Piperazine amide skeleton compound and application thereof

Abstract

The invention discloses a piperazine amide skeleton compound and application thereof, the piperazine amide skeleton compound has a structure as shown in a formula (I), and the piperazine amide skeleton compound can be used for preparing an MAGL inhibitor and a medicine for preventing and / or treating MAGL-related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and particularly to a piperazine amide skeleton compound and its application. Background Art

[0002] The endogenous cannabinoid 2-AG is a full agonist of CB1 and CB2 receptors and is synthesized "on demand" by a Ca 2+ -dependent mechanism: Ca 2+ influx activates phospholipase C (PLC), which hydrolyzes phosphatidylinositol (PI) to diacylglycerol (DAG), and then 2-AG is generated from DAG by diacylglycerol lipase (DAGL). When 2-AG activates the CB receptor on the target cell, it is absorbed and degraded, thus terminating the signal transduction pathway. Monoacylglycerol lipase (MAGL) is responsible for 85% of 2-AG hydrolysis, generating arachidonic acid (AA) and glycerol, and the downstream AA is metabolized by downstream hydrolases to generate inflammatory mediators such as prostaglandins.

[0003] MAGL is responsible for hydrolyzing 2-AG to generate AA and glycerol and is involved in the signal transduction of the endogenous cannabinoid system. MAGL is highly expressed in the brain, adipose tissue, liver, and intestine. In the brain, MAGL is expressed in the hippocampus, amygdala, and cerebellum. The endogenous cannabinoid signal plays an important role in these tissue sites.

[0004] Therefore, inhibiting MAGL is promising as a target for central nervous system diseases, pain, or liver diseases. Summary of the Invention

[0005] The object of the present invention is to provide a compound having MAGL inhibitory activity.

[0006] The compound having MAGL inhibitory activity provided by the present invention has the structure shown in formula (I):

[0007]

[0008] Wherein, R 1 is independently selected from the following groups which are unsubstituted or substituted by one or more R 1A : aryl, heterocyclic group, heterocyclic ketone group, arylalkyl,

[0009] R 2 are each independently selected from the following groups which are unsubstituted or substituted by one or more R 2A : aryl, heterocyclic group, heterocyclic ketone group, arylalkyl,

[0010] X is a covalent bond, O, S, or -NH-;

[0011] Ra 、R b 、R c 、R d are each independently selected from the following groups which may be substituted or unsubstituted: aryl, heterocyclic group;

[0012] The substituents are one or more, and each substituent is independently -OH, -SH, -CN, halogen, nitro, carboxyl, C 1-8 alkyl, C 1-8 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy.

[0013] In some embodiments, among R 1 、R 2 、R a 、R b 、R c 、R d the aryl groups are each independently C 6 -C 10 aryl groups, specifically each independently such as phenyl, naphthyl.

[0014] In some embodiments, among R 1 、R 2 、R a 、R b 、R c 、R d the heterocyclic groups are 5- to 10-membered heterocyclic groups having 1 to 4 heteroatoms selected from N, O or S; more specifically, 5- to 10-membered heterocyclic groups having 1 to 3 heteroatoms selected from N, O or S; further, 5- to 10-membered heterocyclic groups having 1, 2 or 3 heteroatoms selected from N or O; in some specific examples, the heterocyclic groups are selected from pyrrolidinyl, piperidinyl, pyranyl, morpholinyl, piperazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, indazolyl, benzoxazolyl, benzothiazolyl, purinyl, oxazopyridinyl, 1,2-methylenedioxyphenyl.

[0015] In some embodiments, R 1 、R 2Among them, the heterocyclic ketone group is a 5- to 10-membered heterocyclic ketone group having 1 to 4 heteroatoms selected from N, O, or S; more specifically, a 5- to 10-membered heterocyclic ketone group having 1 to 3 heteroatoms selected from N, O, or S; further, a 5- to 10-membered heterocyclic ketone group having 1, 2, or 3 heteroatoms selected from N or O; in some specific examples, the heterocyclic ketone group is selected from the following groups in which one C is a ketone group: pyrrolidinyl, piperidinyl, pyranyl, morpholinyl, piperazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, coumarinyl, indolyl, quinolinyl, isoquinolinyl, indazolyl, benzoxazolyl, benzothiazolyl, purinyl, oxazolo-pyridyl.

[0016] In some embodiments, R 1 and R 2 wherein the arylalkyl is C 6 -C 10 aryl C 1 -C 3 alkyl; specifically, benzyl, phenethyl.

[0017] In some embodiments, R 1 is selected from the following groups which are unsubstituted or substituted by one or more R 1A : phenyl, pyrrolidinyl, piperidinyl, pyranyl, morpholinyl, piperazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, coumarinyl, indolyl, quinolinyl, isoquinolinyl, indazolyl, benzoxazolyl, benzothiazolyl, purinyl, oxazolo-pyridyl, 1,2-methylenedioxyphenyl, benzyl, phenethyl;

[0018] In some embodiments, R a is selected from phenyl, pyridyl, pyrrolidinyl, piperidinyl, pyranyl, morpholinyl, piperazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyrimidinyl, pyridazinyl, coumarinyl, indolyl, quinolinyl, isoquinolinyl, indazolyl, benzoxazolyl, benzothiazolyl, purinyl, oxazolo-pyridyl.

[0019] In some embodiments, R bSelected from phenyl, pyrrolidinyl, piperidinyl, pyranyl, morpholinyl, piperazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, indazolyl, benzoxazolyl, benzothiazolyl, purinyl, oxazolo-pyridyl, 1,2-methylenedioxyphenyl.

[0020] In some embodiments, Selected from:

[0021] In some embodiments, R 2 Selected from the following groups which are unsubstituted or substituted by one or more R 2A substituents: indolyl, phenyl, pyrrolidinyl, piperidinyl, pyranyl, morpholinyl, piperazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, benzofuranyl, quinolinyl, isoquinolinyl, indazolyl, benzoxazolyl, benzothiazolyl, purinyl, oxazolo-pyridyl, 1,2-methylenedioxyphenyl, benzyl, phenethyl;

[0022] In some embodiments, X is O or S; more specifically, O.

[0023] In some embodiments, R c Selected from phenyl, pyridyl, pyrrolidinyl, piperidinyl, pyranyl, morpholinyl, piperazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyrimidinyl, pyridazinyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, indazolyl, benzoxazolyl, benzothiazolyl, purinyl, oxazolo-pyridyl; more specifically, R c Selected from phenyl.

[0024] In some embodiments, R dSelected from phenyl, pyrrolidinyl, piperidinyl, pyranyl, morpholinyl, piperazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, indazolyl, benzoxazolyl, benzothiazolyl, purinyl, oxazolo-pyridyl; more specifically, R d is selected from phenyl.

[0025] In some embodiments, R 1A is one or more, for example, the number is 1, 2, 3 or 4, more specifically 1 or 2. In some instances, R 1A are each independently selected from -OH, -SH, -CN, cyano, halogen, nitro, carboxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, -CF 3 , CHF 2 or CH 2 F.

[0026] In some embodiments, R 2A is one or more, for example, the number is 1, 2, 3 or 4, more specifically 1 or 2. In some instances, R 2A are each independently selected from -OH, -SH, -CN, cyano, halogen, nitro, carboxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, -CF 3 , CHF 2 or CH 2 F.

[0027] In some embodiments, the compound with MAGL inhibitory activity provided by the present invention has the structure shown in formula (I-a):

[0028] Wherein: represents a single bond or a double bond, and R 2 is as described above.

[0029] In some embodiments, the compound with MAGL inhibitory activity provided by the present invention has the structure shown in formula (I-b):

[0030] Wherein: L is -CH 2 - or -CH=CH-, and R 1 is as described above.

[0031] In some embodiments, the compound with MAGL inhibitory activity provided by the present invention has the structure shown in formula (I-c):

[0032] Wherein: R 2 As described above.

[0033] The present disclosure further provides an isotopically substituted compound of the above compound or a pharmaceutically acceptable salt thereof. In some embodiments, the isotopically substituted compound is a deuterated compound.

[0034] In some specific examples, the present invention provides specific compounds having MAGL inhibitory activity, with the structure as follows:

[0035]

[0036] The present disclosure provides a method for preparing a compound represented by formula (I), that is, 1-substituted piperazine and a substituted carboxylic acid undergo a condensation reaction to prepare the compound of formula (I), and the general formula is as follows:

[0037]

[0038] Wherein R 1 , R 2 As described above.

[0039] Wherein, the compound of formula (I-a) can be prepared according to the following method, starting from compound 2, that is, the commercially available raw material 2 undergoes a coupling reaction, and then a deprotection reaction to prepare compound 4. Then, in the presence of a condensing agent and a base, compound 4 undergoes a condensation reaction to prepare the compound of (I-a), and the general formula is as follows:

[0040]

[0041] Wherein, represents a single bond or a double bond, R 2 As described above.

[0042] The compound of formula (I-b) can be prepared according to the following method: subjecting compound 5 and compound 6 to a nucleophilic substitution reaction or a coupling reaction, and then performing deprotection to prepare compound 8, and then compound 8 undergoes a condensation reaction to obtain the compound of (I-b), and the general formula is as follows:

[0043]

[0044] Wherein: L is -CH 2 - or -CH=CH-, R 1 As described above.

[0045] The compound of formula (I-b) can also be prepared as follows: Using commercially available 4-Boc-1-(5-bromo-2-pyridyl)piperazine or 4-Boc-1-(4-bromo-2-pyridyl)piperazine as starting materials, compound 10 is obtained by performing a Suzuki coupling reaction with a substituted phenylboronic acid, followed by deprotection to prepare compound 11. Then, compound 11 undergoes a condensation reaction to prepare the compound of formula (I-b), and the general formula is as follows:

[0046]

[0047] Wherein: L is -CH 2 - or -CH=CH-, R 1 As described above.

[0048] The compound of formula (I-c) can be prepared by performing a condensation reaction on commercially available starting materials.

[0049]

[0050] Wherein: R 2 As described above.

[0051] The present disclosure also provides a pharmaceutical composition, which comprises the compound of formula (I) as shown above or a pharmaceutically acceptable salt thereof or the above-mentioned isotope-substituted compound, and a pharmaceutically acceptable excipient.

[0052] In some embodiments, the compound of formula (I) as shown above or a pharmaceutically acceptable salt thereof or the above-mentioned isotope-substituted compound is in a therapeutically effective amount.

[0053] In some embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01-99.99% of the above-mentioned compound or a pharmaceutically acceptable salt thereof or the above-mentioned isotope-substituted compound. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the above-mentioned compound or a pharmaceutically acceptable salt thereof or the above-mentioned isotope-substituted compound. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the above-mentioned compound or a pharmaceutically acceptable salt thereof or the above-mentioned isotope-substituted compound. In some embodiments, the pharmaceutical composition contains 1%-99% of the above-mentioned compound or a pharmaceutically acceptable salt thereof or the above-mentioned isotope-substituted compound. In some embodiments, the pharmaceutical composition contains 2%-98% of the above-mentioned compound or a pharmaceutically acceptable salt thereof or the above-mentioned isotope-substituted compound.

[0054] In some embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01% - 99.99% of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains 0.1% - 99.9% of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains 0.5% - 99.5% of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains 1% - 99% of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains 2% - 98% of a pharmaceutically acceptable excipient.

[0055] The present disclosure also provides the use of the compound represented by formula (I) as described above, or a pharmaceutically acceptable salt thereof, the above isotope substitute, or the above pharmaceutical composition in the preparation of a MAGL inhibitor.

[0056] The present disclosure also provides the use of the compound represented by formula (I) as described above, or a pharmaceutically acceptable salt thereof, the above isotope substitute, or the above pharmaceutical composition in the preparation of a drug for preventing and / or treating MAGL-related diseases.

[0057] In some embodiments, the MAGL-related diseases are central nervous system diseases, metabolic disorders, and inflammatory diseases; in some examples, the MAGL-related diseases are depression, anxiety, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, neuropathic pain, inflammatory pain, cancer pain, epilepsy, cancer, fatty liver, non-alcoholic steatohepatitis, liver fibrosis, cholestasis, or inflammatory bowel disease.

[0058] Term Definitions

[0059] On the other hand, in the case where the specific configuration is not defined in the present disclosure, the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereoisomer-enriched mixtures, all of which mixtures are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are included within the scope of the present disclosure.

[0060] In addition, the compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structurally isomeric forms of different energies that can interconvert via a low energy barrier.

[0061] The compounds of the present disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise specified, all stereoisomers are included, such as enantiomers and diastereomers. Compounds of the present disclosure containing asymmetric carbon atoms may be isolated in optically pure form or in racemic form. The optically pure form may be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

[0062] The present disclosure also includes isotopically labeled compounds of the present disclosure that are the same as those described herein, but in which one or more atoms are replaced with atoms having an atomic weight or mass number different from the atomic weight or mass number commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0063] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position is understood to have a deuterium abundance greater than the natural abundance of deuterium (which is 0.015%) by at least 1000-fold (i.e., at least 10% deuterium incorporation). The deuterium in the compounds of the examples may have an abundance greater than the natural abundance of deuterium by at least 1000-fold, at least 2000-fold, at least 3000-fold, at least 4000-fold, at least 5000-fold, at least 6000-fold, or higher. The present disclosure also includes various deuterated forms of the compound of formula I. Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize deuterated forms of the compound of formula I. Commercially available deuterated starting materials may be used in the preparation of deuterated forms of the compound of formula I, or they may be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated borane, tetrahydrofuran solution of tri-deuterated borane, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane, etc.

[0064] The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 30 carbon atoms, preferably an alkyl group containing from 1 to 12 carbon atoms, more preferably from 1 to 10 carbon atoms, more preferably from 1 to 6 carbon atoms, and still more preferably from 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, etc. More preferably, it is an alkyl group containing from 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc.

[0065] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as above. Non-limiting examples of alkoxy include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

[0066] The term "aryl" refers to a 6- to 14-membered monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) all-carbon group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl.

[0067] The term "heterocyclic group" refers to a 3- to 12-membered aromatic or non-aromatic heterocycle containing 1 to 4 heteroatoms selected from O, N, S, etc., a saturated or unsaturated heterocycle, and includes bicyclic groups. It includes, but is not limited to, pyrrolidinyl, piperidinyl, pyranyl, morpholinyl, piperazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, indanyl, indolyl, quinolinyl, isoquinolinyl, indazolyl, benzoxazolyl, benzothiazolyl, purinyl, oxazolo-pyridyl, 1,2-methylenedioxyphenyl. The connection of the heterocyclic substituent can be achieved through a carbon atom or through a heteroatom. The heterocyclic group also includes a group formed by condensing an aryl ring with a heteroaryl, heterocycloalkyl or cycloalkyl ring.

[0068] The term "heterocyclic ketone group" refers to the aforementioned "heterocyclic group" in which one C is a ketone group.

[0069] The term "arylalkyl" refers to a group in which an aryl is linked to an alkyl, and the alkyl is the one connected to the parent structure.

[0070] The term "hydroxyl" refers to -OH.

[0071] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0072] The term "haloalkyl" refers to an alkyl substituted by a halogen, where the alkyl is as defined above.

[0073] The term "haloalkoxy" refers to an alkoxy substituted by a halogen, where the alkoxy is as defined above.

[0074] The term "cyano" refers to -CN.

[0075] The term "nitro" refers to -NO 2 。

[0076] The term "amino" refers to -NH 2 。

[0077] The term "carboxyl" refers to -C(O)OH.

[0078] The term "substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently replaced by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine the possible or impossible substitutions (by experiment or theory) without much effort.

[0079] "Substituted by one or more..." means that it can be substituted by a single or multiple substituents. When substituted by multiple substituents, they can be multiple identical substituents or a combination of one or multiple different substituents.

[0080] The term "each independently selected from" means that they can be the same as or different from each other and are selected from the listed groups.

[0081] In the chemical structure of the compounds described in the present disclosure, the bond represents an unspecified configuration, that is, if there are chiral isomers in the chemical structure, the bond can be or simultaneously include both configurations. Although all the above structural formulas are drawn in certain isomeric forms for simplicity, the present disclosure can include all isomers, such as tautomers, rotamers, geometric isomers, diastereomers, racemates, and enantiomers. In the chemical structure of the compounds described in the present disclosure, the bond does not specify the configuration, that is, the configuration of the bond can be E-type or Z-type, or simultaneously include both E and Z configurations.

[0082] In the present disclosure, the terms "comprising" and "including" can be replaced by "consisting of".

[0083] The term "composition" means a mixture of a drug containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or precursors and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of the composition is to facilitate the administration to an organism, facilitate the absorption of the active ingredient and thus exert its biological activity.

[0084] The term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifying agent that has been approved by the US Food and Drug Administration for use in humans or domestic animals.

[0085] Unless otherwise specified, the "compounds" of the present disclosure can independently exist in the form of salts, mixed salts, or non-salts (such as free acids or free bases). When in the form of salts or mixed salts, they can be pharmaceutically acceptable salts or pharmaceutically acceptable salts.

[0086] The terms "pharmaceutically acceptable salt" and "pharmaceutically acceptable salt" can be used interchangeably and refer to pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0087] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that can retain the biological effectiveness of the free base without other side effects. These salts can be prepared by methods known in the art.

[0088] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that can maintain the biological effectiveness of the free acid without other side effects. These salts can be prepared by methods known in the art.

[0089] The compounds described in the present invention have good inhibitory activity against MAGL and have good therapeutic effects on the central nervous system or pain. BRIEF DESCRIPTION OF THE DRAWINGS

[0090] Figure 1 Results of Oil Red O staining of cells in the blank (C), model (M), IV-39-5 μM, and IV-39-10 μM groups. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0091] The present disclosure will be further described below in conjunction with embodiments, but these embodiments do not limit the scope of the present disclosure. For the experimental methods without specific conditions noted in the embodiments of the present disclosure, they are generally carried out under conventional conditions or according to the conditions recommended by the raw material or commodity manufacturers. For reagents without specific sources noted, such reagents can be obtained from any supplier of molecular biology reagents in the quality / purity for molecular biology applications.

[0092] Unless otherwise specified, all reagents used in the following embodiments are commercially available products.

[0093] In the following preparation methods, the starting compounds and reagents used in each step and the compounds obtained can each be in the form of salts, and examples of such salts include salts similar to the salts of the compounds of the present invention, etc.

[0094] The compounds obtained in each step can be used directly in the next reaction in the form of a reaction mixture or a crude product. Alternatively, the compounds obtained in each step can be separated from the reaction mixture and purified according to methods known per se, such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, column chromatography, etc. When the starting compounds and reagents used in each step are commercially available, the commercially available products can also be used directly.

[0095] In the reactions of each step, although the reaction time varies depending on the types of reagents and solvents used, it is generally from 1 minute to 48 hours, preferably from 10 minutes to 12 hours, unless otherwise stated.

[0096] In the reaction of each step, although the reaction temperature varies depending on the types of reagents and solvents used, it is generally from 0 °C to 300 °C, preferably from 78 °C to 150 °C, unless otherwise specified.

[0097] Preparation of Intermediate in Example 1

[0098] 1. tert-Butyl 4-(2-oxo-1,2-dihydroquinolin-7-yl)piperazine-1-carboxylate (13)

[0099]

[0100] The raw materials 7-bromoquinolin-2(1H)-one (130 mg), N-Boc-piperazine (151.2 mg), Pd(OAc) 2 (6.7 mg), NaOtBu (139.2 mg), and BINAP (36 mg) were added to a sealed tube. Under N 2 4 ml of anhydrous toluene was added under the condition, and the mixture was refluxed for 10 h. After the reaction was complete, heating was stopped, and toluene was removed by evaporation under reduced pressure. The suspension was diluted with water, extracted three times with ethyl acetate, washed three times with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. Purification by column chromatography (dichloromethane:methanol = 20:1) gave 13, 90 mg of white solid, with a yield of 47%.

[0101] 1 H NMR (300 MHz, DMSO-d 6 ) δ (ppm): 11.42 (s, 1H), 7.72 (d, J = 9.4 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 6.88 (dd, J = 8.8, 2.3 Hz, 1H), 6.68 (d, J = 2.0 Hz, 1H), 6.20 (d, J = 9.4 Hz, 1H), 3.52 - 3.43 (m, 4H), 3.26 - 3.19 (m, 4H), 1.43 (s, 9H).

[0102] 2. 7-(Piperazine-1-carbonyl)quinolin-2(1H)-one hydrochloride (14)

[0103]

[0104] Intermediate 13 (72 mg) was dissolved in 5 ml of ethyl acetate, and HCl / EA was added. The mixture was stirred at room temperature for 12 h. After monitoring the reaction to completion by TLC, the reaction was stopped, and filtration was carried out. The filter cake was washed with ethyl acetate to obtain Intermediate 14, 46 mg of white solid, with a yield of 80%.

[0105] 1 H NMR (300 MHz, DMSO-d 6) δ (ppm): 11.73 (s, 1H), 9.55 (s, 2H), 7.80 (d, J = 9.4 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 6.96 (dd, J = 8.8, 2.3 Hz, 1H), 6.78 (d, J = 2.1 Hz, 1H), 6.30 (d, J = 9.4 Hz, 1H), 5.88 (s, 4H), 3.52 - 3.42 (m, 4H).

[0106] Example 2 7-(4-(1H-Indole-2-carbonyl)piperazin-1-yl)quinolin-2(1H)-one (IV-2)

[0107]

[0108] The starting material indole-2-carboxylic acid (64 mg) was dissolved in DMF, HATU (182 mg) and DIPEA (208 μL) were added. After 10 min, intermediate 14 (127 mg) was added, and the mixture was stirred at room temperature for 1 h. After monitoring the reaction to completion by TLC, the reaction was stopped, diluted with water, extracted three times with ethyl acetate, washed three times with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. Purification by column chromatography (dichloromethane:methanol = 50:1) gave the target product IV-2, 30 mg of pale yellow solid, with a yield of 10%.

[0109] 1 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.61 (s, 1H), 11.45 (s, 1H), 7.74 (d, J = 9.4 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.46 (dd, J = 14.4, 8.6 Hz, 2H), 7.20 (t, J = 7.2 Hz, 1H), 7.05 (t, J = 7.3 Hz, 1H), 6.95 - 6.84 (m, 2H), 6.73 - 6.66 (m, 1H), 6.20 (d, J = 9.4 Hz, 1H), 3.93 (s, 4H), 3.41 - 3.35 (m, 4H).

[0110] Example 3 7-(4-(3-Phenoxybenzoyl)piperazin-1-yl)quinolin-2(1H)-one (IV-3)

[0111]

[0112] The raw material 3-phenoxybenzoic acid (68 mg) was dissolved in DMF, HATU (144 mg) and DIPEA (167 μL) were added, and intermediate 14 (100 mg) was added. The mixture was stirred at room temperature for 1 h. After monitoring the reaction to completion by TLC, the reaction was stopped, diluted with water, extracted three times with ethyl acetate, washed three times with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. Purification by column chromatography (methylene chloride:methanol = 50:1) gave the target product IV-3, 55 mg of pale yellow solid, with a yield of 40%.

[0113] 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 11.45 (s, 1H), 7.73 (d, J = 9.4 Hz, 1H), 7.52 - 7.41 (m, 4H), 7.19 (t, J = 7.1 Hz, 2H), 7.14 - 7.09 (m, 2H), 7.05 - 7.01 (m, 1H), 6.88 (dd, J = 8.8, 2.0 Hz, 1H), 6.67 (d, J = 1.7 Hz, 1H), 6.20 (d, J = 9.5 Hz, 1H), 3.74 (s, 2H), 3.51 (s, 2H), 3.25 (m, 4H).

[0114] Example 4 7-(4-(1-Methyl-1H-indole-2-carbonyl)piperazin-1-yl)quinolin-2(1H)-one (IV-4)

[0115]

[0116] The raw material 1-methyl-indole-2-carboxylic acid (56 mg) was dissolved in DMF, HATU (144 mg) and DIPEA (167 μL) were added, and intermediate 14 (100 mg) was added. The mixture was stirred at room temperature for 1 h. After monitoring the reaction to completion by TLC, the reaction was stopped, diluted with water, extracted three times with ethyl acetate, washed three times with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. Purification by column chromatography (methylene chloride:methanol = 50:1) gave the target product IV-4, 30 mg of pale yellow solid, with a yield of 10%.

[0117] 1 H NMR (300 MHz, DMSO-d 6) δ (ppm): 11.46 (s, 1H), 7.74 (d, J = 9.4 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.51 (dd, J = 14.2, 8.6 Hz, 2H), 7.27 (t, J = 7.7 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 6.91 (dd, J = 8.7, 2.3 Hz, 1H), 6.78 - 6.67 (m, 2H), 6.21 (d, J = 9.4 Hz, 1H), 3.83 (m, 4H), 3.79 (s, 4H).

[0118] Example 5 7-(4-(3-(4-Chlorophenoxy)benzoyl)piperazin-1-yl)quinolin-2(1H)-one (IV-9)

[0119]

[0120] The raw material 3-(4-chlorophenoxy)benzoic acid (75 mg) was dissolved in DMF, HATU (137 mg) and DIPEA (156 μL) were added. After 10 min, intermediate 14 (95 mg) was added, and the mixture was stirred at room temperature for 1 h. After monitoring the reaction to completion by TLC, the reaction was stopped, diluted with water, extracted three times with ethyl acetate, washed three times with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. Purification by column chromatography (dichloromethane:methanol = 50:1) gave the target product IV-9, 30 mg of pale yellow solid, with a yield of 21%.

[0121] 1 1H NMR (300 MHz, DMSO-d 6 ) δ (ppm): 11.45 (s, 1H), 7.74 (d, J = 9.4 Hz, 1H), 7.49 - 7.47 (m, 1H), 7.49 - 7.47 (m, 1H), 7.47 - 7.43 (m, 2H), 7.23 (d, J = 7.6 Hz, 1H), 7.17 - 7.04 (m, 4H), 6.89 (dd, J = 8.8, 2.0 Hz, 1H), 6.73 - 6.64 (m, 1H), 6.21 (d, J = 9.4 Hz, 1H), 3.74 (s, 4H), 3.29 (d, J = 25.8 Hz, 4H).

[0122] Example 6 7-(4-(1-Methyl-1H-indole-2-carbonyl)piperazin-1-yl)-3,4-dihydroquinolin-2(1H)-one (IV-8)

[0123]

[0124] Compound IV-4 (56 mg) was dissolved in 5 ml of methanol, 10 mg of palladium carbon was added, H 2React overnight at room temperature under the conditions. After the reaction is completed, perform suction filtration to remove palladium carbon. Rotate the filtrate to dryness and purify by column chromatography (methylene chloride:methanol = 20:1) to obtain the target product IV-8, a pinkish-white solid of 12 mg, with a yield of 23%.

[0125] 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):9.93(s,1H),7.5-7.46(m,1H),7.46-7.40(m,2H),7.20(t,J=7.5Hz,2H),7.13-7.07(m,3H),7.01(d,J=8.2Hz,2H),6.53(dd,J=8.9,1.8Hz,1H),6.44(d,J=1.4Hz,1H),3.72(s,2H),3.47(s,2H),3.07(d,J=12.0Hz,4H),2.76(t,J=8.6Hz,2H),2.40(t,J=7.4Hz,2H).

[0126] Example 7 7-(4-(3-Phenoxybenzoyl)piperazin-1-yl)-3,4-dihydroquinolin-2(1H)-one (IV-7)

[0127]

[0128] Dissolve compound IV-3 (56 mg) in 5 ml of methanol, add 10 mg of palladium carbon, and react overnight at room temperature under H 2 conditions. After the reaction is completed, perform suction filtration to remove palladium carbon. Rotate the filtrate to dryness and purify by column chromatography (methylene chloride:methanol = 20:1) to obtain the target product IV-7, a cream-colored solid of 20.8 mg, with a yield of 35%.

[0129] 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):9.95(s,1H),7.62(d,J=7.8Hz,1H),7.53(d,J=8.0Hz,1H),7.27(t,J=7.3Hz,1H),7.11(t,J=7.3Hz,1H),7.02(d,J=8.2Hz,1H),6.71(s,1H),6.56(dd,J=8.1,1.5Hz,1H),6.48(s,1H),3.78(s,7H),3.21-3.06(m,4H),2.77(t,J=7.2Hz,2H),2.41(t,J=7.7Hz,2H).

[0130] Example 8 (4-(3-Chlorophenyl)piperazin-1-yl)(3-phenoxyphenyl)methanone (IV-11)

[0131]

[0132] Dissolve the raw material 3-phenoxybenzoic acid (64 mg) in DMF, add HATU (137 mg) and DIPEA (156 μL), then add 3-chlorophenylpiperazine (95 mg), and stir at room temperature for 1 h. After monitoring the reaction to completion by TLC, stop the reaction, dilute with water, extract three times with ethyl acetate, wash three times with saturated brine, and dry the organic phase with anhydrous sodium sulfate. Purify by column chromatography (petroleum ether:ethyl acetate = 16:1) to obtain the target product IV-11, 62 mg of pale yellow oil, with a yield of 52%.

[0133] 1 H NMR (300 MHz, DMSO-d 6 ) δ (ppm): 7.51 - 7.46 (m, 1H), 7.46 - 7.39 (m, 2H), 7.27 - 7.21 (m, 1H), 7.21 - 7.16 (m, 2H), 7.13 - 7.06 (m, 3H), 7.03 - 6.99 (m, 1H), 6.96 (t, J = 2.1 Hz, 1H), 6.91 (dd, J = 8.3, 1.9 Hz, 1H), 6.82 (dd, J = 7.8, 1.3 Hz, 1H), 3.70 (s, 2H), 3.46 (s, 2H), 3.20 (d, J = 22.8 Hz, 4H).

[0134] Example 9 (4-(3-chlorophenyl)piperazin-1-yl)(3-(4-fluorophenoxy)phenyl)methanone (IV-12)

[0135]

[0136] Dissolve the raw material 3-(4-fluorophenoxy)benzoic acid (70 mg) in 2 ml of DMF, add HATU (137 mg) and DIPEA (156 μL), add 3-chlorophenylpiperazine (95 mg, 0.36 mol) after 10 min, and stir at room temperature for 1 h. After monitoring the reaction to completion by TLC, stop the reaction, dilute with water, extract three times with ethyl acetate, wash three times with saturated brine, and dry the organic phase with anhydrous sodium sulfate. Purify by column chromatography (petroleum ether:ethyl acetate = 16:1) to obtain the target product IV-12, 47 mg of pale yellow oil, with a yield of 38%.

[0137] 11H NMR (300 MHz, DMSO-d6) δ (ppm): 7.47 (t, J = 7.9 Hz, 1H), 7.32 - 7.20 (m, 3H), 7.20 - 7.12 (m, 3H), 7.08 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H), 7.00 (dd, J = 2.3, 1.4 Hz, 1H), 6.97 (t, J = 2.1 Hz, 1H), 6.91 (dd, J = 8.4, 1.9 Hz, 1H), 6.85 - 6.79 (m, 1H), 3.84 - 3.57 (m, 2H), 3.57 - 3.38 (m, 2H), 3.32 - 3.08 (m, 4H).

[0138] Preparation of Intermediate in Example 10

[0139] 1. tert-Butyl 4-(2-fluoro-4-(trifluoromethyl)phenyl)piperazine-1-carboxylate (15)

[0140]

[0141] Add the raw materials 3-fluoro-4-bromobenzotrifluoride (243 mg), N-Boc-piperazine (372 mg), Pd 2 (dba) 3 (46 mg), NaOtBu (288 mg), and BINAP (62 mg) into a sealed tube. Add 4 ml of anhydrous toluene under N 2 conditions, reflux the reaction for 10 h. After the reaction is complete, stop heating, evaporate toluene under reduced pressure. Dilute the suspension with water, extract three times with ethyl acetate, wash three times with saturated brine, and dry the organic phase with anhydrous sodium sulfate. Purify by column chromatography (petroleum ether:ethyl acetate = 16:1) to obtain 15, 293 mg of yellow solid, with a yield of 84%.

[0142] 1 1H NMR (300 MHz, Chloroform-d) δ (ppm): 7.37 - 7.25 (m, 2H), 6.97 (t, J = 8.4 Hz, 1H), 3.65 - 3.56 (m, 4H), 3.15 - 3.04 (m, 4H), 1.49 (s, 9H).

[0143] 2. 1-(2-Fluoro-4-(trifluoromethyl)phenyl)piperazine hydrochloride (16)

[0144]

[0145] Intermediate 15 (200 mg, 0.57 mmol) was dissolved in ethyl acetate, HCl / EA was added, and the mixture was stirred at room temperature for 12 h. After monitoring the reaction to completion by TLC, the reaction was stopped, and the mixture was filtered by suction. The filter cake was washed with ethyl acetate to obtain Intermediate 16, 149 mg of white solid, with a yield of 92%.

[0146] 1 H NMR (300 MHz, DMSO-d 6 ) δ (ppm): 9.43 (s, 2H), 7.63 (dd, J = 13.0, 1.8 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.28 (t, J = 8.6 Hz, 1H), 3.39 (s, 2H), 3.36 (s, 2H), 3.24 (dd, J = 6.4, 3.4 Hz, 4H).

[0147] 3. tert-Butyl 4-(2-fluoro-4-(trifluoromethyl)phenyl)piperazine-1-carboxylate (17)

[0148]

[0149] N-Boc-piperazine (186 mg, 1 mmol) was dissolved in 5 ml of DMF, and K 2 CO 3 (207 mg), 2-F-4-(trifluoromethyl)benzyl bromide (280 mg) were added, and the mixture was stirred at 60 °C for 3 h. After monitoring the reaction to completion by TLC, the reaction was stopped, diluted with water, and extracted three times with ethyl acetate, washed three times with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. Purification by column chromatography (petroleum ether:ethyl acetate = 16:1) gave 17, 288 mg of white solid, with a yield of 82%.

[0150] 1 H NMR (300 MHz, DMSO-d 6 ) δ (ppm): 7.71 - 7.62 (m, 2H), 7.58 (d, J = 8.0 Hz, 1H), 3.62 (s, 2H), 3.35 - 3.24 (m, 4H), 2.40 - 2.30 (m, 4H), 1.39 (s, 9H).

[0151] 4. 1-(2-Fluoro-4-(trifluoromethyl)phenyl)piperazine hydrochloride (18)

[0152]

[0153] Intermediate 17 (150 mg) was dissolved in 5 ml of ethyl acetate, HCl / EA was added, and the mixture was stirred at room temperature for 12 h. After monitoring the reaction to completion by TLC, the reaction was stopped, and the mixture was filtered by suction. The filter cake was washed with ethyl acetate to obtain Intermediate 18, 108 mg of white solid, with a yield of 89%.

[0154] 1 H NMR(300MHz,DMSO-d 6 ) δ (ppm): 9.96 - 9.36 (m, 2H), 8.00 (t, J = 7.5 Hz, 1H), 7.85 (d, J = 9.6 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 4.39 (s, 2H), 3.81 - 3.49 (m, 8H).

[0155] Example 11 7-(4-(2-Fluoro-4-(trifluoromethyl)phenyl)piperazine-1-carbonyl)quinolin-2(1H)-one (IV-13)

[0156]

[0157] Dissolve the raw material 2-oxo-1,2-dihydroquinoline-7-carboxylic acid (32 mg) in DMF, add HATU (97 mg) and DIPEA (89 μL). After 10 min, add intermediate 16 (73 mg) and stir at room temperature for 1 h. After monitoring the reaction to completion by TLC, stop the reaction, dilute with water, extract three times with ethyl acetate, wash three times with saturated brine, and dry the organic phase with anhydrous sodium sulfate. Purify by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the target product IV-13, 23 mg of pale yellow solid, with a yield of 32%.

[0158] 1 H NMR(300MHz,DMSO-d 6 ) δ (ppm): 11.89 (s, 1H), 7.96 (d, J = 9.6 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.60 (dd, J = 13.0, 1.7 Hz, 1H), 7.54 - 7.47 (m, 1H), 7.34 (s, 1H), 7.23 (dd, J = 8.0, 1.4 Hz, 2H), 6.57 (dd, J = 9.6, 1.3 Hz, 1H), 3.67 (d, J = 89.1 Hz, 4H), 3.18 (d, J = 23.2 Hz, 4H).

[0159] Example 12 7-(4-(2-Fluoro-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)quinolin-2(1H)-one (IV-17)

[0160]

[0161] Dissolve the raw material 2-oxo-1,2-dihydroquinoline-7-carboxylic acid (32 mg) in 2 ml of DMF, add HATU (97 mg) and DIPEA (89 μL), then add intermediate 18 (78 mg), and stir at room temperature for 1 h. After monitoring the reaction to completion by TLC, stop the reaction, dilute with water, extract three times with ethyl acetate, wash three times with saturated brine, and dry the organic phase over anhydrous sodium sulfate. Purify by column chromatography (dichloromethane:methanol = 30:1) to obtain the target product IV-17, 25 mg of a pale yellow solid, with a yield of 33%.

[0162] 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):11.85(s,1H),7.93(d,J=9.6Hz,1H),7.75-7.62(m,3H),7.59(d,J=8.0Hz,1H),7.27(s,1H),7.15(d,J=8.0Hz,1H),6.55(dd,J=9.5,0.7Hz,1H),3.65(s,4H),2.42(d,J=6.0Hz,4H).

[0163] Example 13 7-(4-(4-(Trifluoromethyl)benzyl)piperazine-1-carbonyl)quinolin-2(1H)-one (IV-18)

[0164]

[0165] Dissolve the raw material 2-oxo-1,2-dihydroquinoline-7-carboxylic acid (32 mg) in 2 ml of DMF, add HATU (97 mg) and DIPEA (89 μL), add 1-(4-(trifluoromethyl)benzyl)piperazine (73 mg) after 10 min, and stir at room temperature for 1 h. After monitoring the reaction to completion by TLC, stop the reaction, dilute with water, extract three times with ethyl acetate, wash three times with saturated brine, and dry the organic phase over anhydrous sodium sulfate. Purify by column chromatography (dichloromethane:methanol = 30:1) to obtain the target product IV-18, 33 mg of an off-white solid, with a yield of 46%.

[0166] 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):11.86(s,1H),7.94(d,J=9.7Hz,1H),7.76-7.67(m,3H),7.56(d,J=7.9Hz,2H),7.28(s,1H),7.16(dd,J=8.0,1.5Hz,1H),6.56(dd,J=9.5,1.7Hz,1H),3.66(d,J=21.4Hz,4H),2.43(s,4H).

[0167] Preparation of Intermediate in Example 14

[0168] 1. tert-Butyl 4-(5-(3-(trifluoromethyl)phenyl)pyridin-2-yl)piperazine-1-carboxylate (19a)

[0169]

[0170] 4-Boc-1-(5-bromo-2-pyridyl)piperazine (205 mg), 4-trifluoromethylphenylboronic acid (137 mg), Pd(OAc) 2 (3 mg), Na 2 CO 3 (165 mg) were added to a sealed tube. Under N 2 H 2 O and DMF were added, and the mixture was heated for reaction for 8 h. After the reaction was completed, heating was stopped, diluted with water, extracted three times with ethyl acetate, washed three times with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. Purification by column chromatography (petroleum ether:ethyl acetate = 16:1) gave 19a, 170 mg of white solid, with a yield of 69%.

[0171] 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 8.55 (d, J = 2.6 Hz, 1H), 7.99 (dd, J = 5.9, 2.6 Hz, 1H), 7.95 (d, J = 5.2 Hz, 2H), 7.68 - 7.64 (m, 2H), 6.96 (d, J = 8.9 Hz, 1H), 3.61 - 3.53 (m, 4H), 3.48 - 3.40 (m, 4H), 1.43 (s, 9H).

[0172] 2. tert-Butyl 4-(5-(4-chlorophenyl)pyridin-2-yl)piperazine-1-carboxylate (19c)

[0173]

[0174] The synthesis method referred to Intermediate 19a to obtain Intermediate 19c, a white solid, with a yield of 83%.

[0175] 1 H NMR (300 MHz, DMSO-d 6 ) δ (ppm): 8.47 (d, J = 2.4 Hz, 1H), 7.89 (dd, J = 8.9, 2.6 Hz, 1H), 7.66 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.9 Hz, 1H), 3.55 (dd, J = 6.4, 3.4 Hz, 4H), 3.45 - 3.42 (m, 4H), 1.43 (s, 9H).

[0176] 3. tert-Butyl 4-(5-(3-chloro-4-fluorophenyl)pyridin-2-yl)piperazine-1-carboxylate (19e)

[0177]

[0178] The synthesis method refers to Intermediate 19a to obtain Intermediate 19e, which is a white solid with a yield of 70%.

[0179] 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 8.48 (d, J = 2.5 Hz, 1H), 7.91 (dd, J = 8.9, 2.6 Hz, 1H), 7.85 (dd, J = 7.1, 2.3 Hz, 1H), 7.64 (ddd, J = 8.6, 4.7, 2.4 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 6.93 (d, J = 8.9 Hz, 1H), 3.55 (dd, J = 6.5, 3.5 Hz, 4H), 3.44 (d, J = 6.3 Hz, 4H), 1.43 (s, 9H).

[0180] 4. tert-Butyl 4-(5-(2,4-difluorophenyl)pyridin-2-yl)piperazine-1-carboxylate (19i)

[0181]

[0182] The synthesis method refers to Intermediate 19a to obtain Intermediate 19i, which is a white solid with a yield of 64%.

[0183] 1 H NMR (300 MHz, DMSO-d 6 ) δ (ppm): 8.29 (s, 1H), 7.77 - 7.70 (m, 1H), 7.57 (td, J = 8.9, 6.7 Hz, 1H), 7.35 (ddd, J = 11.5, 9.5, 2.6 Hz, 1H), 7.18 (td, J = 8.6, 2.9 Hz, 1H), 6.95 (d, J = 8.9 Hz, 1H), 3.55 (dd, J = 6.5, 3.5 Hz, 4H), 3.44 (dd, J = 6.2, 3.3 Hz, 4H), 1.43 (s, 9H).

[0184] 5. tert-Butyl 4-(5-(3-fluoro-5-chloro-dichlorophenyl)pyridin-2-yl)piperazine-1-carboxylate (19l)

[0185]

[0186] The synthetic method refers to Intermediate 19a to obtain Intermediate 19l, a white solid, with a yield of 52%.

[0187] 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):11.90(s,1H),8.56(d,J=2.6Hz,1H),8.04-7.91(m,2H),7.76(d,J=8.0Hz,1H),7.64-7.47(m,2H),7.38-7.30(m,2H),7.24(dd,J=7.9,1.0Hz,1H),6.95(d,J=9.0Hz,1H),6.58(dd,J=9.6,1.6Hz,1H),3.73(s,4H),3.62(s,2H),3.47(s,2H).

[0188] 6. 4-(5-(Benzo[d][1,3]dioxol-5-yl)pyridin-2-yl)piperazine-1-carbonyl tert-butyl ester (19m)

[0189] The synthetic method refers to Intermediate 19a to obtain Intermediate 19m, a white solid, with a yield of 50%.

[0190] 1 H NMR(300MHz,Chloroform-d)δ(ppm):8.39(dd,J=2.6,0.7Hz,1H),7.68(dd,J=8.8,2.6Hz,1H),7.03-6.96(m,2H),6.89(dd,J=7.8,0.7Hz,1H),6.72(d,J=8.8Hz,1H),3.59(s,8H),1.51(s,9H),1.27(s,2H).

[0191] 7. 4-(5-(4-Chlorophenyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (19n)

[0192]

[0193] The synthetic method refers to Intermediate 19a to obtain Intermediate 19n, a white solid, with a yield of 83%.

[0194] 1 H NMR(300MHz,DMSO-d 6) δ (ppm): 11.90 (s, 1H), 8.52 (d, J = 2.4 Hz, 1H), 8.00 - 7.92 (m, 2H), 7.76 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 1.8 Hz, 1H), 7.66 - 7.58 (m, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.39 - 7.33 (m, 2H), 7.24 (dd, J = 8.0, 1.4 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 6.58 (dd, J = 9.6, 1.7 Hz, 1H), 3.73 (d, J = 7.5 Hz, 4H), 3.59 (s, 2H), 3.46 (s, 2H).

[0195] Example 15 7-(4-(5-(3-(Trifluoromethyl)phenyl)pyridin-2-yl)piperazine-1-carbonyl)quinolin-2(1H)-one (IV-20)

[0196]

[0197] Dissolve the raw material 2-oxo-1,2-dihydroquinoline-7-carboxylic acid (38 mg) in 2 ml of DMF, add HATU (91 mg) and DIPEA (104 μL). After 10 min, add intermediate 20a (82 mg, 20a is prepared from 19a by deprotection, and the deprotection can be carried out according to the conventional method), and stir at room temperature for 1 h. After monitoring the reaction to completion by TLC, stop the reaction, dilute with water, extract three times with ethyl acetate, wash three times with saturated brine, and dry the organic phase with anhydrous sodium sulfate. Purify by column chromatography (methylene chloride:methanol = 30:1) to obtain the target product IV-20, 34 mg of white solid, with a yield of 35%.

[0198] 1 1H NMR (300 MHz, DMSO-d 6 ) δ (ppm): 11.90 (s, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.00 (dd, J = 9.0, 2.6 Hz, 1H), 7.96 (m, 3H), 7.75 (d, J = 8.0 Hz, 1H), 7.65 (m, 2H), 7.34 (s, 1H), 7.24 (dd, J = 8.0, 1.3 Hz, 1H), 6.97 (d, J = 9.0 Hz, 1H), 6.57 (dd, J = 9.5, 1.6 Hz, 1H), 3.72 (s, 4H), 3.61 (s, 2H), 3.47 (s, 2H).

[0199] Example 16 7-(4-(5-(2,4-Difluorophenyl)pyridin-2-yl)piperazine-1-carbonyl)quinolin-2(1H)-one (IV-34)

[0200]

[0201] For the synthesis method, refer to Compound IV-20. Add Intermediate 20i (20i is prepared by deprotection of 19i, and the deprotection can be carried out according to the conventional method) to obtain the target product IV-34, a off-white solid with a yield of 35%.

[0202] 1 H NMR (300 MHz, DMSO-d 6 ) δ (ppm): 11.90 (s, 1H), 8.30 (s, 1H), 7.96 (d, J = 9.5 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.64 - 7.53 (m, 1H), 7.41 - 7.30 (m, 2H), 7.24 (d, J = 8.0 Hz, 1H), 7.18 (td, J = 8.9, 2.1 Hz, 1H), 6.97 (d, J = 8.9 Hz, 1H), 6.58 (d, J = 9.9 Hz, 1H), 3.72 (d, J = 19.6 Hz, 4H), 3.53 (d, J = 36.1 Hz, 4H).

[0203] Synthesis of the Intermediate in Example 17

[0204] tert-Butyl 4-(4-(3-chloro-5-fluorophenyl)pyridin-2-yl)piperazine-1-carboxylate (21a)

[0205]

[0206] Add 4-Boc-1-(4-bromo-2-pyridyl)piperazine (205 mg), 3-fluoro-5-chlorophenylboronic acid (137 mg), Pd(OAc) 2 (3 mg), and Na 2 CO 3 (165 mg) into a sealed tube. Add H 2 O and DMF under N 2 and reflux for 8 h. After the reaction is completed, stop heating, dilute with water, extract three times with ethyl acetate, wash three times with saturated brine, and dry the organic phase with anhydrous sodium sulfate. Purify by column chromatography (petroleum ether:ethyl acetate = 16:1) to obtain 21a, 140 mg of white solid with a yield of 71%.

[0207] 1 H NMR (300 MHz, DMSO-d 6) δ (ppm): 8.20 (d, J = 5.2 Hz, 1H), 7.78 (s, 1H), 7.70 (d, J = 10.0 Hz, 1H), 7.57 - 7.49 (m, 1H), 7.16 (s, 1H), 7.07 - 7.00 (m, 1H), 3.65 - 3.55 (m, 4H), 3.48 - 3.40 (m, 4H), 1.43 (s, 9H).

[0208] tert-Butyl 4-(4-(4-hydroxyphenyl)pyridin-2-yl)piperazine-1-carboxylate (21b)

[0209]

[0210] The synthesis method refers to Intermediate 21a to obtain Intermediate 21b, which is a white solid with a yield of 60%.

[0211] 1 H NMR (300 MHz, DMSO-d 6 ) δ (ppm): 9.76 (s, 1H), 8.11 (d, J = 5.2 Hz, 1H), 7.62 (d, J = 8.5 Hz, 2H), 6.99 (s, 1H), 6.91 (d, J = 5.1 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 3.58 - 3.51 (m, 4H), 3.46 - 3.41 (m, 4H), 1.43 (s, 9H).

[0212] tert-Butyl 4-(4-(3-hydroxyphenyl)pyridin-2-yl)piperazine-1-carboxylate (21c)

[0213]

[0214] The synthesis method refers to Intermediate 21a to obtain Intermediate 21c, which is a white solid with a yield of 58%.

[0215] 1 H NMR (300 MHz, DMSO-d 6 ) δ (ppm): 9.65 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H), 7.11 - 7.07 (m, 1H), 6.99 (s, 1H), 6.89 (dd, J = 5.2, 1.1 Hz, 1H), 6.87 - 6.81 (m, 1H), 3.56 (dd, J = 6.5, 3.4 Hz, 4H), 3.45 (s, 4H), 1.43 (s, 9H).

[0216] tert-Butyl 4-(4-(4-chloro-2-fluorophenyl)pyridin-2-yl)piperazine-1-carboxylate (21d)

[0217]

[0218] The synthesis method refers to Intermediate 21a to obtain Intermediate 21d, which is an off-white solid with a yield of 80%.

[0219] 1 H NMR (300 MHz, DMSO-d 6 ) δ (ppm): 8.20 (d, J = 5.2 Hz, 1H), 7.68 - 7.57 (m, 2H), 7.43 (dd, J = 8.3, 1.8 Hz, 1H), 6.95 (s, 1H), 6.86 - 6.79 (m, 1H), 3.54 (dd, J = 6.5, 3.4 Hz, 4H), 3.43 (dd, J = 6.0, 3.1 Hz, 4H), 1.42 (s, 9H).

[0220] tert-Butyl 4-(4-(4-chlorophenyl)pyridin-2-yl)piperazine-1-carboxylate (21e)

[0221]

[0222] The synthesis method refers to Intermediate 21a to obtain Intermediate 21e, which is a white solid with a yield of 64%.

[0223] 1 H NMR (300 MHz, DMSO-d 6 ) δ (ppm): 8.19 (d, J = 5.2 Hz, 1H), 7.85 - 7.76 (m, 2H), 7.59 - 7.52 (m, 2H), 7.08 (s, 1H), 6.97 (dd, J = 5.2, 1.2 Hz, 1H), 3.61 - 3.54 (m, 4H), 3.46 - 3.41 (m, 4H), 1.43 (s, 9H).

[0224] Example 18 7-(4-(4-(3-Chloro-5-fluorophenyl)pyridin-2-yl)piperazine-1-carbonyl)quinolin-2(1H)-one (IV-28)

[0225]

[0226] The synthesis method refers to Compound IV-20, adding Intermediate 22a (22a is prepared by deprotection from 21a, and the deprotection can be carried out according to the conventional method) to obtain the target product IV-28, which is a yellow solid with a yield of 47%.

[0227] 11H NMR (300 MHz, DMSO-d 6 ) δ (ppm): 11.90 (s, 1H), 8.21 (d, J = 5.3 Hz, 1H), 7.96 (d, J = 9.6 Hz, 1H), 7.81 - 7.73 (m, 2H), 7.73 - 7.66 (m, 1H), 7.53 (dt, J = 8.6, 1.9 Hz, 1H), 7.35 (s, 1H), 7.24 (dd, J = 8.0, 1.1 Hz, 1H), 7.19 (s, 1H), 7.06 (d, J = 5.2 Hz, 1H), 6.58 (d, J = 9.6 Hz, 1H), 3.75 (s, 4H), 3.56 (d, J = 53.3 Hz, 4H).

[0228] Example 19 7-(4-(4-(4-Hydroxyphenyl)pyridin-2-yl)piperazine-1-carbonyl)quinolin-2(1H)-one (IV-30)

[0229]

[0230] The synthesis method refers to Compound IV-20. Intermediate 22b (22b is prepared by deprotection from 21b, and the deprotection can be carried out according to the conventional method) is added to obtain the target product IV-30, which is a white solid with a yield of 10%.

[0231] 1 1H NMR (300 MHz, DMSO-d 6 ) δ (ppm): 11.89 (s, 1H), 9.77 (s, 1H), 8.12 (d, J = 5.3 Hz, 1H), 7.96 (d, J = 9.6 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.34 (s, 1H), 7.24 (dd, J = 8.0, 1.3 Hz, 1H), 7.03 (s, 1H), 6.94 (d, J = 5.3 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 6.58 (dd, J = 9.6, 1.7 Hz, 1H), 3.72 (d, J = 18.0 Hz, 4H), 3.53 (d, J = 42.6 Hz, 4H).

[0232] Example 20 7-(4-(4-(3-Hydroxyphenyl)pyridin-2-yl)piperazine-1-carbonyl)quinolin-2(1H)-one (IV-31)

[0233]

[0234] The synthesis method refers to compound IV-20. Intermediate 22c (22c is prepared by deprotection of 21c, and the deprotection can be carried out according to the conventional method) is added to obtain the target product IV-31, a white solid, with a yield of 36%.

[0235] 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):11.90(s,1H),9.51(s,1H),8.40(d,J=2.3Hz,1H),7.96(d,J=9.6Hz,1H),7.82(dd,J=8.9,2.5Hz,1H),7.76(d,J=8.0Hz,1H),7.34(s,1H),7.27-7.17(m,2H),7.03(d,J=7.9Hz,1H),6.99-6.96(m,1H),6.94(d,J=9.0Hz,1H),6.71(dd,J=8.0,1.6Hz,1H),6.58(dd,J=9.5,1.5Hz,1H),3.71(d,J=26.3Hz,4H),3.52(d,J=31.3Hz,4H).

[0236] Example 21 7-(4-(4-(4-(4-Chloro-2-fluorophenyl)pyridin-2-yl)piperazine-1-carbonyl)quinolin-2(1H)-one (IV-33)

[0237]

[0238] The synthesis method refers to compound IV-20. Intermediate 22d (22d is prepared by deprotection of 21d, and the deprotection can be carried out according to the conventional method) is added to obtain the target product IV-33, an off-white solid, with a yield of 41%.

[0239] 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):11.90(s,1H),8.21(d,J=5.0Hz,1H),7.96(d,J=9.7Hz,1H),7.75(d,J=8.0Hz,1H),7.63(q,J=11.4,9.9Hz,2H),7.43(d,J=8.3Hz,1H),7.34(s,1H),7.23(d,J=7.7Hz,1H),6.97(s,1H),6.91-6.78(m,1H),6.57(d,J=9.6Hz,1H),3.71(d,J=17.8Hz,4H),3.62-3.43(m,4H).

[0240] Example 22 7-(4-(4-(4-(4-Chlorophenyl)pyridin-2-yl)piperazine-1-carbonyl)quinolin-2(1H)-one (IV-29)

[0241]

[0242] The synthesis method refers to Compound IV-20. Intermediate 22e (22e is prepared by deprotection from 21e, and the deprotection can be carried out according to the conventional method) is added to obtain the target product IV-29, a pale yellow solid, with a yield of 46%.

[0243] 1 H NMR (300 MHz, DMSO-d 6 ) δ (ppm): 11.90 (s, 1H), 8.20 (d, J = 5.2 Hz, 1H), 7.96 (d, J = 9.6 Hz, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.35 (s, 1H), 7.24 (dd, J = 8.0, 1.2 Hz, 1H), 7.12 (s, 1H), 7.03 - 6.96 (m, 1H), 6.58 (dd, J = 9.6, 1.6 Hz, 1H), 3.73 (s, 4H), 3.66 - 3.41 (m, 4H).

[0244] Example 23 6-(4-(5-(3-Chlorophenyl)pyridin-2-yl)piperazine-1-carbonyl)indol-2-one (IV-36)

[0245] The synthesis method refers to Compound IV-20. Intermediate 20n (20n is prepared by deprotection from 19n, and the deprotection can be carried out according to the conventional method) is added to obtain the target product IV-36, an off-white solid, with a yield of 32%.

[0246] 1 H NMR (300 MHz, DMSO-d 6 ) δ (ppm): 10.51 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 7.90 (dd, J = 8.9, 2.5 Hz, 1H), 7.66 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 7.5 Hz, 1H), 7.04 - 6.98 (m, 1H), 6.95 (d, J = 8.9 Hz, 1H), 6.84 (s, 1H), 3.58 (d, J = 23.5 Hz, 11H).

[0247] Example 24 6-(4-(5-(3-Chloro-5-fluorophenyl)pyridin-2-yl)piperazine-1-carbonyl)indol-2-one (IV-37)

[0248] The synthesis method refers to Compound IV-20. Intermediate 20l (20l is prepared by deprotection from 19l, and the deprotection can be carried out according to the conventional method) is added to obtain the target product IV-37, which is a off-white solid with a yield of 35%.

[0249] 1 H NMR (300 MHz, DMSO-d 6 ) δ (ppm): 10.52 (s, 1H), 8.56 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 9.0, 2.5 Hz, 1H), 7.61 (s, 1H), 7.59 - 7.51 (m, 1H), 7.34 (dt, J = 8.8, 1.9 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.04 - 6.98 (m, 1H), 6.94 (d, J = 9.0 Hz, 1H), 6.84 (s, 1H), 3.66 (s, 6H), 3.54 (s, 4H).

[0250] Example 25 6-(4-(5-(4-Chlorophenyl)pyridin-2-yl)piperazine-1-carbonyl)indol-2-one (IV-39)

[0251] The synthesis method refers to Compound IV-20. Intermediate 20c (20c is prepared by deprotection from 19c, and the deprotection can be carried out according to the conventional method) is added to obtain the target product IV-39, which is a off-white solid with a yield of 30%.

[0252] 1 H NMR (300 MHz, DMSO-d 6 ) δ (ppm): 10.52 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 7.91 (dd, J = 8.9, 2.5 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 7.5 Hz, 1H), 7.05 - 6.98 (m, 1H), 6.95 (d, J = 8.9 Hz, 1H), 6.85 (s, 1H), 3.63 (s, 6H), 3.54 (s, 2H), 3.36 (s, 2H).

[0253] Example 26 6-(4-(5-(3-Chloro-4-fluorophenyl)pyridin-2-yl)piperazine-1-carbonyl)indol-2-one (IV-40)

[0254] The synthesis method refers to compound IV-20. Intermediate 20e (20e is prepared by deprotection of 19e, and the deprotection can be carried out according to the conventional method) is added to obtain the target product IV-40, a beige solid with a yield of 35%.

[0255] 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):10.51(s,1H),8.49(d,J=2.6Hz,1H),7.93(dd,J=8.9,2.6Hz,1H),7.87(dd,J=7.1,2.3Hz,1H),7.65(ddd,J=8.6,4.6,2.3Hz,1H),7.47(t,J=9.0Hz,1H),7.29(d,J=7.6Hz,1H),7.01(dd,J=7.5,1.4Hz,1H),6.94(d,J=8.9Hz,1H),6.86-6.83(m,1H),3.65(s,6H),3.54(s,2H),3.51(s,2H).

[0256] Example 27 8-(4-(4-(4-(4-Chlorophenyl)pyridin-2-yl)piperazine-1-carbonyl)quinolin-2(1H)-one (IV-32)

[0257] The synthesis method refers to compound IV-20. Intermediate 22e (22e is prepared by deprotection of 21e, and the deprotection can be carried out according to the conventional method) is added to obtain the target product IV-32, a beige solid with a yield of 30%.

[0258] 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):11.85(s,1H),8.16(d,J=4.8Hz,1H),7.96(s,1H),7.81(d,J=4.2Hz,2H),7.82(d,J=6.2Hz,1H),7.56(d,J=8.6Hz,2H),7.35(s,1H),7.24(d,J=6.8Hz,1H),7.12(s,1H),7.00-6.89(m,1H),6.58(dd,J=9.6,1.6Hz,1H),3.73(s,4H),3.52(s,4H).

[0259] Example 28 7-Chloro-2-(4-(4-(4-chlorophenyl)pyridin-2-yl)piperazine-1-carbonyl)quinazolin-4-(3H)-one (IV-35)

[0260] The synthesis method refers to compound IV-20, add intermediate 22e (22e is prepared by deprotection from 21e, and the deprotection can be carried out according to the conventional method), to obtain the target product IV-35, off-white solid, with a yield of 20%.

[0261] 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):12.95(s,1H),8.21(d,J=5.2Hz,1H),8.10(d,J=2.4Hz,1H),7.91(dd,J=8.7,2.5Hz,1H),7.86-7.78(m,2H),7.75(d,J=8.7Hz,1H),7.61-7.50(m,2H),7.13(s,1H),7.04-6.97(m,1H),3.75(s,4H),3.66(s,4H).

[0262] Example 29 6-(4-(5-(Benzo[d][1,3]dioxol-5-yl)pyridin-2-yl)piperazine-1-carbonyl)indolin-2-one (IV-38)

[0263] The synthesis method refers to compound IV-20, add intermediate 20m (20m is prepared by deprotection from 19n, and the deprotection can be carried out according to the conventional method), to obtain the target product IV-38, off-white solid, with a yield of 43%.

[0264] 1 H NMR(300MHz,DMSO-d 6 )δ(ppm):10.51(s,1H),8.40(d,J=2.4Hz,1H),7.82(dd,J=8.9,2.5Hz,1H),7.28(d,J=7.5Hz,1H),7.22(d,J=1.7Hz,1H),7.09(dd,J=8.1,1.8Hz,1H),7.00(dd,J=7.6,1.4Hz,1H),6.97(d,J=8.1Hz,1H),6.91(d,J=8.9Hz,1H),6.84(s,1H),6.04(s,2H),3.86-3.55(m,6H),3.54(s,2H),3.50(s,2H).

[0265] Biological activity test of the compound

[0266] Example 30 Determination of MAGL inhibitory activity

[0267] 1. Test principle:

[0268] The MAGL inhibitor screening kit of Cayman Company provides a simple and efficient method for screening the inhibitory activity of compounds against human MAGL. The principle is that MAGL hydrolyzes an alternative substrate (ethyl 4-nitrophenylacetate replaces 2-AG) to generate a yellow product (4-nitrophenol), which has a maximum absorption at 405 - 412 nm. By measuring the absorbance at this wavelength, the content of the hydrolyzed product 4-nitrophenol is quantified to characterize the enzyme activity.

[0269] 2. Preparation of Reagents

[0270] (1) Preparation of buffer: Add 3 mL of concentrated buffer (10×) to 27 mL of pure water for dilution. The diluted buffer (1×) contains 10 mM Tris-HCl, pH 7.2, and 1 mM EDTA, which is used for analyzing and diluting MAGL and the positive drug JZL195, and store it at -20 °C for later use.

[0271] (2) Preparation of human recombinant MAGL: Take 30 μL of MAGL protein and add 570 μL of buffer (1×), and store it for later use.

[0272] (3) Preparation of MAGL substrate: Take 150 μL of substrate and add 450 μL of buffer (1×), and store it for later use.

[0273] (4) Preparation of positive drug and compounds: JZL195 is dissolved in DMSO and buffer in a 1:1 ratio to prepare compound solutions and JZL195 solutions with concentrations of 0.001 μM, 0.01 μM, 0.1 μM, 1 μM, 10 μM, and 100 μM respectively, and store them for later use.

[0274] 3. Experimental Procedures

[0275] (1) Background wells: Add 160 μL of buffer (1×) and 10 μL of solvent

[0276] (2) 100% initial enzyme activity wells: Add 150 μL of buffer (1×), 10 μL of enzyme, and 10 μL of solvent

[0277] (3) Positive control and drug wells: Add 150 μL of buffer (1×), 10 μL of enzyme, and 10 μL of positive drug or inhibitor. Repeat the experiment 3 times for each of the above wells. See Table 1 for details:

[0278] Table 1

[0279] Buffer (1×) MAGL Solvent Inhibitor Background 160 μL 10 μL 100% Initial Enzyme Activity 150 μL 10 μL 10 μL Inhibitor 150 μL 10 μL 10 μL

[0280] (4) Mix the substances in the wells and incubate at room temperature for 15 min.

[0281] (5) Add 10 μL of substrate into each well, shake the 96-well plate thoroughly for 10 s, and incubate it at room temperature for 10 min. Read the absorbance at 405 nm using a Multiscan GO (Thermo) microplate reader. Calculate the inhibition rate according to the following formula, and then perform nonlinear regression analysis using GraphPad Prism software, using second-order polynomial regression analysis and analyzing the experimental data by applying a mixed model inhibition fit.

[0282] 4. Results

[0283]

[0284] The results are shown in Table 2. It can be seen from the results that the compounds of the present invention have good MAGL inhibitory activity.

[0285] Table 2

[0286] Example % Inhibition (10 μM) Example % Inhibition (10 μM) IV-2 83 IV-29 88 IV-3 85 IV-30 95 IV-4 85 IV-31 92 IV-7 90 IV-32 93 IV-8 84 IV-33 93 IV-9 92 IV-34 89 IV-11 88 IV-35 95 IV-12 85 IV-36 97 IV-13 85 IV-37 92 IV-17 95 IV-38 89 IV-18 95 IV-39 92 IV-20 85 IV-40 95 IV-28 99

[0287] Referring to a method similar to this example, determine the IC 50 of the compounds of this application. The specific method is as follows: According to the above method, determine the inhibition rates of the application compounds at concentrations of 0.001 μM, 0.01 μM, 0.1 μM, 1 μM, 10 μM, and 100 μM. Use second-order polynomial regression analysis and analyze the experimental data by applying a mixed model inhibition fit to obtain the IC 50 data of the compounds against MAGL inhibition.

[0288] Example 31 Liver Microsome Stability Test

[0289] Compound IV-30 was incubated in rat liver microsomes. 10 μL of the inhibitor methanol solution (100 μM) was pre-incubated with 50 μL of liver microsomes (20 mg / mL). Add 840 μL of 0.1 M PBS (pH = 7.4) containing 50 μL of MgCl 2 (100 mM), and react at 37 °C for 5 min. Then add 50 μL of NADPH (XenoTech, LLC, Lenexa, KS, USA) to the reaction mixture. Samples were collected at 0, 10, 20, 30, and 60 min, and the content of MAGL inhibitor was analyzed using UPLC-MS / MS.

[0290] Add 100 μL of PBS buffer (concentration 0.1 M), 50 μL of MgCl2 (final concentration 5 mM) to each system, add 20 μL of the compound and 10 μL of diluted rat liver microsomes (8 mg / ml, final concentration 0.4 mg / ml) after vortexing, mix well, and incubate at 37 °C for 5 min. The final reaction volume is 200 μL. When incubating for 4 min, open the lid. At 5 min, insert the pipette tip to the bottom of the tube and add 20 μL of NADPH (10 mM) to initiate the reaction. Take a 20 μL sample (0 min), incubate the rest at 37 °C, and take 20 μL samples at 5, 15, 30, 45, 60, and 90 min. Add 100 μL of cold chromatographic methanol (containing imipramine hydrochloride as the internal standard) to the taken samples to terminate the reaction.

[0291] The results are as follows:

[0292] Table 3

[0293] Compound Species <![CDATA[T 1 / 2 (min)]]> Clearance Rate (ml / min / mg) IV-30 Rat 121.58 0.0057

[0294] As can be seen from Table 3 of the results, compound IV-30 has good liver microsome stability, indicating that the compounds of this application have excellent metabolic stability.

[0295] Example 32 Pharmacokinetic Test

[0296] 1. Experimental Materials

[0297] (1) Mobile phase solution: Take 500 mL of Wahaha water, add 2.5 mL of formic acid to it to make an aqueous solution containing 0.5% formic acid, mix well, and perform ultrasonic degassing for 20 min.

[0298] (2) Preparation of stock solutions: Weigh 2.0 mg of compound IV-39 precisely into a 10 mL volumetric flask, dissolve it in water and make up the volume to a stock solution of 200.0 μg / mL. Weigh 2.0 mg of imipramine hydrochloride precisely into a 10 mL volumetric flask, dissolve it in water and make up the volume to a stock solution of 200.0 μg / mL, and dilute it with methanol to 3.000 μg / mL as the internal standard working solution, and store it in a 4 °C refrigerator for later use.

[0299] (3) Preparation of the standard curve samples: Dilute the stock solution of IV-39 with methanol to a series of standard solutions with concentrations of 30000, 15000, 7500, 3000, 1500, 300.0, and 30.00 ng / mL. Precisely pipette 10 μL of the above series of standard solutions, add 50 μL of blank SD rat plasma, add 10 μL of the internal standard working solution, mix well, and then add 230 μL of methanol. The final volume is 300 μL, and the final concentrations of compound IV-39 are 1000, 500.0, 250.0, 100.0, 50.00, 10.00, and 1.000 ng / mL. After vortex mixing for 5 min, centrifuge at 12000 r / min for 10 min, and transfer the supernatant to an autosampler vial for LC-MS / MS analysis to prepare for the plotting of the standard curve.

[0300] (4) LC-MS conditions: The chromatographic column is Waters 5 C18-MS-Ⅱ (2.0 × 250 mm, 5 μm); the mobile phase is 0.5% formic acid in water (A) - methanol (B); isocratic elution is adopted, the proportion of the organic phase is 90%, the flow rate is 0.3 mL / min, the column temperature is 40 °C, and the injection volume is 10 μL.

[0301] (5) Preparation of the test samples: Weigh 0.5 mg of the test sample IV-39 and place it in a 10 mL EP tube. Add 0.125 mL of DMSO, 0.25 mL of Tween-80, and then add 4.2 mL of normal saline injection. After dissolution, sonicate and shake well until the compound is clear to prepare a 0.1 mg / mL preparation; prepare and use it immediately on the day of use. Weigh 5 mg of the test sample IV-39 and place it in a 10 mL EP tube. Add 0.125 mL of DMSO, 0.25 mL of Tween-80, and then add 4.625 mL of normal saline injection. After dissolution, sonicate and shake well until the compound is clear to prepare a 1 mg / mL PO preparation. The administration volume is 10 mL / kg, and the administration dose is 10 mg / kg; prepare and use it immediately on the day of use.

[0302] Example 33 Determination of the concentration of 2-AG in the brain

[0303] ICR male mice (3 mice / group) were used. The test compound IV-39 was dissolved in 10% DMSO, 10% Tween 80, and 80% normal saline to prepare the dosing solution. The dose of the test compound was prepared as 10 mg / kg, and the dosing volume was 10 ml / kg. The test compound was administered by gavage. After administration of the test compound, the brain was isolated at 0 min, 60 min, 120 min, 240 min, and 480 min respectively, and the cerebral hemisphere was extracted. The obtained cerebral hemisphere was frozen on dry ice, and the weight of the frozen tissue was measured. Approximately 100 mg of brain tissue was weighed and homogenized with 9 volumes of normal saline added. After homogenization, the mixture was centrifuged at 15000 rpm for 10 minutes. The supernatant was aliquoted, about 50 μl per tube. The concentration of 2-AG in the brain was measured by the Elisa method.

[0304] Example 34 Determination of the antidepressant effect of the compound on depressed mice

[0305] ICR male mice were used. After 1 week of adaptation, 12 mice were randomly selected as the blank control and raised normally; the remaining 70 mice were placed in 50 ml centrifuge tubes (with holes at the end of the tubes for the mice to breathe), and were restrained for 4 - 8 h per day, increasing from 4 h per day to 8.5 h per day, and continuously restrained for 30 days.

[0306] Model determination:

[0307] The - tail suspension test - was used to determine whether the mice had formed the model (evaluating the despair behavior of the mice): The posterior 1 / 3 of the mouse's tail was fixed with tape and suspended on a bracket, with the head 15 cm from the ground. After the mouse adapted for 2 min, it was photographed, and the immobile time of the mouse within 4 min was counted.

[0308] Grouping and dosing:

[0309] After the model was established, according to the immobile time data in the tail suspension test, the mice were divided into a model group, a positive drug group (fluoxetine, 8 mg / kg), a compound IV-39 - low dose group (4 mg / kg), and a compound IV-39 high dose group (8 mg / kg), with 6 - 8 mice in each group. Compound preparation: 10% DMSO, 40% PEG 400, 5% Tween 80, 45% normal saline. Dosing volume: 10 ml / kg. Administered continuously for 7 days. After 7 days, behavioral tests such as the tail suspension test, open field test, forced swimming test, and sucrose preference test were conducted. After the test, blood was taken, and the brain and hippocampus were taken for biological tests.

[0310] Example 35 Determination of the in vitro anti - non - alcoholic fatty liver effect of the compound

[0311] 1. Instruments and materials

[0312] (1) Cells and reagents: The human hepatoma cell line HepG2 cells were purchased from the Shanghai Institute of Cell Biology, Chinese Academy of Sciences; fetal bovine serum was purchased from Solarbio Science & Technology Co., Ltd.; DMEM high-glucose medium, 0.25% trypsin solution, and PBS solution were purchased from Nanjing KeyGen Biotech Co., Ltd.; DMSO, oleic acid, palmitic acid, and Oil Red O were purchased from Guangdong Xilong Chemical Co., Ltd.

[0313] (2) Main instruments: The MULTISKAN MK3 full-automatic microplate reader (Thermo Scientific, USA), vortex oscillator (QL-902); centrifuge, BT224 electronic balance (Sartouris, Germany); HB-202 constant temperature water bath (Beijing Zhongxi Yuanda); BX51 upright microscope (Olympus, Japan); other equipment and instruments including centrifuge tubes, pipettes, pipettes, etc.

[0314] 2. Experimental methods:

[0315] (1) Cell culture method

[0316] The HepG2 cells were inoculated into DMEM high-glucose culture medium containing 10% fetal bovine serum and allowed to adhere and grow. They were cultured in an incubator at 37 °C, 5% CO 2 saturated humidity. According to the cell growth situation, they were digested with 0.25% trypsin every 1-2 days for subculture.

[0317] (2) Effect of compound IV-39 on the NASH cell model induced by free fatty acids in HepG2 cells

[0318] The HepG2 cells were cultured in 96-well plates. After the cells adhered and grew to 60-70%, they were co-stimulated with free fatty acids (at a molar ratio of palmitic acid:oleic acid of 1:2) and different concentrations of the test drug (compound IV-39) for 24 h. Three parallel wells were set up and divided into a blank group, a model group, and a drug administration group. The blank group was replaced with blank DMEM, and the drug administration group was added with compound IV-39 at concentrations of 5 μM and 10 μM prepared with DMEM, respectively.

[0319] (3) Observation of intracellular lipid droplets by Oil Red O staining

[0320] The steps of Oil Red O staining are as follows: The cells were washed 3 times with PBS solution, fixed with 10% neutral formaldehyde for 30 min, washed 2 times with PBS solution, stained with Oil Red O at 37 °C, incubated at 37 °C for 1 h, then the staining solution was discarded and the cells were washed twice with PBS. Under the microscope, the neutral fat in the cells could be specifically stained red, and the lipid accumulation in the cells was observed.

[0321] 3. Experimental results: Observation of the effect of compound IV-39 on the NASH cell model by Oil Red O staining

[0322] The Oil Red O staining results of compound IV-39 are as Figure 1 shown. It can be seen that compared with untreated cells, HepG2 cells exposed to free fatty acids (model group) showed higher intracellular lipid accumulation. After intervention with compound IV-39, the lipid droplet aggregation in HepG2 cells was significantly inhibited; indicating that compound IV-39 prepared by the present invention can significantly inhibit free fatty acid-induced lipid accumulation in a dose-dependent manner at 5 μM and 10 μM, and has the effect of treating non-alcoholic steatohepatitis.

[0323] Example 36 Determination of the in vivo anti-Parkinson's disease effect of the compound

[0324] 1. Experimental method: Mice were acclimated for 1 week; 5 animals were randomly selected from the normal group without any treatment and were normally fed; the remaining 4 groups of mice were intraperitoneally injected with solvent or drug (IV-39, 10 mg / kg) once on the first day, and MPTP (15 mg / kg, injected every 2 h for a total of 4 times) was intraperitoneally injected on the second day. The solvent or drug was injected 1 h after the second injection of MPTP. On the third day, the solvent or drug was intraperitoneally injected once, and the behavioral test was performed 2 h after administration.

[0325] 2. Behavioral experiment - Rotarod test: The instrument was placed 50 cm above the ground. There was a digital time recorder at the bottom of each partition, and the time was recorded when the animal fell. Mice were trained on the instrument for a fixed time, and the rotation speed of the rotarod was 20 rpm. The grip strength of the animals was evaluated using a rotator. Mice were trained continuously for 2 d before drug administration. When performing the behavioral test, a rotarod with a diameter of 7 cm was used to test the grip strength of the animals at a speed of 20 rpm, and the cut-off time was 180 s.

[0326] Example 37 Determination of the cholestatic liver injury effect of the compound

[0327] 1. Experimental method:

[0328] (1) Eighteen male C57BL / 6J mice were randomly divided into 3 groups (n = 6) according to body weight after one week of adaptive feeding: blank group, model group (0.1% DDC), and IV-39 administration group (12 mg / kg + 0.1% DDC). The control group was given normal feed, and the other groups were given feed containing 0.1% DDC for 2 weeks. One week after feeding with feed containing 0.1% DDC, the mice in the administration group were intraperitoneally injected with IV-39 (12 mg / kg, 10 mL / kg) every day for one week, and the control group and 0.1% DDC group were injected with the solvent (10 mL / kg) in the same way for 1 week. One hour after the last administration of the mice, blood was collected from the orbital cavity, the mice were sacrificed, the livers were dissected, washed with physiological saline, the surface moisture was blotted dry, the liver lobules were carefully separated and fixed in formalin fixative, and the remaining part of the liver was stored at -80 °C.

[0329] (2) After the blood samples were left standing at room temperature for 30 min, they were centrifuged at 3000 rpm / min at 4 °C for 10 minutes, the upper serum samples were collected, and the contents of alanine aminotransferase (ALT / GPT) and alkaline phosphatase (ALP) in the serum were detected according to the kit instructions.

[0330] (3) Histopathological examination of mouse liver tissue: After the fixed mouse liver tissue was fixed in formalin solution for 24 hours, it was dehydrated with alcohol, embedded in paraffin and cut into sections with a thickness of 5 μm. The prepared sections were stained with hematoxylin and eosin dyes respectively. The sections after HE staining were dehydrated, cleared and mounted and observed under a microscope to record the histopathological morphology of the liver tissue.

Claims

1. A compound of the structure shown in formula (I), or a pharmaceutically acceptable salt or isotopically substituted derivative thereof: Wherein, R 1 independently selected from unsubstituted or one or more R- 1A substituted with the following groups: aryl, heterocyclic group, heterocyclic ketone group, arylalkyl, R 2 Each independently selected from unsubstituted or substituted by one or more R 2A substituted with the following groups: aryl, heterocyclic group, heterocyclic ketone group, arylalkyl, X is a covalent bond, O, S or -NH-; R a 、R b 、R c 、R d each independently selected from the following groups which are substituted or unsubstituted: aryl, heterocyclic group; The substituents are one or more, and each substituent is independently -OH, -SH, -CN, halogen, nitro, carboxyl, C 1-8 alkyl, C 1-8 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy; Preferably, R 1 , R 2 , R a , R b , R c , R d Among them, the aryl groups are each independently C 6 -C 10 aryl groups. Preferably, they are each independently phenyl or naphthyl; R 1 , R 2 , R a , R b , R c , R d Among them, the heterocyclic group is a 5- to 10-membered heterocyclic group having 1 to 4 heteroatoms selected from N, O, or S; preferably, the heterocyclic group is a 5- to 10-membered heterocyclic group having 1 to 3 heteroatoms selected from N, O, or S; more preferably, the heterocyclic group is a 5- to 10-membered heterocyclic group having 1, 2, or 3 heteroatoms selected from N or O; even more preferably, the heterocyclic group is selected from pyrrolidinyl, piperidinyl, pyranyl, morpholinyl, piperazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, indazolyl, benzoxazolyl, benzothiazolyl, purinyl, oxazolopyridyl, or 1,2-methylenedioxyphenyl.

2. The compound of the structure shown in formula (I) according to claim 1, or a pharmaceutically acceptable salt or isotopically substituted derivative thereof, Characterized in that, R 1 and R 2 In this case, the heterocyclic ketone group is a 5- to 10-membered heterocyclic ketone group having 1 to 4 heteroatoms selected from N, O, or S; preferably, it is a 5- to 10-membered heterocyclic ketone group having 1 to 3 heteroatoms selected from N, O, or S; more preferably, it is a 5- to 10-membered heterocyclic ketone group having 1, 2, or 3 heteroatoms selected from N or O; more preferably, the heterocyclic ketone group is selected from the following groups in which one C is a ketone group: pyrrolidinyl, piperidinyl, pyranyl, morpholinyl, piperazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, coumarinyl, indolyl, quinolyl, isoquinolyl, indazolyl, benzoxazolyl, benzothiazolyl, purinyl, oxazolopyridyl; preferably, R 1 and R 2 In this case, the arylalkyl is C 6 -C 10 aryl C 1 -C 3 alkyl; specifically, it is benzyl, phenethyl.

3. The compound of the structure shown in formula (I) according to claim 1, or a pharmaceutically acceptable salt or isotopically substituted derivative thereof, Characterized in that, R 1 selected from unsubstituted or one or more R 1A substituted with the following groups: phenyl, pyrrolidinyl, piperidinyl, pyranyl, morpholinyl, piperazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, indanyl, indolyl, quinolinyl, isoquinolinyl, indazolyl, benzoxazolyl, benzothiazolyl, purinyl, oxazolo-pyridyl, 1,2-methylenedioxyphenyl, benzyl, phenethyl; Preferably, R a is selected from phenyl, pyridyl, pyrrolidinyl, piperidinyl, pyranyl, morpholinyl, piperazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyrimidinyl, pyridazinyl, indanyl, indolyl, quinolinyl, isoquinolinyl, indazolyl, benzoxazolyl, benzothiazolyl, purinyl or oxazolo-pyridyl; Preferably, R b is selected from phenyl, pyrrolidinyl, piperidinyl, pyranyl, morpholinyl, piperazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, indanyl, indolyl, quinolinyl, isoquinolinyl, indazolyl, benzoxazolyl, benzothiazolyl, purinyl, oxazolo-pyridyl or 1,2-methylenedioxyphenyl; More preferably, selected from:

4. The compound of the structure shown in formula (I) according to claim 1, or a pharmaceutically acceptable salt or isotopically substituted derivative thereof, Characterized in that, R 2 selected from unsubstituted or one or more R 2A substituted with the following groups: indolyl, phenyl, pyrrolidinyl, piperidinyl, pyranyl, morpholinyl, piperazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, benzofuranyl, quinolinyl, isoquinolinyl, indazolyl, benzoxazolyl, benzothiazolyl, purinyl, oxazolo-pyridyl, 1,2-methylenedioxyphenyl, benzyl, phenethyl, Preferably, R c is selected from phenyl, pyridyl, pyrrolidinyl, piperidinyl, pyranyl, morpholinyl, piperazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyrimidinyl, pyridazinyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, indazolyl, benzoxazolyl, benzothiazolyl, purinyl, oxazolo-pyridyl; More preferably, R c is selected from phenyl; Preferably, R d is selected from phenyl, pyrrolidinyl, piperidinyl, pyranyl, morpholinyl, piperazinyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, indazolyl, benzoxazolyl, benzothiazolyl, purinyl, oxazolo-pyridyl; More preferably, R d is selected from phenyl.

5. The compound of the structure shown in formula (I) according to claim 1, or a pharmaceutically acceptable salt or isotopically substituted derivative thereof, Characterized in that, X is O or S; preferably O; preferably, the number of R 1A is 1, 2, 3 or 4, preferably 1 or 2; preferably, the number of R 1A are each independently selected from -OH, -SH, -CN, cyano, halogen, nitro, carboxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, -CF 3 , CHF 2 or CH 2 F; preferably, the number of R 2A is 1, 2, 3 or 4, preferably 1 or 2; preferably, the number of R 2A are each independently selected from -OH, -SH, -CN, cyano, halogen, nitro, carboxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, -CF 3 , CHF 2 or CH 2 F.

6. A compound of the structure shown in formula (I-a), formula (I-b) or formula (I-c), or a pharmaceutically acceptable salt or isotopically substituted derivative thereof: Wherein: represents a single bond or a double bond, R 2 as described above; Wherein: L is -CH 2 - or -CH=CH-, R 1 as described above; Wherein: R 2 As described above.

7. A compound of the following structure, or a pharmaceutically acceptable salt or isotopically substituted derivative thereof:

8. A method for preparing the compound of formula (I) according to claim 1 or the compound of formula (I-a), formula (I-b) or formula (I-c) according to claim 6: Wherein, R 1 、R 2 as described in claim 1; Among them, represents a single bond or a double bond, R 2 as described in claim 7; Wherein: L is -CH 2 - or -CH=CH-, R 1 as claimed in claim 7; or, wherein: L is -CH 2 - or -CH=CH-, R 1 as described in claim 7; Wherein: R 2 As described above.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or isotopically substituted derivative thereof, and a pharmaceutically acceptable excipient; preferably, the pharmaceutical composition contains 0.01 - 99.99% of the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or isotopically substituted derivative thereof.

10. Use of the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or isotopically substituted derivative thereof, in the preparation of a MAGL inhibitor; preferably, use of the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or isotopically substituted derivative thereof, in the preparation of a drug for preventing and / or treating MAGL-related diseases; preferably, the MAGL-related diseases are central nervous system diseases, metabolic disorders and inflammatory diseases; more preferably, the MAGL-related diseases are depression, anxiety, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, neuropathic pain, inflammatory pain, cancer pain, epilepsy, cancer, fatty liver, non-alcoholic steatohepatitis, liver fibrosis, cholestasis, inflammatory bowel disease.

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