Use of peptide amide compounds for the preparation of medicaments for the prevention of nausea and vomiting

Abstract

Use of a compound of formula (I) or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or a composition thereof, in the manufacture of a medicament for preventing postoperative nausea and vomiting or chemotherapy-induced nausea and vomiting.

Description

Use of peptide amide compounds in preparing drugs for preventing nausea and vomiting Technical Field

[0001] The present invention relates to a compound of formula (I) or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or cocrystals and compositions thereof, and their use in preparing drugs for preventing postoperative nausea and vomiting or nausea and vomiting caused by chemotherapy. Background Art

[0002] Postoperative nausea and vomiting (PONV) is a postoperative gastrointestinal disorder that primarily occurs within 6 or 24 hours after surgery, though in a minority of patients, it can persist for 3 to 5 days. The incidence of PONV is 30% in general surgical patients and as high as 80% in high-risk patients. PONV can cause varying degrees of distress in patients, including fluid and electrolyte imbalances, wound dehiscence, incisional hernia formation, aspiration, and aspiration pneumonia, leading to decreased patient satisfaction, prolonged hospitalization, and increased medical costs. Therefore, PONV is a significant factor affecting postoperative recovery.

[0003] The pathogenesis of PONV is complex, involving central and peripheral receptors and multiple neural pathways. Central sites involved in the vomiting reflex include the vomiting center and the chemoreceptor trigger zone (CTZ). When receptors in the digestive system, such as the base of the tongue, pharynx, stomach, intestines, common bile duct, or in the cerebral cortex and vestibular apparatus, are stimulated, afferent signals are transmitted to the vomiting center via the vagus nerve, sympathetic nerves, and glossopharyngeal nerve. Furthermore, the CTZ is rich in multiple receptors, such as dopamine, 5-HT3, histamine, opioid, and cholinergic receptors, which directly sense various metabolites, drugs, or toxins in the blood and cerebrospinal fluid and project signals to the vomiting center. Impulsive signals from the vomiting center are then transmitted via the vagus nerve, sympathetic nerves, phrenic nerves, and spinal nerves to the stomach, small intestine, diaphragm, and abdominal wall muscles, triggering vomiting.

[0004] Chemotherapy-induced nausea and vomiting (CINV) is a common complication in cancer patients undergoing chemotherapy. More than 70% of cancer patients experience varying degrees of nausea and vomiting. Severe nausea and vomiting can lead to dehydration, electrolyte imbalance, and nutritional deficiencies, impacting the normal progress of cancer treatment. CINV is generally classified into five types based on the time of onset: acute, delayed, explosive, refractory, and anticipatory. Acute nausea and vomiting typically occurs within minutes to hours after drug administration, peaks 5-6 hours after administration, and usually resolves within 24 hours. Delayed nausea and vomiting often occurs 24 hours after administration and is common with chemotherapy agents such as cisplatin, carboplatin, and cyclophosphamide. It can last for several days, typically 2-5 days.

[0005] It is currently believed that CINV is caused by stimulation of cortical pathways. For example, chemotherapy drugs stimulate the release of neurotransmitters from gastrointestinal chromaffin cells. These neurotransmitters bind to their corresponding receptors, generating nerve impulses that travel through the vagus nerve and sympathetic nerves to directly stimulate the chemoreceptor trigger zone (CTZ), leading to increased salivation, increased breathing, and contractions of the pharyngeal, gastrointestinal, and abdominal muscles, ultimately causing vomiting. Currently, 5-hydroxytryptamine (5-HT) is considered the primary neurotransmitter mediating acute CINV, but its involvement in delayed CINV remains unclear. In addition to 5-HT, other neurotransmitters that induce vomiting include dopamine, histamine, and substance P. The neurokinin-1 (NK-1) receptor for substance P regulates vomiting through both central and peripheral pathways, with the former being the primary pathway. In addition to these chemotherapy-induced emetic mechanisms, chemotherapy drugs and their metabolites can also directly stimulate the medullary chemoemetic zone, which in turn transmits to the central nervous system, causing vomiting. Furthermore, sensory and psychiatric factors can directly stimulate cortical pathways, leading to vomiting.

[0006] Currently, the primary prevention and treatment for PONV and CINV is medication. These medications block one or more receptors, including 5-HT3, dopamine, histamine, cholinergic, and neurokinin receptors, to achieve an antiemetic effect. Commonly used medications include 5-HT3 receptor antagonists (ondansetron, dolasetron, etc.), neurokinin-1 (NK-1) receptor antagonists (aprepitant, rolapitant, etc.), corticosteroids (dexamethasone, etc.), antidopaminers (haloperidol, metoclopramide, etc.), anticholinergics (scopolamine transdermal patch), and antihistamines (dimenhydrinate, promethazine, etc.).

[0007] For surgical patients, postoperative recovery is impacted by various factors, including pain, vomiting, and infection. To help patients recover as quickly as possible, multiple medications are often used, but this can also increase the risk of adverse events. For chemotherapy patients, severe and persistent nausea and vomiting can have a serious impact on their physical and mental well-being due to the need for periodic chemotherapy treatments.

[0008] Although drugs are available for preventing postoperative nausea and vomiting and chemotherapy-induced nausea and vomiting, their use is limited due to unsatisfactory efficacy levels or side effects. Therefore, new drugs with improved efficacy and fewer side effects are needed.

[0009] Summary of the Invention

[0010] The present invention provides a compound of formula (I) or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or cocrystals and compositions thereof, and their use in the preparation of a medicament for preventing postoperative nausea and vomiting or nausea and vomiting caused by chemotherapy:

[0011] in,

[0012] R1 is selected from

[0013] m1, m2, m3, and m4 are each independently selected from 0, 1, 2, 3, or 4; m1 and m2 cannot be 0 at the same time; m3 and m4 cannot be 0 at the same time;

[0014] n1 and n2 are each independently selected from 0, 1, 2, 3 or 4;

[0015] Z is selected from CR zl R z2 or NR z3 ;

[0016] R zl 、R z2 Each independently selected from H, F, Cl, Br, I, OH, CF3, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(=O)-C 1-6 Alkyl, -(CH2) q -C(=O)OC 1-6 Alkyl, -(CH2) q -NR le R lf 、-(CH2) q -COOH, -(CH2) q -CONH2、C 3-8A carbocyclic group or a 3 to 8 membered heterocyclic group, wherein the alkyl, alkoxy, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally further substituted by 0-5 groups selected from F, Cl, Br, I, OH, CF3, =O, carboxyl, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 substituted by a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S, and when the heteroatom is selected from S, it is optionally further S, S═O or S(═O) 2;

[0017] R le 、R lf Each independently selected from H, C 1-6 Alkyl, C(=O)OC 1-6 Alkyl, -C(=O)O-(CH2) q -C 3-8 Carbocyclic or -C(=O)O-(CH2) q -3 to 8 membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally further substituted by 0-5 groups selected from F, Cl, Br, I, OH, CF3, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 is substituted by a substituent of a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S;

[0018] Or, R zl and R z2 The carbon atom to which it is connected forms a 3-10 membered nitrogen-containing heterocyclic ring, wherein the ring is optionally further selected from F, Cl, Br, I, OH, CF3, cyano, nitro, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C · is substituted by a substituent of a carbocyclic group or a 3- to 8-membered heterocyclic group;

[0019] R la 、R lb Each independently selected from F, CF3, NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or 3 to 8 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl or heterocyclic group is optionally further substituted by 0-5 groups selected from F, Cl, Br, I, OH, CF3, nitro, cyano, C1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 is substituted by a substituent of a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S;

[0020] R z3 independently selected from H, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)-C 3-8 Carbocyclyl, -C(=O)OC 3-8 Carbocyclyl, -C(=O)O-(3 to 8 membered heterocyclyl), -S(=O) p -C 1-6 Alkyl, -S(=O) p -C 3-8 Carbocyclyl, -S(=O) p -(3- to 8-membered heterocyclyl), -C(=O)NR 1g R lh 、-S(=O)p-NR li R lj or a 3- to 8-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally further substituted by 0-5 groups selected from F, Cl, Br, I, OH, CF3, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 is substituted by a substituent of a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S;

[0021] R lg 、R lh 、R li' 、R lj Each independently selected from H or C 1-6 alkyl;

[0022] Or, R lg 、R lh The nitrogen atom to which it is connected forms a 3- to 10-membered heterocyclic ring, wherein the ring is optionally further selected from F, Cl, Br, I, OH, CF3, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl or -S(=O) p -C 1-6substituted by an alkyl substituent, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S;

[0023] q is selected from 0, 1, 2, 3 or 4;

[0024] p is selected from 0, 1 or 2;

[0025] a is selected from 0, 1, 2 or 3;

[0026] R 4 Independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or -(CH2) q -C 3-8 Carbocyclic group, the alkyl, alkenyl, alkynyl or carbocyclic group is optionally further substituted by 0-5 groups selected from F, Cl, Br, I, OH, CN, CF3, NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 is substituted by a substituent of a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S;

[0027] R 2 、R 3 、R 7 、R 8 Each independently selected from H, C 1-6 Alkyl, -C(=O)OC 1-4 Alkyl, -C(=O)O-(CH2) q -C 3-8 Carbocyclic group, -C(=O)O-(CH2) q -3 to 8 membered heterocyclic group or The alkyl, carbocyclic or heterocyclic group may be further substituted by 0-5 groups selected from F, Cl, Br, I, OH, CF3, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 is substituted by a substituent of a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S;

[0028] b is selected from 0, 1, 2, 3, 4 or 5;

[0029] c is selected from 0, 1, 2, 3, 4 or 5;

[0030] R 5 、R 6Each independently selected from F, Cl, Br, I, OH, CN, CF3, cyano, nitro, C 1-4 Alkyl, -OR 5a 、-C(O)OR 5b 、-SR 5c 、-S(O)R 5d 、-S(O)2R 5e or -NR 5f R 5g ;

[0031] R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R 5f and R 5g Each independently selected from H or C 1-4 alkyl;

[0032] Or, R 5f and R 5g The nitrogen atom to which it is attached forms a 5- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, O or S.

[0033] Preferably, the compound is selected from formula (II):

[0034] in,

[0035] R1 is selected from

[0036] m1, m2, m3, and m4 are each independently selected from 0, 1, or 2; m1 and m2 cannot be 0 at the same time; m3 and m4 cannot be 0 at the same time;

[0037] n1 and n2 are each independently selected from 0 or 2;

[0038] Z is selected from CR zl R z2 or NR z3 ;

[0039] R la 、R lb independently selected from F or NH2;

[0040] R zl 、R z2 Each independently selected from H, carboxyl, amino, -CH2NH2 or

[0041] or R zl 、R z2Able to form a lactam with the C atom to which it is connected

[0042] R z3 independently selected from H, -C(=O)-C 1-4 Alkyl, -C(=O)OC 1-4 Alkyl, -C(=O)-C 3-6 Carbocyclyl, -C(=O)OC 3-6 Carbocyclyl, -S(=O) p -C 1-4 Alkyl, -S(=O) p -C 3-6 Carbocyclic group, -C(=O)NR 1g R lh 、-S(=O) p -NR li R lj or a 3- to 6-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally further substituted with 0-5 substituents selected from F, Cl, Br, I, OH, CF3, nitro, cyano, amino, methyl, ethyl, methoxy, ethoxy, cyclopropyl or phenyl, and the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S;

[0043] R lg 、R lh 、R li '、R lj Each independently selected from H or C 1-4 alkyl;

[0044] Or, R lg 、R lh The nitrogen atom to which it is attached forms a 4- to 6-membered heterocyclic ring, wherein the ring is optionally further selected from F, CF3, methyl, methoxy, or -S(=O) p -C 1-4 substituted by an alkyl substituent, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S;

[0045] p is selected from 2;

[0046] R 2 、R 3 、R 7 、R 8 Each is independently selected from H, methyl or C(=O)O-tert-butyl.

[0047] Preferably, the compound of formula (II) is selected from one of the following structures:

[0048] Preferably, the compound of formula (II) is selected from:

[0049] In one embodiment of the present invention, the effective dose of the compound is selected from 1 ng-30 mg, 0.01 μg-10 mg, 0.1 μg-1 mg, 1 μg-1000 μg, 10 μg-800 μg, 10 μg-600 μg, 10 μg-400 μg, 10 μg-200 μg, and the effective dose of the hydrate, metabolite, solvate, pharmaceutically acceptable salt or cocrystal of the compound of the formula and the composition thereof are all converted by the effective dose of the compound.

[0050] In one embodiment of the present invention, the administration form is one or more of single administration, multiple administration, continuous administration and target-controlled infusion.

[0051] In one embodiment of the invention, administration is performed by a route selected from the group consisting of intravenous injection, intraarterial injection, intramuscular injection, transdermal absorption, buccal absorption, parenteral intraperitoneal, rectal, transbuccal, nasal, inhalation, by topical delivery, subcutaneous, intrafatty, intraarticular, intraperitoneal or intrathecal.

[0052] In one embodiment of the present invention, administration is by intravenous injection or nasal drops.

[0053] In one embodiment of the present invention, the effective dose for intravenous injection is 40 μg-400 μg, 60 μg-180 μg.

[0054] In some embodiments of the present invention, the compound of formula (I) or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or cocrystals and compositions thereof are administered before the end of surgery.

[0055] In some embodiments of the present invention, a second drug is further included, wherein the second drug is selected from one or more of antiemetics or analgesics.

[0056] In some embodiments of the present invention, the antiemetic is selected from tropisetron, ondansetron, granisetron, dolasetron, azasetron, ramosetron, palonosetron, aprepitant, fosaprepitant, rolapitant, casopitant, vertipitant, dimenhydrinate, promethazine, scopolamine, gabapentin, pregabalin, midazolam, and ephedrine;

[0057] In some embodiments of the present invention, the analgesic is selected from morphine, fentanyl, sufentanil, oxycodone, hydromorphone, pethidine, butorphanol, nalbuphine, dezocine, pentazocine, buprenorphine, flurbiprofen axetil, ketorolac, lornoxicam, diclofenac, parecoxib, celecoxib, acetaminophen, tramadol, dexmedetomidine, ketamine, dexketamine, gabapentin, and pregabalin.

[0058] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0059] "Alkyl" refers to a linear and branched monovalent saturated hydrocarbon group, the main chain includes 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, and most preferably 1 to 2 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. The alkyl group may be optionally further replaced by 0, 1, 2, 3, 4 or 5 groups selected from F, Cl, Br, I, =O, hydroxyl, -SR 19 , nitro, cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, -(CH2) k -C(=O)-R 19 、-(CH2) k -C(=O)-OR 19 、-(CH2) k -C(=O)-NR 19 R 19a 、-(CH2) k -S(=O) j -R 19 、-OC(=O)-OR 19 or -NR 19 R 19a substituted by a substituent, wherein R 19 and R 19a Each independently selected from H, hydroxyl, amino, carboxyl, C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, 3 to 10-membered carbocyclyl, 4 to 10-membered heterocyclyl, 3 to 10-membered carbocyclyloxy or 4 to 10-membered heterocyclyloxy, k is selected from 0, 1, 2, 3, 4 or 5, j is selected from 0, 1 or 2. The alkyl, k, j, R 19 and R 19a , which is defined as above.

[0060] "Alkylene" refers to straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2) v-(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene; the alkylene may be optionally further substituted by 0, 1, 2, 3, 4 or 5 groups selected from F, Cl, Br, I, =O, hydroxyl, -SR 19 , nitro, cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, -(CH2) k -C(=O)-R 19 、-(CH2) k -C(=O)-OR 19 、-(CH2) k -C(=O)-NR 19 R 19a 、-(CH2) k -S(=O)jR 19 、-OC(=O)-OR 19 or -NR 19 R 19a When the number of substituents in the alkylene group is greater than or equal to 2, the substituents may be fused together to form a cyclic structure. The alkylene group appearing herein has the same definition as above.

[0061] "Alkoxy" refers to a monovalent radical of an O-alkyl group, wherein alkyl is as defined herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentoxy, 2-pentoxy, 3-pentoxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 3-methyl-1-butoxy, and 2-methyl-1-butoxy.

[0062] "Alkenyl" refers to a linear or branched monovalent unsaturated hydrocarbon radical having at least one, typically one, two or three, carbon-carbon double bonds, with a backbone comprising from 2 to 10 carbon atoms, more preferably from 2 to 6 carbon atoms, and more preferably from 2 to 4 carbon atoms in the backbone. Examples of alkenyl radicals include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene; the alkenyl group may be further optionally substituted by 0, 1, 2, 3, 4 or 5 groups selected from F, Cl, Br, I, =O, hydroxyl, -SR 19 , nitro, cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, -(CH2) k -C(=O)-R 19 、-(CH2) k -C(=O)-OR 19 、-(CH2) k -C(=O)-NR 19 R 19a 、-(CH2) k -S(=O) j -R 19 、-OC(=O)-OR 19 or -NR 19 R 19a The alkenyl group appearing herein has the same meaning as above.

[0063] "Alkynyl" refers to a linear or branched monovalent unsaturated hydrocarbon radical having at least one, typically one, two or three, carbon-carbon triple bonds, with a backbone comprising 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and more preferably 2 to 4 carbon atoms in the backbone. Examples of alkynyl radicals include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl and 4-decynyl. The alkynyl radical may be optionally further substituted with 0, 1, 2, 3, 4 or 5 radicals selected from the group consisting of F, Cl, Br, I, ═O, hydroxy, -SR 19 , nitro, cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, -(CH2) k -C(=O)-R 19 、-(CH2) k -C(=O)-OR 19 、-(CH2) k -C(=O)-NR 19 R 19a 、-(CH2) k -S(=O) j -R 19 、-OC(=O)-OR 19 or -NR 19 R 19a The alkynyl group appearing herein has the same meaning as defined above.

[0064] "Cycloalkyl" refers to a monovalent saturated carbocyclic hydrocarbon group, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. The cycloalkyl group may be optionally further substituted with 0, 1, 2, 3, 4, or 5 groups selected from F, Cl, Br, I, ═O, hydroxy, -SR, 19 , nitro, cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, -(CH2) k -C(=O)-R 19 、-(CH2) k-C(=O)-OR 19 、-(CH2) k -C(=O)-NR 19 R 19a 、-(CH2) k -S(=O) j -R 19 、-OC(=O)-OR 19 or -NR 19 R 19a The cycloalkyl group mentioned herein has the same meaning as above.

[0065] "Carbocycle" refers to a saturated or unsaturated aromatic or non-aromatic ring, which may be a 3- to 10-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring system. The carbocyclic group may be connected to a bridged ring or a spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, phenyl, or naphthyl. The carbocyclic group may be further optionally substituted by 0, 1, 2, 3, 4, or 5 groups selected from F, Cl, Br, I, ═O, hydroxy, -SR 19 , nitro, cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, -(CH2) k -C(=O)-R 19 、-(CH2) k -C(=O)-OR 19 、-(CH2) k -C(=O)-NR 19 R 19a 、-(CH2) k -S(=O) j -R 19 、-OC(=O)-OR 19 or -NR 19 R 19a The carbocycles appearing herein have the same definition as above.

[0066] "Heterocycle" refers to a saturated or unsaturated aromatic or non-aromatic ring, which may be a 3- to 10-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring system, and contains 1 to 4 heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic ring. The N and S optionally substituted in the heterocyclic ring may be oxidized to various oxidation states. The heterocyclic group may be attached to a heteroatom or a carbon atom, and the heterocyclic group may be attached to a bridged ring or a spirocyclic ring. Non-limiting examples include oxiranyl, glycidyl, aziridine, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, oxepinyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, pyridinyl, piperidinyl, homopiperidinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl , tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindole, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolinyl, dithianyl, dithioquinolyl, dihydrothiophenyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclohexyl, 3-azabicycloheptyl, azabicyclohexyl, 3H-indolylquinolizinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclooctanyl, azabicyclononanyl, oxatricyclododecyl, azaadamantyl, and oxaspiroheptanyl. The heterocyclic group may be optionally further substituted by 0, 1, 2, 3, 4 or 5 groups selected from F, Cl, Br, I, =O, hydroxyl, -SR 19 , nitro, cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, -(CH2) k -C(=O)-R 19 、-(CH2) k -C(=O)-OR 19 、-(CH2) k -C(=O)-NR 19 R 19a 、-(CH2) k -S(=O) j -R 19、-OC(=O)-OR 19 or -NR 19 R 19a The heterocycles appearing herein have the same meaning as above.

[0067] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0068] "Pharmaceutical composition" means a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or stereoisomers, solvates, pharmaceutically acceptable salts or cocrystals, and other ingredients, wherein the other ingredients include physiologically / pharmaceutically acceptable carriers and excipients.

[0069] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0070] An "effective amount" refers to that amount of a compound that will elicit the physiological or medical response of a tissue, system, or subject that is being sought, and includes an amount of the compound that, when administered to a subject, is sufficient to prevent or alleviate to some extent one or more symptoms of the disorder or condition being treated.

[0071] "Solvate" refers to a compound of the present invention or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, it is a hydrate. DETAILED DESCRIPTION

[0072] The technical solutions of the present invention are described in detail below with reference to the accompanying drawings and embodiments, but the protection scope of the present invention includes but is not limited to them.

[0073] Synthesis Example:

[0074] Compound 1: (2R)-N-[(1R)-1-(2-acetyl-2,7-diazaspiro[3.5]nonane-7-carbonyl)-5-amino-pentyl]-2-[[(2R)-2-[[(2R)-2-amino-3-phenyl-propionyl]amino]-3-phenylpropionyl]amino]-4-methyl-pentanamide (CAS No.: 2269511-95-5) was prepared according to the method described in WO2019015644.

[0075] The remaining compounds 2-8 were prepared according to the method described in WO2019015644.

[0076] Formulation example: Compound 1 injection was prepared with reference to WO2021036975A1.

[0077] Example 1:

[0078] This study is a multicenter, randomized, double-blind, placebo-controlled Phase III clinical study conducted in China to evaluate the efficacy and safety of Compound 1 injection for postoperative analgesia in subjects undergoing elective laparoscopic surgery under general anesthesia. 276 subjects undergoing elective laparoscopic surgery under general anesthesia were enrolled and randomly divided into two groups, Compound 1 group (136 subjects) and placebo group (135 subjects). All subjects received the first intravenous injection of Compound 1 or placebo injection within 5 minutes after the first NRS score, and the end time of the first postoperative administration was recorded as 0 minutes. 8 and 16 hours after the end of the first administration, with a time window of ±15 minutes, the subjects were given an intravenous injection of the corresponding dose of Compound 1 injection or placebo injection.

[0079] Resting NRS pain scores were assessed within 5 minutes before the first postoperative dose, and at 15 minutes ± 5 minutes, 30 minutes ± 5 minutes, 1 hour ± 5 minutes, 2 hours ± 15 minutes, 4 hours ± 15 minutes, 8 hours (within 30 minutes before the second postoperative dose), 12 hours ± 30 minutes, 16 hours (within 30 minutes before the final postoperative dose), 20 hours ± 30 minutes, and 24 hours ± 1 hour after the first postoperative dose. The NRS pain score for rest refers to the NRS score when the subject is at rest and motionless (e.g., sitting or lying down). If the subject was not awake at the time of the NRS assessment, the current NRS score was 2 points if the previous NRS score was ≥ 2 points. If the previous NRS score was < 2 points, the current NRS score was based on the previous score. It was also necessary to record that the subject was not awake at the time of the assessment.

[0080] If the resting pain NRS score is ≥4 at any pain scoring time point after the first postoperative medication, or if the subject complains of pain at any time point and the resting pain NRS score is ≥4, morphine injection can be given (it is recommended that the time from the subject receiving the NRS score to the subject actually receiving the morphine injection is ≤30 minutes, the first intravenous injection is 3 mg, and subsequent additional injections are required. It is recommended that the interval between two rescue treatments is ≥2 hours, and it is recommended that the time between the rescue drug and the study drug administration is ≥1 hour) intravenous rescue treatment.

[0081] Prophylactic antiemetic treatment is prohibited during the study. After the first postoperative dose, researchers may administer antiemetics based on nausea and vomiting, and the dosage of antiemetics should be recorded. Tropisetron is the preferred antiemetic (2.5 mg intravenous injection for the first time, with additional doses as needed, not to exceed 10 mg within 24 hours). If tropisetron is ineffective, researchers may use other medications according to clinical practice.

[0082] Primary efficacy outcome: SPID after the first postoperative administration of compound 1 0-24h The hypothesis of superiority to the placebo group was established, that is, the compound 1 group had a better effect on postoperative analgesia in subjects undergoing elective laparoscopic surgery under general anesthesia than the placebo group.

[0083] Secondary efficacy outcome: SPID after the first postoperative administration of compound 1 group 0-12h , PID at each time point, the average cumulative use of rescue analgesics within 0-12h and 0-24h after the first postoperative administration, and the proportion of rescue analgesics used within 0-24h after the first postoperative administration were significantly lower than those in the placebo group; the duration of analgesia and the time to start using rescue analgesics in the compound 1 group were significantly longer than those in the placebo group; the proportion of NRS scores ≤3 points within 0-12h and 0-24h after the first postoperative administration, and the postoperative analgesia satisfaction scores of the subjects and research physicians in the compound 1 group were significantly higher than those in the placebo group.

[0084] Safety results: The Compound 1 group was generally well tolerated, with a similar overall incidence of TEAEs (adverse events) and similar types of TEAEs to those in the placebo group. The incidence of major TEAEs (including nausea and vomiting) in the Compound 1 group was significantly lower than that in the placebo group. Only the placebo group experienced TEAEs leading to discontinuation and withdrawal from the trial. The types and incidence of adverse reactions in the Compound 1 group were generally consistent with those in the placebo group, and the incidence of adverse reactions (including nausea and vomiting) in the Compound 1 group was significantly lower than that in the placebo group.

[0085] Example 2:

[0086] This multicenter, randomized, double-blind, placebo / active-controlled study enrolled approximately 387 subjects undergoing elective abdominal surgery under general anesthesia and randomly divided them into three groups: compound 1 group (129 patients), tramadol group (129 patients), and placebo group (129 patients).

[0087] After surgery, MOAA / S scores were performed every 5 minutes ± 1 minute. Within 5 minutes of awakening (defined as an initial MOAA / S score of 5), the first resting pain intensity score (NRS, Numeric Rating Scale, 0-10 represents varying degrees of pain, with 0 representing no pain, higher numbers indicating more severe pain, and 10 representing the most severe pain) was performed. It is recommended that the interval between two NRS assessments should not exceed 30 minutes. Within 4 hours after surgery, subjects who met all inclusion criteria and did not meet any exclusion criteria were randomized in a 1:1:1 ratio to one of the compound 1, tramadol, or placebo groups. Randomization was recommended within 10 minutes after the first NRS score of 4 or higher.

[0088] After successful randomization, to avoid prolonged pain, the investigator should administer the first injection of Compound 1 (1 μg / kg / time), Tramadol Hydrochloride Injection (50 mg / time), or Placebo to the subject as soon as possible (recommended within 15 minutes after successful randomization). The end time of the first postoperative study drug administration is recorded as 0 minutes. At 8 hours (±15 minutes) and 16 hours (±15 minutes) after the first administration, the subject should receive another injection of Compound 1, Tramadol Hydrochloride Injection, or Placebo at the corresponding dose, for a total of three doses.

[0089] Resting NRS pain scores were assessed 15 min ± 5 min, 30 min ± 5 min, 1 h ± 5 min, 2 h ± 15 min, 4 h ± 15 min, 8 h ± 30 min (and within 30 min before the second dose of study drug), 12 h ± 30 min, 16 h ± 30 min (and within 30 min before the third dose of study drug), 20 h ± 30 min, and 24 h ± 1 h after the first dose of study drug. The resting NRS pain score refers to the NRS score when the subject is at rest (e.g., sitting or lying down). If the subject was not awake at the time of the NRS assessment, the current NRS score was 2 if the previous NRS score was ≥ 2. If the previous NRS score was < 2, the current NRS score was based on the previous score. The subject's absence at the time of the assessment should also be recorded.

[0090] Subjects who complain of pain at any time point after the first dose of study drug and whose resting pain NRS score is ≥4 may be given intravenous rescue treatment with flurbiprofen axetil injection (it is recommended that the time from the subject receiving the NRS score to the actual injection of flurbiprofen axetil injection be ≤30 minutes. The recommended initial intravenous injection is 50 mg, with subsequent doses as needed. The recommended interval between two rescue treatments is ≥3 hours. It is also recommended that the interval between rescue medication and study drug administration be ≥1 hour. However, if the pain is severe, rescue can be given at any time). It is recommended that subjects withdraw from the study and receive other routine clinical analgesic treatments at the discretion of the investigator if their pain is still not controlled after using rescue medication ≥4 times. The rescue medication should be used for rescue treatment. The rescue situation (including the resting NRS score before rescue, the time of each rescue medication use, the amount of rescue medication used, etc.) must be recorded truthfully.

[0091] Prophylactic antiemetic treatment is prohibited during the study. After the first postoperative dose, researchers may administer antiemetics based on nausea and vomiting, and the dosage of antiemetics should be recorded. Tropisetron is the preferred antiemetic (2.5 mg is recommended for the initial intravenous injection, with subsequent doses as needed, not to exceed 10 mg within 24 hours). If tropisetron is ineffective, researchers may use other medications according to clinical practice.

[0092] Primary efficacy outcome: SPID after the first postoperative administration of compound 1 0-24h The non-inferiority to tramadol injection was established, and the SPID of compound 1 group after the first administration was 0-24h The hypothesis of superiority to the placebo group was established, that is, the effect of compound 1 group for postoperative analgesia in subjects undergoing elective abdominal surgery under general anesthesia was non-inferior to tramadol injection and superior to the placebo group.

[0093] Secondary efficacy outcome: SPID after the first postoperative administration of compound 1 group 0-12h , PID at each time point, the average cumulative use of rescue analgesics within 0-12h and 0-24h after the first postoperative administration, and the proportion of rescue analgesics used within 0-24h after the first postoperative administration were comparable to those in the tramadol group, and significantly lower than those in the placebo group; the duration of analgesia and the time to start using rescue analgesics in the compound 1 group were comparable to those in the tramadol group, and significantly longer than those in the placebo group; the proportion of NRS scores ≤3 within 0-12h and 0-24h after the first postoperative administration in the compound 1 group, and the postoperative analgesia satisfaction scores of the subjects and research physicians were comparable to those in the tramadol group as a whole, and significantly higher than those in the placebo group.

[0094] Safety Results: The Compound 1 group was generally well tolerated, with no serious adverse events. The overall incidence of TEAEs (adverse events) and ADRs (adverse reactions) was similar to that of the placebo group and significantly lower than that of the tramadol group. Most TEAEs / ADRs were Grade 1-2 and resolved without intervention or with minimal intervention. The types of TEAEs / ADRs were generally consistent across groups. The incidence of decreased thyroid-stimulating hormone in the Compound 1 group was slightly higher than that of the tramadol and placebo groups, while the incidence of nausea and vomiting was lower than that of the tramadol and placebo groups. Furthermore, the proportion of subjects using tropisetron within 0-24 hours after the first dose of Compound 1 and the cumulative medication dosage were significantly lower than those in the tramadol and placebo groups. The proportion of subjects using other antiemetics within 0-24 hours was slightly lower than that in the tramadol and placebo groups, while the cumulative medication dosage was higher than that in the tramadol and placebo groups.

[0095] Abdominal surgery, female sex, smoking history, and postoperative opioid use are known risk factors for postoperative nausea and vomiting (PONV). Compound 1 injection has completed two studies of postoperative analgesia following abdominal surgery. Both studies used morphine (Example 1) and flurbiprofen axetil (Example 2) as rescue analgesics. Prophylactic antiemetics were also prohibited during the studies. The results are summarized below.

[0096] In the safety analysis set of Example 1, the incidence of nausea during treatment was 17.6% in the Compound 1 group and 27.4% in the placebo group; the incidence of vomiting was 15.4% in the Compound 1 group and 32.6% in the placebo group. The proportion of antiemetics used within 0-24 hours after the first dose and the average cumulative amount used were significantly lower in the Compound 1 group than in the placebo group.

[0097] Considering that this study is for morphine rescue analgesia, patients may experience nausea and vomiting due to the use of rescue drugs. Therefore, we conducted a further analysis of the incidence of nausea and vomiting in subjects who did not receive rescue analgesia. The results showed that in the safety focus, the incidence of nausea and vomiting in the compound 1 group of subjects who did not receive rescue analgesia (not using morphine) was lower than that in the placebo group, with a reduction rate of 25.7% and 20.1% relative to the placebo. In the patients who did not use morphine for rescue in the study of Example 1, the difference between the compound 1 group and the placebo group was smaller than the overall situation, which may be related to the small sample size and large individual differences. Most phase III studies on PONV prevention have a large sample size (such as >500 cases) to make the expected difference.

[0098] In Example 2, flurbiprofen axetil is a known nonsteroidal anti-inflammatory drug, and neither domestic nor international guidelines mention it as a cause of PONV. It is preliminarily believed that studies using flurbiprofen axetil as a rescue analgesic medication better reflect the effects of Compound 1 on PONV. In the safety analysis set, the incidence of nausea and vomiting in the Compound 1 group was lower than that in the placebo group, with reductions of 50% and 47.9% relative to placebo.

[0099] Comparison of the incidence of postoperative nausea and vomiting between Example 1 and Example 2

[0100] In summary, both Phase III studies showed that Compound 1 injection has the effect of preventing and / or alleviating PONV in patients undergoing abdominal surgery.

[0101] Example 3: Multicenter, randomized, double-blind, placebo-controlled dose study of compound 1 injection for preventing postoperative nausea and vomiting

[0102] Study duration: Treatment duration: 24 hours after surgery; Follow-up duration: 48 hours after surgery

[0103] Protocol: This is a multicenter, randomized, double-blind, placebo-controlled study. Approximately 200 subjects undergoing elective laparoscopic abdominal or gynecological surgery under general anesthesia will be enrolled and randomly divided into the compound 1-60 μg group (50 subjects), the compound 1-120 μg group (50 subjects), the compound 1-180 μg group (50 subjects), and the placebo group (50 subjects) at a ratio of 1:1:1:1.

[0104] Within 15 minutes before the end of surgery, the study drug was administered once. The dosing schedule was as follows:

[0105] Compound 1-60 μg group: Administer 60 μg of compound 1 once within 15 minutes before the end of surgery by intravenous push, with the intravenous push time being no less than 30 seconds;

[0106] Compound 1-120 μg group: Compound 1 120 μg was injected once within 15 minutes before the end of surgery, and the intravenous push time was no less than 30 seconds;

[0107] Compound 1-180 μg group: 180 μg of compound 1 was injected once within 15 minutes before the end of surgery, and the intravenous push time was no less than 30 seconds;

[0108] Placebo group: Administer placebo once within 15 minutes before the end of surgery by intravenous injection, with the injection time being no less than 30 seconds;

[0109] The primary efficacy endpoint was the response (CR) rate at 24 hours after surgery (CR was defined as no vomiting or retching within 24 hours after surgery and no use of rescue medication);

[0110] Secondary efficacy endpoints included the following: the proportion of subjects who experienced postoperative nausea; the proportion of subjects who experienced significant postoperative nausea (defined as a VAS score ≥4 cm); the proportion of subjects who experienced postoperative vomiting (vomiting [even if a very small amount of gastric contents were expelled] or retching [muscle movements to vomit, but no gastric contents were expelled]); the proportion of subjects who used rescue medication after surgery; the time to the first onset of vomiting (vomiting or retching) or the administration of rescue medication (whichever occurred first) within 24 hours after surgery; the cumulative amount of analgesics administered within 24 hours after surgery; and subject and investigator satisfaction scores for PONV.

[0111] Safety endpoints: incidence and severity of adverse events; vital signs, 12-ECG, physical examination, and laboratory tests.

[0112] Screening period: D-14 to randomization success (the day of randomization is defined as D1).

[0113] Subjects who plan to undergo laparoscopic abdominal or gynecological surgery will sign the informed consent form of this study and complete the screening according to the trial flow chart. Subjects who successfully screened will receive a random number before dosing.

[0114] Surgical anesthesia is performed using general anesthesia; other anesthetic methods (such as spinal block anesthesia, nerve block anesthesia, and local infiltration anesthesia) are prohibited. For anesthesia induction, propofol / pofol, sufentanil / remifentanil, and muscle relaxants are recommended; midazolam is prohibited. For anesthesia maintenance, sevoflurane, remifentanil / sufentanil, and muscle relaxants are recommended; propofol / pofol is prohibited. Other intraoperative medications are at the discretion of the investigator.

[0115] Treatment period: start of study drug administration - 24 hours after surgery

[0116] Subjects who met all inclusion criteria and did not meet any exclusion criteria were given one injection of Compound 1 or placebo within 15 minutes before the end of surgery (defined as the completion of the last suture of the wound).

[0117] Any antiemetic or antiemetic drug other than study drugs and protocol-specified rescue drugs was prohibited from being used from 24 hours before the start of surgery (defined as the start of skin incision) to 24 hours after the end of surgery. Prophylactic antiemetics were also prohibited.

[0118] Within 24 hours after surgery, if the subject experiences 1 or more episodes of vomiting, retching, or nausea and requires antiemetic treatment, after evaluation by the investigator, the subject may receive rescue antiemetic medication as specified in the protocol (tropisetron is preferred for rescue antiemetics, with an initial intravenous injection of 2.5 mg recommended, followed by additional doses as needed, not exceeding 10 mg within 24 hours). If tropisetron is ineffective, the investigator may use other medications according to clinical routine.

[0119] Within 30 minutes after the procedure, the PCA pump containing morphine hydrochloride injection was activated. Subjects were encouraged to self-press the PCA pump if they experienced pain. PCA parameters were set to: 1 mg / ml concentration, continuous infusion of 0 ml / L, single PCA compression for 2 ml, and a 10-minute lockout period. If the patient continued to complain of pain, additional morphine hydrochloride injection (3 mg) could be administered intravenously after evaluation by the investigator.

[0120] The occurrence of vomiting and any nausea were monitored and recorded for 24 hours after surgery. Subjects were asked to record any spontaneous nausea, retching, or vomiting within 24 hours after surgery and to rate the severity of nausea using a visual analog scale (VAS; 0 cm = no nausea, 10 cm = the worst nausea that is unbearable). Investigators asked subjects about the occurrence of nausea, retching, or vomiting in the previous 12 hours at 12 hours ± 1 hour and 24 hours ± 1 hour after surgery.

[0121] PONV satisfaction scores were calculated by the subjects and investigators 24 h ± 1 h after administration.

[0122] The amount of rescue antiemetics and the cumulative amount of analgesics used by each subject within 24 hours after surgery were recorded.

[0123] Follow-up period: 24 hours to 48 hours after surgery

[0124] Collect the subjects' vital signs, physical examination, 12-hour ECG, laboratory tests, adverse events, and concomitant medications. For subjects who have received the study drug and withdraw early, they must complete a full set of pre-discharge examinations as much as possible.

[0125] Inclusion criteria (all of the following criteria must be met to be eligible): 1. 18 ≤ ≤ 75 years old, regardless of gender; 2. American Society of Anesthesiologists (ASA) grade I-III; 3. 18 kg / m 2 ≤BMI≤40kg / m 2 4. Inpatients planning elective laparoscopic abdominal or gynecological surgery under general anesthesia, with an expected anesthesia duration of ≥1 hour; 5. Subjects whose risk of postoperative nausea and vomiting (PONV) is determined by the investigator to be moderate or high (score ≥2) using the Apfel simplified risk score; 6. Agree to participate in this trial and voluntarily sign the informed consent form;

[0126] Exclusion criteria (patients will be excluded if they meet any of the following criteria):

[0127] Previous and concurrent diseases

[0128] 1. History or evidence of any of the following diseases before screening: 1) Respiratory system diseases: severe chronic obstructive pulmonary disease, acute exacerbation of chronic obstructive pulmonary disease, severe airway stenosis, huge pharyngeal tumor, history of tracheoesophageal fistula or airway tear, severe respiratory tract infection within 2 weeks before screening; 2) Central nervous system diseases: subjects with epilepsy, Parkinson's disease, or other central nervous system diseases that cause nausea and vomiting, such as craniocerebral injury, intracranial mass, intracranial aneurysm, etc.; 3) Cardiovascular system diseases: uncontrolled hypertension [systolic blood pressure (SBP) ≥ 170 mmHg and / or diastolic blood pressure (DBP) ≥ 105 mmHg without antihypertensive drug treatment, or SBP > 1 after antihypertensive drug treatment] 60mmHg and / or DBP>100mmHg], severe heart failure (class III-IV according to the New York Heart Association [NYHA]), unstable angina, acute myocardial infarction, severe arrhythmia, history of tachycardia / bradycardia requiring drug treatment, II-III degree atrioventricular block (excluding pacemaker users) within 6 months before screening; 4) Digestive system diseases: subjects with intestinal obstruction or other digestive system diseases that may cause nausea and vomiting as determined by the investigator; 5) subjects with clearly diagnosed vestibular disorders other than motion sickness (including but not limited to peripheral vestibular syndrome, central vestibular syndrome, etc.); 6) subjects with a history of obvious, chronic dizziness.

[0129] Previous and concomitant medications

[0130] 2. Any of the following drugs or treatments were used during the screening period:

[0131] 1) Subjects who have received antiemetic drugs / drugs with antiemetic effects within 24 hours before surgery or who have used antiemetic drugs / drugs with antiemetic effects for less than 5 half-lives before surgery (calculated based on the longest time); 2) Subjects with malignant tumors who have received chemotherapy within 4 weeks before screening;

[0132] Laboratory and other tests

[0133] 3. Laboratory examination indicators during the screening period meet one of the following criteria: 1) White blood cell count <3.0×10 9 / L; 2) Platelet count <80×10 9 / L; 3) Hemoglobin <70g / L; 4) Prothrombin time (PT) prolonged by more than 3 seconds above the upper limit of normal value; 5)

[0134] Activated partial thromboplastin time (APTT) prolonged by more than 10 seconds; 6) Alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) > 3 × ULN; 7) Total bilirubin > 2 × ULN; 8) Serum creatinine > 2 × ULN; 9) Fasting blood glucose ≥ 11.1 mmol / L;

[0135] Other situations

[0136] 4. Subjects who are expected to continue to be intubated after surgery; 5. Subjects who are expected to need to have a nasogastric or oral tube placed after surgery; 6. Subjects with a history of severe drug allergy or allergy to the trial drugs specified in the protocol; 7. Subjects with a history of drug abuse, drug abuse, or alcoholism within 3 months before screening, where alcoholism means an average daily alcohol intake of more than 2 units of alcohol (1 unit = 360 mL of 5% alcohol beer or 45 mL of 40% alcohol liquor or 150 mL of wine); 8. Subjects who have experienced nausea, retching, or vomiting within 24 hours before anesthesia induction (except those caused by bowel preparation); 9. Subjects who have participated in any clinical study within 3 months before screening (defined as receiving trial drugs or placebo); 10. Pregnant and lactating women; women of childbearing potential or men who are unwilling to use contraception throughout the study and within 3 months after the end of the study (including male subjects); 11. Subjects who, according to the investigator, have any other factors that are not suitable for participation in this clinical study.

[0137] Exit criteria: 1. The subject may withdraw consent and withdraw from the trial at any time; 2. If any medical condition occurs before or during medication, which may cause risks to the subject if the subject continues to take the medication, the researcher may decide that the subject should terminate the study drug treatment and / or withdraw from the study; 3. If the subject seriously violates the protocol, which poses a potential risk to the subject's safety and / or affects the objectivity and integrity of the key data of the study, the researcher will advise the subject to withdraw after judgment; 4. Other situations where the researcher believes it is necessary to withdraw.

[0138] Statistical analysis: SAS EG 8.3 or above was used for statistical analysis.

[0139] For continuous variables, list the number of cases, number of missing cases, mean, standard deviation, median, quartiles (Q1 and Q3), minimum, and maximum values. For categorical variables, describe the frequency and percentage. In this study, unless otherwise specified, "baseline" was defined as the last nonmissing observation before the first dose of study drug.

[0140] All analyses were performed separately by treatment or dose group unless otherwise stated.

[0141] Analyze the dataset

[0142] Full Analysis Set (FAS): Based on the Intention To Treat Principle (ITT), it includes all subjects who have been randomized, received at least one study drug and had at least one efficacy evaluation.

[0143] Per-Protocol Set (PPS): Includes all subjects in the FAS who have good study compliance, complete data on primary efficacy endpoints, and no major protocol deviations during the study period. Major protocol deviations are excluded from the PPS before the database is locked. Major protocol deviations are those that affect the primary efficacy endpoints.

[0144] Safety Set (SS): includes all subjects who have been randomized, received at least one study drug, and have post-drug safety evaluation data.

[0145] Effectiveness Analysis

[0146] The primary endpoint was to describe the 24-hour postoperative response (CR) rate in each group. A logistic regression model was constructed using the proportion of subjects experiencing nausea, significant nausea, and vomiting within 24 hours of surgery as the dependent variable (CR defined as no vomiting or retching within 24 hours of surgery and no use of rescue medication). The independent variables were the baseline Apfel simplified risk score, cumulative postoperative morphine consumption, and treatment group. The odds ratios (ORs) and 95% confidence intervals (CIs) for the 24-hour postoperative CR rate were calculated for each trial group, with the placebo group as the control. P values ​​were also presented, and the corresponding bar graphs were plotted.

[0147] Secondary study endpoints:

[0148] The proportion of subjects experiencing nausea, overt nausea, and vomiting within 24 hours after surgery were statistically described by trial group. Logistic regression models were constructed using the proportion of subjects experiencing nausea, overt nausea, and vomiting within 24 hours after surgery as dependent variables, and the baseline Apfel simplified risk score and treatment group as independent variables. Using the placebo group as the control, the odds ratios (ORs) and 95% confidence intervals (CIs) for the percentages of nausea, overt nausea, and vomiting within 24 hours after surgery were calculated for each dose of the trial drug, with P values ​​presented and corresponding bar graphs plotted.

[0149] The proportion of subjects who used rescue medication within 24 hours after surgery was statistically described according to the trial groups, and the chi-square test or Fisher's exact probability method was used to analyze the differences between the groups.

[0150] The median time to the first occurrence of vomiting (vomiting or retching) within 24 hours after surgery or the time to the administration of rescue treatment (whichever occurred first) was statistically described according to the trial groups, and Kaplan-Meier curves were drawn. The Log-rank method was used to compare the trial drug groups and the placebo group.

[0151] Subject and investigator PONV satisfaction scores: Descriptive statistics were performed on the subject and investigator PONV satisfaction scores according to each trial group, and the Kruskal-Wallis test was used for inter-group comparisons, and the Wilcoxon rank-sum test was used for comparisons between each dose group of the trial drug and the placebo group.

[0152] Security Analysis

[0153] Adverse events:

[0154] Adverse events (AEs) were coded using the International Conference on Harmonization of Clinical Oncology (ICH) International Medical Dictionary (MedDRA 27.0 or later) and categorized by system organ class (SOC) and preferred term (PT). The severity of adverse events was graded according to the Common Terminology Criteria for Adverse Events (CTCAE V5.0), unless otherwise specified. The number, incidence, and frequency of all treatment-emergent adverse events (TEAEs), grade 3 or higher TEAEs, TEAEs related to study drug, serious adverse events (SAEs), SAEs related to study drug, and TEAEs leading to premature withdrawal from the study were calculated, and the number and percentage were summarized by system organ class, preferred term, and group.

[0155] The table presents detailed information about the AEs. Detailed description of AEs that occurred during treatment after drug administration.

[0156] Various inspections:

[0157] Laboratory test parameters were statistically described. Descriptive statistics were performed based on baseline and post-treatment measurement time points, changes from baseline, and group-by-group laboratory test parameter results. Cross-tabulations were created to assess clinical judgment of laboratory test parameters based on baseline and post-treatment measurement time points, and group-by-group laboratory test parameter results. All test parameter results and abnormal, clinically significant results were tabulated.

[0158] Cross-tabulations were made for the results of 12-ECG, vital signs, physical examination and other indicators based on the baseline and post-treatment measurement time points and each group, and the results of all and abnormal clinically significant examination indicators were presented in a table.

[0159] Main efficacy results: The response (CR) rates of compound 1 at all doses 24 hours after surgery were higher than those of the placebo group, and the differences with the placebo group were statistically significant (P < 0.05). Among them, the CR rate of the 120 μg group 24 hours after surgery was the highest.

[0160] Secondary efficacy results showed that the proportion of subjects experiencing nausea, severe nausea, vomiting, and the use of rescue medication within 24 hours after surgery was lower in all dose groups of Compound 1 than in the placebo group (detailed data are shown in the table below). The time to first onset of vomiting (vomiting or retching) or the administration of rescue medication within 24 hours after surgery (mean ± standard deviation) was 11.6677 ± 10.6449 hours in the placebo, 60 μg, 120 μg, and 180 μg groups, respectively, 18.3109 ± 9.6700 hours, 20.1119 ± 8.4192 hours, and 19.7203 ± 8.7225 hours. The time to first onset of vomiting (vomiting or retching) or the administration of rescue medication within 24 hours after surgery was later in all dose groups of Compound 1 than in the placebo group (P < 0.05). The PONV satisfaction scores (mean ± standard deviation) of the subjects in the placebo, 60 μg, 120 μg, and 180 μg groups were 7.9 ± 2.27, 9.0 ± 1.89, 9.1 ± 1.52, and 9.0 ± 1.65 points, respectively. The PONV satisfaction scores of the subjects in each dose group of compound 1 were higher than those in the placebo group (P < 0.05). The PONV satisfaction scores of the researchers were 7.9 ± 2.03, 8.9 ± 1.84, 8.9 ± 1.71, and 9.0 ± 1.39 points, respectively. The PONV satisfaction scores of the researchers in each dose group of compound 1 were higher than those in the placebo group (P < 0.05).

[0161] Example 3 Efficacy Results

[0162] Safety results suggest that Compound 1 has a favorable overall safety profile, with a lower incidence of TEAEs and a slightly higher incidence of ADRs compared to the placebo group. All TEAEs (adverse events) and ADRs were Grade 1-2, with no serious adverse events (TESAs), leading to study withdrawal, or death. The TEAEs and ADRs observed in this study were generally consistent with those in previous studies, with no new adverse events or safety signals observed.

[0163] Example 4: Multicenter, randomized, double-blind, positive-controlled dose-finding study of Compound 1 injection for the prevention of chemotherapy-induced nausea and vomiting (CINV)

[0164] Study time: Treatment duration: within 120 hours after the first administration of high-emetic risk chemotherapy drugs; Follow-up duration: 10±1 days after the first administration of high-emetic risk chemotherapy drugs.

[0165] Protocol: This multicenter, randomized, double-blind, positive-controlled study enrolled approximately 180 cancer patients undergoing high-emetic risk chemotherapy for the first time. They were randomly divided into three groups (1:1:1 ratio), with 60 subjects in each group. The study drug was administered 30 ± 10 minutes before the start of high-emetic risk chemotherapy. The dosing schedule was as follows:

[0166] Administer the medicines in the following order:

[0167] 1) Compound 1 (blank) / Compound 1: Administer once 30 ± 10 minutes before the start of high-emetic risk chemotherapy drugs by intravenous push, with an intravenous push time of no less than 30 seconds;

[0168] 2) Dolasetron mesylate injection / Dolasetron mesylate injection simulant: After administration of Compound 1 / Compound 1 (blank), 5 ml (100 mg) of Dolasetron mesylate injection / simulant was administered intravenously. No dilution was required during administration. The infusion line was flushed with normal saline before and after administration. The intravenous injection time was no less than 30 seconds.

[0169] 3) Aprepitant injection: After administration of dolasetron mesylate injection / simulant, administer 18 mL (130 mg) of aprepitant solution intravenously. No dilution is required. Flushing the infusion line with normal saline before and after administration should be performed. The intravenous injection should last for at least 2 minutes.

[0170] 4) Dexamethasone tablets: Administer dexamethasone 6 mg orally 30 ± 10 minutes before the start of high-emetic risk chemotherapy drugs, and administer dexamethasone 3.75 mg orally every day from Day 2 to Day 4.

[0171] Primary efficacy endpoint:

[0172] Response (CR) rate 24 hours after administration of high-emetic risk chemotherapy drugs (acute phase) (CR is defined as no vomiting or retching within 24 hours after chemotherapy and no use of rescue medication).

[0173] Vomiting: Expelling even a very small amount of stomach contents; Regurgitation: Muscle movements to vomit occur, but stomach contents are not expelled.

[0174] Secondary efficacy endpoints:

[0175] Response (CR) rates 0-120 hours (overall phase) and 24-120 hours (delayed phase) after administration of high-emetic-risk chemotherapy drugs;

[0176] The proportion of participants with no nausea (nausea VAS score ≤ 5 mm) and mild nausea (nausea VAS score ≤ 25 mm) 0-24 hours and 24-120 hours after administration of high-risk chemotherapy drugs;

[0177] The proportion of participants who did not vomit 0-24 hours and 24-120 hours after administration of high-emetic-risk chemotherapy drugs;

[0178] The proportion of participants who used rescue medication 0-24 hours and 24-120 hours after administration of high-emetic-risk chemotherapy drugs;

[0179] The first occurrence of vomiting (vomiting or retching) or the time of rescue treatment within 120 hours after administration of high-emetic-risk chemotherapy drugs (whichever occurs first);

[0180] Mean VAS scores at 24 ± 1 hour and 120 ± 1 hour after administration of high-emetic-risk chemotherapy drugs;

[0181] Functional Living Index for Vomiting / Nausea (FLIE) score;

[0182] Subject and investigator satisfaction scores for CINV prevention.

[0183] Safety endpoints:

[0184] The incidence and severity of adverse events;

[0185] Vital signs, 12-hour ECG, physical examination, and laboratory tests, etc.

[0186] Pharmacokinetic endpoints:

[0187] The plasma concentration of compound 1 at the predetermined time point.

[0188] Screening period: D-14 to D-1 (the day of administration of high-risk emetic chemotherapy drugs is recorded as D1)

[0189] Subjects who plan to receive high-emetic risk chemotherapy for the first time should sign the informed consent form of this study, complete the screening examination, and check the inclusion and exclusion criteria.

[0190] Before the administration of high-risk emetic chemotherapy drugs, subjects who have been assigned random numbers will be trained in research-related scales, including the record of nausea and vomiting after chemotherapy, the visual analog scale (VAS) assessment of nausea severity, the rescue medication record form, the satisfaction assessment form, the Vomiting / Nausea Functional Life Index (FLIE), etc.

[0191] Treatment observation period: D1 to D5 (the day the trial drug is administered – 120 hours after the start of administration of high-risk chemotherapy drugs)

[0192] Before administering the trial drug, the inclusion and exclusion criteria were verified. Subjects who met all inclusion criteria and none of the exclusion criteria were randomly assigned to Groups A, B, or C in a 1:1:1 ratio. After receiving a randomization number, they received different CINV prophylaxis regimens. Pre-chemotherapy study drug administration was completed 30 ± 10 minutes before the start of high-emetic-risk chemotherapy drugs, as detailed in the dosing regimen. Prophylactic antiemetic medication was required on Days 1 through 4.

[0193] The time of starting administration of chemotherapy drugs with high emetogenic risk was recorded as 0 min.

[0194] On D1, 12-ECG examinations were performed within 30 minutes before the administration of Compound 1 / Compound 1 (blank) and 30 seconds to 5 minutes and 1 hour ± 10 minutes after the administration of Compound 1 / Compound 1 (blank).

[0195] If vomiting, retching, or nausea occurs at any time within 120 hours after the start of administration of high-emetic-risk chemotherapy drugs, the subject must record the occurrence of post-chemotherapy nausea and vomiting and complete the Post-chemotherapy Nausea and Vomiting Record Form. Within 2±0.5 hours, 4±1 hours, 8±1 hours, and 12-24 hours after the start of administration of high-emetic-risk chemotherapy drugs, the researcher should inquire about the occurrence of vomiting, retching, and nausea during each time period and verify the completeness of the subject's record. Any omissions should be supplemented. Thereafter, the researcher should inquire about the occurrence of vomiting, retching, and nausea during each time period every 24±2 hours and verify the completeness of the subject's record. If any omissions are found, the researcher should supplement the subject's record. If the subject has been discharged from the hospital, a telephone visit will be conducted.

[0196] If patients complain of nausea at any time point, the severity of nausea should be assessed using a 100-mm visual analog scale (VAS) and recorded in the Post-Chemotherapy Nausea and Vomiting Record Form. A VAS score ≤ 5 mm is considered to be absent, and a VAS score ≤ 25 mm is considered to be mild nausea.

[0197] If a subject experiences 1 or more episodes of vomiting, retching, or nausea at any time and the subject complains of requiring antiemetic treatment, rescue antiemetic treatment may be administered after evaluation by the investigator. The antiemetic medication will be determined by the investigator. If rescue medication occurs in the hospital, the investigator will record the use of rescue medication. If the subject has been discharged from the hospital, they may take antiemetic medication on their own. The investigator will confirm whether the subject has taken rescue medication during the visit and verify the completeness of the subject's records, supplementing any omissions.

[0198] 24 ± 1 hour and 120 ± 1 hour after the start of high-emetic chemotherapy, subjects were required to complete the CINV Prevention Subject Satisfaction Rating Form and the Functional Living Index for Vomiting / Nausea (FLIE) Scale. The investigator was required to confirm with the subject that the corresponding scales had been completed and to complete the Investigator Satisfaction Rating Form. (If the subject has been discharged, the scales can be submitted to the investigator for review during the follow-up visit.)

[0199] Subjects were randomly assigned to the PK subgroup, and a total of 90 subjects were planned to be included in the PK subgroup for PK blood collection. Subjects included in the PK subgroup were randomly divided into Group A, Group B, and Group C in a 1:1:1 ratio (30 subjects in each group). Venous blood was collected for PK analysis at four time points: immediately (+5 min), 2h (±1h), 6h (±2h), and 12h (±2h) after the administration of Compound 1 / Compound 1 (blank). PK blood collection should not be on the same arm as the dosing vein. When the PK blood collection time point conflicts with the ECG examination time, the ECG examination will be performed first.

[0200] During the treatment observation period, the anti-tumor treatment regimen received by the subjects must be recorded every day, including the use of anti-tumor drugs and non-drug treatments.

[0201] Follow-up period: D6~D10±1

[0202] During D6 to D8 after the start of administration of high-risk emetic chemotherapy drugs: the subjects returned to the hospital for follow-up, and the post-chemotherapy nausea and vomiting record form, remedial medication record form, subject satisfaction score form, and FLIE scale filled out by the subjects during the treatment observation period were collected and compared with the investigator's visit inquiry records to confirm their accuracy.

[0203] The subjects' vital signs, physical examination, 12-ECG, laboratory tests, pregnancy tests, adverse events, and concomitant medications / treatments (including anti-tumor treatment regimens on D6 and thereafter) were collected, and the relevant data were recorded in the study medical records and EDC system.

[0204] D10±1 (telephone follow-up is acceptable): Collect the subjects' adverse events and concomitant medication / treatment status.

[0205] For subjects who have received investigational drugs and have not completed the follow-up period (D6 to D8), if they withdraw early, they must try to complete the full set of pre-discharge examinations (the same as those required for D6 to D8) and collect AE and concomitant medication / treatment information as much as possible.

[0206] Selection criteria (all of the following criteria must be met to be eligible):

[0207] 1. Age ≥ 18 years old, regardless of gender;

[0208] 2. Patients who have not received chemotherapy drugs before and plan to receive a single-day intravenous chemotherapy regimen with a high risk of emetics, including but not limited to AC combination regimen (all chemotherapy regimens containing anthracyclines and cyclophosphamide), carboplatin AUC ≥ 4, and carmustine > 250 mg / m 2 , cisplatin, cyclophosphamide> 1500 mg / m 2 , dacarbazine, doxorubicin ≥ 60 mg / m2 Ifosfamide ≥ 2 g / m 2 (single dose), nitrogen mustard, gosatuzumab, streptozotocin and other treatment options;

[0209] 3. Histologically or cytologically confirmed malignant solid tumor;

[0210] 4. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1;

[0211] 5. Expected survival period ≥ 3 months;

[0212] 6. The subject has adequate bone marrow, kidney and liver function;

[0213] a) Absolute neutrophil count ≥ 1.5 × 10 9 / L, white blood cell count ≥3.0×10 9 / L;

[0214] b) Platelet count ≥75×10 9 / L;

[0215] c) Hemoglobin ≥70 g / L;

[0216] d) Aspartate aminotransferase (AST) ≤ 3 × ULN (≤ 5 × ULN for patients with hepatocellular carcinoma or liver metastasis);

[0217] e) Alanine aminotransferase (ALT) ≤ 3 × ULN (≤ 5 × ULN for patients with hepatocellular carcinoma or liver metastasis);

[0218] f) serum total bilirubin ≤2×ULN (≤3×ULN for patients with hepatocellular carcinoma or liver metastasis);

[0219] g) Creatinine ≤ 2 × ULN;

[0220] 7. Agree to participate in this trial and voluntarily sign the informed consent form.

[0221] Exclusion criteria (patients will be excluded if they meet any of the following criteria):

[0222] 1. Subjects with the following medical history before screening:

[0223] a) Suffering from primary or metastatic central nervous system malignant tumors;

[0224] b) Suffering from epilepsy, Parkinson's disease, or other central nervous system diseases that cause nausea and vomiting;

[0225] c) Suffering from intestinal obstruction or other digestive system diseases that may cause nausea and vomiting as determined by the investigator;

[0226] d) Suffering from clearly diagnosed vestibular disorders other than motion sickness (including but not limited to peripheral vestibular syndrome, central vestibular syndrome, etc.);

[0227] e) history of obvious, chronic dizziness;

[0228] f) QT interval > 450ms at screening, or taking concomitant medications for QT prolongation, or having risk factors for QT prolongation or corresponding arrhythmia events (heart failure, hyperkalemia, history or family history of long QT syndrome);

[0229] 2. Allergy or contraindications to the investigational drugs or other research drugs specified in the protocol (including chemotherapy drugs, investigational drugs and simulant components, dolasetron, aprepitant, dexamethasone, etc.);

[0230] 3. Subjects who have experienced nausea, retching or vomiting within 24 hours before randomization;

[0231] 4. Received or planned to receive abdominal or pelvic radiotherapy within 7 days before randomization during the study;

[0232] 5. Plan to administer high-emetic risk chemotherapy drugs again within 5 days after administration of high-emetic risk chemotherapy drugs, or plan to receive high-emetic risk chemotherapy drugs for multiple days within one chemotherapy cycle;

[0233] 6. Subjects who have received antiemetic drugs / drugs with antiemetic effects for less than 5 half-lives before chemotherapy, including but not limited to various 5-HT3 receptor antagonists (such as tropisetron, ondansetron, etc.), NK-1 receptor antagonists (such as aprepitant, fosaprepitant, etc.), systemic corticosteroids (such as dexamethasone, methylprednisolone, etc.), antidopamine drugs (such as amisulpride, droperidol, etc.), antihistamines (such as diphenhydramine, promethazine, etc.), etc.;

[0234] 7. Subjects who have received or plan to receive other drugs that affect the evaluation of nausea and vomiting before chemotherapy during the study, including but not limited to benzodiazepines, opioids, and systemic glucocorticoids with a half-life of less than 5 years;

[0235] 8. Subjects who have received or plan to receive specific CYP3A4 substrates, CYP3A4 inhibitors, or inducers for less than 5 half-lives before chemotherapy during the study;

[0236] 9. Participated in any clinical study within 1 month before screening (defined as receiving trial drugs or placebo);

[0237] 10. History of substance abuse, drug use, or alcoholism within 3 months prior to screening; alcoholism is defined as an average daily alcohol intake of >2 units of alcohol (1 unit = 360 mL of 5% alcohol beer, 45 mL of 40% alcohol liquor, or 150 mL of wine);

[0238] 11. Active hepatitis B (HBsAg positive and HBV-DNA higher than the upper limit of the normal range), positive hepatitis C antibody test, syphilis infection (anti-TP test positive), human immunodeficiency virus (HIV) infection (anti-HIV positive) during the screening period;

[0239] 12. Pregnant and lactating women; women of childbearing potential or male subjects (including male subjects) who are unwilling to practice contraception during the entire study period and within 3 months after the last dose of the investigational drug;

[0240] 13. Subjects who the researcher believes have any other factors that make them unsuitable for participation in this clinical study.

[0241] Exit criteria:

[0242] 1. During the study, it was discovered that the subjects violated the inclusion and exclusion criteria when they were enrolled, and the researchers judged that the safety of the subjects was affected.

[0243] 2. The subject withdraws informed consent.

[0244] 3. The researcher determines that the subject is not suitable for continuing the study treatment due to the occurrence of AE.

[0245] 4. Unblinding of trial drugs.

[0246] 5. Pregnancy.

[0247] 6. Serious non-compliance with the protocol-specified procedures, including study treatment, which, in the investigator's judgment, affects safety assessment or efficacy analysis.

[0248] 7. Lost to follow-up.

[0249] 8.Others.

[0250] Statistical analysis:

[0251] Statistical analysis software used was SAS EG 8.3 or above.

[0252] For continuous variables, list the number of cases, number of missing cases, mean, standard deviation, median, quartiles (Q1 and Q3), minimum, and maximum values. For categorical variables, describe the frequency and percentage. In this study, unless otherwise specified, "baseline" was defined as the last nonmissing observation before the first dose of the trial drug.

[0253] All analyses were performed separately by treatment group unless otherwise stated.

[0254] Analyze the dataset

[0255] Full Analysis Set (FAS): Based on the Intention To Treat Principle (ITT), it includes all subjects who have been randomized, received the trial drug at least once, and had at least one efficacy evaluation.

[0256] Per-Protocol Set (PPS): Includes all subjects in the FAS who have good study compliance, complete data on primary efficacy endpoints, and no major protocol deviations during the study period. Major protocol deviations are excluded from the PPS before the database is locked. Major protocol deviations are those that affect the primary efficacy endpoints.

[0257] Safety analysis set (SS) includes all subjects who have been randomized, received the investigational drug at least once, and have post-drug safety evaluation data.

[0258] Pharmacokinetics analysis set (PKS): includes all subjects who have been randomized, received the study drug at least once, had at least one measurable concentration, and had no protocol deviation that affected the PK data.

[0259] Effectiveness Analysis

[0260] The primary endpoint of the study was to statistically describe the response (CR) rate 24 hours after administration of high-emetic-risk chemotherapy drugs in each group; the response (CR) rate 24 hours after administration of high-emetic-risk chemotherapy drugs was analyzed according to the trial groups (CR was defined as no vomiting or retching within 24 hours after administration of high-emetic-risk chemotherapy drugs and no use of rescue medication) using the chi-square test or Fisher's exact probability method.

[0261] Secondary study endpoints:

[0262] The response (CR) rates at 0-120 h (overall phase) and 24-120 h (delayed phase) after administration of high-emetic-risk chemotherapy drugs, the proportion of subjects without nausea at 0-24 h and 24-120 h after administration of high-emetic-risk chemotherapy drugs, the proportion of subjects without vomiting at 0-24 h and 24-120 h after administration of high-emetic-risk chemotherapy drugs, the proportion of subjects using rescue medication at 0-24 h and 24-120 h after administration of high-emetic-risk chemotherapy drugs, and the mean VAS scores at 24±1 h and 120±1 h after administration of high-emetic-risk chemotherapy drugs were statistically described according to the trial groups. Quantitative indicators were compared between groups using analysis of variance or nonparametric tests, and qualitative indicators were analyzed using chi-square test or Fisher's exact probability method.

[0263] The median time to the first onset of vomiting (vomiting or retching) or the time to rescue treatment (whichever occurred first) within 120 hours after administration of high-emetic-risk chemotherapy drugs was statistically described according to the trial groups. Kaplan-Meier curves were drawn, and the log-rank method was used to compare the trial drug groups.

[0264] CINV prevention satisfaction scores of subjects and investigators and the Functional Life Index for Vomiting / Nausea (FLIE): Descriptive statistics were performed on the satisfaction scores of subjects and investigators and the Functional Life Index for Vomiting / Nausea (FLIE) according to each trial group, and the satisfaction scores were compared between groups using the non-parametric Wilcoxon rank sum test.

[0265] Security Analysis

[0266] Adverse events:

[0267] Adverse events (AEs) were coded using the ICH Medical Dictionary for Regulatory Activities (MedDRA 27.0 or later) and categorized by system organ class (SOC) and preferred term (PT). The severity of adverse events was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) [Version 5.0], unless otherwise specified. The number, incidence, and frequency of all treatment-emergent adverse events (TEAEs), Grade 3 or higher TEAEs, TEAEs related to the investigational drug, serious adverse events (SAEs), SAEs related to the investigational drug, and TEAEs leading to premature withdrawal from the study were calculated. The number and percentage were summarized by system organ class, preferred term, and group.

[0268] The table presents detailed information about the AEs. Detailed description of AEs that occurred during treatment after drug administration.

[0269] Various inspections:

[0270] Laboratory test parameters were statistically described. Descriptive statistics were performed based on baseline and post-treatment measurement time points, changes from baseline, and group-by-group laboratory test parameter results. Cross-tabulations were created to assess clinical judgment of laboratory test parameters based on baseline and post-treatment measurement time points, and group-by-group laboratory test parameter results. All test parameter results and abnormal, clinically significant results were tabulated.

[0271] Cross-tabulations were made for the results of 12-ECG, vital signs, physical examination and other indicators based on the baseline and post-treatment measurement time points and each group, and the results of all and abnormal clinically significant examination indicators were presented in a table.

[0272] Pharmacokinetic indicators:

[0273] According to different dosing groups, descriptive statistical analysis was performed on the blood concentration of compound 1 at different time points.

[0274] The plasma concentration data from this study were combined with data from other clinical trials for Compound 1 to develop a population pharmacokinetic model. This model was used to assess the impact of covariates on the pharmacokinetic profile of Compound 1. Additionally, exposure-response analyses were performed for specific efficacy and safety endpoints. The results of these population pharmacokinetic and exposure-response analyses are presented in separate reports.

[0275] The results of the present study indicate that Compound 1 injection has the effect of preventing and / or alleviating CINV induced by chemotherapy, and has a good overall safety profile.

Claims

1. Use of a compound of formula (I) or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or cocrystals and compositions thereof in the preparation of a medicament for preventing postoperative nausea and vomiting or nausea and vomiting caused by chemotherapy: in, R1 is selected from m1, m2, m3, m4 are each independently selected from 0, 1, 2, 3 or 4; m1 and m2 cannot be 0 at the same time; m3 and m4 cannot be 0 at the same time; n1, n2 are each independently selected from 0, 1, 2, 3 or 4; Z is selected from CR zl R z2 or NR z3 ; R zl , R z2 Each independently selected from H, F, Cl, Br, I, OH, CF3, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(=O)-C 1-6 Alkyl, -(CH2) q -C(=O)OC 1-6 Alkyl, -(CH2) q -NR le R lf 、-(CH2) q -COOH, -(CH2) q -CONH2, C 3-8 A carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the alkyl, alkoxy, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally further substituted by 0-5 groups selected from F, Cl, Br, I, OH, CF3, =O, carboxyl, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 The substituent is substituted by a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S, and when the heteroatom is selected from S, it is further selected to be S, S═O or S(═O)2; R le , R lf Each independently selected from H, C 1-6 Alkyl, C(=O)OC 1-6 Alkyl, -C(=O)O-(CH2)qC 3-8 Carbocyclic or -C(=O)O-(CH2) q -3 to 8 membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally further substituted by 0-5 groups selected from F, Cl, Br, I, OH, CF3, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 is substituted by a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S; Or, R zl and R z2 The carbon atom to which it is connected forms a 3-10 membered nitrogen-containing heterocyclic ring, wherein the ring is optionally further selected from F, Cl, Br, I, OH, CF3, cyano, nitro, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 substituted by a substituent of an alkynyl, C· carbocyclic group or a 3- to 8-membered heterocyclic group; R la , R lb Each independently selected from F, CF3, NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkyl or 3 to 8 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl or heterocyclic group is optionally further substituted by 0-5 groups selected from F, Cl, Br, I, OH, CF3, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 The substituent of the carbocyclic group or the 3- to 8-membered heterocyclic group is substituted, The heterocyclyl group contains 1 to 3 heteroatoms selected from N, O or S; R z3 independently selected from H, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)-C 3-8 Carbocyclic group, -C(=O)OC 3-8 Carbocyclic group, -C(=O)O-(3 to 8 membered heterocyclic group), -S(=O) p -C 1-6 Alkyl, -S(=O) p -C 3-8 Carbocyclic group, -S(=O) p -(3 to 8 membered heterocyclyl), -C(=O)NR 1g R lh 、-S(=O) p -NR li R lj or a 3- to 8-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally further substituted by 0-5 groups selected from F, Cl, Br, I, OH, CF3, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 The substituent is a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S; R lg , R lh , R li '、R lj Each independently selected from H or C 1-6 alkyl; Or, R lg , R lh The nitrogen atom to which it is connected forms a 3- to 10-membered heterocyclic ring, wherein the ring is optionally further selected from F, Cl, Br, I, OH, CF3, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl or -S(=O) p -C 1-6 The heterocyclic group is substituted by a substituent of an alkyl group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S; q is selected from 0, 1, 2, 3 or 4; p is selected from 0, 1 or 2; a is selected from 0, 1, 2 or 3; R 4 Independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or -(CH2)qC 3-8 The alkyl, alkenyl, alkynyl or carbocyclic group may be further substituted by 0-5 groups selected from F, Cl, Br, I, OH, CN, CF3, NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 is substituted by a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S; R 2 , R 3 , R 7 , R 8 Each independently selected from H, C 1-6 Alkyl, -C(=O)OC 1-4 Alkyl, -C(=O)O-(CH2) q -C 3-8 Carbocyclic group, -C(=O)O-(CH2) q -3 to 8 membered heterocyclic group or The alkyl, carbocyclic or heterocyclic group may be further substituted by 0-5 groups selected from F, Cl, Br, I, OH, CF3, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 The substituent is a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S; b is selected from 0, 1, 2, 3, 4 or 5; c is selected from 0, 1, 2, 3, 4 or 5; R 5 , R 6 Each independently selected from F, Cl, Br, I, OH, CN, CF3, cyano, nitro, C 1-4 Alkyl, -OR 5a 、-C(O)OR 5b 、-SR 5c 、-S(O)R 5d 、-S(O)2R 5e or -NR 5f R 5g ; R 5a , R 5b , R 5c , R 5d , R 5e , R 5f and R 5g Each is independently selected from H or C1-4 alkyl; Or, R 5f and R 5g The nitrogen atom to which it is attached forms a 5- to 6-membered heterocyclic ring, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S.

2. The use according to claim 1, characterized in that The compound is selected from formula (II): in, R1 is selected from m1, m2, m3, m4 are each independently selected from 0, 1 or 2; m1 and m2 cannot be 0 at the same time; m3 and m4 cannot be 0 at the same time; n1, n2 are each independently selected from 0 or 2; Z is selected from CR zl R z2 or NR z3 ; R la , R lb Independently selected from F, NH2; R zl , R z2 Each independently selected from H, carboxyl, Amino, -CH2NH2 or or R zl , R z2 Able to form a lactam with the C atom to which it is attached R z3 independently selected from H, -C(=O)-C 1-4 Alkyl, -C(=O)OC 1-4 Alkyl, -C(=O)-C 3-6 Carbocyclic group, -C(=O)OC 3-6 Carbocyclic group, -S(=O) p -C 1-4 Alkyl, -S(=O) p -C 3-6 Carbocyclic group, -C(=O)NR 1g R lh 、-S(=O) p -NR li R lj or a 3- to 6-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally further substituted by 0-5 substituents selected from F, Cl, Br, I, OH, CF3, nitro, cyano, amino, methyl, ethyl, methoxy, ethoxy, cyclopropyl or phenyl, and the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S; R lg , R lh , R li '、R lj Each independently selected from H or C 1-4 alkyl; Or, R lg , R lh The nitrogen atom to which it is attached forms a 4- to 6-membered heterocyclic ring, wherein the ring is optionally further selected from F, CF3, methyl, methoxy, or -S(=O) p -C 1-4 The heterocyclic group is substituted by a substituent of an alkyl group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S; p is selected from 2; R 2 , R 3 , R 7 , R 8 Each is independently selected from H, methyl or C(═O)O-tert-butyl.

3. The use according to claim 2, characterized in that The compound of formula (II) is selected from:

4. The method of claim 3, wherein the pharmaceutically acceptable salt is selected from propionate, methanesulfonate, acetate, citrate, D-tartrate, benzenesulfonate, phosphate, aspartate, L-tartrate, maleate, fumarate, benzoate, lactate, hydrochloride, formate, hydrobromide, sulfate, nitrate, phosphate, trifluoroacetate, succinate, mandelate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylate, citrate, glutamate, cinnamate, p-toluenesulfonate, benzenesulfonate, ethanesulfonate or trifluoromethanesulfonate.

5. The use according to claim 4, characterized in that The administration form is selected from one or more of single administration, multiple administration, continuous administration and target-controlled infusion.

6. The use according to claim 4, characterized in that The administration route is selected from oral, injection, instillation, transdermal absorption, buccal absorption, parenteral intraperitoneal, rectal, transbuccal, nasal drops, inhalation, local delivery, subcutaneous, intrafatty, intraarticular, intraperitoneal or intrathecal; preferably intravenous injection, intravenous instillation, arterial injection, intramuscular injection, subcutaneous injection, intraarticular injection, intraperitoneal injection, intrathecal injection or nasal drops.

7. The use according to claim 6, characterized in that The compound of formula (I) or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal and the composition thereof are administered before the end of the surgery.

8. The use according to any one of claims 1 to 7, further comprising a second drug, wherein the second drug is selected from one or more of an antiemetic or an analgesic.

9. The use according to claim 8, wherein The antiemetic is selected from tropisetron, ondansetron, granisetron, dolasetron, azasetron, ramosetron, palonosetron, aprepitant, fosaprepitant, rolapitant, casopitant, vertepitant, dimenhydrinate, promethazine, scopolamine, gabapentin, pregabalin, midazolam, and ephedrine; The analgesic is selected from morphine, fentanyl, sufentanil, oxycodone, hydromorphone, pethidine, butorphanol, nalbuphine, dezocine, pentazocine, buprenorphine, flurbiprofen axetil, ketorolac, lornoxicam, diclofenac, parecoxib, celecoxib, acetaminophen, tramadol, dexmedetomidine, ketamine, dexketamine, gabapentin, and pregabalin.

10. The use according to any one of claims 5 to 9, characterized in that The effective dose of the compound is selected from 1ng-30mg, 0.01μg-10mg, 0.1μg-1mg, 1μg-1000μg, 10μg-800μg, 10μg-600μg, 10μg-400μg, 10μg-200μg, and the effective dose of the hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal of the compound and the combination thereof are all converted by the effective dose of the compound.

11. The use according to claim 10, characterized in that The effective dose for intravenous injection is selected from 40 μg-400 μg, 60 μg-180 μg.

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