WO2021042911A1 - Magl抑制剂及其制备方法、用途 - Google Patents

Magl抑制剂及其制备方法、用途 Download PDF

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WO2021042911A1
WO2021042911A1 PCT/CN2020/104989 CN2020104989W WO2021042911A1 WO 2021042911 A1 WO2021042911 A1 WO 2021042911A1 CN 2020104989 W CN2020104989 W CN 2020104989W WO 2021042911 A1 WO2021042911 A1 WO 2021042911A1
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Prior art keywords
aryl
alkyl
group
membered heteroaryl
maglz
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PCT/CN2020/104989
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English (en)
French (fr)
Inventor
张贵民
王进欣
姚景春
赵桂芳
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鲁南制药集团股份有限公司
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Priority claimed from CN201910836454.5A external-priority patent/CN111518020A/zh
Priority claimed from CN201910856962.XA external-priority patent/CN112552229A/zh
Priority claimed from CN201910854235.XA external-priority patent/CN112552228A/zh
Priority to MX2022002720A priority Critical patent/MX2022002720A/es
Priority to EP20861878.5A priority patent/EP4043436A4/en
Priority to CA3150147A priority patent/CA3150147A1/en
Application filed by 鲁南制药集团股份有限公司 filed Critical 鲁南制药集团股份有限公司
Priority to CN202080061346.6A priority patent/CN114401946A/zh
Priority to KR1020227007788A priority patent/KR20220058553A/ko
Priority to BR112022004068A priority patent/BR112022004068A2/pt
Priority to JP2022513078A priority patent/JP2022546958A/ja
Priority to AU2020343737A priority patent/AU2020343737A1/en
Priority to US17/640,785 priority patent/US20230090255A1/en
Publication of WO2021042911A1 publication Critical patent/WO2021042911A1/zh

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Definitions

  • the present invention relates to the field of medicine, in particular to a MAGL inhibitor and its preparation method and application.
  • MAGL Monoacylglycerol Lipase
  • the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:
  • R is H or a C 1-5 alkyl group, and the C 1-5 alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, neobutyl, N-pentyl, isopentyl, neopentyl, cyclopentyl or halogen, hydroxy, carboxy, C 1-3 alkyl, C 1-3 alkoxy, C 3-8 cycloalkyl, C 3-8 Heterocyclic group, C 3-8 cycloalkoxy group, aryl group, heteroaryl group substituted C 1-5 alkyl group; the number of R is 0, 1, 2, 3 or 4;
  • Ar 1 and Ar 2 are each independently selected from C 5-18 aryl, heteroaryl, (C6-10 aryl)-C1-4 alkyl-, (C6-10 aryl)-C1-4 alkyl -(C6-10 aryl), (5 to 10-membered heteroaryl)-C1-4 alkyl-(C6-10 aryl), (C6-10 aryl)-(C6-10 aryl), ( C6-10 aryl)-O-(C6-10 aryl), (C6-10 aryl)-O-(5 to 10-membered heteroaryl), (5 to 10-membered heteroaryl)-O-( 5 to 10 membered heteroaryl), (5 to 10 membered heteroaryl)-(5 to 10 membered heteroaryl), any substitution position;
  • X 1 and X 2 are each independently selected from H, hydroxy, carboxy, halogen, acyloxy, C 1-3 alkyl, C 1-3 alkoxy, C 3-8 cycloalkyl, C 3-8 hetero Cyclic group, C 3-8 cycloalkoxy, aryl, heteroaryl, C 1-3 alkyl, C 1-3 alkoxy, C 3-8 ring substituted by hydroxy, carboxy, halogen, alkyl
  • One or more of an alkyl group, a C 3-8 heterocyclic group, a C 3-8 cycloalkoxy group, an aryl group, and a heteroaryl group, and the substituent positions are arbitrary.
  • Ar 1 and Ar 2 are each independently selected from phenyl, C5-18 aryl, heteroaryl, (C6-10 aryl)-(C6-10 aryl), (C6-10 Aryl)-O-(C6-10 aryl);
  • X 1 and X 2 are each independently selected from one or more of H, hydroxyl, halogen, C1-3 alkyl, C1-3 alkoxy, substituted
  • the base position is any position.
  • Ar 1 and Ar 2 are each independently selected from one or more substituents in benzene, naphthalene, diphenyl ether, indole, and biphenyl, and the substitution position is arbitrary.
  • Ar 1 and Ar 2 are each independently selected from C 5-18 aryl, heteroaryl, (C6-10 aryl)-C1-4 alkyl-, (C6-10 aryl)-C1-4 Alkyl-(C6-10 aryl), (5 to 10-membered heteroaryl)-C1-4 alkyl-(C6-10 aryl), (C6-10 aryl)-(C6-10 aryl) , (C6-10 aryl)-O-(C6-10 aryl), (C6-10 aryl)-O-(5 to 10-membered heteroaryl), (5 to 10-membered heteroaryl)-O -(5 to 10 membered heteroaryl), (5 to 10 membered heteroaryl)-(5 to 10 membered heteroaryl), any substitution position;
  • X 1 and X 2 are each independently selected from H, hydroxy, carboxy, halogen, acyloxy, C 1-3 alkyl, C 1-3 alkoxy, C 3-8 cycloalkyl, C 3-8 hetero Cyclic group, C 3-8 cycloalkoxy, aryl, heteroaryl, C 1-3 alkyl, C 1-3 alkoxy, C 3-8 ring substituted by hydroxy, carboxy, halogen, alkyl
  • One or more of an alkyl group, a C 3-8 heterocyclic group, a C 3-8 cycloalkoxy group, an aryl group, and a heteroaryl group, and the substituent positions are arbitrary.
  • the Ar 1 and Ar 2 are each independently selected from C 5-18 aryl, heteroaryl, (C6-10 aryl)-C1-4 alkyl, (C6-10 aryl)-C1 -4 alkyl-(C6-10 aryl), (5 to 10-membered heteroaryl)-C1-4 alkyl-(C6-10 aryl), (C6-10 aryl)-(C6-10 aryl) Group), (C6-10 aryl)-O-(C6-10 aryl), (C6-10 aryl)-O-(5 to 10-membered heteroaryl), (5 to 10-membered heteroaryl) -O-(5 to 10-membered heteroaryl), (5 to 10-membered heteroaryl)-(5 to 10-membered heteroaryl), any substitution position;
  • X 1 and X 2 are each independently selected from H, hydroxy, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 3-8 heterocyclyl, C 3-8 cycloalkoxy, and One or more of hydroxy, carboxyl, halogen, alkyl-substituted C 1-3 alkyl, and C 1-3 alkoxy, and the position of the substituent is arbitrary.
  • Ar 1 is one or more of benzene, naphthalene, diphenyl ether, and biphenyl, and the substitution position is arbitrary;
  • X 1 is one or more of H, methoxy, hydroxyl, fluorine, and chlorine, and the position of the substituent is arbitrary;
  • Ar 2 is benzene
  • X 2 is one or more of H, methyl, dimethyl, methoxy, hydroxy, fluorine, and chlorine, and the position of the substituent is arbitrary.
  • substitution position of Ar 1 is in the meta position.
  • the Ar 1 is one of benzofuranyl, benzimidazolyl, benzoxazolyl, indolyl, benzothienyl, quinolinyl, isoquinolinyl, and purinyl.
  • substitution position is arbitrary;
  • X 1 is one or more of H, methyl, methoxy, hydroxy, fluorine, chlorine, and bromine, and the position of the substituent is arbitrary;
  • Ar 2 is a phenyl group, the position of the substituent is arbitrary;
  • X 2 is one or more of H, methyl, dimethyl, methoxy, hydroxy, fluorine, and chlorine, and the position of the substituent is arbitrary.
  • the above formula 1 can be defined as formula III, as shown in the following formula
  • R 1 is selected from hydroxyl, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, methoxy
  • R 2 is selected from hydroxyl, fluorine, chlorine, bromine, iodine, methyl, ethyl Groups, propyl groups, methoxy groups, phenyl groups, and aromatic groups substituted by hydroxy, hydroxy, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, and methoxy groups.
  • the number of R 1 , R 2 is 0 or 1 or 2 or 3 or 4; the linking mode of R 1 , R 2 and the mother core is not limited to a single single bond connection.
  • the present invention provides a compound of formula b, This compound is used to synthesize a compound of formula I, wherein the Ar 2 and X 2 are those described in formula 1.
  • Fragment A within the dotted line is used instead.
  • the present invention provides a method for synthesizing a compound of formula I, the specific steps are as follows: salt of b or b with Reaction to obtain I; the Ar 1 and X 1 are described in formula 1.
  • the condensing agent is selected from HBTU, DMC, HOBT, HOBT/EDCI, HATU, HATU/DIEPA, DCC, CDI, isopropyl Chloroformate; its structural formulas are as follows:
  • the salt of b or b is obtained by deprotecting a;
  • the base is an organic base, such as N,N-diisopropylethylamine (DIPEA), diethylamine (DEA) or triethylamine (TEA).
  • DIPEA N,N-diisopropylethylamine
  • DEA diethylamine
  • TEA triethylamine
  • the salt of a or a is composed of sm and Or its salt reaction
  • the preparation of sm can be obtained by the prior art, or can be synthesized by those skilled in the art through a limited number of experiments on the basis of the prior art without creative labor.
  • the addition of condensing agent and alkali in this step of the reaction is more conducive to the progress of the reaction.
  • the condensing agent is selected from HBTU, DMC, HOBT, HOBT/EDCI, HATU, HATU/DIEPA, DCC, CDI, isopropyl chloroformate .
  • the reducing agent is preferably at least one of NaBH 4 , KBH 4 , and NaBH 4 /LiCl.
  • the solvents selected for the above or following reactions in the present invention are conventional solvents in the field.
  • the principle of selection is to dissolve the reactants but not participate in the reaction, extract the product or make the corresponding product crystallize in it and separate the impurities.
  • the numbers a, b, etc. used in the present invention are numbers that are convenient to use for describing the general formula. They can be transformed into other numbers in specific embodiments, such as 1, 2, 3, etc., all for convenience of description and do not affect the structural formula.
  • the essence of its reaction equation belongs to the expression of the general formula and the general reaction equation. Those skilled in the art can judge that the substituents of the intermediates in all the above synthetic routes are determined according to the structure of the target compound.
  • the substitution on the benzene ring can be one or more of the meta, meta, and para positions; for the substitution in the aromatic heterocyclic ring, it can be in the 2-, 3-, 4-, 5-position, etc. One or more of.
  • substituents “one or more” and “one or more” all refer to the number of selected substituents, and the specific number is one, two, three, four...specifically,
  • “Ar 1 is benzene, the position of substitution is arbitrary, X 1 is fluorine, one or more of chlorine, and the position of the substituent is arbitrary” includes the para (two), meta (two), and para positions of the phenyl group.
  • (One) can be replaced by one Cl, two Cl, three Cl, or two meta positions are replaced by one Cl and one F respectively, or one Cl in the adjacent position and one F in the para position, and so on.
  • the solvents selected for the above or following reactions in the present invention are conventional solvents in the field.
  • the principle of selection is to dissolve the reactants but not participate in the reaction, extract the product or make the corresponding product crystallize in it and separate the impurities.
  • the reaction when the reactants are in excess, the reaction can be terminated by adding a substance that can react with the excess reactants to perform a quenching reaction.
  • a substance that can react with the excess reactants to perform a quenching reaction.
  • water quenching or saturated ammonium chloride quenching can be used.
  • the purification method of the product in each step of the reaction is selected from the group consisting of extraction, crystallization, solvent removal, and column chromatography; the operations are all conventional techniques in the field. The personnel can handle it according to the specific situation.
  • the general formula and general formula synthesis method of the present invention can derive specific compounds that are not limited to these specific substances, and under the guidance of the general formula and general formula synthesis method of the present invention, those skilled in the art can obtain specific compounds without creative work. , Are all within the scope of the present invention.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned compound, namely the compound covered by the general formula of I target compound and its specific substance representatives, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable pharmaceutical excipients .
  • the application provides a pharmaceutical composition, which comprises the compound described in the application or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition includes, but is not limited to, an oral dosage form, a parenteral dosage form, a topical dosage form, and a rectal dosage form.
  • the composition may be in liquid, solid, semi-solid, gel or aerosol form.
  • the pharmaceutical composition can be oral tablets, capsules, pills, powders, sustained-release preparations, solutions and suspensions, sterile solutions, suspensions or emulsions for parenteral injection, and Ointments or creams for external use, or suppositories for rectal administration.
  • the pharmaceutical composition is in a unit dosage form suitable for single administration of precise doses.
  • the present invention provides all the above-mentioned compounds or their pharmaceutically acceptable salts and pharmaceutical compositions thereof, and their use as monoacylglycerol esterase inhibitors; or their use in the preparation and treatment of pathologies with monoacylglycerol esterase metabolic pathways.
  • the use of drugs that characterize the disease or condition are examples of compounds or their pharmaceutically acceptable salts and pharmaceutical compositions thereof, and their use as monoacylglycerol esterase inhibitors; or their use in the preparation and treatment of pathologies with monoacylglycerol esterase metabolic pathways.
  • the present invention provides a method for inhibiting monoacylglycerol esterase of all the above-mentioned compounds or their pharmaceutically acceptable salts and pharmaceutical compositions thereof.
  • the method includes methods for inhibiting monoacylglycerol esterase in vivo and in vitro. Also provided are methods for treating monoacylglycerol esterase-mediated diseases or disorders with all the above-mentioned compounds or their pharmaceutically acceptable salts and pharmaceutical compositions thereof.
  • the condition is selected from: metabolic disorders (such as obesity); nephropathy (such as acute inflammatory kidney injury and diabetic nephropathy); vomiting or vomiting (such as chemotherapy-induced vomiting); nausea (such as refractory nausea or Chemotherapy-induced nausea); eating disorders (e.g., anorexia or bulimia); neuropathy (e.g., diabetic neuropathy, pellagra neuropathy, alcoholic neuropathy, beriberi neuropathy); neurodegenerative disorders [Multiple Sexual sclerosis (MS), Parkinson's disease (PD), Huntington's disease, dementia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), epilepsy, frontotemporal dementia, sleep disorders, Creutzfeldt-Jakob disease (CJD) Or prion disease]; schizophrenia; depression; bipolar disorder; tremor; dyskinesia; dystonia; spasticity; Tourette's syndrome; withdrawal syndrome [alcohol withdrawal syndrome, antidepressant withdrawal Syndrome, antipsychotic withdrawal syndrome, benz
  • MS multiple sclerosis
  • Devick s disease
  • CNS neuropathy central pontine myelinolysis
  • syphilitic myelopathy leukoencephalopathy
  • Leukodystrophy Leukodystrophy
  • Guillain-Barré syndrome chronic inflammatory demyelinating polyneuropathy
  • anti-myelin-associated glycoprotein (MAG) peripheral neuropathy Charcot-Marie-Tooth disease
  • peripheral neuropathy Myelopathy
  • optic neuropathy progressive inflammatory neuropathy
  • optic neuritis transverse myelitis
  • cognitive impairment such as cognitive impairment related to Down’s syndrome; cognitive impairment related to Alzheimer’s disease ; Cognitive impairment related to PD; mild cognitive impairment (MCI), dementia, cognitive impairment after chemotherapy (PCCI), postoperative cognitive dysfunction (POCD)].
  • MCI mild cognitive impairment
  • POCD postoperative cognitive dysfunction
  • the present invention provides the use of MAGL inhibitors in preparing medicines for treating diseases related to MAGL inhibitors.
  • the disease associated with the MAGL inhibitor is pain, migraine, irritable bowel syndrome, or ulcerative colitis.
  • the pain is traumatic pain or pathological pain.
  • the pathological pain is inflammatory pain or endogenous pain.
  • biogenic inflammatory pain chemical inflammatory pain, blood-derived pain, immunogenic pain, endocrine-derived pain, pain caused by metabolic disease, neurogenic pain, or cardiogenic pain.
  • the pain is transient pain, acute pain or chronic pain.
  • the pain is nervous system pain, cardiovascular system pain, blood system pain, respiratory system pain, digestive system pain, endocrine system pain, urinary system pain, motor system pain or immune system pain.
  • the migraine is ordinary migraine, typical migraine, and cluster migraine.
  • the irritable bowel syndrome is constipation-type irritable bowel syndrome, diarrhea-type irritable bowel syndrome, and constipation-diarrhea alternating-type irritable bowel syndrome.
  • the MAGL inhibitor of the present invention can reduce the number of writhing times in mice caused by acetic acid, prolong the incubation time, and prolong the pain threshold of heat-stimulated mice of the mice's hot plate pain reaction. Has a significant analgesic effect.
  • the MAGL inhibitor of the present invention can significantly prolong the clotting time of migraine models, increase the number of tail suspension activities, and significantly increase the 5-HT level in brain tissue. It has a significant therapeutic effect on migraine.
  • the MAGL inhibitor of the present invention can significantly reduce the AWR score of the irritable bowel syndrome model and reduce the 5-HT levels in the colon and serum. It suggests that it has a significant therapeutic effect on irritable bowel syndrome. Thus, it was confirmed that the compound has the biological activity of preventing and treating irritable bowel syndrome.
  • the MAGL inhibitor of the present invention can significantly increase the length of the colon in the ulcerative colitis model, reduce the total number of blood in the stool, and reduce the IL-1 content.
  • the manufacturer's instructions for the use of the kit can be used, or the reaction and purification can be carried out in a manner known in the art or the instructions of this application.
  • the above-mentioned techniques and methods can be implemented according to the descriptions in a number of summary and more specific documents cited and discussed in this specification according to conventional methods well-known in the art.
  • groups and their substituents can be selected by those skilled in the art to provide stable structural parts and compounds.
  • alkyl refers to a saturated linear or branched hydrocarbon.
  • exemplary alkyl groups include, but are not limited to, linear or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C1-6 alkyl and C1-4 alkyl, respectively And C 1-3 alkyl.
  • Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl Base, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl Butyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl Base, isopentyl, neopentyl, hexyl, etc.
  • the C 1-4 alkyl group mentioned in the text includes C 1-3 alkyl group, C 1-2 alkyl group, C 2-3 alkyl group, and C 2-4 alkyl group. Specific examples include but are not limited to methyl, ethyl , Propyl, isopropyl, n-butyl, isobutyl, neobutyl.
  • Alkoxy refers to alkyloxy.
  • the C 1-3 alkoxy group mentioned herein includes C 1-2 alkoxy group and C 2-3 alkoxy group, specific examples but not limited to methoxy group, ethoxy group, propoxy group and isopropoxy group.
  • cycloalkyl refers to a saturated or partially unsaturated hydrocarbon, such as a monocyclic 5-8 membered ring system or a bicyclic 8-12 membered ring system.
  • the C 3-8 cycloalkyl group described herein contains 3-8, 3-6, 4-6, 6-8, 3-7, or 5-8 carbons, and is referred to herein as a C3-8 cycloalkyl group, C3-6 cycloalkyl or C4-6 cycloalkyl is only different in form, and the meaning is equivalent.
  • Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, or cyclopropyl.
  • heterocyclyl contains a monocyclic 5-8 membered ring system or a bicyclic 8-12 membered ring system containing one or more heteroatoms (e.g., one to three heteroatoms, such as nitrogen, oxygen, and sulfur).
  • C 3-8 heterocyclic group means a monocyclic or polycyclic group having 3 to 8 atoms, which includes a C 3-6 heterocyclic group, a C 4-8 heterocyclic group, a C 5-8 heterocyclic group, and a C 5-8 heterocyclic group.
  • heterocyclic groups include, but are not limited to, morpholinyl, thiomorpholinyl, furanyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3 -Dioxanyl.
  • the C 3-8 cycloalkoxy group is a cycloalkyloxy group, wherein the cycloalkyl group has the same definition as the above cycloalkyl group.
  • aryl refers to an aromatic mono- or multi-carbon ring group of 6 to 12 carbon atoms having at least one aromatic ring.
  • the C6-10 aryl group mentioned in the text includes C6-8 aryl, C6-10 aryl, C6-9 aryl, C7-10 aryl, C8-10 aryl, C6 aryl, C7 aryl, C8 aryl , C9 aryl, C10 aryl.
  • Specific examples include, but are not limited to, phenyl, mono- or poly-hydrocarbyl substituted phenyl, pentacyclopentadienyl, indenyl, naphthyl, and chamomile cyclohydrocarbyl.
  • the phenyl substituted by the mono- or poly-hydrocarbyl group includes but is not limited to tolyl, ethyl phenyl, dimethyl phenyl, propyl phenyl, isopropyl phenyl, methyl ethyl phenyl; trimethyl phenyl , Butyl phenyl, methyl propyl phenyl, methyl isopropyl phenyl, diethyl phenyl, dimethyl ethyl phenyl, tetramethyl phenyl, tert-butyl phenyl, 1,2 ,3,4-Tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl and 1H-indenyl.
  • the C5-18 aryl groups mentioned in the text include C6-10 aryl groups, C11-12 aryl groups, C13-15 aryl groups and C16-18 aryl groups, such as pentyl phenyl, methyl butyl phenyl, methyl iso Butyl phenyl, methyl tert-butyl phenyl, ethyl propyl phenyl, ethyl isopropyl phenyl, methyl methyl propyl phenyl, methyl methyl isopropyl phenyl, trimethyl Ethyl phenyl, pentamethyl phenyl, etc.
  • heteroaryl or heteroaromatic ring or "heteroaromatic group” mentioned in the text refers to a monocyclic aromatic group containing one or more heteroatoms (for example, one to three heteroatoms, such as nitrogen, oxygen, and sulfur).
  • the 5- to 10-membered heteroaryl group described herein includes 5- to 9-membered heteroaryl, 5- to 8-membered heteroaryl, 5- to 7-membered heteroaryl, 5- to 6-membered heteroaryl, and 6- to 10-membered heteroaryl.
  • heteroaryl ring may be connected to adjacent groups through carbon or nitrogen.
  • heteroaryl groups include, but are not limited to: benzofuranyl, isobenzofuranyl, benzo[b]thienyl, benzo[c]thienyl, isoindolyl, benzo[d]isoxazole Group, benzo[c]isoxazolyl, benzo[d]oxazolyl, benzo[d]isothiazolyl, benzo[c]isothiazolyl, benzo[d]thiazolyl, benzo[ d]imidazo
  • R is selected from H and substituted or unsubstituted C 1-5 alkyl groups, the unsubstituted C 1
  • the alkyl group of -5 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, neobutyl, n-pentyl, isopentyl, neopentyl, cyclopentyl;
  • the substituted C 1-5 alkyl group is halogen, hydroxy, amino, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 3-8 cycloalkyl, C 3-8 heterocyclic group, C 3-8 cycloalkoxy, aryl, heteroaryl substituted C 1-5 alkyl.
  • the R is n-propyl or
  • Halogen refers to F, Cl, Br or I.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left.
  • CH 2 O is equivalent to OCH 2 .
  • the "compounds" mentioned in this application include all stereoisomers, geometric isomers, tautomers and isotopes.
  • the compounds of the present application may be asymmetric, for example, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, for example, enantiomers and diastereomers.
  • the compounds of the present application containing asymmetrically substituted carbon atoms can be isolated in an optically pure form or in a racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using chiral raw materials or chiral reagents.
  • the compounds of the application also include tautomeric forms.
  • the tautomeric form is derived from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.
  • the compounds of this application also include all isotopes of atoms, whether in intermediates or final compounds.
  • Isotopic atoms include atoms that have the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • the compounds of this application include compounds in which part of hydrogen or all hydrogen (H) is replaced by tritium (T) and/or deuterium (D); it also includes the replacement of part or all of 12 C by 13 C and/or 14 C Compounds; and other isotopes (such as N, O, P, S) between substitution compounds, such as 14 N and 15 N; 18 O and 17 O; 31 P and 32 P; 35 S and 36 S, etc.
  • the compounds described herein may have one or more stereoisomeric centers, and each isomeric center may exist in the form of R or S configuration or a combination thereof.
  • the compounds described herein may have one or more double bonds, and each double bond may exist in the E (trans) or Z (cis) configuration or a combination thereof.
  • a specific stereoisomer, regioisomer, diastereomer, enantiomer or epimer shall be understood to include all possible isomers, such as stereoisomers Isomers, structural isomers, diastereomers, enantiomers or epimers and mixtures thereof. Therefore, the compounds described herein include all stereoisomers, structural isomers, diastereomers, enantiomers or epimeric forms that differ in configuration and their corresponding mixtures.
  • treatment and other similar synonyms include alleviating, alleviating or ameliorating the symptoms of a disease or condition, inhibiting the disease or condition, for example, preventing the development of the disease or condition, alleviating the disease or condition, making the disease or condition better, and relieving the disease or condition.
  • symptoms caused by a disease, or stop the symptoms of a disease or disease prevent other symptoms, ameliorate or prevent the underlying metabolic cause that causes the symptoms, in addition, the term encompasses the purpose of prevention.
  • the term also includes obtaining therapeutic effects and/or preventive effects.
  • the therapeutic effect refers to curing or improving the underlying disease being treated.
  • the cure or improvement of one or more physiological symptoms related to the underlying disease is also a therapeutic effect.
  • the composition can be administered to patients who are at risk of suffering from a specific disease, or even if a disease diagnosis has not been made, the composition can be administered to patients who have developed one or more physiological symptoms of the disease.
  • an "effective amount” for treatment is the amount of the composition containing the compound disclosed herein that is required to provide significant disease relief clinically. Techniques such as dose escalation tests can be used to determine the effective amount suitable for any individual case.
  • administration refers to methods capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral route, transduodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration.
  • parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical and rectal administration topical and rectal administration.
  • Those skilled in the art are familiar with the application techniques that can be used for the compounds and methods described herein, for example in Goodman and Gilman, The Pharmaceutical Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Science (current edition), Mack Publishing Co., Those discussed in Easton, Pa.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the present application, and is relatively non-toxic, that is, the substance can be administered to an individual without causing adverse biological reactions Or interact with any component included in the composition in an undesirable manner.
  • pharmaceutical composition refers to a mixture of the compound of the present application and at least one pharmaceutically acceptable substance.
  • pharmaceutically acceptable substances include, but are not limited to, carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and/or excipients.
  • carrier refers to a relatively non-toxic substance that facilitates the introduction of the compound of the present application into cells or tissues.
  • pharmaceutically acceptable salt refers to a salt that retains the biological efficacy of the free acid and free base of the specified compound, and has no adverse effects in biology or other aspects.
  • the compounds of the present application also include pharmaceutically acceptable salts.
  • a pharmaceutically acceptable salt refers to a form in which the base group in the parent compound is converted into a salt form.
  • Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of base groups such as amine (amino) groups.
  • the pharmaceutically acceptable salt of the present application can be synthesized from the parent compound, that is, the basic group in the parent compound reacts with 1-4 equivalents of acid in a solvent system. Suitable salts are listed in Remingtong's Pharmaceutical Scicences, 17 th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977).
  • the salt in this application refers to the acid salt formed with organic acid/inorganic acid, and the basic salt formed with organic base/inorganic base.
  • the basic functional group of the compound of the general formula is pyridine or imidazole (but not limited to pyridine or imidazole)
  • the acidic functional group is carboxylic acid (but not limited to carboxylic acid)
  • zwitterion internal salt
  • N-Boc-4 piperidine carboxylic acid (458.6 mg, 2 mmol, 1 eq) was dissolved in 15 ml DCM, DIPEA (0.7 ml, 4 mmol, 2 eq) was added, HATU (912 mg, 2.4 mmol, 1.2 eq) was added, and the mixture was stirred at room temperature for 10 min.
  • Aniline (0.365ml, 4mmol, 2eq) was added, stirred at room temperature for 12h, washed twice with water, washed twice with 0.1M diluted hydrochloric acid, and distilled under reduced pressure to remove the solvent to obtain Intermediate a without purification.
  • Example 2-23 The preparation process of Example 2-23 is based on the general formula synthesis method, which is similar to Example 1, wherein b in Examples 22 and 23 is replaced with The MS results of each target product are equivalent to the theoretical values, and the NMR results are as follows:
  • R 1 is selected from hydroxyl, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, methoxy
  • R 2 is selected from hydroxyl, hydroxyl, fluorine, chlorine, bromine, iodine, methyl , Ethyl, propyl, methoxy, phenyl, and aromatic groups substituted by hydroxy, hydroxy, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, methoxy.
  • the number of R 1 and R 2 is 0 or 1 or 2 or 3 or 4; the way of linking R 1 and R 2 with the mother core is not limited to a single bond.
  • N-Boc-4-piperidine carboxylic acid (20) (229.3 mg, 1 mmol) was dissolved in 10 mL CH 2 Cl 2 and DIPEA (0.35 mL, 2 mmol) and HATU (456 mg, 1.2 mmol) were added.
  • the mixture was stirred at room temperature for 10 min and added 3-Chloroaniline (0.21 mL, 2 mmol), stirred at room temperature for 6 h, washed three times with water, three times with 10% dilute hydrochloric acid, dried over anhydrous Na 2 SO 4 , and removed CH 2 Cl 2 by rotary evaporation to obtain intermediate 21 h without further purification.
  • 100% inhibition control wells should be set up (in a 96-well plate, add 150 microliters of 1X assay buffer, 10 microliters of MAGL, and 10 microliters of DMSO, set up three replicate wells), background wells (each well Add 160 microliters of 1Xassay buffer and 10 microliters of DMSO, and set up three replicate wells). Then, graphad prism 5.0 was used to calculate and fit the IC50 curve of each inhibitor, and the specific values are shown in Table 2.
  • MAGLZ-II-10 0.662 MAGLZ-II-11 0.096 MAGLZ-II-12 ND MAGLZ-II-13 0.926 MAGLZ-II-14 0.333 MAGLZ-II-15 ND MAGLZ-II-16 0.018 MAGLZ-II-17 0.015 MAGLZ-II-18 0.670 MAGLZ-II-19 2.82 MAGLZ-II-18(c) 0.0026 MAGLZ-II-18(a) 2.15 MAGLZ-II-20 9.92 MAGLZ-II-21 ND MAGLZ-II-22 1.77 MAGLZ-II-23 4.03 MAGLZ-II-24 0.275 MAGLZ-II-25 0.139 MAGLZ-II-26 12.2 MAGLZ-II-27 2.90 MAGLZ-II-29 0.252 MAGLZ-II-30 0.011 MAGLZ-II-31 ND MAGLZ-II-11(a) 2.15
  • Detection reagents MAGLZ-II-11, MAGLZ-II-16, MAGLZ-II-17;
  • Administration method subcutaneous injection
  • Test tissue brain, heart, liver, spleen, lung, kidney, pancreas, blood;
  • the three test substances were distributed in the tested brain. Among them, MAGLZ-II-16 had the highest content in the brain, followed by MAGLZ-II-17, and MAGLZ-II-11 was the lowest (see Table 3).
  • Example 38 The effect of the MAGL inhibitor of the present invention on reserpine-induced depression in mice
  • Group design 50 animals per batch, 3 batches; each batch of animals is randomly divided into 5 groups according to body weight: low, medium, and high-dose groups of test products, blank control group and model group. Trial product.
  • MAGLZ-II-17 All indicators of Kruskal-Wallis test are statistically different (P ⁇ 0.05); Mann-Whitney U test
  • the eyelids of the middle dose group had statistical differences (P ⁇ 0.05), but the average value was smaller than that of the model group, and there was no statistical difference in other indicators (P>0.05);
  • MAGLZ-II-16 All indicators of Kruskal-Wallis test are statistically different (P ⁇ 0.05); Mann-Whitney U test
  • the head contact in the middle dose group was statistically different from the model group (P ⁇ 0.05), the average value was larger than that of the model group, and the trend was the same as that of the blank control group, and there was no statistical difference in other indicators (P>0.05);
  • the head contact and voluntary activities of the high-dose group were statistically different from the model group (P ⁇ 0.05), the average value was larger than that of the model group, and the trend was the same as that of the blank control group. There was no statistical difference in other indicators (P>0.05) .
  • MAGLZ-II-16 has a certain effect on reserpine-induced depression.
  • MAGLZ-II-17 may have a strengthening effect on reserpine-induced depression.
  • mice Male ICR mice weighing 18-22g. Animals move under the normal 12h light and 12h dark schedule. The ambient temperature and relative humidity are maintained at 22 ⁇ 1°C and 55 ⁇ 5%, respectively.
  • mice 7 groups of experimental mice, 10 in each group, set as control group (normal saline group), positive control group (fluoxetine hydrochloride capsule, 5mg/kg), 5 MAGLZ-II series administration treatment groups: MAGLZ respectively -II-06, MAGLZ-II-07, MAGLZ-II-11, MAGLZ-II-17, MAGLZ-II-18, the administration concentration is 5mg/kg.
  • All drugs were administered by gavage at a dose of 20 mL/kg body weight, once a day, for 10 days. One hour after the last administration, the animal behavior test was started.
  • mice forced swimming experiment was tested according to the method established by Porsolt (Porsalt R D. Behavior despair in mice: A primary screening test for antidepressants [J]. Arch. Int. Pharmacolodyn. 1977, 229).
  • the mice were forced to swim alone in an open cylindrical container (10cm in diameter and 25cm in height).
  • the water temperature of the container was 25 ⁇ 1°C and the water depth was 19cm.
  • the total time that each animal remained immobile during 6 minutes was recorded as no Active time (in seconds).
  • Each mouse was judged to be immobile when it stopped struggling, and remained suspended in the water, making only the necessary movements to keep its head above the water surface. The reduction in immobile time indicates an antidepressant effect.
  • mice were hung on the tail at a distance of 10 mm from the tail of the box (250 mm ⁇ 250 mm ⁇ 300 mm) and a head distance of 5 cm from the bottom. The noise was tested in a dark room with minimal background, each mouse was hung for 6 minutes, and the immobility time was recorded at the last 4 minute interval. The criterion is that the mouse stops struggling and is completely still.
  • each compound group of the MAGLZ-II series compound MAGLZ-II series can significantly shorten the cumulative immobility time of tail-suspended mice (P ⁇ 0.05) (Table 6).
  • Example 40 The effect of the MAGL inhibitor of the present invention on the number of writhing times in mice caused by acetic acid
  • mice 200 male ICR mice, (20 ⁇ 2)g, were randomly divided into 20 groups according to their body weight, each with 10 mice.
  • the specific grouping situation is as follows: Model group: equal volume of 0.5% sodium carboxymethyl cellulose, ig
  • Positive control group diclofenac sodium 10mg/kg, ig
  • MAGLZ-II-11 low-dose group 7.5mg/kg, ig
  • MAGLZ-II-11 middle dose group 15mg/kg, ig
  • MAGLZ-II-11 high-dose group 30mg/kg, ig
  • MAGLZ-II-11a low-dose group 7.5mg/kg, ig
  • MAGLZ-II-11a middle dose group 15mg/kg, ig
  • MAGLZ-II-11a high-dose group 30mg/kg, ig
  • MAGLZ-II-18a low-dose group 7.5mg/kg, ig
  • MAGLZ-II-18a middle dose group 15mg/kg, ig
  • MAGLZ-II-18a high-dose group 30mg/kg, ig
  • MAGLZ-II-18 low-dose group 7.5mg/kg, ig
  • MAGLZ-II-18 middle dose group 15mg/kg, ig
  • MAGLZ-II-18 high-dose group 30mg/kg, ig
  • MAGLZ-II-18c low-dose group 7.5mg/kg, ig
  • MAGLZ-II-18c middle dose group 15mg/kg, ig
  • MAGLZ-II-18c high-dose group 30mg/kg, ig
  • MAGLZ-II-10 low-dose group 7.5mg/kg, ig
  • MAGLZ-II-10 middle dose group 15mg/kg, ig
  • MAGLZ-II-10 high-dose group 30mg/kg, ig
  • each compound was prepared into a suspension with 0.5% sodium carboxymethylcellulose, and then according to the dosage setting, each administration group was given by gavage; the model group was given an equal volume of 0.5% sodium carboxymethylcellulose by gavage.
  • Intraperitoneal injection of acetic acid in mice caused large and long-lasting painful stimuli in the deep abdominal cavity, causing the mice to writhe.
  • a 0.7% acetic acid saline solution of 0.1ml/10g was intraperitoneally injected.
  • the MAGLZ-II-11, MAGLZ-II-11a, MAGLZ-II-18a, and MAGLZ-II-18c of the present invention can significantly reduce the number of writhing in mice caused by acetic acid and prolong the incubation time.
  • Example 41 The effect of the MAGL inhibitor of the present invention on the painful response of the hot plate in mice
  • mice Put (20 ⁇ 2)g female ICR mice on a smart hot plate instrument at 55 ⁇ 0.5°C, and record the latency (s) from the time when the sole of the mouse touches the hot plate to the hindfoot response after licking as an indicator of pain threshold, and the response is eliminated. Mice with an incubation period of ⁇ 5s or >30s or jumping.
  • Example 40 The grouping and administration are the same as in Example 40.
  • the intragastric administration was continued for 7 days, and the pain threshold of mice in each administration group was measured at 30, 60, 90, and 120 minutes after the last administration, and the pain threshold was calculated as 60s if the pain threshold exceeded 60s.
  • the MAGLZ-II-11, MAGLZ-II-11a, MAGLZ-II-18a, MAGLZ-II-18, and MAGLZ-II-18c of the present invention can significantly prolong the pain threshold of heat-stimulated mice.
  • Example 42 Effect of the MAGL inhibitor of the present invention on the pain threshold of mice with inflammatory pain
  • mice Male SD rats (180 ⁇ 20) g were injected with complete Freund's adjuvant 50 ⁇ L/mouse on the right back plantar, and the control group was injected with corresponding volume of 0.5% sodium carboxymethylcellulose to establish a foot swelling inflammatory pain model. After the model was established, the drug was administered continuously for 7 days, and the rats were given intragastrically once a day. The pain threshold (s) of mice at different time periods after administration was measured before administration, on day 1, day 3, and day 7 after administration.
  • Example 40 The grouping and administration are the same as in Example 40.
  • the MAGLZ-II-11, MAGLZ-II-11a, MAGLZ-II-18a, MAGLZ-II-18, and MAGLZ-II-18c of the present invention can significantly prolong the pain threshold of mice with inflammatory pain.
  • Example 43 The therapeutic effect of the MAGL inhibitor of the present invention on irritable bowel syndrome rats induced by early mother-infant separation
  • Irritable bowel syndrome (Irritable Bowel Syndrome IBS): It is a common functional gastrointestinal disease, manifested by chronic abdominal pain, abdominal discomfort and changes in bowel habits, and there is no obvious intestinal pathology. This experiment mainly explores the therapeutic effect of MAGL inhibitor on irritable bowel syndrome rats induced by early mother-infant separation.
  • Blank group equal volume of 0.5% sodium carboxymethyl cellulose, ig
  • Model group equal volume of 0.5% sodium carboxymethyl cellulose, ig
  • MAGLZ-II-11 low-dose group 7.5mg/kg, ig
  • MAGLZ-II-11 middle dose group 15mg/kg, ig
  • MAGLZ-II-11 high-dose group 30mg/kg, ig
  • MAGLZ-II-11a low-dose group 7.5mg/kg, ig
  • MAGLZ-II-11a middle dose group 15mg/kg, ig
  • MAGLZ-II-11a high-dose group 30mg/kg, ig
  • MAGLZ-II-18a low-dose group 7.5mg/kg, ig
  • MAGLZ-II-18a middle dose group 15mg/kg, ig
  • MAGLZ-II-18a high-dose group 30mg/kg, ig
  • MAGLZ-II-18 low-dose group 7.5mg/kg, ig
  • MAGLZ-II-18 middle dose group 15mg/kg, ig
  • MAGLZ-II-18 high-dose group 30mg/kg, ig
  • MAGLZ-II-18c low-dose group 7.5mg/kg, ig
  • MAGLZ-II-18c middle dose group 15mg/kg, ig
  • MAGLZ-II-18c high-dose group 30mg/kg, ig
  • MAGLZ-II-10 low-dose group 7.5mg/kg, ig
  • MAGLZ-II-10 middle dose group 15mg/kg, ig
  • MAGLZ-II-10 high-dose group 30mg/kg, ig
  • each compound was prepared into a suspension with 0.5% sodium carboxymethylcellulose, and then according to the dosage setting, each administration group was given by gavage; the model group was given an equal volume of 0.5% sodium carboxymethylcellulose by gavage.
  • the newborn SD male rats are separated from the lactating female rats for 3 hours every day, that is, starting at 8:30 in the morning, and the lactating female rats are taken out of the cage , Then remove the newborn rat from the cage and place it in a separate cage, and then transfer this cage to the next room. After 3 hours, that is, at 11:30, return the newborn rat to the original cage. They were reunited, weaned on the 22nd day after birth, and were divided into cages on the 30th day until the 60 days were grouped and administered for a total of 20 days.
  • intragastric administration was performed once a day for 20 days.
  • Test index Abdominal wall withdrawal reflex score (AWR), test method: rats were fasted for 18 hours before the experiment, freely drinking, and anesthetized the rats with ether. Insert the paraffin oil-coated balloon into the rat’s colorectal 4.0cm, and use tape to The extra-anal catheter is fixed at the base of the rat's tail, and the catheter is connected to a syringe and a sphygmomanometer through a three-way connection. The rat was placed in a plexiglass observation box (20cm ⁇ 12cm ⁇ 9cm) for observation, and the experiment was started after the rat was awakened and fully adapted to the environment for 30 minutes.
  • AWR Abdominal wall withdrawal reflex score
  • test method rats were fasted for 18 hours before the experiment, freely drinking, and anesthetized the rats with ether. Insert the paraffin oil-coated balloon into the rat’s colorectal 4.0cm, and use tape to The extra-anal catheter is fixed
  • the pressures of 20, 40, and 60mmHg were given respectively, and the expansion was continued for 20s each time, the stimulation interval was 4min, and the AWR score was repeated 3 times for each pressure.
  • the AWR scoring is based on a single-blind method. The scoring standard: 0 points: no obvious behavior changes; 1 point: only simple head movement; 2 points: abdominal muscles begin to contract, but not lifted off the table; 3 points: abdominal muscles contracted significantly Flatten or lift the lower abdominal wall away from the desktop; 4 points: arched abdominal wall or bowed with the body and pelvis.
  • Colon histological observation After the colon expansion experiment, take the rat's distal colon (5-6cm from the anus) and perform conventional HE staining to observe the inflammation and injury of the intestinal wall.
  • MAGLZ-II-11, MAGLZ-II-11a, MAGLZ-II-18a, MAGLZ-II-18, MAGLZ-II-18c can significantly reduce AWR score, lower colon and serum 5- HT level.
  • Example 44 The effect of the MAGL inhibitor of the present invention on reserpine-induced migraine in mice
  • mice 210 male ICR mice, (20 ⁇ 2) g, were randomly divided into 21 groups according to their body weight, each with 10 mice.
  • the specific grouping situation is as follows: Blank group: equal volume of 0.5% sodium carboxymethyl cellulose, ig
  • Model group equal volume of 0.5% sodium carboxymethyl cellulose, ig
  • Positive control group Zolmitriptan 0.5mg/kg, ig
  • MAGLZ-II-11 low-dose group 7.5mg/kg, ig
  • MAGLZ-II-11 middle dose group 15mg/kg, ig
  • MAGLZ-II-11 high-dose group 30mg/kg, ig
  • MAGLZ-II-11a low-dose group 7.5mg/kg, ig
  • MAGLZ-II-11a middle dose group 15mg/kg, ig
  • MAGLZ-II-11a high-dose group 30mg/kg, ig
  • MAGLZ-II-18a low-dose group 7.5mg/kg, ig
  • MAGLZ-II-18a middle dose group 15mg/kg, ig
  • MAGLZ-II-18a high-dose group 30mg/kg, ig
  • MAGLZ-II-18 low-dose group 7.5mg/kg, ig
  • MAGLZ-II-18 middle dose group 15mg/kg, ig
  • MAGLZ-II-18 high-dose group 30mg/kg, ig
  • MAGLZ-II-18c low-dose group 7.5mg/kg, ig
  • MAGLZ-II-18c middle dose group 15mg/kg, ig
  • MAGLZ-II-18c high-dose group 30mg/kg, ig
  • MAGLZ-II-10 low-dose group 7.5mg/kg, ig
  • MAGLZ-II-10 middle dose group 15mg/kg, ig
  • MAGLZ-II-10 high-dose group 30mg/kg, ig
  • each compound was prepared into a suspension with 0.5% sodium carboxymethylcellulose, and then according to the dosage setting, each administration group was given by gavage; the model group was given an equal volume of 0.5% sodium carboxymethylcellulose by gavage.
  • mice Except for the blank control group by subcutaneous injection of normal saline, the other groups were injected subcutaneously with reserpine solution (0.2mg/kg) for a total of 10 days. After the injection of reserpine, the mice showed closed eyes, crouched and less moved, diarrhea, and eating The model is considered to be successful when the typical symptoms of reserpine are reduced, such as small amount and arched back.
  • both the blank control group and the model group were given intragastric administration of the solvent, and the other groups were given the corresponding drugs and doses respectively.
  • the administration was continued for 10 days.
  • the 5-HT detection method is: the sample is precipitated with a 10% perchloric acid solution 1:1, and the supernatant is taken for detection after centrifugation.
  • Chromatographic conditions Chromatographic column is SHIMADZU VP-ODS C 18 column (250*4.6mm, 5um), mobile phase is methanol-0.01mol/L potassium acetate buffer (10:90, V/V, use 0.2mol/L Adjust the pH to 4.00 with citric acid) isocratic elution, column temperature 25°C, flow rate 1.00ml/min, detection wavelength 275nm.
  • MAGLZ-II-11, MAGLZ-II-11a, MAGLZ-II-18a, MAGLZ-II-18, MAGLZ-II-18c can significantly prolong the clotting time.
  • MAGLZ-II-11, MAGLZ-II-11a, MAGLZ-II-18a, MAGLZ-II-18, MAGLZ-II-18c can significantly increase the number of tail suspension activities.
  • MAGLZ-II-11, MAGLZ-II-11a, MAGLZ-II-18a, MAGLZ-II-18, MAGLZ-II-18c can significantly increase reserpine-induced low 5-HT model The level of 5-HT in mouse brain tissue.
  • mice were quarantined for 7 days after entering the room, and healthy male mice were selected as test animals.
  • the main inspection contents during the quarantine period include, but are not limited to: whether it is consistent with the quantity and quality indicators of the animals required at the time of application; general status; weight; the above-mentioned unqualified animals are not included in this test.
  • Model building After the quarantine, the mice were randomly divided into 21 groups with 10 mice in each group. The normal group was free to drink normal water, and the other groups were free to drink 1.0%-1.5% DSS solution for modeling. After 7 days of modeling, all models were free to drink normal water for 7 days. This 14 days constitutes a modeling cycle for four consecutive Cycle, modeling and administering at the same time.
  • Blank group equal volume of 0.5% sodium carboxymethyl cellulose, ig
  • Model group equal volume of 0.5% sodium carboxymethyl cellulose, ig
  • Positive control group Mesalazine (100mg/kg), ig
  • MAGLZ-II-11 low-dose group 7.5mg/kg, ig
  • MAGLZ-II-11 middle dose group 15mg/kg, ig
  • MAGLZ-II-11 high-dose group 30mg/kg, ig
  • MAGLZ-II-11a low-dose group 7.5mg/kg, ig
  • MAGLZ-II-11a middle dose group 15mg/kg, ig
  • MAGLZ-II-11a high-dose group 30mg/kg, ig
  • MAGLZ-II-18a low-dose group 7.5mg/kg, ig
  • MAGLZ-II-18a middle dose group 15mg/kg, ig
  • MAGLZ-II-18a high-dose group 30mg/kg, ig
  • MAGLZ-II-18 low-dose group 7.5mg/kg, ig
  • MAGLZ-II-18 middle dose group 15mg/kg, ig
  • MAGLZ-II-18 high-dose group 30mg/kg, ig
  • MAGLZ-II-18c low-dose group 7.5mg/kg, ig
  • MAGLZ-II-18c middle dose group 15mg/kg, ig
  • MAGLZ-II-18c high-dose group 30mg/kg, ig
  • MAGLZ-II-10 low-dose group 7.5mg/kg, ig
  • MAGLZ-II-10 middle dose group 15mg/kg, ig
  • MAGLZ-II-10 high-dose group 30mg/kg, ig
  • each compound was prepared into a suspension with 0.5% sodium carboxymethylcellulose, and then according to the dosage setting, each administration group was given by gavage; the model group was given an equal volume of 0.5% sodium carboxymethylcellulose by gavage.
  • Experimental end point four cycles of experimental administration, anatomy on the third and fourth days of the recovery period of the fourth cycle.
  • Detection indicators weigh the weight of the mice twice a week after starting the administration; observe the diarrhea and blood in the stool, and record the number of blood in the stool.
  • the animals were dissected, weighed, the animals were anesthetized, blood was taken, and the serum was stored at -80°C. Take the spleen, weigh the spleen, and calculate the spleen index.
  • ELISA detects the content of IL-1 ⁇ in serum. The colorectal was cut, and the length of the colorectal was measured, fixed with formaldehyde, HE stained, and pathological changes were detected.
  • Table 14 The effect of the MAGL inhibitor of the present invention on the length of the colon, the number of blood in the stool, and the content of IL-1
  • MAGLZ-II-11, MAGLZ-II-11a, MAGLZ-II-18a, MAGLZ-II-18, MAGLZ-II-18c can significantly increase the length of the colon, reduce the total number of blood in the stool, and reduce IL -1 content.

Abstract

本发明属于药物领域，涉及一种作为MAGL抑制剂的式（Ⅰ）化合物及其药学上可接受的盐，及其制备方法、用途，和用于制备其的中间体。

Description

MAGL抑制剂及其制备方法、用途 技术领域
本发明涉及药物领域，特别涉及一种MAGL抑制剂及其制备方法和用途。
背景领域
单酰基甘油脂肪酸酶(Monoacylglycerol Lipase,MAGL)是一类促进脂肪分解成甘油和脂肪酸的丝氨酸水解酶，在人侵袭性肿瘤细胞和原发性肿瘤细胞内高表达。高水平的MAGL能够通过提高自由脂肪酸的水平来维持肿瘤细胞的高致病性。MAGL已成为抗肿瘤药物研发的重要靶点。
发明内容：
本发明提供式I化合物或其药学上可接受的盐：
Figure PCTCN2020104989-appb-000001
其中，R为H或C 1-5的烷基，所述C 1-5的烷基选自甲基，乙基，丙基，异丙基，正丁基，异丁基，新丁基，正戊基，异戊基，新戊基，环戊基或被卤素、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 3-8环烷基、C 3-8杂环基、C 3-8环烷氧基、芳基、杂芳基取代的C 1-5的烷基；R的个数为0,1,2,3或4；
Ar 1、Ar 2分别独立地选自C 5-18的芳基、杂芳基，(C6-10芳基)-C1-4烷基-，(C6-10芳基)-C1-4烷基-(C6-10芳基)，(5至10元杂芳基)-C1-4烷基-(C6-10芳基)，(C6-10芳基)-(C6-10芳基)，(C6-10芳基)-O-(C6-10芳基)，(C6-10芳基)-O-(5至10元杂芳基)，(5至10元杂芳基)-O-(5至10元杂芳基)，(5至10元杂芳基)-(5至10元杂芳基)，取代位置任意；
X 1、X 2分别独立地选自H，羟基，羧基，卤素，酰氧基，C 1-3烷基，C 1-3烷氧基，C 3-8环烷基，C 3-8杂环基，C 3-8环烷氧基，芳基，杂芳基，被羟基、羧基、卤素、烷基取代的C 1-3烷基、C 1-3烷氧基、C 3-8环烷基、C 3-8杂环基、C 3-8环烷氧基、芳基、杂芳基中的一种或 多种，取代基位置任意。
在一些实施例中，Ar 1、Ar 2分别独立地选自苯基，C5-18的芳基、杂芳基，(C6-10芳基)-(C6-10芳基)，(C6-10芳基)-O-(C6-10芳基)；X 1、X 2分别独立地选自H，羟基，卤素，C1-3烷基，C1-3烷氧基中的一个或多个，取代基位置为任意位置。
在一些实施方案中，Ar 1、Ar 2分别独立地选自苯，萘，二苯醚，吲哚，联苯中的一种或多种取代基，取代位置任意。
上述式I化合物或其药学上可接受的盐，所述的R取H，则相应的结构式为
Figure PCTCN2020104989-appb-000002
其中，Ar 1、Ar 2分别独立地选自C 5-18的芳基、杂芳基，(C6-10芳基)-C1-4烷基-，(C6-10芳基)-C1-4烷基-(C6-10芳基)，(5至10元杂芳基)-C1-4烷基-(C6-10芳基)，(C6-10芳基)-(C6-10芳基)，(C6-10芳基)-O-(C6-10芳基)，(C6-10芳基)-O-(5至10元杂芳基)，(5至10元杂芳基)-O-(5至10元杂芳基)，(5至10元杂芳基)-(5至10元杂芳基)，取代位置任意；
X 1、X 2分别独立地选自H，羟基，羧基，卤素，酰氧基，C 1-3烷基，C 1-3烷氧基，C 3-8环烷基，C 3-8杂环基，C 3-8环烷氧基，芳基，杂芳基，被羟基、羧基、卤素、烷基取代的C 1-3烷基、C 1-3烷氧基、C 3-8环烷基、C 3-8杂环基、C 3-8环烷氧基、芳基、杂芳基中的一种或多种，取代基位置任意。
具体的，所述Ar 1、Ar 2分别独立地选自C 5-18的芳基、杂芳基，(C6-10芳基)-C1-4烷基，(C6-10芳基)-C1-4烷基-(C6-10芳基)，(5至10元杂芳基)-C1-4烷基-(C6-10芳基)，(C6-10芳基)-(C6-10芳基)，(C6-10芳基)-O-(C6-10芳基)，(C6-10芳基)-O-(5至10元杂芳基)，(5至10元杂芳基)-O-(5至10元杂芳基)，(5至10元杂芳基)-(5至10元杂芳基)，取代位置任意；
X 1、X 2分别独立地选自H，羟基，卤素，C 1-3烷基，C 1-3烷氧基，，C 3-8杂环基，C 3-8环烷氧基，被羟基、羧基、卤素、烷基取代的C 1-3烷基、C 1-3烷氧基中的一种或多种，取代基位置任意。
在一些实施方案中，Ar 1为苯，萘，二苯醚，联苯中的一种或多种，取代位置任意；
X 1为H，甲氧基，羟基，氟，氯中的一种或多种，取代基位置任意；
Ar 2为苯；
X 2为H，甲基，二甲基，甲氧基，羟基，氟，氯中的一种或多种，取代基位置任意。
在具体方案中所述Ar 1的取代位置在间位。
在一些实施方案中，所述Ar 1为苯并呋喃基、苯并咪唑基、苯并恶唑基、吲哚基、苯并噻吩基、喹啉基、异喹啉基、嘌呤基中的一种或多种，取代位置任意；
X 1为H，甲基，甲氧基，羟基，氟，氯，溴中的一种或多种，取代基位置任意；
Ar 2为苯基，取代基位置任意；
X 2为H，甲基，二甲基，甲氧基，羟基，氟，氯中的一种或多种，取代基位置任意。在一些实施例中，上述式1可以限定为式III，如下式所示
Figure PCTCN2020104989-appb-000003
其中，所述的R 1选自羟基、氟、氯、溴、碘、甲基、乙基、丙基、甲氧基；R 2选自羟基、氟、氯、溴、碘、甲基、乙基、丙基、甲氧基、苯基、以及被羟基、羟基、氟、氯、溴、碘、甲基、乙基、丙基、甲氧基取代的芳香基。R 1、R 2的个数为0或1或2或3或4；R 1、R 2与母核的链接方式不限于单个单键连接。
本发明提供一种如式b化合物，
Figure PCTCN2020104989-appb-000004
该化合物用于合成式I化合物，其中，所述Ar 2、X 2为式1所述。
在有些实施例中，
Figure PCTCN2020104989-appb-000005
中虚线内的片段A用
Figure PCTCN2020104989-appb-000006
Figure PCTCN2020104989-appb-000007
代替。
本发明提供一种如式I化合物的合成方法，具体步骤如下：
Figure PCTCN2020104989-appb-000008
b或b的盐与
Figure PCTCN2020104989-appb-000009
反应，得到I；所述Ar 1、X 1为式1所述。
所述b或b的盐与
Figure PCTCN2020104989-appb-000010
反应，得到I；该步反应中加入缩合剂和碱，更有利于反应进行，所述的缩合剂选自HBTU、DMC、HOBT、HOBT/EDCI、HATU、HATU/DIEPA、D C C、C D I、异丙基氯甲酸酯；其结构式分别如下：
所述b或b的盐是由a脱保护而得；
Figure PCTCN2020104989-appb-000011
所述的碱为有机碱，如N，N-二异丙基乙胺(DIPEA)、二乙胺(DEA)或三乙胺(TEA)。
所述a或a的盐是由sm与
Figure PCTCN2020104989-appb-000012
或其盐反应而得；
Figure PCTCN2020104989-appb-000013
其中，sm的制备可由现有技术得到，或者由本领域技术人员在现有技术的基础上通过有限次的试验无需付出创造性劳动即可合成得到。该步反应中加入缩合剂和碱，更有利于反应进行，所述的缩合剂选自HBTU、DMC、HOBT、HOBT/EDCI、HATU、HATU/DIEPA、DCC、CDI、异丙基氯甲酸酯。
在一些具体实施方式中，可以采取以下方法进行：
Figure PCTCN2020104989-appb-000014
其中，所述的还原剂优选NaBH 4、KBH 4、NaBH 4/LiCl中的至少一种。
未经特别说明，本发明上述或下述的各步反应所选用的溶剂为本领域常规溶剂，其选用原则是溶解反应物但不参与反应，萃取产物或使相应产物在其中结晶与杂质分离，如水、卤代烷烃、烷胺、脂肪烃类、酯类、醇类、芳香烃类、醚类、杂环类溶剂；具体选自，但不限于这些溶剂：甲醇、乙醇、丙醇、异丙醇、乙醚、乙酸乙酯、乙酸、环己烷、二氯甲烷、三氯甲烷、四氢呋喃、吡啶、二乙胺、三乙胺、二甲基甲酰胺、甲苯及其中至少两种的混合。
本发明所用a，b等编号是为了叙述通式方便采用的编号，它们在具体实施例中可以将其变形为其它编号，如1,2,3等，均是为了方便叙述，不影响其结构式及其反应方程式的实质属于通式及通式反应方程式的表达。本领域技术人员能够判断上述所有合成路线中的各中间体的取代基均根据目标化合物的结构而定。
通式I目标化合物通式所涵盖的化合物及其具体物质代表中的手性异构或顺反异构体及异构体间以任何比例的混合物亦涵盖在通式I目标化合物通式所涵盖的化合物及其具体物质代表范围内。
关于“取代位置任意”可理解为在价键适宜的情况下的任何一个选择。如在苯环上的取代，可为临位、间位、对位中的一个或多个；如在芳杂环中的取代，可为2-、3-、4-、5-位等中的一个或多个。关于取代基的选择，“一个或多个”、“一种或多种”均指所选取代基的个数，且具体个数为一个、二个、三个、四个……具体的，如“Ar 1为苯，取代位置任意，X 1为氟，氯中的一种或多种，取代基位置任意”包括苯基的临位(两个)、间位(两个)、对 位(一个)上可以被一个Cl、两个Cl、三个Cl取代或两个间位被一个Cl和一个F分别取代或临位上一个Cl而对位上一个F取代，依次类推。
未经特别说明，本发明上述或下述的各步反应所选用的溶剂为本领域常规溶剂，其选用原则是溶解反应物但不参与反应，萃取产物或使相应产物在其中结晶与杂质分离，如水、卤代烷烃、烷胺、脂肪烃类、酯类、醇类、芳香烃类、醚类、杂环类溶剂；具体选自，但不限于这些溶剂：甲醇、乙醇、丙醇、异丙醇、乙醚、乙酸乙酯、乙酸、环己烷、二氯甲烷、三氯甲烷、四氢呋喃、吡啶、二乙胺、三乙胺、二甲基甲酰胺、甲苯及其中至少两种的混合。
未经特别说明，本发明上述或下述的各反应中，当反应物有过量时，反应终止可采用加入可与过量反应物反应的物质进行淬灭反应。如有的实施例中可采用水淬灭或采用饱和氯化铵淬灭。
未经特别说明，本发明上述或下述的各反应中，各步反应中的产物的纯化方式选自萃取、结晶、除溶剂、柱层析；其操作均为本领域常规技术，本领域技术人员能够根据具体情况进行处理。
本发明的通式以及通式合成方法可以衍生出不限于这些具体物质，且在本发明的通式和通式合成方法的指导下，本领域技术人员不需要付出创造性劳动即可得到的具体化合物，均在本发明范围内。
虽然本文已经显示和描述了本发明的优选实施方案，但对本领域技术人员显而易见的是，此类实施方案仅通过举例的方式提供。现在，本领域技术人员会想到不背离本发明的许多改变、变化和替代。应理解的是，对本发明所述的本发明实施方案的各种替代可用于实施本发明。所附权利要求旨在限定本发明范围，并且由此覆盖了在这些权利要求范围内的方法和结构及其等同形式。
本发明提供药物组合物，包含上述化合物，即I目标化合物通式所涵盖的化合物及其具体物质代表，或其药学上可接受的盐，和一种或多种药学上可接受的药用辅料。
本申请提供了一种药物组合物，其包含本申请所述的化合物或其药学可接受的盐和药学可接受的载体。所述药物组合物包括但不限于口服剂型、胃肠外给药剂型、外用剂型和直肠给药剂型。所述组合物可以是液体、固体、半固体、凝胶或气溶胶形式。在一些实施方式中，所述药物组合物可以是口服的片剂、胶囊、丸剂、粉剂、缓释制剂、溶液和悬浮液，用于胃肠外注射的无菌溶液、悬浮液或乳液，用于外用的软膏或乳膏，或者用于直肠给药的栓剂。在其它实施方式中，所述药物组合物为适合单次施予精确剂量的单位剂型。
本发明提供了上述所有化合物或其药学上可接受的盐及其药物组合物，其作为单酰基甘油酯酶抑制剂的用途；或其用于制备治疗具有单酰基甘油酯酶代谢途径的病理学特征的疾病或病症的药物的用途。
本发明提供了上述所有化合物或其药学上可接受的盐及其药物组合物用于抑制单酰基甘油酯酶的方法。该方法包括体内和体外抑制单酰基甘油酯酶的方法。还提供了上述所有化合物或其药学上可接受的盐及其药物组合物用于治疗单酰基甘油酯酶介导的疾病或病症的方法。
其中，所述病症选自：代谢紊乱(例如肥胖症)；肾病(例如急性炎症性肾损伤及糖尿病肾病)；呕吐或涌吐(例如化学疗法诱导的呕吐)；恶心(例如难治性恶心或化学疗法诱导的恶心)；进食障碍(例如厌食症或贪食症)；神经病变(例如糖尿病神经病变、糙皮病性神经病变、酒精性神经病变、脚气病神经病变)；神经变性病症[多发性硬化(MS)、帕金森病(PD)、亨廷顿病、痴呆、阿尔茨海默病、肌萎缩侧索硬化(ALS)、癫痫、额颞叶痴呆、睡眠障碍、克雅氏病(CJD)或朊病毒病]；精神分裂症；抑郁症；双相障碍；震颤；运动障碍；张力失常；痉挛状态；图雷特氏综合征；戒断综合征[戒酒综合征、抗抑郁药停药综合征、抗精神病药停药综合征、苯并二氮停药综合征、大麻戒断、新生儿戒断、尼古丁戒断或阿片类戒断]；外伤性脑损伤；非外伤性脑损伤；脊髓损伤；癫痫发作；与异常细胞生长或增殖有关的病症[例如良性肿瘤或癌症，例如良性皮肤肿瘤、脑瘤、乳头状瘤、前列腺肿瘤、脑肿瘤(胶质母细胞瘤、髓上皮瘤、髓母细胞瘤、神经母细胞瘤、星形细胞瘤、星形母细胞瘤、室管膜瘤、少突神经胶质瘤、丛肿瘤、神经上皮瘤、骨骺肿瘤、室管膜母细胞瘤、恶性脑膜瘤、肉瘤病、黑色素瘤、神经鞘瘤)、黑色素瘤、转移性肿瘤、肾癌、膀胱癌、脑癌、胶质母细胞瘤(GBM)、胃肠癌、白血病或血癌]；炎症性病症[例如阑尾炎、滑囊炎、结肠炎、肠易激综合征、溃疡性结肠炎、膀胱炎、皮炎、静脉炎、鼻炎、肌腱炎、扁桃体炎、血管炎、寻常痤疮、慢性前列腺炎、肾小球肾炎、超敏反应、IBS、盆腔炎性疾病、结节病、HIV脑炎、狂犬病、脑脓肿、神经炎症、中枢神经系统(CNS)炎症]；免疫系统病症(例如移植排斥或乳糜泻)；创伤后应激障碍(PTSD)；急性应激障碍；惊恐障碍；物质诱导性焦虑；强迫症(OCD)；广场恐怖症；特定恐怖症；社交恐怖症；焦虑症；注意缺陷障碍(ADD)；注意缺陷多动障碍(ADHD)；疼痛[例如急性疼痛；慢性疼痛；炎症性疼痛；内脏痛；手术后疼痛；偏头痛；下腰痛；关节疼痛；腹痛；胸痛；乳房切除术后疼痛综合征；月经疼痛；子宫内膜异位症疼痛；由物理创伤所致的疼痛；头痛；窦性头痛；紧张性头痛、蛛网膜炎、疱疹病毒疼痛、糖尿病性疼痛；由选自以下的病症所致的疼痛：骨关节炎、类风湿性关节炎、骨关节炎、 脊椎炎、痛风、阵痛、肌骨骼疾病、皮肤病、牙痛、胃灼热、烧伤、晒伤、蛇咬伤、毒蛇咬伤、蜘蛛咬伤、昆虫叮咬、神经源性膀胱、间质性膀胱炎、尿路感染(UTI)、鼻炎、接触性皮炎/超敏反应、发痒、湿疹、咽炎、黏膜炎、肠炎、肠易激综合征(IBS)、胆囊炎及胰腺炎；神经性疼痛(例如神经性腰痛、复杂性区域疼痛综合征、支柱三叉神经痛、灼性神经痛、中毒性神经病、反射性交感神经营养不良、糖尿病神经病变、化学治疗剂所致的慢性神经病变或坐骨神经痛疼痛)]；脱髓鞘病[例如多发性硬化(MS)、德维克氏病、CNS神经病变、脑桥中央髓鞘溶解、梅毒性脊髓病、脑白质病、脑白质营养不良症、格林-巴利综合征、慢性炎症性脱髓鞘性多神经病、抗髓磷脂相关糖蛋白(MAG)周围神经病变、夏科-马里-图思病、周围神经病变、脊髓病变、视神经病变、进展性炎症性神经病变、视神经炎、横贯性脊髓炎]；及认知损害[例如与唐氏综合征有关的认知损害；与阿尔茨海默病有关的认知损害；与PD有关的认知损害；轻度认知损害(MCI)、痴呆、化学疗法后认知损害(PCCI)、手术后认知功能障碍(POCD)]。
本发明提供MAGL抑制剂制备治疗MAGL抑制剂相关的疾病药物中的用途。
在一些实施例中，MAGL抑制剂相关的疾病是疼痛、偏头痛、肠易激综合征或溃疡性结肠炎。
在上述用途中所述疼痛为创伤性疼痛或病理性疼痛。进一步地，所述病理性疼痛为炎性疼痛或内源性疼痛。更进一步地为，生物源性炎症疼痛、化学源性炎症疼痛、血液源性疼痛、免疫源性疼痛、内分泌源性疼痛、代谢性病变引起的疼痛、神经源性疼痛或心源性疼痛。
在上述用途中，所述疼痛为短暂性疼痛、急性疼痛或慢性疼痛。
在上述用途中，所述疼痛为神经系统疼痛、心血管系统疼痛、血液系统疼痛、呼吸系统疼痛、消化系统疼痛、内分泌系统疼痛、泌尿系统疼痛、运动系统疼痛或免疫系统疼痛。
在上述用途中，所述偏头痛为普通型偏头痛、典型性偏头痛、丛集性偏头痛。
在上述用途中，所述肠易激综合症为便秘型肠易激综合症、腹泻型肠易激综合症、便秘腹泻交替型肠易激综合症。
本发明MAGL抑制剂能够减少醋酸引起的小鼠扭体次数，延长潜伏时间，延长小鼠热板致痛反应的热刺激小鼠痛阈。具有显著的镇痛效果。
在一些实施例中，本发明MAGL抑制剂能够显著延长偏头痛模型凝血时间，增加悬尾活动次数，显著升高脑组织中5-HT水平。对于偏头痛呈现显著的治疗效果。
本发明MAGL抑制剂能够显著降低肠易激综合症模型AWR评分、降低结肠及血清中 5-HT水平。提示对肠易激综合征具有显著的治疗效果。从而证实了该类化合物具有防治肠易激综合症的生物活性。
本发明MAGL抑制剂能够显著增加溃疡性结肠炎模型中结肠长度，减少便血总次数，降低IL-1含量。
某些化学术语
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本申请主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”都属非限制性描述。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4 TH ED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/Vis光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本申请的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
本文所用术语“烷基”是指饱和直链或支链的烃。示例性烷基包括，但不限于，1-6、1-4或1-3个碳原子的直链或支链的烃，在本文分别称为C1-6烷基、C 1-4烷基和C 1-3烷基。示例性烷基包括，但不限于甲基、乙基、丙基、异丙基、2-甲基-1-丁基、3-甲基-2-丁基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-1-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2,2-二甲基-1-丁基、3,3-二甲基-1-丁基、2-乙基-1-丁基、丁基、异丁基、叔丁基、戊基、异戊基、新戊基、己基等。
文中所述C 1-4烷基，包括C 1-3烷基、C 1-2烷基、C 2-3烷基、C 2-4烷基，具体举例包括但 不限于甲基，乙基，丙基，异丙基，正丁基，异丁基，新丁基。
烷氧基即烷基氧基。文中所述C 1-3烷氧基，包含C 1-2烷氧基、C 2-3烷氧基，具体举例但不限于甲氧基，乙氧基，丙氧基，异丙氧基。
本文所用术语“环烷基”是指饱和的或部分不饱和的烃，如单环5-8元环体系或双环8-12元环体系。文中所述C 3-8环烷基，包含3-8、3-6、4-6、6-8、3-7或5-8个碳，在本文中称作C3-8环烷基、C3-6环烷基或C4-6环烷基只是形式不同，意义是等同的。示例性的环烷基包括，但不限于，环己基、环戊基、环戊烯基、环丁基或环丙基。
如本文所用的术语“杂环基”含有一个或多个杂原子(例如一至三个杂原子，例如氮、氧和硫)的单环5-8元环体系或双环8-12元环体系。如本文所述C 3-8杂环基表示具有3至8个原子的单环或多环基团，其包含C 3-6杂环基、C 4-8杂环基、C 5-8杂环基、C 4-7杂环基、C 3-7杂环基、C 6-8杂环基；其具有至少一个含有1、2、3或4个选自N、O或S的环杂原子的环，其中的环都不是芳香族的。杂环基的实例包括但不限于吗啉基、硫代吗啉基、呋喃基、哌嗪基、哌啶基、吡喃基、吡咯烷基、四氢吡喃基、四氢呋喃基和1,3-二噁烷基。
C 3-8环烷氧基即环烷基氧基，其中所述的环烷基同上述环烷基的释义。
本文所用的术语“芳基”是指具有至少一个芳族环的6至12个碳原子的芳族单或多碳环基团。文中所述C6-10芳基，包含C6-8芳基、C6-10芳基C6-9芳基、C7-10芳基、C8-10芳基、C6芳基、C7芳基、C8芳基、C9芳基、C10芳基。具体举例包含但不限于苯基，一元或多元烃基取代的苯基，并环戊二烯基，茚基，萘基，甘菊环烃基。其中一元或多元烃基取代的苯基包括但不限于甲苯基，乙基苯基，二甲基苯基，丙基苯基，异丙基苯基，甲基乙基苯基；三甲基苯基，丁基苯基，甲基丙基苯基，甲基异丙基苯基，二乙基苯基，二甲基乙基苯基，四甲基苯基，叔丁基苯基，1,2,3,4-四氢萘基，1,2-二氢萘基，茚满基和1H-茚基。
文中所述C5-18的芳基包括C6-10芳基、C11-12芳基、C13-15芳基以及C16-18芳基，如戊基苯基，甲基丁基苯基，甲基异丁基苯基，甲基叔丁基苯基，乙基丙基苯基，乙基异丙基苯基，甲基甲基丙基苯基，甲基甲基异丙基苯基，三甲基乙基苯基，五甲基苯基等。
文中所述杂芳基或杂芳环或“杂芳族基团”是指含有一个或多个杂原子(例如一至三个杂原子，例如氮、氧和硫)的单环芳族5-8元环体系或双环芳族8-12元环体系。文中所述5至10元杂芳基包含5至9元杂芳基、5至8元杂芳基、5至7元杂芳基、5至6元杂芳基、6至10元杂芳基、6至9元杂芳基、6至8元杂芳基、7至10元杂芳基、7至9元杂芳基、8至10元杂芳基、9至10元杂芳基、5元杂芳基、6元杂芳基、7元杂芳基、8元杂芳基、 9元杂芳基、10元杂芳基。如果可能，所述杂芳基环可通过碳或氮连接至相邻基团。实例包括但不限于：呋喃基、噻吩基、1H-1,2,3-三唑基、2H-1,2,3-三唑基、嘧啶基、吡嗪基、1,3,5-三嗪基、1,2,4-三嗪基、1,2,3-三嗪基、1,2,4-噁二唑基、1,3,4-噁二唑基、8-12元双环杂芳基的实例包括但不限于：苯并呋喃基、异苯并呋喃基、苯并[b]噻吩基、苯并[c]噻吩基、异吲哚基、苯并[d]异噁唑基、苯并[c]异噁唑基、苯并[d]噁唑基、苯并[d]异噻唑基、苯并[c]异噻唑基、苯并[d]噻唑基、苯并[d]咪唑基、苯并[d]咪唑基、和苯并[d][1,2,3]三唑基、噁唑基、噻唑基、咪唑基、吡咯基、吡唑基、异噁唑基、异噻唑基、1,2,4-噁二唑-5-基、1,2,4-噁二唑-3-基、1,3,4-噁二唑基、1,2,5-噁二唑基、1,2,3-噁二唑基、1,2,4-噻二唑-5-基、1,2,4-噻二唑-3-基、1,2,5-噻二唑基、1,3,4-噻二唑基、1,2,3-噻二唑基、1,2,4-三唑基、1,2,3-三唑基、四唑基、吲哚基、苯并噻唑基、苯并噁唑基、苯并咪唑基、苯并异噻唑基和咪唑并[1,2-α]吡啶基,哒嗪基、1,2,4-噁二唑基、1,2,4-噻二唑基、吡啶基、苯并异噁唑基。
本文中所述“苯，萘……中的一种或多种取代基”或“苯，萘……中的一种或多种”均是指苯基、萘基……中的一种或二种或三种。
术语“酰氧基”即“酰基氧基”是指基团—O-C(＝O)-R；R选自H以及取代或未取代的C 1-5的烷基，所述未取代的C 1-5的烷基选自甲基，乙基，丙基，异丙基，正丁基，异丁基，新丁基，正戊基，异戊基，新戊基，环戊基；所述取代的C 1-5的烷基为被卤素、羟基、氨基、羧基、C 1-3烷基、C 1-3烷氧基、C 3-8环烷基、C 3-8杂环基、C 3-8环烷氧基、芳基、杂芳基取代的C 1-5的烷基。在有些实施例中，所述R为正丙基或
Figure PCTCN2020104989-appb-000015
卤素，本文所用术语“卤”或“卤素”是指F、Cl、Br或I。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，CH 2O等同于OCH 2。
本申请所述的“化合物”是指包括所有立体异构体、几何异构体、互变异构体和同位素。本申请化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本申请的含有不对称取代碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。本申请化合物还包括互变异构体形式。互变异构体形式来源于一个单键与相邻的双键交换并一起伴随一个质子的迁移。本申请的化合物还包括所有同位素的原子，无论是在中间体或最后的化合物。同位素的原子包括具有相同的原子数，但不同质量数。例如，氢的同位素包括氚和氘。也就是说，本申请的化 合物包括部分氢或全部氢(H)被氚(T)和/或氘(D)所替代的化合物；还包括部分或全部 12C被 13C和/或 14C替代的化合物；以及其他同位素(如N,O,P,S)之间替代的化合物,如 14N与 15N； 18O与 17O； 31P与 32P； 35S与 36S等。本文所述化合物可具有一个或多个立体异构中心，且各个异构中心可以以R或S构型或其组合的形式存在。类似地，本文所述化合物可具有一个或多个双键，且各双键可以以E(反式)或Z(顺式)构型或其组合的形式存在。一个特定的立体异构体、结构异构体(regioisomer)、非对映异构体、对映异构体或差向异构体应被理解为包括所有可能的异构体，如立体异构体、结构异构体、非对映异构体、对映异构体或差向异构体及其混合物。因此，本文所述化合物包括所有构型上不同的立体异构体、结构异构体、非对映异构体、对映异构体或差向异构体形式以及其相应的混合物。用于转化特定立体异构体或使特定立体异构体保持原状的技术，以及拆分立体异构体混合物的技术是本领域熟知的，本领域技术人员能够就具体情况选择适合的方法。参见，例如Fumiss et al.(eds.),VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；and Heller,Acc.Chem.Res.1990,23,128。
术语“任选/任意”或“任选地/任意地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。
某些药学术语
本文所用的术语“治疗”和其它类似的同义词包括缓解、减轻或改善疾病或病症症状，抑制疾病或病症，例如阻止疾病或病症的发展，缓解疾病或病症，使疾病或病症好转，缓解由疾病或病症导致的症状，或者中止疾病或病症的症状，预防其它症状，改善或预防导致症状的潜在代谢原因，此外，该术语包含预防的目的。该术语还包括获得治疗效果和/或预防效果。所述治疗效果是指治愈或改善所治疗的潜在疾病。此外，对与潜在疾病相关的一种或多种生理症状的治愈或改善也是治疗效果，例如尽管患者可能仍然受到潜在疾病的影响，但观察到患者情况改善。就预防效果而言，可向具有患特定疾病风险的患者施用所述组合物，或者即便尚未做出疾病诊断，但向出现该疾病的一个或多个生理症状的患者施用所述组合物。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种活性物质(如本申请的化合物)的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合 物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、外用和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington's,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。
本文针对制剂、组合物或成分所用术语“可接受的”是指对接受治疗的受试者的一般健康情况没有长期的有害影响。
本文所用术语“药学可接受的”是指不影响本申请化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
本文所用术语“药物组合物”是指本申请的化合物与至少一种药学可接受的物质相混的混合物。所述药学可接受的物质包括但不限于载体、稳定剂、稀释剂、分散剂、悬浮剂、增稠剂和/或赋形剂。
本文所用术语“载体”是指相对无毒的物质，其有助于将本申请的化合物引入到细胞或组织中。
本文所用术语“药学可接受的盐”是指保留了指定化合物的游离酸和游离碱的生物效力，并且在生物学或其它方面上没有不良作用的盐。本申请化合物还包括药学可以接受的盐。药学可接受的盐是指把母体化合物中的碱基基团转换成盐的形式。药学可接受的盐包括，但不仅限于，碱基基团例如胺(氨)基的无机或有机酸盐类。本申请药学可接受的盐可以由母体化合物合成，即母体化合物中的碱性基团与1-4当量的酸在一个溶剂系统中反应。合适的盐列举在Remingtong’s Pharmaceutical Scicences,17 th ed.,Mack Publishing Company,Easton,Pa.,1985,p.1418和Journal of Pharmaceutical Science,66,2(1977)中。
除特别指示外，本申请中的盐指用有机酸/无机酸形成的酸式盐，以及用有机碱/无机碱形成的碱式盐。另外，当通式化合物的碱性官能团是吡啶或咪唑(但不限制于吡啶或咪唑)，酸性官能团是羧酸(但不限制于羧酸)时就会形成两性离子(内盐)，内盐也包括在本申请中的盐内。
具体实施方式：
本发明的具体化合物代表均可以通过本发明公开的通式合成方法合成出来。下面结合具体的实施方式对本发明做进一步描述，但本发明并不受其限制。且在本发明的通式、通式合成方法及具体的实施方式的指导下，本领域技术人员不需要付出创造性劳动即可得到的其它具体化合物，均在本发明范围内。
实施例1
Figure PCTCN2020104989-appb-000016
的合成
中间体a的制备：
N-Boc-4哌啶甲酸(458.6mg，2mmol，1eq)溶于15mlDCM，加入DIPEA(0.7ml，4mmol，2eq)，加入HATU(912mg，2.4mmol，1.2eq)，室温搅拌10min。加入苯胺(0.365ml，4mmol，2eq)，室温搅拌12h，水洗两次，0.1M稀盐酸洗两次，减压蒸馏除去溶剂，得到中间体a，无需纯化。
中间体b的制备：
中间体a溶于10ml乙酸乙酯，加入2mlHCl/EA溶液，室温搅拌24h，析出白色固体，抽滤，乙酸乙酯洗涤，得到中间体b白色固体347.5mg(72.4％)。
MAGLZ-II-01的制备：
中间体b(120mg，0.5mmol，1.5eq)溶于10mlDMF，加入TEA(0.23ml，1.65mmol，5eq),室温搅拌30min，加入HATU(152mg，0.4mmol，1.2eq),加入4-苯氧基苯甲酸(71.4mg，0.33mmol，1eq)，室温搅拌2h，反应完全，在反应液中加入饱和氯化钠溶液，乙酸乙酯萃取3次，合并有机相，饱和氯化钠溶液洗3次，无水硫酸钠干燥，经柱层析分离纯化(石油醚/乙酸乙酯＝1：1)得到目标化合物淡黄色固体102.4mg(76.8％)。
1HNMR(CDCl 3)δ(ppm):7.80-7.88(m,1H),7.47-7.54(m,2H),7.29-7.39(m,5H),6.96-7.19(m,6H),2.79-3.05(m,2H),2.45-2.58(m,1H),1.65-2.06(m,6H)。.MS结果与理论值相当。
实施例2-23制备过程以通式合成方法为基础，与实施例1相似，其中实施例22和23中的 b更换为
Figure PCTCN2020104989-appb-000017
各目标产物的MS结果均与理论值相当，NMR结果如下:
Figure PCTCN2020104989-appb-000018
Figure PCTCN2020104989-appb-000019
Figure PCTCN2020104989-appb-000020
Figure PCTCN2020104989-appb-000021
Figure PCTCN2020104989-appb-000022
实施例24-实施例30的合成目标产物的描述按照如下结构式为基础：
Figure PCTCN2020104989-appb-000023
其中，所述的R 1选自羟基、氟、氯、溴、碘、甲基、乙基、丙基、甲氧基；R 2选自羟基、羟基、氟、氯、溴、碘、甲基、乙基、丙基、甲氧基、苯基、以及被羟基、羟基、氟、氯、溴、碘、甲基、乙基、丙基、甲氧基取代的芳香基。R 1、R 2的个数为0或1或2或3或4；R 1、R 2与母核的链接方式不限于单键。
Figure PCTCN2020104989-appb-000024
Figure PCTCN2020104989-appb-000025
Figure PCTCN2020104989-appb-000026
实施例34 MAGLZ-II-11F的制备：
Figure PCTCN2020104989-appb-000027
原料N-Boc-4-哌啶甲酸(20)(229.3mg，1mmol)溶解于10mL CH 2Cl 2中，加入DIPEA(0.35mL，2mmol)、HATU(456mg，1.2mmol)，室温搅拌10min,加入3-氯苯胺(0.21mL，2mmol)，室温搅拌6h，水洗三次，10％稀盐酸洗三次，无水Na 2SO 4干燥，旋蒸除去CH 2Cl 2得到中间体21h，无需进一步纯化。
将中间体21h溶解于10mLEtOAc中，加入4M HCl/EtOAc溶液(2mL)，室温搅拌12h，有白色固体析出，抽滤并用EtOAc洗涤滤饼得到中间体22h白色固体188.1mg，收率68.4％。
Figure PCTCN2020104989-appb-000028
将中间体24(62.5mg，0.3mmol)溶于无水DMF中，加入HATU(136.8mg，0.36mmol)，TEA(151.8mg，1.5mmol)，常温搅拌30min，再加入盐酸盐中间体22h(107.33mg，0.39mmol)， 室温搅拌12h，停止反应，加饱和食盐水，EtOAc萃取三次，合并有机相，饱和食盐水洗三次，无水Na 2SO 4干燥，柱层析分离纯化(石油醚：乙酸乙酯＝1:1)得到黄色固体94.9mg，收率74.1％。
表征数据：
1H NMR(300MHz,CDCl 3)δ(ppm):7.65(s,1H),7.40-7.45(t,1H),7.34-7.36(d,2H),7.23-7.28(d,1H),7.14-7.16(m,2H),7.07-7.10(m,1H),2.96(s,1H),2.88(s,1H),2.52-2.58(t,2H),2.04(s,1H),1.74-1.86(m,2H),1.59(s,4H),1.24-1.28(m,3H),1.02-1.07(t,3H)；[M+Na] +：451.2。
实施例35 MAGLZ-II-11J的合成
Figure PCTCN2020104989-appb-000029
将原料N-Boc-L-酪氨酸(0.5mmol，140.5mg)溶解于10mL无水CH 2Cl 2中，加入中间体II-11(179.5mg，0.5mmol)，DMAP(0.1mmol，12.2mg)，反应冷却至0℃，加入溶于3mL无水CH 2Cl 2中的DCC(0.55mmol，113.4mg)，搅拌10min，反应升至室温，室温搅拌12h，反应不完全，停止反应后，抽滤，滤液旋干，加20mL CH 2Cl 2，饱和食盐水洗三次，无水硫酸钠干燥。柱层析分离纯化(二氯甲烷：甲醇＝100:1)得到中间体25白色固体52.6mg，收率16.9％。
Figure PCTCN2020104989-appb-000030
将中间体25(37mg)溶解于10mL EtOAc中，加入4M HCl/EtOAc溶液(2mL)，室温搅拌12h，有白色固体析出，抽滤并用EtOAc洗涤滤饼得到滤饼，滤饼加10mL碳酸氢钠，EtOAc萃取三次，合并有机相，饱和食盐水洗三次，无水硫酸钠干燥，旋蒸除去EtOAc， 得到淡白色固体12mg，收率40％。
MAGLZ-II-11J的表征数据： 1H NMR(300MHz,DMSO-d 6)δ(ppm):11.95(s,1H),10.14(s,1H),7.83(s,1H),7.54-7.56(d,1H),7.48-7.51(t,1H),7.44-7.46(d,1H),7.28-7.34(m,2H),7.10-7.12(m,2H),7.04-7.07(d,2H),6.69-6.71(d,2H),4.40-4.49(m,1H),4.26-4.30(t,1H),4.00-4.06(m,2H),3.61(s,1H),3.07-3.14(d,2H),2.89-2.98(d,2H),2.60-2.65(m,1H),1.58-1.78(m,4H)；[M+Na] +544.17。
实施例36：MAGL酶分析
采用Cayman的MAGL抑制剂筛选试剂盒，根据其说明书，以4-硝基苯乙酸的乙醇溶液作为MAGL的底物，底物的终浓度为236UM.96孔板中每孔加入150微升的1Xassay buffer，10微升的重组人MAGL蛋白,以及10微升的不同浓度的MAGL inhibitor(1nM-1000nM间的六个点).JZL195(阳性对照抑制剂)作为阳性对照孔，室温孵育5min后，每孔加入10微升的MAGL底物，将86孔震荡10秒，室温下放置10min，检测410nm的吸光值。其中，还要设置100％抑制对照孔(96孔板中每孔加入150微升的1Xassay buffer，10微升的MAGL,以及10微升的DMSO,设置三个复孔)，背景孔(每孔加入160微升的1Xassay buffer以及10微升的DMSO,设置三个复孔)。然后采用graphad prism 5.0计算拟合各抑制剂的IC50曲线，具体值见表2。
表2 活性数据
化合物编号MAGLX IC50(μM)
MAGLZ-II-01 0.045
MAGLZ-II-02 0.027
MAGLZ-II-03 0.749
MAGLZ-II-04 ND
MAGLZ-II-05 4.07
MAGLZ-II-06 1.96
MAGLZ-II-07 0.576
MAGLZ-II-08 1.34
MAGLZ-II-09 10.8
MAGLZ-II-10 0.662
MAGLZ-II-11 0.096
MAGLZ-II-12 ND
MAGLZ-II-13 0.926
MAGLZ-II-14 0.333
MAGLZ-II-15 ND
MAGLZ-II-16 0.018
MAGLZ-II-17 0.015
MAGLZ-II-18 0.670
MAGLZ-II-19 2.82
MAGLZ-II-18(c) 0.0026
MAGLZ-II-18(a) 2.15
MAGLZ-II-20 9.92
MAGLZ-II-21 ND
MAGLZ-II-22 1.77
MAGLZ-II-23 4.03
MAGLZ-II-24 0.275
MAGLZ-II-25 0.139
MAGLZ-II-26 12.2
MAGLZ-II-27 2.90
MAGLZ-II-29 0.252
MAGLZ-II-30 0.011
MAGLZ-II-31 ND
MAGLZ-II-11(a) 2.15
MAGLZ-II-11F 0.126
MAGLZ-II-11J 1.60
实施例37 本发明MAGL抑制剂组织分布试验
检测试剂：MAGLZ-II-11、MAGLZ-II-16、MAGLZ-II-17；
试验对象：小鼠；
给药剂量：16mg/kg(制剂浓度：8mg/ml)；
给药方式：皮下注射；
取样时间：给药后1、2、5小时后取样；
检测组织：脑、心、肝、脾、肺、肾、胰腺、血；
实验结果表明：
3个受试物在检测的脑中都有分布，其中，MAGLZ-II-16在脑内的含量最高，MAGLZ-II-17次之，MAGLZ-II-11最低(见表3)。
表3 组织分布图
Figure PCTCN2020104989-appb-000031
实施例38 本发明MAGL抑制剂对利血平致小鼠抑郁的作用
1)基本信息
种属：ICR小鼠
微生物等级：SPF级
购入动物数量和性别：雄性：75只，雌性：75只
使用动物数量和性别：雄性：75只，雌性：75只
体重：接收时13～18g
2)动物分组
组别设计：每批动物50只，共3批；将每批动物按体重随机分为5组：供试品低、中、 高剂量组、空白对照组和模型组，每批测试一种供试品。
3)试验方法
3.1每天一次皮下注射给药，剂量4、8、16mg/kg，共6天。最后一次给药2h后，除空白对照组外每只动物皮下注射利血平4mg/kg，之后2h测定唤醒、手指接触、畏惧、头部触摸、自主活动、直立、眼睑闭合等指标。
4)统计分析
数据统计及分析采用SPSS 17.0版软件和office 2016由计算机完成，数据统计采用Kruskal-Wallis检验。如果Kruskal-Wallis检验结果显著(P≤0.05)，则进一步用Mann-Whitney U非参数检验法进行多重比较检验。
5)结果见表4A、4B、4C
表4A
Figure PCTCN2020104989-appb-000032
注：模型组与空白组比较：*P＜0.05，**P＜0.01；给药组与模型组比较，*P＜0.05，**P＜0.01。
表4B
Figure PCTCN2020104989-appb-000033
注：模型组与空白组比较：*P＜0.05，**P＜0.01；给药组与模型组比较，*P＜0.05，**P＜0.01。
表4C
Figure PCTCN2020104989-appb-000034
注：模型组与空白组比较：*P＜0.05，**P＜0.01；给药组与模型组比较，*P＜0.05，**P＜0.01。
5.1)MAGLZ-II-11：
非参数检验
Kruskal-Wallis检验各指标均有统计学差异(P＜0.05)；
比较组间差异
Mann-Whitney U检验
模型组和空白对照组相比具有统计学差异(P＜0.05)，说明造模结果良好；低、中剂量组和模型组相比没有统计学差异(P＞0.05)；高剂量组和模型对照组相比自主活动和直立表现出统计学差异(P＜0.01，P＜0.05)，指标变化趋势同空白对照组相一致。
5.2)MAGLZ-II-17：Kruskal-Wallis检验各指标均有统计学差异(P＜0.05)；Mann-Whitney U检验
模型组和空白对照组相比具有统计学差异(P＜0.05)，说明造模结果良好；
低剂量和模型组相比没有统计学差异(P＞0.05)；
中剂量组眼睑和模型组相比具有统计学差异(P＜0.05)，但平均值比模型组小，其它指标没有统计学差异(P＞0.05)；
高剂量组眼睑和模型组相比具有统计学差异(P＜0.01)，但平均值比模型组小，其它指标没有统计学差异(P＞0.05)；
5.3)MAGLZ-II-16：Kruskal-Wallis检验各指标均有统计学差异(P＜0.05)；Mann-Whitney U检验
模型组和空白对照组相比具有统计学差异(P＜0.05)，说明造模结果良好；
低剂量和模型组相比没有统计学差异(P＞0.05)；
中剂量组头部接触和模型组相比有统计学差异(P＜0.05)，平均值比模型组大，与空白对照组趋势变化相同，其它指标没有统计学差异(P＞0.05)；
高剂量组头部接触和自主活动与模型组相比具有统计学差异(P＜0.05)，平均值比模型组大，与空白对照组趋势变化相同，其它指标没有统计学差异(P＞0.05)。
6)结论
6.1)本试验条件下，MAGLZ-II-11对利血平致抑郁具有一定的影响作用。
6.2)本试验条件下，MAGLZ-II-16对利血平致抑郁具有一定的影响作用。
6.3)本试验条件下，MAGLZ-II-17可能具有加强对利血平致抑郁的影响作用。
实施例39 本发明MAGL抑制剂对小鼠强迫游泳和小鼠悬尾模型的作用
1材料与方法
1.1实验动物
体重18～22g雄性ICR小鼠。动物在正常的12h光照，12h黑暗时间表下活动。环境温度和相对湿度分别保持在22±1℃和55±5％。
1.2实验方法
1.2.1动物分组和给药方法
7组实验小鼠，每组10只，设为对照组(生理盐水组)，阳性对照组(盐酸氟西汀胶囊，5mg/kg)，5个MAGLZ-II系列给药处理组：分别为MAGLZ-II-06、MAGLZ-II-07、MAGLZ-II-11、MAGLZ-II-17、MAGLZ-II-18，给药浓度为5mg/kg。
所有药物通过灌胃以20mL/kg体重的剂量使用，1次/天，持续10天。最后一次给药1h后，开始进行动物行为学的检测。
1.2.2小鼠强迫游泳试验
小鼠强迫游泳实验根据Porsolt(Porsalt R D.Behavioural despair in mice:A primary screening test for antidepressants[J].Arch.Int.Pharmacolodyn.1977,229)建立的方法进行检测。小鼠单独在开放的圆柱形容器(直径10cm，高25cm)中强迫游泳，该容器水温25±1℃，水深19cm，每只动物在6分钟的过程中保持不动的总时间被记录为不动时间(以秒为单位)。每只小鼠在停止挣扎时被判定为不动，并且在水中保持悬浮不动，只做出必要的动作以保持头部高于水面。不动时间的减少表明具有抗抑郁作用。
1.2.3小鼠悬尾试验
尾部悬浮试验(TST)根据Porsolt等(Porsolt R D,Le Pichon M,Jalfre M.Depression:a new animal model sensitive to antidepressant treatments[J].Nature,1977,266(5604):730-732)建立的方法进行检测。使用悬尾夹子，在距离盒子(250mm×250mm×300mm)尾部10mm，头部距离底部5cm处将小鼠分别悬挂在尾部。在具有最小背景的黑暗房间中测试噪声，每只小鼠悬挂6分钟，在最后4分钟间隔记录不动时间。判定标准是小鼠停止挣扎，完全静止不动。
1.2.4数据处理
所有数据以
Figure PCTCN2020104989-appb-000035
表示，组间比较采用单因素方差分析。
2结果
2.1 MAGLZ-II系列化合物对小鼠强迫游泳行为的影响
MAGLZ-II系列化合物对小鼠强迫游泳行为影响实验表明阳性对照药盐酸氟西汀、 MAGLZ-II系列化合物组均能明显缩短小鼠强迫游泳累积不动时间(P＜0.05)(表5)。
表5 MAGLZ-II系列化合物对小鼠强迫游泳行为的影响
Figure PCTCN2020104989-appb-000036
注：与对照组比较， *P＜0.05， **P＜0.01。
2.2 MAGLZ-II系列化合物对小鼠悬尾行为的影响
与对照组相比，MAGLZ-II系列化合物MAGLZ-II系列各化合物组能明显缩短悬尾小鼠的累计不动时间(P＜0.05)(表6)。
表6 MAGLZ-II系列化合物对小鼠悬尾行为的影响
Figure PCTCN2020104989-appb-000037
注：与对照组比较， *P＜0.05， **P＜0.01。
3讨论
小鼠强迫游泳和小鼠悬尾是较为常用的、经典的抑郁症动物模型。模型所体现出的小鼠绝望、行为扭曲等状态是体外模拟抑郁症的显著特征，同时由于其对抗抑郁药物比较敏感且便于操作，因此是抗抑郁药物常用的筛选模型。本研究采用这两种经典的抑郁动物模型对MAGLZ-II系列化合物的抗抑郁活性进行进一步的评价与验证。结果表明，MAGLZ-II系列化合物能显著缩短小鼠强迫游泳和小鼠悬尾的累积不动时间，表明MAGLZ-II系列化合物具有明确的抗抑郁作用。
实施例40 本发明MAGL抑制剂对醋酸引起的小鼠扭体次数的影响
1.动物分组及给药
雄性ICR小鼠200只，(20±2)g，按体重随机分为20组，每组10只，具体分组情况如下：模型组：等体积的0.5％羧甲基纤维素钠，ig
阳性对照组：双氯芬酸钠10mg/kg，ig
MAGLZ-II-11低剂量组：7.5mg/kg，ig
MAGLZ-II-11中剂量组：15mg/kg，ig
MAGLZ-II-11高剂量组：30mg/kg，ig
MAGLZ-II-11a低剂量组：7.5mg/kg，ig
MAGLZ-II-11a中剂量组：15mg/kg，ig
MAGLZ-II-11a高剂量组：30mg/kg，ig
MAGLZ-II-18a低剂量组：7.5mg/kg，ig
MAGLZ-II-18a中剂量组：15mg/kg，ig
MAGLZ-II-18a高剂量组：30mg/kg，ig
MAGLZ-II-18低剂量组：7.5mg/kg，ig
MAGLZ-II-18中剂量组：15mg/kg，ig
MAGLZ-II-18高剂量组：30mg/kg，ig
MAGLZ-II-18c低剂量组：7.5mg/kg，ig
MAGLZ-II-18c中剂量组：15mg/kg，ig
MAGLZ-II-18c高剂量组：30mg/kg，ig
MAGLZ-II-10低剂量组：7.5mg/kg，ig
MAGLZ-II-10中剂量组：15mg/kg，ig
MAGLZ-II-10高剂量组：30mg/kg，ig
各化合物分别用0.5％羧甲基纤维素钠配制成混悬液，然后按照剂量设定，各给药组灌胃给药；模型组灌胃给予等体积0.5％羧甲基纤维素钠。
2.实验方法及数据处理
小鼠腹腔注射醋酸，引起腹腔深部大面积而较持久的疼痛刺激，致使小鼠产生扭体反应。各剂量组给药1h后，腹腔注射0.7％醋酸生理盐水溶液0.1ml/10g。
记录腹腔注射醋酸后至开始出现扭体的时间(疼痛潜伏时间)。
记录自注射醋酸致痛后每只小鼠在20min内出现的扭体反应次数，计算各给药组的扭体抑制率。
扭体抑制率＝[(对照组扭体次数-药物组扭体次数)/对照组扭体次数]×100％
实验数据以
Figure PCTCN2020104989-appb-000038
表示，采用SPSS15.0软件进行方差分析。
3.实验结果
实验结果见表7。
表7 本发明MAGL抑制剂对醋酸引起的小鼠扭体次数的影响
Figure PCTCN2020104989-appb-000039
Figure PCTCN2020104989-appb-000040
与模型组比较，*P＜0.05，**P＜0.01，***P＜0.001。
由表1所示的实验结果可知，
与模型组相比，本发明MAGLZ-II-11，MAGLZ-II-11a，MAGLZ-II-18a，MAGLZ-II-18c能够显著减少醋酸引起的小鼠扭体次数，延长潜伏时间。
实施例41 本发明MAGL抑制剂对小鼠热板致痛反应的影响
将雌性ICR小鼠(20±2)g，置55±0.5℃的智能热板仪上，记录小鼠足底接触热板至出现舔后足反应的潜伏期(s)为痛阈指标，剔除反应潜伏期＜5s或＞30s或跳跃的小鼠。
分组及给药同实施例40。
连续灌胃给药7天，于末次给药后30、60、90、120min时分别测定各给药组小鼠的痛阈1次，痛阈值超过60s者以60s计算。
实验结果见表8。
表8 本发明MAGL抑制剂对小鼠热板致痛痛阈的影响
Figure PCTCN2020104989-appb-000041
Figure PCTCN2020104989-appb-000042
与模型组比较，*P＜0.05，**P＜0.01，***P＜0.001。
与模型组相比，本发明MAGLZ-II-11，MAGLZ-II-11a，MAGLZ-II-18a，MAGLZ-II-18，MAGLZ-II-18c能够显著延长热刺激小鼠痛阈。
实施例42 本发明MAGL抑制剂对炎性疼痛小鼠的痛阈的影响
雄性SD鼠(180±20)g，右后足底注射完全弗氏佐剂50μL/只，对照组注射相应体积的0.5％羧甲基纤维素钠，建立足肿胀炎性疼痛模型。造模后连续给药7d，每天灌胃1次。于给药前、造模后第1天、第3天、第7天分别测量给药后不同时间段小鼠的痛阈(s)。
分组及给药同实施例40。
表9 本发明MAGL抑制剂对炎性疼痛小鼠的痛阈的影响
Figure PCTCN2020104989-appb-000043
Figure PCTCN2020104989-appb-000044
与模型组比较，*P＜0.05，**P＜0.01，***P＜0.001。
与模型组相比，本发明MAGLZ-II-11，MAGLZ-II-11a，MAGLZ-II-18a，MAGLZ-II-18，MAGLZ-II-18c能够显著延长炎性疼痛小鼠痛阈。
实施例43 本发明MAGL抑制剂对对早期母婴分离诱导的肠易激综合征大鼠的治疗作用
肠易激综合征(Irritable Bowel Syndrome IBS)：是一种常见的功能性肠胃道疾病，表 现为慢性腹痛，腹部不适和排便习惯改变，且无明显的肠道病变。本实验主要探讨MAGL抑制剂对早期母婴分离诱导的肠易激综合征大鼠的治疗作用。
1.动物分组及给药
SD大鼠200只，(20±2)g，按体重随机分为20组，每组10只，具体分组情况如下：
空白组：等体积的0.5％羧甲基纤维素钠，ig
模型组：等体积的0.5％羧甲基纤维素钠，ig
MAGLZ-II-11低剂量组：7.5mg/kg，ig
MAGLZ-II-11中剂量组：15mg/kg，ig
MAGLZ-II-11高剂量组：30mg/kg，ig
MAGLZ-II-11a低剂量组：7.5mg/kg，ig
MAGLZ-II-11a中剂量组：15mg/kg，ig
MAGLZ-II-11a高剂量组：30mg/kg，ig
MAGLZ-II-18a低剂量组：7.5mg/kg，ig
MAGLZ-II-18a中剂量组：15mg/kg，ig
MAGLZ-II-18a高剂量组：30mg/kg，ig
MAGLZ-II-18低剂量组：7.5mg/kg，ig
MAGLZ-II-18中剂量组：15mg/kg，ig
MAGLZ-II-18高剂量组：30mg/kg，ig
MAGLZ-II-18c低剂量组：7.5mg/kg，ig
MAGLZ-II-18c中剂量组：15mg/kg，ig
MAGLZ-II-18c高剂量组：30mg/kg，ig
MAGLZ-II-10低剂量组：7.5mg/kg，ig
MAGLZ-II-10中剂量组：15mg/kg，ig
MAGLZ-II-10高剂量组：30mg/kg，ig
各化合物分别用0.5％羧甲基纤维素钠配制成混悬液，然后按照剂量设定，各给药组灌胃给药；模型组灌胃给予等体积0.5％羧甲基纤维素钠。
2.实验方法及数据处理
SD新生大鼠出生后，在出生的第2-21天，每天将新生的SD雄性大鼠与哺乳期母鼠分离3小时，即早上8:30开始，将哺乳期母鼠从笼中拎出，然后将新生大鼠从笼中移出放入另一单独的笼中，再将此笼转移到隔壁房间，3小时后，即11:30，再将新生大鼠返回到最 初的笼中，使其团聚，出生后第22天开始断奶，第30天进行分笼，直到60天分组，给药，共20天。
给药期内，进行灌胃给药，每天一次，持续给药20天。
实验终点：实验相应检测指标完成后，进行解剖。
检测指标：腹壁撤退反射评分(AWR)，检测方法：大鼠于实验前18h禁食，自由饮水，乙醚麻醉大鼠，将涂有石蜡油的气囊插入大鼠结直肠内4.0cm，用胶布将肛门外导管固定于大鼠尾根部，导管经三通连接注射器和血压计。将大鼠放入有机玻璃观察箱内(20cm×12cm×9cm)观察，待大鼠苏醒并完全适应环境30min后开始实验。分别给予20、40、60mmHg压力，每次持续扩张20s，刺激间隔4min，每个压力均重复进行3次AWR评分。AWR评分采用单盲法，评分标准：0分：无明显行为变化；1分：仅有简单的头部运动；2分：腹部肌肉开始收缩，但未抬离桌面；3分：腹肌明显收缩变平或下腹壁抬离桌面；4分：腹壁拱起或伴身体、骨盆躬起。
实验结束后。解剖、称量体重，麻醉动物，取血，高效液相检测血清中5-HT的含量。冰上取脑，预冷0.5％羧甲基纤维素钠清洗一下，随后用滤纸吸干，随即置于冻存管中，﹣20℃保存备用，高效液相检测脑组织中5-HT的含量。
结肠组织学观察：结肠扩张实验结束后，取大鼠远端结肠(距肛门5-6cm)，进行常规HE染色，观察肠壁炎症和损伤情况。
数据以mean±SD呈现，组别之间的差异用t tests或one-way ANOVA方法统计，P<0.05认为有显著差异。
3.实验结果
实验结果见表10。
表10 本发明MAGL抑制剂对肠易激综合征大鼠AWR评分及5-HT的影响
Figure PCTCN2020104989-appb-000045
Figure PCTCN2020104989-appb-000046
与空白组比较， #P＜0.05， ##P＜0.01， ###P＜0.001；
与模型组比较，*P＜0.05，**P＜0.01，***P＜0.001。
由表10所示的实验结果可知，
与模型组相比，本发明MAGLZ-II-11，MAGLZ-II-11a，MAGLZ-II-18a，MAGLZ-II-18，MAGLZ-II-18c能够显著降低AWR评分、降低结肠及血清中5-HT水 平。
实施例44 本发明MAGL抑制剂对利血平致小鼠偏头痛的影响
1.动物分组及给药
雄性ICR小鼠210只，(20±2)g，按体重随机分为21组，每组10只，具体分组情况如下：空白组：等体积的0.5％羧甲基纤维素钠，ig
模型组：等体积的0.5％羧甲基纤维素钠，ig
阳性对照组：佐米曲普坦0.5mg/kg，ig
MAGLZ-II-11低剂量组：7.5mg/kg，ig
MAGLZ-II-11中剂量组：15mg/kg，ig
MAGLZ-II-11高剂量组：30mg/kg，ig
MAGLZ-II-11a低剂量组：7.5mg/kg，ig
MAGLZ-II-11a中剂量组：15mg/kg，ig
MAGLZ-II-11a高剂量组：30mg/kg，ig
MAGLZ-II-18a低剂量组：7.5mg/kg，ig
MAGLZ-II-18a中剂量组：15mg/kg，ig
MAGLZ-II-18a高剂量组：30mg/kg，ig
MAGLZ-II-18低剂量组：7.5mg/kg，ig
MAGLZ-II-18中剂量组：15mg/kg，ig
MAGLZ-II-18高剂量组：30mg/kg，ig
MAGLZ-II-18c低剂量组：7.5mg/kg，ig
MAGLZ-II-18c中剂量组：15mg/kg，ig
MAGLZ-II-18c高剂量组：30mg/kg，ig
MAGLZ-II-10低剂量组：7.5mg/kg，ig
MAGLZ-II-10中剂量组：15mg/kg，ig
MAGLZ-II-10高剂量组：30mg/kg，ig
各化合物分别用0.5％羧甲基纤维素钠配制成混悬液，然后按照剂量设定，各给药组灌胃给药；模型组灌胃给予等体积0.5％羧甲基纤维素钠。
2.实验方法及数据处理
除空白对照组皮下注射生理盐水外，其余各组均皮下注射利血平溶液(0.2mg/kg)，共 计10天，若注射利血平后小鼠出现闭目、蜷伏少动、腹泻、进食量少、弓背等典型的利血平化症状时，则认为造模成功。
于造模后第5天开始，空白对照组和模型组均给予溶媒灌胃，其余各组分别给予对应药物和剂量进行灌胃，连续给药10天，于末次给药1小时后，称重，眼内眦取血检测血凝时间；取全血，冰上取脑，-20℃保存用于后续实验。
实验终点：造模给药时间持续10天，第10天末次给药1小时后进行检测，取血，实验结束。
检测指标：实验开始后，称量小鼠体重，两天一次；
行为学检测：悬尾活动，于实验第9天，距小鼠尾部1cm处用胶布粘合，钢针穿过胶布，挂入暗箱中，使小鼠呈倒挂状，观察2min内小鼠挣扎的次数(小鼠由倒挂向上翻转的总次数)。
末次给药1小时后，称重；毛细管取眼内眦血检测凝血时间；
取血，高效液相检测血清中5-HT的含量。冰上取脑，预冷0.5％羧甲基纤维素钠清洗一下，随后用滤纸吸干，随即置于冻存管中，﹣20℃保存备用，高效液相检测脑组织中5-HT的含量。
5-HT检测方法为：样本采用10％高氯酸溶液1:1沉淀，离心后取上清检测。色谱条件：色谱柱为SHIMADZU VP-ODS C 18柱(250*4.6mm,5um),流动相为甲醇-0.01mol/L的醋酸钾缓冲液(10:90，V/V，用0.2mol/L柠檬酸调PH至4.00)等度洗脱，柱温25℃，流速1.00ml/min，检测波长275nm。
数据以mean±SD呈现，组别之间的差异用t tests或one-way ANOVA方法统计，P<0.05认为有显著差异。
3.实验结果
实验结果见下表11-13。
表11 本发明MAGL抑制剂对凝血时间的影响
Figure PCTCN2020104989-appb-000047
Figure PCTCN2020104989-appb-000048
与模型组比较， #P＜0.05， ##P＜0.01， ###P＜0.001。
由表11所示的实验结果可知，
与模型组相比，本发明MAGLZ-II-11，MAGLZ-II-11a，MAGLZ-II-18a，MAGLZ-II-18，MAGLZ-II-18c能够显著延长凝血时间。
表12 本发明MAGL抑制剂对悬尾次数的影响
Figure PCTCN2020104989-appb-000049
Figure PCTCN2020104989-appb-000050
与模型组比较， #P＜0.05， ##P＜0.01， ###P＜0.001。
由表12所示的实验结果可知，
与模型组相比，本发明MAGLZ-II-11，MAGLZ-II-11a，MAGLZ-II-18a，MAGLZ-II-18，MAGLZ-II-18c能够显著增加悬尾活动次数。
表13 本发明MAGL抑制剂对脑组织5-羟色胺的影响
Figure PCTCN2020104989-appb-000051
Figure PCTCN2020104989-appb-000052
与模型组比较， #P＜0.05， ##P＜0.01， ###P＜0.001。
由表13所示的实验结果可知，
与模型组相比，本发明MAGLZ-II-11，MAGLZ-II-11a，MAGLZ-II-18a，MAGLZ-II-18，MAGLZ-II-18c能够显著升高利血平致低5-HT模型小鼠脑组织中5-HT水平。
实施例45 MAGL抑制剂对小鼠溃疡性结肠炎的作用研究
1.动物分组及给药
健康雄性SPF级BALB/c小鼠，8周龄，体质量(20±2)g。
小鼠入室后检疫7天，选择健康雄性小鼠作为受试动物。检疫期的主要检查内容包括但不限于：是否与申请时要求的动物数量与质量指标一致；一般状态；体重；以上检疫不合格动物不纳入本试验。
造模：检疫结束后，将小鼠随机分为21组，每组10只小鼠。正常组自由饮用正常水，其余组自由饮用1.0％-1.5％DSS溶液造模，造模7天后，造模组都自由饮用正常水7天，以此14天为一个造模周期，连续四个周期，造模同时给药。
空白组：等体积的0.5％羧甲基纤维素钠，ig
模型组：等体积的0.5％羧甲基纤维素钠，ig
阳性对照组：美沙拉嗪(100mg/kg)，ig
MAGLZ-II-11低剂量组：7.5mg/kg，ig
MAGLZ-II-11中剂量组：15mg/kg，ig
MAGLZ-II-11高剂量组：30mg/kg，ig
MAGLZ-II-11a低剂量组：7.5mg/kg，ig
MAGLZ-II-11a中剂量组：15mg/kg，ig
MAGLZ-II-11a高剂量组：30mg/kg，ig
MAGLZ-II-18a低剂量组：7.5mg/kg，ig
MAGLZ-II-18a中剂量组：15mg/kg，ig
MAGLZ-II-18a高剂量组：30mg/kg，ig
MAGLZ-II-18低剂量组：7.5mg/kg，ig
MAGLZ-II-18中剂量组：15mg/kg，ig
MAGLZ-II-18高剂量组：30mg/kg，ig
MAGLZ-II-18c低剂量组：7.5mg/kg，ig
MAGLZ-II-18c中剂量组：15mg/kg，ig
MAGLZ-II-18c高剂量组：30mg/kg，ig
MAGLZ-II-10低剂量组：7.5mg/kg，ig
MAGLZ-II-10中剂量组：15mg/kg，ig
MAGLZ-II-10高剂量组：30mg/kg，ig
各化合物分别用0.5％羧甲基纤维素钠配制成混悬液，然后按照剂量设定，各给药组灌胃给药；模型组灌胃给予等体积0.5％羧甲基纤维素钠。
2.试验过程及方法
实验终点：实验给药四个周期，第四个周期的恢复期的第三、四天进行解剖。
检测指标：开始给药后，称量小鼠体重，一周两次；观察小鼠腹泻、便血情况，记录便血次数。
实验结束后，解剖、称量体重，麻醉动物，取血，血清-80℃保存。取脾脏，称取脾脏重量，计算脾脏指数。ELISA检测血清中IL-1β的含量。剪取结直肠，并测量结直肠长度，甲醛固定，HE染色，检测病理变化。
数据以mean±SD呈现，组别之间的差异用t tests或one-way ANOVA方法统计，P<0.05认为有显著差异。
3.结果与讨论
实验结果见表14。
表14 本发明MAGL抑制剂对溃疡性结肠炎小鼠结肠长度、便血次数、IL-1含量的影响
Figure PCTCN2020104989-appb-000053
Figure PCTCN2020104989-appb-000054
与空白组比较， #P＜0.05， ##P＜0.01， ###P＜0.001；
与模型组比较，*P＜0.05，**P＜0.01，***P＜0.001。
与模型组相比，本发明MAGLZ-II-11，MAGLZ-II-11a，MAGLZ-II-18a，MAGLZ-II-18，MAGLZ-II-18c能够显著增加结肠长度，减少便血总次数，降低IL-1含量。
由于已经通过以上实施例描述了本发明，任何等同替换对于本发明来说都是显而易见的并且包含在本发明之中。

Claims (21)

  1. 式I化合物或其药学上可接受的盐：
    Figure PCTCN2020104989-appb-100001
    其中，R为H或C 1-5的烷基，所述C 1-5的烷基选自甲基，乙基，丙基，异丙基，正丁基，异丁基，新丁基，正戊基，异戊基，新戊基，环戊基，或被卤素、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 3-8环烷基、C 3-8杂环基、C 3-8环烷氧基、芳基、杂芳基取代的C 1-5的烷基；R的个数为0,1,2,3或4；
    Ar 1、Ar 2分别独立地选自C 5-18的芳基、杂芳基，(C6-10芳基)-C1-4烷基-，(C6-10芳基)-C1-4烷基-(C6-10芳基)，(5至10元杂芳基)-C1-4烷基-(C6-10芳基)，(C6-10芳基)-(C6-10芳基)，(C6-10芳基)-O-(C6-10芳基)，(C6-10芳基)-O-(5至10元杂芳基)，(5至10元杂芳基)-O-(5至10元杂芳基)，(5至10元杂芳基)-(5至10元杂芳基)，取代位置任意；
    X 1、X 2分别独立地选自H，羟基，羧基，卤素，酰氧基，C 1-3烷基，C 1-3烷氧基，C 3-8环烷基，C 3-8杂环基，C 3-8环烷氧基，芳基，杂芳基，被羟基、羧基、卤素、烷基取代的C 1-3烷基、C 1-3烷氧基、C 3-8环烷基、C 3-8杂环基、C 3-8环烷氧基、芳基、杂芳基中的一种或多种，取代基位置任意。
  2. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于，其中，R为H或C 1-5的烷基，所述C 1-5的烷基选自甲基，乙基，丙基，异丙基，正丁基，异丁基，新丁基，正戊基，异戊基，新戊基，环戊基或被卤素、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 3-8环烷基、C 3-8杂环基、C 3-8环烷氧基、芳基、杂芳基取代的C 1-5的烷基；R的个数为0,1,2,3或4；
    Ar 1、Ar 2分别独立地选自C 5-18的芳基、杂芳基，(C6-10芳基)-C1-4烷基-，(C6-10芳基)-C1-4烷基-(C6-10芳基)，(5至10元杂芳基)-C1-4烷基-(C6-10芳基)，(C6-10芳基)-(C6-10芳基)，(C6-10芳基)-O-(C6-10芳基)，(C6-10芳基)-O-(5至10元杂芳基)，(5至10元杂芳基)-O-(5至10元杂芳基)，(5至10元杂芳基)-(5至10元杂芳基)，取代位置任意；
    X 1、X 2分别独立地选自H，羟基，羧基，卤素，C 1-3烷基，C 1-3烷氧基，C 3-8环烷基，C 3-8杂环基，C 3-8环烷氧基，芳基，杂芳基，被羟基、羧基、卤素、烷基取代的C 1-3烷基、C 1-3 烷氧基、C 3-8环烷基、C 3-8杂环基、C 3-8环烷氧基、芳基、杂芳基中的一种或多种，取代基位置任意。
  3. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于，其中，所述Ar 1、Ar 2分别独立地选自苯基，C5-18的芳基、杂芳基，(C6-10芳基)-(C6-10芳基)，(C6-10芳基)-O-(C6-10芳基)；X 1、X 2分别独立地选自H，羟基，卤素，酰氧基，C1-3烷基，C1-3烷氧基中的一个或多个，取代基位置为任意位置。
  4. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于，其中，所述Ar 1为苯，萘，二苯醚，吲哚基，联苯中的一种或多种取代基，取代位置任意。
  5. 如权利要求1所述的式I化合物或其药学上可接受的盐，所述的R取H，则相应的结构式为
    Figure PCTCN2020104989-appb-100002
    其中，Ar 1、Ar 2分别独立地选自C 5-18的芳基、杂芳基，(C6-10芳基)-C1-4烷基-，(C6-10芳基)-C1-4烷基-(C6-10芳基)，(5至10元杂芳基)-C1-4烷基-(C6-10芳基)，(C6-10芳基)-(C6-10芳基)，(C6-10芳基)-O-(C6-10芳基)，(C6-10芳基)-O-(5至10元杂芳基)，(5至10元杂芳基)-O-(5至10元杂芳基)，(5至10元杂芳基)-(5至10元杂芳基)，取代位置任意；
    X 1、X 2分别独立地选自H，羟基，羧基，卤素，C 1-3烷基，C 1-3烷氧基，C 3-8环烷基，C 3-8杂环基，C 3-8环烷氧基，芳基，杂芳基，被羟基、羧基、卤素、烷基取代的C 1-3烷基、C 1-3烷氧基、C 3-8环烷基、C 3-8杂环基、C 3-8环烷氧基、芳基、杂芳基中的一种或多种，取代基位置任意。
  6. 如权利要求5所述的化合物或其药学上可接受的盐，其特征在于，所述Ar 1、Ar 2分别独立地选自C5-18的芳基、杂芳基，(C6-10芳基)-C1-4烷基-，(C6-10芳基)-C1-4烷基-(C6-10芳基)，(5至10元杂芳基)-C1-4烷基-(C6-10芳基)，(C6-10芳基)-(C6-10芳基)，(C6-10芳基)-O-(C6-10芳基)，(C6-10芳基)-O-(5至10元杂芳基)，(5至10元杂芳基)-O-(5至10元杂芳基)，(5至10元杂芳基)-(5至10元杂芳基)，取代位置任意；X 1、X 2分别独立地选自H，羟基，卤素，C1-3烷基，C1-3烷氧基，C3-8杂环基，C3-8环烷氧基，被羟基、卤素、烷基取代的C1-3烷基、C1-3烷氧基中的一种或多种，取代基位置任意。
  7. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于，其中，
    Ar 1为苯基，萘基，二苯醚基，联苯基中的一种或多种，取代位置任意；
    X 1为H，甲氧基，羟基，氟，氯中的一种或多种，取代基位置任意；
    Ar 2为苯基，取代基位置任意；
    X 2为H，甲基，二甲基，甲氧基，羟基，氟，氯中的一种或多种，取代基位置任意。
  8. 如权利要求5所述的化合物或其药学上可接受的盐，其特征在于，所述Ar 1的取代位置在间位。
  9. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于，其中，
    所述Ar 1为苯并呋喃基、苯并咪唑基、苯并恶唑基、苯并噻吩基、吲哚基、喹啉基、异喹啉基、嘌呤基中的一种或多种，取代位置任意；
    X 1为H，甲基，甲氧基，羟基，氟，氯，溴中的一种或多种，取代基位置任意；
    Ar 2为苯基，取代基位置任意；
    X 2为H，甲基，二甲基，甲氧基，羟基，氟，氯中的一种或多种，取代基位置任意。
  10. 如权利要求1所述的式I化合物或其药学上可接受的盐，其特征在于，具体结构式选自，
    Figure PCTCN2020104989-appb-100003
    Figure PCTCN2020104989-appb-100004
    Figure PCTCN2020104989-appb-100005
    Figure PCTCN2020104989-appb-100006
  11. 如权利要求1的化合物，其为式III
    Figure PCTCN2020104989-appb-100007
    或其药学上可接受的盐；其中，所述的R 1选自羟基、氟、氯、溴、碘、甲基、乙基、丙基、甲氧基；R 2选自羟基、氟、氯、溴、碘、甲基、乙基、丙基、甲氧基、苯基、以及被羟基、羟基、氟、氯、溴、碘、甲基、乙基、丙基、甲氧基取代的芳香基。R 1、R 2的个数为0或1或2或3或4；R 1、R 2与母核的链接方式不限于单个单键连接。
  12. 一种用于合成如式I化合物的化合物，如式b所示，
    Figure PCTCN2020104989-appb-100008
    所述X 2、Ar 2如权利要求1所描述。
  13. 一种如式I化合物的合成方法，具体步骤如下：
    Figure PCTCN2020104989-appb-100009
    b或b的盐与
    Figure PCTCN2020104989-appb-100010
    反应，得到I；所述X 1、X 2、Ar 1、Ar 2为苯，萘，二苯醚，联苯中的一种或多种，取代位置任意；X 1为H，甲氧基，羟基，氟，氯中的一种或多种，取代基位置任意。
  14. 如权利要求13所述的合成方法，其特征在于，所述b或b的盐与
    Figure PCTCN2020104989-appb-100011
    反应， 得到I；该步反应中加入缩合剂和碱，更有利于反应进行，所述的缩合剂选自HBTU、DMC、HOBT、HOBT/EDCI、HATU、HATU/DIEPA、DCC、CDI、异丙基氯甲酸酯。
  15. 如权利要求13所述的合成方法，其特征在于，所述b或b的盐是由a脱保护而得；
    Figure PCTCN2020104989-appb-100012
  16. 如权利要求13所述的合成方法，其特征在于，所述a或a的盐是由sm与
    Figure PCTCN2020104989-appb-100013
    或其盐反应而得；
    Figure PCTCN2020104989-appb-100014
  17. 药物组合物，其包含权利要求1至11中任一项的化合物或药学上可接受的盐及药学上可接受的载体。
  18. 如权利要求1至11中任一项的化合物或药学上可接受的盐，其用于制备治疗MAGL介导的疾病或病症的药物中的用途。
  19. 如权利要求18的用途，其特征在于，其中所述病症选自：代谢紊乱，肾病，呕吐或涌吐或恶心，进食障碍，神经病变，精神分裂症，抑郁症，双相障碍，震颤，运动障碍，戒断综合征，外伤性脑损伤，非外伤性脑损伤，脊髓损伤，癫痫发作，与异常细胞生长或增殖有关的病症[例如良性肿瘤或癌症，炎症性病症，免疫系统病症，肠易激综合征，溃疡性 结肠炎，急性应激障碍，物质诱导性焦虑，强迫症，焦虑症；注意缺陷障碍，注意缺陷多动障碍，疼痛，偏头痛；脱髓鞘病，及认知损害。
  20. 抑制MAGL的方法，其包括使所述MAGL与权利要求1至11中任一项的化合物或药学上可接受的盐接触。
  21. 治疗哺乳动物中MAGL介导的疾病或病症的方法，所述方法包括向所述哺乳动物给药治疗有效量的权利要求1至11中任一项的化合物或药学上可接受的盐。
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DATABASE REGISTRY ANONYMOUS: "4-Piperidinecarboxamide, N-(3-chlorophenyl)-1-(3-methoxybenzoyl)", XP055789116, retrieved from STN Database accession no. 508188-16-7 *
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