WO2019020070A1 - 哌嗪并杂芳基类衍生物、其制备方法及其在医药上的应用 - Google Patents

哌嗪并杂芳基类衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2019020070A1
WO2019020070A1 PCT/CN2018/097170 CN2018097170W WO2019020070A1 WO 2019020070 A1 WO2019020070 A1 WO 2019020070A1 CN 2018097170 W CN2018097170 W CN 2018097170W WO 2019020070 A1 WO2019020070 A1 WO 2019020070A1
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group
compound
formula
alkyl
cycloalkyl
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PCT/CN2018/097170
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English (en)
French (fr)
Inventor
李心
何威
陈阳
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Application filed by 江苏恒瑞医药股份有限公司, 上海恒瑞医药有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to JP2020502945A priority Critical patent/JP2020528062A/ja
Priority to RU2020105275A priority patent/RU2745431C1/ru
Priority to US16/632,973 priority patent/US11247998B2/en
Priority to AU2018305614A priority patent/AU2018305614B2/en
Priority to KR1020207003425A priority patent/KR20200032702A/ko
Priority to CA3070004A priority patent/CA3070004A1/en
Priority to EP18837963.0A priority patent/EP3660018A4/en
Priority to CN201880004423.7A priority patent/CN109952305B/zh
Priority to BR112020001299-8A priority patent/BR112020001299A2/pt
Publication of WO2019020070A1 publication Critical patent/WO2019020070A1/zh
Priority to ZA2019/08609A priority patent/ZA201908609B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the invention belongs to the field of medicine and relates to piperazine and heteroaryl derivatives, a preparation method thereof and application thereof in medicine.
  • the present invention relates to a piperazine-heteroaryl derivative represented by the formula (I), a process for producing the same, a pharmaceutical composition containing the same, and as a capsid protein inhibitor, particularly in prevention And/or use in the treatment of diseases such as hepatitis B, influenza, herpes and AIDS.
  • HBV infection chronic hepatitis B virus (HBV) infection is already a global health problem. According to the World Health Organization, about 2 billion people worldwide have been infected with HBV, 240 million of whom are chronic HBV infections. About 650,000 people die each year from HBV. Liver failure, cirrhosis and hepatocellular carcinoma (HCC) caused by infection. In global cirrhosis and HCC patients, the proportions caused by HBV infection were 30% and 45%, respectively. Although prophylactic HBV vaccines can be used, chronic HBV infection has become a worldwide medical problem due to the lack of effective treatments.
  • alpha-interferon preparations such as pegylated alpha-interferon
  • nucleoside analogues that inhibit HBV DNA polymerase such as lamivudine, adefovir. Wait.
  • interferon preparations have severe side effects, poor tolerance, and only a small percentage of patients may have a sustained clinical response to interferon therapy (Lancet. 2005 Jan 8-14; 365(9454): 123-9.; N Engl J Med. 2005 Jun 30;352(26):2682-95.;Hepatology.2009 May;49(5Suppl):S103-11).
  • nucleoside analog drugs exert antiviral effects by blocking the synthesis of HBV DNA strands.
  • existing nucleoside analog drugs also have problems such as inducing reverse transcriptase-producing drug-resistant mutations and poor efficacy against drug-resistant strains.
  • these drugs are often difficult to completely eliminate HBV infection, even if it is long-term medication can not cure; once discontinued, it may also lead to severe withdrawal rebound, so often need to take medication for life (Hepatology.2009 May; 49 (5 Suppl) :S112-21). Therefore, there is an urgent need to develop new, safe and effective drugs for chronic hepatitis B.
  • HBV hepatitis B virus
  • Hepadnaviridae an envelope of the hepadnavirus family
  • dsDNA partially double-stranded DNA virus.
  • the outermost layer of mature HBV virions is an envelope protein wrapped in HBV nucleocapsid (Nucleocapsid).
  • the nucleocapsid is also called Core Particle, and is composed of Capsid protein, HBV Relaxed circular DNA (rcDNA), and HBV reverse transcriptase which binds to the 5' end of the negative strand of rcDNA.
  • rcDNA Upon infection, rcDNA is converted to covalently closed loop DNA (cccDNA) in the host cell nucleus as a replication template for HBV.
  • cccDNA covalently closed loop DNA
  • An important step in HBV replication is the Encapsidation.
  • Pregenomic RNA (pgRNA) transcribed from cccDNA needs to be encapsulated in the capsid protein together with HBV reverse transcriptase to complete the assembly step in order to promote subsequent reverse transcription.
  • HBV reverse transcriptase HBV reverse transcriptase, pgRNA needs to be properly encapsulated by the capsid protein. Therefore, blocking the assembly of capsid proteins, or accelerating the degradation of capsid proteins, can block the assembly process of the capsid, thereby affecting viral replication.
  • capsid protein assembly inhibitors are considered as new targets for anti-hepatitis B drug development. Because of the different mechanisms of action with traditional antiviral drugs, combination therapy with capsid protein inhibitors and DNA polymerase inhibitors should work together to suppress HBV replication and prevent drug resistance, providing safer and more resistant to chronic hepatitis B infection. Effective treatment.
  • HAPs heteroaryldihydropyrimidines
  • phenylacrylamides such as GLS-4, NVR-3778, and the like.
  • Related patents are: WO2001068642, WO2014029193, WO2015011281, WO2016016196, WO2017076791 and WO2016113273, etc., but most of the compounds directed at this target are in the clinical research stage, and no listed drugs appear. Therefore, it is necessary to continue to develop drugs for capsid protein inhibitors to improve the safety and effectiveness of drugs, and to overcome the problem of chronic HBV infection at an early date.
  • Capsid protein inhibitors interfere with the normal assembly of capsid proteins by binding to the assembly domain of the core protein dimerization motif, thereby affecting HBV replication. Therefore, good pharmacokinetic absorption and high bioavailability (which can result in higher concentrations of compounds in the body) can more effectively block HBV replication.
  • the present invention provides a capsid protein inhibitor of the novel structure represented by the general formula (I), wherein the substituent on the heteroaryl group is an amide, preferably the amine group in the amide group is a secondary amine, and the present invention is designed
  • the comparative example corresponds to the NR 1 R 2 moiety in the general formula (1), and R 1 R 2 is cyclized together with the nitrogen atom to form a tertiary amine, which is verified by the comparative example in the amide group on the heteroaryl group.
  • the amine group is a secondary amine
  • the biological activity is significantly improved, which has a significant inhibitory effect on the normal assembly of the HBV capsid protein, and the drug absorption is good and the bioavailability is high.
  • the novel structure of the compound represented by the general formula (I) has no effect or less influence on the proliferation inhibition of HepG2 cells in vitro, and shows good safety.
  • Ring A is an aryl group and a heteroaryl group
  • Y is N or CR 5 ;
  • Q is N or CH
  • R 1 is selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and The heteroaryl groups are each independently optionally further selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, Substituting one or more substituents of aryl, heteroaryl, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 ;
  • R 2 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, The aryl and heteroaryl are each independently optionally further selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, hetero Substituting one or more substituents of a cyclic group, an aryl group, a heteroaryl group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 ;
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • R 4 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a hetero group.
  • R 5 is selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl base;
  • R 6 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an amino group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • n 0, 1, 2 or 3;
  • n 0, 1 or 2;
  • s 0, 1, 2, 3 or 4.
  • the compound of the formula (I) according to the invention is a compound of the formula (II):
  • Rings A, Y, Q, R 1 , R 3 , R 4 , s and n are as defined in formula (I).
  • the compound of the formula (I), the formula (IV), the formula (V) and the formula (VI) of the formula (I) according to the present invention are Compound shown:
  • Ring A, R 1 , R 3 , R 4 , s and n are as defined in formula (I).
  • the compound of the formula (I) according to the invention wherein the ring A is a phenyl or pyridyl group.
  • the compound of the formula (I) according to the invention is of the formula (VII), formula (VIII), formula (IX) and formula (X) Compounds shown:
  • G is C or N
  • R 1 , R 3 , R 4 , s and n are as defined in the formula (I).
  • the compound of the formula (I) according to the invention wherein R 1 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl and aryl, wherein The alkyl, cycloalkyl, heterocyclyl and aryl groups are optionally further substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy and hydroxy.
  • the compound of the formula (I) according to the present invention is of the formula (VII-A), the formula (VIII-A), and the formula (IX- A) and the compound of the formula (XA):
  • G is C or N
  • R 8 is an alkyl group, preferably a methyl group
  • R 9 is alkyl, wherein said alkyl group is optionally further substituted with one or more halogens;
  • R 3 , R 4 , s and n are as defined in the formula (I).
  • the compound of the formula (I) according to the invention wherein R 3 is a hydrogen atom or an alkyl group.
  • the compound of the formula (I) according to the invention wherein R 4 is selected from a hydrogen atom, a halogen, a halogenated alkyl group or a cyano group.
  • Typical compounds of formula (I) include, but are not limited to:
  • a tautomer a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of the formula (IA):
  • R a is a hydrogen atom or an alkyl group
  • Ring A is an aryl group and a heteroaryl group
  • Y is N or CR 5 ;
  • Q is N or CH
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • a cyclic group, an aryl group, a heteroaryl group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 preferably a hydrogen atom or an alkyl group;
  • R 4 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a hetero group.
  • R 5 is selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl base;
  • R 6 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an amino group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • n 0, 1, 2 or 3;
  • n 0, 1 or 2;
  • s 0, 1, 2, 3 or 4;
  • the invention provides a compound of the formula (IC):
  • Ring A is an aryl group and a heteroaryl group
  • Y is N or CR 5 ;
  • Q is N or CH
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • a cyclic group, an aryl group, a heteroaryl group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 preferably a hydrogen atom or an alkyl group;
  • R 4 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a hetero group.
  • R 5 is selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl base;
  • R 6 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an amino group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • n 0, 1, 2 or 3;
  • n 0, 1 or 2;
  • s 0, 1, 2, 3 or 4.
  • Typical compounds of formula (IA) include, but are not limited to:
  • the invention provides a compound of the formula (IIIA):
  • M is trifluoroacetic acid or hydrochloric acid
  • R 1 is selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and The heteroaryl groups are each independently optionally further selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, Substituting one or more substituents of aryl, heteroaryl, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 ;
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • a cyclic group, an aryl group, a heteroaryl group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 preferably a hydrogen atom or an alkyl group;
  • t is 0 or 1;
  • n 0, 1, 2 or 3;
  • Typical intermediate compounds include, but are not limited to:
  • the invention provides a process for the preparation of a compound of formula (I) according to the invention, the process comprising the steps of:
  • R a is a hydrogen atom or an alkyl group
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • a cyclic group, an aryl group, a heteroaryl group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 preferably a hydrogen atom or an alkyl group;
  • Rings A, Y, Q, R 1 , R 2 , R 4 , s and n are as defined in the general formula (I).
  • the invention provides a process for the preparation of a compound of formula (I) according to the invention, the process comprising the steps of:
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • a cyclic group, an aryl group, a heteroaryl group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 preferably a hydrogen atom or an alkyl group;
  • Rings A, Y, Q, R 1 , R 2 , R 4 , s and n are as defined in the general formula (I).
  • the invention provides a method of preparing a compound of formula (II) according to the invention, the method comprising the steps of:
  • R a is a hydrogen atom or an alkyl group
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • a cyclic group, an aryl group, a heteroaryl group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 preferably a hydrogen atom or an alkyl group;
  • Rings A, Y, Q, R 1 , R 4 , s and n are as defined in formula (II).
  • the invention provides a method of preparing a compound of formula (II) according to the invention, the method comprising the steps of:
  • a compound of the formula (IC) is reacted with a compound of the formula (IIB) or a salt thereof to give a compound of the formula (II);
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • a cyclic group, an aryl group, a heteroaryl group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 preferably a hydrogen atom or an alkyl group;
  • Rings A, Y, Q, R 1 , R 4 , s and n are as defined in formula (II).
  • the present invention provides a process for the preparation of a compound of the formula (III), formula (IV), formula (V) and formula (VI) according to the invention, the process comprising The following steps:
  • R a is a hydrogen atom or an alkyl group
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • a cyclic group, an aryl group, a heteroaryl group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 preferably a hydrogen atom or an alkyl group;
  • Rings A, R 1 , R 4 , s and n are as defined in the formula (I).
  • the present invention provides a process for the preparation of the compound of the formula (III), which comprises the following:
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • a cyclic group, an aryl group, a heteroaryl group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 preferably a hydrogen atom or an alkyl group;
  • M is trifluoroacetic acid or hydrochloric acid
  • t is 0 or 1;
  • Rings A, R 1 , R 4 , s and n are as defined in formula (III).
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen, a racemate, an enantiomer a form, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention also relates to a process for the preparation of the above composition, which comprises the compound of the formula (I) or a tautomer thereof, a mesogen, a racemate, an enantiomer, a non- The enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is admixed with a pharmaceutically acceptable carrier, diluent or excipient.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the preparation of a capsid protein inhibitor.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the prevention and/or treatment of a viral infection.
  • the virus may be hepatitis B virus, influenza virus, herpes virus, and HIV, and the diseases may be hepatitis B, influenza, herpes, and AIDS.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, Or a pharmaceutically acceptable salt thereof for use as a medicament.
  • the drug is preferably a drug for preventing and/or treating a viral infection.
  • the virus may be hepatitis B virus, influenza virus, herpes virus, and HIV, and the diseases may be hepatitis B, influenza, herpes, and AIDS.
  • the present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use as a capsid protein inhibitor.
  • the present invention also relates to a method for preventing and/or treating a viral infection disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I) as a capsid protein inhibitor or a mutual transformation thereof.
  • a compound of the formula (I) as a capsid protein inhibitor or a mutual transformation thereof.
  • the virus may be hepatitis B virus, influenza virus, herpes virus, and HIV, and the diseases may be hepatitis B, influenza, herpes, and AIDS.
  • the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, Provides pleasing and tasty pharmaceutical preparations. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture.
  • excipients may be inert excipients, granulating agents, disintegrating agents, binders, and lubricating agents. These tablets may be uncoated or may be coated by a known technique which masks the taste of the drug or delays disintegration and absorption in the gastrointestinal tract and thus provides sustained release over a longer period of time.
  • Oral formulations can also be provided in soft gelatine capsules in which the active ingredient is mixed with an inert solid diluent or the active ingredient in admixture with a water-soluble vehicle or an oil vehicle.
  • the aqueous suspension contains the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspensions, dispersing or wetting agents.
  • the aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • the oil suspension can be formulated by suspending the active ingredient in vegetable oil or mineral oil.
  • the oil suspension may contain a thickening agent.
  • the above sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an antioxidant.
  • compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oil phase can be a vegetable oil, or a mineral oil or a mixture thereof.
  • Suitable emulsifiers can be naturally occurring phospholipids, and emulsions can also contain sweeteners, flavoring agents, preservatives, and antioxidants.
  • Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • the pharmaceutical compositions of the invention may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, and the injection or microemulsion may be injected into the bloodstream of the patient by a local injection.
  • the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention.
  • a continuous intravenous drug delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.
  • compositions of the invention may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspensions.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oils may conveniently be employed as a solvent or suspension medium. Any blended fixed oil can be used for this purpose.
  • fatty acids can also be prepared as injections.
  • the compounds of the invention may be administered in the form of a suppository for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
  • the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient. , the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment modality such as the mode of treatment, the daily amount of the compound of the present invention or the type of pharmaceutically acceptable salt may be Traditional treatment options to verify.
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
  • the alkyl group of the atom is a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl,
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, carboxylate, -OR 6 , -C(O)R 6 , -C(O)OR 6 And -S(O) m R 6 .
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group, a carboxylate group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 .
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. One carbon atom.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • a polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
  • spirocycloalkyl refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have complete Conjugate ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group, a carboxylate group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 .
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O).
  • a hetero atom of m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • ring atoms Preferably comprising from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; most preferably from 3 to 8 ring atoms, wherein from 1 to 3 are heteroatoms; most preferably from 3 to 6 ring atoms, wherein from 1 to 2 It is a hetero atom.
  • monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine.
  • the group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like are preferably piperidinyl, piperazinyl or morpholinyl.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O). ) m (where m is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group.
  • spiroheterocyclyl groups include:
  • fused heterocyclyl refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining rings
  • the atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused heterocyclic groups include:
  • bridge heterocyclyl refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total A ⁇ -electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bridge heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group, a carboxylate group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 .
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. More preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle An alkylthio group, a carboxyl group or a carboxylate group.
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 to 10 members, and has 1 to 3 hetero atoms; more preferably 5 or 6 members, and 1 to 2 hetero atoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridyl Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, tetrazolyl, pyridyl, thienyl, pyrazolyl or pyrimidinyl , thiazolyl; more selective pyridyl.
  • the heteroaryl ring may be fuse
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group, a carboxylate group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 .
  • amino protecting group is intended to keep the amino group unchanged during the reaction of other parts of the molecule, and to protect the amino group with a group which is easily removed.
  • Non-limiting examples include t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with from 1 to 3 substituents selected from halogen, alkoxy or nitro.
  • the amino protecting group is preferably p-methoxybenzyl.
  • haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • hydroxy refers to an -OH group.
  • halogen means fluoro, chloro, bromo or iodo.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • carboxylate group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
  • acyl halide refers to a compound containing a -C(O)-halogen group.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but is not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
  • R 6 and m are as defined in the formula (I).
  • the preparation method of the salt used includes the following steps:
  • a compound of the formula (IIB') is reacted with a compound of the formula (I-2) and bis(trichloromethyl)carbonate under basic conditions to give a compound of the formula (I-3);
  • the compound of the formula (I-3) and carbon monoxide are reacted under basic conditions in the presence of a catalyst to obtain a compound of the formula (IA);
  • a compound of the formula (IA) is reacted with a compound of the formula (IB) or a salt thereof to give a formula (I).
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • the inorganic bases including but not limited to sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, Sodium bicarbonate, potassium carbonate or cesium carbonate;
  • Catalysts include, but are not limited to, palladium on carbon, Raney nickel, platinum dioxide, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, 2-dicyclohexylphosphino-2,4,6-triisopropyl Biphenyl, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, 1,1'-bis(dibenzylphosphine)dichlorodipentadium iron palladium, tris(dibenzylidene) Acetone) dipalladium or 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride or 2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl.
  • Condensing agents include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-di Propylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7- Azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, O-(7-azabenzotriazol-1-yl) -N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate Ester, benzo
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • R a is a hydrogen atom or an alkyl group, preferably a hydrogen atom, a methyl group or an ethyl group;
  • X is a halogen, preferably bromine
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • a cyclic group, an aryl group, a heteroaryl group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 preferably a hydrogen atom or an alkyl group;
  • Rings A, Y, Q, R 1 , R 2 , R 4 , s and n are as defined in the general formula (I).
  • the preparation method of the salt used includes the following steps:
  • a compound of the formula (IIB') is reacted with a compound of the formula (I-4) and bis(trichloromethyl)carbonate under basic conditions to give a compound of the formula (IA);
  • the compound of the formula (IA) is hydrolyzed under basic conditions to obtain a compound of the formula (IC);
  • a compound of the formula (IC) is condensed with a compound of the formula (IB) or a salt thereof to give a compound of the formula (I);
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • the inorganic bases including but not limited to sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, Sodium bicarbonate, potassium carbonate or cesium carbonate;
  • Condensing agents include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-di Propylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7- Azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, O-(7-azabenzotriazol-1-yl) -N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate Ester, benzo
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • R a is an alkyl group, preferably a methyl group or an ethyl group
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • a cyclic group, an aryl group, a heteroaryl group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 preferably a hydrogen atom or an alkyl group;
  • Rings A, Y, Q, R 1 , R 2 , R 4 , s and n are as defined in the general formula (I).
  • the preparation method of the salt used includes the following steps:
  • a compound of the formula (IA) is reacted with a compound of the formula (IIB) or a salt thereof under basic conditions to give a compound of the formula (II);
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • the inorganic bases including but not limited to sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, Sodium bicarbonate, potassium carbonate or cesium carbonate;
  • Condensing agents include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-di Propylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7- Azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, O-(7-azabenzotriazol-1-yl) -N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate Ester, benzo
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • R a is a hydrogen atom or an alkyl group, preferably a hydrogen atom, a methyl group or an ethyl group;
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • a cyclic group, an aryl group, a heteroaryl group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 preferably a hydrogen atom or an alkyl group;
  • Rings A, Q, Y, R 1 , R 4 , s and n are as defined in formula (II).
  • the preparation method of the salt used includes the following steps:
  • a compound of the formula (IC) is reacted with a compound of the formula (IIB) or a salt thereof under basic conditions to give a compound of the formula (II);
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • the inorganic bases including but not limited to sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, Sodium bicarbonate, potassium carbonate or cesium carbonate;
  • Condensing agents include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-di Propylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7- Azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, O-(7-azabenzotriazol-1-yl) -N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate Ester, benzo
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • a cyclic group, an aryl group, a heteroaryl group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 preferably a hydrogen atom or an alkyl group;
  • Rings A, Q, Y, R 1 , R 4 , s and n are as defined in formula (II).
  • the preparation method of the salt used includes the following steps:
  • a compound of the formula (IIB') is reacted with a compound of the formula (III-1) and bis(trichloromethyl)carbonate under basic conditions to obtain a compound of the formula (III-a);
  • the compound of the formula (III-a) is subjected to hydrolysis under basic conditions to obtain a compound of the formula (III-b);
  • a compound of the formula (III-b) is reacted with a compound of the formula (IIB) or a salt thereof to give a compound of the formula (III);
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • the inorganic bases including but not limited to sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, Sodium bicarbonate, potassium carbonate or cesium carbonate;
  • Condensing agents include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-di Propylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7- Azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, O-(7-azabenzotriazol-1-yl) -N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate Ester, benzo
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • R a is an alkyl group, preferably a methyl group or an ethyl group
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • a cyclic group, an aryl group, a heteroaryl group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 preferably a hydrogen atom or an alkyl group;
  • Rings A, R 1 , R 4 , s and n are as defined in formula (III).
  • a compound of the formula (IIB') is reacted with a compound of the formula (IV-1) and bis(trichloromethyl)carbonate under basic conditions to give a compound of the formula (IV-a);
  • the compound of the formula (IV-a) is subjected to hydrolysis under basic conditions to obtain a compound of the formula (IV-b);
  • a compound of the formula (IV-b) is reacted with a compound of the formula (IIB) or a salt thereof to give a compound of the formula (IV);
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • the inorganic bases including but not limited to sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, Sodium bicarbonate, potassium carbonate or cesium carbonate;
  • Catalysts include, but are not limited to, palladium on carbon, Raney nickel, platinum dioxide, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, 2-dicyclohexylphosphino-2,4,6-triisopropyl Biphenyl, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, 1,1'-bis(dibenzylphosphine)dichlorodipentadium iron palladium, tris(dibenzylidene) Acetone) dipalladium or 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride or 2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl.
  • Condensing agents include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-di Propylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7- Azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, O-(7-azabenzotriazol-1-yl) -N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate Ester, benzo
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • R a is an alkyl group, preferably a methyl group or an ethyl group
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • a cyclic group, an aryl group, a heteroaryl group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 preferably a hydrogen atom or an alkyl group;
  • Rings A, R 1 , R 4 , s and n are as defined in the formula (I).
  • the preparation method of the salt used includes the following steps:
  • the compound of the formula (III-4) is deprotected under acidic conditions to obtain a compound of the formula (IIIA) or a salt thereof;
  • the third step the compound of the formula (IIIA) or a salt thereof is reacted with a compound of the formula (IIB') or a salt thereof and bis(trichloromethyl)carbonate to obtain a compound of the formula (III);
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • the inorganic bases including but not limited to sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, Sodium bicarbonate, potassium carbonate or cesium carbonate;
  • Agents that provide acidic conditions include, but are not limited to, hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me 3 SiCl, and TMSOT f ;
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • M is trifluoroacetic acid or hydrochloric acid
  • R a is a hydrogen atom or an alkyl group, preferably a hydrogen atom, a methyl group or an ethyl group
  • R b is an amino protecting group, preferably a tert-butoxycarbonyl group
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • a cyclic group, an aryl group, a heteroaryl group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 preferably a hydrogen atom or an alkyl group;
  • the preparation method of the salt used includes the following steps:
  • the compound of the formula (V-2) is subjected to a reduction reaction in the presence of a reducing agent to obtain a compound of the formula (V-3);
  • the compound of the formula (V-3) is oxidized with an oxidizing agent to obtain a compound of the formula (V-4);
  • the compound of the formula (V-4) is oxidized in the presence of an oxidizing agent to obtain a compound of the formula (V-a);
  • a compound of the formula (V-a) is condensed with a compound of the formula (IIB) or a salt thereof to obtain a compound of the formula (V);
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • the inorganic bases including but not limited to sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, Sodium bicarbonate, potassium carbonate or cesium carbonate;
  • Reducing agents include, but are not limited to, lithium aluminum hydride, NaBH 4 , NaBH 4 -ZnCl 2 , and diisobutylaluminum hydride (DIBAL-H).
  • Oxidizing agents include, but are not limited to, pyridinium chlorochromate (PCC), Jones reagent, Collins reagent, pyridinium dichromate (PDC), oxalyl chloride (Swern oxidation), carbodiimide, sodium chlorite, and potassium permanganate. .
  • PCC pyridinium chlorochromate
  • PDC pyridinium dichromate
  • Swern oxidation oxalyl chloride
  • carbodiimide sodium chlorite
  • potassium permanganate potassium permanganate
  • Condensing agents include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-di Propylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7- Azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, O-(7-azabenzotriazol-1-yl) -N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate Ester, benzo
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • a cyclic group, an aryl group, a heteroaryl group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 preferably a hydrogen atom or an alkyl group;
  • Rings A, R 1 , R 4 , s and n are as defined in the formula (V).
  • the preparation method of the salt used includes the following steps:
  • a compound of the formula (IIB') is reacted with a compound of the formula (VI-1) and bis(trichloromethyl)carbonate under basic conditions to give a compound of the formula (VI-2);
  • a compound of the formula (VI-a) is reacted with a compound of the formula (IIB) or a salt thereof to give a compound of the formula (VI);
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • the inorganic bases including but not limited to sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, Sodium bicarbonate, potassium carbonate or cesium carbonate;
  • Condensing agents include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-di Propylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7- Azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, O-(7-azabenzotriazol-1-yl) -N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate Ester, benzo
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • R a is a hydrogen atom or an alkyl group, preferably a hydrogen atom, a methyl group or an ethyl group;
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • a cyclic group, an aryl group, a heteroaryl group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 preferably a hydrogen atom or an alkyl group;
  • Rings A, R 1 , R 4 , s and n are as defined in the formula (I).
  • the preparation method of the salt used includes the following steps:
  • a compound of the formula (VII-1) is reacted with a compound of the formula (III-1) and bis(trichloromethyl)carbonate under basic conditions to obtain a compound of the formula (VII-a);
  • the compound of the formula (IV-a) is subjected to hydrolysis under basic conditions to obtain a compound of the formula (VII-b);
  • a compound of the formula (VII-b) is subjected to a condensation reaction with a compound of the formula (IIB) or a salt thereof to obtain a compound of the formula (VII);
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • the inorganic bases including but not limited to sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, Sodium bicarbonate, potassium carbonate or cesium carbonate;
  • Condensing agents include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-di Propylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7- Azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, O-(7-azabenzotriazol-1-yl) -N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate Ester, benzo
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • R a is an alkyl group, preferably a methyl group or an ethyl group
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • a cyclic group, an aryl group, a heteroaryl group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 preferably a hydrogen atom or an alkyl group;
  • R 1 , R 4 , s and n are as defined in the formula (I).
  • the preparation method of the salt used includes the following steps:
  • a compound of the formula (VII-1) is reacted with a compound of the formula (IV-1) and bis(trichloromethyl)carbonate under basic conditions to give a compound of the formula (VIII-a);
  • the compound of the formula (VIII-a) is subjected to hydrolysis under basic conditions to obtain a compound of the formula (VIII-b);
  • a compound of the formula (VIII-b) is subjected to a condensation reaction with a compound of the formula (IIB) or a salt thereof to give a compound of the formula (VIII);
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • the inorganic bases including but not limited to sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, Sodium bicarbonate, potassium carbonate or cesium carbonate;
  • Condensing agents include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-di Propylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7- Azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, O-(7-azabenzotriazol-1-yl) -N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate Ester, benzo
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • R a is an alkyl group, preferably a methyl group or an ethyl group
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • a cyclic group, an aryl group, a heteroaryl group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 preferably a hydrogen atom or an alkyl group;
  • R 1 , R 4 , s and n are as defined in the formula (I).
  • the compound of the formula (VII-a) is reacted with a compound of the formula (VII-B) or a salt thereof to give a compound of the formula (VII-A); or a compound of the formula (VIII-a) and a compound of the formula (VII-B)
  • the compound or a salt thereof is reacted to obtain a compound of the formula (VIII-A);
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • organic bases including, but not limited to, triethylamine, 1 M bistrimethylsilylamine lithium tetrahydrofuran solution, N,N-diisopropyl B.
  • the inorganic bases including but not limited to sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, Sodium bicarbonate, potassium carbonate or cesium carbonate;
  • Condensing agents include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-di Propylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7- Azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, O-(7-azabenzotriazol-1-yl) -N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate Ester, benzo
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-di Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;
  • G is C or N
  • R a is a hydrogen atom or an alkyl group, preferably a hydrogen atom, a methyl group or an ethyl group;
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • a cyclic group, an aryl group, a heteroaryl group, -OR 6 , -C(O)R 6 , -C(O)OR 6 and -S(O) m R 6 preferably a hydrogen atom or an alkyl group;
  • R 8 is an alkyl group, preferably a methyl group
  • R 9 is alkyl, wherein said alkyl group is optionally further substituted with one or more halogens;
  • R 4 and s are as defined in the formula (I).
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methyl silane
  • the measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.
  • the CombiFlash Rapid Preparer uses the Combiflash Rf200 (TELEDYNE ISCO).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Companies such as Dare Chemicals.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the microwave reaction used a CEM Discover-S Model 908860 microwave reactor.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature and is 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC), the developing agent used for the reaction, the column chromatography eluent system used for the purification of the compound, and the thin layer chromatography developing solvent system including: A: Methylene chloride/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added. Adjustment with alkaline or acidic reagents such as acetic acid.
  • dicobalt octacarbonyl (2.26 g, 6.62 mmol) and potassium carbonate (4.57 g, 33.09 mmol) were dissolved in 20 mL of methanol, and the reaction was stirred at 60 ° C for 15 minutes.
  • the crude compound 11a (16.84 g, 47.13 mmol) was dissolved in 50 mL of methanol, and a pre-prepared sodium hydroxide solution (sodium hydroxide (12 g, 282.76 mmol) dissolved in 60 mL of water) was added dropwise at 0 ° C, and slowly warmed to room temperature. The reaction was stirred for 4 hours. The reaction mixture was concentrated to drynessnessnessnessnessnessnessnessnessnessnessness In the next step.
  • sodium hydroxide solution sodium hydroxide (12 g, 282.76 mmol
  • the fourth step starting material compound 2d was replaced with the starting material 2,6-difluoro-4-pyridinamine (Shanghai Bied Pharmaceutical Technology Co., Ltd.) to obtain the title compound 20 (10 mg).
  • the first starting material compound 3a was replaced with the starting material compound 7b, and the third step starting material compound 3d was replaced with the starting material compound 2-chloro-3-fluoropyridin-4-amine (Shanghai Bi De Pharmaceutical Technology Co., Ltd. Company), the title compound 25 (20 mg) was obtained.
  • the compound 29f (60 mg, 210.28 ⁇ mol) was dissolved in 10 mL of methanol, and a palladium carbon hydrogenation catalyst (wet) (22.38 mg, 210.28 ⁇ mol) was added thereto, and the reaction was stirred for 16 hours. The reaction mixture was filtered, and the ⁇
  • Example 39 Using the synthetic route of Example 39, the first step starting material compound 6a was replaced with the compound (2R)-1-((4-methoxybenzyl)amino)propan-1-ol (using a known method "Organic and Biomolecular Chemistry” , 2014, 12, 16, 2584 - 2591 "prepared” to give the title compound 42 (20 mg).
  • the third step starting material compound 1e was replaced with the compound 1-methylcyclopropyl 1-amine (Shanghai Bied Pharmaceutical Technology Co., Ltd.) to obtain the title compound 48 (20 mg).
  • Example 7 Using the synthetic route of Example 7, the first step starting material compound 7a was replaced with the starting compound (R)-3-iodo-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine. -5(4H)-tert-butyl carboxylic acid (prepared by the method disclosed in the patent application "WO2017198744A1") to give the title compound 49 (20 mg)
  • Example 11 Using the synthetic route of Example 11, the third step of the starting compound 1e was replaced with the starting compound t-butylamine (Nippon Pharmaceutical Group Chemical Co., Ltd.) to obtain the title compound 50 (180 mg).
  • the third step of the starting compound 1e was replaced with the starting compound (S)-2-fluoro-1-methyl-ethylamine hydrochloride (Shanghai Bied Pharmaceutical Technology Co., Ltd.) to obtain the title compound. 51 (20 mg).
  • the title compound 52 (20 mg) was obtained from the title compound (2S)-1,1,1-trifluoropropyl-2-amine hydrochloride.
  • the first step starting material 6a was replaced with the starting material (R)-2-((4-methoxybenzyl)amino)propan-1-ol (using a known method "Bioorganic & Medicinal Chemistry Letters, 2015, 25(5), 1086-1091 "prepared” to give the title compound 53 (90 mg)
  • the first step starting material compound 6a was replaced with the starting material (R)-2-((4-methoxybenzyl)amino)propan-1-ol, and the fourth step starting compound 2d was replaced.
  • the title compound 54 (88 mg) was obtained.
  • the first step starting material compound 6a was replaced with the starting material (R)-2-((4-methoxybenzyl)amino)propan-1-ol, and the fourth step starting compound 2d was replaced.
  • the title compound (e) was replaced with the title compound (2S)-1,1,1-trifluoropropyl-2-amine hydrochloride to give the title compound 55 (20 mg).
  • Example 6 Using the synthetic route of Example 6, the first starting material compound 6a was replaced with the starting compound (S)-1-((4-methoxybenzyl)amino)propan-2-ol (using a known method "Organic and Biomolecular Chemistry, 2014, 12, 16, 2584-2591 "Prepared", the fourth step starting compound 2d was replaced with the starting compound 3d to give the title compound 56 (10 mg).
  • Example 39 Using the synthetic route of Example 39, the first starting material compound 6a was replaced with the starting compound 1-((4-methoxybenzyl)amino)propan-2-ol (using a known method "Organic and Biomolecular Chemistry, 2014" The title compound (d) was replaced with the starting compound 3d to give the title compound 57 (220 mg).
  • Example 6 Using the synthetic route of Example 6, the fourth step starting compound 2d was replaced with the starting compound 4-fluoro-3-methylaniline (Shanghai Bied Pharmaceutical Technology Co., Ltd.) to give the title compound 58 (14 mg).
  • Example 11 Using the synthesis route of Example 11, the first step starting material compound 3d was replaced with the compound 2d, and the third step starting material compound 1e was replaced with the starting compound pyrrolidine (Nippon Pharmaceutical Group Chemical Co., Ltd.) to obtain the title compound 59 (10 mg).
  • Test Example 1 In vitro anti-HBV activity test of the compound of the present invention (quantitative analysis of intracellular HBV DNA)
  • HepG2.2.15 cells are stable expression cell lines that integrate the HBV genome and can be secreted outside the cell by replication, transcription, translation, and packaging into viral particles carrying HBV DNA.
  • quantitative PCR was used to quantitatively analyze the HBV DNA produced by HepG2.2.15 in vitro proliferation, and the compounds of the present invention were screened for inhibition of HBV DNA replication by inhibiting assembly of HBV capsid protein.
  • HepG2.2.15 cells were cultured in DMEM/high glucose medium (10% FBS, 400 ⁇ g/ml G418) and passaged every 3 days.
  • DMEM/high glucose medium 10% FBS, 400 ⁇ g/ml G418)
  • a cell suspension was prepared from fresh cell culture medium, and cultured at 40 °C in a 40-well cell/well 96-well plate (Corning, #3599), 5% carbon dioxide.
  • the compound was dissolved in pure DMSO at a concentration of 20 mM, and then the first concentration of 2 mM was prepared in DMSO, and diluted to 8 concentrations in 4 fold, and the control wells were added to 90 ⁇ l of DMSO. Diluted 200 times with DMEM/high glucose medium.
  • the cell culture plate inoculated on the first day was taken out, the medium in the well plate was aspirated by a vacuum suction device, and the prepared compound medium containing each concentration was separately added to each well, and cultured at 200 ⁇ l/well at 37 ° C. 72 hours.
  • the cultured cells were exchanged with fresh medium containing the same compound in the same manner as the next day, and cultured at 37 ° C for 72 hours.
  • the cell culture plate was taken out, centrifuged at 300 g for 3 minutes, and the culture supernatant was collected at 200 ⁇ l/well.
  • HBV DNA extraction in cell culture supernatants was performed using Qiagen automated DNA extraction equipment. Refer to the reagents and instrument instructions for specific methods.
  • the extracted DNA was eluted with DNA elution buffer at 100 ⁇ l/well.
  • the extracted DNA was subjected to quantitative PCR analysis of HBV DNA using Taipu Biotechnology Hepatitis B Virus Nucleic Acid Quantitative Detection Kit. The specific method is described in the kit.
  • the quantitative standard curve was carried out in parallel using the standard sample of the kit. Each sample was quantitatively converted according to a standard curve.
  • the EC 50 value of the compound was calculated from each concentration of the compound and the corresponding DNA value using Graphpad Prism software. Emax is the effect value of the compound to minimize HBV DNA replication.
  • the compounds of the present invention were assayed by inhibiting the assembly of HBV capsid protein and thereby inhibiting the in vitro activity of HBV DNA replication by the above test, and the measured EC 50 values are shown in Table 1.

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Abstract

本发明涉及哌嗪并杂芳基类衍生物、其制备方法及其在医药上的应用。特别地，本发明涉及通式(I)所示的哌嗪并杂芳基类衍生物、其制备方法、含有该衍生物的药物组合物，以及其作为衣壳蛋白抑制剂，特别是在预防和/或治疗乙型肝炎、流感、疱疹和艾滋病等疾病中的用途。其中通式(I)中的各基团的定义与说明书中的定义相同。

Description

哌嗪并杂芳基类衍生物、其制备方法及其在医药上的应用 技术领域
本发明属于医药领域，涉及哌嗪并杂芳基类衍生物、其制备方法及其在医药上的应用。特别地，本发明涉及通式(I)所示的哌嗪并杂芳基类衍生物、其制备方法、含有该衍生物的药物组合物，以及其作为衣壳蛋白抑制剂，特别是在预防和/或治疗乙型肝炎、流感、疱疹和艾滋病等疾病中的用途。
背景技术
慢性B型肝炎病毒(HBV)感染已经是一种全球健康问题，据世界卫生组织报道，全球约20亿人曾感染HBV，其中2.4亿人为慢性HBV感染者，每年约有65万人死于HBV感染所致的肝衰竭、肝硬化和肝细胞癌(HCC)。全球肝硬化和HCC患者中，由HBV感染引起的比例分别为30％和45％。尽管可以使用预防性的HBV疫苗，但由于缺乏有效治药物，致使慢性HBV感染已成为全世界医疗问题。
目前，治疗慢性HBV的药物主要有两类：α-干扰素制剂(如聚乙二醇化α-干扰素)和抑制HBV DNA聚合酶的核苷类似物(如拉米夫定、阿德福韦等)。但是，干扰素类制剂具有严重的副作用，耐受性差，并且只有小部分患者可能对干扰素治疗具有持续的临床响应(Lancet.2005 Jan 8-14；365(9454):123-9.；N Engl J Med.2005 Jun 30；352(26):2682-95.；Hepatology.2009 May；49(5Suppl):S103-11)。作为逆转录酶的竞争性抑制剂，核苷类似物药物通过阻碍HBV DNA链的合成从而发挥抗病毒疗效。但现有核苷类似物药物也存在诱导逆转录酶产生耐药突变、对耐药株疗效不佳等问题。此外，这类药物通常难以彻底清除HBV感染，即使是长期服药也无法根治；一旦停药，还可能导致严重的停药反跳，因此常常需要终身服药(Hepatology.2009 May；49(5 Suppl):S112-21)。因此，迫切需要开发用于慢性乙型肝炎的新型、安全且有效的药物。
慢性HBV感染治愈率低的原因与乙型肝炎病毒(HBV)的特性有很大关系，HBV是嗜肝DNA病毒家族(Hepadnaviridae)的一种包膜、部分双链DNA(dsDNA)病毒。成熟的HBV病毒颗粒最外层为包膜蛋白，包裹着HBV核衣壳(Nucleocapsid)。核衣壳又称核心颗粒(Core particle)，由衣壳蛋白(Capsid protein)、HBV松弛环状DNA(Relaxed circular DNA，rcDNA)及结合在rcDNA负链5’端的HBV逆转录酶构成。在感染时，rcDNA在宿主细胞核中转变为共价闭环DNA(cccDNA)，作为HBV复制模板。HBV复制过程中，1个重要步骤就是衣壳装配(Encapsidation)。cccDNA转录出的前基因组RNA(Pregenomic RNA，pgRNA)需要同HBV逆转录酶一起被包裹在衣壳蛋白中，完成装配步骤，才能促发后续逆 转录。在逆转录以前，HBV逆转录酶，pgRNA需要被衣壳蛋白正确包裹。因此，阻断衣壳蛋白装配，或加快衣壳蛋白降解，都会阻断衣壳装配过程，从而影响病毒复制。此外，构成核心蛋白二聚化基序(Dimerization motif)及装配结构域(Assemblydomain)的N-端149个氨基酸残基(Cp149)没有人体蛋白质同源序列。因此，衣壳蛋白装配抑制剂被视为抗乙肝药物开发的新靶点。由于与传统抗病毒药物作用机理不同，衣壳蛋白抑制剂可与DNA聚合酶抑制剂的组合疗法应协同遏制HBV复制，并且防止出现耐药性，提供对慢性乙型肝炎感染的更安全且更有效治疗。
目前，衣壳蛋白抑制剂的药物主要有两类：杂芳基二氢嘧啶类(HAPs)和苯基丙烯酰胺类，如GLS-4、NVR-3778等。有关专利如：WO2001068642、WO2014029193、WO2015011281、WO2016016196、WO 2017076791和WO2016113273等，但针对该靶点的化合物大都处于临床研究阶段，并没有上市药物出现。因此，还需要继续开发针对衣壳蛋白抑制剂的药物，以提高药物的安全性和有效性，早日攻克慢性HBV感染的难题。
衣壳蛋白抑制剂通过结合到核心蛋白二聚化基序的装配结构域来干扰衣壳蛋白的正常装配，从而影响HBV的复制。因此，好的药代吸收和高的生物利用度(可以使得体内具有较高浓度的化合物)，能更加有效的阻断HBV的复制。
本发明提供了一种通式(I)所示的新型结构的衣壳蛋白抑制剂，其杂芳基上的取代基为酰胺，优选为酰胺基中的胺基为二级胺，本发明设计了对比例(实施例59)相当于通式(1)中NR 1R 2部分，R 1R 2与氮原子一起成环形成三级胺，通过对比例验证了杂芳基上酰胺基中的胺基为二级胺时，生物活性有显著提升，其对HBV衣壳蛋白正常装配具有明显的抑制作用，并且其药代吸收良好，生物利用度高。同时通式(I)所示的新型结构的化合物对HepG2细胞体外增殖抑制没有影响或影响较小，表现出较好的安全性。
发明内容
本发明的目的在于提供一种通式(I)所示的化合物：
Figure PCTCN2018097170-appb-000001
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，
其中：
环A为芳基和杂芳基；
Y为N或CR 5；
Q为N或CH；
R 1选自烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选进一步被选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6中的一个或多个取代基所取代；
R 2选自氢原子、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选进一步被选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6中的一个或多个取代基所取代；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；
R 4相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；
R 5选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R 6选自氢原子、烷基、卤代烷基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
n为0、1、2或3；
m为0、1或2；且
s为0、1、2、3或4。
在本发明一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物为通式(II)所示的化合物：
Figure PCTCN2018097170-appb-000002
其中：
环A、Y、Q、R 1、R 3、R 4、s和n如通式(I)中所定义。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物通式(III)、通式(IV)、通式(V)和通式(VI)所示的化合物：
Figure PCTCN2018097170-appb-000003
其中：
环A、R 1、R 3、R 4、s和n如通式(I)中所定义。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物，其中环A为苯基或吡啶基。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物为通式(VII)、通式(VIII)、通式(IX)和通式(X)所示的化合物：
Figure PCTCN2018097170-appb-000004
其中：
G为C或N；
R 1、R 3、R 4、s和n如通式(I)中所定义。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物，其中R 1选自烷基、卤代烷基、环烷基、杂环基和芳基，其中所述的烷基、环烷基、杂环基和芳基任选进一步被选自卤素、烷基、烷氧基和羟基中的一个或多个取代基所取代。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物，其为通式(VII-A)、通式(VIII-A)、通式(IX-A)和通式(X-A)所示的化合物：
Figure PCTCN2018097170-appb-000005
其中：
G为C或N；
R 8为烷基，优选为甲基；
R 9为烷基，其中所述的烷基任选进一步被一个或多个卤素所取代；
R 3、R 4、s和n如通式(I)中所定义。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物，其中R 3为氢原子或烷基。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物，其中R 4选自氢原子、卤素、卤代烷基或氰基。
典型的通式(I)的化合物，包括但不限于：
Figure PCTCN2018097170-appb-000006
Figure PCTCN2018097170-appb-000007
Figure PCTCN2018097170-appb-000008
Figure PCTCN2018097170-appb-000009
Figure PCTCN2018097170-appb-000010
Figure PCTCN2018097170-appb-000011
Figure PCTCN2018097170-appb-000012
Figure PCTCN2018097170-appb-000013
Figure PCTCN2018097170-appb-000014
Figure PCTCN2018097170-appb-000015
Figure PCTCN2018097170-appb-000016
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐。
另一方面，本发明提供一种通式(IA)所示的化合物，：
Figure PCTCN2018097170-appb-000017
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
其中：
R a为氢原子或烷基；
环A为芳基和杂芳基；
Y为N或CR 5；
Q为N或CH；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
R 4相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；
R 5选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R 6选自氢原子、烷基、卤代烷基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
n为0、1、2或3；
m为0、1或2；且
s为0、1、2、3或4；
另一方面，本发明提供一种通式(IC)所示的化合物：
Figure PCTCN2018097170-appb-000018
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
其中：
环A为芳基和杂芳基；
Y为N或CR 5；
Q为N或CH；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
R 4相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；
R 5选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、 硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R 6选自氢原子、烷基、卤代烷基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
n为0、1、2或3；
m为0、1或2；且
s为0、1、2、3或4。
其为制备根据通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的中间体。
典型的通式(IA)的化合物，包括但不限于：
Figure PCTCN2018097170-appb-000019
Figure PCTCN2018097170-appb-000020
Figure PCTCN2018097170-appb-000021
Figure PCTCN2018097170-appb-000022
另一方面，本发明提供一种通式(IIIA)的所示化合物，：
Figure PCTCN2018097170-appb-000023
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
其中：
M为三氟乙酸或盐酸；
R 1选自烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选进一步被选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6中的一个或多个取代基所取代；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、 卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
t为0或1；且
n为0、1、2或3；
其为制备根据通式(III)化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的中间体。
典型的中间体化合物，包括但不限于：
Figure PCTCN2018097170-appb-000024
另一方面，本发明提供一种制备根据本发明所述的通式(I)所示的化合物的方法，该方法包括以下步骤：
Figure PCTCN2018097170-appb-000025
将通式(IA)化合物与通式(IB)化合物或其盐反应，得到通式(I)化合物；
其中：
R a为氢原子或烷基；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
环A、Y、Q、R 1、R 2、R 4、s和n如通式(I)中所定义。
另一方面，本发明提供一种制备根据本发明所述的通式(I)所示的化合物的方法，该方法包括以下步骤：
Figure PCTCN2018097170-appb-000026
将通式(IC)化合物与通式(IB)化合物或其盐反应，得到通式(I)化合物；
其中：
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
环A、Y、Q、R 1、R 2、R 4、s和n如通式(I)中所定义。
另一方面，本发明提供一种制备根据本发明所述的通式(II)所示的化合物的方法，该方法包括以下步骤：
Figure PCTCN2018097170-appb-000027
将通式(IA)化合物与通式(IIB)化合物或其盐反应，得到通式(II)化合物；
其中：
R a为氢原子或烷基；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
环A、Y、Q、R 1、R 4、s和n如通式(II)中所定义。
另一方面，本发明提供一种制备根据本发明所述的通式(II)所示的化合物的方法，该方法包括以下步骤：
Figure PCTCN2018097170-appb-000028
将通式(IC)化合物与通式(IIB)化合物或其盐反应，得到通式(II)化合物；
其中：
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
环A、Y、Q、R 1、R 4、s和n如通式(II)中所定义。
另一方面，本发明提供一种制备根据本发明所述的通式(III)、通式(IV))、通式(V)和通式(VI)所示的化合物的方法，该方法包括以下步骤：
Figure PCTCN2018097170-appb-000029
将通式(III-a)化合物与通式(IIB)化合物或其盐反应，得到通式(III)化合物；
或
Figure PCTCN2018097170-appb-000030
将通式(IV-a)化合物与通式(IIB)化合物或其盐反应，得到通式(IV)化合物；
Figure PCTCN2018097170-appb-000031
将通式(V-a)化合物与通式(IIB)化合物或其盐反应，得到通式(V)化合物；
或
Figure PCTCN2018097170-appb-000032
将通式(VI-a)化合物与通式(IIB)化合物或其盐反应，得到通式(VI)化合物；
其中：
其中：
R a为氢原子或烷基；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
环A、R 1、R 4、s和n如通式(I)中所定义。
另一方面，本发明提供一种制备所述的通式(III)所示的化合物的方法，该方法包括以下：
Figure PCTCN2018097170-appb-000033
将通式(IIIA)化合物或其盐与通式(IIB’)化合物或其盐和双(三氟甲基)碳酸酯反应，得到通式(III)化合物；
其中：
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
M为三氟乙酸或盐酸；
t为0或1；
环A、R 1、R 4、s和n如通式(III)中所定义。
本发明的另一方面涉及一种药物组合物，其含有治疗有效剂量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。本发明还涉及一种制备上述组合物的方法，其包括将通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐与药学上可接受的载体、稀释剂或赋形剂相混合。
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物，在制备衣壳蛋白抑制剂中的用途。
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物，在制备用于预防和/或治疗病毒性感染疾病的药物中的用途。所述病毒可以为乙型肝炎病毒、流感病毒、疱疹病毒和艾滋病毒，所述疾病可以为乙型肝炎、流感、疱疹和艾滋病。
本发明进一步涉及一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其可药用盐，其用作药物。所述药物优选为用于预防和/或治疗病毒性感染疾病的药物。所述病毒可以为乙型肝炎病毒、流感病毒、疱疹病毒和艾滋病毒，所述疾病可以为乙型肝炎、流感、疱疹和艾滋病。
本发明还涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物，其用作衣壳蛋白抑制剂。
本发明还涉及一种预防和/或治疗病毒性感染疾病的方法，其包括向需要其的患者施用治疗有效剂量的作为衣壳蛋白抑制剂的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，或包含其的药物组合物。所述病毒可以为乙型肝炎病毒、流感病毒、疱疹病毒和艾滋病毒，所述疾病可以为乙型肝炎、流感、疱疹和艾滋病。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药物组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂、和润滑 剂。这些片剂可以不包衣，或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水混悬液的赋形剂。此类赋形剂是混悬剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使活性成分悬浮于植物油或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油、或矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本发明的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶解于油相的无菌注射水包油微乳，可通过局部大量注射将注射液或微乳注入患者的血流中。或者，最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内药物递送装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
本发明的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和混悬剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合等；另外，最佳的治疗方式如治疗的模式、本发明化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
发明的详细说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链 基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基、羧酸酯基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基和环烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基、羧酸酯基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。 优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2018097170-appb-000034
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2018097170-appb-000035
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2018097170-appb-000036
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基、羧酸酯基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至 20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；最优选包含3至8个环原子，其中1～3是杂原子；最优选包含3至6个环原子，其中1～2是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等，优选哌啶基、哌嗪基或吗啉基。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为3元/6元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2018097170-appb-000037
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2018097170-appb-000038
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多 环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2018097170-appb-000039
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2018097170-appb-000040
等。
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基、羧酸酯基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2018097170-appb-000041
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其 中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为咪唑基、四唑基、吡啶基、噻吩基、吡唑基或嘧啶基、噻唑基；更有选吡啶基。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，其非限制性实例包括：
Figure PCTCN2018097170-appb-000042
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基、羧酸酯基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6。
术语“氨基保护基”是为了使分子其它部位进行反应时氨基保持不变，用易于脱去的基团对氨基进行保护。非限制性实施例包含叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基等。这些基团可任选地被选自卤素、烷氧基或硝基中的1-3个取代基所取代。所述氨基保护基优选为对甲氧苄基。
术语“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。
术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代基”指＝O。
术语“羰基”指C＝O。
术语“羧基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基、环烷基如上所定义。
术语“酰卤”指含有-C(O)-卤素的基团的化合物。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
R 6和m如通式(I)中所定义。
本发明化合物的合成方法
为了完成本发明的目的，本发明采用如下技术方案：
方案一
本发明通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2018097170-appb-000043
第一步，通式(IIB′)化合物与通式(I-2)化合物和双(三氯甲基)碳酸酯在碱性条件下，发生反应得到通式(I-3)化合物；
第二步，通式(I-3)化合物和一氧化碳在碱性条件下，在催化剂存在下，发生反应得到通式(IA)化合物；
第三步，通式(IA)化合物与通式(IB)化合物或其盐进行反应，得到通式(I)化
合物；
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、1M双三甲基硅基胺基锂四氢呋喃溶液、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、氢氧化钠、磷酸钾、碳酸钠、碳酸氢钠、碳酸钾或碳酸铯；
催化剂包括但不限于钯/碳、雷尼镍、二氧化铂、四-三苯基膦钯、二氯化钯、醋酸钯、2-二环己基磷-2,4,6-三异丙基联苯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、1,1’-双(二苄基磷)二氯二戊铁钯、三(二亚苄基丙酮)二钯或2-双环己基膦-2',6'-二甲氧基联苯，优选为[1,1'-双(二苯基膦基)二茂铁]二氯化钯或2-双环己基膦-2',6'-二甲氧基联苯。
缩合剂包括但不限于1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷，优选为2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；
上述反应优选在溶剂中进行，所用溶剂包括但不限于：乙酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物；
其中：
R a为氢原子或烷基，优选为氢原子、甲基或乙基；
X为卤素，优选为溴；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
环A、Y、Q、R 1、R 2、R 4、s和n如通式(I)中所定义。
方案二
本发明通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2018097170-appb-000044
第一步，通式(IIB′)化合物与通式(I-4)化合物和双(三氯甲基)碳酸酯在碱性条件下，发生反应得到通式(IA)化合物；
第二步，通式(IA)化合物在碱性条件下，发生水解反应得到通式(IC)化合物；
第三步，通式(IC)化合物与通式(IB)化合物或其盐，发生缩合反应，得到通式(I)化合物；
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、1M双三甲基硅基胺基锂四氢呋喃溶液、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、氢氧化钠、磷酸钾、碳酸钠、碳酸氢钠、碳酸钾或碳酸铯；
缩合剂包括但不限于1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷，优选为2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；
上述反应优选在溶剂中进行，所用溶剂包括但不限于：乙酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物；
其中：
R a为烷基，优选为甲基或乙基；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
环A、Y、Q、R 1、R 2、R 4、s和n如通式(I)中所定义。
方案三
本发明通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异 构体、非对映异构体或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2018097170-appb-000045
通式(IA)化合物与通式(IIB)化合物或其盐在碱性条件下发生反应，得到通式(II)化合物；
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、1M双三甲基硅基胺基锂四氢呋喃溶液、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、氢氧化钠、磷酸钾、碳酸钠、碳酸氢钠、碳酸钾或碳酸铯；
缩合剂包括但不限于1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷，优选为2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；
上述反应优选在溶剂中进行，所用溶剂包括但不限于：乙酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物；
其中：
R a为氢原子或烷基，优选为氢原子、甲基或乙基；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
环A、Q、Y、R 1、R 4、s和n如通式(II)中所定义。
方案四
本发明通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2018097170-appb-000046
通式(IC)化合物与通式(IIB)化合物或其盐在碱性条件下发生反应，得到通式(II)化合物；
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、1M双三甲基硅基胺基锂四氢呋喃溶液、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、氢氧化钠、磷酸钾、碳酸钠、碳酸氢钠、碳酸钾或碳酸铯；
缩合剂包括但不限于1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷，优选为2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；
上述反应优选在溶剂中进行，所用溶剂包括但不限于：乙酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物；
其中：
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
环A、Q、Y、R 1、R 4、s和n如通式(II)中所定义。
方案五
本发明通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2018097170-appb-000047
第一步，通式(IIB′)化合物与通式(III-1)化合物和双(三氯甲基)碳酸酯在碱性条件下，发生反应得到通式(III-a)化合物；
第二步，通式(III-a)化合物在碱性条件下，发生水解反应得到通式(III-b)化合物；
第三步，通式(III-b)化合物与通式(IIB)化合物或其盐发生反应，得到通式(III)化合物；
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、1M双三甲基硅基胺基锂四氢呋喃溶液、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、氢氧化钠、磷酸钾、碳酸钠、碳酸氢钠、碳酸钾或碳酸铯；
缩合剂包括但不限于1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷，优选为2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；
上述反应优选在溶剂中进行，所用溶剂包括但不限于：乙酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物；
其中：
R a为烷基，优选为甲基或乙基；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
环A、R 1、R 4、s和n如通式(III)中所定义。
方案六
本发明通式(IV)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2018097170-appb-000048
第一步，通式(IIB′)化合物与通式(IV-1)化合物和双(三氯甲基)碳酸酯在碱性条件下，发生反应得到通式(IV-a)化合物；
第二步，通式(IV-a)化合物在碱性条件下，发生水解反应得到通式(IV-b)化合物；
第三步，通式(IV-b)化合物与通式(IIB)化合物或其盐发生反应，得到通式(IV)化合物；
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、1M双三甲基硅基胺基锂四氢呋喃溶液、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、氢氧化钠、磷酸钾、碳酸钠、碳酸氢钠、碳酸钾或碳酸铯；
催化剂包括但不限于钯/碳、雷尼镍、二氧化铂、四-三苯基膦钯、二氯化钯、醋酸钯、2-二环己基磷-2,4,6-三异丙基联苯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、1,1’-双(二苄基磷)二氯二戊铁钯、三(二亚苄基丙酮)二钯或2-双环己基膦-2',6'-二甲氧基联苯，优选为[1,1'-双(二苯基膦基)二茂铁]二氯化钯或2-双环己基膦-2',6'-二甲氧基联苯。
缩合剂包括但不限于1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷，优选为2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；
上述反应优选在溶剂中进行，所用溶剂包括但不限于：乙酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物；
其中：
R a为烷基，优选为甲基或乙基；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
环A、R 1、R 4、s和n如通式(I)中所定义。
方案七
本发明通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2018097170-appb-000049
第一步，通式(III-3)化合物和通式(IIB)化合物或其盐，在碱性条件下，在缩合剂存在下，发生反应得到通式(III-4)；
第二步，通式(III-4)化合物在酸性条件下，脱保护得到通式(IIIA)化合物或其盐；
第三步，通式(IIIA)化合物或其盐与通式(IIB′)的化合物或其盐和双(三氯甲基)碳酸酯发生反应，得到通式(III)化合物；
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、1M双三甲基硅基胺基锂四氢呋喃溶液、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、氢氧化钠、磷酸钾、碳酸钠、碳酸氢钠、碳酸钾或碳酸铯；
提供酸性的条件的试剂包括但不限于氯化氢、三氟乙酸、甲酸、乙酸、盐酸、硫酸、甲磺酸、硝酸、磷酸、对苯甲磺酸、Me 3SiCl和TMSOT f；
上述反应优选在溶剂中进行，所用溶剂包括但不限于：乙酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物；
其中：
M为三氟乙酸或盐酸；R a为氢原子或烷基，优选为氢原子、甲基或乙基；
R b为氨基保护基，优选为叔丁氧羰基；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
t为0或1；环A、R 1、R 4、s和n如通式(III)中所定义。
方案八
本发明通式(V)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2018097170-appb-000050
第一步，通式(IIB′)化合物和通式(V-1)化合物在碱性条件下，发生反应得到通式(V-2)化合物；
第二步，通式(V-2)化合物，在还原剂存在下，发生还原反应得到通式(V-3)化合物；
第三步，通式(V-3)化合物和氧化剂发生氧化反应，得到通式(V-4)化合物；
第四步，通式(V-4)化合物，在氧化剂存在下，发生氧化反应得到通式(V-a)化合物；
第五步，通式(V-a)化合物与通式(IIB)化合物或其盐发生缩合反应，得到通式(V)化合物；
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、1M双三甲基硅基胺基锂四氢呋喃溶液、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、氢氧化钠、磷酸钾、碳酸钠、碳酸氢钠、碳酸钾或碳酸铯；
还原剂包括但不限于氢化铝锂、NaBH 4、NaBH 4-ZnCl 2和二异丁基氢化铝(DIBAL-H)。
氧化剂包括但不限于氯铬酸吡啶盐(PCC)、Jones试剂、Collins试剂、重铬酸吡啶盐(PDC)、草酰氯(Swern氧化)、碳二亚胺、亚氯酸钠和高锰酸钾。
缩合剂包括但不限于1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷，优选为2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；
上述反应优选在溶剂中进行，所用溶剂包括但不限于：乙酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物；
其中：
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
环A、R 1、R 4、s和n如通式(V)中所定义。
方案九
本发明通式(VI)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2018097170-appb-000051
第一步，通式(IIB′)化合物与通式(VI-1)化合物和双(三氯甲基)碳酸酯在碱性条件下，发生反应得到通式(VI-2)化合物；
第二步，通式(VI-a)化合物与通式(IIB)化合物或其盐发生反应，得到通式(VI)化合物；
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、1M双三甲基硅基胺基锂四氢呋喃溶液、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、氢氧化钠、磷酸钾、碳酸钠、碳酸氢钠、碳酸钾或碳酸铯；
缩合剂包括但不限于1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷，优选为2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；
上述反应优选在溶剂中进行，所用溶剂包括但不限于：乙酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物；
其中：
R a为氢原子或烷基，优选为氢原子、甲基或乙基；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
环A、R 1、R 4、s和n如通式(I)中所定义。
方案十
本发明通式(VII)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2018097170-appb-000052
第一步，通式(VII-1)化合物与通式(III-1)化合物和双(三氯甲基)碳酸酯在碱性条件下，发生反应得到通式(VII-a)化合物；
第二步，通式(IV-a)化合物在碱性条件下，发生水解反应得到通式(VII-b)化合物；
第三步，通式(VII-b)化合物与通式(IIB)化合物或其盐，发生缩合反应，得到通式(VII)化合物；
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、1M双三甲基硅基胺基锂四氢呋喃溶液、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、氢氧化钠、磷酸钾、碳酸钠、碳酸氢钠、碳酸钾或碳酸铯；
缩合剂包括但不限于1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷，优选为2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；
上述反应优选在溶剂中进行，所用溶剂包括但不限于：乙酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物；
其中：
R a为烷基，优选为甲基或乙基；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
R 1、R 4、s和n如通式(I)中所定义。
方案十一
本发明通式(VIII)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2018097170-appb-000053
第一步，通式(VII-1)化合物与通式(IV-1)化合物和双(三氯甲基)碳酸酯在碱性条件下，发生反应得到通式(VIII-a)化合物；
第二步，通式(VIII-a)化合物在碱性条件下，发生水解反应得到通式(VIII-b)化合物；
第三步，通式(VIII-b)化合物与通式(IIB)化合物或其盐，发生缩合反应，得到通式(VIII)化合物；
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、1M双三甲基硅基胺基锂四氢呋喃溶液、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、氢氧化钠、磷酸钾、碳酸钠、碳酸氢钠、碳酸钾或碳酸铯；
缩合剂包括但不限于1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷，优选为2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；
上述反应优选在溶剂中进行，所用溶剂包括但不限于：乙酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物；
其中：
R a为烷基，优选为甲基或乙基；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
R 1、R 4、s和n如通式(I)中所定义。
方案十二
本发明通式(VII-A)或通式(VIII-A)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2018097170-appb-000054
通式(VII-a)化合物与通式(VII-B)化合物或其盐发生反应，得到通式(VII-A)化合物；或通式(VIII-a)化合物与通式(VII-B)化合物或其盐发生反应，得到通式(VIII-A)化合物；
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、1M双三甲基硅基胺基锂四氢呋喃溶液、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、氢氧化钠、磷酸钾、碳酸钠、碳酸氢钠、碳酸钾或碳酸铯；
缩合剂包括但不限于1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷，优选为2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；
上述反应优选在溶剂中进行，所用溶剂包括但不限于：乙酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物；
其中：
G为C或N；
R a为氢原子或烷基，优选为氢原子、甲基或乙基；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳 基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
R 8为烷基，优选为甲基；
R 9为烷基，其中所述的烷基任选进一步被一个或多个卤素所取代；
R 4和s如通式(I)中所定义。
具体实施方式
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商：Thermo，型号：Finnigan LCQ advantage MAX)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC1200VWD和Waters HPLC e2695-2489高压液相色谱仪。
手性HPLC分析测定使用Agilent 1260DAD高效液相色谱仪。
高效液相制备使用Waters 2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH & Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，C：石油醚/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
(R)-N 7-(3,4,5-三氟苯基)-N 1-(1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺
Figure PCTCN2018097170-appb-000055
第一步
1-溴-N-(3,4,5-三氟苯基)-5,6-二氢咪唑并[1,5-a]吡嗪-7(8H)-甲酰胺1c
将3,4,5-三氟苯胺1a(0.365g，2.48mmol，采用公知的方法“Tetrahedron Letters,51(17),2010,2265-2268”制备而得)和1-溴-5,6,7,8-四氢咪唑并[1,5-a]吡嗪1b(501.36mg，2.48mmol，上海书亚医药有限公司)溶解于30mL二氯甲烷中，再加入三乙胺(753.26mg，7.44mmol)和双(三氯甲基)碳酸酯(294.53mg，992.54μmol)，搅拌反应12小时。反应液减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，得标题化合物1c(300mg，产率：32.2％)。
MS m/z(ESI):376.1[M+1]。
第二步
7-((3,4,5-三氟苯基)氨基甲酰基)-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-1-羧酸甲酯1d
一氧化碳气氛下，将八羰基二钴(525.03mg，1.54mmol)、碳酸钾(1.06g，7.68mmol)溶解于20mL甲醇中，60℃条件下，搅拌反应15分钟。再加入化合物1c(300 mg，767.71μmol)和2-氯乙酸甲酯(499.88mg，4.61mmol)，搅拌反应8小时。反应液冷却至室温，过滤，滤液减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，得标题化合物1d(70mg，产率：21.8％)。
MS m/z(ESI):355.3[M+1]。
第三步
(R)-N 7-(3,4,5-三氟苯基)-N 1-(1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺
将化合物1d(70mg，197.58μmol)和(2R)-1,1,1-三氟丙基-2-胺盐酸盐1e(59.09mg，395.16μmol，采用专利申请“CN102875270A”公开的方法制备而得)溶解于10mL四氢呋喃中，于0℃，滴加0.988μL的1M双三甲基硅基胺基锂四氢呋喃溶液，加毕，缓慢升至室温，搅拌反应6小时。反应液减压浓缩，所得残余物中加入15mL水，用乙酸乙酯萃取(15mL×3)，合并有机相，减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，得标题化合物1(15mg，产率：17.4％)。
MS m/z(ESI):436.2[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.31(s,1H),8.30(d,1H),7.70(s,1H),7.25-7.31(m,2H),5.05(s,2H),4.78-4.86(m,1H),4.21-4.24(m,2H),3.94-3.96(m,2H),1.31-1.44(dd,3H)。
实施例2
(R)-N 5-(3,4-二氟苯基)-N 3-(1,1,1-三氟丙-2-基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺
Figure PCTCN2018097170-appb-000056
第一步
5-叔丁基3-甲基6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二羧酸酯2b
一氧化碳气氛下，将八羰基二钴(2.26g，6.62mmol)、碳酸钾(4.57g，33.09mmol)溶解于20mL甲醇中，于60℃，搅拌反应15分钟。再加入3-溴-6,7-二氢吡唑并[1,5-a]吡嗪-5(4H)-羧酸叔丁酯2a(1g，3.31mmol，采用公知的方法“ACS Medicinal  Chemistry Letters,2015,6(1),37-41”制备而得)和2-氯乙酸甲酯(2.15g，19.86mmol)，搅拌反应16小时。反应液减压浓缩，加入100mL乙酸乙酯，过滤，用100mL乙酸乙酯洗涤，滤液减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，得标题化合物2b(0.5g，产率：53％)。
MS m/z(ESI):282.1[M+1]。
第二步
4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-羧酸甲酯三氟乙酸盐2c
将化合物2b(600mg，2.13mmol)溶解于10mL的二氯甲烷中，加入三氟乙酸(2.43g，21.33mmol)，加毕，搅拌反应12小时。反应液减压浓缩，得粗品标题化合物2c(250mg)，产物不经纯化，直接用于下一步反应。
MS m/z(ESI):182.0[M+1]。
第三步
5-((3,4-二氟苯基)氨基甲酰基)-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-羧酸甲酯2e
将粗品化合物2c(200mg，1.10mmol)、3,4-二氟苯胺2d(142.51mg，1.10mmol)和三乙胺(335.08mg，3.31mmol)溶解于10mL四氢呋喃中，于0℃，加入双(三氯甲基)碳酸酯(114.64mg，386.33μmol)，缓慢升至室温，搅拌反应3小时。反应液减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，得标题化合物2e(100mg，产率：26.9％)。
MS m/z(ESI):337.4[M+1]。
第四步
(R)-N 5-(3,4-二氟苯基)-N 3-(1,1,1-三氟丙-2-基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺2
将化合物2e(100mg，297.36μmol)和化合物1e(133.40mg，892.08μmol)溶解于20mL四氢呋喃中，于0℃，滴加4.46mL的1M双三甲基硅基胺基锂四氢呋喃溶液，加毕，缓慢升至室温，搅拌反应3小时。反应液中加入2mL饱和氯化铵、10mL水，用乙酸乙酯萃取(20mL×2)，合并有机相，减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，所得粗品用高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：碳酸氢铵，水，乙腈)纯化，得标题化合物2(15mg，产率：12.1％)。
MS m/z(ESI):418.2[M+1]。
1H NMR(400MHz,CD 3OD)δ8.07(s,1H),7.51-7.46(m,1H),7.22-7.16(m,2H),5.05(s,2H),4.88-4.82(m,1H),4.29-4.26(m,2H),4.05-4.02(m,2H),1.42-1.40(m,3H)。
实施例3
(R)-N 7-(3-氰基-4-氟苯基)-N 1-(1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a]吡嗪 -1,7(8H)-二甲酰胺3
Figure PCTCN2018097170-appb-000057
第一步
(R)-1-((1,1,1-三氟丙-2-基)氨基甲酰基)-5,6-二氢咪唑并[1,5-a]吡嗪-7(8H)-甲酸叔丁酯3b
氩气氛下，将7-叔丁基1-甲基5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酸酯3a(469.78mg，1.67mmol，采用专利申请“US20110034443A1”公开的方法制备而得)和化合物1e(249.74mg，1.67mmol)溶解于20mL四氢呋喃中，冰水浴下，滴加3.3mL的1M双三甲基硅基胺基锂四氢呋喃溶液，反应温度升至室温，搅拌反应1小时。反应液减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，得标题化合物3b(130mg，产率：21.5％)。
MS m/z(ESI):363.2[M+1]。
第二步
(R)-N-(1,1,1-三氟丙-2-基)-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-1-甲酰胺三氟乙酸盐3c
依次将化合物3b(130mg，358.77μmol)和三氟乙酸(204.54mg，1.79mmol)溶解于2mL二氯甲烷中，搅拌反应2小时。反应液减压浓缩，得粗品标题化合物3c(135mg)，产物不经纯化，直接用于下一步反应。
第三步
(R)-N 7-(3-氰基-4-氟苯基)-N 1-(1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺3
将粗品化合物3c(50mg，190.67μmol)、5-氨基-2-氟苯甲腈3d(25.96mg，190.67μmol，采用公知的方法“Bioorganic & Medicinal Chemistry Letters,2006,16(19),5176-5182”制备而得)和三乙胺(28.94mg，286.01μmol)溶解于10mL四氢呋喃中，冰水浴下，加入双(三氯甲基)碳酸酯(28.29mg，95.34μmol)，搅拌反应1小时。反应液减压浓缩，残余物用高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：碳 酸氢铵，水，乙腈)纯化，得标题化合物3(2mg，产率：2.5％)。
MS m/z(ESI):425.1[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.22(s,1H),8.32(d,1H),7.95(d,1H),7.81-7.77(m,2H),7.47-7.43(m,1H),4.96(s,2H),4.81-4.74(m,1H),4.17-4.10(m,2H),3.89-3.86(m,2H),1.39-1.35(dd,3H)。
实施例4
(R)-N 5-(3,4,5-三氟苯基)-N 3-(1,1,1-三氟丙-2-基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺4
Figure PCTCN2018097170-appb-000058
第一步
5-((3,4,5-三氟苯基)氨基甲酰基)-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-羧酸甲酯4a
将化合物2c(100mg，338.74μmol)、化合物1a(49.83mg，338.74μmol)和三氟乙酸(342.77mg，3.39mmol)溶解于10mL四氢呋喃中，于0℃，加入双(三氯甲基)碳酸酯(35.18mg，118.56 3μmol)，缓慢升至室温，搅拌反应3小时。反应液减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，得标题化合物4a(50mg，产率：25.0％)。
MS m/z(ESI):355.1[M+1]。
第二步
(R)-N 5-(3,4,5-三氟苯基)-N 3-(1,1,1-三氟丙-2-基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺4
将化合物4a(50mg，141.13μmol)和1e(63.31mg，423.39μmol)溶解于20mL四氢呋喃中，于0℃，滴加2.12mL的1M双三甲基硅基胺基锂四氢呋喃溶液，加毕，缓慢升至室温，搅拌反应3小时。反应液中加入2mL饱和氯化铵、10mL水，用乙酸乙酯萃取(20mL×2)，合并有机相，减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，所得粗品用高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：碳酸氢铵，水，乙腈)纯化，得标题化合物4(5mg，产率：4％)。
MS m/z(ESI):436.0[M+1]。
1H NMR(400MHz,CD 3OD)δ8.07(s,1H),7.30-7.26(m,2H),5.04(s,2H),4.88-4.82(m,1H),4.28-4.26(m,2H),4.04-4.01(m,2H),1.42-1.40(m,3H)。
实施例5
(R)-N 7-(3,4-二氟苯基)-N 1-(1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺5
Figure PCTCN2018097170-appb-000059
第一步
7-((3,4-二氟苯基)氨基甲酰基)-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-1-羧酸乙酯5b
将5,6,7,8-四氢咪唑并[1,5-a]吡嗪-1-羧酸乙酯5a(100mg，512.25μmol，采用专利申请“CN102464661A”公开的方法制备而得)和化合物2d(79.36mg，614.70μmol)加入20mL四氢呋喃中，冰水浴条件下，加入双(三氯甲基)碳酸酯(76.01mg，256.13μmol)，升至室温搅拌反应1小时。反应液减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，得标题化合物5b(110mg，产率：61.3％)。
MS m/z(ESI):351.1[M+1]。
第二步
(R)-N 7-(3,4-二氟苯基)-N 1-(1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺5
将化合物5b(75mg，214.09μmol)和化合物1e(48.02mg，321.14μmol)加入至20mL四氢呋喃中，冰水浴条件下，加入双三甲基硅基胺基锂(107.47mg，642.27μmol)，搅拌反应1小时。反应液减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，所得粗品用高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：碳酸氢铵，水，乙腈)纯化，得标题化合物5(20mg，产率：30.4％)。
MS m/z(ESI):418.2[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.09(s,1H),8.31(d,1H),7.76(s,1H),7.64-7.60(m,1H),7.34-7.23(m,2H),4.94(s,2H),4.79-4.77(m,1H),4.16-4.14(m,2H),3.88-3.85(m,2H),1.37-1.35(dd,3H)。
实施例6
(S)-N 7-(3,4-二氟苯基)-6-甲基-N 1-((R)-1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a] 吡嗪-1,7(8H)-二甲酰胺6
Figure PCTCN2018097170-appb-000060
第一步
(S)-5-(((1-羟丙基-2-基)(4-甲氧基苄基)氨基)甲基)-1H-咪唑-4-羧酸甲酯6c
将(S)-2-((4-甲氧基苄基)氨基)丙-1-醇6a(34.92g，179.08mmol，采用公知的方法“Bioorganic & Medicinal Chemistry Letters,2015,25(5),1086-1091”制备而得)溶解于600mL四氢呋喃中，再加入5-醛基咪唑-4-甲酸甲酯6b(23g，149.23mmol，采用专利申请“US2008/318935”公开的方法制备而得)，分批加入三乙酰氧基硼氢化钠(47.44g，223.85mmol)，搅拌反应12小时。反应液过滤，滤液减压浓缩，所得残余物中加入600mL乙酸乙酯，用水洗涤(200mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，得粗品标题化合物6c(40g)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):334.2[M+1]。
第二步
(S)-7-(4-甲氧基苄基)-6-甲基-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-1-羧酸甲酯6d
将粗品化合物6c(11g，33.03mmol)和三苯基膦(12.98g，49.49mmol)(国药试剂)溶解于400mL四氢呋喃中，冰浴下缓慢滴加入偶氮二甲酸二异丙酯(10g，49.45mmol，上海韶远试剂有限公司)，缓慢升至室温，搅拌反应12小时。反应液减压浓缩，所得残余物中加入400mL乙酸乙酯，用水洗涤(100mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物用硅胶柱色谱法以洗脱剂体系A纯化，得标题化合物6d(4.5g，产率：43.2％)。
MS m/z(ESI):315.9[M+1]。
第三步
(S)-6-甲基-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-1-羧酸甲酯三氟乙酸盐6e
将化合物6d(0.6g，2.33mmol)溶解于2mL三氟乙酸中，微波加热至100℃，反应5分钟。反应液冷却至室温，减压浓缩，得粗品标题化合物6e(0.6g)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):196.1[M+1]。
第四步
(S)-7–((3,4-二氟苯基)氨基甲酰基)-6-甲基-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-1-羧酸甲酯6f
将粗品化合物6e(240mg，776.09μmol)溶解于15mL四氢呋喃中，加入化合物2d(150.3mg，1.16mmol)和三乙胺(314.13mg，3.10mmol)，冰浴下加入双(三氯甲基)碳酸酯(92.12mg，310.44μmol)，升至室温搅拌反应12小时。反应液减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，得标题化合物6f(0.19g，产率：69.9％)。
MS m/z(ESI):351.1[M+1]。
第五步
(S)-N 7-(3,4-二氟苯基)-6-甲基-N 1-((R)-1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺6
将化合物6f(190mg，542.36μmol)溶解于20mL四氢呋喃中，加入化合物1e(121.66mg，813.54μmol)，冰浴下滴加4mL的1M双三甲基硅基胺基锂四氢呋喃溶液，加毕，搅拌反应2小时。反应液中加入10mL水，用乙酸乙酯萃取(20mL×2)，合并有机相，减压浓缩，所得残余物用高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：碳酸氢铵，水，乙腈)纯化，得标题化合物6(25mg，产率：10.6％)。
MS m/z(ESI):432.1[M+1]。
1H NMR(400MHz,DMSO-d 6)δ9.28(s,1H),8.25(d,1H),7.73(s,1H),7.54-7.45(m,1H),7.21-7.15(m,2H),5.27(s,1H),4.95-4.92(m,1H),4.86-4.80(m,2H),4.28-4.22(m,2H),1.50-1.45(m,3H),1.20(d,3H)。
实施例7
(S)-N 5-(3,4-二氟苯基)-6-甲基-N 3-((R)-1,1,1-三氟丙-2-基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺7
Figure PCTCN2018097170-appb-000061
第一步
(S)-5-叔丁基3-甲基6-甲基-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二羧酸酯7b
一氧化碳气氛下，将(S)-3-碘-6-甲基-6,7-二氢吡唑并[1,5-a]吡嗪-5(4H)-羧酸叔丁酯7a(8.3g，22.85mmol，采用专利申请“WO2016113273A1”公开的方法制备)、醋酸钯(1.03g，4.57mmol)、1,1'-双(二苯基膦)二茂铁(2.53g，4.57mmol)和三乙胺(9.64mL，68.56mmol)溶解于150mL甲醇中，于55℃，搅拌反应15小时。反应液通过硅藻土过滤，滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系C纯化，得标题化合物7b(6.3g，产率：93.34％)。
第二步
(S)-6-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-羧酸甲酯三氟乙酸盐7c
将化合物7b(6.3g，21.33mmol)溶解于20mL二氯甲烷，加入三氟乙酸(14.1mL，190.91mmol)，搅拌反应2小时。反应液减压浓缩，得粗品标题化合物7c(14g)，产物不经纯化，直接用于下一步反应。
MS m/z(ESI):196.1[M+1]。
第三步
(S)-5-((3,4-二氟苯基)氨基甲酰基)-6-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-羧酸甲酯7e
将粗品化合物7c(2g，3.23mmol)、三乙胺(1.64g，16.17mmol)溶解于20mL二氯甲烷中，搅拌10分钟。冰浴条件下，加入1,2-二氟-4-苯异氰酸酯(601.87mg，3.88mmol，采用公知的方法“European Journal of Medicinal Chemistry,2016,115,1-13”制备)，反应20分钟。反应温度上升至室温，搅拌反应20分钟。反应液依次用硅胶柱色谱法以洗脱剂体系C和A纯化，得标题化合物7e(1g，产率：88.27％)。
MS m/z(ESI):351.1[M+1]。
第四步
(S)-5-((3,4-二氟苯基)氨基甲酰基)-6-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-羧酸7f
将化合物7e(500mg，1.43mmol)、氢氧化钠(285.45mg，7.14mmol)溶解于5mL甲醇、四氢呋喃和水混合溶剂中(V:V:V＝2:2:1)。于40℃，搅拌反应1小时。再于35℃，搅拌反应15小时。反应液减压浓缩，加入10mL水，滴加6M盐酸于上述溶液至pH为2，过滤，收集滤饼，得粗品标题化合物7f(450mg)，产物不经纯化，直接用于下一步反应。
MS m/z(ESI):337.4[M+1]。
第五步
(S)-N 5-(3,4-二氟苯基)-6-甲基-N 3-((R)-1,1,1-三氟丙-2-基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺7
将粗品化合物7f(80mg，237.89μmol)、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(67.16mg，285.47μmol)、N,N-二异丙基乙胺(122.98mg，951.55μmol)溶解于3mL N,N-二甲基甲酰胺中，反应10分钟，加入化合物1e(53.36mg，356.83μmol)，搅拌反应3小时。反应液减压浓缩，所得残余物用薄层色谱法以展开剂体系C纯化，所得粗品用高效液相制备(Waters-2767，洗脱体系：碳酸氢铵，水，乙腈)纯化，得标题化合物7(70mg，产率：68.22％)。
MS m/z(ESI):432.1[M+1]。
1H NMR(400MHz,CD 3OD)δ8.09(m,1H),7.49-7.47(m,1H),7.16-7.13(m,2H),5.32(d,1H),5.01-4.99(m,1H),4.84-4.80(m,1H),4.66(d,1H),4.32-4.29(m,1H),4.17(d,1H),1.40(d,3H),1.21(d,3H)。
实施例8
(S)-N 3-(叔丁基)-N 5-(3,4-二氟苯基)-6-甲基-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺8
Figure PCTCN2018097170-appb-000062
将粗品化合物7f(150mg，446.04μmol)、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(157.41mg，669.06μmol)、N,N-二异丙基乙胺(230.58mg，1.78mmol)溶解于3mL N,N-二甲基甲酰胺中，反应10分钟，加入叔丁胺(48.93mg，669.06μmol)，搅拌反应3小时。反应液加入30mL水，乙酸乙酯(30mL×2)萃取，合并有机相，有机相减压浓缩，所得残余物用薄层色谱法以展开剂体系C纯化，所得粗品用高效液相制备(Waters-2767，洗脱体系：碳酸氢铵，水，乙腈)纯化，得标题化合物8(30mg，产率：17.18％)。
MS m/z(ESI):392.2[M+1]。
1H NMR(400MHz,CD 3OD)δ8.02(s,1H),7.53-7.50(m,1H),7.20-7.17(m,2H),5.31(d,1H),5.01-4.98(m,1H),4.68(d,1H),4.33-4.29(m,1H),4.18(d,1H),1.46(s,9H),1.23(d,3H)。
实施例9
(R)-N 5-(3-氰基-4-氟苯基)-N 3-(1,1,1-三氟丙-2-基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺9
Figure PCTCN2018097170-appb-000063
第一步
5-(3-氰基-4-氟苯基)氨基甲酰基)-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-羧酸甲酯9a
将化合物2c(50mg，275.95μmol)、化合物3d(38.56mg，275.95μmol)和三乙胺(279.23mg，2.76mmol)溶解于10mL四氢呋喃中，0℃下，加入双(三氯甲基)碳酸酯(32.76mg，110.38μmol)，缓慢升至室温，搅拌反应3小时。反应液减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，得标题化合物9a(20mg，产率：21.1％)。
MS m/z(ESI):344.2[M+1]。
第二步
5-(3-氰基-4-氟苯基)氨基甲酰基)-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-甲酸9b
将化合物9a(100mg，291.28μmol)溶于10mL甲醇中，加入氢氧化锂(139.52mg，5.83mmol)和2mL水，搅拌反应3小时。反应液减压浓缩，加入10mL水，滴加6M盐酸于上述溶液至pH为2，反应液减压浓缩，得粗品标题化合物9b(95.91mg)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):330.1[M+1]。
第三步
(R)-N 5-(3-氰基-4-氟苯基)-N 3-(1,1,1-三氟丙-2-基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺9
将粗品化合物9b(95.91mg，291.28μmol)溶于10mL N,N-二甲基甲酰胺中，加入化合物1e(34.34mg，303.69μmol)，三乙胺(92.19mg，911.06μmol)，0℃加入O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(85.74mg，364.43μmol)，搅拌反应12小时。反应液减压浓缩，所得残余物用高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：碳酸氢铵，水，乙腈)纯化，得标题化合物9(5mg，产率：3.88％)。
MS m/z(ESI):425.1[M+1]。
1H NMR(400MHz,CD 3OD)δ8.07(s,1H),7.87-7.85(m,2H),7.32-7.27(m,1H), 5.06(s,2H),4.86-4.84(m,1H),4.29-4.27(m,2H),4.06-4.03(m,2H),1.42(d,3H)。
实施例10
(S)-N 3-(叔丁基)-6-甲基-N 5-((3,4,5-三氟苯基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺10
Figure PCTCN2018097170-appb-000064
第一步
(S)-6-甲基-5-((3,4,5-三氟苯基)氨基甲酰基)-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-羧酸甲酯10a
将化合物1a(1.17g，7.92mmol)和化合物7c(1.63g，5.28mmol)溶解于30mL二氯甲烷中，再加入三乙胺(2.14g，21.22mmol)和双(三氯甲基)碳酸酯(626.8mg，2.11mmol)，搅拌反应2小时。反应液减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，得标题化合物10a(730mg，产率：37.5％)。
MS m/z(ESI):369.1[M+1]。
第二步
(S)-6-甲基-5-((3,4,5-三氟苯基)氨基甲酰基)-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-羧酸10b
将化合物10a(730mg，1.98mmol)、氢氧化钠(396.45mg，9.91mmol)溶解于10mL甲醇、四氢呋喃和水混合溶剂中(V:V:V＝2:2:1)，于40℃搅拌反应1小时，再于35℃，搅拌反应15小时。反应液减压浓缩，加入10mL水，滴加6M盐酸于上述溶液至pH为2，过滤，收集滤饼，得粗品标题化合物10b(702mg，1.98mmol)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):355.4[M+1]。
第三步
(S)-N 3-(叔丁基)-6-甲基-N 5-(3,4,5-三氟苯基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二
甲酰胺10
将粗品化合物10b(85mg，239.92μmol)、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(67.74mg，287.91μmol)、N,N-二异丙基乙胺(129.21mg，719.76μmol)溶解于3mL N,N-二甲基甲酰胺中，反应10分钟，加入叔丁胺(35.09mg，479.84μmol)，搅拌反应3小时。反应液减压浓缩，所得残余物用薄层色谱法以展开剂体系C纯化，所得粗品用高效液相制备(Waters-2767，洗脱体系：碳酸氢铵，水，乙腈)纯化，得标题化合物10(50mg，产率：50.90％)。
MS m/z(ESI):410.2[M+1]。
1H NMR(400MHz,CD 3OD)δ8.00(s,1H),7.30-7.28(m,2H),5.31(d,1H),4.98-4.96(m,1H),4.69(d,1H),4.31-4.27(m,1H),4.17(d,1H),1.44(s,9H),1.22(d,3H)。
实施例11
(S)-N 7-(3-氰基-4-氟苯基)-6-甲基-N 1-((R)-1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7-(8H)-二甲酰胺11
Figure PCTCN2018097170-appb-000065
第一步
(S)-7-((3-氰基-4-氟苯基)氨基甲酰基)-6-甲基-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-1-羧酸甲酯11a
将粗品化合物6e(9.2g，47.13mmol)溶解于50mL四氢呋喃中，加入化合物3d(6.5g，47.13mmol)和三乙胺(5.82g，56.55mmol)，于0℃，加入双(三氯甲基)碳酸酯(4.9g，16.49mmol)，缓慢升至室温，搅拌反应12小时。反应液过滤，滤液减压浓缩，得粗品标题化合物11a(16.84g)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):358.1[M+1]。
第二步
(S)-7-((3-氰基-4-氟苯基)氨基甲酰基)-6-甲基-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-1-甲酸11b
将粗品化合物11a(16.84g，47.13mmol)溶解于50mL甲醇中，于0℃下，滴加入预制的氢氧化钠溶液(氢氧化钠(12g，282.76mmol)溶于60mL水)，缓慢升至室温，搅拌反应4小时。反应液减压浓缩除去有机溶剂，所得残余物用二氯甲烷洗涤，用6M盐酸调节水相pH为1至2，减压浓缩，得粗品标题化合物11b(16.18g)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):344.1[M+1]。
第三步
(S)-N 7-(3-氰基-4-氟苯基)-6-甲基-N 1-((R)-1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7-(8H)-二甲酰胺11
将粗品化合物11b(13g，37.87mmol)、化合物1e(7.4g，49.23mmol)和三乙胺(11.6g，113.6mmol)溶解于200mL N,N-二甲基甲酰胺中，冷却到0℃，加入O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(29g，75.73mmol)，缓慢升至室温，搅拌反应12小时。反应液加入300mL乙酸乙酯，水洗(100mL×3)，有机相减压浓缩，所得残余物用高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：碳酸氢铵，水，乙腈)纯化，得标题化合物11(1.8g，产率：10.8％)。
MS m/z(ESI):439.0[M+1]。
1H NMR(400MHz,CD 3OD)δ7.87-7.85(m,1H),7.73-7.70(m,2H),7.69-7.27(m,1H),5.30-5.26(d,1H),4.83-4.82(m,1H),4.85-4.72(m,2H),4.23-4.21(m,2H),1.43(d,3H),1.20(d,3H)。
实施例12
(S)-N 1–(叔丁基)-N 7-(3,4-二氟苯基)-6-甲基-5,6-二氢咪唑并[1,5-a]吡嗪-1,7-(8H)-二甲酰胺12
Figure PCTCN2018097170-appb-000066
将化合物6f(2.11g，6.27mmol)溶于15mL四氢呋喃中，加入叔丁胺(600mg，8.16mmol)，0℃下，滴加1M双三甲基硅基胺基锂四氢呋喃溶液(5g，31.37mmol)，搅拌反应2小时。反应液中加水100mL，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。所得残余物用高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：碳酸氢铵，水，乙腈)纯化，得标题化合物12(120 mg，产率：4.9％)。
MS m/z(ESI):392.1[M+1]。
1H NMR(400MHz,CD 3OD)δ7.65(s,1H),7.50-7.49(m,1H),7.19-7.17(m,2H),5.25-5.21(d,1H),4.92-4.90(m,1H),4.77-4.73(m,1H),4.20-4.18(m,2H),1.46(s,9H),1.19-1.17(d,3H)。
实施例13(S)-6-甲基-N 1-(3-甲基氧杂环丁烷-3-基)-N 7-(3,4,5-三氟苯基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺13
Figure PCTCN2018097170-appb-000067
第一步
(S)-6-甲基-7-((3,4,5-三氟苯基)氨基甲酰基)-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-1-甲酸甲酯13a
将粗品化合物6e(140.00mg，452.72μmol)溶解于15mL四氢呋喃中，加入化合物1a(99.89mg，679.08μmol)和三乙胺(183.24mg，1.81mmol)，于0℃，加入双(三氯甲基)碳酸酯(53.74mg，181.09μmol)，缓慢升至室温，搅拌反应12小时。反应液减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，得标题化合物13a(88mg，产率：52.8％)。
MS m/z(ESI):369.1[M+1]。
第二步(S)-6-甲基-7-((3,4,5-三氟苯基)氨基甲酰基)-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-1-羧酸13b
将化合物13a(75mg，203.63μmol)溶于10mL甲醇中，加入氢氧化钠(81.45mg，2.04mmol)和2mL水，搅拌反应3小时。反应液减压浓缩，得粗品标题化合物13b(75mg)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):355.0[M+1]。
第三步
(S)-6-甲基-N 1-(3-甲基氧杂环丁烷-3-基)-N 7-(3,4,5-三氟苯基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺13
将粗品化合物13b(75mg，211.69μmol)溶于10mL N,N-二甲基甲酰胺中，加入3-甲基-3-氨基氧杂环丁烷13c(27.66mg，317.53μmol，上海书亚医药科技有限公司)和三乙胺(64.26mg，635.07μmol)，0℃下，加入O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(99.61mg，423.38μmol)，室温搅拌反应12小时。反应液减压浓缩，所得残余物用高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：碳酸氢铵，水，乙腈)纯化，得标题化合物13(16mg，产率：17.9％)。
MS m/z(ESI):424.0[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.87(s,1H),8.36(s,1H),7.68(s,1H),7.33-7.27(m,2H),5.27-5.20(m,1H),4.92(d,2H),4.73(d,2H),4.78-4.73(m,1H),4.52(d,2H),4.26-4.20(m,2H),1.73(s,3H),1.20(d,3H)。
实施例14
(S)-6-甲基-N 3-(3-甲基氧杂环丁烷-3-基)-N 5-(3,4,5-三氟苯基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺14
Figure PCTCN2018097170-appb-000068
将粗品化合物10b(100mg，282.26μmol)、化合物13c(36.89mg，423.39μmol)、N,N-二异丙基乙胺(42.84mg，423.39μmol)溶解于10mL N,N-二甲基甲酰胺中，加入O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(79.69mg，338.71μmol)，搅拌反应1小时。反应液减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，所得粗品用高效液相制备(Waters-2767，洗脱体系：碳酸氢铵，水，乙腈)纯化，得标题化合物14(80mg，产率：66.94％)。
MS m/z(ESI):424.5[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.89(s,1H),8.37(s,1H),7.99(s,1H),7.33-7.17(m,2H),5.33(d,1H),5.00-4.98(m,1H),4.88(d,2H),4.71(d,1H),4.52(d,2H),4.34-4.31(m,1H),4.21-4.18(m,1H),1.72(s,3H),1.25(d,3H)。
实施例15
(S)-N 5-(3-氰基-4-氟苯基)-6-甲基-N 3-((R)-1,1,1-三氟丙-2-基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺15
Figure PCTCN2018097170-appb-000069
第一步
(S)-5-(叔丁氧基羰基)-6-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-甲酸15a
将化合物7b(525mg，1.78mmol)、一水合氢氧化锂(373mg，8.9mmol)溶解于10mL甲醇、四氢呋喃和水混合溶剂中(V:V:V＝2:2:1)，搅拌反应16小时。反应液减压浓缩，加入10mL水，滴加6M盐酸于上述溶液至pH为2，用乙酸乙酯萃取(20mL×2)，合并有机相，减压浓缩，得粗品标题化合物15a(500mg)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):282.2[M+1]。
第二步
(S)-6-甲基-3-(((R)-1,1,1-三氟丙-2-基)氨基甲酰基)-6,7-二氢吡唑并[1,5-a]吡嗪-5(4H)-羧酸叔丁酯15b
将粗品化合物15a(500mg，1.78mmol)、化合物1e(479mg，3.2mmol)和N,N-二异丙基乙胺(360mg，3.56mmol)溶解于20mL N,N-二甲基甲酰胺中，加入O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(628mg，2.67mmol)，搅拌反应2小时。反应液减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，得标题化合物15b(600mg，产率：89.56％)。
MS m/z(ESI):377.2[M+1]
第三步
(S)-6-甲基-N-((R)-1,1,1-三氟丙-2-基)-4,5,6,7-四氢吡唑并[1,5-a]哌嗪-3-甲酰胺三氟乙酸盐15c
将化合物15b(500mg，1.33mmol)溶解于20mL二氯甲烷，加入三氟乙酸(758mg，6.65mmol)，搅拌反应2小时。反应液减压浓缩，得粗品标题化合物15c(500 mg)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):277.2[M+1]。
第四步
(S)-N 5-(3-氰基-4-氟苯基)-6-甲基-N 3-((R)-1,1,1-三氟丙-2-基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺15
将粗品化合物15c(50mg，128μmol)溶解于10mL四氢呋喃中，加入化合物3d(26mg，192μmol)和三乙胺(26mg，256μmol)，于0℃，加入双(三氯甲基)碳酸酯(13mg，45μmol)，升至室温搅拌反应1小时。反应液减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，所得粗品用高效液相制备(Waters-2767，洗脱体系：碳酸氢铵，水，乙腈)纯化，得标题化合物15(20mg，产率：35.61％)。
MS m/z(ESI):439.2[M+1]。
1H NMR(400MHz,CDCl 3)δ7.87-7.86(m,1H),7.83(s,1H),7.70-7.68(m,1H),7.42(s,1H),7.20-7.16(m,1H),6.01(d,1H),5.34-5.23(m,2H),4.92-4.89(m,1H),4.84(d,1H),4.38-4.34(m,1H),4.25(d,1H),1.49(d,3H),1.27(d,3H)。
实施例16
(S)-N 5-(2,6-二氟吡啶-4-基)-6-甲基-N 3-((R)-1,1,1-三氟丙-2-基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺16
Figure PCTCN2018097170-appb-000070
第一步
2,6-二氟-4-吡啶异氰酸酯16b
将2,6-二氟-4-氨基吡啶16a(500mg，3.84mmol)、N,N-二异丙基乙胺(583mg，5.76mmol)溶解于25mL甲苯，加入双(三氯甲基)碳酸酯(297mg，4.61mmol)，110℃下搅拌反应4小时。反应液减压浓缩，得粗品标题化合物16b(1g)，产物不经纯化直接用于下一步反应。
第二步
(S)-N5-(2,6-difluoropyridin-4-yl)-6-methyl-N3-((R)-1,1,1-trifluoropropan-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
(S)-N 5-(2,6-二氟吡啶-4-基)-6-甲基-N 3-((R)-1,1,1-三氟丙-2-基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺16
将粗品化合物15c(100mg，256μmol)溶解于10mL二氯甲烷中，加入粗品化合物16b(80mg)和三乙胺(78mg，769μmol)，搅拌反应2小时。反应液减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，所得粗品用高效液相制备(Waters-2767，洗脱体系：碳酸氢铵，水，乙腈)纯化，得标题化合物16(20mg，产率：18.05％)。
MS m/z(ESI):433.5[M+1]
1H NMR(400MHz,CDCl 3)δ8.19(s,1H),7.84(s,1H),7.31(s,1H),7.10(s,1H),6.05(d,1H),5.34(d,1H),5.27-5.25(m,1H),4.90-4.88(m,1H),4.84(d,1H),4.38-4.34(m,1H),4.28(d,1H),1.48(d,3H),1.29(d,3H)。
实施例17
(R)-N 5-(3,4,5-三氟苯基)-N 3-(1,1,1-三氟丙-2-基)-6,7-二氢-[1,2,3]三氮唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺17
Figure PCTCN2018097170-appb-000071
第一步
(5-((3,4,5-三氟苯基)氨基甲酰基)-4,5,6,7-四氢-[1,2,3]三氮唑并[1,5-a]吡嗪-3-基)甲基乙酸酯17b
将(4,5,6,7-四氢-[1,2,3]三氮唑并[1,5-a]吡嗪-3-基)甲基乙酸酯17a(350mg，2mmol)(采用公知的方“Journal of Medicine Chemistry，2014,57(9),3687-3706”制备)、二异丙基乙胺(790mg，6mmol)溶解于20mL二氯甲烷中，搅拌10分钟。冰浴下，加入1,2,3-三氟-5-苯异氰酸酯17f(400mg，2mmol，百灵威科技有限公司)，反应20分钟，升温至室温，搅拌反应20分钟。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系C和A纯化，得标题化合物17b(190mg，产率：25.24％)。
MS m/z(ESI):370.1[M+1]。
第二步
3-(羟甲基)-N-(3,4,5-三氟苯基)-6,7-二氢-[1,2,3]三氮唑并[1,5-a]吡嗪-5(4H)-甲酰胺17c
将化合物17b(190mg，0.51mmol)溶解于5mL甲醇和水(V:V＝4:1)的混合溶剂中，加入氢氧化锂(108mg，2.57mmol)，搅拌2小时。反应液中加水20mL，乙酸乙酯萃取(15mL×3)，合并有机相，减压浓缩，得粗品标题化合物17c(65mg)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):328.1[M+1]。
第三步
3-甲酰基-N-(3,4,5-三氟苯基)-6,7-二氢-[1,2,3]三氮唑并[1,5-a]吡嗪-5(4H)-甲酰胺17d
将粗品化合物17c(65mg，0.2mmol)溶解于5mL二氯甲烷中，加入氯铬酸吡啶盐(138mg，0.64mmol)和硅胶(140mg，100-200目)，搅拌3小时。过滤，减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，得标题化合物17d(30mg，产率：43.12％)。
MS m/z(ESI):326.1[M+1]。
第四步
(5-((3,4,5-三氟苯基)氨基甲酰基)-4,5,6,7-四氢-[1,2,3]三氮唑并[1,5-a]吡嗪-3-羧酸17e
将化合物17d(30mg，0.1mmol)溶解于5mL乙腈和水混合溶剂中(V:V＝3:2)，加入氨基磺酸(20mg，0.2mmol)，搅拌10分钟，加入亚氯酸钠(20mg，0.2mmol)，搅拌2小时。依次加入0.5mL饱和亚硫酸钠溶液和10mL水，乙酸乙酯萃取(10mL×3)，合并有机相，减压浓缩，得粗品化合物17e(25mg)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):342.1[M+1]。
第五步
(R)-N 5-(3,4,5-三氟苯基)-N 3-(1,1,1-三氟丙-2-基)-6,7-二氢-[1,2,3]三氮唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺17
将粗品化合物17e(25mg，73.2μmol)、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(35mg，146.5μmol)、N,N-二异丙基乙胺(47mg，366.2μmol)溶解于3mL N,N-二甲基甲酰胺中，反应10分钟，加入化合物1e(33mg，220μmol)，搅拌反应3小时。反应液减压浓缩，所得残余物用薄层色谱法以展开剂体系C纯化，得标题化合物17(5mg，产率：15.6％)。
MS m/z(ESI):437.1[M+1]。
1H NMR(400MHz,CD 3OD)δ7.29-7.27(m,2H),4.60(br,1H),4.54(t,2H),4.04(t,2H),2.80(s,2H),1.45(d,3H)。
实施例18
(S)-6-甲基-N 7-(3,4,5-三氟苯基)-N 1-((R)-1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺18
Figure PCTCN2018097170-appb-000072
采用实施例6合成路线，将第四步原料化合物2d替换为原料化合物1a，制得标题化合物18(2.8mg)。
MS m/z(ESI):450.2[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.86(s,1H),8.33(d,1H),7.73(s,1H),7.33-7.28(m,2H),5.29(d,1H),4.92(d,1H),4.85-4.76(m,2H),4.28-4.22(m,2H),1.44(d,3H),1.34(d,3H)。
实施例19
N 3-(3-甲基氧杂环丁烷-3-基)-N 5-(3,4,5-三氟苯基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺19
Figure PCTCN2018097170-appb-000073
第一步
5-((3,4,5-三氟苯基)氨基甲酰基)-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-甲酸19a
将化合物4a(3g，8.74mmol)溶于20mL甲醇和20mL四氢呋喃中，加入氢氧化钠(3.39g，84.67mmol)和10mL水，搅拌反应16小时。反应液减压浓缩，加入20mL水，滴加6M盐酸于上述溶液至pH为2，反应液减压浓缩，得粗品标题化合物19a(100mg)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):341.1[M+1]。
第二步
(N 3-(3-甲基氧杂环丁烷-3-基)-N 5-(3,4,5-三氟苯基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺19
将粗品化合物19a(100mg，293.90μmol)、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(69.14mg，293.90μmol)、三乙胺(29.74mg，293.90μmol)溶解于5mL N,N-二甲基甲酰胺中，反应10分钟，加入化合物13c(108.96mg，881.69μmol)，搅拌反应3小时。反应液加入10mL水，乙酸乙酯(20mL×2)萃取，合并有机相，减压浓缩，所得残余物用薄层色谱法以展开剂体系C纯化，所得粗品用高效液相制备(Waters-2767，洗脱体系：碳酸氢铵，水，乙腈)纯化，得标题化合物19(20mg，产率：16.62％)。
MS m/z(ESI):410.1[M+1]。
1H NMR(400MHz,CD 3OD)δ7.95(s,1H),7.30-7.26(m,2H),5.01(s,2H),4.88(d,2H),4.50(d,2H),4.28-4.25(m,2H),4.04-4.01(m,2H),1.71(s,3H)。
实施例20
(S)-N 7-(2,6-二氟吡啶-4-基)-6-甲基N 1-((R)-1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7-(8H)-二甲酰胺20
Figure PCTCN2018097170-appb-000074
采用实施例6合成路线，将第四步原料化合物2d替换为原料2,6-二氟-4-吡啶胺(上海毕得医药科技有限公司)，制得标题化合物20(10mg)。
MS m/z(ESI):433.1[M+1]。
1H NMR(400MHz,CD 3OD)δ7.69(s,1H),7.11-7.09(d,2H),5.33-5.29(m,1H),4.97-4.77(m,1H),4.56-4.41(m,1H),4.27-4.21(m,1H),3.80-3.45(m,2H),1.38(d,3H),1.15(d,3H)。
实施例21
(R)-N 3-(仲丁基)-N 5-(3,4,5-三氟苯基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺21
Figure PCTCN2018097170-appb-000075
将化合物19a(96mg，282.26μmol)溶于10mL N,N-二甲基甲酰胺中，加入(R)-丁-2-胺(20.64mg，282.26μmol，梯希爱(上海)化成工业发展有限公司)和三乙胺(85.69mg，846.78μmol)，0℃下，加入O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(79.69mg，338.71μmol)，升温到室温，反应12小时。反应液减压浓缩，所得残余物用高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：碳酸氢铵，水，乙腈)纯化，得标题化合物21(10mg，产率：8.96％)。
MS m/z(ESI):396.1[M+1]。
1H NMR(400MHz,CD 3OD)δ8.00(s,1H),7.30-7.26(m,2H),5.04(s,2H),4.27-4.25(m,2H),4.04-4.00(m,3H),1.60-1.56(m,2H),1.22(d,3H),0.96(t,3H)。
实施例22
(S)-N 3-((R-仲-丁基))-N 5-(3,4-二氟苯基)-6-甲基-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺22
Figure PCTCN2018097170-appb-000076
采用实施例7的合成路线，将原料化合物1e替换为原料化合物(R)-丁-2-胺，制得标题化合物22(20mg)。
MS m/z(ESI):392.1[M+1]。
1H NMR(400MHz,CDCl 3)δ7.69(s,1H),7.53-7.50(m,1H),7.23(s,1H),7.06-7.02(m,2H),5.62(d,1H),5.23(d,2H),4.82(d,1H),4.31-4.28(m,1H),4.28(d,1H),4.07(d,1H),1.60-1.57(m,2H),1.22(d,6H),0.99(t,3H)。
实施例23
(S)-N 5-(3,4-二氟苯基)-N 3-异丙基-6-甲基-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺23
Figure PCTCN2018097170-appb-000077
采用实施例7的合成路线，将第五步原料化合物1e替换为原料异丙胺，制得标题化合物23(25mg)。
MS m/z(ESI):378.1[M+1]。
1H NMR(400MHz,CD 3OD)δ8.00(s,1H),7.50-7.45(m,1H),7.18-7.14(m,2H),5.35-5.30(m,1H),4.99-4.95(m,1H),4.69-4.62(m,1H),4.32-4.22(m,1H),4.22-4.12(m,2H),1.23-1.16(m,9H)。
实施例24
(S)-N 5-(3,4-二氟苯基)-N 3-(1-甲氧基-2-甲基丙烷-2-基)-6-甲基-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺24
Figure PCTCN2018097170-appb-000078
采用实施例7的合成路线，将第五步原料化合物1e替换为原料1-甲氧基-2-甲基丙烷-2-胺(国药上海化学试剂)，制得标题化合物24(15mg)。
MS m/z(ESI):422.1[M+1]
1H NMR(400MHz,CDCl 3)δ7.69(s,1H),7.56-7.51(m,1H),7.15-7.09(m,3H),6.13(s,1H),5.26-5.22(m,1H),5.20(d,1H),4.85(d,1H),4.36-4.32(m,1H),4.22(d,1H),3.47(s,3H),3.44(s,2H),1.50(s,6H),1.25(d,3H)。
实施例25(S)-N 5-(3-氯-2-氟吡啶-4-基)-6-甲基-N 3-((R)-1,1,1-三氟丙-2-基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺25
Figure PCTCN2018097170-appb-000079
采用实施例3合成路线，将第一步原料化合物3a替换为原料化合物7b，将第三步原料化合物3d替换为原料化合物2-氯-3-氟吡啶-4-胺(上海毕得医药科技有限公司)，制得标题化合物25(20mg)。
MS m/z(ESI):449.1[M+1]。
1H NMR(400MHz,CD 3OD)δ8.09(s,1H),8.04(d,1H),7.87(t,1H),5.42(d,1H),5.02(t,1H),4.84(t,1H),4.77(d,1H),4.38-4.35(m,1H),4.21(d,1H),1.41(d,3H),1.29(d,3H)。
实施例26
(R)-N 1-(仲丁基)-N 7-(3,4,5-三氟苯基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺26
Figure PCTCN2018097170-appb-000080
采用实施例1的合成路线，将第三步原料化合物1e替换为原料化合物(R)-丁-2-胺，制得标题化合物26(4mg)。
MS m/z(ESI):396.2[M+1]。
1H NMR(400MHz,CD 3OD)δ7.68(s,1H),7.31-7.29(m,2H),5.05(s,2H),4.23-4.21(m,2H),4.01-3.95(m,3H),1.61-1.58(m,2H),1.24-1.23(m,3H),0.96(t,3H)。
实施例27
(S)-N 3-(四氢呋喃-3-基)-N 5-(3,4,5-三氟苯基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺27
Figure PCTCN2018097170-appb-000081
将粗品化合物19a(100mg，293.90μmol)、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(138.29mg，587.79μmol)、三乙胺(148.70mg，1.47mmol)溶解于3mL N,N-二甲基甲酰胺中，反应10分钟，加入(S)-四氢呋喃-3-胺盐酸盐27a(72.64mg，587.79μmol，上海毕得医药科技有限公司)，搅拌反应3小时。反应液加入10mL水，乙酸乙酯萃取(20mL×2)，合并有机相，有机相减压浓缩，所得残余物用薄层色谱法以展开剂体系C纯化，所得粗品用高效液相制备(Waters-2767，洗脱体系：碳酸氢铵，水，乙腈)纯化，得标题化合物27(20mg，产率：16.62％)。
MS m/z(ESI):410.1[M+1]。
1H NMR(400MHz,CD 3OD)δ8.02(s,1H),7.30-7.26(m,2H),5.03(s,2H),4.56-4.55(m,1H),4.27-4.25(m,2H),4.04-3.95(m,4H),3.85-3.84(m,1H),3.72-3.71(m,1H),2.32-2.27(m,1H),2.02-1.96(m,1H)。
实施例28
(S)-N 5-(3,4-二氟苯基)-N 3-(1-羟基-2-甲基丙烷-2-基)-6-甲基-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺28
Figure PCTCN2018097170-appb-000082
采用实施例7合成路线，将第五步原料化合物1e替换为原料2-氨基-2-甲基丙烷-1-醇(韶远化学试剂有限公司)，制得标题化合物28(10mg)。
MS m/z(ESI):408.1[M+1]。
1H NMR(400MHz,CDCl 3)δ7.70(s,1H),7.57-7.52(m,1H),7.16-7.10(m,3H),5.94(s,1H),5.25-5.23(m,1H),5.22(d,1H),4.83(d,1H),4.59-4.58(m,1H),4.37-4.32(m,1H),4.21(d,1H),3.77-3.69(m,2H),1.45(s,6H),1.25(d,3H)。
实施例29
(R)-N 5-(3,4-二氟苯基)-2-甲基-N 3-(1,1,1-三氟丙-2-基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺29
Figure PCTCN2018097170-appb-000083
第一步
2-(苄基((3-甲基-1H-吡唑-5-基)甲基)氨基)乙-1-醇29b
将3-甲基-1H-吡唑-5-甲醛29a(5.1g，45.41mmol，上海毕得医药科技有限公司)溶解于100mL二氯甲烷，加入2-(苄基氨基)乙醇(6.87g，45.41mmol)，搅拌反应1小时。加入醋酸硼氢化钠(9.62g，45.41mmol)，搅拌反应16小时。反应液减压浓缩，所得残余物用硅胶柱色谱法以洗脱剂体系C和A纯化，得到标题化合物29b(11g，产率：98.75％)。
MS m/z(ESI):246.1[M+1]。
第二步
N-苄基-2-氯-N-((3-甲基-1H-吡唑-5-基)甲基)乙-1-胺29c
将化合物29b(11g，44.84mmol)溶解于200mL二氯甲烷中，冷却至0℃，滴加二氯亚砜(16.00g，134.52mmol)，40℃反应16小时。反应液冷却至室温，减压浓缩，得到粗品标题化合物29c(11.8g)。产物不经纯化直接用于下一步反应。
MS m/z(ESI):264.1[M+1]。
第三步
5-苄基-2-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪29d
将粗品化合物29c(11.8g，44.74mmol)溶解于200mL乙腈中，冷却到0℃， 加入三乙胺(46g，447.37mmol)，80℃反应16小时。反应液冷却至室温，减压浓缩，加入100mL水，乙酸乙酯萃取(200mL×2)，合并有机相，有机相减压浓缩，得到粗品标题化合物29d(10.17g)。产物不经纯化直接用于下一步反应。
MS m/z(ESI):228.1[M+1]。
第四步
5-苄基-3-溴-2-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪29e
将粗品化合物29d(228mg，1.0mmol)溶解于10mL乙腈中，0℃下，加入N-溴代丁二酰亚胺(180mg，1.0mmol)，缓慢升至室温，搅拌反应16小时。反应液减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，得标题化合物29e(185mg，产率：60.6％)。
MS m/z(ESI):306.1[M+1]。
第二步
5-苄基-2-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-羧酸甲酯29f
一氧化碳气氛下，将八羰基二钴(226mg，662μmol)、碳酸钾(457mg，3.31mmol)加入10mL甲醇中，60℃搅拌反应45分钟。再加入化合物29e(100mg，327μmol)和2-氯乙酸甲酯(215mg，1.98mmol)，搅拌反应16小时。反应液减压浓缩，加入100mL乙酸乙酯，过滤，用100mL乙酸乙酯洗涤，滤液减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，得标题化合物29f(60mg，产率：64.39％)。
MS m/z(ESI):286.2[M+1]。
第三步
2-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-羧酸甲酯29g
氢气氛下，将化合物29f(60mg，210.28μmol)溶解于10mL甲醇中，加入钯碳加氢催化剂(湿)(22.38mg，210.28μmol)，搅拌反应16小时。反应液过滤，滤液减压浓缩，得粗品标题化合物29g(30mg)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):196.2[M+1]。
采用实施例2中合成路线，将第三步原料化合物2c替换为原料粗品化合物29g，制得标题化合物29(10mg)。
MS m/z(ESI):432.2[M+1]。
1H NMR(400MHz,CD 3OD)δ7.49-7.44(m,1H),7.19-7.14(m,2H),4.96(s,2H),4.87-4.83(m,1H),4.20-4.17(m,2H),4.01-3.96(m,2H),2.40(s,3H),1.42-1.39(m,3H)。
实施例30
N 1-((3-甲基氧杂环丁烷-3-基)-N 7-(3,4,5-三氟苯基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺30
Figure PCTCN2018097170-appb-000084
采用实施例1的合成路线，将第五步原料化合物1e替换为原料化合物13c，制得标题化合物30(5mg)。
MS m/z(ESI):410.0[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.39(s,1H),7.80(s,1H),7.67(s,1H),7.31-7.26(m,2H),5.02(s,2H),4.54-4.51(d,2H),4.23-4.20(m,2H),3.96-3.93(m,2H),3.57-3.53(m,2H),1.72(s,3H)。
实施例31
(R)-N 5-(3,4-二氟苯基)-N 3-(1,1,1-三氟丙-2-基)-6,7-二氢-[1,2,3]三氮唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺31
Figure PCTCN2018097170-appb-000085
采用实施例17的合成路线，将第一步原料化合物17f替换为原料化合物7d，制得标题化合物31(20mg)。
MS m/z(ESI):419.1[M+1]。
1H NMR(400MHz,CDCl 3)δ8.11(s,1H)，8.09(s,1H),7.56-7.52(m,1H),7.13-7.08(m,1H),7.06(br,1H),5.35-5.32(m,1H),4.99(s,1H),4.94(s,1H),4.68(s,2H),2.26(t,2H),1.42(d,3H)。
实施例32
(R)-N 7-(2,6-二氟吡啶-4-基)-N 1-(1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺32
Figure PCTCN2018097170-appb-000086
采用实施例16的合成路线，将第二步原料化合物15c替换为原料化合物3c，制得标题化合物32(25mg)。
MS m/z(ESI):419.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.79(s,1H),8.33(s,1H),7.70(s,1H),7.10(s,2H),5.08(s,2H),4.84-4.80(m,1H),4.26-4.23(m,2H),3.99-3.96(m,2H),1.44(d,3H)。
实施例33
(S)-6-甲基-N 5-(3,4,5-三氟苯基)-N 3-((R)-1,1,1-三氟丙-2-基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺33
Figure PCTCN2018097170-appb-000087
采用实施例7的合成路线，将第三步原料化合物7d替换为化合物17f，制得标题化合物33(20mg)。
MS m/z(ESI):450.0[M+1]。
1H NMR(400MHz,CD 3OD)δ8.09(s,1H),7.30-7.27(m,2H),5.36(d,1H),4.98-4.95(m,1H),4.83-4.80(m,1H),4.70(d,1H),4.31-4.27(m,1H),4.20(d,1H),1.41(d,3H),1.22(d,3H)。
实施例34
(S)-N 5-(3,4-二氟苯基)-6-甲基-N 3-((S)-四氢呋喃-3-基)-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺34
Figure PCTCN2018097170-appb-000088
将粗品化合物7f(150mg，446.04μmol)、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(157.41mg，669.06μmol)、N,N-二异丙基乙胺(230.58mg，1.78mmol)溶解于3mL N,N-二甲基甲酰胺中，反应10分钟，加入化合物27a(82.3mg，669.06μmol)，搅拌反应3小时。反应液加入30mL水，乙酸乙酯(30mL×2)萃取，合并有机相，减压浓缩，所得残余物用薄层色谱法以展开剂体系C纯化，所得粗品用高效液相制备(Waters-2767，洗脱体系：碳酸氢铵，水，乙腈)纯化，得标题化合物34(30mg，产率：16.54％)。
MS m/z(ESI):406.2[M+1]。
1H NMR(400MHz,CD 3OD)δ8.05(s,1H),7.52-7.47(m,1H),7.20-7.17(m,2H),5.33(d,1H),5.00-4.99(m,1H),4.70(d,1H),4.56-4.54(m,1H),4.34-4.32(m,1H),4.21-4.20(m,1H),4.04-3.95(m,2H),3.85-3.83(m,1H),3.73-3.72(m,1H),2.32-2.27(m,1H),2.01-1.94(m,3H),1.24(d,1H)。
实施例35
N 1-(3-甲基四氢呋喃-3-基)-N 7-(3,4,5-三氟苯基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7-(8H)-二甲酰胺35
Figure PCTCN2018097170-appb-000089
采用实施例1的合成路线，将第五步原料化合物1e替换为原料3-甲基四氢呋喃-3-胺(上海毕得医药科技有限公司)，制得标题化合物35(16mg)。
MS m/z(ESI):424.1[M+1]。
1H NMR(400MHz,DMSO-d 6)δ8.87(s,1H),8.35(s,1H),7.67(s,1H),7.31-7.27(m,2H),5.03(s,2H),4.21(t,2H),4.10(d,1H),3.96-3.92(m,4H),3.75(d,1H),2.46-2.41(m,1H),2.09-2.01(m,1H),1.59(s,3H)。
实施例36
(R)-N 2-(3,4-二氟苯基)-N 8-(1,1,1-三氟丙-2-基)-3,4-二氢吡咯并[1,2-a]吡嗪-2,8(1H)-二甲酰胺36
Figure PCTCN2018097170-appb-000090
氢气氛下，将吡咯并[1,2-a]吡嗪-8-羧酸甲酯36a(500mg，2.84mmol，采用专利申请“US2015/51189A1”公开的方法制备而得)和钯碳(698.38mg，2.84mmol)于10mL甲醇中，搅拌16小时。反应液过滤，减压浓缩，得粗品1,2,3,4-四氢吡咯并[1,2-a]吡嗪-8-羧酸甲酯36b(511mg，产率：100％)。
MS m/z(ESI):181.2[M+1]。
采用实施例2的合成路线，将第三步原料化合物2c替换为原料粗品化合物36b， 制得标题化合物36(10mg)。
MS m/z(ESI):417.1[M+1]。
1H NMR(400MHz,CD 3OD)δ7.51-7.46(m,1H),7.19-7.15(m,2H),6.71-6.70(m,2H),5.00(s,2H),4.85-4.82(m,1H),4.11-4.09(m,2H),3.94-3.91(m,2H),1.39(d,3H)。
实施例37
(R)-N 7-(2-(二氟甲基)吡啶-4-基)-N 1-(1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺37
Figure PCTCN2018097170-appb-000091
第一步
7-((2-(二氟甲基)吡啶-4-基)氨基甲酰基)-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-1-羧酸乙酯37c
将2-(二氟甲基)吡啶-4-胺37a(73.83mg，512.25μmol，采用专利申请“WO2015/118057A1”公开的方法制备而得)、5,6,7,8-四氢咪唑并[1,5-a]吡嗪-1-羧酸乙酯37b(100mg，512.25μmol，上海毕得医药科技有限公司)和三乙胺(103.67mg，1.02mmol)溶解于10mL四氢呋喃中，于0℃，加入双(三氯甲基)碳酸酯(60.80mg，204.09μmol)，缓慢升至室温，搅拌反应3小时。反应液减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，得标题化合物37c(120mg，产率：64.2％)。
MS m/z(ESI):366.2[M+1]。
第二步
(R)-N 7-(2-(二氟甲基)吡啶-4-基)-N 1-(1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺37
将化合物37c(100mg，273.72μmol)和化合物1e(30.95mg，273.72μmol)溶解于10mL四氢呋喃中，于0℃，滴加1mL的1M双三甲基硅基胺基锂四氢呋喃溶液，加毕，缓慢升至室温，搅拌反应6小时。反应液减压浓缩，所得残余物用高效液相制备(Waters 2767-SQ Detecor2，洗脱体系：碳酸氢铵，水，乙腈)纯化，得标题化合物37(20mg，产率：16.9％)。
MS m/z(ESI):433.2[M+1]。
1H NMR(400MHz,CD 3OD)δ8.42(d,1H),7.88-7.87(m,1H),7.70-7.66(m,2H),6.80-6.53(m,1H),5.10(s,2H),4.83-4.81(m,1H),4.26-4.24(m,2H),4.00-3.98(m, 2H),1.44(d,3H)。
实施例38
(S)-N 3,N 5-双(3,4-二氟苯基)-6-甲基-6,7-二氢吡唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺38
Figure PCTCN2018097170-appb-000092
将粗品化合物7f(80mg，237.89μmol)、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(83.95mg，356.83μmol)、N,N-二异丙基乙胺(92.23mg，713.66μmol)溶解于3mL N,N-二甲基甲酰胺中，反应10分钟，加入化合物2d(46.07mg，356.83μmol)，搅拌16小时。反应液加入10mL水，乙酸乙酯萃取(40mL×2)，合并有机相，有机相减压浓缩，所得残余物用薄层色谱法以展开剂体系C纯化，所得粗品用高效液相制备(Waters-2767，洗脱体系：碳酸氢铵，水，乙腈)纯化，得标题化合物38(10mg，产率：9.4％)。
MS m/z(ESI):448.1[M+1]。
1H NMR(400MHz,CD 3OD)δ8.18(s,1H),7.83-7.81(m,1H),7.52-7.50(m,1H),7.41-7.39(m,1H),7.24-7.17(m,3H),5.39(d,1H),5.04-5.01(m,1H),4.75(d,1H),4.38-4.36(m,1H),4.22(d,1H),1.26(d,3H)。
实施例39
(S)-N 5-(3,4-二氟苯基)-6-甲基-N 3-((R)-1,1,1-三氟丙-2-基)-6,7-二氢-[1,2,3]三氮唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺39
Figure PCTCN2018097170-appb-000093
Figure PCTCN2018097170-appb-000094
第一步
(S)-4-((1-羟丙基-2-基)(4-甲氧基苄基)氨基))丁基-2炔-1-基乙酸酯39b
将化合物6a(3.00g，15.00mmol)溶解于60mL二氧六环中，再加4-氯丁基-2-炔-1-基乙酸酯39a(5.73g，39.00mmol，采用公知的方法“Journal of Medicine Chemistry,2014,57(9),3687-3706”制备)，加入三乙胺(4.7g，46.00mmol)，60℃搅拌反应12小时。反应液过滤，滤液减压浓缩，所得残余物用硅胶柱色谱法以洗脱剂体系A纯化，得标题化合物39b(2.20g，产率：42.2％)。
MS m/z(ESI):306.2[M+1]。
第二步
(S)-4-((1-氯丙基-2-基)(4-甲氧基苄基)氨基)丁基-2炔-1-基乙酸酯39c
将化合物39b(2.20g，7.20mmol)和吡啶(854mg，10.08mmol)溶解于30mL二氯甲烷中，冰浴下缓慢滴加入氯化亚砜(1.50g，12.60mmol)，缓慢升至室温，搅拌反应2小时。反应液中加入100mL二氯甲烷，用水洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，得标题化合物39c(2.20g)，产物不经纯化直接用于下一步反应。
第三步
(S)-(5-(4-甲氧基苄基)-6-甲基-4,5,6,7-四氢-[1,2,3]三氮唑并[1,5-a]吡嗪-3-基)甲基乙酸酯39d
将粗品化合物39c(2.20g，6.79mmol)溶解于20mL N,N-二甲基甲酰胺中，加入叠氮化钠(574mg，8.83mmol，)，80℃反应12小时。反应液冷却至室温，加入50mL乙酸乙酯，用水洗涤(20mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩所得残余物用硅胶柱色谱法以洗脱剂体系A纯化，得标题化合物39d(1.30g，产率：57.9％)。
MS m/z(ESI):331.1[M+1]。
第四步
(S)-(6-甲基-4,5,6,7-四氢-[1,2,3]三氮唑并[1,5-a]哌嗪-3-基)甲基乙酸酯三氟乙酸盐39e
将化合物39d(1.30g，2.33mmol)溶解于5mL三氟乙酸中，微波加热至100℃，反应5分钟。反应液冷却至室温，减压浓缩，得粗品标题化合物39e(1.28g)，产物不经纯化直接用于下一步反应。
第五步
(S)-(5-((3,4-二氟苯基)氨基甲酰基)-6-甲基-4,5,6,7-四氢-[1,2,3]三氮唑并[1,5-a]吡嗪-3-基)甲基乙酸酯39f
将粗品化合物39e(200mg，0.62mmol)、化合物2d(228mg，1.90mmol)和三乙胺(290mg，2.86mmol)溶解于10mL四氢呋喃中，冰水浴下，加入双(三氯甲基)碳酸酯(87mg，0.3mmol)，搅拌反应3小时。反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系C纯化，得标题化合物39f(90mg，产率：40.1％)。
MS m/z(ESI):366.1[M+1]。
采用实施例17的合成路线，将第二步原料化合物17b替换为化合物39f制得标题化合物39(20mg)。
MS m/z(ESI):433.1[M+1]。
1H NMR(400MHz,CD 3OD)δ7.50-7.48(m,1H),7.18-7.16(m,2H),5.43(d,1H),5.08-5.06(m,1H),4.89-4.87(m,1H),4.74(d,1H),4.60(d,1H),4.49-4.46(m,1H),1.49(d,3H),1.21(d,3H)。
实施例40
(S)-N 5-(4-氟-3-甲基苯基-)-6-甲基-N 3-((R)-1,1,1-三氟丙-2-基)-6,7-二氢-[1,2,3]三氮唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺40
Figure PCTCN2018097170-appb-000095
采用实施例39的合成路线，第五步原料化合物2d替换为3-甲基-4氟苯胺40a，制得标题化合物40(25mg)。
MS m/z(ESI):429.1[M+1]
1H NMR(400MHz,CD 3OD)δ7.29-7.26(m,1H),7.21-7.20(m,1H),6.99-6.94(m,1H),5.45-5.41(d,1H),5.09-5.08(m,2H),4.76-4.71(d,1H),4.63-4.59(m,1H),4.52-4.51(d,1H),2.27-2.26(d,3H),1.48-1.46(d,3H),1.23-1.22(d,3H)。
实施例41
(S)-N 7-(3,4-二氟苯基)-6-甲基-N 1-((S)-1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺41
Figure PCTCN2018097170-appb-000096
采用实施例6的合成路线，将原料化合物1e替换为原料化合物(2S)-1,1,1-三氟 丙基-2-胺盐酸盐(上海毕得医药科技有限公司)，制得标题化合物41(110mg)。
MS m/z(ESI):432.1[M+1]。
1H NMR(400MHz,CDCl 3)δ7.54-7.51(m,1H),7.50(s,1H),7.21-7.02(m,3H),6.83(s,1H),5.26-5.16(m,1H),5.15-5.04(m,1H),4.95-4.92(m,1H),4.86-4.80(m,1H),4.28-4.22(m,1H),4.01-4.05(m,1H),1.48(d,3H),1.20(d,3H)。
实施例42
(R)-N 5-(3,4-二氟苯基)-7-甲基-N 3-((R)-1,1,1-三氟丙-2-基)-6,7-二氢[1,2,3]三氮唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺42
Figure PCTCN2018097170-appb-000097
采用实施例39的合成路线，将第一步原料化合物6a替换化合物(2R)-1-((4-甲氧基苄基)氨基)丙-1-醇(采用公知的方法“Organic and Biomolecular Chemistry,2014,12,16,2584–2591”制备而得)，制得标题化合物42(20mg)。
MS m/z(ESI):433.1[M+1]。
1H NMR(400MHz,CD 3OD)δ7.50-7.48(m,1H),7.15-7.12(m,2H),5.16(d,1H),5.02(d,1H),4.77-4.75(m,1H),4.13-4.10(m,1H),3.77(m,1H),3.06-3.03(m,1H),1.67(d,3H),1.44(d,3H)。
实施例43
(S)-N 5-(3,4-二氟苯基)-6-甲基-N 3-((S)-1,1,1-三氟丙-2-基)-6,7-二氢[1,2,3]三氮唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺43
Figure PCTCN2018097170-appb-000098
采用实施例17的合成路线，将第二步原料化合物17b替换为化合物39f，原料化合物1e替换为原料化合物(2S)-1,1,1-三氟丙基-2-胺盐酸盐，制得标题化合物43(30mg)。
MS m/z(ESI):433.3[M+1]
1H NMR(400MHz,CDCl 3)δ7.53-7.50(m,1H),7.30(d,1H),7.15(dd,1H),7.06-7.04(m,1H),6.84(s,1H),5.37-5.32(m,1H),5.27(d,1H),4.89-4.85(m,2H),4.61(d,1H),4.52-4.48(m,1H),1.50(d,3H),1.26(d,3H)。
实施例44
(R)-N 5-(3-氰基-4-氟苯基)-7-甲基-N 3-((R)-1,1,1-三氟丙-2-基)-6,7-二氢[1,2,3]三氮唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺44
Figure PCTCN2018097170-appb-000099
采用实施例39的合成路线，将第一步原料化合物6a替换为化合物(2R)-1-((4-甲氧基苄基)氨基)丙-1-醇，第五步原料化合物2d替换为化合物3d，制得标题化合物44(15mg)。
MS m/z(ESI):440.3[M+1]。
1H NMR(400MHz,CD 3OD)δ7.86-7.84(m,1H),7.73-7.70(m,1H),7.29(t,1H),5.19(d,1H),5.05(d,1H),4.85-4.82(m,1H),4.12(d,1H),3.77-3.73(m,1H),3.64-3.62(m,1H),1.69(d,3H),1.46(d,3H)。
实施例45
(S)-N 5-(3-氰基-4-氟苯基)-6-甲基-N 3-((R)-1,1,1-三氟丙-2-基)-6,7-二氢[1,2,3]三氮唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺45
Figure PCTCN2018097170-appb-000100
第一步
(S)-(5-((3-氰基-4-氟苯基)氨基甲酰基)-6-甲基-4,5,6,7-四氢-[1,2,3]三氮唑并[1,5-a]吡嗪-3-基)甲基乙酸酯45a
将粗品化合物39e(400mg，1.24mmol)、化合物3d(450mg，3.80mmol)和三乙胺(580mg，5.80mmol)溶解于20mL四氢呋喃中，冰水浴下，加入双(三氯甲基) 碳酸酯(180mg，0.6mmol)，搅拌反应3小时。反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系C纯化，得标题化合物45a(195mg，产率：40.1％)。
MS m/z(ESI):373.1[M+1]。
第二步
(S)-N-(3-氰基-4-氟苯基)-3-(羟甲基)-6-甲基-6,7-二氢-[1,2,3]三氮唑并[1,5-a]吡嗪-5(4H)-甲酰胺45b
将化合物45a(190mg，0.51mmol)溶解于5mL甲醇和水(V:V＝4:1)的混合溶剂中，加入氢氧化锂(108mg，2.57mmol)，搅拌2小时。反应液中加水20mL，乙酸乙酯萃取(15mL×3)，合并有机相，减压浓缩，得粗品标题化合物45b(120mg)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):331.2[M+1]。
第三步
(S)-N-(3-氰基-4-氟苯基)-3-甲酰基-6-甲基-6,7-二氢-[1,2,3]三氮唑并[1,5-a]吡嗪-5(4H)-甲酰胺45c
将粗品化合物45b(100mg，0.3mmol)溶解于5mL二氯甲烷中，加入氯铬酸吡啶盐(138mg，0.64mmol)和硅胶(140mg，100-200目)，搅拌3小时。过滤，减压浓缩，所得残余物用薄层色谱法以展开剂体系A纯化，得标题化合物45c(60mg，产率：43.1％)。
MS m/z(ESI):329.5[M+1]。
第四步
(S)-(5-((3-氰基-4-氟苯基)氨基甲酰基)-6-甲基-4,5,6,7-四氢-[1,2,3]三氮唑并[1,5-a]吡嗪-3-羧酸45d
将化合物45c(30mg，0.1mmol)溶解于5mL乙腈和水混合溶剂中(V:V＝3:2)，加入氨基磺酸(20mg，0.2mmol)，搅拌10分钟，加入亚氯酸钠(20mg，0.2mmol)，搅拌2小时。依次加入0.5mL饱和亚硫酸钠溶液和10mL水，乙酸乙酯萃取(10mL×3)，合并有机相，减压浓缩，得粗品化合物45d(25mg)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):345.2[M+1]。
第五步
S)-N 5-(3-氰基-4-氟苯基)-6-甲基-N 3-((R)-1,1,1-三氟丙-2-基)-6,7-二氢[1,2,3]三氮唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺45
将粗品化合物45d(20mg，58.0μmol)、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(105mg，146.5μmol)、N,N-二异丙基乙胺(150mg，366.2μmol)溶解于3mL N,N-二甲基甲酰胺中，反应10分钟，加入化合物1e(50mg，110μmol)，搅拌反应3小时。反应液减压浓缩，所得残余物用薄层色谱法以展开剂体系C纯化，得标题化合物45(8mg，产率：31.3％)。
MS m/z(ESI):440.3[M+1]。
1H NMR(400MHz,CD 3OD)δ7.87-7.84(m,1H),7.73-7.70(m,1H),7.29(t,1H),5.45(t,1H),5.08-5.06(m,1H),4.92-4.89(m,1H),4.77(d,1H),4.62(d,1H),4.50(d,1H),1.46(d,3H),1.21(d,3H)。
实施例46
(S)-N 7-(3-氰基-4-氟苯基)-6-甲基-N 1-(1-甲基环丁基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺46
Figure PCTCN2018097170-appb-000101
采用实施例11的合成路线，将第三步原料化合物1e替换为化合物1-甲基环丁基1-胺(上海毕得医药科技有限公司)，制得标题化合物46(20mg)。
MS m/z(ESI):411.4[M+1]。
1H NMR(400MHz,CD 3OD)δ7.86-7.84(m,1H),7.72-7.70(m,1H),7.65(s,1H),7.28(t,1H),5.26(d,1H),4.92-4.89(m,1H),4.78(d,1H),4.20-4.17(m,2H),2.45-2.43(m,2H),2.10-2.07(m,2H),1.92-1.90(m,2H),1.55(s,3H),1.20(d,3H)。
实施例47
(R)-N 7-(3-氰基-4-氟苯基)-5-甲基-N 1-((R)-1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺47
Figure PCTCN2018097170-appb-000102
采用实施例6的合成路线，将第一步原料化合物6a替换为原料化合物(2S)-1-((4-甲氧基苄基)氨基)丙-1-醇，第四步原料化合物2d替换为原料化合物3d，制得标题化合物47(12mg)。
MS m/z(ESI):439.2[M+1]
1H NMR(400MHz,CDCl 3)δ7.88(dd,1H),7.62-7.61(m,1H),7.57(s,1H),7.22-7.17(m,3H),5.20(d,1H),5.03(d,1H),4.84-4.80(m,1H),4.42-4.40(m,1H),4.25-4.21(dd,1H),3.58-3.53(dd,1H),1.64(d,3H),1.47(d,3H)。
实施例48
(S)-N 7-(3-氰基-4-氟苯基)-6-甲基-N 1-(1-甲基环丙基)-5,6-二氢咪唑并[1,5-a]吡 嗪-1,7(8H)-二甲酰胺48
Figure PCTCN2018097170-appb-000103
采用实施例11的合成路线，将第三步原料化合物1e替换为化合物1-甲基环丙基1-胺(上海毕得医药科技有限公司)，制得标题化合物48(20mg)。
MS m/z(ESI):397.3[M+1]。
1H NMR(400MHz,CD 3OD)δ7.86-7.84(m,1H),7.72-7.70(m,1H),7.63(s,1H),7.29(t,1H),5.28(d,1H),4.91-4.89(m,1H),4.80(d,1H),4.20-4.17(m,2H),1.44(s,3H),1.20(d,3H),0.71-0.68(m,2H),0.68-0.66(m,2H)。
实施例49
(R)-N 5-(3-4-二氟苯基-)-6-甲基-N 3-((R)-1,1,1-三氟丙-2-基)-6,7-二氢咪唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺49
Figure PCTCN2018097170-appb-000104
采用实施例7的合成路线，将第一步原料化合物7a替换为原料化合物(R)-3-碘-6-甲基-6,7-二氢吡唑并[1,5-a]吡嗪-5(4H)-羧酸叔丁酯(采用专利申请“WO2017198744A1”公开的方法制备)，制得标题化合物49(20mg)
MS m/z(ESI):432.2[M+1]
1H NMR(400MHz,CD 3OD)δ8.11(m,1H),7.52-7.47(m,1H),7.21-7.16(m,2H),5.38-5.33(d,2H),5.02-4.99(m,1H),4.74-4.69(d,1H),4.36-4.33(m,1H),4.23-4.19(d,1H),1.43-1.42(d,3H),1.27-1.25(d,3H)。
实施例50
(S)-N 1-(叔丁基)–N 7-(3-氰基-4-氟苯基-)-6-甲基-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺50
Figure PCTCN2018097170-appb-000105
采用实施例11的合成路线，第三步原料化合物1e替换为原料化合物叔丁胺(国药集团化学试剂有限公司)制得标题化合物50(180mg)。
MS m/z(ESI):399.2[M+1]
1H NMR(400MHz,CD 3OD)δ7.90-7.88(m,1H),7.75-7.67(m,1H),7.33(s,1H),7.31-7.29(m,1H),5.28-5.24(d,1H),4.94(m,1H),4.81-4.77(m,1H),4.26-4.20(m,2H),1.48(d,9H),1.22-1.20(d,3H)。
实施例51
(S)-N 7-(3-氰基-4-氟苯基)–N 1-((R)-1-氟丙-2-基)-6-甲基-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺51
Figure PCTCN2018097170-appb-000106
采用实施例11的合成路线，第三步原料化合物1e替换为原料化合物(S)-2-氟-1-甲基-乙胺盐酸盐(上海毕得医药科技有限公司)，制得标题化合物51(20mg)。
MS m/z(ESI):403.2[M+1]
1H NMR(400MHz,CD 3OD)δ7.89-7.87(m,1H),7.77-7.74(m,1H),7.73(s,1H),7.31-7.29(m,1H),5.31-5.27(d,1H),4.94-4.92(m,1H),4.83-4.78(d,1H),4.52-4.50(d,1H),4.40-4.39(m,2H),4.25-4.22(m,2H),1.32-1.30(d,3H),1.22-1.20(d,3H)。
实施例52
(S)-N 7-(3-氰基-4-氟苯基)-6-甲基-N 1-((S)-1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺52
Figure PCTCN2018097170-appb-000107
采用实施例11的合成路线，将第三步原料化合物1e替换为原料化合物(2S)-1,1,1-三氟丙基-2-胺盐酸盐，制得标题化合物52(20mg)。
MS m/z(ESI):439.2[M+1]
1H NMR(400MHz,CDCl 3)δ7.91(dd,1H),7.63-7.62(m,1H),7.50(s,1H),7.20-7.14(m,3H),5.22-5.16(m,2H),4.95(d,1H),4.85-4.83(m,1H),4.26-4.23(m,1H),4.11-4.08(dd,1H),1.48(d,3H),1.26(d,3H)。
实施例53
(R)-N 7-(3,4-二氟苯基-)-6-甲基-N 1-((R)-1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺53
Figure PCTCN2018097170-appb-000108
采用实施例6的合成路线，将第一步原料6a替换为原料(R)-2-((4-甲氧基苄基)氨基)丙-1-醇(采用公知的方法“Bioorganic & Medicinal Chemistry Letters,2015,25(5),1086-1091”制备而得)，制得标题化合物53(90mg)
MS m/z(ESI):432.2[M+1]
1H NMR(400MHz,CD3OD)δ7.71(s,1H),7.52-7.47(m,1H),7.21-7.17(m,2H),5.31-5.27(d,1H),4.94-4.92(m,1H),4.76-4.84(m,2H),4.24-4.22(m,2H),1.45-1.43(d,3H),1.23-1.21(d,3H)。
实施例54
(R)-N 7-(3-氰基-4-氟苯基-)-6-甲基-N 1-((R)-1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺54
Figure PCTCN2018097170-appb-000109
采用实施例6的合成路线，将第一步原料化合物6a替换为原料(R)-2-((4-甲氧基苄基)氨基)丙-1-醇，将第四步原料化合物2d替换为3d，制得标题化合物54(88mg)。
MS m/z(ESI):439.2[M+1]
1H NMR(400MHz,CD3OD)δ7.89-7.87(m,1H),7.75-7.73(m,1H),7.71(s,1H),7.33-7.29(m,1H),5.32-5.28(d,1H),4.95-4.93(m,1H),4.85-4.82(m,2H),4.25-4.22(m,2H),1.45-1.43(d,3H),1.23-1.22(d,3H)。
实施例55
(R)-N 7-(3-氰基-4-氟苯基)-6-甲基-N 1-((S)-1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺55
Figure PCTCN2018097170-appb-000110
采用实施例6的合成路线，将第一步原料化合物6a替换为原料(R)-2-((4-甲氧基苄基)氨基)丙-1-醇，将第四步原料化合物2d替换为3d，将第五步原料化合物1e替换为原料化合物(2S)-1,1,1-三氟丙基-2-胺盐酸盐，制得标题化合物55(20mg)。
MS m/z(ESI):439.2[M+1]
1H NMR(400MHz,CDCl 3)δ7.86(dd,1H),7.70-7.65(m,2H),7.30-7.26(m,3H),5.30(d,1H),4.94-4.93(m,1H),4.81-4.76(m,2H),4.26-4.17(m,2H),1.43(d,3H),1.20(d,3H)。
实施例56
(S)-N 7-(3-氰基-4-氟苯基)-5-甲基-N 1-((R)-1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺56
Figure PCTCN2018097170-appb-000111
采用实施例6的合成路线，将第一步原料化合物6a替换为原料化合物(S)-1-((4-甲氧基苄基)氨基)丙-2-醇(采用公知的方法“Organic and Biomolecular Chemistry,2014,12,16,2584–2591”制备而得)，第四步原料化合物2d替换为原料化合物3d，制得标题化合物56(10mg)。
MS m/z(ESI):439.2[M+1]
1H NMR(400MHz,CD 3OD)δ7.88-7.86(m,1H),7.83(s,1H),7.76-7.72(m,1H),7.33-7.28(m,1H),5.16-5.11(d,1H),5.03-4.98(m,1H),4.85-4.81(m,2H),4.04-4.00(m,1H),3.72-3.66(m,1H),1.60-1.56(d,3H),1.44-1.42(d,3H)。
实施例57
N 5-(3-氰基-4-氟苯基-)-7-甲基-N 3-((R)-1,1,1-三氟丙-2-基)-6,7-二氢-[1,2,3]三氮唑并[1,5-a]吡嗪-3,5(4H)-二甲酰胺57
Figure PCTCN2018097170-appb-000112
采用实施例39的合成路线，将第一步原料化合物6a替换为原料化合物1-((4-甲氧基苄基)氨基)丙-2-醇(采用公知的方法“Organic and Biomolecular Chemistry,2014,12,16,2584–2591”制备而得)，第五步原料化合物2d替换为原料化合物3d，制得标题化合物57(220mg)。
MS m/z(ESI):440.2[M+1]
1H NMR(400MHz,CD 3OD)δ7.85-7.87(m,1H),7.72-7.75(m,1H),7.28-7.33(m,1H)，5.01-5.06(d,1H),5.16-5.21(d,1H),4.80-4.81(m,2H),4.13-4.17(m,1H),3.75-3.80(m,1H),1.69-1.70(d,3H),1.18-1.21(d,3H)。
实施例58
(S)-N 7-(4-氟-3-甲基苯基-)-6-甲基-N 1-((R)-1,1,1-三氟丙-2-基)-5,6-二氢咪唑并[1,5-a]吡嗪-1,7(8H)-二甲酰胺58
Figure PCTCN2018097170-appb-000113
采用实施例6的合成路线，将第四步原料化合物2d替换为原料化合物4-氟-3-甲基苯胺(上海毕得医药科技有限公司)，制得标题化合物58(14mg)。
MS m/z(ESI):427.9[M+1]
1H NMR(400MHz,CD 3OD)7.71(s,1H),7.29-7.27(m,1H),7.22-7.20(m,1H),6.99-6.94(m,1H),5.30-5.25(d,1H),4.94-4.92(m,1H),4.81-4.75(m,2H),4.24-4.21(m,2H),2.27-2.26(d,3H),1.45-1.43(d,3H),1.20-1.19(d,3H)。
实施例59
(S)-N-(3,4-二氟苯基)-6-甲基-1-(吡咯烷-1-羰基)-5,6-二氢咪唑并[1,5-a]吡嗪-7(8H)-甲酰胺59
Figure PCTCN2018097170-appb-000114
采用实施例11合成路线，将第一步原料化合物3d替换为化合物2d，将第三步原料化合物1e替换为原料化合物吡咯烷(国药集团化学试剂有限公司)，制得标题化合物59(10mg)。
MS m/z(ESI):389.8[M+1]。
1H NMR(400MHz,CDCl 3)δ7.69(s,1H),7.52-7.47(m,1H),7.20-7.16(m,3H),5.26(d,1H),4.93-4.90(m,1H),4.77(d,1H),4.23-4.21(m,2H),4.04-4.01(m,2H),3.63-3.60(m,2H),2.01-1.93(m,4H),1.22(d,3H)。
生物学评价
测试例1、本发明化合物体外抗HBV活性测试(细胞内HBV DNA定量分析)
一、实验材料及仪器
1.QIAamp 96 DNA QIAcube HT Kit(Qiagen)
2.QIAcube HT plasticware(Qiagen)
3.乙型肝炎病毒核酸定量检测试剂盒(泰普生物)
4.DNA提取设备(QIAcube)(Qiagen)
5.QuantStudio 6 Fiex(ABI,ThermFisher)
6.酶标仪(BMG)
7.HepG2.2.15细胞(上海瑞鹿生物技术有限公司)
二、实验步骤
HepG2.2.15细胞是整合了HBV基因组的稳定表达细胞株，可通过复制、转录、翻译、并包装成带有HBV DNA的病毒颗粒分泌到细胞外。本研究采用定量PCR的方法对HepG2.2.15体外增殖产生的HBV DNA进行定量分析，筛选本发明化合物通过对HBV衣壳蛋白装配抑制进而抑制HBV DNA复制的活性。
HepG2.2.15细胞在DMEM/高葡萄糖培养基(10％FBS,400μg/ml G418)中培养，每3天传代一次。实验当天以新鲜细胞培养基制取细胞悬液，以40,000细胞/孔96孔板(Corning,#3599)，5％二氧化碳，于37℃培养。第二天先将化合物溶解在纯DMSO中浓度为20mM，再用DMSO配制成首个浓度2mM，并以4倍依次稀释成8个浓度，设置对照的孔加入90μl DMSO。用含DMEM/高葡萄糖培养基稀释200倍。取出第一天接种的细胞培养板，用负压吸取装置吸出孔板内的培养基，再将配制好的含有各浓度的化合物培养基分别加入各孔中，以200μl/孔，于37℃培养72小时。第五天，用含有同样化合物的新鲜培养基对该培养细胞进行换液，方法等同第二天，再于37℃培养72小时。第八天，取出细胞培养板，以300g离心3分钟，收集培养上清液200μl/孔。采用Qiagen自动DNA提取设备进行细胞培养上清液内HBV DNA提取，具体方法参考试剂和仪器使用说明。最后以100μl/孔，用DNA洗脱缓冲液洗脱提取的DNA。采用泰普生物的乙型肝炎病毒核酸定量检测试剂盒对提取的DNA进行HBV DNA定量PCR分析，具体方法参考试剂盒说明。定量标准曲线采用试剂盒自带标准样品，平行进行实验。根据标准曲线对各个样品进行定量换算。最后用Graphpad Prism软件根据化合物各浓度与相应的DNA值计算化合物的EC 50值。Emax为化合物最大限度抑制HBV DNA复制的效应值。
本发明化合物通过对HBV衣壳蛋白装配抑制进而抑制HBV DNA复制体外活性通过以上的试验进行测定，测得的EC 50值见表1。
表1 本发明化合物抗HBV活性测试(细胞内HBV DNA定量分析)的EC 50值
实施例编号 EC 50(nM) Emax(％)
2 30 100
4 27 100
6 4 100
7 38 100
8 15 100
9 28 100
10 29 100
11 18 100
12 32 100
13 35 100
14 44 100
15 29 100
16 50 100
17 70 80
39 19 100
40 20 100
41 24 100
42 75 100
43 39 99
44 60 99
45 38 102
46 65 97
47 82 100
48 93 98
58 15 100
59对照例 5271 90
结论：本发明化合物对HBV DNA复制具有明显的抑制作用，与对照例59相比，具有显著优势。对照例59与本申请化合物结构上主要区别为酰胺基中的氨基为三级胺，由此可见本申请化合物中酰胺基中的二级胺对生物活性有显著提升。
测试例2、本发明化合物对HepG2细胞体外增殖的影响
一、实验材料及仪器
1.HepG2细胞(ATCC)
2.CellTiter-Glo TM细胞增殖试剂盒(Promega)
3.自动移液工作站(Bravo)：Agilent Technologies公司
4.酶标仪(VICTOR 3)：PerkinElmer公司
5.CO 2培养箱(Fisher Scientific)
6.离心机(Fisher Scientific)
二、实验步骤
取对数生长期的HepG2细胞，用胰蛋白酶消化制备细胞悬液，以6,000细胞/孔96孔板(底透白色96孔板，PerkinElmer)，5％二氧化碳，于37℃培养16-20小时。第二天，化合物溶解在纯DMSO中浓度为20mM，利用自动移液工作站(Bravo)对化合物进行梯度稀释，3倍稀释，每个化合物设8个浓度点，对照的孔为DMSO；接着用EMEM(含10％FBS)培养基对DMSO配制的各浓度点化合物进行200倍稀释。取出第一天接种的细胞培养板，用负压吸取装置吸出孔板内的培养基，再将配制好的含有各浓度的化合物培养基分别加入各孔中，以100μl/孔，于37℃培养72小时。第五天，取出96孔细胞培养板，向各孔中加入新鲜配制的CellTiter Glo，以100μl/孔，放置5-10分钟，用白色封底膜(PerkinElmer)将该96 孔板底部封膜，置于酶标仪中，用酶标仪测定Luminescence信号。用Graphpad Prism软件根据化合物各浓度与相应的增殖抑制信号值计算化合物的CC 50值。
本发明化合物对HepG2细胞体外增殖抑制的影响通过以上的试验进行测定，测得的CC 50值见表2。
表2 本发明化合物对HepG2细胞体外增殖抑制的CC 50值
实施例编号 CC 50(μM)
2 >100
4 >100
6 >100
7 >100
8 >100
9 >100
10 >100
11 >100
12 >100
13 >100
14 >100
15 >100
16 >100
17 >100
39 >100
40 >100
41 >100
42 >100
43 >100
44 >100
45 >100
46 >100
47 >100
48 >100
58 >100
结论：本发明化合物对HepG2细胞体外增殖抑制没有影响或影响较小，表现出高的安全性。
药代动力学评价
测试例3、本发明化合物的药代动力学测试
1、摘要
以大鼠为受试动物，应用LC/MS/MS法测定了大鼠灌胃给予实施例1化合物、实施例2化合物、实施例4化合物、实施例6化合物、实施例7化合物、实施例11化合物、实施例39化合物、实施例42化合物、实施例44化合物、实施例45化合物和实施例47化合物后不同时刻血浆中的药物浓度。研究本发明化合物在大鼠体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1 试验药品
实施例1化合物、实施例2化合物、实施例4化合物、实施例6化合物、实施例7化合物、实施例11化合物、实施例39化合物、实施例42化合物、实施例44化合物、实施例45化合物和实施例47化合物。
2.2 试验动物
健康成年SD大鼠44只，雌雄各半，4只/组，购自上海杰思捷实验动物有限公司，动物生产许可证号：SCXK(沪)2013-0006。
2.3 药物配制
称取一定量药物，加5％体积的DMSO、5％体积的吐温80和90％体积的生理盐水配制成0.2mg/mL的无色澄清透明液体。
2.4 给药
SD大鼠禁食过夜后灌胃给药，给药剂量均为2.0mg/kg，给药体积均为10.0mL/kg。
3.操作
大鼠灌胃给药实施例1化合物、实施例2化合物、实施例4化合物、实施例6化合物、实施例7化合物、实施例11化合物、实施例39化合物、实施例42化合物、实施例44化合物、实施例45化合物和实施例47化合物，于给药前及给药后0.5，1.0，2.0，4.0，6.0，8.0，11.0，24.0小时由眼眶采血0.1mL，置于肝素化试管中，3500转/分钟离心10分钟分离血浆，于-20℃保存，给药后2小时进食。
测定不同浓度的药物灌胃给药后大鼠血浆中的待测化合物含量：取给药后各时刻的大鼠血浆25μL，加入内标溶液喜树碱40μL(100ng/mL)，乙腈200μL，涡旋混合5分钟，离心10分钟(4000转/分钟)，血浆样品取上清液0.2μL进行LC/MS/MS分析。
4、药代动力学参数结果
本发明化合物的药代动力学参数如下：
Figure PCTCN2018097170-appb-000115
Figure PCTCN2018097170-appb-000116
结论：本发明化合物的药代吸收好，生物利用度高，具有药代动力学优势。

Claims (19)

  1. 一种通式(I)所示的化合物：
    Figure PCTCN2018097170-appb-100001
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，
    其中：
    环A为芳基和杂芳基；
    Y为N或CR 5；
    Q为N或CH；
    R 1选自烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选进一步被选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6中的一个或多个取代基所取代；
    R 2选自氢原子、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选进一步被选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6中的一个或多个取代基所取代；
    R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；
    R 4相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；
    R 5选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    R 6选自氢原子、烷基、卤代烷基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    n为0、1、2或3；
    m为0、1或2；且
    s为0、1、2、3或4。
  2. 根据权利要求1所述的通式(I)所示的化合物，其为通式(II)所示的化合物：
    Figure PCTCN2018097170-appb-100002
    其中：
    环A、Y、Q、R 1、R 3、R 4、s和n如权利要求1中所定义。
  3. 根据权利要求1或2所述的通式(I)所示的化合物，其为通式(III)、通式(IV)、通式(V)和通式(VI)所示的化合物：
    Figure PCTCN2018097170-appb-100003
    其中：
    环A、R 1、R 3、R 4、s和n如权利要求1中所定义。
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物，其中环A为苯基或吡啶基。
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物，其为通式(VII)、通式(VIII)、通式(IX)和通式(X)所示的化合物：
    Figure PCTCN2018097170-appb-100004
    Figure PCTCN2018097170-appb-100005
    其中：
    G为C或N；
    R 1、R 3、R 4、s和n如权利要求1中所定义。
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物，其中R 1选自烷基、卤代烷基、环烷基、杂环基和芳基，其中所述的烷基、环烷基、杂环基和芳基任选进一步被选自卤素、烷基、烷氧基和羟基中的一个或多个取代基所取代。
  7. 根据权利要求1至6中任一项所述的通式(I)所示的化合物，其为通式(VII-A)、通式(VIII-A)、通式(IX-A)和通式(X-A)所示的化合物：
    Figure PCTCN2018097170-appb-100006
    其中：
    G为C或N；
    R 8为烷基，优选为甲基；
    R 9为烷基，其中所述的烷基任选进一步被一个或多个卤素所取代；
    R 3、R 4、s和n如权利要求1中所定义。
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物，其中R 3为氢原子或烷基。
  9. 根据权利要求1至8中任一项所述的通式(I)所示的化合物，其中R 4选自氢原子、卤素、烷基、卤代烷基或氰基。
  10. 根据权利要求1至9中任一项所述的通式(I)所示的化合物，其选自：
    Figure PCTCN2018097170-appb-100007
    Figure PCTCN2018097170-appb-100008
    Figure PCTCN2018097170-appb-100009
  11. 一种通式(IA)所示的化合物：
    Figure PCTCN2018097170-appb-100010
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
    其中：
    R a为氢原子或烷基；
    环A为芳基和杂芳基；
    Y为N或CR 5；
    Q为N或CH；
    R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
    R 4相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；
    R 5选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    R 6选自氢原子、烷基、卤代烷基、氨基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    n为0、1、2或3；
    m为0、1或2；且
    s为0、1、2、3或4。
  12. 根据权利要求11所述的通式(IA)所示的化合物，其选自：
    Figure PCTCN2018097170-appb-100011
  13. 一种通式(IIIA)所示的化合物：
    Figure PCTCN2018097170-appb-100012
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
    其中：
    M为三氟乙酸或盐酸；
    R 1选自烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选进一步被选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6中的一个或多个取代基所取代；
    R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
    t为0或1；且
    n为0、1、2或3。
  14. 一种化合物，其选自：
    Figure PCTCN2018097170-appb-100013
  15. 一种制备根据权利要求1所述的通式(I)所示的化合物的方法，该方法包括以下步骤：
    Figure PCTCN2018097170-appb-100014
    将通式(IA)化合物与通式(IB)化合物或其盐反应，得到通式(I)化合物；
    其中：
    R a为氢原子或烷基；
    R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
    环A、Y、Q、R 1、R 2、R 4、s和n如权利要求1中所定义。
  16. 一种制备根据权利要求2所述的通式(II)所示的化合物的方法，该方法包括以下步骤：
    Figure PCTCN2018097170-appb-100015
    将通式(IA)化合物与通式(IIB)化合或其盐反应，得到通式(II)化合物；
    其中：
    R a为氢原子或烷基；
    R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 6、-C(O)R 6、-C(O)OR 6和-S(O) mR 6；优选为氢原子或烷基；
    环A、Y、Q、R 1、R 4、s和n如权利要求1中所定义。
  17. 一种药物组合物，其含有治疗有效量的根据权利要求1至10中任一项所述的通式(I)所示的化合物，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  18. 根据权利要求1至10中任一项所述的通式(I)所示的化合物或根据权利要求17所述的药物组合物在制备衣壳蛋白抑制剂中的用途。
  19. 根据权利要求1至10中任一项所述的通式(I)所示的化合物或根据权利要求17所述的药物组合物在制备治疗病毒性感染疾病的药物中的用途，所述病毒优选乙型肝炎病毒、流感病毒、疱疹病毒和艾滋病毒，所述疾病优选乙型肝炎、流感、疱疹和艾滋病。
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CN111484497A (zh) * 2019-01-25 2020-08-04 江苏恒瑞医药股份有限公司 咪唑并[1,5-a]吡嗪类衍生物的可药用盐、晶型及其制备方法
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WO2020221824A1 (en) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Novel indolizine-2-carboxamides active against the hepatitis b virus (hbv)
WO2020221811A1 (en) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Novel oxalyl piperazines active against the hepatitis b virus (hbv)
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WO2022022613A1 (zh) * 2020-07-29 2022-02-03 江苏恒瑞医药股份有限公司 一种三氮唑并[1，5-a]吡嗪制备方法及其应用
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US11845752B2 (en) 2020-10-15 2023-12-19 Aligos Therapeutics, Inc. Substituted imidazo[1,5-a]pyrazines for the treatment of hepatitis B
WO2022166778A1 (zh) * 2021-02-04 2022-08-11 江苏恒瑞医药股份有限公司 一种衣壳蛋白抑制剂的药物组合物及其制备方法

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