WO2021115380A1 - 一类具有神经保护作用的化合物及其制备方法和用途 - Google Patents

一类具有神经保护作用的化合物及其制备方法和用途 Download PDF

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WO2021115380A1
WO2021115380A1 PCT/CN2020/135289 CN2020135289W WO2021115380A1 WO 2021115380 A1 WO2021115380 A1 WO 2021115380A1 CN 2020135289 W CN2020135289 W CN 2020135289W WO 2021115380 A1 WO2021115380 A1 WO 2021115380A1
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alkyl
cycloalkyl
group
compound
hydrogen
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PCT/CN2020/135289
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English (en)
French (fr)
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梁波
陈焕明
刘刚
张志军
夏天
华波
金秋
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上海挚盟医药科技有限公司
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Priority to IL293759A priority Critical patent/IL293759A/en
Priority to CN202080085775.7A priority patent/CN114829359A/zh
Priority to BR112022011283A priority patent/BR112022011283A2/pt
Priority to US17/783,796 priority patent/US20230054304A1/en
Priority to KR1020227023702A priority patent/KR20220114018A/ko
Priority to JP2022535463A priority patent/JP7450980B2/ja
Priority to CA3161323A priority patent/CA3161323A1/en
Priority to EP20899991.2A priority patent/EP4074707A4/en
Priority to AU2020399047A priority patent/AU2020399047B2/en
Publication of WO2021115380A1 publication Critical patent/WO2021115380A1/zh

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    • C07F9/02—Phosphorus compounds
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    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
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Definitions

  • the present invention relates to the field of biomedicine, in particular to a class of compounds with neuroprotective effects, and preparation methods and uses thereof.
  • Stroke is an acute cerebrovascular disease, including ischemic and hemorrhagic strokes.
  • the incidence of ischemic stroke accounts for 60% to 70% of the total number of strokes. Stroke has high incidence, high mortality and causes The characteristic of high residual rate.
  • neuroprotective agents include free radical scavengers, glutamate antagonists, calcium channel antagonists, cell membrane stabilizers, etc.
  • neuroprotective agents due to the complexity of the pathogenesis of stroke, there are no neuroprotective agents with ideal effects in clinical practice. Due to the high incidence and great harm of stroke, the development of new neuroprotective agents is of great significance.
  • the purpose of the present invention is to provide a compound represented by formula I, a preparation method thereof, and its use in neuroprotection.
  • the first aspect of the present invention provides a compound represented by formula I or a stereoisomer or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 5 ', R 6 , R 6 ', R 7 , R 8 , R 9 are independently selected from the following group: hydrogen, halogen, amino, hydroxyl, carboxyl , Nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 3-6 cycloalkyl, halo Substitute C 3-6 cycloalkyl, C 1-6 alkylamino;
  • R 5 and R 6 or R 5 'and R 6 ' can be cyclized to form a substituted or unsubstituted 3-8 membered saturated or unsaturated cycloalkyl group or contain one or more (for example, 2, 3, or 4) Heterocycloalkyl groups of heteroatoms selected from N, S and O, said substitution refers to substitution by one or more (for example, 2, 3, or 4) substituents selected from the following group: hydrogen, halogen, C 1-6 alkyl;
  • X is selected from the following group:
  • R 10 , R 11 , R 12 , and R 13 are each independently selected from the following group: hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, halogenated C 1- 6 alkyl, halo C 3-6 cycloalkyl, halo C 1-6 alkoxy, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-6 member containing one or more (E.g. 2, 3, or 4) heteroaryl groups selected from heteroatoms of N, S and O, 3-8 membered saturated or unsaturated containing one or more (e.g.
  • 2, 3 or 4 are selected from Heterocycloalkyl of N, S and O heteroatoms, said substitution refers to substitution by one or more (for example, 2, 3, or 4) substituents selected from the following group: hydrogen, halogen, C 1- 6 alkyl;
  • Ring A is a substituted or unsubstituted 3-8 membered saturated or unsaturated cycloalkyl group or a substituted or unsubstituted 3-8 membered ring containing one or more (for example, 2, 3, or 4) selected from N, S Heterocycloalkyl with a heteroatom of O and O, said substitution refers to substitution by one or more (for example, 2, 3, or 4) substituents selected from the group consisting of hydrogen, halogen, C 1-6 alkyl ;
  • W is selected from the following group: O, S, NR 19 ;
  • R 19 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, halogenated C 3-6 cycloalkyl, C 6-10 aryl, A substituted or unsubstituted 3-8 membered saturated or unsaturated heterocycloalkyl or heteroaryl group containing one or more (for example, 2, 3 or 4) heteroatoms selected from N, S and O, said Substitution refers to substitution by one or more (for example, 2, 3, or 4) substituents selected from the following group: hydrogen, halogen, C 1-6 alkyl;
  • n 0 or 1
  • n 0 or 1
  • Z is N or CR 18 ;
  • R 18 is selected from the group consisting of hydrogen, hydroxy, halogen, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 alkoxy, C 1-6 alkylamino;
  • R 15 , R 16 , and R 17 are each independently selected from the following group: hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 3-15 membered saturated or unsaturated containing one Or more (e.g.
  • heterocycloalkyl or heteroaryl groups of heteroatoms selected from N, S and O, -(C 1-6 alkylene) (3-15 membered saturated or non- Saturated heterocycloalkyl or heteroaryl containing one or more (for example, 2, 3, 4 or 5) heteroatoms selected from N, S and O); the alkyl group, cycloalkyl group, aryl group , Heteroaryl, heterocycloalkyl are optionally substituted by one or more (for example, 2, 3 or 4) substituents selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkylene hydroxy, 0, -NR 20 R 21 , cyano, C 2-6 alkynyl, C 2-6 alkenyl, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkyl substituted or unsubstituted Substituted 3-8 membered heterocycloalkyl, halogenated C 1-6 alkyl
  • R 20 and R 21 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, and halogenated C 3-6 cycloalkyl;
  • n 0;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 5 ', R 6 , R 6 ', R 7 , R 8 , R 9 are independently selected from the following group: hydrogen, halogen, C 1-6 alkane Group, C 3-6 cycloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 3-6 cycloalkyl, halogenated C 1-6 alkoxy;
  • X is selected from the following group:
  • R 10 , R 11 , R 12 , and R 13 are each independently selected from the following group: hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, halo C 1-6 alkyl, halo C 3 -6 cycloalkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-6 member containing one or more (for example, 2, 3, or 4) selected from N, S and O Heteroatomic heteroaryl, said substitution refers to substitution by one or more (for example, 2, 3, or 4) substituents selected from the following group: hydrogen, halogen, C 1-6 alkyl;
  • Ring A is a substituted or unsubstituted 3-8 membered cycloalkyl group or a substituted or unsubstituted 3-8 membered ring containing one or more (for example, 2, 3, or 4) heteroatoms selected from N, S and O
  • the substitution refers to one or more (for example, 2, 3, or 4) substituents selected from the group consisting of hydrogen, halogen, and C 1-6 alkyl;
  • W is O
  • Z is N or CR 18 ;
  • R 18 is selected from the group consisting of hydrogen, hydroxy, halogen, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 alkoxy, C 1-6 alkylamino;
  • R 20 and R 21 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, and halogenated C 3-6 cycloalkyl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 5 ', R 6 , R 6 ', R 7 , R 8 , R 9 are independently selected from the following group: hydrogen, halogen, C 1-6 alkane Group, C 3-6 cycloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 3-6 cycloalkyl, halogenated C 1-6 alkoxy;
  • X is selected from the following group:
  • R 10 and R 11 are each independently selected from the following group: hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, halogenated C 3-6 cycloalkyl, A substituted or unsubstituted C 6-10 aryl group, a substituted or unsubstituted 5-6 membered heteroaryl group containing one or more (for example, 2, 3, or 4) heteroatoms selected from N, S and O ,
  • the substitution refers to substitution by one or more (for example, 2, 3, or 4) substituents selected from the following group: hydrogen, halogen, C 1-6 alkyl;
  • Ring A is a substituted or unsubstituted 3-8 membered cycloalkyl group or a substituted or unsubstituted 3-8 membered ring containing one or more (for example, 2, 3, or 4) heteroatoms selected from N, S and O
  • the substitution refers to one or more (for example, 2, 3, or 4) substituents selected from the group consisting of hydrogen, halogen, and C 1-6 alkyl;
  • W is O
  • Z is N or CR 18 ;
  • R 18 is selected from the group consisting of hydrogen, hydroxy, halogen, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 alkoxy, C 1-6 alkylamino;
  • Y is COOR 15 ;
  • R 1 and R 3 are Cl.
  • R 2 , R 4 , R 5 , R 5 ′, R 6 , R 6 ′, R 7 , R 8 , and R 9 are hydrogen.
  • X is selected from the following group:
  • R 10 , R 11 , R 12 , and R 13 are each independently selected from the following group: hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, halogenated C 1- 6 alkyl, halo C 3-6 cycloalkyl, halo C 1-6 alkoxy, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-6 member containing one or more (E.g. 2, 3, or 4) heteroaryl groups selected from heteroatoms of N, S and O, 3-8 membered saturated or unsaturated containing one or more (e.g.
  • 2, 3 or 4 are selected from Heterocycloalkyl of N, S and O heteroatoms, said substitution refers to substitution by one or more (for example, 2, 3, or 4) substituents selected from the following group: hydrogen, halogen, C 1- 6 alkyl;
  • Ring A is a substituted or unsubstituted 3-8 membered saturated or unsaturated cycloalkyl group or a substituted or unsubstituted 3-8 membered ring containing one or more (for example, 2, 3, or 4) selected from N, S Heterocycloalkyl with a heteroatom of O and O, said substitution refers to substitution by one or more (for example, 2, 3, or 4) substituents selected from the group consisting of hydrogen, halogen, C 1-6 alkyl .
  • W is O.
  • n 0.
  • Z is N or CR 18 ;
  • R 18 is selected from the group consisting of hydrogen, hydroxy, halogen, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 alkoxy, C 1-6 alkylamino.
  • R 20 and R 21 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, and halogenated C 3-6 cycloalkyl.
  • Y and R 8 are cyclized to form
  • Y is selected from the following group: COOR 15 , R 15 is as defined above;
  • Z is selected from the following group: N, C(OH).
  • Y is COOR 15 ;
  • R 15 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 3-15 membered saturated or non- Saturated heterocycloalkyl containing one or more (for example, 2, 3 or 4) heteroatoms selected from N, S and O; the alkyl, cycloalkyl, aryl, and heterocycloalkyl groups are optionally Ground is substituted by one or more (for example, 2, 3 or 4) substituents selected from the group consisting of hydrogen, halogen, hydroxyl, -NR 20 R 21 , cyano, C 2-6 alkynyl, C 2-6 Alkenyl, C 1-6 alkyl, C 3-10 cycloalkyl; R 20 and R 21 are as described above;
  • Y is COOR 15 ;
  • R 15 is selected from the following group: C 1-6 alkyl, C 3-8 cycloalkyl, 3-15 membered saturated or unsaturated containing one or more (for example 2, 3, or 4) heterocycloalkyl groups of heteroatoms selected from N, S, and O; the heterocycloalkyl groups are optionally selected from the following group by one or more (for example, 2, 3, or 4) Substituent substitution of: hydrogen, halogen, C 1-6 alkyl, C 3-10 cycloalkyl;
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , and R 9 are each independently selected from the following group: hydrogen and halogen;
  • R 5 , R 5 ′, R 6 , and R 6 ′ are hydrogen
  • W is O
  • Z is N or C(OH);
  • Y is COOR 15 ;
  • R 10 and R 11 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, and halogenated C 3-6 cycloalkyl;
  • R 20 and R 21 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, and halogenated C 3-6 cycloalkyl;
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , and R 9 are each independently selected from the following group: hydrogen and halogen;
  • R 5 , R 5 ′, R 6 , and R 6 ′ are hydrogen
  • W is O
  • Z is N or C(OH);
  • Y is COOR 15 ;
  • R 20 and R 21 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 1-6 alkyl, and halogenated C 3-6 cycloalkyl;
  • R 22 is selected from the group consisting of hydrogen, C 1-6 alkyl
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , and R 9 are each independently selected from the following group: hydrogen and halogen;
  • R 5 , R 5 ′, R 6 , and R 6 ′ are hydrogen
  • W is O
  • Y is COOR 15 ;
  • R 15 is selected from the following group: hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl; the alkyl, cycloalkyl is optionally substituted by one or more (for example, 2, 3 or 4) C 1-6 alkoxy substitution;
  • R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , and R 9 are each independently selected from the following group: hydrogen and halogen;
  • R 5 , R 5 ′, R 6 , and R 6 ′ are hydrogen
  • W is O
  • Y is COOR 15 ;
  • R 15 is C 1-6 alkyl substituted with C 1-6 alkoxy
  • the C 1-6 alkoxy group is selected from the following group: methoxy, ethoxy, propyl Oxy, isopropoxy and butoxy;
  • the C 1-6 alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, and p-pentyl.
  • the compound is as described below.
  • the second aspect of the present invention provides a method for preparing the compound according to the first aspect of the present invention or its stereoisomer, or a pharmaceutically acceptable salt thereof, which comprises the following steps:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 5 ', R 6 , R 6 ', R 7 , R 8 , R 9 , W, X, Z, Y, m, and n are as they are Defined in the first aspect of the invention.
  • the cyclization reagent is selected from the group consisting of phosgene (phosgene), bis(trichloromethyl) carbonate, N,N'-carbonyldiimidazole (CDI), thiophosgene , N,N'-thiocarbonyldiimidazole (TCDI), fatty aldehyde, aromatic aldehyde, fatty ketone, aromatic ketone, phosphorus oxychloride, cyanogen bromide, or a combination thereof.
  • phosgene phosgene
  • CDI N,N'-carbonyldiimidazole
  • TCDI thiophosgene
  • TCDI N,N'-thiocarbonyldiimidazole
  • fatty aldehyde aromatic aldehyde
  • fatty ketone aromatic ketone
  • aromatic ketone aromatic ketone
  • phosphorus oxychloride cyanogen bromide
  • the fatty aldehyde is selected from the group consisting of paraformaldehyde, n-butyraldehyde, or a combination thereof.
  • the fatty ketone is selected from the group consisting of cyclobutanone, 3-oxetanone, or a combination thereof.
  • the aromatic aldehyde is benzaldehyde.
  • the third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more of the compounds or stereoisomers of the first aspect of the present invention, or their pharmaceutically acceptable Of salt.
  • the fourth aspect of the present invention provides a use of the compound of the first aspect of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof, for the preparation of a medicine, and the medicine is used for prevention and /Or to treat diseases or conditions affected by neuronal damage.
  • the disease or condition affected by neuronal damage is selected from the group consisting of neuropathic pain, migraine, inflammatory pain, chronic pain, stroke, brain injury, depression, Alzheimer's disease , Epilepsy, affective disorders, neurodegenerative diseases.
  • the fifth aspect of the present invention provides a neuroprotective agent comprising one or more of the compounds described in the first aspect of the present invention or their stereoisomers, or pharmaceutically acceptable salts thereof.
  • the sixth aspect of the present invention provides a method for preventing and/or treating diseases or conditions affected by neuronal damage, including the steps of: administering to a patient in need a preventive and/or therapeutically effective amount of the third aspect of the present invention
  • the pharmaceutical composition includes
  • the seventh aspect of the present invention provides a method for preventing and/or treating cerebral infarction, comprising the steps of: administering a preventive and/or therapeutically effective amount of the pharmaceutical composition according to the third aspect of the present invention to a patient in need.
  • the inventor unexpectedly prepared a compound with a novel structure and a neuroprotective effect.
  • the compound of the present invention can effectively pass through the blood-brain barrier and has good neuroprotective effects, and can be used to treat stroke, pain and other diseases.
  • halogen refers to F, Cl, Br or I.
  • C 1-6 alkyl refers to a linear or branched alkyl group including 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isopropyl Butyl, tert-butyl, neopentyl, p-pentyl, or similar groups.
  • C 2-6 alkenyl refers to a linear or branched alkenyl group having 2 to 6 carbon atoms containing a double bond, and includes, without limitation, vinyl, propenyl, butene Group, isobutenyl, pentenyl and hexenyl, etc.
  • C 2-6 alkynyl refers to a straight-chain or branched alkynyl group having 2 to 6 carbon atoms containing a triple bond, and includes, without limitation, ethynyl, propynyl, butylene Alkynyl, isobutynyl, pentynyl and hexynyl, etc.
  • C 3-8 cycloalkyl or “cycloalkyl” refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring (including spirocycloalkyl, bridged cycloalkyl ( Structure as shown in compound 04033 )), including without limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • C 3-6 cycloalkyl has a similar meaning.
  • C 1-6 alkoxy refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, and includes, without limitation, a methoxy group, an ethoxy group, and a propoxy group. , Isopropoxy and butoxy, etc. Preferably it is a C 1-4 alkoxy group.
  • C 1-6 alkylamino refers to C 1-6 alkyl-NH-.
  • heterocycloalkyl and “heterocyclyl” refer to a 3-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O, S (including heterospirocycloalkane Group, heterocycloalkyl, heterobridged cycloalkyl), including (but not limited to) the following groups:
  • the term “unsaturated” refers to the presence of a double bond structure in the corresponding structure.
  • saturated means that there is no double bond structure in the corresponding structure.
  • the heterocycloalkyl group may be substituted or unsubstituted, and the substituted heterocycloalkyl group has the structure shown in compound 04132
  • aromatic ring or “aryl” have the same meaning, and are preferably “C 6-10 aryl”.
  • C 6-10 aryl group refers to an aromatic ring group having 6 to 10 carbon atoms that does not contain a hetero atom in the ring, such as phenyl, naphthyl, and the like.
  • aromatic heterocycle or “heteroaryl” has the same meaning and refers to a heteroaromatic group containing one to more heteroatoms.
  • C 3-10 heteroaryl refers to an aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen and 3-10 carbon atoms.
  • Non-limiting examples include: furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.
  • Heteroaryl groups can be optionally substituted or unsubstituted.
  • halo refers to substitution by halogen.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • the specific substituents are the substituents correspondingly described in the foregoing, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different in each position.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents such as (but not limited to): halogen, hydroxyl, carboxy (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-to 12-membered heterocyclic group, aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, C1-C6 alkoxy group, C1-C10 sulfonyl group, etc.
  • the present invention provides a compound represented by formula I or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
  • each group is as defined above.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 5 ', R 6 , R 6 ', R 7 , R 8 , R 9 , R 10 Any one of, R 11 , R 12 , R 13 , R 15 , R 16 , R 17 , R 18 , R 19 , ring A, W, X, Y, Z, m, and n is the specific compound of the present invention, respectively The corresponding group in.
  • the compound is preferably the compound prepared in the embodiment.
  • the compound is selected from the following group:
  • the compound is selected from the following group:
  • the term "pharmaceutically acceptable salt” refers to a salt formed by a compound of the present invention and an acid or base suitable for use as a medicine.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts are the salts of the compounds of this invention with acids.
  • Acids suitable for salt formation include, but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, trifluoroacetic acid (TFA), sulfuric acid, nitric acid, phosphoric acid and other inorganic acids; formic acid, acetic acid, trifluoroacetic acid, propionic acid, butadiene Acid, naphthalenedisulfonic acid (1,5), asiatic acid, oxalic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, lactic acid, Malic acid, tartaric acid, citric acid, picric acid, salicylic acid, benzoic acid, phenylpropionic acid, gluconic acid, ascorbic acid, niacin, isonicotinic acid, methanesulfonic acid, ethanesulfonic acid, sulfamic acid, p-to
  • a base such as alkali metal salt (such as sodium or potassium salt), alkaline earth metal salt (such as magnesium salt or calcium salt), ammonium salt (such as lower alkanolammonium Salt and other pharmaceutically acceptable amine salts), such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butyl Base amine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.
  • alkali metal salt such as sodium or potassium salt
  • alkaline earth metal salt such as magnesium salt or calcium salt
  • ammonium salt such as lower alkanolammonium Salt and other pharmaceutically acceptable amine salts
  • methylamine salt such as sodium or potassium salt
  • alkaline earth metal salt such as magnesium salt or
  • stereoisomer or “optical isomer” means that the chiral carbon atom involved in the compound of the present invention can be in the R configuration, or in the S configuration, or a combination thereof.
  • the preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
  • the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 5 ', R 6 , R 6 ', R 7 , R 8 , R 9 , W, X, Z, Y, m and n are as above Defined.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more of the compounds or stereoisomers or pharmaceutically acceptable salts thereof.
  • the compound of the present invention can effectively pass through the blood-brain barrier and has excellent neuroprotective effects
  • the compound of the present invention and the pharmaceutical composition containing the compound of the present invention as the main active ingredient can be used to treat, prevent and alleviate diseases related to neuronal damage.
  • the compounds of the present invention can be used to treat the following diseases (but not limited to): neuropathic pain, migraine, inflammatory pain, chronic pain, stroke, brain injury, depression, Alzheimer's disease, epilepsy, Affective disorders, neurodegenerative diseases, etc.
  • the pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/agent, more preferably, 1-200 mg of the compound of the present invention/agent.
  • the "one dose” is a capsule, tablet or injection.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween
  • wetting agents such as sodium lauryl sulfate
  • coloring agents such as sodium lauryl sulfate
  • flavoring agents such as pepperminophen, sorbitol, etc.
  • antioxidants
  • the pharmaceutical composition is injection, capsule, tablet, pill, powder or granule.
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycty
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage form of the compound of the present invention for topical administration includes ointment, powder, patch, propellant and inhalant.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compound of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • the treatment method of the present invention can be administered alone or in combination with other treatment means or therapeutic drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment.
  • the administered dose is usually 1 to 2000 mg, preferably 1 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration and the patient's health status, which are all within the skill range of a skilled physician.
  • the present invention has the following main advantages:
  • the present invention provides a class of compounds with novel structures and neuroprotective effects, which can effectively pass through the blood-brain barrier.
  • the compound of the present invention has better neuroprotective activity, better in vivo efficacy, better safety, better pharmacokinetic properties, and better druggability.
  • the compounds of the present invention are expected to be used in the treatment and/or prevention of diseases and disorders affected by neuronal damage.
  • CDI N,N'-carbonyldiimidazole
  • TCDI thiocarbonyldiimidazole
  • Step 2 Compound 04047 Dissolve compound 2 (100mg, 0.28mmol) in 1,4-dioxane (3mL), add paraformaldehyde (CAS: 30525-89-4, 25mg, 0.845mmol), and heat the reaction solution Stir at 110°C for 16 hours. It was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain compound 04047 (yellow solid, 51.1 mg, yield 50%).
  • paraformaldehyde CAS: 30525-89-4, 25mg, 0.845mmol
  • reaction solution was filtered, the filtrate was washed with water and saturated sodium chloride solution in turn, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • a rat model of focal cerebral ischemia and reperfusion was prepared by the internal carotid artery suture method. Rats were injected intraperitoneally with 7% chloral hydrate (6.0 mL/kg), and the depth of anesthesia was appropriate for severely irritated animals with mild reactions. The rats in anesthetized state are tightened with rubber bands (hind limbs fixed above the knee joint, forelimbs fixed above the wrist joint) and head, the animal is fixed on the operating table in the supine position, and the animal shaver is used to shave from the head to the chest. Hair, alcohol disinfects the skin. The neck is cut in the middle, and the subcutaneous tissue is bluntly separated.
  • the experimental animals were divided into model group, edaravone group (6mg/kg) and test compound group (5mg/kg).
  • the animals were assigned to each group in a single blind with an equal probability.
  • the animals were given intravenous administration once immediately after reperfusion, and the animals in the model group were given an equal volume of normal saline.
  • the animals were sacrificed 24 hours after ischemia, the brains were taken, stained, and photographed to determine the area of cerebral infarction.
  • the degree of cerebral infarction was determined by TTC staining method. After evaluating the symptoms of neurological deficits, the animals were sacrificed with CO 2 and the brain was decapitated. The olfactory bulb, cerebellum and lower brain stem were removed. The blood stains on the surface of the brain were washed with normal saline, and the remaining water stains on the surface were removed. Placed at -20°C for 20 minutes, after removal Immediately make a coronal section vertically downward on the plane of the line of sight, and cut a slice every 2 mm backwards, and incubate the brain slices in 1% TTC dye solution (37°C for 20 minutes). Normal brain tissues are stained dark red, and ischemic brain The tissue was pale white. After rinsing with saline, the brain slices were quickly arranged in a row from front to back, and the remaining water stains on the surface were absorbed and photographed.
  • Calculation of cerebral infarct area The photos are processed with Image J software, and the corresponding area of the left brain and the area of the non-infarct focus of the right brain are calculated to obtain the percentage of the infarct area.
  • Quantitative data are expressed as mean ⁇ standard error.
  • GraphPad Prism (6.01) software is used to perform one-way ANOVA for each drug efficacy index, and Fisher’s LSD test is used to test the differences between groups after the variance test is significant. P ⁇ 0.05 was defined as a significant difference.
  • Table 1 shows the degree of neurological deficit symptoms and the area of cerebral infarction in each group of animals.
  • the compounds 04007, 04015, 0441, 04050, 04089 can significantly reduce the cerebral infarct area of model rats.
  • compounds 04007, 04015, 0441, 04050 at a dose of 5 mg/kg and compound 04089 at a dose of 0.5 mg/kg are equivalent to or better than edaravone at a dose of 6 mg/kg. Edaravone.

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Abstract

涉及一类具有神经保护作用的化合物及其制备方法和用途。具体地，化合物具有式I所示结构，其中各基团和取代基的定义如说明书中所述；还公开了所述化合物的制备方法及其在神经保护方面的用途。

Description

一类具有神经保护作用的化合物及其制备方法和用途 技术领域
本发明涉及生物医药领域，具体地涉及一类具有神经保护作用的化合物及其制备方法和用途。
背景技术
脑卒中是一种急性脑血管疾病，包括缺血性和出血性卒中，其中缺血性卒中的发病率占脑卒中总数的60％～70％，脑卒中具有发病率高、死亡率高和致残率高的特点。
神经保护的分子作用机制、开发神经保护药物是脑卒中治疗的热门研究领域之一。目前常用的神经保护剂包括自由基清除剂、谷氨酸拮抗剂、钙通道拮抗剂、细胞膜稳定剂等，但是由于脑卒中发病机制的复杂性，临床上至今没有效果十分理想的神经保护剂。由于脑卒中的高发病率及巨大危害，开发新型神经保护剂的意义重大。
发明内容
本发明的目的在于提供一种式I所示化合物及其制备方法和其在神经保护方面的用途。
本发明的第一方面，提供了式I所示化合物或其立体异构体、或其药学上可接受的盐：
Figure PCTCN2020135289-appb-000001
其中，
R 1、R 2、R 3、R 4、R 5、R 5’、R 6、R 6’、R 7、R 8、R 9分别独立选自下组：氢、卤素、氨基、羟基、羧基、硝基、氰基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 3-6环烷基、卤代C 3-6环烷基、C 1-6烷基胺基；
R 5与R 6或者R 5’与R 6’可以环合形成取代或未取代的3-8元饱和或不饱和的环烷基或含有一个或多个(例如2、3、或4个)选自N、S和O的杂原子的杂环烷基，所述取代是指被选自下组的一个或多个(例如2、3、或4个)取代基取代：氢、卤素、C 1-6烷基；
X选自下组：
Figure PCTCN2020135289-appb-000002
Figure PCTCN2020135289-appb-000003
R 10、R 11、R 12、R 13分别独立选自下组：氢、卤素、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 3-6环烷基、卤代C 1-6烷氧基、取代或未取代的C 6-10芳基、取代或未取代的5-6元含有一个或多个(例如2、3、或4个)选自N、S和O的杂原子的杂芳基、3-8元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基，所述取代是指被选自下组的一个或多个(例如2、3、或4个)取代基取代：氢、卤素、C 1-6烷基；
环A为取代或未取代的3-8元饱和或不饱和的环烷基或取代或未取代的3-8元含有一个或多个(例如2、3、或4个)选自N、S和O的杂原子的杂环烷基，所述取代是指被选自下组的一个或多个(例如2、3、或4个)取代基取代：氢、卤素、C 1-6烷基；
W选自下组：O、S、NR 19；
R 19选自下组：氢、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、卤代C 3-6环烷基、C 6-10芳基、取代或未取代的3-8元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基或杂芳基，所述取代是指被选自下组的一个或多个(例如2、3、或4个)取代基取代：氢、卤素、C 1-6烷基；
m为0或1；
n为0或1；
Z为N或CR 18；
R 18选自下组：氢、羟基、卤素、氨基、氰基、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 3-6环烷基、卤代C 1-6烷氧基、C 1-6烷基胺基；
Y选自下组：COOR 15、CONR 16R 17、C 6-10芳基、3-8元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基或杂芳基，所述杂环烷基任选地被一个或多个(例如2、3或4个)选自下组的取代基取代：＝O、 氢、卤素、C 1-6烷基；
R 15、R 16、R 17分别独立选自下组：氢、C 1-6烷基、C 3-8环烷基、C 6-10芳基、3-15元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基或杂芳基、-(C 1-6亚烷基)(3-15元饱和或不饱和的含有一个或多个(例如2、3、4或5个)选自N、S和O的杂原子的杂环烷基或杂芳基)；所述烷基、环烷基、芳基、杂芳基、杂环烷基任选地被一个或多个(例如2、3或4个)选自下组的取代基取代：氢、卤素、羟基、C 1-6亚烷基羟基、＝O、-NR 20R 21、氰基、C 2-6炔基、C 2-6烯基、C 1-6烷基、C 3-8环烷基、C 1-6烷基取代或未取代的含一个或多个(例如2、3或4个)选自N、S和O的杂原子的3-8元杂环烷基、卤代C 1-6烷基、氨基和羧基取代的C 1-6烷基、C 1-6烷氧基、含一个或多个(例如2、3或4个)选自N、S和O的杂原子的5-10元杂芳基、C 6-12芳基、-COO(C 1-6烷基)；
R 20和R 21独立选自下组：氢、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、卤代C 3-6环烷基；
或者Y与R 8环合形成
Figure PCTCN2020135289-appb-000004
在另一优选例中，m＝1，n＝0；
R 1、R 2、R 3、R 4、R 5、R 5’、R 6、R 6’、R 7、R 8、R 9分别独立选自下组：氢、卤素、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 3-6环烷基、卤代C 1-6烷氧基；
X选自下组：
Figure PCTCN2020135289-appb-000005
R 10、R 11、R 12、R 13分别独立选自下组：氢、卤素、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、卤代C 3-6环烷基、取代或未取代的C 6-10芳基、取代或未取代的5-6元含有一个或多个(例如2、3、或4个)选自N、S和O的杂原子的杂芳基，所述取代是指被选自下组的一个或多个(例如2、3、或4个)取代基取代：氢、卤素、C 1-6烷基；
环A为取代或未取代的3-8元环烷基或取代或未取代的3-8元含有一个或多个(例如2、3、或4个)选自N、S和O的杂原子的杂环烷基，所述取代是指被选自下组的一个或多个(例如2、3、或4个)取代基取代：氢、卤素、C 1-6烷基；
W为O；
Z为N或CR 18；
R 18选自下组：氢、羟基、卤素、氨基、氰基、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 3-6环烷基、卤代C 1-6烷氧基、C 1-6烷基胺基；
Y选自下组：COOR 15、取代或未取代的3-8元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基或杂芳基，所述杂环烷基任选地被一个或多个(例如2、3或4个)选自下组的取代基取代：＝O、氢、卤素、C 1-6烷基；
R 15选自下组：氢、C 1-6烷基、C 3-8环烷基、C 6-10芳基、3-15元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基或杂芳基、-(C 1-6亚烷基)(3-15元饱和或不饱和的含有一个或多个(例如2、3、4或5个)选自N、S和O的杂原子的杂环烷基或杂芳基)；所述烷基、环烷基、芳基、杂芳基、杂环烷基任选地被一个或多个(例如2、3或4个)选自下组的取代基取代：氢、卤素、羟基、C 1-6亚烷基羟基、＝O、-NR 20R 21、氰基、C 2-6炔基、C 2-6烯基、C 1-6烷基、C 3-10环烷基、C 1-6烷基取代或未取代的含一个或多个(例如2、3或4个)选自N、S和O的杂原子的3-8元杂环烷基、卤代C 1-6烷基、氨基和羧基取代的C 1-6烷基、C 1-6烷氧基、含一个或多个(例如2、3或4个)选自N、S和O的杂原子的5-10元杂芳基、C 6-12芳基、-COO(C 1-6烷基)；
R 20和R 21独立选自下组：氢、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、卤代C 3-6环烷基；
或者Y与R 8环合形成
Figure PCTCN2020135289-appb-000006
在另一优选例中，m＝0，n＝1；
R 1、R 2、R 3、R 4、R 5、R 5’、R 6、R 6’、R 7、R 8、R 9分别独立选自下组：氢、卤素、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 3-6环烷基、卤代C 1-6烷氧基；
X选自下组：
Figure PCTCN2020135289-appb-000007
R 10、R 11分别独立选自下组：氢、卤素、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、卤代C 3-6环烷基、取代或未取代的C 6-10芳基、取代或未取代的5-6元含有一个或多个(例如2、3、或4个)选自N、S和O的杂原子的杂芳基，所述取代是指被选自下组的一个或多个(例如2、3、或4个)取代基取代：氢、卤素、C 1-6烷基；
环A为取代或未取代的3-8元环烷基或取代或未取代的3-8元含有一个或多 个(例如2、3、或4个)选自N、S和O的杂原子的杂环烷基，所述取代是指被选自下组的一个或多个(例如2、3、或4个)取代基取代：氢、卤素、C 1-6烷基；
W为O；
Z为N或CR 18；
R 18选自下组：氢、羟基、卤素、氨基、氰基、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 3-6环烷基、卤代C 1-6烷氧基、C 1-6烷基胺基；
Y为COOR 15；
R 15选自下组：氢、C 1-6烷基、C 3-8环烷基、C 6-10芳基、3-15元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基或杂芳基；所述烷基、环烷基、芳基、杂芳基、杂环烷基任选地被一个或多个(例如2、3或4个)选自下组的取代基取代：氢、卤素、羟基、＝O、氰基、C 2-6炔基、C 2-6烯基、C 1-6烷基、C 3-8环烷基、C 1-6烷基取代或未取代的含一个或多个(例如2、3或4个)选自N、S和O的杂原子的3-8元杂环烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、含一个或多个(例如2、3或4个)选自N、S和O的杂原子的5-10元杂芳基、C 6-12芳基。
在另一优选例中，R 1和R 3为Cl。
在另一优选例中，R 2、R 4、R 5、R 5’、R 6、R 6’、R 7、R 8、R 9为氢。
在另一优选例中，X选自下组：
Figure PCTCN2020135289-appb-000008
R 10、R 11、R 12、R 13分别独立选自下组：氢、卤素、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 3-6环烷基、卤代C 1-6烷氧基、取代或未取代的C 6-10芳基、取代或未取代的5-6元含有一个或多个(例如2、3、或4个)选自N、S和O的杂原子的杂芳基、3-8元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基，所述取代是指被选自下组的一个或多个(例如2、3、或4个)取代基取代：氢、卤素、C 1-6烷基；
环A为取代或未取代的3-8元饱和或不饱和的环烷基或取代或未取代的3-8元含有一个或多个(例如2、3、或4个)选自N、S和O的杂原子的杂环烷基，所述取代是指被选自下组的一个或多个(例如2、3、或4个)取代基取代：氢、卤素、C 1-6烷基。
在另一优选例中，W为O。
在另一优选例中，m＝1，n＝0。
在另一优选例中，m＝0，n＝1。
在另一优选例中，Z为N或CR 18；
R 18选自下组：氢、羟基、卤素、氨基、氰基、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 3-6环烷基、卤代C 1-6烷氧基、C 1-6烷基胺基。
在另一优选例中，Y选自下组：COOR 15、3-8元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基或杂芳基，所述杂环烷基任选地被一个或多个(例如2、3或4个)选自下组的取代基取代：＝O、氢、卤素、C 1-6烷基；
R 15选自下组：氢、C 1-6烷基、C 3-8环烷基、C 6-10芳基、3-15元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基或杂芳基、-(C 1-6亚烷基)(3-15元饱和或不饱和的含有一个或多个(例如2、3、4或5个)选自N、S和O的杂原子的杂环烷基或杂芳基)；所述烷基、环烷基、芳基、杂芳基、杂环烷基任选地被一个或多个(例如2、3或4个)选自下组的取代基取代：氢、卤素、羟基、C 1-6亚烷基羟基、＝O、-NR 20R 21、氰基、C 2-6炔基、C 2-6烯基、C 1-6烷基、C 3-10环烷基、C 1-6烷基取代或未取代的含一个或多个(例如2、3或4个)选自N、S和O的杂原子的3-8元杂环烷基、卤素取代的C 1-6烷基、氨基和羧基取代的C 1-6烷基、C 1-6烷氧基、含一个或多个(例如2、3或4个)选自N、S和O的杂原子的5-10元杂芳基、C 6-12芳基、-COO(C 1-6烷基)；
R 20和R 21独立选自下组：氢、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、卤代C 3-6环烷基。
在另一优选例中，Y与R 8环合形成
Figure PCTCN2020135289-appb-000009
在另一优选例中，Y选自下组：COOR 15、
Figure PCTCN2020135289-appb-000010
R 15如上文所定义；
Z选自下组：N、C(OH)。
在另一优选例中，Y为COOR 15；R 15选自下组：氢、C 1-6烷基、C 3-8环烷基、C 6-10芳基、3-15元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基；所述烷基、环烷基、芳基、杂环烷基任选地被一个或多个(例如2、3或4个)选自下组的取代基取代：氢、卤素、羟基、-NR 20R 21、氰基、C 2-6炔基、C 2-6烯基、C 1-6烷基、C 3-10环烷基；R 20、R 21如上文所述；
Z为N。
在另一优选例中，Y为COOR 15；R 15选自下组：C 1-6烷基、C 3-8环烷基、3-15元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基；所述杂环烷基任选地被一个或多个(例如2、3或4个)选自下组的取代基取代：氢、卤素、C 1-6烷基、C 3-10环烷基；
Z为C(OH)。
在另一优选例中，R 1、R 2、R 3、R 4、R 7、R 8、R 9分别独立选自下组：氢、卤素；
R 5、R 5’、R 6、R 6’分别为氢；
W为O；
X为
Figure PCTCN2020135289-appb-000011
Z为N或C(OH)；
Y为COOR 15；
R 10、R 11分别独立选自下组：氢、卤素、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、卤代C 3-6环烷基；
R 15选自下组：氢、C 1-6烷基、C 3-8环烷基、C 6-10芳基、3-15元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基或杂芳基、-(C 1-6亚烷基)(3-15元饱和或不饱和的含有一个或多个(例如2、3、4或5个)选自N、S和O的杂原子的杂环烷基或杂芳基)；所述烷基、环烷基、芳基、杂芳基、杂环烷基任选地被一个或多个(例如2、3或4个)选自下组的取代基取代：氢、卤素、羟基、C 1-6亚烷基羟基、＝O、-NR 20R 21、氰基、C 2-6炔基、C 2-6烯基、C 1-6烷基、C 3-8环烷基、C 1-6烷基取代或未取代的含一个或多个(例如2、3或4个)选自N、S和O的杂原子的3-8元杂环烷基、卤代C 1-6烷基、氨基和羧基取代的C 1-6烷基、C 1-6烷氧基、含一个或多个(例如2、3或4个)选自N、S和O的杂原子的5-10元杂芳基、C 6-12芳基、-COO(C 1-6烷基)；
R 20和R 21独立选自下组：氢、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、卤代C 3-6环烷基；
对于m和n，m＝1且n＝0，或m＝0且n＝1。
在另一优选例中，R 1、R 2、R 3、R 4、R 7、R 8、R 9分别独立选自下组：氢、卤素；
R 5、R 5’、R 6、R 6’分别为氢；
W为O；
X为
Figure PCTCN2020135289-appb-000012
Z为N或C(OH)；
Y为COOR 15；
R 15选自下组：氢、C 1-6烷基、C 3-8环烷基、C 6-10芳基、3-15元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基或杂芳基、-(C 1-6亚烷基)(3-15元饱和或不饱和的含有一个或多个(例如2、3、4或5个)选自N、S和O的杂原子的杂环烷基或杂芳基)；所述烷基、环烷基、芳基、杂芳基、杂环烷基任选地被一个或多个(例如2、3或4个)选自下组的取代基取代：氢、卤素、羟基、C 1-6亚烷基羟基、＝O、-NR 20R 21、氰基、C 2-6炔基、C 2-6烯基、C 1-6烷基、C 3-8环烷基、C 1-6烷基取代或未取代的含一个或多个(例如2、3或4个)选自N、S和O的杂原子的3-8元杂环烷基、卤代C 1-6烷基、氨基和羧基取代的C 1-6烷基、C 1-6烷氧基、含一个或多个(例如2、3或4个)选自N、S和O的杂原子的5-10元杂芳基、C 6-12芳基、-COO(C 1-6烷基)；
R 20和R 21独立选自下组：氢、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、卤代C 3-6环烷基；
R 22选自下组：氢、C 1-6烷基；
对于m和n，m＝1且n＝0，或m＝0且n＝1。
在另一优选例中，R 1、R 2、R 3、R 4、R 7、R 8、R 9分别独立选自下组：氢、卤素；
R 5、R 5’、R 6、R 6’分别为氢；
W为O；
X为
Figure PCTCN2020135289-appb-000013
Z为N；
Y为COOR 15；
R 15选自下组：氢、C 1-6烷基、C 3-8环烷基；所述烷基、环烷基任选地被一个或多个(例如2、3或4个)C 1-6烷氧基取代；
对于m和n，m＝1且n＝0，或m＝0且n＝1。
在另一优选例中，R 1、R 2、R 3、R 4、R 7、R 8、R 9分别独立选自下组：氢、卤素；
R 5、R 5’、R 6、R 6’分别为氢；
W为O；
X为
Figure PCTCN2020135289-appb-000014
Z为N；
Y为COOR 15；
R 15为C 1-6烷氧基取代的C 1-6烷基；
m＝1且n＝0。
在另一优选例中，在“C 1-6烷氧基取代的C 1-6烷基”中，所述C 1-6烷氧基选自下组：甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基；
所述C 1-6烷基选自下组：甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、新戊基、特戊基。
在另一优选例中，所述化合物如下文所述。
本发明的第二方面，提供了一种本发明第一方面所述的化合物或其立体异构体、或其药学上可接受的盐的制备方法，包括如下步骤：
Figure PCTCN2020135289-appb-000015
将式I’化合物与环化试剂反应，得到式I化合物；
其中，R 1、R 2、R 3、R 4、R 5、R 5’、R 6、R 6’、R 7、R 8、R 9、W、X、Z、Y、m和n如本发明第一方面所定义。
在另一优选例中，所述环化试剂选自下组：光气(碳酰氯)、二(三氯甲基)碳酸酯、N,N'-羰基二咪唑(CDI)、硫代光气、N,N'-硫羰基二咪唑(TCDI)、脂肪醛、芳香醛、脂肪酮、芳香酮、三氯氧磷、溴化氰、或其组合。
在另一优选例中，所述脂肪醛选自下组：多聚甲醛、正丁醛、或其组合。
在另一优选例中，所述脂肪酮选自下组：环丁酮、3-氧杂环丁酮、或其组合。
在另一优选例中，所述芳香醛为苯甲醛。
本发明的第三方面，提供了一种药物组合物，包含药学上可接受的载体和一种 或多种本发明第一方面所述的化合物或其立体异构体、或其药学上可接受的盐。
本发明的第四方面，提供了一种本发明第一方面所述的化合物或其立体异构体、或其药学上可接受的盐的用途，用于制备药物，所述药物用于预防和/或治疗受神经元损伤影响的疾病或病症。
在另一优选例中，所述受神经元损伤影响的疾病或病症选自下组：神经性疼痛、偏头痛、炎症痛、慢性疼痛、脑卒中、脑损伤、抑郁症、阿尔茨海默病、癫痫、情感障碍性疾病、神经退行性疾病。
本发明的第五方面，提供了一种神经保护剂，包含一种或多种本发明第一方面所述的化合物或其立体异构体、或其药学上可接受的盐。
本发明的第六方面，提供了一种预防和/或治疗受神经元损伤影响的疾病或病症的方法，包括步骤：向所需患者施用预防和/或治疗有效量的本发明第三方面所述的药物组合物。
本发明的第七方面，提供了一种预防和/或治疗脑梗的方法，包括步骤：向所需患者施用预防和/或治疗有效量的本发明第三方面所述的药物组合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，意外地制备了一种结构新颖的具有神经保护作用的化合物。本发明化合物可以有效通过血脑屏障并具有良好的神经保护作用，可用于治疗脑卒中、疼痛等疾病。在此基础上，发明人完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
在本发明中，术语“卤素”指F、Cl、Br或I。
在本发明中，“C 1-6烷基”是指包括1-6个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、新戊基、特戊基、或类似基团。
在本发明中，术语“C 2-6烯基”是指具有2至6个碳原子的含有一个双键的直链或支链烯基，非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。
在本发明中，术语“C 2-6炔基”是指具有2至6个碳原子的含有一个三键的直链或支链炔基，非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。
在本发明中，术语“C 3-8环烷基”或“环烷基”是指在环上具有3至8个碳原子的环状烷基(包括螺环烷基、桥环烷基(如化合物04033中所示结构
Figure PCTCN2020135289-appb-000016
))，非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。术语“C 3-6环烷基”具有类似含义。
在本发明中，术语“C 1-6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C 1-4烷氧基。
在本发明中，术语“C 1-6烷基胺基”是指C 1-6烷基-NH-。
在本发明中，术语“杂环烷基”和“杂环基”为含1、2或3个选自N、O、S的杂原子的3-8元杂环基(包括杂螺环烷基、杂并环烷基、杂桥环烷基)，包括(但并不限于)如下基团：
Figure PCTCN2020135289-appb-000017
术语“不饱和”是指对应结构中存在双键结构。术语“饱和”是指对应结构中不存在双键结构。所述杂环烷基可以是取代或未取代的，取代的杂环烷基如化合物04132中所示结构
Figure PCTCN2020135289-appb-000018
在本发明中，术语“芳环”或“芳基”具有相同的含义，优选为“C 6-10芳基”。术语“C 6-10芳基”是指在环上不含杂原子的具有6至10个碳原子的芳香族环基，如苯基、萘基等。
在本发明中，术语“芳香杂环”或“杂芳基”具有相同的含义，指包含一个到多 个杂原子的杂芳族基团。例如“C 3-10杂芳基”是指含有1～4个选自氧、硫和氮中的杂原子以及3-10个碳原子的芳香杂环。非限制性例子包括：呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
在本发明中，术语“卤代”是指被卤素取代。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：卤素、羟基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、C1-C6烷氧基、C1-C10磺酰基等。
化合物
本发明提供了式I所示化合物或其立体异构体、或其药学上可接受的盐，
Figure PCTCN2020135289-appb-000019
其中，各基团如上文所定义。
在另一优选例中，所述的化合物中，R 1、R 2、R 3、R 4、R 5、R 5’、R 6、R 6’、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 15、R 16、R 17、R 18、R 19、环A、W、X、Y、Z、m和n中任一个分别为本发明所述具体化合物中所对应的基团。
在另一优选例中，所述化合物优选为实施例中所制备的化合物。
在另一优选例中，所述化合物选自下组：
Figure PCTCN2020135289-appb-000020
Figure PCTCN2020135289-appb-000021
在另一优选例中，所述化合物选自下组：
Figure PCTCN2020135289-appb-000022
Figure PCTCN2020135289-appb-000023
Figure PCTCN2020135289-appb-000024
如本文所用，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、三氟乙酸(TFA)、硫酸、硝酸、磷酸等无机酸；甲酸、乙酸、三氟乙酸、丙酸、丁二酸、萘二磺酸(1,5)、亚细亚酸、草酸、戊酸、二乙基乙酸、丙二酸、琥珀酸、富马酸、庚二酸、己二酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、水杨酸、苯甲酸、苯丙酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲磺酸、乙磺酸、氨基磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸；以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。
另一类优选的盐是本发明化合物与碱形成的盐，例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐)，例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐，以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
所述的“立体异构体”或“光学异构体”指本发明化合物所涉及手性碳原子可以为R构型，也可以为S构型，或其组合。
制备方法
下面更具体地描述本发明式I结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
典型地，本发明化合物的制备工艺流程如下，其中所用原料和试剂如无特殊说明，均可通过商业途径购买。
Figure PCTCN2020135289-appb-000025
将式I’化合物与环化试剂反应，得到式I化合物；
其中，R 1、R 2、R 3、R 4、R 5、R 5’、R 6、R 6’、R 7、R 8、R 9、W、X、Z、Y、m和n如上文所定义。
药物组合物和施用方法
本发明还提供了一种药物组合物，包含药学上可接受的载体和一种或多种所述的化合物或其立体异构体、或其药学上可接受的盐。
由于本发明化合物可以有效的通过血脑屏障并具有优异神经保护作用，因此本发明化合物以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与神经元损伤相关的疾病。根据现有技术，本发明化合物可用于治疗以下疾病(但并不限于)：神经性疼痛、偏头痛、炎症痛、慢性疼痛、脑卒中、脑损伤、抑郁症、阿尔茨海默病、癫痫、情感障碍性疾病、神经退行性疾病等。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有1-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊、药片或注射剂。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2020135289-appb-000026
)、润湿剂(如十二烷基硫酸钠)、 着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜 的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的其他化合物联合给药。
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选1～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
与现有技术相比，本发明具有以下主要优点：
(1)本发明提供了一类结构新颖的具有神经保护作用的化合物，该类化合物可以有效的通过血脑屏障。
(2)本发明化合物具有更好的神经保护活性、更好的体内药效、更好的安全性、更好的药代性质以及更好的成药性。
(3)本发明化合物有望用于治疗和/或预防受神经元损伤影响的疾病和病症。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1化合物04013的制备
Figure PCTCN2020135289-appb-000027
步骤一、化合物2
在25℃下，往化合物1(2.0g,14.5mmol)的乙醇(20mL)溶液中缓慢滴加二氯亚砜(20mL)。反应体系加热至60℃并搅拌过夜。减压浓缩，残余物用水(50mL)和乙酸乙酯(50mL X 2)萃取，合并有机相用无水硫酸钠干燥，减压浓缩，得到白色固体化合物2(0.90g,收率:37.5％)
步骤二、化合物04006-1
在25℃，化合物2(0.90g,5.4mmol)和化合物3(1.0g,5.0mmol)的甲醇(20mL)溶液搅拌1小时，加入氰基硼氢化钠(0.38g,6.0mmol)，搅拌过夜。用碳酸氢钠水溶液(100mL)淬灭反应，减压浓缩除去甲醇，乙酸乙酯(100mL X 3)萃取，合并的有机相用无水硫酸钠干燥，减压浓缩，残余物用硅胶柱纯化得到白色固体化合物04006-1(0.90g,收率:53％)。
MS(ESI):Calcd.for C 15H 14Cl 2N 2O 3 340；Found 341[M+H] +.
步骤三、化合物04013
在25℃，往化合物04006-1(200mg,0.58mmol)的乙酸乙酯(10mL)溶液中加入CDI(N,N'-羰基二咪唑)(200mg,0.62mmol)，搅拌16小时。反应液直接过滤，滤饼用乙酸乙酯打浆，过滤，干燥得到灰白色固体化合物04013(65mg，产率：30％)。
MS(ESI):Calcd.for C 16H 12Cl 2N 2O 4 366；Found 367[M+H] +.
HNMR(400MHz,CD 3OD):δ8.83(s,1H),8.24-8.22(d,J＝8.0Hz,1H),7.97-7.95(d,J＝8.0Hz,1H),7.45(s,1H),7.12(s,1H),4.93(s,2H),4.53-4.48(q,J＝6.8Hz,2H)，1.48-1.44(t,J＝6.8Hz,3H).
实施例2化合物04015的制备
Figure PCTCN2020135289-appb-000028
步骤一、化合物04015
在25℃下，往化合物04006-1(0.2g，0.58mmol)的乙酸乙酯(10mL)溶液中加入TCDI(硫羰基二咪唑)(118mg,0.6mmol)，搅拌16小时。反应液用水洗涤，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用制备板纯化得到化合物04015(22mg，产率：10％)。
MS(ESI):Calcd.for C 16H 12Cl 2N 2O 3S 382；Found 383[M+H] +.
HNMR(400MHz,CD 3OD):δ8.83(s,1H),8.28(d,J＝8.0Hz,1H),7.91(d,J＝8.0Hz,1H),7.48(s,1H),7.07(s,1H),4.83(s,2H),4.52(q,J＝6.0Hz,2H)，1.47(t,J＝6.0Hz,3H).
实施例3化合物04016的制备
Figure PCTCN2020135289-appb-000029
步骤一、化合物04016
在25℃，往化合物04006-1(200mg,0.59mmol)和三乙胺(178mg,1.76mmol)的甲苯(10mL)溶液中加入三氯氧磷(0.55mL)，反应体系在氮气保护下加热至70℃反应16小时。减压浓缩，残余物加入乙醇(20mL)，搅拌半个小时。减压浓缩，残余物用制备色谱纯化得到04016(49.7mg,收率:19.6％)。
MS(ESI):Calcd.for C 17H 17Cl 2N 2O 5P 430；Found 431[M+H] +.
HNMR(400MHz,CDCl 3):δ8.70(d,J＝2.4Hz,1H),8.13-8.10(d,J＝8.8Hz,1H),7.87-7.80(dd,d,J＝8.8Hz，2.0Hz,1H),7.43(s,1H),7.15(d,J＝2.4Hz,1H),4.88-4.70(m,2H),4.47(q,J＝7.2Hz，2H),4.35-4.24(m,2H),1.47-1.42(t,J＝7.2Hz,3H),1.38-1.32(t,J＝7.2Hz,3H).
实施例4化合物04056的制备
Figure PCTCN2020135289-appb-000030
步骤一、化合物04056
将化合物04006-1(200mg,0.59mmol)溶于乙腈(5mL)中，然后加入三乙胺(178mg,1.77mmol)，滴加溴化氰(79mg,0.76mmol)的乙腈(5mL)溶液，在25℃搅拌1小时。反应液用水(20mL)稀释后用乙酸乙酯(3x 50mL)萃取。有机相合并后用无水硫酸钠干燥，减压浓缩，残余物用中性氧化铝柱层析(展开剂：二氯甲烷/甲醇＝100:1～100:8)纯化后得到化合物04056(40.3mg,收率19％)为黄色固体。
LCMS:[M+H] +＝366.0
1H NMR 1H NMR(400MHz,DMSO-d 6)δ8.05(s,1H),7.79–7.63(m,2H),7.34(d,J＝13.0Hz,2H),6.88(d,J＝7.7Hz,1H),4.41(d,J＝3.9Hz,2H),4.23(d,J＝6.8Hz,2H),1.27(t,J＝6.7Hz,3H).
实施例5化合物04022的制备
Figure PCTCN2020135289-appb-000031
步骤一、化合物04022
将化合物04006-1(300mg,0.88mmol)及多聚甲醛(CAS:30525-89-4)(79mg,2.64mmol)溶于1，4二氧六环(10mL)，升温至110℃搅拌16小时。将反应液浓缩后用硅胶柱层析(展开剂：二氯甲烷)纯化得到化合物04022(白色固体，154mg，收率50％)。
LCMS:[M+H] +＝353.1
1H NMR(400MHz,CDCl 3)δ8.56(s,1H),8.07(d,J＝8.6Hz,1H),7.46(d,J＝8.5Hz,1H),7.25(d,J＝1.9Hz,1H),6.97(d,J＝1.9Hz,1H),5.50(s,2H),4.71(s,2H),4.45(q,J＝7.1Hz,2H),1.42(t,J＝7.1Hz,3H).
实施例6化合物04046的制备
Figure PCTCN2020135289-appb-000032
步骤一、化合物04046
将化合物04006-1(50mg,0.15mmol)溶于氯仿(5mL)，加入环丁酮2(0.1mL)以及两滴四氯化锡(二氯甲烷2M溶液)，反应液升温至90℃搅拌16小时。冷却至25℃后将反应液浓缩并用中性氧化铝柱层析(展开剂：二氯甲烷)纯化得到化合物04046(黄色固体，6.0mg，收率10.4％)。
LCMS:[M+H] +＝393.1
1H NMR(400MHz,CDCl 3)δ8.48(s,1H),7.93(d,J＝8.5Hz,1H),7.39(dd,J＝8.5,2.3Hz,1H),7.15(d,J＝2.0Hz,1H),6.75(s,1H),4.55(s,2H),4.40–4.33(m,2H),2.51–2.38(m,4H),2.11–2.01(m,1H),1.86–1.77(m,1H),1.34(t,J＝7.2Hz,3H).
实施例7化合物04044的制备
Figure PCTCN2020135289-appb-000033
步骤一、化合物04044
将化合物04006-1(50mg,0.15mmol)、化合物2(0.1mL)以及SnCl 4(2滴,2M二氯甲烷溶液)溶于三氯甲烷(8mL)，升温至90℃搅拌16小时。冷却至25℃后将以上溶液浓缩，残余物用制备色谱进行纯化得到化合物04044(淡黄色固体2.0mg，收率3.4％)。
LCMS:[M+H] +＝395.0
1H NMR(400MHz,CDCl 3)δ8.15(s,1H),7.96(d,J＝8.6Hz,1H),7.29(d,J＝2.1Hz,1H),7.15(s,1H),6.89(d,J＝8.1Hz,1H),4.79–4.72(m,1H),4.45–4.39(m,4H),1.69–1.62(m,2H),1.41(t,J＝7.1Hz,3H),1.32–1.25(m,2H),1.01–0.88(m,3H).
实施例8化合物04045的制备
Figure PCTCN2020135289-appb-000034
步骤一、化合物04045
将化合物04006-1(50mg,0.15mmol)、化合物2(0.1mL)以及SnCl 4(2滴,2M二氯甲烷溶液)溶于三氯甲烷(8mL)，升温至90℃搅拌16小时.冷却至25℃后将以上溶液浓缩，残留物用制备色谱进行纯化得到化合物04045(12.3mg，收率20％)。
LCMS:[M+H] +＝429.0
1H NMR(400MHz,CDCl 3)δ8.64(s,1H),8.08(d,J＝8.4Hz,1H),7.54(t,J＝7.8Hz,1H),7.46–7.35(m,5H),7.27(s,1H),6.88(s,1H),6.84(s,1H),4.48–4.40(m,4H),1.43(t,J＝7.1Hz,3H).
实施例9化合物04024的制备
Figure PCTCN2020135289-appb-000035
步骤一、化合物04024
在25℃，向化合物04006(2g，6.4mmol)的二甲基亚砜(15mL)溶液中加入CDI(2.1g,12.8mmol)，搅拌0.5小时。将反应液缓慢倒入10mL冰水中，出现大量白色絮状固体，搅拌0.5小时，过滤，滤饼减压干燥，得到化合物04024(1.5g，产率：69％)。
MS(ESI):Calcd.for C 14H 8Cl 2N 2O 4 338；Found 339[M+H] +.
1H NMR(400MHz,DMSO-d 6):δ8.84(s,1H),8.16(d,J＝8.4Hz,1H),8.09(d,J＝8.4Hz,1H),7.75(s,1H),7.45(s,1H),2.06(s,2H).
实施例10化合物04019的制备
Figure PCTCN2020135289-appb-000036
步骤一、化合物04019
在25℃，往化合物04024(0.2g，0.59mmol)的二氯甲烷(10mL)溶液中依次加入DCC(243mg,1.18mmol)，环己醇(295mg,2.95mmol)和DMAP(144mg,1.18mmol)，搅拌18小时。LCMS检测原料反应完全，将反应液过滤，滤液浓缩，残余物用硅胶柱分离纯化(洗脱剂为石油醚：乙酸乙酯＝10：1至2：1)得到化合物04019(33.12mg，产率：13％)。
MS(ESI):Calcd.for C 20H 18Cl 2N 2O 4 420；Found 421[M+H] +.
1HNMR(400MHz,DMSO-d 6):δ8.86(s,1H),8.16(d,J＝8.0Hz,1H),8.09(d,J＝8.0Hz,1H),7.75(s,1H),7.46(s,1H),5.06(s,2H),5.00–4.96(m,1H),1.98-1.87(m,2H),1.80-1.70(m,2H),1.70-1.50(m,2H),1.50–1.20(m,4H).
实施例11化合物04020的制备
Figure PCTCN2020135289-appb-000037
步骤一、化合物04020
往化合物04024(0.3g，0.89mmol)的二氯甲烷(10mL)溶液中依次加入DCC(550mg,2.67mmol)，异丙醇(162mg,2.67mmol)和DMAP(218mg,1.78mmol)，在25℃搅拌18小时。LCMS检测原料反应完全，将反应液过滤，滤液减压浓缩，残余物通过硅胶柱纯化(洗脱剂为石油醚/乙酸乙酯＝2/1)得到化合物04020(23.71mg，产率：8％)。
MS(ESI):Calcd.for C 17H 14Cl 2N 2O 4 380；Found 381[M+H] +.
1HNMR(400MHz,CD 3OD):δ8.89(s,1H),8.26(d,J＝8.0Hz,1H),8.16(d,J＝8.0Hz,1H),7.56(s,1H),7.38(s,1H),5.36-5.29(m,1H),5.06(s,2H),1.44(d,J＝6.4Hz,6H).
实施例12化合物04071的制备
Figure PCTCN2020135289-appb-000038
步骤一、化合物2
在0℃将化合物04006(4.0g，12.8mmol)慢慢加入到氯化亚砜(80mL)中，反应液升温到90℃搅拌1小时，反应体系变成棕红色溶液。减压浓缩除去多余的氯化亚砜后得到棕灰色固体。在0℃将该棕灰色固体慢慢加入到化合物3(20mL)中，然后升温到25℃并搅拌2小时。减压浓缩后，残留物用硅胶柱层析(展开剂为二氯甲烷/甲醇＝10:1)分离纯化得到油状物。将该油状物加入水(100mL)中，冷冻干燥后得到化合物4(2.0g，收率40％)。
LCMS:[M+H] +＝384.1；386.1.
步骤二、化合物04071
将化合物4(800mg，1.04mmol)溶于二甲基亚砜(15mL)，缓慢加入CDI(675mg,4.16mmol),在25℃搅拌1小时，反应液减压浓缩，残留物用制备型液相色谱纯化得到化合物04071(308.5mg,收率36％)。
LCMS:[M+H] +＝410.0,412.0
1H NMR(400MHz,DMSO-d 6)δ8.87(d,J＝2.4Hz,1H),8.17(d,J＝8.4Hz,1H),8.10-8.07(m,1H),7.73(d,J＝2.4Hz,1H),7.45(d,J＝2.4Hz,1H),5.06(s,2H),4.41(t,J＝5.6Hz,2H),2.63(t,J＝5.6Hz,2H),2.22(s,6H).
实施例13化合物04167和化合物04067的制备
Figure PCTCN2020135289-appb-000039
步骤一、化合物04167
将化合物04024(1.1g,3.243mmol)溶于二甲基甲酰胺(50mL)中，然后 依次加入化合物2(2.79g,16.107mmol)，DMAP(1.19g,9.731mmol)，PPTS(2.44g,9.731mmol)和DCC(1.0g,4.865mmol)。反应体系加热至50℃搅拌4小时。冷却至25℃，用乙酸乙酯(100mL)稀释后搅拌0.5小时。过滤，滤液用水洗，饱和氯化钠溶液洗，无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化后得到化合物04167(1.07g,产率66％)为白色固体。
LCMS:[M+H] +＝494.1.
步骤二、化合物04067
将化合物04167(1g,2.023mmol)溶于二氯甲烷(10mL)中，然后加入三氟乙酸(5mL)，反应液在25℃搅拌1小时。减压浓缩，残留物用pre-HPLC(0.1％甲酸/乙腈/水)纯化。得到化合物04067(583mg，收率67％)。
LCMS:[M+H] +＝394.0
1H NMR(400MHz,CD 3OD)δ8.88(d,J＝2.4Hz,1H),8.28(d,J＝8.4Hz,1H),8.15-8.13(m,1H),7.54(s,1H),7.33(s,1H),5.57-5.53(m,1H),5.06(s,2H),4.06-4.01(m,2H),3.91-3.87(m,2H).
实施例14化合物04068的制备
Figure PCTCN2020135289-appb-000040
步骤一、化合物04068
将化合物04024(3g,8.9mmol)溶于二甲基甲酰胺(20mL)中，然后加入DCC(2.7g,13.3mmol)，DMAP(110mg,0.9mmol)和化合物2(1.6g,13.3mmol),25℃搅拌3小时。反应液中加入乙酸乙酯(100mL)后有固体析出。过滤，滤液用水洗涤。将有机相分离并减压浓缩，残留物用硅胶柱层析(二氯甲烷/甲醇＝100:1到100:5)纯化得到化合物04068(500mg,产率14％)为黄色固体。
LCMS:[M+H] +＝408.1.
1H NMR(400MHz,DMSO-d 6)δ8.87(d,J＝2.0Hz,1H),8.19(d,J＝8.4Hz,1H),8.11(dd,J＝8.4,2.4Hz,1H),7.74(d,J＝2.4Hz,1H),7.45(d,J＝2.4Hz,1H),5.20-5.14(m,1H),5.06(s,2H),3.71-3.68(m,2H),3.14-3.11(m,2H),2.30(s,3H).
实施例15化合物04115和化合物04034的制备
Figure PCTCN2020135289-appb-000041
步骤一、化合物04115
将化合物04006(1.2g，3.8mmol)溶于二甲基亚砜(10mL)，加入TCDI(1.37g，7.7mmol)，溶液于氮气保护下在25℃搅拌2小时。用10毫升水稀释反应液并用稀盐酸调节溶液PH值小于7，用乙酸乙酯(3x50mL)萃取，以无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(展开剂为DCM/MeOH＝100/1)纯化得到化合物04115(黄色固体，1.2g，收率89％)。
LCMS:[M+H] +＝351.0.
步骤二、化合物04034
将化合物04115(120mg，0.34mmol)、化合物3(60mg，0.51mmol)和碳酸钾(94mg，0.68mmol)溶于二甲基甲酰胺(2mL)，反应液于25℃搅拌1小时，用水(10mL)稀释并用乙酸乙酯(3x 50mL)萃取，所得有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(展开剂为石油醚/乙酸乙酯＝2/1)纯化，得到化合物04034(白色固体，55.7mg，收率42％)。
LCMS:[M+H] +＝393.1.
1H NMR(400MHz,DMSO-d 6)δ8.90(d,J＝2.0Hz,1H),8.24-8.18(m,2H),7.78(d,J＝2.4Hz,1H),7.44(d,J＝2.0Hz,1H),5.02-5.01(m,4H),3.67(t,J＝2.4Hz,1H).
实施例16化合物04033的制备
Figure PCTCN2020135289-appb-000042
步骤一、化合物04033
将化合物04115(150mg，0.42mmol)、化合物2(85mg，0.55mmol)、DCC(112mg，0.55mmol)和DMAP(15mg、0.04mmol)溶于二甲基甲酰胺(2mL)，25℃搅拌3小时。反应液用水(30mL)稀释后用乙酸乙酯(3x50mL)萃取，有机相用 无水硫酸钠干燥，减压浓缩后的残留物用硅胶柱层析(展开剂为石油醚/乙酸乙酯＝2/1)纯化得到化合物04033(白色固体，32.8mg,收率16％)。
LCMS:[M+H] +＝491.1.
1H NMR(400MHz,DMSO-d 6)δ8.89(d,J＝1.6Hz,1H),8.20-8.16(m,2H),7.78(s,1H),7.44(s,1H),5.10(d,J＝9.2Hz,1H),5.02(s,2H),2.42-2.39(m,1H),2.15-2.06(m,1H),1.81-1.71(m,2H),1.42-1.27(m,2H),1.15-1.10(m,1H),0.98-0.85(m,9H).
实施例17化合物04132和化合物04032的制备
Figure PCTCN2020135289-appb-000043
步骤一、化合物04132
将化合物04115(1.06g,3.00mmol)、化合物3(1.01g,3.90mmol)、DCC(803mg,3.90mmol)和DMAP(36.6mg,0.30mmol)溶于二甲基甲酰胺(10mL)，在25℃搅拌3小时。反应液用水(100mL)稀释后用乙酸乙酯(3x 100mL)萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(展开剂为石油醚/乙酸乙酯＝5/1)纯化，得到化合物04132(黄色固体，750mg，收率42％)。
LCMS:[M+H] +＝597.1.
步骤二、化合物04032
将化合物04132(298mg,0.50mmol)溶于水(3mL)，加入三氟乙酸(3mL)和乙酸(3mL)，反应升温至50℃搅拌2小时。将反应液减压浓缩，残留物用制备型HPLC纯化后得到化合物04032(白色固体，38.1mg，收率15％)。
LCMS:[M+H] +＝517.1.
1H NMR(400MHz,DMSO-d 6):δ8.88(s,1H),8.25-8.16(m,2H),7.78(s,1H),7.45(s,1H),6.99-6.37(m,1H),5.36-4.96(m,5H),4.94-4.40(m,2H),3.80-3.58(m,1H),3.59-3.40(m,2H),3.23-3.19(m,2H).
实施例18化合物04135和化合物04035的制备
Figure PCTCN2020135289-appb-000044
步骤一、化合物04135
将化合物04115(400mg,1.1mmol)、化合物2(381mg,1.4mmol)、DCC(288mg,1.4mmol)和DMAP(12mg,0.1mmol)溶于二甲基甲酰胺(3mL)，在25℃搅拌3小时。反应液用水(30mL)稀释，用乙酸乙酯(3x 50mL)萃取，有机相用无水硫酸钠干燥，检验浓缩，残留物用硅胶柱层析(展开剂为石油醚/乙酸乙酯＝2/1)纯化，得到化合物04135(白色固体，150mg，收率23％)。
LCMS:[M+H] +＝597.1.
步骤二、化合物04035
将化合物04135(150mg,0.25mmol)溶于水，加入三氟乙酸(2mL)和乙酸(4mL)，反应液在50℃搅拌2小时。减压浓缩，残留物用制备型HPLC纯化后得到化合物04035(白色固体，91.1mg，收率70％)。
LCMS:[M+H] +＝517.1,[M+H+2] +＝519.1
1H NMR(400MHz,cd3od)δ8.81(d,J＝2.2Hz,1H),8.29(d,J＝8.4Hz,1H),8.12(dd,J＝8.4,2.4Hz,1H),7.56(d,J＝2.2Hz,1H),7.29(s,1H),4.98(s,3H),4.62–4.47(m,5H),3.94(dd,J＝18.6,7.5Hz,2H),3.83–3.74(m,1H),3.50(d,J＝6.4Hz,1H).
实施例19化合物04036的制备
Figure PCTCN2020135289-appb-000045
步骤一、化合物3
将化合物04115(900mg,2.5mmol))、化合物2(1.03g,3.1mmol)、DCC(670mg,3.25mmol)和DMAP(30mg,0.25mmol)溶于二甲基甲酰胺(10mL)，25℃搅拌3小时。反应液用水(30mL)稀释后用乙酸乙酯(3x 50mL)萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(展开剂为石油醚/乙酸乙酯＝2/1)纯化，得到化合物3(白色固体，300mg，收率18％)。
步骤二、化合物4
将化合物3(150mg,0.22mmol)溶于二氯甲烷(10mL)，加入三氟乙酸(5mL)，25℃搅拌18小时。将反应液减压浓缩，残留物用制备型HPLC纯化得到化合物4(白色固体，80mg，收率63％)。
LCMS:[M+H] +＝574.1.
步骤三、化合物04036
将化合物4(80mg,0.14mmol)溶于三氟乙酸(2mL)，反应液用微波加热至75°反应10分钟。反应液减压浓缩，残留物用制备型HPLC纯化得到化合物04036(白色固体，20.1mg，收率27％)。
LCMS:[M+H] +＝518.1.
1H NMR(400MHz,DMSO-d 6)δ8.94(d,J＝2.3Hz,1H),8.45–8.07(m,1H),7.76(d,J＝2.4Hz,0H),7.39(dd,J＝33.6,5.4Hz,2H),7.21(d,J＝8.5Hz,2H),5.02(s,2H),3.41(d,J＝4.5Hz,1H),3.14(s,1H),2.88(d,J＝6.3Hz,1H).
实施例20化合物04048的制备
Figure PCTCN2020135289-appb-000046
步骤一、化合物04048
将化合物04115(1g,2.8mmol)、叔丁醇(980mg,14.1mmol)、DCC(640mg,3.1mmol)和DMAP(68mg,0.56mmol)溶于二甲基甲酰胺(15mL)，25℃搅拌3小时。反应液用水(60mL)稀释后用乙酸乙酯(3x100mL)萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(展开剂：石油醚/乙酸乙酯＝2/1)纯化得到化合物04048(白色固体，28.5mg，收率2.5％)。
LCMS:[M+H] +＝411.1.
1H NMR(400MHz,DMSO-d 6)δ8.85(s,1H),8.15(s,2H),7.79(d,J＝2.1Hz,1H),7.45(d,J＝1.9Hz,1H),5.01(s,2H),1.58(s,9H).
实施例21化合物04049的制备
Figure PCTCN2020135289-appb-000047
步骤一、化合物04049
将化合物04115(350mg,1mmol)、异丙醇(300mg,5mmol)、DCC(250mg,1.2mmol)和DMAP(12mg,0.1mmol)溶于二甲基甲酰胺(3mL)，25℃搅拌3小时。反应液用水(30mL)稀释后用乙酸乙酯(3x50mL)萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(展开剂：石油醚/乙酸乙酯＝2/1)纯化得到化合物04049(白色固体，10.7mg，收率2.7％)。
LCMS:[M+H] +＝397.1,[M+H+2] +＝399.1
1H NMR(400MHz,DMSO-d 6)δ8.87(d,J＝1.8Hz,1H),8.18(dt,J＝8.4,5.3Hz,2H),7.78(d,J＝2.3Hz,1H),7.45(d,J＝2.2Hz,1H),5.25–5.15(m,1H),5.02(s,2H),1.36(d,J＝6.2Hz,6H).
实施例22化合物04050的制备
Figure PCTCN2020135289-appb-000048
步骤一、化合物04050
将化合物04115(350mg,1.0mmol)、化合物2(170mg,2.0mmol)、DCC(247mg,1.2mmol)和DMAP(12mg,0.1mmol)溶于二甲基甲酰胺(3mL)，25℃搅拌3小时。反应液用水(30mL)稀释后用乙酸乙酯(3x50mL)萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(展开剂：二氯甲烷/四氢呋喃＝100/1)纯化得到化合物04050(白色固体，72mg，收率18％)
LCMS:[M+H] +＝407.0,[M+H+2] +＝409.0
1H NMR(400MHz,DMSO-d 6)δ8.89(d,J＝2.0Hz,1H),8.23-8.14(m,2H),7.78(d,J＝2.4Hz,1H),7.73(d,J＝2.4Hz,1H),5.02(s,2H),4.41(t,J＝6.4Hz,2H),2.91(s,1H),2.68-2.66(m,2H).
实施例23化合物04052的制备
Figure PCTCN2020135289-appb-000049
步骤一、化合物04052
将化合物04115((200mg,0.56mmol)、化合物2(57mg,0.67mmol)、DCC(138mg,0.67mmol)和DMAP(7mg,0.067mmol)溶于二甲基甲酰胺(3mL)，25℃搅拌3小时。反应液用水(20mL)稀释后用乙酸乙酯(3x30mL)萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(展开剂：二氯甲烷/四氢呋喃＝100/1)纯化得到化合物04052(白色固体，49mg，收率21％)
LCMS:[M+H] +＝421.0
1H NMR(400MHz,DMSO-d 6)δ8.88(s,1H),8.22-8.16(m,2H),7.78(d,J＝2.0Hz,1H),7.43(d,J＝1.6Hz,1H),5.21-5.17(m,1H),5.08(s,2H),2.95(s,1H),2.65-2.63(m,2H),1.40(d,J＝6.0Hz,3H).
实施例24化合物04055的制备
Figure PCTCN2020135289-appb-000050
步骤一、化合物4
将化合物04006(1.5g,4.8mmol)溶于氯化亚砜(15mL)，在90℃搅拌2小时后将氯化亚砜在抽真空的条件下蒸发除去得到黑色的化合物2(粗产物)。 在0℃将以上化合物2加入化合物3(10mL)，反应液在25℃搅拌3小时。减压浓缩，残留物用硅胶柱层析(展开剂：二氯甲烷/甲醇＝10/1)纯化后得到化合物4(棕色固体，2.1g，收率100％)。
LCMS:[M+H] +＝384.2.
步骤二、化合物04055
将化合物4(700mg,1.82mmol)溶于二甲基亚砜(20mL)，加入TCDI(649mg,3.64mmol)，在氮气保护的条件下在25℃搅拌3小时。反应液用乙酸乙酯(200mL)稀释后用饱和氯化钠溶液(3x50mL)洗涤，有机相用无水硫酸钠干燥，减压浓缩，残留物用制备型液相色谱纯化得到化合物04055(67.1mg，产率8.6％)。
LCMS:[M+H] +＝426.0,[M+H+2] +＝428.0
1H NMR(400MHz,DMSO-d 6)δ8.88(s,1H),8.27-8.07(m,2H),7.78(d,J＝2.4Hz,1H),7.44(s,1H),5.02(s,2H),4.42(t,J＝5.6Hz,2H),2.66(t,J＝5.6Hz,2H),2.24(s,6H).
实施例25化合物04169及化合物04069的制备
Figure PCTCN2020135289-appb-000051
步骤一、化合物04169
将化合物04115(2.09g,5.9mmol)溶于二甲基甲酰胺(100mL)中，然后加入DCC(1.8g,8.9mmol)、DMAP(2.16g,17.7mmol),PPTS(4.4g,17.7mmol)和化合物2(5.0g,29.4mmol),反应液在50℃搅拌4小时。反应液中加入乙酸乙酯(100mL)后有固体析出，过滤，滤液用水洗涤。分离出的有机相减压浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝100/1)纯化得到化合物04169(黄色固体，1.6g,收率53％)。
LCMS:[M+H] +＝510.0.
步骤二、化合物04069
将化合物04169(1.0mg,1.96mmol)溶于二氯甲烷(6mL)中，然后加入三氟乙酸(3mL),在25℃反应1小时。减压浓缩，残留物用制备型液相色谱纯化得到化合物04069(黄色固体，420.6mg,收率48％)。
LCMS:[M+H] +＝410.0
1H NMR(400MHz,CD 3OD)δ8.89(d,J＝2.4Hz,1H),8.36(d,J＝8.4Hz,1H),8.18(dd,J＝8.4,2.4Hz,1H),7.58(d,J＝2.4Hz,1H),7.30(d,J＝2.4Hz,1H),5.63-5.60(m,1H),5.00(s,2H),4.57-4.52(m,2H),4.37-4.32(m,2H).
实施例26化合物04007的制备
Figure PCTCN2020135289-appb-000052
步骤一、化合物04007
将化合物04115(2g,5.6mmol)溶于二甲基甲酰胺(20mL)中，然后加入DCC(1.7g,8.5mmol)、DMAP(68mg,0.56mmol)和化合物2(1.0g,8.5mmol),在25℃搅拌3小时。反应液中加入乙酸乙酯(100mL)后有固体析出，过滤，滤液用水洗涤。有机相减压浓缩，残留物用硅胶柱层析(二氯甲烷/甲醇＝100/1)纯化得到化合物04007(500mg,收率21％)为黄色固体。
LCMS:[M+H] +＝424.0.
1HNMR(400MHz,DMSO-d 6)δ8.89(d,J＝1.6Hz,1H),8.25-8.19(m,2H),7.78(d,J＝2.4Hz,1H),7.44(d,J＝2.4Hz,1H),5.21-5.15(m,1H),5.02(s,2H),3.72-3.68(m,2H),3.15-3.12(m,2H),2.30(s,3H).
实施例27化合物04047的制备
Figure PCTCN2020135289-appb-000053
步骤一、化合物2
将化合物04006(200mg,0.64mmol)溶于氯化亚砜(3mL)，加热至90℃搅拌1小时，冷却至0℃，将异丙醇(10mL)加入反应液，升温至25℃搅拌30分钟。将反应液减压蒸干后加入二氯甲烷(50mL)，所得溶液依次用碳酸氢钠饱和溶液(3x 50mL)、水(2x 50mL)和饱和氯化钠溶液(2x 50mL)洗涤，有 机相用无水硫酸钠干后减压浓缩，残留物用硅胶层析柱(展开剂：二氯甲烷/甲醇＝10/1)纯化得到化合物2(棕色固体，260mg，收率100％)。
LCMS:[M+H] +＝355.1.
步骤二、化合物04047将化合物2(100mg，0.28mmol)溶于1，4-二氧六环(3mL)，加入多聚甲醛(CAS:30525-89-4，25mg，0.845mmol)，反应液加热至110℃搅拌16小时。减压浓缩，残留物用制备型液相色谱纯化后得到化合物04047(黄色固体，51.1mg，收率50％)。
LCMS:[M+H] +＝367.1
1H NMR(400MHz,CDCl 3)δ8.57(d,J＝2.5Hz,1H),8.04(d,J＝8.6Hz,1H),7.44(dd,J＝8.7,2.7Hz,1H),7.24(d,J＝2.3Hz,1H),6.96(d,J＝2.1Hz,1H),5.49(s,2H),5.34–5.28(m,1H),4.69(s,2H),1.40(d,J＝6.3Hz,6H).
实施例28化合物04051的制备
Figure PCTCN2020135289-appb-000054
步骤一、化合物3
将化合物04006(1.5g,4.8mmol)溶于氯化亚砜(15mL)，加热至90℃搅拌2小时。将反应液减压浓缩后加入化合物2(3mL)，所得溶液在25℃搅拌5小时。减压浓缩，残留物用制备型液相色谱纯化，得到化合物3(黄色固体，590mg，收率32％)。
LCMS:[M+H] +＝379.1
步骤二、化合物04051
将化合物3(110mg,0.29mmol)溶于1，4-二氧六环(3mL)，加入多聚甲醛(CAS:30525-89-4)(79mg,0.87mmol)，在氮气保护下将反应液加热至110℃搅拌3小时。减压浓缩，残留物用硅胶柱层析(展开剂：石油醚/乙酸乙酯＝1/1)纯化后得到化合物04051(粉色固体，27.3mg，收率24％)。
LCMS:[M+H] +＝391.0
1H NMR(400MHz,CDCl 3)δ8.57(d,J＝2.0Hz,1H),8.05(d,J＝8.8Hz, 1H),7.44(dd,J＝8.8,2.4Hz,1H),7.25(s,1H),6.97(s,1H),5.50(s,2H),5.33-5.27(m,1H),4.70(s,2H),2.69-2.55(m,2H),2.02(s,1H),1.49(d,J＝6.0Hz,3H).
实施例29化合物04038的制备
Figure PCTCN2020135289-appb-000055
步骤一、化合物3
往化合物2(0.60g,5.1mmol)和化合物1(1.0g,5.2mmol)的甲醇(10mL)溶液中加入冰醋酸(1mL),在25℃搅拌2小时,然后加入氰基硼氢化钠(1.0g,15.7mmol)，继续搅拌1小时。减压浓缩，残留物用硅胶柱层析纯化得到白色化合物3(600mg,收率:39.5％)。
MS(ESI):Calcd.for C 13H 9Cl 2N 3O 293；Found 294[M+H] +.
步骤二、化合物4
往化合物3(0.20g,0.68mmol)的乙醇(6mL)和水(3mL)的混合溶液中加入盐酸羟胺(47mg,1.4mmol)和碳酸氢钠(114mg,1.4mmol)，将反应体系加热到80℃并搅拌2小时。冷却到25℃，减压浓缩，加入水(10mL)，25℃搅拌30分钟。用二氯甲烷萃取，无水硫酸钠干燥，减压浓缩得到白色化合物4(166mg,收率:74.9％)。
MS(ESI):Calcd.for C 13H 12Cl 2N 4O 2 326；Found 327[M+H] +.
步骤三、化合物5
往化合物4(0.13g,0.40mmol)的二甲基亚砜(6mL)溶液中加入CDI(129mg，0.80mmol)和DBU(122mg，0.80mmol)。反应体系在25℃搅拌60分钟，加水(50mL)稀释，用1N HCl调节PH＝3，乙酸乙酯萃取，无水硫酸钠干燥，减压浓缩，残留物用制备色谱纯化得到白色化合物5(52mg,收率：36.9％)。
MS(ESI):Calcd.for C 14H 10Cl 2N 4O 3 352；Found 353[M+H] +.
HNMR(400MHz,DMSO-d 6):δ12.70(s,1H),9.86(s,1H),8.12-8.07(d,J＝2.0Hz,1H),7.73–7.66(d,J＝8.8Hz,1H),7.46-7.42(d,J＝2.0Hz,1H),7.24-7.16(m,2H),7.06-7.01(dd,J＝2.0Hz,8.8Hz,1H),4.42-4.34(d,J＝5.6Hz,2H).
步骤四、化合物04038
将化合物5(584mg,1.66mmol)溶于二甲基亚砜(5mL)，缓慢加入TCDI(295mg,1.66mmol)。反应体系在25℃搅拌1小时，用乙酸乙酯萃取，饱和氯化钠溶液洗涤，无水硫酸钠干燥。减压浓缩，残留物用制备型液相色谱纯化得化合物04038(白色固体，299.3mg,收率45.8％)。
LCMS:[M+H] +＝394.97.
1H NMR(400MHz,DMSO-d 6):δ13.03(s,1H),8.92(d,J＝1.2Hz,1H),8.13-8.22(m,2H),7.78(d,J＝2.4Hz,1H),7.44(d,J＝2.4Hz,1H),5.04(s,2H).
实施例30化合物04039的制备
Figure PCTCN2020135289-appb-000056
步骤一、化合物2
在冰浴条件下，往化合物1(1.0g,8.4mmol)的二甲基甲酰胺(15mL)溶液中分批加入叠氮化钠(4.4g，67.7mmol)，反应体系加热到140℃反应40小时。冷却到25℃，过滤，滤液用饱和碳酸氢钠水溶液调节PH值到6左右，乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩得到黄色固体化合物2(0.30g,收率：22.0％)。
MS(ESI):Calcd.for C 6H 6N 6 162；Found 163[M+H] +.
步骤二、化合物4
往化合物2(100mg,0.62mmol)和化合物3(120mg,0.63mmol)的甲醇(10mL)溶液中加入冰醋酸(4滴),氮气保护下在25℃搅拌2小时，加入氰基硼氢化钠(101mg,1.57mmol),继续搅拌1小时,减压浓缩，残留物用制备色谱纯化得到白色化合物4(27.66mg,收率:13.3％)。
MS(ESI):Calcd.for C 13H 10Cl 2N 6O 336；Found 337[M+H] +.
HNMR(400MHz,CD 3OD):δ8.12(s,1H),7.94–7.88(d,J＝8.4Hz,1H),7.28-7.25(d,J＝2.0Hz,1H),7.19-7.16(d,J＝2.0Hz,1H),7.09-7.04(dd,J＝2.0Hz,8.4Hz,1H),4.45(s,2H).
步骤三、化合物04039
将化合物4(168mg，0.5mmol)溶于二甲基亚砜(2mL)，加入TCDI(178mg，1.0mmol)，反应液在25℃搅拌1小时。减压浓缩，残留物用制备型液相色谱纯化得到化合物04039(白色固体，1.2mg，产率0.6％)。
LCMS:[M+H] +＝379.1
1H NMR(400MHz,DMSO-d 6):δ9.87(s,1H),8.74(s,1H),8.25(d,J＝7.6Hz,1H),8.05(s,1H),7.42(s,1H),7.18(s,1H),4.94(s,2H).
实施例31化合物04040的制备
Figure PCTCN2020135289-appb-000057
步骤一、化合物04040
将化合物1(176mg，0.5mmol)溶于二甲基亚砜(2mL)，加入TCDI(106mg，0.59mmol)，在25℃搅拌3小时。将反应液倒入水(50mL)中，用乙酸乙酯(3x 10mL)萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用制备型液相色谱纯化得到化合物04040(白色固体，76.9mg，收率39.1％)。
LCMS:[M+H] +＝398.0
1H NMR(400MHz,CDCl 3)δ11.05(br,1H),7.98(d,J＝8.0Hz,1H),7.44(s,1H),7.03(s,1H),6.98(s,1H),6.95(d,J＝12.0Hz,1H),4.77(s,2H),4.44(q,J＝8.0Hz,2H),1.43(t,J＝4.0Hz,3H).
实施例32化合物04042的制备
Figure PCTCN2020135289-appb-000058
步骤一、化合物04042
将化合物1(200mg,0.65mmol)溶于二甲基亚砜(2mL)，加入TCDI(139mg,0.78mmol)，在25℃搅拌1小时。将反应液倒入水(100mL)中，用乙酸乙酯(3x 50mL)萃取，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(展开剂：乙酸乙酯/石油醚＝3/1)纯化得到化合物04042(白色固体，24.5mg，收率12％)。
LCMS:[M+H] +＝351.0.
1H NMR(400MHz,CDCl 3)δ7.97(d,J＝8.4Hz,1H),7.94(s,1H),7.51(d,J＝8.8Hz,1H),7.46(d,J＝2.0Hz,1H),7.05(s,1H),4.89(s,2H).
实施例33化合物04041的制备
Figure PCTCN2020135289-appb-000059
步骤一、化合物2
将化合物1(7.6g，50mmol)溶于N,N-二甲基甲酰胺(100mL)，加入碘甲烷(21.3g，150mmol)。反应体系冷却至0℃后分批缓慢的加入氢化钠(60％，6g，150mmol)，，搅拌1小时，加入水(20mL)淬灭反应。将以上得到的溶液用乙酸乙酯(3x 200mL)萃取，有机相依次用水(2x 200mL)、饱和氯化钠溶液(200mL)洗涤，无水硫酸钠干燥，减压浓缩后得到化合物2(黄色油状液体，9.0g，收率99％)。
LCMS:[M+H] +＝181.2
步骤二、化合物3
将化合物2(9.0g，50mmol)溶于四氯化碳(100mL)，加入NBS(26.7g，150mmol)以及AIBN(1.64g，10mmol)。反应体系加热至80℃搅拌16小时，反应液直接用于下一步反应。
LCMS:[M+H] +＝339.0.
步骤三、化合物4
向步骤二所得到的反应液中加入AgNO 3(25.5g，150mmol)和水(10mL)，25℃搅拌1小时。将反应液过滤，滤液用水(300mL)稀释后用乙酸乙酯(3x 200mL)萃取，有机相依次用水(2x 200mL)、饱和氯化钠溶液(200mL)洗涤后用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(展开剂：石油醚/二氯甲烷＝1/100)纯化，得到化合物4(红色油状液体，6.0g，收率62％)。
LCMS:[M+H] +＝195.1.
步骤四、化合物6
将化合物4(5.82g，30mmol)溶于DCE(100mL)，加入化合物5(5.31g，30mmol)、NaBH(OAc) 3(15.9g，75mmol)和乙酸(10mL)，在25℃搅拌3小时。将反应液过滤并浓缩得到化合物6(灰色固体，5.5g，收率52％)。
LCMS:[M+H] +＝356.1.
步骤五、化合物7
将化合物6(1.07g，3.0mmol)溶于二氯甲烷(10mL)，加入BBr 3(3.76g，15.0mmol)，反应溶液于25℃搅拌2小时。将反应液浓缩并用硅胶柱层析(展开剂：二氯甲烷/甲醇＝4/1)纯化得到化合物7(棕色固体，500mg，收率51％)。
LCMS:[M+H] +＝328.0.
步骤六、化合物8
将化合物7(164mg，0.5mmol)溶于乙醇(3mL)，加入氯化亚砜(590mg，5.0mmol)，反应溶液在70℃搅拌16小时。减压浓缩，残留物用硅胶柱层析(展开剂：石油醚/乙酸乙酯＝5/1)纯化得到化合物8(黄色固体，70mg，收率40％)。
LCMS:[M+H] +＝356.1.
步骤7、化合物04041
将化合物8(71.0mg，0.2mmol)溶于二甲基亚砜(2mL)，加入TCDI(71.2mg，0.4mmol)，在25℃搅拌1小时。反应液用水(50mL)稀释之后用乙酸乙酯(3x 50mL)萃取，有机相用饱和氯化钠溶液(100mL)洗涤、无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(展开剂：石油醚/乙酸乙酯＝5/1)纯化后得到化合物04041(类白色固体，10.2mg，收率13％)。
LCMS:[M-H] +＝397.9.
1H NMR(400MHz,DMSO-d 6):δ10.57(s,1H),7.75(d,J＝8.1Hz,1H), 7.64(s,2H),6.98(s,1H),6.94(d,J＝8.2Hz,1H),5.44(s,2H),4.34(q,J＝7.1Hz,2H),1.31(t,J＝7.1Hz,3H).
实施例34化合物04075的制备
Figure PCTCN2020135289-appb-000060
步骤一、化合物6
将化合物5(6g,18.4mmol,1.0eq)溶于二甲基亚砜(60mL)中，然后加入TCDI(6.6g,36.8mmol,2.0eq)，在25℃下搅拌1小时。将反应液用乙酸乙酯稀释，依次用水和饱和氯化钠溶液洗涤。合并后的有机相用无水硫酸钠干燥，减压浓缩，残留物用柱层析(二氯甲烷/甲醇＝4/1)纯化后得到化合物6(1.2g,17％)，为棕色固体。
LCMS:[M-H] -＝368.0
步骤二、化合物04075
将化合物6(300mg,0.81mmol,1.0eq)溶于二甲基甲酰胺(6mL)中，然后加入化合物7(503mg,4.1mmol,5.0eq)，DCC(252mg,1.2mmol,1.5eq),DMAP(300mg,2.4mmol,3.0eq)和PPTS(600mg,2.4mmol,3.0eq)。反应液在50℃搅拌4小时，冷却至25℃后将反应液用乙酸乙酯稀释并搅拌0.5h。过滤，滤液用水洗，饱和氯化钠溶液洗，无水硫酸钠干燥，减压浓缩，残留物用柱层析(二氯甲烷/甲醇＝5/1)纯化，得到化合物04075(15mg,4％)为白色固体。
LCMS:[M-H] -＝437.0
1H NMR(400MHz,DMSO-d 6)δ7.77(d,J＝8.0Hz,1H),7.62(s,2H),6.95-6.93(m,2H),5.43(s,2H),5.15-5.08(m,1H),3.71-3.63(m,2H),3.17-3.10(m,2H),2.29(s,3H).
实施例35化合物04077的制备
Figure PCTCN2020135289-appb-000061
步骤一、化合物04077
将化合物04015(120mg,0.337mmol,1.0eq)溶于二甲基甲酰胺(9mL)中，然后加入化合物2(87mg,0.507mmol,1.5eq)和碳酸铯(220mg,0.675mmol,2.0eq)，在60℃搅拌1小时。冷却至25℃后反应液用乙酸乙酯(30mL)稀释，然后依次用水、饱和氯化钠溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，残留物用prep-HPLC(0.1％甲酸/乙腈/水)纯化后得到化合物04077(30.5mg,22％)为白色固体。
LCMS:[M+H] +＝398.9
1H NMR(400MHz,DMSO-d 6)δ8.86-8.85(m,1H),8.22(dd,J＝8.4,0.8Hz,1H),8.15(dd,J＝8.4,2.4Hz,1H),7.75(d,J＝2.4Hz,1H),7.41(d,J＝2.4Hz,1H),4.99(s,2H),4.93(t,J＝5.6Hz,1H),4.32(t,J＝4.8Hz,2H),3.71-3.69(m,2H).
实施例36化合物04089的制备
Figure PCTCN2020135289-appb-000062
步骤一、化合物04089
将化合物04015(1.5g,4.22mmol,1.0eq)溶于二甲基甲酰胺(二甲基甲酰胺，90mL)中，然后依次加入DCC(1.3g,6.33mmol,1.5eq)，DMAP(1.55g,12.67mmol,3.0eq)，PPTS(3.18g,12.67mmol,3.0eq)和化合物2(1.91g,21.11mmol,5.0eq)，升温至50℃搅拌4.5小时。冷却至25℃，加入乙酸乙酯(60mL)，搅拌0.5小时。过滤反应液，滤液依次用水、饱和氯化钠溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(PE/EA＝2:1)纯化后得到化合物04078(333mg,18％)。
LCMS:[M+H] +＝427.0
1H NMR(400MHz,DMSO-d 6)δ8.88(dd,J＝2.4,0.8Hz,1H),8.22-8.18(m,2H),7.77(d,J＝2.4Hz,1H),7.43(d,J＝2.4Hz,1H),5.01(s,2H),4.47-4.38(m,2H),3.74-3.67(m,2H),3.50(q,J＝6.8Hz,2H),1.11(t,J＝7.2Hz,3H).
实施例37化合物04081的制备
Figure PCTCN2020135289-appb-000063
步骤一、化合物2
将化合物1(8.0g,43.7mmol,1.0eq)加入氯化亚砜(30mL)中，升温至90℃搅拌1小时。反应液冷却至25℃，减压浓缩得到化合物2(10g,100％)，无需纯化直接用于下一步反应。
步骤二、化合物4
将化合物2(10g,43.7mmol,1.0eq)溶于四氢呋喃(60mL)中，加入化合物3(20mL)，在25℃搅拌16小时。将反应液减压浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝4/1)纯化后得到化合物4(12.5g,100％)。
LCMS:[M-H] -＝254.0
步骤三、化合物5
将化合物4(12g,43.7mmol,1.0eq)溶于甲醇(150mL)，加入雷尼镍(1.0g)，反应在1个大气压的氢气气氛下在25℃搅拌16小时。过滤反应液，滤液减压浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化后得到化合物4(8.0g,81％)。
LCMS:[M+H] +＝226.1
步骤四、化合物7
将化合物5(7.5g,33.3mmol,1.0eq)溶于甲醇/乙酸(10:1,400mL)的混合溶剂，加入化合物6(7.5g,39.3mmol,1.18eq)。反应液在25℃搅拌30分钟，加入氰基硼氢化钠(8.37g,133.2mmol,4.0eq)，继续搅拌0.5小时。浓缩反应液,残留物加入乙酸乙酯(800mL)和水(100mL)，用饱和碳酸氢钠水溶液调节pH值为7-8。有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化得到化合物7(12g,90％)为褐色油状物。
LCMS:[M+H] +＝400.1
步骤五、化合物04081
将化合物7(4g,10.0mmol,1.0eq)溶于二甲基亚砜(40mL)，加入TCDI(1.87g,10.49mmol,1.05eq)，在25℃搅拌2小时。用乙酸乙酯(500mL)稀释，饱和氯化钠溶液洗三次。有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝20/1)纯化后得到化合物04081(815.6mg，18.4％)
LCMS:[M+H] +＝441.9
1H NMR(400MHz,CDCl 3)δ10.90(s,1H),8.01(d,J＝8.8Hz,1H),7.44(d,J＝2.4Hz,1H),7.04–7.01(m,1H),6.98(d,J＝2.0Hz,1H),6.96-6.93(m,1H),4.76(s,2H),4.53–4.51(m,2H),3.78–3.76(m,2H),3.58(q,J＝6.8Hz,2H),1.23(t,J＝6.8Hz,3H).
实施例38化合物04080的制备
Figure PCTCN2020135289-appb-000064
步骤一、化合物2
将化合物1(8.5g,26.0mmol,1.0eq)加入氯化亚砜(20mL)，升温至在90℃搅拌1h。反应液降温至25℃，减压浓缩得到化合物2(10g，100％)为褐色油状物，无需纯化直接用于下一步反应。
步骤二、化合物4
将化合物2(10g,26.0mmol,1.0eq)溶于四氢呋喃(60mL)，加入化合物3(20mL)，在25℃搅拌16h。浓缩反应液，用乙酸乙酯(500mL)稀释，然后用碳酸钠水溶液将PH值调至7-8，水相用乙酸乙酯萃取。合并后的有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝4/1)纯化后得到化合物4(4g,38％)为棕色固体。
LCMS:[M+H] +＝400.0
步骤三、化合物04080
将化合物4(4g,10.0mmol,1.0eq)溶于二甲基亚砜(25mL)，加入TCDI(2.1g,12.0mmol,1.2eq)，在25℃搅拌1小时。加入乙酸乙酯(100mL)和饱和碳酸钠水溶液(100mL)，继续搅拌1小时。分液，有机相用饱和氯化钠溶液洗三次，然后用无水硫酸钠干燥。减压浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝20/1)纯化后得到化合物04080(1.0734g，24％)
LCMS:[M-H] -＝440.0
1H NMR(400MHz,DMSO-d 6)δ10.48(s,1H),7.75(d,J＝8.0Hz,1H),7.66-7.61(m,2H),6.99(s,1H),6.95(d,J＝8.0Hz,1H),5.44(s,2H),4.44-4.37(m,2H),3.69-3.67(m,2H),3.48(q,J＝6.8Hz,2H),1.10(t,J＝6.8Hz,3H).
实施例39化合物04096的制备
Figure PCTCN2020135289-appb-000065
步骤一、化合物04096
将化合物04024(1.1g,3.2mmol,1.0eq)溶于二甲基甲酰胺(20mL)，加入DMAP(1.19g,9.73mmol,3.0eq)，DCC(1.0g,4.87mmol,1.5eq)，PPTS(5.01g,9.73mmol,3.0eq)和化合物1(1.46g,16.22mmol,5.0eq)，升温至50℃搅拌4.5小时。冷却至25℃，向反应液中加入乙酸乙酯(80mL)，搅 拌0.5小时，过滤，滤液用水(3x 20mL)洗，饱和氯化钠溶液(20mL)洗，有机相用无水硫酸钠干燥，减压浓缩，残留物通过硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化得到04096(485.8mg,36％)为白色固体。
LCMS:[M+H] +＝411.0
1H NMR(400MHz,,DMSO-d 6)δ8.85(d,J＝2.0Hz,1H),8.16–8.14(m,1H),8.10–8.07(m,1H),7.72(d,J＝2.4Hz,1H),7.43(d,J＝2.4Hz,1H),5.04(s,2H),4.43–4.41(m,2H),3.71–3.68(m,2H),3.49(q,J＝6.8Hz,2H),1.10(t,J＝6.8Hz,3H).
实施例40化合物04097的制备
Figure PCTCN2020135289-appb-000066
步骤一、化合物2
将化合物1(6.0g,19.16mmol,1.0eq)加入氯化亚砜(20mL)，升温至90℃搅拌20分钟，反应液变成黄色澄清溶液。反应液冷却至25℃，减压浓缩，得到的粗品化合物2(10g)为褐色油状物，无需纯化直接用于下一步反应。
步骤二、化合物4
将粗品化合物2(10g)溶于四氢呋喃(10mL)，加入化合物3(10mL)，在25℃搅拌16小时。浓缩反应液，残留物用乙酸乙酯(500mL)溶解，然后用碳酸钠水溶液将PH值调至7-8。分液后得到的水相用乙酸乙酯萃取，合并后的有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝4/1)纯化后得到化合物4(1.6g,两步收率21％)为白色固体。
LCMS:[M+H] +＝385.0
步骤三、化合物04097
将化合物4(1.6g,4.15mmol,1.0eq)溶于乙腈(40mL)，加入溴化氰(660mg,6.23mmol,1.5eq)和三乙胺(630mg,6.23mmol,1.5eq)，在25℃搅拌2小时。用乙酸乙酯(300mL)稀释，饱和氯化钠溶液洗涤，有机相用无水硫酸钠干燥，减压浓缩，残留物用pre-HPLC(0.1％甲酸/乙腈/水)纯化后得到化合物04097(51mg，4％)为白色固体。
LCMS:[M+H] +＝410.0
1H NMR(400MHz,DMSO-d 6)δ8.84(s,1H),8.09–8.02(m,2H),7.70(s,1H),7.45–7.39(m,1H),7.18(s,1H),4.91(s,2H),4.44–4.38(m,2H),3.72–3.66(m,2H),3.52–3.47(m,2H),1.15–1.09(m,3H).
实施例41化合物04102的制备
Figure PCTCN2020135289-appb-000067
步骤一、化合物04102
将化合物1(300mg,0.914mmol,1.0eq)溶于乙腈(35mL)，加入溴化氰(97mg,0.914mmol,1.0eq)，在25℃搅拌30分钟，然后滴加三乙胺(92mg,0.914mmol,1.0eq)，搅拌过夜。减压浓缩反应液，残留物用pre-HPLC(0.1％甲酸/乙腈/水)纯化得到化合物04102(10.8mg,3％)为白色固体。
LCMS:[M+H] +＝353.0
1H NMR(400MHz,DMSO-d 6)δ7.83-7.81(m,2H),7.47(d,J＝2.4Hz,1H),6.85(d,J＝2.0Hz,1H),6.75(dd,J＝8.1,2.1Hz,1H),4.86(s,2H).
实施例42化合物04099的制备
Figure PCTCN2020135289-appb-000068
步骤一、化合物04099
将化合物1(2.0g，5.0mmol，1.0eq)溶于二甲基亚砜(10mL)，加入羰 基二咪唑(1.22g，7.5mmol，1.5eq)，氮气保护下在25℃搅拌16小时。补加羰基二咪唑(406mg，2.5mmol，0.5eq)，继续搅拌3小时。反应液用水(20mL)稀释，然后滴加稀盐酸(2M)水溶液调节pH值为3-4。反应液用乙酸乙酯(20mL x 3)萃取，合并后的有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化得到04099(1.31g，61％)为白色固体。
LCMS:[M+H] +＝426.0
1H NMR(400MHz,CDCl 3)δ10.85(s,1H),7.94(d,J＝8.4Hz,1H),7.42(d,J＝2.4Hz,1H),7.08–7.07(m,1H),7.01–6.98(m,1H),6.97–6.96(m,1H),4.83(s,2H),4.53–4.50(m,2H),3.79–3.76(m,2H),3.58(q,J＝7.2Hz,2H),1.23(t,J＝7.2Hz,3H).
实施例43化合物04100的制备
Figure PCTCN2020135289-appb-000069
步骤一、化合物04100
将化合物1(300mg,0.91mmol,1.0eq)溶于二甲基亚砜(10mL)，加入CDI(220mg,1.36mmol,1.5eq)，在25℃搅拌3小时。向反应液中加入水(10mL)，用稀盐酸调节pH值为3-4，再用乙酸乙酯(3x 10mL)萃取。合并后的有机相用无水硫酸钠干燥，减压浓缩，残留物用pre-HPLC(0.1％甲酸/乙腈/水)纯化得到化合物04100(50mg,16％)为白色固体。
LCMS:[M+H] +＝354.0
1H NMR(400MHz,DMSO-d 6)δ11.48(s,1H),7.84(d,J＝8.5Hz,1H),7.71(d,J＝2.4Hz,1H),7.44(d,J＝2.4Hz,1H),7.08–7.04(m,2H),4.97(s,2H).
实施例44化合物04103的制备
Figure PCTCN2020135289-appb-000070
步骤一、化合物04103
将化合物1(528mg,1.32mmol,1.0eq)溶于二甲基亚砜(6mL)，加入CDI(257mg,1.58mmol,1.2eq)，在25℃搅拌1小时。加入乙酸乙酯(15mL)和饱和碳酸钠水溶液(15mL)，继续搅拌1小时。分液后有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，残留物用反相柱层析(0.1％甲酸/乙腈/水)纯化得到化合物04103(305.5mg,45％)为白色固体。
LCMS:[M+H] +＝426.0
1H NMR(400MHz,DMSO-d 6)δ10.49(s,1H),7.75(d,J＝8.0Hz,1H),7.44-7.43(m,2H),7.02(s,1H),6.97-6.95(m,1H),5.07(s,2H),4.42-4.01(m,2H),3.70-3.69(m,2H),3.49(q,J＝6.8Hz,2H),1.10(t,J＝6.8Hz,3H).
实施例45化合物04104的制备
Figure PCTCN2020135289-appb-000071
步骤一、化合物04104
将化合物1(500mg,1.6mmol,1.0eq)溶于二甲基亚砜(15mL)，加入CDI(377mg,2.4mmol,1.5eq)，在25℃搅拌2小时。向反应液中加入水(15mL)，然后用稀盐酸调节pH值为3-4，再用乙酸乙酯(3x 20mL)萃取。合并后的有机相用无水硫酸钠干燥，减压浓缩，残留物用反相柱层析(0.1％甲酸/乙腈/水)纯化得到化合物04104(53mg,6％)为白色固体。
LCMS:[M+H] +＝354.0
1H NMR(400MHz,DMSO-d 6)δ7.74(d,J＝8.0Hz,1H),7.44-7.42(m,2H),6.94(s,1H),6.86(d,J＝8.0Hz,1H),5.03(s,2H).
实施例46化合物04105的制备
Figure PCTCN2020135289-appb-000072
步骤一、化合物04105
将化合物1(400mg,1.000mmol,1.0eq)溶于乙腈(6mL)，加入溴化氰(106mg,1.000mmol,1.0eq)，在25℃搅拌0.5小时。加入三乙胺(101mg,1.000mmol,1.0eq)，继续搅拌1小时。过滤反应也，得到的固体用乙腈打浆，过滤干燥后得到化合物04105(64.6mg,16％)为白色固体。
LCMS:[M+H] +＝425.0
1H NMR(400MHz,DMSO-d 6)δ10.48(s,1H),7.65(d,J＝8.1Hz,1H),6.99(s,1H),6.92(s,1H),6.88(d,J＝8.1Hz,1H),6.79(s,1H),6.49(s,1H),4.42-4.39(m,4H),3.69-3.67(m,2H),3.48(q,J＝7.0Hz,2H),1.09(t,J＝7.0Hz,3H).
实施例47化合物04106的制备
Figure PCTCN2020135289-appb-000073
步骤一、化合物04106
将化合物1(100mg,0.305mmol,1.0eq)溶于二甲基亚砜(5mL)，加入溴化氰(32mg,0.305mmol,1.0eq)，在25℃搅拌0.5小时。加入三乙胺(31mg,0.305mmol,1.0eq)，搅拌过夜。反应液用乙酸乙酯(30mL)稀释，然后依次用水洗，饱和氯化钠溶液洗，有机相用无水硫酸钠干燥，减压浓缩，残留物用pre-HPLC(0.1％甲酸/乙腈/水)纯化得到化合物04106(15.9mg,15％)为白色固体。
LCMS:[M+H] +＝352.9
1H NMR(400MHz,DMSO-d 6)δ12.00(brs,1H),7.74(d,J＝8.1Hz,1H),7.20(d,J＝1.9Hz,2H),6.91(s,1H),6.88–6.85(m,1H),5.00(s,2H).
实施例48化合物04107的制备
Figure PCTCN2020135289-appb-000074
步骤一、化合物3
将化合物1(30mg,0.0879mmol,1.0eq)加入甲苯(3mL)，依次加入化合物2(30mg,0.1758mmol,2.0eq)和对甲苯磺酸一水合物(3mg,0.0176mmol,0.2eq)，升温至100℃搅拌16小时。冷却25℃，将反应液减压浓缩，得到化合物3(43mg,99％)为棕色胶状物，无需纯化直接用于下一步反应。
LCMS:[M+H] +＝494.1
步骤二、化合物04107
将化合物3(43mg,0.0869mmol,1.0eq)溶于二氯甲烷(1mL)，加入三氟乙酸(0.2mL)，反应液在25℃搅拌15分钟。用饱和碳酸氢钠水溶液调节溶液pH值为7，分液后用二氯甲烷萃取，合并后的有机相用无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析纯化得到化合物04107(收率13％)。
LCMS:[M+H] +＝394.0
化合物对大鼠局灶性脑缺血再灌注的保护作用研究
1.材料和方法
1.1实验动物
Sprague Dawley(SD)大鼠，雄性，SPF级，体重250～280克
1.2受试药品
化合物04007、04015、04041、04047、04050、04089
市售依达拉奉注射液，南京先声东元制药有限公司产品，规格10mg/mL
1.3实验方法
1.3.1局灶性脑缺血再灌注模型的制备
采用颈内动脉线栓法制备大鼠局灶性脑缺血再灌模型(Middle cerebral artery occlusion,MCAO)。大鼠腹腔注射7％水合三氯乙醛(6.0mL/kg)，麻醉深度以重度刺激动物有轻微反应为宜。将处于麻醉状态的大鼠用皮筋束紧四肢(后肢固定膝关节以上，前肢固定腕关节以上)及头部，动物仰卧位固定于手术台上，以动物剃毛器自头端向胸部方向剃毛，酒精消毒皮肤。颈部正中切开，钝性分离皮下组织。分离颈前三角表面的薄层筋膜，拨起低边-锁骨舌骨肌下缘，可见与此肌肉平行的纵行搏动的动脉，打开动脉壳，暴露右侧颈动脉分叉，分离右侧颈总动脉、颈外动脉、颈内动脉，轻轻剥离迷走神经，结扎并剪断颈外动脉。夹闭颈总动脉近心端，从颈外动脉的结扎线的远端作一切口，插入栓线，经过颈 总动脉分叉进入颈内动脉，然后徐徐插入至有轻微阻力为止(自分叉处约20mm)，阻断大脑中动脉的所有血供。以丝线在颈外动脉切口下方稍固定栓线，松开颈总动脉近心端夹闭丝线，将浸有消毒生理盐水的纱布覆盖于创面上，将大鼠放置在保温垫上保温。右侧脑缺血2.0h后，轻轻拔出栓线，恢复血供进行再灌注，用固定栓线的丝线结扎颈外动脉，缝合皮肤，消毒。
1.3.2动物分组与给药
实验动物分为模型组、依达拉奉组(6mg/kg)和待测化合物组(5mg/kg)。待测化合物配置：以5％DMAC+5％Solutol HS 15+90％Saline配置成浓度为1mg/mL的溶液。
制备缺血模型后，将动物机率均等单盲分配至各组。动物于再灌注后立即静脉给药1次，模型组动物给与等体积的生理盐水。缺血后24小时后处死动物，取脑，染色，拍照测定脑梗死面积。
1.3.3脑梗死面积的测定
脑梗死程度的测定，采用TTC染色法进行脑梗死程度的测定。动物神经缺陷症状评价完毕后以CO 2处死，断头取脑，去除嗅球、小脑和低位脑干，用生理盐水冲洗大脑表面血迹，吸去表面残留水迹，于－20℃放置20min，取出后立即于视线交叉平面垂直向下作冠状切面，并向后每隔2mm切一片，将脑片置于1％TTC染液中孵育(37℃20min)，正常脑组织染成深红色，缺血脑组织则呈苍白色，用生理盐水冲洗后，迅速将脑片从前向后按顺序排成一排，吸干表面残留水迹，拍照。
脑梗死面积的计算：照片用Image J软件处理，计算左脑相应面积以及右脑非梗死灶面积，求出梗死范围百分比。
2.实验结果
2.1统计分析
定量资料表示为均值±标准误，各药效指标采用GraphPad Prism(6.01)软件进行单因素方差分析(one-way ANOVA)，方差检验显著后再采用Fisher’s LSD test检验组间差异。将P＜0.05定义为具有显著性差异。
2.2待测化合物对大鼠脑缺血再灌急性损伤的影响
各组动物神经缺陷症状的程度及脑梗死面积情况见表1。
表1
Figure PCTCN2020135289-appb-000075
可以看出，与模型组相比，除了化合物04047对模型大鼠脑梗死面积的减少效果不显著外，化合物04007、04015、04041、04050、04089均能显著减少模型大鼠的脑梗死面积，表现出良好的神经保护作用。与阳性对照药依达拉奉组相比，5mg/kg剂量的化合物04007、04015、04041、04050以及0.5mg/kg剂量的化合物04089与6mg/kg剂量的依达拉奉药效相当或者优于依达拉奉。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (13)

  1. 式I所示化合物或其立体异构体、或其药学上可接受的盐：
    Figure PCTCN2020135289-appb-100001
    其中，
    R 1、R 2、R 3、R 4、R 5、R 5’、R 6、R 6’、R 7、R 8、R 9分别独立选自下组：氢、卤素、氨基、羟基、羧基、硝基、氰基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 3-6环烷基、卤代C 3-6环烷基、C 1-6烷基胺基；
    R 5与R 6或者R 5’与R 6’可以环合形成取代或未取代的3-8元饱和或不饱和的环烷基或含有一个或多个(例如2、3、或4个)选自N、S和O的杂原子的杂环烷基，所述取代是指被选自下组的一个或多个(例如2、3、或4个)取代基取代：氢、卤素、C 1-6烷基；
    X选自下组：
    Figure PCTCN2020135289-appb-100002
    Figure PCTCN2020135289-appb-100003
    R 10、R 11、R 12、R 13分别独立选自下组：氢、卤素、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 3-6环烷基、卤代C 1-6烷氧基、取代或未取代的C 6-10芳基、取代或未取代的5-6元含有一个或多个(例如2、3、或4个)选自N、S和O的杂原子的杂芳基、3-8元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基，所述取代是指被选自下组的一个或多个(例如2、3、或4个)取代基取代：氢、卤素、C 1-6烷基；
    环A为取代或未取代的3-8元饱和或不饱和的环烷基或取代或未取代的3-8元含有一个或多个(例如2、3、或4个)选自N、S和O的杂原子的杂环烷基，所述取代是指被选自下组的一个或多个(例如2、3、或4个)取代基取代：氢、卤素、C 1-6烷基；
    W选自下组：O、S、NR 19；
    R 19选自下组：氢、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、卤代C 3-6环烷基、C 6-10芳基、取代或未取代的3-8元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基或杂芳基，所述取代是指被选自下组的一个或多个(例如2、3、或4个)取代基取代：氢、卤素、C 1-6烷基；
    m为0或1；
    n为0或1；
    Z为N或CR 18；
    R 18选自下组：氢、羟基、卤素、氨基、氰基、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 3-6环烷基、卤代C 1-6烷氧基、C 1-6烷基胺基；
    Y选自下组：COOR 15、CONR 16R 17、C 6-10芳基、3-8元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基或杂芳基，所述杂环烷基任选地被一个或多个(例如2、3或4个)选自下组的取代基取代：＝O、氢、卤素、C 1-6烷基；
    R 15、R 16、R 17分别独立选自下组：氢、C 1-6烷基、C 3-8环烷基、C 6-10芳基、3-15元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基或杂芳基、-(C 1-6亚烷基)(3-15元饱和或不饱和的含有一个或多个(例如2、3、4或5个)选自N、S和O的杂原子的杂环烷基或杂芳基)；所述烷基、环烷基、芳基、杂芳基、杂环烷基任选地被一个或多个(例如2、3或4个)选自下组的取代基取代：氢、卤素、羟基、C 1-6亚烷基羟基、＝O、-NR 20R 21、氰基、C 2-6炔基、C 2-6烯基、C 1-6烷基、C 3-8环烷基、C 1-6烷基取代或未取代的含一个或多个(例如2、3或4个)选自N、S和O的杂原子的3-8元杂环烷基、卤代C 1-6烷基、氨基和羧基取代的C 1-6烷基、C 1-6烷氧基、含一个或多个(例如2、3或4个)选自N、S和O的杂原子的5-10元杂芳基、C 6-12芳基、-COO(C 1-6烷基)；
    R 20和R 21独立选自下组：氢、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、卤代C 3-6环烷基；
    或者Y与R 8环合形成
    Figure PCTCN2020135289-appb-100004
  2. 如权利要求1所述的化合物或其立体异构体、或其药学上可接受的盐，其特征在于，m＝1，n＝0；
    R 1、R 2、R 3、R 4、R 5、R 5’、R 6、R 6’、R 7、R 8、R 9分别独立选自下组：氢、卤素、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 3-6环烷基、卤代C 1-6烷氧 基；
    X选自下组：
    Figure PCTCN2020135289-appb-100005
    R 10、R 11、R 12、R 13分别独立选自下组：氢、卤素、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、卤代C 3-6环烷基、取代或未取代的C 6-10芳基、取代或未取代的5-6元含有一个或多个(例如2、3、或4个)选自N、S和O的杂原子的杂芳基，所述取代是指被选自下组的一个或多个(例如2、3、或4个)取代基取代：氢、卤素、C 1-6烷基；
    环A为取代或未取代的3-8元环烷基或取代或未取代的3-8元含有一个或多个(例如2、3、或4个)选自N、S和O的杂原子的杂环烷基，所述取代是指被选自下组的一个或多个(例如2、3、或4个)取代基取代：氢、卤素、C 1-6烷基；
    W为O；
    Z为N或CR 18；
    R 18选自下组：氢、羟基、卤素、氨基、氰基、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 3-6环烷基、卤代C 1-6烷氧基、C 1-6烷基胺基；
    Y选自下组：COOR 15、取代或未取代的3-8元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基或杂芳基，所述杂环烷基任选地被一个或多个(例如2、3或4个)选自下组的取代基取代：＝O、氢、卤素、C 1-6烷基；
    R 15选自下组：氢、C 1-6烷基、C 3-8环烷基、C 6-10芳基、3-15元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基或杂芳基、-(C 1-6亚烷基)(3-15元饱和或不饱和的含有一个或多个(例如2、3、4或5个)选自N、S和O的杂原子的杂环烷基或杂芳基)；所述烷基、环烷基、芳基、杂芳基、杂环烷基任选地被一个或多个(例如2、3或4个)选自下组的取代基取代：氢、卤素、羟基、C 1-6亚烷基羟基、＝O、-NR 20R 21、氰基、C 2-6炔基、C 2-6烯基、C 1-6烷基、C 3-10环烷基、C 1-6烷基取代或未取代的含一个或多个(例如2、3或4个)选自N、S和O的杂原子的3-8元杂环烷基、卤代C 1-6烷基、氨基和羧基取代的C 1-6烷基、C 1-6烷氧基、含一个或多个(例如2、3或4个)选自N、S和O的杂原子的5-10元杂芳基、C 6-12芳基、-COO(C 1-6烷基)；
    R 20和R 21独立选自下组：氢、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、卤代C 3-6环烷基；
    或者Y与R 8环合形成
    Figure PCTCN2020135289-appb-100006
  3. 如权利要求1所述的化合物或其立体异构体、或其药学上可接受的盐，其特征在于，m＝0，n＝1；
    R 1、R 2、R 3、R 4、R 5、R 5’、R 6、R 6’、R 7、R 8、R 9分别独立选自下组：氢、卤素、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 3-6环烷基、卤代C 1-6烷氧基；
    X选自下组：
    Figure PCTCN2020135289-appb-100007
    R 10、R 11分别独立选自下组：氢、卤素、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、卤代C 3-6环烷基、取代或未取代的C 6-10芳基、取代或未取代的5-6元含有一个或多个(例如2、3、或4个)选自N、S和O的杂原子的杂芳基，所述取代是指被选自下组的一个或多个(例如2、3、或4个)取代基取代：氢、卤素、C 1-6烷基；
    环A为取代或未取代的3-8元环烷基或取代或未取代的3-8元含有一个或多个(例如2、3、或4个)选自N、S和O的杂原子的杂环烷基，所述取代是指被选自下组的一个或多个(例如2、3、或4个)取代基取代：氢、卤素、C 1-6烷基；
    W为O；
    Z为N或CR 18；
    R 18选自下组：氢、羟基、卤素、氨基、氰基、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 3-6环烷基、卤代C 1-6烷氧基、C 1-6烷基胺基；
    Y为COOR 15；
    R 15选自下组：氢、C 1-6烷基、C 3-8环烷基、C 6-10芳基、3-15元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基或杂芳基；所述烷基、环烷基、芳基、杂芳基、杂环烷基任选地被一个或多个(例如2、3或4个)选自下组的取代基取代：氢、卤素、羟基、＝O、氰基、C 2-6炔基、C 2-6烯基、C 1-6烷基、C 3-8环烷基、C 1-6烷基取代或未取代的含一个或多个(例如2、3或4个)选自N、S和O的杂原子的3-8元杂环烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、含一个或多个(例如2、3或4个)选自N、S和O的杂原子的5-10元杂芳基、C 6-12芳基。
  4. 如权利要求2所述的化合物或其立体异构体、或其药学上可接受的盐，其特征在于，
    Y选自下组：COOR 15、
    Figure PCTCN2020135289-appb-100008
    R 15如权利要求2所定义；
    Z选自下组：N、C(OH)。
  5. 如权利要求3所述的化合物或其立体异构体、或其药学上可接受的盐，其特征在于，
    Y为COOR 15；R 15选自下组：C 1-6烷基、C 3-8环烷基、3-15元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基；所述杂环烷基任选地被一个或多个(例如2、3或4个)选自下组的取代基取代：氢、卤素、C 1-6烷基、C 3-10环烷基；
    Z为C(OH)。
  6. 如权利要求1所述的化合物或其立体异构体、或其药学上可接受的盐，其特征在于，
    R 1、R 2、R 3、R 4、R 7、R 8、R 9分别独立选自下组：氢、卤素；
    R 5、R 5’、R 6、R 6’分别为氢；
    W为O；
    X为
    Figure PCTCN2020135289-appb-100009
    Z为N或C(OH)；
    Y为COOR 15；
    R 10、R 11分别独立选自下组：氢、卤素、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、卤代C 3-6环烷基；
    R 15选自下组：氢、C 1-6烷基、C 3-8环烷基、C 6-10芳基、3-15元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基或杂芳基、-(C 1-6亚烷基)(3-15元饱和或不饱和的含有一个或多个(例如2、3、4或5个)选自N、S和O的杂原子的杂环烷基或杂芳基)；所述烷基、环烷基、芳基、杂芳基、杂环烷基任选地被一个或多个(例如2、3或4个)选自下组的取代基取代：氢、卤素、羟基、C 1-6亚烷基羟基、＝O、-NR 20R 21、氰基、C 2-6炔基、C 2-6烯基、C 1-6烷基、C 3-8环烷基、C 1-6烷基取代或未取代的含一个或多个(例如2、3或4个)选自N、S和O的杂原子的3-8元杂环烷基、卤代C 1-6烷基、氨基和羧基取代的C 1-6烷基、C 1-6烷氧基、含一个或多个(例如2、3或4个)选自N、S和O的杂原子的5-10元杂芳基、C 6-12芳基、-COO(C 1-6烷基)；
    R 20和R 21独立选自下组：氢、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、卤代C 3-6环烷基；
    对于m和n，m＝1且n＝0，或m＝0且n＝1。
  7. 如权利要求1所述的化合物或其立体异构体、或其药学上可接受的盐，其特征在于，
    R 1、R 2、R 3、R 4、R 7、R 8、R 9分别独立选自下组：氢、卤素；
    R 5、R 5’、R 6、R 6’分别为氢；
    W为O；
    X为
    Figure PCTCN2020135289-appb-100010
    Z为N或C(OH)；
    Y为COOR 15；
    R 15选自下组：氢、C 1-6烷基、C 3-8环烷基、C 6-10芳基、3-15元饱和或不饱和的含有一个或多个(例如2、3或4个)选自N、S和O的杂原子的杂环烷基或杂芳基、-(C 1-6亚烷基)(3-15元饱和或不饱和的含有一个或多个(例如2、3、4或5个)选自N、S和O的杂原子的杂环烷基或杂芳基)；所述烷基、环烷基、芳基、杂芳基、杂环烷基任选地被一个或多个(例如2、3或4个)选自下组的取代基取代：氢、卤素、羟基、C 1-6亚烷基羟基、＝O、-NR 20R 21、氰基、C 2-6炔基、C 2-6烯基、C 1-6烷基、C 3-8环烷基、C 1-6烷基取代或未取代的含一个或多个(例如2、3或4个)选自N、S和O的杂原子的3-8元杂环烷基、卤代C 1-6烷基、氨基和羧基取代的C 1-6烷基、C 1-6烷氧基、含一个或多个(例如2、3或4个)选自N、S和O的杂原子的5-10元杂芳基、C 6-12芳基、-COO(C 1-6烷基)；
    R 20和R 21独立选自下组：氢、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、卤代C 3-6环烷基；
    R 22选自下组：氢、C 1-6烷基；
    对于m和n，m＝1且n＝0，或m＝0且n＝1。
  8. 如权利要求1所述的化合物或其立体异构体、或其药学上可接受的盐，其特征在于，
    R 1、R 2、R 3、R 4、R 7、R 8、R 9分别独立选自下组：氢、卤素；
    R 5、R 5’、R 6、R 6’分别为氢；
    W为O；
    X为
    Figure PCTCN2020135289-appb-100011
    Z为N；
    Y为COOR 15；
    R 15选自下组：氢、C 1-6烷基、C 3-8环烷基；所述烷基、环烷基任选地被一个或多个(例如2、3或4个)C 1-6烷氧基取代；
    对于m和n，m＝1且n＝0，或m＝0且n＝1。
  9. 如权利要求1所述的化合物或其立体异构体、或其药学上可接受的盐，其特征在于，
    R 1、R 2、R 3、R 4、R 7、R 8、R 9分别独立选自下组：氢、卤素；
    R 5、R 5’、R 6、R 6’分别为氢；
    W为O；
    X为
    Figure PCTCN2020135289-appb-100012
    Z为N；
    Y为COOR 15；
    R 15为C 1-6烷氧基取代的C 1-6烷基；
    m＝1且n＝0。
  10. 如权利要求1所述的化合物或其立体异构体、或其药学上可接受的盐，其特征在于，所述化合物选自下组：
    Figure PCTCN2020135289-appb-100013
    Figure PCTCN2020135289-appb-100014
    Figure PCTCN2020135289-appb-100015
  11. 一种权利要求1所述的化合物或其立体异构体、或其药学上可接受的盐的制备方法，其特征在于，包括如下步骤：
    Figure PCTCN2020135289-appb-100016
    将式I’化合物与环化试剂反应，得到式I化合物；
    其中，R 1、R 2、R 3、R 4、R 5、R 5’、R 6、R 6’、R 7、R 8、R 9、W、X、Z、Y、m和n如权利要求1所定义。
  12. 一种药物组合物，其特征在于，包含药学上可接受的载体和一种或多种权利要求1所述的化合物或其立体异构体、或其药学上可接受的盐。
  13. 一种权利要求1所述的化合物或其立体异构体、或其药学上可接受的盐的用途，其特征在于，用于制备药物，所述药物用于预防和/或治疗受神经元损伤影响的疾病或病症。
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