Spiro-skeleton-containing substituted aromatic heterocyclic compound as well as preparation method and application thereof

Abstract

The invention discloses a substituted aromatic heterocyclic compound containing a spiro skeleton as well as a preparation method and application thereof, and relates to the field of medicinal chemistry, in particular to the substituted aromatic heterocyclic compound containing the spiro skeleton or pharmaceutically acceptable salt of the substituted aromatic heterocyclic compound, a necessary composition containing the compounds and medical application of the substituted aromatic heterocyclic compound. The invention relates to an application of a monoacylglyceridase inhibitor, in particular to application of the monoacylglyceridase inhibitor as a monoacylglyceridase (MAGL) inhibitor in preparation of drugs for preventing and / or treating MAGL-related diseases. Comprise depression, schizophrenia, bi-directional disorder, dyskinesia, traumatic brain injury, neuroinflammation, Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, anxiety disorder, pain, metabolic disorder, alcoholic fatty liver disease, non-alcoholic fatty liver disease, hepatic fibrosis, cholestasis, nephropathy and other related diseases.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and relates to a substituted heteroaromatic compound containing a spiro skeleton, specifically to a substituted heteroaromatic MAGL inhibitor containing a spiro skeleton, and its application in the preparation of drugs for preventing and / or treating MAGL-related diseases. Background Art

[0002] The endogenous cannabinoid system (ECS) is a biological regulatory system present in the central nervous system and peripheral tissues of most vertebrates. It is involved in regulating many physiological processes such as the balance of cells, tissues, organs and organisms, brain development, neurotransmitter release and synaptic plasticity, as well as cytokine release of microglia, and is considered a potential strategy for treating various diseases, including central nervous system diseases, pain, cancer, and metabolic diseases, etc.

[0003] Studies have found that the endogenous cannabinoid system is mainly composed of cannabinoid receptors (CB1, CB2), endogenous cannabinoids (AEA, 2-AG), enzymes responsible for the synthesis and degradation of endogenous cannabinoids, and related endogenous cannabinoid transporters. CB1 receptors are highly expressed in the central nervous system, including the cerebellum, hippocampus, and cerebral cortex, etc. CB2 receptors are mainly present in the immune system and are involved in the regulation of immune diseases. Research shows that active ingredients such as tetrahydrocannabinol and cannabidiol can produce anti-anxiety, anti-inflammatory, and analgesic effects by directly activating CB receptors. However, directly activating CB receptors will cause some inevitable side effects. In order to avoid these side effects and make the endogenous cannabinoid system pathway a more effective disease treatment strategy, N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), which are endogenous ligands of CB receptors, have become the focus of attention.

[0004] 2-AG is a full agonist of CB receptors in the body. By increasing the level of 2-AG in the body, it indirectly activates CB receptors and avoids side effects such as hypothermia and tonic syncope caused by direct activation. This makes 2-AG an important active substance in the body and is involved in the regulation of multiple pathways. MAGL, as the main hydrolase of 2-AG (accounting for 85%), is therefore considered a promising drug target.

[0005] In 1976, the monoacylglycerol lipase (MAGL) protein was first purified from rat adipose tissue. In subsequent studies, it was found that the primary structure of MAGL consists of 303 amino acids with a molecular weight of 33.4 kDa. The catalytic site is composed of a common triad in the serine hydrolase family (Ser122, Asp239, and His269). MAGL is a membrane-bound serine hydrolase present in the central nervous system and peripheral tissues such as the liver, kidney, testis, lung, prostate, and small intestine. MAGL activity has a core function in various biological systems, especially in the endocannabinoid signaling and AA metabolism. MAGL is the key enzyme for the hydrolysis of the endocannabinoid 2-AG, playing a dominant role in regulating the 2-AG level in the body. It participates in regulating the endocannabinoid signaling network system and is related to various physiological processes such as pain, inflammation, depression, and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. MAGL is also a key metabolic enzyme and has been found to participate in the occurrence and development of liver diseases through different mechanisms, and also participates in peripheral diseases such as fat and glucose metabolism in a very complex way. The endocannabinoid signaling plays an important role in central and peripheral tissue sites. Therefore, inhibiting MAGL is promising as a target for central nervous system diseases, pain, liver diseases, or cancer. Summary of the Invention

[0006] Objectives of the Invention: The first objective of the present invention is to provide a spirocyclic skeleton-containing substituted heteroaromatic compound, the second objective is to provide a pharmaceutical composition containing the compound, and the third objective is to provide the application of the compound and its pharmaceutical composition in the preparation of drugs.

[0007] Technical Solution: In the first aspect of the present invention, a spirocyclic compound having the structure shown in Formula I or a pharmaceutically acceptable salt thereof is provided:

[0008]

[0009] Wherein: R 1 is selected from 1) or 2): 1) the following groups which are unsubstituted or substituted by R 1A : aryl, heterocyclic group, cycloalkyl, alkyl; 2) R a -(CH2) m -X-R b -, wherein R a is the following group which is unsubstituted or substituted by R 1B : aryl, alkyl; R b is the following group which is unsubstituted or substituted by R 1C : aryl, heteroaryl, alkylene; m is 0 or 1, X is -NR c -, -C(O)-, O or S; R c is H, methyl, ethyl, n-propyl or isopropyl; Preferably, Rc is H or methyl;

[0010] R 2 is unsubstituted or substituted by R 2A with the following groups: alkyl, cycloalkyl, heterocyclic group, alkenyl, cycloalkenyl, aryl, heteroaryl;

[0011] R 1A 、R 1B 、R 1C and R 2A are independently H, -OH, -SH, -CN, -NH2, halogen, nitro, carboxyl, C 1-8 alkyl, C 1-8 cycloalkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C alkoxy substituted by cyano, or O or S forms a carbonyl or thioketone group with C in R 1-6 or R 1 or R 2 ;

[0012] n is an integer from 0 to 5, preferably 0, 1, 2 or 3; more preferably 0, 1 or 2;

[0013] A is -(CH2) P -, and p is 1, 2 or 3.

[0014] In some embodiments, when R 1 is 1), wherein the aryl is a 6-12 membered aryl; preferably, the aryl is phenyl or naphthyl; and / or, the heterocyclic group is "a 5-12 membered heterocyclic group having 1-4 selected from N, O or S; preferably, the heterocyclic group is "a 5-12 membered heterocyclic group having 1-3 selected from N, O or S; more preferably, the heterocyclic group is "a 5-10 membered heterocyclic group having 1-3 selected from N, O or S; further preferably, the heterocyclic group is "a 5-10 membered heterocyclic group having 1 or 2 selected from N, O or S; still more preferably, the heterocyclic group is furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, naphthyl, indolyl, quinolinyl, isoquinolinyl, indazolyl, benzoxazolyl, benzothiazolyl, benzquinolinone, thiophenopyridine, cyclopentane, cyclohexane, piperidine ring, morpholine ring, piperazine ring, tetrahydrofuran, tetrahydropyran; and / or, the cycloalkyl is a 3-10 membered cycloalkyl, preferably cyclopropane, cyclobutane, cyclopentane, cyclohexane; and / or, the alkyl is C 1-10 alkyl, preferably C 1-6 alkyl.

[0015] In some embodiments, when R 1 is 2), wherein the aryl is a 6- to 12-membered aryl; preferably, the aryl is phenyl; and / or, the heteroaryl is "a 5- to 12-membered heteroaryl having 1 to 4 members selected from N, O, or S; preferably, the heteroaryl is "a 5- to 12-membered heteroaryl having 1 to 3 members selected from N, O, or S; more preferably, the heteroaryl is "a 5- to 10-membered heteroaryl having 1 to 3 members selected from N, O, or S; further preferably, the heteroaryl is "a 5- to 10-membered heteroaryl having 1 or 2 members selected from N, O, or S; further preferably, the heteroaryl is "a 5- to 6-membered heteroaryl having 1 or 2 members selected from N, O, or S; still more preferably, the heteroaryl is furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, naphthyl, indolyl, quinolinyl, isoquinolinyl, indazolyl, benzoxazolyl, benzothiazolyl, benzquinolinone, thienopyridine; and / or, the alkyl is C 1-10 alkyl, preferably C 1-6 alkyl, more preferably C 1-4 alkyl; and / or, the alkylene is C 1-10 alkylene, preferably C 1-6 alkylene, more preferably C 1-4 alkylene.

[0016] In some embodiments, R 1A is selected from H, -OH, -SH, -CN, -NH2, halogen, nitro, carboxyl, C 1-4 alkyl, C 1-6 cycloalkyl, C 1-4 alkoxy, C 1-6 haloalkyl substituted with 1 to 3 halogens, C 1-4 haloalkoxy, or C 1-4 alkoxy substituted with a cyano group, or O or S forms a carbonyl or thioketone group with C in R 1 or R 2 ; further preferably, R 1A , R 1B , R 1C are independently H, -OH, -SH, -CN, -NH2, halogen, nitro, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropane, cyclohexane, cyclobutane, cyclopentane, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, trifluoromethyl, or O or S forms a carbonyl or thioketone group with C in R 1 or R 2 ; R 1B is selected from H, -OH, -SH, -CN, -NH2, halogen, nitro, carboxyl, C1-4 alkyl, C 1-6 cycloalkyl, C 1-4 alkoxy, C substituted with 1 - 3 halogens 1-6 haloalkyl, C 1-4 haloalkoxy or C substituted with a cyano group 1-4 alkoxy, or O or S forms a carbonyl or thioketone group with C in R 1 or R 2 ; Further preferably, R 1A , R 1B , R 1C are independently H, -OH, -SH, -CN, -NH2, halogen, nitro, carboxyl, methyl, ethyl, n - propyl, isopropyl, n - butyl, isobutyl, sec - butyl, tert - butyl, cyclopropane, cyclohexane, cyclobutane, cyclopentane, methoxy, ethoxy, n - propoxy, isopropoxy, n - butoxy, isobutoxy, sec - butoxy, tert - butoxy, trifluoromethyl or O or S forms a carbonyl or thioketone group with C in R 1 or R 2 ; R 1C is selected from H, -OH, -SH, -CN, -NH2, halogen, nitro, carboxyl, C 1-4 alkyl, C 1-6 cycloalkyl, C 1-4 alkoxy, C substituted with 1 - 3 halogens 1-6 haloalkyl, C 1-4 haloalkoxy or C substituted with a cyano group 1-4 alkoxy, or O or S forms a carbonyl or thioketone group with C in R 1 or R 2 ; Further preferably, R 1A , R 1B , R 1C are independently H, -OH, -SH, -CN, -NH2, halogen, nitro, carboxyl, methyl, ethyl, n - propyl, isopropyl, n - butyl, isobutyl, sec - butyl, tert - butyl, cyclopropane, cyclohexane, cyclobutane, cyclopentane, methoxy, ethoxy, n - propoxy, isopropoxy, n - butoxy, isobutoxy, sec - butoxy, tert - butoxy, trifluoromethyl or O or S forms a carbonyl or thioketone group with C in R 1 or R 2 forms a carbonyl or thioketone group.

[0017] In some embodiments, in R 2 , the aryl is a 6 - 12 - membered aryl; preferably, the aryl is phenyl; and / or, in R 2 , the aryl is a 6 - 12 - membered aryl; preferably, the aryl is phenyl; and / or, in R 2Among them, the heterocyclic group is a 5- to 12-membered heterocyclic group having 1 to 4 members selected from N, O or S; preferably, the heterocyclic group is a 5- to 12-membered heterocyclic group having 1 to 3 members selected from N, O or S; more preferably, the heterocyclic group is a 5- to 10-membered heterocyclic group having 1 to 3 members selected from N, O or S; further preferably, the heterocyclic group is a 5- to 10-membered heterocyclic group having 1 or 2 members selected from N, O or S; further preferably, the heterocyclic group is "a 5- to 6-membered heterocyclic group having 1 or 2 members selected from N, O or S; even more preferably, the heterocyclic group is furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, naphthyl, indolyl, quinolinyl, isoquinolinyl, indazolyl, benzoxazolyl, benzothiazolyl, benzquinolinone, thiophenopyridine, cyclopentane, cyclohexane, piperidine ring, morpholine ring, piperazine ring, tetrahydrofuran, tetrahydropyran, 1,3-dioxolane; and / or, R 2 Among them, the alkyl group is C 1-10 alkyl group, preferably C 1-6 alkyl group, more preferably C 1-4 alkyl group; and / or, the alkenyl group is C 2-10 alkenyl group, preferably C 2-6 alkenyl group, more preferably C 2-4 alkenyl group; and / or, the cycloalkenyl group is cyclopropene, cyclobutene, cyclopentene or cyclohexene.

[0018] In some embodiments, R 2A is H, -OH, -SH, -CN, -NH2, halogen, nitro, carboxyl, C 1-4 alkyl group, C 1-4 alkoxy group, C substituted with 1 to 3 halogens 1-6 haloalkyl group, C 1-4 haloalkoxy group or C substituted with a cyano group 1-4 alkoxy group; further preferably, R 2A is H, -OH, -SH, -CN, -NH2, halogen, nitro, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, trifluoromethyl, trifluoromethoxy.

[0019] The halogen in the present invention is fluorine, chlorine, bromine or iodine; preferably fluorine or chlorine.

[0020] In some embodiments, the present invention further provides a spiro compound shown by the following formula II or formula III or formula IV or a pharmaceutically acceptable salt thereof:

[0021]

[0022] Among them, n, R1 and R2 are as described above.

[0023] In some embodiments, the present invention also provides a compound shown in the following structure or a pharmaceutically acceptable salt thereof:

[0024]

[0025]

[0026]

[0027] The second aspect of the present invention is to provide a method for preparing the compound described in the first aspect.

[0028] In some embodiments, the compound of formula (II) of the present invention can be prepared by the following steps:

[0029] Using methyl N-Boc-4-piperidinecarboxylate (1.1) as the starting material, at -78 °C, after deprotonation under the strong base condition of lithium diisopropylamide, a nucleophilic substitution reaction occurs with bromoacetonitrile to obtain intermediate 1.2; subsequently, intermediate 1.2 is reduced and cyclized under a hydrogen pressurized environment with Raney nickel catalysis to reduce the cyano group to obtain the key spiro intermediate 1.3; intermediate 1.3 is then catalyzed by the Pd2dba3 / Xantphos system under basic conditions to undergo Buchwald coupling reaction with various bromoaryl heterocycles to generate intermediate 1.4; subsequently, the protecting group is removed to obtain intermediate 1.5; finally, intermediate 1.5 undergoes amide condensation reaction with various carboxylic acid derivatives to obtain the compound shown in formula (II).

[0030]

[0031] In some other embodiments, the compound of formula (III) of the present invention can be prepared by the following steps:

[0032] Using 4-methoxybenzylamine (2.1) as the starting material, under an ice bath, after deprotonation under the basic condition of triethylamine, a nucleophilic substitution reaction occurs with bromoacetonitrile to obtain intermediate 2.2; subsequently, using ethyl N-Boc-4-piperidinecarboxylate as the raw material, at -78 °C, after adding LDA for deprotonation under basic conditions, intermediate 2.2 is added to undergo cyclization reaction to obtain intermediate 2.3; then intermediate 2.3 is deprotected with an aqueous solution of ammonium cerium nitrate at 0 °C to obtain intermediate 2.4; intermediate 2.4 is catalyzed by the Pd2dba3 / Xantphos system under basic conditions to undergo Buchwald coupling reaction with various bromoaryl heterocycles to generate intermediate 2.5; subsequently, the protecting group is removed to obtain intermediate 2.6; finally, intermediate 2.6 undergoes amide condensation reaction with various carboxylic acid derivatives to obtain the compound shown in formula (III).

[0033]

[0034] In some other embodiments, the compound of formula (IV) of the present invention can be prepared by the following steps:

[0035] Using tert-butyl 1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (3.1) as the starting material, under basic conditions, catalyzed by the Pd2dba3 / Xantphos system, a Buchwald coupling reaction occurs with various brominated heteroaromatic rings to generate intermediate 3.2; subsequently, the protecting group is removed to obtain intermediate 3.3; finally, intermediate 3.3 undergoes an amide condensation reaction with various carboxylic acid derivatives to obtain the compound shown in formula (IV).

[0036]

[0037] The compound shown in formula (4.3) can be prepared by the following route. Using compound 4.1 as the raw material, under the weak basic conditions of Cu(OAc)2 / pyridine, a Chan-Lam coupling reaction occurs with different phenylboronic acids to obtain intermediate 4.2. Subsequently, hydrolysis gives the corresponding carboxylic acid, the compound shown in formula (4.3).

[0038]

[0039] The compound shown in formula (5.5) can be prepared by the following route. Using compound 5.1 as the starting material, a Heck reaction occurs with ethyl acrylate to obtain intermediate 5.2. Intermediate 5.2 then cyclizes in a concentrated hydrochloric acid acidic environment to obtain 5.3. Under the action of a Pd catalyst, compound 5.3 undergoes a cyano-bromination reaction with zinc cyanide to obtain intermediate 5.4. Finally, intermediate 5.4 undergoes cyano hydrolysis to obtain the compound shown in formula (5.5).

[0040]

[0041] In a third aspect of the present invention, there is provided a pharmaceutical composition comprising the compound as described in the first aspect, its pharmaceutically acceptable salt or stereoisomer or its prodrug, and a pharmaceutically acceptable carrier.

[0042] "Pharmaceutically acceptable salts" can be synthesized from parent compounds containing acid or base groups by conventional chemical methods. Generally, the preparation of such salts involves reacting these compounds in the form of free acids or bases with a stoichiometric amount of the appropriate base or acid in water, an organic solvent, or a mixture of both. Generally, non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. When the compound contains relatively acidic functional groups, base addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compound contains relatively basic functional groups, acid addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, where the inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogen phosphates, dihydrogen phosphates), sulfuric acid (forming sulfates or bisulfates), hydroiodic acid, phosphorous acid, etc.; and organic acid salts, where the organic acids include, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, ferulic acid, suberic acid, fumaric acid, lactic acid, pyruvic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, and methanesulfonic acid, and similar acids; organic acid salts also include salts of organic acids such as amino acids (such as arginine, etc.), glucuronic acid, etc. When certain specific compounds contain both basic and acidic functional groups, they can be converted into either base or acid addition salts. Preferably, the salt is contacted with a base or acid in a conventional manner, and then the parent compound is separated to regenerate the free form of the compound. The free form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

[0043] The "pharmaceutically acceptable carrier" described in the present invention can be an excipient widely used in the field of drug production. Excipients are mainly used to provide a safe, stable, and functional drug composition, and can also provide a method for the active ingredient to dissolve at the desired rate after the subject receives the administration, or to promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical excipients can be inert fillers, or provide certain functions, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipients can include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesives, glidants, wetting agents, gelling agents, absorption retardants, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweetening agents.

[0044] The pharmaceutical composition of the present invention can be prepared by any method known to those skilled in the art according to the disclosed content. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or freeze-drying processes.

[0045] The pharmaceutical composition of the present invention can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The pharmaceutical composition of the present invention can also be in a controlled-release or sustained-release dosage form (such as liposomes or microspheres). Examples of solid oral preparations include but are not limited to powders, capsules, cachets, soft gelatin capsules and tablets. Examples of liquid preparations for oral or mucosal administration include but are not limited to suspensions, emulsions, elixirs and solutions. Examples of topical preparations include but are not limited to emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum preparations. Examples of preparations for parenteral administration include but are not limited to injectable solutions, dry powder preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, injectable suspensions and injectable emulsions. Examples of other suitable preparations of the pharmaceutical composition include but are not limited to eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.

[0046] The fourth aspect of the present invention provides the use of all the above compounds or their pharmaceutically acceptable salts and their pharmaceutical compositions in the preparation of monoacylglycerol lipase inhibitor drugs.

[0047] The present invention provides the use of all the above compounds or their pharmaceutically acceptable salts and their pharmaceutical compositions in the preparation of drugs for preventing and / or treating MAGL-related diseases

[0048] Wherein, the MAGL-related diseases are central nervous system diseases, pain, metabolic disorders or inflammatory diseases; in some examples, MAGL-related diseases include depression, schizophrenia, bipolar disorder, movement disorders, traumatic brain injury, neuroinflammation, Parkinson's disease, Alzheimer's disease, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, Tourette's syndrome, anxiety disorder, neuropathic pain, inflammatory pain, cancer pain, cancer, vomiting, nausea, eating disorders, metabolic disorders, alcoholic fatty liver disease, non-alcoholic fatty liver disease, liver fibrosis, cholestasis, inflammatory bowel disease, sepsis or kidney diseases, etc.

[0049] Unless otherwise specified, the terms involved in the present invention have the following definitions:

[0050] The term "alkyl" refers to a saturated aliphatic hydrocarbon group having 1 to 4 carbon atoms, including straight-chain and branched-chain groups, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, etc. The alkyl group can be substituted or unsubstituted.

[0051] The term "haloalkyl" refers to an alkyl group substituted by halogen, preferably an alkyl group as defined above, which is substituted by one or more identical or different halogen atoms, such as -CH2Cl, -CF3, -CH2CF3, -CH2CCl3, etc.

[0052] The term "alkoxy" refers to -O-(unsubstituted alkyl) or -O-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc. "C1-C4 alkoxy" refers to a straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, etc. A straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms is preferred, and methoxy or ethoxy is particularly preferred.

[0053] The term "heterocyclic group" refers to a 3- to 12-membered aromatic or non-aromatic or saturated heterocycle containing 1 to 4 heteroatoms selected from O, N, S, etc., and includes bicyclic groups. "Heterocyclic group" thus includes heteroaryl groups mentioned in the present application, and also includes its dihydro and tetrahydro analogs. Further examples of "heterocyclic group" include, but are not limited to, benzimidazolyl, benzofuranyl, benzopyranyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, dihydroindolyl, indolyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinopyridinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexallydroazepinyl, piperazinyl, piperidinyl, pyridin-2-one, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl and tetrahydrothienyl and their N-oxides.

[0054] The term "heteroaryl" refers to a 4- to 12-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from O, N, S, etc., and includes bicyclic groups. Further examples include, but are not limited to, benzimidazolyl, benzofuranyl, benzopyranyl, benzpyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, dihydroindolyl, indolyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexallydroazepinyl, piperazinyl, piperidinyl, pyridin-2-one, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl and their N-oxides. The attachment of the heterocyclic substituent can be achieved through a carbon atom or through a heteroatom.

[0055] The term "aryl" denotes a monocyclic or bicyclic group of all-carbon atoms having 1 to 10 carbon atoms and having a fully conjugated π electron system. Non-limiting examples are phenyl and naphthyl. The aryl can be substituted or unsubstituted.

[0056] The term "carbonyl group" is an organic functional group (C=O) formed by connecting carbon and oxygen atoms through a double bond.

[0057] The term "halogen" denotes fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. Specific embodiments

[0058] The present disclosure will be further described below in conjunction with examples, but these examples do not limit the scope of the present disclosure. For the experimental methods without specific conditions in the embodiments of the present disclosure, they are generally carried out according to conventional conditions or according to the conditions recommended by the raw material or commodity manufacturers. For reagents without specific sources, the reagents can be obtained from any supplier of molecular biology reagents with the quality / purity for molecular biology applications.

[0059] Unless otherwise specified, all reagents used in the following examples are commercially available products.

[0060] Example 1: Synthesis of 2-(3-chlorophenyl)-8-(3-phenoxybenzoyl)-2,8-diazaspiro[4.5]decan-1-one (V-1)

[0061] tert-Butyl 2-(3-chlorophenyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (2)

[0062]

[0063] Dissolve tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (100 mg, 0.39 mmol) in 6 mL of 1,4-dioxane. Successively add m-chlorobromobenzene (151 mg, 0.79 mmol), tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol), Xantphos (34.2 mg, 0.06 mmol), and cesium carbonate (257 mg, 0.79 mmol). Heat the reaction solution to 100 °C and reflux for 6 hours. After monitoring the reaction by TLC until completion, cool the reaction to room temperature. Remove 1,4-dioxane by distillation under reduced pressure. Redissolve the concentrated solution in 10 mL of ethyl acetate, wash successively with water (10 mL × 2) and saturated brine (10 mL × 2), and then dry over anhydrous sodium sulfate for more than 2 hours. Filter by suction. After concentrating the filtrate under reduced pressure, perform column chromatography purification (petroleum ether:ethyl acetate = 8:1) to obtain 118 mg of the intermediate 4 as a white solid powder, with a yield of 99.7%. 1 1H NMR (300 MHz, DMSO-d6) δ 7.89 (t, J = 2.1 Hz, 1H), 7.58 (ddd, J = 8.3, 2.2, 1.0 Hz, 1H), 7.40 (t, J = 8.2 Hz, 1H), 7.23 - 7.16 (m, 1H), 3.92 - 3.77 (m, 4H), 2.96 (s, 2H), 2.08 (t, J = 6.9 Hz, 2H), 1.67 - 1.45 (m, 4H), 1.41 (s, 9H).

[0064] 2-(3-chlorophenyl)-8-(3-phenoxybenzoyl)-2,8-diazaspiro[4.5]decan-1-one (V-01)

[0065]

[0066] Dissolve the intermediate 2 (120 mg, 0.33 mmol) in 2 mL of hydrogen chloride / dioxane solution. Stir the reaction at room temperature for 2 hours. After monitoring the reaction by TLC until completion, concentrate the solvent under reduced pressure to obtain a white solid powder, which is directly used in the next step of the reaction.

[0067] Dissolve 3-phenoxybenzoic acid (64 mg, 0.30 mmol), HATU (125 mg, 0.33 mmol) and DIPEA (116 mg, 0.90 mmol) in dichloromethane, then add the above-mentioned white solid intermediate 3. Stir at room temperature for about 4 hours. After monitoring the reaction by TLC, dilute the reaction solution with 10 mL of water, extract the aqueous phase with dichloromethane (6 mL×3), combine the organic phases, wash with saturated brine (10 mL×2), and then dry with anhydrous sodium sulfate for more than 2 hours. Filter by suction, concentrate the filtrate under reduced pressure, and then carry out column chromatography separation and purification (petroleum ether: ethyl acetate = 2:1) to obtain 93 mg of white solid powder, yield: 67.0%. M.P. 140 - 142 °C, 1 H NMR (400 MHz, Chloroform-d) δ 7.73 (t, J = 2.1 Hz, 1H), 7.58 (dd, J = 8.1, 2.1 Hz, 1H), 7.42 - 7.39 (m, 1H), 7.38 (s, 1H), 7.37 - 7.35 (m, 1H), 7.32 (t, J = 8.1 Hz, 1H), 7.19 - 7.14 (m, 3H), 7.09 - 7.04 (m, 4H), 4.54 - 4.19 (m, 1H), 3.93 - 3.73 (m, 3H), 3.49 - 3.22 (m, 2H), 2.23 - 2.10 (m, 2H), 2.07 - 1.88 (m, 2H), 1.57 - 1.40 (m, 1H), 1.38 - 1.21 (m, 1H).

[0068] Example 2: Synthesis of 8-(3-(4-chlorophenoxy)benzoyl)-2-(3-chlorophenyl)-2,8-diazaspiro[4.5]decan-1-one (V-02)

[0069] Methyl 3-(4-chlorophenoxy)benzoate (5):

[0070]

[0071] Methyl 3-hydroxybenzoate (304 mg, 2.00 mmol) was dissolved in 10 mL of anhydrous dichloromethane. 4-Chlorophenylboronic acid (469 mg, 3.00 mmol), cupric acetate anhydrous (363 mg, 2.00 mmol), pyridine (316 mg, 4.00 mmol) and 4A molecular sieve were added successively. The reaction mixture was stirred at room temperature for 24 hours. After most of the starting materials had reacted as monitored by TLC, the mixture was filtered under reduced pressure. The reaction solution was washed successively with water (20 mL×2) and saturated brine (20 mL×2), and then dried over anhydrous sodium sulfate for 2 hours. After filtration, the filtrate was concentrated under reduced pressure and then purified by column chromatography (petroleum ether: ethyl acetate = 50:1) to obtain 226 mg of a colorless transparent oil, with a yield of 43%. 1 1H NMR (300 MHz, DMSO-d6) δ 7.75 (dt, J = 7.7, 1.3 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.51 - 7.48 (m, 1H), 7.48 - 7.45 (m, 2H), 7.36 (ddd, J = 8.2, 2.6, 1.1 Hz, 1H), 7.13 - 7.10 (m, 1H), 7.10 - 7.07 (m, 1H), 3.84 (s, 3H).

[0072] 3-(4-Chlorophenoxy)benzoic acid (6):

[0073]

[0074] The intermediate 5 (200 mg, 0.76 mmol) was dissolved in 5 mL of tetrahydrofuran, and then 1.5 mL of 2.5 N sodium hydroxide solution was added. The reaction mixture was heated to 50 °C and kept for 2 hours. After the reaction was completed as monitored by TLC, the solvent was removed by distillation under reduced pressure. The concentrated solution was cooled to 0 °C, and the pH was adjusted to 4 with 2 N dilute hydrochloric acid solution, and a solid precipitated. After filtration and drying, 161 mg of white solid powder of intermediate 3-(4-chlorophenoxy)benzoic acid was obtained, with a yield of 85%. 1 1H NMR (300 MHz, DMSO-d6) δ 13.18 (s, 1H), 7.73 (dt, J = 7.7, 1.3 Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.51 - 7.48 (m, 1H), 7.47 - 7.44 (m, 2H), 7.32 (ddd, J = 8.2, 2.6, 1.1 Hz, 1H), 7.14 - 7.11 (m, 1H), 7.11 - 7.07 (m, 1H).

[0075] 8-(3-(4-Chlorophenoxy)benzoyl)-2-(3-chlorophenyl)-2,8-diazaspiro[4.5]decane-1-one (V-02)

[0076]

[0077] Using the same synthesis method as V-01, an amide condensation reaction was carried out with intermediate 3 and intermediate 6 as raw materials to obtain 92 mg of white solid powder, with a yield of 62%. M.P. 117 - 119 °C, 1 H NMR(300MHz,Chloroform-d)δ7.73(t,J=2.1Hz,1H),7.57(ddd,J=8.3,2.2,1.0Hz,1H),7.44-7.37(m,1H),7.36-7.34(m,1H),7.33-7.29(m,2H),7.20-7.14(m,2H),7.08-7.04(m,2H),7.00(d,J=2.2Hz,1H),6.98(d,J=2.2Hz,1H),4.54-4.16(m,1H),3.96-3.76(m,3H),3.48-3.21(m,1H),2.22-2.09(m,2H),2.08-1.90(m,2H),1.84-1.65(m,1H),1.57-1.42(m,1H),1.30-1.24(m,1H). 13 C NMR(101MHz,Chloroform-d)δ176.78,169.46,157.29,155.17,140.43,137.78,134.63,130.19,129.94,129.90,128.91,124.63,121.75,120.55,119.74,119.70,117.53,116.97,44.90,38.60,33.34,29.81.

[0078] Example 3: Synthesis of 2-(3-chlorophenyl)-8-(3-(4-fluorophenoxy)benzoyl)-2,8-diazaspiro[4.5]decanone (V-03)

[0079]

[0080] Using the same synthesis method as V-01, an amide condensation reaction was carried out with intermediate 3 and 3-(4-fluorophenoxy)benzoic acid as raw materials to obtain 96 mg of white solid powder, with a yield of 67%. M.P. 132 - 134 °C, 11H NMR (300 MHz, Chloroform-d) δ 7.71 (t, J = 2.1 Hz, 1H), 7.55 (dd, J = 8.5, 2.1 Hz, 1H), 7.39 - 7.33 (m, 1H), 7.30 (t, J = 8.1 Hz, 1H), 7.16 - 7.11 (m, 2H), 7.09 - 7.05 (m, 1H), 7.03 (s, 1H), 7.02 - 6.96 (m, 4H), 4.50 - 4.25 (m, 1H), 3.89 - 3.75 (m, 3H), 3.44 - 3.19 (m, 2H), 2.20 - 2.08 (m, 2H), 2.06 - 1.92 (m, 2H), 1.80 - 1.64 (m, 1H), 1.57 - 1.42 (m, 1H). 13 13C NMR (101 MHz, Chloroform-d) δ 176.80, 169.56, 160.34, 158.06, 157.93, 152.11, 152.09, 140.42, 137.66, 134.62, 130.10, 129.91, 124.62, 121.24, 121.10, 121.01, 119.73, 119.06, 117.52, 116.67, 116.44, 116.32, 44.91, 44.34, 44.15, 38.57, 33.31, 32.08, 29.74.

[0081] Example 4: Synthesis of 2-(3-chlorophenyl)-8-(3-((6-fluoropyridin-3-yl)oxy)benzoyl)-2,8-diazaspiro[4.5]decan-1-one (V-04)

[0082] Methyl 3-((6-fluoropyridin-3-yl)oxy)benzoate (7)

[0083]

[0084] Using the same synthesis method as for Intermediate 5, methyl m-hydroxybenzoate and (6-fluoropyridin-3-yl)boronic acid were used as starting materials to carry out Chan-Lam coupling, obtaining 104 mg of a colorless transparent oil, with a yield of 21%. 1 1H NMR (300 MHz, DMSO-d6) δ 8.14 - 8.09 (m, 1H), 7.85 - 7.78 (m, 1H), 7.78 - 7.74 (m, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.51 - 7.48 (m, 1H), 7.41 - 7.35 (m, 1H), 7.28 (dd, J = 8.9, 3.4 Hz, 1H), 3.85 (s, 3H).

[0085] 3-((6-Fluoropyridin-3-yl)oxy)benzoic acid (8)

[0086]

[0087] Using the same synthetic method as for Intermediate 6, an ester hydrolysis reaction was carried out with Intermediate 7 as the raw material to obtain 80 mg of a white solid powder with a yield of 85%. 1 H NMR (300 MHz, DMSO-d6) δ 13.24 (s, 1H), 8.13 (s, 1H), 7.86 - 7.78 (m, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.48 (s, 1H), 7.39 - 7.33 (m, 1H), 7.29 (dd, J = 8.9, 3.3 Hz, 1H).

[0088] 2-(3-Chlorophenyl)-8-(3-((6-fluoropyridin-3-yl)oxy)benzoyl)-2,8-diazaspiro[4.5]decan-1-one (V-04)

[0089]

[0090] Using the same synthetic method as for V-01, an amide condensation reaction was carried out with Intermediate 3 and Intermediate 8 as the raw materials to obtain 84 mg of a white solid powder with a yield of 58%. M.P. 148 - 150 °C 1 H NMR (300 MHz, Chloroform-d) δ 8.02 (dd, J = 3.1, 1.6 Hz, 1H), 7.73 (t, J = 2.1 Hz, 1H), 7.57 (ddd, J = 8.3, 2.2, 1.0 Hz, 1H), 7.50 (ddd, J = 9.2, 6.4, 3.0 Hz, 1H), 7.45 - 7.39 (m, 1H), 7.32 (t, J = 8.1 Hz, 1H), 7.21 (dt, J = 7.6, 1.2 Hz, 1H), 7.19 - 7.14 (m, 1H), 7.09 - 7.04 (m, 2H), 6.97 (dd, J = 8.8, 3.5 Hz, 1H), 4.56 - 4.20 (m, 1H), 3.95 - 3.75 (m, 3H), 3.50 - 3.23 (m, 2H), 2.22 - 2.10 (m, 2H), 2.08 - 1.92 (m, 2H), 1.61 - 1.15 (m, 2H).

[0091] Example 5: Synthesis of 2-(3-Chlorophenyl)-8-(5-(4-fluorophenoxy)nicotinoyl)-2,8-diazaspiro[4.5]decan-1-one (V-05)

[0092] Methyl 5-(4-fluorophenoxy)nicotinate (10)

[0093]

[0094] Using the same synthetic method as for Intermediate 5, methyl 5-hydroxy nicotinate and 4-fluorophenylboronic acid were used as raw materials to undergo Chan-Lam coupling to obtain 89 mg of a colorless transparent oily substance, with a yield of 18%. 1 H NMR (300 MHz, DMSO-d6) δ 8.86 - 8.82 (m, 1H), 8.69 - 8.64 (m, 1H), 7.64 (dd, J = 2.9, 1.8 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.29 - 7.23 (m, 2H), 3.85 (s, 3H).

[0095] 5-(4-fluorophenoxy)nicotinic acid (11)

[0096]

[0097] Using the same synthetic method as for Intermediate 6, an ester hydrolysis reaction was carried out with Intermediate 10 as the raw material to obtain 73 mg of a white solid powder, with a yield of 87%. 1 H NMR (300 MHz, DMSO-d6) δ 13.71 (s, 1H), 8.84 (d, J = 1.8 Hz, 1H), 8.65 (d, J = 2.8 Hz, 1H), 7.64 (dd, J = 2.9, 1.7 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.29 - 7.23 (m, 2H).

[0098] 2-(3-chlorophenyl)-8-(5-(4-fluorophenoxy)nicotinoyl)-2,8-diazaspiro[4.5]decane-1-one (V-05)

[0099]

[0100] Using the same synthetic method as for V-01, an amide condensation reaction was carried out with Intermediate 3 and Intermediate 11 as raw materials to obtain 79 mg of a white solid powder, with a yield of 55%. M.P. 157 - 159 °C 11H NMR (400 MHz, Chloroform-d) δ 8.44 (s, 1H), 8.41 (s, 1H), 7.74 - 7.70 (m, 1H), 7.56 (dd, J = 8.3, 2.2 Hz, 1H), 7.35 - 7.30 (m, 2H), 7.16 (dd, J = 8.0, 1.9 Hz, 1H), 7.14 - 7.12 (m, 1H), 7.12 - 7.09 (m, 1H), 7.08 - 7.07 (m, 1H), 7.07 - 7.03 (m, 1H), 4.46 - 4.19 (m, 1H), 3.93 - 3.78 (m, 3H), 3.58 - 3.29 (m, 2H), 2.22 - 2.11 (m, 2H), 2.08 - 1.95 (m, 2H), 1.61 - 1.50 (m, 1H), 1.44 - 1.18 (m, 1H). 13 13C NMR (101 MHz, Chloroform-d) δ 176.58, 166.90, 160.83, 158.40, 154.51, 151.10, 151.07, 141.57, 141.50, 140.35, 134.64, 132.46, 129.91, 124.69, 122.93, 121.33, 121.24, 119.76, 117.55, 117.06, 116.83, 44.88, 44.28, 44.09, 38.75, 33.42, 32.11, 30.01.

[0101] Example 6: Synthesis of 8-(2-Naphthyl)-2-(3-chlorophenyl)-2,8-diazaspiro[4.5]decan-1-one (V-06)

[0102]

[0103] Using the same synthesis method as V-01, an amide condensation reaction was carried out with intermediate 3 and 2-naphthoic acid as raw materials to obtain 80 mg of white solid powder, with a yield of 64%. M.P. 136 - 138 °C 11H NMR (400 MHz, Chloroform-d) δ 7.96 (s, 1H), 7.92 (d, J = 3.4 Hz, 1H), 7.90 (s, 1H), 7.89 (d, J = 5.0 Hz, 1H), 7.75 - 7.73 (m, 1H), 7.61 - 7.58 (m, 1H), 7.57 - 7.56 (m, 1H), 7.56 - 7.55 (m, 1H), 7.55 - 7.51 (m, 1H), 7.32 (t, J = 8.2 Hz, 1H), 7.16 (dd, J = 7.9, 2.0 Hz, 1H), 4.78 - 4.13 (m, 1H), 4.05 - 3.76 (m, 3H), 3.49 - 3.29 (m, 2H), 2.24 - 2.14 (m, 2H), 2.12 - 2.01 (m, 2H), 1.58 - 1.19 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 176.90, 170.51, 140.47, 134.63, 133.69, 133.25, 132.75, 129.90, 128.43, 128.41, 127.83, 127.10, 126.77, 126.69, 124.60, 124.22, 119.76, 117.53, 44.92, 44.48.

[0104] Example 7: Synthesis of 2-(3-chlorophenyl)-8-(3-hydroxybenzoyl)-2,8-diazaspiro[4.5]decan-1-one (V-07)

[0105]

[0106] Using the same synthesis method as V-01, an amide condensation reaction was carried out with intermediate 3 and m-hydroxybenzoic acid as raw materials to obtain 83 mg of white solid powder, with a yield of 72%. M.P. 180 - 182 °C 1 1H NMR (300 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.83 (t, J = 2.1 Hz, 1H), 7.54 (dd, J = 7.9, 1.7 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.22 - 7.10 (m, 2H), 6.80 - 6.66 (m, 3H), 4.36 - 4.07 (m, 1H), 3.77 (t, J = 7.0 Hz, 2H), 3.64 - 3.42 (m, 1H), 3.23 - 2.98 (m, 2H), 2.15 - 2.00 (m, 2H), 1.71 - 1.35 (m, 4H). 1313C NMR (101 MHz, DMSO-d6) δ 177.48, 169.47, 157.77, 141.33, 137.85, 133.62, 130.80, 130.11, 124.19, 119.49, 118.14, 117.54, 116.83, 113.86, 45.00, 44.06, 32.77, 31.98, 28.33.

[0107] Example 8: Synthesis of 8-(3-hydroxybenzoyl)-2-(3-(trifluoromethyl)phenyl)-2,8-diazaspiro[4.5]decan-1-one (V-08)

[0108] tert-Butyl 1-oxo-2-(3-(trifluoromethyl)phenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate (12)

[0109]

[0110] Using the same synthetic method as for Intermediate 2, a C-N coupling reaction was carried out between tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate and 1-bromo-4-(trifluoromethyl)benzene to obtain 201 mg of a white solid powder with a yield of 64%. 1 1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.68 - 7.60 (m, 1H), 7.52 (d, J = 7.8 Hz, 1H), 3.89 (t, J = 6.9 Hz, 2H), 3.33 - 3.26 (m, 2H), 3.08 - 2.97 (m, 2H), 2.15 (t, J = 6.9 Hz, 2H), 2.04 - 1.93 (m, 2H), 1.80 - 1.71 (m, 2H), 1.41 (s, 9H).

[0111] 8-(3-hydroxybenzoyl)-2-(3-(trifluoromethyl)phenyl)-2,8-diazaspiro[4.5]decan-1-one (V-08)

[0112]

[0113] Using the same synthetic method as for V-01, an amide condensation reaction was carried out with Intermediate 13 and m-hydroxybenzoic acid as raw materials to obtain 88 mg of a white solid powder with a yield of 70%. M.P. 122 - 124 °C 11H NMR (300 MHz, Chloroform-d) δ 8.56 (s, 1H), 7.95 (s, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 6.92 - 6.85 (m, 3H), 4.54 - 4.33 (m, 1H), 3.98 - 3.76 (m, 3H), 3.43 - 3.18 (m, 2H), 2.27 - 2.12 (m, 2H), 2.08 - 1.88 (m, 2H), 1.76 - 1.47 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 177.24, 170.96, 157.15, 139.68, 136.26, 131.74, 131.42, 131.10, 130.78, 129.82, 129.50, 125.23, 122.78, 122.52, 121.26, 121.22, 120.13, 117.78, 117.49, 116.44, 116.40, 116.36, 116.32, 114.10, 45.03, 44.51, 44.27, 38.77, 38.67, 33.16, 32.10, 29.55.

[0114] Example 9: Synthesis of 8-(3-Hydroxybenzoyl)-2-(3-(trifluoromethyl)phenyl)-2,8-diazaspiro[4.5]decan-1-one (V-09)

[0115] tert-Butyl 1-oxo-2-(3-(trifluoromethoxy)phenyl)-2,8-diazaspiro[4.5]decane-8-carboxylate (14)

[0116]

[0117] Using the same synthesis method as Intermediate 2, a C-N coupling reaction was carried out between tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate and 1-bromo-4-(trifluoromethoxy)benzene to obtain 232 mg of a white solid powder with a yield of 71%. 1 1H NMR (300 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.60 - 7.55 (m, 1H), 7.55 - 7.49 (m, 1H), 7.14 (d, J = 7.9 Hz, 1H), 3.91 - 3.80 (m, 4H), 3.08 - 2.85 (m, 2H), 2.10 (t, J = 7.0 Hz, 2H), 1.67 - 1.57 (m, 2H), 1.55 - 1.48 (m, 2H), 1.41 (s, 9H).

[0118] 8-(3-Hydroxybenzoyl)-2-(3-(trifluoromethyl)phenyl)-2,8-diazaspiro[4.5]decan-1-one (V-09)

[0119]

[0120] Using the same synthetic method as V-01, an amide condensation reaction was carried out with intermediate 15 and m-hydroxybenzoic acid as raw materials to obtain 85 mg of white solid powder with a yield of 65%. M.P. 105-107 °C, 1 H NMR(300MHz,Chloroform-d)δ8.45(s,1H),7.70(s,1H),7.54(dd,J=8.5,2.1Hz,1H),7.40(t,J=8.3Hz,1H),7.22(t,J=7.7Hz,1H),7.04(d,J=7.0Hz,1H),6.92-6.85(m,3H),4.56-4.30(m,1H),3.97-3.75(m,3H),3.43-3.17(m,2H),2.27-2.11(m,2H),2.05-1.87(m,2H),1.76-1.44(m,2H).

[0121] Example 10: Synthesis of 2-(3-chloro-4-fluorophenyl)-8-(3-hydroxybenzoyl)-2,8-diazaspiro[4.5]dec-1-one (V-10)

[0122] tert-Butyl 2-(3-chloro-4-fluorophenyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (16)

[0123]

[0124] Using the same synthetic method as intermediate 2, a C-N coupling reaction was carried out between tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate and 2-chloro-1-fluoro-4-iodobenzene to obtain 166 mg of white solid powder with a yield of 56%. 1 H NMR(300MHz,DMSO-d6)δ8.04-7.96(m,1H),7.68-7.60(m,1H),7.50-7.40(m,1H),3.91-3.76(m,4H),3.08-2.82(m,2H),2.15-2.03(m,2H),1.68-1.55(m,2H),1.54-1.46(m,2H),1.41(s,9H).

[0125] 2-(3-chloro-4-fluorophenyl)-8-(3-hydroxybenzoyl)-2,8-diazaspiro[4.5]decan-1-one (V-10)

[0126]

[0127] Using the same synthesis method as V-01, an amide condensation reaction was carried out with intermediate 17 and m-hydroxybenzoic acid as raw materials to obtain 81 mg of white solid powder, with a yield of 67%. M.P. 188 - 190 °C, 1 H NMR (300 MHz, Chloroform-d) δ 7.77 (dd, J = 6.5, 2.7 Hz, 1H), 7.73 (s, 1H), 7.54 - 7.44 (m, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.14 (t, J = 8.8 Hz, 1H), 6.95 - 6.87 (m, 2H), 6.88 (d, J = 2.1 Hz, 1H), 6.86 (d, J = 1.9 Hz, 1H), 4.61 - 4.13 (m, 1H), 3.96 - 3.65 (m, 3H), 3.45 - 3.14 (m, 2H), 2.24 - 2.08 (m, 2H), 2.08 - 1.85 (m, 2H), 1.57 - 1.39 (m, 1H), 1.37 - 1.20 (m, 1H).

[0128] Example 11: Synthesis of 2-(5-chlorothiazol-2-yl)-8-(3-hydroxybenzoyl)-2,8-diazaspiro[4.5]decan-1-one (V-11)

[0129] tert-Butyl 2-(5-chlorothiazol-2-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (18)

[0130]

[0131] Using the same synthesis method as intermediate 2, a C-N coupling reaction was carried out between tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate and 2-bromo-5-chlorothiazole to obtain 167 mg of light yellow solid powder, with a yield of 57%. 1 H NMR (300 MHz, DMSO-d6) δ 7.60 (s, 1H), 4.00 (t, J = 7.1 Hz, 2H), 3.86 - 3.76 (m, 2H), 3.13 - 2.91 (m, 2H), 2.19 (t, J = 7.1 Hz, 2H), 1.67 - 1.53 (m, 4H), 1.42 (s, 9H).

[0132] 2-(5-Chlorothiazol-2-yl)-8-(3-hydroxybenzoyl)-2,8-diazaspiro[4.5]decan-1-one (V-11)

[0133]

[0134] Using the same synthetic method as V-01, the intermediate 19 and m-hydroxybenzoic acid were used as raw materials to carry out an amide condensation reaction, obtaining 69 mg of white solid powder with a yield of 59%. M.P. 217 - 219 °C, 1 H NMR (300 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.60 (s, 1H), 7.24 (t, J = 7.8 Hz, 1H), 6.85 - 6.81 (m, 1H), 6.81 - 6.77 (m, 1H), 6.77 - 6.75 (m, 1H), 4.01 (t, J = 7.1 Hz, 2H), 3.75 - 3.46 (m, 1H), 3.31 - 3.12 (m, 3H), 2.26 - 2.21 (m, 2H), 1.75 - 1.63 (m, 4H). 13 C NMR (101 MHz, DMSO-d6) δ 177.15, 169.48, 157.77, 155.09, 137.76, 136.12, 130.11, 119.50, 117.54, 116.85, 113.86, 44.81, 44.52, 43.97, 38.36, 32.59, 31.90, 29.01.

[0135] Example 12: Synthesis of 2-(3-chlorobenzyl)-8-(3-hydroxybenzoyl)-2,8-diazaspiro[4.5]decane-1-one (V-12)

[0136] 2-(3-Chlorobenzyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (20)

[0137]

[0138] Dissolve tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.79 mmol) in 5 mL of acetonitrile, and then successively add 3-chlorobenzyl bromide (162 mg, 0.79 mmol) and sodium hydroxide (63 mg, 1.58 mmol). React the reaction solution at room temperature for 10 hours. After detecting the end of the reaction by TLC, add 20 mL of water to the reaction solution and extract it with ethyl acetate (10 mL × 3). After combining the organic phases, wash them successively with water (20 mL × 2) and saturated brine (20 mL × 2), and then dry them with anhydrous sodium sulfate for 2 hours. Filter by suction, concentrate the filtrate under reduced pressure to obtain 216 mg of a colorless transparent oily substance with a yield of 72%, which is directly used for the next step. 1 H NMR (300 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.45 - 7.38 (m, 1H), 7.19 (d, J = 8.0 Hz, 1H), 4.91 (s, 2H), 3.91 - 3.76 (m, 4H), 3.08 - 2.82 (m, 2H), 2.24 - 1.98 (m, 2H), 1.68 - 1.55 (m, 2H), 1.54 - 1.46 (m, 2H) 1.42 (s, 9H).

[0139] 2-(3-Chlorobenzyl)-8-(3-hydroxybenzoyl)-2,8-diazaspiro[4.5]decan-1-one (V-12)

[0140]

[0141] Using the same synthesis method as V-01, an amide condensation reaction was carried out with intermediate 21 and m-hydroxybenzoic acid as raw materials to obtain 78 mg of a white solid powder with a yield of 65%. M.P. 97 - 99 °C 1 H NMR (300 MHz, Chloroform-d) δ 8.38 (s, 1H), 7.30 (d, J = 1.7 Hz, 1H), 7.28 (s, 1H), 7.25 (dd, J = 7.2, 2.0 Hz, 1H), 7.22 - 7.20 (m, 1H), 7.15 - 7.09 (m, 1H), 6.93 - 6.89 (m, 2H), 6.89 - 6.85 (m, 1H), 4.46 (s, 2H), 4.00 - 3.73 (m, 1H), 3.32 - 3.18 (m, 4H), 2.09 - 1.90 (m, 4H), 1.82 - 1.73 (m, 1H), 1.64 - 1.38 (m, 2H). 1313C NMR (101 MHz, Chloroform-d) δ 177.81, 170.89, 157.25, 138.22, 136.47, 134.63, 130.20, 129.79, 128.08, 127.99, 126.12, 117.72, 117.37, 113.96, 46.33, 44.34, 43.41, 43.29, 38.84, 33.10, 32.06, 29.77.

[0142] Example 13: Synthesis of 2-(3-chlorophenyl)-8-(1-methyl-1H-indole-2-carbonyl)-2,8-diazaspiro[4.5]decan-1-one (V-13)

[0143]

[0144] Using the same synthesis method as V-01, an amide condensation reaction was carried out with intermediate 3 and 1-methyl-1H-indole-2-carboxylic acid as raw materials to obtain 78 mg of a white solid powder with a yield of 62%. M.P. 165 - 167 °C, 1 1H NMR (300 MHz, Chloroform-d) δ 7.75 (t, J = 2.1 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.58 (dd, J = 8.5, 2.7 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.20 - 7.13 (m, 2H), 6.65 (s, 1H), 4.54 - 4.17 (m, 2H), 3.87 (s, 3H), 3.86 - 3.80 (m, 2H), 3.49 (ddd, J = 13.4, 9.4, 2.9 Hz, 2H), 2.19 (t, J = 6.8 Hz, 2H), 2.13 - 2.00 (m, 2H), 1.69 - 1.64 (m, 1H), 1.44 - 1.19 (m, 1H). 13 13C NMR (101 MHz, Chloroform-d) δ 176.82, 163.24, 140.45, 137.89, 134.66, 131.87, 129.92, 126.48, 124.65, 123.32, 121.54, 120.30, 119.77, 117.54, 109.88, 103.27, 44.92, 44.46, 31.14, 29.77.

[0145] Example 14: Synthesis of 2-(3-chlorobenzyl)-8-(1-methyl-1H-indole-2-carbonyl)-2,8-diazaspiro[4.5]decan-1-one (V-14)

[0146]

[0147] Using the same synthesis method as V-01, an amide condensation reaction was carried out with intermediate 21 and 1-methyl-1H-indole-2-carboxylic acid as raw materials to obtain 88 mg of white solid powder with a yield of 67%. M.P. 134 - 136 °C, 1 H NMR(300MHz,Chloroform-d)δ7.64(d,J=7.9Hz,1H),7.39(d,J=8.1Hz,1H),7.34 - 7.30(m,1H),7.29 - 7.27(m,2H),7.22(s,1H),7.19 - 7.15(m,1H),7.14 -

[0148] 7.10(m,1H),6.64(s,1H),4.45(s,2H),3.86(s,3H),3.47 - 3.35(m,2H),3.24(t,J=7.0Hz,2H),2.07 - 1.97(m,4H),1.61 - 1.50(m,2H),1.42 - 1.24(m,2H). 13 C NMR(101MHz,Chloroform-d)δ177.38,163.21,138.48,137.86,134.65,131.97,130.15,128.08,127.95,126.50,126.14,123.25,121.52,120.25,109.86,103.20,46.24,43.22,43.08,31.13,30.10.

[0149] Example 15: Synthesis of 2-(3-chlorophenyl)-8-(2-oxo-1,2-dihydroquinoline-7-carbonyl)-2,8-diazaspiro[4.5]dec-1-one (V-15)

[0150]

[0151] Using the same synthesis method as V-01, an amide condensation reaction was carried out with intermediate 3 and 2-oxo-1,2-dihydroquinoline-7-carboxylic acid as raw materials to obtain 68 mg of white solid powder with a yield of 52%. M.P. 291 - 292 °C, 11H NMR (300 MHz, DMSO-d6) δ 11.87 (s, 1H), 7.98 - 7.88 (m, 2H), 7.74 (d, J = 7.9 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.42 (t, J = 8.2 Hz, 1H), 7.32 (s, 1H), 7.24 - 7.15 (m, 2H), 6.56 (d, J = 9.6 Hz, 1H), 4.43 - 4.12 (m, 1H), 3.89 - 3.79 (m, 2H), 3.67 - 3.50 (m, 1H), 3.24 - 3.12 (m, 2H), 2.21 - 2.08 (m, 2H), 1.80 - 1.51 (m, 4H).

[0152] Example 16: Synthesis of 2-(3-chlorobenzyl)-8-(2-oxo-1,2-dihydroquinoline-7-carbonyl)-2,8-diazaspiro[4.5]dec-1-one (V-16)

[0153]

[0154] Using the same synthesis method as V-01, an amide condensation reaction was carried out with intermediate 21 and 2-oxo-1,2-dihydroquinoline-7-carboxylic acid as raw materials to obtain 74 mg of a light pink solid powder with a yield of 54%. M.P. 161 - 163 °C 1 1H NMR (300 MHz, DMSO-d6) δ 11.85 (s, 1H), 7.94 (d, J = 9.6 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.41 - 7.33 (m, 2H), 7.32 - 7.29 (m, 1H), 7.19 - 7.13 (m, 2H), 6.55 (d, J = 9.5 Hz, 1H), 4.40 (s, 2H), 3.73 - 3.45 (m, 1H), 3.27 - 3.10 (m, 4H), 2.05 - 1.95 (m, 2H), 1.76 - 1.62 (m, 2H), 1.58 - 1.36 (m, 2H), 1.33 - 1.12 (m, 1H). 13 13C NMR (101 MHz, DMSO-d6) δ 177.38, 168.71, 162.35, 140.29, 140.03, 139.14, 138.15, 133.69, 131.04, 128.67, 127.84, 127.76, 126.52, 123.36, 120.51, 120.09, 113.75, 45.55, 44.30, 43.48, 43.23, 38.72, 32.81, 32.11, 29.01.

[0155] Example 17: Synthesis of 8-(2-chloro-3-methoxybenzoyl)-2-(3-chlorophenyl)-2,8-diazaspiro[4.5]decan-1-one (V-17)

[0156]

[0157] Using the same synthesis method as V-01, an amide condensation reaction was carried out with intermediate 3 and 2-chloro-3-methoxybenzoic acid as raw materials to obtain 85 mg of white solid powder, with a yield of 65%. M.P. 134 - 136 °C, 1 H NMR (300 MHz, Chloroform-d) δ 7.76 - 7.72 (m, 1H), 7.58 - 7.51 (m, 1H), 7.32 (dd, J = 8.1, 2.4 Hz, 1H), 7.29 - 7.25 (m, 1H), 7.14 (d, J = 7.8 Hz, 1H), 7.00 - 6.85 (m, 2H), 4.50 - 4.38 (m, 1H), 3.94 (s, 3H), 3.89 - 3.74 (m, 2H), 3.71 - 3.43 (m, 2H), 3.29 - 3.08 (m, 1H), 2.25 - 2.05 (m, 3H), 2.04 - 1.84 (m, 1H), 1.76 - 1.68 (m, 1H), 1.61 - 1.40 (m, 1H). 13 C NMR (101 MHz, Chloroform-d) δ 176.86, 166.70, 155.22, 134.61, 129.88, 128.36, 119.76, 119.23, 118.94, 117.50, 112.19, 44.93, 44.32, 43.10, 33.07, 32.10, 29.71.

[0158] Example 18: Synthesis of 2-(3-chlorophenyl)-8-(4-chlorothieno[2,3-b]pyridine-5-carbonyl)-2,8-diazaspiro[4.5]decan-1-one (V-18)

[0159] 4-chlorothieno[2,3-b]pyridine-5-carboxylic acid (23)

[0160]

[0161] Ethyl 4-chlorothieno[2,3-b]pyridine-5-carboxylate (160 mg, 0.66 mmol) was dissolved in 5 mL of ethanol, and then 1.5 mL of 2.5 N sodium hydroxide solution was added. The reaction solution was heated to 70 °C and kept for reaction for 2 hours. After monitoring the reaction by TLC until completion, the reaction solution was cooled to 0 °C, and the pH was adjusted to 4 with 2 N dilute hydrochloric acid solution, and a solid precipitated. It was filtered by suction and dried to obtain 114 mg of white solid powder with a yield of 81%. 1 1H NMR (300 MHz, DMSO-d6) δ 13.85 (s, 1H), 8.95 (s, 1H), 8.14 (d, J = 6.1 Hz, 1H), 7.62 (d, J = 6.0 Hz, 1H).

[0162] 2-(3-Chlorophenyl)-8-(4-chlorothieno[2,3-b]pyridine-5-carbonyl)-2,8-diazaspiro[4.5]dec-1-one (V-18)

[0163]

[0164] Using the same synthesis method as V-01, an amide condensation reaction was carried out with intermediate 3 and intermediate 23 as raw materials to obtain 81 mg of white solid powder with a yield of 59%. M.P. 152 - 154 °C 1 1H NMR (300 MHz, Chloroform-d) δ 8.51 (d, J = 17.6 Hz, 1H), 7.78 - 7.68 (m, 2H), 7.61 - 7.54 (m, 1H), 7.49 (t, J = 6.1 Hz, 1H), 7.32 (t, J = 8.1 Hz, 1H), 7.16 (dd, J = 8.0, 2.0 Hz, 1H), 4.51 - 4.40 (m, 1H), 3.92 - 3.78 (m, 2H), 3.76 - 3.57 (m, 2H), 3.36 - 3.17 (m, 1H), 2.26 - 2.10 (m, 3H), 1.80 - 1.70 (m, 1H), 1.56 - 1.26 (m, 2H).

[0165] Example 19: Synthesis of 2-(3-chlorophenyl)-8-(furan-2-carbonyl)-2,8-diazaspiro[4.5]decane-1-one (V-19)

[0166]

[0167] Using the same synthesis method as V-01, an amide condensation reaction was carried out with intermediate 3 and 2-furoic acid as raw materials to obtain 106 mg of white solid powder with a yield of 89.0%. 11H NMR (400 MHz, Chloroform-d) δ 7.72 (t, J = 2.1 Hz, 1H), 7.56 (dd, J = 8.2, 2.2 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.29 (t, J = 8.2 Hz, 1H), 7.13 (dd, J = 7.9, 2.0 Hz, 1H), 6.99 (d, J = 3.4 Hz, 1H), 6.48 (dd, J = 3.5, 1.8 Hz, 1H), 4.33 (ddd, J = 13.8, 6.1, 4.2 Hz, 2H), 3.81 (t, J = 6.9 Hz, 2H), 3.50 (s, 2H), 2.15 (t, J = 6.9 Hz, 2H), 2.06 (ddd, J = 13.7, 9.6, 4.0 Hz, 2H), 1.63 (ddd, J = 10.9, 7.4, 4.0 Hz, 2H).

[0168] Example 20: Synthesis of 2-(3-chlorophenyl)-8-(thiazole-2-carbonyl)-2,8-diazaspiro[4.5]decan-1-one (V-20)

[0169]

[0170] Using the same synthesis method as V-01, an amide condensation reaction was carried out with intermediate 3 and thiazole-2-carboxylic acid as raw materials to obtain 100 mg of white solid powder, yield: 88.4%. 1 1H NMR (300 MHz, DMSO-d6) δ 8.03 (q, J = 3.2 Hz, 2H), 7.90 (t, J = 2.1 Hz, 1H), 7.64 - 7.57 (m, 1H), 7.41 (t, J = 8.1 Hz, 1H), 7.21 (dd, J = 7.9, 1.8 Hz, 1H), 5.04 (d, J = 13.6 Hz, 1H), 4.32 (d, J = 13.3 Hz, 1H), 3.86 (t, J = 6.9 Hz, 2H), 3.63 (t, J = 12.3 Hz, 1H), 3.24 (d, J = 12.3 Hz, 1H), 2.24 - 2.14 (m, 2H), 1.69 (t, J = 19.4 Hz, 4H).

[0171] Example 21: Synthesis of 2-(3-chlorophenyl)-8-(1H-imidazole-2-carbonyl)-2,8-diazaspiro[4.5]decan-1-one (V-21)

[0172]

[0173] Using the same synthetic method as V-01, an amide condensation reaction was carried out with intermediate 3 and 2-imidazolecarboxylic acid as raw materials to obtain 68 mg of white solid powder, yield: 57.1%. 1 H NMR(400MHz,DMSO-d6)δ12.90(s,1H),7.91(t,J=2.1Hz,1H),7.63-7.58(m,1H),7.42(t,J=8.2Hz,1H),7.25(s,1H),7.21(dd,J=8.1,1.9Hz,1H),7.08(s,1H),5.42(d,J=

[0174] 13.3Hz,1H),4.36(d,J=13.2Hz,1H),3.86(t,J=6.9Hz,2H),3.62(t,J=12.4Hz,1H),3.13(t,J=12.1Hz,1H),2.24-2.14(m,2H),1.80-1.61(m,4H).

[0175] Example 22: Synthesis of 2-(3-chlorophenyl)-8-(1H-imidazole-5-carbonyl)-2,8-diazaspiro[4.5]decan-1-one (V-22)

[0176]

[0177] Using the same synthetic method as V-01, an amide condensation reaction was carried out with intermediate 3 and 4-imidazolecarboxylic acid as raw materials to obtain 35 mg of white solid powder, yield: 58.8%. 1 H NMR(300MHz,DMSO-d6)δ12.59(s,1H),7.90(s,1H),7.72(s,1H),7.59(d,J=8.6Hz,2H),7.41(t,J=8.2Hz,1H),7.20(d,J=7.9Hz,1H),5.09(s,1H),4.32(s,1H),3.84(t,J=6.9Hz,2H),3.03(s,1H),2.54(s,1H),2.15(t,J=7.0Hz,2H),1.62(dd,J=33.6,13.0Hz,4H).

[0178] Example 23: Synthesis of 2-(3-chlorophenyl)-8-(5-chlorothiophene-2-carbonyl)-2,8-diazaspiro[4.5]decan-1-one (V-23)

[0179]

[0180] Using the same synthetic method as V-01, an amide condensation reaction was carried out with intermediate 3 and 5-chlorothiophene-2-carboxylic acid as raw materials to obtain 115 mg of white solid powder, yield: 85.2%. 1 H NMR(400MHz,Chloroform-d)δ7.71(t,J=2.1Hz,1H),7.57-7.53(m,1H),7.30(t,J=8.1Hz,1H),7.16-7.12(m,1H),7.10(d,J=3.9Hz,1H),6.87(d,J=3.9Hz,1H),4.24(ddd,J=13.6,6.2,4.1Hz,2H),3.82(t,J=6.9Hz,2H),3.50(ddd,J=13.3,9.4,3.5Hz,2H),2.14(t,J=6.9Hz,2H),2.04(ddd,J=13.5,9.4,4.0Hz,2H),1.63(ddd,J=13.8,6.3,3.8Hz,2H).

[0181] Example 24: Synthesis of 2-(3-chlorophenyl)-8-(4,5-dichlorothiophene-2-carbonyl)-2,8-diazaspiro[4.5]decan-1-one (V-24)

[0182]

[0183] Using the same synthetic method as V-01, an amide condensation reaction was carried out with intermediate 3 and 4,5-dichlorothiophene-2-carboxylic acid as raw materials to obtain 140 mg of white solid powder, yield: 95.0%. 1 H NMR(300MHz,DMSO-d6)δ7.89(t,J=2.1Hz,1H),7.64-7.56(m,2H),7.40(d,J=8.2Hz,1H),7.21(ddd,J=8.0,2.1,0.9Hz,1H),4.14(d,J=13.3Hz,2H),3.85(t,J=6.9Hz,2H),2.69(s,2H),2.14(t,J=6.9Hz,2H),1.77(td,J=12.1,10.9,4.0Hz,2H),1.62(d,J=13.7Hz,2H).

[0184] Example 25: Synthesis of 2-(3-chlorophenyl)-8-(3-((4-fluorobenzyl)oxy)benzoyl)-2,8-diazaspiro[4.5]decan-1-one (V-25)

[0185]

[0186] Dissolve V-07 (20 mg, 0.05 mmol) and 4-fluorobenzyl bromide (14.7 mg, 0.08 mmol) in 1 mL of acetonitrile, add triethylamine (10.5 mg, 0.10 mmol), and stir at room temperature for about 7 hours. After monitoring the reaction by TLC, remove the solvent by distillation under reduced pressure. Dilute the reaction solution with 5 mL of water, extract the aqueous phase with ethyl acetate (6 mL × 3), combine the organic phases, wash with saturated brine (6 mL × 2), and then dry over anhydrous sodium sulfate for more than 2 hours. Filter by suction, concentrate the filtrate under reduced pressure, and then separate and purify by column chromatography (methylene chloride:methanol = 40:1) to obtain 11 mg of white solid powder with a yield of 43.0%. 1 H NMR (300 MHz, DMSO-d6) δ 7.89 (t, J = 2.1 Hz, 1H), 7.59 (ddd, J = 8.3, 2.1, 1.0 Hz, 1H), 7.55 - 7.47 (m, 2H), 7.44 - 7.39 (m, 1H), 7.39 - 7.33 (m, 1H), 7.27 - 7.17 (m, 3H), 7.08 (ddd, J = 8.4, 2.6, 0.9 Hz, 1H), 7.00 (dd, J = 2.6, 1.3 Hz, 1H), 6.96 (dt, J = 7.6, 1.2 Hz, 1H), 5.12 (s, 2H), 4.28 (s, 1H), 3.83 (s, 2H), 3.56 (s, 1H), 3.18 (s, 2H), 2.12 (d, J = 6.7 Hz, 2H), 1.57 (d, J = 51.4 Hz, 4H).

[0187] Example 26: Synthesis of 2-(5-chloropyridin-3-yl)-8-(3-hydroxybenzoyl)-2,8-diazaspiro[4.5]decan-1-one (V-26)

[0188] 2-(5-chloropyridin-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (24)

[0189]

[0190] Using the same synthetic method as Intermediate 2, 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester undergoes a C-N coupling reaction with 3-bromo-5-chloropyridine to obtain 110 mg of white solid powder with a yield of 76.5%. 11H NMR (300 MHz, DMSO-d6) δ 8.85 (d, J = 2.3 Hz, 1H), 8.40 (d, J = 2.2 Hz, 1H), 8.32 (t, J = 2.2 Hz, 1H), 3.86 (q, J = 7.8, 7.4 Hz, 4H), 2.98 (s, 2H), 1.99 (s, 2H), 1.66 - 1.49 (m, 4H), 1.41 (s, 9H).

[0191] 2-(5-Chloropyridin-3-yl)-8-(3-hydroxybenzoyl)-2,8-diazaspiro[4.5]decan-1-one (V-26)

[0192]

[0193] Using the same synthetic method as V-01, an amide condensation reaction was carried out with intermediate 25 and m-hydroxybenzoic acid as raw materials to obtain 10 mg of white solid powder, yield: 39.1%. 1 1H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.87 (s, 1H), 8.45 - 8.38 (m, 1H), 8.33 (s, 1H), 7.24 (t, J = 7.8 Hz, 1H), 6.85 - 6.72 (m, 3H), 4.27 (s, 1H), 3.87 (d, J = 7.4 Hz, 2H), 3.60 (s, 1H), 3.17 (s, 2H), 2.16 (s, 2H), 1.61 (d, J = 37.4 Hz, 4H).

[0194] Example 27: Synthesis of 2-(3-chlorophenyl)-7-(3-hydroxybenzoyl)-2,7-diazaspiro[3.5]nonan-1-one (V-27)

[0195] tert-Butyl 2-(3-chlorophenyl)-1-oxo-2,7-diazaspiro[3.5]nonane-7-carboxylate (27)

[0196]

[0197] Using the same synthetic method as intermediate 2, a C-N coupling reaction was carried out between tert-butyl 1-oxo-2,7-diazaspiro[3.5]nonane-7-carboxylate and m-chlorobromobenzene to obtain 72 mg of white solid powder, yield: 98.6%. 11H NMR (300 MHz, DMSO-d6) δ 7.44 - 7.37 (m, 2H), 7.28 (ddd, J = 8.2, 2.0, 1.1 Hz, 1H), 7.18 - 7.13 (m, 1H), 3.63 (d, J = 15.6 Hz, 4H), 3.29 - 3.16 (m, 2H), 1.79 (t, J = 5.2 Hz, 4H), 1.41 (s, 9H).

[0198] 2-(3-Chlorophenyl)-7-(3-hydroxybenzoyl)-2,7-diazaspiro[3.5]nonan-1-one (V-27)

[0199]

[0200] Using the same synthetic method as V-01, an amide condensation reaction was carried out between intermediate 28 and m-hydroxybenzoic acid to obtain 18 mg of a white solid powder, yield: 69.8%. 1 1H NMR (300 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.43 - 7.37 (m, 2H), 7.32 - 7.20 (m, 2H), 7.18 - 7.12 (m, 1H), 6.89 - 6.71 (m, 3H), 3.99 (s, 1H), 3.64 (s, 2H), 3.50 (s, 1H), 2.88 (s, 1H), 2.73 (s, 1H), 1.87 (s, 4H).

[0201] Example 28: Synthesis of 7-(2-(3-chlorophenyl)-1-oxo-2,7-diazaspiro[3.5]nonane-7-carbonyl)quinolin-2(1H)-one (V-28)

[0202]

[0203] Using the same synthetic method as V-01, an amide condensation reaction was carried out between intermediate 28 and 1,2-dihydro-2-oxo-7-quinolinecarboxylic acid to obtain 51 mg of a white solid powder, yield: 34.7%. 1 1H NMR (300 MHz, DMSO-d6) δ 11.87 (s, 1H), 7.94 (d, J = 9.6 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.33 - 7.27 (m, 2H), 7.20 (dd, J = 8.0, 1.5 Hz, 1H), 7.18 - 7.13 (m, 1H), 6.56 (dd, J = 9.5, 1.8 Hz, 1H), 3.99 (s, 1H), 3.66 (s, 2H), 3.52 (s, 2H), 2.71 (d, J = 12.7 Hz, 1H), 1.91 (s, 4H).

[0204] Example 29: Synthesis of 7-(2-chloro-3-methoxybenzoyl)-2-(3-chlorophenyl)-2,7-diazaspiro[3.5]nonan-1-one (V-29)

[0205]

[0206] Using the same synthesis method as V-01, an amide condensation reaction was carried out between intermediate 28 and 2-chloro-3-methoxybenzoic acid to obtain 170 mg of white solid powder, yield: 97.0%. 1 H NMR(400MHz,DMSO-d6)δ7.43-7.36(m,3H),7.31-7.26(m,1H),7.21-7.13(m,2H),6.95(ddd,J=21.5,7.5,1.4Hz,1H),3.99(dq,J=12.8,6.4,6.0Hz,1H),3.88(d,J=2.0Hz,3H),3.69-3.60(m,2H),3.59-3.51(m,1H),3.31-3.26(m,1H),3.22-3.10(m,1H),1.99-1.90(m,2H),1.86-1.77(m,2H).

[0207] Example 30: Synthesis of 7-(3-hydroxybenzoyl)-2-(3-(trifluoromethyl)phenyl)-2,7-diazaspiro[3.5]nonan-1-one (V-30)

[0208] tert-Butyl 1-oxo-2-(3-(trifluoromethyl)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (29)

[0209]

[0210] Using the same synthesis method as intermediate 2, a C-N coupling reaction was carried out between tert-butyl 1-oxo-2,7-diazaspiro[3.5]nonane-7-carboxylate and 1-bromo-3-(trifluoromethyl)benzene to obtain 70 mg of white solid powder. Yield: 87.5%. 1 HNMR(300MHz,DMSO-d6)δ7.66(d,J=2.0Hz,1H),7.64-7.55(m,2H),7.48-7.42(m,1H),3.65(d,J=13.0Hz,4H),3.30-3.17(m,2H),1.87-1.73(m,4H),1.41(s,9H).

[0211] 7-(3-Hydroxybenzoyl)-2-(3-(trifluoromethyl)phenyl)-2,7-diazaspiro[3.5]nonan-1-one (V-30)

[0212]

[0213] Using the same synthesis method as V-01, an amide condensation reaction was carried out between intermediate 30 and m-hydroxybenzoic acid to obtain 120 mg of white solid powder, yield: 95.2%. 1 H NMR(300MHz,Chloroform-d)δ7.63(s,1H),7.48(d,J=8.2Hz,1H),7.41-7.32(m,2H),7.24(d,J=7.8Hz,1H),7.10(d,J=7.8Hz,1H),6.80(t,J=2.0Hz,1H),6.75(ddt,J=7.3,4.6,1.1Hz,2H),3.85(s,2H),3.63(s,1H),3.45(d,J=5.5Hz,3H),1.88(t,J=52.1Hz,4H).

[0214] Example 31: Synthesis of 7-(3-Hydroxybenzoyl)-2-(3-(trifluoromethoxy)phenyl)-2,7-diazaspiro[3.5]nonan-1-one (V-31)

[0215] tert-Butyl 1-oxo-2-(3-(trifluoromethoxy)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (31)

[0216]

[0217] Using the same synthesis method as intermediate 2, a C-N coupling reaction was carried out between tert-butyl 1-oxo-2,7-diazaspiro[3.5]nonane-7-carboxylate and 1-bromo-3-(trifluoromethoxy)benzene to obtain 230 mg of white solid powder. Yield: 92.0%. 1 H NMR(300MHz,DMSO-d6)δ7.51(t,J=8.2Hz,1H),7.37-7.27(m,2H),7.09(ddt,J=8.2,2.2,1.0Hz,1H),3.70-3.57(m,4H),3.31-3.16(m,2H),1.87-1.72(m,4H),1.41(s,9H).

[0218] 7-(3-Hydroxybenzoyl)-2-(3-(trifluoromethoxy)phenyl)-2,7-diazaspiro[3.5]nonan-1-one (V-31)

[0219]

[0220] Using the same synthesis method as V-01, an amide condensation reaction was carried out between intermediate 28 and m-hydroxybenzoic acid to obtain 110 mg of a white solid powder, with a yield of 73.4%. 1 H NMR(300MHz,DMSO-d6)δ9.70(s,1H),7.51(t,J=8.2Hz,1H),7.36(d,J=2.4Hz,1H),7.34-7.29(m,1H),7.24(t,J=7.8Hz,1H),7.09(ddt,J=8.2,2.3,1.1Hz,1H),6.81(tt,J=7.8,1.3Hz,2H),6.77-6.74(m,1H),3.93(s,1H),3.66(s,2H),3.49(s,2H),2.81(d,J=47.9Hz,1H),1.88(s,4H).

[0221] Example 32: Synthesis of 2-(3-chlorophenyl)-8-(3-ethoxypropionyl)-2,8-diazaspiro[4.5]decan-1-one (V-32)

[0222] 2-(3-chlorophenyl)-8-(3-ethoxypropionyl)-2,8-diazaspiro[4.5]decan-1-one (V-32)

[0223]

[0224] Using the same synthesis method as V-01, an amide condensation reaction was carried out with intermediate 3 and 3-ethoxypropionic acid as raw materials to obtain 121 mg of a white solid powder, with a yield of 84%. 1 H NMR(300MHz,DMSO-d6)δ7.89(t,J=2.1Hz,1H),7.59(ddd,J=8.4,2.2,1.0Hz,1H),7.41(t,J=8.2Hz,1H),7.20(ddd,J=8.0,2.1,0.9Hz,1H),4.29-4.16(m,1H),3.84(q,J=8.0Hz,3H),3.59(t,J=6.6Hz,2H),3.41(q,J=7.0Hz,2H),3.26-3.13(m,1H),2.86(ddd,J=14.1,10.6,4.0Hz,1H),2.69-2.53(m,2H),2.11(t,J=6.9Hz,2H),1.79-1.62(m,1H),1.53(td,J=11.7,6.3Hz,3H),1.09(t,J=7.0Hz,3H).

[0225] Example 33: Synthesis of 2-(3-chlorophenyl)-8-(1-oxo octyl)-2,8-diazaspiro[4.5]decan-1-one (V-33)

[0226] 2-(3-chlorophenyl)-8-(1-oxo octyl)-2,8-diazaspiro[4.5]decan-1-one (V-33)

[0227]

[0228] Using the same synthesis method as V-01, an amide condensation reaction was carried out with intermediate 3 and octanoic acid as raw materials to obtain 110 mg of white solid powder, with a yield of 72%. 1 H NMR (300 MHz, DMSO-d6) δ 7.89 (t, J = 2.1 Hz, 1H), 7.70 - 7.54 (m, 1H), 7.41 (t, J = 8.2 Hz, 1H), 7.20 (dd, J = 7.8, 2.1 Hz, 1H), 4.24 (dd, J = 10.4, 6.4 Hz, 1H), 3.83 (t, J = 6.9 Hz, 3H), 3.19 (t, J = 11.7 Hz, 1H), 2.84 (td, J = 11.8, 4.4 Hz, 1H), 2.30 (tt, J = 10.3, 5.4 Hz, 2H), 2.11 (t, J = 6.9 Hz, 2H), 1.68 (t, J = 10.4 Hz, 1H), 1.58 - 1.50 (m, 3H), 1.27 (qd, J = 7.3, 3.9 Hz, 10H), 0.90 - 0.82 (m, 3H).

[0229] Example 34: Synthesis of 1-[2-(3-chlorophenyl)-1-oxo-2,8-diazaspiro[4.5]decan-8-yl]pentane-1,4-dione (V-34)

[0230] 1-[2-(3-chlorophenyl)-1-oxo-2,8-diazaspiro[4.5]decan-8-yl]pentane-1,4-dione (V-34)

[0231]

[0232] Using the same synthesis method as V-01, an amide condensation reaction was carried out with intermediate 3 and levulinic acid as raw materials to obtain 108 mg of white solid powder, with a yield of 75%. 11H NMR (300 MHz, DMSO-d6) δ 7.89 (t, J = 2.1 Hz, 1H), 7.59 (ddd, J = 8.3, 2.2, 1.0 Hz, 1H), 7.41 (t, J = 8.2 Hz, 1H), 7.20 (ddd, J = 8.0, 2.1, 0.9 Hz, 1H), 4.25 - 4.11 (m, 1H), 3.93 - 3.75 (m, 3H), 3.29 - 3.12 (m, 1H), 2.93 - 2.79 (m, 1H), 2.67 - 2.59 (m, 2H), 2.59 - 2.52 (m, 2H), 2.11 (s, 5H), 1.71 (td, J = 12.4, 4.2 Hz, 1H), 1.62 - 1.45 (m, 3H).

[0233] Example 35: Synthesis of 2-(3-chlorophenyl)-8-[(3-hydroxycyclohexyl)carbonyl]-2,8-diazaspiro[4.5]decan-1-one (V-35)

[0234] 2-(3-chlorophenyl)-8-[(3-hydroxycyclohexyl)carbonyl]-2,8-diazaspiro[4.5]decan-1-one (V-35)

[0235]

[0236] Using the same synthesis method as V-01, an amide condensation reaction was carried out with intermediate 3 and 3-hydroxycyclohexanecarboxylic acid as raw materials to obtain 98 mg of white solid powder, with a yield of 62%. 1 1H NMR (300 MHz, DMSO-d6) δ 7.89 (t, J = 2.1 Hz, 1H), 7.59 (ddd, J = 8.3, 2.1, 1.0 Hz, 1H), 7.41 (t, J = 8.1 Hz, 1H), 7.20 (ddd, J = 8.0, 2.1, 0.9 Hz, 1H), 4.47 (s, 1H), 4.28 - 4.16 (m, 1H), 3.85 (q, J = 7.7 Hz, 3H), 3.22 (t, J = 12.3 Hz, 1H), 2.93 - 2.85 (m, 1H), 2.12 (t, J = 7.0 Hz, 2H), 1.77 - 1.31 (m, 12H).

[0237] Example 36: Synthesis of 2-(3-chlorophenyl)-8-(2-ethyl-1-oxobutyl)-2,8-diazaspiro[4.5]decan-1-one (V-36)

[0238] 2-(3-chlorophenyl)-8-(2-ethyl-1-oxobutyl)-2,8-diazaspiro[4.5]decan-1-one (V-36)

[0239]

[0240] Using the same synthetic method as V-01, an amide condensation reaction was carried out with intermediate 3 and 2-ethylbutyric acid as raw materials to obtain 130 mg of white solid powder with a yield of 89%. 1 H NMR(300MHz,DMSO-d6)δ7.90(t,J=2.1Hz,1H),7.59(ddd,J=8.4,2.2,1.0Hz,1H),7.41(t,J=8.2Hz,1H),7.20(ddd,J=8.0,2.1,0.9Hz,1H),4.33(d,J=13.4Hz,1H),4.08-3.94(m,1H),3.83(t,J=7.0Hz,2H),3.23(t,J=11.5Hz,1H),2.87(dt,J=14.1,7.4Hz,1H),2.65(td,J=8.4,4.3Hz,1H),2.13(dd,J=7.6,6.3Hz,2H),1.66(td,J=12.3,3.9Hz,1H),1.59-1.44(m,5H),1.37(td,J=12.5,5.2Hz,2H),0.80(q,J=7.2Hz,6H).

[0241] Example 37: Synthesis of 2-(3-chlorophenyl)-8-[2-(tetrahydro-1H-pyrrol-1-yl)acetyl]-2,8-diazaspiro[4.5]decan-1-one (V-37)

[0242] 2-(3-chlorophenyl)-8-[2-(tetrahydro-1H-pyrrol-1-yl)acetyl]-2,8-diazaspiro[4.5]decan-1-one (V-37)

[0243]

[0244] Using the same synthetic method as V-01, an amide condensation reaction was carried out with intermediate 3 and 2-(1-pyrrolidinyl)acetic acid as raw materials to obtain 112 mg of white solid powder with a yield of 76%. 11H NMR (300 MHz, DMSO-d6) δ 7.89 (t, J = 2.1 Hz, 1H), 7.58 (ddd, J = 8.4, 2.2, 1.0 Hz, 1H), 7.41 (t, J = 8.2 Hz, 1H), 7.20 (ddd, J = 8.0, 2.1, 0.9 Hz, 1H), 4.21 (dd, J = 13.4, 4.4 Hz, 1H), 3.93 (d, J = 13.7 Hz, 1H), 3.83 (t, J = 6.9 Hz, 2H), 3.44 (s, 2H), 3.19 (td, J = 12.7, 3.0 Hz, 1H), 2.87 (ddd, J = 13.6, 10.0, 4.4 Hz, 1H), 2.58 (d, J = 5.9 Hz, 4H), 2.12 (t, J = 6.9 Hz, 2H), 1.71 (p, J = 3.2 Hz, 5H), 1.55 (d, J = 7.4 Hz, 3H).

[0245] Example 38: Synthesis of 2-(3-chlorophenyl)-8-[3-(1,4-oxazepan-4-yl)propanoyl]-2,8-diazaspiro[4.5]decan-1-one (V-38)

[0246] 2-(3-chlorophenyl)-8-[3-(1,4-oxazepan-4-yl)propanoyl]-2,8-diazaspiro[4.5]decan-1-one (V-38)

[0247]

[0248] Using the same synthesis method as for V-01, an amide condensation reaction was carried out with intermediate 3 and 3-(4-morpholinyl)propionic acid as raw materials to obtain 83 mg of a white solid powder, with a yield of 52%. 1 1H NMR (300 MHz, Chloroform-d) δ 7.69 (t, J = 2.1 Hz, 1H), 7.53 (dd, J = 8.3, 2.2 Hz, 1H), 7.39 - 7.27 (m, 1H), 7.12 (dd, J = 8.3, 1.8 Hz, 1H), 4.27 (dt, J = 13.3, 4.9 Hz, 1H), 3.90 (d, J = 13.7 Hz, 1H), 3.79 (td, J = 6.9, 2.6 Hz, 2H), 3.71 (t, J = 4.7 Hz, 4H), 3.35 - 3.12 (m, 2H), 2.72 (t, J = 6.9 Hz, 2H), 2.56 (dt, J = 8.6, 3.0 Hz, 2H), 2.50 (q, J = 4.2 Hz, 4H), 2.21 - 2.04 (m, 2H), 1.91 - 1.80 (m, 2H), 1.55 (d, J = 11.8 Hz, 2H).

[0249] Example 39: Synthesis of 9-[(2-chloro-3-methoxyphenyl)carbonyl]-2-(3-chlorophenyl)-2,9-diazaspiro[5.5]undecan-1-one (V-39)

[0250] 2-(3-chlorophenyl)-1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylic acid 2-methylpropan-2-yl ester (34)

[0251]

[0252] Dissolve 1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylic acid 2-methylpropan-2-yl ester (200 mg, 0.74 mmol) in 6 mL of 1,4-dioxane. Successively add m-chlorobromobenzene (285 mg, 1.49 mmol), tris(dibenzylideneacetone)dipalladium (34.1 mg, 0.037 mmol), Xantphos (64.6 mg, 0.11 mmol), and cesium carbonate (485.6 mg, 1.48 mmol). Heat the reaction solution to 100 °C and reflux for 4 hours. After monitoring the reaction by TLC and completion, cool the reaction to room temperature. Distill off 1,4-dioxane under reduced pressure. The concentrated solution is redissolved in 10 mL of ethyl acetate and washed successively with water (10 ml × 2) and saturated brine (10 ml × 2), and then dried over anhydrous sodium sulfate for more than 2 hours. Filter by suction. After concentrating the filtrate under reduced pressure, perform column chromatography purification (petroleum ether:ethyl acetate = 2:1) to obtain 280 mg of the intermediate 34 as a white solid powder. The yield is 99.1%. 1 HNMR (300 MHz, DMSO-d6) δ 7.40 (t, J = 7.9 Hz, 1H), 7.35 (t, J = 2.0 Hz, 1H), 7.30 (ddd, J = 8.0, 2.1, 1.1 Hz, 1H), 7.21 (ddd, J = 7.9, 2.0, 1.1 Hz, 1H), 3.77 - 3.54 (m, 4H), 3.09 (s, 2H), 1.95 - 1.81 (m, 6H), 1.50 (dt, J = 13.6, 4.0 Hz, 2H), 1.40 (s, 9H).

[0253] 9-[(2-chloro-3-methoxyphenyl)carbonyl]-2-(3-chlorophenyl)-2,9-diazaspiro[5.5]undecan-1-one (V-39)

[0254]

[0255] Intermediate 34 (280 mg, 0.74 mmol) was dissolved in 2 mL of hydrogen chloride / dioxane solution, and the reaction was stirred at room temperature for 2 hours. After monitoring the reaction by TLC and completion of the reaction, the solvent was removed by concentration under reduced pressure to obtain a white solid powder, which was directly used for the next reaction.

[0256] 2-Chloro-3-methoxybenzoic acid (200 mg, 1.08 mmol), HATU (511 mg, 1.18 mmol) and DIPEA (289 mg, 3.24 mmol) were dissolved in dichloromethane, and then the above-mentioned white solid intermediate 34 was added. The mixture was stirred at room temperature for about 4 hours. After monitoring the reaction by TLC and completion of the reaction, the reaction solution was diluted with 10 mL of water, and the aqueous phase was extracted with dichloromethane (6 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 2), and then dried over anhydrous sodium sulfate for more than 2 hours. After filtration by suction, the filtrate was concentrated under reduced pressure and then separated and purified by column chromatography (ethyl acetate: petroleum ether = 3:1) to obtain 307 mg of a white solid powder, yield: 76.5%. 1 HNMR (300 MHz, DMSO-d6) δ 8.48 (t, J = 2.6 Hz, 2H), 7.94 (t, J = 2.2 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.17 (dd, J = 8.3, 2.2 Hz, 1H), 6.89 (d, J = 7.5 Hz, 1H), 4.05 (dd, J = 13.4, 6.1 Hz, 1H), 3.88 (s, 3H), 3.66 (s, 2H), 3.46 (d, J = 10.0 Hz, 1H), 3.27 - 3.19 (m, 1H), 3.17 - 3.05 (m, 1H), 2.00 (d, J = 9.9 Hz, 2H), 1.91 (s, 4H), 1.64 (d, J = 13.7 Hz, 1H), 1.51 (d, J = 13.5 Hz, 1H).

[0257] Example 40: Synthesis of 9-[(2-chloro-3-methoxyphenyl)carbonyl]-2-(5-chloropyridin-3-yl)-2,9-diazaspiro[5.5]undecan-1-one (V-40)

[0258] 2-(5-Chloropyridin-3-yl)-1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylic acid 2-methylpropan-2-yl ester (36)

[0259]

[0260] Dissolve 2-methylpropyl 1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (200 mg, 0.74 mmol) in 6 mL of 1,4-dioxane. Then, successively add 3-bromo-5-chloropyridine (286 mg, 1.49 mmol), tris(dibenzylideneacetone)dipalladium(0) (34.1 mg, 0.037 mmol), Xantphos (64.6 mg, 0.11 mmol), and cesium carbonate (485.6 mg, 1.48 mmol). Heat the reaction mixture to 100 °C and reflux for 4 hours. After monitoring the reaction by TLC until completion, cool the reaction to room temperature. Distill off 1,4-dioxane under reduced pressure. Redissolve the concentrated solution in 10 mL of ethyl acetate, wash it successively with water (10 mL × 2) and saturated brine (10 mL × 2), and then dry it over anhydrous sodium sulfate for more than 2 hours. Filter by suction. After concentrating the filtrate under reduced pressure, purify it by column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain 280 mg of the intermediate 36 as a white solid powder, with a yield of 98.9%. 1 H NMR (300 MHz, DMSO-d6) δ 8.48 (dd, J = 3.1, 2.2 Hz, 2H), 7.94 (t, J = 2.2 Hz, 1H), 3.66 (d, J = 4.5 Hz, 4H), 3.11 (s, 2H), 1.89 (d, J = 3.4 Hz, 6H), 1.51 (d, J = 13.7 Hz, 2H), 1.40 (s, 9H).

[0261] 9-[(2-Chloro-3-methoxyphenyl)carbonyl]-2-(5-chloropyridin-3-yl)-2,9-diazaspiro[5.5]undecan-1-one (V-40)

[0262]

[0263] Dissolve the intermediate 36 (280 mg, 0.74 mmol) in 2 mL of hydrogen chloride / dioxane solution, and stir the reaction at room temperature for 2 hours. After monitoring the reaction by TLC until completion, concentrate the solvent under reduced pressure to obtain a white solid powder, which is directly used in the next step of the reaction.

[0264] Dissolve 2-chloro-3-methoxybenzoic acid (160 mg, 0.85 mmol), HATU (407 mg, 0.93 mmol) and DIPEA (289 mg, 2.55 mmol) in dichloromethane, then add the above-mentioned white solid intermediate 37. Stir at room temperature for about 4 hours. After monitoring the reaction by TLC and completion of the reaction, dilute the reaction solution with 10 mL of water, extract the aqueous phase with dichloromethane (10 mL × 3), combine the organic phases, wash with saturated brine (10 mL × 2), and then dry over anhydrous sodium sulfate for more than 2 hours. Filter by suction, concentrate the filtrate under reduced pressure, and then perform column chromatography separation and purification (ethyl acetate: petroleum ether = 3:1) to obtain 307 mg of white solid powder, yield: 76.5%. 1 1H NMR (300 MHz, DMSO-d6) δ 8.48 (t, J = 2.6 Hz, 2H), 7.94 (t, J = 2.2 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.17 (dd, J = 8.3, 2.2 Hz, 1H), 6.89 (d, J = 7.5 Hz, 1H), 4.05 (dd, J = 13.4, 6.1 Hz, 1H), 3.88 (s, 3H), 3.66 (s, 2H), 3.46 (d, J = 10.0 Hz, 1H), 3.27 - 3.19 (m, 1H), 3.17 - 3.05 (m, 1H), 2.00 (d, J = 9.9 Hz, 2H), 1.91 (s, 4H), 1.64 (d, J = 13.7 Hz, 1H), 1.51 (d, J = 13.5 Hz, 1H).

[0265] Example 41: Synthesis of 2-butyl-8-[(2-chloro-3-methoxyphenyl)carbonyl]-2,8-diazaspiro[4.5]decan-1-one (V-41)

[0266] 2-butyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylic acid 2-methylpropan-2-yl ester (38)

[0267]

[0268] Dissolve tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.78 mmol) in 6 mL of anhydrous N,N-dimethylformamide. Successively add 1-bromobutane (129.3 mg, 0.94 mmol) and sodium hydroxide (78.63 mg, 1.97 mmol). Heat the reaction solution to 70 °C and then reflux for 4 hours. After monitoring the reaction by TLC until completion, cool the reaction to room temperature. Dilute with 20 mL of ethyl acetate, wash successively with water (10 ml × 2) and saturated brine (10 ml × 2), and then dry with anhydrous sodium sulfate for more than 2 hours. Filter by suction, concentrate the filtrate under reduced pressure, and then purify by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 234 mg of the intermediate 38 as a white oil, with a yield of 95.8%. 1 H NMR(300MHz,DMSO-d6)δ3.81(d,J=13.1Hz,2H),3.26(t,J=6.9Hz,2H),3.16(t,J=7.1Hz,2H),2.89(s,2H),1.90(t,J=6.9Hz,2H),1.61-1.41(m,4H),1.39(s,9H),1.37-1.20(m,4H),0.87(t,J=7.3Hz,3H).

[0269] 2-Butyl-8-[(2-chloro-3-methoxyphenyl)carbonyl]-2,8-diazaspiro[4.5]dec-1-one (V-41)

[0270]

[0271] Dissolve the intermediate 38 (234 mg, 0.75 mmol) in 2 mL of hydrogen chloride / dioxane solution, and stir the reaction at room temperature for 2 hours. After monitoring the reaction by TLC until completion, concentrate the solvent under reduced pressure to obtain a white solid powder, which is directly used for the next step of the reaction.

[0272] Dissolve 2-chloro-3-methoxybenzoic acid (116 mg, 0.62 mmol), TCFH (209 mg, 0.74 mmol) and NMI (280 mg, 3.42 mmol) in acetonitrile, and then add the above white solid intermediate 37. Stir at room temperature for about 4 hours. After monitoring the reaction by TLC until completion, distill off the acetonitrile under reduced pressure. Re-dissolve the concentrated solution in 10 mL of ethyl acetate, dilute the reaction solution with 10 mL of water, extract the aqueous phase with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated brine (10 mL × 2), and then dry with anhydrous sodium sulfate for more than 2 hours. Filter by suction, concentrate the filtrate under reduced pressure, and then separate and purify by column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain 120 mg of a white solid powder, with a yield of 50.9%.

[0273] 1 1H NMR (300 MHz, DMSO-d6) δ 7.38 (td, J = 7.9, 4.2 Hz, 1H), 7.17 (ddd, J = 8.4, 3.4, 1.4 Hz, 1H), 6.89 (ddd, J = 16.3, 7.5, 1.3 Hz, 1H), 4.30 (d, J = 13.3 Hz, 1H), 3.88 (d, J = 1.7 Hz, 3H), 3.31 - 3.20 (m, 3H), 3.20 - 2.97 (m, 4H), 2.04 - 1.84 (m, 2H), 1.71 - 1.49 (m, 2H), 1.42 (ddd, J = 14.9, 11.8, 5.7 Hz, 3H), 1.34 - 1.12 (m, 3H), 0.86 (t, J = 7.3 Hz, 3H).

[0274] Example 42: Synthesis of 8-[(2-chloro-3-methoxyphenyl)carbonyl]-2-(cyclohexylmethyl)-2,8-diazaspiro[4.5]decan-1-one (V-42)

[0275] Synthesis of 8-[(2-chloro-3-methoxyphenyl)carbonyl]-2-(cyclohexylmethyl)-2,8-diazaspiro[4.5]decan-1-one (V-42)

[0276] 2-(Cyclohexylmethyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylic acid 2-methylpropan-2-yl ester (40)

[0277]

[0278] Dissolve tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (200 mg, 0.78 mmol) in 6 mL of anhydrous N,N-dimethylformamide, and successively add (bromomethyl)cyclohexane (167 mg, 0.94 mmol) and sodium hydroxide (78.63 mg, 1.97 mmol). Heat the reaction solution to 70 °C and reflux for 4 hours. After monitoring the reaction by TLC until completion, cool the reaction to room temperature. Dilute with 20 mL of ethyl acetate, wash successively with water (10 ml × 2) and saturated brine (10 ml × 2), and then dry over anhydrous sodium sulfate for more than 2 hours. Filter by suction, concentrate the filtrate under reduced pressure, and purify by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 230 mg of the intermediate 38 as a white oil, with a yield of 83.4%. 11H NMR (300 MHz, DMSO-d6) δ 3.81 (d, J = 13.3 Hz, 2H), 3.26 (t, J = 6.9 Hz, 2H), 2.99 (d, J = 7.0 Hz, 2H), 2.89 (s, 2H), 1.93 (dt, J = 10.9, 6.9 Hz, 2H), 1.73 - 1.42 (m, 7H), 1.39 (s, 9H), 1.30 (d, J = 13.3 Hz, 3H), 1.15 (t, J = 9.7 Hz, 2H), 0.85 (t, J = 11.7 Hz, 2H).

[0279] 8-[(2-Chloro-3-methoxyphenyl)carbonyl]-2-(cyclohexylmethyl)-2,8-diazaspiro[4.5]decan-1-one (V-42)

[0280]

[0281] Dissolve intermediate 40 (230 mg, 0.65 mmol) in 2 mL of hydrogen chloride / dioxane solution, and stir the reaction at room temperature for 2 hours. After monitoring the reaction by TLC and completion, concentrate the solvent under reduced pressure to obtain a white solid powder, which is directly used for the next step of the reaction.

[0282] Dissolve 2-chloro-3-methoxybenzoic acid (99.74 mg, 0.69 mmol), TCFH (179.98 mg, 0.64 mmol) and NMI (241.4 mg, 2.94 mmol) in acetonitrile, then add the above-mentioned white solid intermediate 41, and stir at room temperature for about 4 hours. After monitoring the reaction by TLC and completion, distill off the acetonitrile under reduced pressure. The concentrated solution is redissolved in 10 mL of ethyl acetate, the reaction solution is diluted with 10 mL of water, the aqueous phase is extracted with ethyl acetate (10 mL × 3), the combined organic phases are washed with saturated brine (10 mL × 2), and then dried over anhydrous sodium sulfate for more than 2 hours. Filter by suction, concentrate the filtrate under reduced pressure, and perform column chromatography purification (petroleum ether:ethyl acetate = 4:1) to obtain 115 mg of a white solid powder, yield: 51.3%. 11H NMR (300 MHz, DMSO-d6) δ 7.37 (td, J = 8.0, 4.1 Hz, 1H), 7.17 (ddd, J = 8.4, 3.3, 1.4 Hz, 1H), 6.89 (ddd, J = 16.9, 7.6, 1.4 Hz, 1H), 4.38 - 4.22 (m, 1H), 3.88 (d, J = 1.6 Hz, 3H), 3.25 (dd, J = 9.9, 4.3 Hz, 3H), 3.16 - 3.03 (m, 2H), 3.02 - 2.95 (m, 2H), 2.03 - 1.85 (m, 2H), 1.78 - 1.38 (m, 9H), 1.35 - 1.20 (m, 2H), 1.13 (d, J = 8.6 Hz, 2H), 0.83 (d, J = 11.6 Hz, 2H).

[0283] Other compounds were prepared according to a similar method.

[0284] Biological activity test of compounds

[0285] Example 43: Determination of MAGL inhibitory activity

[0286] 1. Experimental method

[0287] MAGL can hydrolyze 2-AG in cells to generate arachidonic acid and glycerol. For a certain amount of reaction substrate, different enzyme activities catalyze the generation of different amounts of products. The level of enzyme activity can be investigated by detecting the amount of products. Using Cayman's MAGL inhibitor screening kit, according to its instructions, dilute MAGL at a certain concentration, add Buffer buffer, and then add compounds at various concentrations. At the same time, set up a blank control group, an initial enzyme activity group, and a JZL-195 positive control group. After incubating for 5 minutes, add the substrate 4-nitrophenyl acetate (4-NPA) to initiate the reaction. After incubating for another 10 minutes, measure the change in absorbance before and after hydrolysis by an enzyme-labeling instrument to indirectly measure the activity of the MAGL enzyme. Finally, calculate the inhibition rate of the compound. The IC 50 value can be calculated by non-linear fitting using Graphpad prism 5.0 software based on the inhibition rates at different concentrations to obtain the IC 50 value.

[0288] 2. Experimental results

[0289] The specific results are shown in Tables 1 - 2.

[0290] Table 1. Results of MAGL inhibition rate (%)

[0291]

[0292] Table 2. Results of MAGL inhibition IC 50 results

[0293]

[0294]

[0295] As shown in Table 1 and Table 2, the compounds obtained in the present invention have good inhibitory activity against MAGL.

[0296] Example 44: Selectivity test of compounds

[0297] FAAH is the main degrading enzyme of another endogenous ligand AEA in the endogenous cannabinoid system. To avoid cross-reactivity, the inhibitory activity of V-07, V-15, and V-17 against the FAAH enzyme was tested at a concentration of 100 μM to further verify the selectivity of these compounds. The in vitro enzyme inhibitory activity screening of these three compounds against FAAH all used a kit from Cayman Chemical Company, USA (Fatty Acid Amide Hydrolase Inhibitor screening assay kit, Cayman, USA).

[0298] Experimental principle: FAAH hydrolyzes the substrate AMC arachidonoyl amide to obtain the fluorescent product 7-amino-4-methylcoumarin. The excitation wavelength of the product is 340 - 360 nm, and the emission wavelength is 450 - 465 nm. The average fluorescence intensity was measured using a microplate reader to indirectly measure the activity of the FAAH enzyme, and thus the inhibitory activity of the compound was calculated.

[0299] Experimental results:

[0300] Table 3 Inhibitory activity of V-07, V-15, and V-17 against FAAH, n = 3

[0301]

[0302] As shown in Table 3, the inhibition rates of the three compounds against FAAH at this concentration were all lower than 50%, showing good selectivity. The selectivity of V-17, which has the best inhibitory activity against MAGL, compared to FAAH is approximately 1470 times. The results prove that the spiro skeleton compounds of the present invention are MAGL inhibitors with good selectivity.

Claims

1. A spirocyclic compound having a structure represented by Formula I or a pharmaceutically acceptable salt thereof: in: R 1 Selected from 1) or 2): 1) unsubstituted or replaced by R 1A Substituted groups: aryl, heterocyclic, cycloalkyl, alkyl; 2) R a -(CH2) m -XR b -, where R a is unsubstituted or replaced by R 1B Substituted groups: aryl, alkyl; R b is unsubstituted or replaced by R 1C Substituted groups: aryl, heteroaryl, alkylene; m is 0 or 1, X is -NR c -, -C(O)-, O or S; R c is H, methyl, ethyl, n-propyl or isopropyl; preferably, R c is H or methyl; R 2 is unsubstituted or replaced by R 2A Substituted: alkyl, cycloalkyl, heterocyclyl, alkenyl, cycloalkenyl, aryl, heteroaryl; R 1A 、R 1B 、R 1C and R 2A are independently H, -OH, -SH, -CN, -NH2, halogen, nitro, carboxyl, C 1-8 Alkyl, C 1-8 Cycloalkyl, C 1-8 Alkoxy, C 2-8 Alkenyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy or C substituted by cyano 1-6 Alkoxy, either O or S with R 1 or R 2 The C in the group forms a carbonyl or thiol group; n is an integer from 0 to 5, preferably 0, 1, 2 or 3; more preferably 0, 1 or 2; A is -(CH2) P -, p is 1, 2 or 3.

2. The spirocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein When R 1 When 1), wherein the aryl group is a 6-12 membered aryl group; preferably, the aryl group is a phenyl group or a naphthyl group; and / or, the heterocyclic group is a 5-12 membered heterocyclic group having 1-4 groups selected from N, O or S; preferably, the heterocyclic group is a 5-12 membered heterocyclic group having 1-3 groups selected from N, O or S; more preferably, the heterocyclic group is a 5-10 membered heterocyclic group having 1-3 groups selected from N, O or S; further preferably, the heterocyclic group is a 5-10 membered heterocyclic group having 1 or 2 groups selected from N, O or S; further preferably Preferably, the heterocyclic group is furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, naphthyl, indolyl, quinolyl, isoquinolyl, indazolyl, benzoxazolyl, benzothiazolyl, benzoquinolinone, thienopyridine, cyclopentane, cyclohexane, piperidine ring, morpholine ring, piperazine ring, tetrahydrofuran, tetrahydropyran; and / or, the cycloalkyl group is a 3-10 membered cycloalkyl group, preferably cyclopropane, butane, cyclopentane, cyclohexane; and / or, the alkyl group is C 1-10 Alkyl, preferably C 1-6 alkyl; When R 1 2), wherein the aryl group is a 6-12 membered aryl group; preferably, the aryl group is a phenyl group; and / or, the heteroaryl group is a 5-12 membered heteroaryl group having 1-4 groups selected from N, O or S; preferably, the heteroaryl group is a 5-12 membered heteroaryl group having 1-3 groups selected from N, O or S; more preferably, the heteroaryl group is a 5-10 membered heteroaryl group having 1-3 groups selected from N, O or S; further preferably, the heteroaryl group is a 1 or 2 group selected from N, O or S. 5-10 membered heteroaryl; further preferably, the heteroaryl is a 5-6 membered heteroaryl having 1 or 2 selected from N, O or S; further preferably, the heteroaryl is furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, naphthyl, indolyl, quinolyl, isoquinolyl, indazolyl, benzoxazolyl, benzothiazolyl, benzoquinolinonyl, thienopyridine; and / or, the alkyl is C 1-10 Alkyl, preferably C 1-6 Alkyl, more preferably C 1-4 Alkyl; and / or, the alkylene is C 1-10 Alkylene, preferably C 1-6 Alkylene, more preferably C 1-4 Alkylene.

3. The spirocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 1A 、R 1B 、R 1C Independently H, -OH, -SH, -CN, -NH2, halogen, nitro, carboxyl, C 1-4 Alkyl, C 1-6 Cycloalkyl, C 1-4 Alkoxy, substituted by 1-3 halogens C 1-6 Halogenated alkyl, C 1-4 Haloalkoxy or C substituted by cyano 1-4 Alkoxy, either O or S with R 1 or R 2 C in forms a carbonyl or thiol group; preferably, R 1A 、R 1B 、R 1C are independently H, -OH, -SH, -CN, -NH2, halogen, nitro, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropane, cyclohexane, cyclobutane, cyclopentane, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, trifluoromethyl, or O or S and R 1 or R 2 The C in the group forms a carbonyl or thiol group.

4. The spirocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 2 wherein the aryl group is a 6-12 membered aryl group; preferably, the aryl group is a phenyl group; and / or, R 2 wherein the heterocyclic group is a 5-12 membered heterocyclic group having 1-4 groups selected from N, O or S; preferably, the heterocyclic group is a 5-12 membered heterocyclic group having 1-3 groups selected from N, O or S; more preferably, the heterocyclic group is a 5-10 membered heterocyclic group having 1-3 groups selected from N, O or S; further preferably, the heterocyclic group is a 5-10 membered heterocyclic group having 1 or 2 groups selected from N, O or S; further preferably, the heterocyclic group is a "5-10 membered heterocyclic group having 1 or 2 groups selected from N, O or S" 5-6 membered heterocyclic group; further preferably, the heterocyclic group is furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, naphthyl, indolyl, quinolyl, isoquinolyl, indazolyl, benzoxazolyl, benzothiazolyl, benzoquinolinone, thienopyridine, cyclopentane, cyclohexane, piperidine ring, morpholine ring, piperazine ring, tetrahydrofuran, tetrahydropyran, 1,3-oxypentacyclic ring; and / or, R 2 In which the alkyl group is C 1-10 Alkyl, preferably C 1-6 Alkyl, more preferably C 1-4 Alkyl; and / or, the alkenyl is C 2-10 Alkenyl, preferably C 2-6 Alkenyl, more preferably C 2-4 alkenyl; And / or, the cycloalkenyl group is cyclopropene, cyclobutene, cyclopentene or cyclohexene.

5. The spirocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R 2A H, -OH, -SH, -CN, -NH2, halogen, nitro, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, substituted by 1-3 halogens C 1-6 Halogenated alkyl, C 1-4 Haloalkoxy or C substituted by cyano 1-4 Alkoxy; further preferably, R 2A It is H, -OH, -SH, -CN, -NH2, halogen, nitro, carboxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, trifluoromethyl, trifluoromethoxy.

6. A spirocyclic compound represented by the following formula II, III or IV, or a pharmaceutically acceptable salt thereof: in, n, R1 and R2 are as described in claim 1.

7. A spirocyclic compound represented by the following structure or a pharmaceutically acceptable salt thereof:

8. The method for preparing the spirocyclic compound according to claim 6: The compound of formula (II) can be prepared by the following steps: The compound of formula (III) can be prepared by the following steps: The compound of formula (IV) can be prepared by the following steps:

9. A pharmaceutical composition comprising the spirocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, and a pharmaceutically acceptable carrier.

10. Use of the spirocyclic compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or the pharmaceutical composition according to claim 9, in the preparation of a monoacylglycerol esterase inhibitor; preferably, use of the spirocyclic compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or the pharmaceutical composition according to claim 9, in the preparation of a medicament for preventing and / or treating a MAGL-related disease; preferably, the MAGL-related disease is a central nervous system disease, pain, metabolic disorder or inflammatory disease; more preferably, the MAGL-related disease includes depression, schizophrenia, bipolar disorder, movement disorder, traumatic brain injury, neuroinflammation, Parkinson's disease, Alzheimer's disease, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, Tourette's syndrome, anxiety, neuralgia, inflammatory pain, cancer pain, cancer, vomiting, nausea, eating disorders, metabolic disorders, alcoholic fatty liver disease, non-alcoholic fatty liver disease, liver fibrosis, cholestasis, inflammatory bowel disease, sepsis or kidney disease.

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