CN104557954A - Anti-HCV (hepatitis c virus) macrocyclic compound - Google Patents
Anti-HCV (hepatitis c virus) macrocyclic compound Download PDFInfo
- Publication number
- CN104557954A CN104557954A CN201310485061.7A CN201310485061A CN104557954A CN 104557954 A CN104557954 A CN 104557954A CN 201310485061 A CN201310485061 A CN 201310485061A CN 104557954 A CN104557954 A CN 104557954A
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- group
- cycloalkyl
- halogen
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- 0 C*C1(CC1)F Chemical compound C*C1(CC1)F 0.000 description 6
- UQKBJAVUJOGNIU-UHFFFAOYSA-N NC1C=CC=CC1S Chemical compound NC1C=CC=CC1S UQKBJAVUJOGNIU-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Abstract
The invention discloses an anti-HCV (hepatitis c virus) macrocyclic compound which is represented as a formula (I) in the specification. A1 is O, S, CH2, NH or NR'; A2 is NH, O or a connecting bond; when Z3 is C and connected with O, Z1 is N or CRZ1, Z2 is CRZ2, RZ1 and RZ2 can jointly form a 5-7-memebered carbon ring with carbon atoms connected with RZ1 and RZ2; when Z1 is C and is connected with O, Z2 is CH, Z3 is C-Ar, and Ar is aryl or ceteroary; Q is alkylidene or cyclohexylidene replaced or substituted by N, O, S heteroatoms. The compound has an excellent anti-HCV effect.
Description
Technical field
The present invention relates to the compound that a class has antiviral activity, espespecially the macrocylc compound of anti-hepatitis c virus.
Background technology
Hepatitis C virus (HCV) is the Etiological causing chronic hepatic diseases.WHO statistics shows, the whole world about has 1.7 hundred million people to infect hepatitis C virus, accounts for 3% of population in the world.Hepatitis C virus (HCV) is a positive chain RNA being about 9.6kb, comprises 5 ' non-coding region (5 '-UTR), open reading frame (ORF) and 3 ' non-coding region (3 '-UTR).ORF translates generation polypeptide chain, it is processed at least 10 kinds of different protein subsequently, comprising a kind of shell (core) albumen, two kinds of envelope proteins (E1 and E2) and Nonstructural Protein (NS2, NS3, NS4a, NS4b, NS5a and NS5b).
Long-acting polyoxyethylene glycol drum Interferon, rabbit (pegIFN-α) and ribavirin (RBV) combined utilization are the optimal drugs for the treatment of the third liver over the past decade.But still have gene drum HCV infection person over half invalid to this combination antiviral therapy, and the toxic side effect of IFN and RBV is comparatively large and reach 1 year the course for the treatment of, therefore significantly limit its application clinically.
Medicine boceprevir and telaprevir ratifying to go on the market by U.S. FDA in 2011 is all designed the NS3/4a serine protease of target HCV virus.These two kinds of medicine combined standard methods for the treatment of all can improve the curative ratio of hepatitis C patients significantly, but have comparatively severe side effect also.Existing anti-HCV medicament only can cause the side effect of similar influenza mostly, and the potential side effect of Boceprevir then comprises anaemia and occurs the mental disorder be inclined to of committing suiside or kill a person.And hepatitis C there is no effective vaccine at present, therefore, Improvement anti-HCV medicament becomes the task of top priority.
Summary of the invention
The object of the present invention is to provide the compound shown in a kind of formula (1), or its oxynitride, hydrate, solvate, meta-bolites or pharmacy acceptable salt or prodrug,
Wherein, A
1for O, S, CH
2, NR ', O (CHR ')
1 ~ 2, S (CHR ')
1 ~ 2or NH (CHR ')
1 ~ 2, wherein, R ' is hydrogen or the (C for being optionally substituted by halogen or not being optionally substituted by halogen
1-C
6) alkyl;
A
2for NH, O or connecting key;
Work as Z
3for C, and when being connected with O, Z
1for N or CR
z1, Z
2for CR
z2, wherein, R
z1for hydrogen, halogen, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group, NH
2, ((C
1-C
6) alkyl) NH or ((C
1-C
6) alkyl)
2n, R
z2for hydrogen, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group, 6 ~ 10 yuan of aryl or be selected from heteroatomic 5 ~ 10 yuan of heteroaryls of N, O and S containing 1 ~ 2; Or R
z1, R
z2connected carbon atom forms one jointly by R
e, R
f, R
gand R
hreplace or unsubstituted 5 ~ 7 yuan of carbocyclic rings;
Work as Z
1for C, and when being connected with O, Z
2for CH, Z
3for C-Ar, Ar are unsubstituted or by 1 ~ 3 R
arthe aryl of 6 ~ 10 yuan of any replacement or be selected from heteroatomic 5 ~ 10 yuan of heteroaryls of N, O and S containing 1 ~ 2; Wherein, R
arbe selected from substituents group: halogen, amino, (C
1-C
8) alkyl, (C
1-C
8) alkoxyl group, hydroxyl-(C
1-C
8) alkyl and (C
1-C
8) alkylamidoalkyl;
Q is unsubstituted or by 1 ~ 5 R
q' replace-(CH
2)
x-U-(CH
2)
y-V-; Wherein, x, y be independently 0 ~ 9 integer and 1≤x+y≤9, U, V be independently connecting key ,-O-,-S-,-S (O)-,-S (O
2)-,-NH-,-((C
1~ C
6) alkyl) N-,-C (O)-, (C
2-C
4) alkenylene, (C
6-C
10) arylidene ,-(C
6-C
10) arylidene-O-, (C
3~ C
8) cycloalkylidene or containing 1 ~ 3 independently selected from the heteroatomic (C of N, O, S
2~ C
7) sub-Heterocyclylalkyl, wherein, R
q' be halogen, hydroxyl, sulfydryl, NH
2, ((C
1~ C
6) alkyl) NH, ((C
1~ C
6) alkyl)
2n, (C
1~ C
6) alkoxyl group, (C
1~ C
6) alkyl, (C
2~ C
6) thiazolinyl or (C
2~ C
6) alkynyl;
R
a, R
b, R
c, R
d, R
e, R
f, R
gand R
hbe H, OH, halogen or-L independently
1-R
m; L
1for connecting key, O, S, SO, SO
2or NR
n; R
mfor hydrogen, or, R
mfor not to be substituted or by 1 ~ 3 R
mthe substituting group be selected from following group of ' replacement: (C
1-C
8) alkyl, N ≡ C-(C
1-C
6) alkyl, (C
2-C
8) thiazolinyl, (C
2-C
8) alkynyl, (C
3-C
8) cycloalkyl, ((C
3-C
8) cycloalkyl) (C
1-C
6) alkyl, 6 ~ 10 yuan of aryl and containing 1 ~ 2 independently selected from heteroatomic 5 ~ 10 yuan of heteroaryls of N, O, S; R
nfor H, (C
1-C
6) alkyl or (C
3-C
8) cycloalkyl, wherein, R
m' be selected from substituting group in following group: halogen, (C
1-C
6) alkyl, optionally by (C
1-C
6) alkoxyl group or (C
3-C
8) cycloalkyloxy replace (C
1-C
6) alkyl, halo (C
1-C
6) alkyl, (C
3-C
8) cycloalkyl, (C
1-C
6) alkoxyl group, 6 ~ 10 yuan of aryl, containing 1 ~ 2 independently selected from N, O, S heteroatomic 5 ~ 10 yuan of heteroaryls, NH
2, ((C
1-C
6) alkyl) NH and ((C
1-C
6) alkyl)
2n;
R
1for not to be substituted or by 1 ~ 3 R
1the substituting group be selected from following group of ' replacement: (C
1-C
8) alkyl, (C
2-C
8) thiazolinyl, (C
2-C
8) alkynyl, (C
6-C
10) aryl, ((C
6-C
10) aryl) (C
1-C
4) alkyl, (C
3-C
8) cycloalkyl, ((C
3-C
8) cycloalkyl) (C
1-C
4) alkyl, (C
4-C
8) cycloalkenyl group, ((C
4-C
8) cycloalkenyl group) (C
1-C
4) alkyl, (C
2-C
7) Heterocyclylalkyl, ((C
2-C
7) Heterocyclylalkyl) (C
1-C
4) alkyl, (C
3-C
10) heteroaryl and ((C
3-C
10) heteroaryl) (C
1-C
4) alkyl; R
1' be selected from substituting group in following group: halogen, OH, CN, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, NH
2, ((C
1-C
6) alkyl) NH and ((C
1-C
6) alkyl)
2n;
R
2for hydrogen, OH, NH
2, (C
1-C
8) alkyl, (C
3-C
8) cycloalkyl, (C
1-C
8) alkoxyl group, (C
3-C
8) cycloalkyloxy, (C
1-C
8) alkyl-OC (O)-, ((C
1-C
8) alkoxyl group) (C
1-C
8) alkyl, (C
1-C
8) alkylamino radical, (C
3-C
8) cycloalkanes amido, (C
2-C
7) heterocycle alkylamino radical, (C
6-C
10) aryl amine, (C
1-C
8) alkoxy amide base, (C
6-C
10) aryloxy amide group, (C
1-C
8) alkylcarboxamido, (C
3-C
8) cycloalkyl sulfonamido, (C
2-C
7) Heterocyclylalkyl sulfonamido, (C
6-C
10) aryl sulfonamido or (C
1-C
8) alkylamino radical sulfonamido.
In a preferred embodiment of the present invention, work as Z
3for C, and when being connected with O, R
z1, R
z2connected carbon atom forms one jointly by R
e, R
f, R
g, R
hthe 6 yuan of aromatic rings replaced, the structure of general formula (I) compound is such as formula shown in (Ia):
A
1for O, S, CH
2, NR ', O (CHR ')
1 ~ 2, S (CHR ')
1 ~ 2or NH (CHR ')
1 ~ 2, wherein, R ' is hydrogen or the (C for being optionally substituted by halogen or not being optionally substituted by halogen
1-C
6) alkyl;
Preferably A
1for O, S, CH
2or NR ', wherein, R ' is hydrogen or the C for being optionally substituted by halogen or not being optionally substituted by halogen
1-C
4alkyl, preferred C
1-C
2alkyl.
A
2for NH, O or connecting key.
Q is unsubstituted or by 1 ~ 3 R
q' replace-(CH
2)
x-U-(CH
2)
y-V-; Wherein, x, y be independently 0 ~ 9 integer and 2≤x+y≤7, U, V be independently connecting key ,-O-,-S-,-S (O)-,-S (O
2)-,-NH-,-((C
1~ C
4) alkyl) N-,-C (O)-, (C
2-C
3) alkenylene, (C
6-C
8) arylidene ,-(C
6-C
8) arylidene-O-, (C
3~ C
6) cycloalkylidene or containing 1 ~ 2 independently selected from the heteroatomic (C of N, O, S
2~ C
5) sub-Heterocyclylalkyl, wherein, R
q' be halogen, hydroxyl, sulfydryl, NH
2, ((C
1~ C
4) alkyl) NH, ((C
1~ C
4) alkyl)
2n, (C
1~ C
4) alkoxyl group, (C
1~ C
4) alkyl, (C
2~ C
4) thiazolinyl or (C
2~ C
4) alkynyl;
Be preferably, Q is unsubstituted or by 1 R
q' replace-(CH
2)
x-U-(CH
2)
y-V-; Wherein, x, y be independently 0 ~ 9 integer and 3≤x+y≤6, U, V be independently connecting key ,-O-,-S-,-S (O)-,-S (O
2)-,-NH-,-((C
1~ C
2) alkyl) N-,-C (O)-, vinylidene, phenylene ,-phenylene-O-, (C
5~ C
6) cycloalkylidene, containing 1 ~ 2 independently selected from the heteroatomic (C of N, O, S
4~ C
5) sub-Heterocyclylalkyl, wherein, R
q' be halogen, hydroxyl, sulfydryl, NH
2, ((C
1~ C
2) alkyl) NH, ((C
1~ C
2) alkyl)
2n, (C
1~ C
2) alkoxyl group, (C
1~ C
2) alkyl, (C
2~ C
3) thiazolinyl or (C
2~ C
3) alkynyl; Be more preferably Q be-(CH
2)
3 ~ 6-; Be Q be best-(CH
2)
4 ~ 5-.
R
a, R
b, R
c, R
d, R
e, R
f, R
gand R
hbe H, OH, halogen or-L independently
1-R
m; L
1for connecting key, O, S, SO, SO
2or NR
n; R
mfor hydrogen, or, R
mfor not to be substituted or by 1 ~ 3 R
mthe substituting group be selected from following group of ' replacement: (C
1-C
6) alkyl, N ≡ C-(C
1-C
4) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
3-C
7) cycloalkyl, ((C
3-C
7) cycloalkyl) (C
1-C
4) alkyl, 6 ~ 10 yuan of aryl and containing 1 ~ 2 independently selected from heteroatomic 5 ~ 6 yuan of heteroaryls of N, O, S; R
nfor H, (C
1-C
4) alkyl or (C
3-C
7) cycloalkyl, wherein, R
m' be selected from substituting group in following group: halogen, (C
1-C
4) alkyl, optionally by (C
1-C
4) alkoxyl group or (C
3-C
6) cycloalkyloxy replace (C
1-C
4) alkyl, halo (C
1-C
4) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
4) alkoxyl group, 6 yuan of aryl, containing 1 ~ 2 independently selected from N, O, S heteroatomic 5 ~ 6 yuan of heteroaryls, NH
2, ((C
1-C
4) alkyl) NH and ((C
1-C
4) alkyl)
2n;
Be preferably, R
a, R
b, R
c, R
d, R
e, R
f, R
gand R
hbe H, OH, halogen or-L independently
1-R
m; L
1for connecting key, O, S, SO, SO
2or NR
n; R
mfor hydrogen, or, R
mfor not to be substituted or by 1 R
mthe substituting group be selected from following group of ' replacement: (C
1-C
4) alkyl, N ≡ C-(C
1-C
2) alkyl, (C
2-C
4) thiazolinyl, (C
2-C
4) alkynyl, (C
3-C
6) cycloalkyl, ((C
3-C
6) cycloalkyl) (C
1-C
2) alkyl, phenyl and containing 1 ~ 2 independently selected from heteroatomic 5 ~ 6 yuan of heteroaryls of N, O, S; R
nfor H, (C
1-C
2) alkyl or (C
3-C
6) cycloalkyl, wherein, R
m' be selected from substituting group in following group: halogen, (C
1-C
2) alkyl, optionally by (C
1-C
2) alkoxyl group or (C
5-C
6) cycloalkyloxy replace (C
1-C
2) alkyl, halo (C
1-C
2) alkyl, (C
5-C
6) cycloalkyl, (C
1-C
2) alkoxyl group, phenyl, containing 1 ~ 2 independently selected from N, O, S heteroatomic 5 ~ 6 yuan of heteroaryls, NH
2, ((C
1-C
2) alkyl) NH and ((C
1-C
2) alkyl)
2n.
R
1for not to be substituted or by 1 ~ 3 R
1the substituting group be selected from following group of ' replacement: (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl, ((C
6-C
10) aryl) (C
1-C
2) alkyl, (C
3-C
7) cycloalkyl, ((C
3-C
7) cycloalkyl) (C
1-C
2) alkyl, (C
4-C
7) cycloalkenyl group, ((C
4-C
7) cycloalkenyl group) (C
1-C
2) alkyl, (C
2-C
6) Heterocyclylalkyl, ((C
2-C
6) Heterocyclylalkyl) (C
1-C
2) alkyl, (C
4-C
6) heteroaryl and ((C
4-C
6) heteroaryl) (C
1-C
2) alkyl; R
1' be selected from substituting group in following group: halogen, OH, CN, (C
1-C
4) alkyl, (C
2-C
4) thiazolinyl, (C
2-C
4) alkynyl, (C
1-C
4) alkoxyl group, NH
2, ((C
1-C
4) alkyl) NH and ((C
1-C
4) alkyl)
2n;
Be preferably, R
1for not to be substituted or by 1 R
1the substituting group be selected from following group of ' replacement: (C
1-C
4) alkyl, (C
2-C
4) thiazolinyl, (C
2-C
4) alkynyl, phenyl, phenyl (C
1-C
2) alkyl, (C
3-C
6) cycloalkyl, ((C
3-C
6) cycloalkyl) (C
1-C
2) alkyl, (C
5-C
6) cycloalkenyl group, ((C
5-C
6) cycloalkenyl group) (C
1-C
2) alkyl, (C
2-C
5) Heterocyclylalkyl, ((C
2-C
5) Heterocyclylalkyl) (C
1-C
2) alkyl, (C
4-C
5) heteroaryl and (C
4-C
5heteroaryl) (C
1-C
2) alkyl; R
1' be selected from substituting group in following group: halogen, OH, CN, (C
1-C
2) alkyl, (C
2-C
3) thiazolinyl, (C
2-C
3) alkynyl, (C
1-C
2) alkoxyl group, NH
2, ((C
1-C
2) alkyl) NH and ((C
1-C
2) alkyl)
2n;
More preferably, R
1for:
R
2for hydrogen, OH, NH
2, (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
6) alkoxyl group, (C
3-C
7) cycloalkyloxy, (C
1-C
6) alkyl-OC (O)-, ((C
1-C
6) alkoxyl group) (C
1-C
6) alkyl, (C
1-C
6) alkylamino radical, (C
3-C
7) cycloalkanes amido, (C
2-C
6) heterocycle alkylamino radical, (C
6-C
8) aryl amine, (C
1-C
6) alkoxy amide base, (C
6-C
8) aryloxy amide group, (C
1-C
6) alkylcarboxamido, (C
3-C
7) cycloalkyl sulfonamido, (C
2-C
6) Heterocyclylalkyl sulfonamido, (C
6-C
10) aryl sulfonamido or (C
1-C
6) alkylamino radical sulfonamido;
Be preferably, R
2for hydrogen, OH, NH
2, (C
1-C
4) alkyl, (C
3-C
6) cycloalkyl, (C
1-C
4) alkoxyl group, (C
3-C
6) cycloalkyloxy, (C
1-C
4) alkyl-OC (O)-, ((C
1-C
2) alkoxyl group) (C
1-C
4) alkyl, (C
1-C
4) alkylamino radical, (C
3-C
6) cycloalkanes amido, (C
4-C
5) heterocycle alkylamino radical, anilino, (C
1-C
4) alkoxy amide base, phenoxy group amide group, (C
1-C
4) alkylcarboxamido, (C
3-C
6) cycloalkyl sulfonamido, (C
4-C
5) Heterocyclylalkyl sulfonamido, phenyl sulfonamido or (C
1-C
4) alkylamino radical sulfonamido; More preferably R
2for methyl.
In another preferred embodiment of the present invention, work as Z
1for C, and when being connected with O, the structure of general formula (I) compound is such as formula shown in (Ib):
A
1for O, S, CH
2, NR ', O (CHR ')
1 ~ 2, S (CHR ')
1 ~ 2or NH (CHR ')
1 ~ 2, wherein, R ' is hydrogen or the (C for being optionally substituted by halogen or not being optionally substituted by halogen
1-C
6) alkyl;
Preferably, A
1for O, S, CH
2or NR ', wherein, R ' is hydrogen or the C for being optionally substituted by halogen or not being optionally substituted by halogen
1-C
4alkyl, preferred C
1-C
2alkyl.
A
2for NH, O or connecting key.
Q is unsubstituted or by 1 ~ 3 R
q' replace-(CH
2)
x-U-(CH
2)
y-V-; Wherein, x, y be independently 0 ~ 9 integer and 2≤x+y≤7, U, V be independently connecting key ,-O-,-S-,-S (O)-,-S (O
2)-,-NH-,-((C
1~ C
4) alkyl) N-,-C (O)-, (C
2-C
3) alkenylene, (C
6-C
8) arylidene ,-(C
6-C
8) arylidene-O-, (C
3~ C
6) cycloalkylidene or containing 1 ~ 2 independently selected from the heteroatomic (C of N, O, S
2~ C
5) sub-Heterocyclylalkyl, wherein, R
q' be halogen, hydroxyl, sulfydryl, NH
2, ((C
1~ C
4) alkyl) NH, ((C
1~ C
4) alkyl)
2n, (C
1~ C
4) alkoxyl group, (C
1~ C
4) alkyl, (C
2~ C
4) thiazolinyl or (C
2~ C
4) alkynyl;
Be preferably, Q is unsubstituted or by 1 R
q' replace-(CH
2)
x-U-(CH
2)
y-V-; Wherein, x, y be independently 0 ~ 9 integer and 3≤x+y≤6, U, V be independently connecting key ,-O-,-S-,-S (O)-,-S (O
2)-,-NH-,-((C
1~ C
2) alkyl) N-,-C (O)-, vinylidene, phenylene ,-phenylene-O-, (C
5~ C
6) cycloalkylidene, containing 1 ~ 2 independently selected from the heteroatomic (C of N, O, S
4~ C
5) sub-Heterocyclylalkyl, wherein, R
q' be halogen, hydroxyl, sulfydryl, NH
2, ((C
1~ C
2) alkyl) NH, ((C
1~ C
2) alkyl)
2n, (C
1~ C
2) alkoxyl group, (C
1~ C
2) alkyl, (C
2~ C
3) thiazolinyl or (C
2~ C
3) alkynyl; Be more preferably Q be-(CH
2)
3 ~ 6-; Be Q be best-(CH
2)
4 ~ 5-.
Ar is unsubstituted or by 1 ~ 3 R
arthe phenyl of any replacement or be selected from heteroatomic 5 ~ 6 yuan of heteroaryls of N, O and S containing 1 ~ 2; Wherein, R
arbe selected from substituents group: halogen, amino, C
1-C
6alkyl, C
1-C
6alkoxyl group, hydroxyl-(C
1-C
6) alkyl and (C
1-C
6) alkylamidoalkyl;
Be preferably, Ar is unsubstituted or by 1 R
arthe phenyl of any replacement or be selected from heteroatomic 5 ~ 6 yuan of heteroaryls of N, O and S containing 1 ~ 2; Wherein, R
arbe selected from substituents group: halogen, amino, C
1-C
4alkyl, C
1-C
4alkoxyl group, hydroxyl-(C
1-C
4) alkyl and (C
1-C
4) alkylamidoalkyl.
R
a, R
b, R
cand R
dbe H, OH, halogen or-L independently
1-R
m; L
1for connecting key, O, S, SO, SO
2or NR
n; R
mfor hydrogen, or, R
mfor not to be substituted or by 1 ~ 3 R
mthe substituting group be selected from following group of ' replacement: (C
1-C
6) alkyl, N ≡ C-(C
1-C
4) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
3-C
7) cycloalkyl, ((C
3-C
7) cycloalkyl) (C
1-C
4) alkyl, 6 ~ 10 yuan of aryl and containing 1 ~ 2 independently selected from heteroatomic 5 ~ 6 yuan of heteroaryls of N, O, S; R
nfor H, (C
1-C
4) alkyl or (C
3-C
7) cycloalkyl, wherein, R
m' be selected from substituting group in following group: halogen, (C
1-C
4) alkyl, optionally by (C
1-C
4) alkoxyl group or (C
3-C
6) cycloalkyloxy replace (C
1-C
4) alkyl, halo (C
1-C
4) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
4) alkoxyl group, 6 yuan of aryl, containing 1 ~ 2 independently selected from N, O, S heteroatomic 5 ~ 6 yuan of heteroaryls, NH
2, ((C
1-C
4) alkyl) NH and ((C
1-C
4) alkyl)
2n;
Be preferably, R
a, R
b, R
cand R
dbe H, OH, halogen or-L independently
1-R
m; L
1for connecting key, O, S, SO, SO
2or NR
n; R
mfor hydrogen, or, R
mfor not to be substituted or by 1 R
mthe substituting group be selected from following group of ' replacement: (C
1-C
4) alkyl, N ≡ C-(C
1-C
2) alkyl, (C
2-C
4) thiazolinyl, (C
2-C
4) alkynyl, (C
3-C
6) cycloalkyl, ((C
3-C
6) cycloalkyl) (C
1-C
2) alkyl, phenyl and containing 1 ~ 2 independently selected from heteroatomic 5 ~ 6 yuan of heteroaryls of N, O, S; R
nfor H, (C
1-C
2) alkyl or (C
3-C
6) cycloalkyl, wherein, R
m' be selected from substituting group in following group: halogen, (C
1-C
2) alkyl, optionally by (C
1-C
2) alkoxyl group or (C
5-C
6) cycloalkyloxy replace (C
1-C
2) alkyl, halo (C
1-C
2) alkyl, (C
5-C
6) cycloalkyl, (C
1-C
2) alkoxyl group, phenyl, containing 1 ~ 2 independently selected from N, O, S heteroatomic 5 ~ 6 yuan of heteroaryls, NH
2, ((C
1-C
2) alkyl) NH and ((C
1-C
2) alkyl)
2n.
R
1for not to be substituted or by 1 ~ 3 R
1the substituting group be selected from following group of ' replacement: (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl, ((C
6-C
10) aryl) (C
1-C
2) alkyl, (C
3-C
7) cycloalkyl, ((C
3-C
7) cycloalkyl) (C
1-C
2) alkyl, (C
4-C
7) cycloalkenyl group, ((C
4-C
7) cycloalkenyl group) (C
1-C
2) alkyl, (C
2-C
6) Heterocyclylalkyl, ((C
2-C
6) Heterocyclylalkyl) (C
1-C
2) alkyl, (C
4-C
6) heteroaryl and ((C
4-C
6) heteroaryl) (C
1-C
2) alkyl; R
1' be selected from substituting group in following group: halogen, OH, CN, (C
1-C
4) alkyl, (C
2-C
4) thiazolinyl, (C
2-C
4) alkynyl, (C
1-C
4) alkoxyl group, NH
2, ((C
1-C
4) alkyl) NH and ((C
1-C
4) alkyl)
2n;
Be preferably, R
1for not to be substituted or by 1 R
1the substituting group be selected from following group of ' replacement: (C
1-C
4) alkyl, (C
2-C
4) thiazolinyl, (C
2-C
4) alkynyl, phenyl, phenyl (C
1-C
2) alkyl, (C
3-C
6) cycloalkyl, ((C
3-C
6) cycloalkyl) (C
1-C
2) alkyl, (C
5-C
6) cycloalkenyl group, ((C
5-C
6) cycloalkenyl group) (C
1-C
2) alkyl, (C
2-C
5) Heterocyclylalkyl, ((C
2-C
5) Heterocyclylalkyl) (C
1-C
2) alkyl, (C
4-C
5) heteroaryl and (C
4-C
5heteroaryl) (C
1-C
2) alkyl; R
1' be selected from substituting group in following group: halogen, OH, CN, (C
1-C
2) alkyl, (C
2-C
3) thiazolinyl, (C
2-C
3) alkynyl, (C
1-C
2) alkoxyl group, NH
2, ((C
1-C
2) alkyl) NH and ((C
1-C
2) alkyl)
2n;
More preferably, R
1for:
R
2for hydrogen, OH, NH
2, (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
6) alkoxyl group, (C
3-C
7) cycloalkyloxy, (C
1-C
6) alkyl-OC (O)-, ((C
1-C
6) alkoxyl group) (C
1-C
6) alkyl, (C
1-C
6) alkylamino radical, (C
3-C
7) cycloalkanes amido, (C
2-C
6) heterocycle alkylamino radical, (C
6-C
8) aryl amine, (C
1-C
6) alkoxy amide base, (C
6-C
8) aryloxy amide group, (C
1-C
6) alkylcarboxamido, (C
3-C
7) cycloalkyl sulfonamido, (C
2-C
6) Heterocyclylalkyl sulfonamido, (C
6-C
10) aryl sulfonamido or (C
1-C
6) alkylamino radical sulfonamido;
Be preferably, R
2for hydrogen, OH, NH
2, (C
1-C
4) alkyl, (C
3-C
6) cycloalkyl, (C
1-C
4) alkoxyl group, (C
3-C
6) cycloalkyloxy, (C
1-C
4) alkyl-OC (O)-, ((C
1-C
2) alkoxyl group) (C
1-C
4) alkyl, (C
1-C
4) alkylamino radical, (C
3-C
6) cycloalkanes amido, (C
4-C
5) heterocycle alkylamino radical, anilino, (C
1-C
4) alkoxy amide base, phenoxy group amide group, (C
1-C
4) alkylcarboxamido, (C
3-C
6) cycloalkyl sulfonamido, (C
4-C
5) Heterocyclylalkyl sulfonamido, phenyl sulfonamido or (C
1-C
4) alkylamino radical sulfonamido; More preferably R
2for methyl.
In the present invention,
expression both can be double bond also can be singly-bound.
Particular compound of the present invention is:
Another object of the present invention is to provide the purposes of compound of the present invention in preparation prophylaxis of viral infections or antiviral drug, the preferred hepatitis virus of described virus, particularly preferably hepatitis C virus.
Another object of the present invention is to provide the application of the compound shown in formula (I) in the disease of HCV infection.
The patient that another object of the present invention is to give HCV infection is applied with the compound shown in formula (I) of effective amount.
Another object of the present invention is to provide the compound shown in formula (I) and HCV NS3/4a proteinase inhibitor, HCV NS5b AG14361 or other anti-medication combined patient being used for the treatment of HCV infection of third liver.
The synthesis technique flow process of formula (I) compound is as follows:
Compound M prepares reference literature WO2008096001
Compound N prepare reference literature WO2013017026
Embodiment
The synthesis of embodiment 1 Compound I 1
By compound M1 (preparing according to the method for WO2008096001) (30mg, 0.066mmo1) dissolve in dimethyl sulfoxide (DMSO) (DMSO) (2mL), nitrogen replacement, potassium tert.-butoxide (30mg is added at 0 DEG C, 0.26mmo1), then drip dimethyl sulfoxide (DMSO)/1 of compound N 1 (preparing according to the method for WO2013017026) (20mg, 0.066mg), 4-dioxane (1/2,3mL) solution.Add rear reaction stirring at room temperature 1 hour, it is complete that some plate detects raw material primitive reaction.Reaction solution shrend is gone out, and 1N hcl acidifying pH to 1, is extracted with ethyl acetate.Ethyl acetate washed with water is washed, and salt is washed, anhydrous sodium sulfate drying, and decompression is spin-dried for and obtains crude product.This crude product obtains 30mg crude product with preparing silica-gel plate (methylene chloride/methanol=20/1) purifying, point plate is pure not, continue to obtain 19mg product as off-white solid, 41% yield with preparing silica-gel plate (petrol ether/ethyl acetate=1/1) purifying.
1H NMR(400MHz，CDCl
3)δ10.94(brs，1H)，8.36(d，J=8.4Hz，1H)，8.24(d，J=8.0Hz，1H)，8.07(d，J=2.4Hz，1H)，7.84(t，J=8.0Hz，1H)，7.65-7.58(m，2H)，7.44(dd，J=8.4Hz，2.4Hz，1H)，6.34(s，1H)，5.97-5.94(m，1H)，5.72-5.66(m，1H)，5.08(t，J=10.4Hz，1H)，4.63(td，J=9.2Hz，2.4Hz，1H)，3.48-3.42(m，2H)，3.09(s，3H)，3.04-2.92(m，3H)，2.63-2.59(m，2H)，2.48-2.44(m，2H)，2.38-2.31(m，1H)，1.98-1.86(m，3H)，1.78-1.71(m，1H)，1.54-1.47(m，3H)，1.46-1.37(m，2H)，1.17-1.10(m，1H)，1.06-0.99(m，1H).
The synthesis of embodiment 2 Compound I 2
Method is with the synthesis of Compound I 1 in embodiment 1, and compound N 2 is prepared according to document (WO2013017026) method, 68% yield.
1H NMR(400MHz，CDCl
3)δ10.99(brs，1H)，8.36-8.30(m，2H)，7.94(d，J=8.0Hz，1H)，7.78(t，J=8.0Hz，1H)，7.62-7.58(m，2H)，7.31-7.26(m，1H)，6.34(s，1H)，6.02-5.97(m，1H)，5.72-5.66(m，1H)，5.07(t，J=10.4Hz，1H)，4.63(td，J=9.2Hz，2.4Hz，1H)，3.48-3.42(m，2H)，3.08(s，3H)，3.02-2.92(m，3H)，2.63-2.59(m，2H)，2.50-2.44(m，2H)，2.38-2.31(m，1H)，2.04-1.98(m，1H)，1.96-1.86(m，2H)，1.76-1.69(m，1H)，1.54-1.47(m，3H)，1.46-1.37(m，2H)，1.17-1.10(m，1H)，1.06-0.99(m，1H)；ES-LCMS m／z705.2(M+H).
The synthesis of embodiment 3 Compound I 3
Method is with the synthesis of Compound I 1 in embodiment 1, and compound N 3 is prepared according to document (WO2013017026) method, 25% yield.
1H NMR(400MHz，CDCl
3)δ10.88(brs，1H)，8.27(d，J=1.6Hz，1H)，8.05-8.02(m，2H)，7.58(d，J=8.8Hz，1H)，7.55-7.51(m，3H)，7.48-7.46(m，1H)，7.25(s，1H)，6.38(s，1H)，5.72-5.66(m，1H)，5.50-5.46(m，1H)，5.06(t，J= 10.4Hz，1H)，4.62(td，J=9.2Hz，2.4Hz，1H)，3.52-3.38(m，2H)，3.04(s，3H)，3.01-2.92(m，2H)，2.90-2.82(m，1H)，2.63-2.57(m，2H)，2.50-2.39(m，2H)，2.32-2.21(m，1H)，2.04-1.99(m，2H)，1.96-1.91(m，1H)，1.89-1.82(m，1H)，1.78-1.69(m，1H)，1.53-1.47(m，3H)，1.46-1.37(m，2H)，1.17-1.10(m，1H)，1.06-0.99(m，1H)；ES-LCMS m/z731.2(M+H).
Following compound N i (wherein i=1,2,3......26) prepare according to document WO2013017026:
M1 is prepared according to the embodiment 1 of P61 ~ 64 in document WO2008096001
According to above-mentioned raw materials compound N i (wherein i=1,2....26) and M1 again according to the Compound I k (wherein k=4,5.....9) in the method synthetic table 1 of embodiment 1.
Table 1 Compound I k (wherein, k=4,5.....9, i=1,2....26)
HCV inhibition of DNA replication Activity determination experiment in effect example 1HCV replicon transfectional cell
HCV replicon transfectional cell: pSGR-399LM transfection Huh7 cell is cultivated in the DMEM substratum closing 10%FBS and G418 (0.5mg/mL), goes down to posterity with the ratio of 1:3 ~ 1:5, the rule of 3 ~ 4 days/time.Transfectional cell is inoculated in 96 orifice plates, 37 DEG C, 5%CO
2cultivate 24 hours.
Sample preparation: sample (the i.e. Compound I k adding different concns in the Huh7 cell of HCV replicon transfection, wherein k=1, 2, 3), each concentration establishes multiple hole, and (compound that Positive control wells adds is as BILN2061 to set no sample control wells and Positive control wells, have another name called Xi Luruiwei, chemical name: (2R, 6S, 12Z, 13aS, 14aR, 16aS)-6-[[(cyclopentyloxy) carbonyl] is amino]-1, 2, 3, 6, 7, 8, 9, 10, 11, 13a, 14, 15, 16, 16a-ten tetrahydrochysene-2-[[7-methoxyl group-8-methyl-2-[2-[(1-methylethyl) is amino]-4-thiazolyl]-4-quinolyl] oxygen base]-5, 16-dioxo ring third is [e] pyrrolo-[1 also, 2-a] [1, 4] diaza cyclopentadecylene-14a (5H)-carboxylic acid).Sample is from 1000nM, and 3 times of dilutions, 9 concentration, add respectively, continue cultivation 72 hours.
Fluoroscopic examination: drug treating, after 72 hours, by lysis, adds Renilla luciferase substrate.On fluorescence microplate reader, read relative luminous intensity (RLU), calculate HCV viral suppression and EC
50value.
The HCV viral suppression of table 2 Compound I 1 ~ I3
A represents EC
50≤ 100nM, B represent 100nM<EC
50≤ 1000nM
Conclusion: the HCV viral suppression EC of compound 1 ~ 3
50value is all less than 100nM, all has HCV HIV suppression active.
Claims (11)
1. the compound shown in formula (1), or its oxynitride, hydrate, solvate, meta-bolites or pharmacy acceptable salt or prodrug,
Wherein, A
1for O, S, CH
2, NR ', O (CHR ')
1 ~ 2, S (CHR ')
1 ~ 2or NH (CHR ')
1 ~ 2, wherein, R ' is hydrogen or the (C for being optionally substituted by halogen or not being optionally substituted by halogen
1-C
6) alkyl;
A
2for NH, O or connecting key;
Work as Z
3for C, and when being connected with O, Z
1for N or CR
z1, Z
2for CR
z2, wherein, R
z1for hydrogen, halogen, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group, NH
2, ((C
1-C
6) alkyl) NH or ((C
1-C
6) alkyl)
2n, R
z2for hydrogen, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group, 6 ~ 10 yuan of aryl or be selected from heteroatomic 5 ~ 10 yuan of heteroaryls of N, O and S containing 1 ~ 2; Or R
z1, R
z2connected carbon atom forms one jointly by R
e, R
f, R
gand R
hreplace or unsubstituted 5 ~ 7 yuan of carbocyclic rings;
Work as Z
1for C, and when being connected with O, Z
2for CH, Z
3for C-Ar, Ar are unsubstituted or by 1 ~ 3 R
arthe aryl of 6 ~ 10 yuan of any replacement or be selected from heteroatomic 5 ~ 10 yuan of heteroaryls of N, O and S containing 1 ~ 2; Wherein, R
arbe selected from substituents group: halogen, amino, (C
1-C
8) alkyl, (C
1-C
8) alkoxyl group, hydroxyl-(C
1-C
8) alkyl and (C
1-C
8) alkylamidoalkyl;
Q is unsubstituted or by 1 ~ 5 R
q' replace-(CH
2)
x-U-(CH
2)
y-V-; Wherein, x, y be independently 0 ~ 9 integer and 1≤x+y≤9, U, V be independently connecting key ,-O-,-S-,-S (O)-,-S (O
2)-,-NH-,-((C
1~ C
6) alkyl) N-,-C (O)-, (C
2-C
4) alkenylene, (C
6-C
10) arylidene ,-(C
6-C
10) arylidene-O-, (C
3~ C
8) cycloalkylidene or containing 1 ~ 3 independently selected from the heteroatomic (C of N, O, S
2~ C
7) sub-Heterocyclylalkyl, wherein, R
q' be halogen, hydroxyl, sulfydryl, NH
2, ((C
1~ C
6) alkyl) NH, ((C
1~ C
6) alkyl)
2n, (C
1~ C
6) alkoxyl group, (C
1~ C
6) alkyl, (C
2~ C
6) thiazolinyl or (C
2~ C
6) alkynyl;
R
a, R
b, R
c, R
d, R
e, R
f, R
gand R
hbe H, OH, halogen or-L independently
1-R
m; L
1for connecting key, O, S, SO, SO
2or NR
n; R
mfor hydrogen, or, R
mfor not to be substituted or by 1 ~ 3 R
mthe substituting group be selected from following group of ' replacement: (C
1-C
8) alkyl, N ≡ C-(C
1-C
6) alkyl, (C
2-C
8) thiazolinyl, (C
2-C
8) alkynyl, (C
3-C
8) cycloalkyl, ((C
3-C
8) cycloalkyl) (C
1-C
6) alkyl, 6 ~ 10 yuan of aryl and containing 1 ~ 2 independently selected from heteroatomic 5 ~ 10 yuan of heteroaryls of N, O, S; R
nfor H, (C
1-C
6) alkyl or (C
3-C
8) cycloalkyl, wherein, R
m' be selected from substituting group in following group: halogen, (C
1-C
6) alkyl, optionally by (C
1-C
6) alkoxyl group or (C
3-C
8) cycloalkyloxy replace (C
1-C
6) alkyl, halo (C
1-C
6) alkyl, (C
3-C
8) cycloalkyl, (C
1-C
6) alkoxyl group, 6 ~ 10 yuan of aryl, containing 1 ~ 2 independently selected from N, O, S heteroatomic 5 ~ 10 yuan of heteroaryls, NH
2, ((C
1-C
6) alkyl) NH and ((C
1-C
6) alkyl)
2n;
R
1for not to be substituted or by 1 ~ 3 R
1the substituting group be selected from following group of ' replacement: (C
1-C
8) alkyl, (C
2-C
8) thiazolinyl, (C
2-C
8) alkynyl, (C
6-C
10) aryl, ((C
6-C
10) aryl) (C
1-C
4) alkyl, (C
3-C
8) cycloalkyl, ((C
3-C
8) cycloalkyl) (C
1-C
4) alkyl, (C
4-C
8) cycloalkenyl group, ((C
4-C
8) cycloalkenyl group) (C
1-C
4) alkyl, (C
2-C
7) Heterocyclylalkyl, ((C
2-C
7) Heterocyclylalkyl) (C
1-C
4) alkyl, (C
3-C
10) heteroaryl and ((C
3-C
10) heteroaryl) (C
1-C
4) alkyl; R
1' be selected from substituting group in following group: halogen, OH, CN, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, NH
2, ((C
1-C
6) alkyl) NH and ((C
1-C
6) alkyl)
2n;
R
2for hydrogen, OH, NH
2, (C
1-C
8) alkyl, (C
3-C
8) cycloalkyl, (C
1-C
8) alkoxyl group, (C
3-C
8) cycloalkyloxy, (C
1-C
8) alkyl-OC (O)-, ((C
1-C
8) alkoxyl group) (C
1-C
8) alkyl, (C
1-C
8) alkylamino radical, (C
3-C
8) cycloalkanes amido, (C
2-C
7) heterocycle alkylamino radical, (C
6-C
10) aryl amine, (C
1-C
8) alkoxy amide base, (C
6-C
10) aryloxy amide group, (C
1-C
8) alkylcarboxamido, (C
3-C
8) cycloalkyl sulfonamido, (C
2-C
7) Heterocyclylalkyl sulfonamido, (C
6-C
10) aryl sulfonamido or (C
1-C
8) alkylamino radical sulfonamido.
2. compound as claimed in claim 1, is characterized in that, work as Z
3for C, and when being connected with O, R
z1, R
z2connected carbon atom forms one jointly by R
e, R
f, R
g, R
hthe 6 yuan of aromatic rings replaced, the structure of general formula (I) compound is such as formula shown in (Ia):
A
1for O, S, CH
2, NR ', O (CHR ')
1 ~ 2, S (CHR ')
1 ~ 2or NH (CHR ')
1 ~ 2, wherein, R ' is hydrogen or the (C for being optionally substituted by halogen or not being optionally substituted by halogen
1-C
6) alkyl;
A
2for NH, O or connecting key;
Q is unsubstituted or by 1 ~ 3 R
q' replace-(CH
2)
x-U-(CH
2)
y-V-; Wherein, x, y be independently 0 ~ 9 integer and 2≤x+y≤7, U, V be independently connecting key ,-O-,-S-,-S (O)-,-S (O
2)-,-NH-,-((C
1~ C
4) alkyl) N-,-C (O)-, (C
2-C
3) alkenylene, (C
6-C
8) arylidene ,-(C
6-C
8) arylidene-O-, (C
3~ C
6) cycloalkylidene or containing 1 ~ 2 independently selected from the heteroatomic (C of N, O, S
2~ C
5) sub-Heterocyclylalkyl, wherein, R
q' be halogen, hydroxyl, sulfydryl, NH
2, ((C
1~ C
4) alkyl) NH, ((C
1~ C
4) alkyl)
2n, (C
1~ C
4) alkoxyl group, (C
1~ C
4) alkyl, (C
2~ C
4) thiazolinyl or (C
2~ C
4) alkynyl;
R
a, R
b, R
c, R
d, R
e, R
f, R
gand R
hbe H, OH, halogen or-L independently
1-R
m; L
1for connecting key, O, S, SO, SO
2or NR
n; R
mfor hydrogen, or, R
mfor not to be substituted or by 1 ~ 3 R
mthe substituting group be selected from following group of ' replacement: (C
1-C
6) alkyl, N-C-(C
1-C
4) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
3-C
7) cycloalkyl, ((C
3-C
7) cycloalkyl) (C
1-C
4) alkyl, 6 ~ 10 yuan of aryl and containing 1 ~ 2 independently selected from heteroatomic 5 ~ 6 yuan of heteroaryls of N, O, S; R
nfor H, (C
1-C
4) alkyl or (C
3-C
7) cycloalkyl, wherein, R
m' be selected from substituting group in following group: halogen, (C
1-C
4) alkyl, optionally by (C
1-C
4) alkoxyl group or (C
3-C
6) cycloalkyloxy replace (C
1-C
4) alkyl, halo (C
1-C
4) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
4) alkoxyl group, 6 yuan of aryl, containing 1 ~ 2 independently selected from N, O, S heteroatomic 5 ~ 6 yuan of heteroaryls, NH
2, ((C
1-C
4) alkyl) NH and ((C
1-C
4) alkyl)
2n;
R
1for not to be substituted or by 1 ~ 3 R
1the substituting group be selected from following group of ' replacement: (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl, ((C
6-C
10) aryl) (C
1-C
2) alkyl, (C
3-C
7) cycloalkyl, ((C
3-C
7) cycloalkyl) (C
1-C
2) alkyl, (C
4-C
7) cycloalkenyl group, ((C
4-C
7) cycloalkenyl group) (C
1-C
2) alkyl, 3--> (C
2-C
6) Heterocyclylalkyl, ((C
2-C
6) Heterocyclylalkyl) (C
1-C
2) alkyl, (C
4-C
6) heteroaryl and ((C
4-C
6) heteroaryl) (C
1-C
2) alkyl; R
1' be selected from substituting group in following group: halogen, OH, CN, (C
1-C
4) alkyl, (C
2-C
4) thiazolinyl, (C
2-C
4) alkynyl, (C
1-C
4) alkoxyl group, NH
2, ((C
1-C
4) alkyl) NH and ((C
1-C
4) alkyl)
2n;
R
2for hydrogen, OH, NH
2, (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
6) alkoxyl group, (C
3-C
7) cycloalkyloxy, (C
1-C
6) alkyl-OC (O)-, ((C
1-C
6) alkoxyl group) (C
1-C
6) alkyl, (C
1-C
6) alkylamino radical, (C
3-C
7) cycloalkanes amido, (C
2-C
6) heterocycle alkylamino radical, (C
6-C
8) aryl amine, (C
1-C
6) alkoxy amide base, (C
6-C
8) aryloxy amide group, (C
1-C
6) alkylcarboxamido, (C
3-C
7) cycloalkyl sulfonamido, (C
2-C
6) Heterocyclylalkyl sulfonamido, (C
6-C
10) aryl sulfonamido or (C
1-C
6) alkylamino radical sulfonamido.
3. compound as claimed in claim 1, is characterized in that, work as Z
1for C, and when being connected with O, the structure of general formula (I) compound is such as formula shown in (Ib):
A
1for O, S, CH
2, NR ', O (CHR ')
1 ~ 2, S (CHR ')
1 ~ 2or NH (CHR ')
1 ~ 2, wherein, R ' is hydrogen or the (C for being optionally substituted by halogen or not being optionally substituted by halogen
1-C
6) alkyl;
A
2for NH, O or connecting key;
Q is unsubstituted or by 1 ~ 3 R
q' replace-(CH
2)
x-U-(CH
2)
y-V-; Wherein, x, y be independently 0 ~ 9 integer and 2≤x+y≤7, U, V be independently connecting key ,-O-,-S-,-S (O)-,-S (O
2)-,-NH-,-((C
1~ C
4) alkyl) N-,-C (O)-, (C
2-C
3) alkenylene, (C
6-C
8) arylidene ,-(C
6-C
8) arylidene-O-, (C
3~ C
6) cycloalkylidene or containing 1 ~ 2 independently selected from the heteroatomic (C of N, O, S
2~ C
5) sub-Heterocyclylalkyl, wherein, R
q' be halogen, hydroxyl, sulfydryl, NH
2, ((C
1~ C
4) alkyl) NH, ((C
1~ C
4) alkyl)
2n, (C
1~ C
4) alkoxyl group, (C
1~ C
4) alkyl, (C
2~ C
4) thiazolinyl or (C
2~ C
4) alkynyl;
Ar is unsubstituted or by 1 ~ 3 R
arthe phenyl of any replacement or be selected from heteroatomic 5 ~ 6 yuan of heteroaryls of N, O and S containing 1 ~ 2; Wherein, R
arbe selected from substituents group: halogen, amino, C
1-C
6alkyl, C
1-C
6alkoxyl group, hydroxyl-(C
1-C
6) alkyl and (C
1-C
6) alkylamidoalkyl;
R
a, R
b, R
cand R
dbe H, OH, halogen or-L independently
1-R
m; L
1for connecting key, O, S, SO, SO
2or NR
n; R
mfor hydrogen, or, R
mfor not to be substituted or by 1 ~ 3 R
mthe substituting group be selected from following group of ' replacement: (C
1-C
6) alkyl, N ≡ C-(C
1-C
4) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
3-C
7) cycloalkyl, ((C
3-C
7) cycloalkyl) (C
1-C
4) alkyl, 6 ~ 10 yuan of aryl and containing 1 ~ 2 independently selected from heteroatomic 5 ~ 6 yuan of heteroaryls of N, O, S; R
nfor H, (C
1-C
4) alkyl or (C
3-C
7) cycloalkyl, wherein, R
m' be selected from substituting group in following group: halogen, (C
1-C
4) alkyl, optionally by (C
1-C
4) alkoxyl group or (C
3-C
6) cycloalkyloxy replace (C
1-C
4) alkyl, halo (C
1-C
4) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
4) alkoxyl group, 6 yuan of aryl, containing 1 ~ 2 independently selected from N, O, S heteroatomic 5 ~ 6 yuan of heteroaryls, NH
2, ((C
1-C
4) alkyl) NH and ((C
1-C
4) alkyl)
2n;
R
1for not to be substituted or by 1 ~ 3 R
1the substituting group be selected from following group of ' replacement: (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
6-C
10) aryl, ((C
6-C
10) aryl) (C
1-C
2) alkyl, (C
3-C
7) cycloalkyl, ((C
3-C
7) cycloalkyl) (C
1-C
2) alkyl, (C
4-C
7) cycloalkenyl group, ((C
4-C
7) cycloalkenyl group) (C
1-C
2) alkyl, (C
2-C
6) Heterocyclylalkyl, ((C
2-C
6) Heterocyclylalkyl) (C
1-C
2) alkyl, (C
4-C
6) heteroaryl and ((C
4-C
6) heteroaryl) (C
1-C
2) alkyl; R
1' be selected from substituting group in following group: halogen, OH, CN, (C
1-C
4) alkyl, (C
2-C
4) thiazolinyl, (C
2-C
4) alkynyl, (C
1-C
4) alkoxyl group, NH
2, ((C
1-C
4) alkyl) NH and ((C
1-C
4) alkyl)
2n;
R
2for hydrogen, OH, NH
2, (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
6) alkoxyl group, (C
3-C
7) cycloalkyloxy, (C
1-C
6) alkyl-OC (O)-, ((C
1-C
6) alkoxyl group) (C
1-C
6) alkyl, (C
1-C
6) alkylamino radical, (C
3-C
7) cycloalkanes amido, (C
2-C
6) heterocycle alkylamino radical, (C
6-C
8) aryl amine, (C
1-C
6) alkoxy amide base, (C
6-C
8) aryloxy amide group, (C
1-C
6) alkylcarboxamido, (C
3-C
7) cycloalkyl sulfonamido, (C
2-C
6) Heterocyclylalkyl sulfonamido, (C
6-C
10) aryl sulfonamido or (C
1-C
6) alkylamino radical sulfonamido.
4. compound as claimed in claim 2 or claim 3, is characterized in that, A
1for O, S, CH
2or NR ', wherein, R ' is hydrogen or the C for being optionally substituted by halogen or not being optionally substituted by halogen
1-C
4alkyl, preferred C
1-C
2alkyl.
5. compound as claimed in claim 2, is characterized in that, R
a, R
b, R
c, R
d, R
e, R
f, R
gand R
hbe H, OH, halogen or-L independently
1-R
m; L
1for connecting key, O, S, SO, SO
2or NR
n; R
mfor hydrogen, or, R
mfor not to be substituted or by 1 R
mthe substituting group be selected from following group of ' replacement: (C
1-C
4) alkyl, N ≡ C-(C
1-C
2) alkyl, (C
2-C
4) thiazolinyl, (C
2-C
4) alkynyl, (C
3-C
6) cycloalkyl, ((C
3-C
6) cycloalkyl) (C
1-C
2) alkyl, phenyl and containing 1 ~ 2 independently selected from heteroatomic 5 ~ 6 yuan of heteroaryls of N, O, S; R
nfor H, (C
1-C
2) alkyl or (C
3-C
6) cycloalkyl, wherein, R
m' be selected from substituting group in following group: halogen, (C
1-C
2) alkyl, optionally by (C
1-C
2) alkoxyl group or (C
5-C
6) cycloalkyloxy replace (C
1-C
2) alkyl, halo (C
1-C
2) alkyl, (C
5-C
6) cycloalkyl, (C
1-C
2) alkoxyl group, phenyl, containing 1 ~ 2 independently selected from N, O, S heteroatomic 5 ~ 6 yuan of heteroaryls, NH
2, ((C
1-C
2) alkyl) NH and ((C
1-C
2) alkyl)
2n.
6. compound as claimed in claim 3, is characterized in that, R
a, R
b, R
cand R
dbe H, OH, halogen or-L independently
1-R
m; L
1for connecting key, O, S, SO, SO
2or NR
n; R
mfor hydrogen, or, R
mfor not to be substituted or by 1 R
mthe substituting group be selected from following group of ' replacement: (C
1-C
4) alkyl, N ≡ C-(C
1-C
2) alkyl, (C
2-C
4) thiazolinyl, (C
2-C
4) alkynyl, (C
3-C
6) cycloalkyl, ((C
3-C
6) cycloalkyl) (C
1-C
2) alkyl, phenyl and containing 1 ~ 2 independently selected from heteroatomic 5 ~ 6 yuan of heteroaryls of N, O, S; R
nfor H, (C
1-C
2) alkyl or (C
3-C
6) cycloalkyl, wherein, R
m' be selected from substituting group in following group: halogen, (C
1-C
2) alkyl, optionally by (C
1-C
2) alkoxyl group or (C
5-C
6) cycloalkyloxy replace (C
1-C
2) alkyl, halo (C
1-C
2) alkyl, (C
5-C
6) cycloalkyl, (C
1-C
2) alkoxyl group, phenyl, containing 1 ~ 2 independently selected from N, O, S heteroatomic 5 ~ 6 yuan of heteroaryls, NH
2, ((C
1-C
2) alkyl) NH and ((C
1-C
2) alkyl)
2n;
Ar is unsubstituted or by 1 R
arthe phenyl of any replacement or be selected from heteroatomic 5 ~ 6 yuan of heteroaryls of N, O and S containing 1 ~ 2; Wherein, R
arbe selected from substituents group: halogen, amino, C
1-C
4alkyl, C
1-C
4alkoxyl group, hydroxyl-(C
1-C
4) alkyl and (C
1-C
4) alkylamidoalkyl.
7. compound as claimed in claim 2 or claim 3, is characterized in that, R
1for not to be substituted or by 1 R
1the substituting group be selected from following group of ' replacement: (C
1-C
4) alkyl, (C
2-C
4) thiazolinyl, (C
2-C
4) alkynyl, phenyl, phenyl (C
1-C
2) alkyl, (C
3-C
6) cycloalkyl, ((C
3-C
6) cycloalkyl) (C
1-C
2) alkyl, (C
5-C
6) cycloalkenyl group, ((C
5-C
6) cycloalkenyl group) (C
1-C
2) alkyl, (C
2-C
5) Heterocyclylalkyl, ((C
2-C
5) Heterocyclylalkyl) (C
1-C
2) alkyl, (C
4-C
5) heteroaryl and (C
4-C
5heteroaryl) (C
1-C
2) alkyl; R
1' be selected from substituting group in following group: halogen, OH, CN, (C
1-C
2) alkyl, (C
2-C
3) thiazolinyl, (C
2-C
3) alkynyl, (C
1-C
2) alkoxyl group, NH
2, ((C
1-C
2) alkyl) NH and ((C
1-C
2) alkyl)
2n; Preferably, R
1for:
8. as claimed in claim 2 or claim 3 compound, is characterized in that, Q is unsubstituted or by 1 R
q' replace-(CH
2)
x-U-(CH
2)
y-V-; Wherein, x, y be independently 0 ~ 9 integer and 3≤x+y≤6, U, V be independently connecting key ,-O-,-S-,-S (O)-,-S (O
2)-,-NH-,-((C
1~ C
2) alkyl) N-,-C (O)-, vinylidene, phenylene ,-phenylene-O-, (C
5~ C
6) cycloalkylidene, containing 1 ~ 2 independently selected from the heteroatomic (C of N, O, S
4~ C
5) sub-Heterocyclylalkyl, wherein, R
q' be halogen, hydroxyl, sulfydryl, NH
2, ((C
1~ C
2) alkyl) NH, ((C
1~ C
2) alkyl)
2n, (C
1~ C
2) alkoxyl group, (C
1~ C
2) alkyl, (C
2~ C
3) thiazolinyl or (C
2~ C
3) alkynyl; Preferably Q is-(CH
2)
3 ~ 6-.
9. compound is characterized in that as claimed in claim 2 or claim 3, R
2for hydrogen, OH, NH
2, (C
1-C
4) alkyl, (C
3-C
6) cycloalkyl, (C
1-C
4) alkoxyl group, (C
3-C
6) cycloalkyloxy, (C
1-C
4) alkyl-OC (O)-, ((C
1-C
2) alkoxyl group) (C
1-C
4) alkyl, (C
1-C
4) alkylamino radical, (C
3-C
6) cycloalkanes amido, (C
4-C
5) heterocycle alkylamino radical, anilino, (C
1-C
4) alkoxy amide base, phenoxy group amide group, (C
1-C
4) alkylcarboxamido, (C
3-C
6) cycloalkyl sulfonamido, (C
4-C
5) Heterocyclylalkyl sulfonamido, phenyl sulfonamido or (C
1-C
4) alkylamino radical sulfonamido; Preferably R
2for methyl.
10. compound as claimed in claim 2 or claim 3, it is characterized in that, this compound is one of following compounds:
The purposes of 11. compounds according to claim 1 in preparation prophylaxis of viral infections or antiviral drug, the preferred hepatitis virus of described virus, particularly preferably hepatitis C virus.
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090149491A1 (en) * | 2007-11-13 | 2009-06-11 | Dong Liu | Carbocyclic oxime hepatitis c virus serine protease inhibitors |
| CN101535294A (en) * | 2006-11-17 | 2009-09-16 | 泰博特克药品有限公司 | Macrocyclic inhibitors of hepatitis C virus |
| CN101580535A (en) * | 2008-05-16 | 2009-11-18 | 太景生物科技股份有限公司 | Hcv protease inhibitors |
| CN101627020A (en) * | 2007-02-08 | 2010-01-13 | 泰博特克药品有限公司 | The macrocyclic phenylcarbamates that suppresses HCV |
| WO2011034518A1 (en) * | 2009-09-15 | 2011-03-24 | Taigen Biotechnology Co., Ltd. | Hcv protease inhibitors |
| US20110178107A1 (en) * | 2010-01-20 | 2011-07-21 | Taigen Biotechnology Co., Ltd. | Hcv protease inhibitors |
| CN102140100A (en) * | 2010-01-27 | 2011-08-03 | 爱博新药研发(上海)有限公司 | Polycyclic compound for inhibiting hepatitis C virus efficiently, preparation method thereof and application thereof |
| CN102911254A (en) * | 2011-08-02 | 2013-02-06 | 上海唐润医药科技有限公司 | HCV (hepatitis C virus) protease inhibitor |
-
2013
- 2013-10-16 CN CN201310485061.7A patent/CN104557954A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101535294A (en) * | 2006-11-17 | 2009-09-16 | 泰博特克药品有限公司 | Macrocyclic inhibitors of hepatitis C virus |
| CN101627020A (en) * | 2007-02-08 | 2010-01-13 | 泰博特克药品有限公司 | The macrocyclic phenylcarbamates that suppresses HCV |
| US20090149491A1 (en) * | 2007-11-13 | 2009-06-11 | Dong Liu | Carbocyclic oxime hepatitis c virus serine protease inhibitors |
| CN101580535A (en) * | 2008-05-16 | 2009-11-18 | 太景生物科技股份有限公司 | Hcv protease inhibitors |
| WO2011034518A1 (en) * | 2009-09-15 | 2011-03-24 | Taigen Biotechnology Co., Ltd. | Hcv protease inhibitors |
| US20110178107A1 (en) * | 2010-01-20 | 2011-07-21 | Taigen Biotechnology Co., Ltd. | Hcv protease inhibitors |
| CN102140100A (en) * | 2010-01-27 | 2011-08-03 | 爱博新药研发(上海)有限公司 | Polycyclic compound for inhibiting hepatitis C virus efficiently, preparation method thereof and application thereof |
| CN102911254A (en) * | 2011-08-02 | 2013-02-06 | 上海唐润医药科技有限公司 | HCV (hepatitis C virus) protease inhibitor |
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