7.13(dd,J=9.9,2.3Hz,1H),6.86 (td,J=9.2,2.4Hz,1H),2.62(s,2H),2.53(d,J=14.8Hz,2H),2.27(dd,J=19.3,8.6Hz,2H),2.04(s,3H),1.76(t,J=12.9Hz,4H).

[0209] Example 12

[0210] (1r,4r)-6'-fluoro-N,N-bis(methyl-d3)-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine-3',3'-d2

[0211] Under nitrogen protection at -60°C, compounds 9-2 (200 mg, 1.1 mmol) and 4-6 (246.5 mg, 1.1 mmol) were dissolved in 10 mL of DCM. TMSOTf (367.96 mg, 1.66 mmol) was added dropwise, and the reaction mixture was gradually brought to room temperature and reacted for 16 hours. After the reaction, the pH was adjusted to 7-8 with 1 M NaOH solution, followed by extraction with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound 12 (259.62 mg, yield 57.81%). Compound 12 was further purified by silica gel column chromatography (DCM / MeOH = 97:3), and the weaker polar fraction was collected to give compound 12-A.

[0212] LCMS:[M+H] + =387.2.

[0213] 1 H NMR (400MHz, DMSO) δ10.97(s,1H),7.36(d,J=4.0Hz,4H),7.34–7.23(m,2H),7.13(d,J=9.8Hz,1H),6.86(d d,J=12.7,5.6Hz,1H),2.62(s,2H),2.53(d,J=9.1Hz,2H),2.26(t,J=13.9Hz,2H),1.76(t,J=12.8Hz,4H).

[0214] Example 13

[0215] (1r,4r)-6'-fluoro-N,N-bis(methyl-d3)-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine-4',4'-d2

[0216] Under nitrogen protection at -60°C, compounds 10-2 (150 mg, 0.83 mmol) and 4-6 (184.88 mg, 0.83 mmol) were dissolved in 10 mL of DCM. TMSOTf (275.98 mg, 1.24 mmol) was added dropwise, and the reaction mixture was gradually brought to room temperature and reacted for 16 hours. After the reaction, the pH was adjusted to 7-8 with 1 M NaOH solution, followed by extraction with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound 13 (279.95 mg, yield 83.11%). Compound 13 was further purified by silica gel column chromatography (DCM / MeOH = 97:3), and the weaker polar fraction was collected to give compound 13-A.

[0217] LCMS:[M+H] + =387.2.

[0218] 1 H NMR (400MHz, DMSO) δ10.97(s,1H),7.37(d,J=4.2Hz,4H),7.32–7.24(m,2H),7.13(dd,J=9.9,2.3Hz,1H),6.86( td,J=9.4,2.5Hz,1H),3.87(d,J=4.7Hz,2H),2.68–2.52(m,2H),2.26(t,J=13.7Hz,2H),1.76(t,J=12.4Hz,4H).

[0219] Example 14

[0220] (1r,4r)-6'-fluoro-N-methyl-N-(methyl-d3)-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine-4',4'-d2

[0221] Under nitrogen protection at -60°C, compounds 10-2 (140 mg, 0.77 mmol) and 5-5 (170.22 mg, 0.77 mmol) were dissolved in 10 mL of DCM. TMSOTf (257.57 mg, 1.16 mmol) was added dropwise, and the reaction mixture was gradually brought to room temperature and reacted for 16 hours. After the reaction, the pH was adjusted to 7-8 with 1 M NaOH solution, followed by extraction with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound 14 (121.26 mg, yield 38.88%). Compound 14 was further purified by silica gel column chromatography (DCM / MeOH = 97:3), and the weaker polar fraction was collected to give compound 14-A.

[0222] LCMS:[M+H] + =384.2.

[0223] 1 H NMR (400MHz, DMSO) δ10.97(s,1H),7.37(d,J=4.1Hz,4H),7.32–7.23(m,2H),7.19–7.07(m,1H),6.86(dd,J=12.8,5.5 Hz,1H),3.87(d,J=4.9Hz,2H),2.69–2.54(m,2H),2.28(dd,J=27.4,12.8Hz,2H),2.04(s,3H),1.76(t,J=12.5Hz,4H).

[0224] Example 15

[0225] (1r,4r)-6'-fluoro-N-methyl-N-(methyl-d3)-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine-3',3',4',4'-d4

[0226] At room temperature, LAH (0.6 g, 0.014 g) was added to a THF (20 mL) solution of compound 10-1 (2 g, 0.01 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated. It was diluted with water, extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (EA / PE = 1 / 1) to give compound 15-1 (1.4 g, 75.94% yield) as a yellow solid.

[0227] Under nitrogen protection at -60°C, compounds 15-1 (150 mg, 0.82 mmol) and 5-5 (180.38 mg, 0.82 mmol) were dissolved in 10 mL of DCM. TMSOTf (272.94 mg, 1.23 mmol) was added dropwise, and the reaction mixture was gradually brought to room temperature and reacted for 16 hours. After the reaction, the pH was adjusted to 7-8 with 1 M NaOH solution, followed by extraction with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound 15 (152.52 mg, yield 45.9%). Compound 15 was further purified by silica gel column chromatography (DCM / MeOH = 97:3), and the weaker polar fraction was collected to give compound 15-A.

[0228] LCMS:[M+H] + =386.2.

[0229] 1 H NMR (400MHz, DMSO) δ10.97(s,1H),7.37(d,J=4.2Hz,4H),7.33–7.23(m,2H),7.13(dd,J=9.9,2.4Hz,1H),6.86(t d,J=9.4,2.5Hz,1H),2.57(dd,J=31.4,11.1Hz,2H),2.26(t,J=13.8Hz,2H),2.04(s,3H),1.76(t,J=13.0Hz,4H).

[0230] Example 16

[0231] (1r,4r)-6'-fluoro-N,N-bis(methyl-d3)-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine-3',3',4',4'-d4

[0232] Under nitrogen protection at -60°C, compounds 15-1 (150 mg, 0.82 mmol) and 4-6 (182.85 mg, 0.82 mmol) were dissolved in 10 mL of DCM. TMSOTf (272.94 mg, 1.23 mmol) was added dropwise, and the reaction mixture was gradually brought to room temperature and reacted for 16 hours. After the reaction, the pH was adjusted to 7-8 with 1 M NaOH solution, followed by extraction with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound 16 (150.27 mg, yield 44.88%). Compound 16 was further purified by silica gel column chromatography (DCM / MeOH = 97:3), and the weaker polar fraction was collected to give compound 16-A.

[0233] LCMS:[M+H] + =389.2.

[0234] 1 H NMR(400MHz,DMSO)δ10.98(s,1H),7.37(d,J=4.2Hz,4H),7.33–7.23(m,2H),7.13(dd,J=9.9,2.2Hz, 1H), 6.86 (td, J=9.3, 2.4Hz, 1H), 2.68–2.51 (m, 2H), 2.26 (t, J=14.1Hz, 2H), 1.76 (t, J=12.8Hz, 4H).

[0235] Example 17

[0236] (1r,4r)-6'-fluoro-N-methyl-N-(methyl-d3)-4-(phenyl-d5)-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine-4',4'-d2

[0237] Under nitrogen protection at -60°C, compounds 10-2 (150 mg, 0.83 mmol) and 6-2 (186.55 mg, 0.83 mmol) were dissolved in 10 mL of DCM. TMSOTf (275.98 mg, 1.24 mmol) was added dropwise, and the reaction mixture was gradually brought to room temperature and reacted for 16 hours. After the reaction, the pH was adjusted to 7-8 with 1 M NaOH solution, followed by extraction with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound 17 (130.55 mg, yield 38.56%). Compound 17 was further purified by silica gel column chromatography (DCM / MeOH = 97:3), and the weaker polar fraction was collected to give compound 17-A.

[0238] LCMS:[M+H] + =389.2.

[0239] 1 H NMR (400MHz, DMSO) δ10.98(s,1H),7.30(dd,J=8.7,4.6Hz,1H),7.13(dd,J=9.9,2.3Hz,1H),6.86(td,J=9.4,2. 4Hz, 1H), 3.87 (d, J = 4.8Hz, 2H), 2.67–2.53 (m, 2H), 2.26 (t, J = 13.7Hz, 2H), 2.04 (s, 3H), 1.76 (t, J = 12.8Hz, 4H).

[0240] Example 18

[0241] (1r,4r)-6'-fluoro-N-methyl-N-(methyl-d3)-4-(phenyl-d5)-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine-3',3'-d2

[0242] Under nitrogen protection at -40°C, compounds 6-2 (150 mg, 0.666 mmol) and 9-2 (144.73 mg, 0.799 mmol) were dissolved in 10 mL of DCM. TMSOTf (221.64 mg, 0.998 mmol) was added dropwise, and the reaction mixture was gradually brought to room temperature and reacted for 16 hours. After the reaction, the pH was adjusted to 7-8 with 1 M NaOH solution, followed by extraction with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound 18 (117.87 mg, yield 44.67%). Compound 18 was further purified by silica gel column chromatography (DCM / MeOH = 97:3), and the weaker polar fraction was collected to give compound 18-A.

[0243] LCMS:[M+H] + =389.2.

[0244] 1 H NMR (400MHz, DMSO) δ10.97(s,1H),7.30(dd,J=8.6,4.6Hz,1H),7.12(d,J=10.1Hz,1H),6.95–6.7 4(m,1H),2.62(s,2H),2.57-2.55(m,2H),2.26(t,J=13.7Hz,2H),2.06(s,3H),1.79-1.72(m,4H).

[0245] Example 19

[0246] (1r,4r)-6'-fluoro-N,N-bis(methyl-d3)-4-(phenyl-d5)-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine-3',3'-d2

[0247] Compounds 7-2 (180 mg, 0.788 mmol) and 9-2 (171.39 mg, 0.946 mmol) were dissolved in 10 mL of DCM under nitrogen protection at -40 °C. TMSOTf (262.47 mg, 1.182 mmol) was added dropwise, and the reaction mixture was gradually brought to room temperature and reacted for 16 hours. After the reaction, the pH was adjusted to 7-8 with 1 M NaOH solution, followed by extraction with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound 19 (168.2 mg, yield 23.41%). Compound 19 was further purified by silica gel column chromatography (DCM / MeOH = 20:1), and the weaker polar fraction was collected to give compound 19-A.

[0248] LCMS:[M+H] + =392.3.

[0249] 1HNMR (400MHz, DMSO) δ10.97(s,1H),7.30(dd,J=8.7,4.6Hz,1H),7.13(dd,J=9.8,2.3Hz,1H ),6.91–6.81(m,1H),2.62(s,2H),2.56-2.54(m,2H),2.32-2.22(m,2H),1.79-1.72(m,4H).

[0250] Example 20

[0251] (1r,4r)-6'-fluoro-N,N-bis(methyl-d3)-4-(phenyl-d5)-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine-4',4'-d2

[0252] Under nitrogen protection at -60°C, compounds 10-2 (150 mg, 0.83 mmol) and 7-2 (189.05 mg, 0.83 mmol) were dissolved in 10 mL of DCM. TMSOTf (275.98 mg, 1.24 mmol) was added dropwise, and the reaction mixture was gradually brought to room temperature and reacted for 16 hours. After the reaction, the pH was adjusted to 7-8 with 1 M NaOH solution, followed by extraction with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound 20 (195.36 mg, yield 57.26%). Compound 20 was further purified by silica gel column chromatography (DCM / MeOH = 97:3), collecting the weaker polar fraction to obtain compound 20-A.

[0253] LCMS:[M+H] + =392.3.

[0254] 1 H NMR (400MHz, DMSO) δ10.98(s,1H),7.30(dd,J=8.7,4.6Hz,1H),7.13(dd,J=9.9,2.5Hz,1H),6.86(td,J=9 .4, 2.5Hz, 1H), 3.87 (d, J = 4.7Hz, 2H), 2.66–2.52 (m, 2H), 2.26 (t, J = 13.9Hz, 2H), 1.76 (t, J = 12.4Hz, 4H).

[0255] Example 21

[0256] (1r,4r)-6'-fluoro-N-methyl-N-(methyl-d3)-4-(phenyl-d5)-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine-5',7',8'-d3

[0257] Compounds 4-3 (180 mg, 0.99 mmol) and 6-2 (222.63 mg, 0.99 mmol) were dissolved in 10 mL of DCM under nitrogen protection at -60 °C. TMSOTf (329.35 mg, 1.48 mmol) was added dropwise, and the reaction mixture was gradually brought to room temperature and reacted for 16 hours. After the reaction, the pH was adjusted to 7-8 with 1 M NaOH solution, followed by extraction with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound 21 (143.76 mg, yield 35.86%). Compound 21 was further purified by silica gel column chromatography (DCM / MeOH = 97:3), and the weaker polar fraction was collected to give compound 21-A.

[0258] LCMS:[M+H] + =390.2.

[0259] 1 H NMR (400MHz, DMSO) δ10.97 (s, 1H), 3.88 (t, J = 5.3Hz, 2H), 2.67–2.52 (m, 4H), 2.26 (t, J = 13.9Hz, 2H), 2.04 (s, 3H), 1.76 (t, J = 12.4Hz, 4H).

[0260] Example 22

[0261] (1r,4r)-6'-fluoro-N,N-bis(methyl-d3)-4-(phenyl-d5)-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine-5',7',8'-d3

[0262] Under nitrogen protection at -60°C, compounds 4-3 (220 mg, 1.21 mmol) and 7-2 (275.74 mg, 1.21 mmol) were dissolved in 10 mL of DCM, and TMSOTf (402.53 mg, 1.81 mmol) was added dropwise. The reaction system was gradually raised to room temperature and reacted for 16 hours. After the reaction, the pH was adjusted to 7-8 with 1 M NaOH solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound 22 (145.46 mg, yield 29.15%). Compound 22 was further purified by silica gel column chromatography (DCM / MeOH = 97:3), and the weaker polar fraction was collected to give compound 22-A.

[0263] LCMS:[M+H] + =393.3.

[0264] 1 H NMR (400MHz, DMSO) δ10.97 (s, 1H), 3.88 (t, J = 5.4Hz, 2H), 2.67–2.53 (m, 4H), 2.28 (dd, J = 26.1, 11.8Hz, 2H), 1.76 (t, J = 12.3Hz, 4H).

[0265] Example 23

[0266] (1r,4r)-6'-fluoro-N,N-dimethyl-4-(phenyl-d5)-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine-4',4'-d2

[0267] Under nitrogen protection at -60°C, compound 10-2 (180 mg, 1 mmol) and 4-(dimethylamino)-4-(phenyl-d5)cyclohexane-1-one (prepared by a similar method to compound 7-2 in Example 7) (220.87 mg, 1 mmol) were dissolved in DCM (10 mL), and TMSOTf (331.19 mg, 1.5 mmol) was added dropwise. The reaction system was gradually raised to room temperature and reacted for 16 hours. After the reaction, the pH was adjusted to 7-8 with 1M NaOH solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound 23 (216.03 mg, yield 53.58%). Compound 23 was further purified by silica gel column chromatography (DCM / MeOH = 97:3), and the weaker polar fraction was collected to give compound 23-A.

[0268] LCMS:[M+H] + =386.2.

[0269] 1 H NMR (400MHz, DMSO) δ10.98(s,1H),7.30(dd,J=8.7,4.6Hz,1H),7.13(dd,J=9.9,2.4Hz,1 H),6.86(m,1H),3.87(m,2H),2.66–2.52(m,2H),2.26(m,2H),2.04(s,6H),1.76(m,4H).

[0270] Example 24

[0271] (1r,4r)-6'-fluoro-N,N-dimethyl-4-(phenyl-d5)-44',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine-3',3'-d2

[0272] Under nitrogen protection at 25°C, 200 mg (0.8995 mmol) of 4-(dimethylamino)-4-(phenyl-d5)cyclohexane-1-one and 9-2 (195.59 mg, 1.079 mmol) were dissolved in 10 mL of DCM, and TMSOTf (299.88 mg, 1.349 mmol) was added dropwise. The reaction was carried out at room temperature for 16 hours. After the reaction, the pH was adjusted to 7-8 with 1 M NaOH solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound 24 (183.2 mg, yield 51.92%). Compound 24 was further purified by silica gel column chromatography (DCM / MeOH = 20:1), and the weaker polar fraction was collected to give compound 24-A.

[0273] LCMS:[M+H] + =386.2.

[0274] 1 H NMR (400MHz, DMSO) δ10.97(s,1H),7.30(dd,J=8.7,4.6Hz,1H),7.13(dd,J=9.9,2.2Hz,1H),6.90 –6.81(m,1H),2.62(s,2H),2.55(s,2H),2.26(t,J=13.8Hz,2H),2.05(s,6H),1.79-1.72(m,4H).

[0275] Example 25

[0276] (1r,4r)-6'-fluoro-N-methyl-N-(methyl-d3)-4-(phenyl-d5)-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine-3',3',4',4'-d4

[0277] Under nitrogen protection at -60°C, compounds 15-1 (185 mg, 1 mmol) and 6-2 (227.54 mg, 1 mmol) were dissolved in 10 mL of DCM, and TMSOTf (336.62 mg, 1.5 mmol) was added dropwise. The reaction system was gradually raised to room temperature and reacted for 16 hours. After the reaction, the pH was adjusted to 7-8 with 1 M NaOH solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound 25 (163.94 mg, yield 39.5%). Compound 25 was further purified by silica gel column chromatography (DCM / MeOH = 97:3), and the weaker polar fraction was collected to give compound 25-A.

[0278] LCMS:[M+H] + =391.3.

[0279] 1 H NMR (400MHz, DMSO) δ10.97(s,1H),7.30(m,1H),7.13(m,1H),6.86(m,1H),2.68–2.52(m,2H),2.33–2.21(m,2H),2.04(s,3H),1.76(m,4H).

[0280] Example 26

[0281] (1r,4r)-6'-fluoro-N,N-bis(methyl-d3)-4-(phenyl-d5)-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indole]-4-amine-3',3',4',4'-d4

[0282] Under nitrogen protection at -60°C, compounds 15-1 (180.98 mg, 0.98 mmol) and 7-2 (221.39 mg, 0.98 mmol) were dissolved in 10 mL of DCM, and TMSOTf (327.52 mg, 1.47 mmol) was added dropwise. The reaction system was gradually raised to room temperature and reacted for 16 hours. After the reaction, the pH was adjusted to 7-8 with 1 M NaOH solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give compound 26 (152.55 mg, yield 37.48%). Compound 26 was further purified by silica gel column chromatography (DCM / MeOH = 97:3), and the weaker polar fraction was collected to give compound 26-A.

[0283] LCMS:[M+H]+ =394.3.

[0284] 1 H NMR(400MHz,DMSO)δ10.97(s,1H),7.30(dd,J=8.7,4.6Hz,1H),7.13(dd,J=9.9,2.5Hz,1H), 6.90–6.81(m,1H),2.61–2.52(m,2H),2.27(dd,J=18.9,9.0Hz,2H),1.76(t,J=12.8Hz,4H).

[0285] Using similar or improved methods described above, and with corresponding deuterated raw materials as reactants, the following compounds were synthesized:

[0286] The chemical structure of the reference compound Cebranopadol is as follows:

[0287] Prepared according to the method of Example 24 in International Patent Document WO2004043967A1.

[0288] Biological test examples

[0289] Test Example 1: Opioid Receptor Agonistaltic Activity - Cell Function Test

[0290] (1) Experimental materials

[0291] Table 1-1 Experimental Materials, Reagents and Instruments

[0292] (2) Experimental methods

[0293] Preparation of (1x Stimulation) buffer:

[0294] Dilute the 5x Stimulation buffer from the Cisbio cAMP-Gi kit with ddH2O at a ratio of 1:4 to obtain a (1x Stimulation) buffer (add 0.5 mM IBMX).

[0295] Preparation of the test solution:

[0296] Each analyte was prepared into a 5 mM stock solution using DMSO, and then serially diluted to 10 different concentrations at a factor of 3.16 using a gradient dilution method. Finally, the stock solution was diluted with 1x Stimulation buffer to prepare the analyte solution.

[0297] Preparation of cell suspension:

[0298] Digest CHO-OPRK1 / CHO-Mu / CHO-OPRD1 cells, wash with culture medium, centrifuge (1000 rpm) for 5 minutes, and discard the supernatant. Add 3 mL of PBS, mix well, and centrifuge again (1000 rpm) for 5 minutes, discarding the supernatant. Finally, resuspend the cells in 1x Stimulation buffer, adjust the cell density, and obtain a cell suspension.

[0299] Test method:

[0300] Activation mode: Cell suspension (5 μL / well, approximately 3000 cells / well) and test solutions of various concentrations (4 μL / well) were added sequentially to 96-well plates and incubated at 37°C for 20 minutes; 1 μL of Forskolin solution was added, and after gentle shaking, the plate was incubated at 37°C for 45 minutes.

[0301] Add the detection reagents cAMP-d2 and Anti-cAMP cryptate (5 μL / well), and let the 96-well plate stand at room temperature for 60 minutes.

[0302] The effects of the compound on opioid receptor agonists were determined using a PE Envision multi-functional microplate reader. Based on the effect values ​​at different concentration test points of the compound sample, GraphPad Prism software was used to fit the curves of the compound's agonistic effect on opioid receptors, and the EC50 was calculated. 50 Numerical value.

[0303] (3) Experimental Results

[0304] Table 1-2 Results of the test on the NOP and opioid receptor agonist activity of the compounds of the present invention EC 50 (nM)

[0305] (4) Experimental Conclusion

[0306] As shown in Tables 1-2, compared to Sibopardo, the representative compounds of this invention have at least comparable agonistic activity against NOP and MOR receptors.

[0307] Test Example 2: Mouse Hot Plate Test

[0308] (1) Experimental materials

[0309] Table 2-1 Solvent Information

[0310] Table 2-2 Information on experimental animals

[0311] Table 2-3 Experimental Instrument Information

[0312] (2) Experimental methods

[0313] SPF-grade male mice, weighing between 22-28g, were placed at an ambient temperature of approximately 25℃. A hot plate temperature of 55℃ was set, and the maximum pain threshold was set to 60s. The time from placement to licking the hind paw or jumping was recorded as the pain threshold. All mice were first tested for their baseline pain threshold; a baseline pain threshold of 5-30s was considered acceptable, and mice that did not meet the standard were culled. Acceptable mice were randomly divided into three groups according to weight: a negative control group and three dosage groups (low, medium, and high) for each compound, with 8-10 animals in each group. Each treatment group received an intravenous injection of the test compound (0.1ml / 10g), and the pain threshold was measured at 0.5, 2, 4, 6, and 22 hours post-treatment. Experimental data are expressed as mean ± standard deviation (Mean ± SD). Paired t-tests were used for self-comparison, with P < 0.05 considered statistically significant. If effective, the ED was calculated using GraphPad Prism 8 software with a non-linear fitting method. 50 Calculate the maximum posterior analgesic effect (MPE%) using the formula below.

[0314] Maximum analgesic effect (MPE%) = (Post-drug pain threshold - Baseline pain threshold) / (60 - Baseline pain threshold) × 100%

[0315] (3) Experimental Results

[0316] Table 2-4 Results of the hot plate test in mice

[0317] " / " indicates that it was not measured;

[0318] (4) Experimental Conclusion

[0319] As shown in Tables 2-4, compared to Sibopardo, the representative compounds of this invention, MED and ED... 50 And / or the maximum effective value is increased by more than 2 times, exhibiting superior analgesic activity on mouse hot plate.

[0320] Test Example 3: Acute Toxicity Test in Mice

[0321] (1) Experimental materials

[0322] Table 3-1 Solvent Information

[0323] Table 3-2 Information on experimental animals

[0324] Table 3-3 Experimental Instrument Information

[0325] (2) Experimental methods

[0326] For intravenous administration to mice, an acute toxicity test was first conducted on one mouse at a dose of 10 mL / kg, and the mortality rate after administration was recorded. If no mortality occurred at a dose of 10 mL / kg, the dose was increased to 12.5 mL / kg for subsequent mice; if mortality occurred at a dose of 10 mL / kg, the dose was decreased to 8 mL / kg for subsequent mice. LD50 was calculated using SPSS software and the probability unit method. 50 Then through LD 50 / ED 50 The therapeutic index of the compounds was calculated to compare the safety windows between the compounds.

[0327] (4) Experimental Results

[0328] Table 3-4 Results of Acute Toxicity Tests in Mice

[0329] (4) Experimental Conclusion

[0330] As shown in Tables 3-4, the representative compound of this invention has a therapeutic index that is at least about 1 times higher than that of cibopardo, and has a superior safety window for acute toxicity in mice.

[0331] Test Example 4: Rat Pharmacokinetic Study

[0332] (1) Experimental materials

[0333] Table 4-1 Solvent Information

[0334] Table 4-2 Information on Laboratory Animals

[0335] Table 4-3 Experimental Instrument Information

[0336] (2) Experimental methods

[0337] Rat pharmacokinetic (PK) assay: SD rats were administered the target compound at a dose of 0.03 mg / kg (based on free bases) via tail vein injection. Blood samples of 0.3 mL were collected from the jugular vein of rats before administration and at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, and 10 h after administration. The whole blood samples were centrifuged at 4000 rpm for 10 min to separate plasma. The plasma concentrations of the target compound at different time points were determined using LC-MS / MS, and pharmacokinetic parameters were calculated using WinNonlin 8.0 software.

[0338] Brain tissue sample determination: 5 min after drug administration, 0.3 mL of blood was collected from the jugular vein of rats. The whole blood sample was centrifuged at 4000 r / min for 10 min to separate plasma. Then, the rats were anesthetized with isoflurane, the heart was exposed by thoracotomy, the perfusion needle was inserted into the apex of the heart, the right atrial appendage was cut open, and a sufficient volume of physiological saline was perfused. Finally, the brain tissue was dissected, the surface moisture was blotted with filter paper, weighed, and homogenized with an appropriate amount of physiological saline (1:4, w:v) to prepare a brain tissue homogenate. The drug concentration in plasma and brain tissue at different time points was measured using LC-MS / IMIS, and the brain-blood ratio (brain permeation parameter) was calculated.

[0339] (3) Experimental Results

[0340] Table 4-4. Results of rat PK with brain penetration test " / " indicates that it was not measured;

[0341] (4) Experimental Conclusion

[0342] As shown in Table 4-4, the representative compound of this invention has a half-life that is more than twice longer than that of Sibopardo, and a brain penetration rate that is more than 30% higher, resulting in a superior brain penetration effect.

[0343] All publicly available documents, patents, patent applications, and published patent applications used in this document are incorporated herein by reference in their entirety. Although the invention has been described in detail by way of example for clarity of understanding, various obvious changes and modifications will be apparent to those skilled in the art. Therefore, the related descriptions and embodiments of the invention should not be construed as limiting the scope of the invention.

Claims

1. A compound represented by Formula (II), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R 11 R 12 R 13 R 21 R 22 R 23 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 Each is independently selected from H and D; And the condition is that R1, R2, R3, R4, R5, R6, R7, R8, R9, R 11 R 12 R 13 R 21 R 22 R 23 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 At least one of them is D.

2. The compound represented by Formula (II) according to claim 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, characterized by, It satisfies one or more of the following conditions: (1) Any one of R1, R2, R3, R4 and R5 is D, or any two are D, or any three are D, or any four are D, or all five are D; preferably, R1, R2, R3, R4 and R5 are all D; (2)R 11 R 12 and R 13 Any one of them is D, or any two are D, or all three are D; preferably, R 11 R 12 and R 13 All are D; (3)R 11 R 12 R 13 R 21 R 22 and R 23 Any one of them is D, or any two are D, or any three are D, or any four are D, or any five are D, or all six are D; preferably, R 11 R 12 and R 13 Both are D, and R 21 R 22 and R 23 All are H; preferably, R 11 R 12 R 13 R 21 R 22 and R 23 All are D; (4)R 31 R 32 R 33 R 34 R 35 R 36 R 37 and R 38 Any one of them is D, or any two are D, or any three are D, or any four are D, or any five are D, or all six are D; preferably, R 31 R 32 R 33 R 34 R 35 R 36 R 37 and R 38 All are D; (5)R 41 R 42 R 43 and R 44 Any one of them is D, or any two are D, or any three are D, or all four are D; preferably, R 41 R 42 R 43 and R 44 All are D; (6) Any one of R6, R7 and R8 is D, or any two of them are D, or all three of them are D; preferably, R6, R7 and R8 are all D; (7) R9 is D; (8) said formula (II) is further represented as formula (II-A):

3. The compound represented by Formula (II) according to claim 1 or 2, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, characterized in that, The formula (II) is further shown as formula (II-1): Among them, R6, R7, R8, R9, R 11 R 12 R 13 R 21 R 22 R 23 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 Each is independently selected from H and D.

4. The compound of formula (II) according to claim 3, its stereoisomer, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of its stereoisomer, characterized in that, It satisfies one or more of the following conditions: (1) R6, R7, R8, R9, R 11 R 12 R 13 R 21 R 22 R 23 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 All are H; (2) the formula (II) is further shown as formula (II-1A):

5. The compound represented by Formula (II) according to claim 1 or 2, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, characterized in that, The formula (II) is further shown as formula (II-2): Among them, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 21 R 22 R 23 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 Each is independently selected from H and D.

6. The compound, stereoisomer thereof, pharmaceutically acceptable salt thereof, or pharmaceutically acceptable salt of a stereoisomer thereof of claim 5, wherein It satisfies one or more of the following conditions: (1)R1, R2, R3, R4, R5, R6, R7, R8, R9, R 21 R 22 R 23 R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 All are H; (2) the formula (II) is further shown as formula (II-2A):

7. The compound represented by Formula (II) according to claim 1 or 2, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, characterized by, Formula (II) is further shown as Formula (II-3): Among them, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 Each is independently selected from H and D.

8. The compound represented by formula (II) according to claim 7, its stereoisomer, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of its stereoisomer, characterized in that, It satisfies one or more of the following conditions: (1)R1, R2, R3, R4, R5, R6, R7, R8, R9, R 31 R 32 R 33 R 34 R 35 R 36 R 37 R 38 R 41 R 42 R 43 and R 44 All are H; (2) the formula (II) is further shown as formula (II-3A):

9. The compound represented by Formula (II) according to claim 1 or 2, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, characterized by, Formula (II) is further shown as Formula (II-2A-1): wherein R1, R2, R3, R4, R5, R6, R7, R8, R 21 , R 22 , R 23 , R 41 , R 42 , R 43 , and R 44 are each independently selected from H and D.

10. The compound represented by formula (II) of claim 9, its stereoisomer, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of its stereoisomer, characterized in that, R 21 R 22 and R 23 All are D, R1, R2, R3, R4, R5, R6, R7, R8, R 41 R 42 R 43 and R 44 Each is independently selected from H and D; preferably, R 21 R 22 R 23 R1, R2, R3, R4, and R5 are all D, R6, R7, R8, and R... 41 R 42 R 43 and R 44 Each is independently selected from H and D; preferably, R 21 R 22 R 23 R1, R2, R3, R4, R5, R 41 and R 42 All are D, R6, R7, R8, R 43 and R 44 Each is independently selected from H and D; preferably, R 21 R 22 R 23 R1, R2, R3, R4, R5, R 43 and R 44 All are D, R6, R7, R8, R 41 and R 42 Each is independently selected from H and D; preferably, R 21 R 22 R 23 R1, R2, R3, R4, R5, R 41 R 42 R 43 and R 44 All are D, and R6, R7, and R8 are each independently selected from H and D; preferably, R1, R2, R3, R4, R5, R6, R7, R8, R 21 R 22 R 23 R 41 R 42 R 43 and R 44 All are D.

11. The compound represented by formula (II) of claim 9, its stereoisomer, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of its stereoisomer, characterized in that, R1, R2, R3, R4, and R5 are all D, R6, R7, R8, and R 21 R 22 R 23 R 41 R 42 R 43 and R 44 Each is independently selected from H and D; preferably, R1, R2, R3, R4, R5, R 41 and R 42 All are D, R6, R7, R8, R 21 R 22 R 23 R 43 and R 44 Each is independently selected from H and D; preferably, R1, R2, R3, R4, R5, R 43 and R 44 All are D, R6, R7, R8, R 21 R 22 R 23 R 41 and R 42 Each is independently selected from H and D; preferably, R1, R2, R3, R4, R5, R 41 R 42 R 43 and R 44 All are D, R6, R7, R8, R 21 R 22 and R 23 Each is independently selected from H and D; preferably, R1, R2, R3, R4, R5, R6, R7, R8, R 41 R 42 R 43 and R 44 Both are D, R 21 R 22 and R 23 Each is independently selected from H and D.

12. The compound represented by formula (II) of claim 9, its stereoisomer, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of its stereoisomer, characterized in that, R 41 R 42 R 43 and R 44 All are D, R1, R2, R3, R4, R5, R6, R7, R8, R 21 R 22 and R 23 Each is independently selected from H and D; preferably, R 41 R 42 All are D, R1, R2, R3, R4, R5, R6, R7, R8, R 21 R 22 R 23 R 43 and R 44 Each is independently selected from H and D; preferably, R 43 R 44 All are D, R1, R2, R3, R4, R5, R6, R7, R8, R 21 R 22 R 23 R 41 and R 42 Each is independently selected from H and D.

13. The compound represented by formula (II) of claim 9, its stereoisomer, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of its stereoisomer, characterized in that, R6, R7, and R8 are each independently selected from the group consisting of H, D, and C1-6alkyl. R1, R2, R3, R4, R5, R 21 , R 22 , R 23 , R 41 , R 42 , R 43 , and R 44 are each independently selected from the group consisting of H and D.

14. The compound represented by formula (II) of claim 9, its stereoisomer, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of its stereoisomer, characterized in that, R1, R2, R3, R4, R5, R6, R7, R8, R 21 , R 22 , R 23 , R 41 , R 42 , R 43 , and R 44 are each H.

15. The compound represented by formula (II) of claim 9, its stereoisomer, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of its stereoisomer, characterized in that, R 21 , R 22 , and R 23 are each D, R1, R2, R3, R4, R5, R6, R7, R 41 , R 42 , R 43 , and R 44 are each H.

16. The compound of formula (II) according to any one of claims 1-15, its stereoisomers, its pharmaceutically acceptable salts, or pharmaceutically acceptable salts of its stereoisomers, characterized in that, The compound is selected from:

17. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (II) according to any one of claims 1-16, its stereoisomer, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of its stereoisomer, and one or more pharmaceutically acceptable carriers or excipients.

18. Use of a compound of formula (II) according to any one of claims 1-16, its stereoisomer, its pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutical composition according to claim 17 in the preparation of a medicament for treating pain disorders or disorders associated with opioid receptor activation.

19. A method for treating pain disorders or disturbances associated with opioid receptor activation, comprising administering to a patient in need a therapeutically effective amount of a compound of formula (II) according to any one of claims 1-16, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17.

20. Use according to claim 18 or method according to claim 19, characterized in that, The pain disorders or disorders mentioned include, but are not limited to, cancer pain, chronic pain, neuropathic pain, osteoarthritis pain, fibromyalgia, and acute pain such as lower back pain, as well as postoperative pain.

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