CN105968101B - Application as the compound of hepatitis c inhibitor and its in drug - Google Patents

Application as the compound of hepatitis c inhibitor and its in drug Download PDF

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CN105968101B
CN105968101B CN201610141716.2A CN201610141716A CN105968101B CN 105968101 B CN105968101 B CN 105968101B CN 201610141716 A CN201610141716 A CN 201610141716A CN 105968101 B CN105968101 B CN 105968101B
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hcv
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heterocycle
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CN105968101A (en
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张英俊
谢洪明
方清洪
刘志强
胡柏林
张健存
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Guangdong HEC Pharmaceutical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • 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
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • 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

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Abstract

The present invention relates to the compound as hepatitis c inhibitor and its applications in drug, it particularly provides such as formula (I) compound represented or its stereoisomer, tautomer, enantiomter, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug, for treating Hepatitis C Virus (HCV) infection or hepatitis C disease.The invention also discloses the pharmaceutical composition containing such compound and use the compounds of this invention or the method for its medicine composite for curing HCV infection or hepatitis C disease.

Description

Application as the compound of hepatitis c inhibitor and its in drug
Invention field
The invention belongs to drug fields, and in particular to for treating the compound, described of Hepatitis C Virus (HCV) infection Composition of compound and application thereof and application method.
Background of invention
HCV is main human pathogen, estimates about 1.7 hundred million people of whole world infection, infects people for human immunodeficiency virus type 1 Several 5 times.And the major part in these HCV infections individual can develop into serious progressive hepatopathy, including cirrhosis and liver Cell cancer.Therefore, chronic HCV infection will be global patient due to hepatopathy the main reason for premature death.
HCV is positive chain RNA virus.According to the ratio to the amino acid sequence derived and the extensive similitude of 5 ' non-translational regions Compared with HCV is classified into the individual category of flaviviridae (Flaviviridae family).All members of flaviviridae It is all the envelope virus particle of the genome containing positive chain RNA, which is turned over by single uninterrupted open reading frame (ORF's) It translates, encodes all known virus specified proteins.
There are considerable heterogeneities in the nucleotide and encoded amino acid sequence of entire HCV genome.? The main genotype of at least seven is identified, and discloses a hypotype more than 50.In by HCV infection cell, viral RNA is turned over It is translated into polyprotein, and is split into 10 kinds body proteins.It is structural proteins in amino terminal, followed by E1 and E2.In addition, also There are 6 kinds of non-structural proteins, i.e. NS2, NS3, NS4A, NS4B, NS5A and NS5B, plays in HCV life cycle very heavy The role wanted (see, e.g., Lindenbach, B.D. and C.M.Rice, Nature.436,933-938,2005).
Distribution of the main genotypes of HCV in the whole world is different, although having carried out lots of genes type to pathogenesis and treatment The research of effect, but still do not know the clinical importance of HCV genetic heterogeneity.
Single-stranded HCV rna gene group length is about 9500 nucleotide, has single open reading frame, and coding is single about The large-scale polyprotein of 3000 amino acid.In infection cell, the polyprotein on multiple sites by leukoprotease and Virus protease cutting, generates structure and non-structural (NS) albumen.For HCV, mature non-structural protein (NS2, NS3, NS4A, NS4B, NS5A and NS5B) formation be to be realized by two kinds of virus proteases.It is generally acknowledged that the first is metal egg White enzyme is cut in NS2-NS3 contact；It is included in NS3 (also referred to herein as NS3 protease) N-terminal region second Serine protease, it mediates all subsequent cutting in the downstream NS3, be in NS3-NS4A cleavage site it is cis-, in remaining NS4A- The site NS4B, NS4B-NS5A, NS5A-NS5B is then trans-.NS4A albumen seems to play NS3 protease cofactor there are many function Effect, and NS3 and other rdrp virus components may be assisted to carry out film positioning.The formation of NS3 albumen and NS4A compound Event is seemingly processed, is improved necessary to proteolytic efficiency on all sites.NS3 albumen also shows ribonucleoside triphosphote Enzyme and RNA helicase activity.NS5B (also known as HCV polymerase herein) is the RNA polymerization dependent on RNA for participating in HCV duplication Enzyme.
Summary of the invention
The compounds of this invention is for treating patient's HCV infection, which selectively inhibits the duplication of HCV virus.
The present invention relates to the methods of HCV-Ab IgG infection.Compound provided by the invention or pharmaceutical composition to HCVGT1a, GT1b, GT2a, GT3a, GT4b, GT5a, GT6a all have good inhibitory effect, while compound provided by the invention or medicine Compositions also have good inhibitory effect to HCVGT1b L31V, GT1b Y93H persister.Therefore, the present invention provides Full genome HCV with overriding resistance inhibits drug, and has preferable bioavilability.
On the one hand, the present invention relates to a kind of compounds, are compound shown in formula (I) compound represented or formula (I) Stereoisomer, geometric isomer, tautomer, enantiomter, nitrogen oxides, hydrate, solvate, metabolism produce Object, pharmaceutically acceptable salt or prodrug,
Wherein, A is-(CR7R7a)m-、-CR7=CR7a-、-(CH2)nO- ,-N=CR7-、-NR7-CR7R7a-、-CR7R7a- NR7-、-O(CH2)n-、-CR7=N- ,-S (CH2)n-、-(CH2)nS- or-NR9a-；
X and X1It is each independently N or CR7b；
Y and Y1Be each independently H, deuterium, alkyl, naphthenic base, heterocycle, aryl, heteroaryl, aryl alkyl ,-C (= O)-(CR8R8a)t-N(R9)-R10Or a-amino acid group；
Wherein a-amino acid group is selected from isoleucine, leucine, lysine, methionine, phenylalanine, threonine, color Propylhomoserin, valine, alanine, asparagine, aspartic acid, glutamic acid, glutamine, proline, serine, to tyrosine, essence Propylhomoserin, histidine, cysteine, glycine, sarcosine, N, N- dimethylglycine, homoserine, norvaline, just bright ammonia Acid, ornithine, homocysteine, homophenylalanin, phenylglycine, adjacent tyrosine, m-Tyrosine or hydroxy-proline institute shape At group；
R1、R2、R3And R4It is each independently H, deuterium, alkyl, aryl alkyl, naphthenic base, heterocycle, heteroaryl or aryl； Or R1、R23-8 circle heterocyclic ring is randomly formed with X-CH, 3-8 member carbocyclic ring, condensed-bicyclic, condenses that miscellaneous bicyclic, spiral shell is bicyclic or spiral shell is miscellaneous double Ring；Or R3、R4With X1- CH is randomly formed 3-8 circle heterocyclic ring, 3-8 member carbocyclic ring, condensed-bicyclic, condenses that miscellaneous bicyclic, spiral shell is bicyclic or spiral shell It is miscellaneous bicyclic；
Each R5And R6Independently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano, alkyl, halogenated alkyl, Alkenyl, alkynyl, heterocycle, naphthenic base, sulfydryl, nitro, aryl, heteroaryl, aryl alkyl, alkoxyalkyl, alkoxy, aryl Amino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heteroaryl oxygroup, heteroaryl alkyl, alkoxy aryl, heteroaryl It is base alkoxy, heterocycle oxygroup, heterocyclylalkoxy, heterocyclylamino group, alkyl acyl, alkyl acyloxy, alkoxyacyl, miscellaneous Ring group alkylamino or aryloxy group；
Each R7、R7a、R7b、R8、R8aAnd R9aIndependently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano, Deuteroalkyl, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, heterocycle, naphthenic base, sulfydryl, nitro, aryl, heteroaryl, Aryl alkyl, alkoxyalkyl, heteroaryl alkyl, cycloalkyl-alkyl, heterocyclylalkyl group, arylamino, heteroaryl amino, aryl Alkylamino, heteroarylalkylamino, heteroaryl oxygroup, alkoxy aryl, heteroarylalkoxy, heterocycle oxygroup, heterocyclylalkoxy Base, heterocyclylamino group, alkyl-OC (=O)-, alkyl-C (=O)-, carbamoyl, alkyl-OS (=O)r, alkyl-S (= O)rO-, alkyl-OS (=O)rO-, alkyl-S (=O)r, heterocycle alkylamino or aryloxy group；
Each R9And R10It independently is H, deuterium, alkyl, naphthenic base, heterocycle, aryl, heteroaryl, aryl alkyl, alkyl-OC (=O)-, alkyl-C (=O)-, carbamoyl, alkyl-OS (=O)r, alkyl-S (=O)rO-, alkyl-S (=O)rOr ammonia Base sulfonyl；
Each f, n and t independently are 0,1,2,3 or 4；
M is 1,2,3 or 4；With
Each r independently is 0,1 or 2；
Wherein each following group: alkyl, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl, aryl alkyl ,-C (=O)-(CR8R8a)t-N(R9)-R10, a-amino acid group, 3-8 circle heterocyclic ring, 3-8 member carbocyclic ring, condensed-bicyclic, condense it is miscellaneous it is bicyclic, Spiral shell is bicyclic, the miscellaneous bicyclic, halogenated alkyl of spiral shell, alkenyl, alkynyl, alkoxyalkyl, heteroaryl alkyl, cycloalkyl-alkyl, heterocycle alkane Base, arylamino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, aryloxy group, heteroaryl oxygroup, alkoxy aryl, Heteroarylalkoxy, heterocycle oxygroup, heterocyclylalkoxy, heterocyclylamino group, alkyl-OC (=O)-, alkyl-C (=O)-, ammonia Base formoxyl, alkyl-OS (=O)r, alkyl-S (=O)rO-, alkyl-S (=O)rOr amino-sulfonyl individually optionally by 1, 2,3 or 4 selected from hydroxyl, deuterium, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio group, alkyl, halogenated Alkyl, alkoxyalkyl, halogenated alkoxy alkyl, alkenyl, alkynyl, naphthenic base, heterocycle, sulfydryl, nitro, aryloxy group, aryl Alkyl-the C of alkoxy, hydroxyl substitution that amino, heteroaryl oxygroup, heteroaryl alkyl, oxo (=O), carboxyl, hydroxyl replace (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2, hydroxyl replace alkyl-S (=O)-, hydroxyl takes Alkyl-the S (=O) in generation2Or replaced the substituent group of the alkoxy of carboxyl substitution.
In some embodiments, each R1、R2、R3And R4It independently is H, C1-6Alkyl, C6-10Aryl C1-6Alkyl, C3-10Cycloalkanes Base, C2-10Heterocycle, C1-9Heteroaryl or C6-10Aryl；Or R1、R2With X-CH be randomly formed 3-8 circle heterocyclic ring, 3-8 member carbocyclic ring, C5-12Condensed-bicyclic, C5-12Condense miscellaneous bicyclic, C5-12Spiral shell is bicyclic or C5-12Spiral shell is miscellaneous bicyclic；Or R3、R4With X1- CH is randomly formed 3- 8 circle heterocyclic rings, 3-8 member carbocyclic ring, C5-12Condensed-bicyclic, C5-12Condense miscellaneous bicyclic, C5-12Spiral shell is bicyclic or C5-12Spiral shell is miscellaneous bicyclic；Wherein institute The 3-8 circle heterocyclic ring stated, 3-8 member carbocyclic ring, C5-12Condensed-bicyclic, C5-12Condense miscellaneous bicyclic, C5-12Spiral shell is bicyclic or C5-12Spiral shell is miscellaneous bicyclic only It is vertical to be optionally selected from H, deuterium, oxo (=O), F, Cl, Br, I, cyano, hydroxyl, C by 1,2,3 or 41-6Alkyl, C1-6Alkyl halide Base, C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C1-6Halogenated alkoxy C1-6Alkyl, C1-6Alkylamino, C1-6Alkylthio group, C6-10Virtue Base amino, C6-10Aryloxy group, C1-9Heteroaryl, C1-9Heteroaryl oxygroup, C1-9Heteroaryl C1-6Alkyl, C3-8Naphthenic base or C2-10Heterocycle Replaced the substituent group of base.
In some embodiments, wherein R1、R2Heterocycle, condensed ring or spiro ring system, which are formed by, with Y-X-CH is selected from following sub- knot Structure formula:
Wherein R3、R4With Y1-X1- CH is formed by heterocycle, condensed ring or spiro ring system and is selected from following subformula:
Wherein, each R15It independently is H, deuterium, oxo (=O), F, Cl, Br, I, cyano, hydroxyl, C1-6Alkyl, C1-6Alkyl halide Base, C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C1-6Halogenated alkoxy C1-6Alkyl, C1-6Alkylamino, C1-6Alkylthio group, C6-10Virtue Base amino, C6-10Aryloxy group, C1-9Heteroaryl, C1-9Heteroaryl oxygroup, C1-9Heteroaryl C1-6Alkyl, C3-8Naphthenic base or C2-10Heterocycle Base；
Each R9bIt independently is hydrogen, deuterium, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Hydroxy alkyl, C1-6Aminoalkyl, C1-6Alcoxyl Base C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, C1-6Alkylthio group C1-6Alkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl, C6-10Virtue Base, C2-10Heterocycle or C3-8Naphthenic base；
With each n1And n2It independently is 1,2,3 or 4.
In other embodiments, each R15It independently is H, deuterium, oxo (=O), F, Cl, Br, I, cyano, hydroxyl, C1-3Alkane Base, C1-3Halogenated alkyl, C1-3Alkoxy, C1-3Alkoxy C1-3Alkyl, C1-3Halogenated alkoxy C1-3Alkyl, C1-3Alkylamino, C1-3 Alkylthio group, C6-10Arylamino, C6-10Aryloxy group, C1-9Heteroaryl, C1-9Heteroaryl oxygroup, C1-9Heteroaryl C1-3Alkyl, C3-8Ring Alkyl or C2-10Heterocycle；With
Each R9bIt independently is hydrogen, deuterium, C1-3Alkyl, C1-3Halogenated alkyl, C1-3Hydroxy alkyl, C1-3Aminoalkyl, C1-3Alcoxyl Base C1-3Alkyl, C1-3Alkylamino C1-3Alkyl, C1-3Alkylthio group C1-3Alkyl, C6-10Aryl C1-3Alkyl, C1-9Heteroaryl, C6-10Virtue Base, C2-10Heterocycle or C3-8Naphthenic base.
In other embodiments, each R15It independently is H, deuterium, oxo (=O), F, Cl, Br, I, cyano, hydroxyl, methyl, second Base, propyl, isopropyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy, methoxy, difluoromethoxy ylmethyl, trifluoro Methoxy, ethoxyl methyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, methylamino, ethylamino, phenyl amino, benzene oxygen Base, pyrrole radicals, morpholinyl or piperazinyl；With
Each R9bIt independently is hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, trifluoromethyl, hydroxymethyl, amino methyl, first Oxygroup methyl, ethoxyl methyl, phenyl methyl, phenyl, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl.
In some embodiments, each R7、R7a、R7bAnd R9aIndependently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano, C1-6Alkyl, C1-6Halogenated alkyl, C2-6Alkenyl, C2-6Alkynyl, C2-10Heterocycle, C3-8Naphthenic base, sulfydryl, nitro, C6-10 Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C3-8Naphthenic base C1-6 Alkyl, C2-10Heterocycle C1-6Alkyl, C6-10Arylamino, C1-9Heteroaryl amino, C6-10Aryl C1-6Alkylamino, C1-9Heteroaryl C1-6Alkylamino, C1-9Heteroaryl oxygroup, C6-10Aryl C1-6Alkoxy, C1-9Heteroaryl C1-6Alkoxy, C2-10Heterocycle oxygroup, C2-10Heterocycle C1-6Alkoxy, C2-10Heterocyclylamino group, C1-6Alkyl-OC (=O)-, C1-6Alkyl-C (=O)-, carbamyl Base, C1-6Alkyl-OS (=O)r-、C1-6Alkyl-S (=O)rO-、C1-6Alkyl-OS (=O)rO-、C1-6Alkyl-S (=O)r-、C2-10 Heterocycle C1-6Alkylamino or C6-10Aryloxy group；With
Each r independently is 0,1 or 2.
In some embodiments, Y and Y1It is each independently H, deuterium, C1-6Alkyl, C3-8Naphthenic base, C2-10Heterocycle, C6-10Virtue Base, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl or-C (=O)-(CR8R8a)t-N(R9)-R10；
Each R8And R8aIt independently is H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano, C1-6Alkyl, C1-6Deuteroalkyl, C1-6 Halogenated alkyl, C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C2-10Heterocycle, C3-8Naphthenic base, sulfydryl, nitro, C6-10Aryl C1-6 Alkyl, C1-6Alkoxy C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C3-8Naphthenic base C1-6Alkyl, C2-10Heterocycle C1-6Alkyl, C6-10 Arylamino, C1-9Heteroaryl amino, C6-10Aryl C1-6Alkylamino, C1-9Heteroaryl C1-6Alkylamino, C1-9Heteroaryl oxygroup, C6-10 Aryl C1-6Alkoxy, C1-9Heteroaryl C1-6Alkoxy, C2-10Heterocycle oxygroup, C2-10Heterocycle C1-6Alkoxy, C2-10Heterocycle Amino, C1-6Alkyl-OC (=O)-, C1-6Alkyl-C (=O)-, carbamoyl, C1-6Alkyl-OS (=O)r-、C1-6Alkyl-S (=O)rO-、C1-6Alkyl-OS (=O)rO-、C1-6Alkyl-S (=O)r-、C2-10Heterocycle C1-6Alkylamino or C6-10Aryloxy group；
R9And R10It is each independently H, deuterium, C1-6Alkyl, C3-8Naphthenic base, C2-10Heterocycle, C6-10Aryl, C1-9Heteroaryl Base, C6-10Aryl C1-6Alkyl, C1-6Alkyl-OC (=O)-, C1-6Alkyl-C (=O)-, carbamoyl, C1-6Alkyl-OS (= O)r-、C1-6Alkyl-S (=O)rO-、C1-6Alkyl-S (=O)rOr amino-sulfonyl；
T is 0,1,2,3 or 4；With
Each r independently is 0,1 or 2.
In other embodiments, R9And R10Be each independently H, deuterium, methyl, ethyl, isopropyl, normal-butyl, isobutyl group, Sec-butyl, tert-butyl, methyl-OC (=O)-, ethyl-OC (=O)-, propyl-OC (=O)-, isopropyl-OC (=O)-, tertiary fourth Base-OC (=O)-, methyl-C (=O)-, ethyl-C (=O)-, isopropyl-C (=O)-, normal-butyl-C (=O)-, isobutyl group-C (=O)-, carbamoyl, methyl-carbamoyl, ethylamino formoxyl, methyl-OS (=O)2, cyclopropyl-OS (=O)2, first Base-S (=O)2O-, cyclopropyl-S (=O)2O- or amino-sulfonyl.
In some embodiments, the compounds of this invention has structure or formula shown in formula (II), (IIa), (IIb) or (III) (II), structural upright isomers, geometric isomer shown in (IIa), (IIb) or (III), tautomer, enantiomter, Nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug:
Wherein, A is-O- ,-S- ,-NH- ,-CH2-S-、-CH2-O-、-CH2-NH-、-O-CH2-、-NH-CH2-、-S-CH2- Or-CH2-CH2-；
Wherein, each R15It independently is H, deuterium, oxo (=O), F, Cl, Br, I, cyano, hydroxyl, C1-3Alkyl, C1-3Alkyl halide Base, C1-3Alkoxy, C1-3Alkoxy C1-3Alkyl, C1-3Halogenated alkoxy C1-3Alkyl, C1-3Alkylamino, C1-3Alkylthio group, C6-10Virtue Base amino, C6-10Aryloxy group, C1-9Heteroaryl, C1-9Heteroaryl oxygroup, C1-9Heteroaryl C1-3Alkyl, C3-8Naphthenic base or C2-10Heterocycle Base；
With each n1And n2It independently is 1,2,3 or 4.
In other embodiments, each R8And R8aIt independently is H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano, C1-6Alkyl, C1-6Deuteroalkyl, C1-6Halogenated alkyl, C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C2-10Heterocycle, C3-8Naphthenic base, sulfydryl, Nitro, C6-10Aryl C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C3-8Naphthenic base C1-6Alkyl, C2-10It is miscellaneous Ring group C1-6Alkyl, C6-10Arylamino, C1-9Heteroaryl amino, C6-10Aryl C1-6Alkylamino, C1-9Heteroaryl C1-6Alkylamino, C1-9Heteroaryl oxygroup, C6-10Aryl C1-6Alkoxy, C1-9Heteroaryl C1-6Alkoxy, C2-10Heterocycle oxygroup, C2-10Heterocycle C1-6Alkoxy, C2-10Heterocyclylamino group, C1-6Alkyl-OC (=O)-, C1-6Alkyl-C (=O)-, carbamoyl, C1-6Alkyl- OS (=O)r-、C1-6Alkyl-S (=O)rO-、C1-6Alkyl-OS (=O)rO-、C1-6Alkyl-S (=O)r-、C2-10Heterocycle C1-6Alkane Amino or C6-10Aryloxy group.
In other embodiments, wherein each R15It independently is H, deuterium, oxo (=O), F, Cl, Br, I, cyano, hydroxyl, first Base, ethyl, propyl, isopropyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy, methoxy, difluoro-methoxy first Base, trifluoromethoxy methyl, ethoxyl methyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, methylamino, ethylamino, phenylamino Base, phenoxy group, pyrrole radicals, morpholinyl or piperazinyl.
In some embodiments, each R5And R6Independently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano, C1-6Alkyl, C1-6Halogenated alkyl, C2-6Alkenyl, C2-6Alkynyl, C2-10Heterocycle, C3-8Naphthenic base, sulfydryl, nitro, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, C1-6Alkoxy, C6-10Arylamino, C1-9Heteroaryl ammonia Base, C6-10Aryl C1-6Alkylamino, C1-9Heteroaryl C1-6Alkylamino, C1-9Heteroaryl oxygroup, C1-9Heteroaryl C1-6Alkyl, C6-10Virtue Base C1-6Alkoxy, C1-9Heteroaryl C1-6Alkoxy, C2-10Heterocycle oxygroup, C2-10Heterocycle C1-6Alkoxy, C2-10Heterocycle ammonia Base, C1-6Alkyl acyl, C1-6Alkyl acyloxy, C1-6Alkoxyacyl, C2-10Heterocycle C1-6Alkylamino or C6-10Aryloxy group.
In other embodiments, each R5And R6It independently is H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyanogen Base, methyl, ethyl, propyl, isopropyl, normal-butyl, tert-butyl, trifluoromethyl, methoxy, methoxyl group, ethyoxyl, ethylene Base, allyl, acetenyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenyl, phenyl oxygroup, phenyl amino, sulfydryl or nitre Base.
In some embodiments, each R8And R8aIndependently be H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano, methyl, ethyl, Isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy Base, ethyoxyl, isopropoxy, methoxy, 1- methoxy ethyl, 2- methoxy ethyl, 1- methoxy-propyl, 2- methoxyl group Propyl, 3- methoxy-propyl, phenyl, pyranose, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, trifluoromethyl, vinyl, alkene Propyl, acetenyl, morpholinyl, sulfydryl, nitro, benzyl or anilino-.
On the other hand, the present invention provides a kind of pharmaceutical composition, described pharmaceutical composition includes any of the aboveization Close object.
In some embodiments, which can also further include pharmaceutically acceptable carrier, figuration Agent, diluent, adjuvant, medium or combinations thereof.
It in other embodiments, further include the drug of other HCV-Ab IgGs, wherein the HCV-Ab IgG Drug is interferon, Ribavirin, interleukin-22, interleukin 6, interleukin 12, promotes to generate the change of 1 type helper T lymphocyte response Close object, RNA interfering, antisense RNA, miaow quinoline not moral, inosine 5 '-monophosphate dehydrogenase inhibitor, amantadine, Rimantadine, bar Tie up former times monoclonal antibody, hepatitis C immunoglobulin, CivacirTM, boceprevir, tirrevir, Erlotinib, his Wei of Dacca, department's beauty Wei, Ah that Wei, vaniprevir, faldaprevir, paritaprevir, Dan Nuopuwei, sovaprevir, grazoprevir、vedroprevir、BZF-961、GS-9256、narlaprevir、ANA975、ombitasvir、EDP239、 Ravidasvir, velpatasvir, samatasvir, elbasvir, MK-8325, GSK-2336805, PPI-461, Xi Lurui Wei, sovaprevir, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX- 136, IDX-316, modithromycin, VBY-376, TMC-649128, mericitabine, Suo Feibuwei, INX-189, IDX-184、IDX102、R-1479、UNX-08189、PSI-6130、PSI-938、PSI-879、nesbuvir、HCV-371、 VCH-916、lomibuvir、MK-3281、dasabuvir、ABT-072、filibuvir、deleobuvir、tegobuvir、A- 837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055, Lei Dipawei, odalasvir, ritonavir、furaprevir、setrobuvir、alisporivir、BIT-225、AV-4025、ACH-3422、MK-2748、 MK-8325、JNJ-47910382、ABP-560、TD-6450、TVB-2640、ID-12、PPI-383、A-848837、RG-7795、 BC-2125, alloferon, nivolumab, WF-10, Nitazoxanide, multiferon, nevirapine, ACH-3422, I Moor Wei, MK-3682, MK-8408, GS-9857, CD-AdNS3, pibrentasvir, RG-101, glecaprevir, BZF- 961、INO-8000、MBL-HCV1、CIGB-230、TG-2349、procvax、CB-5300、miravirsen、chronvac-C、 MK-1075、ACH-0143422、WS-007、MK-7680、MK-2248、MK-8408、IDX-21459、AV-4025、MK-8876、 GSK-2878175、MBX-700、AL-335、JNJ-47910382、AL-704、ABP-560、TD-6450、EDP-239、SB- 9200, ITX-5061, ID-12 or combinations thereof；The interferon is Interferon Alpha-2b, the interferon-' alpha ' of Pegylation, interferon α -2a, the Intederon Alpha-2a of Pegylation, compound alpha-interferon, interferon gamma or combinations thereof.
In other embodiments, wherein it is described others HCV-Ab IgG drug for inhibit HCV reproduction process and/ Or inhibit the function of HCV virus albumen；The HCV reproduction process include HCV enter, HCV shelling, HCV translation, HCV duplication, HCV assembling or HCV release；The HCV virus albumen be selected from metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A or Internal ribosome inlet point (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for NS5B and HCV virus replicate.
On the other hand, the present invention provides the purposes of the compounds of this invention or pharmaceutical composition in medicine preparation, the medicine Object is used to inhibit HCV reproduction process and/or inhibit the function of HCV virus albumen；The HCV reproduction process include HCV enter, HCV shelling, HCV translation, HCV duplication, HCV assembling or HCV release；The HCV virus albumen be selected from metalloproteinases, NS2, Internal ribosome inlet point (IRES) and inosine required for NS3, NS4A, NS4B, NS5A or NS5B and HCV virus replicate Monophosphate dehydrogenase (IMPDH).
On the other hand, the present invention provides the purposes of the compounds of this invention or pharmaceutical composition in medicine preparation, the medicine Object is for preventing, handling, treating or mitigating HCV infection or hepatitis C disease.
Another aspect of the present invention be related to the compound that formula (I), (II), (IIa), (IIb) and (III) is included preparation, The method of separation and purifying.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its The content of his aspect will make more specific complete description below.
Detailed description of the invention book
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula or chemical formula explanation that are appended.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In range.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method and material described herein Trample the present invention.The present invention is not limited to method described herein and material.The one of the document, patent and the similar material that are combined Or more it is different from the application or in the case where contradicting it is (including but not limited to defined term, term application, described Technology, etc.), be subject to the application.
It will further be appreciated that certain features of the invention, be it is clearly visible, carry out in a number of independent embodiments Description, but can also provide in combination in a single embodiment.Conversely, various features of the invention, for brevity, It is described in a single embodiment, but can also be individually or with the offer of any suitable sub-portfolio.
Unless otherwise stated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood identical meaning.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.
Unless otherwise stated, following definition used herein should be applied.For purposes of the present invention, chemical element with The periodic table of elements CAS editions, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can join It examines " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Description in Wiley&Sons, New York:2007, entire contents are incorporated herein by reference.
There is apparent conflict unless otherwise indicated or in context, the article " one " used herein, " one (kind) " " described " is intended to include "at least one" or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more than one Component be taken into account in the embodiment of the embodiment and use or use.
Term " study subject " used in the present invention refers to animal.The typical animal is mammal.It is tested right As, such as also refer to primate (such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, small Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described by Trying object is people.
Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.
Term "comprising" is open language, that is, includes content specified by the present invention, but be not precluded otherwise Content.
" in some embodiments " or " in other embodiments " are used before technical characteristic definition in the present invention, indicate fixed herein The technical characteristic that the technical characteristic of justice can be drawn with others by " in some embodiments " or " in other embodiments " is any Be combined into complete technical solution.
" stereoisomer " refers to identical chemical constitution, but the spatially different change of arrangement mode of atom or group Close object.Stereoisomer includes enantiomter, diastereoisomer, conformer (rotational isomer), geometric isomer (cis/trans) isomers, atropisomer, etc..
" chirality " be with its mirror image cannot be overlapped property molecule；And " achirality " refer to can be overlapped with its mirror image Molecule.
" enantiomter " refers to two isomers that cannot be overlapped but be mutually mirror of a compound.
" diastereoisomer " refer to there are two or multiple chiral centers and its molecule not alloisomerism of mirror image each other Body.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral property and reactivity.Diastereoisomer is mixed Such as electrophoresis and chromatography, such as HPLC can be operated by high resolution analysis to separate by closing object.
Stereochemical definitions used in the present invention and rule generally follow 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.
Many organic compounds exist with optical active forms, i.e., they, which have, rotates the plane of linearly polarized light Ability.When describing optically active compound, indicate molecule about one or more hand using prefix D and L or R and S The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols for the rotation of linearly polarized light caused by appointed compound, Wherein (-) or l indicate that compound is left-handed.Prefix is (+) or the compound of d is dextrorotation.A kind of specific alloisomerism Body is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50:50 mixture of enantiomter Referred to as racemic mixture or racemic modification, when chemical reaction or in the process without stereoselectivity or stereospecificity when, It may occur in which such case.
Any asymmetric atom (for example, carbon etc.) of disclosed compound of present invention can be enriched with racemic or enantiomer Form exist, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer It is excessive.
According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they Mixture, such as the form of racemic modification and non-enantiomer mixture (this depends on the quantity of asymmetric carbon atom) deposits ?.Chiral synthon or chiral reagent preparation can be used in optically active (R)-or (S)-isomers, or is torn open using routine techniques Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing disubstituted cycloalkanes in compound The substituent group of base, naphthenic base may have cis or trans configuration.
The mixture of resulting any stereoisomer can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.
The racemic modification of any gained final product or intermediate can be passed through into those skilled in the art by known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Object can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Particularly, mapping Isomers can be prepared by asymmetric syntheses, for example, can refer to Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。
Term " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can achieve The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the recombination of some bonding electrons come The mutual inversion of phases carried out.The specific example of ketoenol tautomerization is that pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyl are mutual The interconversion of tautomeric.Another tautomeric example is phenol-keto tautomerism.One of phenol-keto tautomerism is specific real Example is the interconversion of pure and mild pyridine -4 (1H) the -one tautomer of pyridine -4-.Unless otherwise noted, the compounds of this invention is all Tautomeric forms are within the scope of the present invention.
Intranuclear tautomerism (Annular tautomerism) is the tautomeric one kind of proton translocation, and wherein proton can To account for two or more positions in heterocycle, the two isomers are coexisted in an equilibrium system, mutual with quite high rate Phase inversion.Such as: 1H- and 3H- imidazoles；1H, 2H- and 4H-1,2,4- triazole；1H- and 2H- iso-indoles.It is involved in the present invention Structure fragment, following structure fragment Aa and Ab or Ba and Bb, be intranuclear tautomerism body；Since two isomers coexist, it is Narration is easy, and the present invention only refers to the structure of one of isomers, i.e., where in office refers to that intranuclear tautomerism body is wherein appointed What a kind of structure, then it represents that also another structure is referred to simultaneously, although such as the chemical combination for only providing the structure fragment containing Aa in the present invention Object, but the compound that the tautomer of the compound contains structure fragment Ab is substantially also while providing；Although such as this hair Only occurs the compound of the structure fragment containing Ba in bright, but the tautomer of the compound contains the compound reality of structure fragment Bb Matter is also to provide simultaneously.
As described in the invention, the compound of the present invention can be optionally replaced one or more substituent groups, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included. It should be appreciated that this term can be used interchangeably " optionally replacing " this term with " substituted or non-substituted ".In general, art " substituted " the one or more hydrogen atoms indicated in given structure of language are replaced specific substituent group.Unless other aspect tables Bright, an optional substituent group can be replaced at various substitutable position of that group.When in given structural formula not Only a position can be replaced one or more substituent groups selected from specific group, then substituent group can identical or differently Replace at various locations.When substituent group is described as " being independently selected from " group, then each substituent group selects independently of one another, therefore Each substituent group can be the same or different from each other.
In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode " each ... independently be " and " ... be each independently " and " ... independently be " can be interchanged, and shall be understood in a broad sense, both may be used To refer among the different groups, does not influence mutually, can also indicate in phase between expressed specific option between the same symbol In same group, do not influenced mutually between expressed specific option between the same symbol.
It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention according to radical species or range.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C1-6Alkyl " refers in particular to the methyl being individually disclosed, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
In each section of the invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then respectively represents it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.
Terminology used in the present invention " alkyl " or " alkyl group ", indicate contain 1 to 20 carbon atom, the straight chain of saturation or Branch univalent hydrocarbyl group, wherein the substituent group institute that the alkyl group can be described optionally by one or more present invention Replace.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1- 12 carbon atoms；In another embodiment, alkyl group contains 1-6 carbon atom；In yet another embodiment, alkyl group Contain 1-4 carbon atom；Also in one embodiment, alkyl group contains 1-3 carbon atom.
The example of alkyl group includes, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n- Pr、-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,- CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), tert-butyl (t-Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyl (- CH (CH3)CH2CH2CH3), 3- amyl (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl-1-butyl (- CH2CH2CH(CH3)2), 2- first Base -1- butyl (- CH2CH(CH3)CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 2- hexyl (- CH (CH3) CH2CH2CH2CH3), 3- hexyl (- CH (CH2CH3)(CH2CH2CH3)), 2- methyl -2- amyl (- C (CH3)2CH2CH2CH3), 3- first Base -2- amyl (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- amyl (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- penta Base (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc..
Term " halogenated alkyl ", or " halogenated alkoxy " indicate alkyl or alkoxy base by one or more halogen atoms Replaced, such example includes, but is not limited to, trifluoromethyl, trifluoromethoxy etc..
Term " hydroxy alkyl " or " alkyl that hydroxyl replaces " indicate that alkyl group is taken by one or more hydroxyl groups In generation, wherein alkyl group has meaning of the present invention.Such example includes, but is not limited to methylol, ethoxy, 1, 2- dihydroxy ethyl etc..
Term " aminoalkyl " or " alkyl that amino replaces " indicate that alkyl group is taken by one or more amino groups In generation, wherein alkyl group has meaning of the present invention.
Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In an embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom；? In another embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can be optionally one or more Replaced the substituent group that the present invention describes.
Term " alkoxyalkyl " indicates that alkoxy base is connected by alkyl with molecule rest part, wherein alkoxy with Alkyl group has meaning as described in the present invention.The example of alkoxy-alkyl group includes, but is not limited to, methoxy methyl Base, methoxy ethyl, 2- methoxy ethyl, methoxy-propyl, ethoxyl methyl, ethoxyethyl group, 1- propoxy methyl, 2- third Oxygroup ethyl, 1- butoxymethyl, 2- methyl-l- Among, 2- butoxymethyl, etc..
Term " alkyl acyl " or " alkoxyacyl " indicate that alkyl or alkoxy pass through acyl group and molecule rest part phase Even, wherein alkyl, alkoxy and acyl group have meaning as described in the present invention.In some embodiments, this kind of embodiment can be with For alkyl-OC (=O)-, alkyl-OS (=O)r, alkyl-C (=O)-, alkyl-S (=O)r-。
Term " alkyl acyloxy " or " alkoxy acyloxy " indicate alkyl or alkoxy by acyloxy and molecule remaining Part is connected, and wherein alkoxy, alkyl and acyloxy have meaning as described in the present invention.In some embodiments, this kind of reality Applying example can be alkyl-C (=O) O-, alkyl-OC (=O) O-, alkyl-S (=O)rO-, alkyl-OS (=O)rO-。
Term " acyl group " refers to remaining monovalent radical after organic or inorganic oxyacid removes hydroxyl, general formula R-M (=O)-.M atom in usual acyl group is all carbon, sulphur.Term " acyloxy " refers to that acyl group passes through oxygen atom and its remaining part of molecule The group general formula of split-phase even is R-M (=O) O-.
Term " halogenated alkoxy alkyl " indicates that halogenated alkoxy passes through the group that alkyl is connected with molecule rest part, Middle halogenated alkoxy and alkyl have meaning as described in the present invention.
Term " alkylamino " or " alkyl amino " include " N- alkyl amino " and " N, N- dialkyl amido ", wherein amino base Group is separately replaced one or two alkyl group.Some of embodiments are that alkyl amino is one or two C1-6Alkyl is connected to the alkylamino group on nitrogen-atoms.Other embodiment is that alkyl amino is one or two C1-3 Alkyl is connected to the alkylamino group on nitrogen-atoms.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amino Base, such example include, but is not limited to, N- methylamino, N- ethylamino, N, N- dimethylamino, N, N- lignocaine etc..
Term " alkyl amino alkyl " indicates that alkylamino passes through the group that alkyl is connected with molecule rest part, wherein alkylamino There is meaning as described in the present invention with alkyl.
Term " alkylthio group " indicates that alkyl group passes through the group that sulphur atom is connected with molecule rest part, and wherein alkyl has There is meaning as described in the present invention.
Term " alkylthio alkyl " indicates that alkylthio group passes through the group that alkyl is connected with molecule rest part, wherein alkylthio group There is meaning as described in the present invention with alkyl.
Term " alkenyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is a carbon-to-carbon sp2Double bond, wherein the alkenyl group can be retouched optionally by one or more present invention Replaced the substituent group stated comprising the positioning of " cis " and " trans ", or the positioning of " E " and " Z ".In an embodiment In, alkenyl group includes 2-8 carbon atom；In another embodiment, alkenyl group includes 2-6 carbon atom；In another reality It applies in scheme, alkenyl group includes 2-4 carbon atom.The example of alkenyl group includes, but is not limited to, vinyl (- CH= CH2), allyl (- CH2CH=CH2) etc..
Term " alkynyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is tri- key of carbon-to-carbon sp, wherein the alkynyl group can be retouched optionally by one or more present invention Replaced the substituent group stated.In one embodiment, alkynyl group includes 2-8 carbon atom；In another embodiment, alkynyl Group includes 2-6 carbon atom；In yet another embodiment, alkynyl group includes 2-4 carbon atom.The example packet of alkynyl group It includes, but is not limited to, acetenyl (- C ≡ CH), propargyl (- CH2C ≡ CH), 1- propinyl (- C ≡ C-CH3) etc..
Term " naphthenic base " indicates containing 3-12 carbon atom, monovalent or multivalence saturation monocycle, bicyclic or three ring bodies System.In one embodiment, naphthenic base includes 3-12 carbon atom；In another embodiment, naphthenic base includes that 3-8 carbon is former Son；In yet another embodiment, naphthenic base includes 3-6 carbon atom.
Term " cycloalkyl-alkyl " indicates that naphthenic base passes through the group that alkyl is connected with molecule rest part, wherein naphthenic base There is meaning as described in the present invention with alkyl.
Term " heterocycle " and " heterocycle " are used interchangeably here, all refer to the saturation comprising 3-12 annular atom or portion Divide unsaturated monocyclic, bicyclic or tricyclic, wherein at least one annular atom is selected from nitrogen, sulphur and oxygen atom, but wherein at least one Ring is not belonging to aromatic.Unless otherwise stated, heterocycle can be carbon-based or nitrogen base, and-CH2Group can optionally by- C (=O)-substitution.The sulphur atom of ring can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can be optionally oxidized to N- oxygen compound.The example of heterocycle includes, but are not limited to: Oxyranyle, azelidinyl, oxetanylmethoxy, thia ring Butyl, pyrrolidinyl, 2- pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydro Furyl, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, Dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dioxanes base, dithianyl, thiophene are disliked Alkyl, high piperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase, sulphur azepineBase, indoline base, 1,2,3,4- tetrahydro isoquinolyl, 1,3- benzo two dislike cyclopentadienyl, 2- oxa- -5- azabicyclo [2.2.1] Hept- 5- base.- CH in heterocycle2Group includes, but are not limited to 2- oxo-pyrrolidine base, oxo-by-C (the O)-example replaced 1,3- thiazolidinyl, 2- piperidone base, 3,5- dioxy piperazine piperidinyl and hybar X base.The reality that sulphur atom is oxidized in heterocycle Example includes, but are not limited to sulfolane base, 1,1- dioxothiomorpholinyl.The heterocyclyl groups can be optionally by one Replaced a or multiple substituent groups described in the invention.
In one embodiment, heterocycle is 3-8 former molecular heterocycle, refers to satisfying comprising 3-8 annular atom And/or the unsaturated monocycle in part, wherein at least one annular atom are selected from nitrogen, sulphur and oxygen atom.Unless otherwise stated, 3-8 original Molecular heterocycle can be carbon-based or nitrogen base, and-CH2Group can be substituted optionally by-C (=O)-.The sulphur atom of ring S- oxide can be optionally oxidized to.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.4-7 atom group At the example of heterocycle include, but are not limited to: azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2- pyrrole Cough up quinoline base, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuryl, Tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiophene It mutters base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dioxanes base, dithianyl, thiophene oxane base, high piperazine base, high piperazine Piperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase, sulphur azepineBase.- CH in heterocycle2- Group includes, but are not limited to 2- oxo-pyrrolidine base, oxo -1,3-thiazoles alkyl, 2- piperidines by-C (=the O)-example replaced Ketone group, 3,5- dioxy piperazine piperidinyl and hybar X base.The example that sulphur atom is oxidized in heterocycle includes, but are not limited to ring Fourth sulfuryl, 1,1- dioxothiomorpholinyl.Described 3-8 former molecular heterocyclyl groups can optionally by one or Replaced multiple substituent groups described in the invention.
In another embodiment, heterocycle is 4 molecular heterocycles of original, refers to the saturation comprising 4 annular atoms Or the unsaturated monocycle in part, wherein at least one annular atom are selected from replaced nitrogen, sulphur and oxygen atom.Unless otherwise stated, 4 Former molecular heterocycle can be carbon-based or nitrogen base, and-CH2Group can be substituted optionally by-C (=O)-.The sulphur of ring is former Son can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.4 atom groups At the example of heterocycle include, but are not limited to: azelidinyl, oxetanylmethoxy, thietanyl.4 atoms The heterocyclyl groups of composition can be optionally replaced one or more substituent groups described in the invention.
In another embodiment, heterocycle is 5 molecular heterocycles of original, refers to the saturation comprising 5 annular atoms Or the unsaturated monocycle in part, wherein at least one annular atom are selected from nitrogen, sulphur and oxygen atom.Unless otherwise stated, 5 atom groups At heterocycle can be carbon-based or nitrogen base, and-CH2Group can be substituted optionally by-C (=O)-.The sulphur atom of ring can be with Optionally it is oxidized to S- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.5 originals are molecular miscellaneous The example of ring group includes, but are not limited to: pyrrolidinyl, 2- pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazoles Quinoline base, imidazolidinyl, tetrahydrofuran base, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur Cyclopenta.- CH in heterocycle2Group includes, but are not limited to 2- oxo-pyrrolidine base, oxygen by-C (=the O)-example replaced Generation -1,3- thiazolidinyl.The example that sulphur atom is oxidized in heterocycle includes, but are not limited to sulfolane base.5 originals Molecular heterocyclyl groups can be optionally replaced one or more substituent groups described in the invention.
In another embodiment, heterocycle is 6 molecular heterocycles of original, refers to the saturation comprising 6 annular atoms Or the unsaturated monocycle in part, wherein at least one annular atom are selected from nitrogen, sulphur and oxygen atom.Unless otherwise stated, 6 atom groups At heterocycle can be carbon-based or nitrogen base, and-CH2Group can be substituted optionally by-C (=O)-.The sulphur atom of ring can be with Optionally it is oxidized to S- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.6 originals are molecular miscellaneous The example of ring group includes, but are not limited to: THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio Quinoline base, piperazinyl, dioxanes base, dithianyl, thiophene oxane base.- CH in heterocycle2The example that group is replaced by-C (=O)- Include, but are not limited to 2- piperidone base, 3,5- dioxy piperazine piperidinyl and hybar X base.Sulphur atom is oxidized in heterocycle Example includes, but are not limited to 1,1- dioxothiomorpholinyl.6 molecular heterocyclyl groups of original can be optional Ground is replaced one or more substituent groups described in the invention.
Also in one embodiment, heterocycle is 7-12 former molecular heterocycle, is referred to comprising 7-12 annular atom The unsaturated spiral shell of saturation or part is bicyclic or condensed-bicyclic, wherein at least one annular atom is selected from nitrogen, sulphur and oxygen atom.Unless In addition illustrate, 7-12 former molecular heterocycle can be carbon-based or nitrogen base, and-CH2Group can optionally by-C (= O)-substitution.The sulphur atom of ring can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen Compound.The example of 7-12 former molecular heterocycle includes, but are not limited to: indoline base, 1,2,3,4- tetrahydroisoquinoline Base, 1,3- benzo two dislike cyclopentadienyl, 2- oxa- -5- azabicyclo [2.2.1] hept- 5- base.Described 7-12 is former molecular miscellaneous Cyclic groups can be optionally replaced one or more substituent groups described in the invention.
Term " heterocycle oxygroup " or " heterocyclylamino group " indicate heterocycle by oxygen atom or nitrogen-atoms and molecule remaining The connected group in part, wherein heterocycle has meaning of the present invention.
Term " heterocyclylalkyl group " includes the alkyl that heterocycle replaces；Term " heterocyclylalkoxy " includes that heterocycle replaces Alkoxy, wherein oxygen atom is connected with the rest part of molecule；Term " heterocycle alkylamino " includes the alkane that heterocycle replaces Amino, wherein nitrogen-atoms is connected with the rest part of molecule.Wherein heterocycle, alkyl, alkoxy and alkylamino have such as this hair The bright meaning, such example include, but is not limited to pyrroles -2- ylmethyl, morpholine -4- base ethyl, morpholine -4- base second Oxygroup, piperazine -4- base oxethyl, piperidin-4-yl ethylamino etc..
Term " aryl " indicates the monocycle containing 6-14 annular atom or 6-12 annular atom or 6-10 annular atom, double The carbocyclic ring system of ring and tricyclic, wherein at least one ring system be it is aromatic, wherein each ring system include 3-7 original Molecular ring, and there are one or more attachment points to be connected with the rest part of molecule.Term " aryl " can be with term " fragrance Ring " is used interchangeably.The example of aryl group may include phenyl, naphthalene and anthracene.The aryl group can individually optional ground quilt Replaced one or more substituent groups described in the invention.
Term " aryloxy group " indicates that aryl passes through the group that oxygen atom is connected with molecule rest part, and wherein aryl has this The invention meaning.
Term " fragrant amino " " arylamino " expression amino group is replaced one or two aryl group, such reality Example includes, but is not limited to N- phenylamino.Some of embodiments are that the aromatic ring in fragrant amino can be further substituted.
Term " aryl alkyl " includes the alkyl that aryl replaces, and wherein alkyl is connected with the rest part of molecule；Term " virtue Base alkoxy " includes the alkoxy that aryl replaces, and wherein oxygen atom is connected with the rest part of molecule；Term " aryl alkane amino " Including the alkylamino that aryl replaces, wherein nitrogen-atoms is connected with the rest part of molecule.Wherein aryl, alkyl, alkoxy and alkane Amino has meaning as described in the present invention.
Monocycle of term " heteroaryl " expression containing 5-12 annular atom or 5-10 annular atom or 5-6 annular atom, Bicyclic and three-ring system, wherein at least one ring system are aromatic, and at least one ring system includes one or more miscellaneous Atom, wherein each ring system includes 5-7 former molecular ring, and has one or more attachment points and molecule rest part It is connected.Term " heteroaryl " can be used interchangeably with term " hetero-aromatic ring " or " heteroaromatics ".The heteroaryl groups are appointed Selection of land is replaced one or more substituent groups described in the invention.In one embodiment, 5-10 original is molecular miscellaneous Aryl includes 1,2,3 or 4 hetero atom for being independently selected from O, S and N.The example of heteroaryl groups includes, but is not limited to, 2- furan Mutter base, 3- furyl, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyl, 4- isoxazolyl, 5- is different Oxazolyl, 2- oxazolyl, 4- oxazolyl, 5- oxazolyl, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridyl group, 3- pyridine Base, 4- pyridyl group, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals, pyridazinyl (such as 3- pyridazinyl), 2- thiazolyl, 4- thiazolyl, 5- thiazolyl, tetrazole radical (such as 5- tetrazole radical), triazolyl (such as 2- triazolyl and 5- triazolyl), 2- thienyl, 3- thienyl, pyrrole Oxazolyl (such as 2- pyrazolyl), isothiazolyl, 1,2,3- oxadiazoles base, 1,2,5- oxadiazoles base, 1,2,4- oxadiazoles base, 1,2,3- Triazolyl, 1,2,3- thio biphosphole base, 1,3,4- thio biphosphole base, 1,2,5- thio biphosphole base, pyrazinyl, 1,3,5- triazine Base；It also include below bicyclic, but it is bicyclic to be not limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indoles Base (such as 2- indyl), purine radicals, quinolyl (such as 2- quinolyl, 3- quinolyl, 4- quinolyl), isoquinolyl (such as 1- isoquinoline Quinoline base, 3- isoquinolyl or 4- isoquinolyl), imidazo [1,2-a] pyridyl group, pyrazolo [1,5-a] pyridyl group, pyrazolo [1,5-a] pyrimidine radicals, imidazo [1,2-b] pyridazinyl, [1,2,4] triazol [4,3-b] pyridazinyl, [1,2,4] triazol [1, 5-a] pyrimidine radicals, [1,2,4] triazol [1,5-a] pyridyl group, etc..
Term " heteroaryloxy " indicates that heteroaryl passes through the group that oxygen atom is connected with molecule rest part, wherein heteroaryl With meaning of the present invention.
Term " heteroaryl amino " " heteroaryl amino " indicates amino group replaced one or two heteroaryl groups.
Term " heteroaryl alkyl " includes the alkyl that heteroaryl replaces, and wherein alkyl is connected with the rest part of molecule；Art Language " heteroarylalkoxy " includes the alkoxy that heteroaryl replaces, and wherein oxygen atom is connected with the rest part of molecule；Term is " miscellaneous Aryl alkane amino " includes the alkylamino that heteroaryl replaces, and wherein nitrogen-atoms is connected with the rest part of molecule.Wherein heteroaryl, Alkyl, alkoxy and alkylamino have meaning as described in the present invention.
Term " carbocylic radical " and " carbocyclic ring " are used interchangeably here, all refer to the saturation comprising 3-12 carbon atom or portion Divide unsaturated monocyclic, bicyclic or tricyclic, but wherein at least one ring is not belonging to aromatic.Unless otherwise stated, on carbocyclic ring - CH2Group can be substituted optionally by-C (=O)-.Carbocylic radical includes 3-8 carbon atom in some embodiments.One In a little embodiments, carbocylic radical includes 5 carbon atoms.In some embodiments, carbocylic radical includes 6 carbon atoms.
Term " condensed-bicyclic ", " condensed-bicyclic base " are used interchangeably here, all refer to unit price or multivalence saturation or Part is unsaturated and ring system, described and ring system refer to the bicyclic system of non-aromatic.Such system may include solely Vertical or conjugation unsaturated system, but its nuclear structure does not include aromatic rings or heteroaromatic (but aromatic group can be made For substituent group thereon).In some embodiments, condensed-bicyclic contains 5-12 carbon atom.
Term " loop coil base ", " spiral shell bicyclic group " are used interchangeably here, and the saturation for referring to unit price or multivalence or part are not Saturated ring system, one of ring is originating from specific ring carbon atom on another ring.In some embodiments, bicyclic contain is screwed togather There is 5-12 carbon atom.
For example, as disclosed below, saturation and ring system (ring B and B ') be referred to as " condensed-bicyclic ", and ring A A carbon atom, referred to as " loop coil " or " spiral shell is bicyclic " are shared in the ring system being saturated with ring B at two.
When the annular atom in " condensed-bicyclic " or " spiral shell is bicyclic " contains at least one hetero atom, " condensed-bicyclic base " or " spiral shell bicyclic group " is referred to as " condensing miscellaneous bicyclic " or " spiral shell is miscellaneous bicyclic ", wherein each ring can be carbocylic radical or heterocycle.? In some embodiments, condenses miscellaneous bicyclic or screw togather miscellaneous bicyclic containing 5-12 carbon atom.
Term " oxo " indicates that quilt=O replaces.
Term " hydroxyl " expression-OH.
Term " amino " expression-NH2。
Term " cyano " expression-CN.
Term " sulfydryl " expression-SH.
Term " nitro " expression-NO2。
Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " hetero atom " refers to O, S, N, P and Si, the form including any oxidation state of N, S and P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the substituted form of hydrogen in heterocycle on nitrogen-atoms, for example, N is (as in 3,4- dihydro-2 h-pyrrole base N), NH (as the NH in pyrrolidinyl) or NR (NR in pyrrolidinyl replaced as N-).
Term " n former molecular ", wherein n is integer, the typical number for describing ring member nitrogen atoms in molecule, described The number of ring member nitrogen atoms is n in molecule.For example, piperidyl is 6 molecular Heterocyclylalkyls of original, and 1,2,3,4- naphthane is The molecular carbocylic radical group of 10 originals.
Contain one or more degrees of unsaturation in " unsaturated " the expression group of term as used in the present invention.
As described in the present invention, substituent group draw one be keyed to formed on the ring at center ring system (as formula (b1), (b2), shown in (b3)) represent substituent group (R5)n、R6、(R15)n1It can be replaced any substitutive position on ring.
When term " blocking group " or " PG " refer to a substituent group and other reacted with functional groups, commonly used to resistance It is disconnected or protect special functionality.For example, " blocking group of amino " refers to that a substituent group is connected to block with amino group Or the functionality of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9- fluorenes methylene oxygen carbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl The substituent group of base is used to block or protect the functionality of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl Blocking group " refers to that the substituent group of carboxyl is used to block or protect the functionality of carboxyl, general carboxyl-protecting group includes- CH2CH2SO2Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxyl methyl, 2- are (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The general description of group can refer to document: T W.Greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme, Stuttgart,2005.
Term " prodrug " used in the present invention, represent a compound be converted into vivo formula (I), (II), (IIa), (IIb) and (III) compound represented.Such conversion is hydrolyzed or in blood or tissue by pro-drug through enzyme in blood It is converted into the influence of precursor structure.Pro-drug compounds of the present invention can be ester, and ester can be used as in existing invention Pro-drug has phenyl ester class, aliphatic (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino Esters of gallic acid.Such as a compound in the present invention includes hydroxyl, it can is acylated to obtain the chemical combination of prodrug form Object.Other prodrug forms include phosphate, if these phosphate compounds are obtained through the di on parent It arrives.Following documents: T.Higuchi and V.Stella, Pro-drugs can be referred to by completely discussing about pro-drug 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。
" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change The metabolite for closing object can be identified that activity can be retouched by such as the present invention by technology well-known in the art It adopts as stating and is experimentally characterized.Such product can be by passing through oxidation, reduction, water to drug compound The methods of solution, amidated, deamidation, esterification, degreasing, enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. documented.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by recorded in books, literature Other methods such as ion-exchanges obtain these salt.Other pharmaceutically acceptable salts include adipate, alginates, resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acid Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphur Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that alkali appropriate obtains includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any The compound of the group of included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be turned by quaternary ammonium With obtaining.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises fitting When, amine cation that nontoxic ammonium, quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid Compound, phosphoric acid compound, nitric acid compound, C1-8Sulphonic acid compound and aromatic sulphonic acid compound.
" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
Any disease of term " treatment " or illness as used in the present invention, refer to improvement disease in some of these embodiments Disease or illness (development for slowing down or prevent or mitigate disease or its at least one clinical symptoms).In other embodiments In, " treatment " refers to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.Another In a little embodiments, " treatment " refers to from body (such as stablizing perceptible symptom) or physiologically (such as stable body Parameter) or above-mentioned two aspect adjust disease or illness.In other embodiments, " treatment ", which refers to, prevents or delays disease or disease Breaking-out, generation or the deterioration of disease.
Pharmaceutical acid-addition salts can be formed with inorganic acid and organic acid, such as acetate, aspartate, benzoic acid Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination Object/hydrochloride, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, apple Hydrochlorate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate, Nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, poly- half Lactobionate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetic acid Salt.
The inorganic acid that salt can be obtained by its derivative includes such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid.
The organic acid that salt can be obtained by its derivative includes such as acetic acid, propionic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, sulfo group water Poplar acid etc..
Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.
Can obtain the inorganic base of salt by its derivative includes, for example, ammonium salt and periodic table I race to XII race metal.? In certain embodiments, which is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salts.
Can obtain the organic base of salt by its derivative includes primary amine, secondary amine and tertiary amine, and substituted amine includes naturally occurring Substituted amine, cyclic amine, deacidite etc..Certain organic amines include, for example, isopropylamine, tardocillin (benzathine), choline salt (cholinate), diethanol amine, diethylamine, lysine, meglumine (meglumine), piperazine And tromethamine.
Officinal salt of the invention can be synthesized with conventional chemical processes by parent compound, alkalinity or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Hydroxide, carbonate, bicarbonate of Mg or K etc.) reaction, or free alkali form and chemistry by making these compounds The suitable acid reaction of metered amount is to be prepared.Such reaction usually carries out in the mixture of water or organic solvent or both. Generally, in appropriate cases, it needs using non-aqueous medium such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile.? Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985)；" pharmaceutical salts handbook: property, selection and application (Handbook of Pharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list that other is suitable for salt can be found in.
In addition, compound disclosed by the invention in the form of their hydrate or can also include it including their salt The form of solvent (such as ethyl alcohol, DMSO, etc.) obtains, for their crystallization.Disclosed compound of present invention can be with pharmacy Upper acceptable solvent (including water) forms solvate inherently or by design；Therefore, the present invention is intended to include solvations And unsolvated form.
Any structural formula that the present invention provides, which is also intended to, indicates these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more A atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Isotope including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as2H,3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I。
On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, for example, its In there are radioactive isotopes, such as3H、14C and18Those of F compound, or wherein there is non radioactive isotope, such as2H and13C.The compound of such isotope enrichment can be used for being metabolized research and (use14C), Reaction kinetics research are (using for example2H or3H), detection or imaging technique, such as positron emission tomography (PET) or including drug or substrate tissue measure of spread Single photon emission computed tomography (SPECT), or can be used in the radiotherapy of patient.18The compound of F enrichment to PET or It is especially desirable for SPECT research.Compound shown in the formula (I) of isotope enrichment can be ripe by those skilled in the art It is substituted described by the embodiment and preparation process in routine techniques or the present invention known using suitable isotope labeling reagent former Carry out used unmarked reagent to prepare.
In addition, higher isotope especially deuterium (that is,2H or D) substitution can provide certain treatment advantages, these advantages are By the higher bring of metabolic stability.For example, Half-life in vivo increase or reduction of volume requirements or therapeutic index obtain improving band Come.It should be appreciated that the deuterium in the present invention is seen as the substituent group of formula (I), (II), (IIa), (IIb) and (III) compound. The concentration of such higher isotope especially deuterium can be defined with isotope enrichment factor.Term used in the present invention is " same The plain enrichment factor in position " refers to the ratio between the isotope abundance and natural abundance of specified isotope.If chemical combination of the present invention The substituent group of object is designated as deuterium, and the compound is for each specified D-atom at least 3500 (at each specified D-atom 52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporations), at least 5000 (75% Deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporations), at least 6333.3 (95% deuteriums Incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporations) or at least 6633.3 (99.5% deuteriums Incorporation) isotope enrichment factor.The pharmaceutical solvate of the present invention can be isotope substitution including wherein recrystallisation solvent Such as D2O, acetone-d6、DMSO-d6Those of solvate.
On the other hand, the present invention relates to the compounds that preparation formula (I), (II), (IIa), (IIb) and (III) are included Intermediate.
The preparation for the compound on the other hand, being included the present invention relates to formula (I), (II), (IIa), (IIb) and (III), The method of separation and purifying.
On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes the compounds of this invention, pharmacy Upper acceptable carrier, excipient, diluent, adjuvant, solvent or their combination.In some embodiments, pharmaceutical composition It can be liquid, solid, semisolid, gel or spray-type.
" joint " indicates the medicine box of the fixed Combination in single dose unit form or the part for combined administration, Middle disclosed compound of present invention and combined partner can be in same time individual applications or can be at a certain time interval It applies respectively, joint companion is especially made to show cooperation, for example act synergistically.Term " co-administered " as used herein or " administering drug combinations " etc. are intended to include single individual (such as the patient) for being applied to selected COMBINATION OF THE INVENTION and needing it, and are intended to Including wherein substance without going through identical administration method or the therapeutic scheme being administered simultaneously.Term " medicine group as used herein Close product " it indicates to mix or combine obtained product for more than one active constituents, and both include the fixation of active constituent Combination also includes non-fixed combinations.Term " fixing joint " indicate active constituent such as disclosed compound of present invention and COMBINATION OF THE INVENTION with Single entities or the form of dosage are administered simultaneously in patient.Term " on-fixed joint " indicates that the active constituent such as present invention comes into the open It closes object and COMBINATION OF THE INVENTION is used as corpus separatum to be successively applied to patient simultaneously, jointly or without specific time limitation ground, wherein should It is applied in patient's body and provides the treatment effective level of two kinds of compounds.The latter applies also for cocktail therapy, such as application 3 Kind or more active constituent.
It should be noted that the term " inhibiting HCV virus albumen " in the present invention shall be understood in a broad sense, it has both included inhibiting The expression of HCV virus albumen also includes the activity level for inhibiting HCV virus albumen, viral assembling and emission levels.Its In, HCV protein expression level includes but is not limited to: the translation skill of viral protein gene, the posttranslational modification of albumen are horizontal, sub For the levels of replication etc. of inhereditary material.
The description of the compounds of this invention
The present invention relates to the methods of HCV-Ab IgG infection.The compounds of this invention or pharmaceutical composition have good suppression to HCV infection Production is used.
On the one hand, the present invention relates to a kind of compounds, are compound shown in formula (I) compound represented or formula (I) Stereoisomer, geometric isomer, tautomer, enantiomter, nitrogen oxides, hydrate, solvate, metabolism produce Object, pharmaceutically acceptable salt or prodrug,
Wherein, A is-(CR7R7a)m-、-CR7=CR7a-、-(CH2)nO- ,-N=CR7-、-NR7-CR7R7a-、-CR7R7a- NR7-、-O(CH2)n-、-CR7=N- ,-S (CH2)n-、-(CH2)nS- or-NR9a-；
X and X1It is each independently N or CR7b；
Y and Y1Be each independently H, deuterium, alkyl, naphthenic base, heterocycle, aryl, heteroaryl, aryl alkyl ,-C (= O)-(CR8R8a)t-N(R9)-R10Or a-amino acid group；
Wherein a-amino acid group is selected from isoleucine, leucine, lysine, methionine, phenylalanine, threonine, color Propylhomoserin, valine, alanine, asparagine, aspartic acid, glutamic acid, glutamine, proline, serine, to tyrosine, essence Propylhomoserin, histidine, cysteine, glycine, sarcosine, N, N- dimethylglycine, homoserine, norvaline, just bright ammonia Acid, ornithine, homocysteine, homophenylalanin, phenylglycine, adjacent tyrosine, m-Tyrosine or hydroxy-proline institute shape At group；
R1、R2、R3And R4It is each independently H, deuterium, alkyl, aryl alkyl, naphthenic base, heterocycle, heteroaryl or aryl； Or R1、R23-8 circle heterocyclic ring is randomly formed with X-CH, 3-8 member carbocyclic ring, condensed-bicyclic, condenses that miscellaneous bicyclic, spiral shell is bicyclic or spiral shell is miscellaneous double Ring；Or R3、R4With X1- CH is randomly formed 3-8 circle heterocyclic ring, 3-8 member carbocyclic ring, condensed-bicyclic, condenses that miscellaneous bicyclic, spiral shell is bicyclic or spiral shell It is miscellaneous bicyclic；
Each R5And R6Independently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano, alkyl, halogenated alkyl, Alkenyl, alkynyl, heterocycle, naphthenic base, sulfydryl, nitro, aryl, heteroaryl, aryl alkyl, alkoxyalkyl, alkoxy, aryl Amino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heteroaryl oxygroup, heteroaryl alkyl, alkoxy aryl, heteroaryl It is base alkoxy, heterocycle oxygroup, heterocyclylalkoxy, heterocyclylamino group, alkyl acyl, alkyl acyloxy, alkoxyacyl, miscellaneous Ring group alkylamino or aryloxy group；
Each R7、R7a、R7b、R8、R8aAnd R9aIndependently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano, Deuteroalkyl, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, heterocycle, naphthenic base, sulfydryl, nitro, aryl, heteroaryl, Aryl alkyl, alkoxyalkyl, heteroaryl alkyl, cycloalkyl-alkyl, heterocyclylalkyl group, arylamino, heteroaryl amino, aryl Alkylamino, heteroarylalkylamino, heteroaryl oxygroup, alkoxy aryl, heteroarylalkoxy, heterocycle oxygroup, heterocyclylalkoxy Base, heterocyclylamino group, alkyl-OC (=O)-, alkyl-C (=O)-, carbamoyl, alkyl-OS (=O)r, alkyl-S (= O)rO-, alkyl-OS (=O)rO-, alkyl-S (=O)r, heterocycle alkylamino or aryloxy group；
Each R9And R10It independently is H, deuterium, alkyl, naphthenic base, heterocycle, aryl, heteroaryl, aryl alkyl, alkyl-OC (=O)-, alkyl-C (=O)-, carbamoyl, alkyl-OS (=O)r, alkyl-S (=O)rO-, alkyl-S (=O)rOr ammonia Base sulfonyl；
Each f, n and t independently are 0,1,2,3 or 4；
M is 1,2,3 or 4；With
Each r independently is 0,1 or 2；
Wherein each following group: alkyl, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl, aryl alkyl ,-C (=O)-(CR8R8a)t-N(R9)-R10, a-amino acid group, 3-8 circle heterocyclic ring, 3-8 member carbocyclic ring, condensed-bicyclic, condense it is miscellaneous it is bicyclic, Spiral shell is bicyclic, the miscellaneous bicyclic, halogenated alkyl of spiral shell, alkenyl, alkynyl, alkoxyalkyl, heteroaryl alkyl, cycloalkyl-alkyl, heterocycle alkane Base, arylamino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, aryloxy group, heteroaryl oxygroup, alkoxy aryl, Heteroarylalkoxy, heterocycle oxygroup, heterocyclylalkoxy, heterocyclylamino group, alkyl-OC (=O)-, alkyl-C (=O)-, ammonia Base formoxyl, alkyl-OS (=O)r, alkyl-S (=O)rO-, alkyl-S (=O)rOr amino-sulfonyl individually optionally by 1, 2,3 or 4 selected from hydroxyl, deuterium, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio group, alkyl, halogenated Alkyl, alkoxyalkyl, halogenated alkoxy alkyl, alkenyl, alkynyl, naphthenic base, heterocycle, sulfydryl, nitro, aryloxy group, aryl Alkyl-the C of alkoxy, hydroxyl substitution that amino, heteroaryl oxygroup, heteroaryl alkyl, oxo (=O), carboxyl, hydroxyl replace (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2, hydroxyl replace alkyl-S (=O)-, hydroxyl takes Alkyl-the S (=O) in generation2Or replaced the substituent group of the alkoxy of carboxyl substitution.
In some embodiments, A is-O- ,-S- ,-NH- ,-CH2-S-、-CH2-O-、-CH2-NH-、-O-CH2-、-NH- CH2-、-S-CH2Or-CH2-CH2-。
In some embodiments, each R5And R6It independently is H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyanogen Base, C1-6Alkyl, C1-6Halogenated alkyl, C2-6Alkenyl, C2-6Alkynyl, C2-10Heterocycle, C3-8Naphthenic base, sulfydryl, nitro, C6-10Virtue Base, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, C1-6Alkoxy, C6-10Arylamino, C1-9Heteroaryl Amino, C6-10Aryl C1-6Alkylamino, C1-9Heteroaryl C1-6Alkylamino, C1-9Heteroaryl oxygroup, C1-9Heteroaryl C1-6Alkyl, C6-10 Aryl C1-6Alkoxy, C1-9Heteroaryl C1-6Alkoxy, C2-10Heterocycle oxygroup, C2-10Heterocycle C1-6Alkoxy, C2-10Heterocycle Amino, C1-6Alkyl acyl, C1-6Alkyl acyloxy, C1-6Alkoxyacyl, C2-10Heterocycle C1-6Alkylamino or C6-10Aryloxy group.
In some embodiments, each R5And R6It independently is H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyanogen Base, C1-3Alkyl, C1-3Halogenated alkyl, C2-4Alkenyl, C2-4Alkynyl, C2-8Heterocycle, C3-8Naphthenic base, sulfydryl, nitro, C6-10Virtue Base, C1-9Heteroaryl, C6-10Aryl C1-3Alkyl, C1-3Alkoxy C1-3Alkyl, C1-3Alkoxy, C6-10Arylamino, C1-9Heteroaryl Amino, C6-10Aryl C1-3Alkylamino, C1-9Heteroaryl C1-3Alkylamino, C1-9Heteroaryl oxygroup, C1-9Heteroaryl C1-3Alkyl, C6-10 Aryl C1-3Alkoxy, C1-9Heteroaryl C1-3Alkoxy, C2-8Heterocycle oxygroup, C2-8Heterocycle C1-3Alkoxy, C2-8Heterocycle ammonia Base, C1-3Alkyl acyl, C1-3Alkyl acyloxy, C1-3Alkoxyacyl, C2-8Heterocycle C1-3Alkylamino or C6-10Aryloxy group.
In some embodiments, each R5And R6It independently is H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyanogen Base, methyl, ethyl, propyl, isopropyl, normal-butyl, tert-butyl, trifluoromethyl, methoxy, methoxyl group, ethyoxyl, ethylene Base, allyl, acetenyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenyl, phenyl oxygroup, phenyl amino, sulfydryl or nitre Base.
In some embodiments, each R1、R2、R3And R4It independently is H, C1-6Alkyl, C6-10Aryl C1-6Alkyl, C3-10Cycloalkanes Base, C2-10Heterocycle, C1-9Heteroaryl or C6-10Aryl；Or R1、R2With X-CH be randomly formed 3-8 circle heterocyclic ring, 3-8 member carbocyclic ring, C5-12Condensed-bicyclic, C5-12Condense miscellaneous bicyclic, C5-12Spiral shell is bicyclic or C5-12Spiral shell is miscellaneous bicyclic；Or R3、R4With X1- CH is randomly formed 3- 8 circle heterocyclic rings, 3-8 member carbocyclic ring, C5-12Condensed-bicyclic, C5-12Condense miscellaneous bicyclic, C5-12Spiral shell is bicyclic or C5-12Spiral shell is miscellaneous bicyclic；Wherein institute The 3-8 circle heterocyclic ring stated, 3-8 member carbocyclic ring, C5-12Condensed-bicyclic, C5-12Condense miscellaneous bicyclic, C5-12Spiral shell is bicyclic or C5-12Spiral shell is miscellaneous bicyclic only It is vertical to be optionally selected from H, deuterium, oxo (=O), F, Cl, Br, I, cyano, hydroxyl, C by 1,2,3 or 41-6Alkyl, C1-6Alkyl halide Base, C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C1-6Halogenated alkoxy C1-6Alkyl, C1-6Alkylamino, C1-6Alkylthio group, C6-10Virtue Base amino, C6-10Aryloxy group, C1-9Heteroaryl, C1-9Heteroaryl oxygroup, C1-9Heteroaryl C1-6Alkyl, C3-8Naphthenic base or C2-10Heterocycle Replaced the substituent group of base.
In some embodiments, R1、R2Heterocycle, condensed ring or spiro ring system, which are formed by, with Y-X-CH is selected from following minor structure Formula:
In some embodiments, wherein R3、R4With Y1-X1- CH is formed by heterocycle, condensed ring or spiro ring system selected from following Subformula:
In some embodiments, each R15It independently is H, deuterium, oxo (=O), F, Cl, Br, I, cyano, hydroxyl, C1-6Alkane Base, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C1-6Halogenated alkoxy C1-6Alkyl, C1-6Alkylamino, C1-6 Alkylthio group, C6-10Arylamino, C6-10Aryloxy group, C1-9Heteroaryl, C1-9Heteroaryl oxygroup, C1-9Heteroaryl C1-6Alkyl, C3-8Ring Alkyl or C2-10Heterocycle.
In some embodiments, each R15It independently is H, deuterium, oxo (=O), F, Cl, Br, I, cyano, hydroxyl, C1-3Alkane Base, C1-3Halogenated alkyl, C1-3Alkoxy, C1-3Alkoxy C1-3Alkyl, C1-3Halogenated alkoxy C1-3Alkyl, C1-3Alkylamino, C1-3 Alkylthio group, C6-10Arylamino, C6-10Aryloxy group, C1-9Heteroaryl, C1-9Heteroaryl oxygroup, C1-9Heteroaryl C1-3Alkyl, C3-8Ring Alkyl or C2-10Heterocycle.
In some embodiments, each R15It independently is H, deuterium, oxo (=O), F, Cl, Br, I, cyano, hydroxyl, methyl, second Base, propyl, isopropyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy, methoxy, difluoromethoxy ylmethyl, trifluoro Methoxy, ethoxyl methyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, methylamino, ethylamino, phenyl amino, benzene oxygen Base, pyrrole radicals, morpholinyl or piperazinyl.
In some embodiments, each R9bIt independently is hydrogen, deuterium, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Hydroxy alkyl, C1-6 Aminoalkyl, C1-6Alkoxy C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, C1-6Alkylthio group C1-6Alkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl, C6-10Aryl, C2-10Heterocycle or C3-8Naphthenic base.
In some embodiments, each R9bIt independently is hydrogen, deuterium, C1-3Alkyl, C1-3Halogenated alkyl, C1-3Hydroxy alkyl, C1-3 Aminoalkyl, C1-3Alkoxy C1-3Alkyl, C1-3Alkylamino C1-3Alkyl, C1-3Alkylthio group C1-3Alkyl, C6-10Aryl C1-3Alkyl, C1-9Heteroaryl, C6-10Aryl, C2-10Heterocycle or C3-8Naphthenic base.
In some embodiments, each R9bIt independently is hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, trifluoromethyl, hydroxyl Methyl, amino methyl, methoxy, ethoxyl methyl, phenyl methyl, phenyl, cyclopropyl, cyclobutyl, cyclopenta or hexamethylene Base.
In some embodiments, each R7、R7a、R7bAnd R9aIndependently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano, C1-6Alkyl, C1-6Halogenated alkyl, C2-6Alkenyl, C2-6Alkynyl, C2-10Heterocycle, C3-8Naphthenic base, sulfydryl, nitro, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C3-8Naphthenic base C1-6Alkyl, C2-10Heterocycle C1-6Alkyl, C6-10Arylamino, C1-9Heteroaryl amino, C6-10Aryl C1-6Alkylamino, C1-9Heteroaryl Base C1-6Alkylamino, C1-9Heteroaryl oxygroup, C6-10Aryl C1-6Alkoxy, C1-9Heteroaryl C1-6Alkoxy, C2-10Heterocycle oxygroup, C2-10Heterocycle C1-6Alkoxy, C2-10Heterocyclylamino group, C1-6Alkyl-OC (=O)-, C1-6Alkyl-C (=O)-, carbamyl Base, C1-6Alkyl-OS (=O)r-、C1-6Alkyl-S (=O)rO-、C1-6Alkyl-OS (=O)rO-、C1-6Alkyl-S (=O)r-、C2-10 Heterocycle C1-6Alkylamino or C6-10Aryloxy group；0,1 or 2 independently are with each r.
In some embodiments, each R7、R7a、R7bAnd R9aIndependently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano, C1-3Alkyl, C1-3Halogenated alkyl, C2-4Alkenyl, C2-4Alkynyl, C2-8Heterocycle, C3-8Naphthenic base, sulfydryl, nitro, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-3Alkyl, C1-3Alkoxy C1-3Alkyl, C1-9Heteroaryl C1-3Alkyl, C3-8Naphthenic base C1-3Alkyl, C2-8Heterocycle C1-3Alkyl, C6-10Arylamino, C1-9Heteroaryl amino, C6-10Aryl C1-3Alkylamino, C1-9Heteroaryl Base C1-3Alkylamino, C1-9Heteroaryl oxygroup, C6-10Aryl C1-3Alkoxy, C1-9Heteroaryl C1-3Alkoxy, C2-8Heterocycle oxygroup, C2-8Heterocycle C1-3Alkoxy, C2-8Heterocyclylamino group, C1-3Alkyl-OC (=O)-, C1-3Alkyl-C (=O)-, carbamoyl, C1-3Alkyl-OS (=O)r-、C1-3Alkyl-S (=O)rO-、C1-3Alkyl-OS (=O)rO-、C1-3Alkyl-S (=O)r-、C2-8It is miscellaneous Ring group C1-3Alkylamino or C6-10Aryloxy group；0,1 or 2 independently are with each r.
In some embodiments, each R7、R7a、R7bAnd R9aIndependently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano, methyl, ethyl, vinyl, acetenyl, cyclopropyl or phenyl；1 or 2 independently are with each r.
In some embodiments, wherein Y and Y1It is each independently H, deuterium, C1-6Alkyl, C3-8Naphthenic base, C2-10Heterocycle, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl or-C (=O)-(CR8R8a)t-N(R9)-R10。
In some embodiments, each R8And R8aIt independently is H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano, C1-6Alkyl, C1-6Deuteroalkyl, C1-6Halogenated alkyl, C2-6Alkenyl, C2-6Alkynyl, C2-10Heterocycle, C3-8Naphthenic base, sulfydryl, nitro, C6-10Virtue Base C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C3-8Naphthenic base C1-6Alkyl, C2-10Heterocycle C1-6Alkane Base, C6-10Arylamino, C1-9Heteroaryl amino, C6-10Aryl C1-6Alkylamino, C1-9Heteroaryl C1-6Alkylamino, C1-9Heteroaryl oxygen Base, C6-10Aryl C1-6Alkoxy, C1-9Heteroaryl C1-6Alkoxy, C2-10Heterocycle oxygroup, C2-10Heterocycle C1-6Alkoxy, C2-10Heterocyclylamino group, C1-6Alkyl acyl, C1-6Alkyl acyloxy, C1-6Alkoxyacyl, C1-6Alkyl sulphonyl, C1-6Alcoxyl Base sulfonyl, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl oxygroup, C1-6Alkyl sulphinyl oxygroup, C1-6Alkyl-OC (= O)-、C1-6Alkyl-C (=O)-, carbamoyl, C1-6Alkyl-OS (=O)r-、C1-6Alkyl-S (=O)rO-、C1-6Alkyl-OS (=O)rO-、C1-6Alkyl-S (=O)r-、C2-10Heterocycle C1-6Alkylamino or C6-10Aryloxy group.
In some embodiments, each R8And R8aIt independently is H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano, C1-4Alkyl, C1-4Deuteroalkyl, C1-4Halogenated alkyl, C2-4Alkenyl, C2-4Alkynyl, C2-8Heterocycle, C3-8Naphthenic base, sulfydryl, nitro, C6-10Virtue Base C1-3Alkyl, C1-3Alkoxy C1-3Alkyl, C1-9Heteroaryl C1-3Alkyl, C3-8Naphthenic base C1-3Alkyl, C2-8Heterocycle C1-3Alkane Base, C6-10Arylamino, C1-9Heteroaryl amino, C6-10Aryl C1-3Alkylamino, C1-9Heteroaryl C1-3Alkylamino, C1-9Heteroaryl oxygen Base, C6-10Aryl C1-3Alkoxy, C1-9Heteroaryl C1-3Alkoxy, C2-8Heterocycle oxygroup, C2-8Heterocycle C1-3Alkoxy, C2-8 Heterocyclylamino group, C1-3Alkyl acyl, C1-3Alkyl acyloxy, C1-3Alkoxyacyl, C1-3Alkyl sulphonyl, C1-3Alkoxy sulphur Acyl group, C1-3Alkyl sulphinyl, C1-3Alkyl sulphonyl oxygroup, C1-3Alkyl sulphinyl oxygroup, C1-4Alkyl-OC (=O)-, C1-4Alkyl-C (=O)-, carbamoyl, C1-4Alkyl-OS (=O)r-、C1-4Alkyl-S (=O)rO-、C1-4Alkyl-OS (= O)rO-、C1-4Alkyl-S (=O)r-、C2-8Heterocycle C1-3Alkylamino or C6-10Aryloxy group.
In some embodiments, each R8And R8aIt independently is H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano, methyl, second Base, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, Methoxyl group, ethyoxyl, isopropoxy, methoxy, 1- methoxy ethyl, 2- methoxy ethyl, 1- methoxy-propyl, 2- first Oxygroup propyl, 3- methoxy-propyl, phenyl, pyranose, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, trifluoromethyl, ethylene Base, allyl, acetenyl, morpholinyl, sulfydryl, nitro, benzyl or anilino-.
In some embodiments, R9And R10It is each independently H, deuterium, C1-6Alkyl, C3-8Naphthenic base, C2-10Heterocycle, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Alkyl-OC (=O)-, C1-6Alkyl-C (=O)-, carbamyl Base, C1-6Alkyl-OS (=O)r-、C1-6Alkyl-S (=O)rO-、C1-6Alkyl-S (=O)rOr amino-sulfonyl.
In some embodiments, R9And R10Be each independently H, deuterium, methyl, ethyl, isopropyl, normal-butyl, isobutyl group, Sec-butyl, tert-butyl, methyl-OC (=O)-, ethyl-OC (=O)-, propyl-OC (=O)-, isopropyl-OC (=O)-, tertiary fourth Base-OC (=O)-, methyl-C (=O)-, ethyl-C (=O)-, isopropyl-C (=O)-, normal-butyl-C (=O)-, isobutyl group-C (=O)-, carbamoyl, methyl-carbamoyl, ethylamino formoxyl, methyl-OS (=O)2, cyclopropyl-OS (=O)2, first Base-S (=O)2O-, cyclopropyl-S (=O)2O- or amino-sulfonyl.
In some embodiments, 0,1,2,3 or 4 t.
In some embodiments, each r independently is 0,1 or 2.
In some embodiments, each n1And n2It independently is 1,2,3 or 4.
In some embodiments, the compounds of this invention has structure shown in formula (II), (IIa), (IIb) or (III), or Structural upright isomers, geometric isomer, tautomer, enantiomerism shown in formula (II), (IIa), (IIb) or (III) Body, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug:
In some embodiments, the compounds of this invention its with structure as follows:
Or its stereoisomer, geometric isomer, tautomer, enantiomter, nitrogen oxides, hydrate, molten Agent compound, metabolite, pharmaceutically acceptable salt or prodrug.
(herein, form of presentation is " shown in formula (I), (II), (IIa), (IIb) or (III) for the compound of the present invention The stereoisomer of compound shown in compound or formula (I), (II), (IIa), (IIb) or (III), geometric isomer, mutually variation Structure body, enantiomter, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable salt are preceding Medicine "), it can be used for producing medical product treatment acute and chronic HCV infection, it is described in the invention including those.Further, originally The compound of invention can be used for producing the product of HCV-Ab IgG.The compound of the present invention can be used for producing a kind of pharmaceuticals as a result, The illness mediated for the alleviation, prevention, management or treatment of HCV.The compound of the present invention may be used as pharmaceutical composition as a result, Active constituent, which may include compound representated by formula (I), (II), (IIa), (IIb) or (III), also At least one pharmaceutically acceptable carrier, adjuvant or diluent can be further included.
Specifically, salt is pharmaceutically acceptable salt.Term " pharmaceutically acceptable " is meant that, used object Matter or composition must be that the mammal on chemistry or toxicity with the other components of composition preparation and for treatment is suitble to match 's.Those skilled in the art can be according to used other components and the object of used treatment such as people, to be specifically chosen " medicine The substance or composition of acceptable on ".
The salt of the compound of the present invention further includes being used to prepare or purifying formula (I), (II), (IIa), (IIb) or (III) institute Show compound intermediate or formula (I), (II), (IIa), (IIb) or (III) shown in compound separation enantiomter Salt, but it is not necessarily pharmaceutically acceptable salt.
If the compound of the present invention be it is alkaline, conceivable salt can be by provided in the literature any suitable Method is prepared, for example, using inorganic acid or organic acid.Wherein, the example of inorganic acid includes but is not limited to hydrochloric acid, hydrogen bromine Acid, sulfuric acid, nitric acid and phosphoric acid etc..The example of organic acid includes but is not limited to acetic acid, maleic acid, succinic acid, mandelic acid, rich horse Acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid；Pyrans saccharic acid, such as glucuronic acid and galacturonic acid；α-hydroxyl Acid, such as citric acid and tartaric acid；Amino acid, such as asparatate and glutamic acid；Aromatic acid, such as benzoic acid and cinnamic acid；Sulphur Acid, such as p-methyl benzenesulfonic acid, ethanesulfonic acid.
If the compound of the present invention be it is acid, conceivable salt can be prepared by suitable method, e.g., Using inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide or alkaline earth metal hydroxide, etc. Deng.Suitable salt includes, but is not limited to, organic salt obtained from amino acids, such as glycine and arginine, ammonia, and such as primaquine, secondary Ammonia and tertiary ammonia and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium Inorganic salts.
The composition of the compounds of this invention, preparation and administration
Described pharmaceutical composition includes any the compound of the present invention.The pharmaceutical composition can also further include Pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium or combinations thereof.Described pharmaceutical composition can be used for controlling Treat Hepatitis C Virus (HCV) infection or hepatitis C disease.
Described pharmaceutical composition further includes the drug of HCV-Ab IgG.The drug of the HCV-Ab IgG can for it is any of not Be same as the compounds of this invention other be used for HCV-Ab IgG drug.For example, can be interferon, Ribavirin, interleukin-22, Bai Jie Element 6, interleukin 12 promote to generate the compound of 1 type helper T lymphocyte response, RNA interfering, antisense RNA, miaow quinoline not moral, inosine 5 '-monophosphate dehydrogenase inhibitor, amantadine, Rimantadine, Ba Wei former times monoclonal antibody, hepatitis C immunoglobulin, CivacirTM, boceprevir, tirrevir, Erlotinib, his Wei of Dacca, take charge of beautiful Wei, Ah that Wei, vaniprevir, Faldaprevir, paritaprevir, Dan Nuopuwei, sovaprevir, grazoprevir, vedroprevir, BZF-961, GS-9256、narlaprevir、ANA975、ombitasvir、EDP239、ravidasvir、velpatasvir、 Samatasvir, elbasvir, MK-8325, GSK-2336805, PPI-461, Xi Luruiwei, sovaprevir, ACH-1095, VX-985、IDX-375、VX-500、VX-813、PHX-1766、PHX-2054、IDX-136、IDX-316、modithromycin、 VBY-376, TMC-649128, mericitabine, Suo Feibuwei, INX-189, IDX-184, IDX102, R-1479, UNX- 08189、PSI-6130、PSI-938、PSI-879、nesbuvir、HCV-371、VCH-916、lomibuvir、MK-3281、 dasabuvir、ABT-072、filibuvir、deleobuvir、tegobuvir、A-837093、JKT-109、Gl-59728、 GL-60667, AZD-2795, TMC647055, Lei Dipawei, odalasvir, ritonavir, furaprevir, setrobuvir、alisporivir、BIT-225、AV-4025、ACH-3422、MK-2748、MK-8325、JNJ-47910382、 ABP-560、TD-6450、TVB-2640、ID-12、PPI-383、A-848837、RG-7795、BC-2125、alloferon、 Nivolumab, WF-10, Nitazoxanide, multiferon, nevirapine, ACH-3422, Debiopharm, MK-3682, MK- 8408、GS-9857、CD-AdNS3、pibrentasvir、RG-101、glecaprevir、BZF-961、INO-8000、MBL- HCV1、CIGB-230、TG-2349、procvax、CB-5300、miravirsen、chronvac-C、MK-1075、ACH- 0143422、WS-007、MK-7680、MK-2248、MK-8408、IDX-21459、AV-4025、MK-8876、GSK-2878175、 MBX-700、AL-335、JNJ-47910382、AL-704、ABP-560、TD-6450、EDP-239、SB-9200、ITX-5061、 ID-12 or combinations thereof；In some embodiments, the interferon is Interferon Alpha-2b, the interferon-' alpha ' of Pegylation, interference Plain α -2a, the Intederon Alpha-2a of Pegylation, compound alpha-interferon, interferon gamma or combinations thereof.Described pharmaceutical composition, into One step includes at least one HCV inhibitor, and the HCV inhibitor is for inhibiting HCV reproduction process and/or inhibiting HCV virus egg White function；The HCV reproduction process includes that HCV enters, HCV shelling, HCV translation, HCV duplication, HCV is assembled or HCV release； The HCV virus albumen is selected from metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A or NS5B and HCV virus duplication Required internal ribosome inlet point (IRES) and inosine monophosphate dehydrogenase (IMPDH).
When available for treatment, the compounds of this invention of therapeutically effective amount, especially formula (I), (II), (IIa), (IIb) Or (III) compound and its pharmaceutically acceptable salt can be used as unprocessed chemicals and give, and be alternatively arranged as pharmaceutical composition The active constituent of object provides.Therefore, the content of present invention also provides pharmaceutical composition, which includes therapeutically effective amount The compounds of this invention, especially formula (I), (II), (IIa), (IIb) or (III) compound or its pharmaceutically acceptable salt and One or more pharmaceutically acceptable carriers, diluent or excipient.Term as used herein " therapeutically effective amount " refers to It is enough to show the total amount of each active component of significant patient benefit (such as viral load reduction).When using individually living When property ingredient is administered alone, which only refers to the ingredient.When combining applications, no matter the term then refers to combination, successively or together When being administered, all cause the combined amount of the active constituent of therapeutic effect.The compounds of this invention, especially formula (I), (II), (IIa), (IIb) or (III) compound and its pharmaceutically acceptable salt are as described above.From compatible with preparation other compositions and For in the sense that harmless to its recipient, carrier, diluent or excipient must be acceptable.Content according to the present invention On the other hand, method for preparing pharmaceutical preparations is also provided, this method include by the compounds of this invention, especially formula (I), (II), (IIa), (IIb) or (III) compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable loads Body, diluent or excipient mix.Term " pharmaceutically acceptable " used in the present invention refers to such compound, original Material, composition and/or dosage form, they within the scope of reasonable medical judgment, be suitable for contacting with patient tissue and without excessive poison Property, irritation, allergy or other problems relative to a reasonable benefit/risk ratio and complication, and effective for both Determine purposes.
Pharmaceutical preparation can be in unit dosage forms, and each unit dose contains the active constituent of predetermined amount.The change of the content of present invention The dosage level of object is closed between about 0.01 mg/kg (mg/kg) body weight/day and about 250 mg/kg body weight/days, it is excellent Selected introductions are between about 0.05mg/kg body weight/day and about 100mg/kg body weight/day, usually with monotherapy for preventing or treating The disease that HCV is mediated.The pharmaceutical composition of the content of present invention can be usually given by daily about 1 to about 5 time or as continuous infusion Object.This kind of dose regimen can be used as therapy in long or short term.It is mixed with carrier material to prepare the amount of the active constituent of single formulation It will be according to disease to be treated, the severity of disease, administration time, administration route, the discharge rate of compound used therefor, treatment Time and patient age, gender, weight and situation and change.Preferred unit dosage forms are the days containing hereinbefore active constituent The unit dosage forms of dosage or divided dose or its appropriate fraction.It can start to control with the low dose of already clearly below compound optimal dose It treats.Hereafter, escalated dose is come until reaching optimum efficiency in this case with lesser increment.In general, most desirably Give compound concentration level be usually can anti-virus aspect provide effective result without regard to cause it is any harmful or Toxic side effect.
When the content of present invention composition include the content of present invention compound and one or more other treatment drugs or When the combination of prophylactic agent, the dosage level of compound and other drug accounts for normal administration usually in monotherapy scheme The about 10-150% of dosage more preferably accounts for the about 10-80% of normal dosage.Pharmaceutical preparation is suitable for passing through any suitable way Diameter administration, for example, by oral (including oral cavity or sublingual), rectum, nose, part (including oral cavity, sublingual or percutaneous), vagina or Parenterally (including in subcutaneous, intradermal, intramuscular, intra-articular, intrasynovial, breastbone, the bet of intrathecal, intralesional, intravenous or corium Penetrate or be transfused) approach.This kind of preparation can be prepared by any known method of art of pharmacy, such as by by active constituent and carrying Body or excipient mixing.It is preferred that oral administration or drug administration by injection.
Pharmaceutical preparation suitable for oral administration is provided by independent unit, such as capsule or tablet；Powder or granule； Solution or suspension in aqueous or non-aqueous liquid；Edible foam formulations or foaming preparations (whip)；Or oil-in-water cream Liquor or water in oil emulsion liquor.
For example, for oral administration in the form of a tablet or capsule, active medicine component can with can pharmaceutically connect The oral, non-toxic inert carrier (such as ethyl alcohol, glycerol, water etc.) received mixes.By the way that compound powder is broken into suitable fine ruler It is very little, and mix with the pharmaceutical carrier (such as the edible carbohydrate such as starch or mannitol) equally crushed to prepare powder.Also Corrigent, preservative, dispersing agent and colorant may be present.
It by preparing pulverulent mixture as described above, and is loaded into the gelatin shell of forming, to prepare capsule.It is filling It fills out before operation, it can be by glidant and lubricant (such as colloidal silicon dioxide, talcum powder, magnesium stearate, calcium stearate or solid-state Polyethylene glycol) it is added in pulverulent mixture.Can also be added when taking capsule by improve drug utilizability disintegrating agent or Solubilizer (such as agar, calcium carbonate or sodium carbonate).
When furthermore needing or is required, suitable adhesive, lubricant, disintegrating agent and colorant can also be mixed mixture In.Suitable adhesive includes starch, gelatin, natural sugar (such as glucose or beta lactose), corn sweetener, natural and synthesis Gummy (such as gum arabic, tragacanth or mosanom), carboxymethyl cellulose, polyethylene glycol etc..For these dosage forms Lubricant includes enuatrol, sodium chloride etc..Disintegrating agent includes but is not limited to starch, methylcellulose, agar, bentonite, xanthan Glue etc..For example, lubricant and disintegrating agent is added by the way that pulverulent mixture, granulation or pre- tabletting is made, and it is tabletted, to make At tablet.By the compound suitably crushed and diluent as described above or base-material, optionally with adhesive, (such as carboxymethyl is fine Tie up element, alginates, gelatin or polyvinylpyrrolidone), dissolve inhibitor (such as paraffin), absorbsion accelerator (quaternary salt) and/or Absorbent (such as bentonite, kaolin or Dicalcium Phosphate) mixing, to prepare pulverulent mixture.Useful binders (such as syrup, shallow lake Slurry, mucialga of arabic gummy (acadiamucilage) or cellulosic material or polymeric material solution) wetting after pressurize sieving, by powder Shape granulating mixture.One alternative of granulation is pulverulent mixture can be passed through tablet press machine, the result is that bad by being formed Agglomerate smashes particle is made again.Can be by the way that stearic acid, stearate be added, talcum powder or mineral oil make particle lubrication to prevent from gluing Onto the punch die of tablet press machine.Then the mixture through lubricating is tabletted.The compound of the content of present invention can also be with free flow Dynamic inert carrier mixing, can be tabletted without passing through granulation or pre- tableting step.Can provide it is transparent or opaque by The protectiveness packet of shellac seal coat, sugar-coat or polymeric material clothing and wax polishing clothing (polish coating of wax) composition Clothing material.Dyestuff can be added in these coating materials and distinguish different unit doses.
Oral liquid such as solution, syrup and elixir can be prepared with dosage unit form, so that specified rate contains There is the compound of predetermined amount.Syrup can be prepared by the way that compound to be dissolved in suitably seasoned aqueous solution, and elixir can lead to It crosses using non-toxic vehicle and prepares.Solubilizer and emulsifier (such as ethoxylated isostearyl alcohols and polyoxyethylene mountain can also be added Pears alcohol ether), preservative, flavoring additive (such as peppermint oil or natural sweetener or saccharin or other artificial sweeteners) etc..
If appropriate, the dosage unit preparations microencapsulation that will can be used to be administered orally.Preparation can also be made and be prolonged When or sustained release, such as by being coated or being embedded in the microparticle materials such as polymer, wax.
It the compounds of this invention, especially formula (I), (II), (IIa), (IIb) or (III) compound and its can pharmaceutically connect The salt received can be given with liposome delivery systems, such as small unilamellar vesicle, big unilamellar liposome and multilamellar liposome.Lipid Body can be made of a variety of phosphatide (such as cholesterol, octadecylamine or phosphatidyl choline).
It the compounds of this invention, especially formula (I), (II), (IIa), (IIb) or (III) compound and its can pharmaceutically connect The salt received can also pass medicine as individual carrier (compound molecule is coupled) by using monoclonal antibody.Compound can also With as can target medicine carrier soluble polymer be coupled.This quasi polymer may include that polyvinylpyrrolidone, pyrans are total Polymers, poly- hydroxypropyhnethacrylamide phenol, polyhydroxyethylaspart or the polyoxygenated replaced by palmitoyl residues Ethylene polylysine.In addition, compound can be coupled with a kind of Biodegradable polymeric, for reaching the controlled release of drug, this Quasi polymer such as polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyrate, polyorthoester, polyacetals, poly- dihydropyran, paracyanogen base third The cross-linked copolymer or amphipathic nature block polymer of olefin(e) acid ester and hydrogel.
Pharmaceutical preparation suitable for percutaneous dosing can be used as discrete patch (discrete patch) to protect in a long time It holds and recipient's epidermis close contact.For example, active constituent can usually can be found in by passing medicine by electro-ionic osmosis patch Pharmaceutical Research 1986,3(6),318。
Pharmaceutical preparation suitable for local administration can be made into ointment, cream, suspension, lotion, powder, solution, paste Agent, gelling agent, spray, aerosol, oil formulation or transdermal patch.
Pharmaceutical preparation suitable for rectally can be used as suppository or provide as enema.
Pharmaceutical preparation (wherein carrier is solid) suitable for nose administration includes that partial size is such as 20-500 micron range Dust base is quickly sucked from the coarse powder agent container close to nose by being administered in a manner of snuffing by nasal passage.Wherein carry Body is liquid, is suitable for aqueous solution agent or oil that the appropriate formulation that nasal mist or nasal drop are administered includes active constituent Property solution.
Include minuteness particle pulvis (dust) or mist agent (mist) suitable for the pharmaceutical preparation by inhalation, can use not Dosage compresed gas aerosol, nebulizer, insufflator or other matters of same type metering deliver the device of aerosol spray Middle preparation.
Pharmaceutical preparation suitable for vagina administration can be with vaginal plug, vagina plug, cream, creme, gelling agent, paste, foam Agent or spray provide.
Pharmaceutical preparation suitable for parenteral includes water-based and non-aqueous sterile injection solution and aqueous and non-aqueous Sterile suspensions, water-based and non-aqueous sterile injection solution can contain antioxidant, buffer, bacteriostatic agent and make the preparation The isotonic solute with receptor's blood waiting, aqueous and non-aqueous sterile suspensions may include suspending agent and thickener.Preparation can be with Unit dose or multi-dose container provide, for example, sealing peace is triumphant and bottle, and can be reserved under the conditions of freeze-drying (freeze-drying), Only sterile liquid carrier, such as water for injection need to be added before use.The injection solution and suspension for facing used time configuration can be by Sterile powder injection, granule and tablet preparation.
It will be appreciated that preparation further includes related with the preparation type other than the ingredient being particularly mentioned above Other ingredients commonly used in the art, be for example suitable for oral administration this kind of preparation may include corrigent.
The purposes of the compounds of this invention and pharmaceutical composition
In the purposes the present invention provides the compound of the present invention or pharmaceutical composition in medicine preparation, the drug can For inhibiting HCV reproduction process and/or inhibiting the function of HCV virus albumen；The HCV reproduction process include HCV enter, HCV shelling, HCV translation, HCV duplication, HCV assembling or HCV release；The HCV virus albumen be selected from metalloproteinases, NS2, Internal ribosome inlet point (IRES) and inosine required for NS3, NS4A, NS4B, NS5A or NS5B and HCV virus replicate Monophosphate dehydrogenase (IMPDH).Any compound of the present invention or pharmaceutical composition can be used for treating Hepatitis C Virus (HCV) infection or hepatitis C disease.
It further comprise administering to a patient other comprising the treatment method that the compounds of this invention or pharmaceutical composition are administered HCV drug, thus, it is possible to the compound of the present invention and other anti-HCV medicaments be carried out combination therapy, wherein the HCV-Ab IgG Drug be interferon, Ribavirin, interleukin-22, interleukin 6, interleukin 12, promote to generate 1 type helper T lymphocyte response Compound, RNA interfering, antisense RNA, miaow quinoline not moral, inosine 5 '-monophosphate dehydrogenase inhibitor, amantadine, Rimantadine, Ba Wei former times monoclonal antibody, hepatitis C immunoglobulin, CivacirTM, boceprevir, tirrevir, Erlotinib, his Wei of Dacca, department Beautiful Wei, Ah that Wei, vaniprevir, faldaprevir, paritaprevir, Dan Nuopuwei, sovaprevir, grazoprevir、vedroprevir、BZF-961、GS-9256、narlaprevir、ANA975、ombitasvir、EDP239、 Ravidasvir, velpatasvir, samatasvir, elbasvir, MK-8325, GSK-2336805, PPI-461, Xi Lurui Wei, sovaprevir, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX- 136, IDX-316, modithromycin, VBY-376, TMC-649128, mericitabine, Suo Feibuwei, INX-189, IDX-184、IDX102、R-1479、UNX-08189、PSI-6130、PSI-938、PSI-879、nesbuvir、HCV-371、 VCH-916、lomibuvir、MK-3281、dasabuvir、ABT-072、filibuvir、deleobuvir、tegobuvir、A- 837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055, Lei Dipawei, odalasvir, ritonavir、furaprevir、setrobuvir、alisporivir、BIT-225、AV-4025、ACH-3422、MK-2748、 MK-8325、JNJ-47910382、ABP-560、TD-6450、TVB-2640、ID-12、PPI-383、A-848837、RG-7795、 BC-2125, alloferon, nivolumab, WF-10, Nitazoxanide, multiferon, nevirapine, ACH-3422, I Moor Wei, MK-3682, MK-8408, GS-9857, CD-AdNS3, pibrentasvir, RG-101, glecaprevir, BZF- 961、INO-8000、MBL-HCV1、CIGB-230、TG-2349、procvax、CB-5300、miravirsen、chronvac-C、 MK-1075、ACH-0143422、WS-007、MK-7680、MK-2248、MK-8408、IDX-21459、AV-4025、MK-8876、 GSK-2878175、MBX-700、AL-335、JNJ-47910382、AL-704、ABP-560、TD-6450、EDP-239、SB- 9200, ITX-5061, ID-12 or combinations thereof.Wherein the interferon be Interferon Alpha-2b, Pegylation interferon-' alpha ', Intederon Alpha-2a, the Intederon Alpha-2a of Pegylation, compound alpha-interferon, interferon gamma or combinations thereof.
And includes the treatment method of the compounds of this invention or pharmaceutical composition administration, further include other HCV-Ab IgG medicines The administration of object, wherein other anti-HCV medicaments can be administered in combination with the compounds of this invention or its pharmaceutical composition, of the present inventionization Close a part of object or pharmaceutical composition as single dosage form or separated compound or pharmaceutical composition as multi-form.Its He can be administered simultaneously with the compounds of this invention or not be administered simultaneously anti-HCV medicament.The case where the latter, administration can be staggered progress As 6h, 12h, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months carry out.
" effective quantity " or " effective dose " of the compound of the present invention or pharmaceutically acceptable composition refer to processing or Mitigate the effective quantity that one or more present invention are previously mentioned the severity of illness.According to the method for the present invention, compound and combination Object can be any dosage and any administration route to be efficiently used for handling or mitigate the severity of disease.Required standard True amount will change according to the case where patient, this is depending on ethnic, the age, the general condition of patient, the severity of infection, Special factor, administration mode, etc..Compound or composition can be administered in combination with one or more other therapeutic agents, such as What the present invention was discussed.
General synthesis process
Generally, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I), (II), (IIa), (IIb) or (III).Following reaction scheme and reality Example is applied for the contents of the present invention to be further illustrated.
Those skilled in the art will realize that: chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent purchase is in quotient Product supplier such as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Imperial chemistry examination is risen in factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Qingdao Agent Co., Ltd and Haiyang Chemical Plant, Qingdao are commercially available.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by sodium metal reflux.Anhydrous methylene chloride It with chloroform is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, DMAC N,N' dimethyl acetamide and N, N- Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.
Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction flask all squeezed by syringe beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is using silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR spectrum with CDC13、DMSO-d6、CD3OD or acetone-d6It (is reported as unit of ppm) for solvent, with TMS (0ppm) or chloroform (7.25ppm) As reference standard.When there is multiplet, following abbreviation will be used: s (singlet, unimodal), d (doublet, it is double Peak), t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, it is wide Peak), dd (doublet of doublets, two bimodal), dt (doublet of triplets, double triplets).Coupling is normal Number is indicated with hertz (Hz).
By outfit G1312A binary pump and a G1316A TCC, (column temperature is maintained at 30 to low resolution mass spectrometry (MS) data DEG C) the spectrometer of Agilent 6320 series LC-MS measure, G1329A automatic sampler and G1315B DAD detector Applied to analysis, the source ESI is applied to LC-MS spectrometer.
Low resolution mass spectrometry (MS) data are by being equipped with G1311A quaternary pump and G1316A TCC (column temperature is maintained at 30 DEG C) 6120 series LC-MS of Agilent spectrometer come what is measured, G1329A automatic sampler and G1315D DAD detector are answered For analyzing, the source ESI is applied to LC-MS spectrometer.
Both the above spectrometer is provided with Agilent Zorbax SB-C18 column, and specification is 2.1 × 30mm, and 5 μm.Note Beam product is determined by sample concentration；Flow velocity is 0.6mL/min；The peak value of HPLC is by 210nm and 254nm UV-Vis wavelength records reading.Mobile phase is that 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid are ultrapure water-soluble Liquid (phase B).Condition of gradient elution is as shown in table 1:
Table 1
Compound purifying is by 1100 series of high efficiency liquid chromatogram (HPLC) of Agilent come what is evaluated, and wherein UV is detected At 210nm and 254nm, Zorbax SB-C18 column, specification be 2.1 × 30mm, 4 μm, 10 minutes, flow velocity 0.6mL/min, (0.1% aqueous formic acid) of (0.1% formic acid acetonitrile solution) of 5-95%, column temperature is maintained at 40 DEG C.
The use of logogram word below is through the present invention:
AlCl3Alchlor
AcOK potassium acetate
AcOH acetic acid
Ac2O acetic anhydride
BBr3Boron tribromide
Boc tert-butoxycarbonyl
n-BuNH2N-butylamine
CuBr2Copper bromide
CH3CN acetonitrile
CDCl3Deuterated chloroform
CH3COONH4,NH4OAc ammonium acetate
CH3COCl chloroacetic chloride
DCM methylene chloride
DIPEA diisopropyl ethyl amine
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
DMSO-d6Deuterated dimethyl sulfoxide
DMAP 4-dimethylaminopyridine
The chloro- 5,6- dicyano -1,4- benzoquinones of DDQ 2,3- bis-
EtOH ethyl alcohol
Et3N triethylamine
EtOAc, EA ethyl acetate
EDCI 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride
EtOH/H2O ethyl alcohol and aqueous mixtures
Et3SiH triethylsilane
FBS fetal calf serum
G grams
H, hr hours
H2O water
HCl hydrogen chloride
The ethyl acetate solution of HCl/EtOAc hydrogen chloride
H2SO4Sulfuric acid
K2CO3Potassium carbonate
KNO3Potassium nitrate
Na2S2O4Sodium thiosulfate
Na2CO3Sodium carbonate
NH4F ammonium fluoride
MnO2Manganese dioxide
MeOH methanol
Ml, mL milliliters
Mmol mMs
PE petroleum ether
Py pyridine
Pd palladium
Pd(dppf)2Cl2Bis- (diphenylphosphine) ferrocene of 1,1'-] palladium chloride
Pd(dppf)Cl2·CH2Cl2Bis- (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex
Pd(PPh3)4Four triphenyl phosphorus palladiums
PBS phosphate buffered saline (PBS)
Rt, r.t. room temperature
Selectfluor selectivity fluorine reagent
Tf trifluoroacetyl group
Tf2O trifluoromethanesulfanhydride anhydride
TFA,CF3COOH trifluoroacetic acid
TLC thin-layered chromatography
THF tetrahydrofuran
TMSCl trim,ethylchlorosilane
TMS trimethylsilyl
Synthetic method
Synthetic method 1
Compound s-10 can be prepared by synthetic method 1, wherein R15、R8aAs defined herein.Compound s- 1 obtains compound s-2 with trifluoromethanesulfonic acid anhydride reactant in the presence of alkali, and compound s-2 bromination obtains compound s-3, chemical combination Object s-3 reacts to obtain compound s-5 in the presence of alkali with compound s-4, and compound s-5 and ammonium acetate cyclization obtain compound S-6, compound s-6 aoxidize to obtain compound s-7, and compound s-7 is deprotected to obtain compound s-8, compound s-8 and compound S-9 obtains compound s-10 by condensation reaction.
Synthetic method 2
Compound s-23 can be prepared by synthetic method 2, wherein R15、R8As defined herein.Compound s- 11 obtain compound s-12 under the action of reducing agent, and compound s-12 acetylation obtains compound s-13, and compound s-13 is de- Methyl obtains compound s-14, and compound s-14 obtains compound s-15 with trifluoromethanesulfonic acid anhydride reactant in the presence of alkali, changes Conjunction object s-15 bromination obtains compound s-16, compound s-16 and compound s-17 and obtains compound s- at ester in the presence of alkali 18, compound s-18 and ammonium acetate react to obtain compound s-19, and compound s-19 reacts under the catalysis of palladium obtains compound It reacts to obtain compound s-23 again with compound s-22 after s-20, compound s-20 deprotection.
Synthetic method 3:
Compound s-27 can be prepared by synthetic method 3, wherein R15、R8Each independently as the present invention determines Justice.Compound s-8 and compound s-20 is coupled under the catalysis of palladium and obtains compound s-24, and compound s-24 is by deprotection Afterwards, compound s-27 is condensed to yield with compound s-26.
Synthetic method 4:
Compound s-28 can be prepared by synthetic method 4, wherein R15、R8、R8aEach independently such as institute of the present invention Definition.Compound s-20 and compound s-23 coupling reaction under the catalysis of palladium obtains compound s-28.
Embodiment
Embodiment 1
Synthetic route:
Synthesis step
The synthesis of step 1) compound 1-2A
At 0 DEG C, by trifluoromethanesulfanhydride anhydride (10.44g, 37.0mmol) be added drop-wise to compound 1-1A (5.0g, 30.83mmol) and in methylene chloride (60mL) solution of pyridine (3.0g, 37.0mmol), 8h, reaction knot are reacted at room temperature after adding 30mL washing is added in beam, and liquid separation, organic phase is dry with anhydrous sodium sulfate, and decompression is spin-dried for, and silica gel column chromatography purifies (PE:EtOAc (V:V)=10:1), obtain product 8.5g, yield 94.4%.
1H NMR(400MHz,DMSO-d6): δ 8.02 (d, J=8.7Hz, 1H), 7.54 (d, J=2.2Hz, 1H), 7.44 (dd, J=8.7,2.4Hz, 1H), 3.02 (t, J=6.0Hz, 2H), 2.66-2.61 (m, 2H), 2.10-2.03 (m, 2H) ppm.
The synthesis of step 2) compound 1-3A
By compound 1-2A (3.0g, 10.2mmol), copper bromide (4.5g, 20.4mmol) is added to EtOH (30mL) solvent In 60 DEG C of reaction 2h, filtered after reaction with diatomite, filtrate is spin-dried for, then with DCM (40mL × 2) dissolve, organic phase washing, Anhydrous sodium sulfate is dry, and decompression is spin-dried for, and silica gel column chromatography purifies (PE:EtOAc (V:V)=6:1), obtains brownish red grease 3.6g, yield 95%.
1H NMR(400MHz,CDCl3): δ 8.22 (d, J=8.7Hz, 1H), 7.31-7.22 (m, 2H), 4.75 (t, J= 4.1Hz, 1H), 3.47-3.33 (m, 1H), 2.99 (dt, J=17.4,4.2Hz, 1H), 2.65-2.45 (m, 2H) ppm.
The synthesis of step 3) compound 1-4A
By compound 1-3A (2.5g, 6.7mmol), DIPEA (1.3g, 10.0mmol), acetonitrile (20mL), which is placed in bottle, to be added Then acetonitrile (10mL) solution of compound 1-7 (1.6g, 7.4mmol) is slowly added dropwise to 50 DEG C in heat, the reaction was continued after adding, Water is added in fully reacting back spin dry reaction liquid, and EtOAc extraction, organic phase is dry, and decompression is spin-dried for, silica gel column chromatography purifying (PE: EtOAc (V:V)=4:1), obtain product 3.0g, yield 88%.
1H NMR(400MHz,CDCl3): δ 8.22 (d, J=8.7Hz, 1H), 7.22 (m, 2H), 5.08 (t, 1H), 4.85 (t,1H),3.47(t,2H),3.17(t,2H),2.99(t,4H),2.65(m,2H),1.25(t,9H)ppm；MS-ESI,m/z: 508.10[M+H]+.
The synthesis of step 4) compound 1-5A
By compound 1-4A (2.7g, 5.3mmol), ammonium acetate (2.5g, 31.8mmol) is added to toluene (30mL) solvent In 115 DEG C of reaction 12h, after reaction be added water (10mL), then with EtOAc (30mL × 2) extract, organic phase wash, it is anhydrous Sodium sulphate is dry, vacuum rotary steam, and silica gel column chromatography purifies (PE:EtOAc (V:V)=6:1), obtains gray solid 1.8g, yield 69%.
1H NMR(400MHz,CDCl3):δ8.12(s,1H),7.32(m,2H),5.18(t,1H),3.85(t,2H),3.27 (t,2H),2.99(t,2H),2.45(m,4H),1.28(t,9H)ppm；MS-ESI,m/z:488.8[M+H]+.
The synthesis of step 5) compound 1-6A
Compound 1-5A (1.8g, 3.7mmol), methylene chloride is added portionwise in manganese dioxide (3.2g, 37mmol) Reaction is stirred at room temperature in (40mL) solution, reacts 4 days, is filtered after fully reacting with diatomite, filtrate washing, dry, silicagel column Chromatographic purifying (PE:EtOAc (V:V)=3:1), obtains product 1.6g, yield 88.9%.
1H NMR(400MHz,CDCl3):δ7.92(s,1H),7.52(m,2H),7.32(m,2H),5.18(t,1H),3.37 (t,2H),2.59(t,2H),2.35(m,2H),1.26(t,9H)ppm；MS-ESI,m/z:485.9[M+H]+.
The synthesis of step 6) compound 1-2
Compound 1-1 (15.0g, 92.49mmol), triethylsilane (70.0g, 601mmol), TFA (300mL) are added The back flow reaction into two mouthfuls of bottles, TLC monitoring reaction course, 6h fully reacting pour into ice water after fully reacting, then use EtOAc (100mL × 2) extraction, organic phase are neutralized with sodium bicarbonate solution, are washed, dry, and decompression is spin-dried for, silica gel column chromatography purifying (PE), product 12.2g, yield 88% are obtained.1H NMR(400MHz,CDCl3): δ 7.20 (t, J=7.8Hz, 1H), 6.93 (d, J =7.4Hz, 1H), 6.73 (d, J=8.1Hz, 1H), 3.90 (s, 3H), 2.97 (d, J=15.4,7.5Hz, 4H), 2.20-2.11 (m,2H)ppm.
The synthesis of step 7) compound 1-3
At 0 DEG C, chloroacetic chloride (6.4g, 82mmol) is slowly added drop-wise to compound 1-2 (10g, 67.5mmol) tri-chlorination In the solution of the DCM (80mL) of aluminium (11.7g, 87.8mmol), rear room temperature is added the reaction was continued 4h, pour into ice water after fully reacting In, it being extracted with DCM (60mL × 2), organic phase is dry, and decompression is spin-dried for, purify (PE:DCM (V:V)=5:1) with silica gel column chromatography, Obtain product 8.9g, yield 70%.1H NMR(400MHz,CDCl3): δ 7.20 (t, J=7.8Hz, 1H), 6.93 (d, J=7.4Hz, 1H), 6.73 (d, J=8.1Hz, 1H), 3.90 (s, 3H), 2.97 (t, J=15.4,7.5Hz, 4H), 2.20-2.11 (m, 2H) ppm.
The synthesis of step 8) compound 1-4
At 0 DEG C, Boron tribromide (8.7g, 35mmol) is slowly added drop-wise to the DCM of compound 1-3 (5.5g, 29mmol) In the solution of (50mL), the reaction was continued after adding, and pours into ice water after fully reacting, is extracted with EtOAc (40mL × 3), organic Mutually dry, decompression is spin-dried for, and silica gel column chromatography purifies (PE:EtOAc (V:V)=6:1), obtains product 2.1g, yield 41%.
1H NMR(400MHz,DMSO-d6): δ 7.66 (d, J=8.4Hz, 1H), 6.69 (d, J=8.4Hz, 1H), 3.13 (t, J=7.5Hz, 2H), 2.72 (t, J=7.5Hz, 2H), 2.44 (s, 3H), 2.01-1.94 (m, 2H) ppm.
The synthesis of step 9) compound 1-5
At 0 DEG C, by trifluoromethanesulfanhydride anhydride (1.3g, 4.7mmol) be added drop-wise to compound 1-4 (0.75g, 4.3mmol) and In methylene chloride (20mL) mixed liquor of pyridine (0.5g, 6.0mmol), 4h, TLC monitoring reaction, reaction are reacted at room temperature after adding Washing is added after completely, organic phase is dry, is spin-dried for, and silica gel column chromatography purifies (PE), obtains product 1.2g, yield 91%.
1H NMR(400MHz,CDCl3): δ 7.76 (d, J=8.6Hz, 1H), 7.19 (d, J=8.6Hz, 1H), 3.35 (t, J =7.5Hz, 2H), 3.05 (t, J=7.6Hz, 2H), 2.61 (s, 3H), 2.23-2.11 (m, 2H) ppm.
The synthesis of step 10) compound 1-6
Compound 1-5 (1.2g, 3.9mmol) and copper bromide (1.7g, 7.6mmol) are added in EtOH (20mL) solvent 60 DEG C of reaction 2h, are filtered with diatomite after reaction, and filtrate is spin-dried for, then are diluted with DCM (20mL × 2), organic phase washing, nothing Aqueous sodium persulfate is dry, vacuum rotary steam, and silica gel column chromatography purifies (PE:EtOAc (V:V)=6:1), obtains compound 1.25g, yield 80.5%.
1H NMR(400MHz,CDCl3): δ 7.78 (d, J=8.6Hz, 1H), 7.22 (d, J=8.6Hz, 1H), 4.43 (s, 2H), 3.36 (t, J=7.6Hz, 2H), 3.07 (t, J=7.6Hz, 2H), 2.29-2.14 (m, 2H) ppm.
The synthesis of step 11) compound 1-8
At 0 DEG C, triethylamine (0.6g, 6mmol) is added drop-wise to compound 1-6 (1.4g, 3.6mmol) and compound 1-7 It in methylene chloride (20mL) mixed liquor of (1.0g, 4.6mmol), is reacted at room temperature after adding, TLC monitoring reaction, after fully reacting Washing is added, organic phase is dry, is spin-dried for, and silica gel column chromatography purifies (PE:EtOAc (V:V)=6:1), obtains product 1.5g, yield 79%.
1H NMR(400MHz,CDCl3): δ 7.78 (d, J=8.6Hz, 1H), 7.22 (d, J=8.6Hz, 1H), 5.13 (s, 1H),4.43(s,2H),3.36(t,2H),3.16(t,2H),3.07(t,4H),2.29(m,4H),1.36(t,9H)ppm；MS- ESI,m/z:522.8[M+H]+.
The synthesis of step 12) compound 1-9
By compound 1-8 (1.1g, 2.1mmol), ammonium acetate (0.81g, 10.5mmol) is added to toluene (20mL) solvent In 115 DEG C of reaction 12h, after reaction be added water (10mL), then with EtOAc (30mL × 2) extract, organic phase wash, it is anhydrous Sodium sulphate is dry, vacuum rotary steam, and silica gel column chromatography purifies (PE:EtOAc (V:V)=4:1), obtains gray solid 0.8g, yield 80%.
1H NMR(400MHz,CDCl3): δ 7.88 (d, J=8.4Hz, 1H), 7.22 (d, J=8.4Hz, 1H), 5.33 (s, 1H),4.83(s,1H),3.36(t,4H),3.16(t,2H),2.86(t,4H),2.29(m,2H),1.35(t,9H)ppm；MS- ESI,m/z:502.8[M+H]+.
The synthesis of step 13) compound 1-11
By compound 1-9 (0.4g, 0.8mmol), pinacol borate 1-10 (0.24g, 0.95mmol), Pd (dppf) Cl2·CH2Cl2(0.07g, 0.086mmol) and AcOK (0.23g, 2.0mmol) are suspended in the DMF of 20mL, under nitrogen protection It is heated to 100 DEG C of reaction 4h.Reaction solution is cooled to room temperature, and the water of 10mL, EtOAc (30mL × 2) extraction is added, and organic phase is used again Washing 2 times, it is dry, it is spin-dried for, silica gel column chromatography purifies (PE:EtOAc (V:V)=4:1), obtains product 0.3g, yield 78%.
1H NMR(400MHz,CDCl3): δ 7.98 (d, J=8.4Hz, 1H), 7.22 (d, J=8.4Hz, 1H), 5.33 (s, 1H),4.83(s,1H),3.36(t,4H),3.16(t,2H),2.86(t,4H),2.29(m,2H),1.35(t,9H),1.25(t, 12H)ppm；MS-ESI,m/z:480.4[M+H]+.
The synthesis of step 14) compound 1-12
By compound 1-11 (0.8g, 1.7mmol), compound 1-6A (0.73g, 1.5mmol), Pd (PPh3)4(0.20g, 0.17mmol) and K2CO3(0.69mg, 5.0mmol) is suspended in EtOH/H2In O (30mL, V:V=3:1), heated under nitrogen protection To 90 DEG C of reaction 3h.After fully reacting, most solutions is screwed out, then extract (20mL × 2) with DCM, merge organic phase, it is dry, It is spin-dried for, silica gel column chromatography purifies (PE:EtOAc (V:V)=2:1), obtains gray solid 0.5g, yield 40%.
1H NMR(400MHz,CDCl3):δ7.98(s,1H),7.52(d,2H),7.32(m,2H),7.22(m,2H),5.33 (s,1H),4.93(s,2H),3.26(m,4H),3.10(m,4H),2.76(m,4H),2.19(m,6H),1.25(m,9H),1.29 (m,9H)ppm；MS-ESI,m/z:689.2[M+H]+.
The synthesis of step 15) compound 1-13
The methylene chloride that HCl/EtOAc (4N, 4mL) is added drop-wise to compound 1-12 (0.5g, 0.7mmol) at 0 DEG C is molten In agent (15mL), drips off rear room temperature and be stirred to react 6h.Fully reacting back spin dry reaction liquid, ethyl acetate mashing purifying obtain brown Solid 0.4g, yield 87%.
MS-ESI,m/z:489.3[M+H]+.
The synthesis of step 16) compound 1
Compound 1-13 (0.40g, 0.82mmol), compound 1-14 (0.316g, 1.8mmol), EDCI (0.377g, 1.97mmol) it is suspended in 10mL methylene chloride with 2- ethyl cyanoacetate (0.07g, 0.49mmol), it will under the conditions of 0 DEG C DIPEA (0.530g, 4.1mmol) is added dropwise in reaction solution, and after dripping off, 2h is stirred at room temperature in immigration.After fully reacting, ammonium hydroxide is added (2mL) stirs 1h, liquid separation, and organic phase is washed with saturated aqueous ammonium chloride, and anhydrous sodium sulfate dries, filters, and decompression is spin-dried for, silica gel Column chromatographic purifying (PE:EtOAc (V:V)=1:1), obtains gray solid 0.35g, yield 53%.
1H NMR(400MHz,CDCl3):δ8.10(s,1H),7.62(d,2H),7.36(m,2H),7.21(m,2H),5.43 (s,1H),5.10(s,2H),3.56(m,4H),3.16(m,4H),3.10(m,4H),2.66(m,4H),2.56(m,2H),2.36 (m,4H),2.09(m,6H),1.05(m,12H)ppm；MS-ESI,m/z:802.7[M+H]+.
Embodiment 2
Synthetic route:
Synthesis step:
The synthesis of step 1) compound 2-4A
Compound 1-3A (2.5g, 6.7mmol), DIPEA (1.3g, 10.0mmol), acetonitrile (20mL) are placed in bottle and added Then heat is slowly added dropwise acetonitrile (10mL) solution of 5- methyl-Boc- proline 2-7 (1.38g, 6.04mmol), adds to 50 DEG C The reaction was continued after complete, fully reacting back spin dry reaction liquid, water is added, EtOAc extraction, organic layer is dry, and decompression is spin-dried for, silicagel column Chromatographic purifying (PE:EtOAc (V:V)=4:1), obtains product 1.5g, yield 44%.
1H NMR(400MHz,CDCl3): δ 8.22 (d, J=8.7Hz, 1H), 7.22 (m, 2H), 5.08 (t, 1H), 4.85 (t,1H),3.47(t,2H),3.17(t,1H),2.99(t,4H),2.65(m,2H),1.35(t,3H),1.25(t,9H)ppm； MS-ESI,m/z:522.1M+H]+.
The synthesis of step 2) compound 2-5A
By compound 2-4A (1.5g, 2.9mmol), ammonium acetate (1.6g, 21mmol) is added in toluene (30mL) solvent Water is added after reaction, then is extracted with EtOAc (30mL × 2) by 115 DEG C of reaction 12h, organic phase washing, and anhydrous sodium sulfate is dry It is dry, vacuum rotary steam, then purified (PE:EtOAc (V:V)=6:1) with silica gel column chromatography, obtain gray solid 1.0g, yield 69%.
1H NMR(400MHz,CDCl3):δ8.12(s,1H),7.32(m,2H),5.18(t,1H),3.85(t,2H),3.27 (t,1H),2.99(t,2H),2.45(m,4H),1.35(t,3H),1.28(t,9H)ppm；MS-ESI,m/z:502.8[M+H]+.
The synthesis of step 3) compound 2-6A
Manganese dioxide (1.7g, 20mmol) is added portionwise to the methylene chloride of compound 2-5A (1.0g, 2.0mmol) In (40mL) solution, reaction 4 days is stirred at room temperature, is filtered after fully reacting with diatomite, filtrate washing, dry, decompression is spin-dried for, silicon Gel column chromatography eluting (PE:EtOAc (V:V)=3:1), obtains product 0.8g, yield 80%.
1H NMR(400MHz,CDCl3):δ7.92(s,1H),7.52(m,2H),7.32(m,2H),5.18(t,1H),3.37 (t,1H),2.59(t,2H),2.35(m,2H),1.35(t,3H),1.26(t,9H)ppm；MS-ESI,m/z:500.8[M+H]+.
The synthesis of step 4) compound 2-8
At 0 DEG C, triethylamine (0.9g, 8.9mmol) is added drop-wise to compound 1-6 (2.3g, 5.95mmol), compound 2- It in methylene chloride (20mL) mixed liquor of 7 (1.23g, 5.36mmol), is reacted at room temperature after adding, TLC monitoring reaction, fully reacting 10mL washing is added afterwards, saturated sodium-chloride is washed, and organic phase is dry, and decompression is spin-dried for, and silica gel column chromatography purifies (PE:EtOAc (V:V) =6:1), obtain product 1.6g, yield 50.3%.
1H NMR(400MHz,CDCl3): δ 7.78 (d, J=8.6Hz, 1H), 7.22 (d, J=8.6Hz, 1H), 5.13 (s, 1H),4.43(s,2H),3.36(t,2H),3.16(t,2H),3.07(t,3H),2.29(m,4H),1.45(t,3H),1.36(t, 9H)ppm,MS-ESI,m/z:535.8[M+H]+.
The synthesis of step 5) compound 2-9
By compound 2-8 (1.6g, 3.0mmol), ammonium acetate (1.4g, 18mmol) is added in toluene (20mL) solvent Water is added after reaction, then is extracted with EtOAc (30mL × 2) by 115 DEG C of reaction 12h, organic phase washing, and anhydrous sodium sulfate is dry Dry, vacuum rotary steam, silica gel column chromatography purifies (PE:EtOAc (V:V)=4:1), obtains gray solid 1.0g, yield 65%.
1H NMR(400MHz,CDCl3): δ 7.88 (d, J=8.4Hz, 1H), 7.22 (d, J=8.4Hz, 1H), 5.33 (s, 1H),4.83(s,1H),3.36(t,4H),3.16(t,1H),2.86(t,4H),2.29(m,2H),1.39(t,3H),1.35(t, 9H)ppm；MS-ESI,m/z:516.2[M+H]+.
The synthesis of step 6) compound 2-11
By compound 2-9 (1.0g, 1.94mmol), pinacol joins borate 1-10 (0.6g, 2.1mmol), Pd (dppf) Cl2·CH2Cl2(0.17g, 0.19mmol) and AcOK (0.57g, 5.82mmol) are suspended in the DMF of 20mL, under nitrogen protection It is heated to 100 DEG C of reaction 4h.Reaction solution is cooled to room temperature, the water of 10mL is added, then extracted 2 times with EtOAc, merges organic phase again It is washed with water 2 times, it is dry, it is spin-dried for, silica gel column chromatography purifies (PE:EtOAc (V:V)=4:1), obtains product 0.9g, yield 90%.
1H NMR(400MHz,CDCl3): δ 7.98 (d, J=8.4Hz, 1H), 7.22 (d, J=8.4Hz, 1H), 5.33 (s, 1H),4.83(s,1H),3.36(t,4H),3.16(t,1H),2.86(t,4H),2.29(m,2H),1.35(t,12H),1.25 (t,12H)ppm；MS-ESI,m/z:494.4[M+H]+.
The synthesis of step 7) compound 2-12
By compound 2-11 (1.0g, 2.0mmol), compound 2-6A (0.9g, 1.8mmol), Pd (PPh3)4(0.23g, 0.2mmol) and K2CO3(0.84mg, 6.1mmol) is suspended in the EtOH/H of 30mL2In O (V:V=3:1), heated under nitrogen protection To 90 DEG C of reaction 3h.After fully reacting, decompression screws out most solutions, then extracts (20mL × 2) with DCM, merges organic phase, does It is dry, it is spin-dried for, silica gel column chromatography purifies (PE:EtOAc (V:V)=2:1), obtains gray solid 1.0g, yield 69%.
1H NMR(400MHz,CDCl3):δ7.98(s,1H),7.52(d,2H),7.32(m,2H),7.22(m,2H),5.33 (s,1H),4.93(s,2H),3.26(m,4H),3.10(m,2H),2.76(m,4H),2.19(m,6H),1.35(t,6H),1.29 (m,9H),1.25(m,9H)ppm；MS-ESI,m/z:717.8[M+H]+.
The synthesis of step 8) compound 2-13
The methylene chloride that HCl/EtOAc (4N, 5mL) is added drop-wise to compound 2-12 (1.1g, 1.5mmol) at 0 DEG C is molten In agent (15mL), drips off rear room temperature and be stirred to react 6h.Fully reacting back spin dry reaction liquid, re-crystallizing in ethyl acetate purify to obtain palm fibre Color solid 0.7g, yield 68.6%.
MS-ESI,m/z:517.9[M+H]+.
The synthesis of step 15) compound 2
By compound 2-13 (0.60g, 0.905mmol), compound 1-14 (0.349g, 1.99mmol), EDCI (0.417g, 2.17mmol) and 2- ethyl cyanoacetate (0.077g, 0.543mmol) are suspended in 10mL methylene chloride, 0 DIPEA (0.585g, 4.525mmol) is added dropwise in reaction solution under the conditions of DEG C, after dripping off, 2h is stirred at room temperature in immigration.It has reacted Quan Hou is added ammonium hydroxide (2mL) and stirs 1h, liquid separation, and organic phase is washed with saturated aqueous ammonium chloride, and anhydrous sodium sulfate dries, filters, Decompression is spin-dried for, and silica gel column chromatography purifies (PE:EtOAc (V:V)=1:1), obtains gray solid 0.6g, yield 79.7%.
1H NMR(400MHz,CDCl3):δ8.10(s,1H),7.62(d,2H),7.36(m,2H),7.21(m,2H),5.43 (s,1H),5.10(s,2H),3.56(m,4H),3.16(m,4H),3.10(m,4H),2.66(m,2H),2.36(m,4H),2.09 (m,6H),1.35(m,6H),1.05(m,12H)ppm；MS-ESI,m/z:832.4[M+H]+。
Embodiment 3
Synthetic route:
Synthesis step:
The synthesis of step 1) compound 3-7
The methylene chloride that HCl/EtOAc (4N, 6mL) is added drop-wise to compound 1-6A (1.8g, 3.7mmol) at 0 DEG C is molten In agent (15mL), drips off rear room temperature and be stirred to react.Fully reacting back spin dry reaction liquid, re-crystallizing in ethyl acetate purify to obtain brown Solid 0.8g, yield 47%.
MS-ESI,m/z:385.8[M+H]+.
The synthesis of step 2) compound 3-9
By compound 3-7 (1.5g, 3.27mmol), compound 1-14 (0.687g, 3.92mmol), EDCI (0.752g, It 3.92mmol) is suspended in 10mL methylene chloride with 2- ethyl cyanoacetate (0.186g, 1.31mmol), under the conditions of 0 DEG C DIPEA (1.27g, 9.82mmol) is added dropwise in reaction solution, after dripping off, 2h is stirred at room temperature in immigration.After fully reacting, ammonia is added Water (2mL) stirs 1h, liquid separation, and organic phase is washed with saturated aqueous ammonium chloride, and anhydrous sodium sulfate dries, filters, and is spin-dried for reaction solution, Silica gel column chromatography purifies (PE:EtOAc (V:V)=1:1), obtains gray solid 1.4g, yield 79%.
1H NMR(400MHz,CDCl3):δ7.92(s,1H),7.52(m,2H),7.32(m,2H),5.18(t,1H),4.18 (t,1H),3.37(t,3H),3.07(t,1H),2.85(m,2H),2.59(m,2H),2.45(m,2H),1.01(m,6H)ppm； MS-ESI,m/z:543.2[M+H]+.
The synthesis of step 3) compound 3-12
By compound 1-11 (0.7g, 1.5mmol), compound 3-9 (0.873g, 1.6mmol), Pd (PPh3)4(0.17g, 0.15mmol) and K2CO3(0.61mg, 4.4mmol) is suspended in the EtOH/H of 30mL2In O (V:V=3:1), add under nitrogen protection Heat is to 90 DEG C of reaction 3h.After fully reacting, decompression screws out most solutions, then extracts (20mL × 2) with DCM, merges organic phase, It is dry, it is spin-dried for, silica gel column chromatography purifies (PE:EtOAc (V:V)=2:1), obtains gray solid 0.8g, yield 70%.
1H NMR(400MHz,CDCl3):δ8.10(s,1H),7.62(d,2H),7.36(m,2H),7.21(m,2H),5.43 (s,1H),5.10(s,2H),3.56(m,4H),3.16(m,4H),3.10(m,4H),2.66(m,4H),2.56(m,3H),2.36 (m,4H),2.09(m,6H),1.05(m,9H)ppm；MS-ESI,m/z:747.5[M+H]+.
The synthesis of step 4) compound 3-13
The methylene chloride that HCl/EtOAc (4N, 4mL) is added drop-wise to compound 3-12 (0.7g, 0.9mmol) at 0 DEG C is molten In agent (15mL), drips off rear room temperature and be stirred to react.Fully reacting back spin dry reaction liquid, re-crystallizing in ethyl acetate purify to obtain brown Solid 0.6g, yield 89%.
MS-ESI,m/z:647.4[M+H]+.
The synthesis of step 5) compound 3
By compound 3-13 (0.60g, 0.835mmol), compound 3-14 (0.21g, 1.0mmol), EDCI (0.192g, It 1.0mmol) is suspended in 10mL methylene chloride with 2- ethyl cyanoacetate (0.048g, 0.334mmol), under the conditions of 0 DEG C DIPEA (0.324g, 2.505mmol) is added dropwise in reaction solution, after dripping off, 2h is stirred at room temperature in immigration.After fully reacting, it is added Ammonium hydroxide (2mL) stirs 1h, liquid separation, and organic phase is washed with saturated aqueous ammonium chloride, and anhydrous sodium sulfate dries, filters, and decompression is spin-dried for Reaction solution, silica gel column chromatography purify (PE:EtOAc (V:V)=1:1), obtain gray solid 0.45g, yield 64%.
1H NMR(400MHz,CDCl3):δ8.10(s,1H),7.62(d,4H),7.36(m,4H),7.21(m,3H),5.43 (s,2H),5.10(s,2H),3.56(m,4H),3.16(m,4H),3.10(m,4H),2.66(m,4H),2.36(m,4H),2.09 (m,6H),1.05(m,6H)ppm；MS-ESI,m/z:837.7[M+H]+.
Embodiment 4
Synthetic route:
Synthesis step:
The synthesis of step 1) compound 4-7
HCl/EtOAc (4N, 4mL) is added drop-wise to the dichloromethane solvent of compound 2-6A (0.8g, 2mmol) at 0 DEG C In (15mL), drips off rear room temperature and be stirred to react.Fully reacting back spin dry reaction liquid, it is solid that re-crystallizing in ethyl acetate purifies to obtain brown Body 0.56g, yield 90%.
MS-ESI,m/z:400.2[M+H]+.
The synthesis of step 2) compound 4-9
By compound 4-7 (0.9g, 2.3mmol), compound 1-14 (0.47g, 2.7mmol), EDCI (0.52g, It 2.7mmol) is suspended in methylene chloride (10mL) with 2- ethyl cyanoacetate (0.13g, 0.91mmol), under the conditions of 0 DEG C DIPEA (0.87g, 6.7mmol) is added dropwise in reaction solution, after dripping off, 2h is stirred at room temperature in immigration.After fully reacting, ammonia is added Water (2mL) stirs 1h, liquid separation, and organic phase is washed with saturated aqueous ammonium chloride, and anhydrous sodium sulfate dries, filters, and decompression is spin-dried for, silicon Gel column chromatography eluting (PE:EtOAc (V:V)=1:1), obtains gray solid 0.8g, yield 60%.
1H NMR(400MHz,CDCl3):δ7.92(s,1H),7.52(m,2H),7.32(m,2H),5.18(t,1H),4.18 (t,1H),3.37(t,3H),2.85(m,2H),2.59(m,2H),2.45(m,2H),1.25(m,3H),1.01(m,6H)ppm； MS-ESI,m/z:557.3[M+H]+.
The synthesis of step 3) compound 4-12
By compound 1-11 (0.731g, 1.5mmol), compound 4-9 (0.853g, 1.5mmol), Pd (PPh3)4 (0.17g, 0.15mmol) and K2CO3(0.61mg, 4.4mmol) is suspended in EtOH/H2In O (30mL, V:V=3:1), nitrogen is protected 90 DEG C of reaction 3h are heated under shield.After fully reacting, decompression screws out most solutions, then is extracted with DCM (20mL × 2), merges Organic phase, dry, decompression is spin-dried for, and silica gel column chromatography purifies (PE:EtOAc (V:V)=2:1), obtains gray solid 0.7g, yield 60%.
1H NMR(400MHz,CDCl3):δ8.10(s,1H),7.62(d,2H),7.36(m,2H),7.21(m,2H),5.43 (s,1H),5.10(s,2H),3.56(m,4H),3.16(m,4H),3.10(m,4H),2.66(m,4H),2.56(m,2H),2.36 (m,4H),2.09(m,6H),1.35(m,3H),1.05(m,9H)ppm；MS-ESI,m/z:792.3[M+H]+.
The synthesis of step 4) compound 4-13
The methylene chloride that HCl/EtOAc (4N, 4mL) is added drop-wise to compound 4-12 (0.8g, 1.0mmol) at 0 DEG C is molten In agent (15mL), drips off rear room temperature and be stirred to react.Fully reacting back spin dry reaction liquid, re-crystallizing in ethyl acetate purify to obtain brown Solid 0.6g, yield 90%.
MS-ESI,m/z:661.5[M+H]+.
The synthesis of step 5) compound 4
By compound 4-13 (0.60g, 0.92mmol), compound 3-14 (0.23g, 1.1mmol), EDCI (0.21g, 1.1mmol) it is suspended in 10mL methylene chloride with 2- ethyl cyanoacetate (0.06g, 0.37mmol), it will under the conditions of 0 DEG C DIPEA (0.360g, 2.8mmol) is added dropwise in reaction solution, and after dripping off, 2h is stirred at room temperature in immigration.After fully reacting, ammonium hydroxide is added (2mL) stirs 1h, liquid separation, and organic phase is washed with saturated aqueous ammonium chloride, and anhydrous sodium sulfate dries, filters, and decompression is spin-dried for, silica gel Column chromatographic purifying (PE:EtOAc (V:V)=1:1), obtains gray solid 0.40g, yield 50%,
1H NMR(400MHz,CDCl3):δ8.10(s,1H),7.62(d,4H),7.36(m,4H),7.21(m,3H),5.43 (s,2H),5.10(s,2H),3.56(m,4H),3.16(m,4H),3.10(m,4H),2.66(m,4H),2.36(m,3H),2.09 (m,6H),1.59(m,3H),1.05(m,6H)ppm；MS-ESI,m/z:852.5[M+H]+。
Embodiment 5
Synthetic route:
Synthesis step:
The synthesis of step 1) compound 5-3
At 0 DEG C, triethylamine (0.98g, 9.68mmol) is added drop-wise to compound 1-6 (2.5g, 5.81mmol) and chemical combination It in methylene chloride (20mL) mixed liquor of object 5-2 (1.5g, 5.81mmol), is reacted at room temperature after adding, TLC monitoring reaction, reaction Water (10mL) is added after completely to wash, saturated sodium-chloride is washed, and organic phase is dry, and decompression is spin-dried for, and silica gel column chromatography purifies (PE:EtOAc (V:V)=6:1), obtain product 2.0g, yield 55%.
1H NMR(400MHz,CDCl3): δ 7.67 (d, J=8.6Hz, 1H), 7.20 (d, J=8.4Hz, 1H), 5.28 (ddd, J=60.3,53.6,16.3Hz, 2H), 4.43 (dt, J=15.2,8.0Hz, 1H), 3.82-3.66 (m, 1H), 3.46- 3.34 (m, 5H), 3.32 (t, J=7.5Hz, 2H), 3.23 (dd, J=10.7,7.7Hz, 1H), 3.05 (t, J=7.4Hz, 2H), 2.61-2.46 (m, 2H), 2.25-2.12 (m, 2H), 1.77 (s, 1H), 1.45 (d, J=10.3Hz, 9H) ppm；MS-ESI,m/ z:566.2[M+H]+.
The synthesis of step 2) compound 5-4
Compound 5-3 (2.1g, 3.71mmol), ammonium acetate (1.72g, 22.3mmol) are added to toluene (20mL) solvent In 115 DEG C of reaction 12h, be added water after reaction, then extract (30mL × 2) with EtOAc, organic phase washing, anhydrous sodium sulfate Dry, vacuum rotary steam, silica gel column chromatography purifies (PE:EtOAc (V:V)=4:1), obtains gray solid 1.5g, yield 74%.
1H NMR(400MHz,CDCl3): δ 7.16 (s, 1H), 7.10 (d, J=8.6Hz, 1H), 5.00 (t, J=7.1Hz, 1H), 3.81 (s, 1H), 3.52 (d, J=4.9Hz, 1H), 3.41-3.32 (m, 4H), 3.11 (dt, J=15.1,6.8Hz, 5H), 2.78 (d, J=47.9Hz, 1H), 2.63-2.39 (m, 2H), 2.25-2.15 (m, 2H), 1.51 (s, 9H) ppm；MS-ESI,m/ z:546.3[M+H]+.
The synthesis of step 3) compound 5-6
By compound 5-4 (1.55g, 2.84mmol), pinacol borate 1-10 (0.866g, 3.41mmol), Pd (dppf)Cl2·CH2Cl2(0.232g, 0.284mmol) and AcOK (0.835g, 8.52mmol) are suspended in the DMF of 20mL, nitrogen 100 DEG C of reaction 4h are heated under gas shielded.Reaction solution is cooled to room temperature, the water of 10mL is added, then extracted 2 times with EtOAc, organic It is mutually washed with water 2 times, dry, decompression is spin-dried for, and silica gel column chromatography purifies (PE:EtOAc (V:V)=3:1), obtains product 1.3g, is produced Rate 87%.
1H NMR(400MHz,CDCl3): δ 7.16 (s, 1H), 7.10 (d, J=8.6Hz, 1H), 5.00 (t, J=7.1Hz, 1H), 3.81 (s, 1H), 3.52 (d, J=4.9Hz, 1H), 3.41-3.32 (m, 4H), 3.11 (m, 5H), 2.78 (d, 1H), 2.63–2.39(m,2H),2.25–2.15(m,2H),1.51(s,9H),1.25(m,12H)ppm；MS-ESI,m/z:524.3[M+ H]+.
The synthesis of step 4) compound 5-7
By compound 5-6 (0.500g, 0.955mmol), compound 4-9 (0.53g, 0.955mmol), Pd (PPh3)4 (0.110g, 0.095mmol) and K2CO3(0.391mg, 2.87mmol) is suspended in the EtOH/H of 30mL2In O (V:V=3:1), nitrogen 90 DEG C of reaction 3h are heated under gas shielded.After fully reacting, decompression screws out most solutions, then is extracted with DCM (20mL × 2), Merge organic phase, dry, decompression is spin-dried for, and silica gel column chromatography purifies (DCM:EtOAc (V:V)=1:2), obtains gray solid 0.5g, yield 70%.
1H NMR(400MHz,CDCl3):δ8.10(s,1H),7.62(d,2H),7.36(m,2H),7.21(m,2H),5.43 (s,1H),5.10(s,2H),3.56(m,4H),3.16(m,4H),3.11(m,5H),3.00(m,4H),2.66(m,4H),2.56 (m,2H),2.36(m,3H),2.09(m,6H),1.35(m,3H),1.05(m,9H)ppm；MS-ESI,m/z:804.8[M+H]+.
The synthesis of step 5) compound 5-8
HCl/EtOAc (4N, 4mL) is added drop-wise to the dichloromethane solution of compound 5-7 (0.6g, 0.7mmol) at 0 DEG C In (15mL), drips off rear room temperature and be stirred to react.Fully reacting back spin dry reaction liquid, ethyl acetate washing purifying obtain brown solid 0.45g, yield 84%.
MS-ESI,m/z:705.4[M+H]+.
The synthesis of step 6) compound 5
By compound 5-8 (0.55g, 0.72mmol), compound 3-14 (0.178g, 0.852mmol), EDCI (0.163g, It 0.852mmol) is suspended in 10mL methylene chloride with 2- ethyl cyanoacetate (0.04g, 0.284mmol), under the conditions of 0 DEG C DIPEA (0.275g, 2.13mmol) is added dropwise in reaction solution, after dripping off, 2h is stirred at room temperature in immigration.After fully reacting, it is added Ammonium hydroxide (2mL) stirs 1h, liquid separation, and organic phase is washed with saturated aqueous ammonium chloride, and anhydrous sodium sulfate dries, filters, and decompression is spin-dried for, Silica gel column chromatography purifies (PE:EtOAc (V:V)=1:3), obtains gray solid 0.35g, yield 55%.
1H NMR(400MHz,CDCl3):δ8.10(s,1H),7.52(d,4H),7.36(m,4H),7.31(m,3H),5.43 (s,2H),5.10(s,2H),3.56(m,4H),3.21(m,5H),3.09(m,4H),3.01(m,4H),2.66(m,4H),2.26 (m,2H),2.09(m,6H),1.59(m,3H),1.05(m,6H)ppm；MS-ESI,m/z:896.0[M+H]+.
Embodiment 6
Synthetic route:
Synthesis step
The synthesis of step 1) compound 7-2A
6- bromine 2- naphthylamine hydrochloride 7-1A (2.00g, 7.73mmol, 1.00eq) is added in DMF (15mL), is added DMAP(0.02g,0.16mmol,0.02eq),Et3N (3.70mL, 2.70mmol, 3.50eq) is down to 0 DEG C, and acetic anhydride is added dropwise (1.09mL, 11.60mmol, 1.50eq) drips and finishes room temperature reaction 3h.After fully reacting, reaction solution is poured into 30mL water, is had white Color solid is precipitated, and after stirring 0.5h, directly filters, and filter cake is washed with water three times, is dried to obtain product 1.78g white solid, produces Rate 87.46%.
1H NMR(400MHz,DMSO-d6): δ 10.20 (s, 1H), 8.31 (s, 1H), 8.10 (s, 1H), 7.84 (d, J= 8.9Hz, 1H), 7.79 (d, J=8.8Hz, 1H), 7.64-7.58 (m, 1H), 7.56 (dd, J=8.7,1.5Hz, 1H), 2.11 (s,3H)ppm.
The synthesis of step 2) compound 7-3A
By compound 7-2A (5.0g, 18.93mmol, 1.00eq), KNO3(2.30g, 22.71mmol, 1.20eq) is added It is dissolved to AcOH (35mL) solvent, at 20 °C, H is added dropwise2SO4(5.14mL, 94.65mmol, 5.00eq), is added dropwise Afterwards, 30 DEG C of reaction 7h.It is directly poured into water (50mL) after reaction, has yellow-brown solid precipitation, directly filter, filter cake water (20mL × 3) washing, is dried to obtain 5.34g yellow-brown solid, yield 91.31%.
1H NMR(400MHz,CDCl3): δ 8.98 (s, 1H), 8.49 (d, J=9.2Hz, 1H), 8.03 (s, 1H), 7.92 (t, J=8.0Hz, 2H), 7.72 (dd, J=9.2,1.4Hz, 1H), 2.31 (s, 3H) ppm.
The synthesis of step 3) compound 7-4A
Compound 7-3A (3.78g, 12.23mmol, 1.00eq) addition THF (20mL) is placed in bottle and is dissolved, is added 6N HCl (10.5mL, 61.10mmol, 5.00eq) is heated to 80 DEG C, reacts 7h.After fully reacting, it is cooled to room temperature, will reacts Liquid pours into 50mL ice water, there is yellow solid precipitation, and filtering, filter cake is washed with water (15mL × 3), dry, obtains product 3.00g Yellow-brown solid, yield 91.90%.1H NMR(400MHz,CDCl3): δ 8.60 (d, J=9.3Hz, 1H), 7.84 (s, 1H), 7.68 (t, J=8.6Hz, 2H), 6.94 (d, J=9.0Hz, 1H), 6.46 (s, 2H) ppm；MS-ESI,m/z:267.1[M+H]+.
The synthesis of step 4) compound 7-5A
Dissolution, ice bath in Isosorbide-5-Nitrae-dioxane (30mL) is added in compound 7-4A (4.00g, 14.97mmol, 1.00eq) Under the conditions of Na is added dropwise2S2O4(8.68g,44.93mmol,3.00eq)、Na2CO3(1.58g, 14.97mmol, 1.00eq's) is water-soluble Liquid (30mL), reacts at room temperature 5h after being added dropwise.It is directly poured into after fully reacting in water (30mL), there is the precipitation of cinerous solid, Filtering, filter cake are washed with water (15mL × 3), dry, obtain product 3.2g cinerous solid, yield 91.01%.
1H NMR(400MHz,CDCl3): δ 7.89 (d, J=1.4Hz, 1H), 7.60 (d, J=9.0Hz, 1H), 7.49 (dd, J=9.0,1.7Hz, 1H), 7.22 (d, J=8.5Hz, 1H), 7.05 (d, J=8.5Hz, 1H), 3.70 (d, J=18.9Hz, 4H) ppm；MS-ESI,m/z:237.2[M+H]+The synthesis of step 5) compound 7-6A
By (S)-N- tertbutyloxycarbonyl pyrrolidines -2- formic acid (9.06g, 42.17mmol, 1.00eq), ethyl chloroformate (4.58g, 42.17g, 1.00eq) is dissolved in DCM (100mL), and at -10 DEG C, Et is slowly added dropwise3N(8.8mL,63.26mmol, 1.50eq), after being added dropwise, 10min, filtering are kept the temperature, filter cake is washed with DCM (10mL × 2), and filtrate is spare.By compound 7- 5A (10g, 42.17mmol, 1.00eq) is dissolved in DCM (80mL), is cooled to -5 DEG C, and above-mentioned filtrate is added dropwise, straight after being added dropwise Meet placement room temperature reaction 2h.It after fully reacting, is directly added into water (100mL), extracts liquid separation, water phase continues DCM (50mL × 2) extraction It takes, merges organic phase, it is dry, it is spin-dried for obtaining crude product 18.00g brownish black solid, yield 95.18%.
1H NMR(400MHz,CDCl3): δ 7.90 (s, 1H), 7.65 (d, J=9.0Hz, 1H), 7.47 (d, J=8.1Hz, 1H), 7.40 (d, J=8.6Hz, 1H), 7.16 (d, J=8.6Hz, 1H), 4.61-4.34 (m, 3H), 4.00 (d, J=5.1Hz, 1H), 2.43 (s, 2H), 2.13 (dd, J=12.8,7.1Hz, 2H), 1.90-1.63 (m, 2H), 1.54 (s, 9H) ppm；MS- ESI,m/z:434.2[M+H]+.
The synthesis of step 6) compound 7-7A
Compound 7-6A (18.00g, 43.27mmol, 1.00eq) is added in acetic acid (80mL), is directly heated to 50 DEG C, React 5h.Part acetic acid is removed after fully reacting, and EtOAc (100mL), water (50mL) stirring is added, is removed with sodium carbonate remaining Acetic acid, until pH=8, then extracts liquid separation, water phase continues to be extracted with EtOAc (20mL × 2), merges organic phase；Organic phase continues It is washed with water (50mL), liquid separation, organic phase is dry, and back-out obtains product 16.03g brown solid, yield 93.06%.
1H NMR(400MHz,CDCl3):δ7.92(s,1H),7.52(m,2H),7.32(m,2H),5.18(t,1H), 3.37-3.21(t,2H),2.59-2.30(t,2H),2.35-2.11(m,2H),1.26(t,9H)ppm；MS-ESI,m/z: 416.2[M+H]+.
The synthesis of step 7) compound 7-1
By compound 5-6 (600mg, 1.15mmol, 1.0eq), compound 7-7A (477mg, 1.15mmol, 1.0eq), carbon Sour potassium (316mg, 2.29mmol, 2.0eq), four triphenyl phosphorus palladiums (29mg, 0.034mmol, 0.03eq) are added to 10mL ethyl alcohol In 3mL water, 90 DEG C of reaction 18h.Reaction solution is poured into 50mL water, is extracted with dichloromethane (30mL × 3), organic phase nothing Aqueous sodium persulfate is dry, is spin-dried for, and silica gel column chromatography purifies (PE:EtOAc (V:V)=1:1), obtains white solid product 0.68g, yield 80.9%.
1H NMR(400MHz,CDCl3): δ 11.61-10.64 (m, 2H), 8.67 (s, 1H), 7.79 (dd, J=98.4, 31.8Hz, 5H), 7.39 (d, J=7.2Hz, 1H), 7.21 (s, 1H), 5.26 (d, J=4.3Hz, 1H), 5.06 (t, J= 7.3Hz,1H),3.93–3.78(m,1H),3.62–3.47(m,2H),3.43–3.29(m,4H),3.27–3.04(m,5H), 2.90-2.70 (m, 1H), 2.51 (ddd, J=19.3,13.9,6.6Hz, 2H), 2.29 (d, J=4.2Hz, 2H), 2.17-2.03 (m, 4H), 1.54 (d, J=11.0Hz, 18H) ppm；MS-ESI,m/z:733.20[M+H]+.
The synthesis of step 8) compound 7-2
Compound 7-1 (0.68g, 0.93mmol, 1.0eq) is added in DCM (15mL), in 0 DEG C of dropwise addition HCl/EtOAc (4N, 3mL) solution drips off room temperature reaction 12h.Solvent is spin-dried for, is added EtOAc (20mL), room temperature is beaten 1h, filters yellowish Color solid is dissolved with water (10mL), then free with sodium carbonate liquor, and solid is precipitated, filters, dry yellow solid product 320mg, yield 63.1%.
1H NMR(600MHz,DMSO-d6): δ 8.48 (d, J=8.3Hz, 1H), 8.04 (s, 1H), 7.78 (d, J= 50.0Hz, 1H), 7.73-7.51 (m, 3H), 7.34 (d, J=7.6Hz, 1H), 7.24 (s, 1H), 4.46 (t, J=7.0Hz, 1H), 4.20 (t, J=7.7Hz, 1H), 3.32 (d, J=7.2Hz, 4H), 3.25 (s, 3H), 3.08 (dt, J=24.6,6.9Hz, 4H), 3.01-2.91 (m, 2H), 2.74 (dd, J=10.1,5.5Hz, 1H), 2.40 (dd, J=13.6,7.1Hz, 1H), 2.29- 2.15 (m, 2H), 2.05 (dd, J=13.7,6.8Hz, 2H), 1.82 (td, J=13.5,6.3Hz, 2H), 1.69-1.52 (m, 1H)ppm；MS-ESI,m/z:533.3[M+H]+.
The synthesis of step 9) compound 7
By compound 7-2 (250mg, 0.469mmol, 1.0eq), compound 7-3 (209mg, 1.03mmol, 2.2eq), 2- Ethyl cyanoacetate (61mg, 0.43mmol, 0.8eq) and DIPEA (35mg, 0.27mmol, 0.5eq) are added to DCM It in (15mL), adds EDCI (227mg, 1.19mmol, 2.2eq), reacts at room temperature 5h.Reaction solution is poured into water (30mL), It is extracted with DCM (15mL × 3), organic phase is dry with anhydrous sodium sulfate, is spin-dried for, and silica gel column chromatography purifies (DCM:EtOAc:MeOH (V:V:V)=5:10:1), obtain white solid product 300mg, yield 72.7%.
1H NMR(400MHz,CDCl3): δ 11.35-10.31 (m, 2H), 8.65 (s, 1H), 7.91 (d, J=45.9Hz, 2H), 7.69 (d, J=23.4Hz, 2H), 7.48 (s, 1H), 7.36 (d, J=6.2Hz, 1H), 7.15 (d, J=19.1Hz, 1H), 5.93-5.71 (m, 2H), 5.70-5.54 (m, 1H), 5.38 (t, J=7.7Hz, 1H), 4.83-4.31 (m, 2H), 4.14-3.98 (m, 1H), 3.88 (d, J=20.9Hz, 2H), 3.73 (d, J=5.9Hz, 6H), 3.66-3.54 (m, 2H), 3.45 (d, J= 8.8Hz, 1H), 3.39 (t, J=22.3Hz, 6H), 3.24-2.88 (m, 7H), 2.79 (dd, J=10.1,9.2Hz, 1H), 2.72-2.58 (m, 1H), 2.51 (dd, J=12.3,7.7Hz, 1H), 2.36 (dd, J=23.8,11.5Hz, 1H), 2.22- 2.11 (m, 2H), 1.99 (s, 2H), 1.17 (dd, J=18.8,5.7Hz, 4H), 0.89 (dd, J=6.9,4.0Hz, 2H) ppm； MS-ESI,m/z:879.3[M+H]+.
Embodiment 7
Synthetic route:
Synthesis step:
The synthesis of step 1) compound 10-1
Compound 2-12 (1.25g, 1.74mmol, 1.0eq) is added in DCM (15mL), in 0 DEG C of dropwise addition HCl/ EtOAc (3mL) solution drips off room temperature reaction 6h.Solvent is spin-dried for, is added EtOAc (20mL), room temperature is beaten 1h, filters light Yellow solid is dissolved with water (10mL), then free with sodium carbonate liquor, and solid is precipitated, filters, dry yellow solid product 800mg, yield 89%.
1H NMR(400MHz,CDCl3): δ 8.43 (s, 1H), 8.00 (s, 1H), 7.71 (d, J=12.3Hz, 4H), 7.40 (d, J=7.9Hz, 1H), 7.21 (s, 1H), 4.71 (dd, J=8.5,5.9Hz, 1H), 4.58-4.43 (m, 1H), 3.43 (ddd, J=30.0,14.4,6.3Hz, 2H), 3.25-3.00 (m, 4H), 2.42 (dd, J=12.8,8.4Hz, 1H), 2.30 (dt, J= 20.9,8.3Hz, 1H), 2.24-2.08 (m, 4H), 1.99 (dd, J=12.6,5.9Hz, 2H), 1.52-1.37 (m, 2H), 1.34–1.25(m,6H)ppm；MS-ESI,m/z:517.3[M+H]+.
The synthesis of step 2) compound 10
By compound 10-1 (280mg, 0.54mmol, 1.0eq), compound 10-2 (294mg, 1.36mmol, 2.5eq), 2- ethyl cyanoacetate (61mg, 0.43mmol, 0.8eq) and DIPEA (35mg, 0.27mmol, 0.5eq) are added to DCM It in (15mL), adds EDCI (227mg, 1.19mmol, 2.2eq), reacts at room temperature 6h.Reaction solution is poured into water (30mL), It is extracted with DCM (15mL × 3), organic phase is dry with anhydrous sodium sulfate, is spin-dried for, and silica gel column chromatography purifies (DCM:EtOAc (V:V) =1:2), obtain faint yellow solid product 368mg, yield 74.2%.
1H NMR(400MHz,CDCl3):δ12.21–10.33(m,2H),8.80–8.46(m,1H),8.07–7.85(m, 2H), 7.82-7.62 (m, 2H), 7.51 (dd, J=42.1,33.3Hz, 1H), 7.33 (s, 1H), 7.26-7.04 (m, 1H), 5.49 (dt, J=14.2,7.7Hz, 2H), 5.28-5.16 (m, 1H), 4.75-4.62 (m, 1H), 4.41-4.29 (m, 2H), 4.03 (dd, J=16.4,9.9Hz, 2H), 3.90-3.68 (m, 6H), 3.54-2.94 (m, 10H), 2.42 (ddd, J=33.7, 17.1,9.5Hz, 2H), 2.20-2.08 (m, 3H), 1.90 (ddd, J=52.2,26.1,7.8Hz, 10H), 1.68-1.49 (m, 3H), 1.40-1.27 (m, 6H), 1.17 (d, J=5.8Hz, 2H) ppm；MS-ESI,m/z:915.5[M+H]+.
Embodiment 8
Synthetic route:
Synthesis step:
The synthesis of step 1) compound 11-2:
By compound 4-7 (1.27g, 2.7mmol), compound 7-3 (0.62g, 3mmol), EDCI (0.62g, 3.3mmol) It is suspended in methylene chloride (20mL) with 2- ethyl cyanoacetate (0.15g, 1.1mmol), under the conditions of 0 DEG C, by DIPEA (1.1g, 8.2mmol) is added dropwise in reaction solution, after dripping off, reacts at room temperature 2h.Screw out solvent, residue ethyl acetate (100mL) extraction, saturated sodium chloride solution (50mL) washing, anhydrous sodium sulfate is dry, screws out solvent, residue silica gel column chromatography It purifies (PE:EtOAc (V:V)=3:1), obtains brown solid 0.93g, yield 60%.
1H NMR(400MHz,CDCl3): δ 13.71-10.69 (m, 1H), 8.57-8.34 (m, 1H), 7.94 (dd, J= 70.9,22.8Hz, 2H), 7.59 (dd, J=24.5,15.0Hz, 1H), 7.43 (s, 1H), 5.96 (dd, J=87.7,33.4Hz, 1H), 5.46 (dd, J=38.5,30.6Hz, 1H), 4.73-4.23 (m, 2H), 3.70 (s, 3H), 3.36 (s, 3H), 2.55- 2.12 (m, 2H), 2.04 (s, 3H), 1.44-1.35 (m, 3H), 1.13 (d, J=5.9Hz, 3H) ppm；MS(ESI,pos.ion) m/z:572.2[M+H]+.
The synthesis of step 2) compound 11-3:
By compound 5-6 (0.65g, 1.2mmol), compound 11-2 (0.69g, 1.2mmol), Pd (PPh3)4(0.2g, 0.12mmol) and K2CO3(0.6g, 3.6mmol) is suspended in the in the mixed solvent of EtOH (20mL) and water (4mL), under nitrogen protection It is heated to 90 DEG C of reactions.Diatomite is crossed, solvent is screwed out, residue is extracted with ethyl acetate (200mL), saturated sodium chloride solution (50mL) washing, anhydrous sodium sulfate is dry, screws out solvent, and residue silica gel column chromatography (PE:EtOAc (V:V)=1:3) purifies, Obtain brown solid 0.45g, yield 44%.
1H NMR(400MHz,CDCl3):δ13.55–10.67(m,1H),8.05–7.82(m,2H),7.75–7.59(m, 3H), 7.41-7.29 (m, 1H), 7.18 (d, J=8.5Hz, 1H), 6.21-5.87 (m, 1H), 5.67-5.36 (m, 1H), 5.05 (t, J=7.3Hz, 1H), 4.46 (ddd, J=76.6,33.7,27.1Hz, 2H), 3.92-3.80 (m, 3H), 3.75-3.66 (m, 2H),3.54(s,1H),3.37(s,6H),3.30(s,2H),3.20–3.04(m,6H),2.64–2.42(m,3H),2.30– 1.95(m,6H),1.51(s,9H),1.26(m,6H)ppm；MS(ESI,pos.ion)m/z:820.4[M+H]+.
The synthesis of step 3) compound 11-4:
Compound 11-3 (0.45g, 0.54mmol) is dissolved in DCM (10mL), under the conditions of 0 DEG C, hydrochloric acid second is slowly added dropwise Acetate solution (4M/L, 3mL) after dripping, reacts at room temperature 3h.Solvent is screwed out, residue is beaten with ethyl acetate, is filtered. Filter cake is dissolved with water (10mL), is added potassium carbonate tune pH value to 8-9, is filtered, obtain product 0.35g, yield 90%.
1H NMR(400MHz,CDCl3):δ13.55–10.67(m,1H),8.05–7.82(m,2H),7.75–7.59(m, 3H), 7.41-7.29 (m, 1H), 7.18 (d, J=8.5Hz, 1H), 6.21-5.87 (m, 1H), 5.67-5.36 (m, 1H), 5.05 (t, J=7.3Hz, 1H), 4.46 (ddd, J=76.6,33.7,27.1Hz, 2H), 3.92-3.80 (m, 3H), 3.75-3.66 (m, 2H),3.54(s,1H),3.37(s,6H),3.30(s,1H),3.20–3.04(m,6H),2.64–2.42(m,3H),2.30– 1.95(m,7H),1.26(m,6H)ppm；MS(ESI,pos.ion)m/z:720.2[M+H]+.
The synthesis of step 4) compound 11:
By compound 11-4 (0.35g, 0.49mmol), compound 11-5 (0.1g, 0.53mmol), EDCI (0.11g, It 0.58mmol) is suspended in methylene chloride (20mL) with 2- ethyl cyanoacetate (0.028g, 0.19mmol), in 0 DEG C of condition Under, DIPEA (0.19g, 1.5mmol) is added dropwise in reaction solution, after dripping off, reacts at room temperature 2h.Screw out solvent, residue second Acetoacetic ester (100mL) dissolution, saturated sodium chloride solution (50mL) washing, anhydrous sodium sulfate is dry, screws out solvent, residue silica gel Column chromatographs (DCM:EtOAc (V:V)=2:1), obtains white solid 0.3g, yield 70%.
1H NMR(400MHz,CDCl3): δ 8.59 (s, 1H), 7.98 (d, J=13.6Hz, 1H), 7.68 (dd, J=20.5, 8.0Hz, 3H), 7.35 (d, J=8.1Hz, 1H), 7.20 (d, J=6.7Hz, 1H), 5.98-5.68 (m, 1H), 5.56 (dd, J= 20.1,6.7Hz,2H),5.36–5.24(m,2H),4.70–4.28(m,3H),4.19–3.82(m,3H),3.79–3.56(m, 6H), 3.40 (s, 6H), 3.29 (d, J=11.8Hz, 2H), 3.14-3.04 (m, 6H), 2.34-1.97 (m, 5H), 1.83-1.40 (m, 4H), 1.39-1.22 (m, 7H), 1.13 (d, J=6.0Hz, 2H), 0.91-0.71 (m, 6H) ppm；MS(ESI,pos.ion) m/z:891.5[M+H]+.
Embodiment 9
Synthetic route:
Synthesis step:
By compound 10-0 (280mg, 0.54mmol, 1.0eq), compound 11-5 (256mg, 1.36mmol, 2.5eq), 2- ethyl cyanoacetate (61mg, 0.43mmol, 0.8eq) and DIPEA (35mg, 0.27mmol, 0.5eq) are added to DCM It in (15mL), adds EDCI (227mg, 1.19mmol, 2.2eq), reacts at room temperature 18h.Reaction solution is poured into water (30mL), It is extracted with DCM (15mL × 3), organic phase is dry with anhydrous sodium sulfate, is spin-dried for, and silica gel column chromatography purifies (DCM:EtOAc (V:V) =1:2), obtain faint yellow solid product 150mg, yield 32.2%.
1H NMR(400MHz,CDCl3): δ 11.96-10.36 (m, 2H), 8.83-8.50 (m, 1H), 7.94 (dd, J= 39.4,12.5Hz, 2H), 7.83-7.62 (m, 2H), 7.46 (dd, J=92.2,12.5Hz, 2H), 7.21 (d, J=17.5Hz, 1H), 5.60-5.40 (m, 2H), 5.26 (dd, J=20.5,11.7Hz, 1H), 4.82-4.63 (m, 1H), 4.39-4.23 (m, 2H), 3.72 (d, J=6.9Hz, 6H), 3.25-3.01 (m, 4H), 2.57-2.25 (m, 2H), 2.14 (dd, J=20.5, 14.8Hz, 3H), 2.05-1.95 (m, 1H), 1.94-1.77 (m, 3H), 1.66 (dd, J=7.2,4.4Hz, 3H), 1.30 (d, J =5.2Hz, 6H), 1.20 (t, J=13.7Hz, 4H), 1.05 (dd, J=15.6,6.7Hz, 2H), 0.99-0.94 (m, 2H), 0.89 (dd, J=13.8,6.3Hz, 6H), 0.77 (dd, J=12.2,6.6Hz, 2H) ppm；MS-ESI,m/z:859.5[M+H]+.
Embodiment 10
Synthetic route:
Synthesis step:
The synthesis of step 1) compound 15-2
Compound 15-1 (0.664g, 2.73mmol, 1.05eq) and compound 1-6 (1.0g, 2.6mmol, 1.0eq) is added Enter in acetonitrile (10mL), triethylamine (0.39g, 3.9mmol, 1.5eq) is added dropwise at 0 DEG C, drips off room temperature reaction 2h.It is spin-dried for molten Agent is added water (20mL), then extracts (20mL × 3) with DCM, and organic phase is dry with anhydrous sodium sulfate, is spin-dried for, and obtains brown oil production Product 1.42g, yield 100%.
1H NMR(400MHz,CDCl3): δ 7.68 (d, J=8.5Hz, 1H), 7.21 (d, J=8.3Hz, 1H), 5.54- 5.35 (m, 1H), 5.20 (dd, J=25.2,13.6Hz, 1H), 4.62 (dt, J=21.6,8.3Hz, 1H), 4.06-3.52 (m, 3H), 3.40-3.22 (m, 1H), 3.06 (t, J=7.5Hz, 2H), 2.83-2.64 (m, 1H), 2.58-2.33 (m, 1H), 2.20 (dt, J=14.2,7.3Hz, 2H), 1.48 (m, 13H), 0.9 (t, J=5.6Hz, 3H) ppm.
The synthesis of step 2) compound 15-3
Compound 15-2 (1.42g, 2.6mmol, 1.0eq) and ammonium acetate (1.2g, 15.6mmol, 6.0eq) are added to In toluene (15mL), 115 DEG C of reaction 20h.Toluene is spin-dried for, is added water (50mL), then extracts (15mL × 3) with DCM, organic phase It is dry with anhydrous sodium sulfate, it is spin-dried for, silica gel column chromatography purifies (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 1.31g, receives Rate 95%.
1H NMR(400MHz,CDCl3): δ 10.97 (d, J=188.0Hz, 1H), 7.83 (d, J=7.2Hz, 1H), 7.19 (s, 1H), 7.11 (d, J=8.5Hz, 1H), 5.33 (d, J=52.9Hz, 1H), 5.19 (t, J=7.0Hz, 1H), 3.98 (dd, J =21.0,13.0Hz, 1H), 3.61-3.22 (m, 1H), 3.12 (dt, J=15.0,7.1Hz, 4H), 2.85-2.59 (m, 1H), 2.29-2.14 (m, 2H), 1.52 (m, 12H), 0.9 (t, J=5.6Hz, 3H) ppm；MS-ESI,m/z:530.2[M+H]+.
The synthesis of step 3) compound 15-4
By compound 15-3 (1.26g, 2.37mmol, 1.0eq), join pinacol borate (0.63g, 2.49mmol, 1.05eq), potassium acetate (0.70g, 7.1mmol, 3.0eq), Pd (dppf)2Cl2(69mg, 0.094mmol, 0.04eq), is added to In DMF (15mL), the lower 100 DEG C of reactions 10h of nitrogen protection.Reaction solution is poured into water (60mL), gray solid, silica gel are filtered to obtain Column chromatographic purifying (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 0.85g, yield 71%.
1H NMR(400MHz,CDCl3): δ 10.89 (d, J=186.4Hz, 1H), 7.78 (s, 1H), 7.67 (d, J= 7.5Hz, 1H), 7.20 (s, 1H), 5.27 (dd, J=42.7,30.3Hz, 2H), 3.97 (dd, J=20.7,13.3Hz, 1H), 3.48-3.40(m,1H),3.38–2.88(m,4H),2.80–2.59(m,1H),2.19–2.07(m,2H),1.52-1.34(m, 12H), 1.36 (s, 12H), 0.9 (t, J=5.6Hz, 3H) ppm；MS-ESI,m/z:508.3[M+H]+.
The synthesis of step 4) compound 15-6
By compound 15-4 (558mg, 1.10mmol, 1.0eq), compound 2-6A (473g, 1.10mmol, 1.0eq), carbon Sour potassium (0.30g, 2.21mmol, 2.0eq), four triphenyl phosphorus palladiums (38mg, 0.033mmol, 0.03eq) are added to ethyl alcohol In (10mL) and water (3mL), under nitrogen protection, 90 DEG C of reaction 6h.Reaction solution is poured into water (50mL), is extracted with dichloromethane (30mL × 3), organic phase is dry with anhydrous sodium sulfate, is spin-dried for, and silica gel column chromatography purifies (PE:EtOAc (V:V)=1:1), obtains white Color solid product 0.70g, yield 87%.
1H NMR(400MHz,CDCl3): δ 11.88-10.35 (m, 2H), 8.67 (d, J=8.1Hz, 1H), 8.22-7.30 (m, 6H), 7.18 (d, J=23.9Hz, 1H), 5.51-5.11 (m, 3H), 4.00 (dd, J=21.1,13.2Hz, 1H), 3.57 (dd, J=32.1,9.6Hz, 3H), 3.30-3.11 (m, 4H), 2.44-2.21 (m, 2H), 2.20-2.08 (m, 2H), 2.00- 1.86 (m, 2H), 1.55-1.34 (m, 21H), 1.32-1.18 (m, 3H), 0.9 (t, J=5.6Hz, 3H) ppm；MS-ESI,m/z: 731.3[M+H]+.
The synthesis of step 5) compound 15-7
Compound 15-6 (0.70g, 0.95mmol, 1.0eq) is added in DCM (10mL), in 0 DEG C of dropwise addition HCl/ EtOAc (4N, 3mL) solution drips off room temperature reaction 10h.Solvent is spin-dried for, is added EtOAc (20mL), room temperature is beaten 1h, filters Faint yellow solid, dissolved with water (10mL), then free with sodium carbonate liquor, solid be precipitated, filters, it is dry that yellow solid produces Product 428mg, yield 85%.
1H NMR(400MHz,DMSO-d6): δ 12.10 (s, 2H), 8.48 (d, J=7.8Hz, 1H), 8.03 (s, 1H), 7.96-7.49 (m, 4H), 7.45-7.08 (m, 2H), 5.37 (d, J=55.4Hz, 1H), 4.70-4.18 (m, 2H), 3.30- 3.15 (m, 1H), 3.15-2.85 (m, 6H), 2.28 (ddd, J=39.8,14.5,9.4Hz, 3H), 2.04 (d, J=5.5Hz, 2H), 1.94-1.65 (m, 5H), 1.32-1.18 (m, 3H), 0.9 (t, J=5.6Hz, 3H) ppm；MS-ESI,m/z:531.4[M+ H]+.
The synthesis of step 6) compound 15
By compound 15-6 (265mg, 0.5mmol, 1.0eq), compound 1-14 (193mg, 1.1mmol, 2.2eq), 2- Ethyl cyanoacetate (57mg, 0.4mmol, 0.8eq) and DIPEA (32mg, 0.25mmol, 0.5eq) are added to DCM (15mL) In, it adds EDCI (211mg, 1.1mmol, 2.2eq), reacts at room temperature 3h.Reaction solution is poured into water (30mL), DCM is used (15mL × 3) extraction, organic phase is dry with anhydrous sodium sulfate, is spin-dried for, silica gel column chromatography purifying (DCM:MeOH (V:V)=10: 1) white solid product 232mg, yield 55%, are obtained.
1H NMR(400MHz,CDCl3):δ12.09–10.24(m,2H),8.63(s,1H),8.19–7.54(m,4H), 7.42 (d, J=39.2Hz, 1H), 7.13 (dd, J=75.7,30.2Hz, 2H), 6.47-5.62 (m, 2H), 5.62-5.26 (m, 3H), 4.38 (dd, J=23.1,15.4Hz, 3H), 4.14 (q, J=7.1Hz, 2H), 3.97 (s, 1H), 3.76 (d, J= 27.7Hz, 6H), 3.46-3.19 (m, 1H), 3.06 (s, 3H), 2.72 (dd, J=26.7,14.6Hz, 1H), 2.59-2.07 (m, 4H), 1.94 (d, J=1.3Hz, 2H), 1.80-1.58 (m, 3H), 1.32-1.18 (m, 4H) 0.89 (m, 15H) ppm；MS-ESI, m/z:845.4[M+H]+.
Embodiment 11
Synthetic route:
Synthesis step:
The synthesis of step 1) compound 16-2
Compound 16-1 (0.81g, 2.73mmol, 1.05eq) and compound 1-6 (1.0g, 2.6mmol, 1.0eq) is added Enter in acetonitrile (10mL), triethylamine (0.39g, 3.9mmol, 1.5eq) is added dropwise at 0 DEG C, drips off room temperature reaction 2h.It screws out molten Agent is added water (20mL), then extracts (20mL × 3) with DCM, and organic phase is dry with anhydrous sodium sulfate, is spin-dried for, and obtains brown oil production Product 1.56g, yield 100%.
1H NMR(400MHz,CDCl3): δ 7.68 (d, J=8.5Hz, 1H), 7.21 (d, J=8.3Hz, 1H), 6.50 (t, 1H), 5.54-5.35 (m, 1H), 5.20 (dd, J=25.2,13.6Hz, 1H), 4.62 (dt, J=21.6,8.3Hz, 1H), 4.06-3.52 (m, 3H), 3.40-3.22 (m, 4H), 3.06 (t, J=7.5Hz, 2H), 2.83-2.64 (m, 1H), 2.58-2.33 (m, 1H), 2.20 (dt, J=14.2,7.3Hz, 2H), 1.48 (m, 10H) ppm.
The synthesis of step 2) compound 16-3
Compound 16-2 (1.56g, 2.6mmol, 1.0eq) and ammonium acetate (1.2g, 15.6mmol, 6.0eq) are added to In toluene (15mL), 115 DEG C of reaction 20h.Toluene is spin-dried for, is added water (50mL), then extracts (15mL × 3) with DCM, organic phase It is dry with anhydrous sodium sulfate, it is spin-dried for, silica gel column chromatography purifies (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 1.38g, receives Rate 91%.
1H NMR(400MHz,CDCl3): δ 10.97 (d, J=188.0Hz, 1H), 7.83 (d, J=7.2Hz, 1H), 7.19 (s, 1H), 7.11 (d, J=8.5Hz, 1H), 6.50 (t, 1H), 5.33 (d, J=52.9Hz, 1H), 5.19 (t, J=7.0Hz, 1H), 3.98 (dd, J=21.0,13.0Hz, 1H), 3.61-3.22 (m, 4H), 3.12 (dt, J=15.0,7.1Hz, 4H), 2.85–2.59(m,1H),2.29–2.14(m,2H),1.52(s,9H)ppm；MS-ESI,m/z:582.2[M+H]+.
The synthesis of step 3) compound 16-4
By compound 16-3 (1.38g, 2.37mmol, 1.0eq), join pinacol borate (0.63g, 2.49mmol, 1.05eq), potassium acetate (0.70g, 7.1mmol, 3.0eq), Pd (dppf)2Cl2(69mg, 0.094mmol, 0.04eq), is added to In DMF (15mL), the lower 100 DEG C of reactions 10h of nitrogen protection.Reaction solution is poured into water (60mL), gray solid, then silicon are filtered to obtain Gel column chromatography eluting (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 0.95g, yield 72%.
1H NMR(400MHz,CDCl3): δ 10.89 (d, J=186.4Hz, 1H), 7.78 (s, 1H), 7.67 (d, J= 7.5Hz, 1H), 7.20 (s, 1H), 6.5 (t, 1H), 5.27 (dd, J=42.7,30.3Hz, 2H), 3.97 (dd, J=20.7, 13.3Hz, 1H), 3.48 (dd, J=35.4,12.0Hz, 1H), 3.38-2.88 (m, 7H), 2.80-2.59 (m, 1H), 2.19- 2.07(m,2H),1.52(s,9H),1.36(s,12H)ppm；MS-ESI,m/z:560.3[M+H]+.
The synthesis of step 4) compound 16-5
By compound 16-4 (615mg, 1.10mmol, 1.0eq), compound 2-6A (473g, 1.10mmol, 1.0eq), carbon Sour potassium (0.30g, 2.21mmol, 2.0eq), four triphenyl phosphorus palladiums (38mg, 0.033mmol, 0.03eq) are added to ethyl alcohol In (10mL) and water (3mL), under nitrogen protection, 90 DEG C of reaction 6h.Reaction solution is poured into water (50mL), is extracted with dichloromethane (30mL × 3), organic phase is dry with anhydrous sodium sulfate, is spin-dried for, and silica gel column chromatography purifies (PE:EtOAc (V:V)=1:1), obtains white Color solid product 0.82g, yield 95%.
1H NMR(400MHz,CDCl3): δ 11.88-10.35 (m, 2H), 8.67 (d, J=8.1Hz, 1H), 8.22-7.30 (m, 6H), 7.18 (d, J=23.9Hz, 1H), 6.50 (t, 1H), 5.51-5.11 (m, 3H), 4.00 (dd, J=21.1, 13.2Hz, 1H), 3.57 (dd, J=32.1,9.6Hz, 3H), 3.30-3.11 (m, 7H), 2.44-2.21 (m, 2H), 2.20- 2.08 (m, 2H), 2.00-1.86 (m, 2H), 1.55 (d, J=6.7Hz, 18H), 1.32-1.18 (m, 3H) ppm；MS-ESI,m/ z:783.3[M+H]+.
The synthesis of step 5) compound 16-6
Compound 16-5 (0.82g, 1.05mmol, 1.0eq) is added in DCM (10mL), in 0 DEG C of dropwise addition HCl/ EtOAc (3mL) solution drips off room temperature reaction 10h.Solvent is spin-dried for, is added EtOAc (20mL), room temperature is beaten 1h, filters light Yellow solid is dissolved with water (10mL), then free with sodium carbonate liquor, and solid is precipitated, filters, dry yellow solid product 543mg, yield 89%.
1H NMR(400MHz,DMSO-d6): δ 12.10 (s, 2H), 8.48 (d, J=7.8Hz, 1H), 8.03 (s, 1H), 7.96-7.49 (m, 4H), 7.45-7.08 (m, 2H), 6.50 (t, 1H), 5.37 (d, J=55.4Hz, 1H), 4.70-4.18 (m, 2H), 3.30-3.15 (m, 4H), 3.15-2.85 (m, 6H), 2.28 (ddd, J=39.8,14.5,9.4Hz, 3H), 2.04 (d, J =5.5Hz, 2H), 1.94-1.65 (m, 2H), 1.32-1.18 (m, 3H) ppm；MS-ESI,m/z:583.4[M+H]+.
The synthesis of step 6) compound 16
By compound 16-6 (291mg, 0.5mmol, 1.0eq), compound 1-14 (193mg, 1.1mmol, 2.2eq), 2- Ethyl cyanoacetate (57mg, 0.4mmol, 0.8eq) is added in DCM (15mL), add EDCI (211mg, 1.1mmol, 2.2eq), 3h is reacted at room temperature.Reaction solution is poured into water (30mL), is extracted with DCM (15mL × 3), organic phase anhydrous slufuric acid Sodium is dry, is spin-dried for, and crosses column, and silica gel column chromatography purifies (DCM:MeOH (V:V)=10:1), obtains white solid product 256mg, yield 57%.
1H NMR(400MHz,CDCl3):δ12.09–10.24(m,2H),8.63(s,1H),8.19–7.54(m,4H), 7.42 (d, J=39.2Hz, 1H), 7.13 (dd, J=75.7,30.2Hz, 2H), 6.47-5.62 (m, 3H), 5.62-5.26 (m, 3H), 4.38 (dd, J=23.1,15.4Hz, 3H), 4.14 (q, J=7.1Hz, 2H), 3.97 (s, 1H), 3.76 (d, J= 27.7Hz, 6H), 3.46-3.19 (m, 3H), 3.06 (s, 4H), 2.72 (dd, J=26.7,14.6Hz, 1H), 2.59-2.07 (m, 4H), 1.94 (d, J=1.3Hz, 2H), 1.80-1.58 (m, 1H), 1.32-1.18 (m, 3H) 0.89 (dd, J=16.3,5.8Hz, 12H)ppm；MS-ESI,m/z:897.4[M+H]+.
Embodiment 12
Synthetic route:
Synthesis step:
The synthesis of step 1) compound 22-2
Compound 22-1 (0.63g, 2.7mmol, 1.05eq) and compound 1-6 (1.0g, 2.6mmol, 1.0eq) is added To in acetonitrile (10mL), triethylamine (0.39g, 3.9mmol, 1.5eq) is added dropwise at 0 DEG C, drips off room temperature reaction 2h.It screws out molten Agent is added water (20mL), then extracts (20mL × 3) with DCM, and organic phase is dry with anhydrous sodium sulfate, is spin-dried for, and obtains brown oil production Product 1.43g, yield 100%.
1H NMR(400MHz,CDCl3): δ 7.68 (d, J=8.5Hz, 1H), 7.21 (d, J=8.3Hz, 1H), 5.54- 5.35 (m, 1H), 5.20 (dd, J=25.2,13.6Hz, 1H), 4.62 (dt, J=21.6,8.3Hz, 1H), 4.06-3.52 (m, 3H), 3.31 (t, J=7.4Hz, 2H), 3.06 (t, J=7.5Hz, 2H), 2.83-2.64 (m, 1H), 2.58-2.33 (m, 1H), 2.20 (dt, J=14.2,7.3Hz, 2H), 1.48 (d, J=10.1Hz, 10H) ppm.
The synthesis of step 2) compound 22-3
Compound 22-2 (1.40g, 2.59mmol, 1.0eq) and ammonium acetate (1.2g, 15.6mmol, 6.0eq) are added to In toluene (15mL), 115 DEG C of reaction 20h.Toluene is spin-dried for, is added water (50mL), then extracts (15mL × 3) with DCM, organic phase It is dry with anhydrous sodium sulfate, it is spin-dried for, silica gel column chromatography purifies (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 1.23g, receives Rate 91.2%.
1H NMR(400MHz,CDCl3): δ 10.97 (d, J=188.0Hz, 1H), 7.83 (d, J=7.2Hz, 1H), 7.19 (s, 1H), 7.11 (d, J=8.5Hz, 1H), 5.33 (d, J=52.9Hz, 1H), 5.19 (t, J=7.0Hz, 1H), 3.98 (dd, J =21.0,13.0Hz, 1H), 3.61-3.22 (m, 2H), 3.12 (dt, J=15.0,7.1Hz, 4H), 2.85-2.59 (m, 1H), 2.29–2.14(m,2H),1.52(s,9H)ppm；MS-ESI,m/z:520.2[M+H]+.
The synthesis of step 3) compound 22-4
By compound 22-3 (1.23g, 2.37mmol, 1.0eq), join pinacol borate (0.63g, 2.49mmol, 1.05eq), potassium acetate (0.70g, 7.1mmol, 3.0eq), Pd (dppf)2Cl2(69mg, 0.094mmol, 0.04eq), is added to In DMF (15mL), the lower 100 DEG C of reactions 10h of nitrogen protection.Reaction solution is poured into water, gray solid, silica gel column chromatography are filtered to obtain It purifies (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 0.74g, yield 63%.
1H NMR(400MHz,CDCl3): δ 10.89 (d, J=186.4Hz, 1H), 7.78 (s, 1H), 7.67 (d, J= 7.5Hz, 1H), 7.20 (s, 1H), 5.27 (dd, J=42.7,30.3Hz, 2H), 3.97 (dd, J=20.7,13.3Hz, 1H), 3.48 (dd, J=35.4,12.0Hz, 1H), 3.38-2.88 (m, 5H), 2.80-2.59 (m, 1H), 2.19-2.07 (m, 2H), 1.52(s,9H),1.36(s,12H)ppm；MS-ESI,m/z:498.4[M+H]+.
The synthesis of step 4) compound 22-5
By compound 22-4 (550mg, 1.10mmol, 1.0eq), compound 7-7A (460g, 1.10mmol, 1.0eq), carbon Sour potassium (0.30g, 2.21mmol, 2.0eq), four triphenyl phosphorus palladiums (38mg, 0.033mmol, 0.03eq) are added to ethyl alcohol In (10mL) and water (3mL), under nitrogen protection, 90 DEG C of reaction 6h.Reaction solution is poured into water (50mL), is extracted with dichloromethane (30mL × 3), organic phase is dry with anhydrous sodium sulfate, is spin-dried for, and silica gel column chromatography purifies (PE:EtOAc (V:V)=1:1), obtains white Color solid product 0.765g, yield 97.8%.
1H NMR(400MHz,CDCl3): δ 11.88-10.35 (m, 2H), 8.67 (d, J=8.1Hz, 1H), 8.22-7.30 (m, 6H), 7.18 (d, J=23.9Hz, 1H), 5.51-5.11 (m, 3H), 4.00 (dd, J=21.1,13.2Hz, 1H), 3.57 (dd, J=32.1,9.6Hz, 3H), 3.14 (dd, J=20.9,13.7Hz, 5H), 2.81-2.62 (m, 1H), 2.44-2.21 (m, 2H), 2.20-2.08 (m, 2H), 2.00-1.86 (m, 2H), 1.55 (d, J=6.7Hz, 18H) ppm；MS-ESI,m/z:707.4 [M+H]+.
The synthesis of step 5) compound 22-6
Compound 22-5 (0.76g, 1.1mmol, 1.0eq) is added in DCM (10mL), in 0 DEG C of dropwise addition HCl/EtOAc (4N, 3mL) solution drips off room temperature reaction 10h.Solvent is spin-dried for, is added EtOAc (20mL), room temperature is beaten 1h, filters yellowish Color solid is dissolved with water (10mL), then free with sodium carbonate liquor, and solid is precipitated, filters, dry yellow solid product 500mg, yield 92%.
1H NMR(400MHz,DMSO-d6): δ 12.10 (s, 2H), 8.48 (d, J=7.8Hz, 1H), 8.03 (s, 1H), 7.96-7.49 (m, 4H), 7.45-7.08 (m, 2H), 5.37 (d, J=55.4Hz, 1H), 4.70-4.18 (m, 2H), 3.30- 3.21 (m, 2H), 3.15-2.85 (m, 7H), 2.28 (ddd, J=39.8,14.5,9.4Hz, 3H), 2.04 (d, J=5.5Hz, 2H),1.94–1.65(m,2H)ppm；MS-ESI,m/z:507.4[M+H]+.
The synthesis of step 6) compound 22
By compound 22-6 (280mg, 0.552mmol, 1.0eq), compound 1-14 (213mg, 1.22mmol, 2.2eq), 2- ethyl cyanoacetate (62mg, 0.44mmol, 0.8eq) and DIPEA (35mg, 0.27mmol, 0.5eq) are added to DCM It in (15mL), adds EDCI (232mg, 1.22mmol, 2.2eq), reacts at room temperature 3h.Reaction solution is poured into water (30mL), It is extracted with DCM (15mL × 3), organic phase is dry with anhydrous sodium sulfate, is spin-dried for, and silica gel column chromatography purifies (DCM:EtOAc:MeOH (V:V:V)=5:10:1), obtain white solid product 270mg, yield 59.50%.
1H NMR(400MHz,CDCl3):δ12.09–10.24(m,2H),8.63(s,1H),8.19–7.54(m,4H), 7.42 (d, J=39.2Hz, 1H), 7.13 (dd, J=75.7,30.2Hz, 2H), 6.47-5.62 (m, 2H), 5.62-5.26 (m, 3H), 4.38 (dd, J=23.1,15.4Hz, 3H), 4.14 (q, J=7.1Hz, 2H), 3.97 (s, 1H), 3.76 (d, J= 27.7Hz, 6H), 3.46-3.19 (m, 1H), 3.06 (s, 4H), 2.72 (dd, J=26.7,14.6Hz, 1H), 2.59-2.07 (m, 5H), 1.94 (d, J=1.3Hz, 2H), 1.80-1.58 (m, 1H), 0.89 (dd, J=16.3,5.8Hz, 12H) ppm；MS-ESI, m/z:821.2[M+H]+.
Embodiment 13
Synthetic route:
Synthesis step:
The synthesis of step 1) compound 31-1
By compound 1-11 (0.8g, 1.7mmol, 1eq), compound 1-5A (0.73g, 1.5mmol, 0.9eq), Pd (PPh3)4(0.20g, 0.17mmol, 0.1eq) and K2CO3The EtOH/H that (0.69mg, 5.0mmol, 3eq) is suspended in2O(30mL, V:V=3:1 in), 90 DEG C of reaction 3h are heated under nitrogen protection.After fully reacting, most solutions are screwed out, then with DCM (20mL × 2) it extracts, merges organic phase, it is dry, it is spin-dried for, silica gel column chromatography purifies (PE:EA (V:V)=2:1), obtains gray solid 0.5g, yield 40%.
1H NMR(400MHz,CDCl3):δ7.98(s,1H),7.52(d,2H),7.22(m,2H),5.33(s,1H),4.93 (s,2H),3.26(m,4H),3.20(m,2H),3.10(m,4H),2.76-2.62(m,4H),2.19-1.95(m,6H),1.25 (m,9H),1.29(m,9H)ppm；MS-ESI,m/z:691.5[M+H]+.
The synthesis of step 2) compound 31-2
HCl/EtOAc (4N, 4mL) is added drop-wise to the dichloromethane of compound 31-1 (0.5g, 0.7mmol, 1eq) at 0 DEG C In alkane solvents (15mL), drips off rear room temperature and be stirred to react 6h.Fully reacting back spin dry reaction liquid, ethyl acetate mashing purifying obtain Brown solid 0.4g, yield 87%.MS-ESI,m/z:491.6[M+H]+.
The synthesis of step 3) compound 31
By compound 31-2 (0.40g, 0.82mmol, 1eq), compound 1-14 (0.316g, 1.8mmol, 2.2eq), EDCI (0.377g, 1.97mmol, 2.4eq) and 2- ethyl cyanoacetate (0.07g, 0.49mmol, 0.6eq) are suspended in dichloro In methane (10mL), DIPEA (0.530g, 4.1mmol, 5eq) is added dropwise in reaction solution under the conditions of 0 DEG C, after dripping off, is moved into 2h is stirred at room temperature.After fully reacting, ammonium hydroxide (2mL) is added and stirs 1h, liquid separation, organic phase is washed with saturated aqueous ammonium chloride, nothing Aqueous sodium persulfate dries, filters, and is spin-dried for, and silica gel column chromatography purifies (PE:EtOAc (V:V)=1:1), obtains gray solid 0.35g, Yield 53%.
1H NMR(400MHz,CDCl3):δ8.10(s,1H),7.62(d,2H),7.21(m,2H),5.43(s,1H),5.10 (s,2H),3.56-3.42(m,4H)3.31(m,2H),3.16-2.83(m,4H),2.72-2.63(m,4H),2.56-2.41(m, 4H),2.38(m,2H),2.36-2.21(m,4H),2.09-1.82(m,6H),1.05(m,12H)ppm；MS-ESI,m/z: 806.3[M+H]+.
Embodiment 14
Synthetic route:
Synthesis step:
The synthesis of step 1) compound 32-2
By compound 1-6 (1.45g, 2.65mmol, 1.0eq) and (3S) -2- (tertbutyloxycarbonyl) -2- azabicyclo [2.2.1] heptane -3- carboxylic acid 32-1 (0.82g, 0.34mmol, 1.1eq) is added in acetonitrile (10mL), is added dropwise three at 0 DEG C Ethamine (0.39g, 3.9mmol, 1.5eq) drips off room temperature reaction 2h.Solvent is screwed out, is added water (20mL), then extracted with DCM (10mL × 3), organic phase is dry with anhydrous sodium sulfate, is spin-dried for, obtains brown oil product 1.45g, yield 100%.
1H NMR(400MHz,CDCl3): δ 7.74-7.61 (m, 1H), 7.20 (d, J=8.5Hz, 1H), 5.28 (ddd, J= 62.1,49.1,16.3Hz, 2H), 4.32 (d, J=51.5Hz, 1H), 3.95 (d, J=29.9Hz, 1H), 3.32 (t, J= 6.0Hz, 2H), 3.06 (t, J=7.2Hz, 2H), 2.97-2.82 (m, 1H), 2.27-2.11 (m, 2H), 2.06-1.94 (m, 1H), 1.85-1.76 (m, 1H), 1.69-1.62 (m, 2H), 1.56 (dd, J=11.3,6.9Hz, 1H), 1.46 (d, J= 18.4Hz,9H),1.36–1.30(m,1H)ppm.
The synthesis of step 2) compound 32-3
Compound 32-2 (1.45g, 2.65mmol, 1.0eq) and ammonium acetate (1.22g, 15.9mmol, 6.0eq) are added To in toluene (10mL), 115 DEG C of reaction 15h.Toluene is spin-dried for, is added water (50mL), then extracts (15mL × 3) with DCM, it is organic It is mutually dry with anhydrous sodium sulfate, it is spin-dried for, silica gel column chromatography purifies (PE:EtOAc (V:V)=5:1), faint yellow solid 1.1g is obtained, Yield 79%.
1H NMR(400MHz,CDCl3): δ 10.73 (d, J=211.3Hz, 1H), 7.84 (d, J=8.5Hz, 1H), 7.12 (t, J=13.6Hz, 2H), 4.43 (d, J=8.5Hz, 1H), 4.16 (s, 1H), 3.41 (d, J=18.3Hz, 1H), 3.11 (dt, J=23.2,7.3Hz, 4H), 2.19 (dt, J=15.0,7.6Hz, 2H), 2.00 (d, J=10.0Hz, 1H), 1.87 (td, J= 11.1,5.1Hz,1H),1.77–1.67(m,4H),1.53(s,9H)ppm；MS-ESI,m/z:528.10[M+H]+.
The synthesis of step 3) compound 32-4
By compound 32-3 (1.03g, 1.95mmol, 1.0eq), join pinacol borate (0.52g, 2.05mmol, 1.05eq), potassium acetate (0.57g, 5.86mmol, 3.0eq), Pd (dppf)2Cl2(57mg, 0.078mmol, 0.04eq) is added To in DMF (10mL), the lower 100 DEG C of reactions 11h of nitrogen protection.Reaction solution is poured into water, gray solid, then silicagel column are filtered to obtain Chromatographic purifying (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 0.96g, yield 97%.
1H NMR(400MHz,CDCl3): δ 10.67 (d, J=221.7Hz, 1H), 7.79 (s, 0.5H), 7.66 (d, J= 7.7Hz, 1H), 7.25 (s, 0.5H), 7.19 (s, 1H), 4.45 (s, 1H), 4.17 (s, 1H), 3.42 (d, J=20.6Hz, 1H), 3.19 (t, J=7.5Hz, 2H), 3.10-3.02 (m, 2H), 2.11 (dd, J=14.6,7.3Hz, 2H), 2.02 (d, J= 9.9Hz, 1H), 1.93-1.84 (m, 1H), 1.74 (dd, J=15.4,10.4Hz, 4H), 1.53 (s, 9H), 1.36 (s, 12H) ppm；MS-ESI,m/z:506.25[M+H]+.
The synthesis of step 4) compound 32-5
By compound 32-4 (0.6g, 1.2mmol, 1eq), compound 7-7A (0.49g, 1.2mmol, 1eq), Pd (PPh3)4 (0.14g, 0.12mmol, 0.1eq) and K2CO3(0.49mg, 3.6mmol, 3eq) is suspended in EtOH/H2In O (30mL, 3:1), nitrogen 90 DEG C of reaction 3h are heated under gas shielded.After fully reacting, most solutions is screwed out, then extracted with DCM (20mL × 2), merged Organic phase, it is dry, it is spin-dried for, silica gel column chromatography purifies (PE:EtOAc (V:V)=2:1), obtains gray solid 0.6g, yield 70%.
1H NMR(400MHz,CDCl3):δ7.98(s,1H),7.72(d,2H),7.32(m,2H),7.22(m,2H),5.53 (s,1H),4.63(s,2H),3.26(m,4H),3.10-2.85(m,4H),2.76-2.51(m,4H),2.23-2.09(m,6H), 1.82-1.69(m,2H),1.25(m,9H),1.29(m,9H)ppm.
The synthesis of step 5) compound 32-6
HCl/EtOAc (4N, 4mL) is added drop-wise to the dichloromethane of compound 32-5 (0.5g, 0.7mmol, 1eq) at 0 DEG C In alkane solvents (15mL), drips off rear room temperature and be stirred to react 6h.Fully reacting back spin dry reaction liquid, ethyl acetate mashing purifying obtain Brown solid 0.36g, yield 79%.
Step 6) synthesizes compound 32
By compound 32-6 (0.67g, 1.02mmol, 1eq), compound 1-14 (0.429g, 2.45mmol, 2.4eq), EDCI (0.472g, 2.45mmol, 2.4eq) and 2- ethyl cyanoacetate (0.116g, 0.817mmol, 0.8eq) are suspended in two In chloromethanes (10mL), DIPEA (0.792g, 6.13mmol, 6eq) is added dropwise in reaction solution under the conditions of 0 DEG C, after dripping off, 2h is stirred at room temperature in immigration.After fully reacting, ammonium hydroxide (2mL) is added and stirs 1h, liquid separation, organic phase saturated aqueous ammonium chloride It washes, anhydrous sodium sulfate dries, filters, and is spin-dried for reaction solution, and silica gel column chromatography purifies (PE:EtOAc (V:V)=1:1), obtains grey Solid 0.4g, yield 51%.
1H NMR(400MHz,CDCl3):δ8.10(s,1H),7.72(d,2H),7.46(m,2H),7.21(m,2H),5.43 (s,1H),5.10(s,2H),3.56-3.45(m,4H)3.16-3.01(m,4H),3.10-2.87(m,4H),2.66-2.51(m, 4H),2.56-2.39(m,2H),2.36(m,4H),2.09-1.93(m,6H),1.81-1.72(m,2H)1.23-1.05(m, 12H)ppm.
Embodiment 15
Synthetic route:
Synthesis step:
The synthesis of step 1) compound 33-2
Lithium (0.56g, 80mmol, 4eq) is added in tetrahydrofuran (20mL), at 0 DEG C be added TMSCl (7.67mL, 60mmol, 3eq), then compound 33-1 (2.08g, 20mmol, 1eq) is added dropwise, after dripping, react at room temperature 6 days.It is added at 0 DEG C Methanol (10mL) quenching reaction, adds water (25mL), and with petroleum ether extraction (40mL × 3), merges the anhydrous sulphur of organic phase Sour sodium is dry, is concentrated at 25 DEG C.Obtain 4.9g yellow oil liquid, yield 98%.
GC/MS:[M+]=250.2.
The synthesis of step 2) compound 33-3
Compound 33-2 (4.9g, 19.6mmol, 1eq) is dissolved in tetrahydrofuran (50mL), DDQ is added dropwise at 40 DEG C The tetrahydrofuran solution (15mL) of (2.22g, 9.8mmol, 0.5eq).1h is reacted at 40 DEG C, and water (100mL) quenching reaction is added, (40mL × 4) are extracted with ethyl acetate again.Merge organic phase, uses water (50mL) respectively, saturated aqueous sodium carbonate (80mL), satisfies It is washed with saline solution (50mL), then dry with anhydrous sodium sulfate, is concentrated at 25 DEG C, obtains 5.0g crude product, yield 103%.
GC/MS:[M+]=248.1.
The synthesis of step 3) compound 33-4
Compound 33-3 (4.96g, 20mmol, 1eq) is dissolved in methanol (50mL), at 0 DEG C be added dropwise bromine (3.1mL, 60mmol, 3eq) methanol solution (10mL), after dripping react at room temperature overnight.Water (100mL) quenching reaction is added, then uses stone Oily ether extracts (100mL × 3), merges organic phase and is washed with saturated salt solution (50mL), and anhydrous sodium sulfate is dry, concentration.It obtains Residue silica gel column chromatography purify (PE), obtain 2.5g product, yield 48%.
1H NMR(400MHz,CDCl3):δ7.17(s,2H),3.09(s,4H)ppm.
The synthesis of step 4) compound 33-5
By compound 33-4 (2.5g, 9.54mmol, 1eq), tributyl (1- ethoxy ethylene) tin (2.93mL, 8.60mmol, 0.9eq) and two triphenylphosphine palladium of dichloro (0.35g, 0.48mmol, 0.05eq) be dissolved in dioxane (25mL), Nitrogen protection, microwave reaction 1h at 100 DEG C.Diatomite filtering, filtrate addition methylene chloride (20mL) and hydrochloric acid (1.5N, 20mL), 2h is stirred at room temperature, then is extracted with methylene chloride (50mL), and organic phase is dry with anhydrous sodium sulfate, is concentrated at 25 DEG C. Residue silica gel column chromatography purifies (PE:EtOAc (V:V)=30:1-20:1), obtains 1.2g white solid, yield 56%.
1H NMR(400MHz,CDCl3): δ 7.62 (d, J=8.4,1H), 7.40 (d, J=8.4,1H), 3.41 (t, J= 7.6Hz, 2H), 3.21 (t, J=7.6Hz, 2H), 2.49 (s, 3H) ppm.
The synthesis of step 5) compound 33-6
By compound 33-5 (1.2g, 5.33mmol, 1eq), copper bromide (2.38g, 10.7mmol, 2eq) is added to EtOH 60 DEG C of reaction 2h, are filtered with diatomite after reaction in (20mL) solvent, and filtrate is spin-dried for, and add DCM (40mL), and use water (20mL) washing, anhydrous sodium sulfate is dry, vacuum rotary steam, then silica gel column chromatography purifying (PE:EtOAc (V:V)=6:1), obtains Brownish red grease 1.38g, yield 85%.
1H NMR(400MHz,CDCl3): δ 7.78 (d, J=8.6Hz, 1H), 7.22 (d, J=8.6Hz, 1H), 4.43 (s, 2H), 3.36 (t, J=7.6Hz, 2H), 3.07 (t, J=7.6Hz, 2H) ppm.
The synthesis of step 6) compound 33-8
At 0 DEG C, triethylamine (0.6g, 6mmol, 1.5eq) is added drop-wise to compound 33-6 (1.1g, 3.6mmol, 1eq), It in methylene chloride (20mL) mixed liquor of compound 1-7 (1.0g, 4.6mmol, 1.3eq), is reacted at room temperature after adding, TLC monitoring Washing (10mL) is added in reaction after fully reacting, saturated sodium-chloride is washed, and organic phase is dry, is spin-dried for, silica gel column chromatography purifying (PE: EtOAc (V:V)=6:1), obtain product 1.29g, yield 82%.
1H NMR(400MHz,CDCl3): δ 7.78 (d, J=8.6Hz, 1H), 7.22 (d, J=8.6Hz, 1H), 5.13 (m, 1H),4.43(s,2H),3.36(m,2H),3.16(m,2H),3.07(m,4H),2.29(m,2H),1.36(t,9H)ppm；MS- ESI,m/z:438.1[M+H]+.
The synthesis of step 7) compound 33-9
Compound 33-8 (1.13g, 2.6mmol, 1.0eq) and ammonium acetate (1.2g, 15.6mmol, 6.0eq) are added to In toluene (15mL), 115 DEG C of reaction 20h.Toluene is spin-dried for, is added water (50mL), then extracts (15mL × 3) with DCM, organic phase It is dry with anhydrous sodium sulfate, it is spin-dried for, crosses column, silica gel column chromatography purifies (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 1.01g, yield 93%.
1H NMR(400MHz,CDCl3): δ 10.97 (s, 1H), 7.83 (d, J=7.2Hz, 1H), 7.19 (s, 1H), 7.11 (d, J=8.5Hz, 1H), 5.33 (d, J=52.9Hz, 1H), 5.19 (t, J=7.0Hz, 1H), 3.98 (dd, J=21.0, 13.0Hz, 1H), 3.61-3.22 (m, 2H), 3.12 (dt, J=15.0,7.1Hz, 4H), 2.85-2.59 (m, 2H), 1.52 (s, 9H)ppm；MS-ESI,m/z:418.2[M+H]+.
The synthesis of step 8) compound 33-11
By compound 33-9 (1.0g, 2.4mmol, 1.0eq), join pinacol borate (0.63g, 2.5mmol, 1.05eq), potassium acetate (0.71g, 7.2mmol, 3.0eq), Pd (dppf)2Cl2(69mg, 0.094mmol, 0.04eq), is added to In DMF (15mL), the lower 100 DEG C of reactions 10h of nitrogen protection.Reaction solution is poured into water, gray solid, then silica gel column layer are filtered to obtain Analysis purifying (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 0.78g, yield 70%.
1H NMR(400MHz,CDCl3): δ 10.89 (s, 1H), 7.78 (s, 1H), 7.67 (d, J=7.5Hz, 1H), 7.20 (s, 1H), 5.27 (dd, J=42.7,30.3Hz, 2H), 3.97 (dd, J=20.7,13.3Hz, 1H), 3.48 (dd, J=35.4, 12.0Hz,1H),3.38–2.88(m,5H),2.80–2.59(m,2H),1.52(s,9H),1.36(s,12H)ppm；MS-ESI, m/z:466.4[M+H]+.
The synthesis of step 9) compound 33-13
By compound 33-11 (512mg, 1.1mmol, 1.0eq), compound 7-7A (460mg, 1.1mmol, 1.0eq), carbon Sour potassium (0.30g, 2.2mmol, 2.0eq), four triphenyl phosphorus palladiums (38mg, 0.033mmol, 0.03eq) are added to ethyl alcohol (10mL) In water (3mL), under nitrogen protection, 90 DEG C of reaction 6h.Reaction solution is poured into water (50mL), (30mL is extracted with dichloromethane × 3), organic phase is dry with anhydrous sodium sulfate, is spin-dried for, and silica gel column chromatography purifies (PE:EtOAc (V:V)=1:1), obtains white solid Body product 0.727g, yield 98%.
1H NMR(400MHz,CDCl3): δ 11.88-10.35 (m, 2H), 8.67 (d, J=8.1Hz, 1H), 8.22-7.30 (m, 6H), 7.18 (d, J=23.9Hz, 1H), 5.51-5.11 (m, 3H), 4.00 (dd, J=21.1,13.2Hz, 1H), 3.57 (dd, J=32.1,9.6Hz, 3H), 3.14 (dd, J=20.9,13.7Hz, 5H), 2.81-2.62 (m, 2H), 2.44-2.21 (m, 2H), 2.00-1.86 (m, 2H), 1.55 (d, J=6.7Hz, 18H) ppm；MS-ESI,m/z:675.4[M+H]+.
The synthesis of step 10) compound 33-14
Compound 33-13 (0.72g, 1.07mmol, 1.0eq) is added in DCM (10mL), in 0 DEG C of dropwise addition HCl/ EtOAc (3mL) solution drips off room temperature reaction 10h.Solvent is spin-dried for, is added EtOAc (20mL), room temperature is beaten 1h, filters light Yellow solid is dissolved with water (10mL), then free with sodium carbonate liquor, and solid is precipitated, filters, dry yellow solid product 471mg, yield 93%.
1H NMR(400MHz,DMSO-d6): δ 12.10 (s, 2H), 8.48 (d, J=7.8Hz, 1H), 8.03 (s, 1H), 7.96-7.49 (m, 4H), 7.45-7.08 (m, 2H), 5.37 (d, J=55.4Hz, 1H), 4.70-4.18 (m, 2H), 3.30- 3.21 (m, 2H), 3.15-2.85 (m, 8H), 2.28 (m, 1H), 2.04 (d, J=5.5Hz, 2H), 1.94-1.65 (m, 2H) ppm； MS-ESI,m/z:475.4[M+H]+.
The synthesis of step 11) compound 33
By compound 33-14 (238mg, 0.5mmol, 1.0eq), compound 1-14 (193mg, 1.1mmol, 2.2eq), 2- Ethyl cyanoacetate (57mg, 0.4mmol, 0.8eq) and DIPEA (32mg, 0.25mmol, 0.5eq) are added to DCM (15mL) In, it adds EDCI (211mg, 1.1mmol, 2.2eq), reacts at room temperature 3h.Reaction solution is poured into water (30mL), DCM is used (15mL × 3) extraction, organic phase is dry with anhydrous sodium sulfate, is spin-dried for, silica gel column chromatography purifying (DCM:MeOH (V:V)=10: 1) white solid product 241mg, yield 61%, are obtained.
1H NMR(400MHz,CDCl3):δ12.09–10.24(m,2H),8.63(s,1H),8.19–7.54(m,4H), 7.42 (d, J=39.2Hz, 1H), 7.13 (dd, J=75.7,30.2Hz, 2H), 6.47-5.62 (m, 2H), 5.62-5.26 (m, 3H), 4.38 (dd, J=23.1,15.4Hz, 3H), 4.14 (q, J=7.1Hz, 2H), 3.97 (s, 1H), 3.76 (d, J= 27.7Hz, 6H), 3.46-3.19 (m, 1H), 3.06 (s, 4H), 2.72 (dd, J=26.7,14.6Hz, 2H), 2.59-2.07 (m, 3H), 1.94 (d, J=1.3Hz, 2H), 1.80-1.58 (m, 1H), 0.89 (dd, J=16.3,5.8Hz, 12H) ppm；MS-ESI, m/z:789.3[M+H]+.
Embodiment 16
Synthetic route:
Synthesis step:
The synthesis of step 1) compound 34-1
By compound 1-1 (8.1g, 50mmol, 1eq), n-butylamine (4.38g, 60mmol, 1.2eq) and TFA (1.14g, 10mmol, 0.2eq) it is added in toluene (100mL), back flow reaction is stayed overnight at 120 DEG C.Solvent is screwed out, ethyl acetate is added (100mL), and washed with saturated sodium bicarbonate aqueous solution (30mL), anhydrous sodium sulfate is dry, concentration.Obtained residue second Nitrile (100mL) dissolution, and Selectfluor (35.4g, 100mmol, 2eq) is added, back flow reaction 3h at 85 DEG C.It cools to again Room temperature is slowly added dropwise concentrated hydrochloric acid (30mL), stirs 10 minutes, adds ethyl acetate (200mL), and be washed with water (50mL × 2).Organic phase is dry with anhydrous sodium sulfate, concentration.Silica gel column chromatography purifies (PE:EtOAc (V:V)=10:1), obtains 4.0g Huang Color oil liquid, yield 40%.
1H NMR(400MHz,CDCl3): δ 7.78 (t, J=7.6Hz, 1H), 7.61 (d, J=8.2Hz, 1H), 7.22 (d, J =8.6Hz, 1H), 3.90 (s, 3H), 3.06 (t, J=12.3Hz, 2H) ppm.
The synthesis of step 2) compound 34-2
By compound 34-1 (4.0g, 20mmol, 1eq), triethylsilane (11.6g, 100mmol, 5eq), TFA (40mL) It is added to back flow reaction in two mouthfuls of bottles, TLC monitoring reaction course, 6h fully reacting is poured into ice water after fully reacting, then used EtOAc (40mL × 2) extraction, organic phase are neutralized with sodium bicarbonate solution, are washed, dry, are spin-dried for, silica gel column chromatography purifying (PE), product 3.35g, yield 91% are obtained.
1H NMR(400MHz,CDCl3): δ 7.20 (t, J=7.8Hz, 1H), 6.93 (d, J=7.4Hz, 1H), 6.73 (d, J =8.1Hz, 1H), 3.90 (s, 3H), 3.23 (t, J=12.3,4H) ppm.
The synthesis of step 3) compound 34-3
At 0 DEG C, by chloroacetic chloride (1.7g, 21.6mmol, 1.2eq) be slowly added drop-wise to compound 34-2 (3.32g, 18mmol, 1eq), in DCM (20mL) solution of alchlor (3.11g, 23.4mmol, 1.3eq), add rear room temperature continue it is anti- It answers, is poured into ice water after fully reacting, extracted with DCM (2 × 20mL), organic phase is dry, it is spin-dried for, silica gel column chromatography purifying (PE: DCM (V:V)=5:1), obtain product 3.38g, yield 83%.
1H NMR(400MHz,CDCl3): δ 7.72 (d, J=8.2Hz, 1H), 6.93 (d, J=8.4Hz, 1H), 3.90 (s, 3H), 3.23 (t, J=12.3,4H), 2.55 (s, 3H) ppm.
The synthesis of step 4) compound 34-4
At 0 DEG C, by Boron tribromide (4.51g, 18mmol, 1.2eq) be slowly added drop-wise to compound 34-3 (3.38g, 15mmol, 1eq) DCM (50mL) solution in, add after the reaction was continued, poured into ice water after fully reacting, with EtOAc (40mL × 3) it extracts, organic phase is dry, is spin-dried for, and silica gel column chromatography purifies (PE:EtOAc (V:V)=6:1), obtains product 2.23g, yield 70%.
1H NMR(400MHz,CDCl3): δ 7.72 (d, J=8.2Hz, 1H), 6.93 (d, J=8.4Hz, 1H), 3.23 (t, J =12.3,4H), 2.55 (s, 3H) ppm.
The synthesis of step 5) compound 34-5
At 0 DEG C, by trifluoromethanesulfanhydride anhydride (3.4g, 12mmol, 1.2eq) be added drop-wise to compound 34-4 (2.12g, 10mmol, 1eq), in methylene chloride (40mL) mixed liquor of pyridine (1.96g, 20mmol, 2eq), reacted at room temperature after adding, TLC Monitoring reaction is added water (10mL) and washes after fully reacting, saturated sodium-chloride is washed, and dry, organic phase is dry, is spin-dried for, silica gel column layer Analysis purifying (PE), obtains product 3.27g, yield 95%.
1H NMR(400MHz,CDCl3): δ 7.82 (d, J=8.2Hz, 1H), 7.11 (d, J=8.4Hz, 1H), 3.23 (t, J =12.3,2H), 3.03 (t, J=12.3,2H), 2.55 (s, 3H) ppm.
The synthesis of step 6) compound 34-6
By compound 34-5 (1.84g, 5.33mmol, 1eq), copper bromide (2.38g, 10.7mmol, 2eq) is added to EtOH 60 DEG C of reaction 2h, are filtered with diatomite after reaction in (20mL) solvent, and filtrate is spin-dried for, and add DCM (40mL), and use water (20mL) washing, anhydrous sodium sulfate is dry, vacuum rotary steam, then silica gel column chromatography purifying (PE:EtOAc (V:V)=6:1), obtains Brownish red grease 1.38g, yield 85%.
1H NMR(400MHz,CDCl3): δ 7.78 (d, J=8.6Hz, 1H), 7.22 (d, J=8.6Hz, 1H), 4.43 (s, 2H), 3.36 (t, J=12.3Hz, 2H), 3.07 (t, J=12.3Hz, 2H) ppm.
The synthesis of step 7) compound 34-7
At 0 DEG C, by triethylamine (0.6g, 6mmol, 1.5eq) be added drop-wise to compound 34-6 (1.52g, 3.6mmol, 1eq), it in methylene chloride (20mL) mixed liquor of L-Boc- proline (1.0g, 4.6mmol, 1.3eq), is reacted at room temperature after adding, TLC monitoring reaction is added water (10mL) and washes after fully reacting, saturated sodium-chloride is washed, and organic phase is dry, is spin-dried for, silica gel column chromatography It purifies (PE:EtOAc (V:V)=6:1), obtains product 1.63g, yield 81%.
1H NMR(400MHz,CDCl3): δ 7.78 (d, J=8.6Hz, 1H), 7.22 (d, J=8.6Hz, 1H), 5.13 (m, 1H),4.43(s,2H),3.36(m,2H),3.16(m,2H),3.07(m,4H),2.29(m,2H),1.36(t,9H)ppm；MS- ESI,m/z:558.1[M+H]+.
The synthesis of step 8) compound 34-8
Compound 34-7 (1.45g, 2.6mmol, 1.0eq) and ammonium acetate (1.2g, 15.6mmol, 6.0eq) are added to In toluene (15mL), 115 DEG C of reaction 20h.Toluene is spin-dried for, is added water (50mL), then extracts (15mL × 3) with DCM, organic phase It is dry with anhydrous sodium sulfate, it is spin-dried for, silica gel column chromatography purifies (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 1.33g, receives Rate 95%.
1H NMR(400MHz,CDCl3): δ 10.97 (s, 1H), 7.83 (d, J=7.2Hz, 1H), 7.19 (s, 1H), 7.11 (d, J=8.5Hz, 1H), 5.33 (d, J=52.9Hz, 1H), 5.19 (t, J=7.0Hz, 1H), 3.98 (dd, J=21.0, 13.0Hz, 1H), 3.61-3.22 (m, 2H), 3.12 (dt, J=15.0,7.1Hz, 4H), 2.85-2.59 (m, 2H), 1.52 (s, 9H)ppm；MS-ESI,m/z:538.2[M+H]+.
The synthesis of step 9) compound 34-9
By compound 34-8 (1.29g, 2.4mmol, 1.0eq), join pinacol borate (0.63g, 2.5mmol, 1.05eq), potassium acetate (0.71g, 7.2mmol, 3.0eq), Pd (dppf)2Cl2(69mg, 0.094mmol, 0.04eq), is added to In DMF (15mL), the lower 100 DEG C of reactions 10h of nitrogen protection.Reaction solution is poured into water, gray solid, then silica gel column layer are filtered to obtain Analysis purifying (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 0.89g, yield 72%.
1H NMR(400MHz,CDCl3): δ 10.89 (s, 1H), 7.78 (s, 1H), 7.67 (d, J=7.5Hz, 1H), 7.20 (s, 1H), 5.27 (dd, J=42.7,30.3Hz, 2H), 3.97 (dd, J=20.7,13.3Hz, 1H), 3.48 (dd, J=35.4, 12.0Hz,1H),3.38–2.88(m,5H),2.80–2.59(m,2H),1.52(s,9H),1.36(s,12H)ppm；MS-ESI, m/z:516.4[M+H]+.
The synthesis of step 10) compound 34-10
By compound 34-9 (567mg, 1.1mmol, 1.0eq), compound 7-7A (460mg, 1.1mmol, 1.0eq), carbon Sour potassium (0.30g, 2.2mmol, 2.0eq), four triphenyl phosphorus palladiums (38mg, 0.033mmol, 0.03eq) are added to ethyl alcohol (10mL) In water (3mL), under nitrogen protection, 90 DEG C of reaction 6h.Reaction solution is poured into water (50mL), (30mL is extracted with dichloromethane × 3), organic phase is dry with anhydrous sodium sulfate, is spin-dried for, and silica gel column chromatography purifies (PE:EtOAc (V:V)=1:1), obtains white solid Body product 0.757g, yield 95%.
1H NMR(400MHz,CDCl3): δ 11.88-10.35 (m, 2H), 8.67 (d, J=8.1Hz, 1H), 8.22-7.30 (m, 6H), 7.18 (d, J=23.9Hz, 1H), 5.51-5.11 (m, 3H), 4.00 (dd, J=21.1,13.2Hz, 1H), 3.57 (dd, J=32.1,9.6Hz, 3H), 3.14 (dd, J=20.9,13.7Hz, 5H), 2.81-2.62 (m, 2H), 2.44-2.21 (m, 2H), 2.00-1.86 (m, 2H), 1.55 (d, J=6.7Hz, 18H) ppm；MS-ESI,m/z:725.4[M+H]+.
The synthesis of step 11) compound 34-11
Compound 34-10 (0.725g, 1.0mmol, 1.0eq) is added in DCM (10mL), in 0 DEG C of dropwise addition HCl/ EtOAc (4N, 3mL) solution drips off room temperature reaction 10h.Solvent is spin-dried for, is added EtOAc (20mL), room temperature is beaten 1h, filters Faint yellow solid, dissolved with water (10mL), then free with sodium carbonate liquor, solid be precipitated, filters, it is dry that yellow solid produces Product 483mg, yield 92%.
1H NMR(400MHz,DMSO-d6): δ 12.10 (s, 2H), 8.48 (d, J=7.8Hz, 1H), 8.03 (s, 1H), 7.96-7.49 (m, 4H), 7.45-7.08 (m, 2H), 5.37 (d, J=55.4Hz, 1H), 4.70-4.18 (m, 2H), 3.30- 3.21 (m, 2H), 3.15-2.85 (m, 8H), 2.28 (m, 1H), 2.04 (d, J=5.5Hz, 2H), 1.94-1.65 (m, 2H) pm； MS-ESI,m/z:525.4[M+H]+.
The synthesis of step 12) compound 34
By compound 34-11 (263mg, 0.5mmol, 1.0eq), compound 1-14 (193mg, 1.1mmol, 2.2eq), 2- Ethyl cyanoacetate (57mg, 0.4mmol, 0.8eq) and DIPEA (32mg, 0.25mmol, 0.5eq) are added to DCM (15mL) In, it adds EDCI (211mg, 1.1mmol, 2.2eq), reacts at room temperature 3h.Reaction solution is poured into water (30mL), DCM is used (15mL × 3) extraction, organic phase is dry with anhydrous sodium sulfate, is spin-dried for, silica gel column chromatography purifying (DCM:MeOH (V:V)=10: 1) white solid product 239mg, yield 57%, are obtained.
1H NMR(400MHz,CDCl3):δ12.09–10.24(m,2H),8.63(s,1H),8.19–7.54(m,4H), 7.42 (d, J=39.2Hz, 1H), 7.13 (dd, J=75.7,30.2Hz, 2H), 6.47-5.62 (m, 2H), 5.62-5.26 (m, 3H), 4.38 (dd, J=23.1,15.4Hz, 3H), 4.14 (q, J=7.1Hz, 2H), 3.97 (s, 1H), 3.76 (d, J= 27.7Hz, 6H), 3.46-3.19 (m, 1H), 3.06 (s, 4H), 2.72 (dd, J=26.7,14.6Hz, 2H), 2.59-2.07 (m, 3H), 1.94 (d, J=1.3Hz, 2H), 1.80-1.58 (m, 1H), 0.89 (dd, J=16.3,5.8Hz, 12H) ppm；MS-ESI, m/z:839.3[M+H]+.
Embodiment 17
Synthetic route:
Synthesis step:
The synthesis of step 1) compound 35-2
Compound 1-6 (1.2g, 3.1mmol, 1.0eq) and compound 35-1 (0.82g, 0.34mmol, 1.1eq) is added To in acetonitrile (10mL), triethylamine (0.47g, 4.6mmol, 1.5eq) is added dropwise at 0 DEG C, drips off room temperature reaction 2h.It screws out molten Agent is added water (20mL), then extracts (20mL × 3) with DCM, and organic phase is dry with anhydrous sodium sulfate, is spin-dried for, and obtains brown oil production Product 1.72g, yield 100%.
1H NMR(400MHz,CDCl3): δ 7.68 (d, J=8.5Hz, 1H), 7.20 (d, J=8.2Hz, 1H), 5.45 (dd, J=63.1,16.2Hz, 1H), 5.12 (dd, J=55.0,16.2Hz, 1H), 4.58 (ddd, J=26.2,8.5,3.4Hz, 1H), 3.51-3.34 (m, 2H), 3.32 (d, J=7.0Hz, 2H), 3.05 (t, J=7.1Hz, 2H), 2.39 (dd, J=12.6, 8.8Hz, 1H), 2.26-2.12 (m, 2H), 2.09 (d, J=12.7Hz, 1H), 1.46 (d, J=3.4Hz, 9H), 0.63 (dd, J =13.4,8.3Hz, 4H) ppm.
The synthesis of step 2) compound 35-3
Compound 35-2 (1.70g, 3.1mmol, 1.0eq) and ammonium acetate (1.4g, 19mmol, 6.0eq) are added to first In benzene (10mL), 115 DEG C of reaction 15h.Toluene is spin-dried for, is added water (50mL), then extracts (15mL × 3) with DCM, organic phase is used Anhydrous sodium sulfate is dry, is spin-dried for, and silica gel column chromatography purifies (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 1.33g, yield 81%.
1H NMR(400MHz,CDCl3): δ 10.88 (d, J=214.7Hz, 1H), 7.85 (d, J=8.4Hz, 1H), 7.18 (s, 1H), 7.11 (d, J=8.5Hz, 1H), 5.13 (s, 1H), 3.53 (d, J=10.0Hz, 1H), 3.20-3.07 (m, 5H), 2.80 (d, J=10.6Hz, 1H), 2.37 (s, 1H), 2.21 (d, J=6.8Hz, 2H), 1.52 (s, 9H), 0.89 (dd, J= 9.6,5.4Hz, 1H), 0.63 (ddd, J=18.6,11.0,4.9Hz, 3H) ppm；MS-ESI,m/z:528.20[M+H]+.
The synthesis of step 3) compound 35-4
By compound 35-3 (1.25g, 2.37mmol, 1.0eq), join pinacol borate (0.63g, 2.49mmol, 1.05eq), potassium acetate (0.69g, 7.11mmol, 3.0eq), Pd (dppf)2Cl2(52mg, 0.071mmol, 0.03eq) is added To in DMF (10mL), the lower 100 DEG C of reactions 16h of nitrogen protection.Reaction solution is poured into water, gray solid, silica gel column layer are filtered to obtain Analysis purifying (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 1.0g, yield 83%.
1H NMR(400MHz,CDCl3): δ 10.83 (d, J=222.3Hz, 1H), 7.81 (s, 1H), 7.66 (d, J= 7.5Hz, 1H), 7.22 (s, 1H), 5.14 (d, J=6.2Hz, 1H), 3.52 (d, J=10.3Hz, 1H), 3.38-2.97 (m, 5H),2.79(s,1H),2.56–2.28(m,1H),2.21–2.08(m,2H),1.52(s,9H),1.36(s,12H),0.90(s, 1H),0.73–0.52(m,3H)ppm；MS-ESI,m/z:506.4[M+H]+.
The synthesis of step 4) compound 35-5
By compound 35-4 (600mg, 1.19mmol, 1.0eq), compound 7-7A (494g, 1.19mmol, 1.0eq), carbon Sour potassium (0.33g, 2.37mmol, 2.0eq), four triphenyl phosphorus palladiums (41mg, 0.035mmol, 0.03eq) are added to ethyl alcohol In (10mL) and water (3mL), under nitrogen protection, 90 DEG C of reaction 10h.Reaction solution is poured into water (50mL), is extracted with methylene chloride It takes (30mL × 3), organic phase is dry with anhydrous sodium sulfate, is spin-dried for, and silica gel column chromatography purifies (PE:EtOAc (V:V)=1:1), obtains White solid product 0.80g, yield 94%.
1H NMR(400MHz,CDCl3): δ 11.56-10.55 (m, 2H), 8.68 (d, J=13.5Hz, 1H), 8.00 (s, 1H), 7.87 (d, J=7.1Hz, 1H), 7.72 (d, J=25.8Hz, 2H), 7.58 (d, J=8.8Hz, 1H), 7.41 (s, 1H), 7.23 (s, 1H), 5.32-5.09 (m, 2H), 3.56 (dd, J=37.5,26.4Hz, 3H), 3.15 (dd, J=26.7,3.2Hz, 4H), 2.84 (dd, J=13.4,10.1Hz, 1H), 2.46-2.25 (m, 2H), 2.20-2.08 (m, 2H), 1.79-170 (m, 4H), 1.61-1.44 (m, 18H), 0.86 (d, J=2.9Hz, 1H), 0.79-0.43 (m, 3H) ppm；MS-ESI,m/z:715.4 [M+H]+.
The synthesis of step 5) compound 35-6
Compound 35-5 (0.80g, 1.1mmol, 1.0eq) is added in DCM (15mL), in 0 DEG C of dropwise addition HCl/EtOAc (4N, 3mL) solution drips off room temperature reaction 15h.Solvent is spin-dried for, is added EtOAc (20mL), room temperature is beaten 1h, filters yellowish Color solid is dissolved with water (10mL), then free with sodium carbonate liquor, and solid is precipitated, filters, dry yellow solid product 590mg, yield 100%.
1H NMR(400MHz,DMSO-d6): δ 8.48 (d, J=8.4Hz, 1H), 8.04 (s, 1H), 7.81 (s, 1H), 7.69 (d, J=11.0Hz, 3H), 7.34 (d, J=7.9Hz, 1H), 7.24 (s, 1H), 4.43 (dt, J=14.8,7.2Hz, 2H), 3.45 (d, J=7.0Hz, 2H), 3.09 (dd, J=16.1,7.5Hz, 4H), 3.01-2.90 (m, 2H), 2.82 (d, J= 9.9Hz, 1H), 2.21 (dt, J=14.2,7.8Hz, 1H), 2.12-1.98 (m, 4H), 1.81 (dd, J=14.0,7.0Hz, 2H), 1.06 (t, J=7.0Hz, 1H), 0.56 (t, J=13.3Hz, 3H) ppm；MS-ESI,m/z:515.2[M+H]+.
The synthesis of step 6) compound 35
By compound 35-6 (280mg, 0.54mmol, 1.0eq), compound 1-14 (209mg, 1.20mmol, 2.2eq), 2- ethyl cyanoacetate (61mg, 0.43mmol, 0.8eq) and DIPEA (35mg, 0.27mmol, 0.5eq) are added to DCM It in (15mL), adds EDCI (227mg, 1.19mmol, 2.2eq), reacts at room temperature 18h.Reaction solution is poured into water (30mL), It is extracted with DCM (15mL × 3), organic phase is dry with anhydrous sodium sulfate, is spin-dried for, and silica gel column chromatography purifies (DCM:EtOAc:MeOH (V:V:V)=5:10:1), obtain white solid product 243mg, yield 53.88%.
1H NMR(400MHz,CDCl3): δ 12.97-10.31 (m, 2H), 8.63 (d, J=7.6Hz, 1H), 7.90 (dd, J =45.6,19.8Hz, 2H), 7.68 (dd, J=21.5,8.3Hz, 2H), 7.39 (d, J=32.9Hz, 2H), 7.19 (s, 1H), 5.64 (dd, J=83.6,38.2Hz, 4H), 4.48-4.26 (m, 1H), 4.15 (dd, J=6.0,4.1Hz, 1H), 4.00-3.87 (m, 1H), 3.83 (s, 1H), 3.73 (s, 3H), 3.62 (s, 3H), 3.13 (dd, J=18.7,11.1Hz, 4H), 2.51 (dd, J =27.9,23.1Hz, 2H), 2.40-2.26 (m, 1H), 2.26-1.96 (m, 5H), 1.79-1.69 (m, 1H), 1.69-1.58 (m,1H),1.05–0.83(m,12H),0.84–0.56(m,4H)ppm；MS-ESI,m/z:829.4[M+H]+.
Embodiment 18
Synthetic route:
Synthesis step:
The synthesis of step 1) compound 36-2
By -1 (2H) -one 36-1 (12g, 68mmol) of 5- methoxyl group -3,4- naphthane, triethylsilane (26.3g, 272mmol), ammonium fluoride (8.3g, 272mmol) is dissolved in trifluoroacetic acid (100mL), 72 DEG C of reaction 6h.Screw out solvent, residue It being dissolved with ethyl acetate (300mL × 2), organic phase is neutralized with sodium bicarbonate solution, is washed, and it is dry, it is spin-dried for, residue silicagel column Chromatographic purifying (PE) obtains colorless oil 10g, yield 90%.
1H NMR(400MHz,CDCl3): δ 7.15 (t, J=7.9Hz, 1H), 6.75 (dd, J=21.5,7.9Hz, 2H), 3.88 (s, 3H), 2.84 (t, J=5.6Hz, 2H), 2.74 (t, J=5.9Hz, 2H), 1.91-1.80 (m, 4H) ppm；MS(ESI, pos.ion)m/z:163.2[M+H]+.
The synthesis of step 2) compound 36-3
Compound 36-2 (11g, 67.8mmol), alchlor (13.7g, 100mmol) are dissolved in DCM (100mL), 0 Chloroacetic chloride (7g, 88mmol) is added dropwise under the conditions of DEG C, after being added dropwise, room temperature reaction is for 24 hours.Reaction solution is poured into ice water, second is used Acetoacetic ester (200mL × 2) extraction, is washed, dry, is spin-dried for, and residue silica gel column chromatography purifies (PE), obtains light yellow oil 4g, yield 28%.
1H NMR(400MHz,CDCl3): δ 7.63 (d, J=8.6Hz, 1H), 6.69 (d, J=8.6Hz, 1H), 3.87 (s, 3H), 3.04 (t, J=5.8Hz, 2H), 2.75-2.57 (m, 2H), 2.55 (s, 3H), 1.75 (td, J=7.3,3.6Hz, 4H) ppm；MS(ESI,pos.ion)m/z:205.1[M+H]+.
The synthesis of step 3) compound 36-4
Compound 36-3 (9g, 44mmol) is dissolved in N-Methyl pyrrolidone (90mL), pyridine hydrobromide salt is added (28g, 176mmol) reacts 4h under the conditions of 180 DEG C.Reaction solution is added in water (400mL), with ethyl acetate (300mL × 2) it extracting, merges organic layer, saturated salt solution (150mL) washing is dry, the purifying of residue silica gel column chromatography (PE:EtOAc (V: V)=10:1), obtain white solid 4g, yield 47.7%.
1H NMR(400MHz,CDCl3): δ 7.58 (d, J=8.4Hz, 1H), 6.73 (d, J=8.4Hz, 1H), 3.10 (t, J =6.1Hz, 2H), 2.82-2.60 (m, 2H), 2.57 (s, 3H), 1.98-1.70 (m, 4H) ppm；MS(ESI,pos.ion)m/z: 191.2[M+H]+.
The synthesis of step 4) compound 36-5
At 0 DEG C, trifluoromethanesulfanhydride anhydride (6.5g, 23mmol) is added drop-wise to compound 36-4 (4g, 21mmol), pyridine In methylene chloride (120mL) mixed liquor of (2.2g, 27mmol), 3h is reacted at room temperature after adding.Reaction solution is washed with water (30mL) It washs, organic phase is dry, is spin-dried for, and residue silica gel column chromatography purifies (PE:EtOAc (V:V)=10:1), obtains colorless oil 2.8g, yield 40%.
1H NMR(400MHz,CDCl3): δ 7.58 (d, J=8.4Hz, 1H), 6.73 (d, J=8.4Hz, 1H), 3.10 (t, J =6.1Hz, 2H), 2.82-2.60 (m, 2H), 2.57 (s, 3H), 1.98-1.70 (m, 4H) ppm；MS(ESI,pos.ion)m/z: 323.2[M+H]+.
The synthesis of step 5) compound 36-6
Compound 36-5 (2.6g, 8mmol), copper bromide (3.6g, 16mmol) are added in ethyl alcohol (50mL), 60 DEG C anti- Answer 2h.Reaction solution is filtered with diatomite, and filtrate is spin-dried for, and is dissolved with DCM (50mL × 2), saturated sodium chloride solution (30mL) washing, Anhydrous sodium sulfate is dry, is spin-dried for, yellow solid 2.8g, yield 87%.
1H NMR(400MHz,CDCl3): δ 7.60 (d, J=8.4Hz, 1H), 6.99 (d, J=8.4Hz, 1H), 4.66 (s, 2H), 3.10 (t, J=6.1Hz, 2H), 2.82-2.60 (m, 2H), 1.98-1.70 (m, 4H) ppm；MS(ESI,pos.ion)m/ z:401.3[M+H]+.
The synthesis of step 6) compound 36-7
At 0 DEG C, triethylamine (1.1g, 10mmol) is added drop-wise to compound 36-6 (2.8g, 7mmol), N- tertiary butyloxycarbonyl In the methylene chloride (60mL) of base-L-PROLINE (2.0g, 9mmol), 8h is reacted at room temperature after adding.Reaction solution is washed with water (20mL) It washs, anhydrous sodium sulfate is dry, is spin-dried for, and residue silica gel column chromatography purifies (PE:EtOAc (V:V)=6:1), obtains colorless oil Object 3g, yield 80%.
1H NMR(400MHz,CDCl3): δ 7.40 (d, J=8.5Hz, 1H), 7.16 (d, J=8.4Hz, 1H), 5.05 (ddd, J=63.0,51.9,16.7Hz, 2H), 4.48-4.26 (m, 1H), 3.64-3.22 (m, 2H), 2.98-2.65 (m, 4H), 2.13-1.67 (m, 8H), 1.43 (d, J=13.2Hz, 9H) ppm；MS(ESI,pos.ion)m/z:536.0[M+H]+.
The synthesis of step 7) compound 36-8
Compound 36-7 (3g, 5.6mmol), ammonium acetate (2.6g, 33mmol) are added in toluene (60mL), 110 DEG C React 12h.Water (20mL) is added after reaction, is extracted with ethyl acetate (50mL × 2), organic phase washing, anhydrous sodium sulfate Dry, vacuum rotary steam, residue silica gel column chromatography purifies (PE:EtOAc (V:V)=4:1), obtains pale tan oil 0.8g, produces Rate 30%.
1H NMR(400MHz,CDCl3): δ 7.43 (s, 1H), 7.21-7.07 (m, 1H), 7.04 (s, 1H), 4.99 (d, J= 5.2Hz, 1H), 3.43 (s, 2H), 3.00-2.75 (m, 4H), 2.24-1.95 (m, 5H), 1.78 (dt, J=48.8,24.0Hz, 4H),1.58–1.41(m,9H)ppm；MS(ESI,pos.ion)m/z:516.1[M+H]+.
The synthesis of step 8) compound 36-9
Compound 36-8 (0.8g, 1.6mmol), pinacol are joined into boron ester (0.5g, 1.9mmol), Pd (dppf) Cl2· CH2Cl2(0.25g, 0.3mmol), AcOK (0.5g, 4.7mmol) are suspended in DMF (20mL), are heated to 100 under nitrogen protection DEG C reaction 4h.Reaction solution is cooled to room temperature, is added water (60mL), filters, after solid is dissolved with methylene chloride, is spin-dried for, silicagel column Chromatographic purifying (PE:EtOAc (V:V)=4:1), obtains pale tan oil 0.65g, yield 80%.
1H NMR(400MHz,CDCl3): δ 10.76 (s, 1H), 7.65 (d, J=7.6Hz, 1H), 7.03 (s, 2H), 5.00 (d, J=5.4Hz, 1H), 3.43 (d, J=5.3Hz, 2H), 2.84 (s, 3H), 2.10 (dd, J=60.9,20.7Hz, 3H), 1.86–1.69(m,6H),1.51(s,9H),1.36(s,12H)ppm；MS(ESI,pos.ion)m/z:494.3[M+H]+.
The synthesis of step 9) compound 36-10
By compound 36-9 (0.65g, 1.3mmol), compound 4-9 (0.64g, 1.03mmol), Pd (PPh3)4(0.23g, 0.2mmol)、K2CO3(0.54g, 4mmol) is dissolved in ethyl alcohol (16mL) and water (4mL), under nitrogen protection, 90 DEG C of reaction 3h.Rotation Solvent out, residue are extracted twice with DCM (80mL), and organic layer is washed with saturated sodium chloride solution (20mL), anhydrous sodium sulfate It is dry, solvent is screwed out, residue silica gel column chromatography purifies (DCM:EtOAc (V:V)=2:1), obtains yellow solid 0.7g, yield 70%.
1H NMR(400MHz,CDCl3): δ 13.87-9.99 (m, 2H), 8.62 (d, J=8.5Hz, 1H), 8.05-7.77 (m, 2H), 7.68 (t, J=8.6Hz, 1H), 7.63-7.48 (m, 1H), 7.20 (s, 1H), 7.06 (s, 1H), 5.49 (dd, J= 45.6,22.5Hz, 1H), 5.03 (d, J=5.4Hz, 1H), 4.29 (s, 1H), 3.98-3.68 (m, 3H), 3.57-3.38 (m, 3H), 2.94 (t, J=30.7Hz, 3H), 2.70 (s, 2H), 2.19 (s, 3H), 2.05 (s, 2H), 1.90-1.66 (m, 9H), 1.52(s,9H),1.34–1.22(m,4H),1.19–1.09(m,5H)ppm；MS(ESI,pos.ion)m/z:774.6[M+H]+.
The synthesis of step 10) compound 36-11
HCl/EtOAc (4N, 4mL) is added drop-wise to the methylene chloride of compound 36-10 (0.7g, 0.9mmol) at 0 DEG C In (16mL), 3h is reacted at room temperature after dripping off.Reaction solution is screwed out, residue is beaten with ethyl acetate, is filtered.Filter cake is with water (10mL) Dissolution adds potassium carbonate tune pH value to 8-9, filters, obtain yellow solid 0.58g, yield 92%.
1H NMR(400MHz,CDCl3): δ 13.87-9.99 (m, 2H), 8.62 (d, J=8.5Hz, 1H), 8.05-7.77 (m, 2H), 7.68 (t, J=8.6Hz, 1H), 7.63-7.48 (m, 1H), 7.20 (s, 1H), 7.06 (s, 1H), 5.49 (dd, J= 45.6,22.5Hz, 1H), 5.03 (d, J=5.4Hz, 1H), 4.29 (s, 1H), 3.98-3.68 (m, 3H), 3.57-3.38 (m, 4H), 2.94 (t, J=30.7Hz, 3H), 2.70 (s, 2H), 2.19 (s, 3H), 2.05 (s, 2H), 1.90-1.66 (m, 9H), 1.34–1.22(m,4H),1.19–1.09(m,5H)ppm；MS(ESI,pos.ion)m/z:674.3[M+H]+.
The synthesis of step 11) compound 36:
Compound 36-11 (0.28g, 0.41mmol), (S) -2- ((methoxycarbonyl base) amino) -3 Methylbutanoic acid 1-14 (0.09g, 0.5mmol), 2- ethyl cyanoacetate (0.024g, 0.165mmol) are dissolved in DCM (10mL), under room temperature Add EDCI (0.1g, 0.5mmol), reacts at room temperature 2h.Add water quenching reaction, DCM (50mL) is added to extract, screws out solvent, residue It is dissolved, is added ammonium hydroxide (1mL) with methanol (20mL), after stirring 5min, is spin-dried for, extracted with DCM (50mL), saturated sodium chloride solution (10mL) washing, anhydrous sodium sulfate is dry, screws out solvent, and residue silica gel column chromatography purifies (DCM:EtOAc:MeOH (V:V:V) =20:10:1), obtain white solid 0.2g, yield 60%.
1H NMR(400MHz,CDCl3):δ10.80(m,2H),8.78–8.40(m,1H),8.02–7.80(m,2H), 7.73–7.48(m,3H),7.19(m,2H),7.05(s,1H),5.63–5.38(m,3H),5.32(s,1H),4.48–4.24(m, 3H),3.94(s,1H),3.85(s,1H),3.77–3.63(m,4H),3.50–3.22(m,2H),3.09–2.78(m,4H), 2.69 (s, 1H), 2.52-2.25 (m, 1H), 2.20 (s, 1H), 2.04 (s, 3H), 1.45 (s, 1H), 1.28 (t, J=7.1Hz, 4H), 1.18 (d, J=6.0Hz, 2H), 1.12 (m, 4H), 1.02-0.76 (m, 11H) ppm；MS(ESI,pos.ion)m/z: 831.6[M+H]+.
Embodiment 19
Synthetic route:
Synthesis step:
By compound 36-11 (0.28g, 0.41mmol), (S) -2- cyclohexyl -2- ((methoxycarbonyl base) amino) acetic acid 37-1 (0.102g, 0.46mmol), 2- ethyl cyanoacetate (0.024g, 0.16mmol) are dissolved in DCM (10mL), room temperature item Add EDCI (0.098g, 0.5mmol) under part, reacts at room temperature 2h.Add water quenching reaction, DCM (50mL) added to extract, screws out solvent, Residue is dissolved with methanol (20mL), is added ammonium hydroxide (1mL), after stirring 5min, is spin-dried for, and is extracted with DCM (50mL), saturated sodium-chloride Solution (10mL) washing, anhydrous sodium sulfate is dry, back-out solvent, the purifying of residue silica gel column chromatography (DCM:EtOAc:MeOH (V: V:V)=20:10:1), obtain white solid 0.2g.
1H NMR(400MHz,CDCl3): δ 12.82-10.07 (m, 2H), 8.86-8.40 (m, 1H), 7.86 (dd, J= 22.5,12.4Hz, 2H), 7.53 (m, 3H), 7.18 (s, 2H), 7.05 (s, 1H), 5.65-5.41 (m, 3H), 5.31 (d, J= 6.7Hz,1H),4.32(m,3H),3.97–3.80(m,3H),3.78–3.61(m,6H),2.87(m,6H),2.48–2.15(m, 4H), 2.06 (s, 1H), 1.45 (s, 3H), 1.28 (m, 6H), 1.21-1.07 (m, 6H), 0.99 (t, J=6.7Hz, 3H), 0.95–0.78(m,6H)ppm；MS(ESI,pos.ion)m/z:871.8[M+H]+.
Embodiment 20
Synthetic route:
Synthesis step:
The synthesis of step 1) compound 38-2
Compound 38-1 (0.664g, 2.73mmol, 1.05eq) and compound 1-6 (1.0g, 2.6mmol, 1.0eq) is added Enter in acetonitrile (10mL), triethylamine (0.39g, 3.9mmol, 1.5eq) is added dropwise at 0 DEG C, drips off room temperature reaction 2h.It screws out molten Agent is added water (20mL), then extracts (20mL × 3) with DCM, and organic phase is dry with anhydrous sodium sulfate, is spin-dried for, and obtains brown oil production Product 1.42g, yield 100%.
1H NMR(400MHz,CDCl3): δ 7.68 (d, J=8.5Hz, 1H), 7.21 (d, J=8.3Hz, 1H), 5.54- 5.35 (m, 1H), 5.20 (dd, J=25.2,13.6Hz, 1H), 4.62 (dt, J=21.6,8.3Hz, 1H), 4.06-3.52 (m, 3H), 3.40-3.22 (m, 2H), 3.06 (t, J=7.5Hz, 2H), 2.83-2.64 (m, 1H), 2.58-2.33 (m, 1H), 2.20 (dt, J=14.2,7.3Hz, 2H), 1.48 (m, 12H), 0.9 (t, J=5.6Hz, 3H) ppm.
The synthesis of step 2) compound 38-3
Compound 38-2 (1.42g, 2.6mmol, 1.0eq) and ammonium acetate (1.2g, 15.6mmol, 6.0eq) are added to In toluene (15mL), 115 DEG C of reaction 20h.Toluene is spin-dried for, is added water (50mL), then extracts (15mL × 3) with DCM, organic phase It is dry with anhydrous sodium sulfate, it is spin-dried for, silica gel column chromatography purifies (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 1.28g, receives Rate 93%.
1H NMR(400MHz,CDCl3): δ 10.97 (d, J=188.0Hz, 1H), 7.83 (d, J=7.2Hz, 1H), 7.19 (s, 1H), 7.11 (d, J=8.5Hz, 1H), 5.33 (d, J=52.9Hz, 1H), 5.19 (t, J=7.0Hz, 1H), 3.98 (dd, J =21.0,13.0Hz, 1H), 3.61-3.22 (m, 2H), 3.12 (dt, J=15.0,7.1Hz, 4H), 2.85-2.59 (m, 1H), 2.29-2.14 (m, 2H), 1.52 (m, 11H), 0.9 (t, J=5.6Hz, 3H) ppm；MS-ESI,m/z:530.2[M+H]+.
The synthesis of step 3) compound 38-4
By compound 38-3 (1.26g, 2.37mmol, 1.0eq), join pinacol borate (0.63g, 2.49mmol, 1.05eq), potassium acetate (0.70g, 7.1mmol, 3.0eq), Pd (dppf)2Cl2(69mg, 0.094mmol, 0.04eq), is added to In DMF (15mL), the lower 100 DEG C of reactions 10h of nitrogen protection.Reaction solution is poured into water (60mL), gray solid, then silicon are filtered to obtain Gel column chromatography eluting (PE:EtOAc (V:V)=5:1), obtains faint yellow solid 0.82g, yield 68%.
1H NMR(400MHz,CDCl3): δ 10.89 (d, J=186.4Hz, 1H), 7.78 (s, 1H), 7.67 (d, J= 7.5Hz, 1H), 7.20 (s, 1H), 5.27 (dd, J=42.7,30.3Hz, 2H), 3.97 (dd, J=20.7,13.3Hz, 1H), 3.48 (dd, J=35.4,12.0Hz, 1H), 3.38-2.88 (m, 5H), 2.80-2.59 (m, 1H), 2.19-2.07 (m, 2H), 1.52 (m, 11H), 1.36 (s, 12H), 0.9 (t, J=5.6Hz, 3H) ppm；MS-ESI,m/z:508.3[M+H]+.
The synthesis of step 4) compound 38-5
By compound 38-4 (558mg, 1.10mmol, 1.0eq), compound 15-5 (473g, 1.10mmol, 1.0eq), carbon Sour potassium (0.30g, 2.21mmol, 2.0eq), four triphenyl phosphorus palladiums (38mg, 0.033mmol, 0.03eq) are added to ethyl alcohol In (10mL) and water (3mL), under nitrogen protection, 90 DEG C of reaction 6h.Reaction solution is poured into water (50mL), is extracted with dichloromethane (30mL × 3), organic phase is dry with anhydrous sodium sulfate, is spin-dried for, and silica gel column chromatography purifies (PE:EtOAc (V:V)=1:1), obtains white Color solid product 0.75g, yield 93%.
1H NMR(400MHz,CDCl3): δ 11.88-10.35 (m, 2H), 8.67 (d, J=8.1Hz, 1H), 8.22-7.30 (m, 6H), 7.18 (d, J=23.9Hz, 1H), 5.51-5.11 (m, 3H), 4.00 (dd, J=21.1,13.2Hz, 1H), 3.57 (dd, J=32.1,9.6Hz, 3H), 3.30-3.11 (m, 5H), 2.44-2.21 (m, 2H), 2.20-2.08 (m, 2H), 2.00- 1.86 (m, 2H), 1.55 (m, 20H), 1.32-1.18 (m, 3H), 0.9 (t, J=5.6Hz, 3H) ppm；MS-ESI,m/z:731.3 [M+H]+.
The synthesis of step 5) compound 38-6
Compound 38-5 (0.75g, 1.03mmol, 1.0eq) is added in DCM (10mL), in 0 DEG C of dropwise addition HCl/ EtOAc (4N, 3mL) solution drips off room temperature reaction 10h.Solvent is spin-dried for, is added EtOAc (20mL), room temperature is beaten 1h, filters Faint yellow solid, dissolved with water (10mL), then free with sodium carbonate liquor, solid be precipitated, filters, it is dry that yellow solid produces Product 502mg, yield 92%.
1H NMR(400MHz,DMSO-d6): δ 12.10 (s, 2H), 8.48 (d, J=7.8Hz, 1H), 8.03 (s, 1H), 7.96-7.49 (m, 4H), 7.45-7.08 (m, 2H), 5.37 (d, J=55.4Hz, 1H), 4.70-4.18 (m, 2H), 3.30- 3.15 (m, 2H), 3.15-2.85 (m, 6H), 2.28 (ddd, J=39.8,14.5,9.4Hz, 3H), 2.04 (d, J=5.5Hz, 2H), 1.94-1.65 (m, 4H), 1.32-1.18 (m, 3H), 0.9 (t, J=5.6Hz, 3H) ppm；MS-ESI,m/z:531.4[M+ H]+.
The synthesis of step 6) compound 38
By compound 38-6 (265mg, 0.5mmol, 1.0eq), compound 1-14 (193mg, 1.1mmol, 2.2eq), 2- Ethyl cyanoacetate (57mg, 0.4mmol, 0.8eq) and DIPEA (32mg, 0.25mmol, 0.5eq) are added to DCM (15mL) In, it adds EDCI (211mg, 1.1mmol, 2.2eq), reacts at room temperature 3h.Reaction solution is poured into water (30mL), DCM is used (15mL × 3) extraction, organic phase is dry with anhydrous sodium sulfate, is spin-dried for, silica gel column chromatography purifying (DCM:MeOH (V:V)=10: 1) white solid product 296mg, yield 70%, are obtained.
1H NMR(400MHz,CDCl3):δ12.09–10.24(m,2H),8.63(s,1H),8.19–7.54(m,4H), 7.42 (d, J=39.2Hz, 1H), 7.13 (dd, J=75.7,30.2Hz, 2H), 6.47-5.62 (m, 2H), 5.62-5.26 (m, 3H), 4.38 (dd, J=23.1,15.4Hz, 3H), 4.14 (q, J=7.1Hz, 2H), 3.97 (s, 1H), 3.76 (d, J= 27.7Hz, 6H), 3.46-3.19 (m, 1H), 3.06 (s, 4H), 2.72 (dd, J=26.7,14.6Hz, 1H), 2.59-2.07 (m, 4H), 1.94 (d, J=1.3Hz, 2H), 1.80-1.58 (m, 3H), 1.32-1.18 (m, 3H) 0.89 (m, 15H) ppm；MS-ESI, m/z:845.4[M+H]+.
Bioexperiment
The analysis of biological Examples 1:HCV Subgenomic replicon
Experiment purpose:
Compound is evaluated to HCV wild type replicon GT1a, GT1b and GT2a and HCV replicon chimera GT3a, GT The inhibiting effect of 4a, GT5a and GT6a and GT1b L31V, GT1b Y93H persister.
Experimental method:
GT1a, GT1b and GT2a replicon active testing: G418 resistant gene NEO and luciferase reporter gene will be had HCV GT1a H77 replicon, GT1b Con1b replicon and GT2a JFH1 replicon RNA point hit method transiently transfect respectively To Huh-7 cell, G418 is added and screens 3~4 weeks, constructs stable transfected cells strain.Huh7-H77 and Huh7-JFH1 are surely turned thin Born of the same parents' strain is diluted to 5 × 104/ mL is inoculated with 200 μ L to 96 orifice plates, Huh7-Con1b stable cell strain is diluted to 1 × 105/ mL, connects Kind 50 μ L to 384 orifice plates.After 16-24h, using 3 times of gradient dilutions, the dilution process of 11 dilution points extremely closes diluted chemical compound Suitable concentration, uses PODTMCompound after dilution is added in 96 orifice plates by 810 microwell plate pretreatment systems, and the DMSO in each hole is whole Concentration is 0.5%.At 37 DEG C, 5%CO2CO2After being incubated for 72h in constant temperature incubation, the luciferase inspection of 40 μ L is added into every hole Test agent (Promega Bright-Glo) after 5min, is detected with chemiluminescence detection system (Envision).Using GraphPad Prism software handles experimental result, calculates the EC50 that compound inhibits each replicon of HCV.
GT3a, GT4a, GT5a, GT6a mosaic type replicon and GT1b L31V, GT1b Y93H persister active testing: logical Electric-shocking method is crossed by HCV GT1b/GT3a-NS5A, HCV GT1b/GT4a-NS5A, HCV GT1b/GT5a-NS5A, HCV GT1b/GT6a-NS5A is fitted into replicon rna and HCV GT1b L31V, HCV GT1b Y93H drug resistance replicon rna are transferred to respectively Cell is then inoculated into the 96 hole experimental plates containing respective concentration compound by Huh7 cell with the density in 10000, every hole. Compound DMSO mother liquor is diluted, is added in 96 hole experimental plates, DMSO final concentration of 0.5%.By cell in 5%CO2, 37 It is cultivated 72 hours under the conditions of DEG C.Luciferase luminous substrate Bright-Glo is added into cell hole, waits after five minutes with chemistry hair Optical detection system Envision detects Luminescence signal value, and initial data (RLU) is for calculating compound inhibitory activity. By suppression percentage import GraphPad Prism software carry out nonlinear fitting be calculated the corresponding curve of compound and its To inhibitory activity (EC50) numerical value of hepatitis C virus replicon.
The results are shown in Table 2 by EC50 of the compound to HCV each genocopy.
Table 2
Conclusion: in table as the result is shown the compounds of this invention to HCVGT1a, GT1b, GT2a, GT3a, GT4b, GT5a, GT6a Replicon all has good inhibitory activity, while also having good inhibition to HCVGT1b L31V, GT1b Y93H persister Activity, i.e. the compounds of this invention are the full genome type HCV inhibitor of anti-drug resistance.
Biological Examples 2:SD P of Rats K screening test
Experimental method:
Male SD rat is taken to be divided into two groups, every group 3, one group of intravenous injection the compounds of this invention, dosage 1.0mg/kg, Another group oral to give the compound 5.0mg/kg.It takes a blood sample 8~9 time points after administration interior for 24 hours.It is built according to sample concentration The standard curve of vertical OK range is measured in plasma sample under MRM mode using AB SCIEX API4000 type LC-MS/MS The concentration of the compound.According to pharmaceutical concentration-time curve, calculated using the non-compartment model method of 6.3 software of WinNonLin Pharmacokinetic parameters.The results are shown in Table 3.
Table 3
Conclusion: the compounds of this invention has preferable bioavilability to table 3 as the result is shown.
It will be apparent to one skilled in the art that the content of present invention is not limited to foregoing illustrative embodiment, and And it can be embodied in other concrete forms without departing from its essential characteristics.Therefore, it is contemplated that each embodiment is in all respects all It is considered illustrative and unrestricted, should refer to the appended claims, rather than these aforementioned embodiments, therefore, All changes in the meaning and scope of the appended claims equivalent are included in this article.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means particular features, structures, materials, or characteristics described in conjunction with this embodiment or example It is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms are different Surely identical embodiment or example is referred to.Moreover, particular features, structures, materials, or characteristics described can be any It can be combined in any suitable manner in one or more embodiment or examples.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example Property, it is not considered as limiting the invention, those skilled in the art are not departing from the principle of the present invention and objective In the case where can make changes, modifications, alterations, and variations to the above described embodiments within the scope of the invention, the scope of the present invention It is defined by the claims and their equivalents.

Claims (17)

1. a kind of compound is the pharmaceutically acceptable salt of compound shown in formula (I) compound represented or formula (I),
Wherein, A is-CR7=CR7a,-N=CR7-、-CR7=N- ,-O- ,-S- or-NH-；
Y and Y1It is each independently-C (=O)-(CR8R8a)t-N(R9)-R10；
Each R5It independently is H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano, C1-6Alkyl, C1-6Halogenated alkyl, C3-8Naphthenic base, sulfydryl, nitro；
Each R6It independently is H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano, C1-6Alkyl, C1-6Halogenated alkyl, C3-8Naphthenic base, mercapto Base, nitro；
Each R7、R7aIt independently is H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano, C1-6Alkyl, sulfydryl, nitro；
Each R8And R8aIt independently is H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Alcoxyl Base, C2-10Heterocycle, sulfydryl, nitro, phenyl, C6-10Aryl C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, C2-10Heterocycle C1-6Alkane Base, C6-10Arylamino, C6-10Aryl C1-6Alkylamino, C6-10Aryl C1-6Alkoxy, C2-10Heterocycle oxygroup, C2-10Heterocycle C1-6Alkoxy, C2-10Heterocyclylamino group, C2-10Heterocycle C1-6Alkylamino or C6-10Aryloxy group；
Each R9And R10It is each independently H or C1-6Alkyl-OC (=O)-；
Each f and t independently is 1 or 2；
Each n independently is 0 or 1；
R1、R2Heterocycle, condensed ring or loop coil are formed with Y-X-CH, the heterocycle, condensed ring, loop coil are selected from following subformula:
R3、R4With Y1-X1- CH forms heterocycle, condensed ring or loop coil, and the heterocycle, condensed ring, loop coil are selected from following subformula:
Each R15It independently is H, deuterium, oxo (=O), F, Cl, Br, I, cyano, hydroxyl, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Alkane Oxygroup, C1-6Alkoxy C1-6Alkyl, C1-6Alkylamino, C1-6Alkylthio group, C1-6Halogenated alkoxy C1-6Alkyl；
Each R9bIt independently is hydrogen, deuterium, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Hydroxy alkyl, C1-6Aminoalkyl, C1-6Alkoxy C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, C1-6Alkylthio group C1-6Alkyl；
With each n1And n2It independently is 1,2,3 or 4.
2. compound according to claim 1, each R15It independently is H, deuterium, oxo (=O), F, Cl, Br, I, cyano, hydroxyl Base, C1-3Alkyl, C1-3Halogenated alkyl, C1-3Alkoxy, C1-3Alkoxy C1-3Alkyl, C1-3Halogenated alkoxy C1-3Alkyl, C1-3Alkane Amino, C1-3Alkylthio group；With
Each R9bIt independently is hydrogen, deuterium, C1-3Alkyl, C1-3Halogenated alkyl, C1-3Hydroxy alkyl, C1-3Aminoalkyl, C1-3Alkoxy C1-3Alkyl, C1-3Alkylamino C1-3Alkyl, C1-3Alkylthio group C1-3Alkyl.
3. compound according to claim 2, each R15It independently is H, deuterium, oxo (=O), F, Cl, Br, I, cyano, hydroxyl Base, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy, methoxy, difluoromethoxy Ylmethyl, trifluoromethoxy methyl, ethoxyl methyl；With
Each R9bIt independently is hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, trifluoromethyl, hydroxymethyl, amino methyl, methoxyl group Methyl, ethoxyl methyl.
4. compound according to claim 1, R9And R10Be each independently H, methyl-OC (=O)-, ethyl-OC (= O)-, propyl-OC (=O)-, isopropyl-OC (=O)-, tert-butyl-OC (=O)-.
5. compound according to claim 1, with structure shown in formula (II), (IIa), (IIb) or (III), or Structure pharmaceutically acceptable salt shown in formula (II), (IIa), (IIb) or (III):
Wherein, A is-O- ,-S- ,-NH-；
Each R15It independently is H, deuterium, oxo (=O), F, Cl, Br, I, cyano, hydroxyl, C1-3Alkyl, C1-3Halogenated alkyl, C1-3Alkane Oxygroup, C1-3Alkoxy C1-3Alkyl, C1-3Halogenated alkoxy C1-3Alkyl, C1-3Alkylamino, C1-3Alkylthio group；
With each n1And n2It independently is 1,2；
Each f independently is 1 and 2；
Each n independently is 0 and 1；
Each R5And R6It independently is H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano, C1-6Alkyl, C1-6Halogenated alkyl, C3-8Cycloalkanes Base, sulfydryl, nitro.
6. compound according to claim 5, each R8And R8aIt independently is H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyanogen Base, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Alkoxy, C2-10Heterocycle, sulfydryl, nitro, C6-10Aryl C1-6Alkyl, C1-6Alcoxyl Base C1-6Alkyl, C2-10Heterocycle C1-6Alkyl, C6-10Arylamino, C6-10Aryl C1-6Alkylamino, C6-10Aryl C1-6Alkoxy, C2-10Heterocycle oxygroup, C2-10Heterocycle C1-6Alkoxy, C2-10Heterocyclylamino group, C2-10Heterocycle C1-6Alkylamino or C6-10Fragrant oxygen Base.
7. compound according to claim 5, wherein each R15It independently is H, deuterium, oxo (=O), F, Cl, Br, I, cyanogen Base, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy, methoxy, difluoro Methoxy, trifluoromethoxy methyl, ethoxyl methyl, methylamino, ethylamino.
8. compound according to claim 5, wherein each R5And R6It independently is H, hydroxyl, amino, F, Cl, Br, I, cyanogen Base, methyl, ethyl, propyl, isopropyl, normal-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Sulfydryl or nitro.
9. any compound according to claim 1, wherein each R8And R8aIndependently be H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano, methyl, ethyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, methoxyl group, ethyoxyl, isopropyl oxygen Base, methoxy, 1- methoxy ethyl, 2- methoxy ethyl, 1- methoxy-propyl, 2- methoxy-propyl, 3- methoxy propyl Base, phenyl, pyranose, trifluoromethyl, morpholinyl, sulfydryl, nitro, benzyl, anilino-.
10. a kind of compound, the pharmaceutically acceptable salt with structure or structure as follows as follows:
11. a kind of pharmaceutical composition, wherein the pharmaceutical composition includes chemical combination of any of claims 1-10 Object and pharmaceutically acceptable carrier, excipient, adjuvant, medium or combinations thereof.
12. pharmaceutical composition according to claim 11, the excipient is diluent.
13. pharmaceutical composition according to claim 11 further includes the drug of other HCV-Ab IgGs.
14. pharmaceutical composition according to claim 13, wherein the drug of the others HCV-Ab IgG is interferon, Li Ba Wei Lin, interleukin-22, interleukin 6, interleukin 12, promote to generate compound, RNA interfering, the antisense of 1 type helper T lymphocyte response RNA, miaow quinoline not moral, inosine 5 '-monophosphate dehydrogenase inhibitor, amantadine, Rimantadine, Ba Wei former times monoclonal antibody, hepatitis C Immunoglobulin, CivacirTM, boceprevir, tirrevir, Erlotinib, his Wei of Dacca, take charge of beautiful Wei, Ah that Wei, Vaniprevir, faldaprevir, paritaprevir, Dan Nuopuwei, sovaprevir, grazoprevir, vedroprevir、BZF-961、GS-9256、narlaprevir、ANA975、ombitasvir、EDP239、ravidasvir、 Velpatasvir, samatasvir, elbasvir, MK-8325, GSK-2336805, PPI-461, Xi Luruiwei, ACH- 1095、VX-985、IDX-375、VX-500、VX-813、PHX-1766、PHX-2054、IDX-136、IDX-316、 Modithromycin, VBY-376, TMC-649128, mericitabine, Suo Feibuwei, INX-189, IDX-184, IDX102、R-1479、UNX-08189、PSI-6130、PSI-938、PSI-879、nesbuvir、HCV-371、VCH-916、 lomibuvir、MK-3281、dasabuvir、ABT-072、filibuvir、deleobuvir、tegobuvir、A-837093、 JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055, Lei Dipawei, odalasvir, ritonavir, furaprevir、setrobuvir、alisporivir、BIT-225、AV-4025、ACH-3422、MK-2748、JNJ- 47910382、ABP-560、TD-6450、TVB-2640、ID-12、PPI-383、A-848837、RG-7795、BC-2125、 Alloferon, nivolumab, WF-10, Nitazoxanide, multiferon, nevirapine, Debiopharm, MK-3682, MK- 8408、GS-9857、CD-AdNS3、pibrentasvir、RG-101、glecaprevir、INO-8000、MBL-HCV1、CIGB- 230、TG-2349、procvax、CB-5300、miravirsen、chronvac-C、MK-1075、ACH-0143422、WS-007、 MK-7680、MK-2248、MK-8408、IDX-21459、MK-8876、GSK-2878175、MBX-700、AL-335、AL-704、 EDP-239, SB-9200, ITX-5061, ID-12 or combinations thereof；The interferon be Interferon Alpha-2b, Pegylation it is dry Disturb plain α, Intederon Alpha-2a, the Intederon Alpha-2a of Pegylation, compound alpha-interferon, interferon gamma or combinations thereof.
15. pharmaceutical composition according to claim 13, wherein the drug of the others HCV-Ab IgG is for inhibiting HCV Reproduction process and/or the function of inhibiting HCV virus albumen；The HCV reproduction process includes that HCV enters, HCV shells, HCV is turned over It translates, HCV duplication, HCV is assembled or HCV release；The HCV virus albumen be selected from metalloproteinases, NS2, NS3, NS4A, Internal ribosome inlet point and inosine monophosphate dehydrogenase required for NS4B, NS5A or NS5B and HCV virus replicate.
16. pharmaceutical composition described in any one of compound of any of claims 1-10 or claim 11-15 The purposes of object in medicine preparation, the drug are used to inhibit HCV reproduction process and/or inhibit the function of HCV virus albumen；Institute Stating HCV reproduction process includes that HCV enters, HCV shelling, HCV translation, HCV duplication, HCV is assembled or HCV release；The HCV disease It is required internal that toxalbumin is selected from metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A or NS5B and HCV virus duplication Ribosomes inlet point and inosine monophosphate dehydrogenase.
17. pharmaceutical composition described in any one of compound of any of claims 1-10 or claim 11-15 The purposes of object in medicine preparation, the drug is for preventing, handling, treating or mitigating HCV infection or hepatitis C disease.
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