CN105968101A - Compounds adopted as hepatitis C inhibitors and applications thereof in medicines - Google Patents
Compounds adopted as hepatitis C inhibitors and applications thereof in medicines Download PDFInfo
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- CN105968101A CN105968101A CN201610141716.2A CN201610141716A CN105968101A CN 105968101 A CN105968101 A CN 105968101A CN 201610141716 A CN201610141716 A CN 201610141716A CN 105968101 A CN105968101 A CN 105968101A
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- 0 C*(c1ncc(C(C)(C)C)[n]1)I Chemical compound C*(c1ncc(C(C)(C)C)[n]1)I 0.000 description 7
- OHPUCEUCBHBIAW-IENPIDJESA-N CC(C)(C)OC(N(C[C@@H](COC)C1)C1C(O)=O)=O Chemical compound CC(C)(C)OC(N(C[C@@H](COC)C1)C1C(O)=O)=O OHPUCEUCBHBIAW-IENPIDJESA-N 0.000 description 1
- QQAGIYFCLWXFHW-UHFFFAOYSA-N CC(C)c(cc1)cc(cc2)c1c1c2[nH]c(C)n1 Chemical compound CC(C)c(cc1)cc(cc2)c1c1c2[nH]c(C)n1 QQAGIYFCLWXFHW-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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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
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- 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
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- 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
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- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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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
- C07D471/08—Bridged systems
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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 invention relates to compounds adopted as hepatitis C inhibitors and applications thereof in medicines, and particularly provides compounds shown as a formula (I) or stereoisomers, tautomers, enantiomers, oxynitrides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof used for treating hepatitis C viraus (HCV) infection or hepatitis C. The invention also discloses pharmaceutical compositions containing the compounds and a method of treating the hepatitis C viraus (HCV) infection or hepatitis C through using the compounds or the pharmaceutical compositions.
Description
Invention field
The invention belongs to drug world, be particularly used for treating the compound, described that hepatitis C virus (HCV) infects
Compositions of compound and application thereof and using method.
Background of invention
HCV is main human pathogen, estimates that about 1.7 hundred million people are infected in the whole world, infects people for human immunodeficiency virus type 1
5 times of number.And the major part in the middle of these HCV infection individualities can develop into serious Progressive symmetric erythrokeratodermia hepatopathy, including liver cirrhosis regulating liver-QI
Cell carcinoma.Therefore, chronic HCV infection will be the main cause of global patient's premature death because of hepatopathy.
HCV is positive chain RNA virus.According to the ratio to the extensive similarity of the aminoacid sequence derived and 5 ' untranslated regions
Relatively, in HCV is classified into the single genus of flaviviridae (Flaviviridae family).All members of flaviviridae
Being all the envelope virus particle containing positive chain RNA genome, this genome is turned over by single uninterrupted open reading frame (ORF's)
Translate, encode all known virus specified proteins.
Considerable heterogeneity is there is in the nucleotide and coded aminoacid sequence of whole HCV genome.?
Identify at least 7 main genotype, and disclose more than 50 hypotype.By in HCV infection cell, viral RNA is turned over
It is translated into polyprotein, and is split into 10 kinds body proteins.Being structural protein at amino terminal, E1 and E2 is following closely.It addition, also
Having 6 kinds of non-structural proteins, i.e. NS2, NS3, NS4A, NS4B, NS5A and NS5B, it plays the heaviest in HCV life cycle
The role that wants (see, e.g., Lindenbach, B.D. and C.M.Rice, Nature.436,933-938,2005).
The distribution in the whole world of the main genotypes of HCV is different, although 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.
Strand HCV rna gene group length is about 9500 nucleotide, has single open reading frame, encode single about
3000 amino acid whose large-scale polyproteins.In infection cell, this polyprotein on multiple sites by leukoprotease and
Virus protein cleavage, produces structure and non-structural (NS) albumen.For HCV, ripe non-structural protein (NS2, NS3,
NS4A, NS4B, NS5A and NS5B) be formed by two-strain protease realize.It is generally acknowledged that the first is metal egg
White enzyme, cuts at NS2-NS3 contact;The second is included in NS3 (also referred to herein as NS3 protease) N end regions
Serine protease, it mediates all of follow-up cutting in NS3 downstream, is cis at NS3-NS4A cleavage site, at remaining NS4A-
NS4B, NS4B-NS5A, NS5A-NS5B site is then trans.NS4A albumen seems there is several functions, plays NS3 protease cofactor
Effect, and NS3 and other rdrp virus components may be assisted to carry out film location.NS3 albumen and the formation of NS4A complex
Seemingly process event, all sites improves necessary to proteolytic efficiency.NS3 albumen also demonstrates ribonucleoside triphosphote
Enzyme and DBPA activity.NS5B (being also known as HCV polymerase herein) is to participate in the RNA polymerization depending on RNA that HCV replicates
Enzyme.
Summary of the invention
The compounds of this invention is for treating patient's HCV infection, and this compound optionally suppresses the duplication of HCV virus.
The present invention relates to the method that HCV-Ab IgG infects.The present invention provide compound or pharmaceutical composition to HCVGT1a,
GT1b, GT2a, GT3a, GT4b, GT5a, GT6a are respectively provided with good inhibition, the compound of present invention offer simultaneously or medicine
Compositions also has good inhibition to HCVGT1b L31V, GT1b Y93H persister.Therefore, the invention provides
The full genome HCV with overriding resistance suppresses medicine, and has preferable bioavailability.
On the one hand, the present invention relates to a kind of compound, it is compound shown in the compound shown in formula (I) or formula (I)
Stereoisomer, geometric isomer, tautomer, enantiomer, nitrogen oxides, hydrate, solvate, metabolism are produced
Thing, 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, cycloalkyl, heterocyclic radical, 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, agedoite, aspartic acid, glutamic acid, glutamine, proline, serine, to tyrosine, essence
Propylhomoserin, histidine, cysteine, glycine, sarcosine, N, N-dimethylglycine, homoserine, norvaline, the brightest ammonia
Acid, ornithine, homocysteine, homophenylalanin, phenylglycine, adjacent tyrosine, m-Tyrosine or hydroxyproline institute shape
The group become;
R1、R2、R3And R4It is each independently H, deuterium, alkyl, aryl alkyl, cycloalkyl, heterocyclic radical, heteroaryl or aryl;
Or R1、R2It is randomly formed 3-8 unit heterocycle, 3-8 unit carbocyclic ring, condensed-bicyclic with X-CH, condenses miscellaneous pair of miscellaneous dicyclo, spiral shell dicyclo or spiral shell
Ring;Or R3、R4With X1-CH is randomly formed 3-8 unit heterocycle, 3-8 unit carbocyclic ring, condensed-bicyclic, condenses miscellaneous dicyclo, spiral shell dicyclo or spiral shell
Miscellaneous dicyclo;
Each R5And R6Independently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, alkyl, haloalkyl,
Thiazolinyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aryl, heteroaryl, aryl alkyl, alkoxyalkyl, alkoxyl, aryl
Amino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heteroaryl epoxide, heteroaryl alkyl, alkoxy aryl, heteroaryl
Base alkoxyl, heterocyclic radical epoxide, 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 group,
Deuteroalkyl, alkyl, haloalkyl, alkoxyl, thiazolinyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aryl, heteroaryl,
Aryl alkyl, alkoxyalkyl, heteroaryl alkyl, cycloalkyl-alkyl, cycloheteroalkylalkyl, arylamino, heteroaryl amino, aryl
Alkylamino, heteroarylalkylamino, heteroaryl epoxide, alkoxy aryl, heteroarylalkoxy, heterocyclic radical epoxide, 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-, heterocyclic radical alkylamino or aryloxy group;
Each R9And R10Independently be H, deuterium, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl, alkyl-OC
(=O)-, alkyl-C (=O)-, carbamoyl, alkyl-OS (=O)r-, alkyl-S (=O)rO-, alkyl-S (=O)r-or ammonia
Base sulfonyl;
Each f, n and t independently be 0,1,2,3 or 4;
M is 1,2,3 or 4;With
Each r independently be 0,1 or 2;
The following group of each of which: alkyl, alkoxyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl ,-C
(=O)-(CR8R8a)t-N(R9)-R10, a-amino acid group, 3-8 unit heterocycle, 3-8 unit carbocyclic ring, condensed-bicyclic, condense miscellaneous dicyclo,
The miscellaneous dicyclo of spiral shell dicyclo, spiral shell, haloalkyl, thiazolinyl, alkynyl, alkoxyalkyl, heteroaryl alkyl, cycloalkyl-alkyl, heterocyclic radical alkane
Base, arylamino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, aryloxy group, heteroaryl epoxide, alkoxy aryl,
Heteroarylalkoxy, heterocyclic radical epoxide, heterocyclylalkoxy, heterocyclylamino group, alkyl-OC (=O)-, alkyl-C (=O)-, ammonia
Base formoxyl, alkyl-OS (=O)r-, alkyl-S (=O)rO-, alkyl-S (=O)r-or amino-sulfonyl individually optionally by 1,
2,3 or 4 are selected from hydroxyl, deuterium, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl, alkylamino, alkylthio group, alkyl, halo
Alkyl, alkoxyalkyl, halogenated alkoxy alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, aryl
Amino, heteroaryl epoxide, heteroaryl alkyl, oxo (=O), carboxyl, the substituted alkoxyl of hydroxyl, hydroxyl substituted alkyl-C
(=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2-, hydroxyl substituted alkyl-S (=O)-, hydroxyl takes
Alkyl-the S (=O) in generation2-or the substituent group of the substituted alkoxyl of carboxyl replaced.
At some embodiments, each R1、R2、R3And R4Independently be H, C1-6Alkyl, C6-10Aryl C1-6Alkyl, C3-10Cycloalkanes
Base, C2-10Heterocyclic radical, C1-9Heteroaryl or C6-10Aryl;Or R1、R2With X-CH be randomly formed 3-8 unit heterocycle, 3-8 unit carbocyclic ring,
C5-12Condensed-bicyclic, C5-12Condense miscellaneous dicyclo, C5-12Spiral shell dicyclo or C5-12The miscellaneous dicyclo of spiral shell;Or R3、R4With X1-CH is randomly formed 3-
8 yuan of heterocycles, 3-8 unit carbocyclic ring, C5-12Condensed-bicyclic, C5-12Condense miscellaneous dicyclo, C5-12Spiral shell dicyclo or C5-12The miscellaneous dicyclo of spiral shell;Wherein institute
The 3-8 unit heterocycle stated, 3-8 unit carbocyclic ring, C5-12Condensed-bicyclic, C5-12Condense miscellaneous dicyclo, C5-12Spiral shell dicyclo or C5-12The miscellaneous dicyclo of spiral shell is only
Stand and be optionally selected from H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, C by 1,2,3 or 41-6Alkyl, C1-6Alkyl halide
Base, C1-6Alkoxyl, 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 epoxide, C1-9Heteroaryl C1-6Alkyl, C3-8Cycloalkyl or C2-10Heterocycle
The substituent group of base is replaced.
In some embodiments, wherein R1、R2The heterocycle, condensed ring or the spiro ring system that are formed with Y-X-CH are selected from following sub-knot
Structure formula:
Wherein R3、R4With Y1-X1Heterocycle, condensed ring or the spiro ring system that-CH is formed is selected from following subformula:
Wherein, each R15Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, C1-6Alkyl, C1-6Alkyl halide
Base, C1-6Alkoxyl, 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 epoxide, C1-9Heteroaryl C1-6Alkyl, C3-8Cycloalkyl or C2-10Heterocycle
Base;
Each R9bIndependently be hydrogen, deuterium, C1-6Alkyl, C1-6Haloalkyl, 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, C2-10Heterocyclic radical or C3-8Cycloalkyl;
With each n1And n2Independently be 1,2,3 or 4.
At other embodiments, each R15Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, C1-3Alkane
Base, C1-3Haloalkyl, C1-3Alkoxyl, C1-3Alkoxy C1-3Alkyl, C1-3Halogenated alkoxy C1-3Alkyl, C1-3Alkylamino, C1-3
Alkylthio group, C6-10Arylamino, C6-10Aryloxy group, C1-9Heteroaryl, C1-9Heteroaryl epoxide, C1-9Heteroaryl C1-3Alkyl, C3-8Ring
Alkyl or C2-10Heterocyclic radical;With
Each R9bIndependently be hydrogen, deuterium, C1-3Alkyl, C1-3Haloalkyl, 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, C2-10Heterocyclic radical or C3-8Cycloalkyl.
At other embodiments, each R15Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, methyl, second
Base, propyl group, 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 R9bIndependently be hydrogen, deuterium, methyl, ethyl, propyl group, isopropyl, trifluoromethyl, hydroxymethyl, amino methyl, first
Epoxide methyl, ethoxyl methyl, phenyl methyl, phenyl, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl.
At some embodiments, each R7、R7a、R7bAnd R9aIndependently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br,
I, cyano group, C1-6Alkyl, C1-6Haloalkyl, C2-6Thiazolinyl, C2-6Alkynyl, C2-10Heterocyclic radical, C3-8Cycloalkyl, sulfydryl, nitro, C6-10
Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C3-8Cycloalkyl C1-6
Alkyl, C2-10Heterocyclic radical C1-6Alkyl, C6-10Arylamino, C1-9Heteroaryl amino, C6-10Aryl C1-6Alkylamino, C1-9Heteroaryl
C1-6Alkylamino, C1-9Heteroaryl epoxide, C6-10Aryl C1-6Alkoxyl, C1-9Heteroaryl C1-6Alkoxyl, C2-10Heterocyclic radical epoxide,
C2-10Heterocyclic radical C1-6Alkoxyl, 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
Heterocyclic radical C1-6Alkylamino or C6-10Aryloxy group;With
Each r independently be 0,1 or 2.
At some embodiments, Y and Y1It is each independently H, deuterium, C1-6Alkyl, C3-8Cycloalkyl, C2-10Heterocyclic radical, C6-10Virtue
Base, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl or-C (=O)-(CR8R8a)t-N(R9)-R10;
Each R8And R8aIndependently be H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, C1-6Alkyl, C1-6Deuteroalkyl, C1-6
Haloalkyl, C1-6Alkoxyl, C2-6Thiazolinyl, C2-6Alkynyl, C2-10Heterocyclic radical, C3-8Cycloalkyl, sulfydryl, nitro, C6-10Aryl C1-6
Alkyl, C1-6Alkoxy C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C3-8Cycloalkyl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl, C6-10
Arylamino, C1-9Heteroaryl amino, C6-10Aryl C1-6Alkylamino, C1-9Heteroaryl C1-6Alkylamino, C1-9Heteroaryl epoxide, C6-10
Aryl C1-6Alkoxyl, C1-9Heteroaryl C1-6Alkoxyl, C2-10Heterocyclic radical epoxide, C2-10Heterocyclic radical C1-6Alkoxyl, C2-10Heterocyclic radical
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-、C2-10Heterocyclic radical C1-6Alkylamino or C6-10Aryloxy group;
R9And R10It is each independently H, deuterium, C1-6Alkyl, C3-8Cycloalkyl, C2-10Heterocyclic radical, 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)r-or amino-sulfonyl;
T is 0,1,2,3 or 4;With
Each r independently be 0,1 or 2.
At other embodiments, R9And R10Be each independently H, deuterium, methyl, ethyl, isopropyl, normal-butyl, isobutyl group,
Sec-butyl, the tert-butyl group, methyl-OC (=O)-, ethyl-OC (=O)-, propyl group-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 the structure shown in formula (II), (IIa), (IIb) or (III), or formula
(II), the structural upright isomer shown in (IIa), (IIb) or (III), geometric isomer, tautomer, enantiomer,
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 R15Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, C1-3Alkyl, C1-3Alkyl halide
Base, C1-3Alkoxyl, 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 epoxide, C1-9Heteroaryl C1-3Alkyl, C3-8Cycloalkyl or C2-10Heterocycle
Base;
With each n1And n2Independently be 1,2,3 or 4.
At other embodiments, each R8And R8aIndependently be H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, C1-6Alkyl,
C1-6Deuteroalkyl, C1-6Haloalkyl, C1-6Alkoxyl, C2-6Thiazolinyl, C2-6Alkynyl, C2-10Heterocyclic radical, C3-8Cycloalkyl, sulfydryl,
Nitro, C6-10Aryl C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C3-8Cycloalkyl C1-6Alkyl, C2-10Miscellaneous
Ring group C1-6Alkyl, C6-10Arylamino, C1-9Heteroaryl amino, C6-10Aryl C1-6Alkylamino, C1-9Heteroaryl C1-6Alkylamino,
C1-9Heteroaryl epoxide, C6-10Aryl C1-6Alkoxyl, C1-9Heteroaryl C1-6Alkoxyl, C2-10Heterocyclic radical epoxide, C2-10Heterocyclic radical
C1-6Alkoxyl, 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-、C2-10Heterocyclic radical C1-6Alkane
Amino or C6-10Aryloxy group.
At other embodiments, the most each R15Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, first
Base, ethyl, propyl group, 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.
At some embodiments, each R5And R6Independently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group,
C1-6Alkyl, C1-6Haloalkyl, C2-6Thiazolinyl, C2-6Alkynyl, C2-10Heterocyclic radical, C3-8Cycloalkyl, sulfydryl, nitro, C6-10Aryl,
C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, C1-6Alkoxyl, C6-10Arylamino, C1-9Heteroaryl ammonia
Base, C6-10Aryl C1-6Alkylamino, C1-9Heteroaryl C1-6Alkylamino, C1-9Heteroaryl epoxide, C1-9Heteroaryl C1-6Alkyl, C6-10Virtue
Base C1-6Alkoxyl, C1-9Heteroaryl C1-6Alkoxyl, C2-10Heterocyclic radical epoxide, C2-10Heterocyclic radical C1-6Alkoxyl, C2-10Heterocyclic radical ammonia
Base, C1-6Alkyl acyl, C1-6Alkyl acyloxy, C1-6Alkoxyacyl, C2-10Heterocyclic radical C1-6Alkylamino or C6-10Aryloxy group.
At other embodiments, each R5And R6Independently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyanogen
Base, methyl, ethyl, propyl group, isopropyl, normal-butyl, the tert-butyl group, trifluoromethyl, methoxy, methoxyl group, ethyoxyl, ethylene
Base, pi-allyl, acetenyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenyl, phenyl epoxide, phenyl amino, sulfydryl or nitre
Base.
At some embodiments, each R8And R8aIndependently be H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, methyl, ethyl,
Isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, deuterated methyl, deuterated ethyl, deuterated propyl group, deuterated isopropyl, methoxy
Base, ethyoxyl, isopropoxy, methoxy, 1-methoxy ethyl, 2-methoxy ethyl, 1-methoxy-propyl, 2-methoxyl group
Propyl group, 3-methoxy-propyl, phenyl, pyranose, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, trifluoromethyl, vinyl, alkene
Propyl group, acetenyl, morpholinyl, sulfydryl, nitro, benzyl or anilino-.
On the other hand, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition comprises an any of the above described change
Compound.
In some embodiments, this pharmaceutical composition can also comprise pharmaceutically acceptable carrier, figuration further
Agent, diluent, adjuvant, vehicle or a combination thereof.
In other embodiments, it further comprises other the medicine of HCV-Ab IgG, wherein said HCV-Ab IgG
Medicine is the change that interferon, ribavirin, interleukin-22, interleukin 6, interleukin 12, promotion produce 1 type helper T lymphocyte response
Compound, RNA interfering, antisense RNA, miaow quinoline not moral, inosine 5 '-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, bar
Dimension former times monoclonal antibody, hepatitis C immunoglobulin, CivacirTM, EBP520, TVR, erlotinib, his Wei of Dacca, U.S. of department
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
Pool 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 a combination thereof;Described 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 a combination thereof.
In other embodiments, other the medicine of HCV-Ab IgG wherein said be used for suppressing HCV reproduction process and/
Or the function of suppression HCV virus protein;Described HCV reproduction process include HCV enter, HCV shelling, HCV translation, HCV replicate,
HCV assembles or HCV release;Described HCV virus protein selected from metalloproteases, NS2, NS3, NS4A, NS4B, NS5A or
NS5B, and the internal ribosome inlet point (IRES) required for HCV virus replication and inosine monophosphate dehydrogenase (IMPDH).
On the other hand, the present invention provides the compounds of this invention or the pharmaceutical composition purposes in preparing medicine, described medicine
Thing is for suppressing HCV reproduction process and/or the function of suppression HCV virus protein;Described HCV reproduction process include HCV enter,
HCV shelling, HCV translation, HCV duplication, HCV assemble or HCV release;Described HCV virus protein selected from metalloproteases, NS2,
NS3, NS4A, NS4B, NS5A or NS5B, and the internal ribosome inlet point (IRES) required for HCV virus replication and inosine
Monophosphate dehydrogenase (IMPDH).
On the other hand, the present invention provides the compounds of this invention or the pharmaceutical composition purposes in preparing medicine, described medicine
Thing is used for preventing, process, treat or alleviate HCV infection or hepatitis C disease.
Another aspect of the present invention relate to the compound that formula (I), (II), (IIa), (IIb) and (III) is comprised preparation,
Separate and the method for purification.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspects and
The content of his aspect will make more specific complete description below.
Detailed description of the invention book
Definition and general terms
Certain embodiments of the present invention be will now be described in more detail, and the example is by the structural formula enclosed or chemical formula explanation.This
Invention intention contains all of replacement, amendment and equivalent technical solutions, and they are included in such as the present invention of claim definition
In the range of.Those skilled in the art will appreciate that many similar with the described herein or method of equivalent and material can be used in reality
Trample the present invention.The present invention is not limited to method described herein and material.At the document combined, patent and similar material one
Or many different from the application or conflicting in the case of (include but not limited to defined term, term application, described
Technology, etc.), be as the criterion with the application.
It will further be appreciated that some feature of the present invention, for clearly visible, carry out in multiple independent embodiments
Describe but it also may provide in combination in single embodiment.Otherwise, the various features of the present invention, for brevity,
Single embodiment is described but it also may individually or with the sub-portfolio being arbitrarily suitable for provide.
Unless otherwise indicated, 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 that identical implication.The all patents that the present invention relates to and public publication are integrally incorporated this by reference
Bright.
Unless otherwise indicated, it should apply following definition used herein.For purposes of the present invention, chemical element with
Periodic table of elements CAS version, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can be joined
Examine " 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 is incorporated herein by.
Context except as otherwise noted or has significantly conflict, article 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.Such as, " component " refers to one or more component, it is possible to have more than one
Component be taken into account in the embodiment of described embodiment and use or use.
Term used in the present invention " study subject " refers to animal.Typical described animal is mammal.Tested right
As, the most also refer to primate (the such as mankind, sex), cattle, sheep, goat, horse, dog, cat, rabbit, rat, little
Mus, fish, bird etc..In certain embodiments, described study subject is primate.In other embodiments, described it is subject to
Try liking people.
Term used in the present invention " patient " refers to people's (including adult and child) or other animals.Implement at some
In scheme, " patient " refers to people.
It is open language that term " comprises ", i.e. includes the content specified by the present invention, but is not precluded from otherwise
Content.
The present invention uses " in some embodiments " or " in other embodiments " before technical characteristic definition, represents fixed herein
The technical characteristic of justice can be any with other the technical characteristic drawn by " in some embodiments " or " in other embodiments "
Be combined into complete technical scheme.
" stereoisomer " refers to have identical chemical constitution, but the change that atom or group spatially arrangement mode is different
Compound.Stereoisomer includes enantiomer, diastereomer, conformer (rotamer), geometric isomer
(cis/trans) isomer, atropisomer, etc..
" chirality " is that have can not the molecule of overlapping character with its mirror image;And " achirality " refer to can be overlapping with its mirror image
Molecule.
" enantiomer " refer to two of a compound can not be overlapping but be mutually the isomer of mirror image relationship.
" diastereomer " refers to two or more chiral centre and the stereoisomerism of its molecule mirror image the most each other
Body.Diastereomer has different physical propertys, such as fusing point, boiling point, spectral quality and reactivity.Diastereomer mixes
Compound can be separated by high resolution analysis operation such as electrophoresis and chromatograph, such as HPLC.
Stereochemical definitions used in the present invention and rule typically 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 compound exist with optical active forms, and i.e. they have and make the plane of linearly polarized light rotate
Ability.When describing optically active compound, prefix D and L or R and S is used to represent that molecule is about one or more hands
The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols rotated for linearly polarized light caused by appointed compound,
Wherein (-) or l represent that compound is left-handed.Prefix for (+) or the compound of d be dextrorotation.A kind of concrete stereoisomerism
Body is enantiomer, and the mixture of this isomer is referred to as enantiomeric mixture.The 50:50 mixture of enantiomer
Be referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereo selectivity or stereospecificity time,
May occur in which this situation.
Come into the open any asymmetric atom (such as, carbon etc.) of compound of the present invention can be enriched with raceme or enantiomer
Presented in, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists
(R)-or (S)-configuration aspect there is 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
Excess.
According to starting material and the selection of method, the compounds of this invention can with in possible isomer or they
Mixture, the such as form of racemic modification and non-enantiomer mixture (this depends on the quantity of asymmetric carbon atom) is deposited
?.Optically active (R)-or (S)-isomer can use chiral synthon or chiral reagent to prepare, or use routine techniques to tear open
Point.If compound contains a double bond, substituent group may be E or Z configuration;If containing dibasic cycloalkanes in compound
Base, the substituent group of cycloalkyl may have cis or trans configuration.
The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties
Pure or the purest geometric isomer, enantiomer, diastereomer, such as, by chromatography and/or fractional crystallization
Method.
By known method, the racemic modification of any gained end-product or intermediate can be passed through those skilled in the art
The method being familiar with splits into optical antipode, e.g., by separating its diastereoisomeric salt obtained.Racemic product
Thing can also be separated by chiral chromatogram, e.g., uses the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping
Isomer can be prepared by asymmetric synthesis, such as, refers 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)。
What term " tautomer " or " tautomeric form " referred to have different-energy can be by low energy barrier (low
Energy barrier) constitutional isomer of mutual inversion of phases.If tautomerism is possible (as in the solution), then can reach
The chemical equilibrium of tautomer.Such as, (also referred to as proton translocation makes a variation proton tautomer (protontautomer) mutually
Structure body (prototropic tautomer)) include being migrated the mutual inversion of phases carried out by proton, such as keto-enol isomerization and
Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) includes being come by the restructuring of some bonding electronss
The mutual inversion of phases carried out.The instantiation of ketoenol tautomerization be pentane-2,4-diketone and 4-hydroxyl amyl-3-alkene-2-ketone mutual
The change of tautomeric.Another example tautomeric is phenol-keto tautomerism.One concrete reality of phenol-keto tautomerism
Example is pyridine-4-alcohol and the change of pyridine-4 (1H)-one tautomer.Unless otherwise noted, the compounds of this invention is all
Tautomeric forms is within the scope of the present invention.
Intranuclear tautomerism (Annular tautomerism) is the tautomeric one of proton translocation, and wherein proton can
To account for the two or more positions in heterocycle, the two isomer coexists in an equilibrium system, mutual with at a relatively high speed
Phase inversion.Such as: 1H-and 3H-imidazoles;1H, 2H-and 4H-1,2,4-triazole;1H-and 2H-iso-indoles.Involved in the present invention
Structure fragment, following structure fragment Aa and Ab, or Ba and Bb, for intranuclear tautomerism body;Owing to two isomers coexist, for
Narration simplicity, the present invention only mentions that the structure of one of which isomer, where the most in office mention that intranuclear tautomerism body is wherein appointed
What a kind of structure, then it represents that the most simultaneously mention another kind of structure, although as the present invention is only given the chemical combination containing Aa structure fragment
Thing, but the compound essence that the tautomer of this compound contains structure fragment Ab is given the most simultaneously;Although such as this
Compound containing Ba structure fragment only occurs in bright, but the compound that the tautomer of this compound contains structure fragment Bb is real
Matter is given the most simultaneously.
As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, as
General formula compound above, or as example special inside embodiment, subclass, and the compounds that the present invention is comprised.
Should be appreciated that " optionally substituted " this term and " substituted or non-substituted " this term can exchange use.It is said that in general, art
Language " substituted " represents that the one or more hydrogen atoms in given structure are replaced by concrete substituent group.Unless other aspect tables
Bright, an optional substituted radical can replace in each commutable position of group.When in given structural formula not
One or more substituent groups that only position can be selected from concrete group are replaced, then substituent group can identical or differently
Replace in each position.When substituent group is described as " being independently selected from " group, and the most each substituent group selects, therefore independently of one another
Each substituent group can be same to each other or different to each other.
In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode used in the present invention
" each ... to independently be " and " ... be each independently " and " ... independently be " can exchange, and all should be interpreted broadly, and it both may be used
To refer in different groups, do not affect mutually between concrete option expressed between same-sign, it is also possible to represent in phase
In same group, do not affect mutually between concrete option expressed between same-sign.
At each several part of this specification, the come into the open substituent group of compound of the present invention is open according to radical species or scope.Special
Not pointing out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.Such as, term
“C1-6Alkyl " refer in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
At each several part of the present invention, describe connection substituent group.When this structure clearly needs linking group, for this
Ma Kushi variable cited by group is interpreted as linking group.Such as, if this structure needs linking group and for this
The Ma Kushi group definition of variable lists " alkyl " or " aryl ", then it should be understood that should " alkyl " or " aryl " represent respectively
The alkylidene group connected or arylene group.
Terminology used in the present invention " alkyl " or " alkyl group ", represent containing 1 to 20 carbon atom, saturated straight chain or
Side chain univalent hydrocarbyl group, wherein, the substituent group institute that described alkyl group can optionally be described 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
Containing 1-4 carbon atom;The most in one embodiment, alkyl group contains 1-3 carbon atom.
The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-pro-pyl (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), the tert-butyl group (t-Bu ,-C (CH3)3), n-pentyl (-
CH2CH2CH2CH2CH3), 2-amyl group (-CH (CH3)CH2CH2CH3), 3-amyl group (-CH (CH2CH3)2), 2-methyl-2-butyl (-C
(CH3)2CH2CH3), 3-methyl-2-butyl (-CH (CH3)CH(CH3)2), 3-methyl isophthalic acid-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 group (-C (CH3)2CH2CH2CH3), 3-first
Base-2-amyl group (-CH (CH3)CH(CH3)CH2CH3), 4-methyl-2-amyl group (-CH (CH3)CH2CH(CH3)2), 3-methyl-3-penta
Base (-C (CH3)(CH2CH3)2), 2-methyl-3-amyl group (-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 " haloalkyl ", or " halogenated alkoxy " expression alkyl or alkoxy base are by one or more halogen atoms
Being replaced, such example comprises, but is not limited to, trifluoromethyl, trifluoromethoxy etc..
Term " hydroxy alkyl " or " the substituted alkyl of hydroxyl " represent that alkyl group is taken by one or more oh groups
In generation, wherein alkyl group has implication of the present invention.Such example comprises, but be not limited to methylol, ethoxy, 1,
2-dihydroxy ethyl etc..
Term " aminoalkyl " or " the substituted alkyl of amino " represent that alkyl group is taken by one or more amino groups
In generation, wherein alkyl group has implication of the present invention.
Term " alkoxyl " represents that alkyl group is connected with molecule remainder by oxygen atom, and wherein alkyl group has
Implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.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.Described alkoxy base can be the most one or more
The substituent group that the present invention describes is replaced.
Term " alkoxyalkyl " represents that alkoxy base is connected with molecule remainder by alkyl, wherein alkoxyl with
Alkyl group has implication 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
Epoxide ethyl, 1-butoxymethyl, 2-methyl-l-Among, 2-butoxymethyl, etc..
Term " alkyl acyl " or " alkoxyacyl " represent that alkyl or alkoxyl are by acyl group and molecule remainder phase
Even, wherein alkyl, alkoxyl have implication as described in the present invention with acyl group.In certain embodiments, this kind of embodiment is permissible
For alkyl-OC (=O)-, alkyl-OS (=O)r-, alkyl-C (=O)-, alkyl-S (=O)r-。
Term " alkyl acyloxy " or " alkoxy acyloxy " represent alkyl or alkoxyl by acyloxy and molecule remaining
Part is connected, and wherein alkoxyl, alkyl have implication as described in the present invention with acyloxy.In certain embodiments, this kind of reality
Executing 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, and formula is R-M
(=O)-.Generally the M atom in acyl group is all carbon, sulfur.Term " acyloxy " refers to that acyl group passes through oxygen atom and its remaining part of molecule
Split-phase group formula even is R-M (=O) O-.
Term " halogenated alkoxy alkyl " represents the group that halogenated alkoxy is connected with molecule remainder by alkyl, its
Middle halogenated alkoxy and alkyl have implication 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 by one or two alkyl group.Some of them embodiment is, alkyl amino is one or two
C1-6Alkyl is connected to the alkylamino group on nitrogen-atoms.Other embodiment is, alkyl amino is one or two C1-3
Alkyl is connected to the alkylamino group on nitrogen-atoms.Suitably alkylamino group can be alkyl monosubstituted amino or dialkyl amino
Base, such example includes, but is not limited to, N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-lignocaine etc..
Term " alkyl amino alkyl " represents the group that alkylamino is connected with molecule remainder, wherein alkylamino by alkyl
With alkyl, there is implication as described in the present invention.
Term " alkylthio group " represents the group that alkyl group is connected with molecule remainder, wherein alkyl tool by sulphur atom
There is implication as described in the present invention.
Term " alkylthio alkyl " represents the group that alkylthio group is connected with molecule remainder, wherein alkylthio group by alkyl
With alkyl, there is implication as described in the present invention.
Term " thiazolinyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, at least one of which insatiable hunger
And site, i.e. there is a carbon-to-carbon sp2Double bond, wherein, described alkenyl group can optionally be retouched by one or more present invention
The substituent group stated is replaced, and it includes " cis " and the location of " trans ", or " E " and the location of " Z ".In an embodiment
In, alkenyl group comprises 2-8 carbon atom;In another embodiment, alkenyl group comprises 2-6 carbon atom;In another reality
Executing in scheme, alkenyl group comprises 2-4 carbon atom.The example of alkenyl group includes, but is not limited to, vinyl (-CH=
CH2), pi-allyl (-CH2CH=CH2) etc..
Term " alkynyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, at least one of which insatiable hunger
And site, i.e. there is carbon-to-carbon sp tri-key, wherein, described alkynyl group can optionally be retouched by one or more present invention
The substituent group stated is replaced.In one embodiment, alkynyl group comprises 2-8 carbon atom;In another embodiment, alkynyl
Group comprises 2-6 carbon atom;In yet another embodiment, alkynyl group comprises 2-4 carbon atom.The example bag of alkynyl group
Include, but be not limited to, acetenyl (-C ≡ CH), propargyl (-CH2C ≡ CH), 1-propinyl (-C ≡ C-CH3) etc..
Term " cycloalkyl " represents containing 3-12 carbon atom, unit price or the saturated monocycle of multivalence, dicyclo or three ring bodies
System.In one embodiment, cycloalkyl comprises 3-12 carbon atom;In another embodiment, to comprise 3-8 carbon former for cycloalkyl
Son;In yet another embodiment, cycloalkyl comprises 3-6 carbon atom.
Term " cycloalkyl-alkyl " represents the group that cycloalkyl is connected with molecule remainder, wherein cycloalkyl by alkyl
With alkyl, there is implication as described in the present invention.
Term " heterocyclic radical " and " heterocycle " are used interchangeably herein, all referring to comprising the saturated of 3-12 annular atoms or portion
Dividing undersaturated monocycle, dicyclo or three rings, at least one of which annular atoms is selected from nitrogen, sulfur and oxygen atom, but at least one of which
Ring is not belonging to the fragrance same clan.Unless otherwise indicated, heterocyclic radical can be carbon back or nitrilo, and-CH2-group can optionally by-
C (=O)-replacement.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 heterocyclic radical includes, but are not limited to: Oxyranyle, azelidinyl, oxetanylmethoxy, thia ring
Butyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrochysene
Furyl, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3-dioxy cyclopenta, two sulfur cyclopenta, THP trtrahydropyranyl,
Dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dialkyl group, dithiane base, thiophene
Alkyl, homopiperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase, sulfur azepineBase, indoline base, 1,2,3,4-tetrahydro isoquinolyl, 1,3-benzodioxole base, 2-oxa--5-azabicyclo [2.2.1]
Hept-5-base.-CH in heterocyclic radical2-group by-C (O)-substituted example include, but not limited to 2-oxo-pyrrolidine base, oxo-
1,3-thiazolidinyl, 2-piperidone base, 3,5-dioxy piperazine piperidinyl and hybar X base.The reality that in heterocyclic radical, sulphur atom is oxidized
Example include, but not limited to sulfolane base, 1,1-dioxothiomorpholinyl.Described heterocyclyl groups can be optionally by one
Individual or multiple substituent groups described in the invention are replaced.
In one embodiment, heterocyclic radical is 3-8 former molecular heterocyclic radical, refers to comprise the full of 3-8 annular atoms
With or the undersaturated monocycle of part, at least one of which annular atoms is selected from nitrogen, sulfur and oxygen atom.Unless otherwise indicated, 3-8 is individual former
Molecular heterocyclic radical can be carbon back or nitrilo, and-CH2-group can be optionally by-C (=O)-replacement.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.4-7 atom group
The example of the heterocyclic radical become includes, but are not limited to: azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2-pyrrole
Cough up quinoline base, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuran base,
Tetrahydro-thienyl, dihydro-thiophene base, 1,3-dioxy cyclopenta, two sulfur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, tetrahydrochysene thiophene
Mutter base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dialkyl group, dithiane base, thiophene alkyl, homopiperazine base, high piperazine
Piperidinyl, oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase, sulfur azepineBase.-CH in heterocyclic radical2-
Group is included, but not limited to 2-oxo-pyrrolidine base, oxo-1,3-thiazoles alkyl, 2-piperidines by-C (=O)-substituted example
Ketone group, 3,5-dioxy piperazine piperidinyl and hybar X base.The example that in heterocyclic radical, sulphur atom is oxidized includes, but not limited to ring
Fourth sulfuryl, 1,1-dioxothiomorpholinyl.Described 3-8 former molecular heterocyclyl groups can optionally by one or
Multiple substituent groups described in the invention are replaced.
In another embodiment, heterocyclic radical is 4 former molecular heterocyclic radicals, refers to comprise the saturated of 4 annular atomses
Or the undersaturated monocycle of part, at least one of which annular atoms is replaced selected from nitrogen, sulfur and oxygen atom.Unless otherwise indicated, 4
Former molecular heterocyclic radical can be carbon back or nitrilo, and-CH2-group can be optionally by-C (=O)-replacement.The sulfur 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
The example of the heterocyclic radical become includes, but are not limited to: azelidinyl, oxetanylmethoxy, thietanyl.4 described atoms
The heterocyclyl groups of composition can optionally be replaced by one or more substituent groups described in the invention.
In another embodiment, heterocyclic radical is 5 former molecular heterocyclic radicals, refers to comprise the saturated of 5 annular atomses
Or the undersaturated monocycle of part, at least one of which annular atoms is selected from nitrogen, sulfur and oxygen atom.Unless otherwise indicated, 5 atom groups
The heterocyclic radical become can be carbon back or nitrilo, and-CH2-group can be optionally by-C (=O)-replacement.The sulphur atom of ring is permissible
Optionally it is oxidized to S-oxide.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.5 former 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, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3-dioxy cyclopenta, two sulfur
Cyclopenta.-CH in heterocyclic radical2-group is included, but not limited to 2-oxo-pyrrolidine base, oxygen by-C (=O)-substituted example
Generation-1,3-thiazolidinyl.The example that in heterocyclic radical, sulphur atom is oxidized includes, but not limited to sulfolane base.Described 5 former
Molecular heterocyclyl groups can optionally be replaced by one or more substituent groups described in the invention.
In another embodiment, heterocyclic radical is 6 former molecular heterocyclic radicals, refers to comprise the saturated of 6 annular atomses
Or the undersaturated monocycle of part, at least one of which annular atoms is selected from nitrogen, sulfur and oxygen atom.Unless otherwise indicated, 6 atom groups
The heterocyclic radical become can be carbon back or nitrilo, and-CH2-group can be optionally by-C (=O)-replacement.The sulphur atom of ring is permissible
Optionally it is oxidized to S-oxide.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.6 former molecular miscellaneous
The example of ring group includes, but are not limited to: THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, sulfur generation
Quinoline base, piperazinyl, dialkyl group, dithiane base, thiophene alkyl.-CH in heterocyclic radical2-group is by-C (=O)-substituted example
Include, but not limited to 2-piperidone base, 3,5-dioxy piperazine piperidinyl and hybar X base.In heterocyclic radical, sulphur atom is oxidized
Example includes, but not limited to 1,1-dioxothiomorpholinyl.6 described former molecular heterocyclyl groups can be optional
Ground is replaced by one or more substituent groups described in the invention.
The most in one embodiment, heterocyclic radical is 7-12 former molecular heterocyclic radical, refers to comprise 7-12 annular atoms
Saturated or part undersaturated spiral shell dicyclo or condensed-bicyclic, at least one of which annular atoms is selected from nitrogen, sulfur and oxygen atom.Unless
Additionally illustrating, 7-12 former molecular heterocyclic radical can be carbon back or nitrilo, and-CH2-group can optionally by-C (=
O)-substitute.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 heterocyclic radical includes, but are not limited to: indoline base, 1,2,3,4-tetrahydroisoquinoline
Base, 1,3-benzodioxole base, 2-oxa--5-azabicyclo [2.2.1] hept-5-base.Described 7-12 former molecular miscellaneous
Cyclic groups can optionally be replaced by one or more substituent groups described in the invention.
Term " heterocyclic radical epoxide " or " heterocyclylamino group " represent heterocyclic radical by oxygen atom or nitrogen-atoms and molecule remaining
The group that part is connected, wherein heterocyclic radical has implication of the present invention.
Term " cycloheteroalkylalkyl " includes the substituted alkyl of heterocyclic radical;Term " heterocyclylalkoxy " includes that heterocyclic radical replaces
Alkoxyl, wherein oxygen atom is connected with the remainder of molecule;Term " heterocyclic radical alkylamino " includes the substituted alkane of heterocyclic radical
Amino, wherein nitrogen-atoms is connected with the remainder of molecule.Wherein heterocyclic radical, alkyl, alkoxyl and alkylamino have such as this
Bright described implication, such example includes, but is not limited to pyrroles's-2-ylmethyl, morpholine-4-base ethyl, morpholine-4-base second
Epoxide, piperazine-4-base oxethyl, piperidin-4-yl ethylamino etc..
Term " aryl " represents containing 6-14 annular atoms, or 6-12 annular atoms, or the monocycle of 6-10 annular atoms, double
Ring and the carbocyclic ring system of three rings, wherein, at least one member ring systems is aromatic, and it is individual former that each of which member ring systems comprises 3-7
Molecular ring, and have one or more attachment point to be connected with the remainder of molecule.Term " aryl " can be with term " fragrance
Ring " exchange use.The example of aromatic yl group can include phenyl, naphthyl and anthracene.Described aromatic yl group can individually optional ground quilt
One or more substituent groups described in the invention are replaced.
Term " aryloxy group " represents the group that aryl is connected with molecule remainder by oxygen atom, and wherein aryl has this
Implication described in invention.
Term " virtue amino " " arylamino " represents that amino group is replaced by one or two aromatic yl group, such reality
Example includes, but is not limited to N-phenylamino.Some of them embodiment is, the aromatic ring on virtue amino can be replaced further.
Term " aryl alkyl " includes the substituted alkyl of aryl, and wherein alkyl is connected with the remainder of molecule;Term " virtue
Base alkoxyl " include the substituted alkoxyl of aryl, wherein oxygen atom is connected with the remainder of molecule;Term " aryl alkane amino "
Including the substituted alkylamino of aryl, wherein nitrogen-atoms is connected with the remainder of molecule.Wherein aryl, alkyl, alkoxyl and alkane
Amino has implication as described in the present invention.
Term " heteroaryl " represents containing 5-12 annular atoms, or 5-10 annular atoms, or the monocycle of 5-6 annular atoms,
Dicyclo and three-ring system, at least one of which member ring systems is aromatic, and at least one member ring systems comprises one or more miscellaneous
Atom, each of which member ring systems comprises 5-7 former molecular ring, and has one or more attachment point and molecule remainder
It is connected.Term " heteroaryl " can exchange with term " hetero-aromatic ring " or " heteroaromatics " and use.Described heteroaryl groups is appointed
Selection of land is replaced by one or more substituent groups described in the invention.In one embodiment, 5-10 is individual former molecular miscellaneous
Aryl comprises 1,2,3 or 4 hetero atom 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-pyridine radicals, 3-pyridine
Base, 4-pyridine radicals, 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-di azoly, 1,2,5-di azoly, 1,2,4-di azoly, 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;Also include following dicyclo, but be not limited to these dicyclos: benzimidazolyl, benzofuranyl, benzothienyl, indole
Base (such as 2-indyl), purine radicals, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl are (such as 1-isoquinoline
Quinoline base, 3-isoquinolyl or 4-isoquinolyl), imidazo [1,2-a] pyridine radicals, pyrazolo [1,5-a] pyridine radicals, 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] pyridine radicals, etc..
Term " heteroaryloxy " represents the group that heteroaryl is connected with molecule remainder, wherein heteroaryl by oxygen atom
There is implication of the present invention.
Term " heteroaryl amino " " heteroaryl amino " represents that amino group is replaced by one or two heteroaryl groups.
Term " heteroaryl alkyl " includes the substituted alkyl of heteroaryl, and wherein alkyl is connected with the remainder of molecule;Art
Language " heteroarylalkoxy " includes the substituted alkoxyl of heteroaryl, and wherein oxygen atom is connected with the remainder of molecule;Term is " miscellaneous
Aryl alkane amino " include the substituted alkylamino of heteroaryl, wherein nitrogen-atoms is connected with the remainder of molecule.Wherein heteroaryl,
Alkyl, alkoxyl and alkylamino have implication as described in the present invention.
Term " carbocylic radical " and " carbocyclic ring " are used interchangeably herein, all referring to comprising the saturated of 3-12 carbon atom or portion
Divide undersaturated monocycle, dicyclo or three rings, but at least one of which ring is not belonging to the fragrance same clan.Unless otherwise indicated, on carbocyclic ring
-CH2-group can be optionally by-C (=O)-replacement.Carbocylic radical comprises 3-8 carbon atom in certain embodiments.One
In a little embodiments, carbocylic radical comprises 5 carbon atoms.In certain embodiments, carbocylic radical comprises 6 carbon atoms.
Term " condensed-bicyclic ", " condensed-bicyclic base " is used interchangeably herein, all referring to the saturated of unit price or multivalence or
Part is undersaturated and member ring systems, and described and member ring systems refers to the bicyclic system of non-aromatic.Such system can comprise solely
Vertical or the unsaturated system of conjugation, but its core texture do not comprise aromatic rings or heteroaromatic (but aromatic group can be made
For substituent group thereon).In certain embodiments, condensed-bicyclic contains 5-12 carbon atom.
Term " volution base ", " spiral shell bicyclic group " is used interchangeably herein, refers to the saturated or part of unit price or multivalence not
Saturated rings system, one of them ring originates from specific ring carbon atom on another ring.In certain embodiments, screw togather dicyclo to contain
There is 5-12 carbon atom.
Such as, as disclosed below, a saturated also member ring systems (ring B and B ') is referred to as " condensed-bicyclic ", and ring A
In two saturated member ring systems, share a carbon atom with ring B, be referred to as " volution " or " spiral shell dicyclo ".
When the annular atoms in " condensed-bicyclic " or " spiral shell dicyclo " contains at least one hetero atom, " condensed-bicyclic base " or
" spiral shell bicyclic group " is referred to as " condensing miscellaneous dicyclo " or " the miscellaneous dicyclo of spiral shell ", and the most each ring can be carbocylic radical or heterocyclic radical.?
In some embodiments, condense miscellaneous dicyclo or screw togather miscellaneous dicyclo and contain 5-12 carbon atom.
Term " oxo " represents that quilt=O replaces.
Term " hydroxyl " expression-OH.
Term " amino " expression-NH2。
Term " cyano group " 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, including the form of any oxidation state of N, S and P;Primary, secondary, tertiary amine and season
The form of ammonium salt;Or the form that in heterocycle, the hydrogen on nitrogen-atoms is replaced, such as, N is (as 3, in 4-dihydro-2 h-pyrrole base
N), NH (NH as in pyrrolidinyl) or NR (NR as in the substituted pyrrolidinyl of N-).
Term " n former molecular ", wherein n is integer, and the number of ring member nitrogen atoms in typical description molecule, described
In molecule, the number of ring member nitrogen atoms is n.Such as, piperidyl is 6 former molecular Heterocyclylalkyls, and 1,2,3,4-naphthane is
10 former molecular carbocylic radical groups.
The term " undersaturated " used in the present invention represents in group containing one or more degrees of unsaturation.
As described in the present invention, substituent group draw formed on a ring being bonded the center of receiving member ring systems (as formula (b1),
(b2), shown in (b3)) represent substituent group (R5)n、R6、(R15)n1Can replace any commutable position on ring.
The when that term " blocking group " or " PG " referring to a substituent group and other reacted with functional groups, it is commonly used to resistance
Disconnected or protect special functional.Such as, " blocking group of amino " refers to that a substituent group is connected with amino group and blocks
Or amino functional in protection compound, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl
(BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9-fluorenes Asia methoxycarbonyl group (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl
The substituent group of base is used for blocking or protect the functional of hydroxyl, suitable blocking group to include acetyl group and silicyl." carboxyl
Blocking group " refer to the substituent group of carboxyl for blocking or protect the functional of carboxyl, general carboxyl-protecting group includes-
CH2CH2SO2Ph, cyano ethyl, 2-(TMS) ethyl, 2-(TMS) ethoxyl methyl, 2-are (to toluene
Sulfonyl) ethyl, 2-(p-nitrophenyl sulfonyl) ethyl, 2-(diphenylphosphino) ethyl, nitro-ethyl, etc..For protection
The description that group is general refers 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 used in the present invention " prodrug ", represent a compound be converted in vivo formula (I), (II), (IIa),
And the compound shown in (III) (IIb).Such conversion is hydrolyzed by prodrug or in blood through enzyme in blood or tissue
It is converted into the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can conduct
Prodrug have phenyl ester class, aliphatic (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino
Esters of gallic acid.A such as compound in the present invention comprises hydroxyl, i.e. can be acylated the chemical combination obtaining prodrug form
Thing.Other prodrug form includes phosphate ester, if these phosphate compounds are that the di on parent obtains
Arrive.It is referred to documents below: T.Higuchi and V.Stella, Pro-drugs about the discussion that prodrug is complete
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 that concrete compound or its salt is in vivo by the product obtained by metabolism.One change
The metabolite of compound can be identified by technology known to art, and its activity can be retouched by such as the present invention
Adopt as stating and experimentally characterize.Such product can be by passing through oxidation, reduction, water to drug compound
Solution, amidated, desamido-effect, esterification, degreasing, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes compound
Metabolite, be fully contacted metabolite produced by a period of time including by the compound of the present invention and mammal.
" pharmaceutically acceptable salt " used in the present invention refers to organic salt and the inorganic salt of the compound of the present invention.Medicine
On, acceptable salt is known to us at art, such as document: S.M.Berge et al., describe
pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,
1977,66:1-19. it is described.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 hydrochlorate, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid
Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document
Additive method such as ion exchange obtain these salt.Other pharmaceutically acceptable salts include adipate, alginate, resist
Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, Camphora hydrochlorate, Camphora 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, bitterness
Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through
The salt that suitable alkali obtains includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any
The quaternary ammonium salt that the compound of the group of comprised N is formed.Water solublity or oil-soluble or dispersion product can be turned into by quaternary ammonium
With obtaining.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt farther includes to fit
When, amine cation that nontoxic ammonium, quaternary ammonium salt and gegenions are formed, such as halogenide, hydroxide, carboxylate, sulphuric acid
Compound, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the association that the compound of one or more solvent molecule and the present invention is formed
Thing.The solvent forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second
Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.
Any disease or disease " treated " in term as used in the present invention, and some embodiment middle fingers improve disease wherein
Disease or disease (i.e. slow down or stop or palliate a disease or the development of its at least one clinical symptoms).In other embodiments
In, " treatment " refers to relax or improve at least one body parameter, including the body parameter may not discovered by patient.At another
In a little embodiments, " treatment " refers to (such as stablize perceptible symptom) from health or physiologically (such as stablize health
Parameter) or above-mentioned two aspect regulation disease or diseases.In other embodiments, " treat " and refer to prevention or postpone disease or disease
The outbreak of disease, occur or deteriorate.
Pharmaceutically useful acid-addition salts can be formed with mineral acid and organic acid, such as acetate, aspartate, benzoic acid
Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination
Thing/hydrochlorate, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid
Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, Fructus Mali pumilae
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.
Such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc. can be included by its derivative mineral acid obtaining salt.
Can by its derivative organic acid obtaining salt include such as acetic acid, propanoic 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, ethyl sulfonic 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 be included by its derivative inorganic base obtaining salt, the metal of the I race of such as ammonium salt and periodic chart to XII race.?
In some embodiment, this salt is derived from sodium, potassium, ammonium, calcium, magnesium, ferrum, silver, zinc and copper;Particularly suitable salt include ammonium, potassium,
Sodium, calcium and magnesium salt.
Can be included that primary amine, secondary amine and tertiary amine, substituted amine include naturally occurring by its derivative organic base obtaining salt
Substituted amine, cyclic amine, deacidite etc..Some organic amine includes, such as, and 2-aminopropane., benzathine benzylpenicillin
(benzathine), choline salt (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine
And trometamol.
The officinal salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety with conventional chemical processes.
It is said that in general, such salt can free acid form Yu stoichiometry by making these compounds suitable alkali (as Na, Ca,
The hydroxide of Mg or K, carbonate, bicarbonate etc.) reaction, or by making free alkali form and the chemistry of these compounds
The suitable acid reaction of metered amount is prepared.Such reaction is generally carried out in water or organic solvent or the mixture of the two.
Usually, in the case of suitably, need to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile.?
Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company,
Easton, Pa., (1985);" pharmaceutical salts handbook: character, select and apply (Handbook of Pharmaceutical
Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim,
Germany, 2002) list of the suitable salt of other can be found in.
It addition, compound disclosed by the invention, including their salt, it is also possible to their hydrate forms or comprise it
The form of solvent (such as ethanol, DMSO, etc.) obtains, for their crystallization.The present invention comes into the open compound can be with pharmacy
Upper acceptable solvent (including water) inherently or passes through design forming solvate;Therefore, it is contemplated that include solvation
And unsolvated form.
Any structural formula that the present invention is given be also intended to represent these compounds not by isotope enrichment form and with
The form of position element enrichment.The compound of isotope enrichment has the structure of the formula description that the present invention provides, except one or many
Individual atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes in the compounds of this invention can be introduced
Including the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, 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, such as, and its
In there is radiosiotope, as3H、14C and18Those compounds of F, or wherein there is non radioactive isotope, as2H and13C.The compound of such isotope enrichment can be used for metabolism research and (uses14C), kinetics research (uses such as2H or3H), detection or imaging technique, such as positron emission tomography (PET) or include medicine or substrate tissue measure of spread
SPECT (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
Embodiment and the preparation process suitable isotope labeling reagent of described use in the routine techniques known or the present invention substitute former
Carry out used unmarked reagent to prepare.
Additionally, higher isotope particularly deuterium is (i.e.,2H or D) replacement can provide some treat advantage, these advantages are
Brought by metabolic stability is higher.Such as, Half-life in vivo increases or volume requirements reduces or therapeutic index obtains improving band
Come.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 particularly deuterium can be defined by the isotope enrichment factor.Term used in the present invention " with
Position element enrichment factor " refer to specified ratio between isotopic isotope abundance and natural abundance.If chemical combination of the present invention
The substituent group of thing is designated as deuterium, and this compound has at least 3500 (at each appointment D-atom for each D-atom specified
The deuterium of 52.5% mixes), at least 4000 (deuterium of 60% mixes), at least 4500 (deuterium of 67.5% mixes), at least 5000 (75%
Deuterium mix), at least 5500 deuterium of 82.5% (mix), at least 6000 (deuterium of 90% mixes), at least 6333.3 (deuteriums of 95%
Mix), at least 6466.7 deuterium of 97% (mix), at least 6600 (deuterium of 99% mixes) or at least 6633.3 (deuteriums of 99.5%
Mix) the isotope enrichment factor.The pharmaceutically useful solvate of the present invention includes that wherein recrystallisation solvent can be that isotope replaces
Such as D2O, acetone-d6、DMSO-d6Those solvates.
On the other hand, the present invention relates to prepare formula (I), compound that (II), (IIa), (IIb) and (III) are comprised
Intermediate.
On the other hand, the present invention relates to the compound that formula (I), (II), (IIa), (IIb) and (III) is comprised preparation,
Separate and the method for purification.
On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition comprises the compounds of this invention, pharmacy
Upper acceptable carrier, excipient, diluent, adjuvant, solvent, or combinations thereof.At some embodiments, pharmaceutical composition
Can be liquid, solid, semi-solid, gel or spray-type.
" combine " fixed Combination represented in single dosage unit form or the medicine box of the part for combined administration, its
The middle present invention comes into the open compound and combined partner can be in same time individual application or can be at a certain time interval
Use respectively, particularly make associating companion show cooperation, such as synergism.As the term is employed herein " co-administered " or
" administering drug combinations " etc. are intended to include the single individuality (such as patient) that selected COMBINATION OF THE INVENTION is applied to need it, and are intended to
Including wherein material without going through identical route of administration or the therapeutic scheme used simultaneously." medicine group as the term is employed herein
Close product " represent the product mixed by more than one active component or obtained by combination, and both included the fixing of active component
Combination also includes non-fixed combinations.Term " fixing joint " represent the active component such as present invention come into the open compound and COMBINATION OF THE INVENTION with
The form of single entities or dosage is applied to patient simultaneously.Term " on-fixed associating " represents that the active component such as present invention comes into the open
Compound and COMBINATION OF THE INVENTION all as corpus separatum simultaneously, common or limit ground without special time and be successively applied to patient, wherein should
It is applied in the treatment effect level providing two kinds of compounds in the patient.The latter applies also for HAART, such as, use 3
Plant or more kinds of active component.
It should be noted that the term " suppression HCV virus protein " in the present invention should be interpreted broadly, it had both included suppression
The expression of HCV virus protein, also includes the activity level suppressing HCV virus protein, the assembling of virus and emission levels.Its
In, HCV protein expression level includes but not limited to: the translation skill of viral protein gene, the post translational modification level of albumen, son
Levels of replication for hereditary material etc..
The description of the compounds of this invention
The present invention relates to the method that HCV-Ab IgG infects.HCV infection is had and well presses down by the compounds of this invention or pharmaceutical composition
Make and use.
On the one hand, the present invention relates to a kind of compound, it is compound shown in the compound shown in formula (I) or formula (I)
Stereoisomer, geometric isomer, tautomer, enantiomer, nitrogen oxides, hydrate, solvate, metabolism are produced
Thing, 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, cycloalkyl, heterocyclic radical, 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, agedoite, aspartic acid, glutamic acid, glutamine, proline, serine, to tyrosine, essence
Propylhomoserin, histidine, cysteine, glycine, sarcosine, N, N-dimethylglycine, homoserine, norvaline, the brightest ammonia
Acid, ornithine, homocysteine, homophenylalanin, phenylglycine, adjacent tyrosine, m-Tyrosine or hydroxyproline institute shape
The group become;
R1、R2、R3And R4It is each independently H, deuterium, alkyl, aryl alkyl, cycloalkyl, heterocyclic radical, heteroaryl or aryl;
Or R1、R2It is randomly formed 3-8 unit heterocycle, 3-8 unit carbocyclic ring, condensed-bicyclic with X-CH, condenses miscellaneous pair of miscellaneous dicyclo, spiral shell dicyclo or spiral shell
Ring;Or R3、R4With X1-CH is randomly formed 3-8 unit heterocycle, 3-8 unit carbocyclic ring, condensed-bicyclic, condenses miscellaneous dicyclo, spiral shell dicyclo or spiral shell
Miscellaneous dicyclo;
Each R5And R6Independently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, alkyl, haloalkyl,
Thiazolinyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aryl, heteroaryl, aryl alkyl, alkoxyalkyl, alkoxyl, aryl
Amino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heteroaryl epoxide, heteroaryl alkyl, alkoxy aryl, heteroaryl
Base alkoxyl, heterocyclic radical epoxide, 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 group,
Deuteroalkyl, alkyl, haloalkyl, alkoxyl, thiazolinyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aryl, heteroaryl,
Aryl alkyl, alkoxyalkyl, heteroaryl alkyl, cycloalkyl-alkyl, cycloheteroalkylalkyl, arylamino, heteroaryl amino, aryl
Alkylamino, heteroarylalkylamino, heteroaryl epoxide, alkoxy aryl, heteroarylalkoxy, heterocyclic radical epoxide, 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-, heterocyclic radical alkylamino or aryloxy group;
Each R9And R10Independently be H, deuterium, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl, alkyl-OC
(=O)-, alkyl-C (=O)-, carbamoyl, alkyl-OS (=O)r-, alkyl-S (=O)rO-, alkyl-S (=O)r-or ammonia
Base sulfonyl;
Each f, n and t independently be 0,1,2,3 or 4;
M is 1,2,3 or 4;With
Each r independently be 0,1 or 2;
The following group of each of which: alkyl, alkoxyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl ,-C
(=O)-(CR8R8a)t-N(R9)-R10, a-amino acid group, 3-8 unit heterocycle, 3-8 unit carbocyclic ring, condensed-bicyclic, condense miscellaneous dicyclo,
The miscellaneous dicyclo of spiral shell dicyclo, spiral shell, haloalkyl, thiazolinyl, alkynyl, alkoxyalkyl, heteroaryl alkyl, cycloalkyl-alkyl, heterocyclic radical alkane
Base, arylamino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, aryloxy group, heteroaryl epoxide, alkoxy aryl,
Heteroarylalkoxy, heterocyclic radical epoxide, heterocyclylalkoxy, heterocyclylamino group, alkyl-OC (=O)-, alkyl-C (=O)-, ammonia
Base formoxyl, alkyl-OS (=O)r-, alkyl-S (=O)rO-, alkyl-S (=O)r-or amino-sulfonyl individually optionally by 1,
2,3 or 4 are selected from hydroxyl, deuterium, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl, alkylamino, alkylthio group, alkyl, halo
Alkyl, alkoxyalkyl, halogenated alkoxy alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, aryl
Amino, heteroaryl epoxide, heteroaryl alkyl, oxo (=O), carboxyl, the substituted alkoxyl of hydroxyl, hydroxyl substituted alkyl-C
(=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2-, hydroxyl substituted alkyl-S (=O)-, hydroxyl takes
Alkyl-the S (=O) in generation2-or the substituent group of the substituted alkoxyl of carboxyl replaced.
In certain embodiments, A is-O-,-S-,-NH-,-CH2-S-、-CH2-O-、-CH2-NH-、-O-CH2-、-NH-
CH2-、-S-CH2-or-CH2-CH2-。
In certain embodiments, each R5And R6Independently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyanogen
Base, C1-6Alkyl, C1-6Haloalkyl, C2-6Thiazolinyl, C2-6Alkynyl, C2-10Heterocyclic radical, C3-8Cycloalkyl, sulfydryl, nitro, C6-10Virtue
Base, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, C1-6Alkoxyl, C6-10Arylamino, C1-9Heteroaryl
Amino, C6-10Aryl C1-6Alkylamino, C1-9Heteroaryl C1-6Alkylamino, C1-9Heteroaryl epoxide, C1-9Heteroaryl C1-6Alkyl, C6-10
Aryl C1-6Alkoxyl, C1-9Heteroaryl C1-6Alkoxyl, C2-10Heterocyclic radical epoxide, C2-10Heterocyclic radical C1-6Alkoxyl, C2-10Heterocyclic radical
Amino, C1-6Alkyl acyl, C1-6Alkyl acyloxy, C1-6Alkoxyacyl, C2-10Heterocyclic radical C1-6Alkylamino or C6-10Aryloxy group.
In certain embodiments, each R5And R6Independently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyanogen
Base, C1-3Alkyl, C1-3Haloalkyl, C2-4Thiazolinyl, C2-4Alkynyl, C2-8Heterocyclic radical, C3-8Cycloalkyl, sulfydryl, nitro, C6-10Virtue
Base, C1-9Heteroaryl, C6-10Aryl C1-3Alkyl, C1-3Alkoxy C1-3Alkyl, C1-3Alkoxyl, C6-10Arylamino, C1-9Heteroaryl
Amino, C6-10Aryl C1-3Alkylamino, C1-9Heteroaryl C1-3Alkylamino, C1-9Heteroaryl epoxide, C1-9Heteroaryl C1-3Alkyl, C6-10
Aryl C1-3Alkoxyl, C1-9Heteroaryl C1-3Alkoxyl, C2-8Heterocyclic radical epoxide, C2-8Heterocyclic radical C1-3Alkoxyl, C2-8Heterocyclic radical ammonia
Base, C1-3Alkyl acyl, C1-3Alkyl acyloxy, C1-3Alkoxyacyl, C2-8Heterocyclic radical C1-3Alkylamino or C6-10Aryloxy group.
In certain embodiments, each R5And R6Independently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyanogen
Base, methyl, ethyl, propyl group, isopropyl, normal-butyl, the tert-butyl group, trifluoromethyl, methoxy, methoxyl group, ethyoxyl, ethylene
Base, pi-allyl, acetenyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenyl, phenyl epoxide, phenyl amino, sulfydryl or nitre
Base.
In certain embodiments, each R1、R2、R3And R4Independently be H, C1-6Alkyl, C6-10Aryl C1-6Alkyl, C3-10Cycloalkanes
Base, C2-10Heterocyclic radical, C1-9Heteroaryl or C6-10Aryl;Or R1、R2With X-CH be randomly formed 3-8 unit heterocycle, 3-8 unit carbocyclic ring,
C5-12Condensed-bicyclic, C5-12Condense miscellaneous dicyclo, C5-12Spiral shell dicyclo or C5-12The miscellaneous dicyclo of spiral shell;Or R3、R4With X1-CH is randomly formed 3-
8 yuan of heterocycles, 3-8 unit carbocyclic ring, C5-12Condensed-bicyclic, C5-12Condense miscellaneous dicyclo, C5-12Spiral shell dicyclo or C5-12The miscellaneous dicyclo of spiral shell;Wherein institute
The 3-8 unit heterocycle stated, 3-8 unit carbocyclic ring, C5-12Condensed-bicyclic, C5-12Condense miscellaneous dicyclo, C5-12Spiral shell dicyclo or C5-12The miscellaneous dicyclo of spiral shell is only
Stand and be optionally selected from H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, C by 1,2,3 or 41-6Alkyl, C1-6Alkyl halide
Base, C1-6Alkoxyl, 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 epoxide, C1-9Heteroaryl C1-6Alkyl, C3-8Cycloalkyl or C2-10Heterocycle
The substituent group of base is replaced.
In certain embodiments, R1、R2The heterocycle, condensed ring or the spiro ring system that are formed with Y-X-CH are selected from following minor structure
Formula:
In certain embodiments, wherein R3、R4With Y1-X1Heterocycle, condensed ring or the spiro ring system that-CH is formed is selected from following
Subformula:
In certain embodiments, each R15Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, C1-6Alkane
Base, C1-6Haloalkyl, C1-6Alkoxyl, C1-6Alkoxy C1-6Alkyl, C1-6Halogenated alkoxy C1-6Alkyl, C1-6Alkylamino, C1-6
Alkylthio group, C6-10Arylamino, C6-10Aryloxy group, C1-9Heteroaryl, C1-9Heteroaryl epoxide, C1-9Heteroaryl C1-6Alkyl, C3-8Ring
Alkyl or C2-10Heterocyclic radical.
In certain embodiments, each R15Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, C1-3Alkane
Base, C1-3Haloalkyl, C1-3Alkoxyl, C1-3Alkoxy C1-3Alkyl, C1-3Halogenated alkoxy C1-3Alkyl, C1-3Alkylamino, C1-3
Alkylthio group, C6-10Arylamino, C6-10Aryloxy group, C1-9Heteroaryl, C1-9Heteroaryl epoxide, C1-9Heteroaryl C1-3Alkyl, C3-8Ring
Alkyl or C2-10Heterocyclic radical.
In certain embodiments, each R15Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, methyl, second
Base, propyl group, 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 certain embodiments, each R9bIndependently be hydrogen, deuterium, C1-6Alkyl, C1-6Haloalkyl, 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, C2-10Heterocyclic radical or C3-8Cycloalkyl.
In certain embodiments, each R9bIndependently be hydrogen, deuterium, C1-3Alkyl, C1-3Haloalkyl, 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, C2-10Heterocyclic radical or C3-8Cycloalkyl.
In certain embodiments, each R9bIndependently be hydrogen, deuterium, methyl, ethyl, propyl group, isopropyl, trifluoromethyl, hydroxyl
Methyl, amino methyl, methoxy, ethoxyl methyl, phenyl methyl, phenyl, cyclopropyl, cyclobutyl, cyclopenta or hexamethylene
Base.
In certain embodiments, each R7、R7a、R7bAnd R9aIndependently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl,
Br, I, cyano group, C1-6Alkyl, C1-6Haloalkyl, C2-6Thiazolinyl, C2-6Alkynyl, C2-10Heterocyclic radical, C3-8Cycloalkyl, sulfydryl, nitro,
C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C3-8Cycloalkyl
C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl, C6-10Arylamino, C1-9Heteroaryl amino, C6-10Aryl C1-6Alkylamino, C1-9Heteroaryl
Base C1-6Alkylamino, C1-9Heteroaryl epoxide, C6-10Aryl C1-6Alkoxyl, C1-9Heteroaryl C1-6Alkoxyl, C2-10Heterocyclic radical epoxide,
C2-10Heterocyclic radical C1-6Alkoxyl, 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
Heterocyclic radical C1-6Alkylamino or C6-10Aryloxy group;Independently be 0,1 or 2 with each r.
In certain embodiments, each R7、R7a、R7bAnd R9aIndependently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl,
Br, I, cyano group, C1-3Alkyl, C1-3Haloalkyl, C2-4Thiazolinyl, C2-4Alkynyl, C2-8Heterocyclic radical, C3-8Cycloalkyl, sulfydryl, nitro,
C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-3Alkyl, C1-3Alkoxy C1-3Alkyl, C1-9Heteroaryl C1-3Alkyl, C3-8Cycloalkyl
C1-3Alkyl, C2-8Heterocyclic radical C1-3Alkyl, C6-10Arylamino, C1-9Heteroaryl amino, C6-10Aryl C1-3Alkylamino, C1-9Heteroaryl
Base C1-3Alkylamino, C1-9Heteroaryl epoxide, C6-10Aryl C1-3Alkoxyl, C1-9Heteroaryl C1-3Alkoxyl, C2-8Heterocyclic radical epoxide,
C2-8Heterocyclic radical C1-3Alkoxyl, 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-、C2-8Miscellaneous
Ring group C1-3Alkylamino or C6-10Aryloxy group;Independently be 0,1 or 2 with each r.
In certain embodiments, each R7、R7a、R7bAnd R9aIndependently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl,
Br, I, cyano group, methyl, ethyl, vinyl, acetenyl, cyclopropyl or phenyl;1 or 2 is independently be with each r.
In certain embodiments, wherein Y and Y1It is each independently H, deuterium, C1-6Alkyl, C3-8Cycloalkyl, C2-10Heterocyclic radical,
C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl or-C (=O)-(CR8R8a)t-N(R9)-R10。
In certain embodiments, each R8And R8aIndependently be H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, C1-6Alkyl,
C1-6Deuteroalkyl, C1-6Haloalkyl, C2-6Thiazolinyl, C2-6Alkynyl, C2-10Heterocyclic radical, C3-8Cycloalkyl, sulfydryl, nitro, C6-10Virtue
Base C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C3-8Cycloalkyl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkane
Base, C6-10Arylamino, C1-9Heteroaryl amino, C6-10Aryl C1-6Alkylamino, C1-9Heteroaryl C1-6Alkylamino, C1-9Heteroaryl oxygen
Base, C6-10Aryl C1-6Alkoxyl, C1-9Heteroaryl C1-6Alkoxyl, C2-10Heterocyclic radical epoxide, C2-10Heterocyclic radical C1-6Alkoxyl,
C2-10Heterocyclylamino group, C1-6Alkyl acyl, C1-6Alkyl acyloxy, C1-6Alkoxyacyl, C1-6Alkyl sulphonyl, C1-6Alcoxyl
Base sulfonyl, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl epoxide, C1-6Alkyl sulphinyl epoxide, 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-、C2-10Heterocyclic radical C1-6Alkylamino or C6-10Aryloxy group.
In certain embodiments, each R8And R8aIndependently be H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, C1-4Alkyl,
C1-4Deuteroalkyl, C1-4Haloalkyl, C2-4Thiazolinyl, C2-4Alkynyl, C2-8Heterocyclic radical, C3-8Cycloalkyl, sulfydryl, nitro, C6-10Virtue
Base C1-3Alkyl, C1-3Alkoxy C1-3Alkyl, C1-9Heteroaryl C1-3Alkyl, C3-8Cycloalkyl C1-3Alkyl, C2-8Heterocyclic radical C1-3Alkane
Base, C6-10Arylamino, C1-9Heteroaryl amino, C6-10Aryl C1-3Alkylamino, C1-9Heteroaryl C1-3Alkylamino, C1-9Heteroaryl oxygen
Base, C6-10Aryl C1-3Alkoxyl, C1-9Heteroaryl C1-3Alkoxyl, C2-8Heterocyclic radical epoxide, C2-8Heterocyclic radical C1-3Alkoxyl, C2-8
Heterocyclylamino group, C1-3Alkyl acyl, C1-3Alkyl acyloxy, C1-3Alkoxyacyl, C1-3Alkyl sulphonyl, C1-3Alkoxyl sulphur
Acyl group, C1-3Alkyl sulphinyl, C1-3Alkyl sulphonyl epoxide, C1-3Alkyl sulphinyl epoxide, 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-、C2-8Heterocyclic radical C1-3Alkylamino or C6-10Aryloxy group.
In certain embodiments, each R8And R8aIndependently be H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, methyl, second
Base, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, deuterated methyl, deuterated ethyl, deuterated propyl group, deuterated isopropyl,
Methoxyl group, ethyoxyl, isopropoxy, methoxy, 1-methoxy ethyl, 2-methoxy ethyl, 1-methoxy-propyl, 2-first
Epoxide propyl group, 3-methoxy-propyl, phenyl, pyranose, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, trifluoromethyl, ethylene
Base, pi-allyl, acetenyl, morpholinyl, sulfydryl, nitro, benzyl or anilino-.
In certain embodiments, R9And R10It is each independently H, deuterium, C1-6Alkyl, C3-8Cycloalkyl, C2-10Heterocyclic radical,
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)r-or amino-sulfonyl.
In certain embodiments, R9And R10Be each independently H, deuterium, methyl, ethyl, isopropyl, normal-butyl, isobutyl group,
Sec-butyl, the tert-butyl group, methyl-OC (=O)-, ethyl-OC (=O)-, propyl group-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 certain embodiments, t is 0,1,2,3 or 4.
In certain embodiments, each r independently be 0,1 or 2.
In certain embodiments, each n1And n2Independently be 1,2,3 or 4.
In certain embodiments, the compounds of this invention has the structure shown in formula (II), (IIa), (IIb) or (III), or
Structural upright isomer shown in formula (II), (IIa), (IIb) or (III), geometric isomer, tautomer, enantiomerism
Body, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug:
In certain embodiments, the compounds of this invention its there is structure shown below:
Or it is its stereoisomer, geometric isomer, tautomer, enantiomer, nitrogen oxides, hydrate, molten
Agent compound, metabolite, pharmaceutically acceptable salt or prodrug.
(in this article, form of presentation is " shown in formula (I), (II), (IIa), (IIb) or (III) for the compound of the present invention
The stereoisomer of compound, geometric isomer shown in compound or formula (I), (II), (IIa), (IIb) or (III), make a variation mutually
Structure body, enantiomer, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable salt or front
Medicine "), may be used for producing medical product treatment acute and chronic HCV infection, described in the invention including those.Further, originally
The compound of invention may be used for producing the goods of HCV-Ab IgG.Thus, the compound of the present invention may be used for producing a kind of pharmaceuticals
It is used for alleviating, stop, control or treat the disease that HCV is mediated.Thus, the compound of the present invention can serve as pharmaceutical composition
Active component, this pharmaceutical composition can include the compound representated by formula (I), (II), (IIa), (IIb) or (III), also
At least one pharmaceutically acceptable carrier, adjuvant or diluent can be comprised further.
Specifically, salt is pharmaceutically acceptable salt.Term " pharmaceutically acceptable " is meant that, the thing used
Matter or compositions must be to be suitable on chemistry or toxicity mating with other components of composition preparation and the mammal for treating
's.Those skilled in the art can be carried out specifically chosen " medicine according to using the object such as people of other components and used treatment
Acceptable on " material or compositions.
The salt of the compound of the present invention also includes for preparation or purification formula (I), (II), (IIa), (IIb) or (III) institute
Show the enantiomer that compound shown in the intermediate of compound or formula (I), (II), (IIa), (IIb) or (III) separates
Salt, but it is not necessarily pharmaceutically acceptable salt.
If the compound of the present invention is alkaline, the most conceivable salt can by provide on document any suitably
Method prepares, and such as, uses mineral acid or organic acid.Wherein, the example of mineral acid includes but not limited to hydrochloric acid, hydrogen bromine
Acid, sulphuric acid, nitric acid and phosphoric acid etc..The example of organic acid includes but not limited to acetic acid, maleic acid, succinic acid, mandelic acid, rich horse
Acid, malonic acid, acetone acid, oxalic acid, glycolic and salicylic acid;Pyrans saccharic acid, such as glucuronic acid and galacturonic acid;α-hydroxyl
Acid, such as citric acid and tartaric acid;Aminoacid, such as aspartic acid and glutamic acid;Aromatic acid, such as benzoic acid and cinnamic acid;Sulphur
Acid, such as p-methyl benzenesulfonic acid, ethyl sulfonic acid etc..
If the compound of the present invention is acid, the most conceivable salt can be prepared by suitable method, e.g.,
Use inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide or alkaline earth metal hydroxide, etc.
Deng.Suitably salt includes, but is not limited to, the organic salt obtained from aminoacid, and such as glycine and arginine, ammonia, such as primaquine, secondary
Ammonia and tertiary ammonia, and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtain from sodium, calcium, potassium, magnesium, manganese, ferrum, copper, zinc, aluminum and lithium
Inorganic salt.
The compositions of the compounds of this invention, preparation and administration
Described pharmaceutical composition comprises the compound of any present invention.This pharmaceutical composition can also comprise further
Pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.Described pharmaceutical composition may be used for controlling
Treat hepatitis C virus (HCV) to infect or hepatitis C disease.
Described pharmaceutical composition comprises the medicine of HCV-Ab IgG further.The medicine of described HCV-Ab IgG can be any of not
It is same as other of the compounds of this invention for the medicine of HCV-Ab IgG.For example, it is possible to be interferon, ribavirin, interleukin-22, Bai Jie
Element 6, interleukin 12, promotion produce 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, EBP520, TVR, erlotinib, his Wei of Dacca, the beautiful Wei of department, 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 a combination thereof;In certain embodiments, described interferon is Interferon Alpha-2b, the interferon-ALPHA of Pegylation, interference
Element α-2a, the Intederon Alpha-2a of Pegylation, compound alpha-interferon, interferon gamma or a combination thereof.Described pharmaceutical composition, enters
One step comprises at least one HCV inhibitor, and described HCV inhibitor is used for suppressing HCV reproduction process and/or suppression HCV virus egg
White function;Described HCV reproduction process includes that HCV enters, HCV shells, HCV translation, HCV duplication, HCV assembling or HCV release;
Described HCV virus protein is selected from metalloproteases, NS2, NS3, NS4A, NS4B, NS5A or NS5B, and HCV virus replication
Required internal ribosome inlet point (IRES) and inosine monophosphate dehydrogenase (IMPDH).
When can be used for treatment, the compounds of this invention of therapeutically effective amount, especially formula (I), (II), (IIa), (IIb)
Or (III) compound and pharmaceutically acceptable salt thereof can give as unprocessed chemical drugs, it is alternatively arranged as drug regimen
The active component of thing provides.Therefore, present invention also provides for pharmaceutical composition, and this pharmaceutical composition 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
Be enough to demonstrate the total amount of each active component of significant patient benefit (such as viral load minimizing).Individually live when using
When property composition is individually dosed, this term only refers to this composition.When combination application, and though this term then refer to combination, successively or with
Time be administered time, all cause the combined amount of the active component of therapeutic effect.The compounds of this invention, especially formula (I), (II),
(IIa), (IIb) or (III) compound and pharmaceutically acceptable salt thereof are described above.From compatible with other compositions of preparation and
To its receiver harmless in the sense that from the point of view of, carrier, diluent or excipient must be acceptable.According to present invention
On the other hand, also providing for the method for preparing pharmaceutical preparation, the method includes 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 mixing.Term used in the present invention " pharmaceutically acceptable " refers to such compound, former
Material, compositions and/or dosage form, they are in the range of rational medicine judges, it is adaptable to patient tissue contacts and without excessively poison
Property, zest, allergy or the other problems symmetrical with rational interests/Hazard ratio and complication, and be both effective to
Determine purposes.
Pharmaceutical preparation can be in unit dosage forms, and each unit dose contains the active component of scheduled volume.The change of present invention
The dosage level of compound is between about 0.01 mg/kg (mg/kg) body weight/day and about 250 mg/kg body weight/day, excellent
Selected introductions, between about 0.05mg/kg body weight/day and about 100mg/kg body weight/day, usually are used for preventing or treating with monotherapy
The disease of HCV mediation.Generally can be by every day about 1 to about 5 time or the drug regimen giving present invention as continuous infusion
Thing.This kind of dose regimen can be used as long-term or short-term therapy.The amount of active component to prepare single dosage form is mixed with carrier material
By according to disease to be treated, the order of severity of disease, administration time, route of administration, the discharge rate of compound used therefor, treatment
Time and patient age, sex, body weight and situation and change.Preferably unit dosage forms is the day containing hereinbefore active component
Dosage or divided dose or the unit dosage forms of its appropriate fraction.The available low dose being already clearly below compound optimal dose starts to control
Treat.Hereafter, escalated dose is carried out with less increment until reaching optimum efficiency in this case.It is said that in general, most desirably
Give the concentration level of compound be generally can anti-virus aspect provide effective result without regard to cause any harmful or
Poisonous side effect.
When the compositions of present invention comprise the compound of present invention and one or more other treatment medicines or
During the combination of prophylactic agent, the dosage level of compound and other medicine, generally in monotherapy scheme, accounts for normal administration
The about 10-150% of dosage, more preferably accounts for the about 10-80% of bio-occlusion pharmaceutical quantities.Pharmaceutical preparation is suitable to by any suitable way
Footpath is administered, such as by oral (including oral cavity or Sublingual), rectum, nose, locally (include oral cavity, Sublingual or percutaneous), vagina or
Parenteral (in including subcutaneous, Intradermal, intramuscular, intraarticular, intrasynovial, breastbone, in sheath, intralesional, intravenous or corium bet
Penetrate or infusion) approach.This kind of preparation can be prepared, such as by by active component and load by any known method of art of pharmacy
Body or excipient mixing.Preferred oral is administered or drug administration by injection.
The pharmaceutical preparation being suitable to oral administration is provided by independent unit, such as capsule or tablet;Powder or granule;
Solution in aqueous or non-aqueous liquid or suspensoid;Edible foam formulations or foaming preparations (whip);Or oil-in-water breast
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 pharmaceutically can connect
The oral, non-toxic inert carrier (such as ethanol, glycerol, water etc.) being subject to mixes mutually.By compound powder being broken into suitable fine chi
Very little, and with by as pulverize pharmaceutical carrier (edible saccharide such as such as starch or mannitol etc.) mixing prepare powder.Also
Correctives, preservative, dispersant and coloring agent can be there is.
By preparing pulverulent mixture as above, and it is loaded in the gelatin shell of shaping, prepares capsule.At dress
Before filling out operation, can be by fluidizer and lubricant (such as colloidal silica, Pulvis Talci, magnesium stearate, calcium stearate or solid-state
Polyethylene Glycol) it is added in pulverulent mixture.Also can add when the lower capsule of clothes by improve medicine utilizability disintegrating agent or
Solubilizing agent (such as agar, calcium carbonate or sodium carbonate).
When needing in addition or be required, it is possible to suitable binding agent, lubricant, disintegrating agent and coloring agent are mixed mixture
In.Suitably binding agent includes starch, gelatin, natural sugar (such as glucose or beta lactose), corn sweetener, natural and synthesis
Natural gum (such as Radix Acaciae senegalis, tragakanta or sodium alginate), carboxymethyl cellulose, Polyethylene Glycol etc..For these dosage forms
Lubricant includes enuatrol, sodium chloride etc..Disintegrating agent includes, but are not limited to starch, methylcellulose, agar, Bentonite, xanthan
Glue etc..Such as, by making pulverulent mixture, pelletize or pre-tabletting, add lubricant and disintegrating agent, tabletted, thus make
Piece agent.By the compound suitably pulverized and diluent as described above or base material, optional and binding agent (such as carboxymethyl fibre
Dimension element, alginate, gelatin or polyvinylpyrrolidone), dissolve inhibitor (such as paraffin), absorption accelerator (quaternary salt) and/or
Absorbent (such as Bentonite, Kaolin or dicalcium phosphate) mixes, and prepares pulverulent mixture.Useful binders (such as syrup, shallow lake
Slurry, mucialga of arabic gummy (acadiamucilage) or cellulosic material or polymeric material solution) pressurize after moistening and sieve, by powder
Shape granulating mixture.The alternative method pelletized is, can be by pulverulent mixture by tablet machine, and result is the best by formation
Agglomerate smashes and makes granule.Can be by adding stearic acid, stearate, Pulvis Talci or mineral oil make particle lubrication to prevent from gluing
On the punch die of tablet machine.Then by the mixture tabletted through lubrication.The compound of present invention also can be with free stream
Dynamic inert carrier mixing, it is not necessary to just can tabletted by granulation or pre-tableting step.Can provide transparent or opaque by
The protectiveness bag that Lac seal coat, sugar-coat or polymeric material clothing and waxiness polishing clothing (polish coating of wax) form
Clothing material.Can be added to dyestuff in these coating materials distinguish different unit dose.
Oral liquid such as solution, syrup and elixir can be prepared with dosage unit form, thus specified rate contains
There is the compound of scheduled volume.Syrup can be prepared by being dissolved in suitably seasoned aqueous solution by compound, and elixir can lead to
Cross use non-toxic vehicle to prepare.Also can add solubilizing agent and emulsifying agent (such as ethoxylated isostearyl alcohols and polyoxyethylene mountain
Pears alcohol ether), preservative, taste masking additive (such as Oleum menthae or natural sweetener or saccharin or other artificial sweeteners) etc..
If appropriate, the dosage unit preparations micro encapsulation of oral administration can be used for.Also preparation can be made and prolong
Time or sustained release, such as by coating or be embedded in the microparticle material such as polymer, wax.
The compounds of this invention, especially formula (I), (II), (IIa), (IIb) or (III) compound and pharmaceutically can connect
The salt being subject to can give with liposome delivery systems, such as small unilamellar vesicle, big unilamellar liposome and multilamellar liposome.Lipid
Body can be made up of multiple phospholipid (such as cholesterol, octadecylamine or phosphatidylcholine).
The compounds of this invention, especially formula (I), (II), (IIa), (IIb) or (III) compound and pharmaceutically can connect
The salt being subject to also can pass medicine by using monoclonal antibody as single carrier (compound molecule is coupled).Compound also may be used
With as can the soluble polymer coupling of target medicine carrier.This base polymer can include that polyvinylpyrrolidone, pyrans are common
Polymers, poly-hydroxypropyhnethacrylamide phenol, polyhydroxyethylaspart or the polyoxygenated replaced by palmitoyl residues
Ethylene polylysine.Additionally, compound can be with a class Biodegradable polymeric coupling, for reaching the controlled release of medicine, this
Base polymer such as polylactic acid, poly-epsilon-caprolactone, poly butyric, poe, polyacetals, poly-dihydropyran, paracyanogen base third
Olefin(e) acid ester and the cross-linked copolymer of hydrogel or amphipathic nature block polymer.
The pharmaceutical preparation being suitable to percutaneous dosing can be as discrete patch (discrete patch) to protect in a long time
Hold and receiver's epidermis close contact.Such as, active component can be passed medicine by by iontophoresis patch, generally can be found in
Pharmaceutical Research 1986,3(6),318。
The pharmaceutical preparation being suitable to topical can be made into ointment, ointment, suspensoid, lotion, powder, solution, paste
Agent, gel, spray, aerosol, oil formulation or transdermal patch.
The pharmaceutical preparation being suitable to rectally can be as suppository or as enema offer.
The pharmaceutical preparation (wherein carrier is solid) being suitable to nose administration includes that particle diameter is such as 20-500 micrometer range
Pulvis grossus, by being administered in snuffing mode, is i.e. quickly sucked from close to the pulvis grossus container of nose by nasal passage.Wherein carry
Body is liquid, be adapted as nasal mist or appropriate formulation that nasal drop is administered includes aqueous solution agent or the oil of active component
Property solution.
Be suitable to the pharmaceutical preparation by inhalation and include minuteness particle powder (dust) or mist agent (mist), can use not
Dosage compresed gas aerosol, nebulizer, insufflator or other matters with type metering deliver the device of aerosol spray
Middle preparation.
The pharmaceutical preparation being suitable to vagina administration can be with vaginal suppository, vagina plug, ointment, cream, gel, paste, foam
Agent or spray provide.
Be suitable to the pharmaceutical preparation of parenteral and include aqueous and non-aqueous sterile injection solution and aqueous and non-aqueous
Sterile suspensions, aqueous and non-aqueous sterile injection solution can contain antioxidant, buffer agent, antibacterial and make described preparation
The solute isotonic with receptor's blood waiting, aqueous and non-aqueous sterile suspensions can include suspending agent and thickening agent.Preparation is permissible
Unit dose or multi-dose container provide, and the peace such as sealed is triumphant and bottle, and under the conditions of lyophilization (lyophilizing) can be saved in,
Only need to add sterile liquid carrier, such as water for injection before use.The injection solution and the suspensoid that face used time configuration can be by
Prepared by sterile powder injection, granule and tablet.
It will be appreciated that in addition to the composition being particularly mentioned above, preparation also includes relevant with described preparation type
Other composition commonly used in the art, this kind of preparation being for example suitable for oral administration can include correctives.
The compounds of this invention and the purposes of pharmaceutical composition
The invention provides compound or the pharmaceutical composition purposes in preparing medicine of the present invention, described medicine can
For suppression HCV reproduction process and/or the function of suppression HCV virus protein;Described HCV reproduction process include HCV enter,
HCV shelling, HCV translation, HCV duplication, HCV assemble or HCV release;Described HCV virus protein selected from metalloproteases, NS2,
NS3, NS4A, NS4B, NS5A or NS5B, and the internal ribosome inlet point (IRES) required for HCV virus replication and inosine
Monophosphate dehydrogenase (IMPDH).Arbitrary compound of the present invention or pharmaceutical composition may be used for treating hepatitis C virus
(HCV) infection or hepatitis C disease.
Comprise the compounds of this invention or the Therapeutic Method of pharmaceutical composition administration, farther include patient is administered other
HCV medicine, thus, it is possible to carry out therapeutic alliance, wherein said HCV-Ab IgG by the compound of the present invention and other anti-HCV medicaments
Medicine be that interferon, ribavirin, interleukin-22, interleukin 6, interleukin 12, promotion produce 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, EBP520, TVR, erlotinib, his Wei, department of Dacca
A 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
Pool 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 a combination thereof.Wherein said interferon be Interferon Alpha-2b, the interferon-ALPHA of Pegylation,
Intederon Alpha-2a, the Intederon Alpha-2a of Pegylation, compound alpha-interferon, interferon gamma or a combination thereof.
And comprise the compounds of this invention or the Therapeutic Method of pharmaceutical composition administration, comprise other HCV-Ab IgG medicines further
The administration of thing, wherein, other anti-HCV medicaments can be with the compounds of this invention or its pharmaceutical composition administering drug combinations, of the present inventionization
Compound or pharmaceutical composition are as single dosage form, or separate compound or pharmaceutical composition are as a part for multi-pharmaceutics.Its
He can be administered simultaneously with the compounds of this invention or not be administered simultaneously by anti-HCV medicament.The situation of the latter, administration can be staggered and be carried out
As 6h, 12h, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months are carried out.
The compound of the present invention or " effective dose " of pharmaceutically acceptable compositions or " effective dose " refer to process or
Alleviate the effective dose that one or more present invention is previously mentioned the severity of disease.The method according to the invention, compound and combination
Thing can be any dosage and any route of administration is efficiently used for the order of severity that processes or palliate a disease.Required standard
Situation according to patient is changed by true amount, and this depends on race, the age, the generic condition of patient, the order of severity of infection,
Special factor, administering mode, etc..Compound or compositions can with one or more other therapeutic agents administering drug combinations, as
The present invention is discussed.
General building-up process
Usually, the compound of the present invention can be prepared by method described in 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
Execute example for being further illustrated by present disclosure.
Those skilled in the art will realize that: chemical reaction described in the invention can be used to prepare perhaps suitably
Other compounds of many present invention, and it is considered as the model in the present invention for other method of the compound of preparing the present invention
Within enclosing.Such as, the synthesis according to the compound of those non-illustrations of the present invention can be successfully by those skilled in the art
Completed by method of modifying, as group is disturbed in suitable protection, by utilizing reagent known to other except described in the invention
, or reaction condition is made the amendment of some routines.It addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged
Ground is applicable to the preparation of other compounds of the present invention.
The embodiments described below, unless other aspects show all of temperature and are set to degree Celsius.Reagent is bought in business
Product supplier such as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical
Company, the most not through being further purified, unless other aspects show during use.General reagent is western Gansu Province chemical industry from Shantou
Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, dragon chemistry examination is risen in Qingdao
Agent company limited, and Haiyang Chemical Plant, Qingdao is commercially available.
Anhydrous tetrahydro furan, dioxane, toluene, ether are to be dried to obtain through metallic sodium backflow.Anhydrous methylene chloride
It is to be dried to obtain through calcium hydride backflow with chloroform.Ethyl acetate, petroleum ether, normal hexane, DMAC N,N' dimethyl acetamide and N, N-
Dimethylformamide is to be dried in advance through anhydrous sodium sulfate to use.
Hereinafter reaction is usually and overlaps a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects
Show), reaction bulb the most suitable rubber closure, substrate is squeezed into by syringe.Glass drying oven is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum with
CDC13、DMSO-d6、CD3OD or acetone-d6For solvent (report in units of ppm), with TMS (0ppm) or chloroform (7.25ppm)
As reference standard.When multiplet occurs when, the abbreviation by following for use: s (singlet, unimodal), d (doublet, double
Peak), t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, wide
Peak), dd (doublet of doublets, two bimodal), dt (doublet of triplets, double triplets).Coupling is normal
Number, represents with hertz (Hz).
By outfit G1312A binary pump and a G1316A TCC, (column temperature is maintained at 30 to Algorithm (MS) data
DEG C) the spectrogrph of Agilent 6320 series LC-MS measure, G1329A automatic sampler and G1315B DAD detector
Being applied to analyze, ESI source is applied to LC-MS spectrogrph.
Algorithm (MS) data are by being equipped with G1311A quaternary pump and G1316A TCC (column temperature is maintained at 30 DEG C)
The spectrogrph of Agilent 6120 series LC-MS measure, G1329A automatic sampler and G1315D DAD detector should
For analyzing, ESI source is applied to LC-MS spectrogrph.
Both the above spectrogrph is provided with Agilent Zorbax SB-C18 post, and specification is 2.1 × 30mm, 5 μm.Note
Beam is long-pending is to be 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.Flowing be mutually 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure water-soluble
Liquid (phase B).Condition of gradient elution is as shown in table 1:
Table 1
Compound purification is evaluated by Agilent 1100 series of high efficiency liquid chromatograph (HPLC), wherein UV detection
At 210nm and 254nm, Zorbax SB-C18 post, specification is 2.1 × 30mm, 4 μm, 10 minutes, and flow velocity is 0.6mL/min,
(0.1% aqueous formic acid) of (the 0.1% formic acid acetonitrile solution) of 5-95%, column temperature is maintained at 40 DEG C.
The use of brief word below runs through the present invention:
AlCl3Aluminum chloride
AcOK potassium acetate
AcOH acetic acid
Ac2O acetic anhydride
BBr3Boron tribromide
Boc tert-butoxycarbonyl
n-BuNH2N-butylamine
CuBr2Copper bromide
CH3CN acetonitrile
CDCl3Deuterochloroform
CH3COONH4,NH4OAc ammonium acetate
CH3COCl chloroacetic chloride
DCM dichloromethane
DIPEA diisopropyl ethyl amine
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
DMSO-d6Deuterated dimethyl sulfoxide
DMAP DMAP
DDQ 2,3-bis-chloro-5,6-dicyano-1,4-benzoquinone
EtOH ethanol
Et3N triethylamine
EtOAc, EA ethyl acetate
EDCI 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride
EtOH/H2O ethanol and aqueous mixtures
Et3SiH triethyl silicane
FBS hyclone
G gram
H, hr hour
H2O water
HCl hydrogen chloride
The ethyl acetate solution of HCl/EtOAc hydrogen chloride
H2SO4Sulphuric acid
K2CO3Potassium carbonate
KNO3Potassium nitrate
Na2S2O4Sodium thiosulfate
Na2CO3Sodium carbonate
NH4F ammonium fluoride
MnO2Manganese dioxide
MeOH methanol
Ml, mL milliliter
Mmol mM
PE petroleum ether
Py pyridine
Pd palladium
Pd(dppf)2Cl2Double (diphenylphosphine) ferrocene of 1,1'-] palladium chloride
Pd(dppf)Cl2·CH2Cl2Double (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 layer chromatography
THF oxolane
TMSCl trim,ethylchlorosilane
TMS TMS
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 under the effect of alkali, and compound s-2 bromination obtains compound s-3, chemical combination
Thing s-3 reacts with compound s-4 under the effect of alkali and obtains compound s-5, and compound s-5 and ammonium acetate cyclization obtain compound
S-6, compound s-6 oxidation obtains compound s-7, and compound s-7 deprotection obtains 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 effect of reducing agent, and it is de-that compound s-12 acetylation obtains compound s-13, compound s-13
Methyl obtains compound s-14, compound s-14, and under the effect of alkali and trifluoromethanesulfonic acid anhydride reactant obtains compound s-15, changes
Compound s-15 bromination obtains compound s-16, compound s-16 and compound s-17 and becomes ester to obtain compound s-under the effect of alkali
18, compound s-18 and ammonium acetate reaction obtain compound s-19, compound s-19 and react under the catalysis of palladium and obtain compound
S-20, reacts with compound s-22 after compound s-20 deprotection again and obtains compound s-23.
Synthetic method 3:
Compound s-27 can be prepared by synthetic method 3, wherein R15、R8Determine such as the present invention independently of one another
Justice.Compound s-8 and compound s-20 coupling under the catalysis of palladium obtains compound s-24, and compound s-24 is through deprotection
After, it is condensed to yield compound s-27 with compound s-26.
Synthetic method 4:
Compound s-28 can be prepared by synthetic method 4, wherein R15、R8、R8aIndependently of one another 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
Step 1) synthesis of compound 1-2A
At 0 DEG C, trifluoromethanesulfanhydride anhydride (10.44g, 37.0mmol) is added drop-wise to compound 1-1A (5.0g,
30.83mmol) with in dichloromethane (60mL) solution of pyridine (3.0g, 37.0mmol), add rear room temperature reaction 8h, reaction knot
Bundle adds 30mL washing, and separatory, organic facies anhydrous sodium sulfate is dried, and decompression is spin-dried for, silica gel column chromatography purification (PE:EtOAc
(V:V)=10:1), obtain product 8.5g, productivity 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.
Step 2) synthesis of compound 1-3A
By compound 1-2A (3.0g, 10.2mmol), copper bromide (4.5g, 20.4mmol) joins EtOH (30mL) solvent
In 60 DEG C reaction 2h, reaction terminate after with kieselguhr filter, filtrate is spin-dried for, then with DCM (40mL × 2) dissolve, organic facies washing,
Anhydrous sodium sulfate is dried, and decompression is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=6:1), obtains brownish red grease
3.6g, productivity 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.
Step 3) synthesis of compound 1-4A
By compound 1-3A (2.5g, 6.7mmol), DIPEA (1.3g, 10.0mmol), acetonitrile (20mL) is placed in bottle and adds
Heat, to 50 DEG C, is then slowly added dropwise acetonitrile (10mL) solution of compound 1-7 (1.6g, 7.4mmol), continues reaction after adding,
Being spin-dried for reactant liquor after reaction completely, add water, EtOAc extracts, and organic facies is dried, and decompression is spin-dried for, silica gel column chromatography purification (PE:
EtOAc (V:V)=4:1), obtain product 3.0g, productivity 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]+.
Step 4) synthesis of compound 1-5A
By compound 1-4A (2.7g, 5.3mmol), ammonium acetate (2.5g, 31.8mmol) joins toluene (30mL) solvent
In 115 DEG C reaction 12h, reaction terminate after add water (10mL), then with EtOAc (30mL × 2) extract, organic facies washing, anhydrous
Sodium sulfate is dried, vacuum rotary steam, silica gel column chromatography purification (PE:EtOAc (V:V)=6:1), obtains gray solid 1.8g, productivity
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]+.
Step 5) synthesis of compound 1-6A
Manganese dioxide (3.2g, 37mmol) is dividedly in some parts compound 1-5A (1.8g, 3.7mmol), dichloromethane
(40mL) reaction being stirred at room temperature in solution, react 4 days, filter with kieselguhr after reaction completely, filtrate is washed, and is dried, silicagel column
Chromatography purification (PE:EtOAc (V:V)=3:1), obtains product 1.6g, productivity 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]+.
Step 6) synthesis of compound 1-2
Compound 1-1 (15.0g, 92.49mmol), triethyl silicane (70.0g, 601mmol), TFA (300mL) are added
Back flow reaction in two mouthfuls of bottles, TLC monitoring reaction course, 6h reaction completely, is poured in frozen water after reaction completely, then is used EtOAc
(100mL × 2) extract, and organic facies sodium bicarbonate solution neutralizes, and washing is dried, and decompression is spin-dried for, silica gel column chromatography purification
(PE), product 12.2g, productivity 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.
Step 7) synthesis of 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 aluminum (11.7g, 87.8mmol), add rear room temperature and continue reaction 4h, after reaction completely, pour frozen water into
In, extracting with DCM (60mL × 2), organic facies is dried, and decompression is spin-dried for, and purifies (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.
Step 8) synthesis of 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)
(50mL), in solution, continue reaction after adding, pour in frozen water after reaction completely, extract with EtOAc (40mL × 3), organic
Being dried mutually, decompression is spin-dried for, silica gel column chromatography purification (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.
Step 9) synthesis of compound 1-5
At 0 DEG C, trifluoromethanesulfanhydride anhydride (1.3g, 4.7mmol) is added drop-wise to compound 1-4 (0.75g, 4.3mmol) and
In dichloromethane (20mL) mixed liquor of pyridine (0.5g, 6.0mmol), adding rear room temperature reaction 4h, TLC monitors reaction, reaction
Adding washing after Wan Quan, organic facies is dried, and is spin-dried for, silica gel column chromatography purification (PE), obtains product 1.2g, productivity 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.
Step 10) synthesis of compound 1-6
Compound 1-5 (1.2g, 3.9mmol) and copper bromide (1.7g, 7.6mmol) are joined in EtOH (20mL) solvent
60 DEG C of reaction 2h, react and filter with kieselguhr after terminating, and filtrate is spin-dried for, then dilutes with DCM (20mL × 2), and organic facies is washed, nothing
Aqueous sodium persulfate is dried, vacuum rotary steam, silica gel column chromatography purification (PE:EtOAc (V:V)=6:1), obtains compound 1.25g, productivity
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.
Step 11) synthesis of 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
In dichloromethane (20mL) mixed liquor of (1.0g, 4.6mmol), adding rear room temperature reaction, TLC monitors reaction, after reaction completely
Adding washing, organic facies is dried, and is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=6:1), obtains product 1.5g, productivity
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]+.
Step 12) synthesis of compound 1-9
By compound 1-8 (1.1g, 2.1mmol), ammonium acetate (0.81g, 10.5mmol) joins toluene (20mL) solvent
In 115 DEG C reaction 12h, reaction terminate after add water (10mL), then with EtOAc (30mL × 2) extract, organic facies washing, anhydrous
Sodium sulfate is dried, vacuum rotary steam, silica gel column chromatography purification (PE:EtOAc (V:V)=4:1), obtains gray solid 0.8g, productivity
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]+.
Step 13) synthesis of 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.Reactant liquor is cooled to room temperature, adds the water of 10mL, and EtOAc (30mL × 2) extracts, and organic facies is used again
Wash 2 times, be dried, be spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=4:1), obtain product 0.3g, productivity 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]+.
Step 14) synthesis of 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), the lower heating of nitrogen protection
To 90 DEG C of reaction 3h.After reaction completely, screw out most solutions, then extract (20mL × 2) with DCM, merge organic facies, be dried,
It is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=2:1), obtains gray solid 0.5g, productivity 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]+.
Step 15) synthesis of compound 1-13
The dichloromethane that HCl/EtOAc (4N, 4mL) is added drop-wise at 0 DEG C compound 1-12 (0.5g, 0.7mmol) is molten
In agent (15mL), reaction 6h after dripping off, is stirred at room temperature.Being spin-dried for reactant liquor after reaction completely, ethyl acetate making beating purification obtains brown
Solid 0.4g, productivity 87%.
MS-ESI,m/z:489.3[M+H]+.
Step 16) synthesis of 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 dichloromethane with 2-oxime cyan-acetic ester (0.07g, 0.49mmol), will under the conditions of 0 DEG C
DIPEA (0.530g, 4.1mmol) is added dropwise in reactant liquor, after dripping off, moves into and 2h is stirred at room temperature.After reaction completely, add ammonia
(2mL) stirring 1h, separatory, organic facies saturated aqueous ammonium chloride washes, and anhydrous sodium sulfate is dried, and filters, and decompression is spin-dried for, silica gel
Column chromatography purification (PE:EtOAc (V:V)=1:1), obtains gray solid 0.35g, productivity 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:
Step 1) synthesis of compound 2-4A
Compound 1-3A (2.5g, 6.7mmol), DIPEA (1.3g, 10.0mmol), acetonitrile (20mL) are placed in bottle and add
Heat, to 50 DEG C, is then slowly added dropwise acetonitrile (10mL) solution of 5-methyl-Boc-proline 2-7 (1.38g, 6.04mmol), adds
Continuing reaction after complete, be spin-dried for reactant liquor after reaction completely, add water, EtOAc extracts, and organic layer is dried, and decompression is spin-dried for, silicagel column
Chromatography purification (PE:EtOAc (V:V)=4:1), obtains product 1.5g, productivity 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]+.
Step 2) synthesis of compound 2-5A
By compound 2-4A (1.5g, 2.9mmol), ammonium acetate (1.6g, 21mmol) joins in toluene (30mL) solvent
115 DEG C of reaction 12h, reaction adds water, then extracts with EtOAc (30mL × 2) after terminating, organic facies is washed, and anhydrous sodium sulfate is done
Dry, vacuum rotary steam, recycle silicon gel column chromatography eluting (PE:EtOAc (V:V)=6:1), obtain gray solid 1.0g, productivity 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]+.
Step 3) synthesis of compound 2-6A
Manganese dioxide (1.7g, 20mmol) is dividedly in some parts the dichloromethane of compound 2-5A (1.0g, 2.0mmol)
(40mL) in solution, reaction 4 day being stirred at room temperature, filter with kieselguhr after reaction completely, filtrate is washed, and is dried, and decompression is spin-dried for, silicon
Gel column chromatography eluting (PE:EtOAc (V:V)=3:1), obtains product 0.8g, productivity 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]+.
Step 4) synthesis of 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-
In dichloromethane (20mL) mixed liquor of 7 (1.23g, 5.36mmol), adding rear room temperature reaction, TLC monitors reaction, and reaction is completely
Rear addition 10mL washes, and saturated sodium-chloride is washed, and organic facies is dried, and decompression is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)
=6:1), obtain product 1.6g, productivity 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]+.
Step 5) synthesis of compound 2-9
By compound 2-8 (1.6g, 3.0mmol), ammonium acetate (1.4g, 18mmol) joins in toluene (20mL) solvent
115 DEG C of reaction 12h, reaction adds water, then extracts with EtOAc (30mL × 2) after terminating, organic facies is washed, and anhydrous sodium sulfate is done
Dry, vacuum rotary steam, silica gel column chromatography purification (PE:EtOAc (V:V)=4:1), obtain gray solid 1.0g, productivity 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]+.
Step 6) synthesis of compound 2-11
By compound 2-9 (1.0g, 1.94mmol), pinacol connection 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.Reactant liquor is cooled to room temperature, adds the water of 10mL, then extracts 2 times with EtOAc, merges organic facies again
Wash with water 2 times, be dried, be spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=4:1), obtain product 0.9g, productivity 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]+.
Step 7) synthesis of 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), the lower heating of nitrogen protection
To 90 DEG C of reaction 3h.After reaction completely, decompression screws out most solutions, then extracts (20mL × 2) with DCM, merges organic facies, dry
Dry, it is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=2:1), obtains gray solid 1.0g, productivity 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]+.
Step 8) synthesis of compound 2-13
The dichloromethane that HCl/EtOAc (4N, 5mL) is added drop-wise at 0 DEG C compound 2-12 (1.1g, 1.5mmol) is molten
In agent (15mL), reaction 6h after dripping off, is stirred at room temperature.Being spin-dried for reactant liquor after reaction completely, re-crystallizing in ethyl acetate purification obtains palm fibre
Color solid 0.7g, productivity 68.6%.
MS-ESI,m/z:517.9[M+H]+.
Step 15) synthesis of compound 2
By compound 2-13 (0.60g, 0.905mmol), compound 1-14 (0.349g, 1.99mmol), EDCI
(0.417g, 2.17mmol) and 2-oxime cyan-acetic ester (0.077g, 0.543mmol) are suspended in 10mL dichloromethane, 0
Under the conditions of DEG C, DIPEA (0.585g, 4.525mmol) is added dropwise in reactant liquor, after dripping off, moves into and 2h is stirred at room temperature.React
Quan Hou, adds ammonia (2mL) stirring 1h, separatory, and organic facies saturated aqueous ammonium chloride is washed, and anhydrous sodium sulfate is dried, and filters,
Decompression is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=1:1), obtains gray solid 0.6g, productivity 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:
Step 1) synthesis of compound 3-7
The dichloromethane that HCl/EtOAc (4N, 6mL) is added drop-wise at 0 DEG C compound 1-6A (1.8g, 3.7mmol) is molten
In agent (15mL), reaction after dripping off, is stirred at room temperature.Being spin-dried for reactant liquor after reaction completely, re-crystallizing in ethyl acetate purification obtains brown
Solid 0.8g, productivity 47%.
MS-ESI,m/z:385.8[M+H]+.
Step 2) synthesis of compound 3-9
By compound 3-7 (1.5g, 3.27mmol), compound 1-14 (0.687g, 3.92mmol), EDCI (0.752g,
3.92mmol) it is suspended in 10mL dichloromethane, under the conditions of 0 DEG C with 2-oxime cyan-acetic ester (0.186g, 1.31mmol)
DIPEA (1.27g, 9.82mmol) is added dropwise in reactant liquor, after dripping off, moves into and 2h is stirred at room temperature.After reaction completely, add ammonia
Water (2mL) stirs 1h, separatory, and organic facies saturated aqueous ammonium chloride is washed, and anhydrous sodium sulfate is dried, and filters, is spin-dried for reactant liquor,
Silica gel column chromatography purification (PE:EtOAc (V:V)=1:1), obtains gray solid 1.4g, productivity 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]+.
Step 3) synthesis of 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 reacts 3h to 90 DEG C.After reaction completely, decompression screws out most solutions, then extracts (20mL × 2) with DCM, merges organic facies,
It is dried, is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=2:1), obtains gray solid 0.8g, productivity 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]+.
Step 4) synthesis of compound 3-13
The dichloromethane that HCl/EtOAc (4N, 4mL) is added drop-wise at 0 DEG C compound 3-12 (0.7g, 0.9mmol) is molten
In agent (15mL), reaction after dripping off, is stirred at room temperature.Being spin-dried for reactant liquor after reaction completely, re-crystallizing in ethyl acetate purification obtains brown
Solid 0.6g, productivity 89%.
MS-ESI,m/z:647.4[M+H]+.
Step 5) synthesis of compound 3
By compound 3-13 (0.60g, 0.835mmol), compound 3-14 (0.21g, 1.0mmol), EDCI (0.192g,
1.0mmol) it is suspended in 10mL dichloromethane, under the conditions of 0 DEG C with 2-oxime cyan-acetic ester (0.048g, 0.334mmol)
DIPEA (0.324g, 2.505mmol) is added dropwise in reactant liquor, after dripping off, moves into and 2h is stirred at room temperature.After reaction completely, add
Ammonia (2mL) stirs 1h, separatory, and organic facies saturated aqueous ammonium chloride is washed, and anhydrous sodium sulfate is dried, and filters, and decompression is spin-dried for
Reactant liquor, silica gel column chromatography purification (PE:EtOAc (V:V)=1:1), obtain gray solid 0.45g, productivity 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:
Step 1) synthesis of compound 4-7
At 0 DEG C, HCl/EtOAc (4N, 4mL) is added drop-wise to the dichloromethane solvent of compound 2-6A (0.8g, 2mmol)
(15mL), in, reaction after dripping off, is stirred at room temperature.Being spin-dried for reactant liquor after reaction completely, it is solid that re-crystallizing in ethyl acetate purification obtains brown
Body 0.56g, productivity 90%.
MS-ESI,m/z:400.2[M+H]+.
Step 2) synthesis of compound 4-9
By compound 4-7 (0.9g, 2.3mmol), compound 1-14 (0.47g, 2.7mmol), EDCI (0.52g,
2.7mmol) it is suspended in dichloromethane (10mL), under the conditions of 0 DEG C with 2-oxime cyan-acetic ester (0.13g, 0.91mmol)
DIPEA (0.87g, 6.7mmol) is added dropwise in reactant liquor, after dripping off, moves into and 2h is stirred at room temperature.After reaction completely, add ammonia
Water (2mL) stirs 1h, separatory, and organic facies saturated aqueous ammonium chloride is washed, and anhydrous sodium sulfate is dried, and filters, and decompression is spin-dried for, silicon
Gel column chromatography eluting (PE:EtOAc (V:V)=1:1), obtains gray solid 0.8g, productivity 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]+.
Step 3) synthesis of 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
Protect down and be heated to 90 DEG C of reaction 3h.After reaction completely, decompression screws out most solutions, then extracts with DCM (20mL × 2), merges
Organic facies, is dried, and decompression is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=2:1), obtains gray solid 0.7g, productivity
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]+.
Step 4) synthesis of compound 4-13
The dichloromethane that HCl/EtOAc (4N, 4mL) is added drop-wise at 0 DEG C compound 4-12 (0.8g, 1.0mmol) is molten
In agent (15mL), reaction after dripping off, is stirred at room temperature.Being spin-dried for reactant liquor after reaction completely, re-crystallizing in ethyl acetate purification obtains brown
Solid 0.6g, productivity 90%.
MS-ESI,m/z:661.5[M+H]+.
Step 5) synthesis of 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 dichloromethane with 2-oxime cyan-acetic ester (0.06g, 0.37mmol), will under the conditions of 0 DEG C
DIPEA (0.360g, 2.8mmol) is added dropwise in reactant liquor, after dripping off, moves into and 2h is stirred at room temperature.After reaction completely, add ammonia
(2mL) stirring 1h, separatory, organic facies saturated aqueous ammonium chloride washes, and anhydrous sodium sulfate is dried, and filters, and decompression is spin-dried for, silica gel
Column chromatography purification (PE:EtOAc (V:V)=1:1), obtains gray solid 0.40g, productivity 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:
Step 1) synthesis of 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
In dichloromethane (20mL) mixed liquor of thing 5-2 (1.5g, 5.81mmol), adding rear room temperature reaction, TLC monitors reaction, reaction
Adding water (10mL) after Wan Quan to wash, saturated sodium-chloride is washed, and organic facies is dried, and decompression is spin-dried for, silica gel column chromatography purification (PE:EtOAc
(V:V)=6:1), obtain product 2.0g, productivity 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]+.
Step 2) synthesis of compound 5-4
Compound 5-3 (2.1g, 3.71mmol), ammonium acetate (1.72g, 22.3mmol) are joined toluene (20mL) solvent
In 115 DEG C reaction 12h, reaction terminate after add water, then with EtOAc extract (30mL × 2), organic facies wash, anhydrous sodium sulfate
It is dried, vacuum rotary steam, silica gel column chromatography purification (PE:EtOAc (V:V)=4:1), obtains gray solid 1.5g, productivity 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]+.
Step 3) synthesis of 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 it are heated under gas shielded.Reactant liquor is cooled to room temperature, adds the water of 10mL, then extracts 2 times with EtOAc, organic
Being washed with water mutually 2 times, be dried, decompression is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=3:1), obtains product 1.3g, produces
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]+.
Step 4) synthesis of 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 it are heated under gas shielded.After reaction completely, decompression screws out most solutions, then extracts with DCM (20mL × 2),
Merging organic facies, be dried, decompression is spin-dried for, silica gel column chromatography purification (DCM:EtOAc (V:V)=1:2), obtains gray solid
0.5g, productivity 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]+.
Step 5) synthesis of compound 5-8
At 0 DEG C, HCl/EtOAc (4N, 4mL) is added drop-wise to the dichloromethane solution of compound 5-7 (0.6g, 0.7mmol)
(15mL), in, reaction after dripping off, is stirred at room temperature.Being spin-dried for reactant liquor after reaction completely, ethyl acetate washing purification obtains brown solid
0.45g, productivity 84%.
MS-ESI,m/z:705.4[M+H]+.
Step 6) synthesis of compound 5
By compound 5-8 (0.55g, 0.72mmol), compound 3-14 (0.178g, 0.852mmol), EDCI (0.163g,
0.852mmol) it is suspended in 10mL dichloromethane, under the conditions of 0 DEG C with 2-oxime cyan-acetic ester (0.04g, 0.284mmol)
DIPEA (0.275g, 2.13mmol) is added dropwise in reactant liquor, after dripping off, moves into and 2h is stirred at room temperature.After reaction completely, add
Ammonia (2mL) stirs 1h, separatory, and organic facies saturated aqueous ammonium chloride is washed, and anhydrous sodium sulfate is dried, and filters, and decompression is spin-dried for,
Silica gel column chromatography purification (PE:EtOAc (V:V)=1:3), obtains gray solid 0.35g, productivity 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
Step 1) synthesis of compound 7-2A
6-bromine 2-naphthylamine hydrochloride 7-1A (2.00g, 7.73mmol, 1.00eq) is added in DMF (15mL), adds
DMAP(0.02g,0.16mmol,0.02eq),Et3N (3.70mL, 2.70mmol, 3.50eq), is down to 0 DEG C, drips acetic anhydride
(1.09mL, 11.60mmol, 1.50eq), drips complete room temperature reaction 3h.After reaction completely, reactant liquor is poured in 30mL water, have white
Color solid separates out, and after stirring 0.5h, directly filters, and filter cake washes 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.
Step 2) synthesis of compound 7-3A
By compound 7-2A (5.0g, 18.93mmol, 1.00eq), KNO3(2.30g, 22.71mmol, 1.20eq) adds
Dissolve to AcOH (35mL) solvent, under the conditions of 20 DEG C, drip H2SO4(5.14mL, 94.65mmol, 5.00eq), drips complete
After, 30 DEG C of reaction 7h.Reaction is directly poured in water (50mL) after terminating, and has yellow-brown solid to separate out, directly filters, filter cake water
(20mL × 3) wash, and are dried to obtain 5.34g yellow-brown solid, productivity 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.
Step 3) synthesis of compound 7-4A
Compound 7-3A (3.78g, 12.23mmol, 1.00eq) is added THF (20mL) and is placed in bottle dissolving, add
6N HCl (10.5mL, 61.10mmol, 5.00eq), is heated to 80 DEG C, reacts 7h.After reaction completely, it is cooled to room temperature, will reaction
Liquid is poured in 50mL frozen water, has yellow solid to separate out, and filters, and filter cake use water (15mL × 3) washs, and is dried, obtains product 3.00g
Yellow-brown solid, productivity 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]+.
Step 4) synthesis of compound 7-5A
Compound 7-4A (4.00g, 14.97mmol, 1.00eq) is added in Isosorbide-5-Nitrae-dioxane (30mL) and dissolves, ice bath
Under the conditions of drip Na2S2O4(8.68g,44.93mmol,3.00eq)、Na2CO3(1.58g, 14.97mmol, 1.00eq's) is water-soluble
Liquid (30mL), drips complete rear chamber temperature reaction 5h.Directly pour in water (30mL) after reaction completely, have cinerous solid to separate out,
Filtering, filter cake use water (15mL × 3) washs, and is dried, obtains product 3.2g cinerous solid, productivity 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]+. step 5) synthesis of compound 7-6A
By (S)-N-tertbutyloxycarbonyl pyrrolidine-2-formic acid (9.06g, 42.17mmol, 1.00eq), ethyl chloroformate
(4.58g, 42.17g, 1.00eq) is dissolved in DCM (100mL), at-10 DEG C, is slowly added dropwise Et3N(8.8mL,63.26mmol,
1.50eq), after dropping, being incubated 10min, filter, filter cake DCM (10mL × 2) washs, and filtrate is standby.By compound 7-
5A (10g, 42.17mmol, 1.00eq) is dissolved in DCM (80mL), is cooled to-5 DEG C, drips above-mentioned filtrate, straight after dropping
Meet placement room temperature reaction 2h.After reaction completely, being directly added into water (100mL), extract separatory, aqueous phase continues DCM (50mL × 2) extraction
Take, merge organic facies, be dried, be spin-dried for obtaining crude product 18.00g brownish black solid, productivity 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]+.
Step 6) synthesis of compound 7-7A
Compound 7-6A (18.00g, 43.27mmol, 1.00eq) is added in acetic acid (80mL), directly heats to 50 DEG C,
Reaction 5h.Remove part acetic acid after reaction completely, add EtOAc (100mL), water (50mL) stirring, remove residue with sodium carbonate
Acetic acid, to pH=8, then extracts separatory, and aqueous phase continues, with EtOAc (20mL × 2) extraction, to merge organic facies;Organic facies continues
Washing with water (50mL), separatory, organic facies is dried, and screws out and obtains product 16.03g brown solid, productivity 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]+.
Step 7) synthesis of compound 7-1
By compound 5-6 (600mg, 1.15mmol, 1.0eq), compound 7-7A (477mg, 1.15mmol, 1.0eq), carbon
Acid potassium (316mg, 2.29mmol, 2.0eq), four triphenyl phosphorus palladiums (29mg, 0.034mmol, 0.03eq) join 10mL ethanol
With in 3mL water, 90 DEG C are reacted 18h.Reactant liquor is poured in 50mL water, extract (30mL × 3) with dichloromethane, organic facies nothing
Aqueous sodium persulfate is dried, and is spin-dried for, silica gel column chromatography purification (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]+.
Step 8) synthesis of compound 7-2
Compound 7-1 (0.68g, 0.93mmol, 1.0eq) is joined in DCM (15mL), drip HCl/EtOAc at 0 DEG C
(4N, 3mL) solution, drips off room temperature reaction 12h.Being spin-dried for by solvent, add EtOAc (20mL), room temperature making beating 1h, sucking filtration obtains yellowish
Color solid, dissolves with water (10mL), then dissociates with sodium carbonate liquor, separates out solid, sucking filtration, is dried to obtain 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]+.
Step 9) synthesis of compound 7
By compound 7-2 (250mg, 0.469mmol, 1.0eq), compound 7-3 (209mg, 1.03mmol, 2.2eq), 2-
Oxime cyan-acetic ester (61mg, 0.43mmol, 0.8eq) and DIPEA (35mg, 0.27mmol, 0.5eq) join DCM
(15mL), in, EDCI (227mg, 1.19mmol, 2.2eq), room temperature reaction 5h are added.Reactant liquor is poured in water (30mL),
Extracting with DCM (15mL × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (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:
Step 1) synthesis of compound 10-1
Compound 2-12 (1.25g, 1.74mmol, 1.0eq) is joined in DCM (15mL), drip HCl/ at 0 DEG C
EtOAc (3mL) solution, drips off room temperature reaction 6h.Being spin-dried for by solvent, add EtOAc (20mL), room temperature making beating 1h, sucking filtration obtains light
Yellow solid, dissolves with water (10mL), then dissociates with sodium carbonate liquor, separates out solid, sucking filtration, is dried to obtain 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]+.
Step 2) synthesis of compound 10
By compound 10-1 (280mg, 0.54mmol, 1.0eq), compound 10-2 (294mg, 1.36mmol, 2.5eq),
2-oxime cyan-acetic ester (61mg, 0.43mmol, 0.8eq) and DIPEA (35mg, 0.27mmol, 0.5eq) joins DCM
(15mL), in, EDCI (227mg, 1.19mmol, 2.2eq), room temperature reaction 6h are added.Reactant liquor is poured in water (30mL),
Extracting with DCM (15mL × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (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:
Step 1) synthesis of 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 dichloromethane (20mL) with 2-oxime cyan-acetic ester (0.15g, 1.1mmol), under the conditions of 0 DEG C, by DIPEA
(1.1g, 8.2mmol) is added dropwise in reactant liquor, after dripping off, and room temperature reaction 2h.Screw out solvent, residue ethyl acetate
(100mL) extraction, saturated nacl aqueous solution (50mL) washs, and anhydrous sodium sulfate is dried, and screws out solvent, residue silica gel column chromatography
Purification (PE:EtOAc (V:V)=3:1), obtains brown solid 0.93g, productivity 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]+.
Step 2) synthesis of 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 mixed solvent of EtOH (20mL) and water (4mL), under nitrogen protection
It is heated to 90 DEG C of reactions.Crossing kieselguhr, screw out solvent, residue ethyl acetate (200mL) extracts, saturated nacl aqueous solution
(50mL) washing, anhydrous sodium sulfate is dried, back-out solvent, residue silica gel column chromatography (PE:EtOAc (V:V)=1:3) purification,
Obtain brown solid 0.45g, productivity 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]+.
Step 3) synthesis of compound 11-4:
Compound 11-3 (0.45g, 0.54mmol) is dissolved in DCM (10mL), under the conditions of 0 DEG C, is slowly added dropwise hydrochloric acid second
Acetate solution (4M/L, 3mL), after dripping, room temperature reaction 3h.Screwing out solvent, residue ethyl acetate is pulled an oar, and filters.
Filter cake use water (10mL) dissolves, and adds potassium carbonate and adjusts pH value to 8-9, sucking filtration, obtains product 0.35g, productivity 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]+.
Step 4) synthesis of compound 11:
By compound 11-4 (0.35g, 0.49mmol), compound 11-5 (0.1g, 0.53mmol), EDCI (0.11g,
0.58mmol) it is suspended in dichloromethane (20mL), 0 DEG C of condition with 2-oxime cyan-acetic ester (0.028g, 0.19mmol)
Under, DIPEA (0.19g, 1.5mmol) is added dropwise in reactant liquor, after dripping off, room temperature reaction 2h.Screw out solvent, residue second
Acetoacetic ester (100mL) dissolves, and saturated nacl aqueous solution (50mL) washs, and anhydrous sodium sulfate is dried, and screws out solvent, residue silica gel
Column chromatography (DCM:EtOAc (V:V)=2:1), obtains white solid 0.3g, productivity 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-oxime cyan-acetic ester (61mg, 0.43mmol, 0.8eq) and DIPEA (35mg, 0.27mmol, 0.5eq) joins DCM
(15mL), in, EDCI (227mg, 1.19mmol, 2.2eq), room temperature reaction 18h are added.Reactant liquor is poured in water (30mL),
Extracting with DCM (15mL × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (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:
Step 1) synthesis of 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), at 0 DEG C, drip triethylamine (0.39g, 3.9mmol, 1.5eq), drip off room temperature reaction 2h.It is spin-dried for molten
Agent, adds water (20mL), then extracts (20mL × 3) with DCM, and organic facies anhydrous sodium sulfate is dried, and is spin-dried for, and obtains brown oil and produces
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.
Step 2) synthesis of compound 15-3
Compound 15-2 (1.42g, 2.6mmol, 1.0eq) and ammonium acetate (1.2g, 15.6mmol, 6.0eq) are joined
In toluene (15mL), 115 DEG C of reaction 20h.Toluene is spin-dried for, adds water (50mL), then extract (15mL × 3) with DCM, organic facies
It is dried with anhydrous sodium sulfate, is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=5:1), obtain faint yellow solid 1.31g, receive
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]+.
Step 3) synthesis of compound 15-4
By compound 15-3 (1.26g, 2.37mmol, 1.0eq), connection pinacol borate (0.63g, 2.49mmol,
1.05eq), potassium acetate (0.70g, 7.1mmol, 3.0eq), Pd (dppf)2Cl2(69mg, 0.094mmol, 0.04eq), joins
In DMF (15mL), the lower 100 DEG C of reaction 10h of nitrogen protection.Being poured into by reactant liquor in water (60mL), sucking filtration obtains gray solid, silica gel
Column chromatography purification (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]+.
Step 4) synthesis of compound 15-6
By compound 15-4 (558mg, 1.10mmol, 1.0eq), compound 2-6A (473g, 1.10mmol, 1.0eq), carbon
Acid potassium (0.30g, 2.21mmol, 2.0eq), four triphenyl phosphorus palladiums (38mg, 0.033mmol, 0.03eq) join ethanol
(10mL) with in water (3mL), under nitrogen protection, 90 DEG C are reacted 6h.Reactant liquor is poured in water (50mL), extract with dichloromethane
(30mL × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (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]+.
Step 5) synthesis of compound 15-7
Compound 15-6 (0.70g, 0.95mmol, 1.0eq) is joined in DCM (10mL), drip HCl/ at 0 DEG C
EtOAc (4N, 3mL) solution, drips off room temperature reaction 10h.Solvent is spin-dried for, adds EtOAc (20mL), room temperature making beating 1h, sucking filtration
Obtain faint yellow solid, dissolve with water (10mL), then dissociate with sodium carbonate liquor, separate out solid, sucking filtration, be dried to obtain yellow solid product
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]+.
Step 6) synthesis of compound 15
By compound 15-6 (265mg, 0.5mmol, 1.0eq), compound 1-14 (193mg, 1.1mmol, 2.2eq), 2-
Oxime cyan-acetic ester (57mg, 0.4mmol, 0.8eq) and DIPEA (32mg, 0.25mmol, 0.5eq) join DCM (15mL)
In, add EDCI (211mg, 1.1mmol, 2.2eq), room temperature reaction 3h.Reactant liquor is poured in water (30mL), use DCM
(15mL × 3) extract, and organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (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:
Step 1) synthesis of 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), at 0 DEG C, drip triethylamine (0.39g, 3.9mmol, 1.5eq), drip off room temperature reaction 2h.Screw out molten
Agent, adds water (20mL), then extracts (20mL × 3) with DCM, and organic facies anhydrous sodium sulfate is dried, and is spin-dried for, and obtains brown oil and produces
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.
Step 2) synthesis of compound 16-3
Compound 16-2 (1.56g, 2.6mmol, 1.0eq) and ammonium acetate (1.2g, 15.6mmol, 6.0eq) are joined
In toluene (15mL), 115 DEG C of reaction 20h.Toluene is spin-dried for, adds water (50mL), then extract (15mL × 3) with DCM, organic facies
It is dried with anhydrous sodium sulfate, is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=5:1), obtain faint yellow solid 1.38g, receive
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]+.
Step 3) synthesis of compound 16-4
By compound 16-3 (1.38g, 2.37mmol, 1.0eq), connection pinacol borate (0.63g, 2.49mmol,
1.05eq), potassium acetate (0.70g, 7.1mmol, 3.0eq), Pd (dppf)2Cl2(69mg, 0.094mmol, 0.04eq), joins
In DMF (15mL), the lower 100 DEG C of reaction 10h of nitrogen protection.Being poured into by reactant liquor in water (60mL), sucking filtration obtains gray solid, then silicon
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]+.
Step 4) synthesis of compound 16-5
By compound 16-4 (615mg, 1.10mmol, 1.0eq), compound 2-6A (473g, 1.10mmol, 1.0eq), carbon
Acid potassium (0.30g, 2.21mmol, 2.0eq), four triphenyl phosphorus palladiums (38mg, 0.033mmol, 0.03eq) join ethanol
(10mL) with in water (3mL), under nitrogen protection, 90 DEG C are reacted 6h.Reactant liquor is poured in water (50mL), extract with dichloromethane
(30mL × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (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]+.
Step 5) synthesis of compound 16-6
Compound 16-5 (0.82g, 1.05mmol, 1.0eq) is joined in DCM (10mL), drip HCl/ at 0 DEG C
EtOAc (3mL) solution, drips off room temperature reaction 10h.Being spin-dried for by solvent, add EtOAc (20mL), room temperature making beating 1h, sucking filtration obtains light
Yellow solid, dissolves with water (10mL), then dissociates with sodium carbonate liquor, separates out solid, sucking filtration, is dried to obtain 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]+.
Step 6) synthesis of compound 16
By compound 16-6 (291mg, 0.5mmol, 1.0eq), compound 1-14 (193mg, 1.1mmol, 2.2eq), 2-
Oxime cyan-acetic ester (57mg, 0.4mmol, 0.8eq) joins in DCM (15mL), add EDCI (211mg, 1.1mmol,
2.2eq), room temperature reaction 3h.Reactant liquor is poured in water (30mL), extract with DCM (15mL × 3), organic facies anhydrous slufuric acid
Sodium is dried, and is spin-dried for, and crosses post, silica gel column chromatography purification (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:
Step 1) synthesis of compound 22-2
Compound 22-1 (0.63g, 2.7mmol, 1.05eq) and compound 1-6 (1.0g, 2.6mmol, 1.0eq) is added
In acetonitrile (10mL), at 0 DEG C, drip triethylamine (0.39g, 3.9mmol, 1.5eq), drip off room temperature reaction 2h.Screw out molten
Agent, adds water (20mL), then extracts (20mL × 3) with DCM, and organic facies anhydrous sodium sulfate is dried, and is spin-dried for, and obtains brown oil and produces
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.
Step 2) synthesis of compound 22-3
Compound 22-2 (1.40g, 2.59mmol, 1.0eq) and ammonium acetate (1.2g, 15.6mmol, 6.0eq) are joined
In toluene (15mL), 115 DEG C of reaction 20h.Toluene is spin-dried for, adds water (50mL), then extract (15mL × 3) with DCM, organic facies
It is dried with anhydrous sodium sulfate, is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=5:1), obtain faint yellow solid 1.23g, receive
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]+.
Step 3) synthesis of compound 22-4
By compound 22-3 (1.23g, 2.37mmol, 1.0eq), connection pinacol borate (0.63g, 2.49mmol,
1.05eq), potassium acetate (0.70g, 7.1mmol, 3.0eq), Pd (dppf)2Cl2(69mg, 0.094mmol, 0.04eq), joins
In DMF (15mL), the lower 100 DEG C of reaction 10h of nitrogen protection.Being poured into water by reactant liquor, sucking filtration obtains gray solid, silica gel column chromatography
Purification (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]+.
Step 4) synthesis of compound 22-5
By compound 22-4 (550mg, 1.10mmol, 1.0eq), compound 7-7A (460g, 1.10mmol, 1.0eq), carbon
Acid potassium (0.30g, 2.21mmol, 2.0eq), four triphenyl phosphorus palladiums (38mg, 0.033mmol, 0.03eq) join ethanol
(10mL) with in water (3mL), under nitrogen protection, 90 DEG C are reacted 6h.Reactant liquor is poured in water (50mL), extract with dichloromethane
(30mL × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (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]+.
Step 5) synthesis of compound 22-6
Compound 22-5 (0.76g, 1.1mmol, 1.0eq) is joined in DCM (10mL), drip HCl/EtOAc at 0 DEG C
(4N, 3mL) solution, drips off room temperature reaction 10h.Being spin-dried for by solvent, add EtOAc (20mL), room temperature making beating 1h, sucking filtration obtains yellowish
Color solid, dissolves with water (10mL), then dissociates with sodium carbonate liquor, separates out solid, sucking filtration, is dried to obtain 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]+.
Step 6) synthesis of compound 22
By compound 22-6 (280mg, 0.552mmol, 1.0eq), compound 1-14 (213mg, 1.22mmol, 2.2eq),
2-oxime cyan-acetic ester (62mg, 0.44mmol, 0.8eq) and DIPEA (35mg, 0.27mmol, 0.5eq) joins DCM
(15mL), in, EDCI (232mg, 1.22mmol, 2.2eq), room temperature reaction 3h are added.Reactant liquor is poured in water (30mL),
Extracting with DCM (15mL × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (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:
Step 1) synthesis of 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 under nitrogen protection, it are heated to.After reaction completely, screw out most solutions, then with DCM (20mL
× 2) extraction, merges organic facies, is dried, is spin-dried for, silica gel column chromatography purification (PE:EA (V:V)=2:1), obtains gray solid
0.5g, productivity 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]+.
Step 2) synthesis of compound 31-2
At 0 DEG C, HCl/EtOAc (4N, 4mL) is added drop-wise to the dichloromethane of compound 31-1 (0.5g, 0.7mmol, 1eq)
In alkane solvents (15mL), reaction 6h after dripping off, is stirred at room temperature.Being spin-dried for reactant liquor after reaction completely, ethyl acetate making beating purification obtains
Brown solid 0.4g, productivity 87%.MS-ESI,m/z:491.6[M+H]+.
Step 3) synthesis of 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-oxime cyan-acetic ester (0.07g, 0.49mmol, 0.6eq) is suspended in dichloro
In methane (10mL), under the conditions of 0 DEG C, DIPEA (0.530g, 4.1mmol, 5eq) is added dropwise in reactant liquor, after dripping off, moves into
2h is stirred at room temperature.After reaction completely, adding ammonia (2mL) stirring 1h, separatory, organic facies saturated aqueous ammonium chloride is washed, nothing
Aqueous sodium persulfate is dried, and filters, is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=1:1), obtains gray solid 0.35g,
Productivity 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:
Step 1) synthesis of 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) joins in acetonitrile (10mL), drips three at 0 DEG C
Ethamine (0.39g, 3.9mmol, 1.5eq), drips off room temperature reaction 2h.Screw out solvent, add water (20mL), then extract with DCM
(10mL × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, and 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.
Step 2) synthesis of compound 32-3
Compound 32-2 (1.45g, 2.65mmol, 1.0eq) and ammonium acetate (1.22g, 15.9mmol, 6.0eq) are added
In toluene (10mL), 115 DEG C of reaction 15h.Toluene is spin-dried for, adds water (50mL), then extract (15mL × 3) with DCM, organic
It is dried with anhydrous sodium sulfate, is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=5:1), obtain faint yellow solid 1.1g,
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]+.
Step 3) synthesis of compound 32-4
By compound 32-3 (1.03g, 1.95mmol, 1.0eq), connection pinacol borate (0.52g, 2.05mmol,
1.05eq), potassium acetate (0.57g, 5.86mmol, 3.0eq), Pd (dppf)2Cl2(57mg, 0.078mmol, 0.04eq), adds
In DMF (10mL), the lower 100 DEG C of reaction 11h of nitrogen protection.Being poured into water by reactant liquor, sucking filtration obtains gray solid, then silicagel column
Chromatography purification (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]+.
Step 4) synthesis of 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 it are heated under gas shielded.After reaction completely, screw out most solutions, then extract with DCM (20mL × 2), merge
Organic facies, is dried, is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=2:1), obtains gray solid 0.6g, productivity
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.
Step 5) synthesis of compound 32-6
At 0 DEG C, HCl/EtOAc (4N, 4mL) is added drop-wise to the dichloromethane of compound 32-5 (0.5g, 0.7mmol, 1eq)
In alkane solvents (15mL), reaction 6h after dripping off, is stirred at room temperature.Being spin-dried for reactant liquor after reaction completely, ethyl acetate making beating purification obtains
Brown solid 0.36g, productivity 79%.
Step 6) synthesis 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-oxime cyan-acetic ester (0.116g, 0.817mmol, 0.8eq) is suspended in two
In chloromethanes (10mL), under the conditions of 0 DEG C, DIPEA (0.792g, 6.13mmol, 6eq) is added dropwise in reactant liquor, after dripping off,
Immigration is stirred at room temperature 2h.After reaction completely, add ammonia (2mL) stirring 1h, separatory, organic facies saturated aqueous ammonium chloride
Washing, anhydrous sodium sulfate is dried, and filters, is spin-dried for reactant liquor, silica gel column chromatography purification (PE:EtOAc (V:V)=1:1), obtains Lycoperdon polymorphum Vitt
Solid 0.4g, productivity 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:
Step 1) synthesis of compound 33-2
Lithium (0.56g, 80mmol, 4eq) is joined in oxolane (20mL), at 0 DEG C add TMSCl (7.67mL,
60mmol, 3eq), then drip compound 33-1 (2.08g, 20mmol, 1eq), after dripping, room temperature reaction 6 days.Add at 0 DEG C
Methanol (10mL) cancellation is reacted, and adds water (25mL), and with petroleum ether extraction (40mL × 3), merges the anhydrous sulfur of organic facies
Acid sodium is dried, and concentrates at 25 DEG C.Obtain 4.9g yellow fluid, yield 98%.
GC/MS:[M+]=250.2.
Step 2) synthesis of compound 33-3
Compound 33-2 (4.9g, 19.6mmol, 1eq) is dissolved in oxolane (50mL), at 40 DEG C, drips DDQ
The tetrahydrofuran solution (15mL) of (2.22g, 9.8mmol, 0.5eq).React 1h at 40 DEG C, add water (100mL) cancellation reaction,
It is extracted with ethyl acetate (40mL × 4) again.Merge organic facies, use water (50mL), saturated aqueous sodium carbonate (80mL) respectively, satisfy
Wash with saline solution (50mL), then be dried with anhydrous sodium sulfate, concentrate at 25 DEG C, obtain the thick product of 5.0g, yield 103%.
GC/MS:[M+]=248.1.
Step 3) synthesis of compound 33-4
Compound 33-3 (4.96g, 20mmol, 1eq) is dissolved in methanol (50mL), at 0 DEG C drip bromine (3.1mL,
60mmol, 3eq) methanol solution (10mL), drip rear room temperature reaction overnight.Add water (100mL) cancellation reaction, then use stone
Oil ether extraction (100mL × 3), merges organic facies saturated aqueous common salt (50mL) and washs, and anhydrous sodium sulfate is dried, and concentrates.Obtain
Residue silica gel column chromatography purification (PE), obtain 2.5g product, productivity 48%.
1H NMR(400MHz,CDCl3):δ7.17(s,2H),3.09(s,4H)ppm.
Step 4) synthesis of compound 33-5
By compound 33-4 (2.5g, 9.54mmol, 1eq), tributyl (1-ethoxy ethylene) stannum (2.93mL,
8.60mmol, 0.9eq) and dichloro two triphenylphosphine palladium (0.35g, 0.48mmol, 0.05eq) be dissolved in dioxane (25mL),
Nitrogen is protected, microwave reaction 1h at 100 DEG C.Kieselguhr filter, filtrate add dichloromethane (20mL) and hydrochloric acid (1.5N,
20mL), stirring 2h, then extract with dichloromethane (50mL) under room temperature, organic facies anhydrous sodium sulfate is dried, and concentrates at 25 DEG C.
Residue silica gel column chromatography purification (PE:EtOAc (V:V)=30:1-20:1), obtains 1.2g white solid, productivity 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.
Step 5) synthesis of compound 33-6
By compound 33-5 (1.2g, 5.33mmol, 1eq), copper bromide (2.38g, 10.7mmol, 2eq) joins EtOH
(20mL) 60 DEG C of reaction 2h in solvent, react and filter with kieselguhr after terminating, and filtrate is spin-dried for, and adds DCM (40mL), and uses water
(20mL) washing, anhydrous sodium sulfate is dried, vacuum rotary steam, then silica gel column chromatography purification (PE:EtOAc (V:V)=6:1), obtains
Brownish red grease 1.38g, productivity 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.
Step 6) synthesis of 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),
In dichloromethane (20mL) mixed liquor of compound 1-7 (1.0g, 4.6mmol, 1.3eq), adding rear room temperature reaction, TLC monitors
Reaction, adds washing (10mL) after reaction completely, and saturated sodium-chloride is washed, and organic facies is dried, and is spin-dried for, silica gel column chromatography purification (PE:
EtOAc (V:V)=6:1), obtain product 1.29g, productivity 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]+.
Step 7) synthesis of compound 33-9
Compound 33-8 (1.13g, 2.6mmol, 1.0eq) and ammonium acetate (1.2g, 15.6mmol, 6.0eq) are joined
In toluene (15mL), 115 DEG C of reaction 20h.Toluene is spin-dried for, adds water (50mL), then extract (15mL × 3) with DCM, organic facies
It is dried with anhydrous sodium sulfate, is spin-dried for, cross post, silica gel column chromatography purification (PE:EtOAc (V:V)=5:1), obtain 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]+.
Step 8) synthesis of compound 33-11
By compound 33-9 (1.0g, 2.4mmol, 1.0eq), connection pinacol borate (0.63g, 2.5mmol,
1.05eq), potassium acetate (0.71g, 7.2mmol, 3.0eq), Pd (dppf)2Cl2(69mg, 0.094mmol, 0.04eq), joins
In DMF (15mL), the lower 100 DEG C of reaction 10h of nitrogen protection.Being poured into water by reactant liquor, sucking filtration obtains gray solid, then silica gel column layer
Analysis purification (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]+.
Step 9) synthesis of compound 33-13
By compound 33-11 (512mg, 1.1mmol, 1.0eq), compound 7-7A (460mg, 1.1mmol, 1.0eq), carbon
Acid potassium (0.30g, 2.2mmol, 2.0eq), four triphenyl phosphorus palladiums (38mg, 0.033mmol, 0.03eq) join ethanol (10mL)
With in water (3mL), under nitrogen protection, 90 DEG C are reacted 6h.Reactant liquor is poured in water (50mL), extract (30mL with dichloromethane
× 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (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]+.
Step 10) synthesis of compound 33-14
Compound 33-13 (0.72g, 1.07mmol, 1.0eq) is joined in DCM (10mL), drip HCl/ at 0 DEG C
EtOAc (3mL) solution, drips off room temperature reaction 10h.Being spin-dried for by solvent, add EtOAc (20mL), room temperature making beating 1h, sucking filtration obtains light
Yellow solid, dissolves with water (10mL), then dissociates with sodium carbonate liquor, separates out solid, sucking filtration, is dried to obtain 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]+.
Step 11) synthesis of compound 33
By compound 33-14 (238mg, 0.5mmol, 1.0eq), compound 1-14 (193mg, 1.1mmol, 2.2eq), 2-
Oxime cyan-acetic ester (57mg, 0.4mmol, 0.8eq) and DIPEA (32mg, 0.25mmol, 0.5eq) join DCM (15mL)
In, add EDCI (211mg, 1.1mmol, 2.2eq), room temperature reaction 3h.Reactant liquor is poured in water (30mL), use DCM
(15mL × 3) extract, and organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (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:
Step 1) synthesis of 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) join in toluene (100mL), at 120 DEG C, back flow reaction is overnight.Screw out solvent, add ethyl acetate
(100mL), and washing with saturated sodium bicarbonate aqueous solution (30mL), anhydrous sodium sulfate is dried, and concentrates.The residue second obtained
Nitrile (100mL) dissolves, and adds Selectfluor (35.4g, 100mmol, 2eq), back flow reaction 3h at 85 DEG C.Cool to again
Room temperature, is slowly added dropwise concentrated hydrochloric acid (30mL), stirs 10 minutes, adds ethyl acetate (200mL), and wash with water (50mL ×
2).Organic facies anhydrous sodium sulfate is dried, and concentrates.Silica gel column chromatography purification (PE:EtOAc (V:V)=10:1), obtains 4.0g yellow
Color fluid, 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.
Step 2) synthesis of compound 34-2
By compound 34-1 (4.0g, 20mmol, 1eq), triethyl silicane (11.6g, 100mmol, 5eq), TFA (40mL)
Joining back flow reaction in two mouthfuls of bottles, TLC monitoring reaction course, 6h reaction completely, is poured in frozen water after reaction completely, then is used
EtOAc (40mL × 2) extracts, and organic facies sodium bicarbonate solution neutralizes, and washing is dried, is spin-dried for, silica gel column chromatography purification
(PE), product 3.35g, productivity 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.
Step 3) synthesis of compound 34-3
At 0 DEG C, chloroacetic chloride (1.7g, 21.6mmol, 1.2eq) is slowly added drop-wise to compound 34-2 (3.32g,
18mmol, 1eq), in DCM (20mL) solution of aluminum chloride (3.11g, 23.4mmol, 1.3eq), add rear room temperature and continue anti-
Should, to pour in frozen water after reaction completely, extract with DCM (2 × 20mL), organic facies is dried, and is spin-dried for, silica gel column chromatography purification (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.
Step 4) synthesis of compound 34-4
At 0 DEG C, Boron tribromide (4.51g, 18mmol, 1.2eq) is slowly added drop-wise to compound 34-3 (3.38g,
15mmol, 1eq) DCM (50mL) solution in, continue reaction after adding, pour in frozen water, with EtOAc (40mL after reaction completely
× 3) extraction, organic facies is dried, and is spin-dried for, silica gel column chromatography purification (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.
Step 5) synthesis of compound 34-5
At 0 DEG C, trifluoromethanesulfanhydride anhydride (3.4g, 12mmol, 1.2eq) is added drop-wise to compound 34-4 (2.12g,
10mmol, 1eq), in dichloromethane (40mL) mixed liquor of pyridine (1.96g, 20mmol, 2eq), add rear room temperature reaction, TLC
Monitoring reaction, adds water (10mL) after reaction completely and washes, and saturated sodium-chloride is washed, and is dried, and organic facies is dried, and is spin-dried for, silica gel column layer
Analysis purification (PE), obtains product 3.27g, productivity 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.
Step 6) synthesis of compound 34-6
By compound 34-5 (1.84g, 5.33mmol, 1eq), copper bromide (2.38g, 10.7mmol, 2eq) joins EtOH
(20mL) 60 DEG C of reaction 2h in solvent, react and filter with kieselguhr after terminating, and filtrate is spin-dried for, and adds DCM (40mL), and uses water
(20mL) washing, anhydrous sodium sulfate is dried, vacuum rotary steam, then silica gel column chromatography purification (PE:EtOAc (V:V)=6:1), obtains
Brownish red grease 1.38g, productivity 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.
Step 7) synthesis of compound 34-7
At 0 DEG C, triethylamine (0.6g, 6mmol, 1.5eq) is added drop-wise to compound 34-6 (1.52g, 3.6mmol,
1eq), in dichloromethane (20mL) mixed liquor of L-Boc-proline (1.0g, 4.6mmol, 1.3eq), add rear room temperature reaction,
TLC monitors reaction, adds water (10mL) and wash after reaction completely, and saturated sodium-chloride is washed, and organic facies is dried, and is spin-dried for, silica gel column chromatography
Purification (PE:EtOAc (V:V)=6:1), obtains product 1.63g, productivity 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]+.
Step 8) synthesis of compound 34-8
Compound 34-7 (1.45g, 2.6mmol, 1.0eq) and ammonium acetate (1.2g, 15.6mmol, 6.0eq) are joined
In toluene (15mL), 115 DEG C of reaction 20h.Toluene is spin-dried for, adds water (50mL), then extract (15mL × 3) with DCM, organic facies
It is dried with anhydrous sodium sulfate, is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=5:1), obtain faint yellow solid 1.33g, receive
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]+.
Step 9) synthesis of compound 34-9
By compound 34-8 (1.29g, 2.4mmol, 1.0eq), connection pinacol borate (0.63g, 2.5mmol,
1.05eq), potassium acetate (0.71g, 7.2mmol, 3.0eq), Pd (dppf)2Cl2(69mg, 0.094mmol, 0.04eq), joins
In DMF (15mL), the lower 100 DEG C of reaction 10h of nitrogen protection.Being poured into water by reactant liquor, sucking filtration obtains gray solid, then silica gel column layer
Analysis purification (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]+.
Step 10) synthesis of compound 34-10
By compound 34-9 (567mg, 1.1mmol, 1.0eq), compound 7-7A (460mg, 1.1mmol, 1.0eq), carbon
Acid potassium (0.30g, 2.2mmol, 2.0eq), four triphenyl phosphorus palladiums (38mg, 0.033mmol, 0.03eq) join ethanol (10mL)
With in water (3mL), under nitrogen protection, 90 DEG C are reacted 6h.Reactant liquor is poured in water (50mL), extract (30mL with dichloromethane
× 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (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]+.
Step 11) synthesis of compound 34-11
Compound 34-10 (0.725g, 1.0mmol, 1.0eq) is joined in DCM (10mL), drip HCl/ at 0 DEG C
EtOAc (4N, 3mL) solution, drips off room temperature reaction 10h.Solvent is spin-dried for, adds EtOAc (20mL), room temperature making beating 1h, sucking filtration
Obtain faint yellow solid, dissolve with water (10mL), then dissociate with sodium carbonate liquor, separate out solid, sucking filtration, be dried to obtain yellow solid product
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]+.
Step 12) synthesis of compound 34
By compound 34-11 (263mg, 0.5mmol, 1.0eq), compound 1-14 (193mg, 1.1mmol, 2.2eq), 2-
Oxime cyan-acetic ester (57mg, 0.4mmol, 0.8eq) and DIPEA (32mg, 0.25mmol, 0.5eq) join DCM (15mL)
In, add EDCI (211mg, 1.1mmol, 2.2eq), room temperature reaction 3h.Reactant liquor is poured in water (30mL), use DCM
(15mL × 3) extract, and organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (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:
Step 1) synthesis of compound 35-2
Compound 1-6 (1.2g, 3.1mmol, 1.0eq) and compound 35-1 (0.82g, 0.34mmol, 1.1eq) is added
In acetonitrile (10mL), at 0 DEG C, drip triethylamine (0.47g, 4.6mmol, 1.5eq), drip off room temperature reaction 2h.Screw out molten
Agent, adds water (20mL), then extracts (20mL × 3) with DCM, and organic facies anhydrous sodium sulfate is dried, and is spin-dried for, and obtains brown oil and produces
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.
Step 2) synthesis of compound 35-3
Compound 35-2 (1.70g, 3.1mmol, 1.0eq) and ammonium acetate (1.4g, 19mmol, 6.0eq) are joined first
In benzene (10mL), 115 DEG C of reaction 15h.Being spin-dried for by toluene, add water (50mL), then extract (15mL × 3) with DCM, organic facies is used
Anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (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]+.
Step 3) synthesis of compound 35-4
By compound 35-3 (1.25g, 2.37mmol, 1.0eq), connection pinacol borate (0.63g, 2.49mmol,
1.05eq), potassium acetate (0.69g, 7.11mmol, 3.0eq), Pd (dppf)2Cl2(52mg, 0.071mmol, 0.03eq), adds
In DMF (10mL), the lower 100 DEG C of reaction 16h of nitrogen protection.Being poured into water by reactant liquor, sucking filtration obtains gray solid, silica gel column layer
Analysis purification (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]+.
Step 4) synthesis of compound 35-5
By compound 35-4 (600mg, 1.19mmol, 1.0eq), compound 7-7A (494g, 1.19mmol, 1.0eq), carbon
Acid potassium (0.33g, 2.37mmol, 2.0eq), four triphenyl phosphorus palladiums (41mg, 0.035mmol, 0.03eq) join ethanol
(10mL) with in water (3mL), under nitrogen protection, 90 DEG C are reacted 10h.Reactant liquor is poured in water (50mL), extract with dichloromethane
Taking (30mL × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=1:1),
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]+.
Step 5) synthesis of compound 35-6
Compound 35-5 (0.80g, 1.1mmol, 1.0eq) is joined in DCM (15mL), drip HCl/EtOAc at 0 DEG C
(4N, 3mL) solution, drips off room temperature reaction 15h.Being spin-dried for by solvent, add EtOAc (20mL), room temperature making beating 1h, sucking filtration obtains yellowish
Color solid, dissolves with water (10mL), then dissociates with sodium carbonate liquor, separates out solid, sucking filtration, is dried to obtain 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]+.
Step 6) synthesis of compound 35
By compound 35-6 (280mg, 0.54mmol, 1.0eq), compound 1-14 (209mg, 1.20mmol, 2.2eq),
2-oxime cyan-acetic ester (61mg, 0.43mmol, 0.8eq) and DIPEA (35mg, 0.27mmol, 0.5eq) joins DCM
(15mL), in, EDCI (227mg, 1.19mmol, 2.2eq), room temperature reaction 18h are added.Reactant liquor is poured in water (30mL),
Extracting with DCM (15mL × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (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:
Step 1) synthesis of compound 36-2
By 5-methoxyl group-3,4-naphthane-1 (2H)-one 36-1 (12g, 68mmol), triethyl silicane (26.3g,
272mmol), ammonium fluoride (8.3g, 272mmol) be dissolved in trifluoroacetic acid (100mL), 72 DEG C reaction 6h.Screw out solvent, residue
Dissolving by ethyl acetate (300mL × 2), organic facies sodium bicarbonate solution neutralizes, and washing is dried, is spin-dried for, residue silicagel column
Chromatography purification (PE), obtains colorless oil 10g, productivity 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]+.
Step 2) synthesis of compound 36-3
Compound 36-2 (11g, 67.8mmol), aluminum chloride (13.7g, 100mmol) are dissolved in DCM (100mL), 0
Chloroacetic chloride (7g, 88mmol), after dropping, room temperature reaction 24h is dripped under the conditions of DEG C.Reactant liquor is poured in frozen water, use second
Acetoacetic ester (200mL × 2) extracts, washing, is dried, is spin-dried for, residue silica gel column chromatography purification (PE), obtains pale yellow oil
4g, productivity 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]+.
Step 3) synthesis of compound 36-4
Compound 36-3 (9g, 44mmol) is dissolved in N-Methyl pyrrolidone (90mL), adds pyridine hydrobromide salt
(28g, 176mmol), reacts 4h under the conditions of 180 DEG C.Reactant liquor is joined in water (400mL), with ethyl acetate (300mL ×
2) extraction, merges organic layer, and saturated aqueous common salt (150mL) washs, and is dried, residue silica gel column chromatography purification (PE:EtOAc (V:
V)=10:1), obtain white solid 4g, productivity 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]+.
Step 4) synthesis of compound 36-5
At 0 DEG C, trifluoromethanesulfanhydride anhydride (6.5g, 23mmol) is added drop-wise to compound 36-4 (4g, 21mmol), pyridine
In dichloromethane (120mL) mixed liquor of (2.2g, 27mmol), add rear room temperature reaction 3h.Reactant liquor water (30mL) is washed
Washing, organic facies is dried, and is spin-dried for, residue silica gel column chromatography purification (PE:EtOAc (V:V)=10:1), obtains colorless oil
2.8g, productivity 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]+.
Step 5) synthesis of compound 36-6
Joining in ethanol (50mL) by compound 36-5 (2.6g, 8mmol), copper bromide (3.6g, 16mmol), 60 DEG C anti-
Answer 2h.Reactant liquor kieselguhr filters, and filtrate is spin-dried for, and dissolves with DCM (50mL × 2), and saturated nacl aqueous solution (30mL) washs,
Anhydrous sodium sulfate is dried, and is spin-dried for, yellow solid 2.8g, productivity 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]+.
Step 6) synthesis of 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 dichloromethane (60mL) of base-L-PROLINE (2.0g, 9mmol), add rear room temperature reaction 8h.Reactant liquor water (20mL) is washed
Washing, anhydrous sodium sulfate is dried, and is spin-dried for, residue silica gel column chromatography purification (PE:EtOAc (V:V)=6:1), obtains colorless oil
Thing 3g, productivity 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]+.
Step 7) synthesis of compound 36-8
Compound 36-7 (3g, 5.6mmol), ammonium acetate (2.6g, 33mmol) are joined in toluene (60mL), 110 DEG C
Reaction 12h.Reaction adds water (20mL) after terminating, and extracts by ethyl acetate (50mL × 2), and organic facies is washed, anhydrous sodium sulfate
It is dried, vacuum rotary steam, residue silica gel column chromatography purification (PE:EtOAc (V:V)=4:1), obtains pale tan oil 0.8g, produce
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]+.
Step 8) synthesis of compound 36-9
By compound 36-8 (0.8g, 1.6mmol), pinacol connection 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.Reactant liquor is cooled to room temperature, adds water (60mL), sucking filtration, after solid with methylene chloride dissolves, is spin-dried for, silicagel column
Chromatography purification (PE:EtOAc (V:V)=4:1), obtains pale tan oil 0.65g, productivity 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]+.
Step 9) synthesis of 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 ethanol (16mL) and water (4mL), under nitrogen protection, and 90 DEG C of reaction 3h.Rotation
Going out solvent, residue DCM (80mL) is extracted twice, and organic layer saturated nacl aqueous solution (20mL) washs, anhydrous sodium sulfate
It is dried, screws out solvent, residue silica gel column chromatography purification (DCM:EtOAc (V:V)=2:1), obtain yellow solid 0.7g, productivity
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]+.
Step 10) synthesis of compound 36-11
At 0 DEG C, HCl/EtOAc (4N, 4mL) is added drop-wise to the dichloromethane of compound 36-10 (0.7g, 0.9mmol)
(16mL), in, rear room temperature reaction 3h is dripped off.Screwing out reactant liquor, residue ethyl acetate is pulled an oar, and filters.Filter cake use water (10mL)
Dissolve, add potassium carbonate and adjust pH value to 8-9, sucking filtration, obtain yellow solid 0.58g, productivity 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]+.
Step 11) synthesis of compound 36:
Compound 36-11 (0.28g, 0.41mmol), (S)-2-((methoxycarbonyl base) amino)-3 Methylbutanoic acid 1-14
(0.09g, 0.5mmol), 2-oxime cyan-acetic ester (0.024g, 0.165mmol) are dissolved in DCM (10mL), under room temperature condition
Add EDCI (0.1g, 0.5mmol), room temperature reaction 2h.The cancellation that adds water is reacted, and adds DCM (50mL) extraction, screws out solvent, residue
Dissolve with methanol (20mL), add ammonia (1mL), after stirring 5min, be spin-dried for, extract with DCM (50mL), saturated nacl aqueous solution
(10mL) washing, anhydrous sodium sulfate is dried, and screws out solvent, residue silica gel column chromatography purification (DCM:EtOAc:MeOH (V:V:V)
=20:10:1), obtain white solid 0.2g, productivity 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-oxime cyan-acetic ester (0.024g, 0.16mmol) are dissolved in DCM (10mL), room temperature bar
EDCI (0.098g, 0.5mmol), room temperature reaction 2h is added under part.The cancellation that adds water is reacted, and adds DCM (50mL) extraction, screws out solvent,
Residue methanol (20mL) dissolves, and adds ammonia (1mL), after stirring 5min, is spin-dried for, extracts with DCM (50mL), saturated sodium-chloride
Solution (10mL) washs, and anhydrous sodium sulfate is dried, back-out solvent, residue silica gel column chromatography purification (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:
Step 1) synthesis of 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), at 0 DEG C, drip triethylamine (0.39g, 3.9mmol, 1.5eq), drip off room temperature reaction 2h.Screw out molten
Agent, adds water (20mL), then extracts (20mL × 3) with DCM, and organic facies anhydrous sodium sulfate is dried, and is spin-dried for, and obtains brown oil and produces
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.
Step 2) synthesis of compound 38-3
Compound 38-2 (1.42g, 2.6mmol, 1.0eq) and ammonium acetate (1.2g, 15.6mmol, 6.0eq) are joined
In toluene (15mL), 115 DEG C of reaction 20h.Toluene is spin-dried for, adds water (50mL), then extract (15mL × 3) with DCM, organic facies
It is dried with anhydrous sodium sulfate, is spin-dried for, silica gel column chromatography purification (PE:EtOAc (V:V)=5:1), obtain faint yellow solid 1.28g, receive
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]+.
Step 3) synthesis of compound 38-4
By compound 38-3 (1.26g, 2.37mmol, 1.0eq), connection pinacol borate (0.63g, 2.49mmol,
1.05eq), potassium acetate (0.70g, 7.1mmol, 3.0eq), Pd (dppf)2Cl2(69mg, 0.094mmol, 0.04eq), joins
In DMF (15mL), the lower 100 DEG C of reaction 10h of nitrogen protection.Being poured into by reactant liquor in water (60mL), sucking filtration obtains gray solid, then silicon
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]+.
Step 4) synthesis of compound 38-5
By compound 38-4 (558mg, 1.10mmol, 1.0eq), compound 15-5 (473g, 1.10mmol, 1.0eq), carbon
Acid potassium (0.30g, 2.21mmol, 2.0eq), four triphenyl phosphorus palladiums (38mg, 0.033mmol, 0.03eq) join ethanol
(10mL) with in water (3mL), under nitrogen protection, 90 DEG C are reacted 6h.Reactant liquor is poured in water (50mL), extract with dichloromethane
(30mL × 3), organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (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]+.
Step 5) synthesis of compound 38-6
Compound 38-5 (0.75g, 1.03mmol, 1.0eq) is joined in DCM (10mL), drip HCl/ at 0 DEG C
EtOAc (4N, 3mL) solution, drips off room temperature reaction 10h.Solvent is spin-dried for, adds EtOAc (20mL), room temperature making beating 1h, sucking filtration
Obtain faint yellow solid, dissolve with water (10mL), then dissociate with sodium carbonate liquor, separate out solid, sucking filtration, be dried to obtain yellow solid product
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]+.
Step 6) synthesis of compound 38
By compound 38-6 (265mg, 0.5mmol, 1.0eq), compound 1-14 (193mg, 1.1mmol, 2.2eq), 2-
Oxime cyan-acetic ester (57mg, 0.4mmol, 0.8eq) and DIPEA (32mg, 0.25mmol, 0.5eq) join DCM (15mL)
In, add EDCI (211mg, 1.1mmol, 2.2eq), room temperature reaction 3h.Reactant liquor is poured in water (30mL), use DCM
(15mL × 3) extract, and organic facies anhydrous sodium sulfate is dried, and is spin-dried for, silica gel column chromatography purification (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]+.
Biotic experiment
Biological Examples 1:HCV Subgenomic replicon is analyzed
Experiment purpose:
Evaluation compound is to HCV wild type replicon GT1a, GT1b and GT2a, and HCV replicon chimera GT3a, GT
4a, GT5a and GT6a, and GT1b L31V, the inhibitory action of GT1b Y93H persister.
Experimental technique:
GT1a, GT1b and GT2a replicon active testing: will be with G418 resistant gene NEO and luciferase reporter gene
The RNA point hit method respectively transient transfection of HCV GT1a H77 replicon, GT1b Con1b replicon and GT2a JFH1 replicon
To Huh-7 cell, add G418 and screen 3~4 weeks, build stable transfected cells strain.Huh7-H77 and Huh7-JFH1 is surely turned thin
Born of the same parents' strain is diluted to 5 × 104/ mL, inoculates 200 μ L to 96 orifice plates, Huh7-Con1b stable cell strain is diluted to 1 × 105/ mL, connects
Plant 50 μ L to 384 orifice plates.After 16-24h, using 3 times of gradient dilutions, diluted chemical compound is extremely closed by the dilution process of 11 dilution point
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 eventually
Concentration is 0.5%.At 37 DEG C, 5%CO2CO2After constant temperature culture hatches 72h, in every hole, add the luciferase inspection of 40 μ L
Test agent (Promega Bright-Glo), after 5min, detects with chemiluminescence detection system (Envision).Use
Experimental result is processed by GraphPad Prism software, the EC50 of computerized compound replicon each to HCV suppression.
GT3a, GT4a, GT5a, GT6a mosaic type replicon and GT1b L31V, GT1b Y93H persister active testing: logical
Cross electric-shocking method by HCV GT1b/GT3a-NS5A, HCV GT1b/GT4a-NS5A, HCV GT1b/GT5a-NS5A, HCV
GT1b/GT6a-NS5A is fitted together to replicon rna and HCV GT1b L31V, HCV GT1b Y93H drug resistance replicon rna proceed to respectively
Huh7 cell, is inoculated into cell in the 96 hole brassboards containing respective concentration compound with the density in 10000, every hole subsequently.
Compound DMSO mother solution is diluted, adds in 96 hole brassboards, DMSO final concentration of 0.5%.By cell at 5%CO2, 37
Cultivate 72 hours under the conditions of DEG C.In cell hole, add luciferase luminous substrate Bright-Glo, send out with chemistry after waiting 5 minutes
Optical detection system Envision detects Luminescence signal value, and initial data (RLU) is used for computerized compound inhibitory activity.
By suppression percent import GraphPad Prism software carry out nonlinear fitting calculate curve corresponding to compound and
Inhibitory activity (EC50) numerical value to hepatitis C virus replicon.
The EC50 result of compound genocopy each to HCV is as shown in table 2.
Table 2
Conclusion: in table, result display the compounds of this invention is to HCVGT1a, GT1b, GT2a, GT3a, GT4b, GT5a, GT6a
Replicon is respectively provided with good inhibitory activity, HCVGT1b L31V, GT1b Y93H persister is also had well suppression simultaneously
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 technique:
Taking male SD rat and be divided into two groups, often group 3, one group of intravenous injection the compounds of this invention, dosage is 1.0mg/kg,
Another group is orally administered to described compound 5.0mg/kg.After administration in 24h take a blood sample 8~9 time points.Build according to sample concentration
The standard curve of vertical OK range, uses AB SCIEX API4000 type LC-MS/MS, measures in plasma sample under MRM pattern
The concentration of described compound.According to pharmaceutical concentration-time curve, the WinNonLin 6.3 non-compartment model method of software is used to calculate
Pharmacokinetic parameters.Result is as shown in table 3.
Table 3
Conclusion: table 3 result display the compounds of this invention has preferable bioavailability.
It will be apparent to one skilled in the art that present invention is not limited to foregoing illustrative embodiment, and
And can be embodied in other concrete form without departing from its essential characteristics.It is therefore contemplated that each embodiment is the most all
It is considered illustrative and nonrestrictive, should refer to appended claims rather than these embodiments aforementioned, therefore,
All changes in the implication of appended claims equivalents and scope are included in herein.
In the description of this specification, reference term " embodiment ", " some embodiments ", " example ", " specifically show
Example " or the description of " some examples " etc. means to combine this embodiment or example describes specific features, structure, material or feature
It is contained at least one embodiment or the example of the present invention.In this manual, the schematic representation of above-mentioned term is differed
Surely identical embodiment or example are referred to.And, the specific features of description, structure, material or feature can be any
One or more embodiments or example combine in an appropriate manner.
Although above it has been shown and described that embodiments of the invention, it is to be understood that above-described embodiment is example
Property, it is impossible to be interpreted as limitation of the present invention, those of ordinary skill in the art is without departing from the principle of the present invention and objective
In the case of above-described embodiment can be changed within the scope of the invention, revise, replace and modification, the scope of the present invention
Limited by claim and equivalent thereof.
Claims (21)
1. a compound, it is the stereoisomer of compound, geometrical isomerism shown in the compound shown in formula (I) or formula (I)
Body, tautomer, enantiomer, nitrogen oxides, hydrate, solvate, metabolite, 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, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl ,-C (=O)-
(CR8R8a)t-N(R9)-R10Or a-amino acid group;
Wherein a-amino acid group selected from isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan,
Valine, alanine, agedoite, aspartic acid, glutamic acid, glutamine, proline, serine, to tyrosine, arginine,
Histidine, cysteine, glycine, sarcosine, N, N-dimethylglycine, homoserine, norvaline, nor-leucine, bird
The base that propylhomoserin, homocysteine, homophenylalanin, phenylglycine, adjacent tyrosine, m-Tyrosine or hydroxyproline are formed
Group;
R1、R2、R3And R4It is each independently H, deuterium, alkyl, aryl alkyl, cycloalkyl, heterocyclic radical, heteroaryl or aryl;Or R1、
R2It is randomly formed 3-8 unit heterocycle, 3-8 unit carbocyclic ring, condensed-bicyclic with X-CH, condenses miscellaneous dicyclo, spiral shell dicyclo or the miscellaneous dicyclo of spiral shell;Or
R3、R4With X1-CH is randomly formed 3-8 unit heterocycle, 3-8 unit carbocyclic ring, condensed-bicyclic, condenses miscellaneous pair of miscellaneous dicyclo, spiral shell dicyclo or spiral shell
Ring;
Each R5And R6Independently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, alkyl, haloalkyl, alkene
Base, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aryl, heteroaryl, aryl alkyl, alkoxyalkyl, alkoxyl, aryl ammonia
Base, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, heteroaryl epoxide, heteroaryl alkyl, alkoxy aryl, heteroaryl
Alkoxyl, heterocyclic radical epoxide, heterocyclylalkoxy, heterocyclylamino group, alkyl acyl, alkyl acyloxy, alkoxyacyl, heterocycle
Base alkylamino or aryloxy group;
Each R7、R7a、R7b、R8、R8aAnd R9aIndependently be H, deuterium, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano group, deuterated
Alkyl, alkyl, haloalkyl, alkoxyl, thiazolinyl, alkynyl, heterocyclic radical, cycloalkyl, sulfydryl, nitro, aryl, heteroaryl, aryl
Alkyl, alkoxyalkyl, heteroaryl alkyl, cycloalkyl-alkyl, cycloheteroalkylalkyl, arylamino, heteroaryl amino, aryl alkane ammonia
Base, heteroarylalkylamino, heteroaryl epoxide, alkoxy aryl, heteroarylalkoxy, heterocyclic radical epoxide, heterocyclylalkoxy, miscellaneous
Ring group amino, alkyl-OC (=O)-, alkyl-C (=O)-, carbamoyl, alkyl-OS (=O)r-, alkyl-S (=O)rO-、
Alkyl-OS (=O)rO-, alkyl-S (=O)r-, heterocyclic radical alkylamino or aryloxy group;
Each R9And R10Independently be H, deuterium, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl, alkyl-OC (=
O)-, alkyl-C (=O)-, carbamoyl, alkyl-OS (=O)r-, alkyl-S (=O)rO-, alkyl-S (=O)r-or amino
Sulfonyl;
Each f, n and t independently be 0,1,2,3 or 4;
M is 1,2,3 or 4;With
Each r independently be 0,1 or 2;
The following group of each of which: alkyl, alkoxyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl ,-C (=
O)-(CR8R8a)t-N(R9)-R10, a-amino acid group, 3-8 unit heterocycle, 3-8 unit carbocyclic ring, condensed-bicyclic, condense miscellaneous dicyclo, spiral shell
The miscellaneous dicyclo of dicyclo, spiral shell, haloalkyl, thiazolinyl, alkynyl, alkoxyalkyl, heteroaryl alkyl, cycloalkyl-alkyl, cycloheteroalkylalkyl,
Arylamino, heteroaryl amino, aryl alkane amino, heteroarylalkylamino, aryloxy group, heteroaryl epoxide, alkoxy aryl, heteroaryl
Base alkoxyl, heterocyclic radical epoxide, heterocyclylalkoxy, heterocyclylamino group, alkyl-OC (=O)-, alkyl-C (=O)-, amino first
Acyl group, alkyl-OS (=O)r-, alkyl-S (=O)rO-, alkyl-S (=O)r-or amino-sulfonyl individually optionally by 1,2,3
Or 4 selected from hydroxyl, deuterium, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl, alkylamino, alkylthio group, alkyl, alkyl halide
Base, alkoxyalkyl, halogenated alkoxy alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, sulfydryl, nitro, aryloxy group, aryl ammonia
Base, heteroaryl epoxide, heteroaryl alkyl, oxo (=O), carboxyl, the substituted alkoxyl of hydroxyl, hydroxyl substituted alkyl-C (=
O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2-, hydroxyl substituted alkyl-S (=O)-, hydroxyl substituted
Alkyl-S (=O)2-or the substituent group of the substituted alkoxyl of carboxyl replaced.
Compound the most according to claim 1, wherein, each R1、R2、R3And R4Independently be H, C1-6Alkyl, C6-10Aryl
C1-6Alkyl, C3-10Cycloalkyl, C2-10Heterocyclic radical, C1-9Heteroaryl or C6-10Aryl;Or R1、R2It is randomly formed 3-8 unit with X-CH
Heterocycle, 3-8 unit carbocyclic ring, C5-12Condensed-bicyclic, C5-12Condense miscellaneous dicyclo, C5-12Spiral shell dicyclo or C5-12The miscellaneous dicyclo of spiral shell;Or R3、R4With
X1-CH is randomly formed 3-8 unit heterocycle, 3-8 unit carbocyclic ring, C5-12Condensed-bicyclic, C5-12Condense miscellaneous dicyclo, C5-12Spiral shell dicyclo or C5-12
The miscellaneous dicyclo of spiral shell;Wherein said 3-8 unit heterocycle, 3-8 unit carbocyclic ring, C5-12Condensed-bicyclic, C5-12Condense miscellaneous dicyclo, C5-12Spiral shell dicyclo
Or C5-12The miscellaneous dicyclo of spiral shell individually optionally by 1,2,3 or 4 selected from H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl,
C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl, C1-6Alkoxy C1-6Alkyl, C1-6Halogenated alkoxy C1-6Alkyl, C1-6Alkane ammonia
Base, C1-6Alkylthio group, C6-10Arylamino, C6-10Aryloxy group, C1-9Heteroaryl, C1-9Heteroaryl epoxide, C1-9Heteroaryl C1-6Alkyl,
C3-8Cycloalkyl or C2-10The substituent group of heterocyclic radical is replaced.
Compound the most according to claim 1, wherein R1、R2Heterocycle, condensed ring or the spiro ring system choosing formed with Y-X-CH
From following subformula:
Wherein R3、R4With Y1-X1Heterocycle, condensed ring or the spiro ring system that-CH is formed is selected from following subformula:
Wherein, each R15Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, C1-6Alkyl, C1-6Haloalkyl,
C1-6Alkoxyl, C1-6Alkoxy C1-6Alkyl, C1-6Halogenated alkoxy C1-6Alkyl, C1-6Alkylamino, C1-6Alkylthio group, C6-10Aryl
Amino, C6-10Aryloxy group, C1-9Heteroaryl, C1-9Heteroaryl epoxide, C1-9Heteroaryl C1-6Alkyl, C3-8Cycloalkyl or C2-10Heterocycle
Base;
Each R9bIndependently be hydrogen, deuterium, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C1-6Aminoalkyl, C1-6Alkoxyl
C1-6Alkyl, C1-6Alkylamino C1-6Alkyl, C1-6Alkylthio group C1-6Alkyl, C6-10Aryl C1-6Alkyl, C1-9Heteroaryl, C6-10Aryl,
C2-10Heterocyclic radical or C3-8Cycloalkyl;
With each n1And n2Independently be 1,2,3 or 4.
Compound the most according to claim 3, each R15Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl
Base, C1-3Alkyl, C1-3Haloalkyl, C1-3Alkoxyl, C1-3Alkoxy C1-3Alkyl, C1-3Halogenated alkoxy C1-3Alkyl, C1-3Alkane
Amino, C1-3Alkylthio group, C6-10Arylamino, C6-10Aryloxy group, C1-9Heteroaryl, C1-9Heteroaryl epoxide, C1-9Heteroaryl C1-3Alkane
Base, C3-8Cycloalkyl or C2-10Heterocyclic radical;With
Each R9bIndependently be hydrogen, deuterium, C1-3Alkyl, C1-3Haloalkyl, C1-3Hydroxy alkyl, C1-3Aminoalkyl, C1-3Alkoxyl
C1-3Alkyl, C1-3Alkylamino C1-3Alkyl, C1-3Alkylthio group C1-3Alkyl, C6-10Aryl C1-3Alkyl, C1-9Heteroaryl, C6-10Aryl,
C2-10Heterocyclic radical or C3-8Cycloalkyl.
Compound the most according to claim 3, each R15Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl
Base, methyl, ethyl, propyl group, isopropyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy, methoxy, difluoromethoxy
Ylmethyl, trifluoromethoxy methyl, ethoxyl methyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, methylamino, ethylamino, benzene
Base amino, phenoxy group, pyrrole radicals, morpholinyl or piperazinyl;With
Each R9bIndependently be hydrogen, deuterium, methyl, ethyl, propyl group, isopropyl, trifluoromethyl, hydroxymethyl, amino methyl, methoxyl group
Methyl, ethoxyl methyl, phenyl methyl, phenyl, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl.
Compound the most according to claim 1, wherein, each R7、R7a、R7bAnd R9aIndependently be H, deuterium, oxo (=O), hydroxyl
Base, amino, F, Cl, Br, I, cyano group, C1-6Alkyl, C1-6Haloalkyl, C2-6Thiazolinyl, C2-6Alkynyl, C2-10Heterocyclic radical, C3-8Cycloalkanes
Base, sulfydryl, nitro, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, C1-9Heteroaryl C1-6
Alkyl, C3-8Cycloalkyl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl, C6-10Arylamino, C1-9Heteroaryl amino, C6-10Aryl C1-6
Alkylamino, C1-9Heteroaryl C1-6Alkylamino, C1-9Heteroaryl epoxide, C6-10Aryl C1-6Alkoxyl, C1-9Heteroaryl C1-6Alkoxyl,
C2-10Heterocyclic radical epoxide, C2-10Heterocyclic radical C1-6Alkoxyl, 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-、C1-6Alkane
Base-S (=O)r-、C2-10Heterocyclic radical C1-6Alkylamino or C6-10Aryloxy group;Independently be 0,1 or 2 with each r.
Compound the most according to claim 1, wherein Y and Y1It is each independently H, deuterium, C1-6Alkyl, C3-8Cycloalkyl,
C2-10Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl ,-C (=O)-(CR8R8a)t-N(R9)-R10;
Each R8And R8aIndependently be H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyano group, C1-6Alkyl, C1-6Deuteroalkyl, C1-6Halo
Alkyl, C1-6Alkoxyl, C2-6Thiazolinyl, C2-6Alkynyl, C2-10Heterocyclic radical, C3-8Cycloalkyl, sulfydryl, nitro, C6-10Aryl C1-6Alkyl,
C1-6Alkoxy C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C3-8Cycloalkyl C1-6Alkyl, C2-10Heterocyclic radical C1-6Alkyl, C6-10Aryl
Amino, C1-9Heteroaryl amino, C6-10Aryl C1-6Alkylamino, C1-9Heteroaryl C1-6Alkylamino, C1-9Heteroaryl epoxide, C6-10Aryl
C1-6Alkoxyl, C1-9Heteroaryl C1-6Alkoxyl, C2-10Heterocyclic radical epoxide, C2-10Heterocyclic radical C1-6Alkoxyl, C2-10Heterocyclic radical ammonia
Base, 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-、C2-10Heterocyclic radical C1-6Alkylamino or C6-10Aryloxy group;
R9And R10It is each independently H, deuterium, C1-6Alkyl, C3-8Cycloalkyl, C2-10Heterocyclic radical, C6-10Aryl, C1-9Heteroaryl,
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)r-or amino-sulfonyl;
T is 0,1,2,3 or 4;With
Each r independently be 0,1 or 2.
Compound the most according to claim 7, R9And R10It is each independently H, deuterium, methyl, ethyl, isopropyl, positive fourth
Base, isobutyl group, sec-butyl, the tert-butyl group, methyl-OC (=O)-, ethyl-OC (=O)-, propyl group-OC (=O)-, isopropyl-OC
(=O)-, the tert-butyl group-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-, ring third
Base-OS (=O)2-, methyl-S (=O)2O-, cyclopropyl-S (=O)2O-or amino-sulfonyl.
Compound the most according to claim 1, it has the structure shown in formula (II), (IIa), (IIb) or (III), or
Structural upright isomer shown in formula (II), (IIa), (IIb) or (III), geometric isomer, tautomer, enantiomerism
Body, 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 R15Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyano group, hydroxyl, C1-3Alkyl, C1-3Haloalkyl,
C1-3Alkoxyl, C1-3Alkoxy C1-3Alkyl, C1-3Halogenated alkoxy C1-3Alkyl, C1-3Alkylamino, C1-3Alkylthio group, C6-10Aryl
Amino, C6-10Aryloxy group, C1-9Heteroaryl, C1-9Heteroaryl epoxide, C1-9Heteroaryl C1-3Alkyl, C3-8Cycloalkyl or C2-10Heterocycle
Base;
With each n1And n2Independently be 1,2,3 or 4.
Compound the most according to claim 9, each R8And R8aIndependently be H, deuterium, hydroxyl, amino, F, Cl, Br, I, cyanogen
Base, C1-6Alkyl, C1-6Deuteroalkyl, C1-6Haloalkyl, C1-6Alkoxyl, C2-6Thiazolinyl, C2-6Alkynyl, C2-10Heterocyclic radical, C3-8Ring
Alkyl, sulfydryl, nitro, C6-10Aryl C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, C1-9Heteroaryl C1-6Alkyl, C3-8Cycloalkyl C1-6
Alkyl, C2-10Heterocyclic radical C1-6Alkyl, C6-10Arylamino, C1-9Heteroaryl amino, C6-10Aryl C1-6Alkylamino, C1-9Heteroaryl
C1-6Alkylamino, C1-9Heteroaryl epoxide, C6-10Aryl C1-6Alkoxyl, C1-9Heteroaryl C1-6Alkoxyl, C2-10Heterocyclic radical epoxide,
C2-10Heterocyclic radical C1-6Alkoxyl, 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
Heterocyclic radical C1-6Alkylamino or C6-10Aryloxy group.
11. compounds according to claim 9, the most each R15Independently be H, deuterium, oxo (=O), F, Cl, Br, I, cyanogen
Base, hydroxyl, methyl, ethyl, propyl group, isopropyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy, methoxy, difluoro
Methoxy, trifluoromethoxy methyl, ethoxyl methyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, methylamino, second ammonia
Base, phenyl amino, phenoxy group, pyrrole radicals, morpholinyl or piperazinyl.
12. according to described compound arbitrary in claim 1-11, each R5And R6Independently be H, deuterium, oxo (=O), hydroxyl,
Amino, F, Cl, Br, I, cyano group, C1-6Alkyl, C1-6Haloalkyl, C2-6Thiazolinyl, C2-6Alkynyl, C2-10Heterocyclic radical, C3-8Cycloalkyl,
Sulfydryl, nitro, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, C1-6Alkoxyl, C6-10Virtue
Base amino, C1-9Heteroaryl amino, C6-10Aryl C1-6Alkylamino, C1-9Heteroaryl C1-6Alkylamino, C1-9Heteroaryl epoxide, C1-9Miscellaneous
Aryl C1-6Alkyl, C6-10Aryl C1-6Alkoxyl, C1-9Heteroaryl C1-6Alkoxyl, C2-10Heterocyclic radical epoxide, C2-10Heterocyclic radical C1-6
Alkoxyl, C2-10Heterocyclylamino group, C1-6Alkyl acyl, C1-6Alkyl acyloxy, C1-6Alkoxyacyl, C2-10Heterocyclic radical C1-6Alkane
Amino or C6-10Aryloxy group.
13. compounds according to claim 12, the most each R5And R6Independently be H, deuterium, oxo (=O), hydroxyl, ammonia
Base, F, Cl, Br, I, cyano group, methyl, ethyl, propyl group, isopropyl, normal-butyl, the tert-butyl group, trifluoromethyl, methoxy, first
Epoxide, ethyoxyl, vinyl, pi-allyl, acetenyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenyl, phenyl epoxide, benzene
Base amino, sulfydryl or nitro.
14. according to the arbitrary described compound of claim 1-11, wherein, each R8And R8aIndependently be H, deuterium, hydroxyl, amino,
F, Cl, Br, I, cyano group, methyl, ethyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, deuterated methyl, deuterated second
Base, deuterated propyl group, deuterated isopropyl, methoxyl group, ethyoxyl, isopropoxy, methoxy, 1-methoxy ethyl, 2-methoxy
Base ethyl, 1-methoxy-propyl, 2-methoxy-propyl, 3-methoxy-propyl, phenyl, pyranose, cyclopropyl, cyclobutyl, ring penta
Base, cyclohexyl, trifluoromethyl, vinyl, pi-allyl, acetenyl, morpholinyl, sulfydryl, nitro, benzyl, anilino-.
15. compounds according to claim 1, its solid with structure shown below or structure shown below is different
Structure body, geometric isomer, tautomer, enantiomer, nitrogen oxides, hydrate, solvate, metabolite, pharmacy
Upper acceptable salt or prodrug:
16. a pharmaceutical composition, wherein said pharmaceutical composition comprises the chemical combination according to any one of claim 1-15
Thing, and pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
17. pharmaceutical compositions according to claim 16, it further comprises other the medicine of HCV-Ab IgG.
18. pharmaceutical compositions according to claim 17, other the medicine of HCV-Ab IgG wherein said is interferon, Li Ba
Wei Lin, interleukin-22, interleukin 6, interleukin 12, promotion produce 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, EBP520, TVR, erlotinib, his Wei of Dacca, the beautiful Wei of department, 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, I
Pool 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 a combination thereof;Described 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 a combination thereof.
19. according to the pharmaceutical composition described in claim 17, and other the medicine of HCV-Ab IgG wherein said is used for suppressing HCV
Reproduction process and/or the function of suppression HCV virus protein;Described HCV reproduction process includes that HCV enters, HCV shells, HCV turns over
Translate, HCV replicates, HCV assembles or HCV release;Described HCV virus protein selected from metalloproteases, NS2, NS3, NS4A,
NS4B, NS5A or NS5B, and the internal ribosome inlet point (IRES) required for HCV virus replication and inosine monophosphate dehydrogenation
Enzyme (IMPDH).
Compound according to any one of 20. claim 1-15 or the drug regimen according to any one of claim 16-19
Thing purposes in preparing medicine, described medicine is for suppressing HCV reproduction process and/or the function of suppression HCV virus protein;Institute
State HCV reproduction process and include that HCV enters, HCV shells, HCV translation, HCV duplication, HCV assembling or HCV release;Described HCV is sick
Toxalbumin is selected from metalloproteases, NS2, NS3, NS4A, NS4B, NS5A or NS5B, and the inside required for HCV virus replication
Ribosome inlet point (IRES) and inosine monophosphate dehydrogenase (IMPDH).
Compound according to any one of 21. claim 1-15 or the drug regimen according to any one of claim 16-19
Thing purposes in preparing medicine, described medicine is used for preventing, process, treat or alleviate HCV infection or hepatitis C disease.
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WO2024017234A1 (en) * | 2022-07-19 | 2024-01-25 | 广东东阳光药业股份有限公司 | Salt of hcv inhibitor, crystal form of salt, pharmaceutical composition of salt, and use of salt |
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WO2021197880A1 (en) | 2020-03-31 | 2021-10-07 | Basf Se | Process for preparation of optically enriched isoxazolines |
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