Spirocyclic cyclohexane derivatives, processes for their preparation and uses thereof

Abstract

The present application relates to a kind of spirocyclic cyclohexane derivatives and its preparation method and use.The present application discloses a kind of compound shown in formula (I), or its stereoisomer or pharmaceutically acceptable salt and their pharmaceutical compositions, and its purposes in the preparation of the drug for treating / preventing NOP and opioid receptor-mediated diseases, and each group in formula (I) is as defined in the specification.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals, and particularly relates to a spirocyclohexane derivative, its stereoisomer or pharmaceutically acceptable salt, its preparation method and its use in the preparation of medicaments for treating related diseases. Background Technology

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

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

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

[0005] This invention provides compounds of formula (I), formula (II), formula (III), formula (IV), and formula (V), their stereoisomers or pharmaceutically acceptable salts, wherein the compounds have excellent effects such as good activity, excellent physicochemical properties, ease of formulation, excellent pharmacokinetic properties, high bioavailability, and low toxicity.

[0006] Compounds of formulas (I), (II), (III), (IV), and (V), their stereoisomers or pharmaceutically acceptable salts,

[0007]

[0008] in,

[0009] Whether ring A is present or not, if ring A is present, it is selected from 3-12 membered carbon rings and 4-15 membered heterocycles;

[0010] In some implementations, ring A may or may not be present. When ring A is present, ring A is selected from 3-8 member monocyclic carbocyclic groups, 6-12 member bicyclic carbocyclic groups, 4-12 member monocyclic heterocyclic groups, and 6-12 member bicyclic heterocyclic groups.

[0011] In some embodiments, ring A may or may not be present. When ring A is present, ring A is selected from 3-6 member monocyclic cycloalkyl, 5-8 member bridged cycloalkyl, 6-12 member spirocyclic cycloalkyl, 5-12 member fused cycloalkyl, 3-6 member monocyclic heterocyclic alkyl, 5-8 member bridged heterocyclic alkyl, 6-12 member spirocyclic heterocyclic alkyl, 5-12 member fused heterocyclic alkyl, phenyl, 8-10 member fused aryl, 5-6 member monocyclic heteroaryl, and 8-12 member fused heteroaryl.

[0012] In some embodiments, ring A may or may not be present. When ring A is present, ring A is selected from 3-6 member monocyclic cycloalkyl, 5-8 member bridged cycloalkyl, 7-11 member spirocyclic cycloalkyl, 7-11 member fused cycloalkyl, 3-6 member monocyclic heterocyclic alkyl, 5-8 member bridged heterocyclic alkyl, 7-11 member spirocyclic heterocyclic alkyl, 7-11 member fused heterocyclic alkyl, phenyl, 8-10 member fused aryl, 5-6 member monocyclic heteroaryl, and 8-11 member fused heteroaryl.

[0013] In some implementations, ring A may or may not exist. When ring A exists, ring A is selected from 1-3 of R. A The following structures are formed by the substitution of groups:

[0014] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or , , , , , , ;

[0015] In some implementations, ring A is selected from... ;

[0016] The condition is that when ring A does not exist, L1 and R A Directly connected;

[0017] X1 and X2 are each independently selected from CR X1 R X2 ,O,S,S(=O),S(=O)2 or NR X1 ;

[0018] In some implementations, X1 is selected from NH;

[0019] In some implementations, X2 is selected from NH or O;

[0020] In some implementations, X2 is selected from O;

[0021] R X1 R X2Each element is independently selected from hydrogen, deuterium, hydroxyl, amino, halogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkoxy groups;

[0022] In some implementation schemes, R X1 R X2 Each is independently selected from hydrogen, C 1-6 alkyl;

[0023] R1 is selected from F, Br, or C. 1-6 Alkoxy;

[0024] In some implementations, R1 is selected from F;

[0025] R2 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy group, -(CR3R4) m -NR5R6;

[0026] In some implementations, R2 is selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy group, -NR5R6, -CH2-NR5R6;

[0027] In some implementations, R2 is selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy group, -NR5R6;

[0028] In some implementations, R2 is selected from C 1-4 Alkoxy, C 1-4 Halogenated alkoxy group, -NR5R6;

[0029] In some embodiments, R2 is selected from methoxy, -OCF3, -N(CH3)2, -N(CH3)(CD3), -N(CD3)2, -N(CH3)(C 3-6 cycloalkyl), -N(CH3)(-CH2-C 3-6 cycloalkyl);

[0030] In some implementations, R2 is selected from -N(CH3)2;

[0031] R3, R4, R5, and R6 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl, -O- (4-8 membered heterocyclic alkyl), -(CH2) r -C 3-8 Cycloalkyl, -(CH2) r -(4-8-membered heterocyclic alkyl), wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced; in some embodiments, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl groups in R3, R4, R5, and R6 are optionally further replaced by 1-3 deuterium, C 1-2 Alkyl, C 1-2 Deuterated alkyl, C 3-6 Cycloalkyl substituted;

[0032] In some implementation schemes, R5 and R6 are each independently selected from C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -(4-6-membered heterocyclic alkyl), wherein the alkyl, alkoxy, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. xReplaced; in some embodiments, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl groups described in R5 and R6 are optionally further replaced by 1-3 deuterium, C 1-2 Alkyl, C 1-2 Deuterated alkyl, C 3-6 Cycloalkyl groups are substituted; in some embodiments, the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl groups described in R5 and R6 are optionally further replaced by 1-3 deuterium or C atoms. 1-2 Alkyl, C 1-2 Deuterated alkyl, C 3-4 Cycloalkyl substituted;

[0033] In some implementations, R5 is selected from C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -(4-6-membered heterocyclic alkyl), wherein the alkyl, alkoxy, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced;

[0034] In some implementations, R6 is selected from C 1-4 Alkyl, C 1-4 Deuterated alkyl; in some embodiments, R6 is selected from C6. 1-2 Alkyl, C 1-2 Deuterated alkyl groups;

[0035] Alternatively, R5 and R6, together with the atoms attached to them, form a 3-8 membered heterocyclic alkyl group or a 3-8 membered heterocyclic alkenyl group, wherein the heterocyclic alkyl group or heterocyclic alkenyl group is further surrounded by 1-5 R atoms. x The heterocyclic alkyl or heterocyclic alkenyl groups are preferably replaced by 1-2 deuterium, halogen, =O, =CH2, =CF2, =CHF, =CH(C) groups. 1-2 Alkyl), =CF(C) 1-2 Alkyl), =C(C) 1-2 Alkyl)2-substituted;

[0036] In some embodiments, R5 and R6, together with the atoms they are attached to, form a 3-6 membered heterocyclic alkyl group or a 3-6 membered heterocyclic alkenyl group, wherein the heterocyclic alkyl group or heterocyclic alkenyl group is further surrounded by 1-3 R atoms. xThe heterocyclic alkyl or heterocyclic alkenyl groups are preferably replaced by 1-2 deuterium, halogen, =O, =CH2, =CF2, =CHF, =CH(C) groups. 1-2 Alkyl), =CF(C) 1-2 Alkyl), =C(C) 1-2 Alkyl)2-substituted;

[0037] In some embodiments, R5 and R6, together with the atoms they are attached to, form a 4-6 membered heterocyclic alkyl group or a 4-6 membered heterocyclic alkenyl group, wherein the heterocyclic alkyl group or heterocyclic alkenyl group is further surrounded by 1-3 R atoms. x The heterocyclic alkyl or heterocyclic alkenyl groups are preferably replaced by 1-2 deuterium, halogen, =O, =CH2, =CF2, =CHF, =CH(C) groups. 1-2 Alkyl), =CF(C) 1-2 Alkyl), =C(C) 1-2 Alkyl)2-substituted;

[0038] Alternatively, R5 and any R A Together with the atoms attached thereto, they form 3-8 membered heterocyclic alkyl groups or 3-8 membered heterocyclic alkenyl groups, wherein the heterocyclic alkyl or heterocyclic alkenyl groups are optionally further surrounded by 1-5 R groups. x The heterocyclic alkyl or heterocyclic alkenyl groups are preferably replaced by 1-2 deuterium, halogen, =O, =CH2, =CF2, =CHF, =CH(C) groups. 1-2 Alkyl), =CF(C) 1-2 Alkyl), =C(C) 1-2 Alkyl)2-substituted;

[0039] In some implementations, R5 is associated with any R A Together with the atoms attached thereto, they form 4-6 membered heterocyclic alkyl groups or 4-6 membered heterocyclic alkenyl groups, wherein the heterocyclic alkyl or heterocyclic alkenyl group is optionally further surrounded by 1-5 R atoms. x The heterocyclic alkyl or heterocyclic alkenyl groups are preferably further replaced by 1-2 halogens, deuterium, or =O.

[0040] L1 is selected from key, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 The alkylene group, wherein one or more CH2 groups are optionally surrounded by 1-5 groups selected from O, S, S(=O), S(=O)2, NR L1 The C (=O) groups are replaced by alkylene, alkenylene, or yntylide groups, which are optionally replaced by 1-5 R groups. x Replaced;

[0041] In some implementations, L1 is selected from key, C 1-4 Alkylene, C 2-4 imidene group, C2-4 The alkylene group, wherein one or more CH2 groups are optionally surrounded by 1-3 groups selected from O, S, S(=O), S(=O)2, NR L1 The C (=O) groups are replaced by alkylene, alkenylene, or yntylide groups, which are optionally replaced by 1-5 R groups. x Replaced;

[0042] In some implementations, L1 is selected from key, C 1-4 Alkylene, C 2-4 imidene group, C 2-4 The alkylene, alkenylene, or ynylene group is optionally surrounded by 1-5 R groups. x Replaced;

[0043] In some implementations, L1 is selected from key, C 2-4 imidene group, C 2-4 Alynyl; in some embodiments, L1 is selected from α, β, ethynyl, propynyl, allyl, propynyl;

[0044] In some implementations, L1 is selected from the key;

[0045] R L1 Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced;

[0046] In some implementation schemes, R L1 Selected from hydrogen, deuterium, and C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced;

[0047] In some implementation schemes, R L1 Selected from hydrogen;

[0048] Each R AEach is independently selected from hydrogen, deuterium, halogen, hydroxyl, =O, cyano, amino, -SF5, -SCF3, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkyl, C 1-6 deuterated alkoxy group, -SC 1-6 Haloalkyl, =CH2, =CF2, =CHF, =CH(C 1-3 Alkyl), =C(C) 1-3 Alkyl)2、=CH(C 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =C(C) 1-3 (halogenated alkyl)2, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl, -O- (4-8 membered heterocycloalkyl), -C(=O)-C 3-8 Cycloalkyl, -C(=O)-(4-8 membered heterocycloalkyl), -NHC(=O)-C 3-8 Cycloalkyl, -C(=O)NH-C 3-8 Cycloalkyl, -NHC(=O)- (4-8 membered heterocyclic alkyl), -C(=O)NH- (4-8 membered heterocyclic alkyl), -S(O)2-C 1-6 Alkyl groups, wherein the alkyl, amino, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl groups are optionally further reinforced with 1-5 R groups. x Replaced;

[0049] In some implementations, each R A Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, =O, cyano, amino, -SF5, -SCF3, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy group, N(C) 1-4 Alkyl group 2, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =C(C) 1-3 Alkyl)2、=CH(C 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =C(C) 1-3 (halogenated alkyl)2, C3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -C(=O)-(4-8 membered heterocycloalkyl), -S(O)2-C 1-4 Alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl may optionally be further reinforced with 1-5 R groups. x Replaced;

[0050] In some implementations, each R A Each is independently selected from hydrogen, deuterium, halogens, =O, -SF5, -SCF3, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy group, N(C) 1-4 Alkyl group 2, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =C(C) 1-3 Alkyl)2、=CH(C 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =C(C) 1-3 (halogenated alkyl)2, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, -C(=O)- (4-6 membered monocyclic heterocyclic alkyl), -C(=O)- (6-8 membered polycyclic heterocyclic alkyl), -S(O)2-C 1-3 Alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl may optionally be further reinforced with 1-5 R groups. x Replaced;

[0051] In some implementations, each R A Each is independently selected from hydrogen, deuterium, halogens, =O, -SF5, -SCF3, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, N(C) 1-4 Alkyl)2, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, =CH2, =CF2, =CHF, =CH(CH3), =CH(CF3), =CF(CH3), =C(CH3)2, =C(CH3)(CF3), -S(O)2-CH3, -C(=O)-(4 membered heterocyclic alkyl), -C(=O)-(7 membered spirocyclic heterocyclic alkyl), wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 Rx Replaced;

[0052] In some implementation schemes, R A Selected from C 1-2 Alkyl, C 1-2 Alkoxy, C 1-2 Haloalkyl, C 1-2 Halogenated alkoxy groups, C 3-4 cycloalkyl;

[0053] In some implementation schemes, R A Selected from -CH3, -OCH3, -CF3, -OCF3, and cyclopropyl;

[0054] In some implementation schemes, R A Selected from -CH3, -OCH3, -CF3;

[0055] Each R x Each is independently selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =NH, -NHCOC 1-3 Alkyl, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl groups, -SF5, -SCF3, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl) (C 1-3 Halogenated alkyl), =C 4-6 Cycloalkyl, =(4-6 membered heterocyclic alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl;

[0056] In some implementations, each R x Each is independently selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, =O, -NHCOC 1-3 Alkyl, -N(C) 1-3 alkyl)2、-NH(C 1-3Alkyl groups, -SF5, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl) (C 1-3 Halogenated alkyl), =C 4-6 Cycloalkyl, =(4-6 membered heterocyclic alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl;

[0057] In some implementations, each R x Each is independently selected from deuterium, F, Cl, cyano, amino, =O, -NHCOC 1-3 Alkyl, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl groups, -SF5, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =C(C) 1-3 Alkyl)2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl;

[0058] In some implementations, each R x Each is independently selected from deuterium, F, Cl, cyano, amino, =O, -NHCOCH3, -N(CH3)2, -NH(CH3), -SF5, =CH2, =CF2, =CHF, =CH(CH3), =C(CH3)2, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl;

[0059] In some implementations, each R x Each is independently selected from deuterium, F, Cl, cyano, =O, -NHCOCH3, -N(CH3)2, -NH(CH3), -SF5, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl;

[0060] The condition is that L1 cannot be a key if ring A does not exist;

[0061] n is an integer between 0 and 5;

[0062] In some implementations, n is an integer between 0 and 3;

[0063] In some implementations, n is an integer from 1 to 2;

[0064] In some implementations, n is 1;

[0065] m is an integer between 0 and 5;

[0066] In some implementations, m is an integer between 0 and 3;

[0067] In some implementations, m is an integer from 1 to 2;

[0068] In some implementations, m is 1;

[0069] r is an integer between 0 and 5;

[0070] In some implementations, r is an integer between 0 and 3;

[0071] In some implementations, r is an integer from 1 to 2;

[0072] In some implementations, r is 1.

[0073] The first specific technical solution relates to a compound of general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof:

[0074]

[0075] in,

[0076] Whether ring A is present or not, if ring A is present, it is selected from 3-12 membered carbon rings and 4-15 membered heterocycles;

[0077] The condition is that when ring A does not exist, L1 and R A Directly connected;

[0078] X1 and X2 are each independently selected from CR X1 R X2 ,O,S,S(=O),S(=O)2 or NR X1 ;

[0079] R X1 R X2 Each element is independently selected from hydrogen, deuterium, hydroxyl, amino, halogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkoxy groups;

[0080] R1 is selected from F, Br, or C. 1-6 Alkoxy;

[0081] R2 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy group, -(CR3R4) m -NR5R6;

[0082] R3, R4, R5, and R6 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl, -O- (4-8 membered heterocyclic alkyl), -(CH2) r -C 3-8 Cycloalkyl, -(CH2) r -(4-8-membered heterocyclic alkyl), wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced;

[0083] Alternatively, R5 and R6, together with the atoms attached to them, form a 3-8 membered heterocyclic alkyl group or a 3-8 membered heterocyclic alkenyl group, wherein the heterocyclic alkyl group or heterocyclic alkenyl group is further surrounded by 1-5 R atoms. x Replaced;

[0084] Alternatively, R5 and any R A Together with the atoms attached thereto, they form 3-8 membered heterocyclic alkyl groups or 3-8 membered heterocyclic alkenyl groups, wherein the heterocyclic alkyl or heterocyclic alkenyl groups are optionally further surrounded by 1-5 R groups. x Replaced;

[0085] L1 is selected from key, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 The alkylene group, wherein one or more CH2 groups are optionally surrounded by 1-5 groups selected from O, S, S(=O), S(=O)2, NR L1 The C (=O) groups are replaced by alkylene, alkenylene, or yntylide groups, which are optionally replaced by 1-5 R groups. x Replaced;

[0086] R L1 Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced;

[0087] Each R A Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, =O, cyano, amino, -SF5, -SCF3, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkyl, C 1-6 deuterated alkoxy group, -SC 1-6 Haloalkyl, =CH2, =CF2, =CHF, =CH(C 1-3 Alkyl), =C(C) 1-3 Alkyl)2、=CH(C 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =C(C) 1-3 (halogenated alkyl)2, C3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl, -O- (4-8 membered heterocycloalkyl), -C(=O)-C 3-8 Cycloalkyl, -C(=O)-(4-8 membered heterocycloalkyl), -NHC(=O)-C 3-8 Cycloalkyl, -C(=O)NH-C 3-8 Cycloalkyl, -NHC(=O)- (4-8 membered heterocyclic alkyl), -C(=O)NH- (4-8 membered heterocyclic alkyl), -S(O)2-C 1-6 Alkyl groups, wherein the alkyl, amino, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl groups are optionally further reinforced with 1-5 R groups. x Replaced;

[0088] Each R x Each is independently selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =NH, -NHCOC 1-3 Alkyl, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl groups, -SF5, -SCF3, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl) (C 1-3 Halogenated alkyl), =C 4-6 Cycloalkyl, =(4-6 membered heterocyclic alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl;

[0089] The condition is that L1 cannot be a key if ring A does not exist;

[0090] n is an integer between 0 and 5;

[0091] m is an integer between 0 and 5;

[0092] r is an integer between 0 and 5.

[0093] Specifically, in the second technical solution, the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, has the structures shown in formulas (II) and (III):

[0094] ;

[0095] The definitions of the other functional groups are consistent with any of the technical solutions mentioned above.

[0096] Specifically, in the third technical solution, the aforementioned compound, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein...

[0097] The presence or absence of ring A; when ring A is present, ring A is selected from 3-8 member monocyclic carbocyclic groups, 6-12 member bicyclic carbocyclic groups, 4-12 member monocyclic heterocyclic groups, and 6-12 member bicyclic heterocyclic groups.

[0098] R2 is selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy group, -NR5R6, or -CH2-NR5R6;

[0099] R5 and R6 are each independently selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -(4-6-membered heterocyclic alkyl), wherein the alkyl, alkoxy, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced;

[0100] Alternatively, R5 and R6, together with the atoms attached to them, form a 3-6 membered heterocyclic alkyl group or a 3-6 membered heterocyclic alkenyl group, wherein the heterocyclic alkyl group or heterocyclic alkenyl group is further surrounded by 1-3 R atoms. x Replaced;

[0101] Alternatively, R5 and any R A Together with the atoms attached thereto, they form 5-7 membered heterocyclic alkyl or 5-7 membered heterocyclic alkenyl groups, wherein the heterocyclic alkyl or heterocyclic alkenyl group is optionally further surrounded by 1-3 R groups. x Replaced;

[0102] L1 is selected from key, C 1-4 Alkylene, C 2-4 imidene group, C 2-4 The alkylene group, wherein one or more CH2 groups are optionally surrounded by 1-3 groups selected from O, S, S(=O), S(=O)2, NR L1 The C (=O) groups are replaced by alkylene, alkenylene, or yntylide groups, which are optionally replaced by 1-5 R groups. x Replaced;

[0103] R L1 Selected from hydrogen, deuterium, and C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced;

[0104] Each R A Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, =O, cyano, amino, -SF5, -SCF3, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy group, N(C) 1-4 Alkyl group 2, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =C(C) 1-3 Alkyl)2、=CH(C 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =C(C) 1-3 (halogenated alkyl)2, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -C(=O)-(4-8 membered heterocycloalkyl), -S(O)2-C 1-4 Alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl may optionally be further reinforced with 1-5 R groups. x Replaced;

[0105] The definitions of the other functional groups are consistent with any of the technical solutions mentioned above.

[0106] Specifically, in the fourth technical solution, the aforementioned compound, its stereoisomer, or a pharmaceutically acceptable salt thereof...

[0107] The presence or absence of ring A, when present, is selected from 3-6 member monocyclic cycloalkyl, 5-8 member bridged cycloalkyl, 6-12 member spirocyclic cycloalkyl, 5-12 member fused cycloalkyl, 3-6 member monocyclic heterocyclic alkyl, 5-8 member bridged heterocyclic alkyl, 6-12 member spirocyclic heterocyclic alkyl, 5-12 member fused heterocyclic alkyl, phenyl, 6-10 member fused aryl, 5-6 member monocyclic heteroaryl, and 8-12 member fused heteroaryl.

[0108] R1 is selected from F;

[0109] R2 is selected from C 1-4 Alkoxy, C 1-4 Halogenated alkoxy group, -NR5R6;

[0110] R5 is selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -(4-6-membered heterocyclic alkyl), wherein the alkyl, alkoxy, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced;

[0111] R6 is selected from C 1-4 alkyl;

[0112] Alternatively, R5 and R6, together with the atoms attached to them, form a 4-6 membered heterocyclic alkyl group or a 4-6 membered heterocyclic alkenyl group, wherein the heterocyclic alkyl group or heterocyclic alkenyl group is further surrounded by 1-3 R atoms. x Replaced;

[0113] Alternatively, R5 and any R A Together with the atoms attached thereto, they form 5-6 membered heterocyclic alkyl groups or 5-6 membered heterocyclic alkenyl groups, wherein the heterocyclic alkyl or heterocyclic alkenyl groups are optionally further surrounded by 1-3 R groups. x Replaced;

[0114] L1 is selected from key, C 1-4 Alkylene, C 2-4 imidene group, C 2-4 The alkylene, alkenylene, or ynylene group is optionally surrounded by 1-5 R groups. x Replaced;

[0115] Each R A Each is independently selected from hydrogen, deuterium, halogens, =O, -SF5, -SCF3, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy group, N(C) 1-4 Alkyl group 2, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =C(C) 1-3 Alkyl)2、=CH(C 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =C(C) 1-3 (halogenated alkyl)2, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, -C(=O)- (4-6 membered monocyclic heterocyclic alkyl), -C(=O)- (6-8 membered polycyclic heterocyclic alkyl), -S(O)2-C 1-3 Alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl may optionally be further reinforced with 1-5 R groups. x Replaced;

[0116] The definitions of the other functional groups are consistent with any of the technical solutions mentioned above.

[0117] Specifically, in the fifth technical solution, the aforementioned compound, its stereoisomer, or a pharmaceutically acceptable salt thereof...

[0118] in,

[0119] Ring A may or may not exist. If ring A exists, ring A is selected from any of the 1-3 selected from R. A The following structures are formed by the substitution of groups:

[0120] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or , , , , , , ;

[0121] R2 is selected from methoxy, -OCF3, -N(CH3)2, -N(CH3)(CD3), -N(CD3)2, -N(CH3)(C 3-6 cycloalkyl), -N(CH3)(-CH2-C 3-6 cycloalkyl) , The cycloalkyl group may optionally be further substituted with 1-2 groups selected from deuterium, =CH2, =CF2;

[0122] Each R A Each is independently selected from hydrogen, deuterium, halogens, =O, -SF5, -SCF3, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, N(C) 1-4 Alkyl)2, C 3-6Cycloalkyl, 4-6 membered heterocyclic alkyl, =CH2, =CF2, =CHF, =CH(CH3), =CH(CF3), =CF(CH3), =C(CH3)2, =C(CH3)(CF3), -S(O)2-CH3, -C(=O)-(4 membered heterocyclic alkyl), -C(=O)-(7 membered spirocyclic heterocyclic alkyl), wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R x Replaced;

[0123] The definitions of the other functional groups are consistent with any of the technical solutions mentioned above.

[0124] The sixth technical solution of the present invention, wherein the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, has the structures shown in formulas (IV) and (V):

[0125]

[0126] R A Selected from C 1-2 Alkyl, C 1-2 Alkoxy, C 1-2 Haloalkyl, C 1-2 Halogenated alkoxy groups, C 3-4 cycloalkyl; in some embodiments, R A Selected from -CH3, -OCH3, -CF3.

[0127] The seventh technical solution of this invention, wherein the compounds of formulas (I), (II), (III), (IV), and (V), their stereoisomers or pharmaceutically acceptable salts, are selected from, but not limited to, the structures in Tables 1 and 2 below:

[0128] Table 1

[0129]

[0130] Table 2

[0131]

[0132] Secondly, the present invention also provides a pharmaceutical composition comprising the compound described in any of the foregoing embodiments, its stereoisomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient.

[0133] Furthermore, the pharmaceutical composition or pharmaceutical preparation of the present invention contains 1-1500 mg of the compound described in any of the preceding embodiments, its stereoisomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient.

[0134] Furthermore, the present invention also provides the use of the compounds described in any of the foregoing embodiments, their stereoisomers or pharmaceutically acceptable salts, in the preparation of medicaments for the treatment / prevention of NOP and opioid receptor-mediated diseases.

[0135] Furthermore, the NOP and opioid receptor-mediated diseases are pain, preferably cancer pain, chronic low back pain, knee osteoarthritis, diabetic peripheral neuropathy, and postoperative pain.

[0136] The present invention also provides a method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound shown in any of the foregoing embodiments, its stereoisomers or pharmaceutically acceptable salts, wherein the disease is preferably pain, and the therapeutically effective amount is preferably 1-1500 mg. In some embodiments, the mammals described in the present invention include humans.

[0137] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the compound disclosed in this application will alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of the compound disclosed in this application required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1- 20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5 -150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-25 0mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg;50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg. ;

[0138] This invention relates to a pharmaceutical composition or formulation comprising a therapeutically effective amount of the compound of the invention or its stereoisomers or pharmaceutically acceptable salts, as well as a carrier and / or excipients. The pharmaceutical composition may be in unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as a "dosage strength"). In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1500 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 25-500 mg, 40-200 mg, 50-100 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, etc. The compounds of the present invention, or their stereoisomers or pharmaceutically acceptable salts, in the following amounts: g, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg.

[0139] A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound of the invention, its stereoisomer or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient, the therapeutically effective amount preferably being 1-1500 mg, wherein the disease is preferably pain.

[0140] A method for treating a mammalian disease, the method comprising administering a pharmaceutical compound of the invention, its stereoisomer or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient to a subject at a daily dose of 1-1500 mg / day, said daily dose being a single dose or multiple doses. In some embodiments, the daily dose includes, but is not limited to, 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, 100- 1000mg / day, 200-1000mg / day, 25-800mg / day, 50-800mg / day, 100-800mg / day, 200-800mg / day, 25-400mg / day, 50-400mg / day, 100-400mg / day, 200-400mg / day. In some embodiments, the daily dose includes, but is not limited to, 1mg / day, 5mg / day, 10mg / day, 20mg / day, 25mg / day, 50mg / day, 75mg / day, 100mg / day, 125mg / day, 150mg / day, 200mg / day, 400mg / day, 600mg / day, 800mg / day, 1000mg / day, 1200mg / day, 1400mg / day, and 1500mg / day.

[0141] This invention relates to a kit that may comprise a single-dose or multi-dose composition containing a compound of the present invention or its stereoisomers or a pharmaceutically acceptable salt thereof, wherein the amount of the compound of the present invention or its stereoisomers or a pharmaceutically acceptable salt thereof is the same as that in the pharmaceutical composition described above.

[0142] In this invention, the amount of the compound of the invention or its stereoisomer or pharmaceutically acceptable salt is converted in each case as a free base.

[0143] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0144] Synthetic route

[0145] Those skilled in the art can prepare the compounds of this invention by combining this literature with known organic synthesis techniques, using commercially available chemicals and / or compounds described in the chemical literature as starting materials. "Commercially available chemicals" are obtained from legitimate commercial sources, and suppliers include: Titan Technology, Energetic Chemicals, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology, among others.

[0146] The index of known chemical substances prepared by the American Chemical Society's Chemical Abstracts Service allows for the selective identification of specific and similar substances.

[0147] The reactants listed in these indexes are available in most public and university libraries, as well as online. Chemicals known but not commercially available in the catalogues may optionally be prepared by custom chemical synthesis plants, many of which offer custom synthesis services to standard chemical supply plants (e.g., those listed above).

[0148] the term

[0149] Unless otherwise specified in this invention, the terminology used in this invention has the following meanings:

[0150] The carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen involved in the groups and compounds described in this invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen involved in the groups and compounds described in this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (also known as heavy hydrogen), and tritium (T, also known as superheavy hydrogen), and the isotopes of oxygen include 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, an isotope of fluorine 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0151] In this article, "halogen" refers to F, Cl, Br, I, or their isotopes.

[0152] "Halogen substitution" refers to the substitution of a hydrogen atom by one or more elements selected from F, Cl, Br, I, or their isotopes. The upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be substituted in the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and this upper limit. When the number of halogen substituents is greater than 1, the same or different halogens can be used for substitution.

[0153] "Deuterated" or "deuterated product" refers to the situation where hydrogen atoms on alkyl, cycloalkyl, alkylene, aryl, heteroaryl, mercapto, heterocycloalkyl, alkenyl, alkynyl, etc., groups are replaced by at least one isotope deuterium. The upper limit of the number of deuterated groups is equal to the sum of the number of hydrogen atoms that can be replaced by the substituted groups. Unless otherwise specified, the number of deuterated groups is any integer between 1 and the upper limit. Preferably, 1 to 20 deuterium atoms are substituted, more preferably 1 to 10 deuterium atoms are substituted, more preferably 1 to 6 deuterium atoms are substituted, and even more preferably 1 to 3 deuterium atoms are substituted.

[0154] "alkyl" refers to a monovalent straight-chain or branched saturated aliphatic hydrocarbon group, and unless otherwise specified, it is an alkyl group with 1 to 20 carbon atoms, preferably an alkyl group with 1 to 8 carbon atoms, more preferably an alkyl group with 1 to 6 carbon atoms, further preferably an alkyl group with 1 to 4 carbon atoms, and even more preferably an alkyl group with 1 to 2 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and their various branched isomers.

[0155] "alkylene" refers to divalent straight-chain and branched saturated alkyl groups. Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0156] "Alkenyl" refers to a straight-chain or branched monovalent unsaturated hydrocarbon group containing one or more carbon-carbon double bonds. Unless otherwise specified, alkynyl groups contain 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples include vinyl, propenyl, allyl, 2-butenyl, 1-butenyl, etc. "Alkenylene" refers to the divalent group of "alkenyl".

[0157] "Alynyl" refers to a straight-chain or branched monovalent unsaturated hydrocarbon group containing one or more carbon-carbon triple bonds. Unless otherwise specified, alkynyl contains 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples include ethynyl, propynyl, propynyl, etc. "Idemynyl" refers to the divalent group of "alkynyl".

[0158] "Alkoxy" or "alkyloxy" refers to -O-alkyl, and unless otherwise specified, it is -OC. 1-8 Alkyl group, preferably -OC 1-6 Alkyl, more preferably -OC 1-4 Alkyl groups, more preferably -OC1-2 Alkyl groups. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy.

[0159] "Haloalkoxy" refers to -O-haloalkyl, and unless otherwise specified, it is -O-haloC. 1-8 Alkyl group, preferably -O-halogenated C 1-6 Alkyl groups, more preferably -O-halogenated C 1-4 Alkyl groups, more preferably -O-halogenated C 1-2 Alkyl groups. Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, etc.

[0160] "Cycloalkyl" refers to a fully saturated hydrocarbon ring, whether substituted or unsubstituted, which can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic rings can be fused, spirocyclic, or bridged rings. Unless otherwise specified, they typically have 3 to 20 carbon atoms. When it is a monocyclic cycloalkyl ring, it preferably has 3-15 carbon atoms, more preferably 3-10 carbon atoms, even more preferably 3-8 carbon atoms, more preferably 3-6 carbon atoms, and even more preferably 3-4 carbon atoms. When it is a bicyclic or polycyclic cycloalkyl ring, it preferably has 4-12 carbon atoms, more preferably 4-11 carbon atoms, even more preferably 5-11 carbon atoms, more preferably 6-11 carbon atoms, and even more preferably 6-10 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. , , , , , , , , , , , wait.

[0161] "Cycloalkenyl" refers to a non-aromatic hydrocarbon ring, whether substituted or unsubstituted, containing at least one unsaturated bond. It can be monocyclic, bicyclic, or polycyclic, and bicyclic or polycyclic rings can be fused, spirocyclic, or bridged. Non-limiting examples include cyclobutenyl, cyclopentenyl, and cyclohexenyl.

[0162] "Heterocyclic alkyl" refers to a fully saturated heterocycle, which generally has 4 to 12 ring members, preferably 4 to 10 ring members, more preferably 4 to 7 ring members, and even more preferably 5 or 6 ring members. In addition to carbon atoms, heterocyclic alkyl groups also contain 1 to 5 heteroatoms selected from N, S, O, Si, P, B, and Se as ring members. Non-limiting examples include nitrogen-based heterocyclic butyl, morpholino, piperazine, piperidinyl, tetrahydropyranyl, and oxocyclic butyl.

[0163] "Heterocyclic alkenyl" refers to a non-aromatic heterocycle containing at least one unsaturated bond, generally having 4 to 12 ring members, preferably 4 to 10 ring members, more preferably 4 to 7 ring members, and even more preferably 5 or 6 ring members. In addition to a carbon atom, the heterocyclic alkyl group also contains 1 to 3 heteroatoms selected from N, S, O, Si, P, B, and Se as ring members. Non-limiting examples include azirrobutyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, and oxoheterobutyl.

[0164] "Heterocyclic" or "heterocyclic group" refers to a substituted or unsubstituted, saturated or unsaturated aromatic or non-aromatic ring. Unless otherwise specified, it contains 1 to 3 heteroatoms selected from N, O, S, P, B, Se, and Si, including monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles, and bicyclic spirocyclic heterocycles. Unless otherwise specified, it is a 3- to 12-membered heterocycle, more preferably a 4- to 12-membered heterocycle, even more preferably a 4- to 10-membered heterocycle, and even more preferably a 4- to 7-membered heterocycle. Its definition includes heterocyclic alkyl and heteroaryl groups. The N and S in the heterocyclic group ring can be oxidized to various oxidation states. Heterocyclic groups can be attached to heteroatoms or carbon atoms. Non-limiting examples include epoxyethyl, azirropropyl, oxacyclobutyl, azirrobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxohexyl, azirroheptyl, pyridinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazoleyl, piperidinyl, piperinyl, morpholinyl, thiomorpholinyl, 1,3-dithioyl, and dioxinyl. Hydrofuranyl, dihydropyranyl, dithiapentylyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl, , , , , , , , , , , wait.

[0165] "Carbocyclic" or "carbocyclic group" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic carbocyclic group, including monocyclic carbocyclic, bicyclic bridged ring, bicyclic fused ring, and bicyclic spirocyclic groups, etc. Unless otherwise specified, it has 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 6 carbon atoms. Its definition includes cycloalkyl and aryl groups. In non-limiting embodiments, monocyclic carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl. The double-ring bridge includes... , , Etc., double-ring parallel rings include , , , and etc., double-ring spiral rings include , , , , and wait.

[0166] "Aryl" refers to a substituted or unsubstituted 5- to 15-membered aromatic carbon ring, including monocyclic and fused-ring aromatic groups. Preferably, it is a 5- to 10-membered aromatic ring, more preferably a 5- to 8-membered aromatic ring; the aryl ring may be fused to a non-aryl ring (e.g., heteroaryl, heterocycloalkyl, or cycloalkyl ring), wherein the aryl ring is the linking site. "xy-membered aryl" indicates that the total number of aryl ring atoms is x to y, which can be a phenyl fused or non-aromatic ring, wherein the aromatic ring is the linking site. For example, "7-12-membered aryl" indicates that the aryl group serves as the linking site, and the total number of ring atoms is 7-12, such as benzocyclobutyl or benzocyclopentyl. Non-limiting examples include phenyl, naphthyl, anthraceneyl, phenanthrene, etc.

[0167] The aryl group may optionally be further replaced by any substituent.

[0168] "Heteroaromatic ring" or "heteroaryl" refers to an aromatic ring, whether substituted or unsubstituted, containing at least one heteroatom or group selected from N, S, O, P, Si, B, Se and their oxidation states. It can be monocyclic, bicyclic, or polycyclic, and can be bridged, fused, or spirocyclic. When bicyclic or polycyclic, it can be a fusion of a heteroaryl group with a non-heteroaromatic ring, such as a cycloalkyl, heterocycloalkyl, or aryl group, or a fusion of two heteroaryl groups, where the heteroaryl ring is the linking site. "xy-membered heteroaryl" indicates that the total number of heteroaryl ring atoms is x to y, which can be a 5-6 membered heteroaryl group, or a 5-6 membered heteroaryl group fused with other rings (e.g., cycloalkyl, heterocycloalkyl, aromatic rings), where the heteroaromatic ring is the linking site. For example, "5-12-membered heteroaryl" indicates that the heteroaryl group serves as the linking site, and the total number of ring atoms is 5-12, such as pyridocyclobutyl or pyridocyclopentyl. Non-limiting embodiments include furanyl, thiopheneyl, pyrrolyl, oxazolyl, thiazolyl, imidazoleyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indoleyl, purineyl, , , , , , The heteroaryl group may be optionally further substituted with any substituent.

[0169] "Spirocyclic" refers to a 5- to 20-membered polycyclic group consisting of substituted or unsubstituted rings sharing a single carbon atom (called a spiro atom). It may contain 0 to 5 double bonds and 0 to 5 heteroatoms or groups selected from N, O, S, P, Si, and their oxidation states. Preferably, it is a 6- to 14-membered spirocyclic group, more preferably a 6- to 12-membered group, and even more preferably a 6- to 10-membered spirocyclic group. The spirocyclic group can be formed between cycloalkyl groups or heterocycloalkyl groups; preferably, it is a tri-spirotri- (representing a three-membered ring spirotri-), tri-spirote, tri-spiropenta, tri-spirohexa, tetra-spirote, tetra-spiropenta, tetra-spirohexa, penta-spiropenta, or penta-spiropenta; non-limiting examples include...

[0170] The spiroring may optionally be further replaced by any substituent.

[0171] "Built rings" refer to polycyclic groups in which rings share two adjacent atoms. One or more rings may contain zero or more double bonds and may be substituted or unsubstituted. Each ring in a built ring system may contain 0 to 5 heteroatoms selected from N, S, O, P, and Si and their oxidation states. Preferably, the rings are 5 to 20 nucleotides, more preferably 5 to 14 nucleotides, more preferably 5 to 12 nucleotides, and even more preferably 5 to 10 nucleotides. Preferred are tri-built tetracyclic rings (representing built rings formed by a three-membered ring and a four-membered ring; according to IUPC nomenclature, this could be a built ring with a three-membered ring or a four-membered ring as the base ring, and the same applies below), tri-built pentacyclic rings, tri-built hexacyclic rings, tetra-built tetracyclic rings, tetra-built pentacyclic rings, tetra-built hexacyclic rings, penta-built pentacyclic rings, penta-built hexacyclic rings, and hexa-built hexacyclic rings. Non-limiting examples include purines, quinolines, isoquinolines, benzopyrans, benzofurans, and benzothiophenes. The cyclic ring may optionally be further replaced by any substituent.

[0172] A "bridged ring" refers to two rings sharing two non-adjacent atoms, which may contain zero or more double bonds and may be substituted or unsubstituted. One or more rings may contain 0 to 5 heteroatoms selected from N, S, O, P, and Si and their oxidation states; the ring atoms comprise 5 to 20 atoms, preferably 5 to 14 atoms, more preferably 5 to 12 atoms, and even more preferably 5 to 10 atoms; non-limiting examples include adamantane, etc.

[0173] .

[0174] “C 1-4 "alkyl acyl" refers to C 1-4 Alkyl-C(O)-. Non-limiting examples include formyl, acetyl, and propionyl groups.

[0175] “C 1-4 "alkylsulfonyl" refers to C 1-4 Alkyl-S(O)2-. Non-limiting examples include methanesulfonyl, ethanesulfonyl, and propanesulfonyl.

[0176] "alkylamino" or "alkylamino" refers to an amino group substituted with one or two alkyl groups, also written as -N-(alkyl)2 or -NH-alkyl, the latter also written as monoalkylamino. Non-limiting examples include dimethylamino, monomethylamino, diethylamino, monoethylamino, etc.

[0177] When the listed linking groups do not specify their linking direction, the linking direction includes both left-to-right and right-to-left reading orders. For example, ALB, where L is selected from -MW-, includes cases like AMWB and AWMB. Furthermore, if the structure contains a linking group, the Markush variables listed for that linking group are understood as linking groups. Specifically, if the Markush variables list "alkyl," "alkenyl," or "alkynyl," then "alkyl" is understood to represent an alkylene linking group, "alkenyl" represents an alkenyl linking group, and "alkynyl" represents an alynyl linking group.

[0178] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or possibility that the event or environment may or may not occur. For example, "optionally substituted F alkyl" means that the alkyl group may but does not have to be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

[0179] Unless otherwise specified, "substitution" or "substituent" refers to any substitution occurring at a position permitted by chemical theory, with the number of substituents conforming to the rules of chemical bonding. Exemplary substituents include, but are not limited to: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Heteroalkyl, C 5-12 Aryl, 5-12 heteroaryl, hydroxyl, C 1-6 Alkoxy, C 5-12 aryloxy groups, thiol groups, C 1-6 Alkylthio, cyano, halogen, C 1-6 alkylthiocarbonyl, C 1-6 Alkyl carbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, amino, phosphonic acid, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2,-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 alkyl)2,-HC(=O)NH(C 1-6Alkyl), -NHC(=O)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 alkyl)2,-SO2NH(C 1-6 Alkyl group, -SO2NH2, -SO2C 1-6 Alkyl groups, etc.

[0180] "Pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, wherein the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0181] "Pharmaceutical composition" means one or more of the compounds described herein or their stereoisomers, solvates, pharmaceutically acceptable salts or eutectics, mixed with other components, wherein the other components contain physiologically / pharmaceuticalally acceptable carriers and / or excipients.

[0182] "Carrier" refers to a system that does not cause significant stimulation to the organism and does not eliminate the biological activity and properties of the given compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug, and deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0183] "Excipient" refers to an agent that is not itself a therapeutic agent but is used as a diluent, excipient, binder, and / or medium to be added to a pharmaceutical composition to improve its disposal or storage properties or to allow or promote the formation of a unit dosage form of the compound or pharmaceutical composition for administration. As is known to those skilled in the art, pharmaceutical excipients can provide a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweeteners. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and croscarmellose (e.g., sodium croscarmellose); (4) tragacanth gum powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter. (9) Oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) Diols, such as propylene glycol; (11) Polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) Esters, such as ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers, such as magnesium hydroxide and aluminum hydroxide; (15) Alginate; (16) Atherless water; (17) Isotonic saline; (18) Ringer's solution; (19) Ethanol; (20) pH buffer solution; (21) Polyesters, polycarbonates and / or polyanhydrides; and (22) Other non-toxic compatible substances used in pharmaceutical preparations.

[0184] "Isomers" include "stereoisomers" and "tautomers." Stereoisomers are isomers that exist in molecules where atoms or groups of atoms are connected in the same order but arranged differently in space. Stereoisomers include cis-trans isomers, optical isomers, and conformational isomers. Tautomers are molecules that can interconvert through a reversible chemical reaction called tautomerization, typically caused by the migration of hydrogen atoms and π bonds (double or triple bonds), resulting in a transformation from one functional group to another. Examples include the following paired compounds: aldehyde / ketone – enol, imine – enamine. Detailed Implementation

[0185] The present invention will be described in detail below through embodiments. Unless otherwise specified, experimental methods under conventional conditions were used in the embodiments. The embodiments are provided to better illustrate the present invention, but should not be construed as limiting the invention to the examples given. Non-essential improvements and adjustments made to the implementation schemes by those skilled in the art based on the above description are still within the scope of protection of the present invention.

[0186] Test methods

[0187] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0188] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0189] The HPLC determination was performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C). 18 100 × 4.6mm, 3.5 μM);

[0190] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used for thin-layer chromatography (TLC) are 0.15 mm-0.20 mm in diameter, and the silica gel plates used for thin-layer chromatography separation and purification are 0.4 mm-0.5 mm in diameter.

[0191] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0192] Example 1:

[0193]

[0194] Step 1: 1A (140 mg, 0.60 mmol, see J. Med. Chem. (1980), 23(4), 424-430. Synthesis) and 1B (90 mg, 0.50 mmol) were dissolved in dry dichloromethane (10 mL). After purging with nitrogen, trimethylsilyl trifluoromethanesulfonate (180 mg, 0.81 mmol) was added. The reaction mixture was stirred at room temperature for 16 h after the addition was complete. After the reaction was complete, 2N sodium hydroxide solution (10 mL) was added and stirred for 30 min. The aqueous phase was extracted twice with dichloromethane after separation. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This crude product was separated by silica gel column chromatography and then purified by prep.HPLC to obtain target compound 1-1 (8 mg, 4.06%) and compound 1-2 (35 mg, 17.8%).

[0195] Prep. HPLC analysis method: Instrument: CAS-05-LCMS-AZ; Column: C18 Column; Mobile phase: A: 10 mmol / L NH4HCO3 in water, B: acetonitrile; Gradient: 5-95% B in A; Flow rate: 1.0 mL / min; Column temperature: 45℃; Wavelength: 210 nm & 254 nm.

[0196] Prep.HPLC preparation method: Instrument: CAS-05-Semi-prep J, Column: C18 Column; Mobile phase: A: 10 mmol / L NH4HCO3 in water, B: acetonitrile; Gradient: 40% B gradient elution, Flow rate: 25 mL / min, Column temperature: 25℃, Wavelength: 210 nm & 254 nm; Cycle time: 10 min; Sample preparation: Sample concentration 5 mg / mL, Acetonitrile solution injection: 1 mL per injection.

[0197] Compound 1-1, retention time 1.827 min, LC-MS (ESI): m / z = 393.2 [M+H] + .

[0198] 1 H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 7.34-7.32 (m, 2H), 7.26-7.24 (m, 2H), 7.16-7.13 (m, 1H), 7.10-7.07 (m, 1H), 6.82-6.76 (m, 1H), 3.94-3.91 (m, 2H), 2.64-2.62 (m, 2H), 2.47-2.44 (m, 2H), 2.36 (s, 3H), 2.01-1.97(m, 2H), 1.94 (s, 6H), 1.82-1.79 (m, 2H), 1.61-1.54 (m, 2H).

[0199] Compounds 1-2, retention time 1.971 min, LC-MS (ESI): m / z = 393.1 [M+H] + .

[0200] 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.35-7.33 (m, 2H), 7.23-7.19 (m, 2H), 7.12-7.10 (m, 2H), 6.87-6.82 (m, 1H), 6.22-6.21 (m, 1H), 4.06-4.02 (m, 2H), 2.96-2.92 (m, 2H), 2.76-2.70 (m, 1H), 2.60-2.55 (m, 1H), 2.43-2.39 (m, 1H), 2.26 (s, 3H), 2.09 (s, 6H), 1.98-1.97 (m, 3H), 1.75-1.68 (m, 1H).

[0201] Example 2:

[0202]

[0203] Step 1: 2A (330 mg, 1.34 mmol, synthesized according to patent WO2009118168 A1) and 1B (200 mg, 1.12 mmol) were dissolved in dry dichloromethane (20 mL). After purging with nitrogen, trimethylsilyl trifluoromethanesulfonate (400 mg, 1.80 mmol) was added. After the addition was complete, the reaction mixture was stirred at room temperature for 16 h. After the reaction was complete, 2N sodium hydroxide solution (20 mL) was added and stirred for 1 h. The aqueous phase was extracted twice with dichloromethane after separation. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography and then purified by prep.HPLC to obtain the crude compound. The crude compound was further resolved by SFC to obtain compound 2-1 (81.6 mg) and compound 2-2 (63.8 mg).

[0204] SFC analysis method: Instrument: CAS-05-ANA-SFC-D; Column: IK Column; Mobile phase: A: CO2, B: 0.05% MNH3 in MeOH; Gradient: 5-60% B in A; Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0205] SFC preparation method: Instrument: CAS-05-Prep-SFC-F; Column: IK Column; Mobile phase: A: CO2, B: 0.1% NH3•H2O in MEOH; Gradient: 40% B gradient elution; Flow rate: 130 mL / min; Column temperature: 25℃; Wavelength: 220 nm; Cycle time: 4.2 min; Sample preparation: Sample concentration 5 mg / ml; Ethanol solution injection: 1 ml each time. After separation, the fractions were dried in a rotary evaporator at a bath temperature of 35℃ to obtain compounds 2-1 and 2-2.

[0206] Compound 2-1: SFC retention time 2.087 min. LC-MS (ESI): m / z = 409.1 [M+H] + .

[0207] 1 H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 7.38-7.36 (m, 2H), 7.18-7.13 (m, 2H), 6.87-6.85 (m, 2H), 6.83-6.78 (m, 1H), 6.22 (s, 1H), 4.60-4.57(m, 1H), 3.72 (s, 3H), 3.52-3.46 (m, 2H), 2.83-2.79 (m, 2H), 2.70-2.56 (m,2H), 2.43-2.39 (m, 1H), 2.09 (s, 6H), 2.06-1.99 (m, 2H), 1.76–1.70 (m, 1H).

[0208] Compound 2-2: SFC retention time 2.199 min. LC-MS (ESI): m / z = 409.1 [M+H] + .

[0209] 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 7.38-7.35 (m, 2H), 7.17-7.14 (m, 4H), 6.88-6.84 (m, 1H), 6.18 (s, 1H), 3.72 (s, 3H), 3.52-3.46 (m,2H), 2.83-2.79 (m, 2H), 2.70-2.56 (m, 2H), 2.43-2.39 (m, 1H), 2.09 (s, 6H),2.06-1.99 (m, 2H), 1.80-1.66 (m, 2H).

[0210] Example 3:

[0211]

[0212] Step 1: Dissolve 3A (200 mg, 0.61 mmol, synthesized according to patent CA1100516 A2) in dry dichloromethane (6 mL), purge under nitrogen protection, and add 4N hydrogen chloride-ethyl acetate solution (2 mL) in an ice bath. After the addition is complete, continue stirring the reaction solution at room temperature for 2 h. After the reaction is complete, concentrate the reaction solution under reduced pressure to obtain crude product 3B (170 mg), which is directly used in the next step of the reaction.

[0213] LC-MS (ESI): m / z = 286.2[M+H] + .

[0214] Step 2: Crude products 3B (170 mg) and 1B (100 mg, 0.56 mmol) were dissolved in dry dichloromethane (20 mL). After purging with nitrogen, trimethylsilyl trifluoromethanesulfonate (200 mg, 0.90 mmol) was added. The reaction mixture was stirred at room temperature for 16 h after the addition was complete. After the reaction was complete, 2N sodium hydroxide solution (20 mL) was added and stirred for 1 h. The aqueous phase was extracted twice with dichloromethane after separation. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product. The crude product was separated by silica gel column chromatography and then purified by prep.HPLC to obtain crude compound. It was further resolved by SFC to obtain compound 3-1 (60 mg) and compound 3-2 (70 mg).

[0215] SFC analysis method: Instrument: CAS-05-ANA-SFC-D; Column: IK Column; Mobile phase: A: CO2, B: 0.05% MNH3 in MeOH; Gradient: 5-80% B in A; Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm.

[0216] SFC preparation method: Instrument: CAS-05-Prep-SFC-F; Column: IK Column; Mobile phase: A: CO2, B: 0.1% NH3•H2O in MEOH; Gradient: 60% B gradient elution; Flow rate: 120 mL / min; Column temperature: 25℃; Wavelength: 220 nm; Cycle time: 4.2 min; Sample preparation: Sample concentration 5 mg / ml; Ethanol solution injection: 1 ml each time. After separation, the fractions were dried in a rotary evaporator at a bath temperature of 35℃ to obtain compounds 3-1 and 3-2.

[0217] Compound 3-1: SFC retention time 3.447 min. LC-MS (ESI): m / z = 447.1 [M+H] + .

[0218] 1 H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 7.81-7.79 (m, 2H), 7.65-7.63 (m, 2H), 7.16-7.15 (m, 1H), 7.11-7.10 (m, 1H), 6.84-6.79 (m, 1H), 6.35(s, 1H), 4.63-4.60 (m, 1H), 3.84-3.81 (m, 2H), 2.93-2.89 (m, 2H), 2.61-2.59(m, 3H), 1.93 (s, 6H), 1.85-1.82 (m, 2H), 1.46-1.43 (m, Compound 3-2 (1H): SFC retention time 5.229 min. LC-MS (ESI): m / z = 447.1 [M+H] + .

[0219] 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 7.81-7.79 (m, 2H), 7.66-7.64 (m, 2H), 7.18-7.15 (m, 1H), 7.12-7.09 (m, 1H), 6.83-6.78 (m, 1H), 3.94-3.92 (m, 2H), 2.65-2.63 (m, 2H), 2.07-1.99 (m, 4H), 1.93 (s, 6H), 1.85-1.82(m, 2H), 1.58-1.52 (m, 2H).

[0220] Biological testing methods

[0221] 1. Assay for the agonistic activity of the orphanone receptor (NOPR)

[0222] CHO cells overexpressing the orphanone receptor (NOPR) (constructed in the laboratory of Beijing Aisiyipu Biotechnology Co., Ltd.) were cultured in F-12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B. Cells were cultured in an incubator at 37ºC and 5% CO2. On the day of the experiment, 1× Stimulation Buffer was prepared according to the LANCE Ultra cAMP kit (Revity, TRF0264) instructions. The test sample stock solution was diluted with DMSO (9-10 concentration points), and then 10 nL / well was transferred to the corresponding well using ECHO. For cell treatment, the old medium was removed and the cells were rinsed once with PBS, then 1 mL of 0.25%-Trypsin-EDTA solution was added, and the cells were incubated at 37ºC for approximately 2 minutes. When the cells detached from the bottom of the dish, approximately 5 mL of preheated 37ºC complete medium was added. Gently pipette the cell suspension to separate aggregated cells, then transfer them to sterile centrifuge tubes and collect the cells by centrifugation at 1000 rpm for 5 minutes. Resuspend the cells in 1× Stimulation Buffer, count them, and adjust the cell density to 1×10⁻⁶. 5Cells / mL were seeded at 10 μL / well in a 384-well plate containing the test sample, centrifuged, and incubated at 37ºC for 10 min. Then, 10 nL / well of Forskolin (2 mM) solution was transferred to the corresponding well using ECHO, centrifuged, and incubated at 37ºC for 30 min. Eu-cAMP was diluted 50-fold with detection buffer, and 4 μL was added to the corresponding well. Ultra-anti-cAMP was diluted 150-fold with detection buffer, and 4 μL was added to the corresponding well. After centrifugation, the cells / well was incubated at room temperature for 1 hour. After incubation, the readings at 665 nm and 620 nm were detected using a microplate reader at a wavelength of 330 nm excitation. The final concentration of DMSO was 0.1%. The ratio and activation rate were calculated using the following formula: Ratio = Signal 665 / Signal 620 10000, Activation Rate (%) = (Ratio) 受试物 Ratio 阴性对照 ) / (Ratio 阳性对照 Ratio 阴性对照 100. EC was fitted using GraphPad Prism software. 50 value.

[0223] Conclusion: The compounds of the present invention, such as the compounds in the examples, have excellent agonistic activity towards NOPR.

[0224] 2. Assay for the agonistic activity of mu-opioid receptors (MOR)

[0225] CHO cells overexpressing the mu opioid receptor (constructed in the laboratory of Beijing Aisiyipu Biotechnology Co., Ltd.) were cultured in F-12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B. Cells were cultured in an incubator at 37ºC and 5% CO2. On the day of the experiment, 1× Stimulation Buffer was prepared according to the LANCE Ultra cAMP kit (Revity, TRF0264) instructions. The test sample stock solution was diluted with DMSO (9-10 concentration points), and then 10 nL / well was transferred to the corresponding experimental well using ECHO. For cell treatment, the old medium was removed and the cells were rinsed once with PBS, then 1 mL of 0.25%-Trypsin-EDTA solution was added, and the cells were incubated at 37ºC for approximately 2 minutes. When the cells detached from the bottom of the dish, approximately 5 mL of preheated 37ºC complete medium was added. Gently pipette the cell suspension to separate aggregated cells, then transfer them to sterile centrifuge tubes and collect the cells by centrifugation at 1000 rpm for 5 minutes. Resuspend the cells in 1× Stimulation Buffer, count them, and adjust the cell density to 2.2×10⁻⁶. 5 Cells / mL were seeded at 10 μL / well in a 384-well plate containing the test sample, centrifuged, and incubated at 37ºC for 10 min. Then, 10 nL / well of Forskolin (6 mM) solution was transferred to the corresponding well using ECHO, centrifuged, and incubated at 37ºC for 30 min. Eu-cAMP was diluted 50-fold with detection buffer, and 4 μL was added to the corresponding well. Ultra-anti-cAMP was diluted 150-fold with detection buffer, and 4 μL was added to the corresponding well. After centrifugation, the cells / well was incubated at room temperature for 1 hour. After incubation, the readings at 665 nm and 620 nm were detected using a microplate reader at a wavelength of 330 nm excitation. The final concentration of DMSO was 0.1%. The ratio and activation rate were calculated using the following formula: Ratio = Signal 665 / Signal 620 10000, Activation Rate (%) = (Ratio) 受试物 Ratio 阴性对照 ) / (Ratio 阳性对照 Ratio 阴性对照 100. EC was fitted using GraphPad Prism software. 50 value.

[0226] Experimental results: MOR EC of some specific compounds 50(nM) and MOR Emax% @10μM are shown in Table 1. For EC 50 A represents EC 50 ≤10 nM, B means 10 nM < EC 50 ≤100nM, C represents EC 50 >100nM.

[0227] Table 1

[0228] Compound numbering <![CDATA[MOR EC 50 (nM)]]> 1-2 B 2-2 B

[0229] Conclusion: The compounds of the present invention, such as the compounds in the examples, have excellent agonistic activity for MOR.

[0230] 3. Kappa opioid receptor (KOR) agonistic activity assay

[0231] CHO cells overexpressing the kappa opioid receptor (constructed in the laboratory of Beijing Aisiyipu Biotechnology Co., Ltd.) were cultured in F-12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B. Cells were cultured in an incubator at 37ºC and 5% CO2. On the day of the experiment, 1× Stimulation Buffer was prepared according to the LANCE Ultra cAMP kit (Revvity, TRF0264) instructions. The test sample stock solution was diluted with DMSO (9-10 concentration points), and then 10 nL / well was transferred to the corresponding experimental well using ECHO. For cell treatment, the old medium was removed and the cells were rinsed once with PBS, then 1 mL of 0.25%-Trypsin-EDTA solution was added, and the cells were incubated at 37ºC for approximately 2 minutes. When the cells detached from the bottom of the dish, approximately 5 mL of preheated 37ºC complete medium was added. Gently pipette the cell suspension to separate aggregated cells, then transfer them to sterile centrifuge tubes and collect the cells by centrifugation at 1000 rpm for 5 minutes. Resuspend the cells in 1× Stimulation Buffer, count them, and adjust the cell density to 2×10⁶ cells / mL. 5Cells / mL were seeded at 10 μL / well in a 384-well plate containing the test sample, centrifuged, and incubated at 37ºC for 10 min. Then, 10 nL / well of Forskolin (1 mM) solution was transferred to the corresponding well using ECHO, centrifuged, and incubated at 37ºC for 30 min. Eu-cAMP was diluted 50-fold with detection buffer, and 4 μL was added to the corresponding well. Ultra-anti-cAMP was diluted 150-fold with detection buffer, and 4 μL was added to the corresponding well. After centrifugation, the cells / well was incubated at room temperature for 1 hour. After incubation, the readings at 665 nm and 620 nm were detected using a microplate reader at a wavelength of 330 nm excitation. The final concentration of DMSO was 0.1%. The ratio and activation rate were calculated using the following formula: Ratio = Signal 665 / Signal 620 10000, Activation Rate (%) = (Ratio) 受试物 Ratio 阴性对照 ) / (Ratio 阳性对照 Ratio 阴性对照 100. EC was fitted using GraphPad Prism software. 50 value.

[0232] 4. Assay for the agonistic activity of delta-opioid receptors (DOR)

[0233] CHO cells overexpressing delta-opioid receptors (constructed in the laboratory of Beijing Aisiyipu Biotechnology Co., Ltd.) were cultured in F-12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B. Cells were cultured in an incubator at 37ºC and 5% CO2. On the day of the experiment, 1× Stimulation Buffer was prepared according to the LANCE Ultra cAMP kit (Revity, TRF0264) instructions. The test sample stock solution was diluted with DMSO (9-10 concentration points), and then 10 nL / well was transferred to the corresponding experimental well using ECHO. For cell treatment, the old medium was removed and the cells were rinsed once with PBS, then 1 mL of 0.25%-Trypsin-EDTA solution was added, and the cells were incubated at 37ºC for approximately 2 minutes. When the cells detached from the bottom of the dish, approximately 5 mL of preheated 37ºC complete medium was added. Gently pipette the cell suspension to separate aggregated cells, then transfer them to sterile centrifuge tubes and collect the cells by centrifugation at 1000 rpm for 5 minutes. Resuspend the cells in 1× Stimulation Buffer, count them, and adjust the cell density to 2×10⁶ cells / mL. 5Cells / mL, seeded at 10 μL / well in a 384-well plate containing the test sample, centrifuged, and incubated at 37ºC for 10 min. Then, 10 nL / well of Forskolin (0.5 mM) solution was transferred to the corresponding well using ECHO, centrifuged, and incubated at 37ºC for 30 min. Eu-cAMP was diluted 50-fold with detection buffer, and 4 μL was added to the corresponding well. Ultra-anti-cAMP was diluted 150-fold with detection buffer, and 4 μL was added to the corresponding well. After centrifugation, the cells / mL were incubated at room temperature for 1 hour. After incubation, the readings at 665 nm and 620 nm were detected using a microplate reader at a wavelength of 330 nm excitation. The final concentration of DMSO was 0.1%. The Ratio and activation rate were calculated using the following formula: Ratio = Signal 665 / Signal 620 10000, Activation Rate (%) = (Ratio) 受试物 Ratio 阴性对照 ) / (Ratio 阳性对照 Ratio 阴性对照 100. EC was fitted using GraphPad Prism software. 50 value.

[0234] Experimental results: DOR EC of some specific compounds 50 (nM) and DOR Emax% @10μM are shown in Table 2. For EC 50 A represents EC 50 ≤10 nM, B means 10 nM < EC 50 ≤100nM, C represents EC 50 >100nM.

[0235] Table 2

[0236] Compound numbering <![CDATA[DOR EC 50 (nM)]]> 1-2 B 2-1 B 2-2 B

[0237] Conclusion: The compounds of the present invention, such as the compounds in the examples, have excellent agonistic activity toward DOR.

[0238] 5. In vitro plasma stability test

[0239] A prepared compound solution is added to a certain amount of biological matrix to prepare stability samples at two concentration levels (low-concentration quality control sample and high-concentration quality control sample), with three copies of each concentration level. Under the required experimental conditions, the peak area ratio of the sample after a certain period of time / the peak area ratio of the sample at point 0 is multiplied by 100% to obtain the stability test result of the compound.

[0240] Conclusion: The compounds of the present invention, such as the compounds in the examples, exhibit good in vitro plasma stability.

[0241] 6. Rat pharmacokinetic test

[0242] Experimental animals: Male SD rats, approximately 180-220 g in size, 6-8 weeks old, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0243] Experimental design: On the day of the experiment, SD rats were randomly divided into groups according to their body weight. They were fasted for 12-14 hours before drug administration but allowed free access to water, and were fed 4 hours after drug administration.

[0244] Before and after administration of isoflurane anesthesia, 0.10 mL of blood was drawn via the orbital cavity and placed in an EDTAK2 centrifuge tube. The centrifuge was then incubated at 5000 rpm for 4 hours. o Centrifuge at 1°C for 10 min and collect plasma. Store all samples at -80°C before analysis. o C. Quantitative analysis of the sample was performed using LC-MS / MS.

[0245] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties in rats.

[0246] 7. Mouse pharmacokinetics test

[0247] Experimental animals: Male C57 mice, 22-25 g, purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0248] Experimental design: On the day of the experiment, ICR mice were randomly divided into groups according to body weight. They were fasted for 12-14 hours before administration but allowed free access to water, and were fed 4 hours after administration.

[0249] Before and after administration of isoflurane anesthesia, 0.04 mL of blood was drawn via the orbital cavity and placed in an EDTAK2 centrifuge tube. The centrifuge was then incubated at 5000 rpm for 4 hours. o Centrifuge at 1°C for 10 min and collect plasma. Store all samples at -80°C before analysis. o C. Quantitative analysis of the sample was performed using LC-MS / MS.

[0250] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties in mice.

[0251] 8. Pharmacokinetics of Beagle Dogs

[0252] Experimental animals: Male beagle dogs, weighing approximately 8-11 kg, purchased from Beijing Mars Biotechnology Co., Ltd.

[0253] Experimental method: On the day of the experiment, beagles were randomly divided into groups according to their body weight. They were fasted for 12-14 hours before administration but allowed free access to water. They were fed 4 hours after administration.

[0254] Blood samples of 1 mL were collected via jugular or limb veins before and after drug administration and placed in EDTAK2 centrifuge tubes. The plasma was collected by centrifugation at 5000 rpm and 4 °C for 10 min. All samples were stored at -80 °C before analysis and quantitative analysis was performed using LC-MS / MS.

[0255] Conclusion: The compounds of the present invention, such as the compounds in the examples, exhibit good pharmacokinetic properties.

[0256] 9. Pharmacokinetics in monkeys

[0257] Experimental animals: Male cynomolgus monkeys, 3-5 kg, 2.5-5 years old, purchased from Hainan Xinzhengyuan Biotechnology Co., Ltd.

[0258] Experimental method: On the day of the experiment, monkeys were randomly divided into groups according to their body weight. They were fasted for 14-18 hours before administration but allowed free access to water, and were fed 4 hours after administration.

[0259] Blood samples of 1.0 mL were collected via venous sampling from each limb before and after administration and placed in EDTAK2 centrifuge tubes. The centrifuge volume was 5000 rpm, 4 mL. o Centrifuge at 1°C for 10 min and collect plasma. Store all samples at -80°C before analysis. o C. Quantitative analysis of the sample was performed using LC-MS / MS.

[0260] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties in monkeys.

[0261] 10. hERG potassium ion channel function test

[0262] Experimental platform: Electrophysiological manual patch-clamp system

[0263] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channels

[0264] Experimental Methods: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents at room temperature using whole-cell patch-clamp technique. Glass microelectrodes were fabricated from glass electrode blanks (BF150-86-10, Sutter) using a stretching device. The tip resistance after perfusion with electrode fluid was approximately 2-5 MΩ. The glass microelectrodes were inserted into the amplifier probe to connect to the patch-clamp amplifier. Clamp voltage and data recording were controlled and recorded using pClamp 10 software via computer, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After obtaining whole-cell recordings, the cells were clamped at -80 mV to induce hERG potassium current (Ik). hERGThe step voltage was applied from -80 mV to +20 mV over 2 s, then repolarized to -50 mV for 1 s before returning to -80 mV. This voltage stimulation was applied every 10 s, and the drug administration process began after the hERG potassium current stabilized (at least 1 minute). Each test concentration of the compound was administered for at least 1 minute, and at least 2 cells (n≥2) were tested for each concentration.

[0265] Data processing: Data analysis and processing were performed using pClamp 10, GraphPad Prism 5, and Excel software. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula:

[0266] Inhibition % = [1 – (I / Io)]×100%

[0267] Where Inhibition % represents the percentage of inhibition of hERG potassium current by the compound, and I and Io represent the amplitude of hERG potassium current before and after drug administration, respectively.

[0268] Compound IC 50 The following equations were fitted and calculated using GraphPad Prism 5 software:

[0269] Y=Bottom + (Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0270] Where X is the Log value of the detected concentration of the test sample, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0271] Conclusion: The compounds of the present invention, such as the compounds in the examples, do not inhibit the hERG potassium channel current.

[0272] 11. CYP450 enzyme inhibition test

[0273] The aim of this study was to evaluate the effects of test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro assay system. Specific probe substrates for CYP450 isoenzymes were co-incubated with human liver microsomes and different concentrations of the test substances. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS) after sample processing, and the changes in CYP enzyme activity were measured. The IC50 values ​​were calculated. 50 The value is used to evaluate the inhibitory potential of the test substance against each CYP enzyme subtype.

[0274] Conclusion: The compounds of this invention, such as those in the examples, do not inhibit the five isoenzymes of human liver microsomal cytochrome P450 (CYP). 12. Liver microsomal stability test

[0275] This experiment used liver microsomes from five genera—human, canine, rat, and mouse—as in vitro models to evaluate the metabolic stability of the test substance.

[0276] At 37°C, 1 µM of the test substance was co-incubated with microsomal protein and coenzyme NADPH. The reaction was terminated by adding ice-cold acetonitrile containing an internal standard after certain time intervals (5, 10, 20, 30, 60 min). The concentration of the test substance in the sample was detected by LC-MS / MS. T1 / 2 was calculated using the ln value of the drug residue in the incubation system and the incubation time. The intrinsic clearance rate (CL) of liver microsomes was further calculated. int(mic) and hepatic intrinsic clearance rate CL int(Liver) .

[0277] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good stability in liver microsomes.

[0278] 13. Caco-2 Permeability Test

[0279] The experiment used monolayers of Caco-2 cells, incubated in triple parallel in 96-well Transwell plates. A transport buffer solution (HBSS, 10 mM HEPES, pH 7.4±0.05) containing either the compound of the present invention (2 μM) or the control compounds digoxin (10 μM), naldolol (2 μM), and metoprolol (2 μM) was added to the dosing well on the apical or basal side. A transport buffer solution containing DMSO was added to the corresponding receiving well. After incubation at 37±1°C for 2 hours, the cell plate was removed, and appropriate amounts of sample were transferred from both the apical and basal sides to new 96-well plates. Acetonitrile containing an internal standard was then added to precipitate the protein. The samples were analyzed using LC MS / MS to determine the concentrations of the compound of the present invention and the control compounds. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to the basal side of the monolayer cells, and from the basal side to the apical side, thereby calculating the efflux rate. Leakage of fluorescein was used to evaluate the integrity of the monolayer cells after 2 hours of incubation.

[0280] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good permeability.

Claims

1. A compound of general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof: in, Whether ring A is present or not, if ring A is present, it is selected from 3-12 membered carbon rings and 4-15 membered heterocycles; The condition is that when ring A does not exist, L1 and R A Directly connected; X1 and X2 are each independently selected from CR X1 R X2 ,O,S,S(=O),S(=O)2 or NR X1 ; R X1 R X2 Each element is independently selected from hydrogen, deuterium, hydroxyl, amino, halogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkoxy groups; R1 is selected from F, Br, or C. 1-6 Alkoxy; R2 is selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy group, -(CR3R4) m -NR5R6; R3, R4, R5, and R6 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl, -O- (4-8 membered heterocyclic alkyl), -(CH2) r -C 3-8 Cycloalkyl, -(CH2) r -(4-8-membered heterocyclic alkyl), wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced; Alternatively, R5 and R6, together with the atoms attached to them, form a 3-8 membered heterocyclic alkyl group or a 3-8 membered heterocyclic alkenyl group, wherein the heterocyclic alkyl group or heterocyclic alkenyl group is further surrounded by 1-5 R atoms. x Replaced; Alternatively, R5 and any R A Together with the atoms attached thereto, they form 3-8 membered heterocyclic alkyl groups or 3-8 membered heterocyclic alkenyl groups, wherein the heterocyclic alkyl or heterocyclic alkenyl groups are optionally further surrounded by 1-5 R groups. x Replaced; L1 is selected from key, C 1-6 Alkylene, C 2-6 imidene group, C 2-6 The alkylene group, wherein one or more CH2 groups are optionally surrounded by 1-5 groups selected from O, S, S(=O), S(=O)2, NR L1 The C (=O) groups are replaced by alkylene, alkenylene, or yntylide groups, which are optionally replaced by 1-5 R groups. x Replaced; R L1 Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced; Each R A Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, =O, cyano, amino, -SF5, -SCF3, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkyl, C 1-6 deuterated alkoxy group, -SC 1-6 Haloalkyl, =CH2, =CF2, =CHF, =CH(C 1-3 Alkyl), =C(C) 1-3 Alkyl)2、=CH(C 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =C(C) 1-3 (halogenated alkyl)2, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, -OC 3-8 Cycloalkyl, -O- (4-8 membered heterocycloalkyl), -C(=O)-C 3-8 Cycloalkyl, -C(=O)-(4-8 membered heterocycloalkyl), -NHC(=O)-C 3-8 Cycloalkyl, -C(=O)NH-C 3-8 Cycloalkyl, -NHC(=O)- (4-8 membered heterocyclic alkyl), -C(=O)NH- (4-8 membered heterocyclic alkyl), -S(O)2-C 1-6 Alkyl groups, wherein the alkyl, amino, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl groups are optionally further reinforced with 1-5 R groups. x Replaced; Each R x Each is independently selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =NH, -NHCOC 1-3 Alkyl, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl groups, -SF5, -SCF3, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl) (C 1-3 Halogenated alkyl), =C 4-6 Cycloalkyl, =(4-6 membered heterocyclic alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl; The condition is that L1 cannot be a key if ring A does not exist; n is an integer between 0 and 5; m is an integer between 0 and 5; r is an integer between 0 and 5.

2. The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, having the structures shown in formula (II) and formula (III): 。 3. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, The presence or absence of ring A; when ring A is present, ring A is selected from 3-8 member monocyclic carbocyclic groups, 6-12 member bicyclic carbocyclic groups, 4-12 member monocyclic heterocyclic groups, and 6-12 member bicyclic heterocyclic groups. R2 is selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy group, -NR5R6, -CH2-NR5R6; R5 and R6 are each independently selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -(4-6-membered heterocyclic alkyl), wherein the alkyl, alkoxy, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced; Alternatively, R5 and R6, together with the atoms attached to them, form a 3-6 membered heterocyclic alkyl group or a 3-6 membered heterocyclic alkenyl group, wherein the heterocyclic alkyl group or heterocyclic alkenyl group is further surrounded by 1-3 R atoms. x Replaced; Alternatively, R5 and any R A Together with the atoms attached thereto, they form 5-7 membered heterocyclic alkyl or 5-7 membered heterocyclic alkenyl groups, wherein the heterocyclic alkyl or heterocyclic alkenyl group is optionally further surrounded by 1-3 R groups. x Replaced; L1 is selected from key, C 1-4 Alkylene, C 2-4 imidene group, C 2-4 The alkylene group, wherein one or more CH2 groups are optionally surrounded by 1-3 groups selected from O, S, S(=O), S(=O)2, NR L1 The C (=O) groups are replaced by alkylene, alkenylene, or yntylide groups, which are optionally replaced by 1-5 R groups. x Replaced; R L1 Selected from hydrogen, deuterium, and C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced; Each R A Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, =O, cyano, amino, -SF5, -SCF3, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy group, -N(C 1-4 Alkyl group 2, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =C(C) 1-3 Alkyl)2、=CH(C 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =C(C) 1-3 (halogenated alkyl)2, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, -C(=O)-(4-8 membered heterocyclic alkyl), -S(O)2-C 1-4 Alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl may optionally be further surrounded by 1-5 R groups. x What it replaced.

4. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, The presence or absence of ring A, when present, is selected from 3-6 member monocyclic cycloalkyl, 5-8 member bridged cycloalkyl, 6-12 member spirocyclic cycloalkyl, 5-12 member fused cycloalkyl, 3-6 member monocyclic heterocyclic alkyl, 5-8 member bridged heterocyclic alkyl, 6-12 member spirocyclic heterocyclic alkyl, 5-12 member fused heterocyclic alkyl, phenyl, 6-10 member fused aryl, 5-6 member monocyclic heteroaryl, and 8-12 member fused heteroaryl. R1 is selected from F; R2 is selected from C 1-4 Alkoxy, C 1-4 Halogenated alkoxy group, -NR5R6; R5 is selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -(4-6-membered heterocyclic alkyl), wherein the alkyl, alkoxy, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced; R6 is selected from C 1-4 alkyl; Alternatively, R5 and R6, together with the atoms attached to them, form a 4-6 membered heterocyclic alkyl group or a 4-6 membered heterocyclic alkenyl group, wherein the heterocyclic alkyl group or heterocyclic alkenyl group is further surrounded by 1-3 R atoms. x Replaced; Alternatively, R5 and any R A Together with the atoms attached thereto, they form a 5-6 membered heterocyclic alkyl group or a 5-6 membered heterocyclic alkenyl group, wherein the heterocyclic alkyl group or heterocyclic alkenyl group is optionally further surrounded by 1-3 R atoms. x Replaced; L1 is selected from key, C 1-4 Alkylene, C 2-4 imidene group, C 2-4 The alkylene, alkenylene, or ynylene group is optionally surrounded by 1-5 R groups. x Replaced; Each R A Each is independently selected from hydrogen, deuterium, halogens, =O, -SF5, -SCF3, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkyl, C 1-4 Deuterated alkoxy group, N(C) 1-4 Alkyl group 2, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =C(C) 1-3 Alkyl)2、=CH(C 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =C(C) 1-3 (halogenated alkyl)2, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, -C(=O)- (4-6 membered monocyclic heterocyclic alkyl), -C(=O)- (6-8 membered polycyclic heterocyclic alkyl), -S(O)2-C 1-3 Alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl may optionally be further surrounded by 1-5 R groups. x What it replaced.

5. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, Whether ring A exists or not, if ring A exists, ring A is selected from any of the 1-3 selected from R. A The following structures are formed by the substitution of groups: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； R2 is selected from methoxy, -OCF3, -N(CH3)2, -N(CH3)(CD3), -N(CD3)2, -N(CH3)(C 3-6 cycloalkyl), -N(CH3)(-CH2-C 3-6 cycloalkyl) , The cycloalkyl group may optionally be further substituted with 1-2 groups selected from deuterium, =CH2, =CF2; Each R A Each is independently selected from hydrogen, deuterium, halogens, =O, -SF5, -SCF3, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Haloalkyl, N(C) 1-4 Alkyl)2, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, =CH2, =CF2, =CHF, =CH(CH3), =CH(CF3), =CF(CH3), =C(CH3)2, =C(CH3)(CF3), -S(O)2-CH3, -C(=O)-(4 membered heterocyclic alkyl), -C(=O)-(7 membered spirocyclic heterocyclic alkyl), wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R x What it replaced.

6. The compound according to claim 1, wherein the stereoisomer or pharmaceutically acceptable salt thereof is selected from one of the structures in Table 1 and Table 2.

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

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

9. Use of the compound of any one of claims 1-6, its stereoisomer or pharmaceutically acceptable salt, or the composition of any one of claims 8-9 in the preparation of a medicament for the treatment / prevention of NOP and opioid receptor-mediated diseases.

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

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