Ferroptosis inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a ferroptosis inhibitor as well as a preparation method and application thereof. The ferroptosis inhibitor is a compound represented by a formula I, pharmaceutically acceptable salts, solvates, isotope substitutes, polymorphic substances, tautomers, enantiomers, diastereoisomers, prodrugs or metabolites thereof, and in the formula, ring A, ring B, ring C and ring substitutions are described in the specification. The compounds of the general formula I have ferroptosis inhibitory activity, and the invention also provides pharmaceutical compositions containing the compounds, and applications of the compounds in preparation of drugs for treating or preventing ferroptosis-mediated diseases.

Description

Technical Field

[0001] This invention relates to ferroptosis inhibitors, their preparation methods, and their uses. Background Technology

[0002] Ferroprelation is an iron-dependent programmed cell death process accompanied by characteristic changes such as lipid peroxidation, increased reactive oxygen species (ROS), glutathione (GSH) depletion, and decreased glutathione peroxidase (GPX4) activity. Ferroprelation-related signaling pathways play an important role in maintaining cellular redox homeostasis.

[0003] The liver is one of the organs with the highest iron content, and abnormalities in the ferroptosis signaling pathway are closely related to various liver diseases. For example, ferroptosis is involved in acute liver injuries such as drug-induced liver injury and hepatic ischemia-reperfusion injury; ferroptosis is involved in autoimmune hepatitis; ferroptosis promotes the development of fatty liver; and ferroptosis also plays a role in viral and alcoholic hepatitis. Therefore, ferroptosis inhibitors are potential drugs for treating liver injuries such as drug-induced liver injury, hepatic ischemia-reperfusion injury, and autoimmune liver diseases.

[0004] Viruses, alcohol, drugs, trauma, and other factors can all cause acute liver injury, which can lead to liver failure in severe cases. Currently, there are few drugs available for treating drug-induced liver injury. Apart from a few drugs with antidotes (such as N-acetylcysteine, the antidote for acetaminophen), glucocorticoids are mainly used. The role of glucocorticoids and most other "hepatoprotective drugs" in drug-induced liver injury, especially for prophylactic use, still lacks high-level clinical evidence. In addition, hepatic ischemia-reperfusion injury often occurs in systemic shock, heart failure, sepsis, and after liver transplantation or surgery. Therefore, research on hepatoprotective drugs is of great significance to organ transplantation technology.

[0005] Studies have shown that inhibiting ferroptosis also has a protective effect on other organs: the ferroptosis inhibitor Ferrostatin-1 (Fer-1) is known to reduce iron accumulation caused by traumatic brain injury, reduce lipid peroxide production, and improve motor and cognitive abilities in animal models. Therefore, ferroptosis inhibitors may become effective drugs for treating neurodegenerative diseases such as Alzheimer's disease. Furthermore, ferroptosis inhibitors can also play a protective role in various organ injuries associated with sepsis. Summary of the Invention

[0006] The first aspect of this invention provides compounds of formula I, pharmaceutically acceptable salts, solvates, isotope-substituted derivatives, polymorphs, tautomers, enantiomers, diastereomers, prodrugs, or metabolites thereof:

[0007]

[0008] In the formula: ring A is a substituted or unsubstituted 5-10 membered heterocycle containing at least 2 nitrogen atoms and at least 1 carbonyl or thiocarbonyl group; ring B is a substituted or unsubstituted saturated or unsaturated 5-10 membered carbon ring or heterocycle, and ring B shares at least one carbon atom with ring A; ring C is a substituted or unsubstituted 3-8 membered cycloalkyl, a substituted or unsubstituted 5-14 membered aryl or heteroaryl, or a substituted or unsubstituted 4-10 membered heterocyclic group, and ring C shares at least 2 atoms with ring B; R1 is a substituted or unsubstituted 3-8 membered cycloalkyl, a substituted or unsubstituted 5-14 membered aryl or heteroaryl, or a substituted or unsubstituted 4-10 membered heterocyclic group.

[0009] In detail, the compound of Formula I, its pharmaceutically acceptable salt, solvate, isotope-substituted product, polymorph, tautomer, enantiomer, diastereomer, prodrug, or metabolite has the structure shown in Formula II or Formula III:

[0010]

[0011] Where X is an oxygen atom or a sulfur atom; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3, where 6 ≥ n + m ≥ 2; x is 0, 1 or 2; y is 0, 1, 2, 3, 4, 5 or 6; z is 0, 1, 2, 3 or 4.

[0012]

[0013] Wherein, ring A and ring B are unsubstituted; z is 0, 1, 2, 3 or 4; each R4 is as defined in claim 4; R1 is a substituted or unsubstituted phenyl, i.e. ring D is a benzene ring; w is 0, 1, 2, 3, 4 or 5.

[0014] A second aspect of the present invention provides a pharmaceutical composition comprising a compound described in any embodiment herein, a pharmaceutically acceptable salt thereof, a solvate thereof, an isotope substitute thereof, a polymorph thereof, a tautomer thereof, an enantiomer thereof, a diastereomer thereof, a prodrug or a metabolite thereof, and a pharmaceutically acceptable carrier thereof.

[0015] A third aspect of the present invention provides the use of the compounds described herein, pharmaceutically acceptable salts, solvates, isotope substitutes, polymorphs, tautomers, enantiomers, diastereomers, prodrugs, or metabolites in the preparation of medicaments for the treatment or prevention of ferroptosis-mediated diseases, or in the preparation of medicaments for the treatment or prevention of liver injury, hepatitis, brain (or nerve) injury, stroke, cerebral hemorrhage, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.

[0016] A fourth aspect of the present invention provides a method for treating or preventing ferroptosis-mediated diseases, the method comprising administering to a desired subject a therapeutically effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, a solvate thereof, an isotope substitute thereof, a polymorph thereof, a tautomer, an enantiomer, a diastereomer, a prodrug or a metabolite thereof, or a pharmaceutical composition thereof. Detailed Implementation

[0017] In the following description, certain specific details are set forth to provide a comprehensive understanding of several embodiments. However, those skilled in the art will understand that the invention can be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout this specification and in the following claims, the word “comprising” and its variations, such as “including” and “containing,” will be interpreted in an open, inclusive sense, that is, as “including but not limited to.” Furthermore, the headings provided herein are for convenience only and do not define the scope or meaning of the claimed invention.

[0018] I. Compounds: This invention provides compounds of formula I, pharmaceutically acceptable salts, solvates, isotope-substituted derivatives, polymorphs, tautomers, enantiomers, diastereomers, prodrugs, or metabolites thereof:

[0019]

[0020] In the formula:

[0021] Ring A is a 5-10 membered heterocycle, substituted or unsubstituted, containing at least two nitrogen atoms and at least one carbonyl or thiocarbonyl group.

[0022] Ring B is a substituted or unsubstituted saturated or unsaturated 5-10 membered carbon ring or heterocycle, and ring B shares at least one carbon atom with ring A.

[0023] The ring C is a substituted or unsubstituted 3-8 membered cycloalkyl, a substituted or unsubstituted 5-14 membered aryl or heteroaryl, or a substituted or unsubstituted 4-10 membered heterocyclic group, and the ring C and ring B share at least 2 atoms.

[0024] R1 is a substituted or unsubstituted 3-8 membered cycloalkyl, a substituted or unsubstituted 5-14 membered aryl or heteroaryl, or a substituted or unsubstituted 4-10 membered heterocyclic group.

[0025] Preferably, ring A contains 2-4 nitrogen atoms and 1-2 carbonyl groups (or thiocarbonyl groups); more preferably, ring A has 5-8 ring atoms; even more preferably, ring A contains 3 nitrogen atoms and 1 carbonyl group, and ring A has 5 ring atoms.

[0026] Preferably, except for one nitrogen atom on ring A which is replaced by R1, the remaining nitrogen atoms may optionally be replaced by 0 to 2 atoms selected from C1-C4 alkyl, halo-C1-C4 alkyl, or amino (NR) groups. a R b The R group is substituted with C1-C4 alkyl, hydroxyl-substituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, benzyl, 5-14 aryl or heteroaryl, 4-10 heterocyclic, or C1-C6 acyl groups; wherein, the R group is substituted with C1-C4 alkyl, hydroxyl-substituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, benzyl, 5-14 aryl or heteroaryl, 4-10 heterocyclic, or C1-C6 acyl groups. a and R b Each is independently selected from H, C1-C4 alkyl, or halogenated C1-C4 alkyl; more preferably, except for one nitrogen atom on ring A which is replaced by R1, the remaining nitrogen atoms on ring A may optionally be replaced by 0-2 C1-C4 alkyl groups.

[0027] Preferably, in Formula I, ring B is a 5-7 membered carbon ring or a heterocycle, and ring B shares 1-2 carbon atoms with ring A.

[0028] It should be understood that when referring to the number of ring atoms in rings A and B in this article, the number of ring atoms includes the atoms shared by both. Furthermore, when ring B shares one carbon atom with ring A, ring A and ring B form a spirocycle, which may produce enantiomers; when ring B shares more than one carbon atom with ring A, ring A and ring B form a fused or bridged ring, which may produce enantiomers and diastereomers, and the hydrogen on the shared carbon atom can be substituted.

[0029] More preferably, ring B is a 5-7 membered carbon ring, and ring B and ring A share one carbon atom to form a spiro ring.

[0030] Preferably, ring B is optionally surrounded by 0-6 radicals selected from halogens, C1-C4 alkyl groups, halogenated C1-C4 alkyl groups, C1-C4 alkoxy groups, halogenated C1-C4 alkoxy groups, and amino groups (NR). a R b Substituents of C1-C4 alkyl, hydroxyl-substituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, benzyl, 5-14 aryl or heteroaryl, 4-10 heterocyclic, and C1-C6 acyl groups; wherein, R a and R b Each is independently selected from H, C1-C4 alkyl, or halogenated C1-C4 alkyl; more preferably, ring B is optionally substituted by 0-4 C1-C4 alkyl or halogen.

[0031] Preferably, ring C is a benzene ring, a naphthalene ring, a thiophene ring, or a furan ring, and ring C shares two atoms with ring B.

[0032] It should be understood that when referring to the number of ring atoms in rings B and C in this article, the number of ring atoms includes atoms shared by both.

[0033] More preferably, ring C is a benzene ring, and ring C and ring B share 2 atoms.

[0034] Preferably, the ring C is optionally surrounded by 0-4 groups selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, hydroxyl, cyano, amino (NR) a R b ), carboxyl group, ester group (COOR) c or OCOR c ), amide group (CONHR) c or NHCOR c Substituents of benzyl, 5-14 aryl or heteroaryl, 4-10 heterocyclic and C1-C6 acyl groups; wherein, R a and R b Each group is independently selected from H, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C6 acyl, and R. c It is independently selected from C1-C4 alkyl and halogenated C1-C4 alkyl; more preferably, the ring C is optionally substituted by 0-4 halogens, C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkyl, or halogenated C1-C4 alkoxy.

[0035] Preferably, R1 is a substituted or unsubstituted 5-14 aryl or heteroaryl group; more preferably, R1 is phenyl, naphthyl, thienyl, benzothienyl, furanyl or benzofuranyl.

[0036] Preferably, R1 is optionally surrounded by 0-5 radicals selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, hydroxyl, cyano, amino (NR) a R b ), carboxyl group, ester group (COOR) c or OCOR c ), amide group (CONHR) c or NHCOR c Substituents of benzyl, 5-14 aryl or heteroaryl, 4-10 heterocyclic and C1-C6 acyl groups; wherein, R a and R b Each group is independently selected from H, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C6 acyl, and R. c R1 is independently selected from C1-C4 alkyl and halogenated C1-C4 alkyl; more preferably, R1 is optionally substituted by 0-5 substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkyl, halogenated C1-C4 alkoxy, and cyano.

[0037] In a preferred embodiment, the compound of formula I has the structure shown in formula II:

[0038]

[0039] In the formula: X is an oxygen atom or a sulfur atom; preferably, X is an oxygen atom, therefore, in the preferred embodiment, X is an oxygen atom.

[0040] Ring A contains 3 nitrogen atoms and 1 carbonyl group (or thiocarbonyl group). Ring A has 5 ring atoms, where x is 0 (i.e., R2 is absent), 1, or 2. Except for one nitrogen atom substituted by R1, the remaining nitrogen atoms in ring A are optionally substituted by 0, 1, or 2 R2 atoms. Each R2 atom is independently selected from halogens, C1-C4 alkyl groups, halo-C1-C4 alkyl groups, C1-C4 alkoxy groups, halo-C1-C4 alkoxy groups, and amino groups (NR). a R b The R group is substituted with C1-C4 alkyl, hydroxyl-substituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, benzyl, 5-14 aryl or heteroaryl, 4-10 heterocyclic, or C1-C6 acyl groups; wherein, the R group is substituted with C1-C4 alkyl, hydroxyl-substituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, benzyl, 5-14 aryl or heteroaryl, 4-10 heterocyclic, or C1-C6 acyl groups. a and R b Each is independently selected from H, C1-C4 alkyl, or halogenated C1-C4 alkyl; preferably, x is 0, therefore, in the preferred embodiment, the nitrogen atoms of ring A are not substituted except for R1 substitution.

[0041] Ring B is a 5-9 membered carbon ring, and ring B and ring A share one carbon atom to form a spiro ring; n is 0, 1, 2 or 3 -CH2-; m is 0, 1, 2 or 3 -CH2-; n and m satisfy the condition 6≥n+m≥2.

[0042] It should be understood that when referring to the number of ring atoms in rings A and B in this article, the number of ring atoms includes those shared by both. Furthermore, when ring B shares a carbon atom with ring A, the spirocycle formed by rings A and B may produce enantiomers.

[0043] Preferably, in Formula II, n is 0 or 1, m is 1 or 2, and the number of atoms in ring B is 5 or 6.

[0044] y is 0 (i.e., R3 is absent), 1, 2, 3, 4, 5, or 6, and ring B is optionally substituted by 0 to 6 R3s; each R3 is selected from halogens, C1-C4 alkyl groups, halo-C1-C4 alkyl groups, C1-C4 alkoxy groups, halo-C1-C4 alkoxy groups, amino groups (NR... a R b Substituents of C1-C4 alkyl, hydroxyl-substituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, benzyl, 5-14 aryl or heteroaryl, 4-10 heterocyclic, and C1-C6 acyl groups; wherein, Ra and R b Each is independently selected from H, C1-C4 alkyl, or halogenated C1-C4 alkyl; preferably, y is 0, therefore, in the preferred embodiment, ring B is not substituted.

[0045] Ring C is a benzene ring, and ring C and ring B share 2 atoms.

[0046] It should be understood that when ring C is absent, ring B is a closed carbon ring with 1+n+m+2 ring atoms; when ring C is absent, the molecule of formula II may still have ferroptosis inhibitory activity, but the inhibitory effect is weak.

[0047] z can be 0 (i.e. R4 is not present), 1, 2, 3 or 4. When ring C is present, its benzene ring can be optionally replaced by 0 to 4 R4s.

[0048] Each R4 is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, hydroxyl, cyano, amino (NR) a R b ), carboxyl group, ester group (COOR) c or OCOR c ), amide group (CONHR) c or NHCOR c Substituents of benzyl, 5-14 aryl or heteroaryl, 4-10 heterocyclic and C1-C6 acyl groups; wherein, R a and R b Each group is independently selected from H, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C6 acyl, and R. c The components are independently selected from C1-C4 alkyl and halogenated C1-C4 alkyl; preferably, the ring C is optionally substituted with 0-4 halogens, C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkyl, or halogenated C1-C4 alkoxy.

[0049] R1 is a substituted or unsubstituted 3-8 membered cycloalkyl, a substituted or unsubstituted 5-14 membered aryl or heteroaryl, or a substituted or unsubstituted 4-10 membered heterocyclic group; preferably, in Formula II, R1 is preferably a substituted or unsubstituted phenyl group, and therefore, in the preferred embodiment, R1 is a substituted or unsubstituted phenyl group.

[0050] R1 is optionally composed of 0-5 radicals selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, hydroxyl, cyano, amino (NR) a R b ), carboxyl group, ester group (COOR) c or OCORc ), amide group (CONHR) c or NHCOR c Substituents of benzyl, 5-14 aryl or heteroaryl, 4-10 heterocyclic and C1-C6 acyl groups; wherein, R a and R b Each group is independently selected from H, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C6 acyl, and R. c R1 is independently selected from C1-C4 alkyl and halogenated C1-C4 alkyl; preferably, R1 is optionally substituted by 0-5 substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkyl, halogenated C1-C4 alkoxy, and cyano.

[0051] In a preferred embodiment, the compound of formula I or II has the structure shown in formula III:

[0052]

[0053] In the formula, each R4 and z is as defined in Formula II; preferably, z is 0, 1 or 2; preferably, in Formula III, each R4 is independently substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl and halo-C1-C4 alkoxy.

[0054] R1 in Formula I or Formula II is preferably a benzene ring, i.e., ring D, which is optionally substituted by w R5 substituents; ring A is a 5-membered heterocycle containing 3 nitrogen atoms and one carbonyl group; ring A is substituted only by ring D; ring A and ring B share 1 carbon atom to form a spirocycle; ring B is not substituted; ring B is a six-membered carbon ring that shares two carbon atoms with ring C benzene ring.

[0055] w can be 0 (i.e. R5 does not exist), 1, 2, 3, 4 or 5, and ring D can be optionally replaced by 0-5 R5s; preferably, w is 0 or 1.

[0056] Each R5 is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, hydroxyl, cyano, amino (NR) a R b ), carboxyl group, ester group (COOR) c or OCOR c ), amide group (CONHR) c or NHCOR c Substituents of benzyl, 5-14 aryl or heteroaryl, 4-10 heterocyclic and C1-C6 acyl groups; wherein, R a and R bEach group is independently selected from H, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C6 acyl, and R. c R5 is independently selected from C1-C4 alkyl, halogenated C1-C4 alkyl; preferably, each R5 is independently halogenated, C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkyl, halogenated C1-C4 alkoxy, cyano.

[0057] Preferably, the compounds of Formula I of the present invention include the compounds shown in Compounds 1 to 22 below, pharmaceutically acceptable salts thereof, solvates, isotopic substitutes, polymorphs, tautomers, enantiomers, diastereomers, prodrugs, or metabolites.

[0058] II. The preparation process of the compound is as follows: The compound of Formula I of the present invention can be prepared by the following exemplary reaction process, wherein R1, R2, R3, R4, x, y, z, m, n and X are as described in any embodiment herein:

[0059]

[0060] Hydrazine raw material a and ketone raw material b are mixed in acetic acid, stirred at room temperature, and potassium cyanide aqueous solution is added dropwise. Stirring continues, and ice water is added dropwise to the reaction solution to induce crystallization. The suspension is stirred continuously, filtered, and the filter cake is washed with pure water and dried under vacuum to obtain product c. If crystals do not form or the particle size is small, the reaction solution is extracted with dichloromethane and sodium hydroxide solution (2 M), the organic layer is washed with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by medium-pressure rapid silica gel chromatography and reverse preparative liquid chromatography. Product c is then lyophilized to obtain product c. Besides using acetic acid directly as a solvent, methanol, ethanol, isopropanol, tert-butanol, and other polar protic solvents can be preferably added.

[0061] III. Uses, Treatment Methods, and Pharmaceutical Compositions

[0062] The compound of Formula I of the present invention is a ferroptosis inhibitor. Therefore, the compound of Formula I of the present invention, its pharmaceutically acceptable salts, solvates, isotope-substituted derivatives, polymorphs, tautomers, enantiomers, diastereomers, prodrugs, or metabolites can be used to modulate the ferroptosis process, and thereby for the treatment or prevention of ferroptosis-mediated diseases. Accordingly, in some embodiments, the present invention also provides the use of the compound of Formula I of the present invention, its pharmaceutically acceptable salts, solvates, isotope-substituted derivatives, polymorphs, tautomers, enantiomers, diastereomers, prodrugs, or metabolites in the preparation of medicaments for the treatment or prevention of ferroptosis-mediated diseases. In some embodiments, the present invention provides a method for treating or preventing ferroptosis-mediated diseases in a subject, the method comprising administering to the subject a therapeutically or preventively effective amount of a compound of Formula I of the present invention, a pharmaceutically acceptable salt, solvate, isotope-substituted product, polymorph, tautomer, enantiomer, diastereomer, prodrug, or metabolite thereof, or a pharmaceutical composition containing a therapeutically or preventively effective amount of a compound of Formula I of the present invention, a pharmaceutically acceptable salt, solvate, isotope-substituted product, polymorph, tautomer, enantiomer, diastereomer, prodrug, or metabolite thereof. The drug may be administered orally, duodenally, by parenteral injection (including intrapulmonary, intranasal, intrathecal, intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), locally, or rectally. Application techniques suitable for the compounds and methods described herein are well known to those skilled in the art, wherein oral administration is a preferred route of administration.

[0063] This invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I of the invention, a pharmaceutically acceptable salt, solvate, isotope-substituted derivative, polymorph, tautomer, enantiomer, diastereomer, prodrug, or metabolite, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition of this invention can be used to modulate the process of ferroptosis, thereby enabling its use in the treatment or prevention of ferroptosis-mediated diseases.

[0064] Pharmaceutical compositions can be formulated using methods known in the art and their administration modalities and dosages determined by a skilled practitioner. For parenteral administration, the compound can be dissolved in sterile water or saline solution or a pharmaceutically acceptable medium for administering non-water-soluble compounds. For enteral administration, the compound can be administered in tablet, capsule, or dissolved in a liquid form. Tablets or capsules can be enteric-coated or in sustained-release formulations. Various suitable formulations are known, including polymer or protein microparticles, ointments, pastes, gels, hydrogels, or solutions encapsulating the compound to be released, which can be applied topically or locally to the compound. Sustained-release transdermal formulations or implants can be used to delay release. Parenteral formulations may, for example, contain excipients such as polyalkylene glycols (e.g., polyethylene glycol), plant-derived oils, or hydrogenated naphthalene. Biocompatible, biodegradable lactide polymers, lactide / glycolic acid copolymers, or polyoxyethylene-polyoxypropylene copolymers can be used to control the release of the compound. Other potentially useful parenteral delivery systems for modulating compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients such as lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate, and deoxycholate, or may be oily solutions for nasal drops, or in gel form.

[0065] The present invention will be described below by way of specific embodiments. It should be understood that these embodiments are merely illustrative and are not intended to limit the scope of the invention. Unless otherwise stated, the materials, reagents, and methods used in the embodiments are conventional materials, reagents, and methods in the art, and are commercially available.

[0066] Example 1: Synthesis of 2-phenyl-1,2,4-triazaspiro[4.4]non-3-one (compound 1)

[0067] Phenylan (0.05 mL, 0.50 mmol) was added to a solution of cyclopentanone (0.045 mL, 0.50 mmol) in acetic acid (0.6 mL). After stirring at room temperature for 15 minutes, an aqueous solution of potassium cyanate (50.7 mg, 0.63 mmol) (0.15 mL) was added dropwise, and stirring continued for another 15 minutes. Ice water (1.25 mL) was added dropwise to the mixture to induce crystallization. The resulting suspension was stirred for 30 minutes, extracted with dichloromethane and 2 M sodium hydroxide solution, washed with saturated brine, and dried over anhydrous sodium sulfate. After 1 hour, the mixture was filtered, the filtrate was concentrated, and purified by medium-pressure rapid silica gel chromatography and preparative liquid chromatography. After lyophilization, a white solid 2-phenyl-1,2,4-triazaspiro[4.4]non-3-one (31.4 mg, yield 28.9%) was obtained. LCMS m / z: 218.05 [M+H] + . 1 H NMR(600 MHz, DMSO-d6) δ 7.58 – 7.54 (m, 3H), 7.28 – 7.24 (m, 2H), 6.90 – 6.86(m, 1H), 6.05 (s, 1H), 1.78 – 1.71 (m, 2H), 1.70 – 1.60 (m, 6H).

[0068] Example 2: Synthesis of 2-phenyl-1,2,4-triazaspiro[4.5]dec-3-one (compound 2)

[0069]

[0070] Phenyzine (0.05 mL, 0.5 mmol) was added to a solution of cyclohexanone (0.05 mL, 0.50 mmol) in acetic acid (0.6 mL). After stirring for 15 minutes at room temperature, an aqueous solution of potassium cyanate (50.7 mg, 0.625 mmol) (0.15 mL) was added dropwise, and stirring continued for another 15 minutes. Ice water (1.25 mL) was then added dropwise to the mixture to induce crystallization. The resulting suspension was stirred for 30 minutes, filtered, and the filter cake was washed with pure water and dried under vacuum to give a white solid 2-phenyl-1,2,4-triazaspiro[4.5]dec-3-one (35.8 mg, yield 31%). LCMS m / z: 232.00 [M+H] + . 1H NMR (600 MHz, DMSO-d6) δ7.71 (s, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.28 – 7.24 (m, 2H), 6.93 – 6.88 (m,1H), 5.96 (s, 1H), 1.70 – 1.62 (m, 2H), 1.60 – 1.48 (m, 6H), 1.47 – 1.38 (s,1H), 1.33 – 1.21 (m, 1H).

[0071] Example 3: Synthesis of 7,7,9-trimethyl-2-phenyl-1,2,4-triazaspiro[4.5]dec-3-one (compound 3)

[0072]

[0073] Phenylan (0.05 mL, 0.5 mmol) was added to a solution of 3,3,5-trimethylcyclohexanone (0.08 mL, 0.50 mmol) in acetic acid (0.6 mL). The mixture was stirred at room temperature for 15 minutes, followed by the addition of 0.15 mL of an aqueous solution of potassium cyanate (50.7 mg, 0.625 mmol). Stirring continued for another 15 minutes. Ice water (1.25 mL) was then added dropwise to induce crystallization. The resulting suspension was stirred for 30 minutes, filtered, and the filter cake was washed with pure water and dried under vacuum to obtain a yellow solid, 7,7,9-trimethyl-2-phenyl-1,2,4-triazaspiro[4.5]dec-3-one (91.1 mg, yield 66.7%). LCMS m / z: 274.10 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 7.62 (d, J = 7.6 Hz, 2H), 7.36 (s, 1H), 7.28- 7.23 (m, 2H), 6.92 – 6.88 (m, 1H), 5.92 (s, 1H), 1.95 – 1.86 (m, 1H), 1.84– 1.76 (m, 1H), 1.73 - 1.64 (m, 1H), 1.39 - 1.22 (m, 3H), 1.10 (s, 3H), 0.90(s, 3H), 0.85 (d, J = 6.5 Hz, 3H), 0.77 (t, J = 12.6 Hz, 1H).

[0074] Example 4: Synthesis of 1'-phenyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (compound 4)

[0075]

[0076] Phenylated hydrazine (0.05 mL, 0.50 mmol) was added to a methanol (0.5 mL) solution containing 3,4-dihydronaphthyl-2(1H)-one (0.066 mL, 0.50 mmol). The mixture was reacted at room temperature for 15 minutes, followed by the addition of 0.15 mL of an aqueous solution of potassium cyanate (50.7 mg, 0.63 mmol) in portions, immediately followed by the addition of acetic acid (1.5 mL). The mixture was stirred for another 15 minutes, then ice water (5 mL) was added. The suspension was extracted with dichloromethane using 2 M sodium hydroxide solution, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After 1 hour, the mixture was filtered, and the filtrate was concentrated and purified by medium-pressure rapid silica gel chromatography and preparative liquid chromatography. The purified solid was lyophilized to give 1'-phenyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (102.8 mg, yield 66.5%). LCMS m / z: 280.05 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.60– 7.56 (m, 2H), 7.27 – 7.21 (m, 2H), 7.13 – 7.05 (m, 4H), 6.93 – 6.88 (m,1H), 6.23 (s, 1H), 3.03 – 2.90 (m, 3H), 2.88 – 2.82 (m, 1H), 2.01 – 1.82 (m, 2H).

[0077] Example 5: Synthesis of 1'-phenyl-1,3-dihydrospiro[indene-2,3'-[1,2,4]triazolidine]-5'-one (compound 5)

[0078] Phenylated hydrazine (0.05 mL, 0.50 mmol) was added to a methanol (0.5 mL) solution containing 2-indanone (66.1 mg, 0.50 mmol). After stirring at room temperature for 15 minutes, a water (0.15 mL) solution containing potassium cyanate (50.7 mg, 0.63 mmol) was added in portions, followed immediately by acetic acid (1.5 mL). Stirring continued for 15 minutes, then ice water (5 mL) was added to induce crystallization. The resulting suspension was stirred for 30 minutes, filtered, and the filter cake was washed with pure water and dried under vacuum to give a white solid, 1'-phenyl-1,3-dihydrospiro[indan-2,3'-[1,2,4]triazolidine]-5'-one (92.2 mg, yield 70.0%). LCMS m / z: 266.05 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.56 (d, J = 7.9 Hz,2H), 7.28 – 7.23 (m, 2H), 7.24 – 7.19 (m, 2H), 7.19 – 7.15 (m, 2H), 6.95 –6.90 (m, 1H), 6.39 (s, 1H), 3.19 - 3.07 (m, 4H).

[0079] Example 6: Synthesis of 7-methoxy-1'-phenyl-3,4-dihydro-2H-spiro[naphthyl-1,3'-[1,2,4]triazolidine]-5'-one (compound 6)

[0080]

[0081] A mixture of 7-methoxy-3,4-dihydronaphthyl-1(2H)-one (88.1 mg, 0.50 mmol), phenylhydrazine (0.05 mL, 0.50 mmol), and acetic acid (0.01 mL) was stirred at 70 °C for 10 min, then diluted with acetic acid (1 mL) and cooled to 45 °C. Water (0.075 mL) was then added, followed by the addition of solid potassium cyanate (202.8 mg, 2.50 mmol) in five portions over 2 hours. The mixture was stirred at room temperature for 1.5 h, followed by the addition of ice water (0.75 mL) to induce crystallization. The resulting suspension was maintained at 0 °C for 1 h. The crude product was filtered, the filter cake was washed with water, and then dried under vacuum to give a pale yellow solid, 77-methoxy-1'-phenyl-3,4-dihydro-2H-spiro[naphthyl-1,3'-[1,2,4]triazolidine]-5'-one (59.3 mg, yield 38.4%). LCMS m / z: 310.10 [M+H] + . 1H NMR (600 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.68 –7.59 (m, 3H), 7.28 – 7.23 (m, 2H), 6.94 – 6.89 (m, 1H), 6.81 (dd, J = 8.4,2.4 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 5.92 (s, 1H), 3.73 (s, 3H), 2.80 –2.66 (m, 2H), 2.07 – 1.96 (m, 2H), 1.83 – 1.76 (m, 1H), 1.70 – 1.61 (m, 1H).

[0082] Example 7: Synthesis of 7-methoxy-1'-phenyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (compound 7)

[0083]

[0084] Phenylated hydrazine (0.05 mL, 0.50 mmol) was added to a methanol (0.5 mL) solution containing 7-methoxy-3,4-dihydronaphthyl-2(1H)-one (0.08 mL, 0.50 mmol). The mixture was stirred at room temperature for 15 minutes, followed by the addition of 0.15 mL of an aqueous solution of potassium cyanate (50.7 mg, 0.63 mmol), immediately followed by the addition of acetic acid (1.5 mL). The mixture was stirred for another 15 minutes, and then ice water (5 mL) was added. The resulting suspension was extracted with dichloromethane and 2 M sodium hydroxide solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After 1 hour, the mixture was filtered, concentrated, and purified by medium-pressure rapid silica gel chromatography and preparative liquid chromatography. The purified solid was lyophilized to give 148.2 mg (95.8% yield) of 7-methoxy-1'-phenyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one. LCMS m / z: 310.05 [M+H] + . 1H NMR (600 MHz, Chloroform-d)δ 7.65 (d, J = 8.1 Hz, 2H), 7.28 – 7.23 (m, 2H), 7.03 – 6.95 (m, 2H), 6.70 (dd, J = 8.4, 2.6 Hz, 1H), 6.54 (s, 1H), 5.30 (s, 1H), 3.71 (s, 3H), 3.07 – 2.95 (m, 3H), 2.85 – 2.75 (m, 1H), 2.10 – 2.02 (m, 1H), 2.00 – 1.93 (m, 1H).

[0085] Example 8: Synthesis of 5-methoxy-1'-phenyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (compound 8)

[0086]

[0087] Phenylated hydrazine (0.05 mL, 0.5 mmol) was added to a methanol (0.5 mL) solution containing 5-methoxy-3,4-dihydronaphthyl-2(1H)-one (88.1 mg, 0.50 mmol). The mixture was stirred at room temperature for 15 minutes, followed by the addition of a fractionally added aqueous solution of potassium cyanate (50.7 mg, 0.625 mmol) (0.15 mL), immediately followed by the addition of acetic acid (1.5 mL). Stirring continued for 15 minutes, followed by the addition of ice water (5 mL). The resulting suspension was stirred for 30 minutes, filtered, and the filter cake was washed with pure water and dried under vacuum to give a yellow solid, 5-methoxy-1'-phenyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (146.7 mg, yield 94.84%). LCMS m / z: 310.10 [M+H] + . 1 H NMR (600 MHz, Chloroform-d) δ 7.71 (d, J= 8.4 Hz, 2H), 7.34 – 7.28 (m, 2H), 7.18 – 7.11 (m, 1H), 7.06 – 7.00 (m, 1H), 6.75 – 6.66 (m, 2H), 5.18 (s, 1H), 3.84 (s, 3H), 3.23 – 2.93 (m, 3H), 2.88 –2.77 (m, 1H), 2.21 – 1.97 (m, 2H).

[0088] Example 9: Synthesis of 6-bromo-1'-phenyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (compound 9)

[0089]

[0090] Phenylated hydrazine (0.05 mL, 0.50 mmol) was added to a methanol (0.5 mL) solution containing 6-bromo-3,4-dihydronaphthyl-2(1H)-one (112.6 mg, 0.50 mmol). The mixture was stirred at room temperature for 15 minutes, followed by the addition of 0.15 mL of an aqueous solution of potassium cyanate (50.7 mg, 0.63 mmol), immediately followed by the addition of acetic acid (1.5 mL). The mixture was stirred for another 15 minutes, followed by the addition of ice water (5 mL). The resulting suspension was extracted with dichloromethane and 2 M sodium hydroxide solution, the organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. After 1 hour, the suspension was filtered, concentrated, and purified by medium-pressure rapid silica gel chromatography and preparative liquid chromatography. The purified solid was lyophilized to give 6-bromo-1'-phenyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (121.4 mg, 67.8% yield). LCMS m / z: 380.00 [M+Na] + . 1 H NMR (600 MHz, Chloroform-d)δ 7.67 (d, J = 7.8 Hz, 2H), 7.35 – 7.27 (m, 4H), 7.06 – 7.01 (m, 1H), 6.94(d, J = 8.4 Hz, 1H), 5.51 (s, 1H), 3.15 – 2.99 (m, 3H), 2.96 – 2.87 (m, 1H), 2.17 – 2.08 (m, 1H), 2.09 – 1.98 (m, 1H).

[0091] Example 10: Synthesis of 6-fluoro-1'-phenyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (compound 10)

[0092]

[0093] Phenylated hydrazine (0.05 mL, 0.50 mmol) was added to a methanol (0.5 mL) solution containing 6-fluoro-3,4-dihydronaphthyl-2(1H)-one (82.1 mg, 0.50 mmol), and the mixture was stirred at room temperature for 15 minutes. Then, an aqueous solution of potassium cyanate (50.7 mg, 0.625 mmol) (0.15 mL) was added in portions, followed immediately by acetic acid (1.5 mL). The mixture was stirred for another 15 minutes, and then ice water (5 mL) was added. The resulting suspension was extracted with dichloromethane and 2M sodium hydroxide solution, the organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. After 1 hour, the solution was filtered, concentrated, and purified by medium-pressure rapid silica gel chromatography and preparative liquid chromatography. The purified solution was then lyophilized to obtain an orange-yellow solid, 6-fluoro-1'-phenyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (115.8 mg, yield 77.9%). LCMS m / z: 298.05 [M+H] + . 1 H NMR (600 MHz, Chloroform-d) δ7.68 (d, J = 7.8 Hz, 2H), 7.34 – 7.29 (m, 2H), 7.06 – 7.00 (m, 2H), 6.90 –6.84 (m, 2H), 5.57 (s, 1H), 3.18 – 2.85 (m, 4H), 2.19 – 1.97 (m, 2H).

[0094] Example 11: Synthesis of 6,8-difluoro-1'-phenyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (compound 11)

[0095]

[0096] Phenylated hydrazine (0.05 mL, 0.50 mmol) was added to a methanol (0.5 mL) solution containing 91.9 mg, 0.50 mmol of 6,8-difluoro-3,4-dihydronaphthyl-2(1H)-one (0.50 mmol). The mixture was stirred at room temperature for 15 minutes. Then, an aqueous solution of potassium cyanate (50.7 mg, 0.625 mmol) (0.15 mL) was added in portions, followed immediately by acetic acid (1.5 mL). The mixture was stirred for another 15 minutes, and then ice water (5 mL) was added. The resulting suspension was extracted with dichloromethane and 2 M sodium hydroxide solution. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After 1 hour, the solution was filtered, concentrated, and purified by medium-pressure rapid silica gel chromatography and preparative liquid chromatography. Lyophilization yielded a yellow solid, 6,8-difluoro-1'-phenyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (113.8 mg, yield 72.2%). LCMS m / z: 316.05 [M+H] + . 1 H NMR (600 MHz, Chloroform-d) δ7.58 (d, J = 7.8 Hz, 2H), 7.26 – 7.21 (m, 2H), 6.98 – 6.94 (m, 1H), 6.65 –6.57 (m, 2H), 5.86 (s, 1H), 3.09 – 3.01 (m, 1H), 2.94 (s, 2H), 2.90 – 2.80 (m, 1H), 2.10 – 2.02 (m, 1H), 1.99 – 1.89 (m, 1H).

[0097] Example 12: Synthesis of 6-chloro-1'-phenyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (compound 12)

[0098]

[0099] Phenylated hydrazine (0.05 mL, 0.50 mmol) was added to a methanol (0.5 mL) solution containing 6-chloro-3,4-dihydronaphthyl-2(1H)-one (90.3 mg, 0.50 mmol). The mixture was stirred at room temperature for 15 minutes, followed by the addition of 0.15 mL of an aqueous solution of potassium cyanate (50.7 mg, 0.63 mmol), immediately followed by the addition of acetic acid (1.5 mL). The mixture was stirred for another 15 minutes, followed by the addition of ice water (5 mL). The resulting suspension was extracted with dichloromethane and 2 M sodium hydroxide solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After 1 hour, the mixture was filtered, concentrated, and purified by medium-pressure rapid silica gel chromatography and preparative liquid chromatography. The purified solid was lyophilized to give 39.2 mg (25.0% yield) of 6-chloro-1'-phenyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one. LCMS m / z: 314.05 [M+H] + . 1 H NMR (600 MHz, Chloroform-d) δ 7.69(d, J = 7.8 Hz, 2H), 7.34 – 7.30 (m, 2H), 7.18 – 7.13 (m, 2H), 7.06 – 6.99(m, 2H), 5.25 (s, 1H), 3.14 – 3.02 (m, 3H), 2.95 – 2.88 (m, 1H), 2.18 – 2.12 (m, 1H), 2.06 – 2.01 (m, 1H).

[0100] Example 13: Synthesis of 6-bromo-1'-p-tolyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (compound 13)

[0101]

[0102] p-Toluidine hydrochloride (79.3 mg, 0.50 mmol) was dissolved in dichloromethane (2.7 mL), washed with 2M sodium hydroxide aqueous solution (7.2 mL), the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain p-toluidine. p-Toluidine was added to a methanol solution (0.5 mL) containing 6-bromo-3,4-dihydronaphthyl-2(1H)-one (112.6 mg, 0.50 mmol), stirred at room temperature for 15 minutes, followed by the addition of a fractionally added aqueous solution of potassium cyanate (50.7 mg, 0.63 mmol) (0.15 mL), immediately followed by the addition of acetic acid (1.5 mL), stirring for another 15 minutes, and then the addition of ice water (5 mL). The resulting suspension was extracted with dichloromethane and 2M sodium hydroxide solution, the organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. After 1 hour, the mixture was filtered, concentrated, and purified by medium-pressure rapid silica gel chromatography and preparative liquid chromatography to obtain a yellow solid, 6-bromo-1'-p-tolyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (111.4 mg, yield 59.8%). LCMS m / z: 372.00 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.45 (d, J = 8.4 Hz,2H), 7.36 – 7.33 (m, 1H), 7.32 – 7.26 (m, 1H), 7.09 – 7.01 (m, 3H), 6.21 (s,1H), 3.02 – 2.81 (m, 4H), 2.22 (s, 3H), 2.01 – 1.81 (m, 2H).

[0103] Example 14: Synthesis of 6-bromo-1'-(4-trifluoromethylphenyl)-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (compound 14)

[0104]

[0105] 4-Trifluoromethylphenylhydrazine (88.1 mg, 0.50 mmol) was added to a methanol (0.5 mL) solution containing 6-bromo-3,4-dihydronaphthyl-2(1H)-one (112.6 mg, 0.50 mmol). After stirring at room temperature for 15 minutes, an aqueous solution of potassium cyanate (50.7 mg, 0.63 mmol) (0.15 mL) was added in portions, followed immediately by acetic acid (1.5 mL). Stirring was continued for 15 minutes, and then ice water (5 mL) was added. The resulting suspension was extracted with dichloromethane and 2M sodium hydroxide solution, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After 1 hour, the mixture was filtered, concentrated, and purified by medium-pressure rapid silica gel chromatography and preparative liquid chromatography to obtain a yellow solid, 6-bromo-1'-(4-trifluoromethylphenyl)-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (123.6 mg, yield 58.0%). LCMS m / z: 426.10 [M+H] + . 1 H NMR (600 MHz, Chloroform-d) δ7.79 (d, J = 9.0 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.33 (s, 1H), 7.30 (d, J= 8.4 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 5.76 (s, 1H), 4.63 (s, 1H), 3.15 –3.01 (m, 3H), 2.97 – 2.89 (m, 1H), 2.17 – 1.98 (m, 2H).

[0106] Example 15: Synthesis of 6-bromo-1'-m-tolyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (compound 15)

[0107]

[0108] To a methanol (0.5 mL) solution containing 6-bromo-3,4-dihydronaphthyl-2(1H)-one (112.6 mg, 0.50 mmol), m-methylphenylhydrazine (0.06 mL, 0.50 mmol) was added. The mixture was stirred at room temperature for 15 minutes, followed by the addition of 0.15 mL of an aqueous solution of potassium cyanate (50.7 mg, 0.625 mmol), immediately followed by the addition of acetic acid (1.5 mL). The mixture was stirred for another 15 minutes, and then ice water (5 mL) was added. The resulting suspension was extracted with dichloromethane and 2 M sodium hydroxide solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After 1 hour, the mixture was filtered, concentrated, and purified by medium-pressure rapid silica gel chromatography and preparative liquid chromatography to obtain a deep yellow solid, 6-bromo-1'-m-tolyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (90.5 mg, 48.6% yield). LCMS m / z: 372.05 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 7.74 (s,1H), 7.43 – 7.37 (m, 2H), 7.35 (s, 1H), 7.29 (dd, J = 8.4, 1.8 Hz, 1H), 7.15– 7.10 (m, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 6.23 (s,1H), 3.01 – 2.94 (m, 2H), 2.90 – 2.84 (m, 2H), 2.25 (s, 3H), 2.00 – 1.80 (m,2H).

[0109] Example 16: Synthesis of 6-bromo-1'-(4-bromophenyl)-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (compound 16)

[0110]

[0111] p-Bromophenylhydrazine (93.5 mg, 0.50 mmol) was added to a methanol (0.5 mL) solution containing 6-bromo-3,4-dihydronaphthyl-2(1H)-one (112.6 mg, 0.50 mmol). After stirring at room temperature for 15 minutes, an aqueous solution of potassium cyanate (50.7 mg, 0.63 mmol) was added in portions (0.15 mL), followed immediately by acetic acid (1.5 mL). Stirring continued for 15 minutes, and then ice water (5 mL) was added. The resulting suspension was extracted with dichloromethane and 2 M sodium hydroxide solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After 1 hour, the suspension was filtered, concentrated, and purified by medium-pressure rapid silica gel chromatography and preparative liquid chromatography to obtain a yellow solid 6-bromo-1'-(4-bromophenyl)-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (122.6 mg, yield 56.1%). LCMS m / z: 457.90 [M+Na] + . 1 H NMR (600 MHz, Chloroform-d) δ 7.59 (d, J= 9.0 Hz, 2H), 7.41 (d, J = 9.0 Hz, 2H), 7.32 (s, 1H), 7.29 (dd, J = 8.4, 1.8Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 5.35 (s, 1H), 3.13 – 3.01 (m, 3H), 2.96 –2.89 (m, 1H), 2.15 – 2.09 (m, 1H), 2.05 – 1.99 (m, 1H).

[0112] Example 17: Synthesis of 6-chloro-1'-(4-trifluoromethylphenyl)-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (compound 17)

[0113]

[0114] 4-Trifluoromethylphenylhydrazine (88.1 mg, 0.50 mmol) was added to a methanol (0.5 mL) solution containing 6-chloro-3,4-dihydronaphthyl-2(1H)-one (90.3 mg, 0.50 mmol). After stirring at room temperature for 15 minutes, an aqueous solution of potassium cyanate (50.7 mg, 0.63 mmol) (0.15 mL) was added in portions, followed immediately by acetic acid (1.5 mL). Stirring was continued for 15 minutes, and then ice water (5 mL) was added. The resulting suspension was extracted with dichloromethane and 2 M sodium hydroxide solution, the organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. After 1 hour, the mixture was filtered, concentrated, and purified by medium-pressure rapid silica gel chromatography and preparative liquid chromatography to obtain a yellow solid, 6-chloro-1'-(4-trifluoromethylphenyl)-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (121.4 mg, yield 59.9%). LCMS m / z: 382.10 [M+H] + . 1 H NMR (600 MHz, Chloroform-d) δ 7.79 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 9.0 Hz, 2H), 7.20 – 7.13 (m, 2H), 7.01 (d, J = 7.8 Hz, 1H), 5.72 (s, 1H), 3.14 – 3.03 (m, 3H), 2.97 – 2.89 (m,1H), 2.17 – 2.09 (m, 1H), 2.08 – 2.00 (m, 1H).

[0115] Example 18: Synthesis of 6-chloro-1'-m-tolyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (compound 18)

[0116]

[0117] To a methanol (0.5 mL) solution containing 90.3 mg (0.50 mmol) of 6-chloro-3,4-dihydronaphthyl-2(1H)-one, m-toluidine (0.06 mL, 0.50 mmol) was added. After stirring at room temperature for 15 minutes, an aqueous solution of potassium cyanate (50.7 mg, 0.63 mmol) (0.15 mL) was added in portions, followed immediately by acetic acid (1.5 mL). Stirring continued for 15 minutes, and then ice water (5 mL) was added. The resulting suspension was extracted with dichloromethane and 2 M sodium hydroxide solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After 1 hour, the suspension was filtered, concentrated, and purified by medium-pressure rapid silica gel chromatography and preparative liquid chromatography to obtain a deep yellow solid, 6-chloro-1'-m-toluyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (76.7 mg, yield 46.8%). LCMS m / z: 328.06 [M+H] + . 1 H NMR (600 MHz, Chloroform-d) δ 7.53 – 7.47 (m,2H), 7.23 – 7.18 (m, 1H), 7.18 – 7.12 (m, 2H), 7.00 (d, J = 7.8 Hz, 1H), 6.86(d, J = 7.2 Hz, 1H), 5.47 (s, 1H), 3.14 – 3.03 (m, 3H), 2.96 – 2.88 (m, 1H), 2.34 (s, 3H), 2.16 – 2.11 (m, 1H), 2.05 – 1.96 (m, 1H).

[0118] Example 19: Synthesis of 1'-(4-bromophenyl)-6-chloro-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (compound 19)

[0119]

[0120] p-Bromophenylhydrazine (93.5 mg, 0.50 mmol) was added to a methanol (0.5 mL) solution containing 6-chloro-3,4-dihydronaphthyl-2(1H)-one (90.3 mg, 0.50 mmol). After stirring at room temperature for 15 minutes, an aqueous solution of potassium cyanate (50.7 mg, 0.63 mmol) (0.15 mL) was added in portions, followed immediately by acetic acid (1.5 mL). Stirring was continued for another 15 minutes, and then ice water (5 mL) was added. The resulting suspension was extracted with dichloromethane and 2 M sodium hydroxide solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After 1 hour, the suspension was filtered, concentrated, and purified by medium-pressure rapid silica gel chromatography and preparative liquid chromatography to obtain a pale yellow solid 1'-(4-bromophenyl)-6-chloro-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (79.4 mg, yield 40.4%). LCMS m / z: 392.00 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 7.92 (s,1H), 7.54 (d, J = 9.0 Hz, 2H), 7.43 (d, J = 9.0 Hz, 2H), 7.22 (s, 1H), 7.17(dd, J = 8.4, 1.8 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.33 (s, 1H), 3.02 –2.93 (m, 2H), 2.92 – 2.80 (m, 2H), 2.01 – 1.92 (m, 1H), 1.91 – 1.80 (m, 1H).

[0121] Example 20: Synthesis of 6-chloro-1'-(4-chlorophenyl)-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (compound 20)

[0122]

[0123] To a methanol (0.5 mL) solution containing 6-chloro-3,4-dihydronaphthyl-2(1H)-one (90.3 mg, 0.50 mmol), p-chlorophenylhydrazine (71.3 mg, 0.5 mmol) was added. After stirring at room temperature for 15 minutes, an aqueous solution of potassium cyanate (50.7 mg, 0.63 mmol) (0.15 mL) was added in portions, followed immediately by acetic acid (1.5 mL). Stirring continued for 15 minutes, and then ice water (5 mL) was added. The resulting suspension was extracted with dichloromethane and 2 M sodium hydroxide solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After 1 hour, the suspension was filtered, concentrated, and purified by medium-pressure rapid silica gel chromatography and preparative liquid chromatography to obtain a milky yellow solid, 6-chloro-1'-(4-chlorophenyl)-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (67.0 mg, yield 38.5%). LCMS m / z: 348.00 [M+H] + . 1 H NMR (600 MHz, Chloroform-d) δ 7.63 (d, J =8.4 Hz, 2H), 7.28 – 7.24 (m, 2H), 7.18 – 7.12 (m, 2H), 7.00 (d, J = 7.8 Hz,1H), 5.46 (s, 1H), 3.14 – 3.02 (m, 3H), 2.96 – 2.87 (m, 1H), 2.15 – 2.09 (m, 1H), 2.06 – 1.98 (m, 1H).

[0124] Example 21: Synthesis of 6-bromo-1'-(4-methoxyphenyl)-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (compound 21)

[0125]

[0126] 4-Methoxyphenylhydrazine hydrochloride (87.3 mg, 0.50 mmol) was dissolved in DCM (2.7 mL), washed with 2 M sodium hydroxide aqueous solution (7.2 mL), and the organic layer was dried over anhydrous sodium sulfate. The filtrate was concentrated to obtain 4-methoxyphenylhydrazine. The above-mentioned 4-methoxyphenylhydrazine was added to a methanol (0.5 mL) solution containing 6-bromo-3,4-dihydronaphthyl-2(1H)-one (112.6 mg, 0.50 mmol). After stirring at room temperature for 15 minutes, an aqueous solution of potassium cyanate (50.7 mg, 0.63 mmol) (0.15 mL) was added in portions, followed immediately by acetic acid (1.5 mL). Stirring was continued for 15 minutes, followed by the addition of ice water (5 mL). The resulting suspension was extracted with dichloromethane and 2 M sodium hydroxide solution, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After 1 hour, the mixture was filtered, concentrated, and purified by medium-pressure rapid silica gel chromatography and preparative liquid chromatography to obtain a pale yellow solid, 6-bromo-1'-(4-methoxyphenyl)-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one (68.1 mg, yield 35.1%). LCMS m / z: 388.05 [M+H] + . 1 H NMR (600 MHz, Chloroform-d) δ 7.57 (d, J = 9.0 Hz, 2H), 7.32 (s, 1H), 7.28 (d, J = 7.8 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.86 (d, J= 9.0 Hz, 2H), 5.43 (s, 1H), 3.78 (s, 3H), 3.14 – 3.00 (m, 3H), 2.96 – 2.87(m, 1H), 2.17 – 2.09 (m, 1H), 2.07 – 1.98 (m, 1H).

[0127] Example 22: Synthesis of 4-(6-bromo-5'-oxo-3,4-dihydro-1H-spiro[naphth-2,3'-[1,2,4]triazolidine]-1'-yl)benzonitrile (compound 22)

[0128]

[0129] 4-Cyanobenzylhydrazine hydrochloride (84.8 mg, 0.50 mmol) was added to a methanol (0.5 mL) solution containing 6-bromo-3,4-dihydronaphthyl-2(1H)-one (112.6 mg, 0.50 mmol). After stirring at room temperature for 15 minutes, an aqueous solution of potassium cyanate (50.7 mg, 0.63 mmol) (0.15 mL) was added in portions, followed immediately by acetic acid (1.5 mL). Stirring continued for 15 minutes, then ice water (5 mL) was added. The resulting suspension was extracted with dichloromethane and 2 M sodium hydroxide solution, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After 1 hour, the solution was filtered, concentrated, and purified by medium-pressure rapid silica gel chromatography and preparative liquid chromatography to obtain a deep yellow solid (57 mg, yield 29.8%). LCMS m / z: 383.00 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.74 – 7.67 (m, 4H), 7.35 (s, 1H), 7.29 (dd, J = 7.8, 1.8Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.47 (s, 1H), 2.99 – 2.92 (m, 2H), 2.91 –2.83 (m, 2H), 1.99 – 1.92 (m, 1H), 1.91 – 1.83 (m, 1H).

[0130] Example 23: Biological Experimental Methods

[0131] Ferrocyte inhibition assay: THLE-2 (human liver immortalized cells), SH-SY5Y (human neuroblastoma cells), and mouse primary glial cells were seeded at a density of 5000 cells per well in 96-well plates. 100 μL of complete culture medium was added to each well, and the plates were incubated overnight at 37°C with 5% CO2 until cell attachment. A series of concentration gradients of the test compounds were prepared (using serial dilution). 10 μL was added to each well and incubated at 37°C with 5% CO2 for 1 hour. Then, RSL3 (a ferroptosis agonist) was added to each well, and the cells were incubated for a further period at 37°C with 5% CO2 before cell viability was assessed. 10 μL of ATP assay reagent was added to each well, and the plates were shaken for 3 minutes to ensure thorough mixing. The plates were then incubated at room temperature for 10 minutes. The reaction mixture was transferred to a white, opaque 96-well plate, and the relative fluorescence intensity of each well was measured using a fluorescence microplate reader. The fluorescence signal intensity was positively correlated with intracellular ATP content (i.e., cell viability). The half-maximum effective concentration (Cg) of the compound was calculated by plotting the logarithm of the compound concentration on the x-axis and relative cell viability (with the fluorescence intensity of the blank control group as 100%) on the y-axis. 50 The positive control was Ferrostatin-1 (Fer-1). The test results are shown in Tables 1 and 2.

[0132]

[0133]

[0134]

[0135] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. The compound represented by Formula I, its pharmaceutically acceptable salt, solvate, isotope-substituted product, polymorph, tautomer, enantiomer, diastereomer, prodrug, or metabolite: ； In the formula: Ring A is a 5-10 membered heterocycle, substituted or unsubstituted, containing at least two nitrogen atoms and at least one carbonyl or thiocarbonyl group; Ring B is a substituted or unsubstituted saturated or unsaturated 5-10 membered carbon ring or heterocycle, and ring B shares at least one carbon atom with ring A; The ring C is a substituted or unsubstituted 3-8 membered cycloalkyl, a substituted or unsubstituted 5-14 membered aryl or heteroaryl, or a substituted or unsubstituted 4-10 membered heterocyclic group, and the ring C and ring B share at least 2 atoms. R1 is a substituted or unsubstituted 3-8 membered cycloalkyl, a substituted or unsubstituted 5-14 membered aryl or heteroaryl, or a substituted or unsubstituted 4-10 membered heterocyclic group.

2. The compound of claim 1, its pharmaceutically acceptable salt, solvate, isotope-substituted derivative, polymorph, tautomer, enantiomer, diastereomer, prodrug, or metabolite, characterized in that, Ring A contains 2-4 nitrogen atoms and 1-2 carbonyl or thiocarbonyl groups, with a ring atom count of 5-8. Except for one nitrogen atom on ring A being substituted by R1, the remaining nitrogen atoms may optionally be replaced by 0-2 groups independently selected from C1-C4 alkyl, halo-C1-C4 alkyl, or amino (NR) groups. a R b The amino group is substituted with C1-C4 alkyl, hydroxyl-substituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, benzyl, 5-14 aryl or heteroaryl, 4-10 heterocyclic, or C1-C6 acyl groups; wherein the amino group (NR) is substituted with a substituent. a R b R a and R b Each is independently selected from H, C1-C4 alkyl, and halo-C1-C4 alkyl; Ring B is a 5-7 membered carbon ring or heterocycle, sharing 1-2 carbon atoms with ring A; ring B is optionally surrounded by 0-6 atoms selected from halogens, C1-C4 alkyl groups, halogenated C1-C4 alkyl groups, C1-C4 alkoxy groups, halogenated C1-C4 alkoxy groups, and amino groups (NR). a R b The amino group (NR) is substituted with C1-C4 alkyl, hydroxyl-substituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, benzyl, 5-14 aryl or heteroaryl, 4-10 heterocyclic, or C1-C6 acyl groups; wherein the amino group (NR) is substituted with a substituent. a R b R a and R b Each is independently selected from H, C1-C4 alkyl, and halo-C1-C4 alkyl; Ring C is a benzene ring, a naphthyl ring, a thiophene ring, or a furan ring, and ring C shares two atoms with ring B; ring C is optionally surrounded by 0-4 atoms independently selected from halogens, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, hydroxyl, cyano, and amino (NR) groups. a R b ), carboxyl group, ester group (COOR) c or OCOR c ), amide group (CONHR) c or NHCOR c Substituents of benzyl, 5-14 aryl or heteroaryl, 4-10 heterocyclic and C1-C6 acyl groups; wherein, the amino group (NR) is substituted with a substituent of 2, 3, 4, 5, 14, 5, 14, 14, 5, 10 ... a R b R a and R b Each group is independently selected from H, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C6 acyl, and R. c Independently selected from C1-C4 alkyl and halo-C1-C4 alkyl; R1 is a substituted or unsubstituted 5-14 aryl or heteroaryl group; R1 is optionally surrounded by 0-5 independent groups selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, hydroxyl, cyano, amino (NR) a R b ), carboxyl group, ester group (COOR) c or OCOR c ), amide group (CONHR) c or NHCOR c Substituents of benzyl, 5-14 aryl or heteroaryl, 4-10 heterocyclic and C1-C6 acyl groups; wherein, the amino group NR a R b R a and R b Each group is independently selected from H, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C6 acyl, and R. c It is independently selected from C1-C4 alkyl and halogenated C1-C4 alkyl.

3. The compound of claim 1, its pharmaceutically acceptable salt, solvate, isotope-substituted derivative, polymorph, tautomer, enantiomer, diastereomer, prodrug, or metabolite, characterized in that, Ring A contains 3 nitrogen atoms and 1 carbonyl group. The ring A has 5 ring atoms. Except for 1 nitrogen atom which is replaced by R1, the remaining nitrogen atoms in ring A can be optionally replaced by 0-2 C1-C4 alkyl groups. Ring B is a 5-7 membered carbon ring, and ring B and ring A share one carbon atom to form a spiro ring; ring B is optionally substituted by 0-4 C1-C4 alkyl groups or halogens; Ring C is a benzene ring, and ring C shares 2 atoms with ring B. Ring C is optionally substituted with 0-4 halogens, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl, or halo-C1-C4 alkoxy. R1 is phenyl, naphthyl, thienyl, benzothienyl, furanyl, or benzofuranyl, and R1 is optionally substituted by 0-5 substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl or halo-C1-C4 alkoxy, or cyano.

4. The compound of claim 1, its pharmaceutically acceptable salt, solvate, isotope-substituted derivative, polymorph, tautomer, enantiomer, diastereomer, prodrug, or metabolite, characterized in that, The compound of formula I has the structure shown in formula II: ； In Formula II: X is an oxygen atom or a sulfur atom; n is 0, 1, 2 or 3, m is 0, 1, 2 or 3, where 6≥n+m≥2; x is 0, 1, or 2; y is 0, 1, 2, 3, 4, 5, or 6; z can be 0, 1, 2, 3, or 4; R1 is as defined in any one of claims 1-3; R2 is selected from halogens, C1-C4 alkyl groups, halogenated C1-C4 alkyl groups, C1-C4 alkoxy groups, halogenated C1-C4 alkoxy groups, and amino groups (NR). a R b The R group is substituted with C1-C4 alkyl, hydroxyl-substituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, benzyl, 5-14 aryl or heteroaryl, 4-10 heterocyclic, or C1-C6 acyl groups; wherein, the R group is substituted with C1-C4 alkyl, hydroxyl-substituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, benzyl, 5-14 aryl or heteroaryl, 4-10 heterocyclic, or C1-C6 acyl groups. a and R b Each is independently selected from H, C1-C4 alkyl, and halo-C1-C4 alkyl; R3 is selected from halogens, C1-C4 alkyl groups, halogenated C1-C4 alkyl groups, C1-C4 alkoxy groups, halogenated C1-C4 alkoxy groups, and amino groups (NR). a R b Substituents of C1-C4 alkyl, hydroxyl-substituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, benzyl, 5-14 aryl or heteroaryl, 4-10 heterocyclic, and C1-C6 acyl groups; wherein, R a and R b Each is independently selected from H, C1-C4 alkyl, and halo-C1-C4 alkyl; R4 is selected from halogens, C1-C4 alkyl groups, C1-C4 alkoxy groups, halogenated C1-C4 alkyl groups, halogenated C1-C4 alkoxy groups, C2-C4 alkenyl groups, C2-C4 alkynyl groups, hydroxyl groups, cyano groups, and amino groups (NR). a R b ), carboxyl group, ester group (COOR) c or OCOR c ), amide group (CONHR) c or NHCOR c Substituents of benzyl, 5-14 aryl or heteroaryl, 4-10 heterocyclic and C1-C6 acyl groups; wherein, R a and R b Each group is independently selected from H, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C6 acyl, and R. c It is independently selected from C1-C4 alkyl and halogenated C1-C4 alkyl.

5. The compound of claim 4, its pharmaceutically acceptable salt, solvate, isotope-substituted derivative, polymorph, tautomer, enantiomer, diastereomer, prodrug, or metabolite, characterized in that, X is an oxygen atom; x is 0, meaning that except for R1 substitution, the nitrogen atoms in ring A are not substituted by substituents; When y is 0, it means that ring B is not substituted; when n is 0 or 1, m is 1 or 2, the number of ring atoms in ring B is 5 or 6. z is 0-4, meaning that the ring C is optionally substituted by 0-4 R4s; each R4 is independently substituted by halogen, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl and halo-C1-C4 alkoxy. R1 is a substituted or unsubstituted phenyl group; R1 is optionally substituted by 0-5 substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, and cyano.

6. The compound of claim 4, its pharmaceutically acceptable salt, solvate, isotope-substituted derivative, polymorph, tautomer, enantiomer, diastereomer, prodrug, or metabolite, characterized in that, The compound of formula II has the structure shown in formula III: ； In Formula III: R1 is a substituted or unsubstituted phenyl group, that is, ring D is a benzene ring; w is 0, 1, 2, 3, 4, or 5. Cyclode D is optionally substituted by 0-5 R5 groups, each R5 group being independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, hydroxyl, cyano, amino (NR) a R b ), carboxyl group, ester group (COOR) c or OCOR c ), amide group (CONHR) c or NHCOR c Substituents of benzyl, 5-14 aryl or heteroaryl, 4-10 heterocyclic and C1-C6 acyl groups; wherein, R a and R b Each group is independently selected from H, C1-C4 alkyl, halo-C1-C4 alkyl, C1-C6 acyl, and R. c Independently selected from C1-C4 alkyl and halo-C1-C4 alkyl; x is 0, y is 0, and rings A and B are not replaced by R2 or R3; z is 0, 1, 2, 3 or 4; each R4 is as defined in claim 4.

7. The compound of claim 6, its pharmaceutically acceptable salt, solvate, isotope-substituted derivative, polymorph, tautomer, enantiomer, diastereomer, prodrug, or metabolite, characterized in that, R1 is a substituted or unsubstituted phenyl group; w is 0 or 1; R5 is selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, and cyano-substituted. z is 0, 1, or 2; each R4 is independently substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkyl, or halo-C1-C4 alkoxy.

8. The compound of claim 6, its pharmaceutically acceptable salt, solvate, isotope-substituted derivative, polymorph, tautomer, enantiomer, diastereomer, prodrug, or metabolite, characterized in that, The compound of formula III has the structure shown in formula IIIa or IIIb:

9. The compound of claim 1, its pharmaceutically acceptable salt, solvate, isotope-substituted derivative, polymorph, tautomer, enantiomer, diastereomer, prodrug, or metabolite, characterized in that, Specifically selected from the following compounds: 2-Phenylacetyl-1,2,4-triazaspiro[4.4]non-3-one; 2-Phenylacetyl-1,2,4-triazaspiro[4.5]dec-3-one; 7,7,9-Trimethyl-2-phenyl-1,2,4-triazaspiro[4.5]dec-3-one; 1'-Phenylacet-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one; 1'-Phenylacetyl-1,3-dihydrospiro[indene-2,3'-[1,2,4]triazolidine]-5'-one; 7-Methoxy-1'-phenyl-3,4-dihydro-2H-spiro[naphthyl-1,3'-[1,2,4]triazolidine]-5'-one; 7-Methoxy-1'-phenyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one; 5-Methoxy-1'-phenyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one; 6-Bromo-1'-phenyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one; 6-Fluoro-1'-phenyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one; 6,8-Difluoro-1'-phenyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one; 6-Chloro-1'-phenyl-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one; 6-Bromo-1'-p-Tolyl-3,4-Dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one 6-Bromo-1'-(4-trifluoromethylphenyl)-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one; 6-Bromo-1'-m-Tolyl-3,4-Dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one; 6-Bromo-1'-(4-Bromophenyl)-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one; 6-Chloro-1'-(4-trifluoromethylphenyl)-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one; 6-Chloro-1'-m-Tolyl-3,4-Dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one; 1'-(4-bromophenyl)-6-chloro-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one; 6-Chloro-1'-(4-chlorophenyl)-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one; 6-Bromo-1'-(4-methoxyphenyl)-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-5'-one; 4-(6-bromo-5'-oxo-3,4-dihydro-1H-spiro[naphthyl-2,3'-[1,2,4]triazolidine]-1'-yl)benzonitrile.

10. A pharmaceutical composition, characterized in that, The compound comprising any one of claims 1 to 9, a pharmaceutically acceptable salt, solvate, isotope-substituted product, polymorph, tautomer, enantiomer, diastereomer, prodrug or metabolite, and a pharmaceutically acceptable carrier.

11. The use of any compound of claims 1 to 9, a pharmaceutically acceptable salt thereof, a solvate thereof, an isotope substitute thereof, a polymorph thereof, a tautomer thereof, an enantiomer thereof, a diastereomer thereof, a prodrug or a metabolite thereof, or a pharmaceutical composition of claim 10, in the preparation of a medicament for treating or preventing ferroptosis-mediated diseases.

12. The application as described in claim 11, characterized in that, The diseases mediated by ferroptosis are selected from any one of (a) to (f): (a) Nervous system diseases: including acute neurological injuries and chronic neurodegenerative diseases, such as ischemic stroke, cerebral hemorrhage, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, and spinal cord injury; (b) Kidney diseases: including acute kidney injury and chronic kidney disease, such as kidney injury induced by ischemia-reperfusion, sepsis, cisplatin, contrast agents, gentamicin, or doxorubicin; and diabetic nephropathy; (c) Liver diseases: including acute liver injury, ischemia-reperfusion liver injury, drug-induced liver injury, alcoholic steatohepatitis, non-alcoholic steatohepatitis, viral hepatitis, and liver fibrosis; (d) Cardiovascular diseases: including ischemia-reperfusion myocardial injury, myocardial infarction, heart failure, cardiomyopathy caused by anthracyclines such as doxorubicin, and atherosclerosis; (e) Organ transplant-related injury: ferroptosis-related injury occurring during the acquisition, preservation, and reperfusion of donor organs in the process of heart, liver, kidney, and lung transplantation; (f) Inflammatory and immune diseases: including sepsis, systemic inflammatory response syndrome, and autoimmune diseases; preferably, the ferroptosis-mediated diseases are various types of liver injury, hepatitis, brain injury, encephalitis, stroke, cerebral hemorrhage, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, and spinal cord injury.

Images