CN103880823A - Spiro compound serving as hepatitis c inhibitor and application thereof in medicine - Google Patents

Spiro compound serving as hepatitis c inhibitor and application thereof in medicine Download PDF

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CN103880823A
CN103880823A CN201310711751.XA CN201310711751A CN103880823A CN 103880823 A CN103880823 A CN 103880823A CN 201310711751 A CN201310711751 A CN 201310711751A CN 103880823 A CN103880823 A CN 103880823A
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independently
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aryl
heterocyclic radical
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CN103880823B (en
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张英俊
张健存
谢洪明
任青云
胡柏林
巫锡伟
付长萍
李石凤
王朝禾
李静
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YICHANG HEC CHANGJIANG PHARMACEUTICAL Co.,Ltd.
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems
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    • 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
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
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Abstract

The invention provides a spiro compound serving as a hepatitis c inhibitor and application thereof in a medicine. The compound is a compound as shown in a formula (I) or a stereisomer, a geometric isomer, a tautomer, nitric oxide, an aquo-complex, a solvate, a metabolite, pharmaceutically acceptable salt or prodrug of the compound as shown in the formula (I). The invention also provides a pharmaceutical composition containing the compound, application of the compound and the pharmaceutical composition in inhibition of HCV (Hepatitis C Virus) copy and HCV virus protein, as well as the application of the compound and the pharmaceutical composition in prevention, handling, treatment or relieving of HCV infection or hepatitis c disease for a patient. The formula I is as shown in the specification.

Description

As the spirocyclic compound of hepatitis c inhibitor and the application in medicine thereof
Invention field
The invention belongs to pharmaceutical field and relate to the compound that is used for the treatment of hepatitis C virus (HCV) and infects, composition and use thereof and the using method of described compound.Especially, compound of the present invention is the spirocyclic compound that can be used as NS5A inhibitor.More specifically, the present invention relates to the pharmaceutical composition of the compound of the NS5A protein function that can suppress to be encoded by hepatitis C virus, described compound and for suppressing the method for NS5A protein function.
Background of invention
HCV is main human pathogen, estimates whole world infection approximately 1.7 hundred million people, is 5 times of human immunodeficiency virus type 1's number of the infected.And the central major part of these HCV infected individuals can develop into the serious hepatopathy that carries out, comprise liver cirrhosis and hepatocellular carcinoma.Therefore, chronic HCV infection will be that global patient is because of hepatopathy main causes of death too early.
At present, the most effective HCV therapy is the drug combination that adopts alpha-interferon and ribavirin, in 40% patient, produces continues the effect.Up-to-date clinical effectiveness shows, during as monotherapy, Pegylation alpha-interferon is better than the alpha-interferon of unmodified.But even use the experimental treatment scheme that comprises Pegylation alpha-interferon and ribavirin combination, most of patient also cannot continue to reduce viral load, and much patient tends to follow some side reactions, and can not treat for a long time.Therefore the method that, new effective treatment HCV infects is urgent required at present.
HCV is positive chain RNA virus.According to the comparison to the aminoacid sequence of deriving and the extensive similarity of 5 ' non-translational region, HCV is classified in an independent genus of flaviviridae (Flaviviridae family).All members of flaviviridae are containing the genomic envelope virus particle of positive chain RNA, and this genome is by the translation of single uninterrupted open reading frame (ORF), all known virus-specific albumen of encoding.
In the genomic Nucleotide of whole HCV and coded aminoacid sequence, there is considerable heterogeneity.Identify at least 7 main genotype, and disclosed more than 50 hypotype.Being subject in HCV cells infected, viral RNA is translated into polyprotein, and is split into 10 kinds body proteins.Be structural protein at N-terminal, E1 and E2 are following closely.In addition, also have 6 kinds of Nonstructural Proteins, i.e. NS2, NS3, NS4A, NS4B, NS5A and NS5B, its in HCV life cycle, playing the part of very important role (referring to, for example, Lindenbach, B.D. and C.M.Rice, Nature.436,933-938,2005).
The oligogene type of HCV is in global distribution difference, although carry out the research of lots of genes type to pathogenesis and therapeutic action, but still do not know the clinical importance of HCV genetic heterogeneity.
Strand HCV rna gene group length is about 9500 Nucleotide, has single open reading frame, single approximately 3000 the amino acid whose large-scale polyproteins of encoding.In cells infected, this polyprotein is cut by leukoprotease and virus protease on multiple sites, produces structure and non-structure (NS) albumen.With regard to HCV, the formation of ripe Nonstructural Protein (NS2, NS3, NS4A, NS4B, NS5A and NS5B) realizes by two-strain proteolytic enzyme.It is generally acknowledged that the first is metalloprotease, cuts at NS2-NS3 contact; The second is included in the serine protease of NS3 (being also called NS3 proteolytic enzyme herein) N end regions, it mediates all follow-up cuttings in NS3 downstream, being cis at NS3-NS4A cleavage site, is trans in all the other NS4A-NS4B, NS4B-NS5A, NS5A-NA5B site.NS4A albumen has seemed several functions, plays NS3 proteolytic enzyme cofactor, and may assist NS3 and other rdrp virus components to carry out film location.The formation of NS3 albumen and NS4A mixture seemingly processes event, it is necessary on all sites, to improve proteolysis efficiency.NS3 albumen also demonstrates ribonucleoside triphosphote enzyme and DBPA activity.NS5B (also claiming HCV polysaccharase herein) participates in the RNA polymerase that depends on RNA that HCV copies.
The compounds of this invention is to be used for the treatment of patient HCV to infect, and this compound selective ground suppresses copying of HCV virus.Specifically, the compounds of this invention is the compound that effectively suppresses NS5A protein function.HCV NS5A albumen is referring to for example Tan, S.-L., Katzel, M.G., Virology2001,284,1-12; And Park, K.-J.; Choi, S.-H, J.Biological Chemistry, 2003.
Abstract of invention
The present invention relates to the method that new spirocyclic compound and anti-HCV infect.The compounds of this invention or pharmaceutical composition infect HCV, particularly HCV NS5A albumen are had to good restraining effect.
On the one hand, the present invention relates to a kind of compound, it is steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or the prodrug of compound shown in the compound shown in formula (I) or formula (I)
Figure BDA0000442505360000021
Wherein, each A and A ' are a key, alkylidene group, alkenylene, cycloalkylidene, sub-Heterocyclylalkyl ,-(CR independently 8r 8a) n-O-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-C (=O)-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-O-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-S (=O) r-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-O-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=S)-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-C (=O)-O-(CR 8r 8a) p-, or each A and A ' are following group independently:
Figure BDA0000442505360000022
Wherein, each X 1or X 2be O, S, NR independently 6or CR 7r 7a;
X 4for (CR 7r 7a) n,-Y 1=N-, O, S or NR 6;
W is carbocylic radical or heterocyclic radical;
Each Y 1and Y 2be N or CR independently 7;
Z is-(CH 2) a-,-CH=CH-,-N=CH-,-(CH 2) a-N (R 5)-(CH 2) b-or-(CH 2) a-O-(CH 2) b-;
Wherein each a and b are 0,1,2 or 3 independently;
Each c is 1 or 2 independently;
Each d is 1 or 2 independently;
Each n is 0,1,2 or 3 independently;
Each p is 0,1,2 or 3 independently;
Each r is 0,1 or 2 independently;
F is 0,1,2,3 or 4;
Each Q 1and Q 2be NR independently 6, O, S, C (=O) or (CR 7r 7a) e;
Each e is 0,1,2,3 or 4 independently;
Each X and X ' are N or CR independently 7;
Each Y and Y ' are the optically active isomer of H, deuterium, alkyl, assorted alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, a-amino acid group or a-amino acid group independently, or each Y and Y ' are following structural unit independently :-[U-(CR 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12,-U-(CR 9r 9a) t-R 12or-[U-(CR 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-O-(CR 9r 9a) t-R 12;
Each U is independently-C (=O)-,-C (=S)-,-S (=O)-or-S (=O) 2-;
Each t is 0,1,2,3 or 4 independently;
Each k is 0,1 or 2 independently;
Each R 1, R 2, R 3and R 4be H, deuterium, alkyl, assorted alkyl, aralkyl, cycloalkyl, heterocyclic radical, heteroaryl or aryl independently, or R 1, R 2form 3-8 unit heterocycle or 3-8 unit carbocyclic ring, C with X-CH 5-12condensed-bicyclic, C 5-12condense assorted dicyclo, C 5-12spiral shell dicyclo or C 5-12the spiral shell dicyclo of mixing; Or R 3, R 4and X '-CH forms 3-8 unit's heterocycle or carbocyclic ring, C 5-12condensed-bicyclic, C 5-12condense assorted dicyclo, C 5-12spiral shell dicyclo or C 5-12the spiral shell dicyclo of mixing;
Each R 5be independently H, deuterium, hydroxyl, alkyl, assorted alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alkoxyl group, alkyl-OC (=O)-, alkyl-C (=O)-, formamyl, alkyl-OS (=O) r-, alkyl-S (=O) ro-, alkyl-S (=O) r-or amino-sulfonyl;
Each R 5abe H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, R independently 13ar 13n-,-C (=O) NR 13r 13a,-OC (=O) NR 13r 13a,-OC (=O) OR 13,-N (R 13) C (=O) NR 13r 13a,-N (R 13) C (=O) OR 13,-N (R 13) C (=O)-R 13, R 13r 13an-S (=O) 2-, R 13s (=O) 2-, R 13s (=O) 2n (R 13a)-, R 13ar 13n-alkyl, R 13s (=O)-alkyl, R 13r 13an-C (=O)-alkyl, R 13ar 13n-alkoxyl group, R 13s (=O)-alkoxyl group, R 13r 13an-C (=O)-alkoxyl group, aryl, heteroaryl, alkoxyl group, alkylamino, alkyl, haloalkyl, thiazolinyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aralkyl, virtue is amino, heteroaryl amino, aryl alkane amino, heteroaryl alkylamino, heteroaryl oxygen base, heteroarylalkyl, alkoxy aryl, heteroaryl alkoxyl group, heterocyclyloxy base, heterocyclic radical alkoxyl group, heterocyclic radical amino, alkyl acyl, alkyl acyloxy, alkoxyl group acyl group, alkyl sulphonyl, alkoxyl group alkylsulfonyl, alkyl sulphinyl, alkyl sulphonyl oxygen base, alkyl sulphinyl oxygen base, heterocyclic radical alkylamino or aryloxy,
Each R 6be hydrogen, deuterium, R independently 13r 13anC (=O)-, R 13oC (=O)-, R 13c (=O)-, R 13r 13anS (=O)-, R 13oS (=O)-, R 13s (=O)-, R 13r 13anS (=O) 2-, R 13oS (=O) 2-, R 13s (=O) 2-, the amino aliphatics of aliphatics, halogenated aliphatic, hydroxyl group aliphatic, amino aliphatics, alkoxyl group aliphatics, alkylamino aliphatics, alkylthio aliphatics, aromatic yl aliphat, heteroaryl aliphatics, heterocyclic radical aliphatics, cycloalkyl aliphatics, aryloxy aliphatics, heterocyclyloxy base aliphatics, cycloalkyl oxy aliphatics, fragrant amino aliphatics, heterocyclic radical, cycloalkyl amino aliphatics, aryl, heteroaryl, heterocyclic radical or carbocylic radical;
Each R 6abe H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, oxo (=O), R independently 13ar 13n-,-C (=O) NR 13r 13a,-OC (=O) NR 13r 13a,-OC (=O) OR 13,-N (R 13) C (=O) NR 13r 13a,-N (R 13) C (=O) OR 13a,-N (R 13) C (=O)-R 13a, R 13r 13an-S (=O) 2-, R 13s (=O) 2-, R 13s (=O) 2n (R 13a)-, R 13ar 13n-alkyl, R 13s (=O)-alkyl, R 13r 13an-C (=O)-alkyl, R 13ar 13n-alkoxyl group, R 13s (=O)-alkoxyl group, R 13r 13an-C (=O)-alkoxyl group, aryl, heteroaryl, alkoxyl group, alkylamino, alkyl, haloalkyl, thiazolinyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aralkyl, virtue is amino, heteroaryl amino, aryl alkane amino, heteroaryl alkylamino, heteroaryl oxygen base, heteroarylalkyl, alkoxy aryl, heteroaryl alkoxyl group, heterocyclyloxy base, heterocyclic radical alkoxyl group, heterocyclic radical amino, alkyl acyl, alkyl acyloxy, alkoxyl group acyl group, alkyl sulphonyl, alkoxyl group alkylsulfonyl, alkyl sulphinyl, alkyl sulphonyl oxygen base, alkyl sulphinyl oxygen base, heterocyclic radical alkylamino or aryloxy,
Each R 7and R 7abe H independently, deuterium, F, Cl, Br, I, aliphatics, assorted alkyl, halogenated aliphatic, hydroxyl group aliphatic, amino aliphatics, alkoxyl group aliphatics, alkylamino aliphatics, alkylthio aliphatics, aromatic yl aliphat, heteroaryl aliphatics, heterocyclic radical aliphatics, cycloalkyl aliphatics, aryloxy aliphatics, heterocyclyloxy base aliphatics, cycloalkyl oxy aliphatics, the amino aliphatics of virtue, the amino aliphatics of heterocyclic radical, cycloalkyl amino aliphatics, aryl, heteroaryl, heterocyclic radical or carbocylic radical,
Each R 8and R 8abe independently H, deuterium, hydroxyl, cyano group, nitro, F, Cl, Br, I, alkyl, assorted alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alkoxyl group, alkyl-OC (=O)-, alkyl-C (=O)-, formamyl, alkyl-OS (=O) r-, alkyl-S (=O) ro-, alkyl-S (=O) r-or amino-sulfonyl;
Each R 9, R 9a, R 10and R 11be H, deuterium, alkyl, assorted alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, haloalkyl, hydroxyalkyl, heteroarylalkyl, heterocyclic radical alkyl or cycloalkyl alkyl independently;
Each R 12be R independently 13ar 13n-,-C (=O) R 13,-C (=S) R 13,-C (=O)-O-R 13,-C (=O) NR 13r 13a,-OC (=O) NR 13r 13a,-OC (=O) OR 13,-N (R 13) C (=O) NR 13r 13a,-N (R 13) C (=O) OR 13a,-N (R 13) C (=O)-R 13a, R 13r 13an-S (=O) 2-, R 13s (=O) 2-, R 13s (=O) 2n (R 13a)-, R 13oS (=O) 2-, alkyl, assorted alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or aralkyl;
Or R 11, R 12can at random form 4-7 ring with the atom being attached thereto; With
With each R 13and R 13abe H, deuterium, alkyl, assorted alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or aralkyl independently; Work as R 13and R 13abe connected on same nitrogen-atoms R 13, R 13acan at random form substituted or non-substituted 3-8 ring, spiral shell dicyclo or condensed-bicyclic with nitrogen-atoms;
Wherein each following group: alkylidene, alkenylene, cycloalkylidene, sub-Heterocyclylalkyl ,-(CR 8R 8a) n-O-(CR 8R 8a) p-,-(CR 8R 8a) n-N (R 5)-(CR 8R 8a) p-,-(CR 8R 8a) n-S (=O) r-N (R 5)-(CR 8R 8a) p-,-(CR 8R 8a) n-C (=O)-N (R 5)-(CR 8R 8a) p-,-(CR 8R 8a) n-N (R 5)-C (=O)-N (R 5)-(CR 8R 8a) p-,-(CR 8R 8a) n-C (=O)-O-(CR 8R 8a) p-,-(CR 8R 8a) n-N (R 5)-S (=O) r-N (R 5)-(CR 8R 8a) p-,-(CR 8R 8a) n-S (=O) r-(CR 8R 8a) p-,-(CR 8R 8a) n-S (=O) r-O-(CR 8R 8a) p-,-(CR 8R 8a) n-C (=O)-(CR 8R 8a) p-,-(CR 8R 8a) n-C (=S)-(CR 8R 8a) p-,-(CR 8R 8a) n-N (R 5)-C (=O)-O-(CR 8R 8a) p-,-[U-(CR 9R 9a) t-N (R 10)-(CR 9R 9a) t] k-U-(CR 9R 9a) t-N (R 11)-(CR 9R 9a) t-R 12,-U-(CR 9R 9a) t-R 12,-[U-(CR 9R 9a) t-N (R 10)-(CR 9R 9a) t] k-U-(CR 9R 9a) t-O-(CR 9R 9a) t-R 12, NR 6, CR 7R 7a, CR 7,-(CH 2) a-,-CH=CH-,-N=CH-,-(CH 2) a-N (R 5)-(CH 2) b-,-(CH 2) a-O-(CH 2) B-, R 13aR 13N-,-C (=O) R 13,-C (=S) R 13,-C (=O)-O-R 13,-C (=O) NR 13R 13a,-OC (=O) NR 13R 13a,-OC (=O) OR 13,-N (R 13) C (=O) NR 13R 13a,-N (R 13) C (=O) OR 13a,-N (R 13) C (=O)-R 13a, R 13R 13aN-S (=O) 2-, R 13S (=O) 2-, R 13S (=O) 2N (R 13a)-, R 13OS (=O) 2-, alkyl-OC (=O)-, alkyl-C (=O)-, alkyl-OS (=O) r-, alkyl-S (=O) rO-,Alkyl-S (=O) r-, R 13R 13aNS (=O)-, R 13OS (=O)-, R 13S (=O)-, alkyl, R 13S (=O)-alkyl, R 13R 13aN-C (=O)-alkyl, R 13aR 13N-alkoxyl, R 13S (=O)-alkoxyl, R 13R 13aN-C (=O)-alkylamino, alkyl, assorted alkyl, carbocylic radical, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, a-amino acid, C 5-12condensed-bicyclic, C 5-12condense assorted dicyclo, C 5-12spiral shell dicyclo or C 5-12the spiral shell dicyclo of mixing, alkoxyl, aliphatic, halogenated aliphatic, hydroxyl group aliphatic, amino aliphatic, alkoxyl aliphatic, alkylamino aliphatic, alkylthio group aliphatic, aromatic yl aliphat, heteroaryl aliphatic, heterocyclic radical aliphatic, cycloalkyl aliphatic, aryloxy group aliphatic, heterocyclyloxy base aliphatic, cycloalkyl oxy aliphatic, the amino aliphatic of virtue, the amino aliphatic of heterocyclic radical, cycloalkyl amino aliphatic, haloalkyl, thiazolinyl, alkynyl, virtue is amino, heteroaryl amino, aryl alkane amino, heteroaryl alkylamino, heteroaryl oxygen base, heteroaryl alkyl, alkoxy aryl, heteroaryl alkoxyl, heterocyclyloxy base, heterocyclic radical alkoxyl, heterocyclic radical amino, heterocyclic radical alkylamino or aryloxy group can be optionally by one or more deuteriums that are selected from, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl, alkylamino, alkylthio group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, heteroaryloxy, oxo (=O), carboxyl, the alkoxyl that hydroxyl replaces, hydroxyl replace alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O) 2-, hydroxyl replace alkyl-S (=O)-, hydroxyl replace alkyl-S (=O) 2-or the substituting group of carboxyl alkoxyl replace.
In some embodiments, wherein W is C therein 3-8carbocylic radical or C 2-10heterocyclic radical.
Therein in some embodiments, wherein
Figure BDA0000442505360000051
structural unit is selected from following minor structure formula:
Figure BDA0000442505360000052
Wherein, each X 3and X 5be O, S, NR independently 6, C (=O) or CR 7r 7a;
Each X 6be CR independently 7r 7a,-Y 1=N-, O, S or NR 6;
Each Y 1be N or CR independently 7;
Each f is 0,1,2,3 or 4 independently;
Each Q 1and Q 2be NR independently 6, O, S, C (=O) or (CR 7r 7a) e;
E is 0,1,2,3 or 4;
Each R 5abe H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, C independently 1-6alkyl acyl, C 1-6alkyl acyloxy, C 1-6alkoxyl group acyl group, C 1-6alkyl sulphonyl, C 1-6alkoxyl group alkylsulfonyl, C 1-6alkyl sulphinyl, C 1-6alkyl sulphonyl oxygen base, C 1-6alkyl sulphinyl oxygen base, C 1-6alkoxyl group, C 1-6alkyl, C 6-10aryl ,-CF 3,-OCF 3, sulfydryl, nitro, C 1-6alkylamino, C 3-10cycloalkyl or C 6-10aryloxy;
Each R 6be hydrogen, deuterium, R independently 13r 13anC (=O)-, R 13oC (=O)-, R 13c (=O)-, R 13r 13anS (=O)-, R 13oS (=O)-, R 13s (=O)-, R 13r 13anS (=O) 2-, R 13oS (=O) 2-, R 13s (=O) 2-, C 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6aminoalkyl group, C 1-6alkoxy C 1-6alkyl, C 1-6alkylamino C 1-6alkyl, C 1-6alkylthio C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl, C 3-10cycloalkyl C 1-6alkyl, C 6-10aryloxy C 1-6alkyl, C 2-10heterocyclyloxy base C 1-6alkyl, C 3-10cycloalkyl oxy C 1-6alkyl, C 6-10the amino C of virtue 1-6alkyl, C 2-10the amino C of heterocyclic radical 1-6alkyl, C 3-10cycloalkyl amino C 1-6alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical or C 3-10carbocylic radical;
With each R 7and R 7abe H, deuterium, F, Cl, Br, I, C independently 1-6alkyl, C 2-6assorted alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6aminoalkyl group, C 1-6alkoxy C 1-6alkyl, C 1-6alkylamino C 1-6alkyl, C 1-6alkylthio C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl, C 3-10cycloalkyl C 1-6alkyl, C 6-10aryloxy C 1-6alkyl, C 2-10heterocyclyloxy base C 1-6alkyl, C 3-10cycloalkyl oxy C 1-6alkyl, C 6-10the amino C of virtue 1-6alkyl, C 2-10the amino C of heterocyclic radical 1-6alkyl, C 3-10cycloalkyl amino C 1-6alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical or C 3-10carbocylic radical.
Therein in some embodiments, wherein,
Figure BDA0000442505360000061
structural unit is selected from following minor structure formula:
Figure BDA0000442505360000062
Figure BDA0000442505360000071
Wherein, X 6for O, S ,-Y 1=N-, NR 6or CR 7r 7a;
Each Y 1be N or CH independently;
Each f is 0,1,2,3 or 4 independently;
Each R 5abe H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, C independently 1-6alkyl acyl, C 1-6alkyl acyloxy, C 1-6alkoxyl group acyl group, C 1-6alkyl sulphonyl, C 1-6alkoxyl group alkylsulfonyl, C 1-6alkyl sulphinyl, C 1-6alkyl sulphonyl oxygen base, C 1-6alkyl sulphinyl oxygen base, C 1-6alkoxyl group, C 1-6alkyl, C 6-10aryl ,-CF 3,-OCF 3, sulfydryl, nitro or C 1-6alkylamino;
Each R 6be hydrogen, deuterium, C independently 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6aminoalkyl group, C 1-6alkoxy C 1-6alkyl, C 1-6alkylamino C 1-6alkyl, C 1-6alkylthio C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl;
With each R 7and R 7abe H, deuterium, F, Cl, Br, I, C independently 1-6alkyl, C 2-6assorted alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6aminoalkyl group, C 1-6alkoxy C 1-6alkyl, C 1-6alkylamino C 1-6alkyl, C 1-6alkylthio C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl, C 3-10cycloalkyl C 1-6alkyl, C 6-10aryloxy C 1-6alkyl, C 2-10heterocyclyloxy base C 1-6alkyl, C 3-10cycloalkyl oxy C 1-6alkyl, C 6-10the amino C of virtue 1-6alkyl, C 2-10the amino C of heterocyclic radical 1-6alkyl, C 3-10cycloalkyl amino C 1-6alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical or C 3-8carbocylic radical.
In some embodiments, wherein each A and A ' are a key, C independently therein 1-6alkylidene group, C 2-6alkenylene, C 3-8cycloalkylidene, C 2-10sub-Heterocyclylalkyl ,-(CR 8r 8a) n-O-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-C (=O)-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-O-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-S (=O) r-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-O-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=S)-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-C (=O)-O-(CR 8r 8a) p-, or each A and A ' are following group independently:
Figure BDA0000442505360000081
Wherein, each X 1and X 2be O, S, NR independently 6or CR 7r 7a;
Each Y 1and Y 2be N or CR independently 7;
Z is-(CH 2) a-,-CH=CH-,-N=CH-,-(CH 2) a-N (R 5)-(CH 2) b-or-(CH 2) a-O-(CH 2) b-;
Each a and b are 0,1,2 or 3 independently;
Each c is 1 or 2 independently;
Each d is 1 or 2 independently;
Each n is 0,1,2 or 3 independently;
Each p is 0,1,2 or 3 independently;
Each r is 0,1 or 2 independently;
Each R 5be H, deuterium, hydroxyl, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-8cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl, C 6-10aryl C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkyl-OC (=O)-, C 1-6alkyl-C (=O)-, formamyl, C 1-6alkyl-OS (=O) r-, C 1-6alkyl-S (=O) ro-, C 1-6alkyl-S (=O) r-or amino-sulfonyl;
Each R 6be hydrogen, deuterium, R independently 13r 13anC (=O)-, R 13oC (=O)-, R 13c (=O)-, R 13r 13anS (=O)-, R 13oS (=O)-, R 13s (=O)-, R 13r 13anS (=O) 2-, R 13oS (=O) 2-, R 13s (=O) 2-, C 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6aminoalkyl group, C 1-6alkoxy C 1-6alkyl, C 1-6alkylamino C 1-6alkyl, C 1-6alkylthio C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl, C 3-10cycloalkyl C 1-6alkyl, C 6-10aryloxy C 1-6alkyl, C 2-10heterocyclyloxy base C 1-6alkyl, C 3-10cycloalkyl oxy C 1-6alkyl, C 6-10the amino C of virtue 1-6alkyl, C 2-10the amino C of heterocyclic radical 1-6alkyl, C 3-10cycloalkyl amino C 1-6alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical or C 3-10carbocylic radical;
Each R 6abe H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, oxo (=O), R independently 13ar 13n-,-C (=O) NR 13r 13a,-OC (=O) NR 13r 13a,-OC (=O) OR 13,-N (R 13) C (=O) NR 13r 13a,-N (R 13) C (=O) OR 13a,-N (R 13) C (=O)-R 13a, R 13r 13an-S (=O) 2-, R 13s (=O) 2-, R 13s (=O) 2n (R 13a)-, R 13ar 13n-C 1-6alkyl, R 13s (=O)-C 1-6alkyl, R 13r 13an-C (=O)-C 1-6alkyl, R 13ar 13n-C 1-6alkoxyl group, R 13s (=O)-C 1-6alkoxyl group, R 13r 13an-C (=O)-C 1-6alkoxyl group, C 6-10aryl, C 1-9heteroaryl, C 1-6alkoxyl group, C 1-6alkylamino, C 1-6alkyl, C 1-6haloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 2-10heterocyclic radical, C 3-8cycloalkyl, sulfydryl, nitro, C 6-10aryl C 1-6alkyl, C 6-10virtue is amino, C 1-9heteroaryl amino or C 6-10aryloxy;
Each R 7and R 7abe H, deuterium, F, Cl, Br, I, C independently 1-6alkyl, C 2-6assorted alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6aminoalkyl group, C 1-6alkoxy C 1-6alkyl, C 1-6alkylamino C 1-6alkyl, C 1-6alkylthio C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl, C 3-10cycloalkyl C 1-6alkyl, C 6-10aryloxy C 1-6alkyl, C 2-10heterocyclyloxy base C 1-6alkyl, C 3-10cycloalkyl oxy C 1-6alkyl, C 6-10the amino C of virtue 1-6alkyl, C 2-10the amino C of heterocyclic radical 1-6alkyl, C 3-10cycloalkyl amino C 1-6alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical or C 3-8carbocylic radical;
Each R 13and R 13abe H, deuterium, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl or C 6-10aryl C 1-6alkyl; Work as R 13and R 13abe connected on same nitrogen-atoms R 13, R 13acan at random form substituted or non-substituted 3-8 ring, spiral shell dicyclo or condensed-bicyclic with nitrogen-atoms;
With each R 8and R 8abe H, deuterium, hydroxyl, cyano group, nitro, F, Cl, Br, I, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl, C 6-10aryl C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkyl-OC (=O)-, C 1-6alkyl-C (=O)-, formamyl, C 1-6alkyl-OS (=O) r-, C 1-6alkyl-S (=O) ro-, C 1-6alkyl-S (=O) r-or amino-sulfonyl.
In some embodiments, wherein each A and A ' are a key ,-CH independently therein 2-,-(CH 2) 2-,-CH=CH-,-CH=CH-CH 2-,-N (R 5)-,-C (=O)-,-C (=S)-,-C (=O)-O-,-C (=O) N (R 5)-,-OC (=O) N (R 5)-,-OC (=O) O-,-N (R 5) C (=O) N (R 5)-,-(R 5) N-S (=O) 2-,-S (=O) 2-,-OS (=O) 2-,-(R 5) N-S (=O)-,-S (=O)-,-OS (=O)-, or each A and A ' are following group independently:
Figure BDA0000442505360000091
Figure BDA0000442505360000101
Wherein, X 1for O or S;
Each Y 1be N or CH independently;
Each R 5be H, deuterium, hydroxyl, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-8cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl, C 6-10aryl C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkyl-OC (=O)-, C 1-6alkyl-C (=O)-, formamyl, C 1-6alkyl-OS (=O) r-, C 1-6alkyl-S (=O) ro-, C 1-6alkyl-S (=O) r-or amino-sulfonyl;
Each R 6be hydrogen, deuterium, C independently 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6aminoalkyl group, C 1-6alkoxy C 1-6alkyl, C 1-6alkylamino C 1-6alkyl, C 1-6alkylthio C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl, C 6-10aryl, C 2-10heterocyclic radical or C 3-8carbocylic radical;
Each R 6abe H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, oxo (=O), R independently 13ar 13n-, C 1-6alkoxyl group, C 1-6alkylamino, C 1-6alkyl, C 1-6haloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, sulfydryl or nitro;
With each R 13and R 13aindependently for being H, deuterium, C 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl or C 6-10aryl C 1-6alkyl; Work as R 13and R 13abe connected on same nitrogen-atoms R 13, R 13acan at random form substituted or non-substituted 3-8 ring, spiral shell dicyclo or condensed-bicyclic with nitrogen-atoms.
Therein in some embodiments, wherein, each R 1, R 2, R 3and R 4independently for being selected from H, deuterium, C 1-8alkyl, C 1-8assorted alkyl, C 6-10aryl C 1-6alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 1-9heteroaryl or C 6-10aryl, or R 1, R 2at random form 3-8 unit heterocycle or 3-8 unit carbocyclic ring, C with X-CH 5-12condensed-bicyclic, C 5-12condense assorted dicyclo, C 5-12spiral shell dicyclo or C 5-12the spiral shell dicyclo of mixing; R 3, R 4and X '-CH at random forms 3-8 unit heterocycle or 3-8 unit carbocyclic ring, C 5-12condensed-bicyclic, C 5-12condense assorted dicyclo, C 5-12spiral shell dicyclo or C 5-12the spiral shell dicyclo of mixing.
In other embodiment, wherein R 1, R 2and X-CH, or R 3, R 4and X '-CH at random forms 3-8 unit heterocycle, C 5-12condensed-bicyclic, C 5-12condense assorted dicyclo, C 5-12spiral shell dicyclo or C 5-12the spiral shell dicyclo of mixing.
In other embodiment, wherein R 1, R 2the heterocycle forming with Y-X-CH or condensed ring or volution system are selected from following minor structure formula:
Wherein, each R 15be H, deuterium, F, Cl, Br, I, cyano group, hydroxyl, C independently 1-3alkyl, C 1-3haloalkyl, C 1-3alkoxyl group, C 1-3alkylamino, C 1-3alkylthio, C 6-10virtue is amino, C 6-10aryloxy, C 1-9heteroaryl, C 1-9heteroaryloxy, C 1-9heteroaryl C 1-3alkyl or C 2-10heterocyclic radical;
Each R 6be hydrogen, deuterium, C independently 1-3alkyl, C 1-3haloalkyl, C 1-3hydroxyalkyl, C 1-3aminoalkyl group, C 1-3alkoxy C 1-3alkyl, C 1-3alkylamino C 1-3alkyl, C 1-3alkylthio C 1-3alkyl, C 6-10aryl C 1-3alkyl, C 1-9heteroaryl, C 6-10aryl, C 2-10heterocyclic radical or C 3-8carbocylic radical;
With each n 1and n 2be 1,2,3 or 4 independently.
In other embodiment, wherein R 3, R 4with the heterocycle that forms of Y '-X '-CH or condensed ring or volution system are selected from following minor structure formula:
Figure BDA0000442505360000112
Wherein, each R 15be H, deuterium, F, Cl, Br, I, cyano group, hydroxyl, C independently 1-3alkyl, C 1-3haloalkyl, C 1-3alkoxyl group, C 1-3alkylamino, C 1-3alkylthio, C 6-10virtue is amino, C 6-10aryloxy, C 1-9heteroaryl, C 1-9heteroaryloxy, C 1-9heteroaryl C 1-3alkyl or C 2-10heterocyclic radical;
Each R 6be hydrogen, deuterium, C independently 1-3alkyl, C 1-3haloalkyl, C 1-3hydroxyalkyl, C 1-3aminoalkyl group, C 1-3alkoxy C 1-3alkyl, C 1-3alkylamino C 1-3alkyl, C 1-3alkylthio C 1-3alkyl, C 6-10aryl C 1-3alkyl, C 1-9heteroaryl, C 6-10aryl, C 2-10heterocyclic radical or C 3-8carbocylic radical;
With each n 1and n 2be 1,2,3 or 4 independently.
In some embodiments, it has structure as shown in the formula (II) therein:
Figure BDA0000442505360000121
Wherein,
Figure BDA0000442505360000122
structural unit is following minor structure formula:
Each Q 1and Q 2be NR independently 6, O, S, C (=O) or (CH 2) e;
E is 0,1,2,3 or 4;
Each f is 0,1,2,3 or 4 independently
Each X 3and X 5be O, S, NR independently 6, C (=O) or CR 7r 7a;
Each X 6be CH independently 2,-Y 1=N-, O, S or NR 6;
Each Y 1be N or CR independently 7;
Each A and A ' are a key, C independently 1-6alkylidene group, C 2-6alkenylene, C 3-8cycloalkylidene, C 2-10sub-Heterocyclylalkyl ,-(CR 8r 8a) n-O-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-C (=O)-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-O-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-S (=O) r-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-O-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=S)-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-C (=O)-O-(CR 8r 8a) p-, or each A and A ' are following group independently:
Figure BDA0000442505360000131
Each R 5be H, deuterium, hydroxyl, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl, C 6-10aryl C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkyl-OC (=O)-, C 1-6alkyl-C (=O)-, formamyl, C 1-6alkyl-OS (=O) r-, C 1-6alkyl-S (=O) ro-, C 1-6alkyl-S (=O) r-or amino-sulfonyl;
Each R 5aand R 6abe H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, C independently 1-6alkyl acyl, C 1-6alkyl acyloxy, C 1-6alkoxyl group acyl group, C 1-6alkyl sulphonyl, C 1-6alkoxyl group alkylsulfonyl, C 1-6alkyl sulphinyl, C 1-6alkyl sulphonyl oxygen base, C 1-6alkyl sulphinyl oxygen base, C 1-6alkoxyl group, C 1-6alkyl, C 6-10aryl ,-CF 3,-OCF 3, sulfydryl, nitro, C 1-6alkylamino, C 3-10cycloalkyl or C 6-10aryloxy;
Each R 6be hydrogen, deuterium, R independently 13r 13anC (=O)-, R 13oC (=O)-, R 13c (=O)-, R 13r 13anS (=O)-, R 13oS (=O)-, R 13s (=O)-, R 13r 13anS (=O) 2-, R 13oS (=O) 2-, R 13s (=O) 2-, C 1-6aliphatics, C 1-6alkoxy C 1-6aliphatics, C 1-6alkylamino C 1-6aliphatics, C 6-10aryl C 1-6aliphatics, C 1-9heteroaryl C 1-6aliphatics, C 2-10heterocyclic radical C 1-6aliphatics, C 3-10cycloalkyl C 1-6aliphatics, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical or C 3-10carbocylic radical; Aliphatics in wherein said group is alkyl, and alkyl is, but is not limited to methyl, ethyl, propyl group, sec.-propyl, butyl or isobutyl-;
Each R 7and R 7abe H, deuterium, F, Cl, Br, I, C independently 1-6aliphatics, C 2-6assorted alkyl, C 1-6alkoxy C 1-6aliphatics, C 1-6alkylamino C 1-6aliphatics, C 6-10aryl C 1-6aliphatics, C 2-10heterocyclic radical C 1-6aliphatics, C 3-10cycloalkyl C 1-6aliphatics, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical or C 3-10carbocylic radical; Aliphatics in wherein said group is alkyl, and alkyl is, but is not limited to methyl, ethyl, propyl group, sec.-propyl, butyl or isobutyl-;
Each R 8and R 8abe H, deuterium, hydroxyl, cyano group, nitro, F, Cl, Br, I, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl, C 6-10aryl C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkyl-OC (=O)-, C 1-6alkyl-C (=O)-, formamyl, C 1-6alkyl-OS (=O) r-, C 1-6alkyl-S (=O) ro-, C 1-6alkyl-S (=O) r-or amino-sulfonyl;
Each R 13and R 13abe H, deuterium, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl or C 6-10aryl C 1-6alkyl; Work as R 13and R 13abe connected on same nitrogen-atoms R 13, R 13acan at random form substituted or non-substituted 3-8 ring, spiral shell dicyclo or condensed-bicyclic with nitrogen-atoms;
Each n is 0,1,2 or 3 independently;
Each p is 0,1,2 or 3 independently;
Each r is 0,1 or 2 independently;
With each Y 4and Y 4' be a key, O, S ,-(CH independently 2) n-,-CH=CH-,-S (=O) r-,-CH 2o-,-CH 2s-,-CF 2-,-CHR 5a-,-CR 5ar 6a,-CH 2s (=O) ror-CH 2n (R 6)-.
In other embodiment, it has structure as shown in the formula (III):
Figure BDA0000442505360000141
In other embodiment, it has suc as formula the structure shown in (IV):
Figure BDA0000442505360000151
Wherein, each Q 2and Q 3be O, S, C (=O), NR independently 6or CR 7r 7a.
In other embodiment, it has the structure as shown in formula V:
Figure BDA0000442505360000152
Wherein e is 1,2,3 or 4.
In some embodiments, wherein, each Y and Y ' are a-amino acid group independently therein.
In other embodiment, wherein a-amino acid group is selected from Isoleucine, leucine, Methionin, methionine(Met), phenylalanine, Threonine, tryptophane, α-amino-isovaleric acid, L-Ala, l-asparagine, aspartic acid, L-glutamic acid, glutamine, proline(Pro), Serine, to tyrosine, arginine, Histidine, halfcystine, glycine, sarkosine, N, N-N-methylsarcosine, homoserine, norvaline, nor-leucine, ornithine, homocysteine, hyperphenylalaninemia, phenylglycocoll, adjacent tyrosine, the group that m-Tyrosine or oxyproline form.
In other embodiment, the a-amino acid in wherein said a-amino acid group is D configuration.
In other embodiment, the a-amino acid in wherein said a-amino acid group is L configuration.
In some embodiments, wherein each Y and Y ' are-[U-(CR independently therein 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12,-U-(CR 9r 9a) t-R 12or-[U-(CR 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-O-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-[U-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-U-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t-U-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-U-(CR independently 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-[C (=O)-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t-U-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-[C (=O)-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-C (=O)-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t-C (=O)-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 11)-(CR 9r 9a) t-C (=O)-R 13.
In other embodiment, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 11)-C (=O)-R 13.
In other embodiment, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 11)-(CR 9r 9a) t-C (=O)-O-R 13.
In other embodiment, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 11)-C (=O)-O-R 13.
In other embodiment, wherein each Y and Y ' are-U-(CR independently 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-[U-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-O-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-U-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t-U-(CR 9r 9a) t-O-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t-C (=O)-(CR 9r 9a) t-O-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-U-(CR independently 9r 9a) t-O-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-O-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 11)-R 12, wherein R 11, R 12can form 4-7 ring with the atom being attached thereto.
In other embodiment, wherein, each R 9, R 9a, R 10and R 11be H, deuterium, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl, C 6-10aryl C 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl;
Each R 12be R independently 13ar 13n-,-C (=O) R 13,-C (=S) R 13,-C (=O)-O-R 13,-C (=O) NR 13r 13a,-OC (=O) NR 13r 13a,-OC (=O) OR 13,-N (R 13) C (=O) NR 13r 13a,-N (R 13) C (=O) OR 13a,-N (R 13) C (=O)-R 13a, R 13r 13an-S (=O) 2-, R 13s (=O) 2-, R 13s (=O) 2n (R 13a)-, R 13oS (=O) 2-, C 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl or C 6-10aryl C 1-6alkyl;
Or R 11, R 12can form 4-7 ring with the atom being attached thereto;
Each R 13and R 13abe H, deuterium, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl or C 6-10aryl C 1-6alkyl; Work as R 13and R 13abe connected on same nitrogen-atoms R 13, R 13acan at random form substituted or non-substituted 3-8 ring, spiral shell dicyclo or condensed-bicyclic with nitrogen-atoms;
Each t is 0,1,2,3 or 4 independently;
With each k be 0,1 or 2 independently.
In other embodiment, wherein, each R 9, R 9a, R 10and R 11be H, deuterium, methyl, ethyl, sec.-propyl, cyclohexyl, isobutyl-or phenyl independently;
Each R 12be-C (=O) R independently 13,-C (=O)-O-R 13,-C (=O) NR 13r 13a, methyl, ethyl, propyl group, phenyl, cyclohexyl, morpholinyl or piperidyl;
Or R 11, R 12can form 4-7 ring with the atom being attached thereto;
With each R 13and R 13abe H, deuterium, methyl, ethyl, propyl group, phenyl, cyclohexyl, morpholinyl or piperidyl independently.
In other embodiment, it has suc as formula the structure shown in (VI):
Figure BDA0000442505360000171
Wherein, each R 14and R 14abe H, deuterium, C independently 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 2-6assorted alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical, C 3-8cycloalkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl;
Wherein said C 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 2-6assorted alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical, C 3-8cycloalkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl can optionally be replaced by one or more substituting groups that are selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
In some embodiments, it has suc as formula the structure shown in (VII) therein:
Figure BDA0000442505360000181
Wherein, each R 14and R 14abe H, deuterium, C independently 1-3hydroxyalkyl, methyl, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, allyl group, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl or C 1-9heteroaryl;
Wherein said C 1-3hydroxyalkyl, methyl, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, allyl group, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl or C 1-9heteroaryl can optionally be replaced by one or more substituting groups that are selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
In some embodiments, it has suc as formula the structure shown in (VIII) therein:
Figure BDA0000442505360000182
Wherein, each R 14and R 14abe H, deuterium, C independently 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 2-6assorted alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical, C 3-8cycloalkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl;
With each n 2be 1,2,3 or 4 independently;
Wherein said C 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 2-6assorted alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical, C 3-8cycloalkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl can optionally be replaced by one or more substituting groups that are selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
In some embodiments, it has suc as formula the structure shown in (IX) therein:
Wherein, each R 14and R 14abe H, deuterium, C independently 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 2-6assorted alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical, C 3-8cycloalkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl;
With each n 1be 1,2,3 or 4 independently;
Wherein said C 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 2-6assorted alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical, C 3-8cycloalkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl can optionally be replaced by one or more substituting groups that are selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
In some embodiments, it has suc as formula the structure shown in (X) therein
Figure BDA0000442505360000192
Wherein, each R 5abe H, deuterium, C independently 1-4alkyl, F, Cl, Br or I;
F is 0,1,2,3 or 4;
Each Y 1be N or CR independently 7;
Each R 6and R 7be H, deuterium, C independently 1-4alkyl, C 6-10aryl, C 2-10heterocyclic radical, C 3-8cycloalkyl or benzyl;
Each R 14and R 14abe H, deuterium, C independently 1-4alkyl, C 6-10aryl, C 2-10heterocyclic radical or C 3-8cycloalkyl;
Each R 16and R 16abe hydroxyl, C independently 1-4alkyl oxy, C 6-10aryloxy, C 2-10heterocyclic radical or C 3-8cycloalkyl;
Wherein
Figure BDA0000442505360000193
structural unit is following minor structure formula:
Each A or A ' are independently selected from following group:
Figure BDA0000442505360000202
Figure BDA0000442505360000211
Wherein R 1, R 2the heterocycle independently forming with N-CH or condensed ring or volution system are selected from following minor structure formula:
Figure BDA0000442505360000212
Wherein R 3, R 4the heterocycle independently forming with N-CH or condensed ring or volution system are selected from following minor structure formula:
Figure BDA0000442505360000213
In some embodiments, it has suc as formula the structure shown in (XI) therein
Wherein, each R 5abe H, deuterium, C independently 1-4alkyl, F, Cl, Br or I;
F is 0,1,2,3 or 4;
Each Q 1and Q 2be NR independently 6, O, S, C (=O) or (CR 7r 7a) e;
X 6for (CR 7r 7a) n,-Y 1=N-, O, S or NR 6;
Each Y 1be N or CR independently 7;
Each i, n and e are 1,2,3 or 4 independently;
Each R 6, R 7and R 7abe H, deuterium, C independently 1-4alkyl, C 6-10aryl, C 2-10heterocyclic radical, C 3-8cycloalkyl or benzyl;
Each R 14and R 14abe H, deuterium, C independently 1-4alkyl, C 6-10aryl, C 2-10heterocyclic radical or C 3-8cycloalkyl;
Each R 16and R 16abe hydroxyl, C independently 1-4alkyl oxy, C 6-10aryloxy, C 2-10heterocyclic radical or C 3-8cycloalkyl;
Wherein said C 1-4alkyl, C 6-10aryl, C 2-10heterocyclic radical, C 3-8cycloalkyl, C 6-10aryloxy can optionally be replaced by one or more substituting groups that are selected from deuterium, F, Cl, Br, hydroxyl, cyano group;
Each A or A ' are independently selected from following group:
Figure BDA0000442505360000221
Wherein R 1, R 2the heterocycle independently forming with N-CH or condensed ring or volution system are selected from following minor structure formula:
Figure BDA0000442505360000222
Wherein R 3, R 4the heterocycle independently forming with N-CH or condensed ring or volution system are selected from following minor structure formula:
Figure BDA0000442505360000223
In other embodiment, wherein, each R 5abe H, deuterium, methyl, ethyl, F, Cl, Br or I independently;
Each R 6, R 7and R 7abe hydrogen, deuterium, methyl, ethyl, sec.-propyl, phenyl, cyclohexyl or benzyl independently;
Each R 14and R 14abe methyl, ethyl, phenyl, cyclohexyl, 1-methyl-propyl, sec.-propyl or the tertiary butyl independently;
With each R 16and R 16abe independently hydroxyl, methoxyl group, oxyethyl group, phenoxy group,
Figure BDA0000442505360000224
or tert.-butoxy;
Wherein said methyl, ethyl, phenyl, cyclohexyl, 1-methyl-propyl, sec.-propyl, isobutyl-, methoxyl group, oxyethyl group, phenoxy group, tert.-butoxy or the tertiary butyl can optionally be replaced by one or more substituting groups that are selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
On the other hand, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition comprises above-mentioned any compound.
In some embodiments, this pharmaceutical composition can also further comprise pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or its combination therein.
In some embodiments, it further comprises the medicine of other anti-HCV therein.
In other embodiment, the medicine of wherein said anti-HCV is that Interferon, rabbit, ribavirin, interleukin-22, interleukin 6, interleukin 12, promotion produce compound, RNA interfering, sense-rna, not moral, inosine 5 '-monophosphate dehydrogenase inhibitor, amantadine, Rimantadine, Ba Wei former times monoclonal antibody (Bavituximab), the Civacir of miaow quinoline that 1 type helper T cell is replied tM, EBP520 (boceprevir), TVR (telaprevir), erlotinib (erlotinib), daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, ABT-450, danoprevir, sovaprevir, MK-5172, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ABT-267, EDP239, PPI-668, GS-5816, samatasvir (IDX-719), MK-8742, MK-8325, GSK-2336805, PPI-461, TMC-435, MK-7009, BI-2013335, ciluprevir, BMS-650032, ACH-1625, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, EP-013420, VBY-376, TMC-649128, R-7128, PSI-7977, INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072, PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055 or its combination.
In other embodiment, wherein said Interferon, rabbit is interferon alpha, Intederon Alpha-2a, the Intederon Alpha-2a of Pegylation, compound alpha-interferon, interferon-gamma or its combination of Interferon Alpha-2b, Pegylation.
In some embodiments, it further comprises at least one HCV inhibitor therein, described HCV inhibitor for suppress HCV reproduction process and suppress HCV viral protein function one of at least; Described HCV reproduction process is selected from the complete viral cycle of the HCV that HCV enters, shells, translates, copies, assembles or discharge.Described HCV viral protein is selected from metalloprotease, NS2, NS3, NS4A, NS4B, NS5A, NS5B; And the needed internal ribosome inlet point of HCV virus replication (IRES) and inosine monophosphate desaturase (IMPDH).
On the other hand, compound of the present invention or pharmaceutical composition its for suppress HCV reproduction process and suppress HCV viral protein function one of at least; Described HCV reproduction process is selected from the complete viral cycle of the HCV that HCV enters, shells, translates, copies, assembles or discharge.Described HCV viral protein is selected from metalloprotease, NS2, NS3, NS4A, NS4B, NS5A, NS5B; And the needed internal ribosome inlet point of HCV virus replication (IRES) and inosine monophosphate desaturase (IMPDH).
On the other hand, the present invention relates to the compounds of this invention or pharmaceutical composition and can be used to for the preparation of the purposes of preventing, process, treat or alleviate the medicine of patient's hepatitis C disease, comprise the compound as described herein or the pharmaceutical composition of the present invention that give patient's significant quantity.
The present invention relates to formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X) or (XI) method of preparation, separation and the purifying of the compound that comprises on the other hand.
Content noted earlier has only been summarized some aspect of the present invention, but is not limited to these aspects.The content of these aspects and other aspect will be done more concrete complete description below.
Circumstantial letter of the present invention
Definition and general terms
The present invention will list the corresponding document of specific content of determining in detail, and embodiment is attended by the diagram of structural formula and chemical formula.The present invention has expectedly contains all choices, variant and coordinator, and these may comprise within the scope of the present invention as claim is defined.Those skilled in the art is by many identification similar or be equal to method described herein and material, and these can be applied in practice of the present invention and go.The present invention is limited to absolutely not the description of method and material.Have a lot of documents distinguish or conflict with similar material and the present patent application, comprising but be never limited to the definition of term, the usage of term, the technology of description, or the scope of being controlled as the present patent application.
Unless the present invention shows other aspects of the following definition of application.According to object of the present invention, chemical element is according to the periodic table of elements, CAS version and chemical physics handbook, 75 thed., 1994 define.In addition, organic chemistry General Principle is shown in " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito, 1999 and " March's Advanced Organic Chemistry ", Michael B.Smith and Jerry March, John Wiley & Sons, New York, 2007, all above-mentioned reference are all incorporated herein by reference.
As described in the invention, compound of the present invention can optionally be replaced by one or more substituting group, as general formula compound above, or example as special in embodiment the inside, and subclass, and the compounds that comprises of the present invention.Should be appreciated that " optional replacement " this term and " replacement or unsubstituted " this term can exchange use.Generally speaking, term " optionally ", no matter whether be positioned at term " replacement " before, represents that one or more hydrogen atoms of give in structure are replaced by concrete substituting group.Unless other aspects show, an optional substituted radical can have a substituting group to replace in each commutable position of group.When one or more substituting group that in given structural formula, not only position can be selected from concrete group replaces, substituting group can replace in each position identical or differently so.Wherein said substituting group can be, but be not limited to, the alkoxyl group that deuterium, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkylamino, alkylthio, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, heteroaryloxy, oxo (=O), carboxyl, hydroxyl replace, alkyl-C (=O) that hydroxyl replaces-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O) 2-, hydroxyl replace alkyl-S (=O)-, hydroxyl replace alkyl-S (=O) 2-, the alkoxyl group of carboxyl substituted etc.
Term " aliphatics " or " fatty group " that the present invention uses, represent straight chain (being non-side chain) or side chain, replaces or the unsubstituted completely saturated or alkyl that contains one or more degrees of unsaturation.Unless otherwise detailed instructions, fatty group contains 1-20 carbon atom, and some of them embodiment is that fatty group contains 1-10 carbon atom, other embodiment is, fatty group contains 1-8 carbon atom, and other embodiment is that fatty group contains 1-6 carbon atom, other embodiment is, fatty group contains 1-4 carbon atom, and other embodiment is that fatty group contains 1-3 carbon atom.Suitable fatty group comprises, but is not limited to, and straight or branched replaces or unsubstituted alkyl, and alkenyl or alkynyl, as methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, hexyl, isobutyl-, sec-butyl, vinyl etc.
Term " halogenated aliphatic " or " halogenated aliphatic base " represent that fatty group is replaced by one or more identical or different halogen atoms, wherein fatty group has implication as described in the present invention, halogen atom is fluorine, chlorine, bromine or iodine, such example comprises, but is not limited to trifluoromethyl, trifluoroethyl, chloromethyl, 2-chlorovinyl etc.
Term " hydroxyl group aliphatic " or " hydroxyl group aliphatic base " represent that fatty group is replaced by one or more oh group, wherein fatty group has implication as described in the present invention, such example comprises, but is not limited to hydroxyethyl, 2-hydroxypropyl, methylol etc.
Term " amino aliphatics " or " amino fatty group " represent that fatty group is replaced by one or more amino group, wherein fatty group has implication as described in the present invention, such example comprises, but is not limited to amino methyl, 2-amino-ethyl, the amino sec.-propyl of 2-etc.
Term " alkyl " represents 1-20 carbon atom, or 1-10 carbon atom, or 1-8 carbon atom, or 1-6 carbon atom, or 1-4 carbon atom, or the saturated straight chain of 1-3 carbon atom or the univalence hydrocarbyl of side chain, wherein alkyl can independently and optionally be replaced by one or more substituting groups described in the invention.The example of alkyl comprises, but is not limited to methyl (Me ,-CH 3), ethyl (Et ,-CH 2cH 3), n-propyl (n-Pr ,-CH 2cH 2cH 3), sec.-propyl (i-Pr ,-CH (CH 3) 2), normal-butyl (n-Bu ,-CH 2cH 2cH 2cH 3), isobutyl-(i-Bu ,-CH 2cH (CH 3) 2), sec-butyl (s-Bu ,-CH (CH 3) CH 2cH 3), the tertiary butyl (t-Bu ,-C (CH 3) 3), n-pentyl (CH 2cH 2cH 2cH 2cH 3), 2-amyl group (CH (CH 3) CH 2cH 2cH 3), 3-amyl group (CH (CH 2cH 3) 2), 2-methyl-2-butyl (C (CH 3) 2cH 2cH 3), 3-methyl-2-butyl (CH (CH 3) CH (CH 3) 2), 3-methyl isophthalic acid-butyl (CH 2cH 2cH (CH 3) 2), 2-methyl-1-butene base (CH 2cH (CH 3) CH 2cH 3), n-hexyl (CH 2cH 2cH 2cH 2cH 2cH 3), 2-hexyl (CH (CH 3) CH 2cH 2cH 2cH 3), 3-hexyl (CH (CH 2cH 3) (CH 2cH 2cH 3)), 2-methyl-2-amyl group (C (CH 3) 2cH 2cH 2cH 3), 3-methyl-2-amyl group (CH (CH 3) CH (CH 3) CH 2cH 3), 4-methyl-2-amyl group (CH (CH 3) CH 2cH (CH 3) 2), 3-methyl-3-amyl group (C (CH 3) (CH 2cH 3) 2), 2-methyl-3-amyl group (CH (CH 2cH 3) CH (CH 3) 2), 2,3-dimethyl-2-butyl (C (CH 3) 2cH (CH 3) 2), 3,3-dimethyl-2-butyl (CH (CH 3) C (CH 3) 3), n-heptyl, n-octyl etc.Term " alkyl " and its prefix " alkane " are used herein, all comprise the saturated carbon chains of straight chain and side chain.Term " alkylene " uses herein, the saturated bivalent hydrocarbon radical that expression obtains from two hydrogen atoms of straight or branched saturated carbon hydride cancellation, and such example comprises, but is not limited to methylene radical, ethylidene, isopropylidene etc.
Term " thiazolinyl " represents 2-12 carbon atom, or 2-8 carbon atom, or 2-6 carbon atom, or the monovalence alkyl of the straight or branched of 2-4 carbon atom, and wherein at least one position is undersaturated condition, and a C-C is sp 2two keys, wherein alkenyl group can independently and optionally be replaced by one or more substituting groups described in the invention, comprises that group has negation, " suitable " or " E ", the location of " Z ", wherein the concrete example of thiazolinyl comprises, but be not limited to vinyl (CH=CH 2), allyl group (CH 2cH=CH 2) etc.
Term " alkynyl " represents 2-12 carbon atom, or 2-8 carbon atom, or 2-6 carbon atom, or the monovalence alkyl of the straight or branched of 2-4 carbon atom, wherein at least one position is undersaturated condition, a C-C is sp triple bond, wherein alkynyl group can independently and optionally be replaced by one or more substituting groups described in the invention, wherein the concrete example of alkynyl comprises, but is not limited to, ethynyl (C ≡ CH), propargyl (CH 2c ≡ CH) etc.
Term " alkyl that hydroxyl replaces " represents that alkyl group is replaced by one or more oh group, and wherein alkyl group has implication of the present invention.Such example comprises, but is not limited to methylol, hydroxyethyl, 1,2-dihydroxy ethyl etc.
Term " haloalkyl " represents that alkyl group is replaced by one or more identical or different halogen atoms, wherein alkyl group has implication as described in the present invention, halogen atom is fluorine, chlorine, bromine or iodine, such example comprises, but is not limited to trifluoromethyl, trifluoroethyl, chloromethyl, methyl fluoride etc.
Term " hydroxyalkyl " represents that alkyl group is replaced by one or more oh group, and wherein alkyl group has implication as described in the present invention, and such example comprises, but is not limited to hydroxyethyl, 2-hydroxypropyl, methylol etc.
Term " aminoalkyl group " represents that alkyl group is replaced by one or more amino group, and wherein alkyl group has implication as described in the present invention, and such example comprises, but is not limited to amino methyl, 2-amino-ethyl, the amino sec.-propyl of 2-etc.
Term " alkylidene group " represents to remove from the saturated hydrocarbyl of straight or branched the saturated bivalent hydrocarbon radical group that two hydrogen atoms obtain.And described alkylidene group can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, deuterium, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro or aryloxy.Such example comprises, but is not limited to methylene radical (CH 2-), ethylidene (CH 2-CH 2-), isopropylidene (CH 2-CH (CH 3)-), ethane-1,1-bis-bases, 2-methoxy propane-1,1-bis-bases, 2-hydroxy propane-1,1-bis-bases, 2-methyl-2-hydroxy propane-1,1-bis-bases etc.
Term " alkenylene " represents to remove from the alkene of straight or branched the alkylene group that two hydrogen atoms obtain.And described alkenylene can be substituted or non-substituted, and wherein substituting group can be, but is not limited to, deuterium, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro or aryloxy.Such example comprises, but be not limited to, vinylidene (CH=CH-), sub-pseudoallyl (C (CH 3)=CH-), 3-methoxyl group propylene-1,1-bis-bases, 2-methyl butene-1,1-bis-bases etc.
The monocycle that term " sub-carbocylic radical " (" cycloalkylidene ") represents to contain 3-12 carbon atom or the dicyclo of 7-12 carbon atom remove the hydrocarbon ring of saturated divalence that two hydrogen atoms obtain, wherein carbocylic radical or cycloalkyl have implication as described in the present invention, such example comprises, but be not limited to cyclopropylidene, sub-cyclobutyl, cyclopentylidene, 1-ring penta-1-alkenylene, 1-ring penta-2-alkenylene etc.
Term " sub-heterocyclic radical " represents monocycle, dicyclo or three-ring system, wherein the upper one or more atoms of ring are independently selected from heteroatoms, and can be completely saturated or comprise one or more degrees of unsaturation, but do not belong to the fragrant same clan, have two tie points and be connected with molecule rest part, wherein heterocyclic radical group has implication as described in the present invention.Such example comprises, but is not limited to piperidines-Isosorbide-5-Nitrae-bis-base, piperazine-Isosorbide-5-Nitrae-bis-base, tetrahydrofuran (THF)-2,4-bis-bases, tetrahydrofuran (THF)-3,4-bis-bases, azetidine-1,3-bis-bases, tetramethyleneimine-1,3-bis-bases etc.
Term " sub-heterocyclic radical alkyl " represents that heterocyclic radical alkyl removes the group that two hydrogen atoms obtain, and wherein heterocyclic radical alkyl has implication as described in the present invention.Such example comprises, but is not limited to morpholine-4-methyl methylene radical, piperidines-N-methyl methylene radical etc.
Term " halo alkylidene group " represents that haloalkyl part has two tie points and is connected with molecule rest part.Wherein alkylidene group has implication as described in the present invention, and such example comprises, but is not limited to two fluoro methylene radical (CF 2-) etc.
Term " arylidene " represents that aryl system has two tie points and is connected with molecule rest part.Wherein aromatic yl group has implication as described in the present invention, and such example comprises, but is not limited to, phenylene, sub-to fluorophenyl etc.
Term " sub-aralkyl " represents that aralkyl system has two tie points to be connected with molecule rest part, and wherein aralkyl has implication as described in the present invention.Such example comprises, but is not limited to benzene methylene, benzene ethylene etc.
Term " inferior heteroaryl " represents that heteroaryl system has two tie points and is connected with molecule rest part.Wherein heteroaryl groups has implication as described in the present invention, and such example comprises, but is not limited to pyridylidene, sub-pyrryl, sub-thiazolyl, sub-imidazolyl etc.
Term " inferior heteroaryl alkyl " represents that heteroarylalkyl system has two tie points and is connected with molecule rest part, wherein heteroarylalkyl has implication as described in the present invention, such example comprises, but is not limited to pyridine-2-ethylene, thiazole-2-methylene, imidazoles-2-ethylene, pyrimidine-2-methylene etc.
Term " sub-condensed-bicyclic base " represents that condensed-bicyclic system has two tie points and is connected with molecule rest part, and wherein condensed-bicyclic base has implication as described in the present invention.Such example comprises, but is not limited to dicyclo [3.1.0] hexane-3,6-bis-bases etc.
Term " Asia condenses assorted bicyclic group " represents to condense assorted bicyclic system to be had two tie points and is connected with molecule rest part.Such example comprises, but is not limited to 3-azabicyclo [3.1.0] hexane-3,6-bis-bases etc.
Term " sub-condensed-bicyclic base alkyl " represents that condensed-bicyclic base alkyl has two tie points and is connected with molecule rest part, and wherein condensed-bicyclic base alkyl has implication as described in the present invention.
Term " Asia condense assorted bicyclic group alkyl " represents to condense assorted bicyclic group alkyl to be had two tie points and is connected with molecule rest part, wherein condenses the bicyclic group alkyl of mixing and has implication as described in the present invention.
Term " sub-spiral shell bicyclic group " represents that spiral shell bicyclic system has two tie points and is connected with molecule rest part, and wherein spiral shell bicyclic group has implication as described in the present invention.Such example comprises, but is not limited to 5-spiral shell [2.4] heptane-5,7-bis-bases, spiral shell [4.4] nonane-2,7-bis-bases etc.
Term " sub-spiral shell mix bicyclic group " represents that the assorted bicyclic system of spiral shell has two tie points and is connected with molecule rest part, and wherein the spiral shell bicyclic group of mixing has implication as described in the present invention.Such example comprises, but is not limited to 5-azaspiro [2.4] heptane-5,7-bis-bases, 2-azaspiro [4.4] nonane-2,7-bis-bases etc.
Term " sub-spiral shell bicyclic group alkyl " represents that spiral shell bicyclic group alkyl system has two tie points and is connected with molecule rest part, and wherein spiral shell bicyclic group alkyl has implication as described in the present invention.
Term " sub-spiral shell mix bicyclic group alkyl " represents that the assorted bicyclic group alkyl system of spiral shell has two tie points and is connected with molecule rest part, and wherein the spiral shell bicyclic group alkyl of mixing has implication as described in the present invention.
Term " assorted alkyl " represents can insert one or more heteroatomss in alkyl chain, and wherein alkyl group and heteroatoms have implication as described in the present invention.Unless otherwise detailed instructions, assorted alkyl group contains 1-10 carbon atom, other embodiment is, assorted alkyl group contains 1-8 carbon atom, and other embodiment is that assorted alkyl group contains 1-6 carbon atom, other embodiment is, assorted alkyl group contains 1-4 carbon atom, and other embodiment is that assorted alkyl group contains 1-3 carbon atom.Such example comprises, but is not limited to CH 3oCH 2-, CH 3cH 2oCH 2-, CH 3sCH 2-, (CH 3) 2nCH 2-, (CH 3) 2cH 2oCH 2-, CH 3oCH 2cH 2-, CH 3cH 2oCH 2cH 2-etc.
Term " alicyclic ", " alicyclic group ", " annular aliphatic base ", " carbocyclic ring ", " carbocylic radical " or " cycloalkyl " refer to monovalence or multivalence, non-aromatic, the undersaturated ring of saturated or part, and do not comprise heteroatoms, comprising the monocycle of 3-12 carbon atom or two rings of 7-12 carbon atom.The bicyclic carbocyclic with 7-12 atom can be two rings [4,5], [5,5], [5,6] or [6,6] system, and the bicyclic carbocyclic simultaneously with 9 or 10 atoms can be two rings [5,6] or [6,6] system.Suitable annular aliphatic base comprises, but is not limited to cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of annular aliphatic base comprises, but be never limited to cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-thiazolinyl, 1-cyclopentyl-2-thiazolinyl, 1-cyclopentyl-3-thiazolinyl, cyclohexyl, 1-cyclohexyl-1-thiazolinyl, 1-cyclohexyl-2-thiazolinyl, 1-cyclohexyl-3-thiazolinyl, cyclohexadienyl, suberyl, ring octyl group, ring nonyl, ring decyl, ring undecyl, cyclo-dodecyl etc.And described " annular aliphatic base " or " carbocyclic ring ", " carbocylic radical ", " cycloalkyl " can be replacements or unsubstituted, wherein substituting group can be, but be not limited to, the alkoxyl group that deuterium, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, hydroxyl replace, alkyl-C (=O) that hydroxyl replaces-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O) 2-, hydroxyl replace alkyl-S (=O)-, hydroxyl replace alkyl-S (=O) 2-, the alkoxyl group of carboxyl substituted etc.
Term " cycloalkyl oxy " or " carbocylic radical oxygen base " comprise cycloalkyl or the carbocylic radical of optional replacement, as defined in the present invention, be connected on Sauerstoffatom, and be connected with all the other molecules by Sauerstoffatom, such example comprises, but is not limited to cyclopropyl oxygen base that cyclopropyl oxygen base, cyclopentyloxy, cyclohexyl oxygen base, hydroxyl replace etc.
Term " cycloalkyl amino " represents that amino group is replaced by one or two optional group of naphthene base replacing, wherein cycloalkyl has implication as described in the present invention, such example comprises, but is not limited to cyclopropylamino that cyclopropylamino, cyclopentyl amino, cyclohexyl amino, hydroxyl replace, dicyclohexyl amino, two cyclopropylaminos etc.
Term " carbocylic radical oxygen base alkoxyl group " represents that alkoxyl group is replaced by one or more carbocylic radical oxygen base groups, wherein alkoxyl group and carbocylic radical oxygen base group have implication as described in the present invention, such example comprises, but is not limited to cyclopropyl Oxymethoxy, cyclopropyl oxygen base oxethyl, cyclopentyloxy oxyethyl group, cyclohexyl oxygen base oxethyl, cyclohexenyl-3-oxygen base oxethyl etc.
Term " cycloalkyl oxy aliphatics " or " cycloalkyl oxy fatty group " represent that fatty group is replaced by the cycloalkyl oxy group of one or more optional replacements, wherein fatty group and cycloalkyl oxy group have implication as described in the present invention, such example comprises, but is not limited to cyclopropyl oxygen ylmethyl, cyclopropyl oxygen base ethyl, cyclopentyloxy methyl, cyclopentyloxy ethyl, cyclohexyl oxygen base ethyl, halogenated cyclopropyl oxygen base ethyl etc.
Term " cycloalkyl amino aliphatics " or " cycloalkyl amino fatty group " represent that fatty group is replaced by the cycloalkyl amino group of one or more optional replacements, wherein fatty group and cycloalkyl amino group have implication as described in the present invention, such example comprises, but is not limited to cyclopropylamino methyl, cyclopropylamino ethyl, cyclopentyl amino methyl, cyclopentyl amino-ethyl, cyclohexyl amino-ethyl, halogenated cyclopropyl amino-ethyl etc.
Term " cycloalkyl aliphatics " or " cycloalkyl fatty group " represent that fatty group can be replaced by one or more group of naphthene base, wherein cycloalkyl and fatty group have implication as described in the present invention, such example comprises, but is not limited to cyclopropyl methyl, cyclopropyl ethyl, cyclopropyl propyl group, cyclopentyl-methyl, cyclohexyl ethyl etc.
Term " cycloalkyl alkoxy " (" carbocylic radical alkoxyl group ") represents that alkoxy base is replaced by one or more cycloalkyl (" carbocylic radical ") group, wherein cycloalkyl (" carbocylic radical ") group and alkoxy base have implication as described in the present invention, such example comprises, but is not limited to cyclo propyl methoxy, cyclopropyl oxyethyl group, cyclopentyl oxyethyl group, cyclohexyl oxyethyl group, cyclohexyl methoxyl group, cyclopropyl propoxy-etc.
Term " heterocycle ", " heterocyclic radical ", " assorted alicyclic " or " heterocycle " commutative use herein, all refer to monocycle, dicyclo or three-ring system, wherein ring is gone up one or more carbon atoms independently and is optionally replaced by heteroatoms, described heteroatoms has implication as described in the present invention, ring can be completely saturated or comprise one or more degrees of unsaturation, but be never the fragrant same clan, only have a tie point to be connected to other molecules and get on.One or more ring hydrogen atoms are independent and optionally replaced by one or more substituting groups described in the invention.Some of them embodiment is, " heterocycle ", " heterocyclic radical ", " assorted alicyclic " or " heterocycle " group are that (1-6 carbon atom and 1-3 the heteroatoms that is selected from N, O, P, S, optionally replaced and obtain for example SO, SO by one or more Sauerstoffatom at this S or P for the monocycle of 3-7 ring 2, PO, PO 2group, in the time that described ring is triatomic ring, wherein only have a heteroatoms), or the dicyclo of 7-10 unit (4-9 carbon atom and be selected from 1-3 the heteroatoms of N, O, P, S optionally replaced and obtains for example SO, SO by one or more Sauerstoffatom at this S or P 2, PO, PO 2group).
Heterocyclic radical can be carbon back or heteroatoms base." heterocyclic radical " equally also comprises heterocyclic group and saturated or the unsaturated ring of part or heterocycle and closes formed group.The example of heterocycle comprises, but be not limited to, pyrrolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, thioxane base, thiazolidyl, oxazolidinyl, piperazinyl, homopiperazine base, azelidinyl, oxa-cyclobutyl, thia cyclobutyl, homopiperidinyl, epoxypropyl, nitrogen heterocyclic heptyl, oxepane base, thia suberyl, 4-methoxyl group-piperidin-1-yl, 1,2,3,6-tetrahydropyridine-1-base, oxygen azepine base, diaza
Figure BDA0000442505360000272
base, sulphur azepine
Figure BDA0000442505360000273
base, pyrroline-1-base, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxy amyl group, pyrazolinyl, dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidyl imidazolinyl, imidazolidyl, 1,2,3,4-tetrahydro isoquinolyl, 1,2,6-thiadiazine alkane 1,1-dioxo-2-base, 4-hydroxyl-Isosorbide-5-Nitrae-azepine phosphine 4-oxide compound-1-base, 2-hydroxyl-1-(piperazine-1-yl) ethyl ketone-4-base, 2-hydroxyl-1-(5,6-dihydro-1,2,4-triazine-1 (4H)-yl) ethyl ketone-4-base, 5,6-dihydro-4H-1,2,4-oxadiazine-4-base, 2-hydroxyl-1-(5,6-dihydropyridine-1 (2H)-yl) ethyl ketone-4-base, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, azabicyclo [2.2.2] hexyl, 2-methyl-5,6,7,8-tetrahydrochysene-[1,2,4] triazoles [1,5-c] pyrimidine-6-base, 4,5,6,7-tetrahydrochysene isoxazole [4,3-c] pyridine-5-base, 3H-indyl 2-oxygen-5-azabicyclo [2.2.1] heptane-5-base, 2-oxygen-5-azabicyclo [2.2.2] octane-5-base, quinolizinyl and N-pyridyl urea.The example of heterocyclic group also comprises, 1,1-dioxy thio-morpholinyl and wherein encircle two carbon atoms by pyrimidine dione base that Sauerstoffatom replaced.And described heterocyclic radical can be replacement or unsubstituted, wherein substituting group can be, but be not limited to, the alkoxyl group that deuterium, oxo (=O), hydroxyl, amino, halogen, cyano group, heteroaryl, alkoxyl group, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, hydroxyl replace, alkyl-C (=O) that hydroxyl replaces-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O) 2-, hydroxyl replace alkyl-S (=O)-, hydroxyl replace alkyl-S (=O) 2-, the alkoxyl group of carboxyl substituted etc.
Term " heterocyclic radical alkyl " comprises the alkyl that heterocyclic radical replaces; Term " heterocyclic radical alkoxyl group " comprises the alkoxyl group that heterocyclic radical replaces, and wherein Sauerstoffatom is connected with the rest part of molecule; Term " heterocyclic radical alkylamino " comprises the alkylamino that heterocyclic radical replaces, and wherein nitrogen-atoms is connected with the rest part of molecule.Wherein heterocyclic radical, alkyl, alkoxyl group and alkylamino have implication as described in the present invention, and such example comprises, but is not limited to pyrroles-2-ylmethyl, morpholine-4-base ethyl, morpholine-4-base oxethyl, piperazine-4-base oxethyl, piperidin-4-yl ethylamino etc.
Term " heterocyclic radical aliphatics " or " heterocyclic radical fatty group " represent the fatty group that heterocyclic radical replaces, wherein heterocyclic radical and fatty group have implication as described in the present invention, such example comprises, but is not limited to pyrroles-2-methyl, piperidines-2-ethyl, piperazine-2-ethyl, piperidines-2-methyl etc.
Term " heterocyclyloxy base " comprises the heterocyclic radical of optional replacement, as defined in the present invention, be connected on Sauerstoffatom, wherein Sauerstoffatom is connected with the rest part of molecule, such example comprises, but is not limited to pyrroles-2-oxygen base, pyrroles-3-oxygen base, piperidines-2-oxygen base, piperidines-3-oxygen base, piperazine-2-oxygen base, piperidines-4-oxygen base etc.
Term " heterocyclic radical amino " represents that amino group is replaced by one or two heterocyclic radical group, wherein nitrogen-atoms is connected with the rest part of molecule, and heterocyclic radical has implication as described in the present invention, such example comprises, but be not limited to pyrroles-2-amino, pyrroles-3-amino, piperidines-2-amino, piperidines-3-amino, piperidines-4-amino, piperazine-2-amino, two pyrroles-2-amino etc.
Term " heterocyclyloxy base alkoxyl group " represents that alkoxyl group is replaced by one or more heterocyclyloxy base groups, wherein alkoxyl group and heterocyclyloxy base group have implication as described in the present invention, such example comprises, but be not limited to pyrroles-2-Oxymethoxy, pyrroles-3-oxygen base oxethyl, piperidines-2-oxygen base oxethyl, piperidines-3-oxygen base oxethyl, piperazine-2-Oxymethoxy, piperidines-4-oxygen base oxethyl etc.
Term " heterocyclyloxy base aliphatics " or " heterocyclyloxy base fatty group " represent that fatty group is replaced by one or more heterocyclyloxy base groups, wherein fatty group and heterocyclyloxy base group have implication as described in the present invention, such example comprises, but be not limited to pyrroles-2-oxygen ylmethyl, piperazine-3-oxygen base ethyl, piperazine-2-oxygen base ethyl, morpholine-2-oxygen ylmethyl, piperidines-2-oxygen base ethyl etc.
Term " the amino aliphatics of heterocyclic radical " or " the amino fatty group of heterocyclic radical " represent that fatty group is replaced by one or more heterocyclic radical amino groups, wherein fatty group and heterocyclic radical amino group have implication as described in the present invention, such example comprises, but is not limited to pyrroles-2-amino methyl, piperazine-3-amino-ethyl, piperazine-2-amino-ethyl, piperidines-2-amino-ethyl, morpholine-2-amino methyl etc.
Term " heteroatoms " represents one or more O, S, N, P and Si atom, comprises the form of N, S and any oxidation state of P; The form of primary, secondary, tertiary amine and quaternary ammonium salt; Or the substituted form of hydrogen in heterocycle on nitrogen-atoms, for example, N (for example 3, the N in 4-dihydro-2 h-pyrrole base), NH (for example NH in pyrrolidyl) or NR (for example, NR in the pyrrolidyl that N-replaces).
Term " halogen " refers to F, Cl, Br or I.
The term " undersaturated " that used in the present invention represents that structure division contains one or more degrees of unsaturation.
The term " alkoxyl group " using in the present invention, relates to alkyl, as defined in the present invention, is connected in main carbochain by Sauerstoffatom, and such example comprises, but is not limited to methoxyl group, oxyethyl group, propoxy-, butoxy etc.And described alkoxyl group can be replacement or unsubstituted, and wherein substituting group can be, but is not limited to, deuterium, hydroxyl, amino, halogen, cyano group, alkoxyl group, alkyl, thiazolinyl, alkynyl, sulfydryl, nitro etc.
Term " alkoxyl group that hydroxyl replaces " represents that alkoxy base is replaced by one or more oh group, and wherein alkoxyl group has implication as described in the present invention, and such example comprises, but be not limited to hydroxyl methoxyl group, 2-hydroxyl-oxethyl, 2-hydroxyl propoxy-, 2-hydroxyl isopropyl oxygen etc.
Term " aminoalkoxy " represents that alkoxy base is replaced by one or more amino group, wherein alkoxyl group has implication as described in the present invention, such example comprises, but is not limited to ammonia methoxyl group, 2-amino ethoxy, the amino propoxy-of 2-, the amino isopropoxy of 2-etc.
Term " azido-alkoxyl group " represents that alkoxyl group is replaced by one or more azido-groups, wherein alkoxyl group has implication as described in the present invention, such example comprises, but is not limited to 2-azido-oxyethyl group, 3-azido-propoxy-, 2-azido-propoxy-etc.
Term " alkoxyl group alkoxyl group " represents that alkoxy base is replaced by one or more alkoxy base, wherein alkoxy base has implication as described in the present invention, such example comprises, but is not limited to methoxymethoxy, methoxy ethoxy, oxyethyl group methoxy base, ethoxy ethoxy, oxyethyl group propoxy-etc.
Term " alkoxyl group aliphatics " or " alkoxyl group fatty group " represent that fatty group is replaced by one or more alkoxy base, wherein fatty group and alkoxy base have implication as described in the present invention, such example comprises, but is not limited to methoxymethyl, ethoxyl methyl, ethoxyethyl group, ethoxy-c thiazolinyl etc.
Term " alkylamino aliphatics " or " alkylamino fatty group " represent that fatty group is replaced by one or more alkylamino groups, wherein fatty group and alkylamino group have implication as described in the present invention, such example comprises, but is not limited to dimethylaminoethyl, methylamino-ethyl, diethylin methyl, diethyllaminoethyl etc.
Term " alkylthio aliphatics " or " alkylthio fatty group " represent that fatty group is replaced by one or more alkylthio groups, wherein fatty group and alkylthio group have implication as described in the present invention, such example comprises, but is not limited to methylmercaptoethyl, methylthio group propyl group, ethylmercapto group ethyl, methylthio group propenyl etc.
Term " haloalkyl ", " haloalkenyl group " and " halogenated alkoxy " represents alkyl, thiazolinyl or alkoxyl group can be by the situations that one or more halogen atom replaced, and such example comprises, but is not limited to trifluoromethyl, the chloro-vinyl of 2-, trifluoromethoxy etc.
Term " aryl " can use separately or as most of " aralkyl ", " aralkoxy " or " aryloxy alkyl ", represent to contain altogether the carbocyclic ring system of monocycle, dicyclo and three rings of 6-14 ring, wherein, at least one member ring systems is aromatic, wherein each member ring systems comprises 3-7 ring, and only has an attachment point to be connected with the rest part of molecule.Term " aryl " can and term " aromatic nucleus " exchange use, as aromatic nucleus can comprise phenyl, naphthyl and anthryl.And described aryl can be replacement or unsubstituted, wherein substituting group can be, but be not limited to, the alkoxyl group that deuterium, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, hydroxyl replace, alkyl-C (=O) that hydroxyl replaces-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O) 2-, hydroxyl replace alkyl-S (=O)-, hydroxyl replace alkyl-S (=O) 2-, the alkoxyl group of carboxyl substituted etc.
Term " aromatic yl aliphat " or " aromatic yl aliphat base " represent that fatty group is replaced by the aromatic yl group of one or more optional replacements, wherein fatty group and aromatic yl group have implication as described in the present invention, such example comprises, but be not limited to styroyl, phenmethyl, to toluene ethyl, styryl etc.
Term " aryloxy " comprises the aryl of optional replacement, as defined in the present invention, be connected on Sauerstoffatom, and be connected with molecule rest part by Sauerstoffatom, wherein aromatic yl group has implication as described in the present invention, such example comprises, but is not limited to phenoxy group, tolyloxy, second phenoxy group etc.
Term " virtue is amino " represents that amino group is replaced by one or two optional aromatic yl group replacing, wherein aryl has implication as described in the present invention, such example comprises, but be not limited to phenyl amino, to fluorophenyl amino, diphenyl amino, xylyl amino, di-p-tolyl amino etc.
Term " aryloxy alcoxyl base " represents that alkoxyl group is replaced by the aryloxy group of one or more optional replacements, wherein alkoxyl group and aryloxy group have implication as described in the present invention, such example comprises, but is not limited to phenoxy group methoxyl group, phenoxy group oxyethyl group, phenoxy group propoxy-etc.
Term " aryloxy aliphatics " or " aryloxy fatty group " represent that fatty group is replaced by the aryloxy group of one or more optional replacements, wherein aryloxy and fatty group have implication as described in the present invention, such example comprises, but is not limited to phenoxymethyl, phenoxy group ethyl, tolyloxy ethyl, phenoxy propyl etc.
Term " fragrant amino aliphatics " or " fragrant amino fatty group " represent that fatty group is replaced by the fragrant amino group of one or more optional replacements, wherein virtue amino and fatty group have implication as described in the present invention, such example comprises, but is not limited to phenylamino methyl, phenylamino ethyl, toluino ethyl, phenylamino propyl group, phenylamino allyl group etc.
Term " alkoxy aryl " represents that alkoxy base is replaced by the aryl of one or more optional replacements, wherein aryl and alkoxyl group have implication of the present invention, such example comprises, but is not limited to phenyl methoxyl group, phenyl ethoxy, p-methylphenyl methoxyl group, phenyl propoxy-etc.
Term " aryl alkane amino " represents that alkylamino group is replaced by the aromatic yl group of one or more optional replacements, wherein aryl and alkylamino have implication of the present invention, such example comprises, but is not limited to phenyl methylamino-, phenyl ethylamino, phenyl the third amino, p-methylphenyl methylamino-etc.
Term " heteroaryl " can use separately or as most of " heteroarylalkyl " or " heteroaryl alkoxyl group ", represent to contain altogether monocycle, dicyclo and the three-ring system of 5-14 ring, wherein at least one member ring systems is aromatic, and at least one member ring systems comprises one or more heteroatomss, wherein heteroatoms has implication of the present invention, wherein each member ring systems comprises 3-7 ring, and only has an attachment point to be connected with molecule rest part.Term " heteroaryl " can use with term " fragrant heterocycle " or " heteroaromatics " exchange.And described heteroaryl can be replacement or unsubstituted, wherein substituting group can be, but be not limited to, the alkoxyl group that deuterium, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, hydroxyl replace, alkyl-C (=O) that hydroxyl replaces-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O) 2-, hydroxyl replace alkyl-S (=O)-, hydroxyl replace alkyl-S (=O) 2-, the alkoxyl group of carboxyl substituted etc.
Other embodiment is that fragrant heterocycle comprises following monocycle, but is not limited to these monocycles: 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methyl-isoxazole-5-base, N-pyrryl, 2-pyrryl, 3-pyrryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, pyrimidine-5-base, pyridazinyl (as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazyl (as 5-tetrazyl), triazolyl (as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazoles base, 1,2,3-thio biphosphole base, 1,3,4-thio biphosphole base, 1,2,5-thio biphosphole base, 1,3,4-thiadiazoles-2-base, pyrazinyl, pyrazine-2-base, 1,3,5-triazines base, benzo [d] thiazol-2-yl, imidazo [1,5-a] pyridine-6-base, also comprise following dicyclo, but be never limited to these dicyclos: benzimidazolyl-, benzofuryl, benzothienyl, indyl (as 2-indyl), purine radicals, quinolyl (as 2-quinolyl, 3-quinolyl, 4-quinolyl) and isoquinolyl (as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl).
Term " heteroaryl oxygen base " comprises the heteroaryl of optional replacement, as defined in the present invention, be connected on Sauerstoffatom, and be connected with molecule rest part by Sauerstoffatom, wherein heteroaryl groups has implication as described in the present invention, such example comprises, but is not limited to pyridine-2-oxygen base, thiazole-2-oxygen base, imidazoles-2-oxygen base, pyrimidine-2-oxygen base etc.
Term " heteroaryl oxygen base aliphatics " or " heteroaryl oxygen base fatty group " represent that fatty group is replaced by the heteroaryl oxygen base group of one or more optional replacements, wherein fatty group and heteroaryl oxygen base group have implication as described in the present invention, such example comprises, but is not limited to pyridine-2-oxygen base ethyl, thiazole-2-oxygen ylmethyl, imidazoles-2-oxygen base ethyl, pyrimidine-2-oxygen base propyl group etc.
No matter term " alkylsulfonyl ", be to use separately or be used in conjunction as " alkyl sulphonyl " with other term, represents respectively the group-SO of divalence 2-.
Term " alkyl sulphonyl " refers to the alkylsulfonyl group that alkyl replaces, and forms alkyl sulphonyl (SO 2alkyl, as-SO 2cH 3).
Term " sulphonamide ", " amino-sulfonyl " and " sulfamyl " represent the amino alkylsulfonyl group replacing, and form sulfamyl (SO 2nH 2).
No matter term " carboxyl " is use separately or be used in conjunction (as " carboxyalkyl "), expression-CO with other terms 2h;
No matter term " carbonyl ", be use separately or be used in conjunction (as " aminocarboxyl " or " acyloxy ") with other terms, represent-(C=O)-.
Term " alkoxyl group of carboxyl substituted " represents that alkoxy base is replaced by one or more carboxylic group, and wherein alkoxyl group and carboxylic group have implication as described in the present invention, and such example comprises, but is not limited to carboxyl methoxyl group, carboxyl oxyethyl group etc.
Term " aralkyl " comprises the alkyl group that aryl replaces.Some of them embodiment is, aromatic alkyl group refers to " more rudimentary aralkyl " group, and aromatic yl group is connected to C 1-6alkyl group on.Other embodiment is that aromatic alkyl group refers to containing C 1-3" the benzene alkylene " of alkyl.Wherein specific examples comprises benzyl, diphenyl methyl, styroyl.Aryl on aralkyl can further be replaced by halogen, alkyl, alkoxyl group, haloalkyl and halogenated alkoxy.
Term " alkylthio " comprises C 1-10the alkyl of straight or branched is connected on the sulphur atom of divalence.Some of them embodiment is that alkylthio is more rudimentary C 1-3alkylthio, such example comprises, but is not limited to methylthio group (CH 3s-).
Term " halogenated alkylthio " comprises C 1-10haloalkyl be connected on bivalent sulfur atom.Some of them embodiment is that halogenated alkylthio is more rudimentary C 1-3halogenated alkylthio, such example comprises, but is not limited to trifluoromethylthio.
Term " alkylamino " comprises " N-alkylamino " and " N, N-dialkyl amido ", and wherein amine groups is replaced by one or two alkyl group respectively independently.Some of them embodiment is that alkylamino is one or two C 1-6alkyl is connected to the more rudimentary alkylamino group on nitrogen-atoms.Other embodiment is that alkylamino is C 1-3more rudimentary alkylamino group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example comprises, but is not limited to N-methylamino-, N-ethylamino, N, N-dimethylamino, N, N-diethylin etc.
Term " alkylamino halogenated alkoxy " represents that halogenated alkoxy is replaced by one or more alkylamino groups, wherein halogenated alkoxy and alkylamino group have implication as described in the present invention, such example comprises, but is not limited to methylamino-two fluoro methoxyl groups, ethylamino trifluoromethoxy etc.
Term " heteroaryl amino " represents that amine groups is replaced by one or two heteroaryl, and wherein heteroaryl has implication of the present invention, and such example comprises, but is not limited to N-thienyl amino etc.Some of them embodiment is that the hetero-aromatic ring on heteroaryl amino can further be substituted.
Term " heteroaryl aliphatics " or " heteroaryl fatty group " represent that fatty group is replaced by one or more heteroaryl, wherein heteroaryl and fatty group have implication of the present invention, such example comprises, but is not limited to thiophene-2-propenyl, pyridine-4-ethyl, imidazoles-2-methyl, furans-2-ethyl, indoles-3-methyl etc.
Term " heteroarylalkyl " represents that alkyl group is replaced by one or more heteroaryl, wherein heteroaryl and alkyl group have implication of the present invention, such example comprises, but is not limited to imidazoles-2-methyl, furans-2-ethyl, indoles-3-methyl etc.
Term " heteroaryl alkylamino " comprises that the heteroarylalkyl group that contains nitrogen-atoms is connected on other groups by nitrogen-atoms, wherein heteroarylalkyl has implication as described in the present invention, such example comprises, but is not limited to pyridine-2-base methylamino-, thiazol-2-yl ethylamino, imidazoles-2-base ethylamino, pyrimidine-2-base the third amino, pyrimidine-2-base methylamino-etc.
Term " aminoalkyl group " comprises the C being replaced by one or more amino 1-10straight or branched alkyl group.Some of them embodiment is, aminoalkyl group is by C that one or more amino group replaced 1-6" more rudimentary aminoalkyl group ", such example comprises, but is not limited to, aminomethyl, aminoethyl, aminopropyl, ammonia butyl and ammonia hexyl.
Term " alkylamino alkyl " comprises the alkyl group being replaced by alkylamino.Some of them embodiment is that alkylamino alkyl is C 1-6more rudimentary alkyl amino alkyl.Other embodiment is that alkylamino alkyl is C 1-3more rudimentary alkyl amino alkyl.Suitable alkyl amino alkyl group can be that monoalkyl or dialkyl group replace, and such example comprises, but is not limited to N-methylamino methyl, N, N-dimethyl aminoethyl, N, N-diethylamino methyl etc.
Term " carboxyalkyl " comprises can be by the C that one or more carboxyl replaced 1-10straight or branched alkyl, such example comprises, but is not limited to carboxymethyl, carboxylic propyl group etc.
Term " aryloxy " comprises the aryl of optional replacement, is connected on Sauerstoffatom, and is connected with molecule rest part by Sauerstoffatom as the present invention is defined, and such example comprises, but is not limited to phenoxy group etc.
Term " heteroaryl alkoxyl group " comprises that the heteroarylalkyl group that contains Sauerstoffatom is connected on other groups by Sauerstoffatom, wherein heteroarylalkyl has implication as described in the present invention, such example comprises, but is not limited to pyridine-2-ylmethoxy, thiazol-2-yl oxyethyl group, imidazoles-2-base oxethyl, pyrimidine-2-base propoxy-, pyrimidine-2-base methoxyl group etc.
Term " cycloalkylalkyl " represents the alkyl group of the optional cycloalkyl substituted replacing, and such example comprises, but is not limited to cyclohexyl methyl.Described cycloalkyl can be further by deuterium, and halogen, alkyl, alkoxyl group and hydroxyl replace.
Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base ", " condensed ring radical " represents saturated or undersaturated and member ring systems or bridged-ring system, relate to also ring or the bridged-ring system of non-aromatic, shown in (a1), encircle A1 and have a key with ring A2, an alkane chain or an assorted alkane chain, wherein j is 0,1,2,3 or 4.Such system can comprise independently or the undersaturated condition of conjugation, but its core texture does not comprise aromatic nucleus or fragrant heterocycle (but aromatic series can be used as the substituting group on it).Each ring in condensed-bicyclic is carbocyclic ring or is assorted alicyclic, and such example comprises, but is not limited to, six hydrogen-furo [3,2-b] furans, 2,3,3a, 4,7,7a-six hydrogen-1H-indenes, 7-azabicyclo [2.3.0] heptane, condensed-bicyclic [3.3.0] octane, condensed-bicyclic [3.1.0] hexane, dicyclo [2.2.1] heptane, 2-azabicyclo [2.2.1] heptane, 1,2,3,4,4a, 5,8,8a-octahydro naphthalene, within these are included in the system of condensed-bicyclic or bridged ring.And described condensed-bicyclic base can be replacement or unsubstituted, wherein substituting group can be, but be not limited to, the alkoxyl group that deuterium, oxo (=O), hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, hydroxyl replace, alkyl-C (=O) that hydroxyl replaces-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O) 2-, hydroxyl replace alkyl-S (=O)-, hydroxyl replace alkyl-S (=O) 2-, the alkoxyl group of carboxyl substituted etc.
Figure BDA0000442505360000311
Term " condenses assorted bicyclic group " and represents saturated or undersaturated and member ring systems or bridged-ring system, relates to also member ring systems or the bridged-ring system of non-aromatic.Such system can comprise independently or the undersaturated condition of conjugation, but its core texture does not comprise aromatic nucleus or fragrant heterocycle (but aromatic series can be used as the substituting group on it).And at least one member ring systems comprises one or more heteroatomss, wherein each member ring systems comprises 3-7 ring, comprise 1-6 carbon atom and 1-3 the heteroatoms that is selected from N, O, P, S, optionally replaced and obtain for example SO, SO by one or more Sauerstoffatom at this S or P 2, PO, PO 2group, such example comprises, but is not limited to six hydrogen-furo [3.2-b] furans, 6-azabicyclo [3.2.0] heptane, 2-azabicyclo [3.1.0] heptane, 3-azabicyclo [3.1.0] heptane, 7-azabicyclo [2.3.0] heptane, 2-azabicyclo [2.2.1] heptane etc.And described in to condense assorted bicyclic group can be to replace or unsubstituted, wherein substituting group can be, but be not limited to, the alkoxyl group that deuterium, oxo (=O), hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, hydroxyl replace, alkyl-C (=O) that hydroxyl replaces-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O) 2-, hydroxyl replace alkyl-S (=O)-, hydroxyl replace alkyl-S (=O) 2-, the alkoxyl group of carboxyl substituted etc.
Term " volution base ", " volution ", " spiral shell bicyclic group ", " spiral shell dicyclo " represent that a ring originates from the upper special ring-type carbon of another ring.For example, ring A and ring B share a carbon atom in two saturated member ring systems, are called as " volution ".Each ring of volution the inside is carbocyclic ring or is assorted alicyclic.Such example comprises, but be not limited to 2,7-diaza spiro [4.4] nonane-2-base, 7-oxygen-2-azaspiro [4.5] decane-2-base, 4-azaspiro [2.4] heptane-5-base, 4-oxaspiro [2.4] heptane-5-base, 5-azaspiro [2.4] heptane-5-base, spiral shell [2.4] heptane base, spiral shell [4.4] nonyl, 7-hydroxyl-5-azaspiro [2.4] heptane-5-base etc.And described spiral shell bicyclic group can be replacement or unsubstituted, wherein substituting group can be, but be not limited to, the alkoxyl group that deuterium, oxo (=O), hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, hydroxyl replace, alkyl-C (=O) that hydroxyl replaces-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O) 2-, hydroxyl replace alkyl-S (=O)-, hydroxyl replace alkyl-S (=O) 2-, the alkoxyl group of carboxyl substituted etc.
Figure BDA0000442505360000321
Term " sub-spiral shell bicyclic group " represents that spiral shell bicyclic group system has two tie points and is connected with molecule rest part, and wherein spiral shell bicyclic group has implication as described in the present invention.
Term " spiral shell mix bicyclic group " represents that a ring originates from the upper special ring-type carbon of another ring.For example, as described above, ring A and ring B share a carbon atom in two saturated member ring systems, are called as " volution ".And at least one member ring systems comprises one or more heteroatomss, wherein each member ring systems comprises 3-7 ring, comprise 1-6 carbon atom and 1-3 the heteroatoms that is selected from N, O, P, S, optionally replaced and obtain for example SO, SO by one or more Sauerstoffatom at this S or P 2, PO, PO 2group, such example comprises, but be not limited to 4-azaspiro [2.4] heptane-5-base, 4-oxaspiro [2.4] heptane-5-base, 5-azaspiro [2.4] heptane-5-base, 7-hydroxyl-5-azaspiro [2.4] heptane-5-base, 5-azaspiro [2.4] heptane-6-base, Isosorbide-5-Nitrae-dioxy-7-azaspiro [4.4] nonane-8-base etc.And the assorted bicyclic group of described spiral shell can be replacement or unsubstituted, wherein substituting group can be, but be not limited to, the alkoxyl group that deuterium, oxo (=O), hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl group, alkylamino, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy, hydroxyl replace, alkyl-C (=O) that hydroxyl replaces-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O) 2-, hydroxyl replace alkyl-S (=O)-, hydroxyl replace alkyl-S (=O) 2-, the alkoxyl group of carboxyl substituted etc.
The carboxyl that a-amino acid group of the present invention is a-amino acid removes the group that hydroxyl forms, it is connected with X or X ', and described a-amino acid group can optionally be replaced by one or more substituting groups that are selected from deuterium, F, Cl, Br, I, hydroxyl or cyano group.For example
Figure BDA0000442505360000322
As described in the invention, a key of substituting group picture is connected to the member ring systems (shown in (a)) forming on the ring at center and represents substituting group (R 5a) fcan on ring, replace any commutable position.For example, formula (a) represents any may all can being substituted substituted position on W1 ring, W2 ring or W ring.
Figure BDA0000442505360000331
As described in the invention, in member ring systems, have two tie points to be connected with other groups, shown in (b), the E end of representative ring W3 all can be connected with other groups with E' end, and the group that in the present invention, E is connected with E' two ends can exchange.
Figure BDA0000442505360000332
As described in the invention, member ring systems the inside dotted line key represents two keys or singly-bound.For example, the structure of formula (c) represents the structure that any one is elected from formula (d) the inside.
Unless other aspects show, structural formula described in the invention comprises that all isomeric forms are (as enantiomerism, diastereo-isomerism, and rotamerism (or conformational isomerism)): the R, the S configuration that for example contain asymmetric center, (Z), (E) isomer of two keys, and (Z), the conformer of (E).Therefore, the single three-dimensional chemical isomer of compound of the present invention or its enantiomer, diastereomer, or the mixture of geometrical isomer (or conformer) all belongs to scope of the present invention.
In addition, it should be noted that, unless otherwise explicitly pointed out, the describing mode " each ... be independently " that adopts in the whole text in this article, " ... be independently " and " ... be independently of one another " can exchange, all should be interpreted broadly, it both can refer in different groups, between same-sign, between expressed concrete option, do not affect mutually, also can be illustrated in identical group, between same-sign, between expressed concrete option, not affect mutually, with R 9for example, structural formula " U-(CR 9r 9a) t-R 12" and structural formula " [U-(CR 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12" R between the two 9concrete option unaffected between mutually, meanwhile, at same chemical formula " [U-(CR 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12" in, multiple R 9concrete option unaffected between mutually.
Term used in the present invention " prodrug ", represents that a compound is converted into the compound shown in formula (I) in vivo.Such conversion is hydrolyzed by prodrug or the impact that is precursor structure through enzymatic conversion in blood or tissue in blood.Prodrug compounds of the present invention can be ester, and what in existing invention, ester can be used as prodrug has phenyl ester class, an aliphatics (C 1-24) ester class, acyloxy methyl ester class, carbonic ether, amino formate and amino acid esters.For example a compound in the present invention comprises hydroxyl, its acidylate can be obtained to the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that hydroxyl phosphorylation on parent obtains.Can be with reference to Publication about Document about the complete discussion of prodrug: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.Rautio et al, Prodrugs:Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S.J.Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.
Unless other aspects show, within all tautomeric forms of compound of the present invention are included in scope of the present invention.In addition, unless other aspects show, the structural formula of compound described in the invention comprises the enriched isotope of one or more different atoms.
" meta-bolites " refers to the product that concrete compound or its salt obtains by metabolism in vivo.The meta-bolites of a compound can identify by the known technology in affiliated field, and its activity can characterize by the method that adopts test as described in the invention.Such product can be by obtaining through oxidation, reduction, hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method to drug compound.Correspondingly, the present invention includes the meta-bolites of compound, comprise compound of the present invention is fully contacted to the meta-bolites that for some time produces with Mammals.
The definition of neutral body chemistry of the present invention and the use of convention be conventionally with reference to Publication about Document: S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; And Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley & Sons, Inc., New York, 1994.Compound of the present invention can comprise asymmetric center or chiral centre, therefore has different steric isomers.The stereoisomeric forms in any ratio that compound of the present invention is all, include, but not limited to, and diastereomer, enantiomer, atropisomer and their mixture, as racemic mixture, have formed a part of the present invention.A lot of organic compound all exist with optical activity form, i.e. the plane of their capable Plane of rotation polarized light.In the time describing optically active compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) are used for naming the symbol of compound plane polarized light rotation, and (-) or l refer to that compound is left-handed, and prefix (+) or d refer to that compound is dextrorotation.The chemical structure of these steric isomers is identical, but their three-dimensional arrangement is different.The mixture that specific steric isomer can be enantiomorph, isomer is commonly referred to enantiomeric mixture.The mixture of enantiomers of 50:50 is called as racemic mixture or racemic modification, and this may cause in chemical reaction process, there is no stereoselectivity or stereospecificity.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack optical activity.
Term " tautomer " or " tautomeric form " refer to that the isomers of the structure of different-energy can transform mutually by low energy barrier.For example proton tautomerism body (being prototropic tautomer) comprises the change by proton shifting, as the isomerization of keto-acid-enol form and imines-enamine.Valence (valency) tautomer comprises the change that reassembles into bonding electron.
" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmacy acceptable salt is for we are known in affiliated field, as document: S.M.Berge et al., J.Pharmaceutical Sciences, 66,1-19,1977 record.The salt that pharmaceutically acceptable nontoxic acid forms comprises, but be not limited to, react the inorganic acid salt forming with amino group and have hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by the additive method recorded on books document as ion exchange method with organic acid salt.Other pharmacy acceptable salts comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate etc.The salt obtaining by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N +(C 1-4alkyl) 4salt.The present invention also intends the quaternary ammonium salt that the compound of the group of having conceived any comprised N forms.Water-soluble or oil soluble or disperse product to obtain by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium etc.Pharmacy acceptable salt further comprises suitable, nontoxic ammonium, and the amine positively charged ion that quaternary ammonium salt and gegenions form, as halogenide, oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C 1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the associated complex that one or more solvent molecules and compound of the present invention form.The solvent that forms solvate comprises, but is not limited to water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid, monoethanolamine.Term " hydrate " refers to that solvent molecule is the associated complex that water forms.
When term " blocking group " or " Pg " refer to a substituting group and other reacted with functional groups, be commonly used to blocking-up or protect special functional.For example; " amino blocking group " refers to that a substituting group is connected to block or protect in compound amino functional with amino group, and suitable amido protecting group comprises ethanoyl, trifluoroacetyl group, tertbutyloxycarbonyl (BOC), carbobenzoxy-(Cbz) (CBZ) and 9-fluorenes Asia methoxycarbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to that the substituting group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises ethanoyl and silyl." carboxy protective group " refer to the substituting group of carboxyl be used for blocking-up or protection carboxyl functional, comprise-CH of general carboxyl-protecting group 2cH 2sO 2ph, cyano ethyl, 2-(TMS) ethyl, 2-(TMS) ethoxyl methyl, 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl alkylsulfonyl) ethyl, 2-(diphenylphosphino) ethyl, nitro-ethyl etc.Can reference: T.W.Greene for the general description of blocking group, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; And P.J.Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
It should be noted that, the term in the present invention " suppresses HCV viral protein " and should be interpreted broadly, and it had both comprised the expression level that suppresses HCV viral protein, also comprised the activity level that suppresses HCV viral protein, assembling and the emission levels of virus.Wherein, HCV protein expression level includes but not limited to: the levels of replication of the translation skill of viral protein gene, the posttranslational modification level of albumen, filial generation genetic material, etc.
The description of the compounds of this invention
The spirocyclic compound the present invention relates to and pharmaceutical preparation thereof, can effectively suppress HCV and infect, and especially can suppress the activity of HCV NS5A albumen.
On the one hand, the present invention relates to a kind of compound, it is steric isomer, the rotamerism of compound shown in the compound shown in formula (I) or formula (I)
Body, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug,
Figure BDA0000442505360000351
Wherein, each A and A ' are a key, alkylidene group, alkenylene, cycloalkylidene, sub-Heterocyclylalkyl ,-(CR independently 8r 8a) n-O-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-C (=O)-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-O-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-S (=O) r-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-O-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=S)-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-C (=O)-O-(CR 8r 8a) p-, or each A and A ' are following group independently:
Figure BDA0000442505360000361
Wherein, each X 1or X 2be O, S, NR independently 6or CR 7r 7a;
X 4for (CR 7r 7a) n,-Y 1=N-, O, S or NR 6;
W is carbocylic radical or heterocyclic radical;
Each Y 1and Y 2be N or CR independently 7;
Z is-(CH 2) a-,-CH=CH-,-N=CH-,-(CH 2) a-N (R 5)-(CH 2) b-or-(CH 2) a-O-(CH 2) b-;
Wherein each a and b are 0,1,2 or 3 independently;
Each c is 1 or 2 independently;
Each d is 1 or 2 independently;
Each n is 0,1,2 or 3 independently;
Each p is 0,1,2 or 3 independently;
Each r is 0,1 or 2 independently;
F is 0,1,2,3 or 4;
Each Q 1and Q 2be NR independently 6, O, S, C (=O) or (CR 7r 7a) e;
Each e is 0,1,2,3 or 4 independently;
Each X and X ' are N or CR independently 7;
Each Y and Y ' are the optically active isomer of H, deuterium, alkyl, assorted alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, a-amino acid group or a-amino acid group independently, or each Y and Y ' are following structural unit independently :-[U-(CR 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12,-U-(CR 9r 9a) t-R 12or-[U-(CR 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-O-(CR 9r 9a) t-R 12;
Each U is independently-C (=O)-,-C (=S)-,-S (=O)-or-S (=O) 2-;
Each t is 0,1,2,3 or 4 independently;
Each k is 0,1 or 2 independently;
Each R 1, R 2, R 3and R 4be H, deuterium, alkyl, assorted alkyl, aralkyl, cycloalkyl, heterocyclic radical, heteroaryl or aryl independently, or R 1, R 2form 3-8 unit heterocycle or 3-8 unit carbocyclic ring, C with X-CH 5-12condensed-bicyclic, C 5-12condense assorted dicyclo, C 5-12spiral shell dicyclo or C 5-12the spiral shell dicyclo of mixing; Or R 3, R 4and X '-CH forms 3-8 unit's heterocycle or carbocyclic ring, C 5-12condensed-bicyclic, C 5-12condense assorted dicyclo, C 5-12spiral shell dicyclo or C 5-12the spiral shell dicyclo of mixing;
Each R 5be independently H, deuterium, hydroxyl, alkyl, assorted alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alkoxyl group, alkyl-OC (=O)-, alkyl-C (=O)-, formamyl, alkyl-OS (=O) r-, alkyl-S (=O) ro-, alkyl-S (=O) r-or amino-sulfonyl;
Each R 5abe H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, R independently 13ar 13n-,-C (=O) NR 13r 13a,-OC (=O) NR 13r 13a,-OC (=O) OR 13,-N (R 13) C (=O) NR 13r 13a,-N (R 13) C (=O) OR 13,-N (R 13) C (=O)-R 13, R 13r 13an-S (=O) 2-, R 13s (=O) 2-, R 13s (=O) 2n (R 13a)-, R 13ar 13n-alkyl, R 13s (=O)-alkyl, R 13r 13an-C (=O)-alkyl, R 13ar 13n-alkoxyl group, R 13s (=O)-alkoxyl group, R 13r 13an-C (=O)-alkoxyl group, aryl, heteroaryl, alkoxyl group, alkylamino, alkyl, haloalkyl, thiazolinyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aralkyl, virtue is amino, heteroaryl amino, aryl alkane amino, heteroaryl alkylamino, heteroaryl oxygen base, heteroarylalkyl, alkoxy aryl, heteroaryl alkoxyl group, heterocyclyloxy base, heterocyclic radical alkoxyl group, heterocyclic radical amino, alkyl acyl, alkyl acyloxy, alkoxyl group acyl group, alkyl sulphonyl, alkoxyl group alkylsulfonyl, alkyl sulphinyl, alkyl sulphonyl oxygen base, alkyl sulphinyl oxygen base, heterocyclic radical alkylamino or aryloxy,
Each R 6be hydrogen, deuterium, R independently 13r 13anC (=O)-, R 13oC (=O)-, R 13c (=O)-, R 13r 13anS (=O)-, R 13oS (=O)-, R 13s (=O)-, R 13r 13anS (=O) 2-, R 13oS (=O) 2-, R 13s (=O) 2-, the amino aliphatics of aliphatics, halogenated aliphatic, hydroxyl group aliphatic, amino aliphatics, alkoxyl group aliphatics, alkylamino aliphatics, alkylthio aliphatics, aromatic yl aliphat, heteroaryl aliphatics, heterocyclic radical aliphatics, cycloalkyl aliphatics, aryloxy aliphatics, heterocyclyloxy base aliphatics, cycloalkyl oxy aliphatics, fragrant amino aliphatics, heterocyclic radical, cycloalkyl amino aliphatics, aryl, heteroaryl, heterocyclic radical or carbocylic radical;
Each R 6abe H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, oxo (=O), R independently 13ar 13n-,-C (=O) NR 13r 13a,-OC (=O) NR 13r 13a,-OC (=O) OR 13,-N (R 13) C (=O) NR 13r 13a,-N (R 13) C (=O) OR 13a,-N (R 13) C (=O)-R 13a, R 13r 13an-S (=O) 2-, R 13s (=O) 2-, R 13s (=O) 2n (R 13a)-, R 13ar 13n-alkyl, R 13s (=O)-alkyl, R 13r 13an-C (=O)-alkyl, R 13ar 13n-alkoxyl group, R 13s (=O)-alkoxyl group, R 13r 13an-C (=O)-alkoxyl group, aryl, heteroaryl, alkoxyl group, alkylamino, alkyl, haloalkyl, thiazolinyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aralkyl, virtue is amino, heteroaryl amino, aryl alkane amino, heteroaryl alkylamino, heteroaryl oxygen base, heteroarylalkyl, alkoxy aryl, heteroaryl alkoxyl group, heterocyclyloxy base, heterocyclic radical alkoxyl group, heterocyclic radical amino, alkyl acyl, alkyl acyloxy, alkoxyl group acyl group, alkyl sulphonyl, alkoxyl group alkylsulfonyl, alkyl sulphinyl, alkyl sulphonyl oxygen base, alkyl sulphinyl oxygen base, heterocyclic radical alkylamino or aryloxy,
Each R 7and R 7abe H independently, deuterium, F, Cl, Br, I, aliphatics, assorted alkyl, halogenated aliphatic, hydroxyl group aliphatic, amino aliphatics, alkoxyl group aliphatics, alkylamino aliphatics, alkylthio aliphatics, aromatic yl aliphat, heteroaryl aliphatics, heterocyclic radical aliphatics, cycloalkyl aliphatics, aryloxy aliphatics, heterocyclyloxy base aliphatics, cycloalkyl oxy aliphatics, the amino aliphatics of virtue, the amino aliphatics of heterocyclic radical, cycloalkyl amino aliphatics, aryl, heteroaryl, heterocyclic radical or carbocylic radical,
Each R 8and R 8abe independently H, deuterium, hydroxyl, cyano group, nitro, F, Cl, Br, I, alkyl, assorted alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alkoxyl group, alkyl-OC (=O)-, alkyl-C (=O)-, formamyl, alkyl-OS (=O) r-, alkyl-S (=O) ro-, alkyl-S (=O) r-or amino-sulfonyl;
Each R 9, R 9a, R 10and R 11be H, deuterium, alkyl, assorted alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, haloalkyl, hydroxyalkyl, heteroarylalkyl, heterocyclic radical alkyl or cycloalkyl alkyl independently;
Each R 12be R independently 13ar 13n-,-C (=O) R 13,-C (=S) R 13,-C (=O)-O-R 13,-C (=O) NR 13r 13a,-OC (=O) NR 13r 13a,-OC (=O) OR 13,-N (R 13) C (=O) NR 13r 13a,-N (R 13) C (=O) OR 13a,-N (R 13) C (=O)-R 13a, R 13r 13an-S (=O) 2-, R 13s (=O) 2-, R 13s (=O) 2n (R 13a)-, R 13oS (=O) 2-, alkyl, assorted alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or aralkyl;
Or R 11, R 12can at random form 4-7 ring with the atom being attached thereto; With
With each R 13and R 13abe H, deuterium, alkyl, assorted alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or aralkyl independently; Work as R 13and R 13abe connected on same nitrogen-atoms R 13, R 13acan at random form substituted or non-substituted 3-8 ring, spiral shell dicyclo or condensed-bicyclic with nitrogen-atoms;
Wherein each following group: alkylidene, alkenylene, cycloalkylidene, sub-Heterocyclylalkyl ,-(CR 8R 8a) n-O-(CR 8R 8a) p-,-(CR 8R 8a) n-N (R 5)-(CR 8R 8a) p-,-(CR 8R 8a) n-S (=O) r-N (R 5)-(CR 8R 8a) p-,-(CR 8R 8a) n-C (=O)-N (R 5)-(CR 8R 8a) p-,-(CR 8R 8a) n-N (R 5)-C (=O)-N (R 5)-(CR 8R 8a) p-,-(CR 8R 8a) n-C (=O)-O-(CR 8R 8a) p-,-(CR 8R 8a) n-N (R 5)-S (=O) r-N (R 5)-(CR 8R 8a) p-,-(CR 8R 8a) n-S (=O) r-(CR 8R 8a) p-,-(CR 8R 8a) n-S (=O) r-O-(CR 8R 8a) p-,-(CR 8R 8a) n-C (=O)-(CR 8R 8a) p-,-(CR 8R 8a) n-C (=S)-(CR 8R 8a) p-,-(CR 8R 8a) n-N (R 5)-C (=O)-O-(CR 8R 8a) p-,-[U-(CR 9R 9a) t-N (R 10)-(CR 9R 9a) t] k-U-(CR 9R 9a) t-N (R 11)-(CR 9R 9a) t-R 12,-U-(CR 9R 9a) t-R 12,-[U-(CR 9R 9a) t-N (R 10)-(CR 9R 9a) t] k-U-(CR 9R 9a) t-O-(CR 9R 9a) t-R 12, NR 6, CR 7R 7a, CR 7,-(CH 2) a-,-CH=CH-,-N=CH-,-(CH 2) a-N (R 5)-(CH 2) b-,-(CH 2) a-O-(CH 2) b-, R 13aR 13N-,-C (=O) R 13,-C (=S) R 13,-C (=O)-O-R 13,-C (=O) NR 13R 13a,-OC (=O) NR 13R 13a,-OC (=O) OR 13,-N (R 13) C (=O) NR 13R 13a,-N (R 13) C (=O) OR 13a,-N (R 13) C (=O)-R 13a, R 13R 13aN-S (=O) 2-, R 13S (=O) 2-, R 13S (=O) 2N (R 13a)-, R 13OS (=O) 2-, alkyl-OC (=O)-, alkyl-C (=O)-, alkyl-OS (=O) r-, alkyl-S (=O) rO-, alkyl-S (=O) r-, R 13R 13aNS (=O)-, R 13OS (=O)-, R 13S (=O)-, alkyl, R 13S (=O)-alkyl, R 13R 13aN-C (=O)-alkyl, R 13aR 13N-alkoxyl, R 13S (=O)-alkoxyl, R 13R 13aN-C (=O)-alkylamino, alkyl, assorted alkyl, carbocylic radical, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, a-amino acid, C 5-12condensed-bicyclic, C 5-12condense assorted dicyclo, C 5-12spiral shell dicyclo or C 5-12the spiral shell dicyclo of mixing, alkoxyl, aliphatic, halogenated aliphatic, hydroxyl group aliphatic, amino aliphatic, alkoxyl aliphatic, alkylamino aliphatic, alkylthio group aliphatic, aromatic yl aliphat, heteroaryl aliphatic, heterocyclic radical aliphatic, cycloalkyl aliphatic, aryloxy group aliphatic, heterocyclyloxy base aliphatic, cycloalkyl oxy aliphatic, the amino aliphatic of virtue, the amino aliphatic of heterocyclic radical, cycloalkyl amino aliphatic, haloalkyl, thiazolinyl, alkynyl, virtue is amino, heteroaryl amino, aryl alkane amino, heteroaryl alkylamino,Heteroaryl oxygen base, heteroaryl alkyl, alkoxy aryl, heteroaryl alkoxyl, heterocyclyloxy base, heterocyclic radical alkoxyl, heterocyclic radical amino, heterocyclic radical alkylamino or aryloxy group can be optionally by one or more deuteriums that are selected from, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl, alkylamino, alkylthio group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, heteroaryloxy, oxo (=O), carboxyl, the alkoxyl that hydroxyl replaces, hydroxyl replace alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O) 2-, hydroxyl replace alkyl-S (=O)-, hydroxyl replace alkyl-S (=O) 2-or the substituting group of carboxyl alkoxyl replace.
In some embodiments, wherein W is C therein 3-8carbocylic radical or C 2-10heterocyclic radical.
Therein in some embodiments, wherein
Figure BDA0000442505360000381
structural unit is selected from following minor structure formula:
Figure BDA0000442505360000382
Figure BDA0000442505360000391
Wherein, each X 3and X 5be O, S, NR independently 6, C (=O) or CR 7r 7a;
Each X 6be CR independently 7r 7a,-Y 1=N-, O, S or NR 6;
Each Y 1be N or CR independently 7;
Each f is 0,1,2,3 or 4 independently;
Each Q 1and Q 2be NR independently 6, O, S, C (=O) or (CR 7r 7a) e;
E is 0,1,2,3 or 4;
Each R 5abe H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, C independently 1-6alkyl acyl, C 1-6alkyl acyloxy, C 1-6alkoxyl group acyl group, C 1-6alkyl sulphonyl, C 1-6alkoxyl group alkylsulfonyl, C 1-6alkyl sulphinyl, C 1-6alkyl sulphonyl oxygen base, C 1-6alkyl sulphinyl oxygen base, C 1-6alkoxyl group, C 1-6alkyl, C 6-10aryl ,-CF 3,-OCF 3, sulfydryl, nitro, C 1-6alkylamino, C 3-10cycloalkyl or C 6-10aryloxy;
Each R 6be hydrogen, deuterium, R independently 13r 13anC (=O)-, R 13oC (=O)-, R 13c (=O)-, R 13r 13anS (=O)-, R 13oS (=O)-, R 13s (=O)-, R 13r 13anS (=O) 2-, R 13oS (=O) 2-, R 13s (=O) 2-, C 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6aminoalkyl group, C 1-6alkoxy C 1-6alkyl, C 1-6alkylamino C 1-6alkyl, C 1-6alkylthio C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl, C 3-10cycloalkyl C 1-6alkyl, C 6-10aryloxy C 1-6alkyl, C 2-10heterocyclyloxy base C 1-6alkyl, C 3-10cycloalkyl oxy C 1-6alkyl, C 6-10the amino C of virtue 1-6alkyl, C 2-10the amino C of heterocyclic radical 1-6alkyl, C 3-10cycloalkyl amino C 1-6alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical or C 3-10carbocylic radical;
With each R 7and R 7abe H, deuterium, F, Cl, Br, I, C independently 1-6alkyl, C 2-6assorted alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6aminoalkyl group, C 1-6alkoxy C 1-6alkyl, C 1-6alkylamino C 1-6alkyl, C 1-6alkylthio C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl, C 3-10cycloalkyl C 1-6alkyl, C 6-10aryloxy C 1-6alkyl, C 2-10heterocyclyloxy base C 1-6alkyl, C 3-10cycloalkyl oxy C 1-6alkyl, C 6-10the amino C of virtue 1-6alkyl, C 2-10the amino C of heterocyclic radical 1-6alkyl, C 3-10cycloalkyl amino C 1-6alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical or C 3-10carbocylic radical.
Therein in some embodiments, wherein,
Figure BDA0000442505360000401
structural unit is selected from following minor structure formula:
Figure BDA0000442505360000402
Figure BDA0000442505360000411
Wherein, X 6for O, S ,-Y 1=N-, NR 6or CR 7r 7a;
Each Y 1be N or CH independently;
Each f is 0,1,2,3 or 4 independently;
Each R 5abe H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, C independently 1-6alkyl acyl, C 1-6alkyl acyloxy, C 1-6alkoxyl group acyl group, C 1-6alkyl sulphonyl, C 1-6alkoxyl group alkylsulfonyl, C 1-6alkyl sulphinyl, C 1-6alkyl sulphonyl oxygen base, C 1-6alkyl sulphinyl oxygen base, C 1-6alkoxyl group, C 1-6alkyl, C 6-10aryl ,-CF 3,-OCF 3, sulfydryl, nitro or C 1-6alkylamino;
Each R 6be hydrogen, deuterium, C independently 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6aminoalkyl group, C 1-6alkoxy C 1-6alkyl, C 1-6alkylamino C 1-6alkyl, C 1-6alkylthio C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl;
With each R 7and R 7abe H, deuterium, F, Cl, Br, I, C independently 1-6alkyl, C 2-6assorted alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6aminoalkyl group, C 1-6alkoxy C 1-6alkyl, C 1-6alkylamino C 1-6alkyl, C 1-6alkylthio C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl, C 3-10cycloalkyl C 1-6alkyl, C 6-10aryloxy C 1-6alkyl, C 2-10heterocyclyloxy base C 1-6alkyl, C 3-10cycloalkyl oxy C 1-6alkyl, C 6-10the amino C of virtue 1-6alkyl, C 2-10the amino C of heterocyclic radical 1-6alkyl, C 3-10cycloalkyl amino C 1-6alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical or C 3-8carbocylic radical.
In some embodiments, wherein each A and A ' are a key, C independently therein 1-6alkylidene group, C 2-6alkenylene, C 3-8cycloalkylidene, C 2-10sub-Heterocyclylalkyl ,-(CR 8r 8a) n-O-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-C (=O)-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-O-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-S (=O) r-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-O-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=S)-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-C (=O)-O-(CR 8r 8a) p-, or each A and A ' are following group independently:
Figure BDA0000442505360000412
Wherein, each X 1and X 2be O, S, NR independently 6or CR 7r 7a;
Each Y 1and Y 2be N or CR independently 7;
Z is-(CH 2) a-,-CH=CH-,-N=CH-,-(CH 2) a-N (R 5)-(CH 2) b-or-(CH 2) a-O-(CH 2) b-;
Each a and b are 0,1,2 or 3 independently;
Each c is 1 or 2 independently;
Each d is 1 or 2 independently;
Each n is 0,1,2 or 3 independently;
Each p is 0,1,2 or 3 independently;
Each r is 0,1 or 2 independently;
Each R 5be H, deuterium, hydroxyl, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-8cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl, C 6-10aryl C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkyl-OC (=O)-, C 1-6alkyl-C (=O)-, formamyl, C 1-6alkyl-OS (=O) r-, C 1-6alkyl-S (=O) ro-, C 1-6alkyl-S (=O) r-or amino-sulfonyl;
Each R 6be hydrogen, deuterium, R independently 13r 13anC (=O)-, R 13oC (=O)-, R 13c (=O)-, R 13r 13anS (=O)-, R 13oS (=O)-, R 13s (=O)-, R 13r 13anS (=O) 2-, R 13oS (=O) 2-, R 13s (=O) 2-, C 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6aminoalkyl group, C 1-6alkoxy C 1-6alkyl, C 1-6alkylamino C 1-6alkyl, C 1-6alkylthio C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl, C 3-10cycloalkyl C 1-6alkyl, C 6-10aryloxy C 1-6alkyl, C 2-10heterocyclyloxy base C 1-6alkyl, C 3-10cycloalkyl oxy C 1-6alkyl, C 6-10the amino C of virtue 1-6alkyl, C 2-10the amino C of heterocyclic radical 1-6alkyl, C 3-10cycloalkyl amino C 1-6alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical or C 3-10carbocylic radical;
Each R 6abe H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, oxo (=O), R independently 13ar 13n-,-C (=O) NR 13r 13a,-OC (=O) NR 13r 13a,-OC (=O) OR 13,-N (R 13) C (=O) NR 13r 13a,-N (R 13) C (=O) OR 13a,-N (R 13) C (=O)-R 13a, R 13r 13an-S (=O) 2-, R 13s (=O) 2-, R 13s (=O) 2n (R 13a)-, R 13ar 13n-C 1-6alkyl, R 13s (=O)-C 1-6alkyl, R 13r 13an-C (=O)-C 1-6alkyl, R 13ar 13n-C 1-6alkoxyl group, R 13s (=O)-C 1-6alkoxyl group, R 13r 13an-C (=O)-C 1-6alkoxyl group, C 6-10aryl, C 1-9heteroaryl, C 1-6alkoxyl group, C 1-6alkylamino, C 1-6alkyl, C 1-6haloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 2-10heterocyclic radical, C 3-8cycloalkyl, sulfydryl, nitro, C 6-10aryl C 1-6alkyl, C 6-10virtue is amino, C 1-9heteroaryl amino or C 6-10aryloxy;
Each R 7and R 7abe H, deuterium, F, Cl, Br, I, C independently 1-6alkyl, C 2-6assorted alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6aminoalkyl group, C 1-6alkoxy C 1-6alkyl, C 1-6alkylamino C 1-6alkyl, C 1-6alkylthio C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl, C 3-10cycloalkyl C 1-6alkyl, C 6-10aryloxy C 1-6alkyl, C 2-10heterocyclyloxy base C 1-6alkyl, C 3-10cycloalkyl oxy C 1-6alkyl, C 6-10the amino C of virtue 1-6alkyl, C 2-10the amino C of heterocyclic radical 1-6alkyl, C 3-10cycloalkyl amino C 1-6alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical or C 3-8carbocylic radical;
Each R 13and R 13abe H, deuterium, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl or C 6-10aryl C 1-6alkyl; Work as R 13and R 13abe connected on same nitrogen-atoms R 13, R 13acan at random form substituted or non-substituted 3-8 ring, spiral shell dicyclo or condensed-bicyclic with nitrogen-atoms;
With each R 8and R 8abe H, deuterium, hydroxyl, cyano group, nitro, F, Cl, Br, I, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl, C 6-10aryl C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkyl-OC (=O)-, C 1-6alkyl-C (=O)-, formamyl, C 1-6alkyl-OS (=O) r-, C 1-6alkyl-S (=O) ro-, C 1-6alkyl-S (=O) r-or amino-sulfonyl.
In some embodiments, wherein each A and A ' are a key ,-CH independently therein 2-,-(CH 2) 2-,-CH=CH-,-CH=CH-CH 2-,-N (R 5)-,-C (=O)-,-C (=S)-,-C (=O)-O-,-C (=O) N (R 5)-,-OC (=O) N (R 5)-,-OC (=O) O-,-N (R 5) C (=O) N (R 5)-,-(R 5) N-S (=O) 2-,-S (=O) 2-,-OS (=O) 2-,-(R 5) N-S (=O)-,-S (=O)-,-OS (=O)-, or each A and A ' are following group independently:
Figure BDA0000442505360000431
Figure BDA0000442505360000441
Wherein, X 1for O or S;
Each Y 1be N or CH independently;
Each R 5be H, deuterium, hydroxyl, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-8cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl, C 6-10aryl C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkyl-OC (=O)-, C 1-6alkyl-C (=O)-, formamyl, C 1-6alkyl-OS (=O) r-, C 1-6alkyl-S (=O) ro-, C 1-6alkyl-S (=O) r-or amino-sulfonyl;
Each R 6be hydrogen, deuterium, C independently 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6aminoalkyl group, C 1-6alkoxy C 1-6alkyl, C 1-6alkylamino C 1-6alkyl, C 1-6alkylthio C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl, C 6-10aryl, C 2-10heterocyclic radical or C 3-8carbocylic radical;
Each R 6abe H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, oxo (=O), R independently 13ar 13n-, C 1-6alkoxyl group, C 1-6alkylamino, C 1-6alkyl, C 1-6haloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, sulfydryl or nitro;
With each R 13and R 13aindependently for being H, deuterium, C 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl or C 6-10aryl C 1-6alkyl; Work as R 13and R 13abe connected on same nitrogen-atoms R 13, R 13acan at random form substituted or non-substituted 3-8 ring, spiral shell dicyclo or condensed-bicyclic with nitrogen-atoms.
Therein in some embodiments, wherein, each R 1, R 2, R 3and R 4independently for being selected from H, deuterium, C 1-8alkyl, C 1-8assorted alkyl, C 6-10aryl C 1-6alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 1-9heteroaryl or C 6-10aryl, or R 1, R 2at random form 3-8 unit heterocycle or 3-8 unit carbocyclic ring, C with X-CH 5-12condensed-bicyclic, C 5-12condense assorted dicyclo, C 5-12spiral shell dicyclo or C 5-12the spiral shell dicyclo of mixing; R 3, R 4and X '-CH at random forms 3-8 unit heterocycle or 3-8 unit carbocyclic ring, C 5-12condensed-bicyclic, C 5-12condense assorted dicyclo, C 5-12spiral shell dicyclo or C 5-12the spiral shell dicyclo of mixing.
In other embodiment, wherein R 1, R 2and X-CH, or R 3, R 4and X '-CH at random forms 3-8 unit heterocycle, C 5-12condensed-bicyclic, C 5-12condense assorted dicyclo, C 5-12spiral shell dicyclo or C 5-12the spiral shell dicyclo of mixing.
In other embodiment, wherein R 1, R 2the heterocycle forming with Y-X-CH or condensed ring or volution system are selected from following minor structure formula:
Figure BDA0000442505360000442
Wherein, each R 15be H, deuterium, F, Cl, Br, I, cyano group, hydroxyl, C independently 1-3alkyl, C 1-3haloalkyl, C 1-3alkoxyl group, C 1-3alkylamino, C 1-3alkylthio, C 6-10virtue is amino, C 6-10aryloxy, C 1-9heteroaryl, C 1-9heteroaryloxy, C 1-9heteroaryl C 1-3alkyl or C 2-10heterocyclic radical;
Each R 6be hydrogen, deuterium, C independently 1-3alkyl, C 1-3haloalkyl, C 1-3hydroxyalkyl, C 1-3aminoalkyl group, C 1-3alkoxy C 1-3alkyl, C 1-3alkylamino C 1-3alkyl, C 1-3alkylthio C 1-3alkyl, C 6-10aryl C 1-3alkyl, C 1-9heteroaryl, C 6-10aryl, C 2-10heterocyclic radical or C 3-8carbocylic radical;
With each n 1and n 2be 1,2,3 or 4 independently.
In other embodiment, wherein R 3, R 4with the heterocycle that forms of Y '-X '-CH or condensed ring or volution system are selected from following minor structure formula:
Figure BDA0000442505360000451
Wherein, each R 15be H, deuterium, F, Cl, Br, I, cyano group, hydroxyl, C independently 1-3alkyl, C 1-3haloalkyl, C 1-3alkoxyl group, C 1-3alkylamino, C 1-3alkylthio, C 6-10virtue is amino, C 6-10aryloxy, C 1-9heteroaryl, C 1-9heteroaryloxy, C 1-9heteroaryl C 1-3alkyl or C 2-10heterocyclic radical;
Each R 6be hydrogen, deuterium, C independently 1-3alkyl, C 1-3haloalkyl, C 1-3hydroxyalkyl, C 1-3aminoalkyl group, C 1-3alkoxy C 1-3alkyl, C 1-3alkylamino C 1-3alkyl, C 1-3alkylthio C 1-3alkyl, C 6-10aryl C 1-3alkyl, C 1-9heteroaryl, C 6-10aryl, C 2-10heterocyclic radical or C 3-8carbocylic radical;
With each n 1and n 2be 1,2,3 or 4 independently.
In some embodiments, it has structure as shown in the formula (II) therein:
Figure BDA0000442505360000452
Wherein,
Figure BDA0000442505360000453
structural unit is following minor structure formula:
Figure BDA0000442505360000461
Each Q 1and Q 2be NR independently 6, O, S, C (=O) or (CH 2) e;
E is 0,1,2,3 or 4;
Each f is 0,1,2,3 or 4 independently
Each X 3and X 5be O, S, NR independently 6, C (=O) or CR 7r 7a;
Each X 6be CH independently 2,-Y 1=N-, O, S or NR 6;
Each Y 1be N or CR independently 7;
Each A and A ' are a key, C independently 1-6alkylidene group, C 2-6alkenylene, C 3-8cycloalkylidene, C 2-10sub-Heterocyclylalkyl ,-(CR 8r 8a) n-O-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-C (=O)-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-O-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-S (=O) r-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-O-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=S)-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-C (=O)-O-(CR 8r 8a) p-, or each A and A ' are following group independently:
Figure BDA0000442505360000462
Figure BDA0000442505360000471
Each R 5be H, deuterium, hydroxyl, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl, C 6-10aryl C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkyl-OC (=O)-, C 1-6alkyl-C (=O)-, formamyl, C 1-6alkyl-OS (=O) r-, C 1-6alkyl-S (=O) ro-, C 1-6alkyl-S (=O) r-or amino-sulfonyl;
Each R 5aand R 6abe H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, C independently 1-6alkyl acyl, C 1-6alkyl acyloxy, C 1-6alkoxyl group acyl group, C 1-6alkyl sulphonyl, C 1-6alkoxyl group alkylsulfonyl, C 1-6alkyl sulphinyl, C 1-6alkyl sulphonyl oxygen base, C 1-6alkyl sulphinyl oxygen base, C 1-6alkoxyl group, C 1-6alkyl, C 6-10aryl ,-CF 3,-OCF 3, sulfydryl, nitro, C 1-6alkylamino, C 3-10cycloalkyl or C 6-10aryloxy;
Each R 6be hydrogen, deuterium, R independently 13r 13anC (=O)-, R 13oC (=O)-, R 13c (=O)-, R 13r 13anS (=O)-, R 13oS (=O)-, R 13s (=O)-, R 13r 13anS (=O) 2-, R 13oS (=O) 2-, R 13s (=O) 2-, C 1-6aliphatics, C 1-6alkoxy C 1-6aliphatics, C 1-6alkylamino C 1-6aliphatics, C 6-10aryl C 1-6aliphatics, C 1-9heteroaryl C 1-6aliphatics, C 2-10heterocyclic radical C 1-6aliphatics, C 3-10cycloalkyl C 1-6aliphatics, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical or C 3-10carbocylic radical;
Each R 7and R 7abe H, deuterium, F, Cl, Br, I, C independently 1-6aliphatics, C 2-6assorted alkyl, C 1-6alkoxy C 1-6aliphatics, C 1-6alkylamino C 1-6aliphatics, C 6-10aryl C 1-6aliphatics, C 2-10heterocyclic radical C 1-6aliphatics, C 3-10cycloalkyl C 1-6aliphatics, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical or C 3-10carbocylic radical;
Each R 8and R 8abe H, deuterium, hydroxyl, cyano group, nitro, F, Cl, Br, I, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl, C 6-10aryl C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkyl-OC (=O)-, C 1-6alkyl-C (=O)-, formamyl, C 1-6alkyl-OS (=O) r-, C 1-6alkyl-S (=O) ro-, C 1-6alkyl-S (=O) r-or amino-sulfonyl;
Each R 13and R 13abe H, deuterium, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl or C 6-10aryl C 1-6alkyl; Work as R 13and R 13abe connected on same nitrogen-atoms R 13, R 13acan at random form substituted or non-substituted 3-8 ring, spiral shell dicyclo or condensed-bicyclic with nitrogen-atoms;
Each n is 0,1,2 or 3 independently;
Each p is 0,1,2 or 3 independently;
Each r is 0,1 or 2 independently;
With each Y 4and Y 4' be a key, O, S ,-(CH independently 2) n-,-CH=CH-,-S (=O) r-,-CH 2o-,-CH 2s-,-CF 2-,-CHR 5a-,-CR 5ar 6a,-CH 2s (=O) ror-CH 2n (R 6)-.
In other embodiment, it has structure as shown in the formula (III):
Figure BDA0000442505360000481
In other embodiment, it has suc as formula the structure shown in (IV):
Wherein, each Q 2and Q 3be O, S, C (=O), NR independently 6or CR 7r 7a.
In other embodiment, it has the structure as shown in formula V:
Figure BDA0000442505360000483
Wherein e is 1,2,3 or 4.
In some embodiments, wherein, each Y and Y ' are a-amino acid group independently therein.
In other embodiment, wherein a-amino acid group is selected from Isoleucine, leucine, Methionin, methionine(Met), phenylalanine, Threonine, tryptophane, α-amino-isovaleric acid, L-Ala, l-asparagine, aspartic acid, L-glutamic acid, glutamine, proline(Pro), Serine, to tyrosine, arginine, Histidine, halfcystine, glycine, sarkosine, N, N-N-methylsarcosine, homoserine, norvaline, nor-leucine, ornithine, homocysteine, hyperphenylalaninemia, phenylglycocoll, adjacent tyrosine, the group that m-Tyrosine or oxyproline form.
In other embodiment, the a-amino acid in wherein said a-amino acid group is D configuration.
In other embodiment, the a-amino acid in wherein said a-amino acid group is L configuration.
In some embodiments, wherein each Y and Y ' are-[U-(CR independently therein 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12,-U-(CR 9r 9a) t-R 12or-[U-(CR 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-O-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-[U-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-U-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t-U-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-U-(CR independently 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-[C (=O)-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t-U-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-[C (=O)-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-C (=O)-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t-C (=O)-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 11)-(CR 9r 9a) t-C (=O)-R 13.
In other embodiment, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 11)-C (=O)-R 13.
In other embodiment, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 11)-(CR 9r 9a) t-C (=O)-O-R 13.
In other embodiment, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 11)-C (=O)-O-R 13.
In other embodiment, wherein each Y and Y ' are-U-(CR independently 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-[U-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-O-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-U-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t-U-(CR 9r 9a) t-O-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t-C (=O)-(CR 9r 9a) t-O-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-U-(CR independently 9r 9a) t-O-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-O-(CR 9r 9a) t-R 12.
In other embodiment, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 11)-R 12, wherein R 11, R 12can form 4-7 ring with the atom being attached thereto.
In other embodiment, wherein, each R 9, R 9a, R 10and R 11be H, deuterium, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl, C 6-10aryl C 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl;
Each R 12be R independently 13ar 13n-,-C (=O) R 13,-C (=S) R 13,-C (=O)-O-R 13,-C (=O) NR 13r 13a,-OC (=O) NR 13r 13a,-OC (=O) OR 13,-N (R 13) C (=O) NR 13r 13a,-N (R 13) C (=O) OR 13a,-N (R 13) C (=O)-R 13a, R 13r 13an-S (=O) 2-, R 13s (=O) 2-, R 13s (=O) 2n (R 13a)-, R 13oS (=O) 2-, C 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl or C 6-10aryl C 1-6alkyl;
Or R 11, R 12can form 4-7 ring with the atom being attached thereto;
Each R 13and R 13abe H, deuterium, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl or C 6-10aryl C 1-6alkyl; Work as R 13and R 13abe connected on same nitrogen-atoms R 13, R 13acan at random form substituted or non-substituted 3-8 ring, spiral shell dicyclo or condensed-bicyclic with nitrogen-atoms;
Each t is 0,1,2,3 or 4 independently;
With each k be 0,1 or 2 independently.
In other embodiment, wherein, each R 9, R 9a, R 10and R 11be H, deuterium, methyl, ethyl, sec.-propyl, cyclohexyl, isobutyl-or phenyl independently;
Each R 12be-C (=O) R independently 13,-C (=O)-O-R 13,-C (=O) NR 13r 13a, methyl, ethyl, propyl group, phenyl, cyclohexyl, morpholinyl or piperidyl;
Or R 11, R 12can form 4-7 ring with the atom being attached thereto;
With each R 13and R 13abe H, deuterium, methyl, ethyl, propyl group, phenyl, cyclohexyl, morpholinyl or piperidyl independently.
In other embodiment, it has suc as formula the structure shown in (VI):
Figure BDA0000442505360000511
Wherein, each R 14and R 14abe H, deuterium, C independently 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 2-6assorted alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical, C 3-8cycloalkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl;
Wherein said C 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 2-6assorted alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical, C 3-8cycloalkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl can optionally be replaced by one or more substituting groups that are selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
In some embodiments, it has suc as formula the structure shown in (VII) therein:
Figure BDA0000442505360000512
Wherein, each R 14and R 14abe H, deuterium, C independently 1-3hydroxyalkyl, methyl, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, allyl group, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl or C 1-9heteroaryl;
Wherein said C 1-3hydroxyalkyl, methyl, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, allyl group, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl or C 1-9heteroaryl can optionally be replaced by one or more substituting groups that are selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
In some embodiments, it has suc as formula the structure shown in (VIII) therein:
Figure BDA0000442505360000521
Wherein, each R 14and R 14abe H, deuterium, C independently 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 2-6assorted alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical, C 3-8cycloalkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl;
With each n 2be 1,2,3 or 4 independently;
Wherein said C 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 2-6assorted alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical, C 3-8cycloalkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl can optionally be replaced by one or more substituting groups that are selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
In some embodiments, it has suc as formula the structure shown in (IX) therein:
Figure BDA0000442505360000522
Wherein, each R 14and R 14abe H, deuterium, C independently 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 2-6assorted alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical, C 3-8cycloalkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl;
With each n 1be 1,2,3 or 4 independently;
Wherein said C 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 2-6assorted alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical, C 3-8cycloalkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl can optionally be replaced by one or more substituting groups that are selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
In some embodiments, it has suc as formula the structure shown in (X) therein
Figure BDA0000442505360000531
Wherein, each R 5abe H, deuterium, C independently 1-4alkyl, F, Cl, Br or I;
F is 0,1,2,3 or 4;
Each Y 1be N or CR independently 7;
Each R 6and R 7be H, deuterium, C independently 1-4alkyl, C 6-10aryl, C 2-10heterocyclic radical, C 3-8cycloalkyl or benzyl;
Each R 14and R 14abe H, deuterium, C independently 1-4alkyl, C 6-10aryl, C 2-10heterocyclic radical or C 3-8cycloalkyl;
Each R 16and R 16abe hydroxyl, C independently 1-4alkyl oxy, C 6-10aryloxy, C 2-10heterocyclic radical or C 3-8cycloalkyl;
Wherein structural unit is following minor structure formula:
Figure BDA0000442505360000533
Each A or A ' are independently selected from following group:
Figure BDA0000442505360000542
Wherein R 1, R 2the heterocycle independently forming with N-CH or condensed ring or volution system are selected from following minor structure formula:
Figure BDA0000442505360000543
Wherein R 3, R 4the heterocycle independently forming with N-CH or condensed ring or volution system are selected from following minor structure formula:
Figure BDA0000442505360000544
In some embodiments, it has suc as formula the structure shown in (XI) therein
Figure BDA0000442505360000551
Wherein, each R 5abe H, deuterium, C independently 1-4alkyl, F, Cl, Br or I;
F is 0,1,2,3 or 4;
Each Q 1and Q 2be NR independently 6, O, S, C (=O) or (CR 7r 7a) e;
X 6for (CR 7r 7a) n,-Y 1=N-, O, S or NR 6;
Each Y 1be N or CR independently 7;
Each i, n and e are 1,2,3 or 4 independently;
Each R 6, R 7and R 7abe H, deuterium, C independently 1-4alkyl, C 6-10aryl, C 2-10heterocyclic radical, C 3-8cycloalkyl or benzyl;
Each R 14and R 14abe H, deuterium, C independently 1-4alkyl, C 6-10aryl, C 2-10heterocyclic radical or C 3-8cycloalkyl;
Each R 16and R 16abe hydroxyl, C independently 1-4alkyl oxy, C 6-10aryloxy, C 2-10heterocyclic radical or C 3-8cycloalkyl;
Wherein said C 1-4alkyl, C 6-10aryl, C 2-10heterocyclic radical, C 3-8cycloalkyl, C 6-10aryloxy can optionally be replaced by one or more substituting groups that are selected from deuterium, F, Cl, Br, hydroxyl, cyano group;
Each A or A ' are independently selected from following group:
Figure BDA0000442505360000552
Wherein R 1, R 2the heterocycle independently forming with N-CH or condensed ring or volution system are selected from following minor structure formula:
Figure BDA0000442505360000561
Wherein R 3, R 4the heterocycle independently forming with N-CH or condensed ring or volution system are selected from following minor structure formula:
Figure BDA0000442505360000562
In other embodiment, wherein, each R 5abe H, deuterium, methyl, ethyl, F, Cl, Br or I independently;
Each R 6, R 7and R 7abe hydrogen, deuterium, methyl, ethyl, sec.-propyl, phenyl, cyclohexyl or benzyl independently;
Each R 14and R 14abe methyl, ethyl, phenyl, cyclohexyl, 1-methyl-propyl, sec.-propyl or the tertiary butyl independently;
With each R 16and R 16abe independently hydroxyl, methoxyl group, oxyethyl group, phenoxy group,
Figure BDA0000442505360000563
or tert.-butoxy;
Wherein said methyl, ethyl, phenyl, cyclohexyl, 1-methyl-propyl, sec.-propyl, isobutyl-, methoxyl group, oxyethyl group, phenoxy group, tert.-butoxy or the tertiary butyl can optionally be replaced by one or more substituting groups that are selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
Therein in some embodiments, it comprises following one of them structure:
Figure BDA0000442505360000564
Figure BDA0000442505360000571
Figure BDA0000442505360000581
Figure BDA0000442505360000591
Or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate or pharmacy acceptable salt.
Compound of the present invention (in this article, form of presentation " formula (I) compound and steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate and pharmacy acceptable salt and prodrug " can be referred to as " compound of the present invention "), can treat acute and chronic HCV for the production of pharmaceutical prod and infect, comprise that those are described in the invention.Further, compound of the present invention can be for the production of the goods of anti-HCV.Thus, compound of the present invention can be used for alleviating, stop, control or treating the illness that HCV mediates for the production of a kind of pharmaceuticals, particularly the protein mediated disease of HCV NS5A.Thus, compound of the present invention can be as the activeconstituents of pharmaceutical composition, and this pharmaceutical composition can comprise the compound of formula (I) representative, can also further comprise at least one pharmaceutically acceptable carrier, assistant agent or thinner.
Specifically, salt is pharmacy acceptable salt.The implication of term " pharmaceutically acceptable " is that the material adopting or composition must be to be applicable to mating with other components of composition preparation and the Mammals being used for the treatment of on chemistry or toxicity.Those skilled in the art can, according to other components of adopt and the such as people of object who is used for treatment, specifically select material or the composition of " pharmaceutically acceptable ".
The salt of compound of the present invention also comprise for the preparation of or purifying formula (I) shown in the salt of enantiomer of compound separation shown in the intermediate of compound or formula (I), but pharmacy acceptable salt not necessarily.
If compound of the present invention is alkaline, conceivable salt can prepare by any suitable method providing on document, for example, uses mineral acid or organic acid.Wherein, the example of mineral acid includes but not limited to hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Organic acid example includes but not limited to acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxalic acid, hydroxyethanoic acid and Whitfield's ointment; Pyrans saccharic acid, as glucuronic acid and galacturonic acid; Alpha-hydroxy acid, as citric acid and tartrate; Amino acid, as aspartic acid and L-glutamic acid; Aromatic acid, as phenylformic acid and styracin; Sulfonic acid, as tosic acid, ethyl sulfonic acid, etc.
If compound of the present invention is acid, conceivable salt can prepare by suitable method, as, use mineral alkali or organic bases, as ammonia (uncle's ammonia, parahelium, tertiary ammonia), alkali metal hydroxide or alkaline earth metal hydroxides, etc.Suitable salt comprises, but is not limited to, and the organic salt obtaining from amino acid, as glycine and arginine, ammonia, as uncle's ammonia, parahelium and tertiary ammonia, and ring-type ammonia, as piperidines, morpholine and piperazine etc., and obtain inorganic salt from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium.
The composition of the compounds of this invention, preparation and administration
Described pharmaceutical composition comprises any compound of the present invention.This pharmaceutical composition can also further comprise pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or its combination.Described pharmaceutical composition can be used for the treatment of hepatitis C virus (HCV) to be infected or hepatitis C disease, and especially, it has good restraining effect to HCV NS5A albumen.
Described pharmaceutical composition further comprises the medicine of anti-HCV.The medicine of described anti-HCV can be any known other medicines for anti-HCV that are different from the compounds of this invention.For example, can be Interferon, rabbit, ribavirin, interleukin-22, interleukin 6, interleukin 12, promote to produce the compound that 1 type helper T cell is replied, RNA interfering, sense-rna, not moral of miaow quinoline, inosine 5 '-monophosphate dehydrogenase inhibitor, amantadine, Rimantadine, Ba Wei former times monoclonal antibody (Bavituximab), CivacirTM, EBP520 (boceprevir), TVR (telaprevir), erlotinib (erlotinib), daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, ABT-450, danoprevir, sovaprevir, MK-5172, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ABT-267, EDP239, PPI-668, GS-5816, samatasvir(IDX-719), MK-8742, MK-8325, GSK-2336805, PPI-461, TMC-435, MK-7009, BI-2013335, ciluprevir, BMS-650032, ACH-1625, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, EP-013420, VBY-376, TMC-649128, R-7128, PSI-7977, INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072, PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055 or its combination.Wherein, described Interferon, rabbit is interferon alpha, Intederon Alpha-2a, the Intederon Alpha-2a of Pegylation, compound alpha-interferon, interferon-gamma or its combination of Interferon Alpha-2b, Pegylation.Described pharmaceutical composition, further comprise at least one HCV inhibitor, described HCV inhibitor for suppress HCV reproduction process and suppress HCV viral protein function one of at least, wherein said HCV reproduction process is selected from the complete viral cycle of the HCV that HCV enters, shells, translates, copies, assembles or discharge; Described HCV viral protein is selected from metalloprotease, NS2, NS3, NS4A, NS4B, NS5A, NS5B; And the needed internal ribosome inlet point of HCV virus replication (IRES) and inosine monophosphate desaturase (IMPDH).
In the time can be used for treating, the compounds of this invention, especially formula (I) compound for the treatment of significant quantity and pharmacy acceptable salt thereof can be used as unprocessed pharmaceutical chemicals and give, and the activeconstituents that also can be used as pharmaceutical composition provides.Therefore, content of the present invention also provides pharmaceutical composition, this pharmaceutical composition comprises this compounds of this invention for the treatment of significant quantity, especially formula (I) compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers, thinner or vehicle.Term as used herein " treatment significant quantity " refers to the total amount that is enough to the each active ingredient that demonstrates significant patient's benefit (for example viral load minimizing).In the time using independent activeconstituents individually dosed, this term only refers to this composition.In the time of Combination application, no matter this term refers to combination, successively or when simultaneously administration, all cause the combined amount of the activeconstituents of result for the treatment of.The compounds of this invention, especially formula (I) compound and pharmacy acceptable salt thereof are described above.From compatible with other compositions of preparation and harmless to its recipient meaning, carrier, thinner or vehicle must be acceptable.According to the present invention, content on the other hand, also be provided for the method for useful in preparing drug formulations, the method comprises the compounds of this invention, and especially formula (I) compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers, thinner or vehicle mix.Term used in the present invention " pharmaceutically acceptable " refers to such compound, raw material, composition and/or formulation, they are in the scope of rational medicine judgement, be applicable to contact with patient tissue and without excessive toxicity, pungency, transformation reactions or with rational interests/risk than symmetrical other problems and complication, and be effective to set purposes.
Pharmaceutical preparation can be unit dosage, the activeconstituents that each unitary dose contains predetermined amount.The dosage level of the compound of content of the present invention is between approximately 0.01 mg/kg (mg/kg) body weight/day and approximately 250 mg/kg body weight/day, preferably, between about 0.05mg/kg body weight/day and about 100mg/kg body weight/day, be usually used for preventing or treating the disease of HCV mediation with monotherapy.Conventionally can or give the pharmaceutical composition of content of the present invention as continuous infusion by every day approximately 1 to approximately 5 time.This class dose regimen can be used as long-term or short-term therapy.The amount of mixing the activeconstituents of preparing single formulation with solid support material will change according to the discharge rate of the severity of disease to be treated, disease, administration time, route of administration, compound used therefor, treatment time and patient age, sex, body weight and situation.Preferred unit dosage is to contain the per daily dose of above-mentioned activeconstituents or the unit dosage of divided dose or its appropriate fraction herein.The available obvious low dose of begin treatment lower than compound optimal dose.After this, carry out escalated dose until reach in this case best effect with less increment.Generally speaking the concentration level that, most desirably gives compound is conventionally can provide effective result and don't as for causing any harmful or poisonous side effect at anti-virus aspect.
When the combination of the compound that comprises content of the present invention when the composition of content of the present invention and one or more other treatment medicines or prophylactic agent, the dosage level of compound and other medicine is conventionally in monotherapy scheme, account for the approximately 10-150% of bio-occlusion pharmaceutical quantities, more preferably account for the approximately 10-80% of bio-occlusion pharmaceutical quantities.Pharmaceutical preparation is suitable for by any suitable administration, for example, by oral (comprising oral cavity or hypogloeeis), rectum, nose, part (comprise oral cavity, hypogloeeis or through skin), vagina or parenteral (comprise in subcutaneous, intracutaneous, intramuscular, intraarticular, synovial membrane, in breastbone, in sheath, intralesional, intravenously or corium hemostasis or infusion) approach.Can prepare this class preparation by any currently known methods in pharmaceutics field, for example, pass through activeconstituents and carrier or mixed with excipients.Preferred oral administration or drug administration by injection.
The pharmaceutical preparation that is suitable for oral administration provides by unit independently, for example capsule or tablet; Powder or granule; Solution in water-based or non-aqueous liquid or suspensoid; Edible foam formulations or foaming preparations (whip); Or O/w emulsion agent or water in oil emulsion liquor.
For instance, for the oral administration with tablet or Capsule form, active medicine component can such as, mix mutually with pharmaceutically acceptable oral nontoxic inert support (ethanol, glycerine, water etc.).By compound powder being broken into suitable fine sizes, and with such as, mixed to prepare powder by the same pharmaceutical carrier of pulverizing (edible carbohydrate such as starch or N.F,USP MANNITOL etc.).Also can there is correctives, sanitas, dispersion agent and tinting material.
By preparing pulverulent mixture as above, and be loaded in the gelatin shell of shaping, prepare capsule.Before filling operation, glidant and lubricant (for example colloidal silica, talcum powder, Magnesium Stearate, calcium stearate or solid polyethylene glycol) can be added in pulverulent mixture.Also can add in the time of the lower capsule of clothes and will improve disintegrating agent or the solubilizing agent (for example agar, calcium carbonate or sodium carbonate) of medicine utilizability.
In addition need or when essential, also suitable tackiness agent, lubricant, disintegrating agent and tinting material can be mixed in mixture.Suitable tackiness agent comprises starch, gelatin, natural sugar (such as glucose or beta lactose), corn sweetener, natural and synthetic gum (such as Sudan Gum-arabic, tragakanta or sodiun alginate), carboxymethyl cellulose, polyoxyethylene glycol etc.Lubricant for these formulations comprises sodium oleate, sodium-chlor etc.Disintegrating agent includes, but are not limited to starch, methylcellulose gum, agar, bentonite, xanthan gum etc.For example, by making pulverulent mixture, granulate or pre-compressing tablet, add lubricant and disintegrating agent, compacting is in blocks, thereby makes tablet.By the compound of suitably pulverizing and thinner as described above or base-material, optionally for example, for example, for example, mix with tackiness agent (carboxymethyl cellulose, alginate, gelatin or polyvinylpyrrolidone), dissolving hold back agent (paraffin), absorption accelerator (quaternary salt) and/or absorption agent (bentonite, kaolin or Si Liaodengji dicalcium phosphate feed grade), prepare pulverulent mixture.For example, after useful binders (syrup, starch slurry, mucialga of arabic gummy (acadiamucilage) or cellulose materials or polymeric material solution) is wetting, pressurization is sieved, and pulverulent mixture is granulated.An alternative method of granulating is, can be by pulverulent mixture by tabletting machine, and result is to smash granulation by forming not good agglomerate again.Can be by adding stearic acid, stearate, talcum powder or mineral oil make particle lubrication to prevent from adhering on the punch die of tabletting machine.Then by the mixture compacting through lubricated in flakes.The compound of content of the present invention also can mix with free-pouring inert support, without just suppressing in flakes by granulation or pre-compressing tablet step.Transparent or the opaque protectiveness coating material being made up of shellac seal coat, sugar-coat or polymeric material clothing and wax polishing clothing (polish coating of wax) can be provided.Dyestuff can be added in these coating materials to distinguish different unitary doses.
Oral liquid for example solution, syrup and elixir can be prepared by dosage unit form, thus the compound that specified rate contains predetermined amount.Syrup can be by compound is dissolved in the suitably seasoned aqueous solution and is prepared, and elixir can be by preparing with nontoxic solvent.Also can add solubilizing agent and emulsifying agent (such as ethoxylation isooctadecanol and polyoxyethylene sorbitol ether), sanitas, flavoring additive (such as spearmint oil or natural sweeteners or asccharin or other artificial sweetners) etc.
If appropriate, can be by the dosage unit preparations micro encapsulation for oral administration.Also preparation can be made to time delay or sustained release, for example, by dressing or be embedded in the microparticle material such as polymkeric substance, wax.
The compounds of this invention, especially formula (I) compound and pharmacy acceptable salt thereof can also give by liposome delivery system, for example small unilamellar vesicle, large unilamellar liposome and multilamellar liposome.Liposome can for example, be made up of multiple phosphatide (cholesterol, octadecylamine or phosphatidylcholine).
The compounds of this invention, especially formula (I) compound and pharmacy acceptable salt thereof also can by use monoclonal antibody as independent carrier (compound molecule is coupling with it) pass medicine.Compound also can with the soluble polymer coupling as can target medicine carrier.This base polymer can comprise polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropylmethyl acrylamide phenol, poly-hydroxyethyl l-asparagine phenol or the polyoxyethylene polylysine being replaced by palmityl residue.In addition, compound can with a class Biodegradable polymeric coupling, for reaching the controlled release of medicine, this base polymer is cross-linking copolymer or the amphipathic nature block polymer of poly(lactic acid), poly-epsilon-caprolactone, polyhydroxybutyrate, poe, polyacetal, poly-dihydropyrane, polybutylcyanoacrylate and hydrogel for example.
The pharmaceutical preparation that is suitable for percutaneous dosing can be used as discrete patch (discrete patch) to keep and recipient's epidermis close contact in long-time.For example, activeconstituents can be by passing medicine by iontophoresis patch, conventionally can be referring to Pharmaceutical Research1986, and 3 (6), 318.
The pharmaceutical preparation that is suitable for topical can be made into ointment, ointment, suspensoid, lotion, powder, solution, paste, gelifying agent, sprays, aerosol, oil formulation or transdermal patch.
The pharmaceutical preparation that is suitable for rectal administration can be used as suppository or provides as enema.
The pharmaceutical preparation (wherein carrier is solid) that is suitable for nose administration comprises that particle diameter is for example dust base of 20-500 micrometer range, by with the administration of snuffing mode, sucks fast from approach the dust base container of nose by nasal passage.Wherein carrier is liquid, is suitable for comprising as the appropriate formulation of nasal mist or nasal drop administration aqueous solution agent or the oily solution agent of activeconstituents.
Be suitable for comprising minuteness particle pulvis (dust) or mist agent (mist) by the pharmaceutical preparation of inhalation, dosage compresed gas aerosol, nebulizer, insufflator or other matters of available dissimilar metering are sent in the device of aerosol spray and are prepared.
The pharmaceutical preparation that is suitable for vagina administration can vaginal suppository, vagina plug, ointment, creme, gelifying agent, paste, foaming agent or sprays provide.
The pharmaceutical preparation that is suitable for parenteral admin comprises water-based and non-aqueous aseptic injectable solution agent and water-based and non-aqueous aseptic suspensoid, water-based and non-aqueous aseptic injectable solution agent can contain antioxidant, buffer reagent, fungistat and make described preparation and the solute for the treatment of that recipient's blood etc. oozes, and water-based and non-aqueous aseptic suspensoid can comprise suspension agent and thickening material.Preparation can unitary dose or multi-dose container provide, the triumphant and bottle of for example peace of sealing, and can being kept under lyophilize (freeze-drying) condition, only need add sterile liquid carrier, for example water for injection before use.Facing injection solution and the suspensoid of used time configuration can be prepared by sterile powder injection, granule and tablet.
It should be understood that, except the composition of mentioning especially above, preparation also comprises other composition that this area relevant with described preparation type is conventional, and this class preparation that is for example suitable for oral administration can comprise correctives.
The purposes of the compounds of this invention and pharmaceutical composition
Preparing the purposes in medicine the invention provides compound of the present invention or pharmaceutical composition, described medicine can for suppress HCV reproduction process and suppress HCV viral protein function one of at least.Described HCV reproduction process is selected from the complete viral cycle of the HCV that HCV enters, shells, translates, copies, assembles or discharge.Described HCV viral protein is selected from metalloprotease, NS2, NS3, NS4A, NS4B, NS5A, NS5B; And the needed internal ribosome inlet point of HCV virus replication (IRES) and inosine monophosphate desaturase (IMPDH).
Arbitrary compound of the present invention or pharmaceutical composition can be used for the treatment of hepatitis C virus (HCV) to be infected or hepatitis C disease, and especially, it has good restraining effect to HCV NS5A albumen.
The methods for the treatment of that comprises the compounds of this invention or pharmaceutical composition administration, further comprise other HCV medicines of patient's administration, thus, compound of the present invention and other anti-HCV medicaments can be carried out to combination therapy, the medicine of wherein said anti-HCV is that Interferon, rabbit, ribavirin, interleukin-22, interleukin 6, interleukin 12, promotion produce compound, RNA interfering, sense-rna, not moral, inosine 5 '-monophosphate dehydrogenase inhibitor, amantadine, Rimantadine, Ba Wei former times monoclonal antibody (Bavituximab), the Civacir of miaow quinoline that 1 type helper T cell is replied tM, EBP520 (boceprevir), TVR (telaprevir), erlotinib (erlotinib), daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, ABT-450, danoprevir, sovaprevir, MK-5172, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ABT-267, EDP239, PPI-668, GS-5816, samatasvir (IDX-719), MK-8742, MK-8325, GSK-2336805, PPI-461, TMC-435, MK-7009, BI-2013335, ciluprevir, BMS-650032, ACH-1625, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, EP-013420, VBY-376, TMC-649128, R-7128, PSI-7977, INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072, PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055 or its combination.Wherein said Interferon, rabbit is interferon alpha, Intederon Alpha-2a, the Intederon Alpha-2a of Pegylation, compound alpha-interferon, interferon-gamma or its combination of Interferon Alpha-2b, Pegylation.
And the methods for the treatment of that comprises the compounds of this invention or pharmaceutical composition administration, further comprise the administration of other anti-HCV medicaments, wherein, other anti-HCV medicaments can with the compounds of this invention or its pharmaceutical composition Combined Preparation, the compounds of this invention or pharmaceutical composition be as single formulation, or the compound separating or pharmaceutical composition are as a part for multi-form.Other anti-HCV medicaments can from simultaneously administration of the compounds of this invention or administration when different.The latter's situation, administration can be staggered and be carried out carrying out as 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months.
" significant quantity " of compound of the present invention or pharmaceutically acceptable composition or " effective dose " refer to the significant quantity of processing or alleviating the severity of illness that one or more the present invention mentions.The method according to this invention, compound and composition can be the severity that any dosage and any route of administration are come effectively for the treatment of or palliated a disease.Essential measuring accurately changes the situation according to patient, and this depends on race, the age, and patient's general condition, the severity of infection, special factor, administering mode, etc.Compound or composition can with one or more other treatment agent Combined Preparation, as discussed in the present invention.
General building-up process
Usually, compound of the present invention can prepare by method described in the invention, unless there is further instruction, wherein substituent definition is suc as formula shown in (I).Reaction scheme below and embodiment are for further illustrating content of the present invention.
Those skilled in the art will realize that: chemical reaction described in the invention can be used for preparing suitably many other compounds of the present invention, and be all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.For example; according to the present invention, the synthetic of the compound of those non-illustrations can successfully be completed by modifying method by those skilled in the art; disturb group as suitable protection, by utilizing other known reagent except described in the invention, or reaction conditions is made to the modification of some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compounds of the present invention admittedly.
The embodiments described below, are decided to be degree Celsius unless other aspects show all temperature.Reagent is bought in goods providers as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, when use all not through being further purified, unless other aspects show.General reagent is from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, and Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu chemical company limited, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao buys and obtains.
Anhydrous tetrahydro furan, dioxane, toluene, ether are to reflux to be dried through sodium Metal 99.5 to obtain.Anhydrous methylene chloride and chloroform are to reflux to be dried through hydrolith to obtain.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.
Below reaction is generally at nitrogen or argon gas direct draught or on anhydrous solvent, overlaps a drying tube (unless showing aspect other), all suitable soft rubber balls beyond the Great Wall of reaction flask, and substrate is squeezed into by syringe.Glassware was all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDC1 3, d 6-DMSO, CD 3oD or d 6-acetone is solvent (report is take ppm as unit), uses TMS (0ppm) or chloroform (7.25ppm) as reference standard.In the time there is multiplet, abbreviation by using below: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, two bimodal), dt (doublet of triplets, two triplets).Coupling constant, represents with hertz (Hz).
Algorithm (MS) data are measured by the spectrograph of the Agilent6320 series LC-MS of outfit G1312A binary pump and a G1316A TCC (column temperature remains on 30 ℃), G1329A automatic sampler and G1315B DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Algorithm (MS) data are measured by the spectrograph of the Agilent6120 series LC-MS of outfit G1311A quaternary pump and G1316A TCC (column temperature remains on 30 ℃), G1329A automatic sampler and G1315D DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Above two kinds of spectrographs have all been equipped with Agilent Zorbax SB-C18 post, and specification is 2.1 × 30mm, 5 μ m.Volume injected is to determine by sample concentration; Flow velocity is 0.6mL/min; The peak value of HPLC is by recording and read at the UV-Vis wavelength at 210nm and 254nm place.Moving phase is 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure water solution (phase B).Condition of gradient elution is as shown in table 1:
Table 1
Time (min) A(CH 3CN，0.1%HCOOH) B(H 2O，0.1%HCOOH)
0-3 5-100 95-0
3-6 100 0
6-6.1 100-5 0-95
6.1-8 5 95
Compound purifying is evaluated by Agilent1100 series of high efficiency liquid chromatography (HPLC), wherein UV detects at 210nm and 254nm place, Zorbax SB-C18 post, specification is 2.1 × 30mm, 4 μ m, 10 minutes, flow velocity was 0.6mL/min, (0.1% aqueous formic acid) of 5-95% (0.1% formic acid acetonitrile solution), column temperature remains on 40 ℃.
The use of brief word below runs through the present invention:
HOAc acetic acid
MeCN, CH 3cN acetonitrile
NH 3ammonia
NH 4c1 ammonia chloride
BBr 3boron tribromide
BSA bovine serum albumin
Br 2bromine
BOC, Boc tert-butoxycarbonyl
Cs 2cO 3cesium carbonate
CHCl 3chloroform
CDC1 3deuterochloroform
Cu copper
CuI cuprous iodide
Et 2o ether
DMF DMF
DMAP DMAP
DMSO dimethyl sulfoxide (DMSO)
EDC, EDCI 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride
Dppa diphenyl phosphate azide
EtOAc ethyl acetate
EA ethyl acetate
HBr Hydrogen bromide
HCl hydrochloric acid
HOAt, HOAT 1-hydroxyl-7-azepine benzotriazole
HOBT 1-hydroxy benzo triazole
H 2hydrogen
H 2o 2hydrogen peroxide
Fe iron
LDA lithium diisopropyl amido
MCPBA metachloroperbenzoic acid
MgSO 4magnesium sulfate
MeOH, CH 3oH methyl alcohol
MeI methyl iodide
CH 2cl 2, DCM methylene dichloride
NMP N-Methyl pyrrolidone
ML, m milliliter
N 2nitrogen
Pd/C palladium/carbon
PE sherwood oil (60 90 ℃ of –)
PBS phosphate buffered saline (PBS)
POC1 3phosphorus oxychloride
Pd (PPh 3) 4four triphenyl phosphorus palladiums
Pd (dppf) Cl 2two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride
K 2cO 3salt of wormwood
KOH potassium hydroxide
RT, rt room temperature
Rt retention time
NaHCO 3sodium bicarbonate
NaBH 4sodium borohydride
NaBH 3cN sodium cyanoborohydride
NaOtBu sodium tert-butoxide
NaOH sodium hydroxide
NaClO 2textone
NaCl sodium-chlor
NaH 2pO 4sODIUM PHOSPHATE, MONOBASIC
NaH sodium hydride
NaI sodium iodide
Na 2sO 4sodium sulfate
TBTU O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester
THF tetrahydrofuran (THF)
Et 3n, TEA triethylamine
TFA trifluoroacetic acid
P (t-bu) 3three (tertiary butyl) phosphine
NBS N-bromo-succinimide
TBAI tetrabutylammonium iodide
H 2o water
TEAF triethylamine formic acid
PPA polyphosphoric acid
Tf 2o trifluoromethanesulfanhydride anhydride
HCl.EA hydrogenchloride ethyl acetate
DIPEA diisopropyl ethyl amine
DME glycol dimethyl ether
HATU 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester
NIS N-N-iodosuccinimide
TFAA trifluoroacetic anhydride
SEMCl 2-(TMS) ethoxymethyl chlorine
Dess-Martin (Dai Si-Martin oxygenant) (1,1,1-triacetoxyl group)-1,1-dihydro-1,2-benzenesulfonyl-3 (1H)-one
TsOH tosic acid
TMSA trimethyl silicane ethyl-acetylene
Maxwell acid 2,2-dimethyl-1,3-dioxane-4,6-diketone
Two (2-methoxy ethyl) the amino sulfur trifluorides of BAST
SbCl 3butter of antimony
SmCl 3samarium trichloride
LiHMDS LHMDS
TMSCl trimethylchlorosilane
PhNTf 2two (trifluoromethane sulphonyl) imines of N-phenyl
TBDMSOTf tertiary butyl dimethyl tosic acid base silane
Et 2nSF 3diethylamide sulfur trifluoride
MTBE methyl tertiary butyl ether
LiN (SiMe 3) 2two (trimethyl silicane) Lithamide
PPh 3meBr brooethyl triphenylphosphine
Lawesson ' s Reagent (Louth reagent) 2, two (the 4-p-methoxy-phenyls)-1 of 4-, 3-bis-sulphur-2,4-phosphine alkane-2,4-disulphide
MTBE methyl tertiary butyl ether
TEBAC benzyltriethylammoinium chloride
I 2iodine
DAST diethylin sulfur trifluoride
IPA Virahol
TCCA TCCA (Trichloroisocyanuric acid)
TEMPO 2,2,6,6-tetramethyl piperidine-nitrogen-oxide compound
IMPDH inosine monophosphate desaturase
IRES internal ribosome inlet point
Synthetic method
Synthetic method 1
Figure BDA0000442505360000671
Compound 16 can prepare by synthetic method 1.Wherein, each A 1, A 2and A 3independently selected from N or CR 7, each X 7or X 8be F independently, Cl, Br, I, the leavings groups such as OTf, and, each X 6, w, R 5a, f, Y 4, R 14aand R 16ahave implication as described in the present invention, Pg is amino protecting group, as Boc, and Fmoc, Cbz etc.There is bromine substitution reaction and obtain compound 2 in compound 1, compound 2 obtains compound 3 in the reaction system of diethyl malonate and alkali, compound 3 reacts and obtains compound 4 in NaCl system, compound 4 is hydrolyzed and obtains compound 5 under the effect of alkali, compound 5 obtains compound 6 under the effect of aluminum chloride and acyl chlorides, compound 6 cyclization under the effect of alkali obtains compound 7, and compound 7 obtains compound 8 under the effect of reductive agent.Compound 9 and compound 9-1 generation condensation reaction obtain the mixture of compound 10 and 11; in acetate system, heat subsequently cyclization and obtain compound 12; compound 12 deprotections obtain compound 13; and further obtain compound 14 with compound 13-2 condensation; compound 14 reacts and obtains compound 15 with connection boric acid pinacol ester under the catalysis of palladium, and compound 15 carries out linked reaction with compound 8 and obtains target compound 16 under the catalysis of palladium.
Synthetic method 2
Figure BDA0000442505360000672
Target compound 26 can prepare by synthetic method 2, wherein, and X 7for F, Cl, Br, I, the leavings groups such as OTf, and, each R 5a, f, W, X 6, Y 4', R 14and R 16have implication as described in the present invention, Pg is amino protecting group, as Boc, and Fmoc, Cbz etc.Compound 9-1-1 issues raw reduction reaction in the effect of borine and obtains compound 17, under Dai Si-Martin's oxidation, obtain subsequently compound 18, compound 18 ammoniacal liquor and oxalic dialdehyde under effect cyclization obtain compound 19, compound 19 reacts with NIS and obtains compound 20, compound 20 is sloughed an iodine and is obtained compound 21 in the reaction system of S-WAT, compound 21 deprotections obtain compound 22, and further obtain compound 23 with compound 13-2-2 generation condensation reaction, compound 23 reacts with TMSA and obtains compound 24 under palladium catalysis, compound 24 is taken off TMS and is obtained compound 25 under the catalysis of alkali, compound 25 carries out linked reaction with compound 8 and obtains target compound 26 under palladium catalysis.
Synthetic method 3
Figure BDA0000442505360000681
Target compound 35 can prepare by synthetic method 3, wherein, and each X 7or X 8be F independently, Cl, Br, I, the leavings groups such as OTf, and, each R 5a, f, W, X 6, Y 2, R 6a, Y 4, Y 2, R 14, R 14a, R 16and R 16ahave implication as described in the present invention, Pg is amino protecting group, as Boc, and Fmoc, Cbz etc.Compound 9-1 and compound 27 condensations obtain compound 28, in ammonium acetate system, heat subsequently cyclization and obtain compound 29, after compound 29 deprotections, obtain compound 30, and further obtain compound 31 with compound 13-2 condensation, compound 31 reacts and obtains compound 32 with connection boric acid pinacol ester under the catalysis of palladium, under palladium catalysis, there is linked reaction with compound 8 and obtain compound 33 in compound 32, compound 33 reacts and obtains compound 34 with connection boric acid pinacol ester under the catalysis of palladium, and further under palladium catalysis, carry out linked reaction with compound 23 and obtain target compound 35.
Synthetic method 4
Figure BDA0000442505360000682
Target compound 40 can prepare by synthetic method 4, wherein, and X 7for F, Cl, Br, I, the leavings groups such as OTf, and, each Y 4, R 5a, w, f, X 6, R 14and R 16there is implication as described in the present invention.Pg is amino protecting group, as Boc, and Fmoc, Cbz etc.Compound 36 deprotections obtain compound 37, and further obtain compound 38 with compound 13-2-2 generation condensation reaction.Compound 38 reacts and obtains compound 39 with connection boric acid pinacol ester under the catalysis of palladium, and linked reaction further occurs under the catalysis of palladium with compound 8 obtains target compound 40.
Synthetic method 5
Figure BDA0000442505360000691
Target compound 49 can prepare by synthetic method 3, wherein, and each X 7or X 8be F independently, Cl, Br, I, the leavings groups such as OTf, and, each Y 4, R 6a, w, R 5a, f, X 6, Y 4', R 14and R 14a, R 16and R 16ahave implication as described in the present invention, Pg is amino protecting group, as Boc, and Fmoc, Cbz etc.Under the effect of alkali, there is condensation reaction and obtain compound 42 in compound 9-1-1 and compound 41, compound 42 heats cyclization and obtains compound 43 in ammonium acetate system, compound 43 reacts and obtains compound 44 with connection boric acid pinacol ester under the catalysis of palladium, compound 44 deprotections obtain compound 45, and further obtain compound 46 with compound 13-2 condensation, under palladium catalysis, there is linked reaction with compound 8 and obtain compound 47 in compound 46, compound 47 reacts and obtains compound 48 with connection boric acid pinacol ester under the catalysis of palladium, and further under palladium catalysis, carry out linked reaction with compound 23 and obtain target compound 49.
Embodiment
Embodiment 1
Figure BDA0000442505360000692
Synthetic route:
Figure BDA0000442505360000701
Step 1) compound 1-2's is synthetic
By NBS(2.16g, 12mmol) with compound 1-1(2.54g, 10mmol) be dissolved in CCl 4(20mL) in, at 0 ℃, slowly splash into dibenzoyl peroxide (0.24g, 1.0mmol), drip and finish, stirring at room temperature, after 15 minutes, refluxes 7.0 hours.After reacting completely, remove CCl 4, residuum adds EtOAc(100mL) after, water (50mL × 3) and saturated common salt water washing respectively, anhydrous sodium sulfate drying, obtains crude product 4.0g after concentrating, and is directly used in next step reaction.
MS(ESI,pos.ion)m/z:335.8[M+H] +；
1H?NMR(400MHz,CDCl 3):δ6.70(t,1H),4.73(d,2H)ppm。
Step 2) compound 1-3 synthetic
By NaH(60%, 3.13g, 78mmol) be suspended in DMF(100mL) in, slowly splash into diethyl malonate (12.54g, 78mmol), to drip and finish, 100 ℃ of reactions were down to room temperature reaction after 40 minutes.Add compound 1-2(11.81g, 35.60mmol), finish, room temperature reaction is after 30 minutes, and 75 ℃ are reacted 1.0 hours.After reacting completely, with saturated ammonium chloride solution (50mL) cancellation reaction, add EtOAc(150mL), separate organic phase, water and saturated common salt water washing respectively, anhydrous sodium sulfate drying, obtains product 14g after concentrating, and is directly used in next step reaction.
1H?NMR(400MHz,CDCl 3):δ6.93(m,1H),4.18-4.13(q,4H),3.84-3.81(m,1H),3.35,3.33(dd,dd,2H),1.23-1.19(m,6H)ppm。
Step 3) compound 1-4's is synthetic
By compound 1-3(14g) be dissolved in DMSO(100mL) in, under room temperature, slowly add NaCl(4.10g, 70mmol) and water (0.64g, 35.6mmol), after adding, 100 ℃ of reactions 3.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(200mL) dilute reaction solution, use saturated common salt water washing, anhydrous sodium sulfate drying, obtains product 9.0g through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=20/1) after concentrating.
1H?NMR(400MHz,CDCl 3):δ6.88(t,1H),4.11-4.06(q,2H),3.05,3.03,3.01(m,m,m,2H),2.69-2.65(m,2H),1.24-1.20(m,3H)ppm。
Step 4) compound 1-5's is synthetic
By compound 1-4(3.42g, 10mmol) be dissolved in methyl alcohol (20mL), splash into the NaOH aqueous solution (0.8g, 20mL) at 0 ℃, drip and finish, room temperature reaction 3.0 hours.After reacting completely, adjust pH to 5 with dilute hydrochloric acid (1M), remove methyl alcohol, water layer is adjusted pH to 2 with dilute hydrochloric acid (1M), with EtOAc(50mL × 3) extraction, organic phase anhydrous Na 2sO 4dry, after concentrating, obtain white solid 2.82g, productive rate: 90%.
MS(ESI,pos.ion)m/z:315.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ9.94(brs,1H),6.93(t,1H),3.05,3.03,3.01(m,m,m,2H),2.79,2.77,2.75(d,d,d,2H)ppm。
Step 5) compound 1-6's is synthetic
At-10 ℃, oxalyl chloride (0.93mL, 11mmol) is slowly splashed into compound 1-5(3.14g, 10mmol) and DCM(40mL DMF(0.05mL)) in solution, drip and finish, room temperature reaction is after 1.0 hours, stand-by without processing.
At-15 ℃, freshly prepd above-claimed cpd (3.32g, 10mmol) is slowly splashed into AlCl 3the DCM(30mL of (1.73g, 13mmol)) in suspension, drip and finish, isothermal reaction 2.0 hours.After reacting completely, reaction solution is slowly poured in frozen water, separate organic layer, DCM(30mL for water layer × 3) extraction, merge organic phase, respectively with clear water and saturated sodium carbonate solution washing, anhydrous sodium sulfate drying, after concentrated, obtain pale yellow powder 2.37g, productive rate: 80% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=10/1).
MS(ESI,pos.ion)m/z:296.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ2.96-2.93(m,2H),2.81-2.78(m,2H)ppm。
Step 6) compound 1-7's is synthetic
At-5 ℃, by sodium hydroxide (1.6g, 40mmol) aqueous solution (1.6mL) slowly splashes into compound 1-6(2.96g, 10mmol), Isosorbide-5-Nitrae-dibromobutane (1.31mL, 11mmol) and TEBAC(0.46g, DMSO(30mL 2.0mmol)) in suspension liquid, drip and finish, be warming up to 60 ℃ of reactions 8.0 hours.After reacting completely, reaction solution is slowly poured in frozen water (100mL), separated out solid.Filter, solid EtOAc(50mL) dissolving after, use saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain product 2.63g, productive rate: 75% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=10/1).
MS(ESI,pos.ion)m/z:351.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ2.65-2.63(m,2H),1.94-1.64(m,6H),1.25-1.15(m,2H)ppm。
Step 7) compound 1-8's is synthetic
At-5 ℃, by CF 3cOOH(9.0mL, 120mmol) slowly splash into compound 1-7(3.5g, 10mmol), NH 4f(1.11g, 30mmol) and Et 3siH(4.79mL, 30mmol) suspension liquid in, drip finish, 50 ℃ reaction 15 hours.After reacting completely, remove trifluoroacetic acid, residuum EtOAc(100mL) dissolve, use respectively sodium carbonate solution and saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain product 2.86g, productive rate: 85% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=20/1).
MS(ESI,pos.ion)m/z:337.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ2.81-2.79(m,4H),1.77-1.46(m,6H),1.34-1.24(m,2H)ppm。
Step 8) compound 1-10's is synthetic
At 0 ℃, by DIPEA(19.5mL, 118mmol) join compound 1-9(23g, 107mmol) with compound H ATU(48.82g, 128.4mmol) THF(250mL) in solution, isothermal reaction is after 0.5 hour, add compound 1-9-2(22.1g in batches, 119mmol), after adding, room temperature reaction 4.0 hours.(100mL) cancellation that after reacting completely, adds water reaction, removes THF, with EtOAc(200mL × 3) extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, obtains crude product after concentrating.Crude product obtained above is dissolved in glacial acetic acid (100mL), and 40 ℃ of reactions are spent the night.After reacting completely, concentration of reaction solution, residuum EtOAc(400mL) dissolve, sodium carbonate solution (150mL × 3) washing, anhydrous sodium sulfate drying, obtains product 31.6g, productive rate: 81% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2) after concentrating.
MS(ESI,pos.ion)m/z:367.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.68(s,1H),7.42-7.40(m,1H),7.30-7.28(m,1H),5.11-5.09(m,1H),3.45-3.43(m,2H),2.94-2.93(m,1H),2.21-2.18(m,2H),2.01-1.91(m,1H),1.49(s,9H)ppm。
Step 9) compound 1-11's is synthetic
By compound 1-10(10g, 27.39mmol) be dissolved in EtOAc(50mL), at 0 ℃, splash into the ethyl acetate solution (60mL of hydrogenchloride, 4M), room temperature reaction 8.0 hours, after reacting completely, filter, repeatedly after drip washing, obtain faint yellow solid 8.16g, productive rate by ethyl acetate: 86.5%.
MS(ESI,pos.ion)m/z:267.1[M+H] +。
Step 10) compound 1-12's is synthetic
By compound 1-11(6.35g, 18.8mmol), compound 1-11-2(4.94g, 28.2mmol) and EDCI(5.4g, 28.2mmol) be dissolved in DCM(100mL), at 0 ℃, slowly drip DIPEA(18.64mL, 112.8mmol) after, room temperature reaction 3.0 hours.After reacting completely, add water (100mL) cancellation reaction, with DCM(150mL × 3) extraction, organic phase saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain solid 6.74g, productive rate: 85% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2).
MS(ESI,pos.ion)m/z:424.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.59-7.51(m,1H),7.34-7.21(m,2H),5.42-5.38(m,2H),4.34-4.30(m,1H),3.87-3.76(m,1H),3.70(s,3H),3.66-3.62(m,1H),3.04-2.98(m,1H),2.25-2.21(m,1H),2.20-2.13(m,2H),1.96-1.94(m,1H),0.88-0.84(m,6H)ppm。
Step 11) compound 1-13's is synthetic
By compound 1-12(3.0g, 7.1mmol), compound 1-12-2(2.72g, 10.7mmol), Pd (dppf) Cl 2cH 2cl 2(0.65g, 0.8mmol) and KOAc(2.09g, 21.3mmol) be placed in reaction flask, N 2under protection, inject DMF(30mL), 90 ℃ are reacted 3.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(200mL) dilute reaction solution, diatomite filtration, filtrate is water (50mL × 3) and saturated common salt water washing respectively, anhydrous sodium sulfate drying, obtains beige solid 2.1g, productive rate: 62.9% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2) after concentrating.
MS(ESI,pos.ion)m/z:471.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.87-7.80(m,1H),7.71-7.66(m,2H),5.47-5.42(m,2H),4.34-4.30(m,1H),3.86-3.84(m,1H),3.70(s,3H),3.64-3.62(m,1H),3.04-2.98(m,1H),2.25-2.21(m,1H),2.20-2.13(m,2H),1.96-1.94(m,1H),1.35(s,12H),0.88-0.84(m,6H)ppm。
Step 12) compound 1-14's is synthetic
By compound 1-8(0.33g, 1.0mmol), compound 1-13(0.99g, 2.1mmol), Pd (PPh 3) 4(0.12g, 0.1mmol) and K 2cO 3(0.35g, 2.5mmol) is suspended in DME(5.0mL) and water (1.0mL) in, under nitrogen protection, 90 ℃ reaction 5.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(20mL) after dilute reaction solution, use respectively clear water and saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain faint yellow solid 0.39g, productive rate: 45% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=50/1).MS(ESI,pos.ion)m/z:864.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.67(q,2H),7.59,7.57(d,d,2H),7.40,7.38(d,d,2H),5.56,5.55(d,d,1H),5.32,5.29(d,d,1H),5.24-5.20(m,2H),4.40-4.32(m,2H),3.84-3.78(m,2H),3.66(s,3H),3.65-3.64(m,2H),3.63(s,3H),2.84-2.82(m,4H),2.39-2.10(m,8H),2.01-1.86(m,4H),1.73-1.52(m,4H),1.50-1.40(m,2H),1.28-1.18(m,2H),1.02-0.89(m,12H)ppm。
Embodiment 2
Synthetic route:
Figure BDA0000442505360000741
Step 1) compound 2-1's is synthetic
By compound 1-9(10.0g, 46.6mmol) be dissolved in THF(100mL) in, under 0 ℃ of nitrogen protection, borine (100mL, 1M in THF) is slowly splashed in reaction flask, drip and finish, isothermal reaction 3 hours.After reacting completely, with methyl alcohol (80mL) cancellation reaction, after concentration of reaction solution, obtain colorless oil 7.04g, productive rate: 75.2% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/2).
1H?NMR(400MHz,CDCl 3):δ3.99-3.87(br,1H),3.68-3.51(m,2H),3.48-3.39(m,1H),3.34-3.25(m,1H),2.05-1.92(m,2H),1.88-1.71(m,2H),1.45(s,9H)ppm。
Step 2) compound 2-2 synthetic
By compound 2-1(7.0g, 34.8mmol) be dissolved in DCM(250mL) in, at 0 ℃, Dai Si-Martin (20.7g, 48.8mmol) oxygenant is added in reaction flask in batches, after adding, room temperature reaction 2.0 hours.After reacting completely, add water (250mL) dilute reaction solution, filter, after filtrate layering, organic layer saturated common salt water washing, anhydrous sodium sulfate drying, obtains colorless oil 3.5g, productive rate: 50.7% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/2) after concentrating.
1H?NMR(400MHz,CDCl 3):δ9.46(d,1H,J=2.8Hz),4.08-4.03(m,1H),3.51-3.42(m,2H),2.01-1.93(m,2H),1.91-1.84(m,2H),1.43(s,9H)ppm。
Step 3) compound 2-3's is synthetic
By compound 2-2(3.5g, 17.6mmol) and ammoniacal liquor (13mL) be dissolved in methyl alcohol (30mL), at 0 ℃, the aqueous solution of oxalic dialdehyde (40%, 8mL) is slowly splashed in reaction flask, drip and finish, room temperature reaction spends the night.After reacting completely, after concentration of reaction solution, obtain white solid 1.99g, productive rate: 47.6% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/2).
MS(ESI,pos.ion)m/z:238.2[M+H] +；
1H?NMR(400MHz,CDCl 3):δ6.96(s,1H),4.94(dd,1H,J=7.68Hz,2.40Hz),3.38(t,2H,J=6.24Hz),2.17-2.03(m,2H),1.99-1.91(m,2H),1.48(s,9H)ppm。
Step 4) compound 2-4's is synthetic
By compound 2-3(2.0g, 8.4mmol) be dissolved in DCM(60mL), at 0 ℃, N-N-iodosuccinimide (3.8g, 16.8mmol) is added in reaction flask in batches to isothermal reaction 1.5 hours.After reacting completely, reaction solution saturated common salt water washing, anhydrous sodium sulfate drying, obtains white solid 2.59g, productive rate: 63.1% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/2) after concentrating.
MS(ESI,pos.ion)m/z:490.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ4.89(dd,1H,J=7.64Hz,2.52Hz),3.36(t,2H),2.14-2.02(m,2H),1.97-1.85(m,2H),1.49(s,9H)ppm。
Step 5) compound 2-5's is synthetic
By compound 2-4(1.6g, 3.27mmol) be suspended in the mixed solvent (50mL) of second alcohol and water (v/v=3/7), S-WAT (3.7g, 29mmol) is added in mixed solution and refluxed 17 hours.After reacting completely, remove ethanol, residuum adds water (50mL), extract by ethyl acetate (50mL × 3), organic phase saturated common salt water washing, anhydrous sodium sulfate drying, obtains white solid 1.0g, productive rate: 84% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/2) after concentrating.
MS(ESI,pos.ion)m/z:364.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.04(d,1H,J=1.84Hz),4.89(dd,1H,J=7.72Hz,2.56Hz),3.36(t,2H),2.18-2.03(m,2H),1.97-1.82(m,2H),1.47(s,9H)ppm。
Step 6) compound 2-6's is synthetic
Under room temperature, the ethyl acetate solution (5mL, 4M) of hydrogenchloride is added drop-wise to compound 2-5(1.50g, 4.13mmol) EtOAc(10mL) in solution, drip and finish, reaction is spent the night.After reacting completely, filter, obtain solid 1.2g, productive rate: 86.5%.Be directly used in next step reaction.MS(ESI,pos.ion)m/z:264.1[M+H] +。
Step 7) compound 2-7's is synthetic
By compound 2-6(1.2g, 3.6mmol), compound 1-12-2(0.68g, 3.9mmol) and EDCI(0.75g, 3.9mmol) be suspended in DCM(20mL) in, stir after 5 minutes at 0 ℃, slowly splash into DIPEA(2.38mL, 14.4mmol), drip and finish, room temperature reaction 2.0 hours.After reacting completely, add DCM(40mL) dilute reaction solution, organic phase is washed with saturated ammonium chloride solution, anhydrous sodium sulfate drying, after concentrated, obtain weak yellow foam solid 1.31g, productive rate: 86.8% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2).
MS(ESI,pos.ion)m/z:421.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.35(s,1H),5.32,5.29(brs,brs,1H),5.20-5.15(m,1H),4.41-4.37(m,1H),3.85-3.78(m,1H),3.69-3.65(m,1H),3.63(s,3H),2.28-2.17(m,3H),2.11-1.96(m,2H),0.97-0.95(m,3H),0.91-0.89(m,3H)ppm。
Step 8) compound 2-8's is synthetic
By compound 2-7(0.58g, 1.38mmol), PdCl 2(PPh 3) 2(98mg; 0.14mmol), tetrabutylammonium iodide (1.53g, 4.14mmol) and CuI(78mg; 0.41mmol) be dissolved in DMF(5mL) in; under nitrogen protection, slowly add triethylamine (2.0mL), stirring at room temperature is after 10 minutes; slowly splash into TMSA(0.98mL; 6.89mmol), drip and finish, 70 ℃ of reactions are spent the night.After reacting completely, diatomite filtration, filtrate adds water (20mL) dilution, EtOAc(20mL for water layer × 3) extraction, merge organic phase, anhydrous sodium sulfate drying, obtains product 0.3g, productive rate: 55.8% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/1) after concentrating.
MS(ESI,pos.ion)m/z:391.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.27(s,1H),5.32,5.30(d,d,1H),5.29-5.24(m,1H),4.41-4.36(m,1H),3.89-3.83(m,1H),3.73-3.65(m,1H),3.63(s,3H),2.31-1.93(m,5H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H),0.32(m,9H)ppm。
Step 9) compound 2-9's is synthetic
By compound 2-8(0.34g, 0.87mmol) and K 2cO 3(0.60g, 4.35mmol) is dissolved in MeOH(2mL) and mixed solvent THF(2mL) in, room temperature reaction 6.0 hours.After reacting completely, except desolventizing, residuum adds water (10mL), with EtOAc(10mL × 3) extraction, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain product 0.23g, productive rate: 82.6% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=2/1).
MS(ESI,pos.ion)m/z:319.4[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.27(s,1H),5.35-5.31(m,1.5H),5.30-5.29(d,0.5H,J=4.0Hz),4.41-4.36(m,1H),3.89-3.83(m,1H),3.73-3.66(m,1H),3.63(s,3H),3.36(s,1H),2.31-1.93(m,5H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 10) compound 2-10's is synthetic
By compound 1-8(0.13g, 0.39mmol), compound 2-9(0.31g, 0.975mmol), PdCl 2(PPh 3) 2(14.1mg, 0.02mmol), CuI(33mg, 0.172mmol), PPh 3(0.23g, 0.86mmol) joins in reaction flask, under nitrogen protection, adds DMF(10mL), slowly splash into triethylamine (5.0mL), to drip and finish, stirring at room temperature is after 10 minutes, and 90 ℃ are reacted 10 hours.After reacting completely, diatomite filtration, in filtrate, add water (20mL), with EtOAc(20mL × 3) extraction, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain product 95mg, productive rate: 30% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=60/1).
MS(ESI,pos.ion)m/z:811.4[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.48(s,2H),5.51-5.47(m,2H),5.32,5.30(d,d,2H),4.41-4.36(m,1H),3.89-3.83(m,2H),3.73-3.66(m,2H),3.63(s,6H),3.12-3.10(m,4H),2.32-1.92(m,10H),1.79-1.58(m,4H),1.53-1.43(m,2H),1.32-1.22(m,2H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H)ppm。
Embodiment 3
Synthetic route:
Figure BDA0000442505360000771
Step 1) compound 3-1's is synthetic
By compound 3-1-0(30g, 107.9mmol) and compound 1-9(25.5g, 118.7mmol) be dissolved in DCM(250mL) in, at 0 ℃, slowly splash into DIPEA(21.4mL, 129.5mmol), drip and finish, room temperature reaction 3.0 hours.After reacting completely, with frozen water (100mL) cancellation reaction, EtOAc(100mL for water layer × 3) extraction, organic phase saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain white solid 40.4g, productive rate: 91% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=10/1).
MS(ESI,pos.ion)m/z:412.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.78-7.75(m,2H),7.65-7.63(m,2H),5.53-5.15(m,2H),4.49-4.39(m,1H),3.59-3.54(m,1H),3.48-3.38(m,1H),2.31-2.21(m,2H),2.12-2.01(m,1H),1.98-1.85(m,1H),1.45(d,9H)ppm。
Step 2) compound 3-2 synthetic
By compound 3-1(15g, 36.4mmol) and ammonium acetate (42g, 54.6mmol) be suspended in toluene (150mL), 110 ℃ reaction 5.0 hours.After reacting completely, be chilled to room temperature, add water (100mL) cancellation reaction, EtOAc(100mL for water layer × 3) extraction, merge organic phase, use saturated common salt water washing, anhydrous Na SO 4dry, after concentrating, obtain product 12.1g, productive rate: 85% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=5/1).
MS(ESI,pos.ion)m/z:392.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.78-7.75(m,2H),7.65-7.63(m,2H),7.21-7.20(m,1H),5.53-5.15(m,2H),4.49-4.39(m,1H),3.59-3.54(m,1H),3.48-3.38(m,1H),2.31-2.21(m,2H),2.12-2.01(m,1H),1.98-1.85(m,1H),1.45(d,9H)ppm。
Step 3) compound 3-3's is synthetic
By compound 3-2(10g, 25.5mmol) be dissolved in EtOAc(50mL) in, then add after the ethyl acetate solution (60mL, 4M) of hydrogenchloride room temperature reaction 8.0 hours.After reacting completely, concentration of reaction solution, residuum adds EtOAc(30mL) after making beating, filter and obtain faint yellow solid 8.0g, productive rate: 86.2%.
MS(ESI,pos.ion)m/z:292.2[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.76-7.73(m,2H),7.66-7.63(m,2H),7.21-7.20(m,1H),5.50-5.22(m,2H),4.49-4.39(m,1H),3.61-3.56(m,1H),3.49-3.39(m,1H),2.31-2.21(m,2H),2.12-2.01(m,1H),1.98-1.85(m,1H)ppm。
Step 4) compound 3-4's is synthetic
By compound 3-3(7.01g, 19.26mmol), compound 1-11-2(5.06g, 28.9mmol) and EDCI(5.56g, 28.9mmol) be dissolved in DCM(100mL), at 0 ℃, slowly splash into DIPEA(21mL, 127mmol) after, room temperature reaction 3.0 hours.After reacting completely, add water (100mL), DCM(100mL for water layer × 3) extraction, merge organic phase, use saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain solid 7.6g, productive rate: 88% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2).
MS(ESI,pos.ion)m/z:450.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.65-7.60(m,2H),7.47-7.43(m,2H),7.22-7.20(m,1H),5.67-5.65(m,1H),5.24-5.22(m,1H),4.34-4.30(m,1H),3.85-3.81(m,1H),3.72(s,3H),3.71-3.64(m,1H),3.00(s,1H),2.34-2.11(m,1H),2.21-1.95(m,5H),1.04-1.02(m,1H),0.88-0.86(d,6H)ppm。
Step 5) compound 3-5's is synthetic
By compound 3-4(4.99g, 11.1mmol), compound 1-12-2(4.24g, 16.7mmol), Pd (dppf) Cl 2cH 2cl 2(0.91g, 1.11mmol) and KOAc(3.30g, 33.4mmol) be placed in reaction flask, N 2under protection, inject DMF(50mL), 90 ℃ are reacted 3.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(200mL) after dilute reaction solution, diatomite filtration, filtrate is water (100mL × 3) and saturated common salt water washing respectively, anhydrous sodium sulfate drying, obtains beige solid 3.95g, productive rate: 71.4% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2) after concentrating.
1H?NMR(400MHz,CDCl 3):δ7.65-7.60(m,2H),7.47-7.43(m,2H),7.22-7.20(m,1H),5.67-5.65(m,1H),5.24-5.22(m,1H),4.34-4.30(m,1H),3.5-3.81(m,1H),3.72(s,3H),3.71-3.64(m,1H),3.00(s,1H),2.34-2.11(m,1H),2.21-1.95(m,5H),1.32-1.45(m,12H),1.04-1.02(m,1H),0.88-0.86(d,6H)ppm。
Step 6) compound 3-6's is synthetic
By compound 1-8(0.33g, 1.0mmol), compound 3-5(0.5g, 1.0mmol), Pd (PPh 3) 4(0.12g, 0.1mmol) and salt of wormwood (0.35g, 2.5mmol) are placed in reaction flask, inject respectively DME(10mL) and pure water (2mL), N 2under protection, 90 ℃ are reacted 5.0 hours.After reacting completely, be chilled to room temperature, add water (50mL) dilute reaction solution, EtOAc(60mL for water layer × 3) extraction, organic phase saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain weak yellow foam shape thing 0.25g, productive rate: 40% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=100/1).
MS(ESI,pos.ion)m/z:626.6[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.67-7.66,7.65-7.64(m,m,2H),7.59(s,1H),7.51-7.50,7.49-7.48(m,m,2H),5.32,5.29(d,d,1H),5.23-5.19(m,1H),4.41-4.36(m,1H),3.85-3.78(m,1H),3.69-3.64(m,1H),3.63(s,3H),2.84-2.81(m,2H),2.75-2.72(m,2H),2.30-1.92(m,5H),1.74-1.54(m,4H),1.53-1.43(m,2H),1.31-1.21(m,2H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 7) compound 3-7's is synthetic
By compound 3-6(0.62g, 1.0mmol), compound 1-12-2(0.28g, 1.1mmol), Pd (dppf) Cl 2cH 2cl 2(81.7mg, 0.1mmol) and KOAc(0.25g, 2.5mmol) be placed in reaction flask, inject DMF(3.0mL), N 2under protection, 90 ℃ are reacted 5.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(30mL) after dilute reaction solution, diatomite filtration, filtrate is water (20mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 0.34g, productive rate: 50% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2).
MS(ESI,pos.ion)m/z:673.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.66-7.65,7.64-7.63(m,m,2H),7.59(s,1H),7.23-7.22,7.21-7.20(m,m,2H),5.32,5.29(d,d,1H),5.23-5.19(m,1H),4.41-4.37(m,1H),3.85-3.78(m,1H),3.69-3.64(m,1H),3.63(s,3H),2.80-2.77(m,2H),2.66-2.63(m,2H),2.30-1.92(m,5H),1.74-1.54(m,6H),1.52-1.41(m,2H),1.33,1.30(q,q,12H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 8) compound 3-8's is synthetic
By compound 3-7(0.67g, 1.0mmol), compound 2-7(0.43g, 1.02mmol), Pd (PPh 3) 4(0.12g, 0.1mmol) and salt of wormwood (0.35g, 2.5mmol) are placed in reaction flask, inject respectively EtOH(10mL) and pure water (2mL), N 2under protection, 90 ℃ are reacted 6.0 hours.After reacting completely, be chilled to room temperature, add water (20mL) dilute reaction solution, EtOAc(20mL for water layer × 3) extraction, organic phase saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 293mg, productive rate: 35% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=50/1).
MS(ESI,pos.ion)m/z:840.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.68-7.65,7.64-7.63(m,m,2H),7.61-7.59,7.58-7.57(m,m,3H),7.40(s,1H),6.08,6.06(d,d,1H),5.44-5.40(m,1H),5.32,5.29(d,d,1H),5.23-5.19(m,1H),4.41-4.37(m,1H),4.34-4.30(m,1H),3.85-3.78(m,2H),3.69-3.66(m,2H),3.65(s,3H),3.63(s,3H),2.95-2.92(m,2H),2.76-2.73(m,2H),2.31-1.92(m,10H),1.73-1.52(m,4H),1.49-1.39(m,2H),1.27-1.17(m,2H),1.02-0.89(m,12H)ppm。
Embodiment 4
Figure BDA0000442505360000791
Synthetic route:
Figure BDA0000442505360000801
Step 1) compound 4-1's is synthetic
By compound 1-10(4.11g, 11.27mmol), compound 1-12-2(4.29g, 16.9mmol), Pd (dppf) Cl 2cH 2cl 2(0.65g, 0.8mmol) and KOAc(2.76g, 28.17mmol) be placed in reaction flask, N 2under protection, add DMF(30mL), 90 ℃ are reacted 3.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(200mL) dilute reaction solution, diatomite filtration, filtrate is water (60mL × 3) and saturated common salt water washing respectively, anhydrous sodium sulfate drying, obtains beige solid 3.02g, productive rate: 65% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2) after concentrating.
MS(ESI,pos.ion)m/z:414.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.69(s,1H),7.45-7.43(m,1H),7.32-7.30(m,1H),5.12-5.10(m,1H),3.45-3.43(m,2H),2.95-2.94(m,1H),2.25-2.22(m,2H),2.01-1.91(m,1H),1.49(s,9H),1.35(s,12H)ppm。
Step 2) compound 4-2 synthetic
By compound 4-1(0.58g, 1.4mmol) be dissolved in EtOAc(5.0mL) in, add after the ethyl acetate solution (5mL, 4M) of hydrogenchloride room temperature reaction 8.0 hours.After reacting completely, concentration of reaction solution, residuum adds EtOAc(10mL) after making beating, filter and obtain faint yellow solid 0.49g, productive rate: 91%.
MS(ESI,pos.ion)m/z:314.2[M+H] +。
Step 3) compound 4-3's is synthetic
By compound 4-2(1.0g, 2.6mmol), compound 4-2-2(0.59g, 3.1mmol), EDCI(0.55g, 2.86mmol) and HOAT(0.35g, 2.6mmol) be suspended in DCM(15mL) in, at 0 ℃, slowly splash into DIPEA(1.72mL, 10.4mmol), drip and finish, room temperature reaction 3.0 hours.After reacting completely, add DCM(40mL) dilute reaction solution, use respectively aqueous ammonium chloride solution and saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain white solid 1.17g, productive rate: 93% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2).
MS(ESI,pos.ion)m/z:485.4[M+H] +；
1H?NMR(400MHz,CDCl 3):δ10.62(brs,1H),8.22(m,1H),7.73-7.65(m,2H),5.72(d,1H,J=8.0Hz),5.43(d,1H,J=8.0Hz),4.35-4.31(m,1H),3.95-3.88(m,1H),3.78-3.75(m,1H),3.69-3.67(m,4H),3.08-3.04(m,1H),2.43-2.37(m,1H),2.25-2.15(m,2H),1.91(s,1H),1.74-1.72(m,1H),1.52-1.50(m,1H),1.35(s,12H),1.24(t,2H,J=8.0Hz),1.12-1.10(m,1H),0.93-0.88(m,1H)ppm。
Step 4) compound 4-4's is synthetic
By compound 3-6(0.62g, 1.0mmol), compound 4-3(0.53g, 1.1mmol), Pd (PPh 3) 4(0.12g, 0.1mmol) and salt of wormwood (0.35g, 2.5mmol) are placed in reaction flask, inject respectively EtOH(10mL) and pure water (2mL), N 2under protection, 90 ℃ are reacted 6.0 hours.After reacting completely, be chilled to room temperature, add water (20mL) dilute reaction solution, EtOAc(20mL for water layer × 3) extraction, organic phase saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 0.36g, productive rate: 40% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=50/1).
MS(ESI,pos.ion)m/z:452.2[M+2H] 2+；
1H?NMR(400MHz,CDCl 3):δ7.80,7.77(d,d,1H),7.70(q,1H),7.66-7.65,7.64-7.62(m,m,2H),7.59(s,1H),7.48-7.47,7.46-7.45(m,2H),7.18,7.16(d,d,1H),5.32,5.29(d,d,1H),5.28,5.26(d,d,1H),5.23-5.19(m,1H),5.13-5.09(m,1H),4.45-4.36(m,2H),3.85-3.77(m,2H),3.69-3.64(m,2H),3.63(s,6H),2.79-2.76(m,2H),2.74-2.71(m,2H),2.42-2.34(m,1H),2.30-1.80(m,9H),1.73-1.39(m,7H),1.27-1.11(m,3H),0.97,0.96(m,m,3H),0.91,0.89(m,m,3H),0.88,0.86(m,m,3H),0.85,0.83,0.81(m,m,m,3H)ppm。
Embodiment 5
Figure BDA0000442505360000811
Synthetic route:
Figure BDA0000442505360000812
Step 1) compound 5-2's is synthetic
By compound 5-1(25g, 125.6mmol), NBS(24.5g, 138.2mmol) and p-TSA(3.4g, 20.9mmol) being placed in reaction flask, under nitrogen protection, 100 ℃ are reacted 2.0 hours.After reacting completely, be chilled to room temperature, add DCM(200mL) after dilute reaction solution, water (50mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain product 24.7g, productive rate: 71% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=5/1).
MS(ESI,pos.ion)m/z:279.9[M+H] +；
1H?NMR(400MHz,CDCl 3):δ8.95(d,1H,J=1.12Hz),8.11-8.14(m,1H),7.66-7.68(m,1H),4.41(s,2H)ppm。
Step 2) compound 5-3 synthetic
By compound 5-2(5.0g, 17.9mmol) and compound 5-2-2(5.36g, 19.7mmol) be dissolved in MeCN(100mL) in, at 0 ℃, slowly splash into DIPEA(3.3mL, 19.7mmol), drip and finish, room temperature reaction 3.0 hours.After reacting completely, concentration of reaction solution, residuum adds water (100mL), then uses EtOAc(100mL × 3) extraction, merge organic phase, anhydrous Na 2sO 4dry, after concentrating, obtain product 8.06g, productive rate: 96% through column chromatographic isolation and purification (PE/EtOAc (v/v)=3/1).
MS(ESI,pos.ion)m/z:470.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ8.88(s,1H),8.04(d,1H,J=3.88Hz),7.65(d,1H,J=4.16Hz),5.61-5.59(m,1H),5.48(d,1H,J=8.32Hz),5.23(d,1H,J=8.3Hz),4.67(t,1H,J=5.72Hz),4.31(t,1H,J=7.52Hz),3.86-3.84(m,1H),3.73-3.71(m,1H),3.66(s,3H),2.34-2.15(m,4H),1.01(t,3H),0.94-0.93(m,3H),0.88-0.85(m,1H)ppm。
Step 3) compound 5-4's is synthetic
By compound 5-3(2.0g, 4.25mmol) and ammonium acetate (4.9g, 83mmol) be suspended in dimethylbenzene (50mL), 130 ℃ reaction 5.0 hours.After reacting completely, be chilled to room temperature, add water (50mL) cancellation reaction, EtOAc(50mL for water layer × 3) extraction, merge organic phase, anhydrous Na 2sO 4dry, after concentrating, obtain product 1.39g, productive rate: 73% through column chromatographic isolation and purification (PE/EtOAc (v/v)=2/1).
MS(ESI,pos.ion)m/z:450.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ8.70(s,1H),7.93(d,1H,J=6.92Hz),7.45(d,1H,J=8.28Hz),5.41(d,1H,J=4.6Hz),5.24-5.22(m,1H),4.32(m,1H),3.85-3.83(m,1H),3.67(s,3H),3.63-3.62(m,3H),3.05-3.03(m,1H),2.31-1.93(m,4H),1.04-1.03(m,1H),0.88(s,3H),0.86(s,3H)ppm。
Step 4) compound 5-5's is synthetic
By compound 5-4(2.33g, 5.2mmol), compound 1-12-2(1.59g, 6.25mmol), Pd (dppf) Cl 2cH 2cl 2(0.43g, 0.52mmol) and KOAc(1.54g, 15.63mmol) be placed in reaction flask, N 2under protection, inject DMF(20mL), 90 ℃ are reacted 3.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(100mL) after diluting reaction, diatomite filtration, filtrate is water (60mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain product 1.68g, productive rate: 65% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=2/1).
MS(ESI,pos.ion)m/z:498.4[M+H] +；
1H?NMR(400MHz,CDCl 3):δ8.76-8.75(m,1H),8.00,7.98(d,d,1H),7.73,7.71(d,d,1H),7.37(s,1H),5.38-5.33(m,1H),5.32,5.29(d,d,1H),4.41-4.36(m,1H),3.85-3.78(m,1H),3.69-3.64(m,1H),3.63(s,3H),2.30-1.92(m,5H),1.39,1.36(m,m,12H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 5) compound 5-6's is synthetic
By compound 5-5(0.36g, 0.72mmol), compound 1-8(0.24g, 0.72mmol), Pd (PPh 3) 4(83mg, 0.07mmol) and salt of wormwood (0.3g, 2.12mmol) are suspended in DME(6.0mL) and water (1.5mL) in, under nitrogen protection, 90 ℃ are reacted 4.0 hours.After reacting completely, add EtOAc(40mL) after dilute reaction solution, water (10mL × 3) and saturated common salt water washing respectively, anhydrous sodium sulfate drying, after concentrated, obtain product 0.2g, productive rate: 45% through column chromatographic isolation and purification (DCM/EtOAc (v/v)=80/1).
MS(ESI,pos.ion)m/z:627.7[M+H] +；
1H?NMR(400MHz,CDCl 3):δ8.77(q,1H),7.82,7.79(d,d,1H),7.67(s,1H),7.60,7.58(d,d,1H),5.38-5.33(m,1H),5.32,5.29(d,d,1H),4.41-4.35(m,1H),3.85-3.78(m,1H),3.69-3.64(m,1H),3.63(s,3H),2.87-2.84(m,2H),2.78-2.75(m,2H),2.30-1.92(m,5H),1.75-1.54(m,4H),1.52-1.42(m,2H),1.30-1.20(m,2H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 6) compound 5-7's is synthetic
By compound 5-6(62.5mg, 0.1mmol), compound 1-13(52mg, 0.11mmol), Pd (PPh 3) 4(12mg, 0.01mmol) and salt of wormwood (35mg, 0.25mmol) are placed in reaction flask, inject respectively DME(2.5mL) and pure water (0.5mL), N 2under protection, 90 ℃ are reacted 6.0 hours.After reacting completely, be chilled to room temperature, add water (10mL) dilute reaction solution, EtOAc(10mL for water layer × 3) extraction, organic phase saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 44mg, productive rate: 50% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=50/1).
MS(ESI,pos.ion)m/z:445.7[M+2H] 2+；
1H?NMR(400MHz,CDCl 3):δ8.75(q,1H),7.85,7.83(d,d,1H),7.80,7.78(d,d,1H),7.69(q,1H),7.67(s,1H),7.57,7.55(d,d,1H),7.18,7.16(d,d,1H),5.38-5.33(m,1H),5.32,5.29(d,d,2H),5.24-5.20(m,1H),4.41-4.35(m,2H),3.85-3.78(m,2H),3.69-3.65(m,2H),3.63(s,6H),2.81-2.79(m,4H),2.38-1.86(m,10H),1.73-1.52(m,4H),1.49-1.39(m,2H),1.27-1.17(m,2H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H)ppm。
Embodiment 6
Synthetic route:
Figure BDA0000442505360000841
Step 1) compound 6-1's is synthetic
By compound 3-2(4.0g, 10.23mmol), compound 1-12-2(2.86g, 11.3mmol), Pd (dppf) Cl 2cH 2cl 2(0.42g, 0.51mmol) and KOAc(2.51g, 25.57mmol) be placed in reaction flask, N 2under protection, inject DMF(20mL), 90 ℃ are reacted 3.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(200mL) dilute reaction solution, diatomite filtration, filtrate is water (80mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain product 3.59g, productive rate: 80% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=2/1).
1H?NMR(400MHz,CDCl 3):δ7.35(m,4H),7.10(s,1H),4.93(t,1H,J=8.2Hz),3.88-3.66(m,2H),2.90(t,1H,J=8.0Hz),2.50-2.47(m,2H),2.27-2.25(m,1H),1.48(s,9H),1.26(s,12H)ppm。
Step 2) compound 6-2 synthetic
By compound 1-8(0.33g, 1.0mmol), compound 6-1(0.44g, 1.0mmol), Pd (PPh 3) 4(0.12g, 0.1mmol) and salt of wormwood (0.35g, 2.5mmol) are placed in reaction flask, inject respectively DME(10mL) and pure water (2mL), N 2under protection, 90 ℃ are reacted 5.0 hours.After reacting completely, be chilled to room temperature, add water (20mL) dilute reaction solution, EtOAc(20mL for water layer × 3) extraction, organic phase saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 255mg, productive rate: 45% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=100/1).
MS(ESI,pos.ion)m/z:569.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.67-7.66,7.65-7.64(m,m,2H),7.59(s,1H),7.51-7.50,7.49-7.48(m,m,2H),4.98-4.92(m,1H),3.64-3.58(m,1H),3.31-3.24(m,1H),2.84-2.81(m,2H),2.75-2.72(m,2H),2.47-2.38(m,1H),2.29-2.17(m,1H),2.10-1.96(m,2H),1.75-1.54(m,4H),1.53-1.43(m,2H),1.41(s,9H),1.31-1.21(m,2H)ppm。
Step 3) compound 6-3's is synthetic
By compound 6-2(0.57g, 1.0mmol), compound 1-12-2(0.28g, 1.1mmol), Pd (dppf) Cl 2cH 2cl 2(81.7mg, 0.1mmol) and KOAc(0.25g, 2.5mmol) be placed in reaction flask, inject DMF(3.0mL), N 2under protection, 90 ℃ are reacted 5.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(30mL) after dilute reaction solution, diatomite filtration, filtrate is water (20mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 0.34g, productive rate: 55% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2).
MS(ESI,pos.ion)m/z:616.6[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.66-7.65,7.64-7.63(m,m,2H),7.59(s,1H),7.23-7.22,7.21-7.20(m,m,2H),4.98-4.92(m,1H),3.64-3.58(m,1H),3.31-3.24(m,1H),2.80-2.77(m,2H),2.66-2.63(m,2H),2.47-2.38(m,1H),2.29-2.17(m,1H),2.10-1.96(m,2H),1.74-1.54(m,6H),1.52-1.43(m,2H),1.41(s,9H),1.33,1.30(q,q,12H)ppm。
Step 4) compound 6-4's is synthetic
Respectively by compound 6-3(0.42g, 0.69mmol), compound 2-5(0.25g, 0.69mmol), salt of wormwood (0.24g, 1.72mmol) is placed in reaction flask, N with tetra-triphenylphosphine palladium (80mg, 0.069mmol) 2under protection, inject respectively DME(8mL) and water (2mL), 90 ℃ are reacted 5.0 hours.After reacting completely, add EtOAc(40mL) dilute reaction solution, water and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain yellow solid 275mg, productive rate: 55% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=80/1).
MS(ESI,pos.ion)m/z:726.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.66-7.65,7.64-7.63(m,m,2H),7.61-7.60,7.59-7.57(m,m,3H),7.47(s,1H),5.24-5.19(m,1H),4.98-4.92(m,1H),3.64-3.58(m,2H),3.31-3.23(m,2H),2.95-2.92(m,2H),2.76-2.73(m,2H),2.57-2.17(m,5H),2.10-1.96(m,3H),1.73-1.56(m,4H),1.53(s,9H),1.47-1.42(m,2H),1.41(s,9H),1.27-1.17m,2H)ppm。
Step 5) compound 6-5's is synthetic
By compound 6-4(0.22g, 0.3mmol) be dissolved in EtOAc(4mL), then splash into after the ethyl acetate solution (2mL, 4M) of hydrogenchloride, drip and finish, room temperature reaction 8 hours.After reacting completely, concentration of reaction solution, after ethyl acetate for residuum (5mL) making beating, filters and obtains yellow solid 0.18g, productive rate: 90%.
MS(ESI,pos.ion)m/z:525.,3[M+H] +。
Step 6) compound 6-6's is synthetic
By compound 6-5(0.17g, 0.26mmol), compound 6-5-2(83.8mg, 0.57mmol), EDCI(0.11g, 0.57mmol) and HOAT(0.07g, 0.52mmol) be suspended in DCM(3mL) in, at 0 ℃, slowly splash into DIPEA(0.5mL, 2.6mmol), drip and finish, room temperature reaction 3 hours.After reacting completely, add DCM(20mL) dilute reaction solution, use respectively aqueous ammonium chloride solution and saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain faint yellow solid 0.13g, productive rate: 65% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=40/1).
MS(ESI,pos.ion)m/z:783.4[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.66-7.65,7.64-7.63(m,m,2H),7.61-7.59,7.58-7.57(m,m,3H),7.40(s,1H),5.44,5.42(m,m,2H),5.31-5.26(m,1H),5.10-5.05(m,1H),4.64-4.57(m,2H),3.88-3.82(m,2H),3.72-3.65(m,2H),3.64(s,6H),2.95-2.92(m,2H),2.76-2.73(m,2H),2.36-1.93(m,8H),1.73-1.52(m,4H),1.49-1.39(m,2H),1.36,1.34(d,d,6H),1.27-1.17(m,2H)ppm。
Embodiment 7
Figure BDA0000442505360000861
Synthetic route:
Figure BDA0000442505360000862
Step 1) compound 7-1's is synthetic
By compound 6-5(0.17g, 0.26mmol), compound 7-1-0(0.12g, 0.57mmol), EDCI(0.11g, 0.57mmol) and HOAT(0.07g, 0.52mmol) be suspended in DCM(3mL) in, at 0 ℃, slowly splash into DIPEA(0.5mL, 2.6mmol), drip and finish, room temperature reaction 3 hours.After reacting completely, add DCM(20mL) dilute reaction solution, use respectively aqueous ammonium chloride solution and saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain faint yellow solid 0.12g, productive rate: 50% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=40/1).
MS(ESI,pos.ion)m/z:460.2[M+2H] 2+；
1H?NMR(400MHz,CDCl 3):δ7.66-7.65,7.64-7.63(m,m,2H),7.61-7.59,7.58-7.57(m,m,3H),7.40(s,1H),5.28-5.24(m,1H),5.21,5.19(d,d,2H),5.09-5.04(m,1H),4.47-4.41(m,2H),3.86-3.80(m,2H),3.70-3.65(m,2H),3.63(s,6H),2.95-2.92(m,2H),2.76-2.73(m,2H),2.36-1.88(m,10H),1.73-1.51(m,10H),1.49-1.31(m,10H),1.27-1.03(m,8H)ppm。
Embodiment 8
Synthetic route:
Figure BDA0000442505360000871
Step 1) compound 8-2's is synthetic
By compound 8-1(3.0g, 13.1mmol) and compound 3-1-0(3.63g, 13.1mmol) be dissolved in DCM(40mL) in, at 0 ℃, slowly add TEA(3.9mL, 26.3mmol), drip and finish, room temperature reaction 2.0 hours.After reacting completely, add water (50mL) cancellation reaction, DCM(50mL for water layer × 3) extraction, merge organic phase, use saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain crude product 3.27g, productive rate: 62.9%.Be directly used in next step reaction.
MS(ESI,pos.ion)m/z:399.3[M+H] +。
Step 2) compound 8-3 synthetic
By compound 8-2(3.27g, 8.2mmol) and ammonium acetate (5.1g, 66mmol) be suspended in toluene (30mL), 110 ℃ reaction 5.0 hours.After reacting completely, be chilled to room temperature, add water (50mL) cancellation reaction, EtOAc(80mL for water layer × 3) extraction, merge organic phase, use saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain product 2.85g, productive rate: 86% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=4/1).
MS(ESI,pos.ion)m/z:407.4[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.45(m,4H),7.20(s,1H),4.93(t,1H,J=8.2Hz),3.88-3.66(m,1H),2.90(t,1H,J=8.0Hz),2.50-2.47(m,2H),2.27-2.25(m,1H),1.48(s,7H),1.26(s,2H),1.12(d,3H,J=6.2Hz)ppm。
Step 3) compound 8-4's is synthetic
By compound 8-3(2.8g, 6.9mmol), compound 1-12-2(1.93g, 7.6mmol), Pd (dppf) Cl 2cH 2cl 2(0.28g, 0.34mmol) and KOAc(1.7g, 17.25mmol) be placed in reaction flask, N 2under protection, inject DME(30mL), 90 ℃ are reacted 2.0 hours.After reacting completely, be chilled to room temperature, add ethyl acetate (200mL) dilute reaction solution, diatomite filtration, filtrate is water (20mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 2.76g, productive rate: 88.2% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2).
MS(ESI,pos.ion)m/z:454.4[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.35(m,4H),7.10(s,1H),4.93(t,1H,J=8.2Hz),3.88-3.66(m,1H),2.90(t,1H,J=8.0Hz),2.50-2.47(m,2H),2.27-2.25(m,1H),1.48(s,9H),1.26(s,12H),1.02(d,3H,J=6.2Hz)ppm。
Step 4) compound 8-5's is synthetic
By compound 8-4(0.26g, 0.58mmol), compound 1-8(0.19g, 0.58mmol), Pd (PPh 3) 4(35mg, 0.03mmol) and salt of wormwood (0.08g, 1.4mmol) are placed in reaction flask, N 2under protection, inject respectively DME(4.0mL) and pure water (1.0mL), 90 ℃ are reacted 4.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(40mL) after dilute reaction solution, water (20mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 185mg, productive rate: 55% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=100/1).
MS(ESI,pos.ion)m/z:583.6[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.67-7.66,7.65-7.64(m,m,2H),7.59(s,1H),7.51-7.50,7.49-7.48(m,m,2H),4.89-4.84(m,1H),3.80-3.73(m,1H),3.09-3.02(m,1H),2.84-2.81(m,2H),2.75-2.72(m,2H),2.33-2.18(m,2H),1.75-1.54(m,5H),1.53-1.44(m,2H),1.42(s,9H),1.31-1.21(m,2H),0.96-0.93(m,3H)ppm。
Step 5) compound 8-6's is synthetic
At 0 ℃, by DIPEA(1.95mL, 11.8mmol) join compound 8-1(2.45g, 10.7mmol) with compound H ATU(4.88g, 12.84mmol) THF(30mL) in solution, isothermal reaction is after 0.5 hour, add compound 1-9-2(2.21g in batches, 11.9mmol), after adding, room temperature reaction 4.0 hours.After reacting completely, add water (50mL) cancellation reaction, remove THF, with EtOAc(50mL × 3) extraction, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, is dissolved in residuum in glacial acetic acid (20mL) after concentrating, and 40 ℃ of reactions are spent the night.After reacting completely, remove glacial acetic acid, residuum EtOAc(100mL) dissolve after, wash with sodium carbonate solution (50mL × 3), anhydrous sodium sulfate drying, obtains product 3.24g, productive rate: 80% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2) after concentrating.
MS(ESI,pos.ion)m/z:381.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.84(d,1H,J=2.9Hz),7.44(d,1H,J=15.0Hz),7.33(dd,1H,J=15.0Hz,2.9Hz),4.88(t,1H,J=16.9Hz),4.27(dd,1H,J=24.8Hz,17.3Hz),3.14(dd,1H,J=24.7Hz,17.3Hz),2.53(dt,1H,J=24.4Hz,17.2Hz),2.21-2.03(m,1H),1.81(dt,1H,J=24.4Hz,17.2Hz),1.41(s,9H),0.95(d,3H,J=12.7Hz)ppm。
Step 6) compound 8-7's is synthetic
By compound 8-6(4.27g, 11.27mmol), compound 1-12-2(4.29g, 16.9mmol), Pd (dppf) Cl 2cH 2cl 2(0.65g, 0.8mmol) and KOAc(2.76g, 28.17mmol) be placed in reaction flask, N 2under protection, add DME(30mL), 90 ℃ are reacted 3.0 hours.After reacting completely, remove DME, add water (50mL), with EtOAc(50mL × 3) extraction, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain beige solid 2.89g, productive rate: 60% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/1).
MS(ESI,pos.ion)m/z:428.4[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.82(dd,1H),7.65,7.63(d,d,1H),7.27,7.25(d,d,1H),5.07-5.02(m,1H),3.85-3.78(m,1H),3.14-3.07(m,1H),2.51-2.42(m,1H),2.30-2.16(m,1H),1.86-1.78(m,1H),1.41(s,9H),1.32,1.29(m,m,12H),0.96-0.93(m,3H)ppm。
Step 7) compound 8-8's is synthetic
By compound 8-7(0.25g, 0.58mmol), compound 8-5(0.34g, 0.58mmol), Pd (PPh 3) 4(35mg, 0.03mmol) and salt of wormwood (80mg, 1.4mmol) are placed in reaction flask, N 2under protection, inject respectively DME(4.0mL) and pure water (1.0mL), 90 ℃ are reacted 4.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(50mL) after dilute reaction solution, water (30mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 0.28g, productive rate: 60% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=80/1).
MS(ESI,pos.ion)m/z:402.2[M+2H] 2+；
1H?NMR(400MHz,CDCl 3):δ7.79,7.77(d,d,1H),7.66-7.62(m,3H),7.59(s,1H),7.56,7.54(d,d,1H),7.48-7.47,7.46-7.45(m,m,2H),5.14-5.09(m,1H),4.89-4.84(m,1H),3.85-3.73(m,2H),3.14-3.02(m,2H),2.79-2.76(m,2H),2.74-2.71(m,2H),2.51-2.42(m,1H),2.33-2.16(m,3H),1.86-1.78(m,1H),1.74-1.54(m,5H),1.46-1.43(m,2H),1.42(m,18H),1.28-1.18(m,2H),0.96-0.93(m,6H)ppm。
Step 8) compound 8-9's is synthetic
By compound 8-8(0.24g, 0.3mmol) be dissolved in EtOAc(4.0mL) in, slowly splash into the ethyl acetate solution (3.0mL, 4M) of hydrogenchloride, drip and finish, room temperature reaction 8.0 hours.After reacting completely, concentration of reaction solution, residuum adds after ethyl acetate (5mL) making beating, filters and obtains faint yellow solid 0.2g, productive rate: 90%.Be directly used in next step reaction.
MS(ESI,pos.ion)m/z:603.3[M+H] +。
Step 9) compound 8-10's is synthetic
By compound 8-9(0.23g, 0.31mmol), compound 1-11-2(0.12g, 0.68mmol), EDCI(0.13g, 0.68mmol) and HOAT(85mg, 0.62mmol) be suspended in DCM(20mL) in, at 0 ℃, slowly splash into DIPEA(0.51mL, 3.1mmol), drip and finish, room temperature reaction 3.0 hours.After reacting completely, add DCM(20mL) dilute reaction solution, use respectively ammonium chloride solution and saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain faint yellow solid 128mg, productive rate: 45% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=50/1).
MS(ESI,pos.ion)m/z:459.2[M+2H] 2+；
1H?NMR(400MHz,CDCl 3):δ7.79,7.77(d,d,1H),7.66-7.62(m,3H),7.59(s,1H),7.56,7.54(d,d,1H),7.48-7.47,7.46-7.45(m,m,2H),5.56,5.55(d,d,1H),5.46,5.44(d,d,1H),5.31-5.26(m,1H),5.07-5.02(m,1H),4.41-4.36(m,1H),4.31-4.27(m,1H),3.92-3.84(m,2H),3.66(s,6H),3.61-3.54(m,2H),2.79-2.76(m,2H),2.74-2.71(m,2H),2.56-2.47(m,1H),2.37-2.09(m,5H),1.83-1.75(m,1H),1.72-1.52(m,5H),1.50-1.40(m,2H),1.28-1.18(m,2H),1.02,1.00(m,m,3H),0.97,0.95(m,m,3H),0.94-0.89(m,12H)ppm。
Embodiment 9
Figure BDA0000442505360000901
Synthetic route:
Figure BDA0000442505360000902
Step 1) compound 9-2's is synthetic
By compound 9-1(11.0g, 44.8mmol) be dissolved in DCM(200mL) in, at-78 ℃, slowly splash into Et 2nSF 3(8.85mL, 67.3mmol), drips and finishes, and isothermal reaction is after 2.0 hours, room temperature reaction 19 hours.After reacting completely, add aqueous ammonium chloride solution (100mL) cancellation reaction, DCM(100mL for water layer × 3) extraction, merge organic phase, saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain weak yellow liquid 7.75g, productive rate: 70% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=20/1).
MS(ESI,pos.ion)m/z:248.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ5.26,5.13(ds,ds,1H),4.55-4.41(m,1H),3.88-3.74(m,1H),3.73(s,3H),3.64-3.58(m,1H),2.52-2.44(m,1H),2.40-2.32(m,1H),1.42-1.47(d,9H,J=20Hz)ppm。
Step 2) compound 9-3 synthetic
By compound 9-2(5.83g, 23.6mmol) be dissolved in THF(30mL) in, at 0 ℃, slowly splash into the aqueous solution (1.98g, 30mL) of lithium hydroxide, drip and finish, room temperature reaction 2.0 hours.After reacting completely, regulate the pH value to 5 of reaction solution with dilute hydrochloric acid (1M), remove after THF, dilute hydrochloric acid for water layer (1M) regulates pH value to 2, with EtOAc(80mL × 3) extraction, merge organic phase, use saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain white solid 5.27g, productive rate: 96%.
MS(ESI,pos.ion)m/z:234.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ8.76(brs,1H),5.28-5.12(m,1H),4.56-4.44(m,1H),3.86-3.58(m,2H),2.77-2.01(m,2H),1.48-1.44(d,9H,J=16Hz)ppm。
Step 3) compound 9-4's is synthetic
By compound 9-3(1.3g, 5.57mmol) be dissolved in THF(20mL) in, at 0 ℃, slowly splash into borine (8.3mL, 1M in THF), drip and finish, room temperature reaction 2.0 hours.After reacting completely, with methyl alcohol (4.0mL) cancellation reaction, remove THF, residuum DCM(50mL) dissolve after, distinguish water (20mL × 3) and saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain colourless soup compound 1.07g, productive rate: 88%.
MS(ESI,pos.ion)m/z:220.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ5.19-5.06(m,1H),4.12-4.04(m,1H),3.99-3.79(m,1H),3.69-3.63(m,1H),3.60-3.46(m,2H),2.25-2.00(m,2H),1.44(s,9H)ppm。
Step 4) compound 9-6's is synthetic
By compound 9-4(1.15g, 5.24mmol) be dissolved in DCM(20mL) in, at 0 ℃, by TCCA(1.22g, 5.24mmol) add in system, then the DCM solution (82mg, 0.52mmol, 3mL) of TEMPO is splashed into, drip and finish, isothermal reaction is after 1.0 hours, room temperature reaction 1.0 hours.After reacting completely, solids removed by filtration, filtrate is washed by saturated sodium bisulfite solution (20mL × 3), anhydrous Na 2sO 4dry, residuum is dissolved in to methanolic ammonia solution (7mL, 7M) after concentrated, to react 0.5 hour at 0 ℃, room temperature continued reaction after 1.0 hours, was again cooled at 0 ℃, slowly splashed into glyoxal water solution (1.1mL, 40%), dripped and finished, room temperature reaction 24 hours.After reacting completely, concentration of reaction solution, residuum adds DCM(50mL) dissolve after, water (30mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 0.67g, productive rate: 50% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=100/1).
MS(ESI,pos.ion)m/z:256.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ6.98(s,2H),5.36-5.13(m,2H),3.72-3.31(m,2H),2.58-2.32(m,2H),1.48(s,9H)ppm。
Step 5) compound 9-7's is synthetic
By compound 9-6(0.63g, 2.47mmol) be dissolved in DCM(8.0mL) in, at 0 ℃, add NIS(1.23g, 5.43mmol), isothermal reaction 2.0 hours.After reacting completely, add DCM(50mL) dilute reaction solution, solids removed by filtration, filtrate, with saturated sodium bisulfite solution (20mL × 3) washing, merges organic phase, uses anhydrous Na 2sO 4dry, after concentrating, obtain yellow solid 1.07g, productive rate: 85.6%.Be directly used in next step reaction.
MS(ESI,pos.ion)m/z:508.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ5.34-5.08(m,2H),3.72-3.28(m,2H),2.58-2.33(m,2H),1.48(s,9H)ppm。
Step 6) compound 9-8's is synthetic
By compound 9-7(1.07g, 2.12mmol) be dissolved in ethanol (6.0mL), add S-WAT (2.14g, 17mmol) and water (6.0mL), 90 ℃ are reacted 30 hours.After reacting completely, solids removed by filtration, concentrated filtrate, residuum adds DCM(40mL) dissolve after, water (20mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain white solid 0.59g, productive rate: 73% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/1).
MS(ESI,pos.ion)m/z:382.2[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.04(s,1H),5.35-5.09(m,2H),3.98-3.63(m,1H),3.58-3.29(m,1H),2.55-2.34(m,2H),1.48(s,9H)ppm。
Step 7) compound 9-9's is synthetic
By compound 9-3(5.0g, 21.45mmol) and compound 3-1-0(4.93g, 17.87mmol) be dissolved in DCM(100mL) in, at 0 ℃, slowly splash into TEA(4.34g, 42.9mmol), drip and finish, room temperature reaction 3.0 hours.(50mL) cancellation that after reacting completely, adds water reaction, DCM(50mL for water layer × 3) extraction, merge organic phase, use saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain product 4.5g, productive rate: 52.2% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=8/1).
MS(ESI,pos.ion)m/z:403.3[M+H] +。
Step 8) compound 9-10's is synthetic
By compound 9-9(4.48g, 11.19mmol) and ammonium acetate (12.5g, 162mmol) be suspended in toluene (50mL), 110 ℃ reflux 5.0 hours.After reacting completely, be chilled to room temperature, add water (50mL) cancellation reaction, EtOAc(80mL for water layer × 3) extraction, merge organic phase, saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain product 4.2g, productive rate: 92% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/1).
MS(ESI,pos.ion)m/z:411.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.56-7.51(m,2H),7.47-7.45(m,2H),7.22(s,1H),5.38-5.29(m,1H),5.25-5.17(m,1H),4.13-4.07,3.62-3.39(m,m,1H),3.68-3.58(m,1H),2.68-2.38(m,2H),1.38(s,9H)ppm。
Step 9) compound 9-11's is synthetic
By compound 9-10(2.0g, 4.87mmol), compound 1-12-2(1.26g, 4.97mmol), Pd (dppf) Cl 2cH 2cl 2(0.07g, 0.097mmol) and KOAc(1.19g, 12.2mmol) be placed in reaction flask, N 2under protection, inject DME(20mL), 90 ℃ are reacted 2.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(100mL) after dilution, diatomite filtration, respectively water (30mL × 3) and saturated common salt water washing of filtrate, anhydrous Na 2sO 4dry, after concentrating, obtain product 1.42g, productive rate: 64% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2).
MS(ESI,pos.ion)m/z:458.4[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.81-7.79(m,2H),7.65-7.60(m,2H),7.28(s,1H),5.39-5.26(m,1H),5.20-5.12(m,1H),4.07-3.99,3.59-3.41(m,m,1H),3.69-3.62(m,1H),2.62-2.51(m,2H),1.34(s,12H),1.28(s,9H)ppm。
Step 10) compound 9-12's is synthetic
By compound 9-11(1.2g, 2.62mmol), compound 1-8(0.88g, 2.62mmol), Pd (PPh 3) 4(0.15g, 0.13mmol) and salt of wormwood (0.90g, 6.55mmol) are placed in reaction flask, N 2under protection, inject respectively DME(12mL) and pure water (3.0mL) after, 90 ℃ reaction 5.0 hours.After reacting completely, be chilled to room temperature, add after ethyl acetate (120mL) dilute reaction solution, water (50mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 0.77g, productive rate: 50% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=100/1).
MS(ESI,pos.ion)m/z:586.6[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.67-7.66,7.65-7.64(m,m,2H),7.51-7.50,7.49-7.48(m,m,2H),7.41(s,1H),5.35-5.28,5.23-5.15(m,m,1H),4.85-4.80(m,1H),4.11-3.99(m,1H),3.73-3.60(m,1H),2.92-2.77(m,3H),2.76-2.72(m,2H),2.27-2.13(m,1H),1.75-1.54(m,4H),1.53-1.44(m,2H),1.42(s,9H),1.31-1.21(m,2H)ppm。
Step 11) compound 9-13's is synthetic
By compound 9-12(0.94g, 1.61mmol), compound 1-12-2(0.45g, 1.77mmol), Pd (dppf) Cl 2cH 2cl 2(66mg, 0.081mmol) and KOAc(0.4g, 4.03mmol) be placed in reaction flask, N 2under protection, inject DMF(8.0mL), 120 ℃ are reacted 4.0 hours.After reacting completely, be chilled to room temperature, add after ethyl acetate (80mL) dilute reaction solution diatomite filtration.Filtrate is water (30mL × 3) and saturated common salt water washing respectively, and anhydrous sodium sulfate drying obtains faint yellow solid 0.56g, productive rate: 55% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2) after concentrating.
MS(ESI,pos.ion)m/z:634.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.66-7.65,7.64-7.63(m,m,2H),7.41(s,1H),7.23-7.22,7.21-7.20(m,m,2H),5.35-5.28,5.23-5.15(m,m,1H),4.85-4.80(m,1H),4.11-3.99(m,1H),3.73-3.60(m,1H),2.92-2.77(m,3H),2.66-2.63(m,2H),2.27-2.13(m,1H),1.74-1.54(m,6H),1.52-1.45(m,2H),1.42(s,9H),1.33,1.30(q,q,12H)ppm。
Step 12) compound 9-14's is synthetic
By compound 9-13(0.27g, 0.42mmol), compound 9-8(0.16g, 0.42mmol), four triphenyl phosphorus palladiums (25mg, 0.02mmol) and salt of wormwood (0.17g, 1.27mmol) are suspended in DME/H 2o(v/v=3/1), in mixed solvent (8.0mL), under nitrogen protection, 90 ℃ are reacted 2.0 hours.After reacting completely, concentration of reaction solution, after residuum adds ethyl acetate (50mL) to dissolve, use saturated common salt water washing, anhydrous sodium sulfate drying, obtains faint yellow solid 0.14g, productive rate: 45% through column chromatographic isolation and purification (eluent: DCM/EtOH (v/v)=80/1) after concentrating.
MS(ESI,pos.ion)m/z:761.4[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.66-7.65,7.64-7.63(m,m,2H),7.61-7.60,7.58-7.57(m,m,2H),7.51(s,1H),7.41(s,1H),5.35-5.28,5.23-5.15(m,m,2H),5.08-5.03(m,1H),4.85-4.80(m,1H),4.11-3.99(m,2H),3.73-3.60(m,2H),3.01-2.73(m,6H),2.34-2.13(m,2H),1.72-1.52(m,4H),1.47-1.43(m,2H),1.42(s,9H),1.41(s,9H),1.27-1.17(m,2H)ppm。
Step 13) compound 9-15's is synthetic
By compound 9-14(0.39g, 0.51mmol) be dissolved in ethyl acetate (4.0mL), drip the ethyl acetate solution (3.0mL, 4M) of hydrogenchloride, drip and finish, room temperature reaction 8.0 hours.After reacting completely, concentration of reaction solution, residuum adds EtOAc(4.0mL) after making beating, filter and obtain faint yellow solid 0.32g, productive rate: 90%.Be directly used in next step reaction.
MS(ESI,pos.ion)m/z:561.3[M+H] +。
Step 14) compound 9-16's is synthetic
By compound 9-15(0.2g, 0.29mmol), compound 1-11-2(0.11g, 0.65mmol), EDCI(0.12g, 0.65mmol) and HOAT(80mg, 0.59mmol) be suspended in DCM(5mL) in, at 0 ℃, slowly splash into DIPEA(0.49mL, 2.97mmol), drip and finish, room temperature reaction 3.0 hours.After reacting completely, add DCM(20mL) dilute reaction solution, use respectively ammonium chloride solution and saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain white solid foam 0.15g, productive rate: 60% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=40/1).
MS(ESI,pos.ion)m/z:875.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.66-7.65,7.64-7.63(m,m,2H),7.61-7.60,7.58-7.57(m,m,2H),7.51(s,1H),7.44(s,1H),7.38(s,1H),5.32,5.29(d,d,2H),5.29-5.24(m,1H),5.19-5.11(m,2H),4.99-4.94(m,1H),4.46-4.40(m,2H),4.13-4.01(m,2H),3.75-3.64(m,2H),3.63(s,6H),3.04-2.73(m,6H),2.36-2.12(m,4H),1.73-1.52(m,4H),1.49-1.38(m,2H),1.27-1.17(m,2H),1.41(s,9H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H)ppm。
Embodiment 10
Figure BDA0000442505360000941
Synthetic route:
Step 1) compound 10-2's is synthetic
At 0 ℃, by DMAP(0.55g, 4.5mmol) join compound 10-1(7.08g, 45.06mmol) MeCN(50mL) in solution, stir after 10 minutes, then splash into tert-Butyl dicarbonate (10.82g, 49.56mmol), drip and finish, isothermal reaction is after 30 minutes, room temperature reaction 2.0 hours.After reacting completely, concentration of reaction solution obtains colourless liquid 7.54g, productive rate: 65% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/1).
MS(ESI,pos.ion)m/z:157.2[M-Boc] +；
1H?NMR(400MHz,CDCl 3):δ4.29-4.26(m,1H),3.71(s,3H),3.25-3.18(m,1H),3.16-3.10(m,1H),2.25-2.20(m,1H),1.84-1.79(m,1H),1.46(s,9H),1.01-0.99(m,3H),0.86-0.84(m,3H)ppm。
Step 2) compound 10-3 synthetic
By compound 10-2(4.85g, 18.86mmol) be dissolved in THF(40mL) in, at 0 ℃, a hydronium(ion) oxidation lithium aqueous solution (1.5g, 20mL) is added in system to room temperature reaction 2.0 hours.After reacting completely, remove THF, add water (50mL), with EtOAc(30mL × 3) washing, after separatory, after dilute hydrochloric acid for water layer (1M) adjust pH to 1, with EtOAc(50mL × 3) extraction, and merge organic phase, use saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain white solid 4.35g, productive rate: 95%.
MS(ESI,pos.ion)m/z:244.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ4.34-4.31(m,1H),3.28-3.22(m,1H),3.20-3.13(m,1H),2.23-2.18(m,1H),1.85-1.80(m,1H),1.46(s,9H),1.01-0.99(m,3H),0.86-0.84(m,3H)ppm。
Step 3) compound 10-4's is synthetic
By compound 10-3(3.18g, 13.1mmol) and compound 3-1-0(3.63g, 13.1mmol) be dissolved in DCM(40mL) in, at 0 ℃, slowly splash into Et 3n(3.9mL, 26.3mmol), drip and finish, room temperature reaction 2.0 hours.After reacting completely, add water (50mL) cancellation reaction, DCM(50mL for water layer × 3) extraction, merge organic phase, use saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain crude product 3.27g, be directly used in next step reaction.
MS(ESI,pos.ion)m/z:413.3[M+H] +。
Step 4) compound 10-5's is synthetic
By compound 10-4(3.37g, 8.2mmol) and ammonium acetate (5.1g, 66mmol) be suspended in toluene (30mL), 110 ℃ reaction 5.0 hours.After reacting completely, be chilled to room temperature, add water (50mL) cancellation reaction, EtOAc(80mL for water layer × 3) extraction, merge organic phase, use saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain product 2.75g, productive rate: 80% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=2/1).
MS(ESI,pos.ion)m/z:421.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.63-7.60(m,2H),7.49-7.45(m,2H),7.31(s,1H),5.04-4.99(m,1H),3.41-3.34(m,1H),3.30-3.24(m,1H),2.25-2.19(m,1H),1.87-1.81(m,1H),1.53(s,9H),1.01-0.99(m,3H),0.86-0.84(m,3H)ppm。
Step 5) compound 10-6's is synthetic
By compound 10-5(2.89g, 6.9mmol), compound 1-12-2(1.93g, 7.6mmol), Pd (dppf) Cl 2cH 2cl 2(0.28g, 0.34mmol) and KOAc(1.7g, 17.25mmol) be placed in reaction flask, N 2protection, injects DME(30mL), 90 ℃ are reacted 2.0 hours.After reacting completely, be chilled to room temperature, add ethyl acetate (200mL) dilute reaction solution, diatomite filtration, filtrate is water (20mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 2.74g, productive rate: 85% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/1).
MS(ESI,pos.ion)m/z:468.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ8.23-8.20(m,2H),7.79-7.76(m,2H),7.23(s,1H),5.04-4.99(m,1H),3.41-3.34(m,1H),3.30-3.24(m,1H),2.25-2.19(m,1H),1.87-1.81(m,1H),1.53(s,9H),1.35,1.32(m,m,12H),1.01-0.99(m,3H),0.86-0.84(m,3H)ppm。
Step 6) compound 10-7's is synthetic
By compound 10-6(0.23g, 0.5mmol), compound 1-8(0.17g, 0.5mmol), Pd (PPh 3) 4(0.12g, 0.05mmol) and salt of wormwood (0.17g, 1.25mmol) are placed in reaction flask, N 2under protection, inject respectively DME(5.0mL) and pure water (1.0mL), 90 ℃ are reacted 5.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(20mL) after dilute reaction solution, water (10mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 178mg, productive rate: 60% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/3).
MS(ESI,pos.ion)m/z:597.6[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.78-7.77,7.76-7.75(m,m,2H),7.72-7.71,7.70-7.69(m,m,2H),7.39(s,1H),5.04-4.99(m,1H),3.41-3.34(m,1H),3.30-3.24(m,1H),2.84-2.81(m,2H),2.75-2.72(m,2H),2.25-2.19(m,1H),1.87-1.81(m,1H),1.74-1.54(m,4H),1.53-1.43(m,2H),1.41(s,9H),1.30-1.21(m,2H),1.01-0.99(m,3H),0.86-0.84(m,3H)ppm。
Step 7) compound 10-8's is synthetic
By compound 10-7(0.96g, 1.61mmol), compound 1-12-2(0.45g, 1.77mmol), Pd (dppf) Cl 2cH 2cl 2(66mg, 0.081mmol) and KOAc(0.4g, 4.03mmol) be placed in reaction flask, N 2under protection, inject DMF(8.0mL), 120 ℃ are reacted 4.0 hours.After reacting completely, be chilled to room temperature, add after ethyl acetate (80mL) dilute reaction solution diatomite filtration.Filtrate is water (30mL × 3) and saturated common salt water washing respectively, and anhydrous sodium sulfate drying obtains faint yellow solid 0.52g, productive rate: 50% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2) after concentrating.
MS(ESI,pos.ion)m/z:644.7[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.77-7.76,7.75-7.74(m,m,2H),7.44-7.43,7.42-7.41(m,m,2H),7.39(s,1H),5.04-4.99(m,1H),3.41-3.34(m,1H),3.30-3.24(m,1H),2.80-2.77(m,2H),2.66-2.63(m,2H),2.25-2.19(m,1H),1.87-1.81(m,1H),1.74-1.54(m,6H),1.52-1.44(m,2H),1.41(s,9H),1.33,1.30(q,q,12H),1.01-0.99(m,3H),0.86-0.84(m,3H)ppm。
Step 8) compound 10-9's is synthetic
By compound 10-3(1.13g, 4.66mmol) be dissolved in THF(10mL) in, under 0 ℃ of nitrogen protection, borine (10mL, 1M in THF) is slowly splashed in reaction flask, drip and finish, isothermal reaction 3 hours.After reacting completely, with methyl alcohol (10mL) cancellation reaction, after concentration of reaction solution, obtain colorless oil 0.8g, productive rate: 75% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/2).
1H?NMR(400MHz,CDCl 3):δ4.37(brs,1H),4.20-4.12(m,1H),3.84-3.73(m,2H),3.06-2.94(m,2H),1.84-1.78(m,1H),1.48(s,9H),1.44-1.38(m,1H),1.01-0.99(m,3H),0.86-0.84(m,3H)ppm。
Step 9) compound 10-10's is synthetic
By compound 10-9(0.8g, 3.48mmol) be dissolved in DCM(10mL) in, at 0 ℃, Dai Si-Martin oxygenant (2.07g, 4.88mmol) is added in reaction flask in batches, after adding, room temperature reaction 2.0 hours.After reacting completely, add water (20mL) and DCM(50mL) dilute reaction solution, filter, after filtrate layering, organic layer saturated common salt water washing, anhydrous sodium sulfate drying, obtains colorless oil 0.39g, productive rate: 50% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/2) after concentrating.
1H?NMR(400MHz,CDCl 3):δ9.69-9.68(m,1H),4.48-4.45(m,1H),3.32-3.15(m,1H),3.01-2.94(m,1H),2.30-2.28,2.27-2.25(m,m,1H),1.76-1.74,1.72-1.71(m,m,1H),1.43(s,9H),1.01-0.99(m,3H),0.86-0.84(m,3H)ppm。
Step 10) compound 10-11's is synthetic
By compound 10-10(0.4g, 1.76mmol) and ammoniacal liquor (2mL) be dissolved in methyl alcohol (3mL), at 0 ℃, the aqueous solution of oxalic dialdehyde (40%, 1mL) is slowly splashed in reaction flask, drip and finish, room temperature reaction spends the night.After reacting completely, after concentration of reaction solution, obtain white solid 0.22g, productive rate: 47% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/2).
MS(ESI,pos.ion)m/z:266.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ6.96(s,2H),5.01-4.96(m,1H),3.41-3.35(m,1H),3.31-3.24(m,1H),2.26-2.20(m,1H),1.85-1.79(m,1H),1.41(s,9H),1.01-0.99(m,3H),0.86-0.84(m,3H)ppm。
Step 11) compound 10-12's is synthetic
By compound 10-11(0.22g, 0.84mmol) be dissolved in DCM(5mL) in, at 0 ℃, N-N-iodosuccinimide (0.38g, 1.68mmol) is added in reaction flask in batches to isothermal reaction 1.5 hours.After reacting completely, add DCM(20mL) after dilute reaction solution, use saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain white solid 0.27g, productive rate: 63% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/2).
MS(ESI,pos.ion)m/z:518.2[M+H] +；
1H?NMR(400MHz,CDCl 3):δ5.14-5.10(m,1H),3.41-3.34(m,1H),3.30-3.23(m,1H),2.37-2.31(m,1H),2.02-1.96(m,1H),1.41(s,9H),1.01-0.99(m,3H),0.86-0.84(m,3H)ppm。
Step 12) compound 10-13's is synthetic
By compound 10-12(0.17g, 0.33mmol) be suspended in the mixed solvent (5mL) of second alcohol and water (v/v=3/7), S-WAT (0.37g, 2.9mmol) is added in mixed solution and refluxed 17 hours.After reacting completely, remove ethanol, residuum adds water (10mL), extract by ethyl acetate (10mL × 3), organic phase saturated common salt water washing, anhydrous sodium sulfate drying, obtains white solid 0.11g, productive rate: 84% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/2) after concentrating.
MS(ESI,pos.ion)m/z:392.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.33(s,1H),4.87-4.83(m,1H),3.41-3.34(m,1H),3.30-3.24(m,1H),2.29-2.24(m,1H),1.92-1.86(m,1H),1.41(s,9H),1.01-0.99(m,3H),0.86-0.84(m,3H)ppm。
Step 13) compound 10-14's is synthetic
By compound 10-13(0.16g, 0.42mmol), compound 10-8(0.27g, 0.42mmol), four triphenyl phosphorus palladiums (25mg, 0.02mmol) and salt of wormwood (0.17g, 1.27mmol) are suspended in DME/H 2o(v/v=3/1), in mixed solvent (8mL), under nitrogen protection, 90 ℃ are reacted 5.0 hours.After reacting completely, concentration of reaction solution, after residuum adds ethyl acetate (20mL) to dissolve, use saturated common salt water washing, anhydrous sodium sulfate drying, obtains faint yellow solid 147mg, productive rate: 45% through column chromatographic isolation and purification (eluent: DCM/EtOH (v/v)=80/1) after concentrating.
MS(ESI,pos.ion)m/z:782.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.80-7.79(m,m,2H),7.76-7.75,7.74-7.73(m,m,2H),7.46(s,1H),7.39(s,1H),5.12-5.08(m,1H),5.04-4.99(m,1H),3.41-3.34(m,2H),3.30-3.24(m,2H),2.95-2.92(m,2H),2.76-2.73(m,2H),2.31-2.19(m,2H),1.91-1.81(m,2H),1.73-1.52(m,4H),1.49-1.42(m,2H),1.41(s,18H),1.27-1.17(m,2H),1.01-0.99(m,3H),0.86-0.84(m,3H)ppm。
Step 14) compound 10-15's is synthetic
By compound 10-14(0.39g, 0.5mmol) be dissolved in ethyl acetate (4.0mL), drip the ethyl acetate solution (3.0mL, 4M) of hydrogenchloride, drip and finish, room temperature reaction 8.0 hours.After reacting completely, concentration of reaction solution, residuum adds EtOAc(4.0mL) making beating, after filtration, obtain faint yellow solid 0.33g, productive rate: 90%.Be directly used in next step reaction.
MS(ESI,pos.ion)m/z:581.8[M+H] +。
Step 15) compound 10-16's is synthetic
By compound 10-15(0.21g, 0.29mmol), compound 1-11-2(0.11g, 0.65mmol), EDCI(0.12g, 0.65mmol) and HOAT(80mg, 0.59mmol) be suspended in DCM(5mL) in, at 0 ℃, slowly splash into DIPEA(0.49mL, 2.97mmol), drip and finish, room temperature reaction 3.0 hours.After reacting completely, add DCM(20mL) dilute reaction solution, use respectively ammonium chloride solution and saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain yellow foam solid 0.14g, productive rate: 55% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=40/1).
MS(ESI,pos.ion)m/z:896.2[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.66-7.65,7.64-7.63(m,m,2H),7.61-7.60,7.58-7.57(m,m,3H),7.39(s,1H),5.32,5.29(d,d,2H),5.23-5.16(m,2H),4.40-4.35(m,2H),3.63(s,6H),3.57-3.50(m,2H),3.45-3.39(m,2H),2.95-2.92(m,2H),2.76-2.73(m,2H),2.34-2.22(m,2H),2.18-2.08(m,2H),1.91-1.81(m,2H),1.73-1.52(m,4H),1.49-1.39(m,2H),1.27-1.17(m,2H),1.01-0.99(m,6H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H),0.86-0.84(m,6H)ppm。
Embodiment 11
Figure BDA0000442505360000991
Synthetic route:
Figure BDA0000442505360000992
Step 1) compound 11-2's is synthetic
Under room temperature, the ethyl acetate solution (5.0mL, 4M) of hydrogenchloride is added drop-wise to compound 11-1(1.72g, 4.13mmol) EtOAc(10mL) in solution, drip and finish, react 8.0 hours.After reacting completely, concentration of reaction solution, residuum adds EtOAc(5.0mL) after making beating, filter and obtain solid 1.38g, productive rate: 86%.Be directly used in next step reaction.
MS(ESI,pos.ion)m/z:317.5[M+H] +。
Step 2) compound 11-3 synthetic
By compound 11-2(1.4g, 3.6mmol), compound 1-11-2(0.69g, 3.9mmol) and EDCI(0.75g, 3.9mmol) be suspended in DCM(10mL) in, at 0 ℃, slowly splash into DIPEA(2.38mL, 14.4mmol), drip and finish, room temperature reaction 2.0 hours.After reacting completely, add DCM(40mL) dilute reaction solution, organic phase is washed with saturated ammonium chloride solution, anhydrous sodium sulfate drying, after concentrated, obtain faint yellow solid 1.45g, productive rate: 85% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2).
MS(ESI,pos.ion)m/z:474.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ8.96(brs,1H),7.68-7.67(m,1H),7.55-7.52(m,1H),7.35-7.32(m,1H),7.14-7.10(m,1H),5.32,5.29(d,d,1H),4.55-4.51(m,1H),4.31-4.26(m,1H),3.63(s,3H),3.62-3.55(m,1H),3.47-3.40(m,1H),2.27-1.99(m,4H),1.94-1.82(m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 3) compound 11-4's is synthetic
By compound 11-3(0.76g, 1.61mmol), compound 1-12-2(0.45g, 1.77mmol), Pd (dppf) Cl 2cH 2cl 2(66mg, 0.081mmol) and KOAc(0.4g, 4.03mmol) be placed in reaction flask, N 2under protection, inject DMF(4.0mL), 120 ℃ are reacted 4.0 hours.After reacting completely, be chilled to room temperature, add after ethyl acetate (40mL) dilute reaction solution diatomite filtration.Filtrate is water (30mL × 3) and saturated common salt water washing respectively, and anhydrous sodium sulfate drying obtains faint yellow solid 0.42g, productive rate: 55% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2) after concentrating.
MS(ESI,pos.ion)m/z:474.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ8.96(m,1H),7.94-7.93(m,1H),7.65-7.64,7.63-7.62(m,m,1H),7.41-7.34(m,2H),5.32,5.30(d,d,1H),4.71-4.66(m,1H),4.31-4.26(m,1H),3.63(s,3H),3.62-3.55(m,1H),3.48-3.40(m,1H),2.27-1.99(m,4H),1.94-1.82(m,1H),1.32,1.29(q,q,12H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 4) compound 11-5's is synthetic
By compound 11-4(0.21g, 0.44mmol), compound 1-8(70mg, 0.21mmol), four triphenyl phosphorus palladiums (25mg, 0.02mmol) and salt of wormwood (87mg, 0.63mmol) are suspended in DME/H 2o(v/v=3/1), in mixed solvent (4.0mL), under nitrogen protection, 90 ℃ are reacted 5.0 hours.After reacting completely, concentration of reaction solution, residuum adds after ethyl acetate (20mL), use saturated common salt water washing, anhydrous sodium sulfate drying, obtains faint yellow solid 82mg, productive rate: 45% through column chromatographic isolation and purification (eluent: DCM/EtOH (v/v)=40/1) after concentrating.
MS(ESI,pos.ion)m/z:435.2[M+2H] 2+；
1H?NMR(400MHz,CDCl 3):δ8.96(m,1H),8.90(m,1H),7.68-7.67,7.66-7.65(m,m,4H),7.53-7.52,7.51-7.49(m,m,4H),5.56,5.55(d,d,1H),5.32,5.29(d,d,1H),4.61-4.57(m,1H),4.33-4.28(m,2H),4.27-4.22(m,1H),3.66(s,3H),3.63(s,3H),3.61-3.55(m,1H),3.47-3.35(m,3H),2.77-2.75(m,4H),2.26-1.86(m,8H),1.75-1.42(m,8H),1.22-1.20(m,2H),1.02-0.89(m,12H)ppm。
Embodiment 12
Figure BDA0000442505360001001
Synthetic route:
Step 1) compound 12-2's is synthetic
At 0 ℃, thionyl chloride (5.5mL, 75.8mmol) is slowly added drop-wise to compound 12-1(10g, 77.5mmol) MeOH(50mL) in solution, isothermal reaction is after 1.0 hours, room temperature reaction 2.0 hours.After reacting completely, add NaHCO 3solution (50mL) cancellation reaction, removes methyl alcohol, DCM(35mL for residuum × 3) extraction, merge organic phase, use saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain colourless liquid 7.5g, productive rate: 67.6% through column chromatographic isolation and purification (eluent: EtOAc).
MS(ESI,pos.ion)m/z:144.2[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.38(br,1H),4.20-4.16(m,1H),3.67(s,3H),2.39-2.23(m,3H),2.14-2.07(m,1H)ppm。
Step 2) compound 12-3 synthetic
At 0 ℃, by DMAP(0.55g, 4.5mmol) join compound 12-2(6.45g, 45.06mmol) MeCN(30mL) in solution, stir after 10 minutes, then splash into tert-Butyl dicarbonate (10.82g, 49.56mmol), drip and finish, isothermal reaction is after 30 minutes, room temperature reaction 2.0 hours.After reacting completely, concentration of reaction solution obtains colourless liquid 5.0g, productive rate: 45.6% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/1).
MS(ESI,pos.ion)m/z:144.2[M-Boc] +；
1H?NMR(400MHz,CDCl 3):δ4.60-4.57(m,1H),3.75(s,3H),2.65-2.55(m,1H),2.50-2.42(m,1H),2.36-2.24(m,1H),2.04-1.96(m,1H),1.45(s,9H)ppm。
Step 3) compound 12-4's is synthetic
At-78 ℃, lithium triethylborohydride (1.79g, 16.9mmol) is slowly added drop-wise to compound 12-3(3.74g, 15.4mmol) toluene (50mL) solution in, after isothermal reaction 70 minutes, add successively DIPEA(3.2mL, 19.4mmol), DMAP(0.19g, 1.54mmol) and TFAA(3mL, 40.4mmol), after adding, room temperature reaction 2.0 hours.After reacting completely, after concentration of reaction solution, obtain yellow liquid 2.26g, productive rate: 64.8% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=10/1).
MS(ESI,pos.ion)m/z:128.2[M-Boc] +；
1H?NMR(400MHz,CDCl 3):δ6.65-6.52(br,1H),4.96-4.91(br,1H),4.68-4.57(m,1H),3.76(s,3H),3.12-3.00(m,1H),2.71-2.61(m,1H),1.49-1.44(br,9H)ppm。
Step 4) compound 12-5's is synthetic
At 0 ℃, chloroiodomethane (1.40g, 7.9mmol) is slowly added drop-wise to zinc ethyl (0.49g, in toluene (6mL) solution 3.94mmol), react after 45 minutes, then splash into compound 12-4(0.3g, toluene (4mL) solution 1.32mmol), drips and finishes, isothermal reaction 18 hours.After reacting completely, add saturated NH 4cl solution (15mL) cancellation reaction, EtOAc(25mL for water layer × 3) extraction, merge organic phase, use anhydrous Na 2sO 4dry, after concentrating, obtain yellow liquid 0.19g, productive rate: 59.7% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=10/1).
MS(ESI,pos.ion)m/z:142.2[M-Boc] +；
1H?NMR(400MHz,CDCl 3):δ4.64-4.51(m,1H),3.70(s,3H),3.56-3.45(m,1H),2.64-2.54(m,1H),2.05-2.01(m,1H),1.50,1.41(s,s,9H),0.75-0.65(m,3H)ppm。
Step 5) compound 12-6's is synthetic
At 0 ℃, the aqueous solution (10mL) of a hydronium(ion) oxidation lithium (0.89g, 21.2mmol) is slowly added drop-wise to compound 12-5(1.02g, 4.23mmol) THF(20mL) in solution, drip and finish, 40 ℃ of reactions 12 hours.After reacting completely, remove THF, add water (10mL), then use EtOAc(25mL × 3) extraction, hydrochloric acid (10%) adjust pH to 1 for water layer after separatory, then use EtOAc(25mL × 3) extraction, merge organic phase, saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain white solid 0.84g, productive rate: 87.5%.
MS(ESI,neg.ion)m/z:226.2[M-H] -；
1H?NMR(400MHz,CD 3OD):δ4.53-4.46(m,1H),3.48-3.42(m,1H),2.70-2.57(m,1H),2.05-2.01(m,1H),1.60-1.54(m,1H),1.48,1.41(s,s,9H),0.89-0.80(m,1H),0.73-0.66(m,1H)ppm。
Step 6) compound 12-7's is synthetic
By compound 12-6(3.91g, 17.22mmol) and compound 3-1-0(5.47g, 19.81mmol) be dissolved in DCM(60mL) in, at 0 ℃, slowly splash into DIPEA(3.4mL, 20.67mmol), drip and finish, room temperature reaction 3.0 hours.After reacting completely, add water (50mL) cancellation reaction, DCM(100mL for water layer × 3) extraction, merge organic phase, use saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain white solid 4.5g, productive rate: 61.7% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=5/1).
MS(ESI,pos.ion)m/z:425.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.77-7.73(m,2H),7.64-7.62(m,2H),5.53-5.09(m,2H),4.78-4.67(m,1H),3.59-3.46(m,1H),2.69-2.62(m,1H),2.43-2.40(m,1H),1.42(s,9H),1.00-0.96(m,1H),0.76-0.69(m,2H)ppm。
Step 7) compound 12-8's is synthetic
Compound 12-7(4.5g, 10.64mmol) and ammonium acetate (16.4g, 212.73mmol) be suspended in dimethylbenzene (50mL), 120 ℃ reaction 5.0 hours.After reacting completely, be chilled to room temperature, add water (50mL) cancellation reaction, EtOAc(100mL for water layer × 3) extraction, merge organic phase, saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain product 2.14g, productive rate: 50% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=8/1).
MS(ESI,pos.ion)m/z:404.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.62-7.52(br,2H),7.49-7.46(d,2H,J=12Hz),7.21(s,1H),5.27-5.24(d,1H,J=10.0Hz),3.31-3.27(m,1H),1.71-1.67(m,2H),1.52(s,9H),0.89-0.86(m,1H),0.64-0.69(m,2H)ppm。
Step 8) compound 12-9's is synthetic
By compound 12-8(2.1g, 5.2mmol), compound 1-12-2(1.59g, 6.25mmol), Pd (dppf) Cl 2cH 2cl 2(0.43g, 0.52mmol) and KOAc(1.54g, 15.63mmol) be placed in reaction flask, N 2under protection, inject DMF(20mL), 90 ℃ are reacted 3.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(100mL) after dilute reaction solution, diatomite filtration, filtrate is water (60mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain product 2.27g, productive rate: 97% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=2/1).
MS(ESI,pos.ion)m/z:452.4[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.81-7.79(d,2H,J=8.04Hz),7.60(br,2H),7.26(s,1H),5.28-5.26(d,1H,J=8.0Hz),3.53(br,1H),3.30-3.27(br,1H),1.67-1.66(m,2H),1.52(s,9H),1.34(s,12H),0.89-0.86(m,1H),0.69-0.64(m,2H)ppm。
Step 9) compound 12-10's is synthetic
Under room temperature, the ethyl acetate solution (5.0mL, 4M) of hydrogenchloride is added drop-wise to compound 12-9(0.9g, 2mmol) EtOAc(10mL) in solution, drip and finish, react 8.0 hours.After reacting completely, concentration of reaction solution, residuum adds EtOAc(5.0mL) after making beating, filter and obtain solid 0.94g, productive rate: 95%.Be directly used in next step reaction.
MS(ESI,pos.ion)m/z:425.2[M+H] +。
Step 10) compound 12-11's is synthetic
By compound 12-10(0.37g, 0.75mmol), compound 1-11-2(0.13g, 0.75mmol) and EDCI(0.3g, 1.58mmol) be suspended in DCM(5.0mL) in, at 0 ℃, slowly splash into DIPEA(1.0mL, 6.01mmol), drip and finish, room temperature reaction 2.0 hours.After reacting completely, add DCM(40mL) dilute reaction solution, organic phase is washed with saturated ammonium chloride solution, anhydrous sodium sulfate drying, after concentrated, obtain faint yellow solid 324mg, productive rate: 85% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2).
MS(ESI,pos.ion)m/z:509.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ8.96(brs,1H),7.68-7.67(m,1H),7.55-7.52(m,1H),7.35-7.32(m,1H),7.14-7.10(m,1H),5.32,5.29(d,d,1H),4.55-4.51(m,1H),4.31-4.26(m,1H),3.63(s,3H),3.62-3.55(m,1H),3.47-3.40(m,1H),2.27-1.99(m,4H),1.94-1.82(m,1H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 11) compound 12-12's is synthetic
By compound 12-11(0.54g, 1.07mmol), compound 1-8(0.36g, 1.07mmol), Pd (PPh 3) 4(0.12g, 0.11mmol) and salt of wormwood (0.37g, 2.67mmol) are placed in reaction flask, N 2under protection, inject respectively DME(5.0mL) and pure water (1.0mL), 90 ℃ are reacted 5.0 hours.After reacting completely, be chilled to room temperature, add after ethyl acetate (50mL) dilute reaction solution, water (20mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 0.41g, productive rate: 60% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=100/1).
MS(ESI,pos.ion)m/z:638.7[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.67-7.66,7.65-7.64(m,m,2H),7.62(s,1H),7.51-7.50,7.49-7.48(m,2H),5.32,5.30(d,d,1H),4.89-4.85(m,1H),4.09-4.04(m,1H),3.63(s,3H),3.45-3.38(m,1H),2.84-2.81(m,2H),2.75-2.72(m,2H),2.46-2.39(m,1H),2.22-2.09(m,1H),2.00-1.98,1.97-1.94(m,m,1H),1.75-1.54(m,4H),1.53-1.36(m,3H),1.30-1.21(m,2H),0.97-0.89(m,7H),0.50-0.46(m,1H)ppm。
Step 12) compound 12-13's is synthetic
By compound 12-10(0.15g, 0.36mmol), compound 4-2-2(68mg, 0.36mmol) and EDCI(69mg, 0.36mmol) be suspended in DCM(10mL) in, at 0 ℃, slowly splash into DIPEA(0.24mL, 1.44mmol), drip and finish, room temperature reaction 3.0 hours.After reacting completely, add DCM(40mL) dilute reaction solution, organic phase is washed with saturated ammonium chloride solution, anhydrous sodium sulfate drying, after concentrated, obtain faint yellow solid 0.16g, productive rate: 85% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2).
MS(ESI,pos.ion)m/z:523.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.64-7.61,7.60-7.57(m,m,4H),7.29(s,1H),5.30,5.28(d,d,1H),4.85-4.82(m,1H),4.09-4.04(m,1H),3.63(s,3H),3.37-3.31(m,1H),2.44-2.36(m,1H),1.97-1.86(m,2H),1.62-1.51(m,1H),1.47-1.40(m,1H),1.35,1.32(q,q,12H),1.27-1.13(m,1H),0.94-0.89(m,7H),0.51-0.47(m,1H)ppm。
Step 13) compound 12-14's is synthetic
By compound 12-13(0.26g, 0.5mmol), compound 12-12(0.32g, 0.5mmol), Pd (PPh 3) 4(57.8mg, 0.05mmol) and salt of wormwood (0.17g, 1.25mmol) are placed in reaction flask, N 2under protection, inject respectively DME(4.0mL) and pure water (1.0mL), 90 ℃ are reacted 3.0 hours.After reacting completely, be chilled to room temperature, add after ethyl acetate (50mL) dilute reaction solution, water (20mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 0.26g, productive rate: 55% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=50/1).
MS(ESI,pos.ion)m/z:477.2[M+2H] 2+；
1H?NMR(400MHz,CDCl 3):δ7.66-7.65,7.64-7.62(m,m,6H),7.48-7.47,7.46-7.45(m,m,4H),5.99,5.97(d,d,1H),5.32,5.30(d,d,1H),4.89-4.82(m,2H),4.13-4.04(m,2H),3.65(s,3H),3.63(s,3H),3.45-3.38(m,1H),3.37-3.31(m,1H),2.77-2.75(m,4H),2.46-2.36(m,2H),2.22-2.09(m,1H),2.00-1.98,1.97-1.94,1.93-1.91(m,m,2H),1.90-1.80(m,1H),1.73-1.52(m,4H),1.50-1.32(m,5H),1.28-1.18(m,2H),1.12-1.02(m,1H),0.98-0.82(m,14H),0.51-0.46(m,2H)ppm。
Embodiment 13
Figure BDA0000442505360001051
Synthetic route:
Figure BDA0000442505360001052
Step 1) compound 13-2's is synthetic
By compound 13-1(10.68g, 46.6mmol) be dissolved in THF(100mL) in, under 0 ℃ of nitrogen protection, slowly splash into borine (100mL, 1M in THF), drip and finish, isothermal reaction 3.0 hours.After reacting completely, with methyl alcohol (80mL) cancellation reaction, after concentration of reaction solution, obtain colorless oil 7.52g, productive rate: 75% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=4/1).
1H?NMR(400MHz,CDCl 3):δ4.20-4.11(m,1H),3.91-3.85(m,2H),3.72-3.65(m,1H),3.34-3.26(m,1H),2.69(brs,1H),2.43-2.33(m,1H),1.52-1.48(m,1H),1.45(s,9H),1.35-1.04(m,3H),0.94-0.80(m,1H)ppm。
Step 2) compound 13-3 synthetic
By compound 13-2(7.49g, 34.8mmol) be dissolved in DCM(250mL) in, at 0 ℃, Dai Si-Martin (20.7g, 48.8mmol) oxygenant is added in reaction flask in batches, after adding, room temperature reaction 2.0 hours.After reacting completely, in reaction solution, add water (250mL), filter, after filtrate layering, organic layer saturated common salt water washing, anhydrous sodium sulfate drying, obtains colorless oil 3.71g, productive rate: 50% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/1) after concentrating.
1H?NMR(400MHz,CDCl 3):δ9.69-9.66(m,1H),4.07-4.02(m,1H),3.90-3.83(m,1H),3.04-2.94(m,1H),1.93-1.71(m,2H),1.44(s,9H),1.29-1.05(m,4H)ppm。
Step 3) compound 13-4's is synthetic
By compound 13-3(3.75g, 17.6mmol) and ammoniacal liquor (13.0mL) be dissolved in methyl alcohol (30mL), at 0 ℃, slowly splash into the aqueous solution of oxalic dialdehyde (40%, 8.0mL), drip and finish, room temperature reaction spends the night.After reacting completely, after concentration of reaction solution, obtain white solid 1.99g, productive rate: 45% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/1).
MS(ESI,pos.ion)m/z:252.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ6.99(s,2H),4.91-4.84(m,1H),4.06-3.98(m,1H),2.97-2.88(m,1H),2.11-2.02(m,1H),1.86-1.74(m,1H),1.73-1.65(m,1H),1.63-1.52(m,1H),1.50(s,9H),1.25-1.03(m,2H)ppm。
Step 4) compound 13-5's is synthetic
By compound 13-4(2.11g, 8.4mmol) be dissolved in DCM(60mL) in, at 0 ℃, N-N-iodosuccinimide (3.8g, 16.8mmol) is added in reaction flask in batches, after adding, isothermal reaction 1.5 hours.After reacting completely, reaction solution saturated common salt water washing, anhydrous sodium sulfate drying, obtains white solid 2.66g, productive rate: 63% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/1) after concentrating.
MS(ESI,pos.ion)m/z:504.2[M+H] +；
1H?NMR(400MHz,CDCl 3):δ4.69-4.63(m,1H),4.62-4.18(m,1H),2.97-2.87(m,1H),2.21-2.12(m,1H),1.85-1.72(m,2H),1.64-1.52(m,1H),1.50(s,9H),1.25-1.06(m,2H)ppm。
Step 5) compound 13-6's is synthetic
By compound 13-5(1.64g, 3.27mmol) be suspended in the mixed solvent (50mL) of second alcohol and water (v/v=3/7), S-WAT (3.7g, 29mmol) is added in mixed solution and refluxed 17 hours.After reacting completely, remove ethanol, residuum adds water (50mL), EtOAc(50mL for water × 3) extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, obtains white solid 0.99g, productive rate: 80.5% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/2) after concentrating.
MS(ESI,pos.ion)m/z:378.2[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.34(s,1H),4.75-4.68(m,1H),4.06-3.99(m,1H),2.97-2.87(m,1H),2.16-2.07(m,1H),1.86-1.69(m,2H),1.64-1.53(m,1H),1.50(s,9H),1.25-1.02(m,2H)ppm。
Step 6) compound 13-7's is synthetic
By compound 13-1(3.96g, 17.28mmol) and compound 13-7-0(5.82g, 19.81mmol) be dissolved in CH 3cN(60mL), in, at 0 ℃, slowly splash into DIPEA(3.4mL, 20.67mmol), drip and finish, room temperature reaction 3.0 hours.After reacting completely, with frozen water (50mL) cancellation reaction, DCM(50mL for water layer × 3) extraction, merge organic phase, use saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain white solid 4.67g, productive rate: 61% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=5/1).
MS(ESI,pos.ion)m/z:445.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.90-7.89,7.88-7.87(dd,dd,1H),7.84,7.82,7.80(d,dd,d,1H),7.69-7.68,7.67-7.66(q,q,1H),5.26(s,2H),4.79-4.74(m,1H),3.96-3.89(m,1H),3.09-3.00(m,1H),2.15-2.06(m,2H),1.42(s,9H),1.27-1.02(m,4H)ppm。
Step 7) compound 13-8's is synthetic
By compound 13-7(4.71g, 10.64mmol) and ammonium acetate (16.4g, 212.73mmol) be suspended in toluene (50mL), 110 ℃ reaction 5.0 hours.After reacting completely, be chilled to room temperature, add water (50mL) cancellation reaction, EtOAc(100mL for water layer × 3) extraction, merge organic phase, use saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain product 2.25g, productive rate: 50% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=8/1).
MS(ESI,pos.ion)m/z:425.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.61(s,1H),7.59,7.57,7.55(d,dd,d,1H),7.22,7.20(d,d,1H),7.11,7.09(dd,dd,1H),4.85-4.79(m,1H),4.28-4.20(m,1H),2.97-2.87(m,1H),2.12-2.03(m,1H),1.87-1.74(m,1H),1.72-1.53(m,2H),1.50(s,9H),1.25-1.02(m,2H)ppm。
Step 8) compound 13-9's is synthetic
By compound 13-8(2.2g, 5.2mmol), compound 1-12-2(1.59g, 6.25mmol), Pd (dppf) Cl 2cH 2cl 2(0.43g, 0.52mmol) and KOAc(1.54g, 15.63mmol) be placed in reaction flask, N 2under protection, inject DMF(30mL), 90 ℃ are reacted 3.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(200mL) after dilute reaction solution, diatomite filtration, filtrate is water (50mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain product 2.08g, productive rate: 85% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=2/1).
MS(ESI,pos.ion)m/z:472.4[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.79,7.77,7.75(d,dd,d,1H),7.52,7.50(d,d,1H),7.26(s,1H),6.95-6.94,6.92-6.91(dd,dd,1H),4.85-4.79(m,1H),4.28-4.20(m,1H),2.97-2.87(m,1H),2.12-2.03(m,1H),1.87-1.74(m,1H),1.72-1.53(m,2H),1.50(s,9H),1.32,1.29(q,q,12H),1.25-1.02(m,2H)ppm。
Step 9) compound 13-10's is synthetic
By compound 13-9(1.23g, 2.62mmol), compound 1-8(0.88g, 2.62mmol), Pd (PPh 3) 4(0.15g, 0.13mmol) and salt of wormwood (0.90g, 6.55mmol) are placed in reaction flask, N 2under protection, inject respectively DME(12mL) and pure water (3.0mL), 90 ℃ are reacted 5.0 hours.After reacting completely, be chilled to room temperature, reaction solution adds EtOAc(100mL) after dilution, respectively water (50mL × 3) and saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 0.94g, productive rate: 60% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=150/1).
MS(ESI,pos.ion)m/z:601.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.60(s,1H),7.56,7.54(d,d,1H),7.46,7.45,7.44,7.43(d,d,d,d,1H),7.14-7.13,7.11(dd,dd,1H),4.85-4.79(m,1H),4.28-4.20(m,1H),2.97-2.87(m,1H),2.85-2.81(m,2H),2.76-2.72(m,2H),2.12-2.03(m,1H),1.87-1.52(m,11H),1.50(s,9H),1.28-1.06(m,2H)ppm。
Step 10) compound 13-11's is synthetic
By compound 13-10(0.96g, 1.61mmol), compound 1-12-2(0.45g, 1.77mmol), Pd (dppf) Cl 2cH 2cl 2(80mg, 0.096mmol) and KOAc(0.4g, 4.02mmol) be placed in reaction flask, N 2under protection, inject DMF(10mL), 90 ℃ are reacted 4.0 hours.After reacting completely, be chilled to room temperature, add after ethyl acetate (100mL) dilute reaction solution diatomite filtration.Filtrate is water (20mL × 3) and saturated common salt water washing respectively, and anhydrous sodium sulfate drying obtains faint yellow solid 0.73g, productive rate: 70% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/1) after concentrating.
MS(ESI,pos.ion)m/z:648.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.62,7.60(d,d,1H),7.59(s,1H),7.18-7.12(m,2H),4.85-4.79(m,1H),4.28-4.20(m,1H),2.97-2.87(m,1H),2.81-2.77(m,2H),2.66-2.63(m,2H),2.12-2.03(m,1H),1.87-1.53(m,9H),1.50(s,9H),1.49-1.42(m,2H),1.33,1.30(q,q,12H),1.25-1.20(m,2H)ppm。
Step 11) compound 13-12's is synthetic
By compound 13-6(0.16g, 0.42mmol), compound 13-11(0.27g, 0.42mmol), the EtOH/H that four triphenyl phosphorus palladiums (25mg, 0.02mmol) and salt of wormwood (0.15g, 1.12mmol) are suspended in 2o(v/v=3/1), in mixed solvent (8.0mL), under nitrogen protection, 90 ℃ are reacted 6.0 hours.After reacting completely, add after ethyl acetate (50mL) dilute reaction solution, use saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain faint yellow solid 0.21g, productive rate: 65% through column chromatographic isolation and purification (eluent: DCM/EtOH (v/v)=80/1).
MS(ESI,pos.ion)m/z:771.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.60(s,1H),7.56,7.55,7.54,7.53(d,d,d,d,1H),7.52,7.49(d,d,1H),7.51(s,1H),7.14-7.13,7.11(dd,dd,1H),4.86-4.79(m,2H),4.28-4.20(m,2H),2.97-2.87(m,4H),2.75-2.72(m,2H),2.12-1.94(m,2H),1.88-1.74(m,2H),1.72-1.51(m,8H),1.50(s,18H),1.48-1.38(m,2H),1.27-1.02(m,6H)ppm。
Step 12) compound 13-13's is synthetic
By compound 13-12(0.39g, 0.51mmol) be dissolved in ethyl acetate (4.0mL), drip the ethyl acetate solution (3.0mL, 4M) of hydrogenchloride, drip and finish, room temperature reaction 8.0 hours.After reacting completely, concentration of reaction solution, residuum adds EtOAc(10mL) after making beating, filter and obtain pale yellow powder shape solid 0.33g, productive rate: 90%.Be directly used in next step reaction.
MS(ESI,pos.ion)m/z:571.7[M+H] +。
Step 13) compound 13-14's is synthetic
By compound 13-13(0.21g, 0.29mmol), compound 6-5-2(96mg, 0.65mmol), EDCI(0.12g, 0.65mmol) and HOAT(80mg, 0.59mmol) be suspended in DCM(5.0mL) in, at 0 ℃, slowly splash into DIPEA(0.41mL, 2.32mmol), drip and finish, room temperature reaction 3.0 hours.After reacting completely, add DCM(20mL) dilute reaction solution, use respectively ammonium chloride solution and saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain faint yellow solid 0.13g, productive rate: 56% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=60/1).
MS(ESI,pos.ion)m/z:415.2[M+2H] 2+；
1H?NMR(400MHz,CDCl 3):δ7.60(s,1H),7.56,7.55,7.54,7.53(d,d,d,d,1H),7.52,7.49(d,d,1H),7.43(s,1H),7.14-7.13,7.11(dd,dd,1H),5.44,5.42(m,m,2H),4.99-4.90(m,2H),4.72-7.65(m,2H),3.87-3.81(m,2H),3.64(s,6H),2.96-2.92(m,2H),2.89-2.80(m,2H),2.75-2.72(m,2H),2.26-2.18(m,1H),2.02-1.93(m,1H),1.84-1.51(m,10H),1.49-1.39(m,2H),1.35,1.33(d,d,6H),1.27-1.14(m,4H),1.12-0.99(m,2H)ppm。
Embodiment 14
Figure BDA0000442505360001081
Synthetic route:
Figure BDA0000442505360001082
Step 1) compound 14-2's is synthetic
By compound 1-8(0.63g, 1.88mmol), compound 14-1(0.63g, 1.88mmol), four triphenyl phosphorus palladiums (0.22g, 0.188mmol) and salt of wormwood (0.78g, 5.64mmol) are suspended in DME/H 2o(v/v=3/1), in mixed solvent (12mL), under nitrogen protection, 90 ℃ are reacted 3.0 hours.After reacting completely, add EtOAc(40mL) dilute reaction solution, water (20mL × 3) and saturated common salt water washing respectively, anhydrous sodium sulfate drying, after concentrated, obtain faint yellow solid 0.43g, productive rate: 50% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2).
1H?NMR(400MHz,CDCl 3):δ8.14-8.13(m,1H),7.98-7.97(m,1H),7.87-7.86,7.85-7.84(m,m,1H),7.83,7.81(m,m,1H),7.74,7.72(m,m,1H),7.55,7.53(m,m,1H),2.85-2.82(m,2H),2.74-2.71(m,2H),1.75-1.54(m,4H),1.53-1.43(m,2H),1.31-1.21(m,2H)ppm。
Step 2) compound 14-3 synthetic
By compound 14-2(0.46g, 1.0mmol), compound 1-12-2(0.26g, 1.02mmol), Pd (dppf) Cl 2cH 2cl 2(81.6mg, 0.1mmol) and KOAc(0.25g, 2.5mmol) be placed in reaction flask, N 2under protection, inject DMF(3.0mL), 90 ℃ are reacted 3.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(30mL) after dilute reaction solution, diatomite filtration, filtrate is water (20mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain product 278mg, productive rate: 50% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=2/1).
MS(ESI,pos.ion)m/z:557.4[M+H] +；
1H?NMR(400MHz,CDCl 3):δ8.28,8.25(m,m,1H),8.23-8.22(m,1H),8.10-7.99,7.98-7.97(m,m,1H),7.85,7.83(m,m,1H),7.57-7.56(m,1H),7.18-7.17,7.16-7.15(m,m,1H),2.81-2.78(m,2H),2.64-2.61(m,2H),1.74-1.54(m,6H),1.52-1.41(m,2H),1.33-1.32,1.30-1.29(m,m,24H)ppm。
Step 3) compound 14-4's is synthetic
By compound 14-3(0.56g, 1.0mmol), compound 2-7(0.88g, 2.1mmol), four triphenyl phosphorus palladiums (0.12g, 0.1mmol) and salt of wormwood (0.35g, 2.5mmol) are suspended in EtOH/H 2o(v/v=3/1), in mixed solvent (12mL), under nitrogen protection, 90 ℃ are reacted 6.0 hours.After reacting completely, add EtOAc(50mL) after dilute reaction solution, use saturated common salt water washing, anhydrous sodium sulfate drying, obtains faint yellow solid 0.36g, productive rate: 40.5% through column chromatographic isolation and purification (DCM/EtOH (v/v)=50/1) after concentrated.
MS(ESI,pos.ion)m/z:445.2[M+2H] 2+；
1H?NMR(400MHz,CDCl 3):δ8.33-8.32(m,1H),8.14-8.13(m,1H),8.01-8.00,7.99-7.98(m,m,1H),7.93,7.90(m,m,1H),7.84(m,2H),7.60(s,1H),7.40(s,1H),6.08,6.05(d,d,1H),5.46,5.44(d,d,1H),5.43-5.36(m,2H),4.41-4.36(m,1H),4.34-4.30(m,1H),3.85-3.78(m,2H),3.66(s,3H),3.65(s,3H),3.64-3.61(m,2H),3.03-3.00(m,2H),2.96-2.93(m,2H),2.32-1.92(m,10H),1.73-1.52(m,4H),1.49-1.39(m,2H),1.27-1.17(m,2H),1.02,1.00(m,m,3H),0.97,0.95(m,m,3H),0.94,0.91(m,m,3H),0.90.0.89(m,m,3H)ppm。
Embodiment 15
Figure BDA0000442505360001091
Synthetic route:
Step 1) compound 15-2's is synthetic
By compound 15-1(2.0g, 15.3mmol) be dissolved in MeOH(20mL) in, slowly splash into thionyl chloride (3.4mL, 46.9mmol) at 0 ℃, drip and finish, 80 ℃ of reactions 3.5 hours.After reacting completely, concentration of reaction solution obtains white solid 2.76g, productive rate: 99.5%, be directly used in next step reaction.
1H?NMR(400Hz,CDCl 3):δ3.68(s,3H),3.58(t,1H),3.56(s,1H),3.32(m,1H),3.02(m,1H),2.77(m,1H),2.52(s,1H),2.21(m,1H),1.96(m,1H)ppm。
Step 2) compound 15-3 synthetic
By compound 15-2(3.1g, 17.1mmol) the disposable chloroformic acid benzyl ester (3.7mL, 26.3mmol) of vigorous stirring and the THF/H of salt of wormwood (10.6g, 76.7mmol) of joining 2o(20mL/10mL), in mixed solution, after adding, room temperature reaction spends the night.After reacting completely, regulate with dilute hydrochloric acid (1M) after the pH value to 3 of reaction solution, with EtOAc(50mL × 3) extraction, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, obtains pale yellow oily liquid body 3.0g, productive rate: 62.8% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=4/1) after concentrating.
1H?NMR(400Hz,CDCl 3):δ7.47(d,2H,J=8.24Hz),7.38(d,2H,J=8.24Hz),7.24(m,1H),5.09(s,2H),4.18(t,1H),3.68(s,3H),3.63(m,1H),3.58(s,1H),3.38(m,1H),3.32(m,1H),2.21(m,1H),1.96(m,1H)ppm。
Step 3) compound 15-4's is synthetic
By compound 15-3(1.0g, 3.6mmol) be dissolved in DCM(20mL) in, add Dai Si-Martin oxygenant (3.0g, 7.1mmol) at 0 ℃ in batches, after adding, room temperature reaction 1.0 hours.After reacting completely, concentration of reaction solution obtains yellow oily liquid 0.79g, productive rate: 79.5% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=5/1).
1H?NMR(400Hz,CDCl 3):δ7.47(d,2H,J=8.24Hz),7.38(d,2H,J=8.24Hz),7.24(m,1H),5.09(s,2H),4.18(t,1H),3.68(s,3H),3.38(m,1H),3.32(m,1H),2.21(m,1H),1.96(m,1H)ppm。
Step 4) compound 15-5's is synthetic
By compound 15-4(1.0g, 3.6mmol) be dissolved in toluene (20mL), add successively ethylene glycol (0.8mL, 15.7mmol) and TsOH(0.14g, 0.8mmol), after adding, backflow is spent the night.After reacting completely, with EtOAc(50mL) dilute reaction solution, use respectively saturated sodium bicarbonate solution (30mL) and saturated nacl aqueous solution (30mL) washing, anhydrous sodium sulfate drying, after concentrated, obtain colourless liquid 0.54g, productive rate: 46.7% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=6/1).
1H?NMR(400Hz,CDCl 3):δ7.47(d,2H,J=8.24Hz),7.38(d,2H,J=8.24Hz),7.24(m,1H),5.09(s,2H),4.18(t,1H),4.05(m,2H),3.95(m,2H),3.68(s,3H),3.38(m,1H),3.32(m,1H),2.21(m,1H),1.96(m,1H)ppm。
Step 5) compound 15-6's is synthetic
By compound 15-5(0.58g, 1.8mmol) be dissolved in MeOH(10mL) in, add the Pd/C(0.5g of catalytic amount), room temperature hydrogenation spends the night.After reacting completely, filter, after filtrate is concentrated, obtain product 0.33g, productive rate: 98.9%.Be directly used in next step reaction.
1H?NMR(400Hz,CDCl 3):δ4.18(t,1H),4.05(m,2H),3.95(m,2H),3.68(s,3H),3.38(m,1H),3.32(m,1H),2.21(m,1H),1.96(m,1H)ppm。
Step 6) compound 15-7's is synthetic
By compound 15-6(3.48g, 18.6mmol), compound 1-11-2(3.26g, 18.6mmol) and EDCI(7.1g, 37mmol) be suspended in DCM(50mL) in, at 0 ℃, slowly splash into DIPEA(12.3mL, 74.4mmol), drip and finish, room temperature reaction spends the night.After reacting completely, reaction solution saturated common salt water washing, anhydrous sodium sulfate drying, obtains pale yellow oily liquid body 2.5g, productive rate: 39.1% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/1) after concentrating.
1H?NMR(400Hz,CDCl 3):δ9.80(s,1H),4.54(d,1H,J=7.25Hz),4.28(m,1H),4.06(m,4H),3.76(m,2H),3.50(s,3H),3.45(s,3H),2.71(m,2H),2.65(m,1H),0.87(m,3H),0.81(m,3H)ppm。
Step 7) compound 15-8's is synthetic
By compound 15-7(0.9g, 2.6mmol) be dissolved in THF(5.0mL) in, add LiOH(0.12g, 5.0mmol) the aqueous solution (5.0mL), after adding, room temperature reaction spends the night.After reacting completely, regulate with dilute hydrochloric acid (1M) after the pH value to 2 of reaction solution, with EtOAc(50mL × 3) extraction, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain white solid 0.85g, productive rate: 99%, be directly used in next step reaction.
1H?NMR(400Hz,CDCl 3):δ9.80(s,1H),4.54(d,1H,J=7.25Hz),4.28(m,1H),4.06(m,4H),3.76(m,2H),3.50(s,3H),2.71(m,2H),2.65(m,1H),0.87(m,3H),0.81(m,3H)ppm。
Step 8) compound 15-9's is synthetic
By compound 15-8(1.78g, 5.4mmol) with compound 3-1-0(1.64g, 5.9mmol) be dissolved in MeCN(30mL) in, slowly splash into DIPEA(1.1mL, 6.7mmol at 0 ℃), drip and finish, room temperature reaction 3.0 hours.After reacting completely, after concentration of reaction solution, obtain faint yellow solid 2.76g, productive rate: 97.3% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/1).
1H?NMR(400Hz,CDCl 3):δ7.82-7.78(m,2H),7.67-7.64(m,2H),5.32,5.29(d,d,1H),5.22(s,2H),5.06-5.02(m,1H),4.36-4.31(m,1H),4.02-4.00(m,4H),3.81-3.77(m,1H),3.63(s,3H),3.56-3.51(m,1H),2.79-2.73(m,1H),2.41-2.34(m,1H),2.18-2.06(m,1H),0.97-0.95(m,3H),0.91-0.89(m,3H)ppm。
Step 9) compound 15-10's is synthetic
By compound 15-9(3.0g, 5.7mmol) be suspended in dimethylbenzene (20mL) with ammonium acetate (4.4g, 57.1mmol), 130 ℃ of reactions are spent the night.After reacting completely, be chilled to room temperature, add EtOAc(40mL) dilute reaction solution, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, obtains yellow solid 2.6g, productive rate: 89.9% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=2/1) after concentrating.
1H?NMR(400Hz,CDCl 3):δ7.45-7.41(m,2H),7.29-7.26(m,3H),5.40-5.36(m,1H),5.32,5.29(d,d,1H),4.42-4.38(m,1H),3.98-3.92(m,5H),3.71-3.69(m,1H),3.63(s,3H),2.83-2.77(m,1H),2.45-2.39(m,1H),2.24-2.11(m,1H),0.97-0.95(m,3H),0.91-0.89(m,3H)ppm。
Step 10) compound 15-11's is synthetic
By compound 15-10(4.0g, 7.9mmol), Pd (dppf) Cl 2cH 2cl 2(0.64g, 0.8mmol), Glacial acetic acid potassium (1.94g, 19.8mmol) and compound 1-12-2(3.11g, 12.2mmol) be placed in reaction flask, add DME(50mL), under nitrogen protection, 90 ℃ are reacted 4.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(200mL) dilute reaction solution, water (100mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain white solid 4.15g, productive rate: 94.7% through column chromatographic isolation and purification (eluent: PE/DCM (v/v)=4/1).
1H?NMR(400Hz,CDCl 3):δ7.64-7.57(m,4H),7.22(s,1H),5.40-5.36(m,1H),5.32,5.29(d,d,1H),4.42-4.38(m,1H),3.98-3.96(m,5H),3.71-3.69,3.67-3.66(m,1H),3.63(s,3H),2.83-2.77(m,1H),2.45-2.39(m,1H),2.24-2.11(m,1H),1.35,1.32(m,m,12H),0.97-0.95(m,3H),0.91-0.89(m,3H)ppm。
Step 11) compound 15-12's is synthetic
By compound 15-11(0.13g, 0.234mmol), compound 1-8(78mg, 0.234mmol), four triphenyl phosphorus palladiums (0.14g, 0.12mmol) and salt of wormwood (0.8g, 5.85mmol) are suspended in DME/H 2o(v/v=3/1), in mixed solvent (4.0mL), under nitrogen protection, 90 ℃ are reacted 3.0 hours.After reacting completely, add EtOAc(20mL) dilute reaction solution, use saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain faint yellow solid 0.13g, productive rate: 81% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=100/1).
MS(ESI,pos.ion)m/z:683.2[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.67-7.66,7.65-7.64(m,m,2H),7.51-7.50,7.49-7.48(m,m,2H),7.35(s,1H),6.07,6.05(d,d,1H),5.40-5.36(m,1H),4.35-4.31(m,1H),3.98-3.96,3.94-3.92(m,m,5H),3.71-3.69(m,1H),3.68-3.66(m,1H),3.65(s,3H),2.84-2.77(m,3H),2.75-2.72(m,2H),2.45-2.39(m,1H),2.28-2.16(m,1H),1.75-1.54(m,4H),1.53-1.43(m,2H),1.31-1.21(m,2H),1.02,1.00(m,m,3H),0.94,0.91(m,m,3H)ppm。
Step 12) compound 15-13's is synthetic
By compound 15-12(0.34g, 0.5mmol), Pd (dppf) Cl 2cH 2cl 2(20.4mg, 0.025mmol), Glacial acetic acid potassium (0.12g, 1.25mmol) and compound 1-12-2(0.15g, 0.6mmol) be placed in reaction flask, add DMF(2.0mL), under nitrogen protection, 90 ℃ are reacted 4.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(20mL) after dilute reaction solution, water (10mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 0.24g, productive rate: 66% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2).
1H?NMR(400Hz,CDCl 3):δ7.66-7.65,7.64-7.63(m,m,2H),7.35(s,1H),7.23-7.22,7.21-7.20(m,m,2H),6.08,6.05(d,d,1H),5.40-5.36(m,1H),4.35-4.31(m,1H),3.98-3.96,3.94-3.92(m,m,5H),3.71-3.69(m,1H),3.65(s,3H),2.83-2.77(m,3H),2.66-2.63(m,2H),2.45-2.39(m,1H),2.28-2.16(m,1H),1.74-1.54(m,6H),1.52-1.41(m,2H),1.33,1.30(q,q,12H),1.02,1.00(m,m,3H),0.93,0.91(m,m,3H)ppm。
Step 13) compound 15-14's is synthetic
By compound 15-13(0.15g, 0.2mmol), compound 2-7(84mg, 0.2mmol), four triphenyl phosphorus palladiums (12mg, 0.01mmol) and salt of wormwood (69mg, 0.5mmol) are suspended in EtOH/H 2o(v/v=3/1), in mixed solvent (4.0mL), under nitrogen protection, 90 ℃ are reacted 3.0 hours.After reacting completely, add EtOAc(20mL) dilute reaction solution, use saturated common salt water washing, anhydrous sodium sulfate drying,
After concentrated, obtain faint yellow solid 98.6mg, productive rate: 55% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=50/1).
MS(ESI,pos.ion)m/z:449.2[M+2H] 2+；
1H?NMR(400MHz,CDCl 3):δ7.66-7.65,7.64-7.63(m,m,2H),7.61-7.60,7.58-7.57(m,m,2H),7.40(s,1H),7.35(s,1H),6.07,6.05(d,d,1H),5.44-5.36(m,2H),5.32,5.29(d,d,1H),4.41-4.37(m,1H),4.35-4.31(m,1H),3.98-3.96,3.94-3.92(m,m,5H),3.86-3.80(m,1H),3.71-3.66(m,1H),3.65(s,3H),3.63(s,3H),2.95-2.92(m,2H),2.83-2.73(m,3H),2.45-2.39(m,1H),2.32-2.04(m,6H),2.03-1.92(m,1H),1.73-1.52(m,4H),1.49-1.39(m,2H),1.27-1.17(m,2H),1.02,1.00(m,m,3H),0.97,0.95(m,m,3H),0.94,0.92(m,m,3H),0.90,0.89(m,m,3H)ppm。
Embodiment 16
Figure BDA0000442505360001131
Synthetic route:
Figure BDA0000442505360001132
Step 1) compound 16-1's is synthetic
At 0 ℃, by DIPEA(1.95mL, 11.8mmol) join compound 12-6(2.43g, 10.7mmol) with compound H ATU(4.88g, 12.84mmol) THF(25mL) in solution, isothermal reaction is after 0.5 hour, add compound 1-7-2(2.21g in batches, 11.9mmol), after adding, room temperature reaction 4.0 hours.After reacting completely, add water (50mL) cancellation reaction, remove THF, EtOAc(50mL for water layer × 3) extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, is dissolved in residuum in glacial acetic acid (20mL) after concentrating, and 40 ℃ of reactions are spent the night.After reacting completely, remove glacial acetic acid, residuum is dissolved in EtOAc(100mL) in, wash with sodium carbonate solution (50mL × 3), anhydrous sodium sulfate drying, obtains product 2.02g, productive rate: 50% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2) after concentrating.
MS(ESI,pos.ion)m/z:378.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.67(dd,1H),7.22,7.20(d,d,1H),7.19,7.17(d,d,1H),5.03-5.00(m,1H),3.31-3.24(m,1H),2.56-2.49(m,1H),2.12-2.07(m,1H),1.53-1.48(m,1H),1.46(s,9H),1.42-1.38(m,1H),1.00-0.97(m,1H)ppm。
Step 2) compound 16-2 synthetic
By compound 16-1(1.03g, 2.74mmol) be dissolved in EtOAc(5.0mL), splash into after the ethyl acetate solution (6.0mL, 4M) of hydrogenchloride room temperature reaction 8.0 hours at 0 ℃.After reacting completely, concentration of reaction solution, residuum adds EtOAc(10mL) stirring to pulp, after filtration, obtain faint yellow solid 0.82g, productive rate: 85.5%.
MS(ESI,pos.ion)m/z:278.2[M+H] +。
Step 3) compound 16-3's is synthetic
By compound 16-2(0.66g, 1.88mmol), compound 1-11-2(0.49g, 2.82mmol) and EDCI(0.54g, 2.82mmol) be suspended in DCM(10mL), at 0 ℃, slowly splash into DIPEA(1.86mL, 11.28mmol) after, room temperature reaction 3.0 hours.After reacting completely, add DCM(50mL) dilute reaction solution, water (20mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain solid 0.69g, productive rate: 85% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2).
MS(ESI,pos.ion)m/z:435.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.67(dd,1H),7.22,7.20(d,d,1H),7.19,7.17(d,d,1H),5.32,5.30(d,d,1H),5.16-5.12(m,1H),4.13-4.08(m,1H),3.63(s,3H),3.42-3.36(m,1H),2.62-2.55(m,1H),2.21-2.09(m,2H),1.53-1.45(m,1H),0.97-0.89(m,7H),0.50-0.46(m,1H)ppm。
Step 4) compound 16-4's is synthetic
By compound 16-3(3.08g, 7.1mmol), compound 1-12-2(2.72g, 10.7mmol), Pd (dppf) Cl 2cH 2cl 2(0.0.57g, 0.7mmol) and KOAc(2.09g, 21.3mmol) be placed in reaction flask, N 2under protection, inject DMF(30mL), 90 ℃ are reacted 3.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(200mL) dilute reaction solution, diatomite filtration, filtrate is water (50mL × 3) and saturated common salt water washing respectively, anhydrous sodium sulfate drying, obtains beige solid 2.22g, productive rate: 65% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2) after concentrating.
MS(ESI,pos.ion)m/z:483.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.82(dd,1H),7.65,7.63(d,d,1H),7.45,7.42(d,d,1H),5.32,5.30(d,d,1H),5.16-5.12(m,1H),4.13-4.08(m,1H),3.63(s,3H),3.42-3.36(m,1H),2.62-2.55(m,1H),2.22-2.09(m,2H),1.53-1.45(m,1H),1.32,1.29(m,12H),0.97-0.89(m,7H),0.50-0.46(m,1H)ppm。
Step 5) compound 16-5's is synthetic
By compound 16-4(0.24g, 0.5mmol), compound 12-12(0.32g, 0.5mmol), Pd (PPh 3) 4(58mg, 0.05mmol) and salt of wormwood (0.17g, 1.25mmol) are placed in reaction flask, N 2under protection, inject respectively DME(6mL) and pure water (2mL), 90 ℃ are reacted 3.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(40mL) after dilute reaction solution, water (20mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 0.23g, productive rate: 50.4% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=50/1).
MS(ESI,pos.ion)m/z:457.2[M+2H] 2+；
1H?NMR(400MHz,CDCl 3):δ7.80,7.78(d,d,1H),7.66-7.65,7.64-7.62(m,m,2H),7.61(s,1H),7.59(q,1H),7.57,7.55(d,d,1H),7.48-7.47,7.46-7.45(m,m,2H),5.32,5.29(d,d,2H),5.14-5.10(m,1H),4.89-4.85(m,1H),4.13-4.04(m,2H),3.63(s,6H),3.45-3.36(m,2H),2.79-2.76(m,2H),2.74-2.71(m,2H),2.62-2.55(m,1H),2.46-2.39(m,1H),2.2-2.09(m,3H),2.00-1.98,1.97-1.94(m,m,1H),1.73-1.36(m,8H),1.28-1.18(m,2H),0.97,0.95(m,m,6H),0.90-0.92(m,2H),0.91,0.89(m,m,6H),0.50-0.46(m,2H)ppm。
Embodiment 17
Figure BDA0000442505360001151
Synthetic route:
Figure BDA0000442505360001152
Step 1) compound 17-1's is synthetic
By compound 11-4(0.24g, 0.5mmol), compound 3-6(0.31g, 0.5mmol), Pd (PPh 3) 4(58mg, 0.05mmol) and salt of wormwood (0.17g, 1.25mmol) are placed in reaction flask, N 2under protection, inject respectively EtOH(6mL) and pure water (2mL), 90 ℃ are reacted 6.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(40mL) after dilute reaction solution, water (20mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 0.22g, productive rate: 50% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=50/1).
MS(ESI,pos.ion)m/z:446.7[M+2H] 2+；
1H?NMR(400MHz,CDCl 3):δ8.90(m,1H),7.66-7.65,7.64-7.62(m,m,2H),7.59(s,1H),7.58-7.57(m,1H),7.48-7.47,7.46(m,m,2H),7.45-7.44,7.43-7.42(m,m,1H),7.37-7.36,7.35-7.34(m,m,1H),7.21,7.19,7.17(m,m,m,1H),5.46,5.44(d,d,1H),5.32,5.29(d,d,1H),5.23-5.19(m,1H),4.62-4.57(m,1H),4.41-4.36(m,1H),4.31-4.26(m,1H),3.85-3.78(m,1H),3.66(s,3H),3.65-3.64(m,1H),3.63(s,3H),3.47-3.35(m,2H),2.79-2.74(m,4H),2.30-1.85(m,10H),1.72-1.52(m,4H),1.50-1.39(m,2H),1.28-1.18(m,2H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H)ppm。
Embodiment 18
Figure BDA0000442505360001161
Synthetic route:
Figure BDA0000442505360001162
Step 1) compound 18-2's is synthetic
By NBS(2.16g, 12mmol) with compound 18-1(2.51g, 10mmol) be dissolved in CCl 4(20mL) in, at 0 ℃, slowly splash into dibenzoyl peroxide (0.24g, 1.0mmol), drip and finish, stirring at room temperature, after 15 minutes, refluxes 7.0 hours.After reacting completely, remove CCl 4, residuum EtOAc(100mL) dissolve, water (50mL × 3) and saturated common salt water washing respectively, anhydrous sodium sulfate drying, obtains crude product 3.2g after concentrating, and is directly used in next step reaction.
MS(ESI,pos.ion)m/z:330.8[M+H] +；
1H?NMR(400MHz,CDCl 3):δ8.18-8.17(m,1H),7.79(m,1H),4.66-4.65(m,2H)ppm。
Step 2) compound 18-3 synthetic
By NaH(60%, 3.13g, 78mmol) be suspended in DMF(100mL) in, slowly splash into diethyl malonate (12.54g, 78mmol), to drip and finish, 100 ℃ of reactions were down to room temperature reaction after 40 minutes.Add compound 18-2(11.74g, 35.60mmol), finish, room temperature reaction is after 30 minutes, and 75 ℃ are reacted 1.0 hours.After reacting completely, with saturated ammonium chloride solution (50mL) cancellation reaction, add EtOAc(150mL), separate organic phase, water and saturated common salt water washing respectively, anhydrous sodium sulfate drying, obtains product 13.0g after concentrating, and is directly used in next step reaction.
1H?NMR(400MHz,CDCl 3):δ8.14(m,1H),7.75(m,1H),4.18-4.13(q,4H),3.83-3.80(m,1H),3.55-3.54,3.53-3.52(m,m,2H),1.23-1.19(t,6H)ppm。
Step 3) compound 18-4's is synthetic
By compound 18-3(13g) be dissolved in DMSO(100mL) in, under room temperature, slowly add NaCl(4.10g, 70mmol) and water (0.64g, 35.6mmol), after adding, 100 ℃ of reactions 3.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(200mL) dilute reaction solution, use saturated common salt water washing, anhydrous sodium sulfate drying, obtains product 8.5g through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=20/1) after concentrating.
1H?NMR(400MHz,CDCl 3):δ8.08-8.07(m,1H),7.75(m,1H),4.08-4.03(q,2H),2.98-2.97,2.96,2.94(m,m,m,2H),2.75,2.74,2.72(d,d,d,2H),1.22-1.19(t,3H)ppm。
Step 4) compound 18-5's is synthetic
By compound 18-4(3.37g, 10mmol) be dissolved in methyl alcohol (20mL), splash into the NaOH aqueous solution (0.8g, 20mL) at 0 ℃, drip and finish, room temperature reaction 3.0 hours.After reacting completely, adjust pH to 5 with dilute hydrochloric acid (1M), remove methyl alcohol, water layer is adjusted pH to 2 with dilute hydrochloric acid (1M), with EtOAc(50mL × 3) extraction, organic phase anhydrous Na 2sO 4dry, after concentrating, obtain white solid 2.78g, productive rate: 90%.
MS(ESI,pos.ion)m/z:309.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ10.32(brs,1H),8.08-8.07(m,1H),7.78(m,1H),3.02-3.01,3.00-2.99,2.98-2.97(m,m,m,2H),2.88,2.86,2.84(d,d,d,2H)ppm。
Step 5) compound 18-6's is synthetic
At-10 ℃, oxalyl chloride (0.93mL, 11mmol) is slowly splashed into compound 18-5(3.09g, 10mmol) and DCM solution (40mL) DMF(0.05mL) in, drip and finish, room temperature reaction is after 1.0 hours, stand-by without processing.
At-15 ℃, freshly prepd above-claimed cpd (3.27g, 10mmol) is slowly splashed into AlCl 3the DCM(30mL of (1.73g, 13mmol)) in suspension, drip and finish, isothermal reaction 2.0 hours.After reacting completely, reaction solution is slowly poured in frozen water, organic layer is separated, DCM(30mL for water layer × 3) extraction, merge organic phase, respectively with clear water and saturated sodium carbonate solution washing, anhydrous sodium sulfate drying, after concentrated, obtain pale yellow powder 2.33g, productive rate: 80.5% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=10/1).
MS(ESI,pos.ion)m/z:292.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ8.38(s,1H),3.22-3.20(m,2H),2.80-2.78(m,2H)ppm。
Step 6) compound 18-7's is synthetic
At-5 ℃, sodium hydroxide (1.6g, the 40mmol) aqueous solution (1.6mL) is slowly splashed into compound 18-6(2.91g, 10mmol), Isosorbide-5-Nitrae-dibromobutane (1.31mL, 11mmol) and TEBAC(0.46g, 2.0mmol) DMSO(30mL) in suspension liquid, 60 ℃ of reactions 8.0 hours.After reacting completely, reaction solution is slowly poured in frozen water (100mL), separated out solid.Filter solid EtOAc(50mL) dissolve, use saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain product 2.59g, productive rate: 75% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=10/1).
MS(ESI,pos.ion)m/z:346.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ8.38(s,1H),3.07-3.06(q,2H),2.03-1.91(m,2H),1.82-1.62(m,4H),1.34-1.24(m,2H)ppm。
Step 7) compound 18-8's is synthetic
At-5 ℃, by CF 3cOOH(9.0mL, 120mmol) slowly splash into compound 18-7(3.45g, 10mmol), NH 4f(1.11g, 30mmol) and Et 3siH(4.79mL, 30mmol) suspension liquid in, drip finish, 50 ℃ reaction 15 hours.After reacting completely, remove trifluoroacetic acid, residuum EtOAc(100mL) dissolve, use respectively sodium carbonate solution and saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain product 2.81g, productive rate: 85% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=20/1).
MS(ESI,pos.ion)m/z:332.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ8.08(dd,1H),3.23-3.20(m,2H),3.04-3.01(m,2H),1.77-1.45(m,8H)ppm。
Step 8) compound 18-9's is synthetic
By compound 18-8(0.33g, 1.0mmol), compound 1-13(0.99g, 2.1mmol), compound Pd (PPh 3) 4(0.12g, 0.1mmol) and salt of wormwood (0.35g, 2.5mmol) are dissolved in DME(8mL) and water (2mL) in, under nitrogen protection, 90 ℃ are reacted 4.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(50mL) after dilute reaction solution, water (20mL × 3) and saturated common salt water washing respectively, anhydrous sodium sulfate drying, after concentrated, obtain product 0.43g, productive rate: 50% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=50/1).
MS(ESI,pos.ion)m/z:858.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ8.70-8.69(dd,1H),7.87-7.86(q,1H),7.76,7.73(d,d,1H),7.66,7.64(d,d,1H),7.62-7.61(q,1H),7.57,7.55(d,d,1H),7.53,7.51(d,d,1H),6.08,6.05(d,d,1H),5.32,5.29(d,d,1H),5.24-5.20(m,2H),4.40-4.32(m,2H),3.84-3.78(m,2H),3.68-3.66(m,2H),3.65(s,3H),3.63(s,3H),3.14-3.11(m,2H),2.94-2.91(m,2H),2.38-2.10(m,8H),2.01-1.86(m,2H),1.71-1.51(m,6H),1.49-1.39(m,2H),1.02,1.00(m,m,3H),0.97,0.95(m,m,3H),0.93,0.91(m,m,3H),0.90,0.89(m,m,3H)ppm。
Embodiment 19
Figure BDA0000442505360001181
Synthetic route:
Figure BDA0000442505360001191
Step 1) compound 19-1's is synthetic
By compound 8-1(1.12g, 4.88mmol) be dissolved in THF(10mL) in, at 0 ℃, slowly splash into borine (7.3mL, 1M in THF), drip and finish, room temperature reaction 2.0 hours.After reacting completely, with methyl alcohol (4.0mL) cancellation reaction, remove THF, residuum DCM(50mL) dissolve water (20mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain colourless soup compound 1.05g, productive rate: 100% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/1).
MS(ESI,pos.ion)m/z:216.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ4.02(s,1H),3.99-3.87(m,1H),3.75-3.68(m,1H),3.66(dd,1H,J=11.6Hz,2.0Hz),3.57(dd,1H,J=11.6Hz,7.4Hz),2.76(t,1H,J=10.5Hz),2.19-2.06(m,2H),1.46(s,9H),1.01(d,3H,J=6.2Hz)ppm。
Step 2) compound 19-3 synthetic
By compound 19-1(1.0g, 4.64mmol) be dissolved in DCM(12mL) in, at 0 ℃, add respectively TCCA(1.08g, 4.64mmol) and TEMPO(64mg, 0.46mmol) DCM(5.0mL) solution, finish, isothermal reaction is after 1.0 hours, room temperature reaction 1.0 hours.After reacting completely, solids removed by filtration, filtrate is washed by saturated sodium bisulfite solution (30mL × 3), organic phase anhydrous Na 2sO 4dry, after concentrating, obtaining compound 19-2 is colourless soup compound.
Compound 19-2 is dissolved in to methanolic ammonia solution (10mL, 7M), reacts after 0.5 hour at 0 ℃, room temperature continues reaction 1.0 hours, is again cooled to after 0 ℃, slowly splash into oxalic dialdehyde the aqueous solution (1.2mL, 40%), drip and finish, room temperature reaction 24 hours.After reacting completely, concentration of reaction solution, residuum DCM(100mL) dissolve water (30mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 0.51g, productive rate: 44% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=100/1).
MS(ESI,pos.ion)m/z:252.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ6.97(s,2H),4.90(t,1H,J=8.0Hz),3.76(dd,1H,J=10Hz,7.2Hz),2.83(t,1H,J=8.0Hz),2.64-2.33(m,2H),2.32-2.12(m,1H),1.47(s,9H),1.09(d,3H,J=6.4Hz)ppm。
Step 3) compound 19-4's is synthetic
By compound 19-3(0.51g, 2.03mmol) be dissolved in DCM(10mL) in, at 0 ℃, add NIS(1.0g, 4.46mmol), after adding, isothermal reaction 2.0 hours.After reacting completely, solids removed by filtration, filtrate is washed by saturated sodium bisulfite solution (30mL × 3), anhydrous Na 2sO 4dry, after concentrating, obtain yellow solid 0.92g, productive rate: 90%.Be directly used in next step reaction.
MS(ESI,pos.ion)m/z:504.2[M+H] +；
1H?NMR(400MHz,CDCl 3):δ4.85(t,1H,J=8.0Hz),3.75(dd,1H,J=10Hz,7.2Hz),2.84(t,1H,J=10Hz),2.52-2.29(m,2H),2.21(d,1H,J=6.6Hz),1.48(s,9H),1.08(d,3H,J=6.4Hz)ppm。
Step 4) compound 19-5's is synthetic
By compound 19-4(0.91g, 1.8mmol) be dissolved in ethanol (10mL), add S-WAT (2.0g, 16mmol) and water (10mL), 90 ℃ are reacted 30 hours.After reacting completely, solids removed by filtration, concentrated filtrate, residuum adds DCM(50mL) dissolve after, water (20mL × 2) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain white solid 0.41g, productive rate: 60% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=6/1).
MS(ESI,pos.ion)m/z:378.2[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.04(s,1H),4.85(t,1H,J=8.4Hz),3.75(dd,1H,J=10.3Hz,7.3Hz),2.82(t,1H,J=10.4Hz),2.58-2.36(m,2H),2.29-2.11(m,1H),1.08(d,3H,J=6.4Hz)ppm。
Step 5) compound 19-6's is synthetic
By compound 19-5(0.63g, 1.66mmol), compound 1-12-2(0.46g, 1.82mmol), Pd (dppf) Cl 2cH 2cl 2(68mg, 0.083mmol) and KOAc(0.41g, 4.14mmol) be placed in reaction flask, N 2under protection, inject DMF(5.0mL), 90 ℃ are reacted 2.0 hours.After reacting completely, be chilled to room temperature, add after ethyl acetate (40mL) dilute reaction solution, diatomite filtration, filtrate is water (20mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 0.53g, productive rate: 85% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2).
MS(ESI,pos.ion)m/z:378.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.69(s,1H),4.90-4.85(m,1H),3.75-3.68(m,1H),3.04-2.97(m,1H),2.44-2.34(m,1H),2.33-2.20(m,1H),1.83-1.75(m,1H),1.41(s,9H),1.38,1.36(m,m,12H),0.96-0.93(m,3H)ppm。
Step 6) compound 19-7's is synthetic
By compound 8-4(0.75g, 1.66mmol), compound 18-8(0.55g, 1.66mmol), Pd (PPh 3) 4(96mg, 0.083mmol) and salt of wormwood (0.57g, 4.14mmol) are placed in reaction flask, N 2under protection, inject respectively EtOH(5mL) and pure water (1.0mL), 90 ℃ are reacted 3.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(50mL) after dilute reaction solution, water (20mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 0.48g, productive rate: 50% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/3).
MS(ESI,pos.ion)m/z:578.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ8.58(s,1H),7.92-7.91,7.90-7.89(m,m,2H),7.75,7.73-7.72(m,m,2H),7.59(s,1H),4.89-4.84(m,1H),3.80-3.73(m,1H),3.25-3.22(m,2H),3.09-3.02(m,1H),2.82-2.79(m,2H),2.33-2.16(m,2H),1.74-1.53(m,7H),1.52-1.43(m,2H),1.41(s,9H),0.96-0.93(m,3H)ppm。
Step 7) compound 19-8's is synthetic
By compound 19-7(0.33g, 0.58mmol), compound 19-6(0.22g, 0.58mmol), Pd (PPh 3) 4(35mg, 0.03mmol) and salt of wormwood (0.08g, 1.4mmol) are placed in reaction flask, N 2under protection, inject respectively EtOH(8.0mL) and pure water (2.0mL), 90 ℃ are reacted 4.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(40mL) after dilute reaction solution, water (20mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 0.19g, productive rate: 45% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=80/1).
MS(ESI,pos.ion)m/z:748.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ8.44(s,1H),7.91-7.90,7.89-7.88(m,m,2H),7.75,7.73-7.72(m,m,2H),7.67(s,1H),7.59(s,1H),5.22-5.17(m,1H),4.89-4.84(m,1H),3.80-3.73(m,2H),3.18-3.15(m,2H),3.09-3.02(m,2H),2.86-2.83(m,2H),2.35-2.16(m,4H),1.76-1.51(m,8H),1.46-1.42(m,2H),1.41(s,18H),0.96-0.93(m,6H)ppm。
Step 8) compound 19-9's is synthetic
By compound 19-8(0.3g, 0.4mmol) be dissolved in EtOAc(4.0mL) in, slowly splash into the ethyl acetate solution (3.0mL, 4M) of hydrogenchloride, drip and finish, room temperature reaction 8.0 hours.After reacting completely, concentration of reaction solution, residuum adds after ethyl acetate (10mL) making beating, filters and obtains faint yellow solid 0.25g, productive rate: 90%.Be directly used in next step reaction.
MS(ESI,pos.ion)m/z:548.5[M+H] +。
Step 9) compound 19-10's is synthetic
By compound 19-9(0.22g, 0.31mmol), compound 1-11-2(0.12g, 0.68mmol), EDCI(0.13g, 0.68mmol) and HOAT(85mg, 0.62mmol) be suspended in DCM(10mL) in, at 0 ℃, slowly splash into DIPEA(0.51mL, 3.1mmol), drip and finish, room temperature reaction 3.0 hours.After reacting completely, add DCM(20mL) dilute reaction solution, use respectively ammonium chloride solution and saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain faint yellow solid 0.15g, productive rate: 55% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=50/1).
MS(ESI,pos.ion)m/z:862.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ8.44(s,1H),7.91-7.90,7.89-7.88(m,m,2H),7.75,7.73-7.72(m,m,2H),7.59(s,1H),7.57(s,1H),5.56,5.55(d,d,1H),5.48-5.43(m,1H),5.32,5.29(d,d,1H),5.07-5.02(m,1H),4.42-4.41,4.40-4.39,4.38-4.37(m,m,m,1H),4.31-4.27(m,1H),3.92-3.85(m,2H),3.66(s,3H),3.63(s,3H),3.61-3.54(m,2H),3.18-3.15(m,2H),2.86-2.83(m,2H),2.38-2.09(m,6H),1.73-1.51(m,8H),1.48-1.38(m,2H),1.02,1.00(m,m,3H),0.97,0.95(m,m,3H),0.94-0.89(m,12H)ppm。
Embodiment 20
Figure BDA0000442505360001221
Synthetic route:
Figure BDA0000442505360001222
Step 1) compound 20-1's is synthetic
By compound 18-8(0.16g, 0.5mmol), compound 3-5(0.25g, 0.5mmol), Pd (PPh 3) 4(58mg, 0.05mmol) and salt of wormwood (0.17g, 1.25mmol) are placed in reaction flask, N 2under protection, inject respectively DME(8.0mL) and pure water (2.0mL), 90 ℃ are reacted 4.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(40mL) after dilute reaction solution, water (20mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 0.14g, productive rate: 45% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=100/1).
MS(ESI,pos.ion)m/z:621.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ8.58(s,1H),7.92-7.91,7.90-7.89(m,m,2H),7.75,7.73-7.72(m,m,2H),7.59(s,1H),6.08,6.05(d,d,1H),5.23-5.19(m,1H),4.34-4.33,4.32-4.31,4.30(m,m,m,1H),3.85-3.78(m,1H),3.69-3.66(m,1H),3.65(s,3H),3.25-3.22(m,2H),2.82-2.79(m,2H),2.30-2.16(m,3H),2.13-1.92(m,2H),1.73-1.54(m,6H),1.52-1.42(m,2H),1.02,1.00(m,m,3H),0.93,0.91(m,m,3H)ppm。
Step 2) compound 20-2 synthetic
By compound 20-1(0.24g, 0.39mmol), compound 2-9(0.15g, 0.468mmol), PdCl 2(PPh 3) 2(14.1mg, 0.02mmol), CuI(33mg, 0.172mmol), PPh 3(0.23g, 0.86mmol) joins in reaction flask, under nitrogen protection, adds DMF(10mL), slowly splash into triethylamine (5.0mL), to drip and finish, stirring at room temperature is after 10 minutes, and 90 ℃ are reacted 10 hours.After reacting completely, diatomite filtration, in filtrate, add water (20mL), with EtOAc(20mL × 3) extraction, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain product 0.1g, productive rate: 30% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=60/1).
MS(ESI,pos.ion)m/z:429.7[M+2H] 2+；
1H?NMR(400MHz,CDCl 3):δ8.78(s,1H),7.99-7.98,7.97-7.96(m,m,2H),7.76-7.75,7.73-7.72(m,m,2H),7.59(s,1H),7.56(s,1H),6.08,6.06(d,d,1H),5.51-5.47(m,1H),5.46,5.44(d,d,1H),5.23-5.19(m,1H),4.41-4.37(m,1H),4.34-4.30(m,1H),3.89-3.78(m,2H),3.73-3.67(m,2H),3.66(s,3H),3.63(s,3H),3.17-3.14(m,2H),2.79-2.76(m,2H),2.32-1.92(m,10H),1.74-1.54(m,6H),1.51-1.41(m,2H),1.02,1.00(m,m,3H),0.97,0.95(m,m,3H),0.93,0.91(m,m,3H),0.90,0.89(m,m,3H)ppm。
Embodiment 21
Figure BDA0000442505360001231
Synthetic route:
Figure BDA0000442505360001232
Step 1) compound 21-2's is synthetic
By PPh 3meBr(5.05g, 14.2mmol) be suspended in THF(50mL) in, at-20 ℃, slowly splash into potassium tert.-butoxide (14.9mL, 14.9mmol, 1.0M) THF solution, drips and finishes, and is warming up to-5 ℃ of reactions after 30 minutes, add compound 21-1(1.72g, 7.07mmol), after adding, room temperature reaction 1.0 hours.After reacting completely, add frozen water (50mL) cancellation reaction, remove THF, EtOAc(50mL for water layer × 3) extraction, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain pale yellow oily liquid body 1.07g, productive rate: 62.9% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=5/1).
MS(ESI,pos.ion)m/z:242.2[M+H] +；
1H?NMR(400MHz,DMSO-d 6):δ5.01(d,2H,J=10.8Hz),4.36(t,1H,J=11.2Hz),3.95(s,2H),3.64(s,3H),3.01(q,1H,J=14.6Hz),2.57-2.50(m,1H),1.38(s,9H)ppm。
Step 2) compound 21-3 synthetic
At 0 ℃, by chloroiodomethane (6.6g, 37.24mmol) be slowly added drop-wise to zinc ethyl (2.3g, in toluene (30mL) solution 18.6mmol), drip and finish, isothermal reaction 45 minutes, slowly splash into again compound 21-2(1.5g, toluene (15mL) solution 6.22mmol), drips and finishes, isothermal reaction 18 hours.After reacting completely, add saturated NH 4cl solution (20mL) cancellation reaction, EtOAc(25mL for water layer × 3) extraction, merge organic phase, anhydrous Na 2sO 4dry, after concentrating, obtain white liquid 0.58g, productive rate: 36.5% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=10/1).
MS(ESI,pos.ion)m/z:156.2[M-Boc] +；
1H?NMR(400MHz,CDCl 3):δ4.47-4.33(m,1H),3.71(s,3H),3.29-3.37(m,2H),2.25-2.17(m,1H),1.86-1.75(m,1H),1.44,1.40(s,s,9H),0.62-0.50(m,4H)ppm。
Step 3) compound 21-4's is synthetic
By compound 21-3(0.69g, 2.7mmol) be dissolved in EtOAc(6.0mL), add after the ethyl acetate solution (5.0mL, 4M) of hydrogenchloride room temperature reaction 8.0 hours.After reacting completely, after concentration of reaction solution, obtain colourless oil liquid 0.5g, productive rate: 96.5%.
MS(ESI,pos.ion)m/z:156.2[M+H] +；
1H?NMR(400MHz,CD 3OD):δ4.66-4.62(m,1H),4.45-4.44(m,1H),3.86(s,3H),3.61-3.60(m,1H),2.39-2.34(m,1H),2.19-2.14(m,1H),1.49-1.46(m,1H),1.19-1.16(m,1H),0.88-0.87(m,1H),0.81-0.79(m,1H)ppm。
Step 4) compound 21-5's is synthetic
By compound 21-4(0.53g, 2.77mmol), compound 1-11-2(0.73g, 4.16mmol) and EDCI(1.06g, 5.55mmol) be suspended in DCM(10mL) in, at 0 ℃, slowly splash into DIPEA(2.4mL, 14.52mmol) after, room temperature reaction 3.0 hours.After reacting completely, add DCM(20mL) dilute reaction solution, use respectively ammonium chloride solution and saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain white liquid 0.60g, productive rate: 70% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/1).
MS(ESI,pos.ion)m/z:313.2[M+H] +；
1H?NMR(400MHz,CDCl 3):δ5.44-5.42(br,1H),4.71-4.68(m,1H),4.29-4.20(m,1H),3.73(s,3H),3.72-3.69(m,1H),3.67(s,3H),3.59-3.54(m,1H),2.20-2.15(m,1H),2.06-2.01(m,1H),1.95-1.90(m,1H),1.05-0.93(m,6H),0.66-0.61(m,4H)ppm。
Step 5) compound 21-6's is synthetic
At 0 ℃, the aqueous solution of lithium hydroxide (0.14g, 3.2mmol) (5mL) is slowly splashed into compound 21-5(0.2g, 0.64mmol) THF solution (5.0mL) in, drip finish, 40 ℃ reaction 12 hours.After reacting completely, remove THF, add water (30mL), then use EtOAc(10mL × 3) extraction, collect water, the pH value of solution is adjusted to 1 with hydrochloric acid (10%), water layer extracts (25mL × 3) with EtOAc again, merging organic phase, anhydrous Na 2sO 4dry, after concentrating, obtain white solid 0.16g, productive rate: 82.8%.
MS(ESI,pos.ion)m/z:299.2[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.06(br,1H),5.76(br,1H),4.73-4.69(m,1H),4.23-4.18(m,1H),3.79(d,1H,J=9.7Hz),3.66(s,3H),3.49(d,1H,J=9.7Hz),2.26-2.18(m,1H),2.07-1.93(m,2H),1.00-0.94(m,6H),0.68-0.64(m,4H)ppm。
Step 6) compound 21-7's is synthetic
By compound 3-1-0(0.31g, 1.11mmol) with compound 21-6(0.3g, 1.0mmol) be dissolved in MeCN(10mL) in, at 0 ℃, slowly splash into DIPEA(0.21mL, 1.27mmol), drip and finish, room temperature reaction 2.0 hours.After reacting completely, in reaction solution, add water (10mL), remove MeCN, residuum EtOAc(30mL) dissolve, use respectively ammonium chloride solution and saturated common salt water washing, anhydrous sodium sulfate drying, obtains faint yellow solid 0.37g, productive rate: 66.7% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/1) after concentrating.
MS(ESI,pos.ion)m/z:495.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.82-7.78(m,2H),7.67-7.64(m,2H),5.32,5.29(br,br,1H),5.31(s,2H),4.72-4.70(m,1H),4.35-4.30(m,1H),3.67(s,3H),3.61-3.59(m,1H),3.55-3.49(m,1H),2.20-2.07(m,2H),1.83-1.76(m,1H),0.97,0.96(m,m,3H),0.91,0.89(m,m,3H),0.52-0.39(m,4H)ppm。
Step 7) compound 21-8's is synthetic
By compound 21-7(0.33g, 0.67mmol) and NH 4oAc(1.04g, 13.43mmol) be suspended in dimethylbenzene (10mL), react 5.0 hours at 120 ℃.After reacting completely, be chilled to room temperature, add water (20mL) cancellation reaction, EtOAc(20mL for water layer × 3) extraction, merge organic phase, saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain yellow solid 0.19g, productive rate: 60% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2).
MS(ESI,pos.ion)m/z:475.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.58(s,1H),7.45-7.41(m,2H),7.29-7.26(m,2H),5.46,5.44(br,br,1H),4.93-4.89(m,1H),4.41-4.37(m,1H),3.71-3.67(m,1H),3.67(s,3H),3.50-3.44(m,1H),2.39-2.32(m,1H),2.23-2.11(m,1H),2.05-1.97(m,1H),0.97,0.95(m,m,3H),0.91,0.89(m,m,3H),0.52-0.39(m,4H)ppm。
Step 8) compound 21-9's is synthetic
By compound 21-8(0.19g, 0.4mmol), compound 1-12-2(0.15g, 0.6mmol), Pd (dppf) Cl 2cH 2cl 2(33mg, 0.04mmol) and KOAc(0.12g, 1.19mmol) be placed in reaction flask, N 2under protection, inject DMF(5.0mL), 90 ℃ are reacted 3.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(50mL) dilute reaction solution, diatomite filtration, filtrate is water (20mL × 3) and saturated common salt water washing respectively, anhydrous sodium sulfate drying, obtains beige solid 0.16g, productive rate: 80% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2) after concentrating.
MS(ESI,pos.ion)m/z:523.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.64-7.57(m,4H),7.21(s,1H),5.46,5.44(br,br,1H),4.93-4.89(m,1H),4.42-4.37(m,1H),3.71-3.67(m,1H),3.66(s,3H),3.50-3.44(m,1H),2.39-2.32(m,1H),2.23-2.11(m,1H),2.05-1.97(m,1H),1.35(m,6H),1.32(m,6H),0.97,0.95(m,m,3H),0.91,0.89(m,m,3H),0.55-0.42(m,4H)ppm。
Step 9) compound 21-10's is synthetic
By compound 18-8(0.17g, 0.52mmol), compound 21-9(0.57g, 1.10mmol), Pd (PPh 3) 4(60.29mg, 0.052mmol) and salt of wormwood (0.22g, 1.57mmol) are placed in reaction flask, N 2under protection, inject respectively DME(6.0mL) and water (1.5mL), 90 ℃ are reacted 3.0 hours, after reacting completely, are chilled to room temperature, add after ethyl acetate (30mL) dilute reaction solution water (10mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 0.25g, productive rate: 50% through column chromatographic isolation and purification (eluent: DCM/EtOH (v/v)=50/1).
MS(ESI,pos.ion)m/z:481.8[M+2H] 2+；
1H?NMR(400MHz,CDCl 3):δ8.52-8.51(dd,1H),7.91-7.90,7.89-7.88(m,m,2H),7.75-7.74,7.73-7.72(m,m,2H),7.71,7.69-7.68(m,m,2H),7.60-7.59,7.58-7.57(m,m,4H),5.32,5.30(d,d,2H),4.93-4.89(m,2H),4.42-4.41,4.40-4.39,4.38-4.37(m,m,m,2H),3.72-3.66(m,2H),3.63(s,6H),3.50-3.44(m,2H),3.04-3.01(m,2H),2.85-2.81(m,2H),2.39-2.32(m,2H),2.23-2.11(m,2H),2.05-1.97(m,2H),1.71-1.50(m,6H),1.49-1.39(m,2H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H),0.55-0.42(m,8H)ppm。
Embodiment 22
Figure BDA0000442505360001261
Synthetic route:
Step 1) compound 22-2's is synthetic
Anhydrous sodium sulphate (3.48g, 24.5mmol) is added in toluene (15mL) solution of (R)-1-phenylethylamine (1.3mL, 10.1mmol), more slowly drips after glyoxylic acid ethyl ester (1mL, 10.1mmol) room temperature reaction 1.0 hours.After reacting completely, filter, after filtrate is concentrated, obtain yellow liquid 1.9g, productive rate: 91.8%.Without being further purified, be directly used in next step reaction.
Step 2) compound 22-3 synthetic
By TFA(0.75mL, 10.1mmol) join compound 22-2(2.0g, 9.7mmol) DMF(15mL) in solution, stir after 10 minutes, then add successively the 1，3-cyclopentadiene (1.29g of new steaming, 19.5mmol) He two drip, after adding, and room temperature reaction 12 hours.After reacting completely, remove DMF, residuum adds NaHCO 3solution (10%, 20mL), uses Na 2cO 3the pH value of solution is adjusted to 8, then uses sherwood oil (25mL × 3) extraction, merge organic phase, saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain light yellow liquid 2.38g, productive rate: 90% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=10/1).
1H?NMR(400MHz,CDCl 3):δ7.35-7.17(m,5H),6.42(br,1H),6.28-6.26(br,1H),4.34-4.30(m,2H),3.82-3.78(m,2H),3.04-3.02(m,1H),2.90(br,1H),2.20(br,1H),2.13(m,1H),1.41(d,3H,J=6.6Hz),0.95(t,3H,J=7.2Hz)ppm。
Step 3) compound 22-4's is synthetic
By Pd/C(0.2g) join compound 22-3(2.0g, 7.37mmol) methyl alcohol (20mL) solution in, at 20 normal atmosphere H 2under atmosphere, room temperature reaction 24 hours.After reacting completely, remove by filter Pd/C, after filtrate is concentrated, obtain yellow liquid 1.2g, productive rate: 96.2%.
MS(ESI,pos.ion)m/z:170.2[M+H] +；
1H?NMR(400MHz,CDCl 3):δ4.21-4.15(m,2H),3.55(br,1H),3.33(br,1H),2.63(br,1H),2.32(br,1H),1.64-1.60(m,2H),1.53-1.47(m,2H),1.42-1.36(m,2H),1.28(t,3H,J=7.1Hz)ppm。
Step 4) compound 22-5's is synthetic
By compound 22-4 (0.68g, 4.02mmol), compound 1-11-2(1.06g, 6.03mmol) and EDCI(1.54g, 8.05mmol) be suspended in DCM(25mL), at 0 ℃, slowly splash into DIPEA(2.1mL, 12.7mmol) after, room temperature reaction spends the night.After reacting completely, add water (30mL) cancellation reaction, DCM(35mL for water layer × 3) extraction, merge organic phase, use saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain white solid 0.74g, productive rate: 56.4% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=2/1).
MS(ESI,pos.ion)m/z:327.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ5.44(br,1H),4.40(br,1H),4.33-4.30(m,1H),4.19-4.14(m,2H),4.02(br,1H),3.66(s,3H),2.74(br,1H),2.04(br,1H),1.91-1.88(m,2H),1.80-1.74(m,2H),1.56-1.54(m,1H),1.43-1.38(m,1H),1.26(t,3H,J=7.1Hz),1.07(d,3H,J=6.8Hz),0.97(d,3H,J=6.8Hz)ppm。
Step 5) compound 22-6's is synthetic
At 0 ℃, the aqueous solution (10mL) of a hydronium(ion) oxidation lithium (0.48g, 11.35mmol) is slowly added drop-wise to compound 22-5(0.74g, 2.27mmol) THF(25mL) in solution, drip and finish, 40 ℃ of reactions 12 hours.After reacting completely, remove THF, residuum adds water (20mL), EtOAc(15mL for water layer × 3) washing, after separatory, hydrochloric acid for water (10%) regulates pH value to 1, then uses EtOAc(25mL × 3) extraction, merge organic phase, saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain white solid 0.55g, productive rate: 81.3%.
MS(ESI,pos.ion)m/z:299.2[M+H] +；
1H?NMR(400MHz,CD 3OD):δ4.52(br,1H),4.20(d,1H,J=7.8Hz),3.93(br,1H),3.63(s,3H),2.73(br,1H),2.01-1.98(m,4H),1.85-1.75(m,2H),1.54-1.46(m,2H),1.05(d,3H,J=6.8Hz),0.98(d,3H,J=6.8Hz)ppm。
Step 6) compound 22-7's is synthetic
By compound 3-1-0(0.31g, 1.11mmol) with compound 22-6(0.3g, 1.0mmol) be dissolved in DCM(30mL) in, at 0 ℃, slowly splash into DIPEA(0.2mL, 1.21mmol), drip and finish, room temperature reaction 3.0 hours.After reacting completely, add water (20mL), with EtOAc(30mL × 3) extraction, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, obtains faint yellow solid 0.33g, productive rate: 66.7% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2) after concentrating.
MS(ESI,pos.ion)m/z:495.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.75(d,2H,J=8.52Hz),7.68(d,2H,J=8.56Hz),5.45(d,1H,J=9.4Hz),5.24(d,1H,J=16.56Hz),4.55-4.59(m,1H),3.67(s,3H),3.57(m,1H),2.73-2.65(m,2H),2.27-2.19(m,1H),2.04(s,1H),1.84-1.77(m,2H),1.49-1.46(m,1H),1.27-1.24(m,1H),1.08-1.07(br,1H),1.05-1.03(m,1H),0.91-0.89(m,6H)ppm。
Step 7) compound 22-8's is synthetic
By compound 22-7(0.33g, 0.67mmol) and NH 4oAc(1.04g, 13.43mmol) be suspended in toluene (8.0mL), 110 ℃ are reacted 5.0 hours.After reacting completely, be chilled to room temperature, add water (20mL) cancellation reaction, EtOAc(20mL for water layer × 3) extraction, merge organic phase, saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain yellow solid 188mg, productive rate: 58.9% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2).
MS(ESI,pos.ion)m/z:476.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ10.35(s,1H),7.64-7.62(d,2H,J=8.52Hz),7.55-7.45(d,2H,J=1.84Hz),7.16(s,1H),5.54-5.46(br,2H),4.57-4.53(m,1H),3.70(s,3H),3.58(m,1H),2.69(m,1H),2.54-2.48(m,1H),1.87-1.76(m,4H),1.47-1.45(m,2H),0.85-0.81(m,6H)ppm。
Step 8) compound 22-9's is synthetic
By compound 22-8(0.19g, 0.40mmol), compound 1-12-2(0.15g, 0.59mmol), Pd (dppf) Cl 2cH 2cl 2(33mg, 0.039mmol) and KOAc(0.12g, 1.19mmol) be placed in reaction flask, N 2under protection, inject DMF(5.0mL), 90 ℃ are reacted 3.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(50mL), diatomite filtration, filtrate is water (20mL × 3) and saturated common salt water washing respectively, anhydrous sodium sulfate drying, obtains beige solid 0.17g, productive rate: 80.3% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2) after concentrating.
MS(ESI,pos.ion)m/z:523.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ10.48(s,1H),7.81-7.75(m,4H),7.43-7.41(d,1H,J=8.0Hz),5.49-5.39(m,2H),4.58-4.53(m,2H),3.67(s,3H),3.57(m,1H),2.65(m,1H),2.54-2.47(m,1H),2.10-2.04(m,2H),1.83-1.79(m,1H),1.49-1.46(m,2H),1.38(s,12H),0.85-0.81(m,6H)ppm。
Step 9) compound 22-10's is synthetic
By compound 22-9(1.37g, 2.62mmol), compound 18-8(0.86g, 2.62mmol), Pd (PPh 3) 4(0.12g, 0.1mmol) and salt of wormwood (0.9g, 6.55mmol) are placed in reaction flask, N 2under protection, inject respectively DME(12mL) and pure water (3.0mL), 90 ℃ are reacted 5.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(100mL) after dilute reaction solution, water (30mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 0.84g, productive rate: 50% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=100/1).
MS(ESI,pos.ion)m/z:646.2[M+H] +；
1H?NMR(400MHz,CDCl 3):δ8.58(s,1H),7.92-7.91,7.90-7.89(m,m,2H),7.76-7.75,7.74-7.73(m,m,2H),7.60(s,1H),5.32,5.30(d,d,1H),5.06-5.02(m,1H),4.80-4.75(m,1H),4.45,4.43,4.41(m,m,m,1H),3.63(s,3H),3.25-3.22(m,2H),2.82-2.79(m,2H),2.55-2.50(m,1H),2.22-2.10(m,1H),2.08-2.00(m,1H),1.83-1.78(m,1H),1.74-1.54(m,9H),1.52-1.37(m,3H),0.97,0.95(m,m,3H),0.91,0.89(m,m,3H)ppm。
Step 10) compound 22-11's is synthetic
By compound 22-6(0.58g, 1.95mmol) and HATU(0.78g, 2.06mmol) be suspended in THF(20mL) in, at 0 ℃, slowly splash into DIPEA(0.41mL, 2.48mmol), drip and finish, isothermal reaction is after 0.5 hour, slowly splash into compound 1-9-2(0.4g, THF(10mL 2.15mmol)) solution, drips and finishes, room temperature reaction 2.0 hours.After reacting completely, remove THF, residuum adds water (20mL), with EtOAc(30mL × 3) extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, obtains brown oily liquids 0.77g, productive rate: 85% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=4/1) after concentrating.
Step 11) compound 22-12's is synthetic
By compound 22-11(1.34g, 2.87mmol) be dissolved in glacial acetic acid (20mL), 40 ℃ of reactions are spent the night.After reacting completely, remove glacial acetic acid, residuum EtOAc(50mL) dissolve, wash with sodium carbonate solution (50mL × 3), anhydrous sodium sulfate drying, after concentrated, obtain brown solid 0.87g, productive rate: 68% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/1).
MS(ESI,pos.ion)m/z:450.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.59-7.52(m,1H),7.32-7.21(m,2H),5.41-5.38(m,2H),4.35-4.32(m,1H),3.87-3.76(m,1H),3.70(s,3H),3.66-3.62(m,1H),2.67-2.65(m,1H),2.20-2.13(m,1H),1.85-1.73(m,4H),1.46-1.43(m,2H),0.88-0.84(m,6H)ppm。
Step 12) compound 22-13's is synthetic
By compound 22-12(0.15g, 0.33mmol), compound 1-12-2(0.13g, 0.49mmol), Pd (dppf) Cl 2cH 2cl 2(27mg, 0.033mmol) and KOAc(97mg, 0.99mmol) be placed in reaction flask, N 2under protection, inject DMF(5.0mL), 90 ℃ are reacted 4.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(40.0mL) dilute reaction solution, diatomite filtration, filtrate is water (30mL × 3) and saturated common salt water washing respectively, anhydrous sodium sulfate drying, obtains beige solid 90mg, productive rate: 55.5% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2) after concentrating.
MS(ESI,pos.ion)m/z:497.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.85-7.80(m,1H),7.72-7.68(m,2H),5.45-5.41(m,2H),4.56-4.48(m,1H),4.33-4.30(m,1H),3.86-3.84(m,1H),3.70(s,3H),3.64-3.62(m,1H),3.04-2.98(m,1H),2.25-2.20(m,1H),2.20-2.13(m,2H),1.87-1.76(m,1H),1.46-1.49(m,2H),1.35(s,12H),0.88-0.84(m,6H)ppm。
Step 13) compound 22-14's is synthetic
By compound 22-13(50mg, 0.1mmol), compound 22-10(65mg, 0.1mmol), Pd (PPh 3) 4(12mg, 0.01mmol) and salt of wormwood (34.5mg, 0.25mmol) are placed in reaction flask, N 2under protection, inject respectively DME(5.0mL) and pure water (1.0mL), 90 ℃ are reacted 3.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(25mL) after dilute reaction solution, water (10mL × 3) and saturated common salt water washing respectively, anhydrous sodium sulfate drying, after concentrated, obtain beige solid 47mg, productive rate: 50% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=50/1).
MS(ESI,pos.ion)m/z:468.8[M+2H] 2+；
1H?NMR(400MHz,CDCl 3):δ8.49(s,1H),7.91-7.90,7.89-7.88(m,m,2H),7.76-7.75,7.74-7.73(m,m,3H),7.60(s,1H),7.56-7.55(q,1H),7.48,7.44(d,d,1H),5.39-5.35(m,1H),5.32,5.29(d,d,2H),5.06-5.02(m,1H),4.80-4.75(m,1H),4.73-4.69(m,1H),4.45-4.40(m,2H),3.63(s,6H),2.96-2.93(m,2H),2.85-2.82(m,2H),2.58-2.50(m,2H),2.22-2.10(m,2H),2.08-2.00(m,1H),1.83-1.35(m,18H),1.31-1.24(m,1H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H)ppm。
Embodiment 23
Figure BDA0000442505360001301
Synthetic route:
Figure BDA0000442505360001311
Step 1) compound 23-2's is synthetic
By compound 3-1-0(2.98g, 10.79mmol) and compound 23-1(2.69g, 11.87mmol) be dissolved in MeCN(250mL) in, at 0 ℃, slowly splash into DIPEA(2.14mL, 12.95mmol), drip and finish, room temperature reaction 3.0 hours.After reacting completely, remove MeCN, residuum adds water (100mL), then uses EtOAc(100mL × 3) extraction, merge organic phase, saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain white solid 4.1g, productive rate: 90% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=10/1).
MS(ESI,pos.ion)m/z:425.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.82-7.78(m,2H),7.67-7.64(m,2H),5.61-5.59(m,1H),5.33(s,2H),4.73-4.69(m,1H),4.35-4.28(m,1H),3.99-3.92(m,1H),1.76-1.74(m,3H),1.42(s,9H)ppm。
Step 2) compound 23-3 synthetic
By compound 23-2(1.54g, 3.64mmol) and ammonium acetate (4.2g, 5.46mmol) be suspended in toluene (30mL), 110 ℃ reaction 5.0 hours.After reacting completely, be chilled to room temperature, add water (50mL) cancellation reaction, EtOAc(50mL for water layer × 3) extraction, merge organic phase, saturated common salt water washing, anhydrous Na SO 4dry, after concentrating, obtain faint yellow solid 1.25g, productive rate: 85% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=6/1).
MS(ESI,pos.ion)m/z:404.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.64(s,1H),7.45-7.41(m,2H),7.35-7.32(m,2H),5.78-5.75(m,1H),5.55-5.52(m,1H),4.24-4.17(m,1H),3.77-3.69(m,1H),1.78-1.77(m,3H),1.39(s,9H)ppm。
Step 3) compound 23-4's is synthetic
By compound 23-3(4.12g, 10.23mmol), compound 1-12-2(2.86g, 11.25mmol), Pd (dppf) Cl 2cH 2cl 2(0.42g, 0.51mmol) and KOAc(2.51g, 25.57mmol) be placed in reaction flask, N 2under protection, inject DMF(40mL), 90 ℃ are reacted 3.0 hours.After reacting completely, be chilled to room temperature, add after ethyl acetate (100mL) dilute reaction solution, diatomite filtration, filtrate is water (80mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain product 3.69g, productive rate: 80% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=2/1).
1H?NMR(400MHz,CDCl 3):δ7.75-7.72(m,2H),7.61-7.58(m,2H),7.28(s,1H),5.78-5.75(m,1H),5.55-5.52(m,1H),4.24-4.17(m,1H),3.77-3.69(m,1H),1.78-1.77(m,3H),1.39(s,9H)ppm。
Step 4) compound 23-5's is synthetic
By compound 23-4(0.45g, 1.0mmol) be dissolved in EtOAc(4mL), then splash into after the ethyl acetate solution (3.0mL, 4M) of hydrogenchloride, drip and finish, room temperature reaction 8.0 hours.After reacting completely, concentration of reaction solution, after ethyl acetate for residuum (5mL) making beating, filters and obtains yellow solid 0.38g, productive rate: 90%.
MS(ESI,pos.ion)m/z:352.5[M+H] +。
Step 5) compound 23-6's is synthetic
By compound 23-5(0.11g, 0.26mmol), compound 1-11-2(50mg, 0.286mmol), EDCI(0.11g, 0.57mmol) and HOAT(0.07g, 0.52mmol) be suspended in DCM(3.0mL) in, at 0 ℃, slowly splash into DIPEA(0.5mL, 2.6mmol), drip and finish, room temperature reaction 3 hours.After reacting completely, add DCM(20mL) dilute reaction solution, use respectively aqueous ammonium chloride solution and saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain faint yellow solid 0.11g, productive rate: 83% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=2/1).
MS(ESI,pos.ion)m/z:509.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.72-7.69(m,2H),7.60-7.58(m,2H),7.23(s,1H),6.08,6.06(d,d,1H),5.74-5.70(m,1H),5.45-5.42(m,1H),4.70-4.67,4.66-4.63(m,m,1H),4.29-4.25(m,1H),4.16-4.13,4.12-4.09(m,m,1H),3.65(s,3H),2.34-2.22(m,1H),1.66-1.65(m,3H),1.35,1.32(q,q,12H),1.02,1.00(m,m,3H),0.93,0.91(m,m,3H)ppm。
Step 6) compound 23-7's is synthetic
By compound 23-6(0.51g, 1.0mmol), compound 18-8(0.33g, 1.0mmol), Pd (PPh 3) 4(58mg, 0.05mmol) and salt of wormwood (0.35g, 2.5mmol) are placed in reaction flask, N 2under protection, inject respectively DME(9.0mL) and pure water (3.0mL), 90 ℃ are reacted 4.0 hours.After reacting completely, be chilled to room temperature, add after ethyl acetate (80mL) dilute reaction solution, water (20mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain white solid 0.38g, productive rate: 60% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=100/1).
MS(ESI,pos.ion)m/z:632.2[M+H] +；
1H?NMR(400MHz,CDCl 3):δ8.58(dd,1H),7.92-7.91,7.90-7.89(m,m,2H),7.77-7.76,7.74-7.73(m,m,2H),7.34(s,1H),5.74-5.70(m,1H),5.45-5.42(m,2H),5.32,5.30(d,d,1H),4.70-4.67,4.66-4.63(m,m,1H),4.45-4.44,4.42,4.40(m,m,m,1H),4.16-4.13,4.12-4.09(m,m,1H),3.63(s,3H),3.25-3.22(m,2H),2.82-2.78(m,2H),2.29-2.17(m,1H),1.73-1.53(m,9H),1.52-1.42(m,2H),0.97,0.95(m,m,3H),0.91,0.89(m,m,3H)ppm。
Step 7) compound 23-8's is synthetic
By compound 23-1(10.58g, 46.6mmol) be dissolved in tetrahydrofuran (THF) (100mL), under 0 ℃ of nitrogen protection, slowly splash into the tetrahydrofuran solution (100mL, 1M) of borine, drip and finish, isothermal reaction 3 hours.After reacting completely, with methyl alcohol (80mL) cancellation reaction, after concentration of reaction solution, obtain colorless oil 7.45g, productive rate: 75% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/2).
1H?NMR(400MHz,CDCl 3):δ5.32-5.29(m,1H),4.63-4.54(m,1H),4.16-4.09(m,1H),3.97-3.92(m,1H),3.88-3.82(m,1H),3.80-3.79(m,1H),3.22(br,1H),1.62-1.61(m,3H),1.43(s,9H)ppm。
Step 8) compound 23-9's is synthetic
By compound 23-8(7.42g, 34.8mmol) be dissolved in DCM(250mL) in, at 0 ℃, Dai Si-Martin (20.7g, 48.8mmol) oxygenant is added in reaction flask in batches, after adding, room temperature reaction 2.0 hours.After reacting completely, add water (150mL) cancellation reaction, filter, filtrate is used saturated common salt water washing, anhydrous sodium sulfate drying, obtains colorless oil 3.72g, productive rate: 50.7% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/1) after concentrating.
1H?NMR(400MHz,CDCl 3):δ9.77-9.75(m,1H),5.41-5.38(m,1H),4.64-4.59(m,1H),4.24-4.17(m,1H),3.96-3.89(m,1H),1.65-1.64(m,3H),1.44(s,9H)ppm。
Step 9) compound 23-10's is synthetic
By compound 23-9(3.71g, 17.6mmol) and ammoniacal liquor (13mL) be dissolved in methyl alcohol (30mL), at 0 ℃, slowly splash into the aqueous solution of oxalic dialdehyde (40%, 8mL), drip and finish, room temperature reaction spends the night.After reacting completely, concentration of reaction solution obtains white solid 2.08g, productive rate: 47.6% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=4/1).
MS(ESI,pos.ion)m/z:250.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.05(s,2H),6.32-6.28(m,1H),5.38-5.35(m,1H),4.23-4.17(m,1H),3.86-3.80(m,1H),1.68-1.67(m,3H),1.40(s,9H)ppm。
Step 10) compound 23-11's is synthetic
By compound 23-10(2.09g, 8.4mmol) be dissolved in DCM(30mL) in, at 0 ℃, N-N-iodosuccinimide (3.8g, 16.8mmol) is added in reaction flask in batches to isothermal reaction 1.5 hours.After reacting completely, reaction solution saturated common salt water washing, anhydrous sodium sulfate drying, obtains white solid 2.65g, productive rate: 63% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/2) after concentrating.
MS(ESI,pos.ion)m/z:502.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ5.52-5.45(m,2H),4.35-4.29(m,1H),3.94-3.88(m,1H),1.67-1.66(m,3H),1.40(s,9H)ppm。
Step 11) compound 23-12's is synthetic
By compound 23-11(1.64g, 3.27mmol) be suspended in the mixed solvent (50mL) of second alcohol and water (v/v=3/7), add S-WAT (3.7g, 29mmol), reflux 17 hours.After reacting completely, remove ethanol, residuum adds water (50mL), extract by ethyl acetate (50mL × 3), merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain white solid 1.03g, productive rate: 84% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/2).
MS(ESI,pos.ion)m/z:376.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.18(s,1H),5.35-5.32(m,1H),5.28-5.24(m,1H),4.29-4.23(m,1H),3.91-3.85(m,1H),1.67-1.66(m,3H),1.40(s,9H)ppm。
Step 12) compound 23-13's is synthetic
By compound 23-12(0.38g, 1.0mmol) be dissolved in EtOAc(4mL), then splash into after the ethyl acetate solution (3.0mL, 4M) of hydrogenchloride, drip and finish, room temperature reaction 8.0 hours.After reacting completely, concentration of reaction solution, after ethyl acetate for residuum (5mL) making beating, filters and obtains yellow solid 0.31g, productive rate: 90%.
MS(ESI,pos.ion)m/z:276.1[M+H] +。
Step 13) compound 23-14's is synthetic
By compound 23-13(90mg, 0.26mmol), compound 1-11-2(50mg, 0.29mmol), EDCI(0.11g, 0.57mmol) and HOAT(0.07g, 0.52mmol) be suspended in DCM(3.0mL) in, at 0 ℃, slowly splash into DIPEA(0.5mL, 2.6mmol), drip and finish, room temperature reaction 3 hours.After reacting completely, add DCM(20mL) dilute reaction solution, use respectively aqueous ammonium chloride solution and saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain faint yellow solid 90mg, productive rate: 80% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=2/1).
MS(ESI,pos.ion)m/z:433.2[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.31(s,1H),5.59-5.55(m,1H),5.52-5.50(m,1H),5.32,5.29(d,d,1H),4.67-4.65,4.63-4.61(m,m,1H),4.45-4.44,4.42,4.40(m,m,m,1H),4.15-4.13,4.11-4.09(m,m,1H),3.63(s,3H),2.29-2.17(m,1H),1.66-1.65(m,3H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 14) compound 23-15's is synthetic
By compound 23-14(43mg, 0.1mmol), compound 1-12-2(28mg, 0.11mmol), Pd (dppf) Cl 2cH 2cl 2(8.2mg, 0.01mmol) and KOAc(25mg, 0.25mmol) be placed in reaction flask, N 2under protection, inject DMF(1.0mL), 90 ℃ are reacted 3.0 hours.After reacting completely, be chilled to room temperature, add after ethyl acetate (10mL) dilute reaction solution, diatomite filtration, filtrate is water (10mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain product 34.6mg, productive rate: 80% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=2/1).
1H?NMR(400MHz,CDCl 3):δ7.61(s,1H),5.81-5.77(m,1H),5.46-5.44(m,1H),5.32,5.29(d,d,1H),4.61-4.59,4.57-4.55(m,m,1H),4.44,4.42,4.40(m,m,m,1H),4.07-4.04,4.03-4.00(m,m,1H),3.63(s,3H),2.29-2.17(m,1H),1.66-1.65(m,3H),1.39,1.36(m,m,12H),0.97,0.95(m,m,3H),0.91,0.89(m,m,3H)ppm。
Step 15) compound 23-16's is synthetic
By compound 23-15(0.43g, 1.0mmol), compound 23-7(0.63g, 1.0mmol), Pd (PPh 3) 4(58mg, 0.05mmol) and salt of wormwood (0.35g, 2.5mmol) are placed in reaction flask, N 2under protection, inject respectively DME(9.0mL) and pure water (3.0mL), 90 ℃ are reacted 6.0 hours.After reacting completely, be chilled to room temperature, add after ethyl acetate (80mL) dilute reaction solution, water (20mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain white solid 0.34g, productive rate: 40% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=50/1).
MS(ESI,pos.ion)m/z:429.7[M+2H] 2+；
1H?NMR(400MHz,CDCl 3):δ8.42(dd,1H),7.91-7.90,7.89-7.88(m,m,2H),7.77-7.76,7.74-7.73(m,m,2H),7.64(s,1H),7.34(s,1H),6.02-5.97(m,1H),5.74-5.70(m,1H),5.56,5.55(d,d,1H),5.45-5.42(m,2H),5.32,5.30(d,d,1H),4.70-4.67(m,1H),4.66-4.63(m,1H),4.44,4.42,4.40(m,m,m,1H),4.28,4.27,4.25(m,m,m,1H),4.16-4.13,4.12-4.09(m,m,2H),3.66(s,3H),3.63(s,3H),3.18-3.15(m,2H),2.86-2.82(m,2H),2.34-2.17(m,2H),1.70-1.51(m,12H),1.48-1.39(m,2H),1.02,1.00(m,m,3H),0.97,0.95(m,m,3H),0.93,0.91(m,m,3H),0.90,0.89(m,m,3H)ppm。
Embodiment 24
Figure BDA0000442505360001351
Synthetic route:
Figure BDA0000442505360001352
Step 1) compound 24-1's is synthetic
At-5 ℃, sodium hydroxide (1.6g, the 40mmol) aqueous solution (1.6mL) is slowly splashed into compound 1-6(2.96g, 10mmol), pentamethylene bromide (1.5mL, 11mmol) and TEBAC(0.46g, 2.0mmol) DMSO(20mL) in suspension liquid, 60 ℃ of reactions 8.0 hours.After reacting completely, reaction solution is slowly poured in frozen water (80mL), separated out solid.Filter solid EtOAc(50mL) dissolve, use saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain product 2.53g, productive rate: 70% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=10/1).
MS(ESI,pos.ion)m/z:365.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ2.66-2.65(m,2H),1.71-1.63(m,2H),1.61-1.53(m,1H),1.51-1.43(m,2H),1.37-1.26(m,5H)ppm。
Step 2) compound 24-2 synthetic
At-5 ℃, by CF 3cOOH(9.0mL, 120mmol) slowly splash into compound 24-1(3.62g, 10mmol), NH 4f(1.11g, 30mmol) and Et 3siH(4.79mL, 30mmol) suspension liquid in, drip finish, 50 ℃ reaction 15 hours.After reacting completely, remove trifluoroacetic acid, residuum EtOAc(100mL) dissolve, use respectively sodium carbonate solution and saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain product 2.96g, productive rate: 85% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=20/1).
MS(ESI,pos.ion)m/z:349.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ2.73-2.71(m,4H),1.77-1.65(m,4H),1.63-1.55(m,4H),1.29-1.21(m,2H)ppm。
Step 3) compound 24-3's is synthetic
By compound 24-2(0.35g, 1.0mmol), compound 1-13(0.99g, 2.1mmol), Pd (PPh 3) 4(0.12g, 0.1mmol) and K 2cO 3(0.35g, 2.5mmol) is suspended in DME(5.0mL) and water (1.0mL) in, under nitrogen protection, 90 ℃ reaction 5.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(20mL) after dilute reaction solution, water and saturated common salt water washing respectively, anhydrous sodium sulfate drying, after concentrated, obtain faint yellow solid 0.39g, productive rate: 45% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=50/1).
MS(ESI,pos.ion)m/z:439.5[M+2H] 2+；
1H?NMR(400MHz,CDCl 3):δ7.79,7.77(d,d,2H),7.70-7.69(q,2H),7.18,7.16(d,d,2H),6.08,6.06(d,d,1H),5.32,5.30(d,d,1H),5.25-5.20(m,2H),4.40-4.32(m,2H),3.84-3.78(m,2H),3.68-3.66(m,2H),3.65(s,3H),3.63(s,3H),2.99-2.97(m,4H),2.39-2.10(m,8H),2.00-1.89(m,2H),1.71-1.60(m,4H),1.30-1.22(m,6H),1.02,1.00(m,m,3H),0.97,0.95(m,m,3H),0.93,0.91(m,m,3H),0.90,0.89(m,m,3H)ppm。
Embodiment 25
Figure BDA0000442505360001361
Synthetic route:
Figure BDA0000442505360001362
Step 1) compound 25-1's is synthetic
At-5 ℃, sodium hydroxide (1.6g, the 40mmol) aqueous solution (1.6mL) is slowly splashed into compound 1-6(2.96g, 10mmol), 1,3-dibromopropane (1.1mL, 11mmol) and TEBAC(0.46g, 2.0mmol) DMSO(30mL) in suspension liquid, 60 ℃ of reactions 8.0 hours.After reacting completely, reaction solution is slowly poured in frozen water (100mL), separated out solid.Filter solid EtOAc(50mL) dissolve, use saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain product 2.35g, productive rate: 70% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=10/1).
MS(ESI,pos.ion)m/z:337.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ2.99-2.98(m,2H),2.39-2.29(m,2H),2.13-2.04(m,2H),1.79-1.57(m,2H)ppm。
Step 2) compound 25-2 synthetic
At-5 ℃, by CF 3cOOH(9.0mL, 120mmol) slowly splash into compound 25-1(3.34g, 10mmol), NH 4f(1.11g, 30mmol) and Et 3siH(4.79mL, 30mmol) suspension liquid in, drip finish, 50 ℃ reaction 15 hours.After reacting completely, remove trifluoroacetic acid, residuum EtOAc(100mL) dissolve, use respectively sodium carbonate solution and saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain product 2.08g, productive rate: 65% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=20/1).
MS(ESI,pos.ion)m/z:323.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ2.74-2.73(m,4H),2.28-2.18(m,2H),1.87-1.78(m,2H),1.52-1.29(m,2H)ppm。
Step 3) compound 25-3's is synthetic
By compound 25-2(0.32g, 1.0mmol), compound 3-5(0.50g, 1.0mmol), Pd (PPh 3) 4(0.12g, 0.1mmol) and K 2cO 3(0.35g, 2.5mmol) is suspended in DME(5.0mL) and water (1.0mL) in, under nitrogen protection, 90 ℃ reaction 5.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(20mL) after dilute reaction solution, water and saturated common salt water washing respectively, anhydrous sodium sulfate drying, after concentrated, obtain faint yellow solid 0.27g, productive rate: 45% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=100/1).
MS(ESI,pos.ion)m/z:612.6[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.67-7.66,7.65-7.64(m,m,2H),7.59(s,1H),7.51-7.50,7.49-7.48(m,m,2H),5.32,5.29(d,d,1H),5.23-5.19(m,1H),4.41-4.36(m,1H),3.85-3.78(m,1H),3.68-3.64(m,1H),3.63(s,3H),2.77-2.75(m,2H),2.68-2.67(m,2H),2.30-1.92(m,7H),1.86-1.77(m,2H),1.59-1.36(m,2H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Step 4) compound 25-4's is synthetic
By compound 25-3(0.3g, 0.5mmol), compound 16-4(0.24g, 0.5mmol), Pd (PPh 3) 4(57.8mg, 0.05mmol) and K 2cO 3(0.17g, 1.25mmol) is suspended in DME(5.0mL) and water (1.0mL) in, under nitrogen protection, 90 ℃ reaction 5.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(20mL) after dilute reaction solution, water and saturated common salt water washing respectively, anhydrous sodium sulfate drying, after concentrated, obtain faint yellow solid 0.18g, productive rate: 40.5% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=50/1).
MS(ESI,pos.ion)m/z:444.2[M+2H] 2+；
1H?NMR(400MHz,CDCl 3):δ7.79,7.77(d,d,1H),7.66-7.65,7.64-7.62(m,m,2H),7.59(m,2H),7.57,7.55(d,d,1H),7.48-7.47,7.46-7.45(m,m,2H),5.32,5.29(m,m,2H),5.23-5.19(m,1H),5.14-5.10(m,1H),4.41,4.39,4.37(m,m,m,1H),4.12,4.11-4.10,4.08(m,m,m,1H),3.85-3.78(m,1H),3.68-3.65(m,1H),3.63(s,6H),3.42-3.36(m,1H),3.00-2.98(m,2H),2.72-2.70(m,2H),2.62-2.55(m,1H),2.30-1.92(m,9H),1.85-1.76(m,2H),1.65-1.44(m,3H),0.97,0.95(m,m,6H),0.94-0.92(m,1H),0.91,0.89(m,m,6H),0.50-0.46(m,1H)ppm。
Embodiment 26
Figure BDA0000442505360001381
Synthetic route:
Figure BDA0000442505360001382
Step 1) compound 26-1's is synthetic
By compound 1-6(2.0g, 6.82mmol), 2,2 '-bis-bromodiethyl ether (1.64g, 7.15mmol), TEBAC(0.3g, 1.36mmol) be suspended in DMSO(20mL) in, at 0 ℃, slowly splash into the aqueous solution (50%, 2.0mL) of NaOH, drip and finish, 50 ℃ are reacted 2.0 hours.After reacting completely, add water (50mL) cancellation reaction, EtOAc(50mL for water layer × 3) extraction, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, obtains yellow oil 1.49g, productive rate: 60% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=15/1) after concentrating.
MS(ESI,pos.ion)m/z:367.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ4.19-4.13(m,2H),3.73-3.68(m,2H),2.70-2.69(m,2H),2.10-2.02(m,2H),1.82-1.73(m,2H)ppm。
Step 2) compound 26-2 synthetic
At-5 ℃, by CF 3cOOH(9.0mL, 120mmol) slowly splash into compound 26-1(3.64g, 10mmol), NH 4f(1.11g, 30mmol) and Et 3siH(4.79mL, 30mmol) suspension liquid in, drip finish, 50 ℃ reaction 15 hours.After reacting completely, remove trifluoroacetic acid, residuum EtOAc(100mL) dissolve, use respectively sodium carbonate solution and saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain product 2.27g, productive rate: 65% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=20/1).
MS(ESI,pos.ion)m/z:353.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ3.75-3.71(m,4H),2.76-2.74(m,4H),1.85-1.79(m,4H)ppm。
Step 3) compound 26-3's is synthetic
By compound 9-1(6.86g, 27.97mmol) be dissolved in DCM(70mL) in, at 0 ℃, Dai Si-Martin reagent (23.7g, 56mmol) is added in reaction system in batches, after adding, room temperature reaction 7.0 hours.After reacting completely, with sodium thiosulfate solution (100mL) cancellation reaction, diatomite filtration, filtrate is used DCM(100mL × 3) extraction, merge organic phase, anhydrous Na 2sO 4dry, after concentrating, obtain weak yellow liquid 5.78g, productive rate: 85% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=6/1).
Step 4) compound 26-4's is synthetic
By compound 26-3(5.81g, 23.9mmol) be dissolved in DCM(70mL) in, at-78 ℃, by Et 2nSF 3(4.85mL, 35.9mmol) slowly splashes in system, drips and finishes, and isothermal reaction is after 2.0 hours, room temperature reaction 19 hours.After reacting completely, with aqueous ammonium chloride solution (50mL) cancellation reaction, DCM(100mL for water layer × 3) extraction, merge organic phase, anhydrous Na 2sO 4dry, after concentrating, obtain weak yellow liquid 5.0g, productive rate: 79% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=20/1).
MS(ESI,pos.ion)m/z:266.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ9.60(brs,1H),4.60-4.57,4.94-4.72(m,m,1H),3.93-3.84(m,2H),3.77(s,3H),2.78-2.48(m,2H),1.44(d,9H,J=16Hz)ppm。
Step 5) compound 26-5's is synthetic
By compound 26-4(5.0g, 18.86mmol) be dissolved in THF(40mL) in, at 0 ℃, lithium hydroxide aqueous solution (1.5g, 20mL) is added in system to room temperature reaction 2.0 hours.After reacting completely, regulate the pH value to 5 of reaction solution with dilute hydrochloric acid (1M), remove THF, after dilute hydrochloric acid for water layer (1M) adjust pH to 2, with EtOAc(80mL × 3) extraction, merge organic phase, use saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain white solid 4.54g, productive rate: 94%.
MS(ESI,pos.ion)m/z:252.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ9.60(brs,1H),4.60-4.57,4.94-4.72(m,m,1H),3.89-3.74(m,2H),2.78-2.48(m,2H),1.44(d,9H,J=16Hz)ppm。
Step 6) compound 26-6's is synthetic
By compound 26-5(2.37g, 9.43mmol) be dissolved in THF(30mL) in, at 0 ℃, splash into borine tetrahydrofuran solution (14.2mL, 1M), drip and finish, room temperature reaction 2.0 hours.After reacting completely, with methyl alcohol (4.0mL) cancellation reaction, remove THF, residuum DCM(100mL) dissolve after, distinguish water (40mL × 3) and saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain colourless soup compound 1.79g, productive rate: 80%.
1H?NMR(400MHz,CDCl 3):δ4.43-4.27(m,1H),3.59-3.34(m,2H),3.60-3.46(m,2H),2.48-2.18(m,2H),1.44(d,9H,J=16Hz)ppm。
Step 7) compound 26-8's is synthetic
By compound 26-6(1.8g, 7.59mmol) be dissolved in DCM(20mL) in, at 0 ℃, by TCCA(1.77g, 7.59mmol) add in system, then by the DCM solution (0.12g of TEMPO, 0.76mmol, 5.0mL) splash in system, drip and finish, after isothermal reaction 1.0 hours, room temperature reaction 1.0 hours.After reacting completely, solids removed by filtration, filtrate is washed by saturated sodium bisulfite solution (40mL × 3), anhydrous Na 2sO 4dry, residuum is dissolved in ammonia methyl alcohol (20mL, 7M) after concentrated, react after 0.5 hour at 0 ℃, then room temperature reaction 1.0 hours.Again be cooled to after 0 ℃, drip oxalic dialdehyde the aqueous solution (2.0mL, 40%), drip finish, room temperature reaction 24 hours.After reacting completely, concentration of reaction solution, residuum DCM(150mL) dissolve after, water (50mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 1.04g, productive rate: 50% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=60/1).
MS(ESI,pos.ion)m/z:274.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.00(s,2H),5.83-5.80(m,1H),4.05-3.79(m,1H),3.74-3.52(m,1H),3.11-2.33(m,2H),1.51(s,9H)ppm。
Step 8) compound 26-9's is synthetic
By compound 26-8(0.93g, 3.4mmol) be dissolved in DCM(30mL) in, at 0 ℃, by NIS(1.7g, 7.5mmol) add in system in batches, after adding, isothermal reaction 2.0 hours.After reacting completely, filter, filtrate is washed by saturated sodium bisulfite solution (50mL × 3), anhydrous Na 2sO 4dry, after concentrating, obtain yellow solid 1.07g, productive rate: 60%.Be directly used in next step reaction.
MS(ESI,pos.ion)m/z:526.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ5.13-5.08(m,1H),3.91-3.87(m,1H),3.58-3.46(m,2H),2.74-2.72(m,1H),1.51(s,9H)ppm。
Step 9) compound 26-10's is synthetic
By compound 26-9(1.03g, 1.96mmol) be dissolved in EtOH(10mL) in, add S-WAT (2.47g, 19.6mmol) and water (10mL), 90 ℃ of reactions 30 hours.After reacting completely, filter concentrated filtrate, residuum DCM(80mL) dissolve after, distinguish water and saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain white solid 0.26g, productive rate: 33% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=6/1).
MS(ESI,pos.ion)m/z:400.2[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.08(s,1H),5.33-4.95(m,1H),3.91-3.87(m,1H),3.78-3.36(m,2H),2.96-2.55(m,1H),1.49(s,9H)ppm。
Step 10) compound 26-11's is synthetic
By compound 3-1-0(2.41g, 8.66mmol) and compound 26-5(2.17g, 8.66mmol) be dissolved in DCM(30mL) in, at 0 ℃, slowly splash into TEA(2.5mL, 17.32mmol), drip and finish, room temperature reaction 3.0 hours.(50mL) cancellation that after reacting completely, adds water reaction, with DCM(30mL × 3) extraction, merge organic phase, anhydrous Na 2sO 4dry, after concentrating, obtain crude product 3.6g, productive rate: 99%.Be directly used in next step reaction.
MS(ESI,pos.ion)m/z:421.3[M+H] +。
Step 11) compound 26-12's is synthetic
By compound 26-11(3.6g, 8.6mmol) and ammonium acetate (7.0g, 86mmol) be suspended in toluene (30mL), 110 ℃ reaction 5.0 hours.After reacting completely, be chilled to room temperature, add water (60mL) cancellation reaction, EtOAc(80mL for water layer × 3) extraction, merge organic phase, anhydrous Na 2sO 4dry, after concentrating, obtain product 1.47g, productive rate: 40% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=6/1).
MS(ESI,pos.ion)m/z:429.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.54-7.52(m,2H),7.48-7.46(m,2H),7.26-7.25(m,1H),5.19-5.18(m,1H),3.70-3.52(m,2H),2.78-2.65(m,2H),1.48(s,9H)ppm。
Step 12) compound 26-13's is synthetic
By compound 26-12(1.4g, 3.27mmol), compound 1-12-2(0.92g, 3.6mmol), Pd (dppf) Cl 2cH 2cl 2(0.13g, 1.16mmol) and KOAc(0.81g, 8.17mmol) be placed in reaction flask, N 2under protection, inject DME(25mL), 90 ℃ are reacted 2.0 hours.After reacting completely, add ethyl acetate (80mL) dilute reaction solution, diatomite filtration, filtrate is water (30mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain solid 1.49g, productive rate: 96% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=1/2).
MS(ESI,pos.ion)m/z:476.4[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.54-7.52(m,2H),7.48-7.46(m,2H),7.26-7.25(m,1H),5.19-5.18(m,1H),3.70-3.52(m,2H),2.78-2.65(m,2H),1.48(s,9H),1.35(s,12H)ppm。
Step 13) compound 26-14's is synthetic
By compound 26-13(2.14g, 4.5mmol), compound 26-2(1.57g, 4.5mmol), Pd (PPh 3) 4(0.26g, 0.225mmol) and salt of wormwood (1.24g, 9.0mmol) are placed in reaction flask, N 2under protection, inject respectively DME(20mL) and pure water (4.0mL), 90 ℃ are reacted 2.0 hours.After reacting completely, add after ethyl acetate (100mL) dilute reaction solution water (30mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 1.67g, productive rate: 60% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=6/1).
MS(ESI,pos.ion)m/z:620.2[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.78-7.77,7.76-7.75(m,m,2H),7.72-7.71,7.70-7.69(m,m,2H),7.46(s,1H),4.93-4.88(m,1H),4.18-4.17,4.15-4.13,4.11-4.08,4.06-4.05(m,m,m,m,1H),3.92-3.91,3.89-3.86,3.84-3.82,3.80-3.79(m,m,m,m,1H),3.75-3.70(m,4H),2.86-2.67(m,5H),2.47-2.26(m,1H),1.82-1.76(m,4H),1.41(s,9H)ppm。
Step 14) compound 26-15's is synthetic
By compound 26-14(1.42g, 2.3mmol), compound 1-12-2(0.64g, 2.53mmol), Pd (dppf) Cl 2cH 2cl 2(90mg, 0.115mmol) and KOAc(0.6g, 5.75mmol) be placed in reaction flask, N 2under protection, inject DMF(15mL), 120 ℃ are reacted 4.0 hours.After reacting completely, with EtOAc(100mL) dilute reaction solution, diatomite filtration, filtrate is water (50mL × 3) and saturated common salt water washing respectively, anhydrous sodium sulfate drying, after concentrated, obtain faint yellow solid 1.07g, productive rate: 70% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=4/1).
MS(ESI,pos.ion)m/z:668.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.77-7.76,7.75-7.74(m,m,2H),7.46(s,1H),7.44-7.43,7.42-7.41(m,m,2H),4.93-4.88(m,1H),4.18-4.17,4.15-4.13,4.11-4.08,4.06-4.05(m,m,m,m,1H),3.92-3.91,3.89-3.86,3.84-3.82,3.80-3.79(m,m,m,m,1H),3.67-3.63(m,4H),2.86-2.68(m,3H),2.61-2.58(m,2H),2.47-2.26(m,1H),1.79-1.73(m,4H),1.41(s,9H),1.33,1.30(m,m,12H)ppm。
Step 15) compound 26-16's is synthetic
By compound 26-15(0.37g, 0.55mmol), compound 26-10(0.22g, 0.55mmol), four triphenyl phosphorus palladiums (32mg, 0.027mmol) and salt of wormwood (0.19g, 1.37mmol) are suspended in EtOH/H 2o(v/v=4/1), in mixed solvent (7.5mL), under nitrogen protection, 90 ℃ are reacted 2.0 hours.After reacting completely, concentration of reaction solution, residuum adds ethyl acetate (50mL) to dissolve, use saturated common salt water washing, anhydrous sodium sulfate drying, obtains faint yellow solid 0.24g, productive rate: 55% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=100/1) after concentrating.
MS(ESI,pos.ion)m/z:813.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.82-7.81,7.80-7.79(m,m,2H),7.78-7.75,7.74-7.73(m,m,2H),7.53(s,1H),7.46(s,1H),5.20-5.15(m,1H),4.93-4.88(m,1H),4.18-4.17,4.15-4.13,4.11-4.08,4.06-4.05(m,m,m,m,1H),3.92-3.91,3.89-3.86,3.84-3.82,3.80-3.79(m,m,m,m,1H),3.74-3.69(m,4H),3.00-2.97(m,2H),2.92-2.68(m,4H),2.53-2.26(m,2H),1.84-1.78(m,4H),1.53(s,9H),1.41(s,9H)ppm。
Step 16) compound 26-17 synthetic
By compound 26-16(0.24g, 0.3mmol) be dissolved in EtOAc(4.0mL) in, drip the ethyl acetate solution (3.0mL, 4M) of hydrogenchloride, drip and finish, room temperature reaction 8.0 hours.After reacting completely, concentration of reaction solution, residuum adds after ethyl acetate (4.0mL) making beating, filters and obtains pale yellow powder shape solid 0.18g, productive rate: 80%.Be directly used in next step reaction.
MS(ESI,pos.ion)m/z:613.3[M+H] +。
Step 17) compound 26-18 synthetic
By compound 26-17(0.20g, 0.26mmol), compound 1-11-2(100mg, 0.57mmol), EDCI(0.11g, 0.57mmol) and HOAT(70mg, 0.52mmol) be suspended in DCM(6.0mL) in, at 0 ℃, slowly splash into DIPEA(0.43mL, 2.6mmol), drip and finish, room temperature reaction 3.0 hours.After reacting completely, add DCM(20mL) dilute reaction solution, use respectively ammonium chloride solution and saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain faint yellow solid 0.19g, productive rate: 80% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=40/1).
MS(ESI,pos.ion)m/z:464.2[M+2H] 2+；
1H?NMR(400MHz,CDCl 3):δ7.66-7.65,7.64-7.63(m,m,2H),7.61-7.60,7.58-7.57(m,m,2H),7.46(s,1H),7.41(s,1H),5.32,5.30(d,d,2H),5.29-5.26(m,1H),5.16-5.11(m,1H),4.47,4.45,4.43(m,m,m,2H),4.21-4.19,4.17-4.15,4.13-4.11,4.09-4.07(m,m,m,m,2H),3.94-3.93,3.91-3.88,3.87-3.84,3.82-3.81(m,m,m,m,2H),3.74-3.69(m,4H),3.63(s,6H),3.00-2.72(m,6H),2.55-2.29(m,2H),2.23-2.11(m,2H),1.84-1.78(m,4H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H)ppm。
Embodiment 27
Figure BDA0000442505360001431
Synthetic route:
Figure BDA0000442505360001432
Step 1) compound 27-1's is synthetic
By compound 1-6(4.2g, 14.34mmol) and compound 10-0(5.23g, 21.51mmol) be dissolved in DMF(15mL) in, under 0 ℃ of nitrogen protection, add NaH(60%, 1.43g, 35.85mmol), after adding, 50 ℃ of reactions 18 hours.After reacting completely, be chilled to room temperature, add water (100mL) cancellation reaction, ethyl acetate for water layer (100mL × 3) extraction, organic phase is water and saturated common salt water washing respectively, anhydrous sodium sulfate drying, obtains product 1.08g, productive rate: 20% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=8/1) after concentrating.
MS(ESI,pos.ion)m/z:377.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ2.78-2.70(m,2H),2.65-2.64(m,2H),2.55-2.45(m,2H),2.35-2.34(m,3H),1.93-1.83(m,4H)ppm。
Step 2) compound 27-2 synthetic
By compound 27-1(1.43g, 3.8mmol) and triethyl silicane (3.7mL, 23mmol) be mixed in reaction flask, 0 ℃ of N 2under protection, slowly inject trifluoroacetic acid (8.0mL), drip and finish, 40 ℃ are reacted 7 hours.After reacting completely, remove trifluoroacetic acid, residuum EtOAc(50mL) dissolve, use respectively sodium carbonate solution and saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain pale yellow oily liquid body 1.1g, productive rate: 80% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=5/1).
MS(ESI,pos.ion)m/z:364.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ2.82-2.70(m,6H),2.53-2.41(m,2H),2.30-2.29(m,3H),1.99-1.87(m,4H)ppm。
Step 3) compound 27-3's is synthetic
By compound 27-2(1.63g, 4.5mmol), compound 6-1(1.97g, 4.5mmol), Pd (PPh 3) 4(0.26g, 0.225mmol) and salt of wormwood (1.24g, 9.0mmol) are placed in reaction flask, N 2under protection, inject respectively DME(20mL) and pure water (4.0mL), 90 ℃ are reacted 5.0 hours.After reacting completely, add after ethyl acetate (100mL) dilute reaction solution water (30mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 1.61g, productive rate: 60% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=6/1).
MS(ESI,pos.ion)m/z:597.2[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.67-7.66,7.65-7.64(m,m,2H),7.59(s,1H),7.51-7.50,7.49-7.48(m,m,2H),4.97-4.93(m,1H),3.64-3.58(m,1H),3.31-3.24(m,1H),2.81-2.74(m,4H),2.69-2.66(m,2H),2.51-2.38(m,3H),2.30-2.29(m,3H),2.28-2.16(m,1H),2.10-1.97(m,2H),1.93-1.87(m,4H),1.53(s,9H)ppm。
Step 4) compound 27-4's is synthetic
By compound 27-3(1.37g, 2.3mmol), compound 1-12-2(0.64g, 2.53mmol), Pd (dppf) Cl 2cH 2cl 2(90mg, 0.115mmol) and KOAc(0.6g, 5.75mmol) be placed in reaction flask, N 2under protection, inject DMF(10mL), 120 ℃ are reacted 4.0 hours.After reacting completely, with EtOAc(100mL) dilute reaction solution, diatomite filtration, filtrate is water (50mL × 3) and saturated common salt water washing respectively, anhydrous sodium sulfate drying, after concentrated, obtain faint yellow solid 0.89g, productive rate: 60% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=4/1).
MS(ESI,pos.ion)m/z:645.4[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.66-7.65,7.64-7.63(m,m,2H),7.59(s,1H),7.23-7.22,7.21-7.20(m,m,2H),4.97-4.93(m,1H),3.64-3.58(m,1H),3.31-3.23(m,1H),2.74-2.66(m,4H),2.59-2.56(m,2H),2.47-2.33(m,3H),2.30-2.29(m,3H),2.27-2.16(m,1H),2.10-1.97(m,2H),1.92-1.82(m,4H),1.53(s,9H),1.33,1.30(m,m,12H)ppm。
Step 5) compound 27-5's is synthetic
By compound 27-4(0.35g, 0.55mmol), compound 2-5(0.2g, 0.55mmol), four triphenyl phosphorus palladiums (32mg, 0.027mmol) and salt of wormwood (0.19g, 1.37mmol) are suspended in EtOH/H 2o(v/v=4/1), in mixed solvent (7.5mL), under nitrogen protection, 90 ℃ are reacted 2.0 hours.After reacting completely, concentration of reaction solution, residuum adds ethyl acetate (50mL) to dissolve, use saturated common salt water washing, anhydrous sodium sulfate drying, obtains faint yellow solid 0.21g, productive rate: 50% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=50/1) after concentrating.
MS(ESI,pos.ion)m/z:754.4[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.66-7.65,7.64-7.63(m,m,2H),7.61-7.60,7.59-7.57(m,m,3H),7.47(s,1H),5.24-5.19(m,1H),4.97-4.93(m,1H),3.64-3.58(m,2H),3.31-3.24(m,2H),2.99-2.95(m,2H),2.88-2.85(m,2H),2.81-2.73(m,2H),2.56-2.31(m,5H),2.30-2.29(m,3H),2.27-2.16(m,2H),2.10-1.87(m,7H),1.53(s,18H)ppm。
Step 6) compound 27-6's is synthetic
By compound 27-5(0.23g, 0.3mmol) be dissolved in EtOAc(4.0mL) in, drip the ethyl acetate solution (3.0mL, 4M) of hydrogenchloride, drip and finish, room temperature reaction 8.0 hours.After reacting completely, concentration of reaction solution, residuum adds after ethyl acetate (4.0mL) making beating, filters and obtains pale yellow powder shape solid 0.19g, productive rate: 90%.Be directly used in next step reaction.
Step 7) compound 27-7's is synthetic
By compound 27-6(0.18g, 0.26mmol), compound 27-6-2(0.12g, 0.57mmol), EDCI(0.11g, 0.57mmol) and HOAT(70mg, 0.52mmol) be suspended in DCM(6.0mL) in, at 0 ℃, slowly splash into DIPEA(0.43mL, 2.6mmol), drip and finish, room temperature reaction 3.0 hours.After reacting completely, add DCM(20mL) dilute reaction solution, use respectively ammonium chloride solution and saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain faint yellow solid 0.19g, productive rate: 78% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=40/1).
MS(ESI,pos.ion)m/z:468.7[M+2H] 2+；
1H?NMR(400MHz,CDCl 3):δ7.66-7.65,7.64-7.63(m,m,2H),7.61-7.59,7.58-7.57(m,m,3H),7.47-7.45(m,2H),7.40(s,1H),7.37-7.27(m,5H),7.23-7.15(m,3H),6.13,6.11(s,s,1H),5.91,5.89(s,s,1H),5.38-5.29(m,3H),5.18-5.13(m,1H),3.91-3.84(m,2H),3.91-3.84(m,2H),3.75-3.67(m,2H),3.64(s,6H),2.99-2.95(m,2H),2.88-2.85(m,2H),2.81-2.73(m,2H),2.51-2.39(m,2H),2.36-2.08(m,9H),2.03-1.87(m,6H)ppm。
Embodiment 28
Figure BDA0000442505360001451
Synthetic route:
Step 1) compound 28-1's is synthetic
At-5 ℃, by sodium hydroxide (1.6g, 40mmol) aqueous solution (1.6mL) slowly splashes into compound 1-6(2.96g, 10mmol), the bromo-3-methylpentane of 1,5-bis-(1.7mL, 11mmol) and TEBAC(0.46g, DMSO(30mL 2.0mmol)) in suspension liquid, 60 ℃ of reactions 8.0 hours.After reacting completely, reaction solution is slowly poured in frozen water (100mL), separated out solid.Filter solid EtOAc(50mL) dissolve, use saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain product 2.63g, productive rate: 70% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=10/1).
MS(ESI,pos.ion)m/z:379.2[M+H] +；
1H?NMR(400MHz,CDCl 3):δ2.68-2.67(m,2H),1.65-1.57(m,2H),1.46-1.33(m,5H),1.10-1.01(m,2H),0.82-0.80(m,3H)ppm。
Step 2) compound 28-2 synthetic
At-5 ℃, by CF 3cOOH(9.0mL, 120mmol) slowly splash into compound 28-1(3.78g, 10mmol), NH 4f(1.11g, 30mmol) and Et 3siH(4.79mL, 30mmol) suspension liquid in, drip finish, 50 ℃ reaction 15 hours.After reacting completely, remove trifluoroacetic acid, residuum EtOAc(100mL) dissolve, use respectively sodium carbonate solution and saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain product 2.02g, productive rate: 56% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=20/1).
MS(ESI,pos.ion)m/z:365.2[M+H] +；
1H?NMR(400MHz,CDCl 3):δ2.74-2.67(m,4H),1.64-1.32(m,7H),1.03-1.00(m,3H),0.89-0.79(m,2H)ppm。
Step 3) compound 28-4's is synthetic
By compound 28-3(5.91g, 29mmol), NBS(5.76g, 32mmol) and p-TSA(1.0g, 5.2mmol) be mixed in reaction flask, 100 ℃ are reacted 0.5 hour.After reacting completely, be chilled to room temperature, add respectively DCM(100mL) and water (50mL) dilute reaction solution, after separatory, DCM(50mL for water layer × 3) extraction, merge organic phase, saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain yellow soup compound 5.72g, productive rate: 70% through column chromatographic isolation and purification (eluent: PE/DCM (v/v)=5/1).
MS(ESI,pos.ion)m/z:285.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.55(d,1H,J=4.0Hz),7.14(d,1H,J=4.0Hz),4.29(s,2H)ppm。
Step 4) compound 28-5's is synthetic
By compound 28-4(5.58g, 19.8mmol) and compound 1-9(4.7g, 21.8mmol) be dissolved in DCM(100mL) in, at 0 ℃, slowly splash into DIPEA(3.62mL, 21.9mmol), drip and finish, room temperature reaction 3.0 hours.After reacting completely, add water (50mL) cancellation reaction, remove DCM, EtOAc(50mL for water layer × 3) extraction, merge organic phase, saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain yellow solid 5.78g, productive rate: 70% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=2/1).
MS(ESI,pos.ion)m/z:418.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.49(d,1H,J=4.0Hz),7.13(t,1H,J=4.0Hz),5.23-5.02(m,2H),4.48-4.37(m,1H),3.60-3.38(m,2H),2.29-2.26(m,2H),2.11-1.92(m,2H),1.44(s,9H)ppm。
Step 5) compound 28-6's is synthetic
By compound 28-5(7.92g, 19mmol) and NH 4oAc(22.2g, 288mmol) be suspended in dimethylbenzene (100mL), react 5.0 hours at 140 ℃.After reacting completely, be chilled to room temperature, add water (100mL) cancellation reaction, EtOAc(100mL for water layer × 3) extraction, merge organic phase, saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain yellow solid 6.94g, productive rate: 92% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=4/1).
MS(ESI,pos.ion)m/z:398.3[M+H] +；
1H?NMR(400MHz,CDCl 3):δ10.51(br,1H),7.07(s,1H),6.94(s,2H),4.91-4.90(m,1H),3.39(s,2H),2.98(s,1H),2.12(s,2H),1.95(s,1H),1.48(s,9H)ppm。
Step 6) compound 28-7's is synthetic
By compound 28-6(1.0g, 2.5mmol), compound 1-12-2(0.96g, 3.8mmol), PdCl 2(dppf) .CH 2cl 2(0.11g, 0.13mmol) and KOAc(0.74g, 7.5mmol) be mixed in reaction flask, under nitrogen protection, add DMF(12mL), 90 ℃ are reacted 4.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(60mL) after dilute reaction solution, diatomite filtration.Filtrate is water (30mL × 3) and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain white solid 0.89g, productive rate: 80% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=3/1).
1H?NMR(400MHz,CDCl 3):δ10.51(br,1H),7.53(s,1H),7.27(s,1H),7.15(s,1H),4.94-4.93(m,1H),3.39(s,2H),2.99(s,1H),2.12-1.94(m,4H),1.49(s,9H),1.34(s,12H),1.24(m,8H)ppm。
Step 7) compound 28-8's is synthetic
By compound 28-7(0.23g, 0.51mmol) be dissolved in ethyl acetate (4.0mL), slowly splash into the ethyl acetate solution (3.0mL, 4M) of hydrogenchloride, drip and finish, room temperature reaction 8.0 hours.After reacting completely, concentration of reaction solution, residuum adds EtOAc(5.0mL) after making beating, filter and obtain faint yellow solid 0.21g, productive rate: 100%.
MS(ESI,pos.ion)m/z:346.2[M+H] +。
Step 8) compound 28-9's is synthetic
By compound 28-8(0.12g, 0.29mmol), compound 1-11-2(0.11g, 0.65mmol), EDCI(0.12g, 0.65mmol) and HOAT(80mg, 0.59mmol) be suspended in DCM(5.0mL) in, at 0 ℃, slowly splash into DIPEA(0.6mL, 3.63mmol), drip and finish, room temperature reaction 3.0 hours.After reacting completely, add DCM(20mL) dilute reaction solution, use respectively ammonium chloride solution and saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain white solid foam 0.12g, productive rate: 80% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=2/1).
MS(ESI,pos.ion)m/z:503.5[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.68,7.67(s,s,1H),7.27(d,1H),7.11(dd,1H),5.56,5.55(d,d,1H),5.42-5.37(m,1H),4.34-4.30(m,1H),3.85-3.78(m,1H),3.66(s,3H),3.65-3.61(m,1H),2.32-1.92(m,5H),1.33,1.30(m,m,12H),1.02,1.00(m,m,3H),0.93,0.91(m,m,3H)ppm。
Step 9) compound 28-10's is synthetic
By compound 28-9(1.70g, 3.4mmol), compound 28-2(1.23g, 3.4mmol), Pd (PPh 3) 4(0.20g, 0.17mmol) and salt of wormwood (1.41g, 10.22mmol) are placed in reaction flask, N 2under protection, inject respectively DME(24mL) and pure water (6mL), 90 ℃ are reacted 4.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(100mL) dilute reaction solution, water and saturated common salt water washing respectively, anhydrous Na 2sO 4dry, after concentrating, obtain faint yellow solid 1.0g, productive rate: 45% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=100/1).
MS(ESI,pos.ion)m/z:660.7[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.40(s,1H),7.04,7.03(d,d,1H),7.01,7.00(s,s,1H),5.42-5.37(m,1H),5.32,5.29(d,d,1H),4.41-4.37(m,1H),3.86-3.79(m,1H),3.69-3.64(m,1H),3.63(s,3H),2.71-2.65(m,4H),2.31-2.05(m,4H),2.02-1.92(m,1H),1.45-1.26(m,7H),1.03-1.00(m,3H),0.97-0.85(m,8H)ppm。
Step 10) compound 28-11's is synthetic
By compound 28-10(1.51g, 2.3mmol), compound 1-12-2(0.64g, 2.53mmol), Pd (dppf) Cl 2cH 2cl 2(90mg, 0.115mmol) and KOAc(0.6g, 5.75mmol) be placed in reaction flask, N 2under protection, inject DMF(10mL), 120 ℃ are reacted 4.0 hours.After reacting completely, with EtOAc(100mL) dilute reaction solution, diatomite filtration, filtrate is water (50mL × 3) and saturated common salt water washing respectively, anhydrous sodium sulfate drying, after concentrated, obtain faint yellow solid 0.97g, productive rate: 60% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=4/1).
MS(ESI,pos.ion)m/z:707.7[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.40(s,1H),7.04,7.03(d,d,1H),6.73,6.72(s,s,1H),5.42-5.37(m,1H),5.32,5.29(d,d,1H),4.41-4.37(m,1H),3.86-3.79(m,1H),3.69-3.64(m,1H),3.63(s,3H),2.66-2.63(m,2H),2.59-2.56(m,2H),2.31-2.05(m,4H),2.02-1.92(m,1H),1.42-1.23(m,19H),1.03-0.95(m,8H),0.90-0.89(m,m,3H)ppm。
Step 11) compound 28-12's is synthetic
By compound 28-11(0.43g, 0.61mmol), compound 2-7(0.25g, 0.61mmol), Pd (PPh 3) 4(70mg, 0.05mmol) and salt of wormwood (0.25g, 1.83mmol) are suspended in EtOH(5mL) with water (1mL) in, under nitrogen protection, 90 ℃ reaction 4.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(50mL) dilute reaction solution, water (20mL × 3) and saturated common salt water washing respectively, anhydrous sodium sulfate drying, obtains product 0.32g, productive rate: 60% through column chromatographic isolation and purification (eluent: EtOAc) after concentrating.
MS(ESI,pos.ion)m/z:437.2[M+2H] 2+；
1H?NMR(400MHz,CDCl 3):δ7.40(s,1H),7.33(s,1H),7.26,7.25(s,s,1H),7.03,7.02(d,d,1H),5.56,5.55(d,d,1H),5.44-5.37(m,2H),5.32,5.29(d,d,1H),4.41-4.37(m,1H),4.34-4.30(m,1H),3.86-3.79(m,2H),3.69-3.67(m,2H),3.66(s,3H),3.63(s,3H),2.98-2.95(m,2H),2.81-2.78(m,2H),2.31-2.05(m,8H),2.02-1.92(m,2H),1.47-1.32(m,5H),1.28-1.22(m,2H),1.03-0.89(m,17H)ppm。
Embodiment 29
Figure BDA0000442505360001491
Synthetic route:
Figure BDA0000442505360001492
Step 1) compound 29-2's is synthetic
By NBS(2.16g, 12mmol) with compound 29-1(2.5g, 10mmol) be dissolved in CCl 4(20mL) in, at 0 ℃, slowly splash into dibenzoyl peroxide (0.24g, 1.0mmol), drip and finish, stirring at room temperature is after 15 minutes, back flow reaction 7.0 hours.After reacting completely, remove CCl 4, residuum EtOAc(100mL) dissolve, water (50mL × 3) and saturated common salt water washing respectively, anhydrous sodium sulfate drying, obtains crude product 3.2g after concentrating, and is directly used in next step reaction.
MS(ESI,pos.ion)m/z:331.8[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.87(s,1H),4.68(s,2H)ppm。
Step 2) compound 29-3 synthetic
By NaH(60%, 3.13g, 78mmol) be suspended in DMF(100mL) in, slowly splash into diethyl malonate (12.54g, 78mmol), to drip and finish, 100 ℃ of reactions were down to room temperature reaction after 40 minutes.Add compound 29-2(11.77g, 35.6mmol), finish, room temperature reaction is after 30 minutes, and 75 ℃ are reacted 1.0 hours.After reacting completely, with saturated ammonium chloride solution (50mL) cancellation reaction, add EtOAc(150mL), separate organic phase, water and saturated common salt water washing respectively, anhydrous sodium sulfate drying, obtains product 14g after concentrating, and is directly used in next step reaction.
1H?NMR(400MHz,CDCl 3):δ7.86(m,1H),4.18-4.13(m,4H),3.91,3.89,3.87(s,d,s,1H),3.57,3.55(dd,dd,2H),1.23,1.21,1.19(s,s,s,6H)ppm。
Step 3) compound 29-4's is synthetic
By compound 29-3(14g) be dissolved in DMSO(100mL) in, under room temperature, slowly add NaCl(4.10g, 70mmol) and water (0.64g, 35.6mmol), after adding, 100 ℃ of reactions 3.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(200mL) dilute reaction solution, use saturated common salt water washing, anhydrous sodium sulfate drying, obtains product 8.0g through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=20/1) after concentrating.
1H?NMR(400MHz,CDCl 3):δ7.72(t,1H),4.08,4.06,4.05,4.03(s,s,s,s,2H),2.96,2.94,2.92(m,m,m,2H),2.75,2.73,2.71(d,m,d,2H),1.22,1.21,1.19(s,s,s,3H)ppm。
Step 4) compound 29-5's is synthetic
By compound 29-4(3.38g, 10mmol) be dissolved in methyl alcohol (20mL), splash into the NaOH aqueous solution (0.8g, 20mL) at 0 ℃, drip and finish, room temperature reaction 3.0 hours.After reacting completely, adjust pH to 5 with dilute hydrochloric acid (1M), remove methyl alcohol, water layer is adjusted pH to 2 with dilute hydrochloric acid (1M), with EtOAc(50mL × 3) extraction, organic phase anhydrous Na 2sO 4dry, after concentrating, obtain white solid 2.79g, productive rate: 90%.
MS(ESI,pos.ion)m/z:312.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ7.75(t,1H),3.01,2.99,2.97(m,m,m,2H),2.91,2.89,2.87(d,m,d,2H)ppm。
Step 5) compound 29-6's is synthetic
At-10 ℃, oxalyl chloride (0.93mL, 11mmol) is slowly splashed into compound 29-5(3.1g, 10mmol) and DCM(40mL DMF(0.05mL)) in solution, drip and finish, room temperature reaction is after 1.0 hours, stand-by without processing.
At-15 ℃, freshly prepd above-claimed cpd (3.32g, 10mmol) is slowly splashed into AlCl 3the DCM(30mL of (1.73g, 13mmol)) in suspension, drip and finish, isothermal reaction 2.0 hours.After reacting completely, reaction solution is slowly poured in frozen water, organic layer is separated, DCM(30mL for water layer × 3) extraction, merge organic phase, respectively with clear water and saturated sodium carbonate solution washing, anhydrous sodium sulfate drying, after concentrated, obtain pale yellow powder 2.33g, productive rate: 80% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=10/1).
MS(ESI,pos.ion)m/z:293.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ3.32,3.30,3.28(d,m,d,2H),2.88,2.86,2.85(d,m,d,2H)ppm。
Step 6) compound 29-7's is synthetic
At-5 ℃, sodium hydroxide (1.6g, the 40mmol) aqueous solution (1.6mL) is slowly splashed into compound 29-6(2.92g, 10mmol), Isosorbide-5-Nitrae-dibromobutane (1.31mL, 11mmol) and TEBAC(0.46g, 2.0mmol) DMSO(30mL) in suspension liquid, 60 ℃ of reactions 8.0 hours.After reacting completely, reaction solution is slowly poured in frozen water (100mL), separated out solid.Filter solid EtOAc(50mL) dissolve, use saturated common salt water washing, anhydrous Na 2sO 4dry, after concentrating, obtain product 1.72g, productive rate: 50% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=10/1).
MS(ESI,pos.ion)m/z:347.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ3.20-3.18(m,2H),2.06-1.94(m,2H),1.84-1.64(m,4H),1.37-1.27(m,2H)ppm。
Step 7) compound 29-8's is synthetic
At-5 ℃, by CF 3cOOH(9.0mL, 120mmol) slowly splash into compound 29-7(3.46g, 10mmol), NH 4f(1.11g, 30mmol) and Et 3siH(4.79mL, 30mmol) suspension liquid in, drip finish, 50 ℃ reaction 15 hours.After reacting completely, remove trifluoroacetic acid, residuum EtOAc(100mL) dissolve, use respectively sodium carbonate solution and saturated common salt water washing, anhydrous sodium sulfate drying, after concentrated, obtain product 2.15g, productive rate: 65% through column chromatographic isolation and purification (eluent: PE/EtOAc (v/v)=20/1).
MS(ESI,pos.ion)m/z:333.1[M+H] +；
1H?NMR(400MHz,CDCl 3):δ3.07-3.04(m,4H),1.81-1.49(m,8H)ppm。
Step 8) compound 29-9's is synthetic
By compound 29-8(33mg, 0.1mmol), compound 3-5(104mg, 0.21mmol), Pd (PPh 3) 4(12mg, 0.01mmol) and salt of wormwood (34.5mg, 0.25mmol) are suspended in DME(2mL) with water (0.4mL) in, under nitrogen protection, 90 ℃ reaction 4.0 hours.After reacting completely, be chilled to room temperature, add EtOAc(20mL) dilute reaction solution, water (10mL × 3) and saturated common salt water washing respectively, anhydrous sodium sulfate drying, after concentrated, obtain product 45.5mg, productive rate: 50% through column chromatographic isolation and purification (eluent: DCM/MeOH (v/v)=50/1).
MS(ESI,pos.ion)m/z:456.2[M+2H] 2+；
1H?NMR(400MHz,CDCl 3):δ8.07-8.06,8.04-8.03(m,m,4H),7.87-7.86,7.85-7.84(m,m,4H),7.59(s,2H),5.32,5.29(d,d,2H),5.23-5.19(m,1H),4.41-4.40,4.39-4.38,4.37-4.36(m,m,m,2H),3.85-3.78(m,2H),3.69-3.64(m,2H),3.63(s,6H),2.87-2.85(m,4H),2.30-1.92(m,10H),1.75-1.43(m,8H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H)ppm。
Embodiment 30
Figure BDA0000442505360001511
Synthetic route:
Figure BDA0000442505360001521
Embodiment 30 prepares according to the synthetic method of similar embodiment 1.
Compound 30-2:MS (ESI, pos.ion) m/z:367.3[M+H] +;
1H?NMR(400MHz,CDCl 3):δ7.68(s,1H),7.42-7.40(m,1H),7.30-7.28(m,1H),5.11-5.09(m,1H),3.45-3.43(m,2H),2.94-2.93(m,1H),2.21-2.18(m,2H),2.01-1.91(m,1H),1.49(s,9H)ppm。
Compound 30-3:MS (ESI, pos.ion) m/z:266.1[M+H] +.
Compound 30-4:MS (ESI, pos.ion) m/z:423.1[M+H] +;
1H?NMR(400MHz,CDCl 3):δ7.59-7.51(m,1H),7.34-7.21(m,2H),5.42-5.38(m,2H),4.34-4.30(m,1H),3.87-3.76(m,1H),3.70(s,3H),3.66-3.62(m,1H),3.04-2.98(m,1H),2.25-2.21(m,1H),2.20-2.13(m,2H),1.96-1.94(m,1H),0.88-0.84(m,6H)ppm。
Compound 30-5:MS (ESI, pos.ion) m/z:471.3[M+H] +;
1H?NMR(400MHz,CDCl 3):δ7.87-7.80(m,1H),7.71-7.66(m,2H),5.47-5.42(m,2H),4.34-4.30(m,1H),3.86-3.84(m,1H),3.70(s,3H),3.64-3.62(m,1H),3.04-2.98(m,1H),2.25-2.21(m,1H),2.20-2.13(m,2H),1.96-1.94(m,1H),1.35(s,12H),0.88-0.84(m,6H)ppm。
Compound 30-6:MS (ESI, pos.ion) m/z:864.1[M+H] +;
1H?NMR(400MHz,CDCl 3):δ7.67(q,2H),7.59,7.57(d,d,2H),7.40,7.38(d,d,2H),5.56,5.55(d,d,1H),5.32,5.29(d,d,1H),5.24-5.20(m,2H),4.40-4.32(m,2H),3.84-3.78(m,2H),3.66(s,3H),3.65-3.64(m,2H),3.63(s,3H),2.84-2.82(m,4H),2.39-2.10(m,8H),2.01-1.86(m,4H),1.73-1.52(m,4H),1.50-1.40(m,2H),1.28-1.18(m,2H),1.02-0.89(m,12H)ppm。
Embodiment 31
Figure BDA0000442505360001531
Synthetic route:
Figure BDA0000442505360001532
Embodiment 31 prepares according to the synthetic method of similar embodiment 2.
Compound 31-1: 1h NMR (400MHz, CDCl 3): δ 3.99-3.87 (br, 1H), 3.68-3.51 (m, 2H), 3.48-3.39 (m, 1H), 3.34-3.25 (m, 1H), 2.05-1.92 (m, 2H), 1.88-1.71 (m, 2H), 1.45 (s, 9H) ppm.
Compound 31-2: 1h NMR (400MHz, CDCl 3): δ 9.46 (d, 1H, J=2.8Hz), 4.08-4.03 (m, 1H), 3.51-3.42 (m, 2H), 2.01-1.93 (m, 2H), 1.91-1.84 (m, 2H), 1.43 (s, 9H) ppm.
Compound 31-3:MS (ESI, pos.ion) m/z:238.2[M+H] +;
1H?NMR(400MHz,CDCl 3):δ6.96(s,1H),4.94(dd,1H,J=7.68Hz,2.40Hz),3.38(t,2H,J=6.24Hz),2.17-2.03(m,2H),1.99-1.91(m,2H),1.48(s,9H)ppm。
Compound 31-4:MS (ESI, pos.ion) m/z:490.1[M+H] +;
1H?NMR(400MHz,CDCl 3):δ4.89(dd,1H,J=7.64Hz,2.52Hz),3.36(t,2H),2.14-2.02(m,2H),1.97-1.85(m,2H),1.49(s,9H)ppm。
Compound 31-5:MS (ESI, pos.ion) m/z:364.1[M+H] +;
1H?NMR(400MHz,CDCl 3):δ7.04(d,1H,J=1.84Hz),4.89(dd,1H,J=7.72Hz,2.56Hz),3.36(t,2H),2.18-2.03(m,2H),1.97-1.82(m,2H),1.47(s,9H)ppm。
Compound 31-6:MS (ESI, pos.ion) m/z:264.1[M+H] +.
Compound 31-7:MS (ESI, pos.ion) m/z:421.1[M+H] +;
1H?NMR(400MHz,CDCl 3):δ7.35(s,1H),5.32,5.29(brs,brs,1H),5.20-5.15(m,1H),4.41-4.37(m,1H),3.85-3.78(m,1H),3.69-3.65(m,1H),3.63(s,3H),2.28-2.17(m,3H),2.11-1.96(m,2H),0.97-0.95(m,3H),0.91-0.89(m,3H)ppm。
Compound 31-8:MS (ESI, pos.ion) m/z:391.5[M+H] +;
1H?NMR(400MHz,CDCl 3):δ7.27(s,1H),5.32,5.30(d,d,1H),5.29-5.24(m,1H),4.41-4.36(m,1H),3.89-3.83(m,1H),3.73-3.65(m,1H),3.63(s,3H),2.31-1.93(m,5H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H),0.32(m,9H)ppm。
Compound 31-9:MS (ESI, pos.ion) m/z:319.5[M+H] +;
1H?NMR(400MHz,CDCl 3):δ7.27(s,1H),5.35-5.31(m,1.5H),5.30-5.29(d,0.5H,J=4.0Hz),4.41-4.36(m,1H),3.89-3.83(m,1H),3.73-3.66(m,1H),3.63(s,3H),3.36(s,1H),2.31-1.93(m,5H),0.97,0.95(m,m,3H),0.90,0.89(m,m,3H)ppm。
Compound 31-10:MS (ESI, pos.ion) m/z:811.4[M+H] +;
1H?NMR(400MHz,CDCl 3):δ7.48(s,2H),5.51-5.47(m,2H),5.32,5.30(d,d,2H),4.41-4.36(m,1H),3.89-3.83(m,2H),3.73-3.66(m,2H),3.63(s,6H),3.12-3.10(m,4H),2.32-1.92(m,10H),1.79-1.58(m,4H),1.53-1.43(m,2H),1.32-1.22(m,2H),0.97,0.95(m,m,6H),0.90,0.89(m,m,6H)ppm。
Embodiment 32
Figure BDA0000442505360001541
Synthetic route:
Figure BDA0000442505360001542
Embodiment 32 prepares according to the synthetic method of similar embodiment 18.
Compound 31-1:MS (ESI, pos.ion) m/z:858.5[M+H] +;
1H?NMR(400MHz,CDCl 3):δ8.70-8.69(dd,1H),7.87-7.86(q,1H),7.76,7.73(d,d,1H),7.66,7.64(d,d,1H),7.62-7.61(q,1H),7.57,7.55(d,d,1H),7.53,7.51(d,d,1H),6.08,6.05(d,d,1H),5.32,5.29(d,d,1H),5.24-5.20(m,2H),4.40-4.32(m,2H),3.84-3.78(m,2H),3.68-3.66(m,2H),3.65(s,3H),3.63(s,3H),3.14-3.11(m,2H),2.94-2.91(m,2H),2.38-2.10(m,8H),2.01-1.86(m,2H),1.71-1.51(m,6H),1.49-1.39(m,2H),1.02,1.00(m,m,3H),0.97,0.95(m,m,3H),0.93,0.91(m,m,3H),0.90,0.89(m,m,3H)ppm。
Embodiment 33
Figure BDA0000442505360001551
Synthetic route:
Embodiment 33 prepares according to the synthetic method of similar embodiment 28.
Compound 33-1:MS (ESI, pos.ion) m/z:418.3[M+H] +;
1H?NMR(400MHz,CDCl 3):δ7.49(d,1H,J=4.0Hz),7.13(t,1H,J=4.0Hz),5.23-5.02(m,2H),4.48-4.37(m,1H),3.60-3.38(m,2H),2.29-2.26(m,2H),2.11-1.92(m,2H),1.44(s,9H)ppm。
Compound 33-2:MS (ESI, pos.ion) m/z:398.3[M+H] +;
1H?NMR(400MHz,CDCl 3):δ10.51(br,1H),7.07(s,1H),6.94(s,2H),4.91-4.90(m,1H),3.39(s,2H),2.98(s,1H),2.12(s,2H),1.95(s,1H),1.48(s,9H)ppm。
Compound 33-3: 1h NMR (400MHz, CDCl 3): δ 10.51 (br, 1H), 7.53 (s, 1H), 7.27 (s, 1H), 7.15 (s, 1H), 4.94-4.93 (m, 1H), 3.39 (s, 2H), 2.99 (s, 1H), 2.12-1.94 (m, 4H), 1.49 (s, 9H), 1.34 (s, 12H), 1.24 (m, 8H) ppm.
Compound 33-4:MS (ESI, pos.ion) m/z:346.2[M+H] +.
Compound 33-5:MS (ESI, pos.ion) m/z:503.5[M+H] +;
1H?NMR(400MHz,CDCl 3):δ7.68,7.67(s,s,1H),7.27(d,1H),7.11(dd,1H),5.56,5.55(d,d,1H),5.42-5.37(m,1H),4.34-4.30(m,1H),3.85-3.78(m,1H),3.66(s,3H),3.65-3.61(m,1H),2.32-1.92(m,5H),1.33,1.30(m,m,12H),1.02,1.00(m,m,3H),0.93,0.91(m,m,3H)ppm。
Compound 33-6:MS (ESI, pos.ion) m/z:660.7[M+H] +;
1H?NMR(400MHz,CDCl 3):δ7.40(s,1H),7.04,7.03(d,d,1H),7.01,7.00(s,s,1H),5.42-5.37(m,1H),5.32,5.29(d,d,1H),4.41-4.37(m,1H),3.86-3.79(m,1H),3.69-3.64(m,1H),3.63(s,3H),2.71-2.65(m,4H),2.31-2.05(m,4H),2.02-1.92(m,1H),1.45-1.26(m,7H),1.03-1.00(m,3H),0.97-0.85(m,8H)ppm。
Compound 33-7:MS (ESI, pos.ion) m/z:707.7[M+H] +;
1H?NMR(400MHz,CDCl 3):δ7.40(s,1H),7.04,7.03(d,d,1H),6.73,6.72(s,s,1H),5.42-5.37(m,1H),5.32,5.29(d,d,1H),4.41-4.37(m,1H),3.86-3.79(m,1H),3.69-3.64(m,1H),3.63(s,3H),2.66-2.63(m,2H),2.59-2.56(m,2H),2.31-2.05(m,4H),2.02-1.92(m,1H),1.42-1.23(m,19H),1.03-0.95(m,8H),0.90-0.89(m,m,3H)ppm。
Compound 33-8:MS (ESI, pos.ion) m/z:437.2[M+2H] 2+;
1H?NMR(400MHz,CDCl 3):δ7.40(s,1H),7.33(s,1H),7.26,7.25(s,s,1H),7.03,7.02(d,d,1H),5.56,5.55(d,d,1H),5.44-5.37(m,2H),5.32,5.29(d,d,1H),4.41-4.37(m,1H),4.34-4.30(m,1H),3.86-3.79(m,2H),3.69-3.67(m,2H),3.66(s,3H),3.63(s,3H),2.98-2.95(m,2H),2.81-2.78(m,2H),2.31-2.05(m,8H),2.02-1.92(m,2H),1.47-1.32(m,5H),1.28-1.22(m,2H),1.03-0.89(m,17H)ppm。
Biologic activity
In order to verify the effect of compound as herein described to HCV, contriver adopts HCV Replicate Sub-system (HCV Replicon System) as evaluation model.HCV replicon reported first is in Science.1999Jul2; 285 (5424), 110-3.HCV Replicate Sub-system has become one of most important instrument of research HCV rna replicon, pathogenic and viral persistence, for example utilized replicon successfully to prove the necessary 5'-NCR Minimum Area of HCV rna replicon, and HCV Replicate Sub-system is successfully used as the evaluation model of antiviral.The present inventor is according to Science.1999Jul2; 285 (5424), 110-3, and J.Virol.2003Mar; 77 (5), 3007-19(is by with reference to being incorporated to herein) described method verifies.
In brief, contriver adopts the Bel7402 Huh-7 of stable transfection HCV genotype GT1a, GT1b respectively or GT2a replicon to test compound as herein described, and adopt Y93H respectively, L31F, P32L, I302V resistant mutants and wild-type HCV1b test compound as herein described.The HCV Replicate Sub-system that used in this article comprises G418 resistant gene NEO and luciferase reporter gene, the levels of replication of HCV in host cell can be characterized by the expression amount of the expression amount of NEO gene or luciferase gene, and then compound described herein can be assessed the action effect of HCV virus replication.In this article, detect the expression amount of NEO gene by real-time quantitative polymerase chain reaction (qPCR), detect the expression amount of luciferase gene by chemoluminescence method.Operating process brief introduction:
1. measure compd E C based on uciferase activity 50:
The Huh-7 cell of transfection HCV Replicate Sub-system is seeded in 96 orifice plates, in each hole, contains 8000 cells.Respectively compound as herein described is carried out to 5 times of gradient dilutions, obtain 10 concentration gradients.Compound as herein described is joined to the hole of the Huh-7 cell that contains transfection HCV Replicate Sub-system, in CO2gas incubator, hatch 72 hours.Xiang Kongzhong adds 40 microlitre luciferase luminous substrate Bright-Glo (Promega company), after 5 minutes, utilize chemiluminescence detection system Topcount microwell plate liquid shwoot light calculating instrument to detect, and utilize respectively GraphPad Prism software to determine the EC of each compound 50(half-maximal effect concentration, concentration for50%of maximal effect).In this article, carry out two batches for the experiment of each compound, and the hole of not adding compound is set as negative control.
2.qPCR detect antibiotics G418 resistant gene NEO genetic testing compd E C 50:
The Huh-7 cell of transfection HCV Replicate Sub-system is seeded in 96 orifice plates, in each hole, contains 8000 cells.Respectively compound as herein described is carried out to 5 times of gradient dilutions, obtain 10 concentration gradients.Compound as herein described is joined to the hole of the Huh-7 cell that contains transfection HCV Replicate Sub-system, in CO2gas incubator, hatch 72 hours.React the expression amount of determining NEO gene by qPCR, and utilize respectively GraphPad Prism software to determine the EC of each compound 50(half-maximal effect concentration, concentration for50%of maximal effect).In this article, carry out two batches for the experiment of each compound, and the hole of not adding compound is set as negative control.
3. result
Based on determined EC above 50, can determine that compound as herein described can suppress HCV genotype 1a, 1b, 2a, 2b, 3a, 3b, 4a, 5a and 6a effectively.Wherein, for the EC of HCV genotype 1b 50scope is 1pm～99nM.Table 2 provides content representative compound of the present invention for HCV1a and the genotypic EC of HCV1b 50value (nM), this EC 50value is based on uciferase activity and definite.
Table 2
Embodiment 1a(nM) 1b(nM) Embodiment 1a(nM) 1b(nM) Embodiment 1a(nM) 1b(nM)
1 0.103 0.025 12 23.763 0.775 23 0.332 0.084
2 1.602 0.073 13 18.643 0.679 24 0.858 0.094
3 3.687 0.039 14 2.875 0.274 25 0.116 0.062
4 0.082 0.021 15 1.682 0.362 26 15.682 0.438
5 0.206 0.051 16 0.306 0.058 27 9.679 0.783
6 2.937 0.089 17 0.083 0.030 28 26.835 1.667
7 5.726 0.182 18 0.217 0.044 29 2.784 0.532
8 0.032 0.009 19 0.429 0.036 30 0.658 0.094
9 7.580 0.231 20 0.068 0.015 31 3.685 0.103
10 10.562 0.355 21 1.672 0.408 32 0.062 0.028
11 9.524 0.624 22 0.068 0.023 33 15.682 0.438
According to the experimental result of Y93H, L31F, P32L, I302V resistant mutants and wild-type HCV1b, the result of simulating by molecule modeling, in conjunction with computer aided design (CAD), prove that the compound of content of the present invention passes through to suppress the mechanism of HCV NS5A albumen, has brought into play superior anti-hepatitis C virus effect.
It will be apparent to one skilled in the art that content of the present invention is not limited to above stated specification embodiment, and can be embodied in other specific form and don't depart from its essential characteristics.Therefore, expect that each embodiment is considered in all respects illustrative and nonrestrictive, should be with reference to appended claims, rather than front this embodiment, therefore, all changes in implication and the scope of appended claims equivalents are all included in herein.
The compound of content of the present invention can by except NS5A suppresses or the mechanism that is different from NS5A inhibition suppress HCV.In one embodiment, the compound of content of the present invention suppresses HCV replicon, and in another embodiment, the compound of content of the present invention suppresses NS5A.The compound of content of the present invention can suppress the Multi-genotype of HCV.
In the description of this specification sheets, the description of reference term " embodiment ", " some embodiment ", " example ", " concrete example " or " some examples " etc. means to be contained at least one embodiment of the present invention or example in conjunction with specific features, structure, material or the feature of this embodiment or example description.In this manual, the schematic statement of above-mentioned term is not necessarily referred to identical embodiment or example.And specific features, structure, material or the feature of description can be with suitable mode combination in any one or more embodiment or example.
Although illustrated and described embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, those of ordinary skill in the art can change above-described embodiment within the scope of the invention in the situation that not departing from principle of the present invention and aim, modification, replacement and modification, and scope of the present invention is limited by claim and equivalent thereof.

Claims (62)

1. a compound, it is steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or the prodrug of compound shown in the compound shown in formula (I) or formula (I)
Figure FDA0000442505350000011
Wherein, each A and A ' are a key, alkylidene group, alkenylene, cycloalkylidene, sub-Heterocyclylalkyl ,-(CR independently 8r 8a) n-O-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-C (=O)-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-O-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-S (=O) r-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-O-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=S)-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-C (=O)-O-(CR 8r 8a) p-, or each A and A ' are following group independently:
Figure FDA0000442505350000012
Wherein, each X 1or X 2be O, S, NR independently 6or CR 7r 7a;
X 4for (CR 7r 7a) n,-Y 1=N-, O, S or NR 6;
W is carbocylic radical or heterocyclic radical;
Each Y 1and Y 2be N or CR independently 7;
Z is-(CH 2) a-,-CH=CH-,-N=CH-,-(CH 2) a-N (R 5)-(CH 2) b-or-(CH 2) a-O-(CH 2) b-;
Wherein each a and b are 0,1,2 or 3 independently;
Each c is 1 or 2 independently;
Each d is 1 or 2 independently;
Each n is 0,1,2 or 3 independently;
Each p is 0,1,2 or 3 independently;
Each r is 0,1 or 2 independently;
F is 0,1,2,3 or 4;
Each Q 1and Q 2be NR independently 6, O, S, C (=O) or (CR 7r 7a) e;
Each e is 0,1,2,3 or 4 independently;
Each X and X ' are N or CR independently 7;
Each Y and Y ' are the optically active isomer of H, deuterium, alkyl, assorted alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, a-amino acid group or a-amino acid group independently, or each Y and Y ' are following structural unit independently :-[U-(CR 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12,-U-(CR 9r 9a) t-R 12or-[U-(CR 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-O-(CR 9r 9a) t-R 12;
Each U is independently-C (=O)-,-C (=S)-,-S (=O)-or-S (=O) 2-;
Each t is 0,1,2,3 or 4 independently;
Each k is 0,1 or 2 independently;
Each R 1, R 2, R 3and R 4be H, deuterium, alkyl, assorted alkyl, aralkyl, cycloalkyl, heterocyclic radical, heteroaryl or aryl independently, or R 1, R 2form 3-8 unit heterocycle or 3-8 unit carbocyclic ring, C with X-CH 5-12condensed-bicyclic, C 5-12condense assorted dicyclo, C 5-12spiral shell dicyclo or C 5-12the spiral shell dicyclo of mixing; Or R 3, R 4and X '-CH forms 3-8 unit's heterocycle or carbocyclic ring, C 5-12condensed-bicyclic, C 5-12condense assorted dicyclo, C 5-12spiral shell dicyclo or C 5-12the spiral shell dicyclo of mixing;
Each R 5be independently H, deuterium, hydroxyl, alkyl, assorted alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alkoxyl group, alkyl-OC (=O)-, alkyl-C (=O)-, formamyl, alkyl-OS (=O) r-, alkyl-S (=O) ro-, alkyl-S (=O) r-or amino-sulfonyl;
Each R 5abe H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, R independently 13ar 13n-,-C (=O) NR 13r 13a,-OC (=O) NR 13r 13a,-OC (=O) OR 13,-N (R 13) C (=O) NR 13r 13a,-N (R 13) C (=O) OR 13,-N (R 13) C (=O)-R 13, R 13r 13an-S (=O) 2-, R 13s (=O) 2-, R 13s (=O) 2n (R 13a)-, R 13ar 13n-alkyl, R 13s (=O)-alkyl, R 13r 13an-C (=O)-alkyl, R 13ar 13n-alkoxyl group, R 13s (=O)-alkoxyl group, R 13r 13an-C (=O)-alkoxyl group, aryl, heteroaryl, alkoxyl group, alkylamino, alkyl, haloalkyl, thiazolinyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aralkyl, virtue is amino, heteroaryl amino, aryl alkane amino, heteroaryl alkylamino, heteroaryl oxygen base, heteroarylalkyl, alkoxy aryl, heteroaryl alkoxyl group, heterocyclyloxy base, heterocyclic radical alkoxyl group, heterocyclic radical amino, alkyl acyl, alkyl acyloxy, alkoxyl group acyl group, alkyl sulphonyl, alkoxyl group alkylsulfonyl, alkyl sulphinyl, alkyl sulphonyl oxygen base, alkyl sulphinyl oxygen base, heterocyclic radical alkylamino or aryloxy,
Each R 6be hydrogen, deuterium, R independently 13r 13anC (=O)-, R 13oC (=O)-, R 13c (=O)-, R 13r 13anS (=O)-, R 13oS (=O)-, R 13s (=O)-, R 13r 13anS (=O) 2-, R 13oS (=O) 2-, R 13s (=O) 2-, the amino aliphatics of aliphatics, halogenated aliphatic, hydroxyl group aliphatic, amino aliphatics, alkoxyl group aliphatics, alkylamino aliphatics, alkylthio aliphatics, aromatic yl aliphat, heteroaryl aliphatics, heterocyclic radical aliphatics, cycloalkyl aliphatics, aryloxy aliphatics, heterocyclyloxy base aliphatics, cycloalkyl oxy aliphatics, fragrant amino aliphatics, heterocyclic radical, cycloalkyl amino aliphatics, aryl, heteroaryl, heterocyclic radical or carbocylic radical;
Each R 6abe H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, oxo (=O), R independently 13ar 13n-,-C (=O) NR 13r 13a,-OC (=O) NR 13r 13a,-OC (=O) OR 13,-N (R 13) C (=O) NR 13r 13a,-N (R 13) C (=O) OR 13a,-N (R 13) C (=O)-R 13a, R 13r 13an-S (=O) 2-, R 13s (=O) 2-, R 13s (=O) 2n (R 13a)-, R 13ar 13n-alkyl, R 13s (=O)-alkyl, R 13r 13an-C (=O)-alkyl, R 13ar 13n-alkoxyl group, R 13s (=O)-alkoxyl group, R 13r 13an-C (=O)-alkoxyl group, aryl, heteroaryl, alkoxyl group, alkylamino, alkyl, haloalkyl, thiazolinyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aralkyl, virtue is amino, heteroaryl amino, aryl alkane amino, heteroaryl alkylamino, heteroaryl oxygen base, heteroarylalkyl, alkoxy aryl, heteroaryl alkoxyl group, heterocyclyloxy base, heterocyclic radical alkoxyl group, heterocyclic radical amino, alkyl acyl, alkyl acyloxy, alkoxyl group acyl group, alkyl sulphonyl, alkoxyl group alkylsulfonyl, alkyl sulphinyl, alkyl sulphonyl oxygen base, alkyl sulphinyl oxygen base, heterocyclic radical alkylamino or aryloxy,
Each R 7and R 7abe H independently, deuterium, F, Cl, Br, I, aliphatics, assorted alkyl, halogenated aliphatic, hydroxyl group aliphatic, amino aliphatics, alkoxyl group aliphatics, alkylamino aliphatics, alkylthio aliphatics, aromatic yl aliphat, heteroaryl aliphatics, heterocyclic radical aliphatics, cycloalkyl aliphatics, aryloxy aliphatics, heterocyclyloxy base aliphatics, cycloalkyl oxy aliphatics, the amino aliphatics of virtue, the amino aliphatics of heterocyclic radical, cycloalkyl amino aliphatics, aryl, heteroaryl, heterocyclic radical or carbocylic radical,
Each R 8and R 8abe independently H, deuterium, hydroxyl, cyano group, nitro, F, Cl, Br, I, alkyl, assorted alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alkoxyl group, alkyl-OC (=O)-, alkyl-C (=O)-, formamyl, alkyl-OS (=O) r-, alkyl-S (=O) ro-, alkyl-S (=O) r-or amino-sulfonyl;
Each R 9, R 9a, R 10and R 11be H, deuterium, alkyl, assorted alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, haloalkyl, hydroxyalkyl, heteroarylalkyl, heterocyclic radical alkyl or cycloalkyl alkyl independently;
Each R 12be R independently 13ar 13n-,-C (=O) R 13,-C (=S) R 13,-C (=O)-O-R 13,-C (=O) NR 13r 13a,-OC (=O) NR 13r 13a,-OC (=O) OR 13,-N (R 13) C (=O) NR 13r 13a,-N (R 13) C (=O) OR 13a,-N (R 13) C (=O)-R 13a, R 13r 13an-S (=O) 2-, R 13s (=O) 2-, R 13s (=O) 2n (R 13a)-, R 13oS (=O) 2-, alkyl, assorted alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or aralkyl;
Or R 11, R 12can at random form 4-7 ring with the atom being attached thereto; With
With each R 13and R 13abe H, deuterium, alkyl, assorted alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or aralkyl independently; Work as R 13and R 13abe connected on same nitrogen-atoms R 13, R 13acan at random form substituted or non-substituted 3-8 ring, spiral shell dicyclo or condensed-bicyclic with nitrogen-atoms;
Wherein each following group: alkylidene, alkenylene, cycloalkylidene, sub-Heterocyclylalkyl ,-(CR 8R 8a) n-O-(CR 8R 8a) p-,-(CR 8R 8a) n-N (R 5)-(CR 8R 8a) p-,-(CR 8R 8a) n-S (=O) r-N (R 5)-(CR 8R 8a) p-,-(CR 8R 8a) n-C (=O)-N (R 5)-(CR 8R 8a) p-,-(CR 8R 8a) n-N (R 5)-C (=O)-N (R 5)-(CR 8R 8a) p-,-(CR 8R 8a) n-C (=O)-O-(CR 8R 8a) p-,-(CR 8R 8a) n-N (R 5)-S (=O) r-N (R 5)-(CR 8R 8a) p-,-(CR 8R 8a) n-S (=O) r-(CR 8R 8a) p-,-(CR 8R 8a) n-S (=O) r-O-(CR 8R 8a) p-,-(CR 8R 8a) n-C (=O)-(CR 8R 8a) p-,-(CR 8R 8a) n-C (=S)-(CR 8R 8a) p-,-(CR 8R 8a) n-N (R 5)-C (=O)-O-(CR 8R 8a) p-,-[U-(CR 9R 9a) t-N (R 10)-(CR 9R 9a) t] k-U-(CR 9R 9a) t-N (R 11)-(CR 9R 9a) t-R 12,-U-(CR 9R 9a) t-R 12,-[U-(CR 9R 9a) t-N (R 10)-(CR 9R 9a) t] k-U-(CR 9R 9a) t-O-(CR 9R 9a) t-R 12, NR 6, CR 7R 7a, CR 7,-(CH 2) a-,-CH=CH-,-N=CH-,-(CH 2) a-N (R 5)-(CH 2) b-,-(CH 2) a-O-(CH 2) b-, R 13aR 13N-,-C (=O) R 13,-C (=S) R 13,-C (=O)-O-R 13,-C (=O) NR 13R 13a,-OC (=O) NR 13R 13a,-OC (=O) OR 13,-N (R 13) C (=O) NR 13R 13a,-N (R 13) C (=O) OR 13a,-N (R 13) C (=O)-R 13a, R 13R 13aN-S (=O) 2-, R 13S (=O) 2-, R 13S (=O) 2N (R 13a)-, R 13OS (=O) 2-, alkyl-OC (=O)-, alkyl-C (=O)-, alkyl-OS (=O) r-, alkyl-S (=O) rO-, alkyl-S (=O) r-, R 13R 13aNS (=O)-, R 13OS (=O)-, R 13S (=O)-, alkyl, R 13S (=O)-alkyl, R 13R 13aN-C (=O)-alkyl, R 13aR 13N-alkoxyl, R 13S (=O)-alkoxyl, R 13R 13aN-C (=O)-alkylamino, alkyl, assorted alkyl, carbocylic radical, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, a-amino acid, C 5-12condensed-bicyclic, C 5-12condense assorted dicyclo, C 5-12spiral shell dicyclo or C 5-12the spiral shell dicyclo of mixing, alkoxyl, aliphatic, halogenated aliphatic, hydroxyl group aliphatic, amino aliphatic, alkoxyl aliphatic, alkylamino aliphatic, alkylthio group aliphatic, aromatic yl aliphat, heteroaryl aliphatic, heterocyclic radical aliphatic, cycloalkyl aliphatic, aryloxy group aliphatic, heterocyclyloxy base aliphatic, cycloalkyl oxy aliphatic, the amino aliphatic of virtue, the amino aliphatic of heterocyclic radical, cycloalkyl amino aliphatic, haloalkyl, thiazolinyl, alkynyl, virtue is amino, heteroaryl amino, aryl alkane amino, heteroaryl alkylamino,Heteroaryl oxygen base, heteroaryl alkyl, alkoxy aryl, heteroaryl alkoxyl, heterocyclyloxy base, heterocyclic radical alkoxyl, heterocyclic radical amino, heterocyclic radical alkylamino or aryloxy group can be optionally by one or more deuteriums that are selected from, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl, alkylamino, alkylthio group, alkyl, thiazolinyl, alkynyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, heteroaryloxy, oxo (=O), carboxyl, the alkoxyl that hydroxyl replaces, hydroxyl replace alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O) 2-, hydroxyl replace alkyl-S (=O)-, hydroxyl replace alkyl-S (=O) 2-or the substituting group of carboxyl alkoxyl replace.
2. compound according to claim 1, wherein W is C 3-8carbocylic radical or C 2-10heterocyclic radical.
3. compound according to claim 1, wherein
Figure FDA0000442505350000051
structural unit is selected from following minor structure formula:
Figure FDA0000442505350000052
Wherein, each X 3and X 5be O, S, NR independently 6, C (=O) or CR 7r 7a;
Each X 6be CR independently 7r 7a,-Y 1=N-, O, S or NR 6;
Each Y 1be N or CR independently 7;
Each f is 0,1,2,3 or 4 independently;
Each Q 1and Q 2be NR independently 6, O, S, C (=O) or (CR 7r 7a) e;
E is 0,1,2,3 or 4;
Each R 5abe H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, C independently 1-6alkyl acyl, C 1-6alkyl acyloxy, C 1-6alkoxyl group acyl group, C 1-6alkyl sulphonyl, C 1-6alkoxyl group alkylsulfonyl, C 1-6alkyl sulphinyl, C 1-6alkyl sulphonyl oxygen base, C 1-6alkyl sulphinyl oxygen base, C 1-6alkoxyl group, C 1-6alkyl, C 6-10aryl ,-CF 3,-OCF 3, sulfydryl, nitro, C 1-6alkylamino, C 3-10cycloalkyl or C 6-10aryloxy;
Each R 6be hydrogen, deuterium, R independently 13r 13anC (=O)-, R 13oC (=O)-, R 13c (=O)-, R 13r 13anS (=O)-, R 13oS (=O)-, R 13s (=O)-, R 13r 13anS (=O) 2-, R 13oS (=O) 2-, R 13s (=O) 2-, C 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6aminoalkyl group, C 1-6alkoxy C 1-6alkyl, C 1-6alkylamino C 1-6alkyl, C 1-6alkylthio C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl, C 3-10cycloalkyl C 1-6alkyl, C 6-10aryloxy C 1-6alkyl, C 2-10heterocyclyloxy base C 1-6alkyl, C 3-10cycloalkyl oxy C 1-6alkyl, C 6-10the amino C of virtue 1-6alkyl, C 2-10the amino C of heterocyclic radical 1-6alkyl, C 3-10cycloalkyl amino C 1-6alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical or C 3-10carbocylic radical;
With each R 7and R 7abe H, deuterium, F, Cl, Br, I, C independently 1-6alkyl, C 2-6assorted alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6aminoalkyl group, C 1-6alkoxy C 1-6alkyl, C 1-6alkylamino C 1-6alkyl, C 1-6alkylthio C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl, C 3-10cycloalkyl C 1-6alkyl, C 6-10aryloxy C 1-6alkyl, C 2-10heterocyclyloxy base C 1-6alkyl, C 3-10cycloalkyl oxy C 1-6alkyl, C 6-10the amino C of virtue 1-6alkyl, C 2-10the amino C of heterocyclic radical 1-6alkyl, C 3-10cycloalkyl amino C 1-6alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical or C 3-10carbocylic radical.
4. compound according to claim 1, wherein,
Figure FDA0000442505350000061
structural unit is selected from following minor structure formula:
Figure FDA0000442505350000071
Wherein, X 6for O, S ,-Y 1=N-, NR 6or CR 7r 7a;
Each Y 1be N or CH independently;
Each f is 0,1,2,3 or 4 independently;
Each R 5abe H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, C independently 1-6alkyl acyl, C 1-6alkyl acyloxy, C 1-6alkoxyl group acyl group, C 1-6alkyl sulphonyl, C 1-6alkoxyl group alkylsulfonyl, C 1-6alkyl sulphinyl, C 1-6alkyl sulphonyl oxygen base, C 1-6alkyl sulphinyl oxygen base, C 1-6alkoxyl group, C 1-6alkyl, C 6-10aryl ,-CF 3,-OCF 3, sulfydryl, nitro or C 1-6alkylamino;
Each R 6be hydrogen, deuterium, C independently 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6aminoalkyl group, C 1-6alkoxy C 1-6alkyl, C 1-6alkylamino C 1-6alkyl, C 1-6alkylthio C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl;
With each R 7and R 7abe H, deuterium, F, Cl, Br, I, C independently 1-6alkyl, C 2-6assorted alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6aminoalkyl group, C 1-6alkoxy C 1-6alkyl, C 1-6alkylamino C 1-6alkyl, C 1-6alkylthio C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl, C 3-10cycloalkyl C 1-6alkyl, C 6-10aryloxy C 1-6alkyl, C 2-10heterocyclyloxy base C 1-6alkyl, C 3-10cycloalkyl oxy C 1-6alkyl, C 6-10the amino C of virtue 1-6alkyl, C 2-10the amino C of heterocyclic radical 1-6alkyl, C 3-10cycloalkyl amino C 1-6alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical or C 3-8carbocylic radical.
5. compound according to claim 1, wherein each A and A ' are a key, C independently 1-6alkylidene group, C 2-6alkenylene, C 3-8cycloalkylidene, C 2-10sub-Heterocyclylalkyl ,-(CR 8r 8a) n-O-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-C (=O)-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-O-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-S (=O) r-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-O-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=S)-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-C (=O)-O-(CR 8r 8a) p-, or each A and A ' are following group independently:
Figure FDA0000442505350000081
Wherein, each X 1and X 2be O, S, NR independently 6or CR 7r 7a;
Each Y 1and Y 2be N or CR independently 7;
Z is-(CH 2) a-,-CH=CH-,-N=CH-,-(CH 2) a-N (R 5)-(CH 2) b-or-(CH 2) a-O-(CH 2) b-;
Each a and b are 0,1,2 or 3 independently;
Each c is 1 or 2 independently;
Each d is 1 or 2 independently;
Each n is 0,1,2 or 3 independently;
Each p is 0,1,2 or 3 independently;
Each r is 0,1 or 2 independently;
Each R 5be H, deuterium, hydroxyl, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-8cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl, C 6-10aryl C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkyl-OC (=O)-, C 1-6alkyl-C (=O)-, formamyl, C 1-6alkyl-OS (=O) r-, C 1-6alkyl-S (=O) ro-, C 1-6alkyl-S (=O) r-or amino-sulfonyl;
Each R 6be hydrogen, deuterium, R independently 13r 13anC (=O)-, R 13oC (=O)-, R 13c (=O)-, R 13r 13anS (=O)-, R 13oS (=O)-, R 13s (=O)-, R 13r 13anS (=O) 2-, R 13oS (=O) 2-, R 13s (=O) 2-, C 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6aminoalkyl group, C 1-6alkoxy C 1-6alkyl, C 1-6alkylamino C 1-6alkyl, C 1-6alkylthio C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl, C 3-10cycloalkyl C 1-6alkyl, C 6-10aryloxy C 1-6alkyl, C 2-10heterocyclyloxy base C 1-6alkyl, C 3-10cycloalkyl oxy C 1-6alkyl, C 6-10the amino C of virtue 1-6alkyl, C 2-10the amino C of heterocyclic radical 1-6alkyl, C 3-10cycloalkyl amino C 1-6alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical or C 3-10carbocylic radical;
Each R 6abe H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, oxo (=O), R independently 13ar 13n-,-C (=O) NR 13r 13a,-OC (=O) NR 13r 13a,-OC (=O) OR 13,-N (R 13) C (=O) NR 13r 13a,-N (R 13) C (=O) OR 13a,-N (R 13) C (=O)-R 13a, R 13r 13an-S (=O) 2-, R 13s (=O) 2-, R 13s (=O) 2n (R 13a)-, R 13ar 13n-C 1-6alkyl, R 13s (=O)-C 1-6alkyl, R 13r 13an-C (=O)-C 1-6alkyl, R 13ar 13n-C 1-6alkoxyl group, R 13s (=O)-C 1-6alkoxyl group, R 13r 13an-C (=O)-C 1-6alkoxyl group, C 6-10aryl, C 1-9heteroaryl, C 1-6alkoxyl group, C 1-6alkylamino, C 1-6alkyl, C 1-6haloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 2-10heterocyclic radical, C 3-8cycloalkyl, sulfydryl, nitro, C 6-10aryl C 1-6alkyl, C 6-10virtue is amino, C 1-9heteroaryl amino or C 6-10aryloxy;
Each R 7and R 7abe H, deuterium, F, Cl, Br, I, C independently 1-6alkyl, C 2-6assorted alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6aminoalkyl group, C 1-6alkoxy C 1-6alkyl, C 1-6alkylamino C 1-6alkyl, C 1-6alkylthio C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl, C 3-10cycloalkyl C 1-6alkyl, C 6-10aryloxy C 1-6alkyl, C 2-10heterocyclyloxy base C 1-6alkyl, C 3-10cycloalkyl oxy C 1-6alkyl, C 6-10the amino C of virtue 1-6alkyl, C 2-10the amino C of heterocyclic radical 1-6alkyl, C 3-10cycloalkyl amino C 1-6alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical or C 3-8carbocylic radical;
Each R 13and R 13abe H, deuterium, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl or C 6-10aryl C 1-6alkyl; Work as R 13and R 13abe connected on same nitrogen-atoms R 13, R 13acan at random form substituted or non-substituted 3-8 ring, spiral shell dicyclo or condensed-bicyclic with nitrogen-atoms;
With each R 8and R 8abe H, deuterium, hydroxyl, cyano group, nitro, F, Cl, Br, I, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl, C 6-10aryl C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkyl-OC (=O)-, C 1-6alkyl-C (=O)-, formamyl, C 1-6alkyl-OS (=O) r-, C 1-6alkyl-S (=O) ro-, C 1-6alkyl-S (=O) r-or amino-sulfonyl.
6. compound according to claim 1, wherein each A and A ' are a key ,-CH independently 2-,-(CH 2) 2-,-CH=CH-,-CH=CH-CH 2-,-N (R 5)-,-C (=O)-,-C (=S)-,-C (=O)-O-,-C (=O) N (R 5)-,-OC (=O) N (R 5)-,-OC (=O) O-,-N (R 5) C (=O) N (R 5)-,-(R 5) N-S (=O) 2-,-S (=O) 2-,-OS (=O) 2-,-(R 5) N-S (=O)-,-S (=O)-,-OS (=O)-, or each A and A ' are following group independently:
Figure FDA0000442505350000101
Wherein, X 1for O or S;
Each Y 1be N or CH independently;
Each R 5be H, deuterium, hydroxyl, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-8cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl, C 6-10aryl C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkyl-OC (=O)-, C 1-6alkyl-C (=O)-, formamyl, C 1-6alkyl-OS (=O) r-, C 1-6alkyl-S (=O) ro-, C 1-6alkyl-S (=O) r-or amino-sulfonyl;
Each R 6be hydrogen, deuterium, C independently 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-6aminoalkyl group, C 1-6alkoxy C 1-6alkyl, C 1-6alkylamino C 1-6alkyl, C 1-6alkylthio C 1-6alkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl, C 6-10aryl, C 2-10heterocyclic radical or C 3-8carbocylic radical;
Each R 6abe H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, oxo (=O), R independently 13ar 13n-, C 1-6alkoxyl group, C 1-6alkylamino, C 1-6alkyl, C 1-6haloalkyl, C 2-6thiazolinyl, C 2-6alkynyl, sulfydryl or nitro;
With each R 13and R 13aindependently for being H, deuterium, C 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl or C 6-10aryl C 1-6alkyl; Work as R 13and R 13abe connected on same nitrogen-atoms R 13, R 13acan at random form substituted or non-substituted 3-8 ring, spiral shell dicyclo or condensed-bicyclic with nitrogen-atoms.
7. compound according to claim 1, wherein, each R 1, R 2, R 3and R 4independently for being selected from H, deuterium, C 1-8alkyl, C 1-8assorted alkyl, C 6-10aryl C 1-6alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 1-9heteroaryl or C 6-10aryl, or R 1, R 2at random form 3-8 unit heterocycle or 3-8 unit carbocyclic ring, C with X-CH 5-12condensed-bicyclic, C 5-12condense assorted dicyclo, C 5-12spiral shell dicyclo or C 5-12the spiral shell dicyclo of mixing; R 3, R 4and X '-CH at random forms 3-8 unit heterocycle or 3-8 unit carbocyclic ring, C 5-12condensed-bicyclic, C 5-12condense assorted dicyclo, C 5-12spiral shell dicyclo or C 5-12the spiral shell dicyclo of mixing.
8. compound according to claim 7, wherein R 1, R 2and X-CH, or R 3, R 4and X '-CH at random forms 3-8 unit heterocycle, C 5-12condensed-bicyclic, C 5-12condense assorted dicyclo, C 5-12spiral shell dicyclo or C 5-12the spiral shell dicyclo of mixing.
9. compound according to claim 7, wherein R 1, R 2the heterocycle forming with Y-X-CH or condensed ring or volution system are selected from following minor structure formula:
Figure FDA0000442505350000111
Wherein, each R 15be H, deuterium, F, Cl, Br, I, cyano group, hydroxyl, C independently 1-3alkyl, C 1-3haloalkyl, C 1-3alkoxyl group, C 1-3alkylamino, C 1-3alkylthio, C 6-10virtue is amino, C 6-10aryloxy, C 1-9heteroaryl, C 1-9heteroaryloxy, C 1-9heteroaryl C 1-3alkyl or C 2-10heterocyclic radical;
Each R 6be hydrogen, deuterium, C independently 1-3alkyl, C 1-3haloalkyl, C 1-3hydroxyalkyl, C 1-3aminoalkyl group, C 1-3alkoxy C 1-3alkyl, C 1-3alkylamino C 1-3alkyl, C 1-3alkylthio C 1-3alkyl, C 6-10aryl C 1-3alkyl, C 1-9heteroaryl, C 6-10aryl, C 2-10heterocyclic radical or C 3-8carbocylic radical;
With each n 1and n 2be 1,2,3 or 4 independently.
10. compound according to claim 7, wherein R 3, R 4with the heterocycle that forms of Y '-X '-CH or condensed ring or volution system are selected from following minor structure formula:
Figure FDA0000442505350000121
Wherein, each R 15be H, deuterium, F, Cl, Br, I, cyano group, hydroxyl, C independently 1-3alkyl, C 1-3haloalkyl, C 1-3alkoxyl group, C 1-3alkylamino, C 1-3alkylthio, C 6-10virtue is amino, C 6-10aryloxy, C 1-9heteroaryl, C 1-9heteroaryloxy, C 1-9heteroaryl C 1-3alkyl or C 2-10heterocyclic radical;
Each R 6be hydrogen, deuterium, C independently 1-3alkyl, C 1-3haloalkyl, C 1-3hydroxyalkyl, C 1-3aminoalkyl group, C 1-3alkoxy C 1-3alkyl, C 1-3alkylamino C 1-3alkyl, C 1-3alkylthio C 1-3alkyl, C 6-10aryl C 1-3alkyl, C 1-9heteroaryl, C 6-10aryl, C 2-10heterocyclic radical or C 3-8carbocylic radical;
With each n 1and n 2be 1,2,3 or 4 independently.
11. compounds according to claim 1, it has structure as shown in the formula (II):
Figure FDA0000442505350000122
Wherein,
Figure FDA0000442505350000131
structural unit is following minor structure formula:
Figure FDA0000442505350000132
Each Q 1and Q 2be NR independently 6, O, S, C (=O) or (CH 2) e;
E is 0,1,2,3 or 4;
Each f is 0,1,2,3 or 4 independently
Each X 3and X 5be O, S, NR independently 6, C (=O) or CR 7r 7a;
Each X 6be CH independently 2,-Y 1=N-, O, S or NR 6;
Each Y 1be N or CR independently 7;
Each A and A ' are a key, C independently 1-6alkylidene group, C 2-6alkenylene, C 3-8cycloalkylidene, C 2-10sub-Heterocyclylalkyl ,-(CR 8r 8a) n-O-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-C (=O)-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-O-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-S (=O) r-N (R 5)-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-(CR 8r 8a) p-,-(CR 8r 8a) n-S (=O) r-O-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=O)-(CR 8r 8a) p-,-(CR 8r 8a) n-C (=S)-(CR 8r 8a) p-,-(CR 8r 8a) n-N (R 5)-C (=O)-O-(CR 8r 8a) p-, or each A and A ' are following group independently:
Figure FDA0000442505350000141
Each R 5be H, deuterium, hydroxyl, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl, C 6-10aryl C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkyl-OC (=O)-, C 1-6alkyl-C (=O)-, formamyl, C 1-6alkyl-OS (=O) r-, C 1-6alkyl-S (=O) ro-, C 1-6alkyl-S (=O) r-or amino-sulfonyl;
Each R 5aand R 6abe H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, C independently 1-6alkyl acyl, C 1-6alkyl acyloxy, C 1-6alkoxyl group acyl group, C 1-6alkyl sulphonyl, C 1-6alkoxyl group alkylsulfonyl, C 1-6alkyl sulphinyl, C 1-6alkyl sulphonyl oxygen base, C 1-6alkyl sulphinyl oxygen base, C 1-6alkoxyl group, C 1-6alkyl, C 6-10aryl ,-CF 3,-OCF 3, sulfydryl, nitro, C 1-6alkylamino, C 3-10cycloalkyl or C 6-10aryloxy;
Each R 6be hydrogen, deuterium, R independently 13r 13anC (=O)-, R 13oC (=O)-, R 13c (=O)-, R 13r 13anS (=O)-, R 13oS (=O)-, R 13s (=O)-, R 13r 13anS (=O) 2-, R 13oS (=O) 2-, R 13s (=O) 2-, C 1-6aliphatics, C 1-6alkoxy C 1-6aliphatics, C 1-6alkylamino C 1-6aliphatics, C 6-10aryl C 1-6aliphatics, C 1-9heteroaryl C 1-6aliphatics, C 2-10heterocyclic radical C 1-6aliphatics, C 3-10cycloalkyl C 1-6aliphatics, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical or C 3-10carbocylic radical;
Each R 7and R 7abe H, deuterium, F, Cl, Br, I, C independently 1-6aliphatics, C 2-6assorted alkyl, C 1-6alkoxy C 1-6aliphatics, C 1-6alkylamino C 1-6aliphatics, C 6-10aryl C 1-6aliphatics, C 2-10heterocyclic radical C 1-6aliphatics, C 3-10cycloalkyl C 1-6aliphatics, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical or C 3-10carbocylic radical;
Each R 8and R 8abe H, deuterium, hydroxyl, cyano group, nitro, F, Cl, Br, I, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl, C 6-10aryl C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkyl-OC (=O)-, C 1-6alkyl-C (=O)-, formamyl, C 1-6alkyl-OS (=O) r-, C 1-6alkyl-S (=O) ro-, C 1-6alkyl-S (=O) r-or amino-sulfonyl;
Each R 13and R 13abe H, deuterium, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl or C 6-10aryl C 1-6alkyl; Work as R 13and R 13abe connected on same nitrogen-atoms R 13, R 13acan at random form substituted or non-substituted 3-8 ring, spiral shell dicyclo or condensed-bicyclic with nitrogen-atoms;
Each n is 0,1,2 or 3 independently;
Each p is 0,1,2 or 3 independently;
Each r is 0,1 or 2 independently;
With each Y 4and Y 4' be a key, O, S ,-(CH independently 2) n-,-CH=CH-,-S (=O) r-,-CH 2o-,-CH 2s-,-CF 2-,-CHR 5a-,-CR 5ar 6a,-CH 2s (=O) ror-CH 2n (R 6)-.
12. compounds according to claim 11, it has structure as shown in the formula (III):
Figure FDA0000442505350000151
13. compounds according to claim 11, it has suc as formula the structure shown in (IV):
Figure FDA0000442505350000152
Wherein, each Q 2and Q 3be O, S, C (=O), NR independently 6or CR 7r 7a.
14. compounds according to claim 11, it has the structure as shown in formula V:
Figure FDA0000442505350000161
Wherein e is 1,2,3 or 4.
15. compounds according to claim 1, wherein, each Y and Y ' are a-amino acid group independently.
16. compounds according to claim 15, wherein a-amino acid group is selected from Isoleucine, leucine, Methionin, methionine(Met), phenylalanine, Threonine, tryptophane, α-amino-isovaleric acid, L-Ala, l-asparagine, aspartic acid, L-glutamic acid, glutamine, proline(Pro), Serine, to tyrosine, arginine, Histidine, halfcystine, glycine, sarkosine, N, N-N-methylsarcosine, homoserine, norvaline, nor-leucine, ornithine, homocysteine, hyperphenylalaninemia, phenylglycocoll, adjacent tyrosine, the group that m-Tyrosine or oxyproline form.
17. compounds according to claim 16, the a-amino acid in wherein said a-amino acid group is D configuration.
18. compounds according to claim 16, the a-amino acid in wherein said a-amino acid group is L configuration.
19. according to the compound described in claim 1-14, and wherein each Y and Y ' are-[U-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12,-U-(CR 9r 9a) t-R 12or-[U-(CR 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-O-(CR 9r 9a) t-R 12.
20. compounds according to claim 19, wherein each Y and Y ' are-[U-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
21. compounds according to claim 20, wherein each Y and Y ' are-U-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t-U-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
22. compounds according to claim 20, wherein each Y and Y ' are-U-(CR independently 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
23. compounds according to claim 20, wherein each Y and Y ' are-[C (=O)-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
24. compounds according to claim 23, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t-U-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
25. compounds according to claim 23, wherein each Y and Y ' are-[C (=O)-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-C (=O)-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
26. compounds according to claim 25, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t-C (=O)-(CR 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
27. compounds according to claim 23, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 11)-(CR 9r 9a) t-R 12.
28. compounds according to claim 27, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 11)-(CR 9r 9a) t-C (=O)-R 13.
29. compounds according to claim 28, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 11)-C (=O)-R 13.
30. compounds according to claim 27, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 11)-(CR 9r 9a) t-C (=O)-O-R 13.
31. compounds according to claim 30, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 11)-C (=O)-O-R 13.
32. compounds according to claim 19, wherein each Y and Y ' are-U-(CR independently 9r 9a) t-R 12.
33. compounds according to claim 32, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-R 12.
34. compounds according to claim 19, wherein each Y and Y ' are-[U-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t] k-U-(CR 9r 9a) t-O-(CR 9r 9a) t-R 12.
35. compounds according to claim 34, wherein each Y and Y ' are-U-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t-U-(CR 9r 9a) t-O-(CR 9r 9a) t-R 12.
36. compounds according to claim 35, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 10)-(CR 9r 9a) t-C (=O)-(CR 9r 9a) t-O-(CR 9r 9a) t-R 12.
37. compounds according to claim 34, wherein each Y and Y ' are-U-(CR independently 9r 9a) t-O-(CR 9r 9a) t-R 12.
38. according to the compound described in claim 37, and wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-O-(CR 9r 9a) t-R 12.
39. compounds according to claim 19, wherein each Y and Y ' are-C (=O)-(CR independently 9r 9a) t-N (R 11)-R 12, wherein R 11, R 12can form 4-7 ring with the atom being attached thereto.
40. compounds according to claim 19, wherein, each R 9, R 9a, R 10and R 11be H, deuterium, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl, C 6-10aryl C 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl;
Each R 12be R independently 13ar 13n-,-C (=O) R 13,-C (=S) R 13,-C (=O)-O-R 13,-C (=O) NR 13r 13a,-OC (=O) NR 13r 13a,-OC (=O) OR 13,-N (R 13) C (=O) NR 13r 13a,-N (R 13) C (=O) OR 13a,-N (R 13) C (=O)-R 13a, R 13r 13an-S (=O) 2-, R 13s (=O) 2-, R 13s (=O) 2n (R 13a)-, R 13oS (=O) 2-, C 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl or C 6-10aryl C 1-6alkyl;
Or R 11, R 12can form 4-7 ring with the atom being attached thereto;
Each R 13and R 13abe H, deuterium, C independently 1-6alkyl, C 2-6assorted alkyl, C 3-10cycloalkyl, C 2-10heterocyclic radical, C 6-10aryl, C 1-9heteroaryl or C 6-10aryl C 1-6alkyl; Work as R 13and R 13abe connected on same nitrogen-atoms R 13, R 13acan at random form substituted or non-substituted 3-8 ring, spiral shell dicyclo or condensed-bicyclic with nitrogen-atoms;
Each t is 0,1,2,3 or 4 independently;
With each k be 0,1 or 2 independently.
41. according to the compound described in claim 40, wherein,
Each R 9, R 9a, R 10and R 11be H, deuterium, methyl, ethyl, sec.-propyl, cyclohexyl, isobutyl-or phenyl independently;
Each R 12be-C (=O) R independently 13,-C (=O)-O-R 13,-C (=O) NR 13r 13a, methyl, ethyl, propyl group, phenyl, cyclohexyl, morpholinyl or piperidyl;
Or R 11, R 12can form 4-7 ring with the atom being attached thereto;
With each R 13and R 13abe H, deuterium, methyl, ethyl, propyl group, phenyl, cyclohexyl, morpholinyl or piperidyl independently.
42. according to the compound shown in claim 11, and it has suc as formula the structure shown in (VI):
Figure FDA0000442505350000181
Wherein, each R 14and R 14abe H, deuterium, C independently 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 2-6assorted alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical, C 3-8cycloalkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl;
Wherein said C 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 2-6assorted alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical, C 3-8cycloalkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl can optionally be replaced by one or more substituting groups that are selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
43. according to the compound described in claim 42, and it has suc as formula the structure shown in (VII):
Figure FDA0000442505350000191
Wherein, each R 14and R 14abe H, deuterium, C independently 1-3hydroxyalkyl, methyl, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, allyl group, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl or C 1-9heteroaryl;
Wherein said C 1-3hydroxyalkyl, methyl, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, allyl group, propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl or C 1-9heteroaryl can optionally be replaced by one or more substituting groups that are selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
44. compounds according to claim 1, it has suc as formula the structure shown in (VIII):
Wherein, each R 14and R 14abe H, deuterium, C independently 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 2-6assorted alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical, C 3-8cycloalkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl;
With each n 2be 1,2,3 or 4 independently;
Wherein said C 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 2-6assorted alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical, C 3-8cycloalkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl can optionally be replaced by one or more substituting groups that are selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
45. compounds according to claim 1, it has suc as formula the structure shown in (IX):
Figure FDA0000442505350000201
Wherein, each R 14and R 14abe H, deuterium, C independently 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 2-6assorted alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical, C 3-8cycloalkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl;
With each n 1be 1,2,3 or 4 independently;
Wherein said C 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl, C 2-6assorted alkyl, C 6-10aryl, C 1-9heteroaryl, C 2-10heterocyclic radical, C 3-8cycloalkyl, C 6-10aryl C 1-6alkyl, C 1-9heteroaryl C 1-6alkyl, C 2-10heterocyclic radical C 1-6alkyl or C 3-8cycloalkyl C 1-6alkyl can optionally be replaced by one or more substituting groups that are selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
46. compounds according to claim 1, it has suc as formula the structure shown in (X)
Figure FDA0000442505350000202
Wherein, each R 5abe H, deuterium, C independently 1-4alkyl, F, Cl, Br or I;
F is 0,1,2,3 or 4;
Each Y 1be N or CR independently 7;
Each R 6and R 7be H, deuterium, C independently 1-4alkyl, C 6-10aryl, C 2-10heterocyclic radical, C 3-8cycloalkyl or benzyl;
Each R 14and R 14abe H, deuterium, C independently 1-4alkyl, C 6-10aryl, C 2-10heterocyclic radical or C 3-8cycloalkyl;
Each R 16and R 16abe hydroxyl, C independently 1-4alkyl oxy, C 6-10aryloxy, C 2-10heterocyclic radical or C 3-8cycloalkyl;
Wherein
Figure FDA0000442505350000211
structural unit is following minor structure formula:
Figure FDA0000442505350000212
Figure FDA0000442505350000221
Each A or A ' are independently selected from following group:
Figure FDA0000442505350000222
Wherein R 1, R 2the heterocycle independently forming with N-CH or condensed ring or volution system are selected from following minor structure formula:
Figure FDA0000442505350000223
Wherein R 3, R 4the heterocycle independently forming with N-CH or condensed ring or volution system are selected from following minor structure formula:
Figure FDA0000442505350000224
47. compounds according to claim 1, it has suc as formula the structure shown in (XI)
Figure FDA0000442505350000231
Wherein, each R 5abe H, deuterium, C independently 1-4alkyl, F, Cl, Br or I;
F is 0,1,2,3 or 4;
Each Q 1and Q 2be NR independently 6, O, S, C (=O) or (CR 7r 7a) e;
X 6for (CR 7r 7a) n,-Y 1=N-, O, S or NR 6;
Each Y 1be N or CR independently 7;
Each i, n and e are 1,2,3 or 4 independently;
Each R 6, R 7and R 7abe H, deuterium, C independently 1-4alkyl, C 6-10aryl, C 2-10heterocyclic radical, C 3-8cycloalkyl or benzyl;
Each R 14and R 14abe H, deuterium, C independently 1-4alkyl, C 6-10aryl, C 2-10heterocyclic radical or C 3-8cycloalkyl;
Each R 16and R 16abe hydroxyl, C independently 1-4alkyl oxy, C 6-10aryloxy, C 2-10heterocyclic radical or C 3-8cycloalkyl;
Wherein said C 1-4alkyl, C 6-10aryl, C 2-10heterocyclic radical, C 3-8cycloalkyl, C 6-10aryloxy can optionally be replaced by one or more substituting groups that are selected from deuterium, F, Cl, Br, hydroxyl, cyano group;
Each A or A ' are independently selected from following group:
Wherein R 1, R 2the heterocycle independently forming with N-CH or condensed ring or volution system are selected from following minor structure formula:
Wherein R 3, R 4the heterocycle independently forming with N-CH or condensed ring or volution system are selected from following minor structure formula:
Figure FDA0000442505350000242
48. according to the compound described in claim 46 or 47 any one, wherein
Each R 5abe H, deuterium, methyl, ethyl, F, Cl, Br or I independently;
Each R 6, R 7and R 7abe hydrogen, deuterium, methyl, ethyl, sec.-propyl, phenyl, cyclohexyl or benzyl independently;
Each R 14and R 14abe methyl, ethyl, phenyl, cyclohexyl, 1-methyl-propyl, sec.-propyl or the tertiary butyl independently;
With each R 16and R 16abe independently hydroxyl, methoxyl group, oxyethyl group, phenoxy group,
Figure FDA0000442505350000243
or tert.-butoxy;
Wherein said methyl, ethyl, phenyl, cyclohexyl, 1-methyl-propyl, sec.-propyl, isobutyl-, methoxyl group, oxyethyl group, phenoxy group, tert.-butoxy or the tertiary butyl can optionally be replaced by one or more substituting groups that are selected from deuterium, F, Cl, Br, hydroxyl, cyano group.
49. compounds according to claim 1, comprise following one of them structure:
Figure FDA0000442505350000244
Figure FDA0000442505350000251
Figure FDA0000442505350000261
Figure FDA0000442505350000271
Or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate or pharmacy acceptable salt.
50. 1 kinds of pharmaceutical compositions, wherein said pharmaceutical composition comprises according to the compound described in any one in claim 1-49.
51. according to the pharmaceutical composition described in claim 50, further comprises pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or its combination.
52. according to the pharmaceutical composition described in claim 50, and it further comprises the medicine of other anti-HCV.
53. according to the pharmaceutical composition described in claim 52, and the medicine of wherein said anti-HCV is that Interferon, rabbit, ribavirin, interleukin-22, interleukin 6, interleukin 12, promotion produce compound, RNA interfering, sense-rna, not moral, inosine 5 '-monophosphate dehydrogenase inhibitor, amantadine, Rimantadine, Ba Wei former times monoclonal antibody (Bavituximab), the Civacir of miaow quinoline that 1 type helper T cell is replied tM, EBP520 (boceprevir), TVR (telaprevir), erlotinib (erlotinib), daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, ABT-450, danoprevir, sovaprevir, MK-5172, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ABT-267, EDP239, PPI-668, GS-5816, samatasvir(IDX-719), MK-8742, MK-8325, GSK-2336805, PPI-461, TMC-435, MK-7009, BI-2013335, ciluprevir, BMS-650032, ACH-1625, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, EP-013420, VBY-376, TMC-649128, R-7128, PSI-7977, INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, HCV-371, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072, PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055 or its combination.
54. according to the pharmaceutical composition described in claim 53, and wherein said Interferon, rabbit is interferon alpha, Intederon Alpha-2a, the Intederon Alpha-2a of Pegylation, compound alpha-interferon, interferon-gamma or its combination of Interferon Alpha-2b, Pegylation.
55. according to the pharmaceutical composition described in any one in claim 50-54, it further comprises at least one HCV inhibitor.
56. according to the pharmaceutical composition described in claim 55, wherein said HCV inhibitor for suppress HCV reproduction process and suppress HCV viral protein function one of at least.
57. according to the pharmaceutical composition described in claim 56, and wherein said HCV reproduction process is selected from the complete viral cycle of the HCV that HCV enters, shells, translates, copies, assembles or discharge.
58. according to the pharmaceutical composition described in claim 56, and described HCV viral protein is selected from metalloprotease, NS2, NS3, NS4A, NS4B, NS5A, NS5B; And the needed internal ribosome inlet point of HCV virus replication (IRES) and inosine monophosphate desaturase (IMPDH).
59. according to the pharmaceutical composition described in any one in the compound described in any one in claim 1-49 or claim 50-58 in the purposes of preparing in medicine, described medicine for suppress HCV and copy and suppress HCV viral protein function one of at least.
60. according to the purposes described in claim 59, and described HCV reproduction process is selected from the complete viral cycle of the HCV that HCV enters, shells, translates, copies, assembles or discharge.
61. according to the purposes described in claim 60, and described HCV viral protein is selected from metalloprotease, NS2, NS3, NS4A, NS4B, NS5A, NS5B; And the needed internal ribosome inlet point of HCV virus replication (IRES) and inosine monophosphate desaturase (IMPDH).
62. according to the pharmaceutical composition described in any one in the compound described in any one in claim 1-49 or claim 50-58 in the purposes of preparing in medicine, described medicine for prevent, process, treat or alleviate patient HCV infect or hepatitis C disease.
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