WO2017173960A1 - Macro-heterocycle for suppressing hepatitis c virus, and preparation and application thereof - Google Patents

Macro-heterocycle for suppressing hepatitis c virus, and preparation and application thereof Download PDF

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WO2017173960A1
WO2017173960A1 PCT/CN2017/079087 CN2017079087W WO2017173960A1 WO 2017173960 A1 WO2017173960 A1 WO 2017173960A1 CN 2017079087 W CN2017079087 W CN 2017079087W WO 2017173960 A1 WO2017173960 A1 WO 2017173960A1
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compound
under
reaction
alkyl
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PCT/CN2017/079087
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French (fr)
Chinese (zh)
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王喆
王栋
陈俊杰
许曼
徐海涛
王晓光
范国钦
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天津长森药业有限公司
上海长森药业有限公司
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Priority to CN201780000221.0A priority Critical patent/CN107074876B/en
Publication of WO2017173960A1 publication Critical patent/WO2017173960A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present application relates to a novel macrocyclic heterocyclic compound and an intermediate thereof, a preparation method and use thereof.
  • Hepatitis C virus infection causes chronic liver diseases such as cirrhosis and liver cancer. Hepatitis C virus infection is one of the major infectious diseases. According to the World Health Organization, there are 170 million hepatitis C victims worldwide, and there are nearly 39 million hepatitis C infected people in China. In recent years, the treatment of hepatitis C has made great progress, and several products have been approved for marketing, including Sofosbuvir, Harvoni (Ledipasvir/Sofosbuvir), Viekirax Pak (ombitasvir/paritaprevir and ritonavir/Exviera), for HCV- The efficacy of genotype 1b is excellent. However, the efficacy of other HCV genotypes and their resistant viruses needs to be improved. Therefore, it is necessary to develop a hepatitis C virus therapeutic drug that is more effective and better tolerated.
  • Hepatitis C virus is the leading cause of most non-A, non-B hepatitis.
  • Hepatitis C virus is a F1aviviridae positive single-stranded RNA virus whose genome contains approximately 10,000 nucleotides and encodes a polymeric protein of approximately 3000 amino acids. It includes a nucleocapsid protein (C) and envelope proteins (E1 and E2), and some non-structural proteins (NS1, NS2, NS3, NS4a, NS5a and NS5b).
  • C nucleocapsid protein
  • E1 and E2 envelope proteins
  • NS1, NS2, NS3, NS4a, NS5a and NS5b non-structural proteins
  • the NS3 proteolytic enzyme has serine protease activity and is considered to be an essential element of viral replication and infection mechanisms.
  • HCV NS3 serine proteases have been found to facilitate cleavage of junction proteins such as NS3/NS4a, NS4a/NS4b, NS4b/NS5a, NS5a/NS5b, and are responsible for the production of four viral proteins during viral replication (see US 2003/0207861). ). Therefore, HCV NS3 serine protease has become the most attractive target for the treatment of hepatitis C virus infection.
  • HCV NS3 serine protease inhibitors such as the patent WO2007/014920 published by Tibotec and Medivir, disclose N-linked serine carbamate macrocyclic polypeptide compounds derived from quinoline and isoquinoline; Abbott Corporation Patent WO2008/074035 discloses a special cycloalkane-derived linear polypeptide compound; a linear and macrocyclic polypeptide compound derived from a special piperidine disclosed in Achi11ion Corporation, WO2008/106130; and a patent issued by Merck, WO2008/057209 A macrocyclic polypeptide compound which is linked from an aromatic ring at the position of the P2 of the HCV NS3 serine protease is disclosed; and a special borate ester is disclosed in the patent of WOHOmix, WO2007/016476, published on Feb.
  • HCV NS3 serine protease formed at the P1 position A linear polypeptide compound is disclosed in US Pat.
  • the structure of large-helix hepatitis C drug is designed to
  • the 14-20 membered ring is a macrocyclic compound mainly composed of different amino acids and monomers through an amide bond and an olefin double bond.
  • the novel macrocyclic compound A which is formed by a special aromatic heterocyclic ring and has a 18-19-membered heterocyclic ring as a core, is characterized by the introduction of different functional groups and the like according to the characteristics of the hepatitis C virus serine protease target.
  • the compounds were structurally modified and optimized to invent a novel HCV NS3 inhibitor that inhibits the activity of hepatitis C virus.
  • the key innovation of the present application is to provide a novel macrocyclic heterocyclic compound with a 18-19-membered heterocyclic ring as a core, and an intermediate thereof, a preparation method and application thereof, which are different from the prior art.
  • the macrocyclic heterocyclic compound of the present application has a preferred inhibitory activity against hepatitis C virus, can be effectively used for treating hepatitis C virus infection, and has low toxic side effects.
  • the application provides a compound of formula A:
  • AB is a single bond or a carbon-carbon double bond; when AB is a single bond, A is selected from oxygen, sulfur or nitrogen, and B is selected from C 1-6 alkyl;
  • n 0, 1 or 2;
  • Q is selected from optionally substituted C 1-6 alkyl, C 2-6 alkenyl , or C 3-6 cycloalkyl, the substituent being selected from halogen C 1-6 alkyl, C 1 -C 6 alkane Oxylate
  • L is independently an oxygen, sulfur, C 2 -C 20 alkenyl group, C 1 -C 20 alkyl group, C 3 -C 20 cycloalkyl group, C 2 -C 20 heterocyclic group, C 6 -C 20 aryl group , C 3 -C 20 heterocyclic aryl, C 1 -C 20 alkylthio, C 1 -C 20 alkoxy, C 3 -C 20 cycloalkoxy, C 2 -C 20 heterocyclooxy, C 1 -C 20 alkylamino, C 1 -C 20 alkoxymonocarbonyl, C 6 -C 20 aryl, or C 6 -C 20 aryloxy;
  • Each of L 1 is independently oxygen, sulfur, C 2 -C 20 alkenyl, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 2 -C 20 heterocyclic, C 6 -C 20 , C 3 -C 20 heterocyclic aryl, C 1 -C 20 alkylthio, C 1 -C 20 alkoxy, C 3 -C 20 cycloalkoxy, C 2 -C 20 heterocyclooxy a C 1 -C 20 alkylamino group, a C 1 -C 20 alkoxycarbonyl group, a C 6 -C 20 aryl group, or a C 6 -C 20 aryloxy group;
  • X is oxygen, sulfur or nitrogen
  • Y is nitrogen or CH
  • R 1 is hydrogen, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 6 -C 20 aryl, C 3 -C 20 heteroaryl, C 1 -C 20 alkylsulfonylamino , C 2 -C 20 heterocyclic sulfonylamino, or C 1 -C 20 alkoxycarbonylamino;
  • R 2 is hydrogen, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 20 alkoxy-carbonyl, C 3 -C 20 cycloalkoxy-carbonyl, C 6 -C 20 Aryl, C 3 -C 20 heterocyclic aryl, C 6 -C 20 aryloxy, C 1 -C 20 alkylsulfonyl, C 3 -C 20 cycloalkylsulfonyl, C 1 -C 20 alkoxy Sulfonyl, C 3 -C 20 cycloalkoxysulfonyl, C 6 -C 20 arylsulfonyl, C 6 -C 20 aryloxysulfonyl, C 1 -C 20 alkylaminosulfonyl, C 3 - C 20 cycloalkylaminosulfonyl or C 6 -C 20 arylaminosulfonyl;
  • R 3 and R 4 are each independently hydrogen, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 20 alkoxy, halogen, hydroxy, cyano, nitro, C 1 - C 20 alkylamino, C 2 -C 20 heterocyclic amino, C 6 -C 20 aryl, C 6 -C 20 arylamino, C 1 -C 20 alkylsulfonylamino, C 2 -C 20 heterocyclic a sulfonylamino group, a C 6 -C 20 arylsulfonylamino group or a C 1 -C 20 alkylaminosulfonylamino group; wherein R 3 and R 4 may be bonded to each other to form a cyclic structure;
  • R 5 and R 6 are each independently hydrogen, halogen, hydroxy, cyano, nitro, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 20 alkoxy, C 1 - C 20 alkylamino, C 2 -C 20 heterocyclic amino, C 6 -C 20 aryl, C 6 -C 20 arylamino, C 1 -C 20 alkylsulfonylamino, C 2 -C 20 heterocyclic Sulfonylamino, C 6 -C 20 arylsulfonylamino or C 1 -C 20 alkylaminosulfonylamino;
  • R 7 and R 8 , R 8 and R 9 or R 9 and R 10 are bonded to each other to form a 5-6 membered heterocyclic ring containing oxygen or nitrogen, and the heterocyclic ring is optionally substituted by a C1-C6 alkyl group;
  • the uncyclized groups in R 7 , R 8 , R 9 and R 10 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, trifluoromethyl, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 1 -C 20 alkylthio, C 1 -C 20 alkoxy-carbonyl, aminocarbonyl, C 1 -C 20 alkylaminocarbonyl, carbonylamino, C1-C 20 alkylcarbonylamino, C 2 -C 20 heterocyclyloxycarbonyl, C 6 -C 20 aryl, C 6 -C 20 aryloxy, C 6 -C 20 aryloxycarbon
  • J is hydrogen, hydroxy, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 20 alkoxy, C 3 -C 20 cycloalkoxy, C 1 -C 20 alkylamino , C 3 -C 20 cycloalkylamino, C 2 -C 20 heterocyclic amino, C 6 -C 20 aryl, C 6 -C 20 arylamino, C 4 -C 20 heterocyclic arylamino, RSO 2 NH- , -SO 2 NH 2 or -SO 2 NHR, wherein R is selected from optionally substituted C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 3 -C 20 cycloalkyl, C 6 -C 20 C 3 -C 20 cycloalkoxy, C 6 -C 20 aryloxy, C 1 -C 20 alkylamino, C 3 -C 20 cycloalkylamino, C 6
  • the heterocyclic ring in each of the above groups contains from 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • AB is a single bond or a carbon-carbon double bond; when AB is a single bond, A is selected from oxygen, sulfur or nitrogen, B is selected from C 1-6 alkyl, and R 3 and R 4 are each independently C 1 -C 6 An alkyl group, a C 3 -C 6 cycloalkyl group, a C 1 -C 6 alkoxy group, a C 1 -C 6 alkylamino group, wherein R 3 and R 4 are bonded to form a 3-7 membered ring structure, optionally C a 1-6 alkyl group; when AB is a carbon-carbon double bond, R 3 and R 4 are each independently hydrogen;
  • R 5 and R 6 are each independently hydrogen, halogen, hydroxy, cyano, nitro, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 - C 6 alkylamino, C 2 -C 6 heterocyclic amino, C 6 -C 10 aryl, C 6 -C 10 arylamino, C 1 -C 6 alkylsulfonylamino, C 2 -C 6 heterocyclic a sulfonylamino group, a C 6 -C 10 arylsulfonylamino group or a C 1 -C 6 alkylaminosulfonylamino group, wherein the heterocyclic ring contains 1-3 nitrogen, oxygen or sulfur atoms;
  • R 7 , R 8 , R 9 and R 10 , R 7 and R 8 , R 8 and R 9 and/or R 9 and R 10 are bonded to each other to form a 5-6 membered heterocyclic ring containing oxygen or nitrogen, and the heterocycle being optionally substituted with C1-C6 alkyl; remaining unpaired cyclic group independently selected from hydrogen, halogen, hydroxy, cyano, nitro, trifluoromethane group, C 1 -C 6 -alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkoxy-carbonyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, carbonylamino, C 1 -C 6 alkyl Carbonylamino, C 2 -C 6 heterocyclyloxycarbonyl, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 6 -C 10 aryloxycarbonyl or C
  • J is hydrogen, hydroxy, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, C 1 -C 6 alkylamino , C 3 -C 6 cycloalkylamino, C 2 -C 6 heterocyclic amino, C 6 -C 10 aryl, C 6 -C 10 arylamino, C 4 -C 10 heterocyclic arylamino, RSO 2 NH- , -SO 2 NH 2 or -SO 2 NHR, wherein R is selected from optionally substituted C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkane Oxy, C 3 -C 6 cycloalkoxy, C 6 -C 10 aryloxy, C 1 -C 6 alkylamino, C 3 -C 6 cycloalky
  • L is a single bond, oxygen, sulfur, C 2 -C 6 alkenyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocyclic, C 6 -C 10 aryl , C 3 -C 6 heterocyclic aryl, C 1 -C 6 alkylthio, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, C 2 -C 6 heterocyclooxy, C 1 -C 6 alkylamino, C 1 -C 6 alkoxycarbonyl, C 6 -C 10 aryl, or C 6 -C 10 aryloxy;
  • L 1 is selected from the group consisting of oxygen, sulfur, C 2 -C 6 alkenyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocyclic, C 6 -C 10 aryl, C 3 -C 6 heterocyclic C 6 -C 10 aryl, C 1 -C 6 alkylthio, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, C 2 -C 6 heterocyclic Alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 alkoxycarbonyl, C 6 -C 10 aryl, or C 6 -C 10 aryloxy;
  • X is oxygen, sulfur or nitrogen
  • Y is nitrogen or CH
  • R 1 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, C 3 -C 6 heteroaryl, C 1 -C 6 alkylsulfonylamino , a C 2 -C 6 heterocyclic sulfonylamino group, or a C 1 -C 6 alkoxycarbonylamino group;
  • R 2 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy-carbonyl, C 3 -C 6 cycloalkoxy-carbonyl, C 6 -C 10 Aryl, C 3 -C 60 heterocyclic C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 1 -C 6 alkylsulfonyl, C 3 -C 6 cycloalkylsulfonyl, C 1 -C 6 alkoxysulfonyl, C 3 -C 6 cycloalkoxysulfonyl, C 6 -C 10 arylsulfonyl, C 6 -C 10 aryloxysulfonyl, C 1 -C 6 alkylaminosulfonate
  • L is a single bond
  • L 1 is selected from oxygen or sulfur
  • X is selected from the group consisting of oxygen, sulfur or nitrogen;
  • Y is selected from nitrogen or CH;
  • R 1 is selected from t-butyl;
  • R 2 is selected from hydrogen
  • A is selected from oxygen, sulfur or nitrogen
  • B is selected from methylene
  • R 3 and R 4 are independently methyl
  • R 3 and R 4 are independently hydrogen.
  • R 5 and R 6 are independently hydrogen
  • R 7 , R 8 , R 9 and R 10 , R 7 and R 8 , R 8 and R 9 or R 9 and R 10 are bonded to each other to form a 5-6 membered heterocyclic ring containing oxygen or nitrogen, and the hetero
  • the ring is optionally substituted with a C 1 -C 6 alkyl group; the remaining uncyclic group is selected from hydrogen;
  • Q is selected from optionally substituted C 1-6 alkyl, C 2-6 alkenyl , or C 3-6 cycloalkyl, said substituent being selected from halogen;
  • J is selected from RSO 2 NH-, -SO 2 NH 2 or -SO 2 NHR, wherein R is selected from an optionally substituted C 3 -C 6 cycloalkyl group, and the substituent is selected from a C 1 -C 6 alkyl group.
  • L is a single bond
  • L 1 is selected from oxygen
  • X is selected from oxygen
  • Q is selected from the group consisting of an optionally substituted methyl, ethyl, vinyl or cyclopropyl group,
  • the substituent is selected from halogen.
  • J is selected from the group consisting of RSO 2 NH-, Or -SO 2 NHR, wherein R is selected from optionally substituted C 3 -C 6 cycloalkyl, the substituent being selected from methyl or ethyl.
  • the compounds of formula A of the present application include macrocyclic polycyclic compounds of formula I or II:
  • Y, R 7 , R 8 , R 9 and R 10 are as defined in the formula A.
  • the compound Va-f is obtained by a condensation reaction using the raw material SM-2 and the raw material SM-2a; wherein R 7 , R 8 , R 9 and R 10 are as defined in the formula A;
  • the preparation of the compound V is carried out under the protection of an inert gas in an organic solvent, the amount of the raw material SM-2a is 1-2 times the molar amount of SM-2; the reaction temperature is 50-100 ° C;
  • the raw material SM-3 is in an anhydrous organic solvent, in the triphenylphosphine and azodicarboxylate (such as diethyl azodicarboxylate or diazodicarboxylic acid) Mitsunobu reaction with another reagent V under the action of propyl ester to form compound 3-1;
  • SM-3 and compound V and other groups in product 3-1 (including X, Y, R 5 , R 6 , R 7 , R 8 , R 9 ) is as defined above for formula A;
  • R 11 is C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl or C 1 -C 6 aminocarbonyl;
  • step 3 Under the protection of an inert gas, the compound 3-2 obtained in step 2) is deprotected from the protective group R 11 and then reacted with another reagent SM-5 under the action of phosgene or triphosgene to form compound 3-3;
  • Reagent SM-5 and each group and parameter in the product (including n, L, L 1 , X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 ) is as defined in the above formula A;
  • R 11 is as defined above;
  • the compound 3-3 obtained in the step 3) is reacted under the action of a palladium catalyst to obtain a macrocyclic product 3-4; each group and parameters in the product (including n, L, L 1) , X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 ) are as defined above for Formula A;
  • the compound 3-4 obtained in the step 4) is subjected to hydrolysis and acidification, and then reacted with SM-6 under the action of a coupling reagent (such as: HATU) to form a final macrocyclic polycyclic compound I; -6 and each group and parameter in the product (including n, L, L 1 , X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , J) are as defined in the above formula A;
  • step 1) under the protection of an inert gas, the SM-3 raw material is dissolved in an organic solvent (such as dichloromethane, tetrahydrofuran or toluene) in triphenylphosphine and azodicarboxylate (such as azo).
  • organic solvent such as dichloromethane, tetrahydrofuran or toluene
  • triphenylphosphine and azodicarboxylate such as azo
  • Mitsunobu reaction with another reagent V under the action of diethyl dicarboxylate or diisopropyl azodicarboxylate to form compound 3-1; the reaction temperature is 0-40 ° C, the triphenylbenzene
  • the amount of phosphorus used is 1-2 times the molar amount of the raw material SM-3, and the amount of the azodicarboxylate is 1-2 times the molar amount of the raw material SM-3;
  • step 2) the compound 3-1 obtained in the step 1) is subjected to an inert gas protection under the action of a strong acid (such as hydrochloric acid, sulfuric acid or trifluoroacetic acid) at a temperature of 10 to 50 ° C to remove the protective group.
  • a strong acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid
  • R 11 such as Boc
  • an amine intermediate is formed, which is then reacted with a coupling reagent (eg, HATU) at an organic solvent such as dichloromethane, tetrahydrofuran or N,N-dimethyl at a temperature of 0-80 ° C.
  • Reaction with reagent SM-4 in formamide gives compound 3-2; the coupling reagent is used in an amount of 1-2.5 times the molar amount of compound 3-1.
  • step 3 the compound 3-2 obtained in the step 2) is subjected to an inert gas protection under the action of a strong acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid at a temperature of 10 to 50 ° C to remove the protective group.
  • a strong acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid
  • R 11 an amine intermediate is formed, and an isocyanate intermediate is formed under the action of phosgene or triphosgene, followed by another reagent SM in an organic solvent (such as dichloromethane, tetrahydrofuran or toluene) at a temperature of 0-40 ° C.
  • the -5 reaction forms the compound 3-3; the triphosgene is used in an amount of from 1 to 2 times the molar amount of the compound 3-2.
  • step 4 the compound 3-3 obtained in the step 3) is dissolved in an anhydrous organic solvent (such as 1,4-dioxane, tetrahydrofuran or toluene) under an inert gas atmosphere, in a palladium catalyst (such as Palladium acetate or tetrakistriphenylphosphine palladium), phosphorus ligands (such as 2-(di-tert-butylphosphino)-1,1'-binaphthyl) and inorganic strong bases (such as barium carbonate) at a temperature of 0 -100 ° C reaction, to obtain a large cyclic product 3-4; palladium catalyst is used in an amount of 0.2-5% by mole of the raw material SM-1; phosphorus ligand is used in an amount of 0.3-10% by mole of the raw material SM-1;
  • the amount of the inorganic base is 1-3 times the molar amount of the raw material SM-1;
  • step 5 the compound 3-4 obtained in the step 4) is subjected to the action of an inorganic strong base such as lithium hydroxide or sodium hydroxide in a solvent such as water, methanol, tetrahydrofuran or 1,4-dioxane.
  • an inorganic strong base such as lithium hydroxide or sodium hydroxide
  • a solvent such as water, methanol, tetrahydrofuran or 1,4-dioxane.
  • the hydrolysis is carried out at 10-60 ° C to remove the protective methoxy group and then acidified to form a carboxylic acid, and then under the action of a coupling reagent (such as: HATU) in an organic solvent (such as dichloromethane, tetrahydrofuran or N).
  • a coupling reagent such as: HATU
  • organic solvent such as dichloromethane, tetrahydrofuran or N.
  • a method of preparing a macrocyclic polycyclic compound of Formula A in Formula A of the present application comprising the following six steps:
  • the raw material SM-3 is in an anhydrous organic solvent, in the triphenylphosphine and azodicarboxylate (such as diethyl azodicarboxylate or diazodicarboxylic acid) Mitsunobu reaction with another reagent V under the action of propyl ester to form compound 3-1;
  • SM-3 and compound V and other groups in product 3-1 are as defined above for formula A;
  • R 11 is C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl or C 1 -C 6 aminocarbonyl;
  • the compound 4-1 obtained in the step 2) is removed from the protecting group R 11 and then reacted with another amino acid derivative reagent SM-4 under the action of a coupling reagent to form a compound 4-2;
  • the definition of each group in the product (including X, Y, R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 ) is as defined in the above formula A; R 11 is as defined above;
  • the compound 4-2 obtained in the step 3) is deprotected from the protecting group R 11 and then reacted with another reagent SM-7 to form a compound 4-3; the reagent SM-7 and each group in the product And the parameters (including n, L, L 1 , X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 ) are as defined above A; R 11 is as defined above;
  • the diene compound 4-3 obtained in the step 4) is subjected to an olefin metathesis cyclization reaction to obtain a macrocyclic product 4 under the action of a ruthenium catalyst (such as a Jane catalyst or a Grubbs catalyst).
  • a ruthenium catalyst such as a Jane catalyst or a Grubbs catalyst.
  • the compound 4-4 obtained in the step 5) is subjected to hydrolysis and acidification, and then reacted with SM-6 under the action of a coupling reagent (for example, HATU) to form a final macrocyclic compound II; SM-6.
  • a coupling reagent for example, HATU
  • various groups and parameters in the product including n, L, L 1 , X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , J) is defined as described in the above formula A;
  • step 1) under the protection of an inert gas, the SM-3 raw material is dissolved in an organic solvent (such as dichloromethane, tetrahydrofuran or toluene) in triphenylphosphine and azodicarboxylate (such as azo).
  • organic solvent such as dichloromethane, tetrahydrofuran or toluene
  • triphenylphosphine and azodicarboxylate such as azo
  • Mitsunobu reaction with another reagent V under the action of diethyl dicarboxylate or diisopropyl azodicarboxylate to form compound 3-1; the reaction temperature is 0-40 ° C, the triphenylbenzene
  • the amount of phosphorus used is 1-2 times the molar amount of the raw material SM-3, and the amount of the azodicarboxylate is 1-2 times the molar amount of the raw material SM-3;
  • step 2) the compound 3-1 obtained in the step 1) is dissolved in an organic solvent (such as ethanol, toluene or tetrahydrofuran) under an inert gas atmosphere, and an ethylene trifluoroborate in a palladium catalyst (such as Pd (The compound 4-1 is obtained by a Suzuki reaction at a temperature of 20-100 ° C under the action of dppf)Cl 2 ) and a base (such as triethylamine); the amount of the ethylene trifluoroborate is the molar amount of the raw material SM-3. 1-4 times; the amount of the palladium catalyst is 0.03-5% times the molar amount of the raw material SM-3; the amount of the base is 1-4 times the molar amount of the raw material SM-3.
  • an organic solvent such as ethanol, toluene or tetrahydrofuran
  • a palladium catalyst such as Pd
  • a base such as triethylamine
  • step 3 the compound 4-1 obtained in the step 2) is subjected to an inert gas protection under the action of a strong acid (such as hydrochloric acid, sulfuric acid or trifluoroacetic acid) at a temperature of 10 to 50 ° C to remove the protective group.
  • a strong acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid
  • R 11 such as Boc
  • an amine intermediate is formed, which is then reacted with a coupling reagent (eg, HATU) at an organic solvent such as dichloromethane, tetrahydrofuran or N,N-dimethyl at a temperature of 0-80 ° C.
  • a coupling reagent eg, HATU
  • the reaction with the reagent SM-4 in the formamide gives the compound 4-2; the coupling reagent is used in an amount of 1-2.5 times the molar amount of the compound 4-1.
  • step 4 the compound 4-2 obtained in the step 3) is subjected to an inert gas protection under the action of a strong acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid at a temperature of 10 to 50 ° C to remove the protective group.
  • a strong acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid
  • R 11 an amine intermediate is formed, which is then reacted with another reagent SM-7 at 10-30 ° C in an organic solvent (such as dichloromethane, tetrahydrofuran or toluene) under the action of a base such as triethylamine.
  • Diene compound 4-3 the base is used in an amount of from 1 to 5 times the molar amount of the compound 4-2.
  • step 5 the diene compound 4-3 obtained in step 4) is dissolved in an anhydrous organic solvent (such as dichloromethane, dichloroethane or toluene) under an inert gas atmosphere, in a ruthenium catalyst (eg: Under the action of Jen's catalyst or Grubbs catalyst, the reaction is carried out at a temperature of 0-100 ° C, and the olefin metathesis cyclization reaction is carried out to obtain a macrocyclic product 4-4; the amount of the ruthenium catalyst is diene compound 4-3 a molar amount of 0.2-10%; the organic solvent is used in an amount of 15-40 times the weight ratio of the diene compound 4-3;
  • anhydrous organic solvent such as dichloromethane, dichloroethane or toluene
  • a ruthenium catalyst eg: Under the action of Jen's catalyst or Grubbs catalyst, the reaction is carried out at a temperature of 0-100 ° C, and the olefin meta
  • step 6 the compound 4-4 obtained in the step 5) is subjected to the action of an inorganic strong base such as lithium hydroxide or sodium hydroxide in a solvent such as water, methanol, tetrahydrofuran or 1,4-dioxane.
  • an inorganic strong base such as lithium hydroxide or sodium hydroxide
  • a solvent such as water, methanol, tetrahydrofuran or 1,4-dioxane.
  • the hydrolysis is carried out at 10-60 ° C to remove the protective methoxy group and then acidified to form a carboxylic acid, and then under the action of a coupling reagent (such as: HATU) in an organic solvent (such as dichloromethane, tetrahydrofuran or N).
  • a coupling reagent such as: HATU
  • organic solvent such as dichloromethane, tetrahydrofuran or N.
  • a sixth aspect of the invention provides a use of a compound, stereoisomer, tautomer, esterified or amidated prodrug, pharmaceutically acceptable salt thereof, or mixture thereof, of the present application It is used to inhibit HCV; or to prepare a drug that inhibits HCV; or to prepare a drug for treating a hepatitis C virus infectious disease or condition.
  • a seventh aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: one or more compounds of Formula A (such as Formula I or II) described herein, or a stereoisomer, tautomer thereof, An esterified or amidated prodrug, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a composition comprising one or more compounds of Formula A (such as Formula I or II) described herein, or a stereoisomer, tautomer thereof, esterification thereof Or an amidated prodrug, or a pharmaceutically acceptable salt thereof, and one or more of the following: (1) an immunomodulatory agent; (2) a hepatitis C virus (HCV) protease inhibitor; (3) Hepatitis C virus (HCV) polymerase inhibitor; (4) nucleoside and nucleoside derivatives not belonging to (2)-(3); (5) hepatitis B virus (HBV) inhibitor; (6) human Immunodeficiency virus (HIV) inhibitors; (7) anticancer drugs; (8) anti-inflammatory drugs; or (9) other compounds not belonging to the above (1)-(8).
  • HCV hepatitis C virus
  • HCV Hepatitis C virus
  • HCV Hepatitis C virus
  • HCV human Immunodeficiency virus
  • anticancer drugs (8) anti-inflammatory drugs; or (9) other compounds not belonging to
  • compositions of the present application include, but are not limited to, oral dosage forms, parenteral dosage forms, topical dosage forms, and rectal administration dosage forms.
  • the pharmaceutical composition may be an oral tablet, capsule, pill, powder, sustained release formulation, solution and suspension, sterile solution, suspension or emulsion for parenteral injection.
  • the pharmaceutical composition is in a unit dosage form suitable for single administration of precise dosages.
  • the amount of the compound ranges from about 0.001 mg/kg body weight/day to about 1000 mg/kg body weight/day. In other embodiments, the amount of the compound ranges from about 0.5 mg/kg body weight/day to about 50 mg/kg body weight/day.
  • the amount of the compound is from about 0.001 g/day to about 7 g/day. In other embodiments, the amount of the compound is from about 0.002 g/day to about 6 g/day. In other embodiments, the amount of the compound is from about 0.005 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.01 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.02 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.05 g/day to about 2.5 g/day. In other embodiments, the amount of the compound is from about 0.1 g/day to about 1 g/day.
  • a dose level below the lower limit of the above range may already be sufficient. In other embodiments, dose levels above the upper limit of the above range may be required.
  • the compound is administered in a single dose, once a day. In other embodiments, the compound is administered in multiple doses more than once a day. In some embodiments, the compound is administered twice daily. In other embodiments, the compound is administered three times a day. In other embodiments, the compound is administered four times a day. In other embodiments, the compound is administered more than four times a day.
  • the individual to which the pharmaceutical composition is administered is a mammal. In other embodiments, the mammal is a human.
  • the pharmaceutical composition further comprises at least one other drug that is co-formulated into a dosage form. In some embodiments, the pharmaceutical composition and at least one other drug are each combined in a separate dosage form into a combined product, such as a kit of parts.
  • the immunomodulatory agent in the above drugs contains an interferon or an interferon derivative.
  • the interferon described therein may be polyethylene glycol interferon.
  • the HIV inhibitors include, but are not limited to, ritonavir (Ritonavir).
  • the hepatitis B virus (HBV) inhibitors include, but are not limited to, lamivudine, telbivudine, adefovir, emtricitabine, entecavir, tenofovir or koviffin.
  • the ninth aspect of the present application provides the use of any of the above pharmaceutical compositions for the preparation of a medicament for inhibiting hepatitis C virus, or for the preparation of a medicament for treating a hepatitis C virus infectious disease or disorder.
  • a method of inhibiting HCV or treating a hepatitis C virus infectious disease or condition, wherein the compound, stereoisomer, tautomer, pharmaceutically acceptable salt thereof, of the present application comprises the step of administering the compound to an individual in need thereof.
  • the individual is a mammal, such as a human.
  • the manufacturer's instructions for use of the kit can be utilized, or the reaction can be carried out and purified according to methods well known in the art or as described in the present application.
  • the above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification.
  • the group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left.
  • CH 2 O is equivalent to OCH 2 .
  • alkyl as used herein includes an optionally substituted alkyl group.
  • optionally substituted alkyl means “unsubstituted alkyl” (alkyl substituted without a substituent) or “substituted alkyl” (alkyl substituted with a substituent) .
  • C 1 -C n as used herein includes C 1 -C 2 , C 1 -C 3 , ... C 1 -C n .
  • the "C 1 -C 4 " group means having from 1 to 4 carbon atoms in the moiety, ie the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbons atom.
  • C 1 -C 4 alkyl refers to an alkyl group having from 1 to 4 carbon atoms, that is, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, and n-butyl Base, isobutyl, sec-butyl and tert-butyl.
  • a numerical range, for example, "1-10” refers to each integer in a given range, for example "1-10 carbon atoms” means that the group may have 1 carbon atom, 2 carbon atoms, 3 Carbon atom, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
  • alkyl refers to an optionally substituted straight or optionally substituted branched saturated aliphatic hydrocarbon.
  • the “alkyl” herein may preferably have from 1 to about 20 carbon atoms, for example from 1 to about 10 carbon atoms, from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms, or from 1 to about 4.
  • Alkyl embodiments herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-1 -butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl 1-yl-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2 - dimethyl-l-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, positive Butyl, isopentyl, neopentyl, tert-amyl and hexyl, as well as longer alkyl groups such as
  • alkyl When a group as defined herein, such as “alkyl” appears numerical range, for example, “C 1 -C 6 alkyl” or “C 1 - 6 alkyl” refers to by a carbon atom, 2 carbon atoms, 3 An alkyl group consisting of a carbon atom, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, and the alkyl group herein also contains an unspecified number range.
  • alkyl refers to an alkyl group that is linked to other groups, such as an alkyl group in an alkoxy group, an alkyl group in an alkylthio group, a hydroxyalkyl group, a haloalkyl group, a cyanoalkyl group, a monoalkylene group.
  • An alkyl group or a "alkyl group” in a dialkylamino group is an alkyl group that is linked to other groups, such as an alkyl group in an alkoxy group, an alkyl group in an alkylthio group, a hydroxyalkyl group, a haloalkyl group, a cyanoalkyl group, a monoalkylene group.
  • An alkyl group or a "alkyl group” in a dialkylamino group is an alkyl group that is linked to other groups, such as an alkyl group in an alkoxy group, an alkyl group in an alkylthio group, a
  • alkoxy refers to an alkyl ether group (O-alkyl), non-limiting examples of which include methoxy, ethoxy, n-propoxy, isopropyl Oxyl, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy groups.
  • the alkenyl group has, but is not limited to, from 2 to about 18 carbon atoms, for example, from 2 to about 10 carbon atoms, or from 2 to about 8 carbon atoms, from 2 to about 6 carbon atoms, from 2 to about 4 carbon atom.
  • the double bond in these groups may be in the cis or trans conformation and should be understood to encompass both isomers.
  • alkenyl group as defined herein appears in the numerical range, for example "C 2 -C 6 alkenyl” or “C 2 - 6 alkenyl” means 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbons
  • An alkenyl group consisting of an atom or 6 carbon atoms, and the alkenyl group herein also covers the case where the numerical range is not specified.
  • alkynyl refers to an optionally substituted straight or branched chain monovalent hydrocarbon radical having at least one C ⁇ C triple bond.
  • the alkynyl group has, but is not limited to, 2 to about 18 carbon atoms, for example, it has 2 to about 10 carbon atoms, or has 2 to about 8 carbon atoms, or 2 to about 6 carbon atoms, or 2 to about 4 carbon atoms.
  • Examples of alkynyl groups herein include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiynyl, and the like.
  • alkynyl groups as defined herein are in the numerical range, for example "C 2 -C 6 alkynyl” or “C 2 -6 alkynyl” means 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbons
  • An alkynyl group consisting of an atom or 6 carbon atoms, the alkynyl group herein also covers the unspecified range of numbers.
  • halo or "halogen-substituted” as used herein, alone or in combination, means that at least one hydrogen atom of an optionally substituted group (eg, alkyl, alkenyl, and alkynyl) is replaced with a halogen (eg, fluoro, Chlorine, bromine, iodine or a combination thereof).
  • a halogen eg, fluoro, Chlorine, bromine, iodine or a combination thereof.
  • two or more hydrogens eg, difluoromethyl, trifluoromethyl
  • Hydrogen eg 1-chloro-1-fluoro-1-iodoethyl.
  • Non-limiting examples of haloalkyl groups are fluoromethyl and bromoethyl.
  • a non-limiting example of a haloalkenyl group is a bromovinyl group.
  • a non-limiting example of a haloalkynyl group is a chloroethynyl group.
  • aryl/aryl refers to an optionally substituted aromatic hydrocarbon radical having from 6 to about 20, such as from 6 to 12 or from 6 to 10 ring-forming carbon atoms, which may be a single Cycloaryl, bicyclic aryl or more cyclic aryl.
  • the bicyclic aryl or more cyclic aryl group may be a monocyclic aryl group fused to other independent rings such as an alicyclic ring, a heterocyclic ring, an aromatic ring or an aromatic heterocyclic ring.
  • Non-limiting examples of monocyclic aryl groups include 6 to about 12, 6 to about 10 or 6 to about 8 monocyclic aryl groups of a ring-constituting carbon atom, such as phenyl; bicyclic aryl groups such as naphthyl;
  • the polycyclic aryl group is, for example, a phenanthryl group, a fluorenyl group or a fluorenyl group
  • heterocyclic aryl or heteroaryl refers to an optionally substituted heteroaryl group containing from about 5 to about 20, such as from 5 to 12 or from 5 to 10 backbones to form a ring atom, At least one (eg, 1-4, 1-3, 1-2) ring-forming atoms are heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin. Heteroatoms, but are not limited to this. The ring of the group does not contain two adjacent O or S atoms.
  • Heteroaryl groups include monocyclic heteroaryl (having one ring), bicyclic heteroaryl (having two rings) or polycyclic heteroaryl (having more than two rings). In embodiments in which two or more heteroatoms are present in the ring, the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other.
  • the bicyclic heteroaryl or more cycloheteroaryl group may be a monocyclic heteroaryl group fused to other independent rings such as an alicyclic ring, a heterocyclic ring, an aromatic ring or an aromatic heterocyclic ring (collectively referred to as a fused ring heteroaryl group). ).
  • Non-limiting examples of monocyclic heteroaryl groups include from 5 to about 12, from 5 to about 10, from 5 to about 7 or 6 monocyclic heteroaryl groups which are backbone-ringed, for example, non-limiting examples thereof Included is pyridyl; fused ring heteroaryl includes benzimidazolyl, quinolinyl, acridinyl.
  • heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, triazine, furan, thiophene, imidazole, triazole, tetrazole, thiazole, isothiazole, 1,2,4-thiadiene Oxazole, pyrrole, pyrazole, oxazole, isoxazole, oxadiazole, benzofuran, benzothiophene, benzothiazole, hydrazine, carbazole, quinoline, isoquinoline, indole, carbazole, benzo Imidazole, pyrrolopyridine, pyrrolopyrimidine, pyrazolopyridine, pyrazolopyrimidine and the like.
  • heterocycle refers to a non-aromatic heterocycle which includes a saturated heterocyclic ring or an unsaturated heterocyclic ring (containing an unsaturated bond).
  • One or more (e.g., 1-4, 1-3, 1-2) ring-forming atoms are heteroatoms such as oxygen, nitrogen or sulfur atoms.
  • the heterocyclic ring may include a single heterocyclic ring (having one ring) or a bicyclic heterocyclic ring (having two bridged rings) or a polyheterocyclic ring (having a ring having two or more bridges); also includes a spiro ring.
  • Heterocyclyl groups can have from 3 to about 20, such as from 3 to about 10, from 3 to 8, 4 to 8, 4 to 7, 5 to about 8, or from 5 to about 6 ring-forming atoms.
  • Non-limiting examples of heterocyclic groups include azinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl ( Homopiperidinyl), oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3- 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, Dihydrothienyl, dihydrofuranyl
  • the term also encompasses all cyclic forms of saccharides including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Examples include, but are not limited to, aziridine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, oxazolidine, thiazolidine, imidazolidine, isoxazolidine, isothiazolidine, pyrazolidine, morpholine, thio? Porphyrin, piperazine, piperidinyl and the like.
  • Heterocyclyl also includes heterocycles having one or more aromatic rings fused (ie, having a common bond), such as 2,3-dihydrobenzofuran, 1,3-benzene And dioxolane, benzo-1,4-dioxane, phthalimide, naphthalimide.
  • the heterocyclic group having one or more aromatic condensations may be bonded to other groups through an aromatic ring or a non-aromatic ring moiety.
  • Other groups may be bonded to the heterocycle via a heteroatom or a carbon atom (ie, the heterocycle is attached or further substituted with the parent molecule).
  • cycloalkyl as used herein, alone or in combination, may be monocyclic cycloalkyl or bicyclic cycloalkyl, and the rings may be bridged or spiro.
  • the cycloalkyl group can have from 3 to 20 carbon atoms, for example from 3 to about 15 ring-forming carbon atoms or from 3 to about 10 ring-forming carbon atoms or from 3 to 6 ring-forming carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and the like.
  • the alkoxy group may be represented by "alkyl-O-"; the cycloalkoxy group may be represented by “cycloalkyl-O-”; the aryloxy group may be represented by “aryl-O-”; the alkylamino group may be represented by " Alkyl-N-”; cycloalkylamino can be represented as “cycloalkyl-N-”; arylamino can be represented as "aryl-N-” wherein alkyl, cycloalkyl and aryl are as defined above.
  • Halogen means fluoro, chloro, bromo, iodo. The preferred are fluorine, chlorine and bromine.
  • the cyano group means "-CN”; the hydroxy group means “-OH”; the thiol group means “-SH”; and the amino group means "-NH 2 ".
  • Sulfonylamino means “RSO 2 NH-” and Aminosulfonyl means “-SO 2 NH 2 " or "-SO 2 NHR", wherein R may be alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, cycloalkoxy, aryloxy , alkylamino, cycloalkylamino, arylamino, ureido, thiourea, phosphate, or borate, these groups are as defined above. structure In the above, the substituent on N is selected from a C 1-6 alkyl group, a C 1-6 alkoxy group or a C 3-6 cycloalkyl group.
  • alkylsulfonylamino group refers to the case where R is an alkyl group in the structural formula represented by a sulfonylamino group
  • alkoxysulfonylamino group refers to a case where R is an alkoxy group in the structural formula represented by a sulfonylamino group, and so on.
  • substituted means that one or more hydrogens are replaced by a specified group on a particular atom. If the normal valence of the specified atom is not exceeded in the existing case, the result of the substitution is one. A stable compound.
  • the terms "subject,” “patient,” or “individual” refer to an individual, including a mammal, and a non-mammal, having a disease, disorder, condition, or the like.
  • mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (eg, chimpanzees and other mites and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domesticated Animals such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs.
  • non-human mammals include, but are not limited to, birds and fish.
  • the mammal is a human.
  • treatment includes alleviating, alleviating or ameliorating the symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing a potential metabolic cause of the symptoms, inhibiting the disease or condition, such as preventing the progression of the disease or condition, Ameliorating a disease or condition, ameliorating the disease or condition, alleviating the symptoms caused by the disease or condition, or terminating the symptoms of the disease or condition, and further, the term includes the purpose of prevention.
  • the term also includes obtaining a therapeutic effect and/or a preventive effect.
  • the therapeutic effect refers to curing or ameliorating the underlying disease to be treated.
  • the healing or amelioration of one or more physiological symptoms associated with a underlying disease is also a therapeutic effect, for example, although the patient may still be affected by the underlying disease, an improvement in the patient's condition is observed.
  • the composition can be administered to a patient at risk of developing a particular disease, or even if a diagnosis of the disease has not been made, the composition is administered to a patient who develops one or more physiological symptoms of the disease.
  • an "effective amount”, “therapeutically effective amount” or “pharmaceutically effective amount” as used herein means that it is sufficient to take a certain course after administration.
  • the result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired change in the biological system.
  • an "effective amount” for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic.
  • An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.
  • administering refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration.
  • parenteral injections including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical and rectal administration topical and rectal administration.
  • the techniques of administration of the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, those discussed in Pa.
  • the compounds and compositions discussed herein are administered orally.
  • pharmaceutically acceptable refers to a substance that does not affect the biological activity or properties of the compounds of the present application and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable biological reactions or in undesirable ways and combinations. Any component contained in the substance interacts.
  • carrier refers to a relatively non-toxic chemical compound or agent that facilitates the introduction of a compound into a cell or tissue.
  • pharmaceutically acceptable salt refers to a salt that retains the biological effectiveness of the free acid and free base of the specified compound, and which has no adverse effects biologically or otherwise.
  • the compounds of the present application also include pharmaceutically acceptable salts.
  • a pharmaceutically acceptable salt refers to a form in which a base group in a parent compound is converted into a salt.
  • Pharmaceutically acceptable salts include, but are not limited to, base or group of inorganic or organic acid salts of amine (amino) groups.
  • the salt in the present application refers to an acid salt formed with an organic acid/inorganic acid, and a basic salt formed with an organic base/inorganic base.
  • the basic functional group of the compound of formula I is pyridine or imidazole (but not limited to pyridine or imidazole)
  • the acidic functional group is a carboxylic acid (but not limited to a carboxylic acid)
  • a zwitterion internal salt
  • the inner salt Also included in the salt in this application.
  • stereoisomer refers to an isomer produced by the different arrangement of atoms in a molecule in space.
  • the compounds of formula I contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. All stereostructures and mixtures of Formula I, including racemic mixtures, are part of the current application.
  • the mixture of diastereomers can be separated into individual diastereomers, based on their different physicochemical properties, using well-known means, for example, resolution of the enantiomers can be carried out with appropriate optically active substances (eg chirality)
  • the alcohol or Mosher ⁇ s molyl chloride reaction is converted to a diastereomer which is separated and converted (e.g., hydrolyzed) to the corresponding single isomer.
  • Some of the compounds of Formula 1 may be atropisomers (e.g., substituted aryl groups) are also part of this application.
  • Enantiomers can also be separated using a chiral column.
  • the compounds of formula I may exist in different tautomeric forms, and such forms are embraced within the scope of the present application. For example, compounds in the form of keto-enol and imine-enamine.
  • HCV Hepatitis C Virus
  • NS3/4A protease NS5A protease
  • NS5B polymerase etc.
  • blocking of hepatitis C virus The replication, inhibition of the function of related proteins, the killing of viruses and so on.
  • the macrocyclic heterocyclic compound of the present application not only has a better inhibitory activity against NS3 hepatitis C virus, but also is significantly superior to the inhibitory activity of other large types of clinically tested macrocyclic compounds;
  • the present application optimizes the preparation method of novel macrocyclic polycyclic compounds and different types of polycyclic small molecule intermediates, and greatly reduces the preparation cost, and is a novel macrocyclic polycyclic hepatitis C virus inhibitor drug.
  • Industrial production provides an effective and practical new method.
  • Some of the large cyclic heterocyclic compounds of the present application have low toxic side effects or are substantially non-toxic, and thus it is possible to further develop a highly effective and non-toxic anti-hepatitis C virus new drug.
  • This application not only designs and synthesizes novel macrocyclic polycyclic compounds for inhibiting hepatitis C virus, but also further explores different structures by inhibiting the activity of hepatitis C virus by macrocyclic compounds containing polycyclic functional groups.
  • the novel macrocyclic compound containing a polycyclic functional group has a relationship with the activity of inhibiting hepatitis C virus, and further developed a novel macrocyclic polycyclic compound which is effective for treating hepatitis C virus infection, and a preparation method thereof.
  • the key innovation of this application is to first synthesize a novel polycyclic compound Va-Vi, and synthesize the general key intermediates 7 and 13, and then synthesize the macrocyclic compound of formula I-II.
  • the raw material SM-2 or SM-2' and the raw material SM-2a are respectively reacted in an organic solvent (e.g., methanol, ethanol, N, N-dimethylformamide, etc.), and heated. Under the conditions (50-100 ° C) by condensation reaction to prepare the compound Va-Vf;
  • an organic solvent e.g., methanol, ethanol, N, N-dimethylformamide, etc.
  • the SM-3 raw material is first dissolved in an anhydrous organic solvent (such as dichloromethane, tetrahydrofuran or toluene) under the action of triphenylphosphine and azodicarboxylate, respectively.
  • anhydrous organic solvent such as dichloromethane, tetrahydrofuran or toluene
  • Another reagent Va-Vf undergoes Mitsunobu reaction to form compound 4; then, the Boc protecting group is removed with hydrochloric acid to form an amine intermediate, and then another protective amino acid derivative SM-4 is formed by the coupling reagent HATU to form compound 5; 5 Removal of the Boc protecting group with hydrochloric acid to form an amine intermediate, followed by phosgene or triphosgene to form an isocyanate intermediate, followed by reaction with neopentyl glycol to form compound 6; 6 in an anhydrous organic solvent, in a palladium catalyst Under the action of the reaction, the macrocyclic key intermediate 7 is obtained; the product 7 is hydrolyzed by the action of lithium hydroxide to form the carboxylic acid 8; the last 8 is passed with another urethane raw material SM-6 under the action of the coupling reagent HATU.
  • the amidation reaction produces the final macrocyclic polycyclic compound LW100201-LW100227 (i.e., I).
  • the desired starting material amino acid derivative SM-6 is most preferably selected from the structures shown in the following structural formula series 4 (SM-6a to SM-6h):
  • the raw materials and reagents referred to in the present application can be purchased commercially or custom-made, unless otherwise specified.
  • the compounds of the present application may contain a non-aromatic double bond and one or more asymmetric centers.
  • the series of compounds can be racemic and racemic mixtures, single enantiomers, tautomers, cis or trans isomers.
  • the compound prepared by the present application (Formula I-II) is a chiral macrocyclic polycyclic compound having a purity higher than 98%, and the optical purity of the natural amino acid and the unnatural amino acid in the product are respectively passed through an optical rotation and chiral column.
  • the structural characterization of each final product was determined by LC-MS or/and hydrogen spectroscopy ( 1 H NMR) analysis, respectively.
  • HCV has a very low level of autonomous replication in normal hepatocytes in vitro, and its only infective animal is a chimpanzee, there is currently no suitable animal model for preclinical efficacy studies of anti-hepatitis C virus drugs.
  • HCV human liver tissue was transplanted into immunodeficient mice to establish a mouse model in vivo, but the breeding of this mouse is technically difficult, the model is unstable, and lacks a normal immune response, which is too different from the pathogenesis of hepatitis C. Therefore, it has not been used to evaluate animal models of hepatitis B efficacy studies.
  • HCV RNA can replicate autonomously in the transfected human hepatoma cell line Huh-7.
  • the above-mentioned effective cell culture model-replicon system accepted in the industry was used for ex vivo experiments, and the drug was evaluated based on the experimental results, wherein the hepatitis C virus target HCV NS3/4A serine protease was used.
  • the main in vitro test results of the inhibitors include:
  • the compounds prepared in the present application can be initially screened for the efficacy of hepatitis C virus infection by the following preclinical inhibitory activity test, and then further confirmed by clinical trials. Other methods will also be apparent to those of ordinary skill in the art.
  • a compound of the present application or a stereoisomer, tautomer, esterified or amidated prodrug thereof, or a pharmaceutically acceptable salt thereof, and mixtures thereof, which are experimentally determined to be infected with hepatitis C virus It has a good curative effect and has obvious inhibitory effect on hepatitis C virus.
  • the results of the inhibitory effect (EC 50 ) of the compound on the hepatitis C virus replicon (EC 50 ) are shown in Table 2 below; wherein the activity range (EC 50 ) is 250-50nM is labeled as “A”, the activity range is labeled “B” at 50-10nM, the activity range is 10-1nM is labeled as “C”, the activity range is 1-0.5nM is labeled as “D”, and the activity range is ⁇ 0.5nM. It is "E”.
  • the level of viral replication in infected cells was achieved by the reporter gene Renilla luciferase.
  • the expression level of the reporter gene has a good linear relationship with the level of RNA replication of HCV and the level of viral protein expression. Eight 2-fold dilutions of the concentration gradient, 3 replicate wells, 3 replicates, and 1 to 2 positive drug controls. The final compound is calculated EC 50.
  • Compound treatment Compounds were serially diluted 1:3 in 9 concentration points, double wells, and added to 96-well plates. The DMSO was set to no compound control. The final concentration of DMSO in the cell culture was 0.5%.
  • Replicon plasmid DNA was linearized with the corresponding restriction enzymes and transcribed into RNA using T7 RNA polymerase.
  • Replicon RNA prepared in vitro transcription was transfected into Huh7 cells by electroporation. The transfected cells were seeded at a density of 10,000 cells per well into 96-well assay plates containing diluted compounds. It was then placed in a 37 ° C, 5% CO 2 incubator for 3 days.
  • Inhibition rate% (CPD-ZPE)/(HPE-ZPE) ⁇ 100%*
  • CPD the signal value of the compound well
  • HPE Hundred percent effect
  • ZPE Zinc percent effect: Ineffective control cell signal value, with 0.5% DMSO instead of compound.
  • the inhibition rate was introduced into the GraphPad Prism software for data processing to obtain a curve corresponding to the compound and its inhibitory activity (EC50) value for the HCV replicon.
  • GT1a is a H77 subtype and GT1b is a Con1 subtype.
  • the non-structural protein gene sequences of GT1a and GT1b were synthesized and inserted into a conventional vector, and a neomycin selection gene was inserted into the vector to construct HCV GT1a (H77) and GT1b (Con1) replicon vectors.
  • HCV GT1a H77
  • GT1b Con1 replicon vectors.
  • the stably transfected cell line obtained by G418 screening can stably replicate the replicon RNA of GT1a and GT1b.
  • Chimeric replicon preparation method GT1b/3a, GT1b/4a, GT1b/5a NS3 chimeric replicon uses the wild type GT1b (Con1) replicon vector as a backbone, and the NS3 fragment of the corresponding genotype is introduced to replace the NS3 gene of GT1b.
  • the NS3 gene sequence of each corresponding genotype was derived from a clinical isolate of NCBI Gene bank. Each resistant mutant replicon was framed by each corresponding chimeric replicon, and NS3 gene-resistant mutations were introduced by point mutation and confirmed by nucleotide sequencing.
  • the intravenous administration group collected samples at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 10h and 24h before and after administration; the oral administration group was 0.25h before and after administration.
  • 0.5h, 1h, 2h, 4h, 6h, 8h, 10h and 24h blood was collected from the jugular vein by about 0.25mL, heparin sodium was anticoagulated, blood samples were collected and placed on ice, and the plasma was separated by centrifugation (centrifugation conditions: 8000 rpm) , 6 minutes, 4 ° C).
  • the collected plasma was stored at –80 °C prior to analysis.
  • the BLQ before Cmax (including “No peak”) is calculated as 0; the BLQ (including “No peak”) appearing after Cmax is not involved in the calculation.
  • WinNonlin Professional v 5.2 calculates the following pharmacokinetic parameters: AUC (0-t), AUC (0- ⁇ ), T1/2, MRT (0- ⁇ ), Cmax, Tmax, F.
  • SD rats were given LW100219 intravenously and orally, and plasma drug concentrations were determined.
  • the Cmax of SD rats after intravenous administration of 5 mg/kg LW100219 was 14886.23 ng/mL
  • AUC (0-t) was 6496.38 h*ng/mL
  • the Cmax of SD rats after oral administration of 20 mg/kg LW100219 was 3632.30 ng/mL
  • AUC (0-t) was 18049.39h*ng/mL
  • the bioavailability of LW100219 in rats was 69.46%.
  • the nuclear magnetic resonance spectrum was analyzed by a Bruker AV-400 (400 MHz) nuclear magnetic instrument. Chemical shifts were recorded with tetramethylsilane as an internal standard and expressed in ppm (CHC1 3 : ⁇ 7.26 ppm). The recorded data information is as follows: chemical shift and its split and coupling constant (s: singlet; d: doublet; t: triplet; q: quartet; br: broad; m: multiplet).
  • the mass spectrometry data was analyzed by a liquid-mass spectrometer of Finnigan LCQ Advantage, among other needs, and all reactions were operated under dry argon-protected anhydrous anaerobic conditions.
  • the solid metal organic compound is stored in an argon-protected dry box.
  • Tetrahydrofuran and diethyl ether are obtained by distillation, and sodium metal and benzophenone are added thereto during distillation.
  • Dichloromethane (DCM), pentane and hexane were treated with calcium hydride.
  • the special raw materials and intermediates involved in this application are provided by Tianjin Changsen Pharmaceutical Co., Ltd., and other chemical reagents from Tianjin Chemical Reagent Company, Aldrich, and Acros. And other reagent suppliers to buy. If the intermediate or product required for the reaction in the synthesis is insufficient for the next step, the synthesis is repeated a plurality of times.
  • the HCV protease (HCVNS3-4A) inhibitory activity test of the compound prepared in the present application was completed by Shanghai WuXi PharmaTech Development Co., Ltd.
  • Alcalase 2.4L Subtilisin-Carlsberg Hydrolyzed Protease
  • CDI N,N'-carbonyldiimidazole
  • HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate
  • NBS N-bromosuccinimide
  • DIAD diisopropyl azodicarboxylate
  • HMPA hexamethylenetetramine
  • PE petroleum ether
  • the benzo[1,3]dioxolane (40 g, 0.327 mol) was dissolved in DCM (2.44 L) and glacial acetic acid (2.277 L), cooled to 15 ° C, and concentrated HNO 3 (325.2 mL) was added dropwise. The temperature was lower than 40 ° C, and after the completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes, cooled to 0 to 5 ° C, and fuming HNO 3 (813 mL) was added dropwise. After the completion of the dropwise addition, the mixture was stirred at room temperature and stirred overnight.
  • the catechol (22 g, 0.2 mol) was dissolved in 824 mL of diethyl ether, cooled to 0 ° C, and 8.8 mL of fuming nitric acid was added dropwise. After the addition was completed, the mixture was returned to room temperature and stirred overnight. The system was poured into 250 mL of ice water, stirred for 20 minutes, and then separated. The aqueous phase was extracted 6 times with 150 mL of diethyl ether. The organic phase was combined, and the organic phase was neutralized with saturated sodium carbonate, then separated, dried over anhydrous sodium sulfate and filtered.
  • the above product (35 g, 0.206 mol) was dissolved in 267 mL of glacial acetic acid, and the fuming HNO 3 (133 mL) was slowly added dropwise with stirring, and the reaction mixture was stirred at room temperature overnight.
  • the reaction solution was diluted with 1.25 L of DCM, poured into 1.25 L of ice water with stirring, and the liquid phase was extracted with 1.25 L to obtain no product.
  • the organic phase was combined, washed once with 1.5 L of water, and washed once with 1.5 L of saturated NaHCO 3 .
  • the mixture was washed once with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness to yield 43.95 g of the product.
  • the ⁇ -keto acid (15.3 g, 67.2 mmol) was dissolved in anhydrous DCM and replaced with argon three times. The mixture was cooled to 0° C., thionyl chloride was added dropwise, and the mixture was stirred to room temperature and stirred for 0.5 h. Nitroaniline (6.0 g, 33.6 mmol) was dissolved in anhydrous DCM, TEA was added, and argon was added three times. The DCM solution obtained above was added dropwise at 0 ° C, and the mixture was added dropwise to room temperature, stirred for 0.5 h, and saturated sodium bicarbonate was added.
  • SM-2 4.4g, 24.4mmol
  • EtOH 185mL
  • argon gas was exchanged three times, the reaction solution was heated to reflux, stirred for 1.5h, and the reaction was monitored by HPLC. The reaction was stopped completely.
  • the catechol (22 g, 0.2 mol) was dissolved in 824 mL of diethyl ether, cooled to 0 ° C, and 8.8 mL of fuming nitric acid was added dropwise. After the addition was completed, the mixture was returned to room temperature and stirred overnight. The system was poured into 250 mL of ice water, stirred for 20 minutes, and then separated. The aqueous phase was extracted 6 times with 150 mL of diethyl ether. The organic phase was combined, the organic phase was neutralized with saturated sodium carbonate, dried and dried to give 38.2 g of crude product. The base catechol 9.6g, the yield is 31.2%.
  • the dinitro substrate (2.3 g, 9.58 mmol) and the catalyst Pd(0) (0.7 g, 5.72 mmol) were dissolved in EtOH (34.1 mL).
  • EtOH 34.1 mL
  • the apparatus was sealed and replaced with hydrogen for 5 times.
  • the mixture was evaporated to dryness.
  • DCM (20 mL) was dissolved.
  • the mixture was evaporated to dryness.
  • the solid was poured into saturated sodium bicarbonate and DCM solution, and the organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give solid o-phenylenediamine (0.94 g).
  • 1 H NMR (CDCl 3 , 400 MHz) ⁇ 8.56 (s, 1H, 6'-H), 8.37 (d, 1H, 4'-H), 7.61 (d, 1H, 2'-H), 7.47 (d, 1H) ,5-H/7-H?), 7.37(t,1H,3'-H), 6.86(d,1H,6-H/8-H?), 1.81(s,6H,2CH 3 ).
  • MS (ESI): m/z 373, 375.30 (M+H).
  • Vanillin (10g, 65.8mmol), triethylamine (13.3g, 136mmol) and DMAP (0.1g) were added to DCM (100mL), then acetic anhydride (8g, 79mmol) was added and reacted for 2h at room temperature, TLC, LC - After the reaction of MS was detected, the system was washed three times with 2N hydrochloric acid, and the organic phase was dried and concentrated to give a crude product, which was purified by column to afford 12 g of white solid.
  • Aluminium trichloride (10.8 g, 80 mmol) was added to dry anhydrous DCM (160 mL). After TLC and LC-MS were detected, poured into a mixed solution of water (550 mL) and concentrated hydrochloric acid (46 mL), then reacted at 55 °C for 1 h, then cooled to 0 °C, precipitated solid, suction filtered, washed with a small amount of water, and dried. The product was dried in 5 g, and the yield in two steps was 65%.
  • Aromatic amine (20 g, 120 mmol) was dissolved in benzene (200 mL) and pyridine (12.4 g, 156 mmol). The bromophenylacetyl chloride (28 g, 156 mmol) was slowly added dropwise and reacted at 20 ° C for 30 minutes. Add 2N HCl, extract with DCM, separate the layers, and dry the organic phase. The column was concentrated to give 20 g of product in a yield of 46%.
  • reaction solution was stirred at room temperature for one hour, then diluted with EA, washed with 5% aqueous citric acid, washed with water, washed with 1M aqueous sodium hydrogen carbonate, and washed 4 times with saturated brine.
  • the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness crystals.
  • the intermediate isocyanate was dissolved in 188 mL of anhydrous THF, and fresh pentanediol (2.28 g, 22 mmol) and 4A molecular sieves were sequentially added. After stirring at room temperature for half an hour, DBU (1.42 mL, 9.5 mmol) was added, and the mixture was stirred for 1 hour, then diluted with EA, filtered over Celite, and the mixture was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness.
  • Substrate 6a (2.78 g, 3.9 mmol), cesium carbonate (3.17 g, 9.7 mmol) and anhydrous toluene (250 mL) were charged to the reactor, followed by palladium acetate (0.22 g, 0.97 mmol) and 2- (di) Butyl phosphorus)-1,1'-binaphthyl (0.49 g, 1.24 mmol). After argon replacement, the mixture was heated to 90 ° C and stirred overnight. After the reaction solution was cooled to room temperature, it was filtered through Celite, and the filter cake was washed with EA. The mother liquid was concentrated under reduced pressure to give a crude product. m.p. ESI-MS[(M+H + )]: m/z 635.22.
  • Example 12 of the preparation of the compound LW100202 this example was reacted with the starting material 8a (0.074 mmol) and SM-6b (0.098 mmol) (reaction shown in Figure 2), and after purification, 48 mg of the final macrocyclic product LW100201 was obtained.
  • the substrate (2 g, 6.1 mmol) was dissolved in anhydrous dichloromethane (24 mL) and triethylamine (0.85 mL) was slowly added and the reaction mixture became viscous; then Boc 2 O (1.4 g, 6.1 mmol) was added.
  • the reaction was stirred at room temperature for 17 hours and LTC showed the reaction was completed.
  • the reaction solution was transferred to a sep. funnel, washed with water (4 mL), EtOAc.
  • the product was 1.84 g, which was purified by column chromatography to yield the product 1.32 g (84.6%).
  • Example LW100202 was prepared as described above. This was obtained by the reaction of starting material 8a (0.065 mmol) and SM-6c (0.13 mmol) to afford 50 mg of the final macrocyclic product LW100203. MS (ESI): m/z 847.2 (M+H)
  • Example 6 Example 11 for the preparation of the compound 4a-8a, this example was purified from the starting material SM-3 (4.8 mmol) and Vb (4.8 mmol) according to the reaction scheme 2 by a five-step reaction to obtain 0.3 g of the product. 8b.
  • Example 11 of the preparation of the compound LW100202 this example was obtained by reacting the starting material 8b (0.10 mmol) and SM-6a (0.10 mmol) to afford 68 mg of the final product LW100205.
  • Example 11 of the preparation of the compound LW100202 this example was obtained by reacting the starting material 8b (0.08 mmol) and SM-6b (0.08 mmol) to afford 52 mg of the final product LW100204.
  • the double-bonded substrate LW100208 (20 mg, 0.139 mmol) was dissolved in 5 mL of ethyl acetate, and then 10% Pd/C (4 mg) was added, and the mixture was hydrogenated at room temperature for 30 minutes, and the reaction was completely monitored by TLC. The mixture was washed with EtOAc (3 mL).
  • the substrate (10 g) was dissolved in anhydrous THF (100 mL) and then cooled to -78. After stirring at -78 °C for 1 h, a solution of Boc 2 O (10.2 g) in tetrahydrofuran was added to the reaction system, and the mixture was slowly warmed to room temperature and stirred overnight. After returning to room temperature and stirring for 12 h, TLC detected the remaining material, and new spots were formed. Ethyl acetate (100 mL), and a solution of 50 mL of EtOAc (EtOAc)
  • NMO (4.61 g) was dissolved in anhydrous tert-butanol (80 mL) and water (80 mL), then potassium phthalate dihydrate (360 mg) was added to the reaction system to cool to 0 °, then the product of the step (14 g)
  • the acetone solution was added to the reaction system, and reacted at room temperature for 8 hours.
  • Water (100 mL) was added to the reaction system, ethyl acetate was added three times, dried and then purified by column chromatography (10.2 g, 66.5%)
  • the substrate (5 g) was dissolved in DCM (70 mL), then sodium periodate reagent (15 g) was added to the reaction system and allowed to react at room temperature for 1 h. TLC detected the reaction of the starting material completely, a new point was formed, suction filtration, DCM washing the filter cake, the filtrate was dried over anhydrous sodium sulfate, and the organic phase was concentrated to give a white solid (2.7 g, 58.8%).
  • step compound (5g) was dissolved in DCM (40mL), cooled to -78 degrees, then DAST (2.8g) was slowly added to the reaction system, the reaction temperature was gradually raised to room temperature, the reaction was carried out for 8 hours, and the TLC detection was new.
  • the product was formed, the starting material was not completely reacted, and the reaction mixture was diluted with 40 ml of LDCM, then 20 mL of water was added, and the reaction was quenched with saturated sodium hydrogen carbonate solution, and extracted with DCM (2*50 mL), dried over anhydrous sodium sulfate, and concentrated to give a colorless oil. (0.9 g, yield: 34%).
  • the difluoro compound (0.5g) was dissolved in THF (6mL), MeOH (2mL ) and H 2 O (2mL), then lithium hydroxide (0.27 g of) was added the reaction system, the reaction at room temperature for 8h, TLC detect product The reaction was completed, the reaction was completed, the reaction mixture was diluted with 15 mL of water, then the pH was adjusted to 3-4 with 1N HCl, extracted with ethyl acetate three times, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by column chromatography (0.2 g, yield: 60.4%) white solid.
  • the substrate 2.1 g was dissolved in DCM (40 mL), carbon tetrachloride (1 g) was added at room temperature, then triphenylphosphine (3.24 g) was slowly added to the reaction system, and the reaction temperature was gradually increased. The temperature was raised to 35 degrees, and the reaction was carried out for 3 hours. The product was formed by TLC. The basic reaction of the starting material was complete. Then the reaction was quenched with water and saturated sodium hydrogen carbonate solution. The mixture was extracted three times with DCM and dried over anhydrous sodium sulfate. , yield: 24%) colorless oil.
  • the intermediate isocyanate was dissolved in 198 mL of THF, and neopentyl glycol (2.4 g, 23.07 mmol) and 4A molecular sieves (13.2 g) were added. After stirring at room temperature for 0.5 h, DBU (1.5 mL, 10 mmol) was added and stirring was continued for 1 h, HPLC The reaction was monitored completely. After adding 396 mL of EA to the reaction mixture, it was diluted with 79 mL of water, washed with 79 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to give 8.2 g of crude product.
  • the macrocyclic product (180 mg, 0.27 mmol) was dissolved in THF / MeOH ( EtOAc. The reaction mixture was dried to dryness and the aqueous phase was adjusted to pH 4 to 5 with 1N HCl. The EA was extracted three times, and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give the product 8d (lw1002-42-37-1, 158.6mg).
  • the double bond substrate LW100210 (120 mg, 0.139 mmol) was dissolved in 10 mL of ethyl acetate. Palladium carbon (10% Pd/C) (50 mg) was carefully added, and the mixture was replaced with hydrogen for 5 times. The reaction was completed by HPLC, the reaction was stopped, the reaction mixture was filtered through celite, and the filtrate was washed three times with ethyl acetate. The filtrate was combined and dried to give 112.5 mg of crude product. Yellow solid.
  • Substrate 5e (1.15 g, 1.15 mmol) was dissolved in DCM, and 6 mL of 4N HCl in 1,4-dioxane solution was added dropwise with stirring. The reaction was stirred at room temperature for 3 h, and the reaction was completely confirmed by HPLC. The solvent of the reaction solution was spin-dried to obtain 1.4 g of the hydrochloride salt, dissolved in 30 mL of LDCM. After the reaction mixture was cooled to 0 ° C, the mixture was stirred to be added with phosgene (0.71 g, 2.4 mmol), and the reaction flask was ventilated twice with argon. 2.1 mL, 25.8 mmol).
  • the silica gel column was purified (PE: EA 15:1 to 5:1) to give the crude compound 7e 70 mg, yield 19.5%, 1 H NMR (CDCl3, 400 MHz) ⁇ 7.40 (m, 3H), 7.28 (m, 2H), 6.98 (m, 1H), 6.15 (s, 1H), 5.30 (m, 1H), 4.80 (d, 1H), 4.50 (m, 1H), 4.31 (m, 1H), 4.20 (m, 1H), 4.02 ( m, 1H), 3.75 (m, 1H), 3.71 (s, 3H, OCH 3 ), 3.31 (d, 1H), 2.50 (m, 1H), 2.31 (m, 1H), 2.20 (m, 1H), 1.81 (m, 6H, 2CH 3 ), 1.25 (s, 6H, 2CH 3 ), 1.06 (s, 9H, 3CH 3 ); MS (ESI): m/z 663.83 (M+H).
  • Carboxylic acid 8e 70mg, 0.11mmol
  • sulfonamide SM-6a 44.6mg, 0.165mg
  • DIEA 0.12 was added dropwise with stirring.
  • HATU 63 mg, 0.165 mmol
  • LW100214 (10 mg) was hydrogenated at room temperature Pd/C to obtain LW100213 7 mg.
  • the carboxylic acid 8f (50 mg, 0.082 mmol) and the sulfonamide SM-6a (32.68 mg, 0.1224 mmol) were dissolved in a DMF solution (5 mL), and the reaction flask was sealed and replaced with argon gas for 3 times. The temperature was lowered to T ⁇ 5 ° C in an ice bath, DIEA (0.092 mL, 0.525 mmol) was added dropwise with stirring, no significant exotherm was added, HATU (46.54 mg, 0.1224 mmol) was added, and the reaction flask was sealed and replaced with argon gas.
  • reaction mixture was diluted with 50 mL of EA, and then transferred to a sep. funnel. The mixture was washed three times with saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated to dryness.
  • the double bond substrate LW100217 (21mg, 0.0343mmol) was dissolved in EA solution (1.5mL), and the Pd/C (5mg) reaction bottle was sealed, hydrogen was replaced 5 times, and reacted at room temperature for 1 hour. Continue to replace the hydrogen reaction for 1 h, leaving very little raw material, continue to replace the hydrogen for 30 min, and found a new HPLC peak. It is speculated that the reaction is excessive and the reaction is stopped.
  • the reaction solution is filtered through celite and then spun dry. The solid was dissolved in DCM (10 mL), EtOAc (EtOAc:EtOAc) After filtration, the filtrate was spun dry to give a pale yellow solid (yield: 42.76%).
  • the carboxylic acid 8f (30 mg, 0.049 mmol) and the sulfonamide SM-6c (20.64 mg, 0.0735 mmol) were dissolved in a DMF solution (3.1 mL), and the reaction flask was sealed and replaced with argon gas for 3 times.
  • the temperature was lowered to T ⁇ 5 ° C in an ice bath, DIEA (0.055 mL, 0.317 mmol) was added dropwise, no significant exotherm was added, HATU (27.95 mg, 0.0735 mmol) was added, the reaction flask was sealed, and then replaced with argon three times.
  • the temperature was raised to 90 ° C, and after 20 min, it was cooled to room temperature, and the reaction was continued for 1.5 h.
  • reaction mixture was monitored by TLC, and it was found that the starting material was completely reacted. After adding 30 mL of EA, the reaction solution was transferred to a separating funnel, and washed with saturated brine for 3 times. The organic phase was separated, dried over anhydrous sodium sulfate and filtered.
  • the substrate Vi (1 g, 2.9 mmol), N-Boc-L hydroxyproline methyl ester SM-3 (0.78 g, 3.2 mmol), triphenylphosphine (1.52 g, 5.8 mmol) was dissolved in anhydrous THF ( 10 mL), after cooling to 0 ° C, DIAD (1.17 g, 5.8 mmol) was added dropwise. After returning to room temperature and stirring for 16 h, the reaction was monitored by TLC. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate (MgSO4).
  • MgSO4 anhydrous sodium sulfate
  • the substrate 13 (0.42 g, 0.68 mmol) was dissolved in THF / MeOH (19 mL / 9.5mL), and then 1N aqueous lithium hydroxide (10 mL) was added, and the mixture was stirred at room temperature for 2 hr. The pH of the HCl was adjusted to 4-5. The EA was extracted three times, and the organic layer was combined and evaporated. ESI-MS[(MH - )]: m/z 601.11.
  • Example 50 which was prepared as described above for the compound LW100228, was reacted with the same intermediate carboxylic acid (0.15 mmol) and SM-6b (0.26 mmol) as in the above example to afford 105 mg of the final product LW100229.

Abstract

Disclosed are a compound for suppressing a hepatitis C virus (HCV), and a preparation method and pharmaceutical application of the compound. The compound is represented by formula A. Various substituents are as defined in the specification.

Description

一类抑制丙肝病毒的大环状杂环化合物及其制备和用途Large cyclic heterocyclic compound for inhibiting hepatitis C virus, preparation and use thereof 技术领域Technical field
本申请涉及一种新型大环状杂环化合物及其中间体、制备方法和用途。The present application relates to a novel macrocyclic heterocyclic compound and an intermediate thereof, a preparation method and use thereof.
背景技术Background technique
丙型肝炎病毒感染造成慢性肝病，如肝硬化和肝癌。丙肝病毒感染是主要传染病之一。根据世界卫生组织统计，全球有1.7亿丙型肝炎受害者，我国将近有3900万丙肝感染者。近年来，丙型肝炎的的治疗已取得了长足的进步，目前已批准上市了几个产品，其中，Sofosbuvir,Harvoni(Ledipasvir/Sofosbuvir),ViekiraxPak(ombitasvir/paritaprevir and ritonavir/Exviera)，对于HCV-genotype 1b的疗效优良。然而，对于其他HCV genotype及其耐药性病毒疗效尚有待提高。所以有必要开发更具有效性与更好耐受性之丙型肝炎病毒治疗药物。Hepatitis C virus infection causes chronic liver diseases such as cirrhosis and liver cancer. Hepatitis C virus infection is one of the major infectious diseases. According to the World Health Organization, there are 170 million hepatitis C victims worldwide, and there are nearly 39 million hepatitis C infected people in China. In recent years, the treatment of hepatitis C has made great progress, and several products have been approved for marketing, including Sofosbuvir, Harvoni (Ledipasvir/Sofosbuvir), Viekirax Pak (ombitasvir/paritaprevir and ritonavir/Exviera), for HCV- The efficacy of genotype 1b is excellent. However, the efficacy of other HCV genotypes and their resistant viruses needs to be improved. Therefore, it is necessary to develop a hepatitis C virus therapeutic drug that is more effective and better tolerated.
至今的各项研究表明，丙型肝炎病毒(HCV)是引起大多数非甲非乙型肝炎的主要病原体。丙型肝炎病毒是一种黄病毒科(F1aviviridae)正单链RNA病毒，其基因组含有大约10000个核苷酸并编码约3000个氨基酸之聚合蛋白。它包括一个核衣壳蛋白(C)和包膜蛋白(E1和E2)，和一些非结构蛋白(NS1,NS2,NS3,NS4a，NS5a和NS5b)。NS3蛋白分解酶具有丝氨酸蛋白酶活性，被认为是病毒复制和感染机制之必需要素。NS3蛋白分解酶之必需性可藉由变异黄热病病毒NS3蛋白酶减少病毒感染之事实而推定。此外，HCV NS3丝氨酸蛋白酶被发现有利于NS3/NS4a，NS4a/NS4b，NS4b/NS5a，NS5a/NS5b等接合处蛋白裂解，而负责在病毒复制过程中四个病毒蛋白之生成(参考US 2003/0207861)。因此，HCV NS3丝氨酸蛋白酶已成为治疗丙型肝炎病毒感染的最具吸引力的目标靶点。Studies to date have shown that hepatitis C virus (HCV) is the leading cause of most non-A, non-B hepatitis. Hepatitis C virus is a F1aviviridae positive single-stranded RNA virus whose genome contains approximately 10,000 nucleotides and encodes a polymeric protein of approximately 3000 amino acids. It includes a nucleocapsid protein (C) and envelope proteins (E1 and E2), and some non-structural proteins (NS1, NS2, NS3, NS4a, NS5a and NS5b). The NS3 proteolytic enzyme has serine protease activity and is considered to be an essential element of viral replication and infection mechanisms. The necessity of the NS3 proteolytic enzyme can be presumed by the fact that the yellow fever virus NS3 protease reduces viral infection. In addition, HCV NS3 serine proteases have been found to facilitate cleavage of junction proteins such as NS3/NS4a, NS4a/NS4b, NS4b/NS5a, NS5a/NS5b, and are responsible for the production of four viral proteins during viral replication (see US 2003/0207861). ). Therefore, HCV NS3 serine protease has become the most attractive target for the treatment of hepatitis C virus infection.
自1999年以来，欧美许多研究所和制药公司广泛深入地研发了各种线型和环状的小分子丙型肝炎病毒抑制剂，具有代表性的HCV NS3丝氨酸蛋白酶抑制剂方面的有关专利及文献如下：W02012092409，W02012092411，WO2011049908，WO2011156337，US20120070416，US20100003214，US20100022578,US20100029715,US20100041889,W02009134624,W02009010804,US20090269305,W02008057 209,W02008057208,W02007015787,W02005037214,W0200218369,W0200009558,W0200009543,W0199964442,W0199907733,W0199907734,W0199950230,W0199846630,WO 199817679,Dunsdon et a1,Biorg.Med.Chem.Lett.2000,10,1571-1579；Linas-Brunetet a1,Biorg.Med.Chem.Lett.2000,10,2267-2270；andS.LaP1ante et a1,Biorg.Med.Chem.Lett.2000,10,2271-22740。Since 1999, many research institutes and pharmaceutical companies in Europe and America have extensively developed various linear and circular small-molecule hepatitis C virus inhibitors, and related patents and literatures on HCV NS3 serine protease inhibitors. As follows: W02012092409, W02012092411, WO2011049908, WO2011156337, US20120070416, US20100003214, US20100022578, US20100029715, US20100041889, W02009134624, W02009010804, US20090269305, W02008057 209, W02008057208, W02007015787, W02005037214, W0200218369, W0200009558, W0200009543, W0199964442, W0199907733, W0199907734, W0199950230, W0199846630 , WO 199817679, Dunsdon et al, Biorg. Med. Chem. Lett. 2000, 10, 1571-1579; Linas-Brunetet a1, Biorg. Med. Chem. Lett. 2000, 10, 2267-2270; and S. LaP1ante et a1 , Biorg. Med. Chem. Lett. 2000, 10, 2271-22740.
此外，其他HCV NS3丝氨酸蛋白酶抑制剂，如Tibotec公司与Medivir公司发表的专利W02007/014920,公开了关于喹啉及异喹啉衍生的N-接合丝氨酸类氨基甲酸酯大环多肽化合物；Abbott公司专利W02008/074035公开了一种特殊环烷衍生的直链多肽化合物；Achi11ion公司专利W02008/106130所公开的由特殊哌啶所衍生的直链和大环多肽化合物；Merck公司发表的专利W02008/057209，则公开了从HCV NS3丝氨酸蛋白酶P2位置上的芳香环连接而成的大环多肽化合物；而2007年2月8日公布的Phenomix公司专利W02007/016476所公开的是以特殊硼酸酯接合在HCV NS3丝氨酸蛋白酶P1位置上形成的 直链多肽化合物；Enanta公司专利W02008/134397所公开的则是用肼基连接于HCV NS3丝氨酸蛋白酶P3位置上所衍生的直链多肽化合物；另外，InterMune公司专利US2005/0267018中公开了一种HCVNS3丝氨酸蛋白酶P2位置上的芳香环与饱和杂环形成的双环稠环所衍生的大环多肽化合物。In addition, other HCV NS3 serine protease inhibitors, such as the patent WO2007/014920 published by Tibotec and Medivir, disclose N-linked serine carbamate macrocyclic polypeptide compounds derived from quinoline and isoquinoline; Abbott Corporation Patent WO2008/074035 discloses a special cycloalkane-derived linear polypeptide compound; a linear and macrocyclic polypeptide compound derived from a special piperidine disclosed in Achi11ion Corporation, WO2008/106130; and a patent issued by Merck, WO2008/057209 A macrocyclic polypeptide compound which is linked from an aromatic ring at the position of the P2 of the HCV NS3 serine protease is disclosed; and a special borate ester is disclosed in the patent of WOHOmix, WO2007/016476, published on Feb. 8, 2007. HCV NS3 serine protease formed at the P1 position A linear polypeptide compound is disclosed in US Pat. A macrocyclic polypeptide compound derived from a bicyclic fused ring formed by an aromatic ring at the P2 position of the serine protease and a saturated heterocyclic ring.
目前一些国际知名的制药公司等研发的抑制丙型肝炎病毒的不同类型的大环状药物己在欧美和日本等国家进入临床I-III期试验，其中大环状丙肝药物结构的特点是设计以14-20元环为主将不同氨基酸和单体通过酰胺键和烯烃双键等合成的大环状化合物。而本申请所公开的含有特殊芳香杂环所形成的以18-19元杂环为核心的新型大环化合物A，是根据丙肝病毒丝氨酸蛋白酶靶点的特征，通过引进不同的官能团等一些有活性的化合物进行结构修饰和优化，从而发明一种抑制丙型肝炎病毒活性更好的新型HCV NS3抑制剂。At present, some internationally renowned pharmaceutical companies have developed different types of macrocyclic drugs that inhibit hepatitis C virus. They have entered clinical phase I-III trials in countries such as Europe, America and Japan. The structure of large-helix hepatitis C drug is designed to The 14-20 membered ring is a macrocyclic compound mainly composed of different amino acids and monomers through an amide bond and an olefin double bond. The novel macrocyclic compound A, which is formed by a special aromatic heterocyclic ring and has a 18-19-membered heterocyclic ring as a core, is characterized by the introduction of different functional groups and the like according to the characteristics of the hepatitis C virus serine protease target. The compounds were structurally modified and optimized to invent a novel HCV NS3 inhibitor that inhibits the activity of hepatitis C virus.
发明内容Summary of the invention
本申请的关键创新点是提供了一种与现有结构不同的以18-19元杂环为核心的新型大环状杂环化合物，以及其中间体，制备方法和应用。本申请的大环状杂环化合物对丙型肝炎病毒具有较佳的抑制活性，可以有效用于治疗丙型肝炎病毒感染，并且具有较低的毒副作用。The key innovation of the present application is to provide a novel macrocyclic heterocyclic compound with a 18-19-membered heterocyclic ring as a core, and an intermediate thereof, a preparation method and application thereof, which are different from the prior art. The macrocyclic heterocyclic compound of the present application has a preferred inhibitory activity against hepatitis C virus, can be effectively used for treating hepatitis C virus infection, and has low toxic side effects.
根据本申请的一个方面，本申请提供了式A的化合物:According to one aspect of the application, the application provides a compound of formula A:
Figure PCTCN2017079087-appb-000001
Figure PCTCN2017079087-appb-000001
或其立体异构体、互变异构体、药学上可接受的盐或它们的混合物；Or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof or a mixture thereof;
其中，among them,
A-B为单键或碳碳双键；当A-B为单键时，A选自氧、硫或氮，B选自C1-6烷基；AB is a single bond or a carbon-carbon double bond; when AB is a single bond, A is selected from oxygen, sulfur or nitrogen, and B is selected from C 1-6 alkyl;
n＝0、1或2；n=0, 1 or 2;
Q选自任选取代的C1-6烷基、C2-6烯基、或C3-6环烷基，所述取代基选自卤素C1-6烷基，C1-C6烷氧基；Q is selected from optionally substituted C 1-6 alkyl, C 2-6 alkenyl , or C 3-6 cycloalkyl, the substituent being selected from halogen C 1-6 alkyl, C 1 -C 6 alkane Oxylate
L独立地为一个氧、硫、C2-C20烯基、C1-C20烷基、C3-C20环烷基、C2-C20杂环基、C6-C20芳基、C3-C20杂环芳基、C1-C20烷硫基、C1-C20烷氧基、C3-C20环烷氧基、C2-C20杂环基氧基、C1-C20烷基氨基、C1-C20烷氧基一羰基、C6-C20芳基、或C6-C20芳氧基；L is independently an oxygen, sulfur, C 2 -C 20 alkenyl group, C 1 -C 20 alkyl group, C 3 -C 20 cycloalkyl group, C 2 -C 20 heterocyclic group, C 6 -C 20 aryl group , C 3 -C 20 heterocyclic aryl, C 1 -C 20 alkylthio, C 1 -C 20 alkoxy, C 3 -C 20 cycloalkoxy, C 2 -C 20 heterocyclooxy, C 1 -C 20 alkylamino, C 1 -C 20 alkoxymonocarbonyl, C 6 -C 20 aryl, or C 6 -C 20 aryloxy;
L1各自独立地为氧、硫、C2-C20烯基、C1-C20烷基、C3-C20环烷基、C2-C20杂环基、C6-C20芳基、C3-C20杂环芳基、C1-C20烷硫基、C1-C20烷氧基、C3-C20环烷氧基、C2-C20杂环基氧基、C1-C20烷基氨基、C1-C20烷氧基羰基、C6-C20芳基、或C6-C20芳氧基； Each of L 1 is independently oxygen, sulfur, C 2 -C 20 alkenyl, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 2 -C 20 heterocyclic, C 6 -C 20 , C 3 -C 20 heterocyclic aryl, C 1 -C 20 alkylthio, C 1 -C 20 alkoxy, C 3 -C 20 cycloalkoxy, C 2 -C 20 heterocyclooxy a C 1 -C 20 alkylamino group, a C 1 -C 20 alkoxycarbonyl group, a C 6 -C 20 aryl group, or a C 6 -C 20 aryloxy group;
X为氧、硫或氮；X is oxygen, sulfur or nitrogen;
Y为氮或CH；Y is nitrogen or CH;
R1为氢、C1-C20烷基、C3-C20环烷基、C6-C20芳基、C3-C20杂环芳基、C1-C20烷基磺酰氨基、C2-C20杂环磺酰氨基、或C1-C20烷氧基羰基氨基；R 1 is hydrogen, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 6 -C 20 aryl, C 3 -C 20 heteroaryl, C 1 -C 20 alkylsulfonylamino , C 2 -C 20 heterocyclic sulfonylamino, or C 1 -C 20 alkoxycarbonylamino;
R2为氢、C1-C20烷基、C3-C20环烷基、C1-C20烷氧基-羰基、C3-C20环烷氧基-羰基、C6-C20芳基、C3-C20杂环芳基、C6-C20芳氧基、C1-C20烷基磺酰基、C3-C20环烷基磺酰基、C1-C20烷氧基磺酰基、C3-C20环烷氧基磺酰基、C6-C20芳基磺酰基、C6-C20芳氧基磺酰基、C1-C20烷氨基磺酰基、C3-C20环烷氨基磺酰基、或C6-C20芳氨基磺酰基；R 2 is hydrogen, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 20 alkoxy-carbonyl, C 3 -C 20 cycloalkoxy-carbonyl, C 6 -C 20 Aryl, C 3 -C 20 heterocyclic aryl, C 6 -C 20 aryloxy, C 1 -C 20 alkylsulfonyl, C 3 -C 20 cycloalkylsulfonyl, C 1 -C 20 alkoxy Sulfonyl, C 3 -C 20 cycloalkoxysulfonyl, C 6 -C 20 arylsulfonyl, C 6 -C 20 aryloxysulfonyl, C 1 -C 20 alkylaminosulfonyl, C 3 - C 20 cycloalkylaminosulfonyl or C 6 -C 20 arylaminosulfonyl;
R3、R4各自独立地为氢、C1-C20烷基、C3-C20环烷基、C1-C20烷氧基、卤素、羟基、氰基、硝基、C1-C20烷基氨基、C2-C20杂环氨基、C6-C20芳基、C6-C20芳基氨基、C1-C20烷基磺酰氨基、C2-C20杂环磺酰氨基、C6-C20芳基磺酰氨基或C1-C20烷基氨基磺酰氨基；其中，R3与R4之间可以相互连接成环状结构；R 3 and R 4 are each independently hydrogen, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 20 alkoxy, halogen, hydroxy, cyano, nitro, C 1 - C 20 alkylamino, C 2 -C 20 heterocyclic amino, C 6 -C 20 aryl, C 6 -C 20 arylamino, C 1 -C 20 alkylsulfonylamino, C 2 -C 20 heterocyclic a sulfonylamino group, a C 6 -C 20 arylsulfonylamino group or a C 1 -C 20 alkylaminosulfonylamino group; wherein R 3 and R 4 may be bonded to each other to form a cyclic structure;
R5和R6各自独立地为氢、卤素、羟基、氰基、硝基、C1-C20烷基、C3-C20环烷基、C1-C20烷氧基、C1-C20烷基氨基、C2-C20杂环氨基、C6-C20芳基、C6-C20芳基氨基、C1-C20烷基磺酰氨基、C2-C20杂环磺酰氨基、C6-C20芳基磺酰氨基或C1-C20烷基氨基磺酰氨基；R 5 and R 6 are each independently hydrogen, halogen, hydroxy, cyano, nitro, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 20 alkoxy, C 1 - C 20 alkylamino, C 2 -C 20 heterocyclic amino, C 6 -C 20 aryl, C 6 -C 20 arylamino, C 1 -C 20 alkylsulfonylamino, C 2 -C 20 heterocyclic Sulfonylamino, C 6 -C 20 arylsulfonylamino or C 1 -C 20 alkylaminosulfonylamino;
R7与R8、R8与R9或R9与R10之间相互连接成含氧或氮的5-6元杂环，且该杂环任选地被C1-C6烷基取代；其余R7、R8、R9和R10中未成环的基团独立地选自氢、卤素、羟基、氰基、硝基、三氟甲烷基、C1-C20烷基、C1-C20烷氧基、C1-C20烷硫基、C1-C20烷氧基-羰基、氨基羰基、C1-C20烷基氨基羰基、羰基氨基、C1-C20烷基羰基氨基、C2-C20杂环基氧基羰基、C6-C20芳基、C6-C20芳氧基、C6-C20芳氧基羰基或C2-C20杂环基；其中所述杂环基含有1-3个氮、氧或硫原子；R 7 and R 8 , R 8 and R 9 or R 9 and R 10 are bonded to each other to form a 5-6 membered heterocyclic ring containing oxygen or nitrogen, and the heterocyclic ring is optionally substituted by a C1-C6 alkyl group; The uncyclized groups in R 7 , R 8 , R 9 and R 10 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, trifluoromethyl, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 1 -C 20 alkylthio, C 1 -C 20 alkoxy-carbonyl, aminocarbonyl, C 1 -C 20 alkylaminocarbonyl, carbonylamino, C1-C 20 alkylcarbonylamino, C 2 -C 20 heterocyclyloxycarbonyl, C 6 -C 20 aryl, C 6 -C 20 aryloxy, C 6 -C 20 aryloxycarbonyl or C 2 -C 20 heterocyclic; Said heterocyclic group contains 1-3 nitrogen, oxygen or sulfur atoms;
J为氢、羟基、C1-C20烷基、C3-C20环烷基、C1-C20烷氧基、C3-C20环烷氧基、C1-C20烷基氨基、C3-C20环烷基氨基、C2-C20杂环氨基、C6-C20芳基、C6-C20芳氨基、C4-C20杂环芳氨基、RSO2NH-、
Figure PCTCN2017079087-appb-000002
-SO2NH2或-SO2NHR，其中R选自任选取代的C1-C20烷基、C1-C20烷氧基、C3-C20环烷基、C6-C20芳基、杂芳基等C3-C20环烷氧基、C6-C20芳氧基、C1-C20烷氨基、C3-C20环烷氨基、、C6-C20芳氨基、C1-C20脲基、C1-C20硫脲基、C1-C20磷酸酯、或C1-C20硼酸酯；所述R上的取代基选自C1-C6烷基、C1-C6烷氧基。J is hydrogen, hydroxy, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 20 alkoxy, C 3 -C 20 cycloalkoxy, C 1 -C 20 alkylamino , C 3 -C 20 cycloalkylamino, C 2 -C 20 heterocyclic amino, C 6 -C 20 aryl, C 6 -C 20 arylamino, C 4 -C 20 heterocyclic arylamino, RSO 2 NH- ,
Figure PCTCN2017079087-appb-000002
-SO 2 NH 2 or -SO 2 NHR, wherein R is selected from optionally substituted C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 3 -C 20 cycloalkyl, C 6 -C 20 C 3 -C 20 cycloalkoxy, C 6 -C 20 aryloxy, C 1 -C 20 alkylamino, C 3 -C 20 cycloalkylamino, C 6 -C 20 aryl, such as aryl or heteroaryl An amino group, a C 1 -C 20 ureido group, a C 1 -C 20 thiourea group, a C 1 -C 20 phosphate ester, or a C 1 -C 20 boronic acid ester; the substituent on the R is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy.
上述各基团中的杂环含有1-3个选自氮、氧和硫的杂原子。The heterocyclic ring in each of the above groups contains from 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur.
根据一些实施方式，在上述式A中，According to some embodiments, in the above formula A,
A-B为单键或碳碳双键；当A-B为单键时，A选自氧、硫或氮，B选自C1-6烷基，R3、R4各自独立地为C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、C1-C6烷基氨基，其中R3、R4连接形成3-7元环结构，其任选被C1-6烷基取代；当A-B为碳碳双键时，R3、R4各自独立地为氢；AB is a single bond or a carbon-carbon double bond; when AB is a single bond, A is selected from oxygen, sulfur or nitrogen, B is selected from C 1-6 alkyl, and R 3 and R 4 are each independently C 1 -C 6 An alkyl group, a C 3 -C 6 cycloalkyl group, a C 1 -C 6 alkoxy group, a C 1 -C 6 alkylamino group, wherein R 3 and R 4 are bonded to form a 3-7 membered ring structure, optionally C a 1-6 alkyl group; when AB is a carbon-carbon double bond, R 3 and R 4 are each independently hydrogen;
R5和R6各自独立地为氢、卤素、羟基、氰基、硝基、C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、C1-C6烷基氨基、C2-C6杂环氨基、C6-C10芳基、C6-C10芳基氨基、C1-C6烷基磺酰氨基、C2-C6杂环磺酰氨基、C6-C10芳基磺酰氨基或C1-C6烷基氨基磺酰氨基，其中所述杂环含有1-3个氮、氧或硫原子；R 5 and R 6 are each independently hydrogen, halogen, hydroxy, cyano, nitro, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 - C 6 alkylamino, C 2 -C 6 heterocyclic amino, C 6 -C 10 aryl, C 6 -C 10 arylamino, C 1 -C 6 alkylsulfonylamino, C 2 -C 6 heterocyclic a sulfonylamino group, a C 6 -C 10 arylsulfonylamino group or a C 1 -C 6 alkylaminosulfonylamino group, wherein the heterocyclic ring contains 1-3 nitrogen, oxygen or sulfur atoms;
R7、R8、R9和R10中，R7与R8、R8与R9和/或R9与R10之间相互连接成含氧或氮的5-6元杂环，且该杂环任选地被C1-C6烷基取代；其余未成环基团独立地选自氢、卤素、 羟基、氰基、硝基、三氟甲烷基、C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、C1-C6烷氧基-羰基、氨基羰基、C1-C6烷基氨基羰基、羰基氨基、C1-C6烷基羰基氨基、C2-C6杂环基氧基羰基、C6-C10芳基、C6-C10芳氧基、C6-C10芳氧基羰基或C2-C6杂环基，其中所述杂环含有1-3个氮、氧或硫原子；In R 7 , R 8 , R 9 and R 10 , R 7 and R 8 , R 8 and R 9 and/or R 9 and R 10 are bonded to each other to form a 5-6 membered heterocyclic ring containing oxygen or nitrogen, and the heterocycle being optionally substituted with C1-C6 alkyl; remaining unpaired cyclic group independently selected from hydrogen, halogen, hydroxy, cyano, nitro, trifluoromethane group, C 1 -C 6 -alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkoxy-carbonyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, carbonylamino, C 1 -C 6 alkyl Carbonylamino, C 2 -C 6 heterocyclyloxycarbonyl, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 6 -C 10 aryloxycarbonyl or C 2 -C 6 heterocyclic Wherein said heterocyclic ring contains 1-3 nitrogen, oxygen or sulfur atoms;
J为氢、羟基、C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、C3-C6环烷氧基、C1-C6烷基氨基、C3-C6环烷基氨基、C2-C6杂环氨基、C6-C10芳基、C6-C10芳氨基、C4-C10杂环芳氨基、RSO2NH-、
Figure PCTCN2017079087-appb-000003
-SO2NH2或-SO2NHR，其中R选自任选取代的C1-C10烷基、C3-C6环烷基、C6-C10芳基、C1-C6烷氧基、C3-C6环烷氧基、C6-C10芳氧基、C1-C6烷氨基、C3-C6环烷氨基、C6-C10芳氨基、C1-C6脲基、C1-C6硫脲基、C1-C6磷酸酯基、或C1-C6硼酸酯基；J is hydrogen, hydroxy, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, C 1 -C 6 alkylamino , C 3 -C 6 cycloalkylamino, C 2 -C 6 heterocyclic amino, C 6 -C 10 aryl, C 6 -C 10 arylamino, C 4 -C 10 heterocyclic arylamino, RSO 2 NH- ,
Figure PCTCN2017079087-appb-000003
-SO 2 NH 2 or -SO 2 NHR, wherein R is selected from optionally substituted C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkane Oxy, C 3 -C 6 cycloalkoxy, C 6 -C 10 aryloxy, C 1 -C 6 alkylamino, C 3 -C 6 cycloalkylamino, C 6 -C 10 arylamino, C 1 - a C 6 ureido group, a C 1 -C 6 thiourea group, a C 1 -C 6 phosphate group, or a C 1 -C 6 borate group;
L为单键、氧、硫、C2-C6烯基、C1-C6烷基、C3-C6环烷基、C2-C6杂环基、C6-C10芳基、C3-C6杂环芳基、C1-C6烷硫基、C1-C6烷氧基、C3-C6环烷氧基、C2-C6杂环基氧基、C1-C6烷基氨基、C1-C6烷氧基羰基、C6-C10芳基、或C6-C10芳氧基；L is a single bond, oxygen, sulfur, C 2 -C 6 alkenyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocyclic, C 6 -C 10 aryl , C 3 -C 6 heterocyclic aryl, C 1 -C 6 alkylthio, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, C 2 -C 6 heterocyclooxy, C 1 -C 6 alkylamino, C 1 -C 6 alkoxycarbonyl, C 6 -C 10 aryl, or C 6 -C 10 aryloxy;
L1选自氧、硫、C2-C6烯基、C1-C6烷基、C3-C6环烷基、C2-C6杂环基、C6-C10芳基、C3-C6杂环C6-C10芳基、C1-C6烷硫基、C1-C6烷氧基、C3-C6环烷氧基、C2-C6杂环基氧基、C1-C6烷基氨基、C1-C6烷氧基羰基、C6-C10芳基、或C6-C10芳氧基；L 1 is selected from the group consisting of oxygen, sulfur, C 2 -C 6 alkenyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocyclic, C 6 -C 10 aryl, C 3 -C 6 heterocyclic C 6 -C 10 aryl, C 1 -C 6 alkylthio, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, C 2 -C 6 heterocyclic Alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 alkoxycarbonyl, C 6 -C 10 aryl, or C 6 -C 10 aryloxy;
X为氧、硫或氮；X is oxygen, sulfur or nitrogen;
Y为氮或CH；Y is nitrogen or CH;
R1为氢、C1-C6烷基、C3-C6环烷基、C6-C10芳基、C3-C6杂环芳基、C1-C6烷基磺酰氨基、C2-C6杂环磺酰氨基、或C1-C6烷氧基羰基氨基；R 1 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, C 3 -C 6 heteroaryl, C 1 -C 6 alkylsulfonylamino , a C 2 -C 6 heterocyclic sulfonylamino group, or a C 1 -C 6 alkoxycarbonylamino group;
R2为氢、C1-C6烷基、C3-C6环烷基、C1-C6烷氧基-羰基、C3-C6环烷氧基-羰基、C6-C10芳基、C3-C60杂环C6-C10芳基、C6-C10芳氧基、C1-C6烷基磺酰基、C3-C6环烷基磺酰基、C1-C6烷氧基磺酰基、C3-C6环烷氧基磺酰基、C6-C10芳基磺酰基、C6-C10芳氧基磺酰基、C1-C6烷氨基磺酰基、C3-C6环烷氨基磺酰基、或C6-C10芳氨基磺酰基。R 2 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy-carbonyl, C 3 -C 6 cycloalkoxy-carbonyl, C 6 -C 10 Aryl, C 3 -C 60 heterocyclic C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 1 -C 6 alkylsulfonyl, C 3 -C 6 cycloalkylsulfonyl, C 1 -C 6 alkoxysulfonyl, C 3 -C 6 cycloalkoxysulfonyl, C 6 -C 10 arylsulfonyl, C 6 -C 10 aryloxysulfonyl, C 1 -C 6 alkylaminosulfonate An acyl group, a C 3 -C 6 cycloalkylaminosulfonyl group, or a C 6 -C 10 arylaminosulfonyl group.
根据一些实施方式，在式A中，According to some embodiments, in Formula A,
L为单键；L is a single bond;
L1选自氧或硫；L 1 is selected from oxygen or sulfur;
X选自氧、硫或氮；X is selected from the group consisting of oxygen, sulfur or nitrogen;
Y选自氮或CH；R1选自叔丁基；Y is selected from nitrogen or CH; R 1 is selected from t-butyl;
R2选自氢；R 2 is selected from hydrogen;
当A-B为单键时，A选自氧、硫或氮，B选自亚甲基，R3和R4独立地为甲基；当A-B为双键时，R3和R4独立地为氢；When AB is a single bond, A is selected from oxygen, sulfur or nitrogen, B is selected from methylene, R 3 and R 4 are independently methyl; when AB is a double bond, R 3 and R 4 are independently hydrogen. ;
R5和R6独立地为氢；R 5 and R 6 are independently hydrogen;
R7、R8、R9和R10中，R7与R8、R8与R9或R9与R10之间相互连接成含氧或氮的5-6元杂环，且该杂环任选地被C1-C6烷基取代；其余未成环基团选自氢；In R 7 , R 8 , R 9 and R 10 , R 7 and R 8 , R 8 and R 9 or R 9 and R 10 are bonded to each other to form a 5-6 membered heterocyclic ring containing oxygen or nitrogen, and the hetero The ring is optionally substituted with a C 1 -C 6 alkyl group; the remaining uncyclic group is selected from hydrogen;
Q选自任选取代的C1-6烷基、C2-6烯基、或C3-6环烷基，所述取代基选自卤素；Q is selected from optionally substituted C 1-6 alkyl, C 2-6 alkenyl , or C 3-6 cycloalkyl, said substituent being selected from halogen;
J选自RSO2NH-、
Figure PCTCN2017079087-appb-000004
-SO2NH2或-SO2NHR，其中R选自任选取代的C3-C6环烷基，所述取代基选自C1-C6烷基。 J is selected from RSO 2 NH-,
Figure PCTCN2017079087-appb-000004
-SO 2 NH 2 or -SO 2 NHR, wherein R is selected from an optionally substituted C 3 -C 6 cycloalkyl group, and the substituent is selected from a C 1 -C 6 alkyl group.
根据一些实施方式，在式A中，According to some embodiments, in Formula A,
L为单键；L is a single bond;
L1选自氧；L 1 is selected from oxygen;
X选自氧；X is selected from oxygen;
其余定义同权利要求3。The remaining definitions are the same as claim 3.
根据一些实施方式，在式A中，Q选自任选取代的甲基、乙基、乙烯基或环丙基，According to some embodiments, in Formula A, Q is selected from the group consisting of an optionally substituted methyl, ethyl, vinyl or cyclopropyl group,
所述取代基选自卤素。The substituent is selected from halogen.
根据一些实施方式，在式A中，J选自RSO2NH-、
Figure PCTCN2017079087-appb-000005
或-SO2NHR，其中R选自任选取代的C3-C6环烷基，所述取代基选自甲基或乙基。According to some embodiments, in Formula A, J is selected from the group consisting of RSO 2 NH-,
Figure PCTCN2017079087-appb-000005
Or -SO 2 NHR, wherein R is selected from optionally substituted C 3 -C 6 cycloalkyl, the substituent being selected from methyl or ethyl.
本申请的式A化合物包括式I或II的大环状多环化合物:The compounds of formula A of the present application include macrocyclic polycyclic compounds of formula I or II:
Figure PCTCN2017079087-appb-000006
Figure PCTCN2017079087-appb-000006
或其立体异构体、互变异构体、药学上可接受的盐或它们的混合物；式I和式II中各基团的定义同式A中的定义。Or a stereoisomer, tautomer, pharmaceutically acceptable salt or mixture thereof; the definitions of each of the groups of formula I and formula II are as defined in formula A.
根据本申请的第二方面，提供式V的多环化合物:According to a second aspect of the present application, a polycyclic compound of formula V is provided:
Figure PCTCN2017079087-appb-000007
Figure PCTCN2017079087-appb-000007
其中，among them,
Y、R7、R8,R9和R10的定义同式A。Y, R 7 , R 8 , R 9 and R 10 are as defined in the formula A.
本申请的第三方面，提供一种制备本申请所述的化合物V的方法，该方法包括:通过下列反应合成杂环化合物V: In a third aspect of the present application, there is provided a process for the preparation of a compound V as described herein which comprises synthesizing a heterocyclic compound V by the following reaction:
Figure PCTCN2017079087-appb-000008
Figure PCTCN2017079087-appb-000008
采用原料SM-2和原料SM-2a通过缩合反应制得化合物Va-f；其中，R7、R8、R9和R10的定义同式A所述；The compound Va-f is obtained by a condensation reaction using the raw material SM-2 and the raw material SM-2a; wherein R 7 , R 8 , R 9 and R 10 are as defined in the formula A;
所述的制备化合物V的缩合反应是在惰性气体保护下，在有机溶剂中进行，原料SM-2a的用量为SM-2摩尔量的1-2倍；反应温度为50-100℃；The preparation of the compound V is carried out under the protection of an inert gas in an organic solvent, the amount of the raw material SM-2a is 1-2 times the molar amount of SM-2; the reaction temperature is 50-100 ° C;
本申请中，最佳的，式V为如下任一结构：In the present application, the best formula V is any of the following structures:
Figure PCTCN2017079087-appb-000009
Figure PCTCN2017079087-appb-000009
本申请的第四方面，提供一种制备本申请的式A中式I的大环状多环化合物的方法，包括以下五个步骤: In a fourth aspect of the present application, there is provided a process for the preparation of a macrocyclic polycyclic compound of formula I of formula A of the present application, comprising the following five steps:
Figure PCTCN2017079087-appb-000010
Figure PCTCN2017079087-appb-000010
1)在惰性气体保护下，原料SM-3在无水有机溶剂中,在三苯基磷和偶氮二羧酸酯(如：偶氮二羧酸二乙酯或者偶氮二羧酸二异丙酯)的作用下与另一试剂V发生Mitsunobu反应，生成化合物3-1；SM-3和化合物V及产物3-1中其它各基团(包括X、Y、R5、R6、R7、R8、R9)的定义同上述式A所述；R11为C1-C6烷基羰基、C1-C6烷氧基羰基或C1-C6氨基羰基；1) Under the protection of an inert gas, the raw material SM-3 is in an anhydrous organic solvent, in the triphenylphosphine and azodicarboxylate (such as diethyl azodicarboxylate or diazodicarboxylic acid) Mitsunobu reaction with another reagent V under the action of propyl ester to form compound 3-1; SM-3 and compound V and other groups in product 3-1 (including X, Y, R 5 , R 6 , R 7 , R 8 , R 9 ) is as defined above for formula A; R 11 is C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl or C 1 -C 6 aminocarbonyl;
2)在惰性气体保护下，将步骤1)中得到的化合物3-1脱去保护基R11后再在偶合试剂(如：HATU)的作用下与另一氨基酸衍生物试剂SM-4反应生成化合物3-2；SM-4及3-2中各基团(包括X、Y、R1、R2、R5、R6、R7、R8、R9、R10)的定义同上述式A所述；R11的定义同上；2) Under the protection of an inert gas, the compound 3-1 obtained in the step 1) is removed from the protecting group R 11 and then reacted with another amino acid derivative reagent SM-4 under the action of a coupling reagent (for example, HATU). Compound 3-2; each of the groups SM-4 and 3-2 (including X, Y, R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 ) has the same meaning as defined above Formula A; R 11 is as defined above;
3)在惰性气体保护下，将步骤2)得到的化合物3-2脱去保护基R11后再在光气或三光气的作用下，与另一试剂SM-5反应形成化合物3-3；试剂SM-5及产物中各基团和参数(包括n、L、L1、X、Y、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10)的定义同上述式A所述；R11的定义同上；3) Under the protection of an inert gas, the compound 3-2 obtained in step 2) is deprotected from the protective group R 11 and then reacted with another reagent SM-5 under the action of phosgene or triphosgene to form compound 3-3; Reagent SM-5 and each group and parameter in the product (including n, L, L 1 , X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 ) is as defined in the above formula A; R 11 is as defined above;
4)在惰性气体保护下，将步骤3)得到的化合物3-3在钯催化剂的作用下，反应得到大环状产物3-4；产物中各基团和参数(包括n、L、L1、X、Y、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10)的定义同上述式A所述；4) Under the protection of an inert gas, the compound 3-3 obtained in the step 3) is reacted under the action of a palladium catalyst to obtain a macrocyclic product 3-4; each group and parameters in the product (including n, L, L 1) , X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 ) are as defined above for Formula A;
5)在惰性气体保护下，将步骤4)得到的化合物3-4经水解酸化后再与SM-6在偶合试剂(如：HATU)的作用下反应生成最终大环状多环化合物I；SM-6及产物中各基团和 参数(包括n、L、L1、X、Y、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、J)的定义同上述式A所述；5) Under the protection of an inert gas, the compound 3-4 obtained in the step 4) is subjected to hydrolysis and acidification, and then reacted with SM-6 under the action of a coupling reagent (such as: HATU) to form a final macrocyclic polycyclic compound I; -6 and each group and parameter in the product (including n, L, L 1 , X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , J) are as defined in the above formula A;
在步骤1)中，在惰性气体保护下，将SM-3原料溶于有机溶剂(如二氯甲烷、四氢呋喃或甲苯)中，在三苯基磷和偶氮二羧酸酯(如：偶氮二羧酸二乙酯或者偶氮二羧酸二异丙酯)的作用下与另一试剂V发生Mitsunobu反应，生成化合物3-1；所述反应温度为0-40℃，所述的三苯基磷用量为原料SM-3摩尔量的1-2倍，所述的偶氮二羧酸酯用量为原料SM-3摩尔量的1-2倍；In step 1), under the protection of an inert gas, the SM-3 raw material is dissolved in an organic solvent (such as dichloromethane, tetrahydrofuran or toluene) in triphenylphosphine and azodicarboxylate (such as azo). Mitsunobu reaction with another reagent V under the action of diethyl dicarboxylate or diisopropyl azodicarboxylate to form compound 3-1; the reaction temperature is 0-40 ° C, the triphenylbenzene The amount of phosphorus used is 1-2 times the molar amount of the raw material SM-3, and the amount of the azodicarboxylate is 1-2 times the molar amount of the raw material SM-3;
在步骤2)中，在惰性气体保护下将步骤1)得到的化合物3-1在强酸(如盐酸、硫酸或三氟乙酸)的作用下，在温度为10-50℃下反应脱去保护基R11(如Boc)后生成胺中间体，再在偶合试剂(如：HATU)的作用下，在温度0-80℃下在有机溶剂(如二氯甲烷、四氢呋喃或N,N-二甲基甲酰胺)中与试剂SM-4反应得到化合物3-2；所述的偶合试剂的用量为化合物3-1摩尔量的1-2.5倍。In step 2), the compound 3-1 obtained in the step 1) is subjected to an inert gas protection under the action of a strong acid (such as hydrochloric acid, sulfuric acid or trifluoroacetic acid) at a temperature of 10 to 50 ° C to remove the protective group. After R 11 (such as Boc), an amine intermediate is formed, which is then reacted with a coupling reagent (eg, HATU) at an organic solvent such as dichloromethane, tetrahydrofuran or N,N-dimethyl at a temperature of 0-80 ° C. Reaction with reagent SM-4 in formamide) gives compound 3-2; the coupling reagent is used in an amount of 1-2.5 times the molar amount of compound 3-1.
在步骤3)中，在惰性气体保护下将步骤2)得到的化合物3-2在强酸(如盐酸、硫酸或三氟乙酸)的作用下，在温度为10-50℃下反应脱去保护基R11后生成胺中间体，再在光气或三光气的作用下生成异氰酸酯中间体，继而在温度0-40℃下在有机溶剂(如二氯甲烷、四氢呋喃或甲苯)中与另一试剂SM-5反应形成化合物3-3；所述的三光气的用量为化合物3-2摩尔量的1-2倍。In step 3), the compound 3-2 obtained in the step 2) is subjected to an inert gas protection under the action of a strong acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid at a temperature of 10 to 50 ° C to remove the protective group. After R 11 , an amine intermediate is formed, and an isocyanate intermediate is formed under the action of phosgene or triphosgene, followed by another reagent SM in an organic solvent (such as dichloromethane, tetrahydrofuran or toluene) at a temperature of 0-40 ° C. The -5 reaction forms the compound 3-3; the triphosgene is used in an amount of from 1 to 2 times the molar amount of the compound 3-2.
在步骤4)中，在惰性气体保护下，将步骤3)得到的化合物3-3溶于无水有机溶剂(如1,4-二氧六环、四氢呋喃或甲苯)中，在钯催化剂(如醋酸钯或四三苯基膦钯)、磷配体(如2-(二叔丁基磷)-1,1’-联萘)及无机强碱(如碳酸铯)的作用下，在温度0-100℃下反应，得到大环状产物3-4；钯催化剂的用量为原料SM-1摩尔量的0.2-5％；磷配体的用量为原料SM-1摩尔量的0.3-10％；无机碱的用量为原料SM-1摩尔量的1-3倍；In step 4), the compound 3-3 obtained in the step 3) is dissolved in an anhydrous organic solvent (such as 1,4-dioxane, tetrahydrofuran or toluene) under an inert gas atmosphere, in a palladium catalyst (such as Palladium acetate or tetrakistriphenylphosphine palladium), phosphorus ligands (such as 2-(di-tert-butylphosphino)-1,1'-binaphthyl) and inorganic strong bases (such as barium carbonate) at a temperature of 0 -100 ° C reaction, to obtain a large cyclic product 3-4; palladium catalyst is used in an amount of 0.2-5% by mole of the raw material SM-1; phosphorus ligand is used in an amount of 0.3-10% by mole of the raw material SM-1; The amount of the inorganic base is 1-3 times the molar amount of the raw material SM-1;
在步骤5)中，将步骤4)得到的化合物3-4在无机强碱(如：氢氧化锂或氢氧化钠)的作用下，在溶剂(如水、甲醇、四氢呋喃或1,4-二氧六环)中，于10-60℃进行水解脱去保护基甲氧基后酸化生成羧酸，再在偶合试剂(如：HATU)的作用下，在有机溶剂(如二氯甲烷、四氢呋喃或N,N一二甲基甲酰胺)中，与SM-6通过酰胺化反应得到大环状多环产物I；所述的偶合试剂的用量为化合物3-4摩尔量的1-2.5倍；酰胺化反应的温度为0-80℃；In step 5), the compound 3-4 obtained in the step 4) is subjected to the action of an inorganic strong base such as lithium hydroxide or sodium hydroxide in a solvent such as water, methanol, tetrahydrofuran or 1,4-dioxane. In the six ring), the hydrolysis is carried out at 10-60 ° C to remove the protective methoxy group and then acidified to form a carboxylic acid, and then under the action of a coupling reagent (such as: HATU) in an organic solvent (such as dichloromethane, tetrahydrofuran or N). , N-dimethylformamide), amidation reaction with SM-6 to obtain a macrocyclic polycyclic product I; the coupling reagent is used in an amount of 1-2.5 times the compound 3-4 molar amount; amidation The reaction temperature is 0-80 ° C;
本申请的第五方面，提供一种制备本申请的式A中如式II所示的大环状多环化合物的方法，包括以下六个步骤: In a fifth aspect of the present application, there is provided a method of preparing a macrocyclic polycyclic compound of Formula A in Formula A of the present application, comprising the following six steps:
Figure PCTCN2017079087-appb-000011
Figure PCTCN2017079087-appb-000011
1)在惰性气体保护下，原料SM-3在无水有机溶剂中,在三苯基磷和偶氮二羧酸酯(如：偶氮二羧酸二乙酯或者偶氮二羧酸二异丙酯)的作用下与另一试剂V发生Mitsunobu反应，生成化合物3-1；SM-3和化合物V及产物3-1中其它各基团(包括X、Y、R5、R6、R7、R8、R9、R10)的定义同上述式A所述；R11为C1-C6烷基羰基、C1-C6烷氧基羰基或C1-C6氨基羰基；1) Under the protection of an inert gas, the raw material SM-3 is in an anhydrous organic solvent, in the triphenylphosphine and azodicarboxylate (such as diethyl azodicarboxylate or diazodicarboxylic acid) Mitsunobu reaction with another reagent V under the action of propyl ester to form compound 3-1; SM-3 and compound V and other groups in product 3-1 (including X, Y, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 ) are as defined above for formula A; R 11 is C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl or C 1 -C 6 aminocarbonyl;
2)在惰性气体保护下，将步骤1)中得到的化合物3-1与乙烯三氟硼酸钾在钯催化剂(如Pd(dppf)Cl2)的作用下，通过Suzuki反应得到化合物4-1；产物中各基团(包括X、Y、R5、R6、R7、R8、R9、R10)的定义同上述式A所述；R11的定义同上；2) Under the protection of an inert gas, the compound 3-1 obtained in the step 1) and the potassium trifluoroborate under the action of a palladium catalyst (such as Pd (dppf) Cl 2 ), through the Suzuki reaction to obtain the compound 4-1; The definition of each group in the product (including X, Y, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 ) is as defined in the above formula A; R 11 is as defined above;
3)在惰性气体保护下，将步骤2)中得到的化合物4-1脱去保护基R11后再在偶合试剂的作用下与另一氨基酸衍生物试剂SM-4反应生成化合物4-2；产物中各基团(包括X、Y、R1、R2、R5、R6、R7、R8、R9、R10)的定义同上述式A所述；R11的定义同上；3) Under the protection of an inert gas, the compound 4-1 obtained in the step 2) is removed from the protecting group R 11 and then reacted with another amino acid derivative reagent SM-4 under the action of a coupling reagent to form a compound 4-2; The definition of each group in the product (including X, Y, R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 ) is as defined in the above formula A; R 11 is as defined above;
4)在惰性气体保护下，将步骤3)得到的化合物4-2脱去保护基R11后再与另一试剂SM-7反应形成化合物4-3；试剂SM-7及产物中各基团和参数(包括n、L、L1、X、Y、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10)的定义同上述式A所述；R11的定义同上；4) Under the protection of an inert gas, the compound 4-2 obtained in the step 3) is deprotected from the protecting group R 11 and then reacted with another reagent SM-7 to form a compound 4-3; the reagent SM-7 and each group in the product And the parameters (including n, L, L 1 , X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 ) are as defined above A; R 11 is as defined above;
5)在惰性气体保护下，将步骤4)得到的双烯化合物4-3在钌催化剂(如:詹氏催化剂或Grubbs催化剂等)的作用下，通过烯烃复分解环化反应得到大环状产物4-4；产物中各基团和参数(包括n、L、L1、X、Y、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10)的定义同上述式A所述； 5) Under the protection of an inert gas, the diene compound 4-3 obtained in the step 4) is subjected to an olefin metathesis cyclization reaction to obtain a macrocyclic product 4 under the action of a ruthenium catalyst (such as a Jane catalyst or a Grubbs catalyst). -4; each group and parameter in the product (including n, L, L 1 , X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 ) is as defined in the above formula A;
6)在惰性气体保护下，将步骤5)得到的化合物4-4经水解酸化后再与SM-6在偶合试剂(如：HATU)的作用下反应生成最终大环状化合物II；SM-6及产物中各基团和参数(包括n、L、L1、X、Y、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、J)的定义同上述式A所述；6) Under the protection of an inert gas, the compound 4-4 obtained in the step 5) is subjected to hydrolysis and acidification, and then reacted with SM-6 under the action of a coupling reagent (for example, HATU) to form a final macrocyclic compound II; SM-6. And various groups and parameters in the product (including n, L, L 1 , X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , J) is defined as described in the above formula A;
在步骤1)中，在惰性气体保护下，将SM-3原料溶于有机溶剂(如二氯甲烷、四氢呋喃或甲苯)中，在三苯基磷和偶氮二羧酸酯(如：偶氮二羧酸二乙酯或者偶氮二羧酸二异丙酯)的作用下与另一试剂V发生Mitsunobu反应，生成化合物3-1；所述反应温度为0-40℃，所述的三苯基磷用量为原料SM-3摩尔量的1-2倍，所述的偶氮二羧酸酯用量为原料SM-3摩尔量的1-2倍；In step 1), under the protection of an inert gas, the SM-3 raw material is dissolved in an organic solvent (such as dichloromethane, tetrahydrofuran or toluene) in triphenylphosphine and azodicarboxylate (such as azo). Mitsunobu reaction with another reagent V under the action of diethyl dicarboxylate or diisopropyl azodicarboxylate to form compound 3-1; the reaction temperature is 0-40 ° C, the triphenylbenzene The amount of phosphorus used is 1-2 times the molar amount of the raw material SM-3, and the amount of the azodicarboxylate is 1-2 times the molar amount of the raw material SM-3;
在步骤2)中，在惰性气体保护下，将步骤1)中得到的化合物3-1溶于有机溶剂(如乙醇、甲苯或四氢呋喃)中，与乙烯三氟硼酸钾在钯催化剂(如Pd(dppf)Cl2)及碱(如三乙胺)的作用下，在温度20-100℃下通过Suzuki反应得到化合物4-1；所述的乙烯三氟硼酸钾用量为原料SM-3摩尔量的1-4倍；所述的钯催化剂用量为原料SM-3摩尔量的0.03-5％倍；所述的碱用量为原料SM-3摩尔量的1-4倍。In step 2), the compound 3-1 obtained in the step 1) is dissolved in an organic solvent (such as ethanol, toluene or tetrahydrofuran) under an inert gas atmosphere, and an ethylene trifluoroborate in a palladium catalyst (such as Pd ( The compound 4-1 is obtained by a Suzuki reaction at a temperature of 20-100 ° C under the action of dppf)Cl 2 ) and a base (such as triethylamine); the amount of the ethylene trifluoroborate is the molar amount of the raw material SM-3. 1-4 times; the amount of the palladium catalyst is 0.03-5% times the molar amount of the raw material SM-3; the amount of the base is 1-4 times the molar amount of the raw material SM-3.
在步骤3)中，在惰性气体保护下将步骤2)得到的化合物4-1在强酸(如盐酸、硫酸或三氟乙酸)的作用下，在温度为10-50℃下反应脱去保护基R11(如Boc)后生成胺中间体，再在偶合试剂(如：HATU)的作用下，在温度0-80℃下在有机溶剂(如二氯甲烷、四氢呋喃或N,N-二甲基甲酰胺)中与试剂SM-4反应得到化合物4-2；所述的偶合试剂的用量为化合物4-1摩尔量的1-2.5倍。In step 3), the compound 4-1 obtained in the step 2) is subjected to an inert gas protection under the action of a strong acid (such as hydrochloric acid, sulfuric acid or trifluoroacetic acid) at a temperature of 10 to 50 ° C to remove the protective group. After R 11 (such as Boc), an amine intermediate is formed, which is then reacted with a coupling reagent (eg, HATU) at an organic solvent such as dichloromethane, tetrahydrofuran or N,N-dimethyl at a temperature of 0-80 ° C. The reaction with the reagent SM-4 in the formamide) gives the compound 4-2; the coupling reagent is used in an amount of 1-2.5 times the molar amount of the compound 4-1.
在步骤4)中，在惰性气体保护下将步骤3)得到的化合物4-2在强酸(如盐酸、硫酸或三氟乙酸)的作用下，在温度为10-50℃下反应脱去保护基R11后生成胺中间体，再在碱(如三乙胺)的作用下，在有机溶剂(如二氯甲烷、四氢呋喃或甲苯)中，于10-30℃与另一试剂SM-7反应形成双烯化合物4-3；所述的碱的用量为化合物4-2摩尔量的1-5倍。In step 4), the compound 4-2 obtained in the step 3) is subjected to an inert gas protection under the action of a strong acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid at a temperature of 10 to 50 ° C to remove the protective group. After R 11 , an amine intermediate is formed, which is then reacted with another reagent SM-7 at 10-30 ° C in an organic solvent (such as dichloromethane, tetrahydrofuran or toluene) under the action of a base such as triethylamine. Diene compound 4-3; the base is used in an amount of from 1 to 5 times the molar amount of the compound 4-2.
在步骤5)中，在惰性气体保护下将步骤4)得到的双烯化合物4-3溶于无水有机溶剂(如二氯甲烷、二氯乙烷或甲苯)中，在钌催化剂(如:詹氏催化剂或Grubbs催化剂等)的作用下，在温度0-100℃下反应，通过烯烃复分解环化反应，得到大环状产物4-4；所述的钌催化剂用量为双烯化合物4-3摩尔量的0.2-10％；所述的有机溶剂用量为双烯化合物4-3重量比的15-40倍；In step 5), the diene compound 4-3 obtained in step 4) is dissolved in an anhydrous organic solvent (such as dichloromethane, dichloroethane or toluene) under an inert gas atmosphere, in a ruthenium catalyst (eg: Under the action of Jen's catalyst or Grubbs catalyst, the reaction is carried out at a temperature of 0-100 ° C, and the olefin metathesis cyclization reaction is carried out to obtain a macrocyclic product 4-4; the amount of the ruthenium catalyst is diene compound 4-3 a molar amount of 0.2-10%; the organic solvent is used in an amount of 15-40 times the weight ratio of the diene compound 4-3;
在步骤6)中，将步骤5)得到的化合物4-4在无机强碱(如：氢氧化锂或氢氧化钠)的作用下，在溶剂(如水、甲醇、四氢呋喃或1,4-二氧六环)中，于10-60℃进行水解脱去保护基甲氧基后酸化生成羧酸，再在偶合试剂(如：HATU)的作用下，在有机溶剂(如二氯甲烷、四氢呋喃或N,N一二甲基甲酰胺)中，与SM-6通过酰胺化反应得到大环状多环产物II；所述的偶合试剂的用量为化合物3-4摩尔量的1-2.5倍；酰胺化反应的温度为0-80℃；In step 6), the compound 4-4 obtained in the step 5) is subjected to the action of an inorganic strong base such as lithium hydroxide or sodium hydroxide in a solvent such as water, methanol, tetrahydrofuran or 1,4-dioxane. In the six ring), the hydrolysis is carried out at 10-60 ° C to remove the protective methoxy group and then acidified to form a carboxylic acid, and then under the action of a coupling reagent (such as: HATU) in an organic solvent (such as dichloromethane, tetrahydrofuran or N). , N-dimethylformamide), amidation reaction with SM-6 to obtain a macrocyclic polycyclic product II; the coupling reagent is used in an amount of 1-2.5 times the compound 3-4 molar amount; amidation The reaction temperature is 0-80 ° C;
本申请的第六方面，提供一种本申请所述化合物、其立体异构体、互变异构体、酯化或酰胺化的前体药物、药学上可接受的盐、或其混合物的用途，它用于抑制HCV；或用于制备抑制HCV的药物；或用于制备治疗丙型肝炎病毒感染性疾病或病症的药物。A sixth aspect of the invention provides a use of a compound, stereoisomer, tautomer, esterified or amidated prodrug, pharmaceutically acceptable salt thereof, or mixture thereof, of the present application It is used to inhibit HCV; or to prepare a drug that inhibits HCV; or to prepare a drug for treating a hepatitis C virus infectious disease or condition.
本申请的第七方面，提供一种药物组合物，包含:一种或多种本申请所述的式A(如式I或II)化合物、或其立体异构体、互变异构体、酯化或酰胺化的前体药物、或其药学上可接受的盐，和药学上可接受的载体。 A seventh aspect of the present invention provides a pharmaceutical composition comprising: one or more compounds of Formula A (such as Formula I or II) described herein, or a stereoisomer, tautomer thereof, An esterified or amidated prodrug, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
本申请的第八方面，提供一种组合物，包括一种或多种本申请所述的式A(如式I或II)化合物、或其立体异构体、互变异构体、酯化或酰胺化的前体药物、或其药学上可接受的盐以及一种或多种下述药物:(1)免疫调节剂；(2)丙型肝炎病毒(HCV)蛋白酶抑制剂；(3)丙型肝炎病毒(HCV)聚合酶抑制剂；(4)不属于(2)-(3)之核苷和核苷衍生物；(5)乙型肝炎病毒(HBV)抑制剂；(6)人类免疫缺损病毒(HIV)抑制剂；(7)抗癌药物；(8)抗炎药物；或(9)不属于上述(1)-(8)之其它化合物。In an eighth aspect of the present invention, there is provided a composition comprising one or more compounds of Formula A (such as Formula I or II) described herein, or a stereoisomer, tautomer thereof, esterification thereof Or an amidated prodrug, or a pharmaceutically acceptable salt thereof, and one or more of the following: (1) an immunomodulatory agent; (2) a hepatitis C virus (HCV) protease inhibitor; (3) Hepatitis C virus (HCV) polymerase inhibitor; (4) nucleoside and nucleoside derivatives not belonging to (2)-(3); (5) hepatitis B virus (HBV) inhibitor; (6) human Immunodeficiency virus (HIV) inhibitors; (7) anticancer drugs; (8) anti-inflammatory drugs; or (9) other compounds not belonging to the above (1)-(8).
本申请的药物组合物包括但不限于口服剂型、胃肠外给药剂型、外用剂型和直肠给药剂型。在一些实施方式中，所述药物组合物可以是口服的片剂、胶囊、丸剂、粉剂、缓释制剂、溶液和悬浮液，用于胃肠外注射的无菌溶液、悬浮液或乳液。在其它实施方式中，所述药物组合物为适合单次施予精确剂量的单位剂型。在其它实施方式中，所述化合物的量在约0.001mg/kg体重/天-约1000mg/kg体重/天的范围内。在其它实施方式中，所述化合物的量的范围为约0.5mg/kg体重/天-约50mg/kg体重/天。在一些实施方式中，所述化合物的量为约0.001g/天-约7g/天。在其它实施方式中，所述化合物的量为约0.002g/天-约6g/天。在其它实施方式中，所述化合物的量为约0.005g/天-约5g/天。在其它实施方式中，所述化合物的量为约0.01g/天-约5g/天。在其它实施方式中，所述化合物的量为约0.02g/天-约5g/天。在其它实施方式中，所述化合物的量为约0.05g/天-约2.5g/天。在其它实施方式中，所述化合物的量为约0.1g/天-约1g/天。在其它实施方式中，低于上述范围下限的剂量水平可能已经是足够的。在其它实施方式中，可能需要高于上述范围上限的剂量水平。在一些实施方式中，以单剂量施用所述化合物，每天一次。在其它实施方式中，以多剂量施用所述化合物，每天不只一次。在一些实施方式中，每天施用两次所述化合物。在其它实施方式中，每天施用三次所述化合物。在其它实施方式中，每天施用四次所述化合物。在其它实施方式中，每天施用四次以上的所述化合物。在一些实施方式中，所述药物组合物施用于的个体为哺乳动物。在其它实施方式中，所述哺乳动物是人。在其它实施方式中，所述药物组合物还包含至少一种其它药物，共同制成一种剂型。在一些实施方式中，所述药物组合物和至少一种其它药物分别以独立的剂型组合成组合产品，如套装药品(kit of part)。Pharmaceutical compositions of the present application include, but are not limited to, oral dosage forms, parenteral dosage forms, topical dosage forms, and rectal administration dosage forms. In some embodiments, the pharmaceutical composition may be an oral tablet, capsule, pill, powder, sustained release formulation, solution and suspension, sterile solution, suspension or emulsion for parenteral injection. In other embodiments, the pharmaceutical composition is in a unit dosage form suitable for single administration of precise dosages. In other embodiments, the amount of the compound ranges from about 0.001 mg/kg body weight/day to about 1000 mg/kg body weight/day. In other embodiments, the amount of the compound ranges from about 0.5 mg/kg body weight/day to about 50 mg/kg body weight/day. In some embodiments, the amount of the compound is from about 0.001 g/day to about 7 g/day. In other embodiments, the amount of the compound is from about 0.002 g/day to about 6 g/day. In other embodiments, the amount of the compound is from about 0.005 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.01 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.02 g/day to about 5 g/day. In other embodiments, the amount of the compound is from about 0.05 g/day to about 2.5 g/day. In other embodiments, the amount of the compound is from about 0.1 g/day to about 1 g/day. In other embodiments, a dose level below the lower limit of the above range may already be sufficient. In other embodiments, dose levels above the upper limit of the above range may be required. In some embodiments, the compound is administered in a single dose, once a day. In other embodiments, the compound is administered in multiple doses more than once a day. In some embodiments, the compound is administered twice daily. In other embodiments, the compound is administered three times a day. In other embodiments, the compound is administered four times a day. In other embodiments, the compound is administered more than four times a day. In some embodiments, the individual to which the pharmaceutical composition is administered is a mammal. In other embodiments, the mammal is a human. In other embodiments, the pharmaceutical composition further comprises at least one other drug that is co-formulated into a dosage form. In some embodiments, the pharmaceutical composition and at least one other drug are each combined in a separate dosage form into a combined product, such as a kit of parts.
上述药物中的免疫调节剂包含干扰素或干扰素衍生物。其中所述的干扰素可为聚乙二醇干扰素。所述的HIV抑制剂包含但不限于利托那韦药物(Ritonavir)。所述的乙型肝炎病毒(HBV)抑制剂包含但不限于:拉米夫定、替比夫定、阿德福韦、恩曲他滨、恩替卡韦、替诺福韦或克来夫定。The immunomodulatory agent in the above drugs contains an interferon or an interferon derivative. The interferon described therein may be polyethylene glycol interferon. The HIV inhibitors include, but are not limited to, ritonavir (Ritonavir). The hepatitis B virus (HBV) inhibitors include, but are not limited to, lamivudine, telbivudine, adefovir, emtricitabine, entecavir, tenofovir or koviffin.
本申请的第九方面，提供上述任一药物组合物在制备抑制丙型肝炎病毒的药物中的应用，或在制备治疗丙型肝炎病毒感染性疾病或病症的药物中的应用。The ninth aspect of the present application provides the use of any of the above pharmaceutical compositions for the preparation of a medicament for inhibiting hepatitis C virus, or for the preparation of a medicament for treating a hepatitis C virus infectious disease or disorder.
本申请的第十方面，提供了本申请的化合物、其立体异构体、互变异构体、药学上可接受的盐抑制HCV或治疗丙型肝炎病毒感染性疾病或病症的方法，所述方法包括将所述化合物施用于有此需求的个体的步骤。优选地，所述个体为哺乳动物，例如为人。In a tenth aspect of the present application, there is provided a method of inhibiting HCV or treating a hepatitis C virus infectious disease or condition, wherein the compound, stereoisomer, tautomer, pharmaceutically acceptable salt thereof, of the present application, The method comprises the step of administering the compound to an individual in need thereof. Preferably, the individual is a mammal, such as a human.
本申请的又一个方面，提供了一种化合物、其立体异构体、互变异构体、药学上可接受的盐，其用于抑制HCV。In still another aspect of the present application, there is provided a compound, a stereoisomer, a tautomer thereof, a pharmaceutically acceptable salt thereof for use in inhibiting HCV.
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本申请各较佳实例。 The above preferred conditions can be arbitrarily combined without departing from the common knowledge in the field, that is, the preferred examples of the present application.
本申请所用试剂和原料均市售可得。The reagents and starting materials used in this application are commercially available.
发明详述Detailed description of the invention
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。The section headings used herein are for the purpose of organizing articles only and are not to be construed as limiting the subject matter. All documents or parts of the literature cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals and papers, are hereby incorporated by reference in their entirety.
化学术语Chemical terminology
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义，以本章的定义为准。Unless otherwise defined, all technical and scientific terms used herein have the same meaning meaning meaning All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety herein in their entirety herein If there are multiple definitions of terms in this article, the definitions in this chapter shall prevail.
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本申请主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。The above description and the following detailed description are to be considered as illustrative and not restrictive. In the present application, the use of the singular includes the plural unless otherwise specified. It should also be noted that "or" or "or" is used to mean "and/or" unless otherwise indicated. In addition, the terms "comprises" and "comprising", "include", "include", and "include" are not limiting.
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4TH ED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/Vis光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本申请的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。The definition of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/Vis spectroscopy and pharmacological methods, are employed unless otherwise indicated. Unless specifically defined, the terms used herein in the descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the manufacturer's instructions for use of the kit can be utilized, or the reaction can be carried out and purified according to methods well known in the art or as described in the present application. The above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification. In the present specification, the group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，CH2O等同于OCH2。When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left. For example, CH 2 O is equivalent to OCH 2 .
除非另有说明，否则所用的通用化学术语，例如但不限于，“烷基”、“胺”、“芳基”等同于其任选取代的形式。例如，本文所用的“烷基”包括任选取代的烷基。Unless otherwise indicated, the general chemical terms used, such as but not limited to, "alkyl", "amine", "aryl" are equivalent to the form optionally substituted. For example, "alkyl" as used herein includes an optionally substituted alkyl group.
术语“任选/任意”或“任选地/任意地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，根据下文的定义，“任选取代的烷基”是指“未取代的烷基”(未被取代基取代的烷基)或“取代的烷基”(被取代基取代的烷基)。The term "optional/arbitrary" or "optionally/arbitrarily" means that the subsequently described event or circumstance may or may not occur, the description including the occurrence or non-occurrence of the event or circumstance. For example, according to the definition below, "optionally substituted alkyl" means "unsubstituted alkyl" (alkyl substituted without a substituent) or "substituted alkyl" (alkyl substituted with a substituent) .
本文所用C1-Cn包括C1-C2、C1-C3、……C1-Cn。举例而言，所述“C1-C4”基团是指该部分中具有1-4个碳原子，即基团包含1个碳原子，2个碳原子、3个碳原子或4个碳原子。因此，举例而言“C1-C4烷基”是指在有1-4个碳原子的烷基，即所述烷基选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基。本文中的数字范围，例如“1-10”是指给定范围中的各个整数，例如“1-10个碳原子”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子或10个碳原子。 C 1 -C n as used herein includes C 1 -C 2 , C 1 -C 3 , ... C 1 -C n . By way of example, the "C 1 -C 4 " group means having from 1 to 4 carbon atoms in the moiety, ie the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbons atom. Thus, for example, "C 1 -C 4 alkyl" refers to an alkyl group having from 1 to 4 carbon atoms, that is, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, and n-butyl Base, isobutyl, sec-butyl and tert-butyl. A numerical range, for example, "1-10" refers to each integer in a given range, for example "1-10 carbon atoms" means that the group may have 1 carbon atom, 2 carbon atoms, 3 Carbon atom, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
本文单独或组合使用的术语“烷基”是指任选取代的直链或任选取代的支链的饱和脂肪族烃类。本文的“烷基”优选可具有1-约20个碳原子，例如具有1-约10个碳原子，具有1-约8个碳原子，或1-约6个碳原子，或1-约4个碳原子或1-约3个碳原子。本文的烷基实施例包括但不限于甲基、乙基、正丙基、异丙基、2-甲基-l-丙基、2-甲基-2-丙基、2-甲基-1-丁基、3-甲基-l-丁基、2-甲基-3-丁基、2,2-二甲基-1-丙基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-l-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2,2-二甲基-l-丁基、3,3-二甲基-1-丁基、2-乙基-1-丁基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基和己基，以及更长的烷基基团，如庚基和辛基等。本文定义的基团，如“烷基”出现数字范围时，例如“C1-C6烷基”或“C1-6烷基”是指可由1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子构成的烷基，本文的烷基也包含未指定数字范围的情况。The term "alkyl" as used herein, alone or in combination, refers to an optionally substituted straight or optionally substituted branched saturated aliphatic hydrocarbon. The "alkyl" herein may preferably have from 1 to about 20 carbon atoms, for example from 1 to about 10 carbon atoms, from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms, or from 1 to about 4. One carbon atom or from 1 to about 3 carbon atoms. Alkyl embodiments herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-1 -butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl 1-yl-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2 - dimethyl-l-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, positive Butyl, isopentyl, neopentyl, tert-amyl and hexyl, as well as longer alkyl groups such as heptyl and octyl. When a group as defined herein, such as "alkyl" appears numerical range, for example, "C 1 -C 6 alkyl" or "C 1 - 6 alkyl" refers to by a carbon atom, 2 carbon atoms, 3 An alkyl group consisting of a carbon atom, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, and the alkyl group herein also contains an unspecified number range.
本文组合使用的“烷基”是指与其他基团链接的烷基，例如烷氧基中的烷基、烷硫基中的烷基、羟基烷基、卤代烷基、氰代烷基、单烷基氨基、二烷基氨基中的“烷基”等。As used herein, "alkyl" refers to an alkyl group that is linked to other groups, such as an alkyl group in an alkoxy group, an alkyl group in an alkylthio group, a hydroxyalkyl group, a haloalkyl group, a cyanoalkyl group, a monoalkylene group. An alkyl group or a "alkyl group" in a dialkylamino group.
本文单独或组合使用的术语“烷氧基”是指烷基醚基(O-烷基)，烷氧基的非限定性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基等。The term "alkoxy" as used herein, alone or in combination, refers to an alkyl ether group (O-alkyl), non-limiting examples of which include methoxy, ethoxy, n-propoxy, isopropyl Oxyl, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy groups.
本文单独或组合使用的术语“烯基”是指任选取代的直链或任选取代的支链的一价烃基，其具有至少一个C＝C双键。所述烯基具有但不限于2-约18个碳原子，例如，具有2-约10个碳原子，或具有2-约8个碳原子，2-约6个碳原子，2-约4个碳原子。这些基团中的双键可以为顺式或反式构象，并应被理解为包含所述两种异构体。实施例包括但不限于乙烯基(CH＝CH2)、1-丙烯基(CH2CH＝CH2)、异丙烯基(C(CH3)＝CH2)、丁烯基和1,3-丁二烯基等。本文定义的烯基出现数字范围时，例如“C2-C6烯基”或“C2-6烯基”是指可由2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子构成的烯基，本文的烯基也涵盖未指定数字范围的情况。The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight or optionally substituted branched monovalent hydrocarbon radical having at least one C=C double bond. The alkenyl group has, but is not limited to, from 2 to about 18 carbon atoms, for example, from 2 to about 10 carbon atoms, or from 2 to about 8 carbon atoms, from 2 to about 6 carbon atoms, from 2 to about 4 carbon atom. The double bond in these groups may be in the cis or trans conformation and should be understood to encompass both isomers. Examples include, but are not limited to, vinyl (CH=CH 2 ), 1-propenyl (CH 2 CH=CH 2 ), isopropenyl (C(CH 3 )=CH 2 ), butenyl, and 1,3- Butadienyl and the like. When an alkenyl group as defined herein appears in the numerical range, for example "C 2 -C 6 alkenyl" or "C 2 - 6 alkenyl" means 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbons An alkenyl group consisting of an atom or 6 carbon atoms, and the alkenyl group herein also covers the case where the numerical range is not specified.
本文单独或组合使用的术语“炔基”是指任选取代的直链或支链的一价烃基，其具有至少一个C≡C三键。所述炔基具有但不限于2-约18个碳原子，例如其具有2-约10个碳原子，或具有2-约8个碳原子，或2-约6个碳原子，或2-约4个碳原子。本文的炔基实施例包括但不限于乙炔基、2-丙炔基、2-丁炔基和1,3-丁二炔基等。本文定义的炔基出现数字范围时，例如“C2-C6炔基”或“C2-6炔基”是指可由2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子构成的炔基基团，本文的炔基也涵盖未指定数字范围的情况。The term "alkynyl" as used herein, alone or in combination, refers to an optionally substituted straight or branched chain monovalent hydrocarbon radical having at least one C≡C triple bond. The alkynyl group has, but is not limited to, 2 to about 18 carbon atoms, for example, it has 2 to about 10 carbon atoms, or has 2 to about 8 carbon atoms, or 2 to about 6 carbon atoms, or 2 to about 4 carbon atoms. Examples of alkynyl groups herein include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiynyl, and the like. Where alkynyl groups as defined herein are in the numerical range, for example "C 2 -C 6 alkynyl" or "C 2 -6 alkynyl" means 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbons An alkynyl group consisting of an atom or 6 carbon atoms, the alkynyl group herein also covers the unspecified range of numbers.
本文单独或组合使用的术语“卤代”或“卤素取代”是指任选被取代的基团(如烷基、烯基和炔基)的其中至少一个氢原子被替换成卤素(如氟、氯、溴、碘或其组合)。在一些实施方式中，使用彼此相同的卤素替换两个或多个氢(例如二氟甲基、三氟甲基)；在其它实施方式中使用彼此并不完全相同的卤素替换两个或多个氢(例如1-氯-1-氟-1-碘乙基)。卤代烷基的非限定性实施例为氟甲基和溴乙基。卤代烯基的非限定性实施例为溴乙烯基。卤代炔基的非限定性实施例为氯乙炔基。The term "halo" or "halogen-substituted" as used herein, alone or in combination, means that at least one hydrogen atom of an optionally substituted group (eg, alkyl, alkenyl, and alkynyl) is replaced with a halogen (eg, fluoro, Chlorine, bromine, iodine or a combination thereof). In some embodiments, two or more hydrogens (eg, difluoromethyl, trifluoromethyl) are replaced with the same halogen as each other; in other embodiments two or more are replaced with halogens that are not identical to each other. Hydrogen (eg 1-chloro-1-fluoro-1-iodoethyl). Non-limiting examples of haloalkyl groups are fluoromethyl and bromoethyl. A non-limiting example of a haloalkenyl group is a bromovinyl group. A non-limiting example of a haloalkynyl group is a chloroethynyl group.
本文单独或组合使用的术语“芳香基/芳基”是指任选取代的芳香烃基，其具有6-约20个，如6-12个或6-10个成环碳原子，其可以是单环芳基、双环芳基或更多环芳基。双环芳基或更多环芳基可以是一个单环芳基与其它独立环，如脂环、杂环、芳环、芳杂环相稠合。 单环芳基的非限定性实施例包括6至约12个、6至约10个或6至约8个成环碳原子的单环芳基，例如苯基；双环芳基例如为萘基；多环芳基例如为菲基、蒽基、薁基。The term "aryl/aryl" as used herein, alone or in combination, refers to an optionally substituted aromatic hydrocarbon radical having from 6 to about 20, such as from 6 to 12 or from 6 to 10 ring-forming carbon atoms, which may be a single Cycloaryl, bicyclic aryl or more cyclic aryl. The bicyclic aryl or more cyclic aryl group may be a monocyclic aryl group fused to other independent rings such as an alicyclic ring, a heterocyclic ring, an aromatic ring or an aromatic heterocyclic ring. Non-limiting examples of monocyclic aryl groups include 6 to about 12, 6 to about 10 or 6 to about 8 monocyclic aryl groups of a ring-constituting carbon atom, such as phenyl; bicyclic aryl groups such as naphthyl; The polycyclic aryl group is, for example, a phenanthryl group, a fluorenyl group or a fluorenyl group
本文单独或组合使用的术语“杂环芳基或杂芳基”是指任意取代的杂芳基，其包含约5至约20个，如5至12个或5至10个骨架成环原子，其中至少一个(如1-4个、1-3个、1-2个)成环原子为杂原子，所述杂原子独立地选自氧、氮、硫、磷、硅、硒和锡中的杂原子，但不限于此。所述基团的环不包含两个相邻的O或S原子。杂芳基包括单环杂芳基(具有一个环)、双环杂芳基(具有两个环)或多环杂芳基(具有两个以上的环)。在环中出现两个或更多杂原子的实施方式中，所述两个或更多杂原子可彼此相同，或者所述两个或更多杂原子中的一些或全部彼此不同。双环杂芳基或更多环杂芳基可以是一个单环杂芳基与其它独立环，如脂环、杂环、芳环、芳杂环相稠合(可统称为稠合环杂芳基)。单环杂芳基的非限定性实施例包括5至约12个、5至约10个、5至约7个或6个骨架成环原子的单环杂芳基，例如其非限定性实施例包括吡啶基；稠合环杂芳基包括苯并咪唑基(benzimidazolyl)、喹啉基(quinolinyl)、吖啶基(acridinyl)。杂芳基的其它实施例包括但不限于：吡啶、嘧啶、吡嗪、哒嗪、三嗪、呋喃、噻吩、咪唑、***、四唑、噻唑、异噻唑、1,2,4-噻二唑、吡咯、吡唑、噁唑、异噁唑、噁二唑、苯并呋喃、苯并噻吩、苯并噻唑、吲哚、吲唑、喹啉、异喹啉、嘌呤、咔唑、苯并咪唑、吡咯并吡啶、吡咯并嘧啶、吡唑并吡啶、吡唑并嘧啶等。吖啶基、吩嗪基、苯并噁唑基、苯并噻二唑基、苯并噁二唑基、苯并***基、异喹啉基、氮茚基(indolizinyl)、异噻唑基(isothiazolyl)、异氮杂茚基(isoindolyl)、噁二唑基(oxadiazolyl)、嘌呤基(purinyl)、酞嗪基(phthalazinyl)、蝶啶基(pteridinyl)、喹唑啉基(quinazolinyl)、喹噁啉基(quinoxalinyl)、三嗪基(triazinyl)和噻二唑基(thiadiazolyl)等，及其氧化物，例如吡啶基-N-氧化物(pyridyl-N-oxide)等。The term "heterocyclic aryl or heteroaryl" as used herein, alone or in combination, refers to an optionally substituted heteroaryl group containing from about 5 to about 20, such as from 5 to 12 or from 5 to 10 backbones to form a ring atom, At least one (eg, 1-4, 1-3, 1-2) ring-forming atoms are heteroatoms independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin. Heteroatoms, but are not limited to this. The ring of the group does not contain two adjacent O or S atoms. Heteroaryl groups include monocyclic heteroaryl (having one ring), bicyclic heteroaryl (having two rings) or polycyclic heteroaryl (having more than two rings). In embodiments in which two or more heteroatoms are present in the ring, the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other. The bicyclic heteroaryl or more cycloheteroaryl group may be a monocyclic heteroaryl group fused to other independent rings such as an alicyclic ring, a heterocyclic ring, an aromatic ring or an aromatic heterocyclic ring (collectively referred to as a fused ring heteroaryl group). ). Non-limiting examples of monocyclic heteroaryl groups include from 5 to about 12, from 5 to about 10, from 5 to about 7 or 6 monocyclic heteroaryl groups which are backbone-ringed, for example, non-limiting examples thereof Included is pyridyl; fused ring heteroaryl includes benzimidazolyl, quinolinyl, acridinyl. Other examples of heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, triazine, furan, thiophene, imidazole, triazole, tetrazole, thiazole, isothiazole, 1,2,4-thiadiene Oxazole, pyrrole, pyrazole, oxazole, isoxazole, oxadiazole, benzofuran, benzothiophene, benzothiazole, hydrazine, carbazole, quinoline, isoquinoline, indole, carbazole, benzo Imidazole, pyrrolopyridine, pyrrolopyrimidine, pyrazolopyridine, pyrazolopyrimidine and the like. Acridinyl, phenazinyl, benzoxazolyl, benzothiadiazolyl, benzooxadiazolyl, benzotriazolyl, isoquinolinyl, indolizinyl, isothiazolyl ( Isothiazolyl), isoindolyl, oxadiazolyl, purinyl, phthalazinyl, pteridinyl, quinazolinyl, quinoxaline Quinoxalinyl, triazinyl, thiadiazolyl, etc., and oxides thereof, such as pyridyl-N-oxide.
本文单独或组合使用的术语“杂环”或“杂环基”是指非芳香杂环，其包括饱和杂环或不饱和杂环(含不饱和键)。其中一个或者多个(如1-4个、1-3个、1-2个)成环的原子是杂原子，如氧、氮或硫原子。杂环可以包括单杂环(具有一个环)或双杂环(具有两个桥合的环)或多杂环(具有两个以上桥合的环)；也包括螺环。杂环基可具有3至约20个，如3-约10个、3-约8个、4-8个、4-7个、5-约8个或5-约6个成环原子。杂环基的非限制性实施例包括吖嗪基(azinyl)、氮杂环丁烷基(azetidinyl)、氧杂环丁基(oxetanyl)、硫杂环丁基(thietanyl)、高哌啶基(homopiperidinyl)、oxepanyl、thiepanyl、oxazepinyl、diazepinyl、thiazepinyl、1,2,3,6-四氢吡啶基(1,2,3,6-tetrahydropyridinyl)、2-吡咯啉基(2-pyrrolinyl)、3-吡咯啉基(3-pyrrolinyl)、吲哚啉基(indolinyl)、2H-吡喃基(2H-pyranyl)、4H-吡喃基(4H-pyranyl)、二氧杂环己基(dioxanyl)、1,3-二氧戊环基(1,3-dioxolanyl)、吡唑啉基(pyrazolinyl)、二硫环己基(dithianyl)、二硫环戊基(dithiolanyl)、二氢吡喃基(dihydropyranyl)、二氢噻吩基(dihydrothienyl)、二氢呋喃基(dihydrofuranyl)、吡唑烷基(pyrazolidinyl)、咪唑啉基(imidazolinyl)、咪唑啶基(imidazolidinyl)、3-氮杂双环[3.1.0]己基(3-azabicyclo[3.1.0]hexyl)、3-氮杂双环[4.1.0]庚基(3-azabicyclo[4.1.0]heptyl)、3H-吲哚基(3H-indolyl)和喹啉基(quinolizinyl)等。该术语还包括糖类的所有环状形式，包括但不限于单糖、二糖和寡糖。实施例还包括但不限于，氮丙啶、四氢呋喃、四氢噻吩、吡咯烷、噁唑烷、噻唑烷、咪唑烷、异噁唑烷、异噻唑烷、吡唑烷、吗啉、硫代吗啉、哌嗪、哌啶基等。杂环基还包括具有一个或多个芳香环稠合(即有一个共同的键)的杂环，例如2,3-二氢苯并呋喃、1,3-苯 并二氧戊环、苯并-1,4-二噁烷、苯二甲酰亚胺，萘二甲酰亚胺。具有一个或多个芳香稠合的杂环基可以通过芳香环或非芳香环部分与其它基团相连接。其它基团可通过杂原子或碳原子与杂环结合(即杂环与母体分子连接或进一步取代)。The term "heterocycle" or "heterocyclyl" as used herein, alone or in combination, refers to a non-aromatic heterocycle which includes a saturated heterocyclic ring or an unsaturated heterocyclic ring (containing an unsaturated bond). One or more (e.g., 1-4, 1-3, 1-2) ring-forming atoms are heteroatoms such as oxygen, nitrogen or sulfur atoms. The heterocyclic ring may include a single heterocyclic ring (having one ring) or a bicyclic heterocyclic ring (having two bridged rings) or a polyheterocyclic ring (having a ring having two or more bridges); also includes a spiro ring. Heterocyclyl groups can have from 3 to about 20, such as from 3 to about 10, from 3 to 8, 4 to 8, 4 to 7, 5 to about 8, or from 5 to about 6 ring-forming atoms. Non-limiting examples of heterocyclic groups include azinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl ( Homopiperidinyl), oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3- 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, Dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl (3) -azabicyclo[3.1.0]hexyl), 3-azabicyclo[4.1.0]heptyl (3-azabicyclo[4.1.0]heptyl), 3H-indolyl and quinolizinyl )Wait. The term also encompasses all cyclic forms of saccharides including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Examples include, but are not limited to, aziridine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, oxazolidine, thiazolidine, imidazolidine, isoxazolidine, isothiazolidine, pyrazolidine, morpholine, thio? Porphyrin, piperazine, piperidinyl and the like. Heterocyclyl also includes heterocycles having one or more aromatic rings fused (ie, having a common bond), such as 2,3-dihydrobenzofuran, 1,3-benzene And dioxolane, benzo-1,4-dioxane, phthalimide, naphthalimide. The heterocyclic group having one or more aromatic condensations may be bonded to other groups through an aromatic ring or a non-aromatic ring moiety. Other groups may be bonded to the heterocycle via a heteroatom or a carbon atom (ie, the heterocycle is attached or further substituted with the parent molecule).
本文单独或组合使用的术语环烷基可以是单环环烷基，也可以是双环环烷基，环之间可以是桥合或螺环。环烷基可以具有3至20个碳原子，例如具有3-约15个成环碳原子或3-约10个成环碳原子或3-6个成环碳原子。实例包括环丙基、环丁基、环戊基、环己基、环庚基、金刚烷基等。The term cycloalkyl as used herein, alone or in combination, may be monocyclic cycloalkyl or bicyclic cycloalkyl, and the rings may be bridged or spiro. The cycloalkyl group can have from 3 to 20 carbon atoms, for example from 3 to about 15 ring-forming carbon atoms or from 3 to about 10 ring-forming carbon atoms or from 3 to 6 ring-forming carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and the like.
烷氧基可表示为“烷基-O-”；环烷氧基可表示为“环烷基-O-”；芳氧基可表示为“芳基-O-”；烷氨基可表示为“烷基-N-”；环烷氨基可表示为“环烷基-N-”；芳氨基可表示为“芳基-N-”，其中的烷基、环烷基和芳基的定义同上。The alkoxy group may be represented by "alkyl-O-"; the cycloalkoxy group may be represented by "cycloalkyl-O-"; the aryloxy group may be represented by "aryl-O-"; the alkylamino group may be represented by " Alkyl-N-"; cycloalkylamino can be represented as "cycloalkyl-N-"; arylamino can be represented as "aryl-N-" wherein alkyl, cycloalkyl and aryl are as defined above.
“卤素”是指氟，氯，溴，碘。首选是氟，氯和溴。氰基是指“-CN”；羟基是指“-OH”；巯基是指“-SH”；氨基是指“-NH2”。"Halogen" means fluoro, chloro, bromo, iodo. The preferred are fluorine, chlorine and bromine. The cyano group means "-CN"; the hydroxy group means "-OH"; the thiol group means "-SH"; and the amino group means "-NH 2 ".
磺酰氨基是指“RSO2NH-”和
Figure PCTCN2017079087-appb-000012
氨基磺酰基是指“-SO2NH2”或"-SO2NHR"，其中R可以是烷基、烷氧基、环烷基、芳基、杂芳基、环烷氧基、芳氧基、烷氨基、环烷氨基、芳氨基、脲基、硫脲基、磷酸酯、或硼酸酯，这些基团的定义同上。结构
Figure PCTCN2017079087-appb-000013
中，N上的取代基选自C1-6烷基、C1-6烷氧基或C3-6环烷基。Sulfonylamino means "RSO 2 NH-" and
Figure PCTCN2017079087-appb-000012
Aminosulfonyl means "-SO 2 NH 2 " or "-SO 2 NHR", wherein R may be alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, cycloalkoxy, aryloxy , alkylamino, cycloalkylamino, arylamino, ureido, thiourea, phosphate, or borate, these groups are as defined above. structure
Figure PCTCN2017079087-appb-000013
In the above, the substituent on N is selected from a C 1-6 alkyl group, a C 1-6 alkoxy group or a C 3-6 cycloalkyl group.
可以理解，烷基磺酰氨基是指磺酰氨基表示的结构式中R为烷基的情况，烷氧基磺酰氨基是指磺酰氨基表示的结构式中R为烷氧基的情况，以此类推。It is understood that the alkylsulfonylamino group refers to the case where R is an alkyl group in the structural formula represented by a sulfonylamino group, and the alkoxysulfonylamino group refers to a case where R is an alkoxy group in the structural formula represented by a sulfonylamino group, and so on. .
术语“被取代的”意思是在一个特定的原子上一个或更多的氢被指定的基团所替代，如果指定的原子的正常化合价在现有的情况下没有超出，那么取代后结果是一个稳定的化合物。The term "substituted" means that one or more hydrogens are replaced by a specified group on a particular atom. If the normal valence of the specified atom is not exceeded in the existing case, the result of the substitution is one. A stable compound.
药学术语Pharmaceutical terminology
某些药学术语本文所用的有关术语“受试者”、“患者”或“个体”是指患有疾病、病症或病况等的个体，包括哺乳动物和非哺乳动物。哺乳动物的实施例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛、马、绵羊、山羊、猪；家养动物，例如兔、狗和猫；实验室动物，包括啮齿类动物，例如大鼠、小鼠和豚鼠等。非人哺乳动物的实施例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方式中，所述哺乳动物为人。Certain pharmacy terms As used herein, the terms "subject," "patient," or "individual" refer to an individual, including a mammal, and a non-mammal, having a disease, disorder, condition, or the like. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (eg, chimpanzees and other mites and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domesticated Animals such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human.
本文所用的术语“治疗”和其它类似的同义词包括缓解、减轻或改善疾病或病症症状，预防其它症状，改善或预防导致症状的潜在代谢原因，抑制疾病或病症，例如阻止疾病或病症的发展，缓解疾病或病症，使疾病或病症好转，缓解由疾病或病症导致的症状，或者中止疾病或病症的症状，此外，该术语包含预防的目的。该术语还包括获得治疗效果和/或预防效果。所述治疗效果是指治愈或改善所治疗的潜在疾病。此外，对与潜在疾病相关的一种或多种生理症状的治愈或改善也是治疗效果，例如尽管患者可能仍然受到潜在疾病的影响，但观察到患者情况改善。就预防效果而言，可向具有患特定疾病风险的患者施用所述组合物，或者即便尚未做出疾病诊断，但向出现该疾病的一个或多个生理症状的患者施用所述组合物。The term "treatment" and other similar synonyms as used herein includes alleviating, alleviating or ameliorating the symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing a potential metabolic cause of the symptoms, inhibiting the disease or condition, such as preventing the progression of the disease or condition, Ameliorating a disease or condition, ameliorating the disease or condition, alleviating the symptoms caused by the disease or condition, or terminating the symptoms of the disease or condition, and further, the term includes the purpose of prevention. The term also includes obtaining a therapeutic effect and/or a preventive effect. The therapeutic effect refers to curing or ameliorating the underlying disease to be treated. In addition, the healing or amelioration of one or more physiological symptoms associated with a underlying disease is also a therapeutic effect, for example, although the patient may still be affected by the underlying disease, an improvement in the patient's condition is observed. In terms of prophylactic effect, the composition can be administered to a patient at risk of developing a particular disease, or even if a diagnosis of the disease has not been made, the composition is administered to a patient who develops one or more physiological symptoms of the disease.
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程 度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物***的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。The term "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" as used herein means that it is sufficient to take a certain course after administration. The amount of at least one agent or compound that substantially alleviates one or more symptoms of the disease or condition being treated. The result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired change in the biological system. For example, an "effective amount" for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic. An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、外用和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington's,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方式中，本文讨论的化合物和组合物通过口服施用。The terms "administering," "administering," "administering," and the like, as used herein, refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration. The techniques of administration of the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, those discussed in Pa. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.
本文针对制剂、组合物或成分所用术语“可接受的”是指对接受治疗的受试者的一般健康情况没有长期的有害影响。The term "acceptable" as used herein with respect to a formulation, composition or ingredient means that there is no long-term detrimental effect on the general health of the subject being treated.
本文所用术语“药学上可接受的”是指不影响本申请化合物的生物活性或性质的物质，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。The term "pharmaceutically acceptable" as used herein, refers to a substance that does not affect the biological activity or properties of the compounds of the present application and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable biological reactions or in undesirable ways and combinations. Any component contained in the substance interacts.
本文所用术语“载体”是指相对无毒的化学化合物或试剂，其有助于将化合物引入到细胞或组织中。The term "carrier," as used herein, refers to a relatively non-toxic chemical compound or agent that facilitates the introduction of a compound into a cell or tissue.
本文所用术语“药学上可接受的盐”是指保留了指定化合物的游离酸和游离碱的生物效力，并且在生物学或其它方面上没有不良作用的盐。本申请化合物还包括药学上可以接受的盐。药学上可接受的盐是指把母体化合物中的碱基基团转换成盐的形式。药学上可接受的盐包括，但不仅限于，碱基基团例如胺(氨)基的无机或有机酸盐类。The term "pharmaceutically acceptable salt" as used herein, refers to a salt that retains the biological effectiveness of the free acid and free base of the specified compound, and which has no adverse effects biologically or otherwise. The compounds of the present application also include pharmaceutically acceptable salts. A pharmaceutically acceptable salt refers to a form in which a base group in a parent compound is converted into a salt. Pharmaceutically acceptable salts include, but are not limited to, base or group of inorganic or organic acid salts of amine (amino) groups.
除特别指示外，本申请中的盐指用有机酸/无机酸形成的酸式盐，以及用有机碱/无机碱形成的碱式盐。另外，当式I化合物的碱性官能团是吡啶或咪唑(但不限制于吡啶或咪唑)，酸性官能团是羧酸(但不限制于羧酸)时就会形成两性离子(内盐)，内盐也包括在本申请中的盐内。Unless otherwise specified, the salt in the present application refers to an acid salt formed with an organic acid/inorganic acid, and a basic salt formed with an organic base/inorganic base. In addition, when the basic functional group of the compound of formula I is pyridine or imidazole (but not limited to pyridine or imidazole), the acidic functional group is a carboxylic acid (but not limited to a carboxylic acid), a zwitterion (internal salt) is formed, and the inner salt Also included in the salt in this application.
本文使用的“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体。式I化合物含有不对称或手性中心，因此，存在不同的立体异构形式。分子式I的所有立体结构和混合物一样，包括外消旋混合物，作为目前申请的一部分。非对映体混合物能够分离成单独的非对映体，基于它们不同的物理化学性质，采用众所周知的手段，例如，对映异构体的拆分可通过与适当的光学活性物质(例如手性醇或Mosher`s莫氏酰氯)反应转换为非对映异构体，将其分离并转化(如水解)为相对应的单一的异构体。式1中的一些化合物可能是阻转异构体(如取代芳基)也是本申请中的一部分。对映异构体也可利用手性色谱柱分离。式I中的化合物可能存在着不同的互变异构形式，这些形式都包含在本申请范围内。例如，酮-烯醇和亚胺-烯胺形式的化合物。As used herein, "stereoisomer" refers to an isomer produced by the different arrangement of atoms in a molecule in space. The compounds of formula I contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. All stereostructures and mixtures of Formula I, including racemic mixtures, are part of the current application. The mixture of diastereomers can be separated into individual diastereomers, based on their different physicochemical properties, using well-known means, for example, resolution of the enantiomers can be carried out with appropriate optically active substances (eg chirality) The alcohol or Mosher`s molyl chloride reaction is converted to a diastereomer which is separated and converted (e.g., hydrolyzed) to the corresponding single isomer. Some of the compounds of Formula 1 may be atropisomers (e.g., substituted aryl groups) are also part of this application. Enantiomers can also be separated using a chiral column. The compounds of formula I may exist in different tautomeric forms, and such forms are embraced within the scope of the present application. For example, compounds in the form of keto-enol and imine-enamine.
本文所述的“抑制HCV(Hepatitis C Virus,丙型肝炎病毒)”是指直接作用于丙肝病毒复制的各个靶点，如NS3/4A蛋白酶、NS5A蛋白酶、NS5B聚合酶等，其包括阻止丙肝病毒的复制，抑制相关蛋白的功能，对病毒的杀灭等。As used herein, "inhibiting HCV (Hepatitis C Virus)" refers to various targets that directly act on the replication of hepatitis C virus, such as NS3/4A protease, NS5A protease, NS5B polymerase, etc., including blocking of hepatitis C virus. The replication, inhibition of the function of related proteins, the killing of viruses and so on.
本申请的积极进步效果在于以下至少之一: The positive progress of this application is at least one of the following:
1)本申请的大环状杂环化合物不仅对NS3丙型肝炎病毒具有较佳的抑制活性，而且明显优于其它不同类型己临床试验的大环状化合物的抑制活性；1) The macrocyclic heterocyclic compound of the present application not only has a better inhibitory activity against NS3 hepatitis C virus, but also is significantly superior to the inhibitory activity of other large types of clinically tested macrocyclic compounds;
2)本申请深入研究了不同大环状杂环化合物的结构与抑制丙肝病毒活性的构效关系，并且发现了一些有效抑制丙肝病毒的大环状杂环化合物结构；2) This application has intensively studied the structure-activity relationship of the structure of different macrocyclic heterocyclic compounds with the inhibition of hepatitis C virus activity, and found some large cyclic heterocyclic compound structures that effectively inhibit hepatitis C virus;
3)本申请优化了新型大环状多环化合物及其不同类型多环小分子中间体的制备方法，较大程度地降低了制备成本，为新型大环状多环丙型肝炎病毒抑制剂药物的产业化生产提供一条有效实用的新方法。3) The present application optimizes the preparation method of novel macrocyclic polycyclic compounds and different types of polycyclic small molecule intermediates, and greatly reduces the preparation cost, and is a novel macrocyclic polycyclic hepatitis C virus inhibitor drug. Industrial production provides an effective and practical new method.
4)本申请的有些大环状杂环化合物具有很低的毒副作用或基本无毒，从而有可能进一步成功研发一个高效无毒的抗丙型肝炎病毒新药。4) Some of the large cyclic heterocyclic compounds of the present application have low toxic side effects or are substantially non-toxic, and thus it is possible to further develop a highly effective and non-toxic anti-hepatitis C virus new drug.
接下来，对本申请涉及的化合物的制备方法做进一步的说明：Next, the preparation method of the compound referred to in the present application is further described:
本申请不仅设计和合成了用于抑制丙型肝炎病毒的新型大环状多环化合物，还进一步通过对含多环官能团的大环状化合物抑制丙型肝炎病毒活性的研究，深入探究了不同结构的新型含多环官能团的大环状化合物与抑制丙型肝炎病毒活性的关系，进一步研发优化了有效用于治疗丙型肝炎病毒感染的新型大环状多环化合物、及其制备方法。This application not only designs and synthesizes novel macrocyclic polycyclic compounds for inhibiting hepatitis C virus, but also further explores different structures by inhibiting the activity of hepatitis C virus by macrocyclic compounds containing polycyclic functional groups. The novel macrocyclic compound containing a polycyclic functional group has a relationship with the activity of inhibiting hepatitis C virus, and further developed a novel macrocyclic polycyclic compound which is effective for treating hepatitis C virus infection, and a preparation method thereof.
本申请的关健创新点是首先合成出了新型多环化合物Va-Vi,并合成出通用关键中间体7及13，然后合成出了式I-II大环状化合物。The key innovation of this application is to first synthesize a novel polycyclic compound Va-Vi, and synthesize the general key intermediates 7 and 13, and then synthesize the macrocyclic compound of formula I-II.
本申请合成新型含多环官能团的大环状化合物过程中的化学试剂和溶剂的英文缩写注释全部汇总列在实施例中仪器及原料说明部分。The abbreviations of chemical reagents and solvents in the process of synthesizing novel macrocyclic compounds containing polycyclic functional groups in the present application are all summarized in the apparatus and raw material description sections of the examples.
下列反应图示1中，分别采用原料SM-2或SM-2’和原料SM-2a在有机溶剂(如：甲醇、乙醇、N,N-二甲基甲酰胺等)中进行反应，在加热条件下(50-100℃)通过缩合反应分别制得化合物Va-Vf；In the following reaction scheme 1, the raw material SM-2 or SM-2' and the raw material SM-2a are respectively reacted in an organic solvent (e.g., methanol, ethanol, N, N-dimethylformamide, etc.), and heated. Under the conditions (50-100 ° C) by condensation reaction to prepare the compound Va-Vf;
反应图示1:中间体Va、Vb、Vc、Vd、Ve、Vf的合成 Reaction Scheme 1: Synthesis of Intermediates Va, Vb, Vc, Vd, Ve, Vf
Figure PCTCN2017079087-appb-000014
Figure PCTCN2017079087-appb-000014
反应图示2:中间体Vg、Vh、Vi的合成 Reaction Scheme 2: Synthesis of Intermediates Vg, Vh, Vi
Figure PCTCN2017079087-appb-000015
Figure PCTCN2017079087-appb-000015
从上述反应图1及图2所示的方法得到本申请中关键的新型多环化合物Va-Vf，Vg-Vi后，为了从不同角度进行结构性能优化创新，本申请设计了下列的合成路线制备了关键中间体7(反应图示3)及13(反应图示4)。接着利用共用中间体7或13为原料，合成了一系列最终产品LW100201-LW100227(即I)及LW100228-LW100229(即II)。具体每一步反应实验以及详细条件和产品分析结果分别列于实施例中。After obtaining the novel polycyclic compounds Va-Vf and Vg-Vi which are the key points in the present application from the above-mentioned reaction schemes of FIG. 1 and FIG. 2, in order to optimize the structural performance from different angles, the present application designs the following synthetic route preparation. Key intermediates 7 (reaction shown in Figure 3) and 13 (reaction shown in Figure 4). Next, using a common intermediate 7 or 13 as a raw material, a series of final products LW100201-LW100227 (i.e., I) and LW100228-LW100229 (i.e., II) were synthesized. Specific reaction experiments and detailed conditions and product analysis results are listed in the examples.
反应图示3： Reaction Figure 3:
Figure PCTCN2017079087-appb-000016
Figure PCTCN2017079087-appb-000016
上述合成反应图示3中，首先将SM-3原料溶于无水有机溶剂(如二氯甲烷、四氢呋喃或甲苯)中，在三苯基磷和偶氮二羧酸酯的作用下，分别与另一试剂Va-Vf发生Mitsunobu反应，生成化合物4；然后用盐酸脱除Boc保护基生成胺中间体,再在偶合试剂HATU的作用下与另一保护的氨基酸衍生物SM-4生成化合物5；5用盐酸脱除Boc保护基生成胺中间体,再在光气或三光气的作用下生成异氰酸酯中间体，继而与新戊二醇反应形成化合物6；6在无水有机溶剂中，在钯催化剂的作用下，反应得到大环状关键中间体7；产物7在氢氧化锂的作用下水解生成羧酸8；最后8与另一氨基甲酸酯原料SM-6在偶合试剂HATU的作用下通过酰胺化反应生成最终的大环状多环化合物LW100201-LW100227(即I)。In the above synthesis reaction scheme 3, the SM-3 raw material is first dissolved in an anhydrous organic solvent (such as dichloromethane, tetrahydrofuran or toluene) under the action of triphenylphosphine and azodicarboxylate, respectively. Another reagent Va-Vf undergoes Mitsunobu reaction to form compound 4; then, the Boc protecting group is removed with hydrochloric acid to form an amine intermediate, and then another protective amino acid derivative SM-4 is formed by the coupling reagent HATU to form compound 5; 5 Removal of the Boc protecting group with hydrochloric acid to form an amine intermediate, followed by phosgene or triphosgene to form an isocyanate intermediate, followed by reaction with neopentyl glycol to form compound 6; 6 in an anhydrous organic solvent, in a palladium catalyst Under the action of the reaction, the macrocyclic key intermediate 7 is obtained; the product 7 is hydrolyzed by the action of lithium hydroxide to form the carboxylic acid 8; the last 8 is passed with another urethane raw material SM-6 under the action of the coupling reagent HATU. The amidation reaction produces the final macrocyclic polycyclic compound LW100201-LW100227 (i.e., I).
以下结构式系列1为本申请通过反应图示2合成的关键中间体化合物6a-6g、7a-7g及8a-8g的具体例子，它们具有结构式图1如下：The following structural formula series 1 is a specific example of the key intermediate compounds 6a-6g, 7a-7g, and 8a-8g synthesized by Reaction Scheme 2 in the present application, which have the structural formulas as shown in FIG.
结构式图1： Structural Figure 1:
Figure PCTCN2017079087-appb-000017
Figure PCTCN2017079087-appb-000017
Figure PCTCN2017079087-appb-000018
Figure PCTCN2017079087-appb-000018
反应图示4：Reaction Figure 4:
Figure PCTCN2017079087-appb-000019
Figure PCTCN2017079087-appb-000019
上述反应图示3中，首先将化合物4(反应图示3中得到)与乙烯三氟硼酸钾在钯催化剂(如：Pd(dppf)Cl2)的作用下，通过Suzuki反应得到化合物10；然后用盐酸脱除Boc保护基生成胺中间体,再在偶合试剂HATU的作用下与另一保护的氨基酸衍生物SM-4生成化合物11；11用盐酸脱除Boc保护基生成胺中间体,再在碱(如三乙胺)的作用下，与酰氯SM-7反应形成化合物12；12在无水有机溶剂(如二氯甲烷、二氯乙烷或甲苯)中，在钌催化剂(如:0.2-10％mol的詹氏催化剂或Grubbs催化剂等)的作用下，通过烯烃复分解环化反应(RCM:ring closing metathesis,0-100℃)，得到反式环烯烃大环状产物13；13在氢氧化锂的作用下水解生成羧酸中间体；最后羧酸中间体与另一氨基甲酸酯原料SM-6在偶合试剂HATU的作用下通过酰胺化反应生成最终的大环状多环化合物LW100228-LW100229(即II)。 In the above reaction scheme 3, first, Compound 4 (obtained in Reaction Scheme 3) and potassium ethylene trifluoroborate are subjected to a Suzuki reaction to obtain Compound 10 under the action of a palladium catalyst (e.g., Pd(dppf)Cl 2 ); Removing the Boc protecting group with hydrochloric acid to form an amine intermediate, and then reacting with another protected amino acid derivative SM-4 under the action of the coupling reagent HATU to form compound 11; 11 removing the Boc protecting group with hydrochloric acid to form an amine intermediate, and then Under the action of a base such as triethylamine, it reacts with acid chloride SM-7 to form compound 12; 12 in an anhydrous organic solvent (such as dichloromethane, dichloroethane or toluene) in a ruthenium catalyst (eg: 0.2- Under the action of 10% mol of Jen's catalyst or Grubbs catalyst, by olefin metathesis cyclization (RCM: ring closing metathesis, 0-100 ° C), a trans-cyclic olefin macrocyclic product 13 is obtained; Hydrolysis to form a carboxylic acid intermediate by the action of lithium; finally the carboxylic acid intermediate and another urethane starting material SM-6 are amidated by the coupling reagent HATU to form the final macrocyclic polycyclic compound LW100228-LW100229 (ie II).
上述合成反应图示4中二终端含双烯的中间体化合物12的烯烃环化反应所用的詹氏催化剂(Zhan Catalyst-1&1B)结构如下列结构式系列2所示:The Zhan Catalyst-1 & 1B structure used for the olefin cyclization reaction of the two terminal diene-containing intermediate compound 12 in the above synthesis scheme is shown in the following structural formula series 2:
结构式系列2：Structural Series 2:
Figure PCTCN2017079087-appb-000020
Figure PCTCN2017079087-appb-000020
以下结构式系列3为本申请通过反应图示3合成的关键中间体化合物12a及13a的具体例子，它们具有结构式如下：The following structural formula series 3 is a specific example of the key intermediate compounds 12a and 13a synthesized by the reaction scheme 3 in the present application, which have the following structural formula:
结构式系列3：Structural Series 3:
Figure PCTCN2017079087-appb-000021
Figure PCTCN2017079087-appb-000021
在上述反应路线2-3中，所需原料氨基酸衍生物SM-6最佳选自下列结构式系列4所示的结构(SM-6a至SM-6h):In the above Reaction Scheme 2-3, the desired starting material amino acid derivative SM-6 is most preferably selected from the structures shown in the following structural formula series 4 (SM-6a to SM-6h):
Figure PCTCN2017079087-appb-000022
Figure PCTCN2017079087-appb-000022
总之，经上述反应路线2和3中的多步反应，合成了各种含不同新型功能团的杂环中间体Va-Vi和最终大环状化合物I-II，表1为本申请合成的新型大环状最终化合物I-II的具体例子,它们具有结构式LW100201-LW100227(I)以及LW100228-LW100229(II)：In summary, various heterocyclic intermediates Va-Vi and final macrocyclic compound I-II containing different novel functional groups were synthesized by the multi-step reaction in the above Reaction Schemes 2 and 3. Table 1 is a novel synthesis of the present application. Specific examples of macrocyclic final compounds I-II having the structural formulas LW100201-LW100227(I) and LW100228-LW100229(II):
表1.新型抗HCV抑制剂Table 1. Novel anti-HCV inhibitors
Figure PCTCN2017079087-appb-000023
Figure PCTCN2017079087-appb-000023
Figure PCTCN2017079087-appb-000024
Figure PCTCN2017079087-appb-000024
Figure PCTCN2017079087-appb-000025
Figure PCTCN2017079087-appb-000025
Figure PCTCN2017079087-appb-000026
Figure PCTCN2017079087-appb-000026
Figure PCTCN2017079087-appb-000027
Figure PCTCN2017079087-appb-000027
Figure PCTCN2017079087-appb-000028
Figure PCTCN2017079087-appb-000028
Figure PCTCN2017079087-appb-000029
Figure PCTCN2017079087-appb-000029
Figure PCTCN2017079087-appb-000030
Figure PCTCN2017079087-appb-000030
Figure PCTCN2017079087-appb-000031
Figure PCTCN2017079087-appb-000031
具体实施方式：detailed description:
本申请所涉及的原料和试剂除特殊说明外均可市售或订制加工购买得到。The raw materials and reagents referred to in the present application can be purchased commercially or custom-made, unless otherwise specified.
本申请中之化合物可含有一非芳香族双键及一个或多个不对称中心。因此，该系列化合物可为消旋和外消旋混合物，单一对映体，互变异构体，顺或反式异构体形式。本申请所制备的化合物(通式I-II)是纯度高于98％的手性大环状多环化合物，产物中天然的氨基酸和非天然的氨基酸光学纯度分别通过旋光度和手性色谱柱测定，每个最终产物的结构表征分别由LC-MS或/和氢谱核磁共振(1HNMR)分析确定。The compounds of the present application may contain a non-aromatic double bond and one or more asymmetric centers. Thus, the series of compounds can be racemic and racemic mixtures, single enantiomers, tautomers, cis or trans isomers. The compound prepared by the present application (Formula I-II) is a chiral macrocyclic polycyclic compound having a purity higher than 98%, and the optical purity of the natural amino acid and the unnatural amino acid in the product are respectively passed through an optical rotation and chiral column. The structural characterization of each final product was determined by LC-MS or/and hydrogen spectroscopy ( 1 H NMR) analysis, respectively.
由于HCV在体外普通肝细胞中自主复制水平极低，且其唯一的可感染动物为黑猩猩，故目前抗丙型肝炎病毒药物的临床前药效研究没有合适的动物试验模型，有人研究将体外感染HCV的人肝组织移植入免疫缺陷小鼠建立在体小鼠模型，但饲养这种小鼠存在技术难度，模型不稳定，而且缺乏正常的免疫反应，与丙型肝炎的发病过程差异太大，故未被用于评价丙肝药效研究的动物模型。1999年之前没有有效繁殖复制HCV的细胞培养***，无法弄清HCV的致病机制和病毒生活周期，使得抗病毒药物的研究进展缓慢。研究者们进行了大量的尝试，直到1999年才克服困难有了突破性的进展，建立了一个有效的细胞培养模型-复制子(replicon)***，这个***的基础是使用基因工程构建的亚基因组的HCVRNA，在转染的人肝癌细胞系Huh-7细胞中可以自主复制。Because HCV has a very low level of autonomous replication in normal hepatocytes in vitro, and its only infective animal is a chimpanzee, there is currently no suitable animal model for preclinical efficacy studies of anti-hepatitis C virus drugs. HCV human liver tissue was transplanted into immunodeficient mice to establish a mouse model in vivo, but the breeding of this mouse is technically difficult, the model is unstable, and lacks a normal immune response, which is too different from the pathogenesis of hepatitis C. Therefore, it has not been used to evaluate animal models of hepatitis B efficacy studies. Before 1999, there was no effective cell culture system for replicating HCV, and the pathogenesis of HCV and the life cycle of the virus could not be clarified, making the research progress of antiviral drugs slow. The researchers made a lot of attempts until 1999 to overcome the difficulties and made breakthroughs, establishing an effective cell culture model-replicon system based on the genetic engineering of the subgenomics. The HCV RNA can replicate autonomously in the transfected human hepatoma cell line Huh-7.
采用本行业内己经接受的上述有效的细胞培养模型-复制子(replicon)***，进行了离体实验，根据实验结果对药物进行评价，其中对丙型肝炎病毒靶点HCV NS3/4A丝氨酸蛋白酶抑制剂主要的离体实验结果数据包括:The above-mentioned effective cell culture model-replicon system accepted in the industry was used for ex vivo experiments, and the drug was evaluated based on the experimental results, wherein the hepatitis C virus target HCV NS3/4A serine protease was used. The main in vitro test results of the inhibitors include:
化合物对丙肝病毒复制子(Replicon)的抑制作用(EC50)。Inhibition of the compound against the hepatitis C virus replicon (EC 50 ).
至今国外临床前和临床试验结果研究表明，这样的离体试验结果与相关体内活性试验结果具有一致性。To date, studies of preclinical and clinical trial results have shown that such in vitro test results are consistent with the results of related in vivo activity tests.
本申请所制备的化合物可藉由下列临床前体外抑制活性测试实验初步测定筛选其对丙型肝炎病毒感染的疗效，然后藉由临床试验进一步加以确认。其他方法对本领域中具一般技术之人员而言亦是显而易见的。The compounds prepared in the present application can be initially screened for the efficacy of hepatitis C virus infection by the following preclinical inhibitory activity test, and then further confirmed by clinical trials. Other methods will also be apparent to those of ordinary skill in the art.
本申请化合物、或其立体异构体、互变异构体、酯化或酰胺化的前体药物、或其药学上可接受的盐及其混合物，经实验测定，均对丙型肝炎病毒感染有较好的疗效，具有明显的抑制丙型肝炎病毒的效果，化合物对丙肝病毒复制子(Replicon)的抑制作用(EC50)测试结果列于下表2；其中，活性范围(EC50)在250-50nM标示为“A”，活性范围在50-10nM标示为“B”，活性范围10-1nM标示为“C”,活性范围1-0.5nM标示为“D”,活性范围<0.5nM标示为“E”。a compound of the present application, or a stereoisomer, tautomer, esterified or amidated prodrug thereof, or a pharmaceutically acceptable salt thereof, and mixtures thereof, which are experimentally determined to be infected with hepatitis C virus It has a good curative effect and has obvious inhibitory effect on hepatitis C virus. The results of the inhibitory effect (EC 50 ) of the compound on the hepatitis C virus replicon (EC 50 ) are shown in Table 2 below; wherein the activity range (EC 50 ) is 250-50nM is labeled as “A”, the activity range is labeled “B” at 50-10nM, the activity range is 10-1nM is labeled as “C”, the activity range is 1-0.5nM is labeled as “D”, and the activity range is <0.5nM. It is "E".
表2:部分本申请的化合物抑制丙型肝炎病毒的活性测试结果Table 2: Results of some of the compounds of the present application inhibiting the activity of hepatitis C virus
Figure PCTCN2017079087-appb-000032
Figure PCTCN2017079087-appb-000032
Figure PCTCN2017079087-appb-000033
Figure PCTCN2017079087-appb-000033
测试方法：testing method:
丙肝病毒复制子(Replicon)***抗病毒实验:Anti-virus experiment of hepatitis C virus replicon system:
用新构建的双报告基因Replicon***完成，感染细胞中病毒复制水平是通过报告基因海肾荧光素酶(Renilla luciferase)检测实现的。报告基因的表达水平与HCV的RNA复制水平及病毒蛋白表达水平里很好的线性关系。8个2倍稀释的浓度梯度，3个复孔，3次重复，设1到2种阳性药物对照。最终计算化合物的EC50。Completed with the newly constructed dual reporter gene Replicon system, the level of viral replication in infected cells was achieved by the reporter gene Renilla luciferase. The expression level of the reporter gene has a good linear relationship with the level of RNA replication of HCV and the level of viral protein expression. Eight 2-fold dilutions of the concentration gradient, 3 replicate wells, 3 replicates, and 1 to 2 positive drug controls. The final compound is calculated EC 50.
HCV复制子瞬转实验HCV replicon transient experiment
化合物处理：对化合物进行1:3系列稀释9个浓度点，双复孔，加入96孔板中。设置DMSO为无加化合物对照。细胞培养液中的DMSO最终浓度为0.5％。Compound treatment: Compounds were serially diluted 1:3 in 9 concentration points, double wells, and added to 96-well plates. The DMSO was set to no compound control. The final concentration of DMSO in the cell culture was 0.5%.
电击转录：复制子质粒DNA用相应的限制性内切酶线性化后，用T7RNA聚合酶将DNA转录成RNA。用电击穿孔法将体外转录制备的复制子RNA转染到Huh7细胞内。转染后的细胞以每孔10,000个细胞的密度接种到含有稀释好化合物的96孔实验板中。随后置于37℃、5％CO2培养箱中培养3天。Electroporation Transcription: Replicon plasmid DNA was linearized with the corresponding restriction enzymes and transcribed into RNA using T7 RNA polymerase. Replicon RNA prepared in vitro transcription was transfected into Huh7 cells by electroporation. The transfected cells were seeded at a density of 10,000 cells per well into 96-well assay plates containing diluted compounds. It was then placed in a 37 ° C, 5% CO 2 incubator for 3 days.
每孔加荧光素酶发光底物Britelite plus，用化学发光检测***Envision检测 Luminescence信号值，原始数据(RLU)用于化合物抑制活性计算。Each well was incubated with the luciferase luminescent substrate Britelite plus, detected by the chemiluminescence detection system Envision Luminescence signal values, raw data (RLU) were used for compound inhibition activity calculations.
数据处理：data processing:
使用如下公式用原始数据计算各孔化合物对丙型肝炎病毒的抑制率：The original data was used to calculate the inhibition rate of each hole compound to hepatitis C virus using the following formula:
抑制率％＝(CPD-ZPE)/(HPE-ZPE)×100％*Inhibition rate%=(CPD-ZPE)/(HPE-ZPE)×100%*
CPD：化合物孔的信号值；CPD: the signal value of the compound well;
HPE(Hundred percent effect)：100％有效作用对照孔信号值，孔中只有DMEM培养液；Hundred percent effect (HPE): 100% effective control well signal value, only DMEM medium in the well;
ZPE(Zero percent effect)：无效作用对照孔信号值，用0.5％DMSO代替化合物。将抑制率导入GraphPad Prism软件进行数据处理得出化合物对应的曲线及其对HCV复制子的抑制活性(EC50)数值。ZPE (Zero percent effect): Ineffective control cell signal value, with 0.5% DMSO instead of compound. The inhibition rate was introduced into the GraphPad Prism software for data processing to obtain a curve corresponding to the compound and its inhibitory activity (EC50) value for the HCV replicon.
亚基因复制子活性(EC50)数值Subgene replicon activity (EC50) value
Figure PCTCN2017079087-appb-000034
Figure PCTCN2017079087-appb-000034
抗药性变异复制子活性(EC50)数值Drug resistance variant replicon activity (EC50)
Figure PCTCN2017079087-appb-000035
Figure PCTCN2017079087-appb-000035
野生型GT1a和GT1b细胞株构建方法：GT1a是H77亚型，GT1b是Con1亚型。合成GT1a和GT1b的非结构蛋白基因序列并***到常规载体中，并在载体中***新霉素筛选基因构建成HCV GT1a(H77)和GT1b(Con1)复制子载体。转染GT1a和GT1b复制子RNA到Huh7细胞后，经过G418筛选得到的稳转细胞株，可稳定复制GT1a和GT1b的复制子RNA。Methods for constructing wild-type GT1a and GT1b cell lines: GT1a is a H77 subtype and GT1b is a Con1 subtype. The non-structural protein gene sequences of GT1a and GT1b were synthesized and inserted into a conventional vector, and a neomycin selection gene was inserted into the vector to construct HCV GT1a (H77) and GT1b (Con1) replicon vectors. After transfecting the GT1a and GT1b replicon RNA into Huh7 cells, the stably transfected cell line obtained by G418 screening can stably replicate the replicon RNA of GT1a and GT1b.
嵌合复制子制备方法：GT1b/3a,GT1b/4a,GT1b/5a NS3嵌合复制子以野生型GT1b(Con1)复制子载体为骨架，将相应基因型的NS3片段导入以取代GT1b的NS3基因，各相应基因型的NS3基因序列来源于NCBI Gene bank的临床分离株。各耐药突变复制子以各相应的嵌合复制子为骨架，NS3基因耐药突变均通过点突变法引入，并运用核苷酸测序法确认。Chimeric replicon preparation method: GT1b/3a, GT1b/4a, GT1b/5a NS3 chimeric replicon uses the wild type GT1b (Con1) replicon vector as a backbone, and the NS3 fragment of the corresponding genotype is introduced to replace the NS3 gene of GT1b. The NS3 gene sequence of each corresponding genotype was derived from a clinical isolate of NCBI Gene bank. Each resistant mutant replicon was framed by each corresponding chimeric replicon, and NS3 gene-resistant mutations were introduced by point mutation and confirmed by nucleotide sequencing.
大鼠分别静脉和口服给予LW100219的药代动力学研究 Pharmacokinetic study of intravenous and oral administration of LW100219 in rats
称取适量受试物，溶于5％DMSO+10％Solutol+85％(20％HP-β-CD)中，配成浓度为1mg/mL和2mg/mL的黄色澄清溶液(pH～7)，分别用于静脉和口服给药。Weigh an appropriate amount of the test substance, dissolved in 5% DMSO + 10% Solutol + 85% (20% HP-β-CD), and prepare a yellow clear solution (pH ~ 7) at a concentration of 1 mg / mL and 2 mg / mL. For intravenous and oral administration, respectively.
给药剂量及给药方式Dosage and method of administration
雄性SD大鼠12只，购于上海西普尔-必凯实验动物有限公司。按下表给药。口服组给药前禁食10-14小时。给药后4小时后恢复饲料。Twelve male SD rats were purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. According to the table below. The oral group was fasted for 10-14 hours before administration. The feed was resumed 4 hours after administration.
Figure PCTCN2017079087-appb-000036
Figure PCTCN2017079087-appb-000036
样本采集及处理Sample collection and processing
静脉给药组在给药前和给药后0.083h，0.25h，0.5h，1h，2h，4h，8h，10h和24h采集样品；口服给药组在给药前和给药后0.25h，0.5h，1h，2h，4h，6h，8h，10h和24h，经颈静脉采血约0.25mL，肝素钠抗凝，血液样本采集后置于冰上，离心分离血浆(离心条件：8000转/分钟，6分钟，4℃)。收集的血浆分析前存放于–80℃。The intravenous administration group collected samples at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 10h and 24h before and after administration; the oral administration group was 0.25h before and after administration. 0.5h, 1h, 2h, 4h, 6h, 8h, 10h and 24h, blood was collected from the jugular vein by about 0.25mL, heparin sodium was anticoagulated, blood samples were collected and placed on ice, and the plasma was separated by centrifugation (centrifugation conditions: 8000 rpm) , 6 minutes, 4 ° C). The collected plasma was stored at –80 °C prior to analysis.
数据分析data analysis
进行血浆药物浓度-时间曲线绘制时，BLQ均记为0。When the plasma drug concentration-time curve was plotted, BLQ was recorded as 0.
进行药代参数计算时，Cmax之前的BLQ(包括“No peak”)按照0计算；Cmax之后出现的BLQ(包括“No peak”)一律不参与计算。When calculating the pharmacokinetic parameters, the BLQ before Cmax (including “No peak”) is calculated as 0; the BLQ (including “No peak”) appearing after Cmax is not involved in the calculation.
WinNonlin Professional v 5.2(Pharsight,USA)计算以下药代动力学参数：AUC(0-t)、AUC(0-∞)、T1/2、MRT(0-∞)、Cmax、Tmax、F。WinNonlin Professional v 5.2 (Pharsight, USA) calculates the following pharmacokinetic parameters: AUC (0-t), AUC (0-∞), T1/2, MRT (0-∞), Cmax, Tmax, F.
药代动力学参数Pharmacokinetic parameters
SD大鼠分别静脉和口服给予LW100219，测定血浆药物浓度。SD大鼠静脉给予5mg/kg LW100219后的Cmax为14886.23ng/mL，AUC(0-t)为6496.38h*ng/mL；SD大鼠口 服给予20mg/kg LW100219后的Cmax为3632.30ng/mL，AUC(0-t)为18049.39h*ng/mL，LW100219在大鼠的生物利用度为69.46％。SD rats were given LW100219 intravenously and orally, and plasma drug concentrations were determined. The Cmax of SD rats after intravenous administration of 5 mg/kg LW100219 was 14886.23 ng/mL, AUC (0-t) was 6496.38 h*ng/mL; the Cmax of SD rats after oral administration of 20 mg/kg LW100219 was 3632.30 ng/mL. AUC (0-t) was 18049.39h*ng/mL, and the bioavailability of LW100219 in rats was 69.46%.
以下通过说明本申请各类化合物和中间体的合成和效果。The synthesis and effects of various compounds and intermediates of the present application are described below.
实施例中涉及到的仪器及原料说明如下:The instruments and materials involved in the examples are as follows:
核磁共振氢谱是Bruker AV-400(400MHz)核磁仪分析得到。化学位移以四甲基硅烷为内标来记录，以ppm为单位来表示(CHC13:δ7.26ppm)。记录的数据信息如下:化学位移及其裂分和偶合常数(s:单重峰；d:双重峰；t：三重峰；q：四重峰；br：宽峰；m：多重峰)。The nuclear magnetic resonance spectrum was analyzed by a Bruker AV-400 (400 MHz) nuclear magnetic instrument. Chemical shifts were recorded with tetramethylsilane as an internal standard and expressed in ppm (CHC1 3 : δ 7.26 ppm). The recorded data information is as follows: chemical shift and its split and coupling constant (s: singlet; d: doublet; t: triplet; q: quartet; br: broad; m: multiplet).
质谱数据除其他需要,都采用菲尼根高级LCQ公司(Finnigan LCQAdvantage)的液质联用仪进行分析，所有反应都在干燥氩气保护的无水无氧条件下进行操作。固体金属有机化合物在氩气保护干燥箱中进行储藏。The mass spectrometry data was analyzed by a liquid-mass spectrometer of Finnigan LCQ Advantage, among other needs, and all reactions were operated under dry argon-protected anhydrous anaerobic conditions. The solid metal organic compound is stored in an argon-protected dry box.
四氢呋喃和***是经过蒸馏得到，蒸馏时在其中加入金属钠和二苯甲酮。二氯甲烷(DCM)，戊烷和己烷是用氢化钙来处理。本申请中涉及的特殊原料和中间体由天津长森药业有限公司等订制加工提供，其他所有化学试剂从天津化学试剂公司、阿尔得里奇公司(Aldrich)、阿克罗公司(Acros)等试剂供应商购买。如合成过程中反应所需的中间体或产物不够下一步等试验，则重复多次合成至足够数量为止。本申请所制备化合物的HCV蛋白酶(HCVNS3-4A)抑制活性测试实验由上海药明康德新药开发有限公司完成。Tetrahydrofuran and diethyl ether are obtained by distillation, and sodium metal and benzophenone are added thereto during distillation. Dichloromethane (DCM), pentane and hexane were treated with calcium hydride. The special raw materials and intermediates involved in this application are provided by Tianjin Changsen Pharmaceutical Co., Ltd., and other chemical reagents from Tianjin Chemical Reagent Company, Aldrich, and Acros. And other reagent suppliers to buy. If the intermediate or product required for the reaction in the synthesis is insufficient for the next step, the synthesis is repeated a plurality of times. The HCV protease (HCVNS3-4A) inhibitory activity test of the compound prepared in the present application was completed by Shanghai WuXi PharmaTech Development Co., Ltd.
SM-3：N-Boc-顺式-4-羟基-L-脯氨酸甲酯SM-3: N-Boc-cis-4-hydroxy-L-valine methyl ester
SM-4：N-Boc-L-叔亮氨酸SM-4: N-Boc-L-tert-leucine
Alcalase 2.4L：枯草杆菌蛋白酶-卡尔斯伯格(Subtilisin-Carlsberg)水解蛋白酶Alcalase 2.4L: Subtilisin-Carlsberg Hydrolyzed Protease
Boc：叔丁氧基羰基Boc: tert-butoxycarbonyl
(Boc)2O：二碳酸二叔丁酯(Boc) 2 O: di-tert-butyl dicarbonate
CDI：N,N’-羰基二咪唑CDI: N,N'-carbonyldiimidazole
DBU：1,8-二氮杂双环[5.4.0]十一碳-7-烯DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene
HATU：2-(7-偶氮苯并三氮唑)-N,N,N’，N’-四甲基脲六氟磷酸酯HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate
NBS：N-溴代丁二酰亚胺NBS: N-bromosuccinimide
DMAP：4-二甲氨基吡啶DMAP: 4-dimethylaminopyridine
DIEA：N,N-二异丙基乙胺DIEA: N,N-diisopropylethylamine
DIAD:偶氮二甲酸二异丙酯DIAD: diisopropyl azodicarboxylate
SOC12：氯化亚砜SOC1 2 : thionyl chloride
POCl3：三氯氧磷POCl 3 : phosphorus oxychloride
Pd/C：钯炭Pd/C: palladium charcoal
HMPA：六亚甲基四胺HMPA: hexamethylenetetramine
HOAc：冰乙酸HOAc: glacial acetic acid
HBr：氢溴酸HBr: hydrobromic acid
HCl:盐酸HCl: hydrochloric acid
TFA：三氟乙酸TFA: trifluoroacetic acid
TsOH：对甲苯磺酸 TsOH: p-toluenesulfonic acid
NaOH：氢氧化纳NaOH: sodium hydroxide
ACN:乙腈ACN: Acetonitrile
DCM:二氯甲烷DCM: dichloromethane
DCE：二氯乙烷DCE: Dichloroethane
DMF：N,N-二甲基甲酰胺DMF: N,N-dimethylformamide
DMSO：二甲亚砜DMSO: dimethyl sulfoxide
Et20：二***Et 2 0: diethyl ether
EA：乙酸乙酯EA: ethyl acetate
PE：石油醚PE: petroleum ether
THF:四氢呋喃THF: tetrahydrofuran
TBME：甲基叔丁基醚TBME: methyl tert-butyl ether
实施例1Example 1
化合物SM-2a的合成Synthesis of Compound SM-2a
Figure PCTCN2017079087-appb-000037
Figure PCTCN2017079087-appb-000037
间溴苯甲醛(93g,0.5mol),BnNEt3Cl(5.72g,25.13mmol)溶于CHCl3(125mL)中。在55℃下缓慢滴加50％NaOH并保持温度(65-70℃)，完毕后保持温度55℃搅拌。3小时后原料基本反应完全。加入930mL水稀释，搅拌充分后不溶物溶解，分出水相，用50％H2SO4调pH至2～3,180mLEA萃取，干燥,旋干得羟基酸58.3g，收率50.5％。M-bromobenzaldehyde (93 g, 0.5 mol), BnNEt 3 Cl (5.72 g, 25.13 mmol) was dissolved in CHCl 3 (125 mL). 50% NaOH was slowly added dropwise at 55 ° C and the temperature was maintained (65-70 ° C), and after completion, the temperature was maintained at 55 ° C with stirring. After 3 hours, the starting material was almost completely reacted. Add 930 mL of water to dilute, stir well, dissolve insoluble matter, separate the aqueous phase, adjust the pH to 2 to 3 with 50% H 2 SO 4 , extract with 180 mL of EA, dry, and spin dry to obtain 58.3 g of hydroxy acid, the yield is 50.5%.
将上述产品(58.3g,0.266mol)溶于EtOH(615mL)中，加入浓H2SO4(63.5mL,1.118mol)，在氮气保护下进行回流反应，2小时后取样检测，反应完毕。减压蒸干溶剂，加入1.5L EA稀释，依次用饱和Na2CO3溶液和饱和NaCl溶液洗涤，无水硫酸钠干燥，过滤，滤液旋干，柱层析纯化得SM-2a17.75g，收率26.1％。The above product (58.3 g, 0.266 mol) was dissolved in EtOH (615 mL), and concentrated H 2 SO 4 (63.5 mL, 1.118 mol) was added and refluxed under nitrogen atmosphere. After 2 hours, the sample was taken and the reaction was completed. The solvent was evaporated under reduced pressure, 1.5L diluted with EA was added, washed successively with saturated Na 2 CO 3 solution and saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, the filtrate by rotary evaporation, purified by column chromatography to give SM-2a17.75g, close The rate is 26.1%.
实施例2Example 2
化合物Va的合成Synthesis of Compound Va
Figure PCTCN2017079087-appb-000038
Figure PCTCN2017079087-appb-000038
将苯并[1,3]二氧戊烷(40g,0.327mol)溶于DCM(2.44L)和冰醋酸(2.277L)中，冷却至15℃，滴加浓HNO3(325.2mL)，保持温度低于40℃，滴加完毕后升至室温搅拌30分钟，冷却至0-5℃，滴加发烟浓HNO3(813mL)，滴加完毕后升至常温反应搅拌过夜。 The benzo[1,3]dioxolane (40 g, 0.327 mol) was dissolved in DCM (2.44 L) and glacial acetic acid (2.277 L), cooled to 15 ° C, and concentrated HNO 3 (325.2 mL) was added dropwise. The temperature was lower than 40 ° C, and after the completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes, cooled to 0 to 5 ° C, and fuming HNO 3 (813 mL) was added dropwise. After the completion of the dropwise addition, the mixture was stirred at room temperature and stirred overnight.
在反应液中加入9.6L冰水搅拌10分钟，静置分层，水相依次用800mL DCM和800mL EA各萃取1次，合并有机相，依次用640mL水洗2次，640mL饱和NaHCO3洗2次，无水硫酸钠干燥，过滤，旋干得粗品24g，收率34.7％。9.6 L of ice water was added to the reaction solution, and the mixture was stirred for 10 minutes, and the mixture was allowed to stand for separation. The aqueous phase was extracted once with 800 mL of DCM and 800 mL of EA, and the organic phases were combined, washed twice with 640 mL of water, and washed twice with 640 mL of saturated NaHCO 3 . Dry with anhydrous sodium sulfate, filter and spin dry to obtain 24 g of crude product, yield: 34.7%.
将上述粗品溶于MeOH(850mL)中，加入SnCl2·2H2O(255g，1.13mol)中，油浴加热回流反应过夜。反应液旋干溶剂，加入500mL EA和200mL水稀释，用1N NaOH调节pH至13后，用硅藻土过滤，滤饼用200mL EA洗涤3次。滤液分层，水相用500mL EA萃取3次，水相加NaCl至饱和后再用500mL EA萃取1次，后合并有机相用饱和NaCl洗涤，无水硫酸钠干燥，过滤，滤液旋干得邻苯二胺SM-210g，收率58％。The above crude product was dissolved in MeOH (850mL) was added SnCl 2 · 2H 2 O (255g , 1.13mol) in an oil bath heated at reflux overnight. The reaction solution was evaporated to dryness. EtOAc EtOAc EtOAc EtOAc. The filtrate was separated, and the aqueous phase was extracted three times with 500 mL of EA. The aqueous phase was added with NaCl to be saturated and then extracted with 500 mL of EA. The organic phase was washed with saturated NaCl, dried over anhydrous sodium sulfate and filtered. Phenylenediamine SM-210g, yield 58%.
将上述邻苯二胺SM-2(8.28g,32.2mmol)，α-羰基酸酯SM-2a(7g,46mmol)溶于无水EtOH(100mL)中，氮气保护下回流反应，6小时后停止反应，放置过周末。反应液过滤，滤饼用EtOH洗涤，滤饼烘干得Va 6.7g,收率60％。ESI-MS[(M+H+)]:m/z344.93,346.93.The above o-phenylenediamine SM-2 (8.28 g, 32.2 mmol), α-carbonyl acid ester SM-2a (7 g, 46 mmol) was dissolved in anhydrous EtOH (100 mL), refluxed under nitrogen, and stopped after 6 hours. Reaction, placed over the weekend. The reaction solution was filtered, and the filter cake was washed with EtOH, and the filter cake was dried to obtain 6.7 g of Va, yield 60%. ESI-MS[(M+H + )]: m/z 344.93, 346.93.
实施例3Example 3
化合物Vb的合成Synthesis of Compound Vb
Figure PCTCN2017079087-appb-000039
Figure PCTCN2017079087-appb-000039
将邻苯二酚(22g,0.2mol)溶于824mL***中，冷却至0℃，滴加发烟硝酸8.8mL，滴加完毕后，恢复至室温搅拌过夜。将体系倒入250mL冰水中，搅拌20分钟后分液，水相用150mL***萃取6次，合并有机相，用饱和碳酸钠中和有机相后，分液，无水硫酸钠干燥，过滤，滤液旋干得38.2g粗品，硅胶柱层析得硝化产物9.6g，收率31.2％.1NMR(CDCl3，400MHz)δ10.65(s,1H),7.68(d,1H),7.28(d,1H),6.93(t,1H),5.82(s,1H).The catechol (22 g, 0.2 mol) was dissolved in 824 mL of diethyl ether, cooled to 0 ° C, and 8.8 mL of fuming nitric acid was added dropwise. After the addition was completed, the mixture was returned to room temperature and stirred overnight. The system was poured into 250 mL of ice water, stirred for 20 minutes, and then separated. The aqueous phase was extracted 6 times with 150 mL of diethyl ether. The organic phase was combined, and the organic phase was neutralized with saturated sodium carbonate, then separated, dried over anhydrous sodium sulfate and filtered. rotary done 38.2g crude product by silica gel column chromatography to give 9.6 g of the nitration product, yield 31.2%. 1 NMR (CDCl 3 , 400MHz) δ10.65 (s, 1H), 7.68 (d, 1H), 7.28 (d, 1H), 6.93 (t, 1H), 5.82 (s, 1H).
将上述产物(42.45g,0.273mol)溶于DMF(842mL)中，加入CH2I2(205mL,2.545mol)，CuO(8.7g,0.109mol)和K2CO3(159g,1.149mol)。用氩气置换3次后，反应液加热升温至160-170℃，2小时后取样检测，反应完毕。反应液浓缩，倒入9L水中，用2.5L EA萃取3次，合并有机相，饱和食盐水洗后干燥，旋干得114g，柱层析纯化得关环产物35g，收率75％。The above product (42.45g, 0.273mol) was dissolved in DMF (842mL) was added CH 2 I 2 (205mL, 2.545mol ), CuO (8.7g, 0.109mol) and K 2 CO 3 (159g, 1.149mol ). After replacing with argon three times, the reaction solution was heated to 160-170 ° C, and after 2 hours, the sample was detected and the reaction was completed. The reaction solution was concentrated, poured into 9 L of water, and extracted with 2.5 L of EA three times. The organic phase was combined, washed with saturated brine, dried, and then evaporated to dryness to afford to afford,
将上述产品(35g，0.206mol)溶于267mL冰醋酸中，搅拌下缓慢滴加发烟HNO3(133mL)，滴加完毕，反应液室温搅拌过夜。反应液加入1.25L DCM稀释，搅拌下倒入1.25L冰水中，分液，水相用1.25L萃取至无产品，合并有机相，依次用1.5L水洗1次，1.5L饱和NaHCO3洗1次，饱和NaCl洗1次，无水硫酸钠干燥，过滤，滤液旋干得双硝化产物43.95g，收率71.1％。The above product (35 g, 0.206 mol) was dissolved in 267 mL of glacial acetic acid, and the fuming HNO 3 (133 mL) was slowly added dropwise with stirring, and the reaction mixture was stirred at room temperature overnight. The reaction solution was diluted with 1.25 L of DCM, poured into 1.25 L of ice water with stirring, and the liquid phase was extracted with 1.25 L to obtain no product. The organic phase was combined, washed once with 1.5 L of water, and washed once with 1.5 L of saturated NaHCO 3 . The mixture was washed once with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness to yield 43.95 g of the product.
将上述产品(31.5g，0.147mol)溶于1.1L MeOH中，加入SnCl2·H2O(332g,1.47mol)。反应液搅拌下加热回流过夜。反应液冷却，浓缩，之后用约4L1N NaOH溶液调pH至10-11，水相过滤，用3L EA萃取3次，合并有机相，用3L饱和NaCl洗涤1次，无水硫酸钠干燥，过 滤，滤液旋干得SM-2’11.07g，收率49.9％。The above product (31.5g, 0.147mol) was dissolved in 1.1L MeOH was added SnCl 2 · H2O (332g, 1.47mol ). The reaction solution was heated to reflux with stirring overnight. The reaction mixture was cooled and concentrated, then the pH was adjusted to 10-11 with a solution of 4 L1N NaOH. The aqueous phase was filtered, and extracted with 3 L of EA. The organic phase was combined, washed with 3 L of saturated NaCl, dried over anhydrous sodium sulfate and filtered. The filtrate was spun dry to give SM-2 '11.07 g, yield 49.9%.
将SM-2’(11g,72mmol)及SM-2a(18.6g,72mmol)溶于无水EtOH中，氩气保护下回流反应，待反应结束后冷却至室温，析出大量黄色固体，过滤，滤饼用EtOH洗涤，滤饼烘干得中间体Vb25.5g,收率70％。1H NMR(DMSO-d6,400MHz)δ12.54(s，1H),8.50(s，1H),8.33-8.31(m，1H),7.74-7.73(m，1H),7.48(t，1H),7.23(d，1H),6.79(d，1H),6.23(s，2H).ESI-MS[(M+H+)]:m/z345.11,347.02。SM-2' (11g, 72mmol) and SM-2a (18.6g, 72mmol) were dissolved in anhydrous EtOH, refluxed under argon atmosphere. After the reaction was completed, cooled to room temperature, a large amount of yellow solid was precipitated, filtered and filtered. The cake was washed with EtOH, and the cake was dried to give an intermediate Vb 25.5 g, yield 70%. </ RTI> <RTIgt; 7.23 (d, 1H), 6.79 (d, 1H), 6.23 (s, 2H). ESI-MS [(M+H+)]: m/z 345.11, 347.02.
实施例4Example 4
化合物Vc的合成Synthesis of Compound Vc
Figure PCTCN2017079087-appb-000040
Figure PCTCN2017079087-appb-000040
将α-酮酸(15.3g,67.2mmol)溶于无水DCM，氩气置换三次，降温至0℃，滴加氯化亚砜，滴毕升至室温搅拌0.5h，待用。将硝基苯胺(6.0g,33.6mmol)溶于无水DCM，加入TEA，氩气置换三次，于0℃滴加前面所得DCM溶液，滴毕，升至室温搅拌0.5h，加入饱和碳酸氢钠洗涤，分液，干燥，旋干，加EA溶解后过滤，滤液旋干，柱层析(PE-PE:EA50:1to 1:1.5)得黄色固体4g，收率23％。1H-NMR((d6-DMSO,400MHz)δ6.33(s,2H),7.10(m,1H),7.58-7.62(m,1H),7.76(d,J＝8.6Hz,1H),7.97-8.05(m,2H),8.17(s,1H),11.24(s,1H).MS(ESI):m/z 447(M+H).The α-keto acid (15.3 g, 67.2 mmol) was dissolved in anhydrous DCM and replaced with argon three times. The mixture was cooled to 0° C., thionyl chloride was added dropwise, and the mixture was stirred to room temperature and stirred for 0.5 h. Nitroaniline (6.0 g, 33.6 mmol) was dissolved in anhydrous DCM, TEA was added, and argon was added three times. The DCM solution obtained above was added dropwise at 0 ° C, and the mixture was added dropwise to room temperature, stirred for 0.5 h, and saturated sodium bicarbonate was added. Washing, liquid separation, drying, spin-drying, adding EA to dissolve, filtration, the filtrate was spin-dried, and column chromatography (PE-PE: EA50: 1 to 1: 1.5) gave 4 g of a yellow solid, yield 23%. 1H-NMR ((d6-DMSO, 400MHz) δ 6.33 (s, 2H), 7.10 (m, 1H), 7.58-7.62 (m, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.97- 8.05 (m, 2H), 8.17 (s, 1H), 11.24 (s, 1H). MS (ESI): m/z 447 (M+H).
在氮气保护条件下，依次将上述产物(2.5g,25.0mmol)、锌粉及氯化铵加入到乙醇的水溶液中，加热回流1h后，反应完全，反应液减压浓缩至干，将所得浓缩物直接过柱纯化(PE:EA3:1)，得产物Vc 1.55g，收率75％。1H-NMR(d6-DMSO,400MHz)δ6.24(s，2H),7.03(d，J＝8.24Hz，1H),7.43-7.47(m,2H),7.69(d，J＝9.04Hz,1H)，8.26(d,J＝7.84Hz，1H),8.43(s,1H),12.65(s,-OH,1H).MS(ESI):m/z343The product (2.5 g, 25.0 mmol), zinc powder and ammonium chloride were successively added to an aqueous solution of ethanol under nitrogen atmosphere, and after heating under reflux for 1 h, the reaction was completed, and the reaction mixture was concentrated to dryness under reduced pressure. The product was directly purified by column (PE: EA3: 1) to give product Vc 1.55 g, yield 75%. 1H-NMR (d6-DMSO, 400MHz) δ 6.24 (s, 2H), 7.03 (d, J = 8.24 Hz, 1H), 7.43-7.47 (m, 2H), 7.69 (d, J = 9.04 Hz, 1H) ), 8.26 (d, J = 7.84 Hz, 1H), 8.43 (s, 1H), 12.65 (s, -OH, 1H). MS (ESI): m/z 343
实施例5Example 5
化合物Vd的合成Synthesis of Compound Vd
Figure PCTCN2017079087-appb-000041
Figure PCTCN2017079087-appb-000041
在250mL的圆底烧瓶中，加入11g(10mmol)邻苯二酚，100mL丙酮，100mL苯及5mg对苯甲磺酸，烧瓶上接索氏提取器，提取器中放置分子筛以吸收反应产生的水。加热回流24小时，更换新的分子筛，继续加热回流24小时。减压浓缩反应液，残留物用石油醚萃取 三次，合并石油醚萃取液，用2N氢氧化钠溶液洗至水相无色，有机相加无水硫酸镁干燥，过滤，滤液旋干，得一淡黄色液体(3.6g,收率24％)。1H NMR(CDCl3,400MHz)δ6.80-6.82(m,4H),1.72(s,6H).In a 250 mL round bottom flask, 11 g (10 mmol) of catechol, 100 mL of acetone, 100 mL of benzene and 5 mg of p-benzoic acid were added, and the flask was placed on a Soxhlet extractor, and the molecular sieve was placed in the extractor to absorb the water produced by the reaction. . The mixture was heated to reflux for 24 hours, replaced with a new molecular sieve, and heated to reflux for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified eluting with EtOAc EtOAc EtOAc EtOAc EtOAc. Light yellow liquid (3.6 g, yield 24%). 1 H NMR (CDCl 3 , 400 MHz) δ 6.80-6.82 (m, 4H), 1.72 (s, 6H).
在一配有温度计和恒压滴液漏斗的250mL三口瓶中加入100mL硝酸(70％)和50mL冰醋酸，冰浴中冷却至10℃，从滴液漏斗中滴加上述产物24.75g(0.165mol)，控制反应温度在15-20℃，滴加完毕后，继续在冰浴中搅拌45min，TLC检测没有原料。在搅拌下将反应液慢慢倾倒入500mL的冷水中，得一黄色固体，搅拌10min，用布氏漏斗抽滤，水洗涤滤饼两次，抽干，真空干燥箱中干燥(40℃)过夜，得30.12g(93.5％)。1HNMR(CDCl3,400MHz)δ7.87(d,1H),7.60(s,1H),6.79(d,1H),1.75(s,6H)。In a 250 mL three-necked flask equipped with a thermometer and a constant pressure dropping funnel, 100 mL of nitric acid (70%) and 50 mL of glacial acetic acid were added, and the mixture was cooled to 10 ° C in an ice bath, and the above product 24.75 g (0.165 mol) was added dropwise from the dropping funnel. ), the reaction temperature was controlled at 15-20 ° C, and after the completion of the dropwise addition, stirring was continued for 45 minutes in an ice bath, and no raw material was detected by TLC. The reaction solution was slowly poured into 500 mL of cold water under stirring to obtain a yellow solid, stirred for 10 min, suction filtered with a Buchner funnel, washed twice with water, dried, and dried in a vacuum oven (40 ° C) overnight. , got 30.12g (93.5%). 1 H NMR (CDCl 3 , 400 MHz) δ 7.87 (d, 1H), 7.60 (s, 1H), 6.79 (d, 1H), 1.75 (s, 6H).
在一配有温度计的250mL三口瓶中加入122mL发烟硝酸(98％)和61mL冰醋酸，冰浴中冷却至10℃，分批小量加入30g(0.153mol)的单硝化产物(用时80min)，控制反应温度在15-20℃，加完后，继续在冰浴中搅拌45min，TLC检测没有原料。在搅拌下将反应液慢慢倾倒入550mL的冷水中，得一黄色固体，搅拌10min，用布氏漏斗抽滤，水洗涤滤饼两次，抽干，真空干燥箱中干燥(40℃)过夜，得33.72g(98％)。1HNMR(CDCl3,400MHz)δ7.23(s,2H),1.81(s,6H)。In a 250 mL three-necked flask equipped with a thermometer, 122 mL of fuming nitric acid (98%) and 61 mL of glacial acetic acid were added, and the mixture was cooled to 10 ° C in an ice bath, and 30 g (0.153 mol) of mononitrated product was added in small portions (80 min). The reaction temperature was controlled at 15-20 ° C. After the addition was completed, stirring was continued for 45 min in an ice bath, and no raw material was detected by TLC. The reaction solution was slowly poured into 550 mL of cold water with stirring to obtain a yellow solid, stirred for 10 min, filtered with a Buchner funnel, washed twice with water, dried, and dried in a vacuum oven (40 ° C) overnight. , got 33.72g (98%). 1 H NMR (CDCl 3 , 400 MHz) δ 7.23 (s, 2H), 1.81 (s, 6H).
将上述产物(5g，21mmol)溶于乙酸乙酯(100mL),加入Pd/C(150mg)，将氢化仪压力调节至0.1MPa，将反应瓶放入氢化仪相应的位置中，将装置密封好，用氢气置换5次，搅拌20h，HPLC监测反应完全。用硅藻土过滤，滤液减压蒸干得粗品4.6g。硅胶柱纯化(PE:EA15:1to 5:1)得SM-2”(2.6g，收率69％)。其盐酸盐的1HNMR(D2O,ppm)δ6.68(s,2H),1.64(s,6H,2CH3).The above product (5g, 21mmol) was dissolved in ethyl acetate (100mL), Pd / C (150mg) was added, the hydrogenation pressure was adjusted to 0.1MPa, the reaction bottle was placed in the corresponding position of the hydrogenation instrument, and the device was sealed. It was replaced with hydrogen for 5 times, stirred for 20 h, and the reaction was completely monitored by HPLC. It was filtered through celite, and the filtrate was evaporated to dryness. Purification by silica gel column (PE: EA 15: 1 to 5:1) afforded SM-2" (2.6 g, yield 69%). 1 H NMR (D 2 O, ppm) δ 6.68 (s, 2H) , 1.64 (s, 6H, 2CH 3 ).
将SM-2”(4.4g，24.4mmol)及SM-2a(6.3g，24.4mmol)溶于EtOH(185mL)，用氩气换气三次，反应液加热至回流，搅拌1.5h，HPLC监测反应完全，停止反应。将反应液放入冰箱2h，有晶体析出，抽滤收集固体，并用冰冷的乙醇洗，得到Vd(5.43g，收率59.5％)，1HNMR(CDCl3,400MHz)δ8.59(s,1H),8.44(d,1H),7.60(d,1H),7.38(t,1H),7.26(s,1H),6.72(s,1H),1.79(s,6H,2CH3)；MS(ESI):m/z373.28(M+H).SM-2" (4.4g, 24.4mmol) and SM-2a (6.3g, 24.4mmol) were dissolved in EtOH (185mL), argon gas was exchanged three times, the reaction solution was heated to reflux, stirred for 1.5h, and the reaction was monitored by HPLC. The reaction was stopped completely. The reaction solution was placed in a refrigerator for 2 hours, crystals were precipitated, and the solid was collected by suction filtration, and washed with ice-cold ethanol to obtain Vd (5.43 g, yield 59.5%), 1 H NMR (CDCl3, 400 MHz) δ 8.59 (s, 1H), 8.44 (d, 1H), 7.60 (d, 1H), 7.38 (t, 1H), 7.26 (s, 1H), 6.72 (s, 1H), 1.79 (s, 6H, 2CH 3 ) ;MS (ESI): m/z 373.28 (M+H).
实施例6Example 6
化合物Ve-Vf的合成Synthesis of Compound Ve-Vf
Figure PCTCN2017079087-appb-000042
Figure PCTCN2017079087-appb-000042
将邻苯二酚(22g,0.2mol)溶于824mL***中，冷却至0℃，滴加发烟硝酸8.8mL，滴加完毕后，恢复至室温搅拌过夜。将体系倒入250mL冰水中，搅拌20分钟后分液，水相用150mL***萃取6次，合并有机相，饱和碳酸钠中和有机相，干燥旋干得38.2g粗品，硅胶柱层析得硝基邻苯二酚9.6g，收率31.2％. The catechol (22 g, 0.2 mol) was dissolved in 824 mL of diethyl ether, cooled to 0 ° C, and 8.8 mL of fuming nitric acid was added dropwise. After the addition was completed, the mixture was returned to room temperature and stirred overnight. The system was poured into 250 mL of ice water, stirred for 20 minutes, and then separated. The aqueous phase was extracted 6 times with 150 mL of diethyl ether. The organic phase was combined, the organic phase was neutralized with saturated sodium carbonate, dried and dried to give 38.2 g of crude product. The base catechol 9.6g, the yield is 31.2%.
将硝基邻苯二酚(0.5g，3.23mmol)和五氧化二磷(0.053g)溶于甲苯(2mL)中，加热升温至75℃，搅拌10min后，滴加丙酮(0.275mL)。每30min加入五氧化二磷(0.053g)，总共加4次，2小时加完。加完后继续反应1小时。反应液降至室温温，将溶液倾倒出于NaOH(20mL，1mol/l)中，分液，有机相加入无水硫酸钠干燥，过滤，旋干，得固体0.15g(收率23.8％)。1HNMR(CDCl3,400MHz)δ7.60(d,1H),7.00(d,1H),6.88(t,1H),1.82(s,6H,2CH3)。Nitro-catechol (0.5 g, 3.23 mmol) and phosphorus pentoxide (0.053 g) were dissolved in toluene (2 mL), and the mixture was heated to 75 ° C, and stirred for 10 min, then acetone (0.275 mL) was added dropwise. Phosphorus pentoxide (0.053g) was added every 30 minutes for a total of 4 additions and 2 hours of addition. The reaction was continued for 1 hour after the addition was completed. The reaction solution was cooled to room temperature, and the solution was poured into NaOH (20 mL, 1 mol/l), and the organic layer was dried over anhydrous sodium sulfate, filtered, and dried to give 0.15 g (yield: 23.8%). 1 H NMR (CDCl 3 , 400 MHz) δ 7.60 (d, 1H), 7.0 (d, 1H), 6.88 (t, 1H), 1.82 (s, 6H, 2CH 3 ).
在25mL三口瓶中，加入发烟硝酸(1.6mL)，冰浴降温。将(0.15g，0.77mmol)溶于HOAc(0.8mL)中，待温度降至0℃，滴加配置溶液，保持T≤5℃。滴加完毕后，反应液在冰浴中继续反应15min，TLC显示反应完全。将反应液倒入20mL冰水中，搅拌10min后过滤，滤饼用大量清水清洗，得二硝基化合物固体100mg，收率54.2％.1HNMR(CDCl3,400MHz)δ7.69(d,1H),6.88(d,1H),1.82(s,6H,2CH3)。To a 25 mL three-necked flask, fuming nitric acid (1.6 mL) was added and the mixture was cooled in an ice bath. (0.15 g, 0.77 mmol) was dissolved in HOAc (0.8 mL), the temperature was dropped to 0 ° C, and the solution was added dropwise maintaining T ≤ 5 °C. After the completion of the dropwise addition, the reaction solution was further reacted for 15 min in an ice bath, and TLC showed that the reaction was completed. The reaction solution was poured into 20 mL of ice water, stirred for 10 min, filtered, and the filter cake was washed with a large amount of water to obtain 100 mg of dinitro compound solid, yield 54.2%. 1 H NMR (CDCl3, 400 MHz) δ 7.69 (d, 1H), 6.88 (d, 1H), 1.82 (s, 6H, 2CH 3 ).
将二硝基底物(2.3g，9.58mmol)和催化剂Pd(0)(0.7g，5.72mmol)溶于EtOH(34.1mL)中，将装置密封好，用氢气置换5次，室温搅拌反应过夜。HPLC检测无原料，将溶液旋干后，加入DCM(20mL)溶解，滴加盐酸二氧六环溶液至无固体析出，过滤得红黑色固体，用石油醚冲洗。将固体倒入饱和碳酸氢钠和DCM溶液中，分液，保留有机相，加入无水硫酸钠干燥，过滤，滤液旋干得固体邻苯二胺(0.94g)，收率54.57％。The dinitro substrate (2.3 g, 9.58 mmol) and the catalyst Pd(0) (0.7 g, 5.72 mmol) were dissolved in EtOH (34.1 mL). The apparatus was sealed and replaced with hydrogen for 5 times. The mixture was evaporated to dryness. After the solution was evaporated to dryness, DCM (20 mL) was dissolved. The mixture was evaporated to dryness. The solid was poured into saturated sodium bicarbonate and DCM solution, and the organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give solid o-phenylenediamine (0.94 g).
将缩丙酮邻苯二胺(1.6g，9.44mmol)和α-羰基酸酯SM-2a(2.18g，7.64mmol)溶于EtOH(30mL)中，将装置密封好，用氩气置换3次，加热回流反应16h(外温90℃)。HPLC检测无原料后，降至室温，将反应液旋干，得褐色固体，硅胶柱层析(DCM装柱，DCM淋洗)分离纯化得两部分淡黄色固体:The acetal o-phenylenediamine (1.6 g, 9.44 mmol) and the α-carbonyl acid ester SM-2a (2.18 g, 7.64 mmol) were dissolved in EtOH (30 mL), and the apparatus was sealed and replaced with argon gas three times. The reaction was heated to reflux for 16 h (external temperature 90 ° C). After HPLC, no raw materials were obtained, and the mixture was cooled to room temperature. The reaction mixture was dried to give a brown solid, which was purified by silica gel column chromatography (DCM column eluting with DCM)
A)先出样品为Ve(LW1002-19-107-1)，1.64g，收率49.59％；HPLC:98.19％纯，(保留时间t＝8.8min，方法：甲醇：水＝30：70).1HNMR(CDCl3,400MHz)δ8.56(s,1H,6’-H),8.37(d,1H,4’-H),7.61(d,1H,2’-H),7.47(d,1H,5-H/7-H？),7.37(t,1H,3’-H),6.86(d,1H,6-H/8-H？),1.81(s,6H,2CH3).MS(ESI):m/z373,375.30(M+H)。A) The first sample is Ve (LW1002-19-107-1), 1.64g, yield 49.59%; HPLC: 98.19% pure, (retention time t = 8.8min, method: methanol: water = 30:70). 1 H NMR (CDCl 3 , 400 MHz) δ 8.56 (s, 1H, 6'-H), 8.37 (d, 1H, 4'-H), 7.61 (d, 1H, 2'-H), 7.47 (d, 1H) ,5-H/7-H?), 7.37(t,1H,3'-H), 6.86(d,1H,6-H/8-H?), 1.81(s,6H,2CH 3 ).MS (ESI): m/z 373, 375.30 (M+H).
B)后出样品为Vf(LW1002-19-107-2)，1.2g，收率36.29％；HPLC：97.87％纯，(保留时间t＝8.3min，方法：甲醇:水30:70),1HNMR(CDCl3,400MHz)δ10.76(br s,1H,OH),8.56(s,1H,6’-H),8.37(d,1H,4’-H),7.64(d,1H,2’-H),7.38(t,1H,3’-H),7.01(d,1H,5-H/7-H),6.68(d,1H,6-H/8-H),1.84(s,6H,2CH3).MS(ESI):m/z373,375.28(M+H)。B) The sample after the exit is Vf (LW1002-19-107-2), 1.2g, yield 36.29%; HPLC: 97.87% pure, (retention time t=8.3min, method: methanol: water 30:70), 1 HNMR (CDCl3, 400MHz) δ 10.76 (br s, 1H, OH), 8.56 (s, 1H, 6'-H), 8.37 (d, 1H, 4'-H), 7.64 (d, 1H, 2' -H), 7.38 (t, 1H, 3'-H), 7.01 (d, 1H, 5-H/7-H), 6.68 (d, 1H, 6-H/8-H), 1.84 (s, 6H, 2CH 3 ). MS (ESI): m/z 373, 372.28 (M+H).
实施例7化合物Vi的合成Synthesis of Compound Vi of Example 7
Figure PCTCN2017079087-appb-000043
Figure PCTCN2017079087-appb-000043
香兰素(10g,65.8mmol)，三乙胺(13.3g,136mmol)和DMAP(0.1g)加入到DCM(100mL)中，然后加入乙酸酐(8g,79mmol)，室温反应2h，TLC、LC-MS检测反应完后，体系用2N盐酸洗3次，有机相干燥浓缩得到粗品，过柱纯化得到白色固体12g,收率94％。1HNMR(300MHz,CDCl3,ppm):δ9.96(s,1H),7.51-7.48(m,2H),7.88-7.22(m,1H),3.92(s,3H),2.36(s,3H).Vanillin (10g, 65.8mmol), triethylamine (13.3g, 136mmol) and DMAP (0.1g) were added to DCM (100mL), then acetic anhydride (8g, 79mmol) was added and reacted for 2h at room temperature, TLC, LC - After the reaction of MS was detected, the system was washed three times with 2N hydrochloric acid, and the organic phase was dried and concentrated to give a crude product, which was purified by column to afford 12 g of white solid. 1 H NMR (300 MHz, CDCl 3 , ppm): δ 9.96 (s, 1H), 7.51-7.48 (m, 2H), 7.88-7.22 (m, 1H), 3.92 (s, 3H), 2.36 (s, 3H) ).
发烟硝酸(10g,155mmol)加入到DCM(200mL)中，冷却至-12度，然后分批加入乙酰基保护的香兰素(20g,103mmol)，TLC跟踪反应至完毕，将反应液缓慢倒入冰水中，分液，水相用DCM萃取3次，合并有机相后用饱和食盐水洗，无水硫酸钠干燥，浓缩得粗品，***打浆,得到产品(1.4g，57％).1HNMR(300MHz,CDCl3,ppm):δ9.92(s,1H),7.72(d,J＝8.4Hz,1H),7.46(d,J＝8.4Hz,1H),3.97(s,3H),2.42(s,3H).The fuming nitric acid (10 g, 155 mmol) was added to DCM (200 mL), cooled to -12 °, then acetyl-protected vanillin (20 g, 103 mmol) was added portionwise, and the reaction was completed by TLC. into ice water, separated, the aqueous phase was extracted three times with DCM, combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product, beating diethyl ether to give the product (1.4g, 57%). 1 HNMR ( 300MHz, CDCl 3 , ppm): δ 9.92 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 3.97 (s, 3H), 2.42 ( s, 3H).
硝化产物(10g,42mmol)加入到乙醇(100mL)中，然后滴加乙酸钠(6.85g,83.5mmol)的水溶液(50mL)，滴毕，加热至回流，TLC、LC-MS检测反应完全，加水，EA萃取，食盐水洗，干燥，浓缩得到粗品8g，直接用于下一步。1HNMR(300MHz,DMSO-d6,ppm):δ9.72(s,1H),7.71(d,J＝8.7Hz,1H),7.21(d,J＝8.4Hz,1H),3.84(s,3H).The nitration product (10 g, 42 mmol) was added to ethanol (100 mL), then aqueous sodium acetate (6.85 g, 83.5 mmol) (50 mL) was added dropwise, and the mixture was evaporated to reflux, and the reaction was completed by TLC and LC-MS. The mixture was extracted with EA, washed with brine, dried and concentrated to give a crude product (8 g). 1 HNMR (300MHz, DMSO-d 6, ppm): δ9.72 (s, 1H), 7.71 (d, J = 8.7Hz, 1H), 7.21 (d, J = 8.4Hz, 1H), 3.84 (s, 3H).
三氯化铝(10.8g,80mmol)加入到干燥的无水DCM(160mL)中，然后分批加入上步化合物(8g,40mmol)，冷却到0度，滴加吡啶，室温搅拌过夜。TLC、LC-MS检测反应完后，倒入水(550mL)和浓盐酸(46mL)的混合溶液中，然后55度反应1h，再冷却到0度，析出固体，抽滤，用少量水洗，烘干得产品5g,两步收率65％。1HNMR(300MHz,DMSO-d6,ppm):δ9.69(s,1H),7.42(d,J＝8.4Hz,1H),7.21(d,J＝8.4Hz,1H).Aluminium trichloride (10.8 g, 80 mmol) was added to dry anhydrous DCM (160 mL). After TLC and LC-MS were detected, poured into a mixed solution of water (550 mL) and concentrated hydrochloric acid (46 mL), then reacted at 55 °C for 1 h, then cooled to 0 °C, precipitated solid, suction filtered, washed with a small amount of water, and dried. The product was dried in 5 g, and the yield in two steps was 65%. 1 HNMR (300MHz, DMSO-d 6, ppm): δ9.69 (s, 1H), 7.42 (d, J = 8.4Hz, 1H), 7.21 (d, J = 8.4Hz, 1H).
二羟基化合物(5g,27.5mmol)溶于DMF(50mL)中，加入二碘甲烷(11g,41.3mmol)，Cs2CO3(26.6g,82.5mmol)。70℃反应4h。反应完全后，将反应液倒入盐水中，乙酸乙酯萃取，有机相干燥，浓缩过柱得到产品1g，收率19％。1HNMR(300MHz,CDCl3,ppm):δ10.12(s,1H),7.56(d,J＝8.1Hz,1H),7.09(d,J＝8.1Hz,1H),6.31(s,2H).The dihydroxy compound (5g, 27.5mmol) was dissolved in DMF (50mL) was added diiodomethane (11g, 41.3mmol), Cs 2 CO 3 (26.6g, 82.5mmol). The reaction was carried out at 70 ° C for 4 h. After completion of the reaction, the reaction solution was poured into brine, extracted with ethyl acetate, and then dried, and then evaporated. 1 H NMR (300 MHz, CDCl 3 , ppm): δ 10.12 (s, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 8.1 Hz, 1H), 6.31 (s, 2H) .
上步产物(28g，144mmol)溶于乙醇:乙酸:水＝2:2:1(300mL)混合溶液中，加入铁粉(24g,432mmol)，加入浓盐酸(11ml)。80℃反应10分钟。冷却至室温，过滤，乙酸乙酯稀释，用NaHCO3溶液洗三次，有机相干燥，旋干，过柱纯化得到产品20g，收率83％。1HNMR(300MHz,CDCl3,ppm):δ9.67(s,1H),7.04(d,J＝8.1Hz,1H),6.31(d,J＝8.1Hz,1H),5.96(s,2H),5.76(s,2H).The product of the above step (28 g, 144 mmol) was dissolved in a mixture of ethanol: acetic acid: water = 2:2:1 (300 mL), and iron powder (24 g, 432 mmol) was added, and concentrated hydrochloric acid (11 ml) was added. The reaction was carried out at 80 ° C for 10 minutes. It was cooled to room temperature, filtered, diluted with ethyl acetate, washed three times with NaHCO 3 solution, and then dried and evaporated to dryness. 1 H NMR (300 MHz, CDCl 3 , ppm): δ 9.67 (s, 1H), 7.04 (d, J = 8.1 Hz, 1H), 6.31 (d, J = 8.1 Hz, 1H), 5.96 (s, 2H) , 5.76 (s, 2H).
芳香胺(20g，120mmol)溶于苯(200mL)中，加入吡啶(12.4g,156mmol)。缓慢滴间溴苯乙酰氯(28g，156mmol)，20℃反应30分钟。加入2N HCl，DCM萃取，分液，有机相干燥。浓缩过柱得20g产品，收率46％。1HNMR(300MHz,CDCl3,ppm):δ9.81(s, 1H),9.72(s,1H),7.57-7.46(m,2H),7.36-7.25(m,3H),6.80(d,J＝8.1Hz,1H),6.16(s,2H),3.77(s,2H).Aromatic amine (20 g, 120 mmol) was dissolved in benzene (200 mL) and pyridine (12.4 g, 156 mmol). The bromophenylacetyl chloride (28 g, 156 mmol) was slowly added dropwise and reacted at 20 ° C for 30 minutes. Add 2N HCl, extract with DCM, separate the layers, and dry the organic phase. The column was concentrated to give 20 g of product in a yield of 46%. 1 H NMR (300 MHz, CDCl 3 , ppm): δ 9.81 (s, 1H), 9.72 (s, 1H), 7.57-7.46 (m, 2H), 7.36-7.25 (m, 3H), 6.80 (d, J) =8.1 Hz, 1H), 6.16 (s, 2H), 3.77 (s, 2H).
将金属钠(2.4g，104mmol)加入到乙醇(250mL)中，加热至50℃，待钠消失，降至室温。分批加入上步产物(2.5g，69mmol)，20℃反应1h。加入水，2N HCl调pH＝6，过滤,乙醇洗。得产品Vi(1.2g),收率52％。1HNMR(300MHz,DMSO-d6,ppm):δ11.84(s,1H),8.13(s,1H),7.96(s,1H),7.73(d,J＝7.8Hz,1H),7.55(d,J＝7.5Hz,1H),7.42-7.36(m,1H),7.35-7.32(m,1H),6.93(d,J＝8.4Hz,1H),6.19(s,2H).Sodium metal (2.4 g, 104 mmol) was added to ethanol (250 mL) and heated to 50 ° C. The product of the above step (2.5 g, 69 mmol) was added portionwise and reacted at 20 ° C for 1 h. Water was added, 2N HCl was adjusted to pH = 6, filtered, and washed with ethanol. The product Vi (1.2 g) was obtained in a yield of 52%. 1 HNMR (300MHz, DMSO-d 6, ppm): δ11.84 (s, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 7.73 (d, J = 7.8Hz, 1H), 7.55 ( d, J = 7.5 Hz, 1H), 7.42 - 7.36 (m, 1H), 7.35-7.32 (m, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.19 (s, 2H).
实例8Example 8
化合物4a的合成Synthesis of Compound 4a
Figure PCTCN2017079087-appb-000044
Figure PCTCN2017079087-appb-000044
将原料SM-3(0.24g,0.96mmol)、化合物Va(0.33g,0.96mmol)以及三苯基磷(0.456g,1.7mmol)溶于无水THF(7mL)中，氩气置换后冷却至0℃，然后逐滴滴加DIAD(0.35g,1.7mmol)。恢复至室温搅拌18h后。浓缩反应液得粗产品，柱层析纯化得产品4a(0.52g，收率95％)。ESI-MS[(M+H+)]:m/z572.09.Starting material SM-3 (0.24 g, 0.96 mmol), compound Va (0.33 g, 0.96 mmol) and triphenylphosphine (0.456 g, 1.7 mmol) were dissolved in anhydrous THF (7 mL), At 0 ° C, DIAD (0.35 g, 1.7 mmol) was then added dropwise. After returning to room temperature and stirring for 18 h. The reaction mixture was concentrated to give a crude product, which was purified by column chromatography to afford product 4a (0.52 g, yield 95%). ESI-MS[(M+H + )]: m/z572.09.
实施例9Example 9
化合物5a的合成Synthesis of Compound 5a
Figure PCTCN2017079087-appb-000045
Figure PCTCN2017079087-appb-000045
将化合物4a(0.52g,0.9mmol)溶于3mL无水DCM，加入3.5mL 4N HCl的1,4-二氧六环溶液。室温搅拌1h，浓缩反应液得胺的盐酸盐。将此盐酸盐及SM-4(0.23g,1mmol)溶于无水DMF中，然后冷却到0℃。氩气保护下，加入DIEA(0.85mL,4.9mmol)以及HATU(0.45g,1.2mmol)。反应液在室温搅拌一小时，然后加入EA稀释，5％柠檬酸水溶液洗，水洗，1M碳酸氢钠水溶液洗，饱和食盐水洗4次。有机相用无水硫酸钠干燥后，减压蒸干得粗产品，柱层析纯化得产品5a(0.5g),两步收率81％。HNMR(CDCl3)δ8.18(s,1H),7.91(d,1H),7.55(d,1H),7.39(s,1H),7.33(t,1H),7.28(s,1H),7.16(s,1H),6.17(s,2H,OCH2O),5.31(m,1H),4.99(t,1H),4.21(m,3H),3.78(s,3H,OCH3),2.36(m,1H),2.06(m,1H),1.28(s,9H,3CH3),1.08(s,9H,3CH3)ppm.ESI-MS[(M+H+)]:m/z685.11. Compound 4a (0.52 g, 0.9 mmol) was dissolved in 3 mL dry DCM and 3.5 mL 4N HCl in 1,4-dioxane. After stirring at room temperature for 1 h, the reaction mixture was concentrated to give theamine. This hydrochloride and SM-4 (0.23 g, 1 mmol) were dissolved in dry DMF then cooled to 0. DIEA (0.85 mL, 4.9 mmol) and HATU (0.45 g, 1.2 mmol) were added under argon. The reaction solution was stirred at room temperature for one hour, then diluted with EA, washed with 5% aqueous citric acid, washed with water, washed with 1M aqueous sodium hydrogen carbonate, and washed 4 times with saturated brine. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness crystals. H NMR (CDCl 3 ) δ 8.18 (s, 1H), 7.91 (d, 1H), 7.55 (d, 1H), 7.39 (s, 1H), 7.33 (t, 1H), 7.28 (s, 1H), 7.16 (s, 1H), 6.17 (s, 2H, OCH 2 O), 5.31 (m, 1H), 4.99 (t, 1H), 4.21 (m, 3H), 3.78 (s, 3H, OCH 3 ), 2.36 ( m, 1H), 2.06 (m, 1H), 1.28 (s, 9H, 3CH 3 ), 1.08 (s, 9H, 3CH 3 ) ppm. ESI-MS [(M+H + )]: m/z 685.11 .
实施例10Example 10
化合物6a的合成Synthesis of Compound 6a
Figure PCTCN2017079087-appb-000046
Figure PCTCN2017079087-appb-000046
将化合物5a(4.96g,7.2mmol)溶于30mL无水DCM，加入35mL 4N HCl的1,4-二氧六环溶液。室温搅拌1h后浓缩反应液得胺中间体。Compound 5a (4.96 g, 7.2 mmol) was dissolved in 30 mL dry DCM and EtOAc (EtOAc) After stirring at room temperature for 1 h, the reaction mixture was concentrated to give an amine intermediate.
将胺中间体溶于126mL无水DCM中，氩气置换后降温至0℃，然后依次加入三光气(3.25g,11mmol)及吡啶(9.4mL)。反应液在0℃搅拌半小时后用EA稀释，接着用水洗，饱和食盐水洗两次。有机相用无水硫酸钠干燥后，减压蒸干得中间体异氰酸酯。The amine intermediate was dissolved in 126 mL of dry DCM, argon, and then cooled to &lt;RTI ID=0.0&gt;&gt; The reaction solution was stirred at 0 ° C for half an hour and then diluted with EA, followed by washing with water and twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to dryness.
将中间体异氰酸酯溶于188mL无水THF中，依次加入新戊二醇(2.28g，22mmol)和4A分子筛。室温搅拌半小时后，加入DBU(1.42mL,9.5mmol)，继续搅拌1h后加入EA稀释，硅藻土过滤，母液依次用水洗，饱和食盐水洗。有机相用无水硫酸钠干燥后，减压蒸干得粗产品，柱层析纯化得产品6a(2.78g，两步总产率53％)。ESI-MS[(M+H+)]:m/z 715.19.The intermediate isocyanate was dissolved in 188 mL of anhydrous THF, and fresh pentanediol (2.28 g, 22 mmol) and 4A molecular sieves were sequentially added. After stirring at room temperature for half an hour, DBU (1.42 mL, 9.5 mmol) was added, and the mixture was stirred for 1 hour, then diluted with EA, filtered over Celite, and the mixture was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. ESI-MS[(M+H + )]: m/z 715.19.
实施例11Example 11
化合物7a的合成Synthesis of Compound 7a
Figure PCTCN2017079087-appb-000047
Figure PCTCN2017079087-appb-000047
将底物6a(2.78g,3.9mmol)、碳酸铯(3.17g,9.7mmol)和无水甲苯(250mL)加入反应器，然后依次加入醋酸钯(0.22g,0.97mmol)和2-(二叔丁基磷)-1,1’-联萘(0.49g,1.24mmol)。氩气置换后加热至90℃搅拌过夜。待反应液冷却至室温后，用硅藻土过滤，EA洗涤滤饼。母液减压浓缩后得粗产品，柱层析纯化后得大环产物7a(1.1g，产率：45％)。ESI-MS[(M+H+)]:m/z635.22.Substrate 6a (2.78 g, 3.9 mmol), cesium carbonate (3.17 g, 9.7 mmol) and anhydrous toluene (250 mL) were charged to the reactor, followed by palladium acetate (0.22 g, 0.97 mmol) and 2- (di) Butyl phosphorus)-1,1'-binaphthyl (0.49 g, 1.24 mmol). After argon replacement, the mixture was heated to 90 ° C and stirred overnight. After the reaction solution was cooled to room temperature, it was filtered through Celite, and the filter cake was washed with EA. The mother liquid was concentrated under reduced pressure to give a crude product. m.p. ESI-MS[(M+H + )]: m/z 635.22.
实施例12Example 12
化合物8a的合成 Synthesis of Compound 8a
Figure PCTCN2017079087-appb-000048
Figure PCTCN2017079087-appb-000048
将7a(0.3g,0.47mmol)溶于THF/MeOH(13mL/6.5mL)中,然后慢慢加入1N氢氧化锂水溶液(7.2mL)，室温搅拌2h后减压浓缩有机溶剂后，用1N HCl调pH至4～5。EA萃取三次，合并有机相，饱和食盐水洗，有机相用无水硫酸钠干燥后，减压蒸干得产品8a(0.25g，收率86％)。ESI-MS[(M-H-)]:m/z 619.24.7a (0.3g, 0.47mmol) was dissolved in THF / MeOH (13mL / 6.5mL), then 1N aqueous lithium hydroxide (7.2mL) was added slowly, stirred at room temperature for 2h, then concentrated in vacuo. Adjust the pH to 4-5. The EA was extracted three times, and the organic phase was combined, washed with brine, and dried over anhydrous sodium sulfate, and then evaporated to dryness to give product 8a (0.25 g, yield 86%). ESI-MS[(MH - )]: m/z 619.24.
实施例13Example 13
化合物LW100202的合成Synthesis of Compound LW100202
Figure PCTCN2017079087-appb-000049
Figure PCTCN2017079087-appb-000049
将8a(46mg,0.074mmol)以及SM-6a(30mg,0.13mmol)溶于无水DMF(3mL)中，然后冷却到0℃。氩气保护下，加入DIEA(0.083mL,0.476mmol)以及HATU(42.4mg,0.11mmol)。反应液在室温搅拌一小时，然后加入EA稀释，5％柠檬酸水溶液洗，水洗，1M碳酸氢钠水溶液洗，半饱和食盐水洗4次。有机相用无水硫酸钠干燥后，减压蒸干得粗产品，柱层析纯化得最终大环产品LW100202(44mg，收率71％)。ESI-MS[(M+H+)]:m/z 833.67.8a (46 mg, 0.074 mmol) and SM-6a (30 mg, 0.13 mmol) were dissolved in anhydrous DMF (3 mL) and then cooled to 0. DIEA (0.083 mL, 0.476 mmol) and HATU (42.4 mg, 0.11 mmol) were added under argon. The reaction solution was stirred at room temperature for one hour, then diluted with EA, washed with 5% aqueous citric acid, washed with water, washed with 1M sodium hydrogen carbonate aqueous solution, and washed four times with half-saturated brine. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. ESI-MS [(M+H + )]: m/z 833.67.
实施例14Example 14
化合物LW100201的合成Synthesis of Compound LW100201
按照上述制备化合物LW100202的实施例12，本实施例用原料8a(0.074mmol)和SM-6b(0.098mmol)反应(反应图示2)，纯化后得到48mg最终大环产物LW100201。ESI-MS[(M+H+)]:m/z835.68.According to the above-mentioned Example 12 of the preparation of the compound LW100202, this example was reacted with the starting material 8a (0.074 mmol) and SM-6b (0.098 mmol) (reaction shown in Figure 2), and after purification, 48 mg of the final macrocyclic product LW100201 was obtained. ESI-MS[(M+H + )]: m/z 835.68.
实施例15Example 15
化合物SM-6c的合成 Synthesis of Compound SM-6c
Figure PCTCN2017079087-appb-000050
Figure PCTCN2017079087-appb-000050
将底物(2g,6.1mmol)溶于无水二氯甲烷(24mL)，慢慢加入三乙胺(0.85mL)，反应液变粘稠；然后加入Boc2O(1.4g,6.1mmol)，反应液在室温搅拌17小时，LTC显示反应完全。反应液转移至分液漏斗中，依次用水(4mL)，饱和碳酸氢钠溶液(4mL)，和饱和食盐水(4mL)洗，有机相用无水硫酸钠干燥，过滤，滤液浓缩后得黄色油状物1.84g，柱层析得纯产物1.32g(84.6％)，无色油状物。1HNMR(CDCl3,400MHz)δ5.79(m,1H),5.28(d,1H),5.10(dd,1H),4.17(m,2H),2.14(m,1H),1.79(m,1H),1.45(m,10H),1.26(t,3H,CH3).The substrate (2 g, 6.1 mmol) was dissolved in anhydrous dichloromethane (24 mL) and triethylamine (0.85 mL) was slowly added and the reaction mixture became viscous; then Boc 2 O (1.4 g, 6.1 mmol) was added. The reaction was stirred at room temperature for 17 hours and LTC showed the reaction was completed. The reaction solution was transferred to a sep. funnel, washed with water (4 mL), EtOAc. The product was 1.84 g, which was purified by column chromatography to yield the product 1.32 g (84.6%). 1 H NMR (CDCl 3 , 400 MHz) δ 5.79 (m, 1H), 5.28 (d, 1H), 5.10 (dd, 1H), 4.17 (m, 2H), 2.14 (m, 1H), 1.79 (m, 1H) , 1.45 (m, 10H), 1.26 (t, 3H, CH 3 ).
在100mL的圆底烧瓶中，将底物(0.3g,1mmol)溶于无水***(10mL)，将反应瓶在丙酮-冰浴(-15℃)中冷却，在剧烈搅拌下，一次性加入重氮甲烷(10mmol)和催化量醋酸钯(0.1mmol)，敞开瓶口，继续在-15℃下剧烈搅拌30分钟。反应液用硅藻土过滤后浓缩，得一棕色油状物。1HNMR(CDCl3,400MHz)δ5.13(brs,1H),4.19-4.23(m,2H),1.60-1.65(m,2H),1.46(s,9H),1.28(t,3H),1.07-1.13(m,1H),0.86-0.89(m,1H),0.50-0.58(m,2H),0.28-0.36(m,2H).In a 100 mL round bottom flask, the substrate (0.3 g, 1 mmol) was dissolved in anhydrous diethyl ether (10 mL), and the reaction flask was cooled in an acetone-ice bath (-15 ° C). Diazomethane (10 mmol) and catalytic amount of palladium acetate (0.1 mmol) were opened and the mixture was stirred vigorously at -15 ° C for 30 minutes. The reaction mixture was filtered with EtOAc (EtOAc)EtOAc. 1 H NMR (CDCl 3 , 400 MHz) δ 5.13 (brs, 1H), 4.19 - 4.23 (m, 2H), 1.60-1.65 (m, 2H), 1.46 (s, 9H), 1.28 (t, 3H), 1.07- 1.13 (m, 1H), 0.86-0.89 (m, 1H), 0.50-0.58 (m, 2H), 0.28-0.36 (m, 2H).
将上述产物(1.52g,6.2mmol)溶于60mL无水THF中，加入CDI(1.13g，6.9mmol),用氩气置换3次，反应液加热至60℃反应4小时后，冷却至室温，加入环丙烷磺酰胺(0.84g，6.9mmol),DBU(1.05g,6.9mmol)，室温搅拌过夜。反应混合物加入80mL乙酸乙酯稀释后，依次用30mL 10％柠檬酸洗2次，30mL饱和食盐水洗，有机相用无水硫酸钠干燥，过滤，滤液旋干，硅胶柱层析(PE:EA50:1to 1:1),得产物0.43g。收率为20.1％。MS(ESI):m/z343.10(M-H).The above product (1.52 g, 6.2 mmol) was dissolved in 60 mL of anhydrous THF, and CDI (1.13 g, 6.9 mmol) was added, and the mixture was replaced with argon gas three times. The reaction mixture was heated to 60 ° C for 4 hours, and then cooled to room temperature. Add cyclopropane sulfonamide (0.84 g, 6.9 mmol), DBU (1.05 g, 6.9 mmol). After the reaction mixture was diluted with 80 mL of ethyl acetate, the mixture was washed twice with 30 mL of 10% citric acid, and then washed with 30 mL of brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to silica gel column chromatography (PE: EA50: 1to 1:1), the product was obtained 0.43g. The yield was 20.1%. MS (ESI): m/z 343.10 (M-H).
将0.3g上述产品溶于100mL 4N盐酸1,4二氧六环溶液中，搅拌过夜，TCL监测反应，反应结束后旋干溶剂，得SM-6c(0.25g)，收率为97％。0.3 g of the above product was dissolved in 100 mL of 4N hydrochloric acid 1,4-dioxane solution, stirred overnight, and the reaction was monitored by TCL. After completion of the reaction, the solvent was evaporated to give EtOAc (EtOAc) (yield: 97%).
实施例16Example 16
化合物LW100203的合成Synthesis of Compound LW100203
按照上述制备化合物LW100202的实施例12，本实施例用原料8a(0.065mmol)和SM-6c(0.13mmol)反应，纯化后得到50mg最终大环产物LW100203。MS(ESI):m/z847.2(M+H)The title compound of Example LW100202 was prepared as described above. This was obtained by the reaction of starting material 8a (0.065 mmol) and SM-6c (0.13 mmol) to afford 50 mg of the final macrocyclic product LW100203. MS (ESI): m/z 847.2 (M+H)
实施例17Example 17
化合物8b的合成 Synthesis of Compound 8b
Figure PCTCN2017079087-appb-000051
Figure PCTCN2017079087-appb-000051
按照上述制备化合物4a-8a的实施例6-实施例11，本实施例从原料SM-3(4.8mmol)及Vb(4.8mmol)开始按反应图示2经五步反应纯化后得到0.3g产物8b。ESI-MS[(M-H-)]:m/z 619.45.According to the above Example 6 - Example 11 for the preparation of the compound 4a-8a, this example was purified from the starting material SM-3 (4.8 mmol) and Vb (4.8 mmol) according to the reaction scheme 2 by a five-step reaction to obtain 0.3 g of the product. 8b. ESI-MS[(MH - )]: m/z 619.45.
实施例18Example 18
化合物LW100205的合成Synthesis of Compound LW100205
Figure PCTCN2017079087-appb-000052
Figure PCTCN2017079087-appb-000052
按照上述制备化合物LW100202的实施例11，本实施例用原料8b(0.10mmol)和SM-6a(0.10mmol)反应，纯化后得到68mg最终产物LW100205。ESI-MS[(M+H+)]:m/z833.71.According to the above-mentioned Example 11 of the preparation of the compound LW100202, this example was obtained by reacting the starting material 8b (0.10 mmol) and SM-6a (0.10 mmol) to afford 68 mg of the final product LW100205. ESI-MS[(M+H + )]: m/z833.71.
实施例19Example 19
化合物LW100204的合成Synthesis of Compound LW100204
Figure PCTCN2017079087-appb-000053
Figure PCTCN2017079087-appb-000053
按照上述制备化合物LW100202的实施例11，本实施例用原料8b(0.08mmol)和SM-6b(0.08mmol)反应，纯化后得到52mg最终产物LW100204。ESI-MS[(M+H+)]:m/z 835.70.According to the above Example 11 of the preparation of the compound LW100202, this example was obtained by reacting the starting material 8b (0.08 mmol) and SM-6b (0.08 mmol) to afford 52 mg of the final product LW100204. ESI-MS[(M+H + )]: m/z 835.70.
实施例20Example 20
化合物LW100206的合成Synthesis of Compound LW100206
Figure PCTCN2017079087-appb-000054
Figure PCTCN2017079087-appb-000054
在50mL三口瓶中加入底物羧酸(约80mg,0.130mmol)，无水DMF(3mL)，搅拌溶解，加入SM-6c(55mg,0.098mmol),用氩气置换3次，置于冰水浴中降温至0-5℃，搅拌10min，约10min内加入DIEA(0.25mL)，并于冰水浴中搅拌5min，加入HATU(140mg)，反应液升至室温，搅拌反应1.5小时后HPLC，显示已经反应完全。加人乙酸乙酯(40mL)稀释后，用半饱和食盐水洗涤4次，无水硫酸镁干燥，过滤，滤液旋干得约100-150mg粗品,prep-HPLC分离得3mgLW100206，MS(ESI):m/z847.2(M+H).Add the substrate carboxylic acid (about 80 mg, 0.130 mmol) to a 50 mL three-necked flask, dry DMF (3 mL), stir to dissolve, add SM-6c (55 mg, 0.098 mmol), replace with argon three times, and place in an ice water bath. The temperature was lowered to 0-5 ° C, stirred for 10 min, DIEA (0.25 mL) was added in about 10 min, and stirred in an ice water bath for 5 min, HATU (140 mg) was added, the reaction solution was allowed to warm to room temperature, and the reaction was stirred for 1.5 hours, and HPLC showed that The reaction is complete. After being diluted with ethyl acetate (40 mL), the mixture was washed with EtOAc EtOAc EtOAc (EtOAc) m/z 847.2 (M+H).
实施例21Example 21
化合物8c的合成Synthesis of Compound 8c
Figure PCTCN2017079087-appb-000055
Figure PCTCN2017079087-appb-000055
在氮气保护条件下，依次将Vc(1.55g，8.88mmol)、SM-3(1.66g,17.8mmol)和三苯基膦加入155mL无水THF中，冰水保护条件下加入DIAD(1.82g,22.2mmol),搅拌反应过夜,TLC检测反应完全。减压浓缩至干，所得浓缩液直接柱层析得到目标产物4c2.0g,收率80％。1H-NMR((d6-DMSO,400MHz)δ1.33(s，5H),1.39(s，4H),2.28-2.32(m,1H),2.60-2.65(m,1H)，3.63-3.69(m,4H)，3.72-3.75(m,1H),4.32(t,J＝8Hz,1H),4.47-4.76(m,1H),6.27(d,J＝1.2Hz，2H),7.37-7.44(m，2H)，7.59-7..67(m,2H)，7.94(d,J＝7.04Hz,1H)，8.10(d，J＝1.2Hz,1H).MS(ESI):m/z 594(M+23) Under nitrogen protection conditions, Vc (1.55g, 8.88mmol), SM-3 (1.66g, 17.8mmol) and triphenylphosphine were added to 155mL anhydrous THF, and DIAD (1.82g, 22.2 mmol), the reaction was stirred overnight, and the reaction was completed by TLC. The organic layer was concentrated to dryness under reduced pressure. 1H-NMR ((d6-DMSO, 400MHz) δ 1.33 (s, 5H), 1.39 (s, 4H), 2.28-2.32 (m, 1H), 2.60-2.65 (m, 1H), 3.63-3.69 (m) , 4H), 3.72-3.75 (m, 1H), 4.32 (t, J = 8 Hz, 1H), 4.47 - 4.76 (m, 1H), 6.27 (d, J = 1.2 Hz, 2H), 7.37-7.44 (m , 2H), 7.59-7..67 (m, 2H), 7.94 (d, J = 7.04 Hz, 1H), 8.10 (d, J = 1.2 Hz, 1H). MS (ESI): m/z 594 ( M+23)
将4c(1.32g,1.81mmol)加入到THF中，再将2mL二氧六环的HCl溶液(9N)加入反应液中，室温搅拌30分钟，TLC点板确定无原料后，蒸除溶剂，得到白色固体盐酸盐0.92g，溶于无水DMF(3mL)中，加入SM-4(0.42g,1.81mmol)，氩气置换3次，反应液降温至0℃，搅拌下依次加入DIEA(1.17g,9.05mmol)和HATU(0.83g,2.17mmol)，恢复至室温搅拌过夜。加入EA(40mL)稀释后，依次用水和饱和氯化钠洗涤，无水硫酸钠干燥，过滤，滤液浓缩，得粗品2g，硅胶柱层析(PE:EA 40:1to 1:1),得黄色固体5c 400mg,两步收率40％。1H-NMR((CDCl3,400MHz)δ1.08(s,9H),1.33(s,5H)，1.39(s,4H)，2.3-2.32(m,1H)，2.62-2.64(m,1H)，3.63-3.69(m，3H)，4.09-4.12(m，1H)，4.18(d,J＝9.8Hz，1H)，4.33(d,J＝11.76Hz,1H),4.72(t,J＝9.04Hz,1H),4.95-4.98(m,1H),5.19-5.21(m,1H),6.25-6.29(m,2H),7.25-7.34(m,2H),7.55-7.57(d,1H),7.66-7.68(d,1H),7.82-7.84(d,1H),8.11(d,1H).4c (1.32g, 1.81mmol) was added to THF, and 2mL of dioxane HCl solution (9N) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. After the TLC dot plate was determined to have no starting material, the solvent was distilled off to obtain White solid hydrochloride 0.92g, dissolved in anhydrous DMF (3mL), added SM-4 (0.42g, 1.81mmol), argon replacement 3 times, the reaction solution was cooled to 0 ° C, and added DIEA (1.17) under stirring g, 9.05 mmol) and HATU (0.83 g, 2.17 mmol). After being diluted with EA (40 mL), the mixture was washed with EtOAc EtOAc EtOAc EtOAc EtOAc Solid 5c 400mg, 40% yield in two steps. 1H-NMR ((CDCl3, 400MHz) δ 1.08 (s, 9H), 1.33 (s, 5H), 1.39 (s, 4H), 2.3-2.32 (m, 1H), 2.62-2.64 (m, 1H), 3.63-3.69(m,3H),4.09-4.12(m,1H), 4.18(d,J=9.8Hz,1H), 4.33(d,J=11.76Hz,1H),4.72(t,J=9.04Hz , 1H), 4.95-4.98 (m, 1H), 5.19-5.21 (m, 1H), 6.25-6.29 (m, 2H), 7.25-7.34 (m, 2H), 7.55-7.57 (d, 1H), 7.66 -7.68(d,1H),7.82-7.84(d,1H),8.11(d,1H).
在25mL单口瓶中，依次加入5c(700mg,1.02mmol)，无水DCM(0.8mL)和盐酸二氧六环溶液(4N,4mL)，室温搅拌1h，HPLC显示无原料。反应液减压浓缩后，用真空油泵继续抽5min，得5c的盐酸盐。溶于无水DCM(10.6mL)，用氩气置换3次，反应液降温至0℃，搅拌下加入三光气，然后逐滴加入吡啶，反应液在0℃搅拌0.5h后，室温继续搅拌15min。加入EA(53mL)稀释后，依次用水(13mL)和饱和氯化钠洗(13mL*2)，无水硫酸钠干燥，过滤，滤液旋干，得中间体异氰酸酯，油泵抽干。将中间体异氰酸酯溶于无水THF(15mL)，加入新戊二醇和4A分子筛(1.75g)，室温搅拌0.5小时后，加入DBU，继续搅拌4小时，HPLC显示无原料。加入EA(53mL)稀释，经硅藻土过滤，滤液依次用水(11mL)，饱和氯化钠洗(11mL*4)，无水硫酸钠干燥，过滤，滤液旋干得粗品1g，硅胶柱层析(PE:EA 40:1to 1:1)，得黄色泡沫状固体6c 450mg,收率40％。1H-NMR(CDCl3,400MHz)δ0.96(s,6H),1.08(s,9H),2.33-2.34(m,1H)，2.62-2.64(m,1H)，3.08-3.1(m,2H),3.37-3.43(m,2H),3.74-3.77(m,3H),4.07-4.08(m,1H)，4.09-4.15(m,1H)，4.22-4.25(d,J＝9.4Hz,1H),4.72(t,J＝9.04Hz,1H),4.32-4.35(m,1H),4.72-4.77(m,1H),5.41-5.43(m,1H),5.98(s,1H),6.27-6.29(m,2H),7.25-7.34(m,2H),7.56-7.58(d,H),7.66-7.7(M,1H),7.83-7.85(d,H),8.13(s，1H).5c (700 mg, 1.02 mmol), anhydrous DCM (0.8 mL) and dioxane hydrochloride (4N, 4 mL) After the reaction mixture was concentrated under reduced pressure, the mixture was furtherly evaporated and evaporated, and then evaporated, Dissolve in anhydrous DCM (10.6mL), replace with argon for 3 times, the reaction solution is cooled to 0 ° C, add triphosgene under stirring, then add pyridine dropwise, the reaction solution is stirred at 0 ° C for 0.5 h, then continue stirring at room temperature for 15 min. . After adding EA (53 mL), it was diluted with water (13 mL) and saturated sodium chloride (13 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give an intermediate isocyanate. The intermediate isocyanate was dissolved in anhydrous THF (15 mL), fresh pentanediol and 4A molecular sieves (1.75 g) were added, and stirred at room temperature for 0.5 hour, then DBU was added and stirring was continued for 4 hours, and HPLC showed no starting material. After adding EA (53 mL), the mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. (PE: EA 40: 1 to 1:1) gave a yellow foamy solid 6c 450 mg, yield 40%. 1H-NMR (CDCl3, 400MHz) δ0.96 (s, 6H), 1.08 (s, 9H), 2.33 - 2.34 (m, 1H), 2.62-2.64 (m, 1H), 3.08-3.1 (m, 2H) , 3.37-3.43 (m, 2H), 3.74-3.77 (m, 3H), 4.07-4.08 (m, 1H), 4.09-4.15 (m, 1H), 4.22-4.25 (d, J = 9.4 Hz, 1H) , 4.72 (t, J = 9.04 Hz, 1H), 4.32-4.35 (m, 1H), 4.72-4.77 (m, 1H), 5.41-5.43 (m, 1H), 5.98 (s, 1H), 6.27-6.29 (m, 2H), 7.25-7.34 (m, 2H), 7.56-7.58 (d, H), 7.66-7.7 (M, 1H), 7.83-7.85 (d, H), 8.13 (s, 1H).
在50mL单口瓶中，依次加入6c(340mg,0.14mmol)，无水甲苯(15mL)，碳酸铯(114mg,0.35mmol)，通氩气5min，加入醋酸钯(8mg,0.0176mmol)，PLn(18.8mg,0.046mmol)，氩气置换3次，反应液用油浴加热至90℃，反应过夜小时，TLC监测原料消失。硅胶柱层析(PE:EA 40:1to 2:1)，得黄色泡沫状固体7c 125mg。1H-NMR(CDCl3,400MHz)δ1.08(s,9H),1.26(s,6H),2.05-2.06(m,1H)，2.23-2.25(m,1H),2.51-2.55(m,1H)，2.78-2.80(m,1H),3.34-3.36(m,1H),3.54-3.57(m,1H),3.70-3.72(m，3H)，4.00-4.02(m，1H)，4.09-4.15(m,1H)，4.22-4.25(m,2H),4.49-4.52(m,1H),4.77-4.80(m,1H),5.23-5.26(m,1H)，6.27-6.29(m,2H),7.0-7.06(m，1H)，7.27-7.29(m，1H)，7.35-7.38(m,2H)，7.40-7.42(m，1H)，7.66-7.69(m,1H).In a 50 mL single-mouth bottle, 6c (340 mg, 0.14 mmol), anhydrous toluene (15 mL), cesium carbonate (114 mg, 0.35 mmol), argon gas for 5 min, palladium acetate (8 mg, 0.0176 mmol), PLn (18.8) Mg, 0.046 mmol), replaced with argon three times, the reaction solution was heated to 90 ° C with an oil bath, and the reaction was allowed to stand overnight. Silica gel column chromatography (PE: EA 40: 1 to 2:1) 1H-NMR (CDCl3, 400MHz) δ 1.08 (s, 9H), 1.26 (s, 6H), 2.05-2.06 (m, 1H), 2.23 - 2.25 (m, 1H), 2.51-2.55 (m, 1H) , 2.78-2.80 (m, 1H), 3.34-3.36 (m, 1H), 3.54-3.57 (m, 1H), 3.70-3.72 (m, 3H), 4.00-4.02 (m, 1H), 4.09-4.15 ( m, 1H), 4.22-4.25 (m, 2H), 4.49-4.52 (m, 1H), 4.77-4.80 (m, 1H), 5.23-5.26 (m, 1H), 6.27-6.29 (m, 2H), 7.0-7.06 (m, 1H), 7.27-7.29 (m, 1H), 7.35-7.38 (m, 2H), 7.40-7.42 (m, 1H), 7.66-7.69 (m, 1H).
在氮气保护条件下，依次将化合物7c(20mg,0.0135mmol)加入THF/甲醇1.6mL中，氮气置换3次，然后滴加1N LiOH溶液，RT条件下反应2h，TLC检测反应完全。反应液浓缩至干，加入1N盐酸调节pH 1-2,用EA萃取3次，无水硫酸钠干燥后过滤浓缩至干，然后进行下一步反应。Under nitrogen protection, compound 7c (20 mg, 0.0135 mmol) was added to THF/methanol 1.6 mL successively, and the mixture was replaced with nitrogen three times. Then, 1N LiOH solution was added dropwise, and the reaction was carried out under RT for 2 h, and the reaction was completely confirmed by TLC. The reaction mixture was concentrated to dryness. EtOAc (EtOAc) was evaporated.
实施例22Example 22
化合物LW00208的合成 Synthesis of Compound LW00208
Figure PCTCN2017079087-appb-000056
Figure PCTCN2017079087-appb-000056
在25mL三口瓶中，依次加入8c(20mg,0.065mmol)和SM-6b(27.5mg,0.098mmol)到无水DMF(3mL)，反应瓶用氩气置换3次，冰水浴降温至0℃，加入HATU(37.3mg,0.098mmol),滴加DIEA，再用氩气置换3次，撤冰浴，升至室温反应1小时，HPLC监测至无原料。加入EA(200mL)稀释后，用半饱和食盐水洗4次，无水硫酸钠干燥，过滤，滤液旋干，得粗品20mg,硅胶柱层析(PE:EA 40:1to 2:1),得LW10020810mg。1H-NMR(CDCl3,400MHz)δ1.00-1.04(m,14H),1.11-1.14(m,4H),1.26-1.29(m,6H),1.31-1.43(m,1H),1.91-1.95(m,1H),1.91-1.95(m,1H),2.37-2.39(m,1H),2.90-2.95(m,1H),3.47-3.55(m,1H),3.71(s,1H),3.92-3.96(m,1H),4.06-4.12(m,1H),4.31-4.39(m,2H),5.11(d,J＝9.8Hz,1H),5.20(d,J＝16.8Hz,1H),5.33-5.36(m,1H),6.26(d,J＝1.56Hz,2H),7.00-7.03(m,1H),7.27-7.30(m,1H),7.36-7.40(m,2H),7.55-7.56(m,1H),7.66-7.69(m,1H).MS(ESI):m/z 831.3(M+H)。8c (20mg, 0.065mmol) and SM-6b (27.5mg, 0.098mmol) were added to anhydrous DMF (3mL) in a 25mL three-necked flask. The reaction flask was replaced with argon three times, and the ice water bath was cooled to 0 °C. HATU (37.3 mg, 0.098 mmol) was added, DIEA was added dropwise, and the mixture was replaced with argon gas for 3 times. The mixture was cooled to room temperature and reacted for 1 hour. After adding EA (200 mL), it was diluted with a half-saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated to dryness to give 20 mg of crude product (PE: EA 40:1 to 2:1) to obtain LW10020810 mg . 1H-NMR (CDCl3, 400MHz) δ1.00-1.04 (m, 14H), 1.11-1.14 (m, 4H), 1.26-1.29 (m, 6H), 1.31-1.43 (m, 1H), 1.91-1.95 ( m, 1H), 1.91-1.95 (m, 1H), 2.37-2.39 (m, 1H), 2.90-2.95 (m, 1H), 3.47-3.55 (m, 1H), 3.71 (s, 1H), 3.92 3.96 (m, 1H), 4.06-4.12 (m, 1H), 4.31-4.39 (m, 2H), 5.11 (d, J = 9.8 Hz, 1H), 5.20 (d, J = 16.8 Hz, 1H), 5.33 -5.36(m,1H), 6.26(d,J=1.56Hz,2H), 7.00-7.03(m,1H), 7.27-7.30(m,1H),7.36-7.40(m,2H),7.55-7.56 (m, 1H), 7.66-7.69 (m, 1H). MS (ESI): m/z
实施例23Example 23
化合物LW00207的合成Synthesis of Compound LW00207
Figure PCTCN2017079087-appb-000057
Figure PCTCN2017079087-appb-000057
将双键底物LW100208(20mg,0.139mmol)溶于5mL乙酸乙酯中，加入10％Pd/C(4mg)，室温氢化30分钟，TLC监测反应完全，反应混合物经硅藻土过滤，滤饼用乙酸乙酯洗涤三次，合并滤液，旋干，得粗品，经制备TLC分离纯化后得纯产物5.5mg黄色固体LW100207。1H-NMR(CDCl3,400MHz)δ1.00-1.04(m,13H),1.11-1.14(m,4H),1.25-1.29(m,10H),1.59-1.64(m,3H),2.36-2.38(m,1H),2.92-2.96(m,2H),3.48-3.53(m,1H),3.71(s,1H),3.94-3.95(m,1H),4.09-4.15(m,2H),4.31-4.37(m,2H),6.26(d,J＝1.56Hz,2H),7.00-7.03(m,1H),7.27-7.30(m,1H),7.36-7.40(m,2H),7.42-7.54(m,1H),7.66-7.68(m,1H).MS(ESI):m/z833.2(M+H)。The double-bonded substrate LW100208 (20 mg, 0.139 mmol) was dissolved in 5 mL of ethyl acetate, and then 10% Pd/C (4 mg) was added, and the mixture was hydrogenated at room temperature for 30 minutes, and the reaction was completely monitored by TLC. The mixture was washed with EtOAc (3 mL). 1.11-1.14 (m, 4H), 1.25-1.29 (m, 10H), 1.59-1.64 (m, 3H), 2.36-2.38 (m, 1H), 2.92-2.96 (m, 2H), 3.48-3.53 (m , 1H), 3.71 (s, 1H), 3.94-3.95 (m, 1H), 4.09-4.15 (m, 2H), 4.31-4.37 (m, 2H), 6.26 (d, J = 1.56 Hz, 2H), 7.00-7.03 (m, 1H), 7.27-7.30 (m, 1H), 7.36-7.40 (m, 2H), 7.42-7.54 (m, 1H), 7.66-7.68 (m, 1H). MS (ESI): m/z 833.2 (M+H).
实施例24Example 24
化合物LW00209的合成 Synthesis of Compound LW00209
Figure PCTCN2017079087-appb-000058
Figure PCTCN2017079087-appb-000058
在25mL三口瓶中，依次加入8c(12mg,0.032mmol)和SM-6c(14mg,0.05mmol)到无水DMF(3mL)，反应瓶用氩气置换3次，冰水浴降温至0℃，加入HATU(20mg,0.05mmol),滴加DIEA，升至室温20℃反应1小时，HPLC监测至反应完全，EA(200mL)稀释，半饱和食盐水洗，无水硫酸钠干燥，过滤，滤液旋干得粗品20mg，硅胶柱层析(PE:EA 40:1to 2:1)，得LW100209 8mg。1H-NMR(CDCl3,400MHz)δ1.00-1.04(m,12H),1.11-1.13(m,4H),1.19-1.36(m,10H),1.70-1.72(m,1H),2.05-2.06(m,1H),2.35-2.36(m,1H),2.70-2.75(m,1H),2.95-2.98(m,1H),3.45-3.52(m,1H),3.71(s,1H),4.08-4.10(m,2H),4.31-4.40(m,3H),5.28-5.35(m,1H),5.95-5.98(m,1H),6.26(m,2H),6.95-7.03(m,1H),7.27-7.30(m,1H),7.34-7.40(m,2H),7.50-7.54(m,1H),7.56-7.69(m,1H).MS(ESI):m/z 845.3(M+H)。8c (12mg, 0.032mmol) and SM-6c (14mg, 0.05mmol) were added to anhydrous DMF (3mL) in a 25mL three-necked flask. The reaction flask was replaced with argon three times, and the ice water bath was cooled to 0 °C. HATU (20 mg, 0.05 mmol), DIEA was added dropwise, and the mixture was warmed to room temperature at 20 ° C for 1 hour, and the reaction was completed by HPLC. EA (200 mL) was diluted, washed with half-saturated brine, dried over anhydrous sodium sulfate and filtered. The crude product was 20 mg, and purified by silica gel column chromatography (PE: EA 40:1 to 2:1) to obtain 8 mg of LW100209. 1H-NMR (CDCl3, 400MHz) δ1.00-1.04 (m, 12H), 1.11-1.13 (m, 4H), 1.19-1.36 (m, 10H), 1.70- 1.72 (m, 1H), 2.05-2.06 ( m, 1H), 2.35-2.36 (m, 1H), 2.70-2.75 (m, 1H), 2.95-2.98 (m, 1H), 3.45-3.52 (m, 1H), 3.71 (s, 1H), 4.08- 4.10 (m, 2H), 4.31-4.40 (m, 3H), 5.28-5.35 (m, 1H), 5.95-5.98 (m, 1H), 6.26 (m, 2H), 6.95-7.03 (m, 1H), 7.27-7.30 (m, 1H), 7.34-7.40 (m, 2H), 7.50-7.54 (m, 1H), 7.56-7.69 (m, 1H). MS (ESI): m/z 845.3 (M+H) .
实施例25Example 25
化合物LW100219的合成Synthesis of Compound LW100219
Figure PCTCN2017079087-appb-000059
Figure PCTCN2017079087-appb-000059
在25mL三口瓶中，依次加入8c(40mg,0.065mmol)和SM-6g(15mg,0.053mmol)到无水DMF(3mL)，反应瓶用氩气置换3次，冰水浴降温至0℃，加入HATU(27mg,0.071mmol),滴加DIEA(52mg,0.402mmol)，升至室温20℃反应16小时，HPLC监测至反应完全，EA(20mL)稀释，半饱和食盐水洗，无水硫酸钠干燥，过滤，滤液旋干得粗品20mg，制备HPLC，得LW100219(10mg)。1H-NMR(CDCl3,400MHz)δ:0.99-1.04(m,14H),1.24-1.34(m,4H),1.23(s,3H),1.26-1.29(m,6H)，1.31-1.43(m,1H)1.89-1.93(m,1H)，1.94-1.99(m,1H)，2.37-2.39(m,1H),2.90-2.95(m,1H)，3.47-3.55(m,1H),3.70(s,1H)，3.92-3.96(m,1H)，4.06-4.12(m,1H)，4.31-4.39(m,2H),5.11(d，J＝9.8Hz,2H)，5.20(d，J＝16.8Hz,1H)5.33-5.36(m,1H),6.24(s,2H)，6.95-7.01(m,1H),7.25-7.29(m,1H),7.36-7.40(m,2H),7.53-7.55(m,1H)7.64-7.66(m,1H).MS(ESI)m/z＝847.3(M+H).8c (40mg, 0.065mmol) and SM-6g (15mg, 0.053mmol) were added to anhydrous DMF (3mL) in a 25mL three-necked flask. The reaction flask was replaced with argon three times, and the ice water bath was cooled to 0 °C. HATU (27 mg, 0.071 mmol), DIEA (52 mg, 0.402 mmol) was added dropwise, and the mixture was stirred at room temperature 20 ° C for 16 hours. The reaction was monitored by HPLC until EA (20 mL) was diluted. After filtration, the filtrate was spun to dryness to give a crude material (20 mg). 1 H-NMR (CDCl 3 , 400 MHz) δ: 0.99-1.04 (m, 14H), 1.24-1.34 (m, 4H), 1.23 (s, 3H), 1.26-1.29 (m, 6H), 1.31-1.43 ( m,1H)1.89-1.93 (m,1H), 1.94-1.99 (m,1H), 2.37-2.39 (m,1H), 2.90-2.95 (m,1H), 3.47-3.55 (m,1H), 3.70 (s, 1H), 3.92-3.96 (m, 1H), 4.06-4.12 (m, 1H), 4.31-4.39 (m, 2H), 5.11 (d, J = 9.8 Hz, 2H), 5.20 (d, J) = 16.8 Hz, 1H) 5.33-5.36 (m, 1H), 6.24 (s, 2H), 6.95-7.01 (m, 1H), 7.25-7.29 (m, 1H), 7.36-7.40 (m, 2H), 7.53 -7.55 (m, 1H) 7.64-7.66 (m, 1H). MS (ESI) m/z = 847.3 (M+H).
实例26Example 26
化合物SM-6e的合成 Synthesis of Compound SM-6e
Figure PCTCN2017079087-appb-000060
Figure PCTCN2017079087-appb-000060
将底物(10g)溶于无水THF(100mL)，冷却至-78度后，逐滴滴加NaHMDS(24mL)。-78度下搅拌1h，将Boc2O(10.2g)四氢呋喃溶液加入反应体系，缓慢升温至室温搅拌反应过夜。恢复至室温搅拌12h，TLC检测原料有剩余，有新点生成。乙酸乙酯(100mL),稀释饱和食盐水50mL加入反应体系，乙酸乙酯萃取三次，无水硫酸钠干燥，浓缩后粗品柱层析分离得黄色油状物(10.4g，收率，74.7％)。The substrate (10 g) was dissolved in anhydrous THF (100 mL) and then cooled to -78. After stirring at -78 °C for 1 h, a solution of Boc 2 O (10.2 g) in tetrahydrofuran was added to the reaction system, and the mixture was slowly warmed to room temperature and stirred overnight. After returning to room temperature and stirring for 12 h, TLC detected the remaining material, and new spots were formed. Ethyl acetate (100 mL), and a solution of 50 mL of EtOAc (EtOAc)
将NMO(4.61g)溶于无水叔丁醇(80mL)和水(80mL)，然后将二水合锇酸钾(360mg)加入反应体系冷却至0度后，然后将上步产物(14g)的丙酮溶液加入反应体系，室温下反应8h。将水(100mL)加入反应体系，乙酸乙酯三次，干燥后柱层析得(10.2g，66.5％)NMO (4.61 g) was dissolved in anhydrous tert-butanol (80 mL) and water (80 mL), then potassium phthalate dihydrate (360 mg) was added to the reaction system to cool to 0 °, then the product of the step (14 g) The acetone solution was added to the reaction system, and reacted at room temperature for 8 hours. Water (100 mL) was added to the reaction system, ethyl acetate was added three times, dried and then purified by column chromatography (10.2 g, 66.5%)
将底物(5g)溶于DCM(70mL)，然后将高碘酸钠试剂(15g)加入反应体系，室温下反应1h。TLC检测原料反应完全，有新点生成，抽滤，DCM洗涤滤饼，滤液无水硫酸钠干燥，有机相浓缩后柱层析得白色固体(2.7g，58.8％)。The substrate (5 g) was dissolved in DCM (70 mL), then sodium periodate reagent (15 g) was added to the reaction system and allowed to react at room temperature for 1 h. TLC detected the reaction of the starting material completely, a new point was formed, suction filtration, DCM washing the filter cake, the filtrate was dried over anhydrous sodium sulfate, and the organic phase was concentrated to give a white solid (2.7 g, 58.8%).
将上步化合物无(5g)溶于DCM(40mL)中，降温至-78度，然后将DAST(2.8g)，缓慢加入反应体系，将反应温度逐渐升至室温，反应8h，TLC检测有新产物生成，原料未反应完全，用40mLDCM稀释反应液，然后加水20mL，饱和碳酸氢钠溶液淬灭反应，DCM(2*50mL)萃取，无水硫酸钠干燥，浓缩后柱层析得到无色油状物(0.9g，收率：34％)。1H-NMR(CDCl3,400MHz)δ:1.24(t,J＝6.8Hz,3H)，1.48(s,18H),1.63-1.71(m,1H)，1.92-1.85(m,1H),2.06-2.15(m,1H),4.20(q,J＝10.4Hz,2H)，5.79-6.09(m,1H)。The above step compound (5g) was dissolved in DCM (40mL), cooled to -78 degrees, then DAST (2.8g) was slowly added to the reaction system, the reaction temperature was gradually raised to room temperature, the reaction was carried out for 8 hours, and the TLC detection was new. The product was formed, the starting material was not completely reacted, and the reaction mixture was diluted with 40 ml of LDCM, then 20 mL of water was added, and the reaction was quenched with saturated sodium hydrogen carbonate solution, and extracted with DCM (2*50 mL), dried over anhydrous sodium sulfate, and concentrated to give a colorless oil. (0.9 g, yield: 34%). 1 H-NMR (CDCl 3 , 400 MHz) δ: 1.24 (t, J = 6.8 Hz, 3H), 1.48 (s, 18H), 1.63-1.71 (m, 1H), 1.92-1.85 (m, 1H), 2.06- 2.15 (m, 1H), 4.20 (q, J = 10.4 Hz, 2H), 5.79-6.09 (m, 1H).
将二氟化合物(0.5g)溶于THF(6mL),MeOH(2mL)和H2O(2mL)中，然后将氢氧化锂(0.27g)加入反应体系，室温下反应8h，TLC检测有产物生成，原料反应完全，用15mL水稀释反应液，然后1NHCl调pH值至3-4，乙酸乙酯萃取三次，无水硫酸钠干燥，有机相浓缩后柱层析得(0.2g，收率：60.4％)白色固体。The difluoro compound (0.5g) was dissolved in THF (6mL), MeOH (2mL ) and H 2 O (2mL), then lithium hydroxide (0.27 g of) was added the reaction system, the reaction at room temperature for 8h, TLC detect product The reaction was completed, the reaction was completed, the reaction mixture was diluted with 15 mL of water, then the pH was adjusted to 3-4 with 1N HCl, extracted with ethyl acetate three times, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by column chromatography (0.2 g, yield: 60.4%) white solid.
将酸(0.6g)溶于DCM(10mL)中，降温至0度，依次加入DMAP(0.73g),环丙基磺酰胺(0.36g)搅拌5min，然后将EDCI(1.14g)加入反应体系，0度反应1h，室温反应24h，TLC检测原料反应完全，有新点生成，加水(20mL),DCM(3*40mL)萃取无水硫酸钠干燥，将有机相浓缩后柱层析得白色固体(0.4g,45％)。 The acid (0.6 g) was dissolved in DCM (10 mL), cooled to 0 °, then DMF (0.73 g) was added, and then propyl sulfonamide (0.36 g) was stirred for 5 min, then EDCI (1.14 g) was added to the reaction system. 0 degree reaction 1h, room temperature reaction for 24h, TLC detection of the raw material reaction is complete, a new point is formed, adding water (20mL), DCM (3 * 40mL) extraction anhydrous sodium sulfate drying, the organic phase is concentrated and column chromatography to obtain a white solid ( 0.4g, 45%).
将上述化合物(0.2g)溶于DCM(5mL)中，加入盐酸二氧六环溶液(2mL，4N)，室温下反应2h，将溶剂浓缩后干燥得黄色固体SM-6e(0.15g)。1H-NMR(DMSO,400MHz)δ:0.92-1.01(m,4H)，1.63-1.67(m,1H)，1.89-1.93(m,1H),2.17-2.53(m,1H),2.85-2.92(m,1H)，5.46(br,3H),5.83-6.12(m,1H)。The above compound (0.2 g) was dissolved in DCM (5 mL), EtOAc (EtOAc) 1 H-NMR (DMSO, 400MHz ) δ: 0.92-1.01 (m, 4H), 1.63-1.67 (m, 1H), 1.89-1.93 (m, 1H), 2.17-2.53 (m, 1H), 2.85-2.92 (m, 1H), 5.46 (br, 3H), 5.83-6.12 (m, 1H).
实例27Example 27
化合物LW100220的合成Synthesis of Compound LW100220
Figure PCTCN2017079087-appb-000061
Figure PCTCN2017079087-appb-000061
在25mL三口瓶中，依次加入8c(40mg,0.065mmol)和SM-6e(15mg,0.052mmol)到无水DMF(3mL)，反应瓶用氩气置换3次，冰水浴降温至0℃，加入HATU(27mg,0.071mmol),滴加DIEA(52mg,0.402mmol)，升至室温20℃反应16小时，HPLC监测至反应完全，EA(20mL)稀释，半饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩后制备HPLC，得LW100220(8.5mg)。1H-NMR(CDCl3,400MHz)δ:1.00-1.04(m,14H),1.11-1.14(m,4H),1.26-1.29(m,6H)，1.31-1.43(m,1H)1.78-1.91(m,1H)，1.97-2.00(m,1H)，2.64-2.66(m,1H),2.84-2.85(m,1H)，3.46-3.48(m,1H),3.68(s,1H)，3.87-3.92(m,1H)，4.05-4.11(m,1H)，4.31-4.39(m,2H),5.30(t，J＝49.8Hz,1H),5.33-5.36(m,1H),6.24(s,2H)，7.00-7.01(m,1H),7.26-7.29(m,1H),7.36-7.38(m,2H),7.53-7.55(m,1H),7.64-7.67(m,1H).MS(ESI)m/z＝857.2(M+H).8c (40mg, 0.065mmol) and SM-6e (15mg, 0.052mmol) were added to anhydrous DMF (3mL) in a 25mL three-necked flask. The reaction flask was replaced with argon three times, and the ice water bath was cooled to 0 °C. HATU (27 mg, 0.071 mmol), DIEA (52 mg, 0.402 mmol) was added dropwise, and the mixture was stirred at room temperature 20 ° C for 16 hours. The reaction was monitored by HPLC until EA (20 mL) was diluted. Filtration, concentration and preparative HPLC gave LW 100220 (8.5 mg). 1 H-NMR (CDCl 3 , 400 MHz) δ: 1.00-1.04 (m, 14H), 1.11-1.14 (m, 4H), 1.26-1.29 (m, 6H), 1.31-1.43 (m, 1H) 1.78-1.91 (m, 1H), 1.97-2.00 (m, 1H), 2.64 - 2.66 (m, 1H), 2.84 - 2.85 (m, 1H), 3.46-3.48 (m, 1H), 3.68 (s, 1H), 3.87 -3.92 (m, 1H), 4.05-4.11 (m, 1H), 4.31-4.39 (m, 2H), 5.30 (t, J = 49.8 Hz, 1H), 5.33-5.36 (m, 1H), 6.24 (s) , 2H), 7.00-7.01 (m, 1H), 7.26-7.29 (m, 1H), 7.36-7.38 (m, 2H), 7.53-7.55 (m, 1H), 7.64-7.67 (m, 1H). (ESI) m/z = 857.2 (M+H).
实例28Example 28
化合物LW100221的合成Synthesis of Compound LW100221
Figure PCTCN2017079087-appb-000062
Figure PCTCN2017079087-appb-000062
在25mL三口瓶中，依次加入8c(40mg,0.065mmol)和SM-6f(15mg,0.052mmol)到无水DMF(3mL)，反应瓶用氩气置换3次，冰水浴降温至0℃，加入HATU(27mg,0.071mmol),滴加DIEA(52mg,0.402mmol)，升至室温20℃反应16小时，HPLC监测至反应完全，EA(20 mL)稀释，半饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩后制备HPLC，得LW100221(8.5mg)。1H-NMR(CDCl3,400MHz)δ:1.01-1.04(m,14H),1.11-1.14(m,4H),1.27(s,3H),1.26-1.29(m,6H)，1.31-1.43(m,1H)1.91-1.94(m,1H)，1.95-1.98(m,1H)，2.31-2.35(m,1H),2.65-2.74(m,1H)，3.39-3.45(m,1H),3.69(s,1H)，3.95-3.99(m,1H)，4.06-4.12(m,1H)，4.33-4.38(m,2H),5.23(t，J＝48.8Hz,1H),5.33-5.36(m,1H),6.24(s,2H)，6.97-7.03(m,1H),7.29-7.38(m,1H),7.40-7.43(m,2H),7.54-7.56(m,1H),7.65-7.67(m,1H).MS(ESI)m/z＝893.7(M+Na).8c (40mg, 0.065mmol) and SM-6f (15mg, 0.052mmol) were added to anhydrous DMF (3mL) in a 25mL three-necked flask. The reaction flask was replaced with argon three times, and the ice water bath was cooled to 0 °C. HATU (27 mg, 0.071 mmol), DIEA (52 mg, 0.402 mmol) was added dropwise, and the mixture was stirred at room temperature 20 ° C for 16 hours. The reaction was monitored by HPLC until EA (20 mL) was diluted. After filtration, concentration and preparative HPLC gave LW100221 (8.5 mg). 1 H-NMR (CDCl 3 , 400 MHz) δ: 1.01-1.04 (m, 14H), 1.11-1.14 (m, 4H), 1.27 (s, 3H), 1.26-1.29 (m, 6H), 1.31-1.43 ( m,1H)1.91-1.94 (m,1H), 1.95-1.98 (m,1H), 2.31-2.35 (m,1H), 2.65-2.74 (m,1H), 3.39-3.45 (m,1H), 3.69 (s, 1H), 3.95-3.99 (m, 1H), 4.06-4.12 (m, 1H), 4.33-4.38 (m, 2H), 5.23 (t, J = 48.8 Hz, 1H), 5.33-5.36 (m , 1H), 6.24 (s, 2H), 6.97-7.03 (m, 1H), 7.29-7.38 (m, 1H), 7.40-7.43 (m, 2H), 7.54-7.56 (m, 1H), 7.65-7.67 (m, 1H). MS (ESI) m / z = 893.7 (M+Na).
实例29Example 29
化合物SM-6d的合成Synthesis of Compound SM-6d
Figure PCTCN2017079087-appb-000063
Figure PCTCN2017079087-appb-000063
在N2保护下，将底物(2.1g)溶于DCM(40mL)中，室温下将四氯化碳(1g)，然后将三苯基膦(3.24g)缓慢加入反应体系，将反应温度逐渐升至35度，反应3h，TLC检测有产物生成，原料基本反应完全，然后加水以及饱和碳酸氢钠溶液淬灭反应，DCM萃取三次，无水硫酸钠干燥，浓缩后柱层析得到(0.6g，收率：24％)无色油状物。1H-NMR(CDCl3,400MHz)δ:1.23-1.26(m,1H)，1.47(s，18H),1.59-1.63(m,1H),1.87-1.91(m,1H),2.46-2.53(m,1H),4.13-4.25(m,2H)，6.08-6.11(m,1H)。Under the protection of N2, the substrate (2.1 g) was dissolved in DCM (40 mL), carbon tetrachloride (1 g) was added at room temperature, then triphenylphosphine (3.24 g) was slowly added to the reaction system, and the reaction temperature was gradually increased. The temperature was raised to 35 degrees, and the reaction was carried out for 3 hours. The product was formed by TLC. The basic reaction of the starting material was complete. Then the reaction was quenched with water and saturated sodium hydrogen carbonate solution. The mixture was extracted three times with DCM and dried over anhydrous sodium sulfate. , yield: 24%) colorless oil. 1 H-NMR (CDCl 3 , 400 MHz) δ: 1.23-1.26 (m, 1H), 1.47 (s, 18H), 1.59-1.63 (m, 1H), 1.87-1.91 (m, 1H), 2.46-2.53 (m) , 1H), 4.13-4.25 (m, 2H), 6.08-6.11 (m, 1H).
将上步产物(0.6g)溶于THF(9mL),MeOH(3mL)和H2O(3mL)中，然后将氢氧化锂(0.38g)加入反应体系，室温下反应8h，TLC检测有新点生成，原料反应完全，用15mL水稀释反应液，然后1NHCl中和反应，调节pH至3-4，EA萃取三次，无水硫酸钠干燥，有机相浓缩后柱层析得白色固体(0.3g，收率：48％)。The product from the previous step (0.6g) was dissolved in THF (9mL), MeOH (3mL ) and H 2 O (3mL), and then lithium hydroxide (0.38 g) added to the reaction system, the reaction at room temperature for 8h, TLC detection new Point formation, the reaction of the starting material was complete, the reaction solution was diluted with 15 mL of water, then neutralized with 1N HCl, the pH was adjusted to 3-4, EA was extracted three times, dried over anhydrous sodium sulfate, and then concentrated, , yield: 48%).
将生成的酸(0.2g)溶于无水四氢呋喃(5mL)中，将CDI(0.12g)加入反应体系，升温至60度搅拌4h，冷却至室温，加入环丙基磺酰胺(0.1g)，DBU(0.11g)室温反应8h，TLC检测原料反应完全，有新产物生成，加20mL EA稀释,10％柠檬酸10mL*2洗涤，饱和食盐水洗涤(20mL),取无水硫酸钠干燥，将有机相旋干粗品经柱层析分离得白色固体，(0.15g，收率53.7％)。The resulting acid (0.2 g) was dissolved in anhydrous tetrahydrofuran (5 mL), CDI (0.12 g) was added to the reaction system, and the mixture was warmed to 60 °C for 4 h, cooled to room temperature, and cyclopropylsulfonamide (0.1 g) was added. DBU (0.11g) was reacted at room temperature for 8h. The reaction of the starting material was completed by TLC. A new product was formed. It was diluted with 20mL EA, washed with 10% citric acid 10mL*2, washed with saturated brine (20mL), dried with anhydrous sodium sulfate. The organic phase was dried <RTI ID=0.0></RTI> tojjjjjjjj
将上述白色固体(0.15g)溶于DCM(5mL)中，室温下，加入盐酸二氧六环溶液(4mL，4N)，室温下反应2h，浓缩溶剂，真空干燥得黄色固体SM-6d(0.14g)。 1H-NMR(DMSO,400MHz)δ:0.75-0.82(m,2H)，1.26-1.32(m,2H)，1.38(s,3H)，1.66-1.70(m,1H),1.92-2.01(m,1H),2.41-2.47(m,1H)，6.02(d,J＝8.4Hz,1H),8.84(br,3H)。The above white solid (0.15 g) was dissolved in DCM (5 mL), EtOAc EtOAc (EtOAc) g). 1 H-NMR (DMSO, 400 MHz) δ: 0.75-0.82 (m, 2H), 1.26-1.32 (m, 2H), 1.38 (s, 3H), 1.66-1.70 (m, 1H), 1.92-2.01 (m) , 1H), 2.41-2.47 (m, 1H), 6.02 (d, J = 8.4 Hz, 1H), 8.84 (br, 3H).
实例30Example 30
化合物LW100222的合成Synthesis of Compound LW100222
Figure PCTCN2017079087-appb-000064
Figure PCTCN2017079087-appb-000064
在25mL三口瓶中，依次加入8c(40mg,0.065mmol)和SM-6d(15mg,0.045mmol)到无水DMF(3mL)，反应瓶用氩气置换3次，冰水浴降温至0℃，加入HATU(27mg,0.071mmol),滴加DIEA(52mg,0.402mmol)，升至室温20℃反应16小时，HPLC监测至反应完全，EA(20mL)稀释，半饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩后制备HPLC，得LW100222(13mg)。1H-NMR(CDCl3,400MHz)δ:1.02-1.05(m,14H),1.11-1.14(m,4H),1.26-1.29(m,6H),1.31-1.43(m,1H),1.91-1.93(m,1H)，1.94-1.98(m,1H)，2.37-2.39(m,1H),2.87-2.92(m,1H)，3.45-3.53(m,1H),3.68(s,1H)，3.90-3.94(m,1H)，4.04-4.10(m,1H)，4.31-4.42(m,2H),5.20(d，J＝16.8Hz,1H),5.33-5.36(m,1H),6.24(s,2H)，7.97-7.02(m,1H),7.26-7.29(m,1H),7.39-7.43(m,2H),7.52-7.54(m,1H),7.64-7.66(m,1H).MS(ESI)m/z＝903.9(M+H).8c (40mg, 0.065mmol) and SM-6d (15mg, 0.045mmol) were added to anhydrous DMF (3mL) in a 25mL three-necked flask. The reaction flask was replaced with argon three times, and the ice water bath was cooled to 0 °C. HATU (27 mg, 0.071 mmol), DIEA (52 mg, 0.402 mmol) was added dropwise, and the mixture was stirred at room temperature 20 ° C for 16 hours. The reaction was monitored by HPLC until EA (20 mL) was diluted. Filtration, concentration and preparative HPLC gave LW 100222 (13 mg). 1 H-NMR (CDCl 3 , 400 MHz) δ: 1.02-1.05 (m, 14H), 1.11-1.14 (m, 4H), 1.26-1.29 (m, 6H), 1.31-1.43 (m, 1H), 1.91 1.93 (m, 1H), 1.94-1.98 (m, 1H), 2.37-2.39 (m, 1H), 2.87-2.92 (m, 1H), 3.45-3.53 (m, 1H), 3.68 (s, 1H), 3.90-3.94 (m, 1H), 4.04-4.10 (m, 1H), 4.31-4.42 (m, 2H), 5.20 (d, J = 16.8 Hz, 1H), 5.33-5.36 (m, 1H), 6.24 ( s, 2H), 7.97-7.02 (m, 1H), 7.26-7.29 (m, 1H), 7.39-7.43 (m, 2H), 7.52-7.54 (m, 1H), 7.64-7.66 (m, 1H). MS (ESI) m / z = 903.9 (M + H).
实例31Example 31
化合物LW100223的合成Synthesis of Compound LW100223
Figure PCTCN2017079087-appb-000065
Figure PCTCN2017079087-appb-000065
在25mL三口瓶中，依次加入8c(40mg,0.065mmol)和SM-6h(15mg,0.043mmol)到无水DMF(3mL)，反应瓶用氩气置换3次，冰水浴降温至0℃，加入HATU(27mg,0.071mmol),滴加DIEA(52mg,0.402mmol)，升至室温20℃反应16小时，HPLC监测至反应完全，EA(20mL)稀释，半饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩后制备HPLC，得LW100223(12mg)。1H-NMR(CDCl3,400MHz)δ:1.00-1.08(m,14H),1.11-1.14(m,4H),1.26-1.29(m,6H),1.31-1.43(m,1H),1.51(s,3H),1.89-1.93(m,1H)，2.19-2.23(m,1H)，2.37-2.39(m, 1H),2.73-2.77(m,1H)，3.47-3.53(m,1H),3.69(s,1H)，3.92-3.94(m,1H)，4.05-4.10(m,1H)，4.29-4.50(m,2H),5.20(d，J＝16.8Hz,1H),5.33-5.36(m,1H),6.24(s,2H)，7.94-7.01(m,1H),7.24-7.26(m,1H),7.27-7.36(m,2H),7.54-7.56(m,1H),7.64-7.66(m,1H).MS(ESI)m/z＝913.15(M-H).8c (40mg, 0.065mmol) and SM-6h (15mg, 0.043mmol) were added to anhydrous DMF (3mL) in a 25mL three-necked flask. The reaction flask was replaced with argon three times, and the ice water bath was cooled to 0 °C. HATU (27 mg, 0.071 mmol), DIEA (52 mg, 0.402 mmol) was added dropwise, and the mixture was stirred at room temperature 20 ° C for 16 hours. The reaction was monitored by HPLC until EA (20 mL) was diluted. Filtration, concentration and preparative HPLC gave LW 100223 (12 mg). 1 H-NMR (CDCl 3 , 400 MHz) δ: 1.00 - 1.08 (m, 14H), 1.11-1.14 (m, 4H), 1.26-1.29 (m, 6H), 1.31-1.43 (m, 1H), 1.51 ( s, 3H), 1.89-1.93 (m, 1H), 2.19-2.23 (m, 1H), 2.37-2.39 (m, 1H), 2.73-2.77 (m, 1H), 3.47-3.53 (m, 1H), 3.69 (s, 1H), 3.92-3.94 (m, 1H), 4.05-4.10 (m, 1H), 4.29-4.50 (m, 2H), 5.20 (d, J = 16.8 Hz, 1H), 5.33-5.36 ( m,1H), 6.24(s,2H),7.94-7.01(m,1H),7.24-7.26(m,1H), 7.27-7.36(m,2H),7.54-7.56(m,1H),7.64- 7.66 (m, 1H). MS (ESI) m / z = 913.15 (MH).
实例32Example 32
化合物8d的合成Synthesis of Compound 8d
Figure PCTCN2017079087-appb-000066
Figure PCTCN2017079087-appb-000066
将Vd(5.4g，14.52mmol)、顺式-N-Boc-L-脯氨酸甲酯(3.92g，15.97mmol)，PPh3(7.62g，29.04mmol)溶于无水THF(25mL)，用氩气置换三次，冷却至0℃后，逐滴加入DIAD(5.72mL，29.04mmol)(用5mL的THF稀释)，恢复至室温搅拌18h，HPLC监测至反应完全，减压蒸干反应液后得粗品26.68g，硅胶柱纯化(PE:EA20:1to7:1)得4d(9.23g，淡黄色泡沫状固体)，收率106％。1HNMR(CDCl3,400MHz)δ8.23(s,1H),8.01(d,1H),7.59(d,1H),7.37(t,1H),7.28(s,1H),7.08(s,1H),5.08(m,1H),4.50(m,1H),3.94(m,2H),3.80(s,3H,CH3),2.63(m,1H),2.41(m,1H),1.86(s,6H,2CH3),1.45(s,9H,3CH3,Boc)；MS(ESI):m/z602.42(M+H)。Vd (5.4 g, 14.52 mmol), cis-N-Boc-L-proline methyl ester (3.92 g, 15.97 mmol), PPh 3 (7.62 g, 29.04 mmol), dissolved in anhydrous THF (25 mL). After being replaced with argon three times, after cooling to 0 ° C, DIAD (5.72 mL, 29.04 mmol) (diluted with 5 mL of THF) was added dropwise, and the mixture was returned to room temperature and stirred for 18 h, and the reaction was completely monitored by HPLC. The crude product was obtained as a crude material (yield: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: 1 H NMR (CDCl 3 , 400 MHz) δ 8.23 (s, 1H), 8.1 (d, 1H), 7.59 (d, 1H), 7.37 (t, 1H), 7.28 (s, 1H), 7.08 (s, 1H) , 5.08 (m, 1H), 4.50 (m, 1H), 3.94 (m, 2H), 3.80 (s, 3H, CH 3 ), 2.63 (m, 1H), 2.41 (m, 1H), 1.86 (s, 6H, 2CH 3 ), 1.45 (s, 9H, 3CH 3 , Boc); MS (ESI): m/z 602.42 (M+H).
将上述产品4d(9.2g，15.32mmol)溶于无水DCM(12.5mL)，加入4N HCl的1,4-二氧六环溶液(62mL)。反应液室温搅拌2h，HPLC监测反应完全。反应液减压蒸干得淡黄色固体。将此产品(8.87g，16.52mmol)、Boc-L-叔亮氨酸(3.82g，16.52mmol)溶于DMF(26.6mL)，换氩气三次，反应液用冰浴降温至0℃，依次加入DIEA(14.4mL，82.6mmol)、 HATU(7.54g，19.83mmol)。恢复至室温搅拌16.5h，HPLC监测反应完全。反应液中加入355mL EA稀释后，依次加入70mL水洗，70mL饱和食盐水洗(4次)，无水硫酸钠干燥、过滤、旋干得粗品17.09g。硅胶柱纯化(PE:EA 15:1to 1:1)得5d(9.37g)，收率79.5％.1HNMR(CDCl3,400MHz)δ8.16(s,1H),7.90(d,1H),7.58(d,1H),7.44(s,1H),7.34(t,1H),7.10(s,1H),4.77(t,1H),4.11-4.25(m,3H),3.80(s,3H,CH3),2.65(m,1H),2.39(m,1H),1.86(s,6H,2CH3),1.28(s,9H,3CH3),1.11(s,9H,3CH3)；MS(ESI):m/z715.60(M+H)。The above product 4d (9.2 g, 15.32 mmol) was dissolved in anhydrous DCM (12.5 mL). The reaction solution was stirred at room temperature for 2 h and then was taken and purified by HPLC. The reaction mixture was evaporated to dryness vacuol This product (8.87g, 16.52mmol), Boc-L-tert-leucine (3.82g, 16.52mmol) was dissolved in DMF (26.6mL), argon was exchanged three times, the reaction solution was cooled to 0 °C with ice bath, in turn DIEA (14.4 mL, 82.6 mmol), HATU (7.54 g, 19.83 mmol) was added. It was returned to room temperature and stirred for 16.5 h, and the reaction was monitored by HPLC. After adding 355 mL of EA to the reaction mixture, it was diluted with 70 mL of water, washed with 70 mL of saturated brine (4 times), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Purification by silica gel column (PE: EA 15: 1 to 1:1) afforded 5d (9.37g), yield: 79.5%. 1 H NMR (CDCl3, 400 MHz) δ 8.16 (s, 1H), 7.90 (d, 1H), 7.58 (d,1H), 7.44(s,1H), 7.34(t,1H), 7.10(s,1H),4.77(t,1H),4.11-4.25(m,3H),3.80(s,3H,CH 3 ), 2.65 (m, 1H), 2.39 (m, 1H), 1.86 (s, 6H, 2CH 3 ), 1.28 (s, 9H, 3CH 3 ), 1.11 (s, 9H, 3CH 3 ); MS (ESI ): m/z 715.60 (M+H).
将上述产品5d(9.37g，13.13mmol)溶于无水DCM(10.2mL)，加入4N HCl的1,4-二氧六环溶液(50.8mL)，室温搅拌1h后,停止反应。浓缩反应液得产品6d(9.59g)，收率112.4％。1HNMR(DMSO-d6,400MHz)δ9.73(s,0.3H),8.24(s,1H),8.09(d,1H),7.69(d,1H),7.48(t,1H),7.43(s,1H),7.22(s,1H),4.88(m,1H),4.55(t,1H),4.21(d,1H),4.06(d,1H),3.93(s br,1H),3.70(s,3H,CH3),2.61(m,1H),2.38(m,1H),1.77(d,6H,2CH3),1.05(s,9H,3CH3)；MS(ESI):m/z615.52(M+H)。The above product 5d (9.37 g, 13.13 mmol) was dissolved in anhydrous DCM (10.2 mL), and 4N HCl 1,4-dioxane solution (50.8 mL) was added, and the mixture was stirred at room temperature for 1 hour, and then the reaction was stopped. The reaction mixture was concentrated to give the product 6d (9.59 g). 1 H NMR (DMSO-d 6 , 400 MHz) δ 9.73 (s, 0.3H), 8.24 (s, 1H), 8.09 (d, 1H), 7.69 (d, 1H), 7.48 (t, 1H), 7.43 ( s, 1H), 7.22 (s, 1H), 4.88 (m, 1H), 4.55 (t, 1H), 4.21 (d, 1H), 4.06 (d, 1H), 3.93 (s br, 1H), 3.70 ( s, 3H, CH 3 ), 2.61 (m, 1H), 2.38 (m, 1H), 1.77 (d, 6H, 2CH 3 ), 1.05 (s, 9H, 3CH 3 ); MS (ESI): m/z 615 .52 (M+H).
将6d(5g，7.69mmol)溶于DCM(133mL)，将反应液降温至0℃后，加入三光气(3.24g，11.54mmol)。滴加吡啶(9.9mL，123.04mmol)。反应液在0℃下继续搅拌0.5h后，HPLC监测反应完全。在反应液中加入400mL EA稀释后，依次用95mL水洗一次，95mL饱和食盐水洗两次，无水硫酸钠干燥，过滤，滤液旋干得中间体异氰酸酯，用油泵抽干。将中间体异氰酸酯溶于198mL THF中，加入新戊二醇(2.4g，23.07mmol)和4A分子筛(13.2g)，室温搅拌0.5h后，加入DBU(1.5mL，10mmol)，继续搅拌1h，HPLC监测反应完全。在反应液中加入396mL EA稀释后，依次用79mL水洗一次，79mL饱和食盐水洗4次，加无水硫酸钠干燥，过滤，旋干得粗品8.2g，过硅胶柱纯化(PE:EA 15:1to 2:1)得到产品7d(3.8468g)，产率67.3％。1HNMR(CDCl3,400MHz)δ8.11(s,1H),7.90(d,1H),7.69(s,1H),7.60(d,1H),7.38(m,2H),7.14(s,1H),5.38(d,1H),4.79(t,1H),4.35(m,1H),4.18(m,1H),4.05(m,1H),3.81(s,3H,CH3),3.71(d,1H),3.32(d,1H),3.08(m,2H),2.69(m,1H),2.31(m,1H),1.86(s,6H,2CH3),1.31(s,6H,2CH3),1.07(s,9H,3CH3)；MS(ESI):m/z743.64(M+H)。After 6 d (5 g, 7.69 mmol) was dissolved in DCM (EtOAc) (EtOAc) Pyridine (9.9 mL, 123.04 mmol) was added dropwise. After the reaction mixture was further stirred at 0 ° C for 0.5 h, the reaction was monitored by HPLC. After adding 400 mL of EA to the reaction mixture, it was diluted with 95 mL of water, washed twice with 95 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness to afford intermediate isocyanate and drained with an oil pump. The intermediate isocyanate was dissolved in 198 mL of THF, and neopentyl glycol (2.4 g, 23.07 mmol) and 4A molecular sieves (13.2 g) were added. After stirring at room temperature for 0.5 h, DBU (1.5 mL, 10 mmol) was added and stirring was continued for 1 h, HPLC The reaction was monitored completely. After adding 396 mL of EA to the reaction mixture, it was diluted with 79 mL of water, washed with 79 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to give 8.2 g of crude product. Purified by silica gel column (PE: EA 15:1to) 2:1) The product 7d (3.8468 g) was obtained in a yield of 67.3%. 1 H NMR (CDCl 3 , 400 MHz) δ 8.11 (s, 1H), 7.90 (d, 1H), 7.69 (s, 1H), 7.60 (d, 1H), 7.38 (m, 2H), 7.14 (s, 1H) , 5.38(d,1H), 4.79(t,1H), 4.35(m,1H), 4.18(m,1H),4.05(m,1H),3.81(s,3H,CH 3 ),3.71(d, 1H), 3.32 (d, 1H), 3.08 (m, 2H), 2.69 (m, 1H), 2.31 (m, 1H), 1.86 (s, 6H, 2CH 3 ), 1.31 (s, 6H, 2CH 3 ) , 1.07 (s, 9H, 3CH 3 ); MS (ESI): m/z 743.64 (M+H).
将7d(500mg，0.67mmol)、碳酸铯(546mg，1.675mmol)、甲苯(42mL)通氩气15min备用)将经氩气置换后的上述试剂加入反应瓶，再通氩气5min后，加入醋酸钯(38.2mg，0.17mmol)和PdLn(85.4mg，0.2144mmol)，氩气置换3次。加热至90℃，反应16h，HPLC监测反应完全。反应液经硅藻土过滤，EA洗涤滤饼，合并滤液，旋干，得粗品0.6947g。过硅胶柱纯化(PE:EA40:1to 4:1)，得大环产物(181.1mg)，收率40.4％。1HNMR(CDCl3,400MHz)δ7.41-7.49(m,4H),7.09(m,2H),5.29(d,1H),4.51(m,1H),4.31(m,3H),4.14(m,2H),4.05(m,1H),3.75(s,2H),3.71(s,3H,CH3),2.51(m,1H),2.18(m,1H),1.81(s,6H,2CH3),1.32(s,6H,2CH3),1.08(s,9H,3CH3)；MS(ESI):m/z663.70(M+H)。7d (500mg, 0.67mmol), cesium carbonate (546mg, 1.675mmol), toluene (42mL) were argon gas for 15min standby). The above reagent after argon replacement was added to the reaction flask, and then argon gas was added for 5 minutes, then acetic acid was added. Palladium (38.2 mg, 0.17 mmol) and PdLn (85.4 mg, 0.2144 mmol) were replaced with argon three times. The mixture was heated to 90 ° C for 16 h, and the reaction was monitored by HPLC. The reaction solution was filtered through celite, and then filtered, and the filtrate was evaporated and evaporated. Purification by silica gel column (PE: EA 40: 1 to 4:1) afforded the product (181.1mg) 1 H NMR (CDCl 3 , 400 MHz) δ 7.41-7.49 (m, 4H), 7.09 (m, 2H), 5.29 (d, 1H), 4.51 (m, 1H), 4.31 (m, 3H), 4.14 (m, 2H), 4.05 (m, 1H), 3.75 (s, 2H), 3.71 (s, 3H, CH 3 ), 2.51 (m, 1H), 2.18 (m, 1H), 1.81 (s, 6H, 2CH 3 ) , 1.32 (s, 6H, 2CH 3 ), 1.08 (s, 9H, 3CH 3 ); MS (ESI): m/z 663.70 (M+H).
将大环产物(180mg，0.27mmol)溶于THF/MeOH(7.4mL/3.7mL)，加入1N氢氧化锂水溶液(4.1mL),反应液室温搅拌2h，HPLC监测反应完全。反应液旋干有机相，水相用1N HCl调pH至4～5。EA萃取三次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，旋干得产品8d(lw1002-42-37-1,158.6mg)，收率90％。1HNMR(DMSO-d6,400MHz)δ7.68(s,1H),7.20-7.45(m,3H),7.09(s,1H),6.98(s,1H),4.60(d,1H),4.11-4.30(m,4H),4.02(m,3H),3.71(m,2H),2.31(m,1H),2.18(m,1H),1.76(s,6H,2CH3),1.34(s,6H,2CH3),0.98(d,9H,3CH3)；MS(ESI):m/z649.70(M+H)。The macrocyclic product (180 mg, 0.27 mmol) was dissolved in THF / MeOH ( EtOAc. The reaction mixture was dried to dryness and the aqueous phase was adjusted to pH 4 to 5 with 1N HCl. The EA was extracted three times, and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give the product 8d (lw1002-42-37-1, 158.6mg). 1 H NMR (DMSO-d 6 , 400 MHz) δ 7.68 (s, 1H), 7.20-7.45 (m, 3H), 7.09 (s, 1H), 6.98 (s, 1H), 4.60 (d, 1H), 4.11 -4.30 (m, 4H), 4.02 (m, 3H), 3.71 (m, 2H), 2.31 (m, 1H), 2.18 (m, 1H), 1.76 (s, 6H, 2CH 3 ), 1.34 (s, 6H, 2CH 3 ), 0.98 (d, 9H, 3CH 3 ); MS (ESI): m/z 649.70 (M+H).
实施例33 Example 33
化合物LW100210的合成Synthesis of Compound LW100210
Figure PCTCN2017079087-appb-000067
Figure PCTCN2017079087-appb-000067
双键底物LW100210(120mg,0.139mmol)溶于10mL乙酸乙酯中，小心加入钯碳(10％Pd/C)(50mg)，用氢气置换5次后，在氢气球氢化下，室温搅拌30分钟，HPLC监测反应完全，停止反应，反应混合物经硅藻土过滤，滤饼用乙酸乙酯洗涤三次，合并滤液，旋干，得粗品112.5mg，经制备TLC分离纯化后得纯产物LW100211 23mg，黄色固体。1HNMR(CDCl3,400MHz)δ10.15(s,1H),9.90(s,1H),7.60(d,1H),7.40(m,3H),7.10(m,1H),7.00(m,1H),5.40(s br,1H),4.80(d,1H),4.40(m,2H),4.16(m,2H),4.10(m,1H),3.69(m,2H),3.42(m,1H),2.95(m,1H),2.60(m,1H),2.05(m,1H),1.82(m,7H),1.68(m,2H),1.40(m,1H),1.30(s,6H),1.26(m,2H),1.15(s,9H),0.90(m,3H)；MS(ESI):m/z863.90(M+H).The double bond substrate LW100210 (120 mg, 0.139 mmol) was dissolved in 10 mL of ethyl acetate. Palladium carbon (10% Pd/C) (50 mg) was carefully added, and the mixture was replaced with hydrogen for 5 times. The reaction was completed by HPLC, the reaction was stopped, the reaction mixture was filtered through celite, and the filtrate was washed three times with ethyl acetate. The filtrate was combined and dried to give 112.5 mg of crude product. Yellow solid. 1 H NMR (CDCl 3 , 400 MHz) δ 10.15 (s, 1H), 9.90 (s, 1H), 7.60 (d, 1H), 7.40 (m, 3H), 7.10 (m, 1H), 7.00 (m, 1H) ), 5.40 (s br, 1H), 4.80 (d, 1H), 4.40 (m, 2H), 4.16 (m, 2H), 4.10 (m, 1H), 3.69 (m, 2H), 3.42 (m, 1H) ), 2.95 (m, 1H), 2.60 (m, 1H), 2.05 (m, 1H), 1.82 (m, 7H), 1.68 (m, 2H), 1.40 (m, 1H), 1.30 (s, 6H) , 1.26 (m, 2H), 1.15 (s, 9H), 0.90 (m, 3H); MS (ESI): m/z 863.90 (M+H).
实施例34Example 34
化合物LW100211的合成Synthesis of Compound LW100211
Figure PCTCN2017079087-appb-000068
Figure PCTCN2017079087-appb-000068
将8d(50mg，0.077mmol),SM-6a(30.8mg，0.1155mmol)溶于DMF(3.1mL)，反应瓶用氩气置换三次后，在冰浴中降温至0℃，依次滴加DIEA(0.085mL，0.4928mmol)，和HATU(44mg，0.1155mmol)，氩气置换三次，升至室温，搅拌1.5h，HPLC监测反应完全，停止反应。在反应液中加入25mL EA稀释，用半饱和食盐水洗涤四次，有机相用无水硫酸钠干燥，抽滤，滤液旋干得粗品153.4mg，过硅胶柱纯化(PE:EA10:1～8:1～6:15:1)，得到粗产物76.7mg，制备板进一步纯化得到纯品LW10021149mg，收率73.8％。1HNMR(CDCl3,400MHz)δ10.15(s,1H),9.90(s,1H),7.80(d,1H),7.38(m,3H),7.12(m,1H),6.98(m,1H),5.78(m,1H),5.25(m,1H),5.12(m,1H),4.80(d,1H),4.40(m,2H),4.16(m,2H),4.10(m,1H),3.69(m,2H),3.42(m,1H),2.90(m,1H),2.30(m,1H),2.05(m,1H),1.82(m,7H),1.68(m,1H),1.40(m,1H),1.30(s,6H),1.26(m,2H),1.15(s,9H),0.90(m,2H)；MS(ESI):m/z861.91(M+H).8d (50mg, 0.077mmol), SM-6a (30.8mg, 0.1155mmol) was dissolved in DMF (3.1mL), the reaction flask was replaced with argon three times, then cooled to 0 ° C in an ice bath, and DIEA was added dropwise. 0.085 mL, 0.4928 mmol), and HATU (44 mg, 0.1155 mmol), argon was replaced three times, warmed to room temperature, stirred for 1.5 h, and the reaction was monitored by HPLC and the reaction was stopped. The reaction mixture was diluted with 25 mL of EA, and washed with a half-saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered and filtered, and then evaporated to dryness to afford 153.4mg of crude product (PE: EA10:1-8 :1~6:15:1), 76.7 mg of the crude product was obtained, and the preparation plate was further purified to obtain pure product LW10021149 mg, yield 73.8%. 1 H NMR (CDCl 3 , 400 MHz) δ 10.15 (s, 1H), 9.90 (s, 1H), 7.80 (d, 1H), 7.38 (m, 3H), 7.12 (m, 1H), 6.98 (m, 1H) , 5.78 (m, 1H), 5.25 (m, 1H), 5.12 (m, 1H), 4.80 (d, 1H), 4.40 (m, 2H), 4.16 (m, 2H), 4.10 (m, 1H), 3.69 (m, 2H), 3.42 (m, 1H), 2.90 (m, 1H), 2.30 (m, 1H), 2.05 (m, 1H), 1.82 (m, 7H), 1.68 (m, 1H), 1.40 (m, 1H), 1.30 (s, 6H), 1.26 (m, 2H), 1.15 (s, 9H), 0.90 (m, 2H); MS (ESI): m/z 861.91 (M+H).
实施例35Example 35
化合物LW100212的合成 Synthesis of Compound LW100212
Figure PCTCN2017079087-appb-000069
Figure PCTCN2017079087-appb-000069
将8d(50mg，0.077mmol)，SM-6c(32.4mg，0.1155mmol)溶于DMF(3.1mL)，反应瓶用氩气置换三次后，置于冰浴中降温至0℃，依次滴加DIEA(0.085mL，0.4928mmol)，和HATU(44mg，0.1155mmol)，在氩气保护下，升至室温，搅拌1.5h，HPLC监测反应完全，停止反应。反应液加入25mL EA稀释后，用半饱和食盐水洗四次，无水硫酸钠干燥，抽滤，滤液旋干得粗品108.7mg，硅胶柱纯化得粗品165mg，制备板进一步纯化得到纯品LW10021249.7mg，收率73.7％。1HNMR(CDCl3,400MHz)δ10.20(s,1H),9.90(s,1H),7.90(d,1H),7.50(m,4H),7.18(m,1H),4.68(m,1H),4.35(m,2H),4.16(m,3H),4.09(m,1H),3.69(m,2H),3.50(m,1H),3.42(m,1H),3.02(m,1H),2.30(m,2H),2.05(m,1H),1.82(m,7H),1.68(m,1H),1.56(m,1H),1.40(m,1H),1.30(s,6H),1.26(m,2H),1.15(m,10H),0.90(m,2H)；MS(ESI):m/z875.99(M+H).8d (50mg, 0.077mmol), SM-6c (32.4mg, 0.1155mmol) was dissolved in DMF (3.1mL), the reaction flask was replaced with argon three times, then placed in an ice bath to cool to 0 ° C, followed by DIEA (0.085 mL, 0.4928 mmol), and HATU (44 mg, 0.1155 mmol). After the reaction mixture was diluted with 25 mL of EA, the mixture was washed with a half-saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and filtered, filtered, and then evaporated to dryness to give 108.7 mg of crude product, which was purified by silica gel column to obtain crude product 165 mg, which was further purified to obtain pure product LW10021249.7 mg The yield was 73.7%. 1 H NMR (CDCl 3 , 400 MHz) δ 10.20 (s, 1H), 9.90 (s, 1H), 7.90 (d, 1H), 7.50 (m, 4H), 7.18 (m, 1H), 4.68 (m, 1H) , 4.35 (m, 2H), 4.16 (m, 3H), 4.09 (m, 1H), 3.69 (m, 2H), 3.50 (m, 1H), 3.42 (m, 1H), 3.02 (m, 1H), 2.30 (m, 2H), 2.05 (m, 1H), 1.82 (m, 7H), 1.68 (m, 1H), 1.56 (m, 1H), 1.40 (m, 1H), 1.30 (s, 6H), 1.26 (m, 2H), 1.15 (m, 10H), 0.90 (m, 2H); MS (ESI): m/z 875.99 (M+H).
实施例36Example 36
化合物8e的合成Synthesis of Compound 8e
Figure PCTCN2017079087-appb-000070
Figure PCTCN2017079087-appb-000070
将Ve(1g,2.7mmol)、三苯基膦(1.4g，5.38mmol)、顺式-N-Boc-4-羟基-L-脯氨酸甲酯(0.74g，3mmol)溶于THF(46mL)。反应瓶用氩气置换三次，降温至0℃，滴加DIAD(1.1mL,5.38mmol)，温度基本保持不变。撤去冰水浴，继续搅拌反应4h后，HPLC检测基本反应完全。旋干反应液,硅胶柱层析纯化(PE:EA30:1to 20:1)得4e(1.4g)，收率87.5％。1HNMR(CDCl3,400MHz)δ8.22(s,1H),7.99(d,1H),7.60(d,1H),7.35(m,2H),7.27(s,1H),4.48(m,1.5H),4.30(m,0.5),3.95(m,1.5H),3.80(s,3H,CH3),3.78(m,0.5H),2.62(m,1H),2.43(m,1H),1.85(s,6H,2CH3),1.46(s,9H,3CH3)；MS(ESI)m/z600.49(M+H)。Ve (1 g, 2.7 mmol), triphenylphosphine (1.4 g, 5.38 mmol), cis-N-Boc-4-hydroxy-L-proline methyl ester (0.74 g, 3 mmol) was dissolved in THF (46 mL) ). The reaction flask was replaced with argon three times, cooled to 0 ° C, and DIAD (1.1 mL, 5.38 mmol) was added dropwise, and the temperature remained substantially unchanged. The ice water bath was removed, and the reaction was further stirred for 4 hours, and the basic reaction was confirmed by HPLC. The reaction mixture was dried and purified by silica gel column chromatography (PE: EA30:1 to 20:1) to give 4e (1.4 g). 1 H NMR (CDCl 3 , 400 MHz) δ 8.22 (s, 1H), 7.99 (d, 1H), 7.60 (d, 1H), 7.35 (m, 2H), 7.27 (s, 1H), 4.48 (m, 1.5H) ), 4.30 (m, 0.5), 3.95 (m, 1.5H), 3.80 (s, 3H, CH 3 ), 3.78 (m, 0.5H), 2.62 (m, 1H), 2.43 (m, 1H), 1.85 (s, 6H, 2CH 3 ), 1.46 (s, 9H, 3CH 3 ); MS (ESI) m/z 600.49 (M+H).
将4e(1.4g,2.33mmol)溶于12mL DCM中，滴加4mL 4N HCl-dioxane，室温搅拌2h，HPLC检测反应完全。旋干得盐酸盐1.35g。将此盐酸盐(1.35g，2.6mmol)、Boc-L-叔亮氨酸(0.6g，2.6mmol)溶于8mL DMF，用氩气换气两次后，反应液降温至0℃，搅拌下滴加DIEA(2.3mL，13mmol)(温度变化不明显)，然后加入HATU(1.2g，3.12mmol)，再用氩气换气两次，室温搅拌6h，HPLC检测反应完全。反应液中加入25mL EA稀释后，依次用水洗(8*2mL)，饱和食盐水洗(8*2mL)，无水硫酸钠干燥，过滤，滤液旋干得粗品2.6g。过30倍硅胶柱纯化(PE:EA20:1～15:1～12:1),得淡黄色固体纯品5e0.65g，收率36％.1NMR(CDCl3,400MHz)δ8.15(s,1H),7.87(d,1H),7.56(d,1H),7.36(m,3H),6.30(s br,1H),4.73(m,1H),4.18(m,2H),4.02(m,1H),3.79(s,3H,OCH3),2.61(m,1H),2.35(m,1H),1.86(d,6H,2CH3),1.59(s,9H,3CH3),1.06(s,9H,3CH3)；MS(ESI):m/z713.67(M+H)。4e (1.4 g, 2.33 mmol) was dissolved in 12 mL of DCM, 4 mL of 4N HCl-dioxane was added dropwise, and the mixture was stirred at room temperature for 2 h. Spin dry to give 1.35 g of the hydrochloride salt. The hydrochloride (1.35 g, 2.6 mmol) and Boc-L-tert-leucine (0.6 g, 2.6 mmol) were dissolved in 8 mL of DMF. After ventilating twice with argon, the reaction mixture was cooled to 0 ° C and stirred. DIEA (2.3 mL, 13 mmol) was added dropwise (the temperature did not change significantly), then HATU (1.2 g, 3.12 mmol) was added, and then argon gas was exchanged twice, stirred at room temperature for 6 h, and the reaction was completely confirmed by HPLC. After the reaction mixture was diluted with 25 mL of EA, the mixture was washed with water (8*2 mL), brine (8*2 mL), dried over anhydrous sodium sulfate and filtered, Purified by a silica gel column (PE: EA20: 1 to 15:1 to 12:1) to give a pale yellow solid product 5e 0.65 g, yield 36%. 1 NMR (CDCl3, 400 MHz) δ 8.15 (s, 1H), 7.87 (d, 1H), 7.56 (d, 1H), 7.36 (m, 3H), 6.30 (s br, 1H), 4.73 (m, 1H), 4.18 (m, 2H), 4.02 (m, 1H), 3.79 (s, 3H, OCH 3 ), 2.61 (m, 1H), 2.35 (m, 1H), 1.86 (d, 6H, 2CH 3 ), 1.59 (s, 9H, 3CH 3 ), 1.06 (s , 9H, 3CH 3); MS (ESI): m / z713.67 (m + H).
将底物5e(1.15g，1.15mmol)溶于DCM，搅拌下滴加6mL 4N HCl的1,4-二氧六环溶液。继续室温搅拌反应3h，HPLC检测反应完全。旋干反应液溶剂得盐酸盐1.4g，溶于30mLDCM，反应液降温至0℃后，搅拌下加入三光气(0.71g，2.4mmol)，反应瓶用氩气换气两次，加入吡啶(2.1mL,25.8mmol)。0℃搅拌0.5h，然后升至室温，继续搅拌0.5h。HPLC检测反应完全。反应液中加入80mL EA稀释后，依次用15mL水和15mL饱和食盐水洗两次，无水硫酸钠干燥，过滤，滤液旋干后，继续用油泵抽1h得异氰酸酯中间体,溶于THF，加入新戊二醇(0.5g，4.83mmol)和4A分子筛(2.75g)，反应混合物在室温下搅拌0.5h，加入DBU(0.31mL,2.1mmol)，继续搅拌反应1h后，HPLC检测发现反应完全。反应液中加入80mL EA稀释后，依次用15mL饱和食盐水洗，得粗品2g。硅胶柱纯化(PE:EA 10:1to 2:1)得纯品6e 0.8g,收率66.7％。1HNMR(CDCl3,400MHz)δ8.14(s,1H),7.83(d,1H),7.55(d,1H),7.41(m,3H),5.90(s,1H),4.73(m,1H),4.21(m,2H),4.13(m,1H),3.80(m,3H,OCH3),3.52(s,2H,),3.11(m,2H),2.65(m,1H),2.30(m,2H),1.82(d,6H,2CH3),0.98(s,15H,5CH3)；MS(ESI):m/z743.68,745.68(M+H)。Substrate 5e (1.15 g, 1.15 mmol) was dissolved in DCM, and 6 mL of 4N HCl in 1,4-dioxane solution was added dropwise with stirring. The reaction was stirred at room temperature for 3 h, and the reaction was completely confirmed by HPLC. The solvent of the reaction solution was spin-dried to obtain 1.4 g of the hydrochloride salt, dissolved in 30 mL of LDCM. After the reaction mixture was cooled to 0 ° C, the mixture was stirred to be added with phosgene (0.71 g, 2.4 mmol), and the reaction flask was ventilated twice with argon. 2.1 mL, 25.8 mmol). Stir at 0 ° C for 0.5 h, then warm to room temperature and continue stirring for 0.5 h. The reaction was confirmed by HPLC. After adding 80 mL of EA to the reaction mixture, the mixture was washed twice with 15 mL of water and 15 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness, and then the oil was pumped for 1 h to obtain the isocyanate intermediate, dissolved in THF, and added Pentanediol (0.5 g, 4.83 mmol) and 4A molecular sieves (2.75 g), the reaction mixture was stirred at room temperature for 0.5 h, then DBU (0.31 mL, 2.1 mmol) was added and the reaction was stirred for 1 h. After adding 80 mL of EA to the reaction mixture, the mixture was diluted with 15 mL of saturated brine to obtain 2 g of crude product. The silica gel column was purified (PE: EA 10:1 to 2:1) to afford pure product 6e 0.8 g, yield 66.7%. 1 H NMR (CDCl 3 , 400 MHz) δ 8.14 (s, 1H), 7.83 (d, 1H), 7.55 (d, 1H), 7.41 (m, 3H), 5.90 (s, 1H), 4.73 (m, 1H) , 4.21 (m, 2H), 4.13 (m, 1H), 3.80 (m, 3H, OCH 3 ), 3.52 (s, 2H,), 3.11 (m, 2H), 2.65 (m, 1H), 2.30 (m) , 2H), 1.82 (d, 6H, 2CH 3), 0.98 (s, 15H, 5CH 3); MS (ESI): m / z743.68,745.68 (m + H).
将6e(0.4g，0.54mmol)溶于30mL无水甲苯(用前通氩气15min)，加入碳酸铯(0.44g，1.35mmol)，反应混合氩气液通5min后，加入醋酸钯(30mg，0.135mmol)、PLn(70mg，0.173mmol)，再用氩气换气三次，反应液加热到90℃，搅拌过夜。第二天，HPLC检测反应完全。将反应混合液经硅藻土过滤，EA洗涤滤饼，合并滤液旋干，得粗品0.65g。硅胶柱纯化(PE:EA 15:1to 5:1)得大环化合物7e 70mg，收率19.5％，1HNMR(CDCl3,400MHz)δ7.40(m,3H),7.28(m,2H),6.98(m,1H),6.15(s,1H),5.30(m,1H),4.80(d,1H),4.50(m,1H),4.31(m,1H),4.20(m,1H),4.02(m,1H),3.75(m,1H),3.71(s,3H,OCH3),3.31(d,1H),2.50(m,1H),2.31(m,1H),2.20(m,1H),1.81(m,6H,2CH3),1.25(s,6H,2CH3),1.06(s,9H,3CH3)；MS(ESI):m/z663.83(M+H).6e (0.4g, 0.54mmol) was dissolved in 30mL of anhydrous toluene (with argon gas for 15min before use), cesium carbonate (0.44g, 1.35mmol) was added, and the reaction was mixed with argon for 5 minutes, then palladium acetate (30mg, 0.135 mmol), PLn (70 mg, 0.173 mmol), and then argon gas was exchanged three times. The reaction mixture was heated to 90 ° C and stirred overnight. The next day, the HPLC assay was complete. The reaction mixture was filtered through celite, and then filtered, and then filtered and evaporated. The silica gel column was purified (PE: EA 15:1 to 5:1) to give the crude compound 7e 70 mg, yield 19.5%, 1 H NMR (CDCl3, 400 MHz) δ 7.40 (m, 3H), 7.28 (m, 2H), 6.98 (m, 1H), 6.15 (s, 1H), 5.30 (m, 1H), 4.80 (d, 1H), 4.50 (m, 1H), 4.31 (m, 1H), 4.20 (m, 1H), 4.02 ( m, 1H), 3.75 (m, 1H), 3.71 (s, 3H, OCH 3 ), 3.31 (d, 1H), 2.50 (m, 1H), 2.31 (m, 1H), 2.20 (m, 1H), 1.81 (m, 6H, 2CH 3 ), 1.25 (s, 6H, 2CH 3 ), 1.06 (s, 9H, 3CH 3 ); MS (ESI): m/z 663.83 (M+H).
将7e(100mg,0.15mmol)溶于THF/MeOH(4mL/2mL)，搅拌下加入1N LiOH水溶液 (2.3mL)，反应液室温搅拌1.5h，HPLC检测反应完全。旋干有机相，水相用1N HCl的水溶液调pH至4—5后，用乙酸乙酯萃取三次(15x 3mL)，合并有机相，加无水硫酸钠干燥，过滤，滤液旋干得8e 130mg,收率128％.MS(ESI)m/z 649.69.7e (100 mg, 0.15 mmol) was dissolved in THF / MeOH (4 mL / 2 mL). (2.3 mL), the reaction mixture was stirred at room temperature for 1.5 h, and the reaction was confirmed by HPLC. The organic phase was dried and the aqueous phase was adjusted to pH 4-5 with aqueous 1N EtOAc. EtOAc (EtOAc) , yield 128%. MS (ESI) m / z 649.69.
实施例37Example 37
化合物LW100214的合成Synthesis of Compound LW100214
Figure PCTCN2017079087-appb-000071
Figure PCTCN2017079087-appb-000071
将羧酸8e(70mg，0.11mmol)和磺酰胺SM-6a(44.6mg，0.165mg)溶于5mL DMF，用氩气换气两次，反应液降温至0℃，搅拌下滴加DIEA(0.12mL,0.72mmol)，然后加入HATU(63mg,0.165mmol)，再换气两次，室温反应1.5h后，送HPLC检测反应完全。Carboxylic acid 8e (70mg, 0.11mmol) and sulfonamide SM-6a (44.6mg, 0.165mg) were dissolved in 5mL DMF, ventilated twice with argon, the reaction solution was cooled to 0 ° C, and DIEA (0.12) was added dropwise with stirring. mL, 0.72 mmol), then HATU (63 mg, 0.165 mmol) was added, and the mixture was ventilated twice, and reacted at room temperature for 1.5 h.
反应液加15mL EA稀释后，用半饱和食盐水洗(10*4mL)，无水硫酸钠干燥，过滤，滤液旋干得140mg。硅胶柱层析(PE:EA15:1to 4:1)得LW100214 14mg,1HNMR(CDCl3)δ7.35(m,5H,ArH),6.98(m,1H),5.67(m,1H),5.35(m,1H),5.19(m,1H),5.10(m,1H),4.31(m,3H),4.01(m,2H),3.67(s,1H)3.43(m,2H),2.88(m,1H),2.60(m,1H),2.00(m,1H),,1.83(s,3H,CH3),1.78(s,3H,CH3),1.62(m,4H),1.11(s,6H,2CH3),1.01(s,9H,3CH3),0.91(m,2H).LCMS(ESI):m/z861.87(M+H).After the reaction mixture was diluted with 15 mL of EA, the mixture was washed with a half-saturated brine (10*4 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. Silica gel column chromatography (PE: EA15: 1to 4: 1) to give LW100214 14mg, 1 HNMR (CDCl 3 ) δ7.35 (m, 5H, ArH), 6.98 (m, 1H), 5.67 (m, 1H), 5.35 (m, 1H), 5.19 (m, 1H), 5.10 (m, 1H), 4.31 (m, 3H), 4.01 (m, 2H), 3.67 (s, 1H) 3.43 (m, 2H), 2.88 (m) , 1H), 2.60 (m, 1H), 2.00 (m, 1H), 1.83 (s, 3H, CH 3 ), 1.78 (s, 3H, CH 3 ), 1.62 (m, 4H), 1.11 (s, 6H, 2CH 3 ), 1.01 (s, 9H, 3CH 3 ), 0.91 (m, 2H). LCMS (ESI): m/z 861.87 (M+H).
实施例38Example 38
化合物LW100213的合成Synthesis of Compound LW100213
参照实施例22，LW100214(10mg)常温Pd/C氢化，得LW100213 7mg.Referring to Example 22, LW100214 (10 mg) was hydrogenated at room temperature Pd/C to obtain LW100213 7 mg.
1HNMR(CDCl3)δ7.35(m,5H,ArH),6.98(m,1H),5.67(m,1H),5.35(m,1H),5.19(m,1H),5.10(m,1H),4.31(m,3H),4.01(m,2H),3.67(s,1H)3.43(m,2H),2.88(m,1H),2.60(m,1H),2.00(m,1H),,1.83(s,3H,CH3),1.78(s,3H,CH3),1.62(m,4H),1.11(s,6H,2CH3),1.01(s,9H,3CH3),0.91(m,2H).MS(ESI)m/z863.90(M+H). 1 H NMR (CDCl 3 ) δ 7.35 (m, 5H, ArH), 6.98 (m, 1H), 5.67 (m, 1H), 5.35 (m, 1H), 5.19 (m, 1H), 5.10 (m, 1H) ), 4.31 (m, 3H), 4.01 (m, 2H), 3.67 (s, 1H), 3.43 (m, 2H), 2.88 (m, 1H), 2.60 (m, 1H), 2.00 (m, 1H), , 1.83 (s, 3H, CH 3 ), 1.78 (s, 3H, CH 3 ), 1.62 (m, 4H), 1.11 (s, 6H, 2CH 3 ), 1.01 (s, 9H, 3CH 3 ), 0.91 ( m, 2H). MS (ESI) m / z 863.90 (M + H).
实施例39Example 39
化合物LW100215的合成 Synthesis of Compound LW100215
Figure PCTCN2017079087-appb-000072
Figure PCTCN2017079087-appb-000072
将酸8e(35mg，0.054mmol)、磺酰胺SM-6c(23.2mg，0.081mmol)溶于DMF，用氩气置换两次，反应液降温至0℃。搅拌下滴加DIEA，然后加入HATU，再用氩气换气两次。反应液室温搅拌1.5h后，送HPLC检测反应完全。反应液加15mL EA稀释后，用半饱和食盐水洗(5x 4mL)，有机相加无水硫酸钠干燥，过滤，滤液旋干得70mg,柱层析纯化(PE:EA10:1to 5:1)得LW10021543mg,收率67％,制备色谱分离纯化,HPLC(220/254nm):96.26％/99.03％；1HNMR(CDCl3,400MHz)δ7.41(m,6H,ArH),7.29(m,1H),6.18(s,1H),5.88(s,1H),4.49(d,1H),4.42(m,2H),4.27(m,1H),4.13(m,2H),3.78(m,2H),3.48(m,1H),3.38(m,1H),2.95(m,2H),2.60(m,1H),2.29(m,2H),2.20(m,2H),1.79(s,3H,CH3),1.76(s,3H,CH3),1.69(m,1H),1.25(m,3H),1.16(s,6H,2CH3),1.08(s,9H,3CH3),0.80(m,2H),0.51(m,3H),0.45(m,3H).LCMS(ESI):m/z875.6.Acid 8e (35 mg, 0.054 mmol) and sulfonamide SM-6c (23.2 mg, 0.081 mmol) were dissolved in DMF, and then twice with argon, and the reaction mixture was cooled to 0 °C. DIEA was added dropwise with stirring, then HATU was added, and argon was used to divert twice. After the reaction solution was stirred at room temperature for 1.5 h, it was subjected to HPLC to confirm the reaction. After the reaction mixture was diluted with 15 mL of EA, the mixture was diluted with EtOAc (5×4 mL), and then dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated to yield 70 mg, purified by column chromatography (PE: EA10:1 to 5:1) LW10021543mg, yield 67%, preparative chromatographic separation and purification, HPLC (220 / 254nm): 96.26% / 99.03%; 1 H NMR (CDCl3, 400MHz) δ 7.41 (m, 6H, ArH), 7.29 (m, 1H), 6.18(s,1H), 5.88(s,1H), 4.49(d,1H), 4.42(m,2H), 4.27(m,1H), 4.13(m,2H),3.78(m,2H),3.48 (m, 1H), 3.38 (m, 1H), 2.95 (m, 2H), 2.60 (m, 1H), 2.29 (m, 2H), 2.20 (m, 2H), 1.79 (s, 3H, CH 3 ) , 1.76 (s, 3H, CH 3 ), 1.69 (m, 1H), 1.25 (m, 3H), 1.16 (s, 6H, 2CH 3 ), 1.08 (s, 9H, 3CH 3 ), 0.80 (m, 2H) ), 0.51 (m, 3H), 0.45 (m, 3H). LCMS (ESI): m/z 875.6.
实施例40Example 40
化合物8f的合成Synthesis of Compound 8f
Figure PCTCN2017079087-appb-000073
Figure PCTCN2017079087-appb-000073
将Vf(1.5g，4.03mmol)，N-Boc-顺式羟脯氨酸甲酯(1.104g，4.5mmol)，PPh3(2.13g，8.12mmol)溶于无水THF(70mL)中，将装置密封好，用氩气置换3次，反应瓶置于冰浴中降温至0℃，滴加DIAD(1.65mL，8.12mmol)。滴加完毕后，撤去冰浴，使其自然恢复至室温，反应4小时，将反应液旋干，硅胶柱层析(PE:EA 15:1～10:1～5:1)，得黄色荧光固体4f(3.52g)。1HNMR(CDCl3,400MHz)δ8.20(s,1H),7.93(m,1H),7.58(m,2H),7.32(m,1H),7.16(d,1H),5.02-5.05(m,1.5H),4.48(m,0.5H),3.92-3.95(m,1.5H),3.80(s,3H,CH3),3.73(m,0.5H),2.64(m,1H),2.37(m,1H),1.75(s,6H,2CH3),1.41(s,9H,3CH3)；MS(ESI):m/z600.42(M+H)。Vf (1.5 g, 4.03 mmol), N-Boc-cis hydroxyproline methyl ester (1.104 g, 4.5 mmol), PPh 3 (2.13 g, 8.12 mmol) in anhydrous THF (70 mL) The device was sealed, replaced with argon three times, and the reaction flask was placed in an ice bath to cool to 0 ° C, and DIAD (1.65 mL, 8.12 mmol) was added dropwise. After the completion of the dropwise addition, the ice bath was removed, and it was naturally returned to room temperature. After reacting for 4 hours, the reaction solution was spun dry, and silica gel column chromatography (PE: EA 15:1 to 10:1 to 5:1) gave yellow fluorescence. Solid 4f (3.52 g). 1 H NMR (CDCl 3 , 400 MHz) δ 8.20 (s, 1H), 7.93 (m, 1H), 7.58 (m, 2H), 7.32 (m, 1H), 7.16 (d, 1H), 5.02-5.05 (m, 1.5H), 4.48 (m, 0.5H), 3.92-3.95 (m, 1.5H), 3.80 (s, 3H, CH 3 ), 3.73 (m, 0.5H), 2.64 (m, 1H), 2.37 (m) , 1H), 1.75 (s, 6H, 2CH 3 ), 1.41 (s, 9H, 3CH 3 ); MS (ESI): m/z 600.42 (M+H).
将4f(3.47g，5.8mmol)溶于DCM(30mL)中，滴加盐酸二氧六环溶液(10mL，40mmol)，溶液变成血红色，几乎无放热，并逐渐析出红色固体。反应3小时后送HPLC，检测反应完全，转入茄瓶中将反应液旋干，得黄色盐酸盐固体(3.39g)。将此固体物和N-Boc-L叔亮氨酸(1.405g，6.24mmol)溶于无水DMF(45mL)中，将装置密封好，用氩气置换3次，于冰盐浴中降温至0℃，缓慢滴加DIEA(8.3mL，30.6mmol)。滴毕，加入HATU(2.8g，7.37mmol)，用氩气置换3次，常温反应过夜。HPLC检测反应完全，加入EA(200mL)稀释，有机相依次用水(75mL)和饱和食盐水(75mL)洗涤后，用无水硫酸钠干燥，过滤，旋干，硅胶柱层析(PE:EA 20:1to 5:1)得淡黄色固体5f(3.3g)，收率74.23％。MS(ESI):m/z713.53(M+H)。4f (3.47 g, 5.8 mmol) was dissolved in DCM (30 mL). EtOAc EtOAc (EtOAc) After 3 hours of reaction, it was sent to HPLC, and the reaction was completed. The mixture was transferred to a flask and the reaction mixture was evaporated to dryness to give a yellow salt (3. The solid and N-Boc-L-tert-leucine (1.405 g, 6.24 mmol) were dissolved in anhydrous DMF (45 mL), the apparatus was sealed, replaced with argon three times, and cooled in an ice salt bath. DIEA (8.3 mL, 30.6 mmol) was slowly added dropwise at 0 °C. After the dropwise addition, HATU (2.8 g, 7.37 mmol) was added, and the mixture was replaced with argon gas three times, and reacted at room temperature overnight. The reaction was completed by HPLC. EtOAc (EtOAc) (EtOAc) : 1to 5:1) gave pale yellow solid 5f (3.3 g), yield 74.23%. MS (ESI): m/z 617.
将5f(3.3g，4.63mmol)溶于DCM(50mL)中，滴加盐酸二氧六环溶液(10mL，40mmol)，溶液变成血红色。反应3小时后送HPLC，检测反应完全，转入茄瓶中将反应液旋干，得黄色固体盐酸盐3.24g，溶于无水DCM(87.8mL)中，加入三光气(2.26g，7.61mmol)，塞好塞子，将反应瓶换氩气3次后，置于冰水浴中降温至T≤5℃，搅拌下滴加吡啶溶液(6.5mL)，反应液逐渐变成翠绿色，放出大量热，滴加完毕后在冰浴中继续搅拌30min，颜色变回橙红色，然后撤去冰浴在室温下继续反应15min。送HPLC反应完全。旋干之后油泵抽干，溶于无水THF(130.68mL)中，加入4A分子筛(8.72g，碾碎)，新戊二醇(1.58g，15.24mmol)，密封好，将反应瓶换气3次后，搅拌室温下滴加DBU(1mL)，无反应现象，搅拌反应过夜。第二天送HPLC反应完全，将反应液过滤，旋干，硅胶柱层析(PE:EA20:1to 3:1)得产物6f1.2g.MS(ESI):m/z743.67(M+H).5f (3.3 g, 4.63 mmol) was dissolved in DCM (50 mL) and dichloromethane hydrochloride (10 mL, 40 <RTIgt; After 3 hours of reaction, it was sent to HPLC, and the reaction was completed. The reaction mixture was transferred to a vial flask and the reaction solution was evaporated to dryness to give 3.24 g of a yellow solid hydrochloride salt, dissolved in anhydrous DCM (87.8 mL), and added to phosgene (2.26 g, 7.61). Mm), plug the plug, change the reaction bottle to argon for 3 times, then cool in the ice water bath to T ≤ 5 ° C, add pyridine solution (6.5 mL) under stirring, the reaction solution gradually turns into emerald green, releasing a large amount Heat, after the addition was completed, stirring was continued for 30 min in an ice bath, the color changed back to orange-red, then the ice bath was removed and the reaction was continued at room temperature for 15 min. The HPLC reaction was completed completely. After spinning, the oil pump was drained, dissolved in anhydrous THF (130.68 mL), 4A molecular sieve (8.72 g, crushed), neopentyl glycol (1.58 g, 15.24 mmol), sealed, and the reaction flask was ventilated. After the second time, DBU (1 mL) was added dropwise at room temperature, and the reaction was stirred. The next day, the HPLC reaction was completed, and the reaction mixture was filtered and evaporated to silica gel column chromatography (PE: EA 20:1 to 3:1) to give product 6f 1.2 g. MS (ESI): m/z 743.67 (M+H ).
将6f(0.6g，0.74mmol),CsCO3(0.6g，1.85mmol)溶于处理过的甲苯(45mL)中，反应液继续通氩气5分钟。加入Pd(OAc)2(42mg，0.185mmol),PLn(94mg，0.24mmol)，装上冷凝管，密封好后，换氩气3次，搅拌升温至90℃，反应过夜。第二天送HPLC，产物点与原料点保留时间几乎一样，将反应液过硅藻土，旋干，得粗品1.1g,硅胶柱层析(PE:EA20:1to2:1)，将所得溶液旋干后用油泵抽干，得淡黄色固体7f185mg，收率34.6％。MS(ESI):m/z663.74(M+H).The 6f (0.6g, 0.74mmol), CsCO 3 (0.6g, 1.85mmol) was dissolved in toluene treated (45mL), the reaction solution was continuously argon for 5 minutes. Pd(OAc) 2 (42 mg, 0.185 mmol), PLn (94 mg, 0.24 mmol) was added, and a condensing tube was attached. After sealing, argon gas was exchanged three times, and the mixture was heated to 90 ° C with stirring, and allowed to react overnight. The next day, the HPLC was carried out, and the product point was almost the same as the retention time of the starting point. The reaction solution was passed through celite and dried to give a crude product (1.1 g, silica gel column chromatography (PE: EA20: 1 to 2:1). After drying, it was drained with an oil pump to give a pale yellow solid, 7f 185 mg, yield 34.6%. MS (ESI): m/z 663.74 (M+H).
将7f溶于THF/MeOH溶液(7.175mL/3.605mL)中，滴入配好的LiOH/H2O溶液(4mL，1N)室温搅拌反应2h后，TLC、HPLC监测反应完全，停止反应。将有机相旋干，滴入HCl溶液(1N)调整溶液PH至4～5之间，用EA萃取水相三次，合并有机相，饱和食盐水洗涤3次，有机相中加入无水硫酸钠干燥30min，过滤，将有机相旋干得淡黄色固体8f201mg.MS(ESI):m/z649.69。The 7f was dissolved in THF / MeOH solution (7.175mL / 3.605mL) was dropwise added with a good LiOH / H 2 O solution (4mL, 1N) the reaction was stirred at room temperature for 2h, TLC, HPLC monitoring of the reaction complete, the reaction was stopped. The organic phase was spin-dried, and the pH of the solution was adjusted to between 4 and 5 by dropwise addition of HCl solution (1 N). The aqueous phase was extracted three times with EA, and the organic phase was combined and washed three times with saturated brine. After 30 min, the organic phase was dried with EtOAc mjjjjjjjj
实施例41Example 41
化合物LW100217的合成 Synthesis of Compound LW100217
Figure PCTCN2017079087-appb-000074
Figure PCTCN2017079087-appb-000074
将缩羧酸8f(50mg，0.082mmol)和磺酰胺SM-6a(32.68mg，0.1224mmol)溶于DMF溶液(5mL)中，将反应瓶密封好，用氩气置换3次，将反应瓶置于冰浴中降温到T≤5℃，搅拌下滴加DIEA(0.092mL，0.525mmol)，无明显放热，加入HATU(46.54mg，0.1224mmol)，密封好反应瓶，再用氩气置换3次，加热升温至90℃，20min后，降至室温，继续反应1.5hr。TLC监测至原料反应完全，反应液加入50mLEA稀释，转至分液漏斗中，加入饱和食盐水洗涤3次，分出有机相，加入无水硫酸钠干燥，过滤，有机相旋干得粗品121mg。硅胶柱层析，得纯品LW100217淡绿色固体37mg，收率63.3％；1HNMR(CDCl3,400MHz)δ10.20(s,1H),9.90(s,1H),7.70(d,1H),7.60(m,1H),7.50(m,1H),7.28(m,1H),7.20(d,1H),7.01(m,1H),5.78(m,1H),5.25(m,1H),5.12(m,1H),4.80(d,1H),4.40(m,2H),4.16(m,2H),4.00(m,1H),3.79(m,2H),3.52(m,1H),3.35(m,1H),2.90(m,1H),2.35(m,1H),1.82(m,7H),1.68(m,1H),1.40(m,1H),1.30(s,6H),1.26(m,2H),1.15(s,9H),0.90(m,2H)；MS(ESI):m/z861.95(M+H).The carboxylic acid 8f (50 mg, 0.082 mmol) and the sulfonamide SM-6a (32.68 mg, 0.1224 mmol) were dissolved in a DMF solution (5 mL), and the reaction flask was sealed and replaced with argon gas for 3 times. The temperature was lowered to T ≤ 5 ° C in an ice bath, DIEA (0.092 mL, 0.525 mmol) was added dropwise with stirring, no significant exotherm was added, HATU (46.54 mg, 0.1224 mmol) was added, and the reaction flask was sealed and replaced with argon gas. Then, the temperature was raised to 90 ° C by heating, and after 20 minutes, the temperature was lowered to room temperature, and the reaction was continued for 1.5 hr. TLC was monitored until the reaction of the starting material was complete. The reaction mixture was diluted with 50 mL of EA, and then transferred to a sep. funnel. The mixture was washed three times with saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Silica gel column chromatography to give 37mg pure LW100217 a pale green solid, yield 63.3%; 1 HNMR (CDCl3,400MHz) δ10.20 (s, 1H), 9.90 (s, 1H), 7.70 (d, 1H), 7.60 (m, 1H), 7.50 (m, 1H), 7.28 (m, 1H), 7.20 (d, 1H), 7.01 (m, 1H), 5.78 (m, 1H), 5.25 (m, 1H), 5.12 ( m,1H), 4.80 (d,1H), 4.40 (m, 2H), 4.16 (m, 2H), 4.00 (m, 1H), 3.79 (m, 2H), 3.52 (m, 1H), 3.35 (m) , 1H), 2.90 (m, 1H), 2.35 (m, 1H), 1.82 (m, 7H), 1.68 (m, 1H), 1.40 (m, 1H), 1.30 (s, 6H), 1.26 (m, 2H), 1.15 (s, 9H), 0.90 (m, 2H); MS (ESI): m/z 861.95 (M+H).
实施例42Example 42
化合物LW100216的合成Synthesis of Compound LW100216
Figure PCTCN2017079087-appb-000075
Figure PCTCN2017079087-appb-000075
将双键底物LW100217(21mg，0.0343mmol)溶于EA溶液(1.5mL)中，加入Pd/C(5mg)反应瓶密封好，氢气置换5次，常温反应1h，发现有1/3原料剩余，继续置换氢气反应1h，剩余极少原料，继续置换氢气30min，发现出现新的HPLC峰，推测反应过度，停止反应，反应液经硅藻土过滤后旋干。将固体溶于DCM(10mL)中，均匀涂抹在制备板TLC上，用展开剂(DCM:MeOH 30:1)展开，2h后取出制备板，刮下硅胶，用DCM(15mL)溶解，超声，过滤，滤液旋干得淡黄色固体LW100216 9mg(收率42.76％)。1HNMR(CDCl3，400MHz)δ10.15(s,1H),9.90(s,1H),7.66(d,1H),7.56(m,1H),7.40(m,1H),7.28(m,1H),7.21(d,1H),7.00(m,1H),6.28(s,1H),5.40(s br,1H),4.80(d,1H),4.46(m,2H),4.16(m,2H),4.10(m,1H),3.69(m,2H),3.42(m,1H),2.95(m,1H),2.60(m,1H),2.05(m,1H),1.82(m,7H),1.68(m,2H), 1.40(m,1H),1.30(s,6H),1.26(m,2H),1.15(s,9H),0.90(m,3H)；MS(ESI):m/z863.90(M+H).The double bond substrate LW100217 (21mg, 0.0343mmol) was dissolved in EA solution (1.5mL), and the Pd/C (5mg) reaction bottle was sealed, hydrogen was replaced 5 times, and reacted at room temperature for 1 hour. Continue to replace the hydrogen reaction for 1 h, leaving very little raw material, continue to replace the hydrogen for 30 min, and found a new HPLC peak. It is speculated that the reaction is excessive and the reaction is stopped. The reaction solution is filtered through celite and then spun dry. The solid was dissolved in DCM (10 mL), EtOAc (EtOAc:EtOAc) After filtration, the filtrate was spun dry to give a pale yellow solid (yield: 42.76%). 1 H NMR (CDCl 3 , 400 MHz) δ 10.15 (s, 1H), 9.90 (s, 1H), 7.66 (d, 1H), 7.56 (m, 1H), 7.40 (m, 1H), 7.28 (m, 1H) , 7.21 (d, 1H), 7.00 (m, 1H), 6.28 (s, 1H), 5.40 (s br, 1H), 4.80 (d, 1H), 4.46 (m, 2H), 4.16 (m, 2H) , 4.10 (m, 1H), 3.69 (m, 2H), 3.42 (m, 1H), 2.95 (m, 1H), 2.60 (m, 1H), 2.05 (m, 1H), 1.82 (m, 7H), 1.68 (m, 2H), 1.40 (m, 1H), 1.30 (s, 6H), 1.26 (m, 2H), 1.15 (s, 9H), 0.90 (m, 3H); MS (ESI): m/z 863 .90 (M+H).
实施例43Example 43
化合物LW100218的合成Synthesis of Compound LW100218
Figure PCTCN2017079087-appb-000076
Figure PCTCN2017079087-appb-000076
将羧酸8f(30mg，0.049mmol)和磺酰胺SM-6c(20.64mg，0.0735mmol)溶于DMF溶液(3.1mL)中，将反应瓶密封好，用氩气置换3次，将反应瓶置于冰浴中降温到T≤5℃，滴加DIEA(0.055mL，0.317mmol)，无明显放热，加入HATU(27.95mg，0.0735mmol)，密封好反应瓶，再用氩气置换3次，升温至90℃，20min后，降至室温，继续反应1.5h。The carboxylic acid 8f (30 mg, 0.049 mmol) and the sulfonamide SM-6c (20.64 mg, 0.0735 mmol) were dissolved in a DMF solution (3.1 mL), and the reaction flask was sealed and replaced with argon gas for 3 times. The temperature was lowered to T ≤ 5 ° C in an ice bath, DIEA (0.055 mL, 0.317 mmol) was added dropwise, no significant exotherm was added, HATU (27.95 mg, 0.0735 mmol) was added, the reaction flask was sealed, and then replaced with argon three times. The temperature was raised to 90 ° C, and after 20 min, it was cooled to room temperature, and the reaction was continued for 1.5 h.
取反应液用TLC监测，发现原料已反应完全，加入30mLEA稀释后，将反应液转移至分液漏斗中，加入饱和食盐水洗涤3次，分出有机相，加入无水硫酸钠干燥，过滤，有机相旋干得粗品80mg,硅胶柱纯化(PE:EA20:1to 2:1)，得纯纯品LW100218，淡绿色固体32mg，收率93.03％。1HNMR(CDCl3,400MHz)δ10.30(s,1H),9.90(s,1H),7.80(d,1H),7.50(m,4H),7.05(m,1H),5.32(m,1H),4.84(m,1H),4.35(m,2H),4.16-4.09(m,4H),3.71(m,2H),3.50(m,1H),3.32(m,1H),2.98(m,1H),2.30(m,2H),2.05(m,1H),1.82(m,7H),1.68(m,1H),1.56(m,1H),1.40(m,1H),1.30(s,6H),1.26(m,2H),1.15(m,10H),0.90(m,2H)；MS(ESI):m/z875.88(M+H).The reaction mixture was monitored by TLC, and it was found that the starting material was completely reacted. After adding 30 mL of EA, the reaction solution was transferred to a separating funnel, and washed with saturated brine for 3 times. The organic phase was separated, dried over anhydrous sodium sulfate and filtered. The organic phase was dried to give a crude product (yield: EtOAc (EtOAc: EtOAc: EtOAc): 1 H NMR (CDCl 3 , 400 MHz) δ 10.30 (s, 1H), 9.90 (s, 1H), 7.80 (d, 1H), 7.50 (m, 4H), 7.05 (m, 1H), 5.32 (m, 1H) , 4.84 (m, 1H), 4.35 (m, 2H), 4.16-4.09 (m, 4H), 3.71 (m, 2H), 3.50 (m, 1H), 3.32 (m, 1H), 2.98 (m, 1H) ), 2.30 (m, 2H), 2.05 (m, 1H), 1.82 (m, 7H), 1.68 (m, 1H), 1.56 (m, 1H), 1.40 (m, 1H), 1.30 (s, 6H) , 1.26 (m, 2H), 1.15 (m, 10H), 0.90 (m, 2H); MS (ESI): m/z 875.88 (M+H).
实施例44Example 44
化合物8g的合成 Synthesis of compound 8g
Figure PCTCN2017079087-appb-000077
Figure PCTCN2017079087-appb-000077
将底物Vi(1g,2.9mmol)、N-Boc-L羟基脯氨酸甲酯SM-3(0.78g,3.2mmol)、三苯基膦(1.52g,5.8mmol)溶于无水THF(10mL)，冷却至0℃后，逐滴滴加DIAD(1.17g,5.8mmol)。恢复至室温搅拌16h，TLC监测反应完全。水淬灭反应，乙酸乙酯萃取。有机相以无水硫酸钠干燥，浓缩后柱层析(heptane/EA＝10/1to 5/1)得到白色泡沫状固体1.25g，收率75％。1HNMR(400MHz,CDCl3):δ1.26(s,9H),2.29-2.36(m,1H),2.56-2.61(m,1H),3.85-3.95(m,2H),4.37-4.46(m,1H),4.94-5.04(m,1H),6.24(s,2H),7.09-7.12(m,1H),7.27-7.36(m,2H),7.45-7.51(m,2H),7.70(s,1H),7.95-7.97(m,1H).The substrate Vi (1 g, 2.9 mmol), N-Boc-L hydroxyproline methyl ester SM-3 (0.78 g, 3.2 mmol), triphenylphosphine (1.52 g, 5.8 mmol) was dissolved in anhydrous THF ( 10 mL), after cooling to 0 ° C, DIAD (1.17 g, 5.8 mmol) was added dropwise. After returning to room temperature and stirring for 16 h, the reaction was monitored by TLC. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate (MgSO4). 1 H NMR (400 MHz, CDCl 3 ): δ 1.26 (s, 9H), 2.29-2.36 (m, 1H), 2.56-2.61 (m, 1H), 3.85-3.95 (m, 2H), 4.37-4.46 (m) , 1H), 4.94-5.04 (m, 1H), 6.24 (s, 2H), 7.09-7.12 (m, 1H), 7.27-7.36 (m, 2H), 7.45-7.51 (m, 2H), 7.70 (s , 1H), 7.95-7.97 (m, 1H).
在25ml单口瓶中，依次加入4g(0.5g,0.88mmol)，无水DCM(3ml)，反应混合物置于冰水浴降，加入盐酸二氧六环溶液(4N,5ml)后，升至室温(约30度)，反应搅拌1h，TLC显示反应完全。浓缩后得到白色固体，直接进行下一步反应。4g (0.5g, 0.88mmol), anhydrous DCM (3ml) was added to a 25ml single-mouth bottle, the reaction mixture was placed in ice water, and the solution was added to dioxane hydrochloride (4N, 5ml) and then raised to room temperature ( About 30 degrees), the reaction was stirred for 1 h, and TLC showed the reaction was completed. After concentration, a white solid was obtained, which was directly subjected to the next reaction.
在50ml三口瓶中，依次加入上步粗品(约0.88mmol)，无水DMF(15ml)，DIEA(697mg,5.4mmol)反应液降温至0度搅拌5min。随后加入Boc-L-叔亮氨酸SM-4(264mg,1.1mmol)以及HATU(418m g,1.1mmol)。氩气置换3次后回复至室温(30度)，反应搅拌过夜。加入乙酸乙酯稀释反应，有机相以半饱和食盐水洗涤三次，无水硫酸钠干燥。浓缩后柱层析(heptane/EA＝5/1)得到淡黄色油状物5g(463mg)，两步收率77％。1HNMR(400MHz,CDCl3):δ1.03(s,9H),1.24(s,3H),2.24-2.31(m,1H),2.54-2.59(m,1H),3.75(s,3H),3.93-3.98(m,1H),4.10-4.15(m,2H),4.18-4.22(m,2H),4.62(d,J＝8.4Hz,1H),4.95-5.01(m,1H),5.25-5.27(m,1H),6.22-6.24(m,2H),7.11(d,J＝8.4Hz,1H),7.24-7.28(m,1H),7.32-7.35(m,1H),7.39(d,J＝8.0Hz,1H),7.48(d,J＝7.6Hz,1H),7.62(s,1H),7.94(s,1H). In a 50 ml three-necked flask, the crude product of the above step (about 0.88 mmol), anhydrous DMF (15 ml), DIEA (697 mg, 5.4 mmol) was cooled to 0 ° and stirred for 5 min. Boc-L-tert-leucine SM-4 (264 mg, 1.1 mmol) and HATU (418 mg, 1.1 mmol) were then added. After argon replacement for 3 times, it was returned to room temperature (30 ° C), and the reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate. After concentration by column chromatography (heptane / EA = 5 / 1), 5 g (463mg) 1 H NMR (400 MHz, CDCl 3 ): δ 1.03 (s, 9H), 1.24 (s, 3H), 2.24 - 2.31 (m, 1H), 2.54-2.59 (m, 1H), 3.75 (s, 3H), 3.93-3.98 (m, 1H), 4.10-4.15 (m, 2H), 4.18-4.22 (m, 2H), 4.62 (d, J = 8.4 Hz, 1H), 4.95-5.01 (m, 1H), 5.25- 5.27(m,1H),6.22-6.24(m,2H), 7.11(d,J=8.4Hz,1H),7.24-7.28(m,1H),7.32-7.35(m,1H),7.39(d, J = 8.0 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.62 (s, 1H), 7.94 (s, 1H).
冰水混合浴下向50mL反应瓶中依次加入5g(460mg,0.67mmol)，无水DCM(3ml)以及盐酸二氧六环溶液(4N,5ml)，反应液30℃搅拌1小时，TLC显示反应完全。浓缩后，用真空油泵继续干燥30min，得黄色泡沫状固体，直接用于下一步反应。5 g (460 mg, 0.67 mmol), anhydrous DCM (3 ml) and dioxane hydrochloride solution (4N, 5 ml) were added to a 50 mL reaction flask under ice-water mixing bath. The reaction mixture was stirred at 30 ° C for 1 hour. complete. After concentration, drying was continued with a vacuum oil pump for 30 min to obtain a yellow foamy solid which was directly used for the next reaction.
在100ml单口瓶中，将LW1002-026-4粗品(1.32mmol)溶于DCM(20ml)，冰水浴下加入三光气(594mg,2.0mmol)，然后逐滴加入吡啶(1.6g,20mmol)，反应液在0℃搅拌1h后，TLC显示反应完全。加入水淬灭反应后，二氯甲烷萃取，有机相以无水硫酸钠干燥，浓缩后得得到中间体异氰酸酯，油泵抽干得到红色泡沫状固体，直接进行下一步反应。In a 100 ml one-necked flask, the crude product of LW1002-026-4 (1.32 mmol) was dissolved in DCM (20 ml), and phosgene (594 mg, 2.0 mmol) was added under ice water, then pyridine (1.6 g, 20 mmol) was added dropwise. After stirring the solution at 0 ° C for 1 h, TLC showed the reaction was completed. After adding water to quench the reaction, the mixture was extracted with methylene chloride. The organic phase was dried over anhydrous sodium sulfate, and then evaporated to afford the intermediate isocyanate, and the oil pump was evaporated to give a red foamy solid.
将中间体异氰酸酯溶于无水THF(10ml)，加入新戊二醇(411mg,3.96mmol)和4A分子筛(2g)，室温搅拌10min后，加入DBU(401mg,2.64mmol)，继续搅拌2小时，TLC显示底物消失。加入EA稀释，经硅藻土过滤，滤液依次用水以及饱和氯化钠溶液洗涤，无水硫酸钠干燥。浓缩后柱层析(heptane/EA＝2/1)得到棕色油状物6g(410mg)，三步收率44％。1HNMR(400MHz,CDCl3):δ0.92(s,6H),1.05(s,9H),2.27-2.32(m,1H),2.57-2.62(m,1H),3.36(s,H),3.51(s,3H),3.75(s,2H),3.82-3.85(m,2H),4.01(s,2H),4.25(dd,J＝8.8Hz,1H),4.64(t,J＝8.8Hz,1H),5.48(d,J＝9.6Hz,1H),6.25(d,J＝6.4Hz,1H),7.10(d,J＝8.4Hz,1H),7.24-7.26(m,1H),7.34-7.41(m,2H),7.47(d,J＝8.0Hz,1H),7.97(s,1H).The intermediate isocyanate was dissolved in anhydrous THF (10 ml), hexane (411 mg, 3.96 mmol) and 4A molecular sieves (2 g) were added and stirred at room temperature for 10 min, then DBU (401 mg, 2.64 mmol) was added and stirring was continued for 2 hours. TLC showed the substrate disappeared. The mixture was diluted with EA and filtered over Celite. Column chromatography after concentration (heptane / EA = 2 / 1) gave 6 g (410mg) of brown oil. 1 H NMR (400 MHz, CDCl 3 ): δ 0.92 (s, 6H), 1.05 (s, 9H), 2.27-2.32 (m, 1H), 2.57-2.62 (m, 1H), 3.36 (s, H), 3.51 (s, 3H), 3.75 (s, 2H), 3.82-3.85 (m, 2H), 4.01 (s, 2H), 4.25 (dd, J = 8.8 Hz, 1H), 4.64 (t, J = 8.8 Hz) , 1H), 5.48 (d, J = 9.6 Hz, 1H), 6.25 (d, J = 6.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.24 - 7.26 (m, 1H), 7.34 -7.41 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.97 (s, 1H).
在50ml单口瓶中，依次加入6g(200mg,0.28mmol)，无水甲苯(20ml,旋蒸除水)，碳酸铯(183mg,0.56mmol)，醋酸钯(12.5mg,0.056mmol)，PLn(25mg,0.07mmol)，氩气置换3次，反应液用油浴加热至90度，反应16h，TLC显示底物仍然剩余部分。浓缩后柱层析(heptane/EA＝4/1～2/1)得到白色固体7g(32mg)，回收原料(6g)62mg。1HNMR(400MHz,CDCl3):δ1.00(s,9H),1.05(s,3H),1.07(s,3H),2.13-2.24(m,1H),2.48-2.53(m,1H),3.32(d,J＝10.8Hz,1H),3.51(t,J＝14.4Hz,1H),3.64-3.71(m,1H),3.70(s,3H),3.87-3.91(m,1H),4.05-4.11(m,1H),4.23-4.27(m,1H),4.75(d,J＝10.8Hz,1H),5.25(d,J＝10.0Hz,1H),6.22(s,2H),6.87-6.99(m,3H),7.09-7.14(m,1H),7.29-7.36(m,2H),7.90(s,1H).MS(ESI):m/z634(M+H).In a 50 ml single-mouth bottle, 6 g (200 mg, 0.28 mmol), anhydrous toluene (20 ml, rotary water removal), cesium carbonate (183 mg, 0.56 mmol), palladium acetate (12.5 mg, 0.056 mmol), PLn (25 mg) , 0.07 mmol), replaced with argon three times, the reaction solution was heated to 90 degrees with an oil bath, and reacted for 16 h. TLC showed the remaining portion of the substrate. After concentration and column chromatography (heptane/EA = 4/1 to 2/1), 7 g (32 mg) of white solid was obtained. 1 HNMR (400MHz, CDCl 3) : δ1.00 (s, 9H), 1.05 (s, 3H), 1.07 (s, 3H), 2.13-2.24 (m, 1H), 2.48-2.53 (m, 1H), 3.32 (d, J = 10.8 Hz, 1H), 3.51 (t, J = 14.4 Hz, 1H), 3.64 - 3.71 (m, 1H), 3.70 (s, 3H), 3.87 - 3.91 (m, 1H), 4.05 -4.11(m,1H),4.23-4.27(m,1H), 4.75(d,J=10.8Hz,1H), 5.25(d,J=10.0Hz,1H),6.22(s,2H),6.87- 6.99 (m, 3H), 7.09-7.14 (m, 1H), 7.29-7.36 (m, 2H), 7.90 (s, 1H). MS (ESI): m/z 634 (M+H).
在50ml单口瓶中，依次加入7g(136mg,0.21mmol)，THF/MeOH(6ml/4ml),和LiOH水溶液(43mg溶于2mL水中)，反应液室温搅拌1h，TLC显示反应完全。HCl水溶液(1N)调PH至2～3，用EA萃取3次，有机相合并，无水硫酸钠干燥浓缩后柱层析(CH2Cl2/MeOH＝10/1),得到白色固体8g(130mg)。1HNMR(400MHz,d6-DMSO):δ0.92(s,9H),1.05(s,3H),1.07(s,3H),1.64-1.72(m,1H),1.91-2.02(m,1H),2.14-2.26(m,1H),3.68(s,1H),3.74-3.84(m,1H),3.96(m,2H),4.19-4.23(m,1H),6.22-6.24(m,2H),6.97-7.02(m,1H),7.08-7.12(m,1H),7.23-7.25(m,1H),7.32-7.39(m,2H),7.51-7.53(m,1H),8.17(s,1H).MS(ESI):m/z620(M+H).In a 50 ml one-necked flask, 7 g (136 mg, 0.21 mmol), THF / MeOH (6 ml / 4 ml), and a solution of LiOH (43 mg in 2 mL of water) were added, and the reaction mixture was stirred at room temperature for 1 h. Aqueous HCl (1N) adjusted to PH 2-3, and extracted three times with EA, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated by column chromatography (CH 2 Cl 2 / MeOH = 10/1), to give a white solid 8g ( 130mg). 1 H NMR (400 MHz, d6-DMSO): δ 0.92 (s, 9H), 1.05 (s, 3H), 1.07 (s, 3H), 1.64-1.72 (m, 1H), 1.91-2.02 (m, 1H) , 2.14 - 2.26 (m, 1H), 3.68 (s, 1H), 3.74 - 3.84 (m, 1H), 3.96 (m, 2H), 4.19 - 4.23 (m, 1H), 6.22 - 6.24 (m, 2H) , 6.97-7.02 (m, 1H), 7.08-7.12 (m, 1H), 7.23-7.25 (m, 1H), 7.32-7.39 (m, 2H), 7.51-7.53 (m, 1H), 8.17 (s, 1H). MS (ESI): m / z 620 (M + H).
实例45 Example 45
化合物LW100224的合成Synthesis of Compound LW100224
Figure PCTCN2017079087-appb-000078
Figure PCTCN2017079087-appb-000078
在25ml三口瓶中，依次加入8g(36mg,0.058mmol)，无水DMF(5ml),和SM-6a(31mg,0.12mmol)，反应瓶用氩气置换3次，冰水浴降温至0℃，滴加DIEA(30mg,0.232mmol)，加入HATU(66mg,0.174mmol)，再用氩气置换3次，升至室温反应过夜。加入乙酸乙酯稀释后，用半饱和食盐水洗4次，有机相以无水硫酸钠干燥浓缩制备HPLC纯化，得到白色固体5mg，纯度95％。1HNMR(400MHz,CDCl3):δ0.75-0.83(m),0.93(s),0.97(s),1.95-1.96(m),2.10-2.15(t),2.26-2.30(t),2.93-2.95(m),2.27-2.29(d),3.41-3.47(m),3.59-3.66(m),3.84-3.97(m),4.11-4.26(m),4.69-4.72(m),5.02-5.32(m),5.60-5.66(m),6.16(s),6.23(s),6.71(s),6.84-6.88(m),6.98(s),7.25-7.29(m),7.85(s),7.95(s).MS(ESI):m/z830(M+H).In a 25 ml three-necked flask, 8 g (36 mg, 0.058 mmol), anhydrous DMF (5 ml), and SM-6a (31 mg, 0.12 mmol) were sequentially added, and the reaction flask was replaced with argon gas three times, and the ice water bath was cooled to 0 ° C. DIEA (30 mg, 0.232 mmol) was added dropwise, HATU (66 mg, 0.174 mmol) was added, and the mixture was replaced with argon gas three times and allowed to react to room temperature overnight. After it was diluted with ethyl acetate, it was washed with a half-saturated brine, and the organic phase was dried over anhydrous sodium sulfate. 1 H NMR (400 MHz, CDCl 3 ): δ 0.75-0.83 (m), 0.93 (s), 0.97 (s), 1.95-1.96 (m), 2.10-2.15 (t), 2.26-2.30 (t), 2.93 -2.95(m), 2.27-2.29(d), 3.41-3.47(m), 3.59-3.66(m),3.84-3.97(m),4.11-4.26(m),4.69-4.72(m),5.02- 5.32(m), 5.60-5.66(m), 6.16(s), 6.23(s), 6.71(s), 6.84-6.88(m), 6.98(s), 7.25-7.29(m), 7.85(s) , 7.95 (s). MS (ESI): m / z 830 (M + H).
实例46Example 46
化合物LW100225的合成Synthesis of Compound LW100225
在25ml三口瓶中，依次加入8g(35mg,0.056mmol)，无水DMF(5ml),和SM-6g(32mg,0.11mmol)，反应瓶用氩气置换3次，冰水浴降温至0℃，滴加DIEA(29mg,0.224mmol)，加入HATU(64mg,0.168mmol)，再用氩气置换3次，升至室温反应过夜。加入乙酸乙酯稀释后，用半饱和食盐水洗4次，有机相以无水硫酸钠干燥浓缩制备HPLC纯化，得到白色固体7mg，纯度92％。1HNMR(400MHz,CDCl3):δ0.79-0.83(m),0.98(s),1.01(s),1.07(s),1.10(s),1.72-2.06(m),2.17-2.21(m),2.31-2.35(m),2.65-2.67(m),3.32(d),3.45-3.52(m),3.65-3.71(m),3.89-4.02(m),4.12-4.37(m),4.76(d),5.09(d),5.15(d),5.28-5.37(m),5.55-5.73(m),6.00(s),6.21(s),6.34(s),6.76(s),6.85-6.92(m),6.97-7.12(m),7.27-7.34(m),7.90(s),7.99(s).MS(ESI):m/z844(M+H).In a 25 ml three-necked flask, 8 g (35 mg, 0.056 mmol), anhydrous DMF (5 ml), and SM-6g (32 mg, 0.11 mmol) were sequentially added, and the reaction flask was replaced with argon gas three times, and the ice water bath was cooled to 0 ° C. DIEA (29 mg, 0.224 mmol) was added dropwise, HATU (64 mg, 0.168 mmol) was added, and the mixture was replaced with argon gas three times and allowed to react to room temperature overnight. After diluting with ethyl acetate, the mixture was washed with EtOAc (EtOAc) EtOAc. 1 H NMR (400 MHz, CDCl 3 ): δ 0.79-0.83 (m), 0.98 (s), 1.01 (s), 1.07 (s), 1.10 (s), 1.72-2.06 (m), 2.17-2.21 (m) ), 2.31-2.35(m), 2.65-2.67(m), 3.32(d), 3.45-3.52(m), 3.65-3.71(m), 3.89-4.02(m), 4.12-4.37(m), 4.76 (d), 5.09(d), 5.15(d), 5.28-5.37(m), 5.55-5.73(m), 6.00(s), 6.21(s), 6.34(s), 6.76(s), 6.85- 6.92(m), 6.97-7.12(m), 7.27-7.34(m), 7.90(s), 7.99(s).MS(ESI): m/z844(M+H).
实例47Example 47
化合物LW100226的合成 Synthesis of Compound LW100226
Figure PCTCN2017079087-appb-000080
Figure PCTCN2017079087-appb-000080
在25ml三口瓶中，依次加入8g(60mg,0.097mmol)，无水DMF(5ml),和SM-6f(59mg,0.19mmol)，反应瓶用氩气置换3次，冰水浴降温至0℃，滴加DIEA(50mg,0.388mmol)，加入HATU(111mg,0.291mmol)，再用氩气置换3次，升至室温反应过夜。加入乙酸乙酯稀释后，用半饱和食盐水洗4次，有机相以无水硫酸钠干燥浓缩制备HPLC纯化，得到白色固体10mg，纯度97％。1HNMR(400MHz,CDCl3):δ0.84-0.87(m),0.98(s),1.00(s),1.08(s),1.09(s),1.62(s),1.74-1.81(m),1.98-2.00(m),2.17-2.32(m),3.31-3.34(d),3.45-3.52(m),3.62-3.69(m),3.83-4.02(m),4.11-4.41(m),4.76-7.78(d),5.31-5.36(m),5.96(s),6.19(s),6.28(s),6.70(s),6.90-6.92(m),6.99-7.11(m),7.28-7.34(m),7.89(s),7.99(s).MS(ESI):m/z890(M+Na).In a 25 ml three-necked flask, 8 g (60 mg, 0.097 mmol), anhydrous DMF (5 ml), and SM-6f (59 mg, 0.19 mmol) were sequentially added, and the reaction flask was replaced with argon gas three times, and the ice water bath was cooled to 0 ° C. DIEA (50 mg, 0.388 mmol) was added dropwise, HATU (111 mg, 0.291 mmol) was added, and then replaced with argon three times, and allowed to react to room temperature overnight. After diluting with ethyl acetate, the mixture was washed with EtOAc (EtOAc) EtOAc. 1 H NMR (400 MHz, CDCl 3 ): δ 0.84-0.87 (m), 0.98 (s), 1.00 (s), 1.08 (s), 1.09 (s), 1.62 (s), 1.74-1.81 (m), 1.98-2.00(m), 2.17-2.32(m), 3.31-3.34(d), 3.45-3.52(m), 3.62-3.69(m), 3.83-4.02(m),4.11-4.41(m),4.76 -7.78(d), 5.31-5.36(m), 5.96(s), 6.19(s), 6.28(s), 6.70(s), 6.90-6.92(m), 6.99-7.11(m), 7.28-7.34 (m), 7.89 (s), 7.99 (s). MS (ESI): m/z 890 (M+Na).
实例48Example 48
化合物LW100227的合成Synthesis of Compound LW100227
Figure PCTCN2017079087-appb-000081
Figure PCTCN2017079087-appb-000081
在25ml三口瓶中，依次加入8g(30mg,0.048mmol)，无水DMF(5ml),和SM-6h(34mg,0.096mmol)，反应瓶用氩气置换3次，冰水浴降温至0℃，滴加DIEA(55mg,0.192mmol)，加入HATU(55mg,0.144mmol)，再用氩气置换3次，升至室温反应过夜。加入乙酸乙酯稀释后，用半饱和食盐水洗4次，有机相以无水硫酸钠干燥浓缩制备HPLC纯化，得到白色固体15mg，纯度99％。1HNMR(400MHz,CDCl3):δ0.84-0.87(m),0.98(s),1.00(s),1.07(s),1.10(s),1.46-1.47(d),1.54-1.64(m),1.90-2.00(m),2.17-2.25(m),3.31-3.34(d),3.46-3.52(m),3.66(s),3.85-4.02(m),4.13-4.40(m),4.79(d),5.29-5.33(m),5.73(d),5.85(d),6.20(s),6.29(s),6.62(s),6.88-6.92(m),7.00-7.11(m),7.28-7.33(m),7.90(s),7.99(s),9.66(s).In a 25 ml three-necked flask, 8 g (30 mg, 0.048 mmol), anhydrous DMF (5 ml), and SM-6h (34 mg, 0.096 mmol) were sequentially added, and the reaction flask was replaced with argon gas three times, and the ice water bath was cooled to 0 ° C. DIEA (55 mg, 0.192 mmol) was added dropwise, HATU (55 mg, 0.144 mmol) was added, and the mixture was replaced with argon three times and allowed to react to room temperature overnight. After diluting with ethyl acetate, the mixture was washed with EtOAc (EtOAc) EtOAc. 1 H NMR (400 MHz, CDCl 3 ): δ 0.84-0.87 (m), 0.98 (s), 1.00 (s), 1.07 (s), 1.10 (s), 1.46-1.47 (d), 1.54-1.64 (m) ), 1.90-2.00(m), 2.17-2.25(m), 3.31-3.34(d), 3.46-3.52(m), 3.66(s), 3.85-4.02(m), 4.13-4.40(m), 4.79 (d), 5.29-5.33(m), 5.73(d), 5.85(d), 6.20(s), 6.29(s), 6.62(s), 6.88-6.92(m), 7.00-7.11(m), 7.28-7.33(m), 7.90(s), 7.99(s), 9.66(s).
实例49Example 49
化合物13的合成 Synthesis of Compound 13
Figure PCTCN2017079087-appb-000082
Figure PCTCN2017079087-appb-000082
将化合物4(0.86g,1.5mmol)、乙烯三氟硼酸钾(0.61g,4.5mmol)以及三乙胺(0.63mL,4.5mmol)溶于15mL无水乙醇中，然后加入Pd(dppf)Cl2(44mg,0.06mmol)，氩气置换后加热至回流搅拌过夜。待反应液冷却至室温后，向混合液中加入10％KHSO4水溶液淬灭反应，然后用EA萃取水相三次。合并有机相，用无水硫酸钠干燥后，减压蒸干得粗产品，柱层析纯化得产物10(0.62g，产率80％)。ESI-MS[(M+H+)]:m/z 520.28.Compound 4 (0.86 g, 1.5 mmol), ethyl trifluoroborate (0.61 g, 4.5 mmol) and triethylamine (0.63 mL, 4.5 mmol) were dissolved in 15 mL absolute ethanol and then Pd(dppf)Cl 2 was added (44 mg, 0.06 mmol), after argon displacement, heated to reflux and stirred overnight. After the reaction solution was cooled to room temperature, a 10% aqueous solution of KHSO 4 was added to the mixture to quench the reaction, and then the aqueous phase was extracted three times with EA. The organic phase was combined, dried over anhydrous sodium sulfate and evaporated to dryness. ESI-MS[(M+H + )]: m/z 520.28.
将化合物10(0.62g,1.2mmol)溶于4mL无水DCM，加入4mL 4N HCl的1,4-二氧六环溶液。室温搅拌1h后浓缩反应液得胺中间体。将胺中间体以及SM-4(0.30g,1.3mmol)溶于无水DMF中，然后冷却到0℃。氩气保护下，加入DIEA(0.85mL,4.9mmol)以及HATU(0.49g,1.3mmol)。反应液在室温搅拌一小时，然后加入EA稀释，5％柠檬酸水溶液洗，水洗，1M碳酸氢钠水溶液洗，饱和食盐水洗4次。有机相用无水硫酸钠干燥后，减压蒸干得粗产品，柱层析纯化得产品11(0.64g),两步收率85％。ESI-MS[(M+H+)]:m/z 633.41.Compound 10 (0.62 g, 1.2 mmol) was dissolved in 4 mL dry DCM and 4 mL 4N HCl in 1,4-dioxane. After stirring at room temperature for 1 h, the reaction mixture was concentrated to give an amine intermediate. The amine intermediate and SM-4 (0.30 g, 1.3 mmol) were dissolved in dry DMF then cooled to 0. DIEA (0.85 mL, 4.9 mmol) and HATU (0.49 g, 1.3 mmol) were added under argon. The reaction solution was stirred at room temperature for one hour, then diluted with EA, washed with 5% aqueous citric acid, washed with water, washed with 1M aqueous sodium hydrogen carbonate, and washed 4 times with saturated brine. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. ESI-MS [(M+H + )]: m/z 633.41.
将化合物11(0.64g,1.0mmol)溶于4mL无水DCM，加入4mL 4N HCl的1,4-二氧六环溶液。室温搅拌1h后浓缩反应液得胺中间体。将胺中间体溶于10mL无水DCM，冷却至0℃后，加入三乙胺(0.56mL,4.0mmol)以及原料SM-7(0.3g,2.0mmol)，室温搅拌半小时后，用EA稀释反应液，有机相用半饱和食盐水洗两次，干燥，过滤，减压干得粗产品，柱层析纯化得产品12(0.51g),两步收率78％。ESI-MS[(M+H+)]:m/z645.45.Compound 11 (0.64 g, 1.0 mmol) was dissolved in 4 mL dry DCM and 4 mL 4N EtOAc in EtOAc. After stirring at room temperature for 1 h, the reaction mixture was concentrated to give an amine intermediate. The amine intermediate was dissolved in 10 mL of dry DCM. After cooling to 0 ° C, triethylamine (0.56 mL, 4.0 mmol) and starting material SM-7 (0.3 g, 2.0 mmol) were added and stirred at room temperature for half an hour, diluted with EA The reaction mixture was washed twice with aq. EtOAc (EtOAc)EtOAc. ESI-MS[(M+H + )]: m/z645.45.
氩气保护下向底物12(0.51g,0.79mmol)的无水二氯甲烷(158mL)溶液中加入詹氏1B催化剂(30mg,0.04mmol)，然后将反应液加热回流过夜。待反应液冷却到室温后，减压浓缩得到粗产品，柱层析纯化得到大环产品13(0.42g,产率86％)。ESI-MS[(M+H+)]:m/z617.55.To a solution of the substrate 12 (0.51 g, 0.79 mmol), m. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a macro-product 13 (0.42 g, yield 86%). ESI-MS[(M+H + )]: m/z 617.55.
实施例50Example 50
化合物LW100228的合成 Synthesis of Compound LW100228
Figure PCTCN2017079087-appb-000083
Figure PCTCN2017079087-appb-000083
将底物13(0.42g,0.68mmol)溶于THF/MeOH(19mL/9.5mL)中,然后慢慢加入1N氢氧化锂水溶液(10mL)，室温搅拌2h后减压浓缩有机溶剂后，用1N HCl调pH至4～5。EA萃取三次，合并有机相，饱和食盐水洗，有机相用无水硫酸钠干燥后，减压蒸干得中间体羧酸(0.37g，产率90％)。ESI-MS[(M-H-)]:m/z 601.11.The substrate 13 (0.42 g, 0.68 mmol) was dissolved in THF / MeOH (19 mL / 9.5mL), and then 1N aqueous lithium hydroxide (10 mL) was added, and the mixture was stirred at room temperature for 2 hr. The pH of the HCl was adjusted to 4-5. The EA was extracted three times, and the organic layer was combined and evaporated. ESI-MS[(MH - )]: m/z 601.11.
将中间体羧酸(89mg,0.15mmol)以及SM-6a(60mg,0.26mmol)溶于无水DMF(6mL)中，然后冷却到0℃。氩气保护下，加入DIEA(0.17mL,0.95mmol)以及HATU(85mg,0.22mmol)。反应液在室温搅拌一小时，然后加入EA稀释，5％柠檬酸水溶液洗，水洗，1M碳酸氢钠水溶液洗，半饱和食盐水洗4次。有机相用无水硫酸钠干燥后，减压蒸干得粗产品,柱层析纯化得最终大环状多环产品LW100225(106mg，产率88％)。ESI-MS[(M+H+)]:m/z815.64.The intermediate carboxylic acid (89 mg, 0.15 mmol) and SM-6a (60 mg, 0.26 mmol) were dissolved in anhydrous DMF (6 mL) and then cooled to 0. DIEA (0.17 mL, 0.95 mmol) and HATU (85 mg, 0.22 mmol) were added under argon. The reaction solution was stirred at room temperature for one hour, then diluted with EA, washed with 5% aqueous citric acid, washed with water, washed with 1M sodium hydrogen carbonate aqueous solution, and washed four times with half-saturated brine. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. ESI-MS[(M+H + )]: m/z 815.64.
实施例51Example 51
化合物LW100229的合成Synthesis of Compound LW100229
按照上述制备化合物LW100228的实施例50，本实施例用与上例中相同的中间体羧酸(0.15mmol)和SM-6b(0.26mmol)反应，纯化后得到105mg最终产物LW100229。ESI-MS[(M+H+)]:m/z817.69. Example 50, which was prepared as described above for the compound LW100228, was reacted with the same intermediate carboxylic acid (0.15 mmol) and SM-6b (0.26 mmol) as in the above example to afford 105 mg of the final product LW100229. ESI-MS[(M+H + )]: m/z 817.69.

Claims (19)

  1. 式A的化合物:Compound of formula A:
    Figure PCTCN2017079087-appb-100001
    Figure PCTCN2017079087-appb-100001
    或其立体异构体、互变异构体、药学上可接受的盐或它们的混合物；Or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof or a mixture thereof;
    其中，among them,
    A-B为单键或碳碳双键；当A-B为单键时，A选自氧、硫或氮，B选自C1-6烷基；AB is a single bond or a carbon-carbon double bond; when AB is a single bond, A is selected from oxygen, sulfur or nitrogen, and B is selected from C 1-6 alkyl;
    n＝0、1或2；n=0, 1 or 2;
    Q选自任选取代的C1-6烷基、C2-6烯基、或C3-6环烷基，所述取代基选自卤素C1-6烷基，C1-C6烷氧基；Q is selected from optionally substituted C 1-6 alkyl, C 2-6 alkenyl , or C 3-6 cycloalkyl, the substituent being selected from halogen C 1-6 alkyl, C 1 -C 6 alkane Oxylate
    L独立地为一个氧、硫、C2-C20烯基、C1-C20烷基、C3-C20环烷基、C2-C20杂环基、C6-C20芳基、C3-C20杂环芳基、C1-C20烷硫基、C1-C20烷氧基、C3-C20环烷氧基、C2-C20杂环基氧基、C1-C20烷基氨基、C1-C20烷氧基一羰基、C6-C20芳基、或C6-C20芳氧基；L is independently an oxygen, sulfur, C 2 -C 20 alkenyl group, C 1 -C 20 alkyl group, C 3 -C 20 cycloalkyl group, C 2 -C 20 heterocyclic group, C 6 -C 20 aryl group , C 3 -C 20 heterocyclic aryl, C 1 -C 20 alkylthio, C 1 -C 20 alkoxy, C 3 -C 20 cycloalkoxy, C 2 -C 20 heterocyclooxy, C 1 -C 20 alkylamino, C 1 -C 20 alkoxymonocarbonyl, C 6 -C 20 aryl, or C 6 -C 20 aryloxy;
    L1各自独立地为氧、硫、C2-C20烯基、C1-C20烷基、C3-C20环烷基、C2-C20杂环基、C6-C20芳基、C3-C20杂环芳基、C1-C20烷硫基、C1-C20烷氧基、C3-C20环烷氧基、C2-C20杂环基氧基、C1-C20烷基氨基、C1-C20烷氧基羰基、C6-C20芳基、或C6-C20芳氧基；Each of L 1 is independently oxygen, sulfur, C 2 -C 20 alkenyl, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 2 -C 20 heterocyclic, C 6 -C 20 , C 3 -C 20 heterocyclic aryl, C 1 -C 20 alkylthio, C 1 -C 20 alkoxy, C 3 -C 20 cycloalkoxy, C 2 -C 20 heterocyclooxy a C 1 -C 20 alkylamino group, a C 1 -C 20 alkoxycarbonyl group, a C 6 -C 20 aryl group, or a C 6 -C 20 aryloxy group;
    X为氧、硫或氮；X is oxygen, sulfur or nitrogen;
    Y为氮或CH；Y is nitrogen or CH;
    R1为氢、C1-C20烷基、C3-C20环烷基、C6-C20芳基、C3-C20杂环芳基、C1-C20烷基磺酰氨基、C2-C20杂环磺酰氨基、或C1-C20烷氧基羰基氨基；R 1 is hydrogen, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 6 -C 20 aryl, C 3 -C 20 heteroaryl, C 1 -C 20 alkylsulfonylamino , C 2 -C 20 heterocyclic sulfonylamino, or C 1 -C 20 alkoxycarbonylamino;
    R2为氢、C1-C20烷基、C3-C20环烷基、C1-C20烷氧基-羰基、C3-C20环烷氧基-羰基、C6-C20芳基、C3-C20杂环芳基、C6-C20芳氧基、C1-C20烷基磺酰基、C3-C20环烷基磺酰基、C1-C20烷氧基磺酰基、C3-C20环烷氧基磺酰基、C6-C20芳基磺酰基、C6-C20芳氧基磺酰基、C1-C20烷氨基磺酰基、C3-C20环烷氨基磺酰基、或C6-C20芳氨基磺酰基；R 2 is hydrogen, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 20 alkoxy-carbonyl, C 3 -C 20 cycloalkoxy-carbonyl, C 6 -C 20 Aryl, C 3 -C 20 heterocyclic aryl, C 6 -C 20 aryloxy, C 1 -C 20 alkylsulfonyl, C 3 -C 20 cycloalkylsulfonyl, C 1 -C 20 alkoxy Sulfonyl, C 3 -C 20 cycloalkoxysulfonyl, C 6 -C 20 arylsulfonyl, C 6 -C 20 aryloxysulfonyl, C 1 -C 20 alkylaminosulfonyl, C 3 - C 20 cycloalkylaminosulfonyl or C 6 -C 20 arylaminosulfonyl;
    R3、R4各自独立地为氢、C1-C20烷基、C3-C20环烷基、C1-C20烷氧基、卤素、羟基、氰基、硝基、C1-C20烷基氨基、C2-C20杂环氨基、C6-C20芳基、C6-C20芳基氨基、C1-C20烷基磺酰氨基、C2-C20杂环磺酰氨基、C6-C20芳基磺酰氨基或C1-C20烷基氨基磺酰氨基；其中，R3与R4之间可以相互连接成环状结构；R 3 and R 4 are each independently hydrogen, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 20 alkoxy, halogen, hydroxy, cyano, nitro, C 1 - C 20 alkylamino, C 2 -C 20 heterocyclic amino, C 6 -C 20 aryl, C 6 -C 20 arylamino, C 1 -C 20 alkylsulfonylamino, C 2 -C 20 heterocyclic a sulfonylamino group, a C 6 -C 20 arylsulfonylamino group or a C 1 -C 20 alkylaminosulfonylamino group; wherein R 3 and R 4 may be bonded to each other to form a cyclic structure;
    R5和R6各自独立地为氢、卤素、羟基、氰基、硝基、C1-C20烷基、C3-C20环烷基、C1-C20烷氧基、C1-C20烷基氨基、C2-C20杂环氨基、C6-C20芳基、C6-C20芳基氨基、C1-C20烷基磺 酰氨基、C2-C20杂环磺酰氨基、C6-C20芳基磺酰氨基或C1-C20烷基氨基磺酰氨基；R 5 and R 6 are each independently hydrogen, halogen, hydroxy, cyano, nitro, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 20 alkoxy, C 1 - C 20 alkylamino, C 2 -C 20 heterocyclic amino, C 6 -C 20 aryl, C 6 -C 20 arylamino, C 1 -C 20 alkylsulfonylamino, C 2 -C 20 heterocyclic Sulfonylamino, C 6 -C 20 arylsulfonylamino or C 1 -C 20 alkylaminosulfonylamino;
    R7与R8、R8与R9或R9与R10之间相互连接成含氧或氮的5-6元杂环，且该杂环任选地被C1-C6烷基取代；其余R7、R8、R9和R10中未成环的基团独立地选自氢、卤素、羟基、氰基、硝基、三氟甲烷基、C1-C20烷基、C1-C20烷氧基、C1-C20烷硫基、C1-C20烷氧基-羰基、氨基羰基、C1-C20烷基氨基羰基、羰基氨基、C1-C20烷基羰基氨基、C2-C20杂环基氧基羰基、C6-C20芳基、C6-C20芳氧基、C6-C20芳氧基羰基或C2-C20杂环基，其中所述杂环基含有1-3个氮、氧或硫原子；R 7 and R 8 , R 8 and R 9 or R 9 and R 10 are bonded to each other to form a 5-6 membered heterocyclic ring containing oxygen or nitrogen, and the heterocyclic ring is optionally substituted by a C1-C6 alkyl group; The uncyclized groups in R 7 , R 8 , R 9 and R 10 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, trifluoromethyl, C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 1 -C 20 alkylthio, C 1 -C 20 alkoxy-carbonyl, aminocarbonyl, C 1 -C 20 alkylaminocarbonyl, carbonylamino, C1-C 20 alkylcarbonylamino, a C 2 -C 20 heterocyclooxycarbonyl group, a C 6 -C 20 aryl group, a C 6 -C 20 aryloxy group, a C 6 -C 20 aryloxycarbonyl group or a C 2 -C 20 heterocyclic group, wherein Said heterocyclic group contains 1-3 nitrogen, oxygen or sulfur atoms;
    J为氢、羟基、C1-C20烷基、C3-C20环烷基、C1-C20烷氧基、C3-C20环烷氧基、C1-C20烷基氨基、C3-C20环烷基氨基、C2-C20杂环氨基、C6-C20芳基、C6-C20芳氨基、C4-C20杂环芳氨基、RSO2NH-、
    Figure PCTCN2017079087-appb-100002
    -SO2NH2或-SO2NHR，其中R选自任选取代的C1-C20烷基、C1-C20烷氧基、C3-C20环烷基、C6-C20芳基、杂芳基等C3-C20环烷氧基、C6-C20芳氧基、C1-C20烷氨基、C3-C20环烷氨基、、C6-C20芳氨基、C1-C20脲基、C1-C20硫脲基、C1-C20磷酸酯、或C1-C20硼酸酯；所述R上的取代基选自C1-C6烷基、C1-C6烷氧基。    J is hydrogen, hydroxy, C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, C 1 -C 20 alkoxy, C 3 -C 20 cycloalkoxy, C 1 -C 20 alkylamino , C 3 -C 20 cycloalkylamino, C 2 -C 20 heterocyclic amino, C 6 -C 20 aryl, C 6 -C 20 arylamino, C 4 -C 20 heterocyclic arylamino, RSO 2 NH- ,
    Figure PCTCN2017079087-appb-100002
    -SO 2 NH 2 or -SO 2 NHR, wherein R is selected from optionally substituted C 1 -C 20 alkyl, C 1 -C 20 alkoxy, C 3 -C 20 cycloalkyl, C 6 -C 20 C 3 -C 20 cycloalkoxy, C 6 -C 20 aryloxy, C 1 -C 20 alkylamino, C 3 -C 20 cycloalkylamino, C 6 -C 20 aryl, such as aryl or heteroaryl An amino group, a C 1 -C 20 ureido group, a C 1 -C 20 thiourea group, a C 1 -C 20 phosphate ester, or a C 1 -C 20 boronic acid ester; the substituent on the R is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy.
    上述各基团中的杂环含有1-3个选自氮、氧和硫的杂原子。The heterocyclic ring in each of the above groups contains from 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur.
  2. 根据权利要求1所述的化合物，其特征在于:在式A中，The compound according to claim 1, wherein in Formula A,
    A-B为单键或碳碳双键；当A-B为单键时，A选自氧、硫或氮，B选自C1-6烷基，R3、R4各自独立地为C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、C1-C6烷基氨基，其中R3、R4连接形成3-7元环结构，其任选被C1-6烷基取代；当A-B为碳碳双键时，R3、R4各自独立地为氢；AB is a single bond or a carbon-carbon double bond; when AB is a single bond, A is selected from oxygen, sulfur or nitrogen, B is selected from C 1-6 alkyl, and R 3 and R 4 are each independently C 1 -C 6 An alkyl group, a C 3 -C 6 cycloalkyl group, a C 1 -C 6 alkoxy group, a C 1 -C 6 alkylamino group, wherein R 3 and R 4 are bonded to form a 3-7 membered ring structure, optionally C a 1-6 alkyl group; when AB is a carbon-carbon double bond, R 3 and R 4 are each independently hydrogen;
    R5和R6各自独立地为氢、卤素、羟基、氰基、硝基、C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、C1-C6烷基氨基、C2-C6杂环氨基、C6-C10芳基、C6-C10芳基氨基、C1-C6烷基磺酰氨基、C2-C6杂环磺酰氨基、C6-C10芳基磺酰氨基或C1-C6烷基氨基磺酰氨基，其中所述杂环含有1-3个氮、氧或硫原子；R 5 and R 6 are each independently hydrogen, halogen, hydroxy, cyano, nitro, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 - C 6 alkylamino, C 2 -C 6 heterocyclic amino, C 6 -C 10 aryl, C 6 -C 10 arylamino, C 1 -C 6 alkylsulfonylamino, C 2 -C 6 heterocyclic a sulfonylamino group, a C 6 -C 10 arylsulfonylamino group or a C 1 -C 6 alkylaminosulfonylamino group, wherein the heterocyclic ring contains 1-3 nitrogen, oxygen or sulfur atoms;
    R7、R8、R9和R10中，R7与R8、R8与R9和/或R9与R10之间相互连接成含氧或氮的5-6元杂环，且该杂环任选地被C1-C6烷基取代；其余未成环基团独立地选自氢、卤素、羟基、氰基、硝基、三氟甲烷基、C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基、C1-C6烷氧基-羰基、氨基羰基、C1-C6烷基氨基羰基、羰基氨基、C1-C6烷基羰基氨基、C2-C6杂环基氧基羰基、C6-C10芳基、C6-C10芳氧基、C6-C10芳氧基羰基或C2-C6杂环基，其中所述杂环含有1-3个氮、氧或硫原子；In R 7 , R 8 , R 9 and R 10 , R 7 and R 8 , R 8 and R 9 and/or R 9 and R 10 are bonded to each other to form a 5-6 membered heterocyclic ring containing oxygen or nitrogen, and the heterocycle being optionally substituted with C1-C6 alkyl; remaining unpaired cyclic group independently selected from hydrogen, halogen, hydroxy, cyano, nitro, trifluoromethane group, C 1 -C 6 -alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkoxy-carbonyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, carbonylamino, C 1 -C 6 alkyl Carbonylamino, C 2 -C 6 heterocyclyloxycarbonyl, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 6 -C 10 aryloxycarbonyl or C 2 -C 6 heterocyclic Wherein said heterocyclic ring contains 1-3 nitrogen, oxygen or sulfur atoms;
    J为氢、羟基、C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、C3-C6环烷氧基、C1-C6烷基氨基、C3-C6环烷基氨基、C2-C6杂环氨基、C6-C10芳基、C6-C10芳氨基、C4-C10杂环芳氨基、RSO2NH-、
    Figure PCTCN2017079087-appb-100003
    -SO2NH2或-SO2NHR，其中R选自任选取代的C1-C10烷基、C3-C6环烷基、C6-C10芳基、C1-C6烷氧基、C3-C6环烷氧基、C6-C10芳氧基、C1-C6烷氨基、C3-C6环烷氨基、C6-C10芳氨基、C1-C6脲基、C1-C6硫脲基、C1-C6磷酸酯基、或C1-C6硼酸酯基；    J is hydrogen, hydroxy, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, C 1 -C 6 alkylamino , C 3 -C 6 cycloalkylamino, C 2 -C 6 heterocyclic amino, C 6 -C 10 aryl, C 6 -C 10 arylamino, C 4 -C 10 heterocyclic arylamino, RSO 2 NH- ,
    Figure PCTCN2017079087-appb-100003
    -SO 2 NH 2 or -SO 2 NHR, wherein R is selected from optionally substituted C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkane Oxy, C 3 -C 6 cycloalkoxy, C 6 -C 10 aryloxy, C 1 -C 6 alkylamino, C 3 -C 6 cycloalkylamino, C 6 -C 10 arylamino, C 1 - a C 6 ureido group, a C 1 -C 6 thiourea group, a C 1 -C 6 phosphate group, or a C 1 -C 6 borate group;
    L为单键、氧、硫、C2-C6烯基、C1-C6烷基、C3-C6环烷基、C2-C6杂环基、C6-C10芳 基、C3-C6杂环芳基、C1-C6烷硫基、C1-C6烷氧基、C3-C6环烷氧基、C2-C6杂环基氧基、C1-C6烷基氨基、C1-C6烷氧基羰基、C6-C10芳基、或C6-C10芳氧基；L is a single bond, oxygen, sulfur, C 2 -C 6 alkenyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocyclic, C 6 -C 10 aryl a C 3 -C 6 heterocyclic aryl group, a C 1 -C 6 alkylthio group, a C 1 -C 6 alkoxy group, a C 3 -C 6 cycloalkoxy group, a C 2 -C 6 heterocycloalkyloxy group, C 1 -C 6 alkylamino, C 1 -C 6 alkoxycarbonyl, C 6 -C 10 aryl, or C 6 -C 10 aryloxy;
    L1选自氧、硫、C2-C6烯基、C1-C6烷基、C3-C6环烷基、C2-C6杂环基、C6-C10芳基、C3-C6杂环C6-C10芳基、C1-C6烷硫基、C1-C6烷氧基、C3-C6环烷氧基、C2-C6杂环基氧基、C1-C6烷基氨基、C1-C6烷氧基羰基、C6-C10芳基、或C6-C10芳氧基；L 1 is selected from the group consisting of oxygen, sulfur, C 2 -C 6 alkenyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocyclic, C 6 -C 10 aryl, C 3 -C 6 heterocyclic C 6 -C 10 aryl, C 1 -C 6 alkylthio, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, C 2 -C 6 heterocyclic Alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 alkoxycarbonyl, C 6 -C 10 aryl, or C 6 -C 10 aryloxy;
    X为氧、硫或氮；X is oxygen, sulfur or nitrogen;
    Y为氮或CH；Y is nitrogen or CH;
    R1为氢、C1-C6烷基、C3-C6环烷基、C6-C10芳基、C3-C6杂环芳基、C1-C6烷基磺酰氨基、C2-C6杂环磺酰氨基、或C1-C6烷氧基羰基氨基；R 1 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, C 3 -C 6 heteroaryl, C 1 -C 6 alkylsulfonylamino , a C 2 -C 6 heterocyclic sulfonylamino group, or a C 1 -C 6 alkoxycarbonylamino group;
    R2为氢、C1-C6烷基、C3-C6环烷基、C1-C6烷氧基-羰基、C3-C6环烷氧基-羰基、C6-C10芳基、C3-C60杂环C6-C10芳基、C6-C10芳氧基、C1-C6烷基磺酰基、C3-C6环烷基磺酰基、C1-C6烷氧基磺酰基、C3-C6环烷氧基磺酰基、C6-C10芳基磺酰基、C6-C10芳氧基磺酰基、C1-C6烷氨基磺酰基、C3-C6环烷氨基磺酰基、或C6-C10芳氨基磺酰基。R 2 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy-carbonyl, C 3 -C 6 cycloalkoxy-carbonyl, C 6 -C 10 Aryl, C 3 -C 60 heterocyclic C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 1 -C 6 alkylsulfonyl, C 3 -C 6 cycloalkylsulfonyl, C 1 -C 6 alkoxysulfonyl, C 3 -C 6 cycloalkoxysulfonyl, C 6 -C 10 arylsulfonyl, C 6 -C 10 aryloxysulfonyl, C 1 -C 6 alkylaminosulfonate An acyl group, a C 3 -C 6 cycloalkylaminosulfonyl group, or a C 6 -C 10 arylaminosulfonyl group.
  3. 根据权利要求1或2所述的化合物，其特征在于:在式A中，The compound according to claim 1 or 2, wherein in Formula A,
    L为单键；L is a single bond;
    L1选自氧或硫；L 1 is selected from oxygen or sulfur;
    X选自氧、硫或氮；X is selected from the group consisting of oxygen, sulfur or nitrogen;
    Y选自氮或CH；R1选自叔丁基；Y is selected from nitrogen or CH; R 1 is selected from t-butyl;
    R2选自氢；R 2 is selected from hydrogen;
    当A-B为单键时，A选自氧、硫或氮，B选自亚甲基，R3和R4独立地为甲基；当A-B为双键时，R3和R4独立地为氢；When AB is a single bond, A is selected from oxygen, sulfur or nitrogen, B is selected from methylene, R 3 and R 4 are independently methyl; when AB is a double bond, R 3 and R 4 are independently hydrogen. ;
    R5和R6独立地为氢；R 5 and R 6 are independently hydrogen;
    R7、R8、R9和R10中，R7与R8、R8与R9或R9与R10之间相互连接成含氧或氮的5-6元杂环，且该杂环任选地被C1-C6烷基取代；其余未成环基团选自氢；In R 7 , R 8 , R 9 and R 10 , R 7 and R 8 , R 8 and R 9 or R 9 and R 10 are bonded to each other to form a 5-6 membered heterocyclic ring containing oxygen or nitrogen, and the hetero The ring is optionally substituted with a C 1 -C 6 alkyl group; the remaining uncyclic group is selected from hydrogen;
    Q选自任选取代的C1-6烷基、C2-6烯基、或C3-6环烷基，所述取代基选自卤素；Q is selected from optionally substituted C 1-6 alkyl, C 2-6 alkenyl , or C 3-6 cycloalkyl, said substituent being selected from halogen;
    J选自RSO2NH-、
    Figure PCTCN2017079087-appb-100004
    -SO2NH2或-SO2NHR，其中R选自任选被C1-C6烷基取代的C3-C6环烷基；    J is selected from RSO 2 NH-,
    Figure PCTCN2017079087-appb-100004
    -SO 2 NH 2 or -SO 2 NHR, wherein R is selected from optionally substituted C 1 -C 6 alkyl C 3 -C 6 cycloalkyl;
    n＝0、1或2。n=0, 1 or 2.
  4. 根据权利要求3所述的化合物，其特征在于，在式A中，The compound according to claim 3, wherein in Formula A,
    L为单键；L is a single bond;
    L1选自氧；L 1 is selected from oxygen;
    X选自氧；X is selected from oxygen;
    其余定义同权利要求3。The remaining definitions are the same as claim 3.
  5. 根据权利要求1至4中任一项所述的化合物，其特征在于，在式A中，Q选自任选取代的甲基、乙基、乙烯基或环丙基，所述取代基选自卤素。The compound according to any one of claims 1 to 4, wherein, in the formula A, Q is selected from the group consisting of an optionally substituted methyl group, an ethyl group, a vinyl group or a cyclopropyl group, and the substituent is selected from the group consisting of halogen.
  6. 根据权利要求1至5中任一项所述的化合物，其特征在于，在式A中，J选自 RSO2NH-或-SO2NHR，其中R选自任选被甲基或乙基取代的C3-C6环烷基。The compound according to any one of claims 1 to 5, wherein, in the formula A, J is selected from the group consisting of RSO 2 NH- or -SO 2 NHR, wherein R is selected from the group consisting of optionally substituted by methyl or ethyl C 3 -C 6 cycloalkyl.
  7. 一种制备权利要求1-6任意一项的式A中化合物I的方法，包括以下五个步骤:A method of preparing Compound I of Formula A of any of claims 1-6, comprising the following five steps:
    Figure PCTCN2017079087-appb-100005
    Figure PCTCN2017079087-appb-100005
    1)在惰性气体保护下，原料SM-3在无水有机溶剂中,在三苯基磷和偶氮二羧酸酯的作用下与另一试剂V发生Mitsunobu反应，生成化合物3-1；化合物V如下所示：1) Under the protection of an inert gas, the raw material SM-3 undergoes Mitsunobu reaction with another reagent V under the action of triphenylphosphine and azodicarboxylate in an anhydrous organic solvent to form compound 3-1; V is as follows:
    Figure PCTCN2017079087-appb-100006
    Figure PCTCN2017079087-appb-100006
    R11为C1-C6烷基羰基、C1-C6烷氧基羰基或C1-C6氨基羰基；SM-3和化合物V及产物3-1中其它各基团的定义同权利要求1-6之一所述；R 11 is C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl or C 1 -C 6 aminocarbonyl; the definitions of SM-3 and other compounds in compound V and product 3-1 are the same One of the requirements 1-6;
    2)在惰性气体保护下，将步骤1)中得到的化合物3-1脱去保护基R11后再在偶合试剂的作用下与另一氨基酸衍生物试剂SM-4反应生成化合物3-2；3-2中各基团和参数的定义同权利要求1-6之一所述；2) Under the protection of an inert gas, the compound 3-1 obtained in the step 1) is removed from the protecting group R 11 and then reacted with another amino acid derivative reagent SM-4 under the action of a coupling reagent to form a compound 3-2; The definition of each group and parameter in 3-2 is as described in one of claims 1-6;
    3)在惰性气体保护下，将步骤2)得到的化合物3-2脱去保护基R11后再在光气或三光气的作用下，与另一试剂SM-5反应形成化合物3-3；试剂SM-5及产物中各基团和参数的定义同权利要求1-6之一所述；3) Under the protection of an inert gas, the compound 3-2 obtained in step 2) is deprotected from the protective group R 11 and then reacted with another reagent SM-5 under the action of phosgene or triphosgene to form compound 3-3; The definition of each group and parameter in the reagent SM-5 and the product is as described in one of claims 1-6;
    4)在惰性气体保护下，将步骤3)得到的化合物3-3在钯催化剂的作用下，反应得到大 环状产物3-4；产物中各基团和参数的定义同权利要求1-6之一所述；4) Under the protection of an inert gas, the compound 3-3 obtained in the step 3) is reacted under the action of a palladium catalyst to obtain a large reaction. a cyclic product 3-4; the definition of each group and parameter in the product is as described in one of claims 1-6;
    5)在惰性气体保护下，将步骤4)得到的化合物3-4经水解酸化后再与SM-6在偶合试剂(如：HATU)的作用下反应生成最终大环状化合物I；SM-6及产物中各基团和参数的定义同权利要求1-6之一所述；5) Under the protection of an inert gas, the compound 3-4 obtained in the step 4) is subjected to hydrolysis and acidification, and then reacted with SM-6 under the action of a coupling reagent (for example, HATU) to form a final macrocyclic compound I; SM-6. And the definition of each group and parameter in the product is as described in one of claims 1-6;
    在步骤1)中，在惰性气体保护下，将SM-3原料溶于有机溶剂中，在三苯基磷和偶氮二羧酸酯的作用下与另一试剂V发生Mitsunobu反应，生成化合物3-1；所述反应温度为0-40℃，所述的三苯基磷用量为原料SM-3摩尔量的1-2倍，所述的偶氮二羧酸酯用量为原料SM-3摩尔量的1-2倍；In step 1), under the protection of an inert gas, the SM-3 raw material is dissolved in an organic solvent, and a Mitsunobu reaction occurs with another reagent V under the action of triphenylphosphine and azodicarboxylate to form a compound 3 The reaction temperature is 0-40 ° C, the amount of the triphenylphosphine is 1-2 times the molar amount of the raw material SM-3, and the amount of the azodicarboxylate is the raw material SM-3 mole. 1-2 times the amount;
    在步骤2)中，在惰性气体保护下将步骤1)得到的化合物3-1在强酸的作用下，在温度为10-50℃下反应脱去保护基R11后生成胺中间体，再在偶合试剂的作用下，在温度0-80℃下在有机溶剂中与试剂SM-4反应得到化合物3-2；所述的偶合试剂的用量为化合物3-1摩尔量的1-2.5倍。In step 2), the compound 3-1 obtained in the step 1) is reacted under the action of a strong acid under the action of a strong acid to remove the protecting group R 11 at a temperature of 10 to 50 ° C to form an amine intermediate, and then The compound 3-2 is obtained by reacting with the reagent SM-4 in an organic solvent at a temperature of 0 to 80 ° C under the action of a coupling reagent; the coupling reagent is used in an amount of 1-2.5 times the molar amount of the compound 3-1.
    在步骤3)中，在惰性气体保护下将步骤2)得到的化合物3-2在强酸的作用下，在温度为10-50℃下反应脱去保护基R11后生成胺中间体，再在光气或三光气的作用下生成异氰酸酯中间体，继而在温度0-40℃下在有机溶剂中与另一试剂SM-5反应形成化合物3-3；所述的三光气的用量为化合物3-2摩尔量的1-2倍。In step 3), the compound 3-2 obtained in the step 2) is subjected to an action of a strong acid under the action of a strong acid to remove the protective group R 11 at a temperature of 10 to 50 ° C to form an amine intermediate, and then The isocyanate intermediate is formed by the action of phosgene or triphosgene, and then reacted with another reagent SM-5 in an organic solvent at a temperature of 0-40 ° C to form a compound 3-3; the amount of the triphosgene is the compound 3- 1-2 times the amount of 2 moles.
    在步骤4)中，在惰性气体保护下，将步骤3)得到的化合物3-3溶于无水有机溶剂中，在钯催化剂、磷配体及无机强碱的作用下，在温度0-100℃下反应，得到大环状产物3-4；钯催化剂的用量为原料SM-1摩尔量的0.2-5％；磷配体的用量为原料SM-1摩尔量的0.3-10％；无机碱的用量为原料SM-1摩尔量的1-3倍；In step 4), the compound 3-3 obtained in the step 3) is dissolved in an anhydrous organic solvent under the protection of an inert gas, under the action of a palladium catalyst, a phosphorus ligand and an inorganic strong base at a temperature of 0-100. The reaction is carried out at ° C to obtain a large cyclic product 3-4; the amount of the palladium catalyst is 0.2-5% by mole of the raw material SM-1; the amount of the phosphorus ligand is 0.3-10% by mole of the raw material SM-1; inorganic base The amount used is 1-3 times the molar amount of the raw material SM-1;
    在步骤5)中，将步骤4)得到的化合物3-4在无机强碱的作用下，在溶剂中，于10-60℃进行水解脱去保护基甲氧基后酸化生成羧酸，再在偶合试剂的作用下，在有机溶剂中，与SM-6通过酰胺化反应得到大环状多环产物I；所述的偶合试剂的用量为化合物3-4摩尔量的1-2.5倍；酰胺化反应的温度为0-80℃。In the step 5), the compound 3-4 obtained in the step 4) is subjected to hydrolysis under a strong inorganic base in a solvent at 10 to 60 ° C to remove the protective methoxy group, and then acidified to form a carboxylic acid, and then The macrocyclic polycyclic product I is obtained by amidation reaction with SM-6 in an organic solvent under the action of a coupling reagent; the coupling reagent is used in an amount of 1-2.5 times the molar amount of the compound 3-4; amidation The temperature of the reaction is 0-80 °C.
  8. 一种制备权利要求1-6任意一项的式A中化合物II的方法，包括以下六个步骤: A process for the preparation of compound II of formula A according to any of claims 1-6, comprising the following six steps:
    Figure PCTCN2017079087-appb-100007
    Figure PCTCN2017079087-appb-100007
    1)在惰性气体保护下，原料SM-3在无水有机溶剂中,在三苯基磷和偶氮二羧酸酯的作用下与另一试剂V发生Mitsunobu反应，生成化合物3-1；化合物V结构如上所述；R10为C1-C6烷基羰基、C1-C6烷氧基羰基或C1-C6氨基羰基；SM-3和化合物V及产物3-1中其它各基团的定义同权利要求1-6之一所述；1) Under the protection of an inert gas, the raw material SM-3 undergoes Mitsunobu reaction with another reagent V under the action of triphenylphosphine and azodicarboxylate in an anhydrous organic solvent to form compound 3-1; The V structure is as described above; R 10 is a C 1 -C 6 alkylcarbonyl group, a C 1 -C 6 alkoxycarbonyl group or a C 1 -C 6 aminocarbonyl group; SM-3 and the other compounds of the compound V and the product 3-1 The definition of a group is as described in one of claims 1-6;
    2)在惰性气体保护下，将步骤1)中得到的化合物3-1与乙烯三氟硼酸钾在钯催化剂的作用下，通过Suzuki反应得到化合物4-1；产物中各基团和参数的定义同权利要求1-6之一所述；2) Under the protection of an inert gas, the compound 3-1 obtained in the step 1) and the potassium trifluoroborate are subjected to a Suzuki reaction under the action of a palladium catalyst to obtain a compound 4-1; definition of each group and parameter in the product As described in one of claims 1-6;
    3)在惰性气体保护下，将步骤2)中得到的化合物4-1脱去保护基R11后再在偶合试剂的作用下与另一氨基酸衍生物试剂SM-4反应生成化合物4-2；产物中各基团和参数的定义同权利要求1-6之一所述；3) Under the protection of an inert gas, the compound 4-1 obtained in the step 2) is removed from the protecting group R 11 and then reacted with another amino acid derivative reagent SM-4 under the action of a coupling reagent to form a compound 4-2; The definition of each group and parameter in the product is as described in one of claims 1-6;
    4)在惰性气体保护下，将步骤3)得到的化合物4-2脱去保护基R11后再与另一试剂SM-7反应形成化合物4-3；试剂SM-7及产物中各基团和参数的定义同权利要求1-6之一所述；4) Under the protection of an inert gas, the compound 4-2 obtained in the step 3) is deprotected from the protecting group R 11 and then reacted with another reagent SM-7 to form a compound 4-3; the reagent SM-7 and each group in the product And the definition of the parameters are as described in one of claims 1-6;
    5)在惰性气体保护下，将步骤4)得到的双烯化合物4-3在钌催化剂的作用下，通过烯烃复分解环化反应得到大环状产物4-4；产物中各基团和参数的定义同权利要求1-6之一所述；5) under the protection of an inert gas, the diene compound 4-3 obtained in the step 4) is subjected to an olefin metathesis cyclization reaction under the action of a ruthenium catalyst to obtain a macrocyclic product 4-4; each group and parameter in the product The definition is as described in one of claims 1-6;
    6)在惰性气体保护下，将步骤5)得到的化合物4-4经水解酸化后再与SM-6在偶合试剂(如：HATU)的作用下反应生成最终大环状化合物II；SM-6及产物中各基团和参数的定义同权利要求1-6之一所述； 6) Under the protection of an inert gas, the compound 4-4 obtained in the step 5) is subjected to hydrolysis and acidification, and then reacted with SM-6 under the action of a coupling reagent (for example, HATU) to form a final macrocyclic compound II; SM-6. And the definition of each group and parameter in the product is as described in one of claims 1-6;
    在步骤1)中，在惰性气体保护下，将SM-3原料溶于有机溶剂中，在三苯基磷和偶氮二羧酸酯的作用下与另一试剂V发生Mitsunobu反应，生成化合物3-1；所述反应温度为0-40℃，所述的三苯基磷用量为原料SM-3摩尔量的1-2倍，所述的偶氮二羧酸酯用量为原料SM-3摩尔量的1-2倍；In step 1), under the protection of an inert gas, the SM-3 raw material is dissolved in an organic solvent, and a Mitsunobu reaction occurs with another reagent V under the action of triphenylphosphine and azodicarboxylate to form a compound 3 The reaction temperature is 0-40 ° C, the amount of the triphenylphosphine is 1-2 times the molar amount of the raw material SM-3, and the amount of the azodicarboxylate is the raw material SM-3 mole. 1-2 times the amount;
    在步骤2)中，在惰性气体保护下，将步骤1)中得到的化合物3-1溶于有机溶剂中，与乙烯三氟硼酸钾在钯催化剂及碱的作用下，在温度20-100℃下通过Suzuki反应得到化合物4-1；所述的乙烯三氟硼酸钾用量为原料SM-3摩尔量的1-4倍；所述的钯催化剂用量为原料SM-3摩尔量的0.03-5％倍；所述的碱用量为原料SM-3摩尔量的1-4倍。In step 2), the compound 3-1 obtained in the step 1) is dissolved in an organic solvent under the protection of an inert gas, and the potassium trifluoroborate under the action of a palladium catalyst and a base at a temperature of 20-100 ° C. The compound 4-1 is obtained by a Suzuki reaction; the amount of the potassium trifluoroborate is 1-4 times the molar amount of the raw material SM-3; and the amount of the palladium catalyst is 0.03-5% of the molar amount of the raw material SM-3. The base is used in an amount of from 1 to 4 times the molar amount of the raw material SM-3.
    在步骤3)中，在惰性气体保护下将步骤2)得到的化合物4-1在强酸的作用下，在温度为10-50℃下反应脱去保护基R11后生成胺中间体，再在偶合试剂的作用下，在温度0-80℃下在有机溶剂中与试剂SM-4反应得到化合物4-2；所述的偶合试剂的用量为化合物3-1摩尔量的1-2.5倍。In step 3), the compound 4-1 obtained in the step 2) is subjected to an inert gas under the action of a strong acid to remove the protecting group R 11 at a temperature of 10 to 50 ° C to form an amine intermediate, and then The compound 4-2 is obtained by reacting with the reagent SM-4 in an organic solvent at a temperature of 0-80 ° C under the action of a coupling reagent; the coupling reagent is used in an amount of 1-2.5 times the molar amount of the compound 3-1.
    在步骤4)中，在惰性气体保护下将步骤3)得到的化合物4-2在强酸的作用下，在温度为10-50℃下反应脱去保护基R11后生成胺中间体，再在碱的作用下，在10-30℃与另一试剂SM-7反应形成化合物4-3；所述的碱的用量为化合物4-2摩尔量的1-5倍。In step 4), the compound 4-2 obtained in the step 3) is subjected to an action of a strong acid under the action of a strong acid to remove the protective group R 11 at a temperature of 10 to 50 ° C to form an amine intermediate, and then The compound 4-3 is formed by reacting with another reagent SM-7 at 10-30 ° C under the action of a base; the base is used in an amount of from 1 to 5 times the molar amount of the compound 4-2.
    在步骤5)中，在惰性气体保护下将步骤4)得到的双烯化合物4-3溶于无水有机溶剂中，在钌催化剂的作用下，在温度0-100℃下反应，通过烯烃复分解环化反应，得到大环状产物4-4；所述的钌催化剂用量为双烯化合物4-3摩尔量的0.2-10％；所述的有机溶剂用量为双烯化合物4-3重量比的15-40倍；In the step 5), the diene compound 4-3 obtained in the step 4) is dissolved in an anhydrous organic solvent under the protection of an inert gas, and reacted at a temperature of 0-100 ° C under the action of a ruthenium catalyst to pass the olefin metathesis. The cyclization reaction gives a large cyclic product 4-4; the amount of the ruthenium catalyst is 0.2-10% by weight of the diene compound 4-3; the amount of the organic solvent is the weight ratio of the diene compound 4-3 15-40 times;
    在步骤6)中，将步骤5)得到的化合物4-4在无机强碱的作用下，在溶剂中，于10-60℃进行水解脱去保护基甲氧基后酸化生成羧酸，再在偶合试剂的作用下，在有机溶剂中，与SM-6通过酰胺化反应得到大环状多环产物II；所述的偶合试剂的用量为化合物4-4摩尔量的1-2.5倍；酰胺化反应的温度为0-80℃；In the step 6), the compound 4-4 obtained in the step 5) is subjected to hydrolysis under a strong inorganic base in a solvent at 10 to 60 ° C to remove the protective methoxy group, and then acidified to form a carboxylic acid, and then The macrocyclic polycyclic product II is obtained by amidation reaction with SM-6 in an organic solvent under the action of a coupling reagent; the coupling reagent is used in an amount of 1-2.5 times the molar amount of the compound 4-4; amidation The reaction temperature is 0-80 ° C;
  9. 权利要求1-6中任意一项所述化合物、其立体异构体、互变异构体、药学上可接受的盐在制备抑制HCV的药物中的应用。Use of a compound according to any one of claims 1 to 6, a stereoisomer, a tautomer thereof, a pharmaceutically acceptable salt thereof for the preparation of a medicament for inhibiting HCV.
  10. 一种药物组合物，其包含一种或多种权利要求1-6中任一项所述的化合物、其立体异构体、互变异构体、或其药学上可接受的盐，和药学上可接受的载体。A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 6, stereoisomers, tautomers thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable An acceptable carrier.
  11. 一种药物组合物，其包括一种或多种权利要求1-6中任意一项所述的化合物、其立体异构体、互变异构体、或其药学上可接受的盐以及至少一种的以下药物：(1)免疫调节剂；(2)丙型肝炎病毒蛋白酶抑制剂；(3)丙型肝炎病毒聚合酶抑制剂；(4)不属于(2)-(3)之核苷和核苷衍生物；(5)乙型肝炎病毒(HBV)抑制剂；(6)人类免疫缺损病毒(HIV)抑制剂；(7)癌症药物；(8)抗炎药物；或(9)不属于上述(1)-(8)之其他化合物。A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 6, stereoisomers, tautomers thereof, or pharmaceutically acceptable salts thereof, and at least one The following drugs: (1) immunomodulators; (2) hepatitis C virus protease inhibitors; (3) hepatitis C virus polymerase inhibitors; (4) nucleosides not belonging to (2)-(3) And nucleoside derivatives; (5) hepatitis B virus (HBV) inhibitors; (6) human immunodeficiency virus (HIV) inhibitors; (7) cancer drugs; (8) anti-inflammatory drugs; or (9) no Other compounds belonging to the above (1) to (8).
  12. 如权利要求11所述的组合物，其中所述的免疫调节剂选自干扰素或干扰素衍生物。The composition of claim 11 wherein said immunomodulatory agent is selected from the group consisting of an interferon or an interferon derivative.
  13. 如权利要求12所述的组合物，其中所述的干扰素是聚乙二醇干扰素。The composition of claim 12 wherein said interferon is peginterferon.
  14. 如权利要求11所述的组合物，其中所述的HIV抑制剂是利托那韦。The composition of claim 11 wherein said HIV inhibitor is ritonavir.
  15. 如权利要求11所述的组合物，其中所述的乙型肝炎病毒(HBV)抑制剂是拉米夫定、替比夫定、阿德福韦、恩曲他滨、恩替卡韦、替诺福韦或克来夫定。The composition according to claim 11, wherein said hepatitis B virus (HBV) inhibitor is lamivudine, telbivudine, adefovir, emtricitabine, entecavir, tenofovir Or Clyde.
  16. 一种权利要求11-15任一项所述的组合物在制备用于抑制HCV的药物或在制备治疗丙型肝炎病毒感染性疾病或病症的药物中的应用。 Use of a composition according to any one of claims 11 to 15 for the manufacture of a medicament for the inhibition of HCV or for the manufacture of a medicament for the treatment of a hepatitis C virus infectious disease or condition.
  17. 一种抑制HCV的方法，其包括将有效量的权利要求1-6中任意一项所述的化合物、其立体异构体、互变异构体、药学上可接受的盐施用于有此需求的个体。A method of inhibiting HCV, which comprises administering an effective amount of a compound according to any one of claims 1 to 6, a stereoisomer, a tautomer thereof, a pharmaceutically acceptable salt thereof, to a need thereof. Individual.
  18. 如权利要求17所述的方法，其中所述个体为哺乳动物，例如为人。The method of claim 17 wherein said individual is a mammal, such as a human.
  19. 权利要求1-6中任意一项所述化合物、其立体异构体、互变异构体、药学上可接受的盐，其用于抑制HCV或治疗丙型肝炎病毒感染性疾病或病症。 A compound, stereoisomer, tautomer, pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 for use in inhibiting HCV or treating a hepatitis C virus infectious disease or condition.
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