CN103373997B - Zinc binding group containing pyridonaphthyridine inhibitor for HDAC (Histone Deacetylase) and mTOR (Mammalian Target of Rapamycin) - Google Patents
Zinc binding group containing pyridonaphthyridine inhibitor for HDAC (Histone Deacetylase) and mTOR (Mammalian Target of Rapamycin) Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and in particular relates to pyridonaphthyridine derivatives which function as inhibitors for HDAC (Histone Deacetylase) and mTOR (Mammalian Target of Rapamycin) and are shown in the general formula (I), and pharmaceutically acceptable salts and isomers of the pyridonaphthyridine derivatives. In the general formula, A, X, Y, W, R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7> and R<8> are defined in the specifications. The invention also relates to a preparation method of the pyridonaphthyridine derivatives, a medicine preparation and a medicine composition comprising the pyridonaphthyridine derivatives, and an application of the pyridonaphthyridine derivatives in the preparation of the medicines for treating and/or preventing the diseases relevant to the activity of the HDAC and the mTOR.
Description
Technical field
The invention belongs to medical art, be specifically related to the pyrido naphthyridine type derivative as HDAC and mTOR inhibitors, its pharmacy acceptable salt and isomer thereof, the preparation method of these compounds, pharmaceutical preparation containing these compounds and pharmaceutical composition, and these compounds, its pharmacy acceptable salt or its isomer treat and/or prevent the application in the medicine of relevant disease active in HDAC and mTOR in preparation.
Background technology
PI3K/AKT path is the place of the most often morphing in human cancer cell, can cause cell proliferation, activation, amplifying signal.
The mitogenetic activation of somatomedin to PI3K/AKT signal pathway finally produces crucial cell cycle and growth control regulatory factor mTOR, mTOR is a kind of cell signalling albumen, its regulate tumor cell is to the reaction of nutrient and somatomedin, and by the effect to vascular endothelial growth factor, control the blood supply of tumour.MTOR inhibitors can make cancer cells hungry, and by suppressing the effect of mTOR to make tumor mass reduction.
Hdac inhibitor is a kind of molecular targeted epigenetic regulation agent; by regulating histone and nonhistones Acetylation status; inducing apoptosis of tumour cell, cell cycle arrest, inhibiting angiogenesis and Nasopharyngeal neoplasms, can be used for the treatment of multiple blood tumor and solid tumor.The hdac inhibitor of current listing has Vorinostat (Vorinostat, SAHA, Zolinza) and Romidepsin (FK-228, Istodax).The research of Curis company finds that hdac inhibitor and the coupling of PI3K inhibitor have synergistic function.Based on this principle, the unit molecule HDAC/PI3K/MTOR Mutiple Targets inhibitor C U-906 that Curis company have developed, preclinical study shows that it all has good anti-tumor activity in vivo and in vitro, compared with PI3K/MTOR inhibitor, improves drug effect, overcomes the generation of resistance.
The present invention has the medicine of excellent antitumor action and the generation of minimizing resistance for target with exploitation simultaneously, has found the inhibiting compound of unit molecule HDAC and mTOR.
Summary of the invention
The technical problem to be solved in the present invention is, provides a kind of HDAC/MTOR inhibitor of pyrido naphthyridine type derivative.
Technical scheme of the present invention is as follows:
Compound shown in general formula (I), its pharmacy acceptable salt, and isomer:
Wherein
X is O or S;
R
1for hydrogen, or not to be substituted or by 1-3 R
9the C replaced
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl, 3-14 unit cycloalkyl, 6-14 unit aryl, 3-14 unit heterocyclic radical, 7-12 unit volution base, 7-12 unit bridged ring base;
A for not exist, or not to be substituted or by 1-3 R
9' the 3-14 unit cycloalkyl, 6-14 unit aryl, 3-14 unit heterocyclic radical, 7-12 unit volution base, the 7-12 unit bridged ring base that replace;
R
2, R
3independently be hydrogen, halogen, cyano group, amino, hydroxyl, alkylsulfonyl ,-SO
2c
1-6alkyl, or the C not being substituted or being selected from by 1-3 halogen atom, hydroxyl, carboxyl substituted
1-6alkyl, C
1-6alkoxyl group;
R
4for hydrogen, cyano group, amino, alkylsulfonyl ,-SO
2c
1-6alkyl, or the C not being substituted or being selected from by 1-3 halogen atom, hydroxyl, carboxyl substituent replacement
1-6alkyl, C
1-6alkoxyl group;
R
5, R
6independently be hydrogen, hydroxyl, halogen, amino, or be not substituted or by 1-3 be selected from halogen atom, C that hydroxyl, carboxyl substituent replace
1-6alkyl, C
1-6alkoxyl group;
R
9and R
9' independently be
(1) hydroxyl, halogen, cyano group ,-(CH
2)
nnR
ar
b,-(CH
2)
nc (O) R
c,-(CH
2)
ns (O)
mr
c,-(CH
2)
ns (O)
mnR
ar
b,-(CH
2)
nnR
as (O)
mr
c,-(CH
2)
nc (O) (CH
2)
nnR
ar
b,-(CH
2)
noC (O) R
c,-(CH
2)
nnR
ac (O) R
c, or-(CH
2)
nnR
ac (O) NR
ar
b, R
cfor not being substituted or being selected from by 1-3 the C of hydroxyl, halogen, cyano group, trifluoromethyl replacement
1-6 alkanebase, C
1-6alkoxyl group,
(2) be not substituted or to be selected from cyano group by 1-3, C that halogen, hydroxyl replace
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
1-6alkoxyl group,
(3) be not substituted or be selected from cyano group, trifluoromethyl, halogen, C by 1-3
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
1-6alkoxyl group ,-(CH
2)
nnR
ar
b,-(CH
2)
nc (O) R
c' ,-(CH
2)
nc (O) (CH
2)
nnR
ar
b,-(CH
2)
ns (O)
mr
c' ,-(CH
2)
ns (O)
mnR
ar
b,-(CH
2)
nnR
as (O)
mr
c' ,-(CH
2)
noC (O) R
c' ,-(CH
2)
nnR
ac (O) R
c' ,-(CH
2)
nnR
ac (O) NR
ar
bthe 3-14 unit cycloalkyl replaced, 6-14 unit aryl, 3-14 unit heterocyclic radical;
R
aand R
bindependently be hydrogen, be not substituted or to be selected from hydroxyl by 1-3, C that halogen, cyano group replace
1-6alkyl;
R
c' for not being substituted or being selected from by 1-3 the C of hydroxyl, halogen, cyano group replacement
1-6alkyl, C
1-6the saturated monocycle alkyl of alkoxyl group, 3-8 unit, the single heterocyclic radical of 3-8 unit;
M is 0,1 or 2;
N is 0 ~ 4;
Y for not exist ,-O-,-S-,-SO-,-SO
2-,-NH-,-CONH-or-SO
2nH-;
W is not for be substituted or by R
dreplace
(1) C
1-8alkylidene group, C
2-8alkenylene, C
2-8alkynyl,
(2) 6-14 unit aryl, 3-14 unit heterocyclic radical, 3-8 unit cycloalkyl,
(3) 6-14 unit aryl C
1-8alkylidene group, 6-14 unit aryl C
2-8alkenylene, 6-14 unit aryl C
2-8alkynyl,
(4) 3-14 unit heterocyclic radical C
1-8alkylidene group, 3-14 unit heterocyclic radical C
2-8alkenylene, 3-14 unit heterocyclic radical C
2-8alkynyl,
(5) 3-8 unit cycloalkyl C
1-8alkylidene group, 3-8 unit cycloalkyl C
2-8alkenylene, 3-8 unit cycloalkyl
c2-8alkynyl,
(6) C
1-8alkylidene group 6-14 unit aryl, C
1-8alkylidene group 3-14 unit heterocyclic radical, C
1-8alkylidene group 3-8 unit cycloalkyl,
(7) C
2-8alkenylene 6-14 unit aryl, C
2-8alkenylene 3-14 unit heterocyclic radical, C
2-8alkenylene 3-8 unit cycloalkyl,
(8) C
2-8alkynyl 6-14 unit aryl, C
2-8alkynyl 3-14 unit heterocyclic radical, C
2-8alkynyl 3-8 unit cycloalkyl,
(9) C
1-8alkylidene group 6-14 unit aryl C
1-8alkylidene group, C
1-8alkylidene group 6-14 unit aryl C
2-8alkenylene, C
1-8alkylidene group 6-14 unit aryl C
2-8alkynyl,
(10) C
2-8alkenylene 6-14 unit aryl C
1-8alkylidene group, C
2-8alkenylene 6-14 unit aryl C
2-8alkenylene, C
2-8alkenylene 6-14 unit aryl C
2-8alkynyl,
(11) C
2-8alkynyl 6-14 unit aryl C
1-8alkylidene group, C
2-8alkynyl 6-14 unit aryl C
2-8alkenylene, C
2-8alkynyl 6-14 unit aryl C
2-8alkynyl,
(12) C
1-8alkylidene group 3-14 unit heterocyclic radical C
1-8alkylidene group, C
1-8alkylidene group 3-14 unit heterocyclic radical C
2-8alkenylene, C
1-8alkylidene group 3-14 unit heterocyclic radical C
2-8alkynyl,
(13) C
2-8alkenylene 3-14 unit heterocyclic radical C
1-8alkylidene group, C
2-8alkenylene 3-14 unit heterocyclic radical C
2-8alkenylene, C
2-8alkenylene 3-14 unit heterocyclic radical C
2-8alkynyl,
(14) C
2-8alkynyl 3-14 unit heterocyclic radical C
1-8alkylidene group, C
2-8alkynyl 3-14 unit heterocyclic radical C
2-8alkenylene, C
2-8alkynyl 3-14 unit heterocyclic radical C
2-8alkynyl,
(15) C
1-8alkylidene group 3-8 unit cycloalkyl C
1-8alkylidene group, C
1-8alkylidene group 3-8 unit cycloalkyl C
2-8alkenylene, C
1-8alkylidene group 3-8 unit cycloalkyl C
2-8alkynyl,
(16) C
2-8alkenylene 3-8 unit cycloalkyl C
1-8alkylidene group, C
2-8alkenylene 3-8 unit cycloalkyl C
2-8alkenylene, C
2-8alkenylene 3-8 unit cycloalkyl C
2-8alkynyl,
(17) C
2-8alkynyl 3-8 unit cycloalkyl C
1-8alkylidene group, C
2-8alkynyl 3-8 unit cycloalkyl C
2-8alkenylene, C
2-8alkynyl 3-8 unit cycloalkyl C
2-8alkynyl,
(18) heterocyclic radical-6-14 unit of 3-14 unit aryl C
1-8alkylidene group, aryl-3-14 unit of 6-14 unit heterocyclic radical C
1-8alkylidene group, heterocyclic radical-3-14 unit of 3-14 unit heterocyclic radical C
1-8alkylidene group,
And described C
1-8alkylidene group, C
2-8alkenylene, C
2-8carbon atom in alkynyl can by O, S, S (O), SO
2, NR
eor CO replaced;
R
dfor hydrogen atom, halogen, hydroxyl, amino, carboxyl, cyano group, formamyl, amino-sulfonyl, C
1-6alkyl, C
1-6alkoxyl group, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkyl carbonyl oxy, C
1-6carbalkoxy, C
1-6alkylamidoalkyl, C
1-6alkyl sulphonyl, C
1-6alkyl sulphinyl, C
1-6alkylsulfonamido, 3-8 unit's cycloalkyl or 3-8 unit heterocyclic radical;
R
efor hydrogen atom, not to be substituted or at least by C that 1 Q replaces
1-6alkyl, 3-8 unit's cycloalkyl or 3-8 unit heterocyclic radical;
Q is halogen, carboxyl, hydroxyl, amino, cyano group, nitro, C
1-6alkoxyl group, halo C
1-6alkoxyl group, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkyl-carbonyl, C
1-6alkyl carbonyl oxy, C
1-6carbalkoxy, formamyl, C
1-6alkyl amine group formyl radical, two (C
1-6alkyl) amido formacyl, amino-sulfonyl, C
1-6alkyl amine group alkylsulfonyl, two (C
1-6alkyl) amido alkylsulfonyl, C
1-6alkylsulfonamido, C
1-6alkyl sulphonyl, C
1-6alkylamidoalkyl, guanidine radicals, 3-8 unit cycloalkyl, 3-8 unit's heterocyclic radical or 6-14 unit aryl;
R
7and R
8be respectively hydrogen atom, C
1-6alkyl or C
1-6alkyl-carbonyl.
Compound shown in general formula (I), its pharmacy acceptable salt, and the optimal technical scheme of isomer is:
Wherein
X is O;
R
1for not to be substituted or by 1-3 R
9the 3-14 unit cycloalkyl replaced, 6-14 unit aryl, 3-14 unit heterocyclic radical, 7-12 unit volution base, 7-12 unit bridged ring base;
A is not for be substituted or by 1-3 R
9' replace 6-14 unit aryl, 3-14 unit heterocyclic radical;
R
2, R
3independently be hydrogen, halogen, cyano group, amino, hydroxyl, trifluoromethyl, or trifluoromethoxy;
R
4for hydrogen, cyano group, or amino;
R
5, R
6independently be hydrogen, hydroxyl, halogen, amino, or C
1-6alkyl;
R
9and R
9' independently be
(1) hydroxyl, halogen, amino, cyano group, or-(CH
2)
nc (O) R
c, R
cfor not being substituted or being selected from by 1-3 the C of hydroxyl, halogen, cyano group, trifluoromethyl replacement
1-6alkyl, C
1-6alkoxyl group,
(2) be not substituted or to be selected from cyano group by 1-3, C that halogen, hydroxyl replace
1-6alkyl, C
1-6alkoxyl group,
(3) be not substituted or be selected from cyano group, trifluoromethyl, halogen, C by 1-3
1-6alkyl, C
1-6alkoxyl group ,-(CH
2)
nnR
ar
b,-(CH
2)
nc (O) R
c' ,-(CH
2)
nc (O) (CH
2)
nnR
ar
b,-(CH
2)
ns (O)
mr
c' ,-(CH
2)
ns (O)
mnR
ar
b,-(CH
2)
nnR
as (O)
mr
c,-(CH
2)
noC (O) R
c,-(CH
2)
nnR
ac (O) R
c,-(CH
2)
nnR
ac (O) NR
ar
bthe saturated monocyclic cycloalkyl of 3-8 unit replaced, 6-14 unit aryl, the single heterocyclic radical of 3-8 unit;
R
aand R
bindependently be hydrogen, be not substituted or to be selected from hydroxyl by 1-3, C that halogen, cyano group replace
1-6alkyl;
R
c' for not being substituted or being selected from by 1-3 the C of hydroxyl, halogen, cyano group replacement
1-6alkyl, C
1-6alkoxyl group;
M is 1 or 2;
N is 0 ~ 4;
Y for not exist ,-O-,-S-,-SO
2-,-CONH-or-SO
2nH-;
W is not for be substituted or by R
dreplace
(1) C
1-8alkylidene group, C
2-8alkenylene,
(2) 6-10 unit aryl, 3-8 unit heterocyclic radical,
(3) 6-10 unit aryl C
1-8alkylidene group, 6-10 unit aryl C
2-8alkenylene,
(4) 3-8 unit heterocyclic radical C
1-8alkylidene group, 3-8 unit heterocyclic radical C
2-8alkenylene,
(5) C
1-8alkylidene group 6-10 unit aryl, C
1-8alkylidene group 3-8 unit heterocyclic radical,
(6) C
2-8alkenylene 6-10 unit aryl, C
2-8alkenylene 3-8 unit heterocyclic radical,
(7) C
1-8alkylidene group 6-10 unit aryl C
1-8alkylidene group, C
1-8alkylidene group 6-10 unit aryl C
2-8alkenylene,
(8) C
2-8alkenylene 6-10 unit aryl C
1-8alkylidene group, C
2-8alkenylene 6-10 unit aryl C
2-8alkenylene,
(9) C
1-8alkylidene group 3-8 unit heterocyclic radical C
1-8alkylidene group, C
1-8alkylidene group 3-8 unit heterocyclic radical C
2-8alkenylene,
(10) C
2-8alkenylene 3-8 unit heterocyclic radical C
1-8alkylidene group, C
2-8alkenylene 3-8 unit heterocyclic radical C
2-8alkenylene,
(11) heterocyclic radical-6-10 unit of 3-8 unit aryl C
1-8alkylidene group, aryl-3-8 unit of 6-10 unit heterocyclic radical C
1-8alkylidene group, heterocyclic radical-3-8 unit of 3-8 unit heterocyclic radical C
1-8alkylidene group,
And described C
1-8alkylidene group, C
2-8carbon atom in alkenylene can by O, S, NR
eor CO replaced;
R
dfor hydrogen atom, halogen, hydroxyl, amino, carboxyl, cyano group, formamyl, amino-sulfonyl, C
1-4alkyl, C
1-4alkoxyl group, C
1-4alkyl amine group, two (C
1-4alkyl) amido, C
1-4alkyl carbonyl oxy, C
1-4carbalkoxy, C
1-4alkylamidoalkyl, C
1-4alkyl sulphonyl, C
1-4alkyl sulphinyl, C
1-4alkylsulfonamido, 3-6 unit's cycloalkyl or 3-6 unit heterocyclic radical;
R
efor hydrogen atom, not to be substituted or at least by C that 1 Q replaces
1-4alkyl, 3-6 unit's cycloalkyl or 3-6 unit heterocyclic radical;
Q is halogen, carboxyl, hydroxyl, amino, cyano group, nitro, C
1-4alkoxyl group, halo C
1-4alkoxyl group, C
1-4alkyl amine group, two (C
1-4alkyl) amido, C
1-4alkyl-carbonyl, C
1-4alkyl carbonyl oxy, C
1-4carbalkoxy, formamyl, C
1-4alkyl amine group formyl radical, two (C
1-4alkyl) amido formacyl, amino-sulfonyl, C
1-4alkyl amine group alkylsulfonyl, two (C
1-4alkyl) amido alkylsulfonyl, C
1-4alkylsulfonamido, C
1-4alkyl sulphonyl, C
1-4alkyl-carbonyl amido, guanidine radicals, 3-6 unit cycloalkyl, 3-6 unit's heterocyclic radical or phenyl;
R
7and R
8be respectively hydrogen atom, C
1-4alkyl or C
1-4alkyl-carbonyl.
Compound shown in general formula (I), its pharmacy acceptable salt, and the optimal technical scheme of isomer is:
Wherein
X is O;
R
1for not to be substituted or by 1-3 R
9the 6-14 unit aryl replaced, the single heterocyclic radical of 3-8 unit;
A is not for be substituted or by 1-3 R
9' replace 6-14 unit aryl, 5-10 unit heterocyclic radical;
R
2, R
3, R
4be respectively hydrogen;
R
5, R
6independently be hydrogen, or C
1-4alkyl;
R
9for
(1) hydroxyl, halogen, cyano group, amino, or-(CH
2)
nc (O) R
c, R
cfor not being substituted or being selected from by 1-3 the C of hydroxyl, halogen, cyano group replacement
1-4alkyl, C
1-4alkoxyl group,
(2) be not substituted or to be selected from cyano group by 1-3, C that halogen, hydroxyl replace
1-4alkyl, C
1-4alkoxyl group,
(3) be not substituted or be selected from cyano group, trifluoromethyl, halogen ,-(CH by 1-3
2)
nc (O) R
c' ,-(CH
2)
nc (O) (CH
2)
nnR
ar
b,-(CH
2)
ns (O)
mr
c' replace 5-8 unit saturated single heterocyclic radical;
R
aand R
bindependently be hydrogen, or be not substituted or be selected from by 1-3 the C of hydroxyl, halogen substiuted
1-4alkyl;
R
c' for not being substituted or being selected from by 1-3 the C of hydroxyl, halogen substiuted
1-4alkyl, C
1-4alkoxyl group;
R
9' be
(1) hydroxyl, halogen, cyano group, amino, or-(CH
2)
nc (O) R
c, R
cfor not being substituted or being selected from by 1-3 the C of hydroxyl, halogen, cyano group, trifluoromethyl replacement
1-4alkyl, C
1-4alkoxyl group,
(2) be not substituted or to be selected from cyano group by 1-3, C that halogen, hydroxyl replace
1-4alkyl, C
1-4alkoxyl group;
M is 1 or 2;
N is 0 ~ 4;
Y for not exist ,-O-,-S-,-CONH-or-SO
2nH-;
W is not for be substituted or by R
dreplace
(1) C
4-8alkylidene group,
(2) phenyl, 5-6 unit heterocyclic radical,
(3) phenyl C
1-6alkylidene group,
(4) 5-6 unit heterocyclic radical C
1-6alkylidene group,
(5) C
2-6alkenylene phenyl, C
2-6alkenylene 5-6 unit heterocyclic radical,
(6) C
2-6alkenylene phenyl C
1-6alkylidene group,
(7) C
2-6alkenylene 5-6 unit heterocyclic radical C
1-6alkylidene group,
(8) heterocyclic radical-5-6 unit of 5-6 unit heterocyclic radical C
1-6alkylidene group,
And described C
4-8alkylidene group, C
1-6alkylidene group, C
2-6carbon atom in alkenylene can by O, S, NR
eor CO replaced;
R
dfor hydrogen atom, halogen, hydroxyl, amino, carboxyl, cyano group, C
1-4alkyl, C
1-4alkoxyl group or 3-6 unit cycloalkyl;
R
efor hydrogen atom, not to be substituted or at least by C that 1 Q replaces
1-4alkyl;
Q is halogen, carboxyl, hydroxyl, amino, cyano group, nitro, C
1-4alkoxyl group, fluoro C
1-4alkoxyl group, C
1-4alkyl amine group, two (C
1-4alkyl) amido, C
1-4alkyl-carbonyl, formamyl, amino-sulfonyl or C
1-4alkyl sulphonyl;
R
7and R
8be respectively hydrogen atom, C
1-4alkyl or C
1-4alkyl-carbonyl.
Compound shown in general formula (I), its pharmacy acceptable salt, and the optimal technical scheme of isomer is:
Wherein
X is O;
R
1for not to be substituted or by 1-3 R
9the 6-10 unit aryl replaced, the saturated single heterocyclic radical of 3-8 unit, the unsaturated single heterocyclic radical of 3-8 unit;
A is not for be substituted or by 1-3 R
9' replace phenyl, naphthyl, 5-6 unit unsaturated single heterocyclic radical, 9-10 unit unsaturated fused heterocycle base;
R
2, R
3, R
4be respectively hydrogen;
R
5, R
6independently be hydrogen, or C
1-4alkyl;
R
9for
(1) hydroxyl, halogen, cyano group, amino, or-C (O) R
c, R
cfor not being substituted or being selected from by 1-3 the C of hydroxyl, halogen, cyano group replacement
1-4alkyl, C
1-4alkoxyl group,
(2) be not substituted or to be selected from cyano group by 1-3, C that halogen, hydroxyl replace
1-4alkyl, C
1-4alkoxyl group,
(3) be not substituted or be selected from cyano group, trifluoromethyl, halogen ,-C (O) R by 1-3
c' ,-C (O) (CH
2)
nnR
ar
b,-S (O)
2r
c' replace 5-6 unit saturated single heterocyclic radical;
R
aand R
bindependently be hydrogen, or be not substituted or be selected from by 1-3 the C of hydroxyl, halogen substiuted
1-4alkyl;
R
c' for not being substituted or being selected from by 1-3 the C of hydroxyl, halogen substiuted
1-4alkyl, C
1-4alkoxyl group;
R
9' be
(1) hydroxyl, halogen, cyano group, amino,
(2) be not substituted or to be selected from cyano group by 1-3, C that halogen, hydroxyl replace
1-4alkyl, C
1-4alkoxyl group;
N is 0 ~ 4;
Y for not exist ,-O-,-S-or-CONH-;
W is not for be substituted or by R
dreplace
(1) C
5-7alkylidene group,
(2) phenyl, furyl, thiazolyl,
(3) ethenylphenyl, vinyl furyl, vinylthiazole base,
And described C
5-7carbon atom in alkylidene group can by O, S, NR
eor CO replaced;
R
dfor hydrogen atom, halogen, hydroxyl, amino, carboxyl, cyano group, C
1-4alkyl or C
1-4alkoxyl group;
R
efor hydrogen atom or C
1-4alkyl;
R
7and R
8be respectively hydrogen atom, methyl, ethyl or ethanoyl.
Compound shown in general formula (I), its pharmacy acceptable salt, and the optimal technical scheme of isomer is:
Wherein
X is O;
R
1for not to be substituted or by 1-3 R
9the saturated single heterocyclic radical of the phenyl replaced, naphthyl, 5-8 unit;
A is not for be substituted or by 1-3 R
9' phenyl, pyridyl, pyrimidyl, pyrazolyl, indazolyl, quinolyl, indyl, the Pyrazolopyridine base that replace;
R
2, R
3, R
4be respectively hydrogen;
R
5, R
6independently be hydrogen, or methyl;
R
9for
(1) amino, or-C (O) R
c, R
cfor the C be not substituted or replaced by 1-3 hydroxyl
1-4alkyl,
(2) be not substituted or to be selected from cyano group by 1-3, C that fluorine replaces
1-4alkyl,
(3) be not substituted or be selected from cyano group, trifluoromethyl ,-C (O) R by 1-3
c' ,-C (O) (CH
2)
nnR
ar
b,-S (O)
2r
c' piperazinyl, the piperidyl that replace;
R
aand R
bindependently be hydrogen, or C
1-4alkyl;
R
c' be C
1-4alkyl;
R
9' be
(1) hydroxyl, halogen, amino,
(2) be not substituted or to be selected from fluorine by 1-3, C that hydroxyl replaces
1-4alkyl, C
1-4alkoxyl group;
N is 0 ~ 2;
Y is-O or-CONH-;
W is C
5-7alkylidene group;
R
7and R
8be respectively hydrogen atom.
Compound shown in general formula (I), its pharmacy acceptable salt, and the optimal technical scheme of isomer is:
Wherein
X is O;
R
1for not to be substituted or by 1-2 R
9the phenyl, piperidyl, the piperazinyl that replace;
A is not for be substituted or by 1-2 R
9' phenyl, pyridyl, pyrimidyl, quinolyl, the indyl that replace;
R
2, R
3, R
4be respectively hydrogen;
R
5, R
6independently be hydrogen, or methyl;
R
9for
(1) amino, or-C (O) R
c, R
cfor the C be not substituted or replaced by 1-2 hydroxyl
1-4alkyl,
(2) be not substituted or to be selected from cyano group by 1-2, C that fluorine replaces
1-4alkyl,
(3) be not substituted or to be selected from cyano group by 1-2, piperazinyl that trifluoromethyl replaces;
R
9' be
(1) halogen, amino, C
1-4alkyl,
(2) be not substituted or to be selected from fluorine by 1-2, C that hydroxyl replaces
1-4alkyl, C
1-4alkoxyl group;
Y is-O-or-CONH-;
W is hexylidene;
R
7and R
8be respectively hydrogen atom.
Compound shown in general formula (I), its pharmacy acceptable salt, and the optimal technical scheme of isomer is:
Wherein
X is O;
R
1for not to be substituted or by 1-2 R
9the phenyl, the piperidyl that replace,
A is not for be substituted or by 1-2 R
9' pyridyl, the pyrimidyl that replace,
R
2, R
3, R
4be respectively hydrogen;
R
5, R
6independently be hydrogen, or methyl;
R
9for methyl, trifluoromethyl, piperazinyl, the C that cyano group replaces
1-4alkyl, or-C (O) R
c, R
cfor the C that hydroxyl replaces
1-4alkyl;
R
9' be amino, methyl or methoxy;
Y is-O-or-CONH-;
W is hexylidene;
R
7and R
8be respectively hydrogen atom.
To give a definition, present invention is described in utilization, and concrete definition mode includes but not limited to following description.
" halogen " of the present invention comprises fluorine atom, chlorine atom, bromine atoms, atomic iodine.
" C of the present invention
1-8alkyl " refer to that the alkane containing 1-8 carbon atom removes the alkyl of the straight or branched that a hydrogen atom derives, specific examples includes but not limited to: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, 2-methyl-propyl, 1-methyl-propyl, 1, 1-dimethyl ethyl, n-pentyl, 3-methyl butyl, 2-methyl butyl, 1-methyl butyl, 1-ethyl propyl, n-hexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3, 3-dimethylbutyl, 2, 2-dimethylbutyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-dimethylbutyl, 2-ethyl-butyl, 1-methyl-2-methyl-propyl, n-heptyl, n-octyl etc." C of the present invention
1-6alkyl " refer in above-mentioned example containing the specific examples of 1-6 carbon atom." C of the present invention
1-4alkyl " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" C of the present invention
2-8thiazolinyl " refer to containing double bond carbonatoms and be the thiazolinyl of the straight or branched of 2-8, specific examples includes but not limited to: vinyl, 1-propenyl, 2-propenyl, 3-propenyl, 1-methyl ethylene, 1-butylene base, crotyl, 3-butenyl, 1-methyl-1-propylene base, 2-methyl-1-propylene base, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl isophthalic acid-butenyl, 2-methyl-1-butene thiazolinyl, 3-methyl-1-butene base, 1-methyl-2-butene base, 2-methyl-2-butene base, 3-methyl-2-butene base, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentene thiazolinyl, 2-methyl-1-pentene thiazolinyl, 3-methyl-1-pentene thiazolinyl, 4-methyl-1-pentene base, 1-methyl-pentenyl, 2-methyl-pentenyl, 3-methyl-pentenyl, 4-methyl-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-crotyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butylene base, 1,2-dimethyl-crotyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butylene base, 1,3-dimethyl-crotyl, Isosorbide-5-Nitrae-dimethyl-crotyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butylene base, 2,3-dimethyl-crotyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butylene base, 3,3-dimethyl-crotyl, 1-ethyl-1-butylene base, 1-ethyl-crotyl, 1-ethyl-3-butenyl, 2-ethyl-1-butylene base, 2-ethyl-crotyl, 2-ethyl-3-butenyl, 1,1,2-trimethylammonium-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-Ethyl-2-Methyl-1-propenyl, 1-Ethyl-2-Methyl-2-propenyl, 1,3-butadiene base, Isosorbide-5-Nitrae-pentadienyl, Isosorbide-5-Nitrae-hexadienyl, 1,3,5-hexatriene base, heptenyl, octenyl etc." C of the present invention
2-6thiazolinyl " refer in above-mentioned example containing the specific examples of 2-6 carbon atom.
" C of the present invention
2-8alkynyl " refer to containing three key carbonatoms and be the alkynyl of the straight or branched of 2-8, specific examples includes but not limited to: ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-methyl-2-butyne base, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base, 1-methyl-valerylene base, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-valerylene base, 1,1-dimethyl-2-butyne base, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butyne base, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl, heptyne base, octyne base etc." C of the present invention
2-6alkynyl " refer in above-mentioned example containing the specific examples of 2-6 carbon atom.
" C of the present invention
1-6alkoxyl group " refer to " C
1-6alkyl " group that is connected with other structures by Sauerstoffatom, as methoxyl group, oxyethyl group, propyl group oxygen base, sec.-propyl oxygen base, butyl oxygen base, isobutyl-oxygen base, tertiary butyl oxygen base, sec-butyl oxygen base, amyl group oxygen base, neo-pentyl oxygen base, hexyl oxygen base etc." C of the present invention
1-4alkoxyl group " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
"-SO of the present invention
2c
1-6alkyl " refer to C
1-6alkyl is by alkylsulfonyl (-SO
2-) be connected with other parts derived group, i.e. (C
1-6alkyl) S (O)
2-, described " C
1-6alkyl " as mentioned before."-SO of the present invention
2c
1-4alkyl " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" halo C of the present invention
1-6alkyl " refer to that one or more " halogen " atom replaces " C
1-6alkyl " the group that derives, described " halogen " and " C
1-6alkyl " as defined hereinabove.
" C of the present invention
2-6alkynyl " refer to containing three key carbonatoms and be the alkynyl of the straight or branched of 2-6, specific examples includes but not limited to: ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-methyl-2-butyne base, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base, 1-methyl-valerylene base, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-valerylene base, 1,1-dimethyl-2-butyne base, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butyne base, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl etc.
" C of the present invention
1-6alkoxyl group " refer to " C
1-6alkyl " group that is connected with other structures by Sauerstoffatom, as methoxyl group, oxyethyl group, propyl group oxygen base, sec.-propyl oxygen base, butyl oxygen base, isobutyl-oxygen base, tertiary butyl oxygen base, sec-butyl oxygen base, amyl group oxygen base, neo-pentyl oxygen base, hexyl oxygen base etc.
" C of the present invention
1-6alkyl amine group " refer to a C
1-6a hydrogen atom in alkyl-substituted amino the group that derives, i.e. C
1-6alkyl-NH-, described " C
1-6alkyl " as mentioned before." C of the present invention
1-4alkyl amine group " refer in above-mentioned example containing the specific examples of 1-4 carbon atom." C of the present invention
1-4alkyl amine group " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" two (C of the present invention
1-6alkyl) amido " refer to two C
1-6two hydrogen atoms of alkyl respectively in substituted-amino the group that derives, i.e. (C
1-6alkyl)
2-N-, described " C
1-6alkyl " as mentioned before." two (C of the present invention
1-4alkyl) amido " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" C of the present invention
1-6alkyl-carbonyl " refer to C
1-6alkyl to be connected derived group, i.e. C by carbonyl-C (O)-with other parts
1-6alkyl-C (O)-, described " C
1-6alkyl " as mentioned before." C of the present invention
1-4alkyl-carbonyl " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" C of the present invention
1-6alkyl carbonyl oxy " refer to C
1-6alkyl to be connected with other parts derived group, i.e. (C by carboxyl-C (O) O-
1-6alkyl) C (O) O-, described " C
1-6alkyl " as mentioned before." C of the present invention
1-4alkyl carbonyl oxy " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" C of the present invention
1-6alkylamidoalkyl " refer to C
1-6alkyl to be connected with other parts derived group, i.e. (C by amide group-C (O) NH-
1-6alkyl) C (O) NH-, described " C
1-6alkyl " as mentioned before." C of the present invention
1-4alkylamidoalkyl " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" C of the present invention
1-6alkyl sulphonyl " refer to C
1-6alkyl is by alkylsulfonyl (-SO
2-) be connected with other parts derived group, i.e. (C
1-6alkyl) S (O)
2-, described " C
1-6alkyl " as mentioned before." C of the present invention
1-4alkyl sulphonyl " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" C of the present invention
1-6alkyl sulphinyl " refer to C
1-6alkyl to be connected with other parts derived group, i.e. (C by alkylsulfonyl (-SO-)
1-6alkyl) S (O)-, described " C
1-6alkyl " as mentioned before." C of the present invention
1-4alkyl sulphinyl " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" C of the present invention
1-6alkylsulfonamido " refer to a C
1-6a hydrogen atom in alkyl sulphonyl substituted-amino the group that derives, i.e. (C
1-6alkyl) S (O)
2nH-, described " C
1-6alkyl sulphonyl " as mentioned before." C of the present invention
1-4alkylsulfonamido " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" halo C of the present invention
1-6alkoxyl group " refer to that one or more " halogen " atom replaces " C
1-6alkoxyl group " the group that derives, described " halogen " and " C
1-6alkoxyl group " as defined hereinabove." halo C of the present invention
1-4alkoxyl group " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" C of the present invention
1-6alkyl amine group formyl radical " refer to C
1-6alkyl amine group to be connected derived group, i.e. (C by carbonyl-C (O)-with other parts
1-6alkyl) NHC (O)-, described " C
1-6alkyl " as mentioned before." C of the present invention
1-4alkyl amine group formyl radical " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" two (C of the present invention
1-6alkyl) amido formacyl " refer to two (C
1-6alkyl) amido to be connected derived group, i.e. (C by carbonyl-C (O)-with other parts
1-6alkyl)
2nC (O)-, described " two (C
1-6alkyl) amido " as mentioned before." two (C of the present invention
1-4alkyl) amido formacyl " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" C of the present invention
1-6alkyl amine group alkylsulfonyl " refer to " C
1-6alkyl-NHSO
2-" mode connects derived group, i.e. (C
1-6alkyl) NHS (O)
2-, described " C
1-6alkyl amine group " as mentioned before." C of the present invention
1-4alkyl amine group alkylsulfonyl " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" two (C of the present invention
1-6alkyl) amido alkylsulfonyl " refer to two (C
1-6alkyl) amido is by alkylsulfonyl-SO
2-be connected with other parts derived group, i.e. (C
1-6alkyl)
2nS (O)
2-, described " C
1-6alkyl " as mentioned before." two (C of the present invention
1-4alkyl) amido alkylsulfonyl " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" C of the present invention
1-6carbalkoxy " refer to C
1-6alkoxyl group to be connected derived group, i.e. (C by-C (O)-with other parts
1-6alkyl) OC (O)-, described " C
1-6alkoxyl group " as mentioned before." C of the present invention
1-4carbalkoxy " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" C of the present invention
1-8alkylidene group " refer to containing 1-8 carbon atom alkane and remove two hydrogen atoms simultaneously after the group of straight or branched that derives, specific examples includes but not limited to: methylene radical, ethylidene, propylidene, butylidene, pentylidene, hexylidene, sub-heptyl, octylene etc." C of the present invention
4-8alkylidene group " refer in above-mentioned example containing the specific examples of 4-8 carbon atom." C of the present invention
5-7alkylidene group " refer in above-mentioned example containing the specific examples of 5-7 carbon atom." C of the present invention
6alkylidene group " refer in above-mentioned example containing the specific examples of 6 carbon atoms.
" C of the present invention
2-8alkenylene " refer to the alkene of the straight or branched that the carbonatoms containing double bond is 2-8 remove two hydrogen atoms simultaneously after the group of straight or branched that derives, specific examples includes but not limited to: vinylidene, propenylidene, crotonylidene, inferior pentenyl, sub-hexenyl, sub-heptenyl, sub-octenyl etc.
" C of the present invention
2-8alkynyl " refer to the alkynes of the straight or branched that the carbonatoms containing three key is 2-8 remove two hydrogen atoms simultaneously after the group of straight or branched that derives, specific examples includes but not limited to: ethynyl, proyl, butynyl, pentynyl, hexin base, heptyne base, octyne base etc.
" 3-14 unit cycloalkyl " of the present invention refers to that annular atoms is all the cyclic group of carbon atom, comprises 3-8 unit's monocyclic cycloalkyl and 8-14 unit condensed ring cycloalkyl; 3-8 unit monocycle alkyl comprises the 3-8 unit monocycle alkyl of saturated 3-8 unit's monocycle alkyl and fractional saturation; " 3-8 unit cycloalkyl, 3-8 unit monocycle alkyl " of the present invention refers to the specific examples containing 3-6 annular atoms in " 3-14 unit cycloalkyl "." 3-6 unit cycloalkyl " of the present invention refers to the specific examples containing 3-6 annular atoms in " 3-14 unit cycloalkyl "; 8-14 unit condensed ring cycloalkyl comprises the 8-14 unit monocycle alkyl of saturated 8-14 unit's monocycle alkyl and fractional saturation.
Saturated 3-8 unit monocycle alkyl, refer to the saturated cyclic alkyl containing 3-8 carbon atom, specific examples includes but not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, 1-methylcyclopropyl groups, 1-pentylcyclopropyl, 1,2-diethyl cyclobutyl, 1-methyl-cyclobutyl, 1-butyl cyclobutyl, 1,3-dimethylcyclobutyl, 1-methylcyclopentyl, 1-butyl cyclopentyl, 1-methylcyclohexyl, 1-ethylcyclopentyl etc.
The 3-8 unit monocycle alkyl of fractional saturation refers to that carbonatoms is the cyclic alkenyl radical of 3-8, and its double bond is positioned at ring, and specific examples includes but not limited to:
Saturated 8-14 unit condensed ring cycloalkyl, refer to containing 8-14 annular atoms by two or more ring texturees each other shared two adjacent atoms couple together the saturated condensed cyclic structure formed, specific examples includes but not limited to:
The 8-14 unit monocycle alkyl of fractional saturation, refer to 8-14 annular atoms by two or more ring texturees each other shared two adjacent atoms couple together the condensed ring thiazolinyl formed, its double bond is positioned at ring, and specific examples includes but not limited to:
" 6-14 unit aryl " of the present invention refers to that annular atoms is all the cyclic aromatic groups of carbon atom, comprises 6-8 unit's monocyclic aryl and 8-14 unit fused ring aryl." 6-10 unit aryl " of the present invention refers to the specific examples containing 6-10 carbon atom in " 6-14 unit aryl ".
6-8 unit monocyclic aryl refers to whole undersaturated aryl, and specific examples includes but not limited to: phenyl, cyclooctatetraenyl etc.
8-14 unit fused ring aryl refers to and to be shared by two or more ring texturees that two adjacent carbon atoms are formed each other, for the condensed ring group of whole undersaturated aromatic nucleus, comprise the whole unsaturated fused ring aryl of 8-14 unit, specific examples includes but not limited to: naphthalene, phenanthrene etc.
" 3-14 unit heterocyclic radical " of the present invention refers to containing 5-14 annular atoms (wherein at least containing a heteroatoms) cyclic group, comprise the saturated single heterocyclic radical of 3-8 unit, single heterocyclic radical of 3-8 unit fractional saturation, the first saturated fused heterocycle base of 6-14, the fused heterocycle base of 6-14 unit fractional saturation, the single heteroaryl of 5-8 unit, the thick heteroaryl of 6-14 unit, described heteroatoms has nitrogen, oxygen and sulphur etc., and comprise carbon atom, nitrogen-atoms and sulphur atom can by oxo simultaneously." 5-10 unit heterocyclic radical " of the present invention refers to the specific examples containing 5-10 annular atoms in " 3-14 unit heterocyclic radical "." 5-6 unit heterocyclic radical " of the present invention refers to the specific examples containing 5-6 annular atoms in " 3-14 unit heterocyclic radical "." 3-8 unit heterocyclic radical " of the present invention refers to the specific examples containing 3-8 annular atoms in " 3-14 unit heterocyclic radical ".
The saturated single heterocyclic radical of 3-8 unit refers to " the single heterocyclic radical of 3-8 unit of the present invention, 3-8 unit heterocyclic radical ", namely the saturated cyclic group containing 3-8 annular atoms (wherein at least containing a heteroatoms), described heteroatoms has nitrogen, oxygen and sulphur etc., comprise carbon atom simultaneously, nitrogen-atoms and sulphur atom can by oxos, specific examples includes but are not limited to ethylenimine, diazacyclo propane, azetidine, 1, 2-diazetidine, tetramethyleneimine, imidazolidine, pyrazolidine, piperidines, piperazine, oxyethane, dioxirane, thiirane, trimethylene oxide, 1, 2-dioxetane, Thietane, tetrahydrofuran (THF), tetramethylene sulfide, 1, 3-dioxolane, 1, 3-dithiolane, tetrahydropyrans, 1, 4-dioxane, 1, 3-dioxane, 1, 3-oxathiane, oxaza propane, Si Qing oxazole, tetrahydrochysene isoxazole, thiazolidine, morpholine etc." the saturated single heterocyclic radical of 5-8 unit " of the present invention refers to the specific examples containing 5-8 annular atoms in " single heterocyclic radical that 3-8 unit is saturated ".
Single heterocyclic radical of 3-8 unit fractional saturation refers to the cyclic alkenyl radical containing 3-8 annular atoms (wherein at least containing a heteroatoms), and its double bond is positioned at ring, and described heteroatoms has nitrogen, oxygen and sulphur etc., comprise carbon atom simultaneously, nitrogen-atoms and sulphur atom can by oxos, and specific examples includes but are not limited to 2H-ethylenimine, 3H-diazacyclo propylene, azete, 1,2-diazetine, pyrrolin, 4,5-glyoxalidine, 4,5-pyrazoline, 1,2,3-triazoles, 1,2,4-triazole, 2-pyridone, 4-pyridone, 1,2-diazacyclo heptantriene, 1,3-diazacyclo heptantriene, Isosorbide-5-Nitrae-diazacyclo heptantriene, Isosorbide-5-Nitrae-dihydro-Isosorbide-5-Nitrae-diazacyclo sarohornene, 1,2-dithia cyclobutene, 2,5-dihydro-thiophene, 1,2-dithiole, 1,3-dithiole, 2H-pyrans, 2H-pyran-2-one, 3,4-dihydro-2H-pyrans, 4H-pyrans, 4H-pyrans-4-ketone, 4,5-dihydro-oxazole, 4,5-dihydro-isoxazole, 2,3-dihydro-isoxazole, 4,5-thiazoline, 2H-1,2-oxazine, 4H-1,2-oxazine, 6H-1,2-oxazine, 2H-1,3-oxazine, 4H-1,3-oxazine, 6H-1,3-oxazine, 2H-1,4-oxazine, 4H-1,4-oxazine, 5,6-dihydro-4H-1,3-oxazine, 2H-1,3-thiazine, 4H-1,3-thiazine, 6H-1,3-thiazine, 2H-1,4-thiazine, 4H-1,4-thiazine, 5,6-dihydro-4H-1,3-thiazine etc.
The saturated fused heterocycle base of 6-14 unit contain 6-14 annular atoms (wherein at least containing a heteroatoms) by two or more ring texturees each other shared two adjacent atoms couple together the saturated condensed cyclic structure formed, described heteroatoms has nitrogen, oxygen and sulphur etc., comprise carbon atom, nitrogen-atoms and sulphur atom can by oxo simultaneously, and specific examples includes but are not limited to octahydro-benzo [d] imidazoles, decahydroquinolyl, octahydro thionaphthene, octahydro cumarone etc.
The fused heterocycle base of 6-14 unit fractional saturation refer to 6-14 annular atoms (wherein at least containing a heteroatoms) by two or more ring texturees each other shared two adjacent atoms couple together the condensed ring thiazolinyl formed, its double bond is positioned at ring, described heteroatoms has nitrogen, oxygen and sulphur etc., comprise carbon atom simultaneously, nitrogen-atoms and sulphur atom can by oxos, specific examples includes but are not limited to six hydrogen Thienoimidazoles, hexahydro furyl imidazoles, 4H-1, 3-benzoxazine, 4, 6-dihydro-1H-furo [3, 4-d] imidazoles, 4, 6-dihydro-1H-thieno-[3, 4-d] imidazoles, 4, 6-dihydro-1H-pyrrolo-[3, 4-d] imidazoles, 4, 5, 6, 7-tetrahydrochysene-1H-benzo [d] imidazoles etc.
5-8 unit single heteroaryl refer to 5-8 annular atoms have aromaticity contain heteroatomic cyclic group, specific examples includes but are not limited to furyl, thienyl, pyrryl, thiazolyl, isothiazolyl, thiadiazolyl group, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazoles base, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidyl, Isosorbide-5-Nitrae-Dioxin base, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazines base, 1,3,4-triazinyl, 1,2,4,5-tetrazine base, oxepin base, thia cycloheptatriene base, nitrogen heterocyclic heptantriene base, 1,3-diazacyclo heptantriene base, azepine cyclooctatetraenyl etc." the unsaturated single heterocyclic radical of 5-6 unit " of the present invention refers to the specific examples containing 5-6 annular atoms in " the single heteroaryl of 5-8 unit "." the unsaturated single heterocyclic radical of 3-8 unit " of the present invention refers to the specific examples containing 3-8 annular atoms in " the single heteroaryl of 5-8 unit ".
The thick heteroaryl of 6-14 unit refer to containing 6-14 annular atoms (wherein at least containing a heteroatoms) by two or more ring texturees each other shared two adjacent atoms couple together the undersaturated condensed cyclic structure with aromaticity formed, specific examples includes but not limited to: benzofuryl, benzisoxa furyl, benzothienyl, indyl, benzoxazolyl, benzimidazolyl-, indazolyl, benzotriazole base, quinolyl, isoquinolyl, acridyl, phenanthridinyl, benzo pyridazinyl, phthalazinyl, quinazolyl, quinoxalinyl, phenol piperazine base, pteridine radicals, purine radicals, naphthyridinyl etc." the unsaturated fused heterocycle base of 9-10 unit " of the present invention refers to the specific examples containing 9-10 annular atoms in " the thick heteroaryl of 6-14 unit ".
" 6-14 unit aryl C of the present invention
1-8alkylidene group " refer to that one replaces C to multiple 6-14 units aryl
1-8alkylidene group the group that derives, described " 6-14 unit aryl ", " C
1-8alkylidene group " as defined hereinabove." 6-10 unit aryl C of the present invention
1-8alkylidene group " refer to the specific examples containing 6-10 annular atoms in " 6-14 unit aryl "." phenyl C of the present invention
1-6alkylidene group " refer to " 6-14 unit aryl ", " C
1-8alkylidene group " in be respectively the specific examples of phenyl, a 1-6 atom.
" 6-14 unit aryl C of the present invention
2-8alkenylene " refer to that one replaces C to multiple 6-14 units aryl
2-8alkenylene the group that derives, described " 6-14 unit aryl ", " C
2-8alkenylene " as defined hereinabove." 6-10 unit aryl C of the present invention
2-8alkenylene " refer to the specific examples containing 6-10 annular atoms in " 6-14 unit aryl ".
" 6-14 unit aryl C of the present invention
2-8alkynyl " refer to that one replaces C to multiple 6-14 units aryl
2-8alkynyl the group that derives, described " 6-14 unit aryl ", " C
2-8alkynyl " as defined hereinabove.
" 3-14 unit heterocyclic radical C of the present invention
1-8alkylidene group " refer to that one replaces C to multiple 3-14 units heterocyclic radical
1-8alkylidene group the group that derives, described " 3-14 unit heterocyclic radical ", " C
1-8alkylidene group " as defined hereinabove." 3-8 unit heterocyclic radical C of the present invention
1-8alkylidene group " refer to the specific examples containing 3-8 annular atoms in " 3-14 unit heterocyclic radical "." 5-6 unit heterocyclic radical C of the present invention
1-6alkylidene group " refer to " 3-14 unit heterocyclic radical ", " C
1-8alkylidene group " be respectively the specific examples of 5-6 annular atoms, a 1-6 atom.
" 3-14 unit heterocyclic radical C of the present invention
2-8alkenylene " refer to that one replaces C to multiple 3-14 units heterocyclic radical
2-8alkenylene the group that derives, described " 3-14 unit heterocyclic radical ", " C
2-8alkenylene " as defined hereinabove." 3-8 unit heterocyclic radical C of the present invention
2-8alkenylene " refer to the specific examples containing 3-8 annular atoms in " 3-8 unit heterocyclic radical ".
" 3-14 unit heterocyclic radical C of the present invention
2-8alkynyl " refer to that one replaces C to multiple 3-14 units heterocyclic radical
2-8alkynyl the group that derives, described " 3-14 unit heterocyclic radical ", " C
2-8alkynyl " as defined hereinabove.
" 3-8 unit cycloalkyl C of the present invention
1-8alkylidene group " refer to that one to multiple 3-8 unit cycloalkyl substituted C
1-8alkylidene group the group that derives, described " 3-8 unit cycloalkyl ", " C
1-8alkylidene group " as defined hereinabove.
" 3-8 unit cycloalkyl C of the present invention
2-8alkenylene " refer to that one to multiple 3-8 unit cycloalkyl substituted C
2-8alkenylene the group that derives, described " 3-8 unit cycloalkyl ", " C
2-8alkenylene " as defined hereinabove.
" 3-8 unit cycloalkyl C of the present invention
2-8alkynyl " refer to that one to multiple 3-8 unit cycloalkyl substituted C
2-8alkynyl the group that derives, described " 3-8 unit cycloalkyl ", " C
2-8alkynyl " as defined hereinabove.
" C of the present invention
1-8alkyl 6-14 unit aryl " refer to that one to multiple C
1-8after alkyl replaces 6-14 unit aryl, this 6-14 unit aryl remove simultaneously a hydrogen atom the group that derives, described " C
1-8alkyl ", " 6-14 unit aryl " as defined hereinabove." C of the present invention
1-8alkyl 6-10 unit aryl " refer to the specific examples containing 6-10 annular atoms in " 6-14 unit aryl ".
" C of the present invention
1-8alkyl 3-14 unit heterocyclic radical " refer to that one to multiple C
1-8after alkyl replaces 3-14 unit heterocyclic radical, this 3-14 unit heterocyclic radical remove simultaneously a hydrogen atom the group that derives, described " C
1-8alkyl ", " 3-14 unit heterocyclic radical " as defined hereinabove." C of the present invention
1-8alkyl 3-8 unit heterocyclic radical " refer to the specific examples containing 3-8 annular atoms in " 3-14 unit heterocyclic radical ".
" C of the present invention
1-8alkyl 3-8 unit cycloalkyl " refer to that one to multiple C
1-8after alkyl replaces 3-8 unit cycloalkyl, this 3-8 unit cycloalkyl remove simultaneously a hydrogen atom the group that derives, described " C
1-8alkyl ", " 3-8 unit cycloalkyl " as defined hereinabove.
" C of the present invention
2-8thiazolinyl 6-14 unit aryl " refer to that one to multiple C
2-8after alkenyl substituted 6-14 unit aryl, this 6-14 unit aryl remove simultaneously a hydrogen atom the group that derives, described " C
2-8thiazolinyl ", " 6-14 unit aryl " as defined hereinabove." C of the present invention
2-8thiazolinyl 6-10 unit aryl " refer to the specific examples containing 6-10 annular atoms in " 6-14 unit aryl "." C of the present invention
2-6thiazolinyl phenyl " refer to " C
2-8thiazolinyl ", be respectively the specific examples of 2-6 atom, phenyl in " 6-14 unit aryl ".
" C of the present invention
2-8thiazolinyl 3-14 unit heterocyclic radical " refer to that one to multiple C
2-8after alkenyl substituted 3-14 unit heterocyclic radical, this 3-14 unit heterocyclic radical remove simultaneously a hydrogen atom the group that derives, described " C
2-8thiazolinyl ", " 3-14 unit heterocyclic radical " as defined hereinabove." C of the present invention
2-8thiazolinyl 3-8 unit heterocyclic radical " refer to the specific examples containing 3-8 annular atoms in " 3-14 unit heterocyclic radical "." C of the present invention
2-6thiazolinyl 5-6 unit heterocyclic radical " refer to " C
2-8thiazolinyl ", be respectively the specific examples of 2-6 atom, a 5-6 annular atoms in " 3-14 unit heterocyclic radical ".
" C of the present invention
2-8thiazolinyl 3-8 unit cycloalkyl " refer to that one to multiple C
2-8after alkenyl substituted 3-8 unit cycloalkyl, this 3-8 unit cycloalkyl remove simultaneously a hydrogen atom the group that derives, described " C
2-8thiazolinyl ", " 3-8 unit cycloalkyl " as defined hereinabove.
" C of the present invention
2-8alkynyl 6-14 unit aryl " refer to that one to multiple C
2-8after alkynyl substituted 6-14 unit aryl, this 6-14 unit aryl remove simultaneously a hydrogen atom the group that derives, described " C
2-8alkynyl ", " 6-14 unit aryl " as defined hereinabove.
" C of the present invention
2-8alkynyl 3-14 unit heterocyclic radical " refer to that one to multiple C
2-8after alkynyl base replaces 3-14 unit heterocyclic radical, this 3-14 unit heterocyclic radical remove simultaneously a hydrogen atom the group that derives, described " C
2-8alkynyl ", " 3-14 unit heterocyclic radical " as defined hereinabove.
" C of the present invention
2-8alkynyl 3-8 unit cycloalkyl " refer to that one to multiple C
2-8after alkynyl substituted 3-8 unit cycloalkyl, this 3-8 unit cycloalkyl remove simultaneously a hydrogen atom the group that derives, described " C
2-8alkynyl ", " 3-8 unit cycloalkyl " as defined hereinabove.
" C of the present invention
1-8alkylidene group 6-14 unit aryl C
1-8alkylidene group " refer to C
1-8alkylidene group connects 6-14 unit aryl and connects C
1-8alkylidene group the group that derives, i.e. C
1-8alkylidene group-6-14 unit aryl-C
1-8alkylidene group, described " C
1-8alkylidene group ", " 6-14 unit aryl ", " C
1-8alkylidene group " as defined hereinabove." C of the present invention
1-8alkylidene group 6-10 unit aryl C
1-8alkylidene group " refer to the specific examples containing 6-10 annular atoms in " 6-14 unit aryl ".
" C of the present invention
1-8alkylidene group 6-14 unit aryl C
2-8alkenylene " refer to C
1-8alkylidene group connects 6-14 unit aryl and connects C
2-8alkenylene the group that derives, i.e. C
1-8alkylidene group-6-14 unit aryl-C
2-8alkenylene, described " C
1-8alkylidene group ", " 6-14 unit aryl ", " C
2-8alkenylene " as defined hereinabove." C of the present invention
1-8alkylidene group 6-10 unit aryl C
2-8alkenylene " refer to the specific examples containing 6-10 annular atoms in " 6-14 unit aryl ".
" C of the present invention
1-8alkylidene group 6-14 unit aryl C
2-8alkynyl " refer to C
1-8alkylidene group connects 6-14 unit aryl and connects C
2-8alkynyl the group that derives, i.e. C
1-8alkylidene group-6-14 unit aryl-C
2-8alkynyl, described " C
1-8alkylidene group ", " 6-14 unit aryl ", " C
2-8alkynyl " as defined hereinabove.
" C of the present invention
2-8alkenylene 6-14 unit aryl C
1-8alkylidene group " refer to C
2-8alkenylene connects 6-14 unit aryl and connects C
1-8alkylidene group the group that derives, i.e. C
2-8alkenylene-6-14 unit aryl-C
1-8alkylidene group, described " C
2-8alkenylene ", " 6-14 unit aryl ", " C
1-8alkylidene group " as defined hereinabove." C2 of the present invention
-8alkenylene 6-10 unit aryl C
1-8alkylidene group " refer to the specific examples containing 6-10 annular atoms in " 6-14 unit aryl "." C of the present invention
2-6alkenylene phenyl C
1-6alkylidene group " refer to " C
2-8alkenylene ", " 6-14 unit aryl ", " C
1-8alkylidene group " in be respectively the specific examples of 2-6 atom, phenyl, a 1-6 atom.
" C of the present invention
2-8alkenylene 6-14 unit aryl C
2-8alkenylene " refer to C
2-8alkenylene connects 6-14 unit aryl and connects C
2-8alkenylene the group that derives, i.e. C
2-8alkenylene-6-14 unit aryl-C
2-8alkenylene, described " C
2-8alkenylene ", " 6-14 unit aryl ", " C
2-8alkenylene " as defined hereinabove." C of the present invention
2-8alkenylene 6-10 unit aryl C
2-8alkenylene " refer to the specific examples containing 6-10 annular atoms in " 6-14 unit aryl ".
" C of the present invention
2-8alkenylene 6-14 unit aryl C
2-8alkynyl " refer to C
2-8alkenylene connects 6-14 unit aryl and connects C
2-8alkynyl the group that derives, i.e. C
2-8alkenylene-6-14 unit aryl-C
2-8alkynyl, described " C
2-8alkenylene ", " 6-14 unit aryl ", " C
2-8alkynyl " as defined hereinabove.
" C of the present invention
2-8alkynyl 6-14 unit aryl C
1-8alkylidene group " refer to " refer to C
2-8alkynyl connects 6-14 unit aryl and connects C
1-8alkylidene group the group that derives, i.e. C
2-8alkynyl-6-14 unit aryl-C
1-8alkylidene group, described " C
2-8alkynyl base ", " 6-14 unit aryl ", " C
1-8alkylidene group " as defined hereinabove.
" C of the present invention
2-8alkynyl 6-14 unit aryl C
2-8alkenylene " refer to C
2-8alkynyl connects 6-14 unit aryl and connects C
2-8alkenylene the group that derives, i.e. C
2-8alkynyl-6-14 unit aryl-C
2-8alkenylene, described " C
2-8alkynyl ", " 6-14 unit aryl ", " C
2-8alkenylene " as defined hereinabove.
" C of the present invention
2-8alkynyl 6-14 unit aryl C
2-8alkynyl " refer to C
2-8alkynyl connects 6-14 unit aryl and connects C
2-8alkynyl the group that derives, i.e. C
2-8alkynyl-6-14 unit aryl-C
2-8alkynyl, described " C
2-8alkynyl ", " 6-14 unit aryl " as defined hereinabove.
" C of the present invention
1-8alkylidene group 3-14 unit heterocyclic radical C
1-8alkylidene group " refer to C
1-8alkylidene group connects 3-14 unit heterocyclic radical and connects C
1-8alkylidene group the group that derives, i.e. C
1-8alkylidene group-3-14 unit heterocyclic radical-C
1-8alkylidene group, described " 3-14 unit heterocyclic radical ", " C
1-8alkylidene group " as defined hereinabove." C of the present invention
1-8alkylidene group 3-8 unit heterocyclic radical C
1-8alkylidene group " refer to the specific examples containing 3-8 annular atoms in " 3-14 unit heterocyclic radical ".
" C of the present invention
1-8alkylidene group 3-14 unit heterocyclic radical C
2-8alkenylene " refer to C
1-8alkylidene group connects 3-14 unit heterocyclic radical and connects C
2-8alkenylene the group that derives, i.e. C
1-8alkylidene group-3-14 unit heterocyclic radical-C
2-8alkenylene, described " C
1-8alkylidene group ", " 3-14 unit heterocyclic radical ", " C
2-8alkenylene " as defined hereinabove." C of the present invention
1-8alkylidene group 3-8 unit heterocyclic radical C
2-8alkenylene " refer to the specific examples containing 3-8 annular atoms in " 3-14 unit heterocyclic radical ".
" C of the present invention
1-8alkylidene group 3-14 unit heterocyclic radical C
2-8alkynyl " refer to C
1-8alkylidene group connects 3-14 unit heterocyclic radical and connects C
2-8alkynyl the group that derives, i.e. C
1-8alkylidene group-3-14 unit heterocyclic radical-C
2-8alkynyl, described " C
1-8alkylidene group ", " 3-14 unit heterocyclic radical ", " C
2-8alkynyl " as defined hereinabove.
" C of the present invention
2-8alkenylene 3-14 unit heterocyclic radical C
1-8alkylidene group " refer to C
2-8alkenylene connects 3-14 unit heterocyclic radical and connects C
1-8alkylidene group the group that derives, i.e. C
2-8alkenylene-3-14 unit heterocyclic radical-C
1-8alkylidene group, described " C
2-8alkenylene ", " 3-14 unit heterocyclic radical ", " C
1-8alkylidene group " as defined hereinabove." C of the present invention
2-8alkenylene 3-8 unit heterocyclic radical C
1-8alkylidene group " refer to the specific examples containing 3-8 annular atoms in " 3-14 unit heterocyclic radical "." C of the present invention
2-6alkenylene 5-6 unit heterocyclic radical C
1-6alkylidene group " refer to " C
2-8alkenylene ", " 3-14 unit heterocyclic radical ", " C
1-8alkylidene group " in specific examples respectively containing 2-6 atom, a 5-6 annular atoms, a 1-6 atom
" C of the present invention
2-8alkenylene 3-14 unit heterocyclic radical C
2-8alkenylene " refer to C
2-8alkenylene connects 3-14 unit heterocyclic radical and connects C
2-8alkenylene the group that derives, i.e. C
2-8alkenylene-3-14 unit heterocyclic radical-C
2-8alkenylene, described " C
2-8alkenylene ", " 3-14 unit heterocyclic radical ", " C
2-8alkenylene " as defined hereinabove." C of the present invention
2-8alkenylene 3-8 unit heterocyclic radical C
2-8alkenylene " refer to the specific examples containing 3-8 annular atoms in " 3-14 unit heterocyclic radical ".
" C of the present invention
2-8alkenylene 3-14 unit heterocyclic radical C
2-8alkynyl " refer to C
2-8alkenylene connects 3-14 unit heterocyclic radical and connects C
2-8alkynyl the group that derives, i.e. C
2-8alkenylene-3-14 unit heterocyclic radical-C
2-8alkynyl, described " C
2-8alkenylene ", " 3-14 unit heterocyclic radical ", " C
2-8alkynyl " as defined hereinabove.
" C of the present invention
2-8alkynyl 3-14 unit heterocyclic radical C
1-8alkylidene group " refer to that one to multiple C
2-8c is replaced after alkynyl substituted 3-14 unit heterocyclic radical
1-8alkylidene group the group that derives, described " C
2-8alkynyl ", " 3-14 unit heterocyclic radical ", " C
1-8alkylidene group " as defined hereinabove.
" C of the present invention
2-8alkynyl 3-14 unit heterocyclic radical C
2-8alkenylene " refer to that one to multiple C
2-8c is replaced after alkynyl substituted 3-14 unit heterocyclic radical
2-8alkenylene the group that derives, described " C
2-8alkynyl ", " 3-14 unit heterocyclic radical ", " C
2-8alkenylene " as defined hereinabove.
" C of the present invention
2-8alkynyl 3-14 unit heterocyclic radical C
2-8alkynyl " refer to C
2-8alkynyl connects 3-14 unit heterocyclic radical and connects C
2-8alkynyl the group that derives, i.e. C
2-8alkynyl-3-14 unit heterocyclic radical-C
2-8alkynyl, described " C
2-8alkynyl ", " 3-14 unit heterocyclic radical " as defined hereinabove.
" C of the present invention
1-8alkylidene group 3-8 unit cycloalkyl C
1-8alkylidene group " refer to C
1-8alkylidene group connects 3-8 unit cycloalkyl and connects C
1-8alkylidene group the group that derives, i.e. C
1-8alkylidene group-3-8 unit cycloalkyl-C
1-8alkylidene group, described " 3-8 unit cycloalkyl ", " C
1-8alkylidene group " as defined hereinabove.
" C of the present invention
1-8alkylidene group 3-8 unit cycloalkyl C
2-8alkenylene " refer to C
1-8alkylidene group connects 3-8 unit cycloalkyl and connects C
2-8alkenylene the group that derives, i.e. C
1-8alkylidene group-3-8 unit cycloalkyl-C
2-8alkenylene, described " C
1-8alkylidene group ", " 3-8 unit cycloalkyl ", " C
2-8alkenylene " as defined hereinabove.
" C of the present invention
1-8alkylidene group 3-8 unit cycloalkyl C
2-8alkynyl " refer to C
1-8alkylidene group connects 3-8 unit cycloalkyl and connects C
2-8alkynyl the group that derives, i.e. C
1-8alkylidene group-3-8 unit cycloalkyl-C
2-8alkynyl, described " C
1-8alkylidene group ", " 3-8 unit cycloalkyl ", " C
2-8alkynyl " as defined hereinabove.
" C of the present invention
2-8alkenylene 3-8 unit cycloalkyl C
1-8alkylidene group " refer to C
2-8alkenylene connects 3-8 unit cycloalkyl and connects C
2-8alkynyl the group that derives, i.e. C
2-8alkenylene-3-8 unit cycloalkyl-C
2-8alkynyl, described " C
2-8alkenylene ", " 3-8 unit cycloalkyl ", " C
1-8alkylidene group " as defined hereinabove.
" C of the present invention
2-8alkenylene 3-8 unit cycloalkyl C
2-8alkenylene " be C
2-8alkenylene connects 3-8 unit cycloalkyl and connects C
2-8alkenylene the group that derives, i.e. C
2-8alkenylene-3-8 unit cycloalkyl-C
2-8alkenylene, described " C
2-8alkenylene ", " 3-8 unit cycloalkyl ", " C
2-8alkenylene " as defined hereinabove.
" C of the present invention
2-8alkenylene 3-8 unit cycloalkyl C
2-8alkynyl " refer to C
2-8alkenylene connects 3-8 unit cycloalkyl and connects C
2-8alkynyl the group that derives, i.e. C
2-8alkenylene-3-8 unit cycloalkyl-C
2-8alkynyl, described " C
2-8alkenylene ", " 3-8 unit cycloalkyl ", " C
2-8alkynyl " as defined hereinabove.
" C of the present invention
2-8alkynyl 3-8 unit cycloalkyl C
1-8alkylidene group " refer to C
2-8alkynyl connects 3-8 unit cycloalkyl and connects C
1-8alkylidene group the group that derives, i.e. C
2-8alkynyl-3-8 unit cycloalkyl-C
1-8alkylidene group, described " C
2-8alkynyl ", " 3-8 unit cycloalkyl ", " C
1-8alkylidene group " as defined hereinabove.
" C of the present invention
2-8alkynyl 3-8 unit cycloalkyl C
2-8alkenylene " refer to C
2-8alkynyl connects 3-8 unit cycloalkyl and connects C
2-8alkenylene the group that derives, i.e. C
2-8alkynyl-3-8 unit cycloalkyl-C
2-8alkenylene, described " C
2-8alkynyl ", " 3-8 unit cycloalkyl ", " C
2-8alkenylene " as defined hereinabove.
" C of the present invention
2-8alkynyl 3-8 unit cycloalkyl C
2-8alkynyl " refer to C
2-8alkynyl connects 3-8 unit cycloalkyl and connects C
2-8alkenylene the group that derives, i.e. C
2-8alkynyl-3-8 unit cycloalkyl-C
2-8alkynyl, described " C
2-8alkynyl ", " 3-8 unit cycloalkyl " as defined hereinabove.
" heterocyclic radical-6-14 unit of 3-14 unit aryl C of the present invention
1-8alkylidene group " refer to that one replaces C after multiple 3-14 units heterocyclic radical replaces 6-14 unit aryl
1-8alkylidene group the group that derives, described " 3-14 unit heterocyclic radical ", " 6-14 unit aryl ", " C
1-8alkylidene group " as defined hereinabove." heterocyclic radical-6-10 unit of 3-8 unit aryl C of the present invention
1-8alkylidene group " refer to the specific examples respectively containing 3-8 annular atoms, a 6-10 annular atoms in " 3-14 unit heterocyclic radical ", " 6-14 unit aryl ".
" aryl-3-14 unit of 6-14 unit heterocyclic radical C of the present invention
1-8alkylidene group " refer to that one replaces C after multiple 6-14 units aryl replaces 3-14 unit heterocyclic radical
1-8alkylidene group the group that derives, described " 6-14 unit aryl ", " 3-14 unit heterocyclic radical ", " C
1-8alkylidene group " as defined hereinabove." aryl-3-8 unit of 6-10 unit heterocyclic radical C of the present invention
1-8alkylidene group " refer to the specific examples respectively containing 6-10 annular atoms, a 3-8 annular atoms in " 6-14 unit aryl ", " 3-14 unit heterocyclic radical ".
" heterocyclic radical-3-14 unit of 3-14 unit heterocyclic radical C of the present invention
1-8alkylidene group " refer to that one replaces C after multiple 3-14 units heterocyclic radical replaces 3-14 unit heterocyclic radical
1-8alkylidene group the group that derives, described " 3-14 unit heterocyclic radical ", " C
1-8alkylidene group " as defined hereinabove." heterocyclic radical-3-8 unit of 3-8 unit heterocyclic radical C of the present invention
1-8alkylidene group " refer to the specific examples containing 3-8 annular atoms in " 3-14 unit heterocyclic radical "." heterocyclic radical-5-6 unit of 5-6 unit heterocyclic radical C of the present invention
1-6alkylidene group " refer to " 3-14 unit heterocyclic radical ", " C
1-8alkylidene group " in respectively containing 5-6 annular atoms, a 1-6 atom specific examples.
" 7-12 unit bridged ring base " of the present invention refer to that any two rings share that two atoms be not directly connected are formed containing 7-12 carbon atom and/or heteroatomic structure, described heteroatoms has nitrogen, oxygen and sulphur etc." 7-12 unit bridged ring " comprises the saturated bridged ring of 7-12 unit, 7-12 unit fractional saturation bridged ring.
The saturated bridged ring of 7-12 unit, refers to that all rings in this bridged ring are saturated cyclic group, and be preferably the saturated bridged ring of 7-9 unit, specific examples includes but not limited to:
7-12 unit fractional saturation bridged ring, refers in this bridged ring to have to have at least a ring to be undersaturated cyclic group, and be preferably 7-8 unit fractional saturation bridged ring, specific examples includes but not limited to:
" 7-12 unit volution " of the present invention refer to a class have two rings to share at least an atom formed containing 7-12 carbon atom and/or heteroatomic structure, described heteroatoms has nitrogen, oxygen and sulphur etc.7-12 unit volution comprises the saturated volution of 7-12 unit, 7-12 unit fractional saturation volution.
The saturated volution of 7-12 unit, refer to that all rings in this volution are saturated cyclic group, specific examples includes but are not limited to:
7-12 unit fractional saturation volution, refer in this volution and have at least a ring to be undersaturated cyclic group, specific examples includes but are not limited to:
" treatment " of the present invention, refers to and alleviates, improves, eliminates or reduce the sign relevant to disease or illness and symptom.
" prevention " of the present invention, refers to the generation or development that prevent or postpone disease or illness or prevents or postpone disease therewith or the relevant sign of illness or symptom.
" composition " of the present invention, refer in pharmaceutical composition, be intended to comprise containing activeconstituents and the inertia complexing or the polymerization that form carrier, or from the decomposition of one or more compositions, or from reaction or any product produced that interacts of other type of one or more compositions, therefore, pharmaceutical composition of the present invention comprises any composition by the compound of formula (I) and one or more pharmaceutically acceptable mixed with excipients being prepared.
Isomer of the present invention comprises all optically active isomers, diastereomer, geometrical isomer and tautomer, the compound of formula (I) comprises one or more asymmetric centers, and can exist as raceme and racemic mixture, single enantiomorph, non-enantiomer mixture and single non-enantiomer mixture thus.It is two strong that the compound that some the present invention describe comprises alkene, and unless specifically stated otherwise, be intended to comprise E geometrical isomer and Z geometrical isomer.Can be there is different hydrogen tie points in the compound that some the present invention describe, be called as tautomer.This example can be ketone and Enol forms thereof, is called keto-enol tautomerism body.The compound of formula (I) comprises single tautomer and composition thereof.The invention is intended to compound this type of isomeric form all of contained (I).Described isomer can obtain abundant purity isomer by standard separation techniques and zinc bromide synthesis.
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention comprises an alkali metal salt, as sodium salt, sylvite, lithium salts etc.; Alkaline earth salt, as calcium salt, magnesium salts etc.; Other metal-salts, as aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt etc.; Inorganic base salts, as ammonium salt; Organic alkali salt, as tertiary octyl group amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, guanidinesalt, diethylamine salt, triethylamine salt, dicyclohexyl amine salt, N, N '-dibenzyl ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-styroyl amine salt, piperazine salt, tetramethyl-amine salt, three (methylol) aminomethane salt; When compound of the present invention is alkalescence, can prepare salt by the pharmaceutically acceptable non-toxic acid comprising mineral acid and organic acid, this type of acid comprises: halogen acid salt, as hydrofluoride, hydrochloride, hydrobromate, hydriodate etc.; Inorganic acid salt, as nitrate, perchlorate, vitriol, phosphoric acid salt etc.; Lower alkyl sulfonate, as mesylate, fluoroform sulphonate, esilate etc.; Arylsulphonate, as benzene sulfonate, P-TOLUENE SULFO ACID 99's salt etc.; Organic acid salt, as acetate, malate, fumarate, succinate, Citrate trianion, tartrate, oxalate, maleate etc.; Amino acid salts, as glycinate, Trimethyl glycine salt, arginic acid salt, ornithine salt, glutaminate, aspartate etc.In order to avoid query, one, two or three salt-forming cations may be had, but this depends on the quantity of carboxyl functional group and described cationic valence mumber.It is evident that for those skilled in the art, the pharmacy acceptable salt of the compounds of this invention in formation such as the free carboxy places of this compound, can be obtained by ordinary method.
" pharmaceutical composition " of the present invention, refers to the pharmaceutical composition of the compound shown in general formula (I) and pharmaceutically acceptable carrier.Its pharmacy acceptable salt and isomer thereof and one or more pharmaceutical carriers make pharmaceutically acceptable pharmaceutical preparation, are applied in modes such as oral, parenterals the patient needing this treatment.During oral administration, conventional solid preparation can be made, as tablet, capsule, pill, granule etc. with the weighting agent of routine, tackiness agent, disintegrating agent, lubricant, thinner etc.; During for administered parenterally, can be made into injection, comprise injection liquid, injectable sterile powder and concentrated solution for injection.When making injection, the ordinary method in existing pharmacy field can be adopted to produce, during preparation injection, can not additives be added, also can add suitable additives according to the character of medicine.
The practical methods preparing this type of formulation is known, or is apparent for those skilled in the art: see, such as Remington ' s Pharmaceutical Sciences, Mack Publishing Co., Eaton, PA, 16
th, Ed, 1980.
Present invention also offers the compound shown in general formula (I), its pharmacy acceptable salt and isomer thereof and prepare the purposes treated and/or prevented in the medicine of tumour.
The present invention also comprises the pharmaceutical composition of the compound containing formula (I) and utilizes the compounds for treating of formula (I) or the method for prophylaxis of tumours disease.
These medical compositions of the present invention can also continue the delivery system administration that the form of disengaging or use continue to disengage.
Part of compounds of the present invention:
General formula of the present invention (I) compound can adopt the method that describes in following flow process and/or other technology known to persons of ordinary skill in the art to synthesize, but is not limited only to following methods.
General formula (I) compound preparation technology:
(1) preparation of intermediate 1:
Raw material 1 (1 equivalent) is added in dioxane, raw material 2 (1.2 equivalent), add the aqueous solution of alkali (as sodium carbonate, salt of wormwood etc.), (or other palladium catalysts are as 1 finally to add four (triphenyl phosphorus) palladium of catalytic amount, 1 '-bis-(diphenylphosphine) ferrocene] palladium chloride dichloromethane complex), abundant displacement nitrogen, system is back flow reaction a few hours under nitrogen protection, cool to room temperature, filter, be dissolved in after organic layer concentrating under reduced pressure in organic solvent, wash successively, saturated common salt is washed, anhydrous sodium sulfate drying, concentrated, column chromatography obtains intermediate 1.
(2) preparation of intermediate 2:
Intermediate 1 (1 equivalent) is dissolved in tetrahydrofuran (THF) (or other polar solvents), under ice bath, adds the aqueous solution of lithium hydroxide (3-4 equivalent), or other basic solutions (as sodium hydroxide).Room temperature reaction, monitors reaction through TLC and completes.Add water in system, dilute hydrochloric acid regulates pH to be slightly acidic, separates out solid, filters, dry, obtains intermediate 2.
(3) preparation of formula I:
Intermediate 2 (1 equivalent) and triethylamine or other tertiary amine (3 equivalent) are dissolved in methylene dichloride, drip isopropyl chlorocarbonate (1 equivalent) under ice bath, drip and finish, react three hours under proceeding to room temperature, not treated, be directly used in next step.Also other can be adopted to generate the method (such as adding diacetyl oxide) of activation acid anhydrides
Raw material 3 (2 equivalent) and triethylamine (or other tertiary amines) are dissolved in methylene dichloride, stir half an hour, then reaction solution is joined in the reaction soln of upper step, continue to be stirred to reaction under continuing room temperature to terminate, water, saturated common salt water washing is used successively, organic phase anhydrous sodium sulfate drying after adding organic solvent diluting, concentrated, anti-phase preparation, obtains target compound.
A, X, Y, W, R in above-mentioned reaction equation
1, R
2, R
3, R
4, R
5, R
6, R
7and R
8as defined hereinabove;
Set forth the beneficial effect of pyrido naphthyridine type derivative of the present invention below by way of anti tumor activity in vitro determination experiment further, but this should be interpreted as that pyrido naphthyridine type derivative of the present invention only has following beneficial effect.
experimental example 1 the compounds of this invention to externalhDAC1, HDAC6
zymetology inhibit activities
Trial-product:
The compounds of this invention 1, self-control, chemical name and structural formula are as mentioned before; Contrast medicine SAHA, HDAC1, HDAC6, mTOR, PI3K α enzyme is all purchased from public institution.
Experimental technique:
(1) 1 times of damping fluid is prepared: comprise 50mM HEPES, pH 7.4,100mM KCl, 0.001%Tween-20,0.05%BSA, 20 μMs of TCEP;
(2) compound gradient dilution: preparation, containing the compound of 0.15mM concentration, is got the compound (10mM) of 15 μ L, added the 100%DMSO of 985 μ L;
4 times of dilutions: the above-mentioned solution getting 20 μ L, add the 100%DMSO of 60 μ L, totally 10 concentration, in two blank well, then add the 100%DMSO of 100 μ L respectively, as maximum value and minimum value contrast, this 96 orifice plate are labeled as motherboard; From 96 hole motherboards, pipette 6 μ L compound solutions to other one piece of 96 orifice plate, add 94 μ L damping fluids, now the concentration of compound is 3 times of final concentration; Shake 10 minutes, mixing;
(3) enzyme solution is prepared
Adopt 1 times of damping fluid, prepare 860 μ L enzyme solution, wherein HDAC1, the enzyme concn of 6 is respectively 6.25nM, 22.7nM;
(4) substrate solution is prepared
Add trypsinase and Boc-lys (AC)-AMC to 1 times of damping fluid, preparation substrate solution; For HDAC1, the concentration of trypsinase and Boc-lys (AC)-AMC is 20 μMs, and for HDAC6, the concentration of trypsinase and Boc-lys (AC)-AMC is respectively 20 μMs, 8 μMs;
(5) operation steps: the compound solution of transferase 45 μ L or contrast solution to 384 orifice plate, in enzyme solution to 384 orifice plate of transferase 45 μ L (hole containing compound), the damping fluid of transferase 45 μ L is in control wells simultaneously, incubated at room 10 minutes, starts reaction in substrate solution to 384 orifice plate of transferase 45 μ L; Room temperature with gentle mixes 60 seconds, HDAC1, and incubated at room is after 20 minutes, and Synergy MX (excite and be respectively 355,460nm with emission wavelength) reads plate 30 minutes; HDAC6, incubated at room is after 5 minutes, and Synergy MX (excite and be respectively 355,460nm with emission wavelength) reads plate 60 minutes;
Data processing
HDAC1,6 zymetology evaluations: adopt Xlfit software to carry out curve fitting, draw IC
50value.
Calculate inhibiting rate (%)=(maximum value-sample respective value)/(maximum value-minimum value) × 100
The IC of each compound is calculated according to inhibiting rate
50value.
Experimental result and conclusion:
The restraining effect of table 1 pair HDAC1, HDAC6 enzymic activity
From table 1, the compounds of this invention 1 pair of HDAC1 enzyme, HDAC6 enzyme have good inhibit activities, are especially significantly better than contrast medicine SAHA to the restraining effect of HDAC1.
experimental example 2 the compounds of this invention to externalmTOR enzyme, PI3K α
zymetology inhibit activities
Trial-product:
The compounds of this invention 1, self-control, chemical name and structural formula are as mentioned before; Contrast medicine SAHA, HDAC1, HDAC6, mTOR, PI3K α enzyme is all purchased from public institution.
Experimental technique:
1.mTOR zymetology is evaluated
(1) 1 times of damping fluid is prepared: comprise 50mM HEPES (pH 7.5), 10mM MgCl
2, 1mM EGTA, 3mMMnCl
2, 0.01%Tween-20,2mM DTT;
(2) compound gradient dilution: 100 times of compounds of the highest final concentration of preparation, if the highest final concentration is 10 μMs, needs preparation containing the compound of 1mM;
4 times of dilutions: the above-mentioned solution getting 20 μ L, add the 100%DMSO of 60 μ L, dilute successively, totally 10 concentration, then in two blank well, add the 100%DMSO of 100 μ L respectively, as a control group (without compound with without enzyme contrast), this 96 orifice plate is labeled as motherboard; From 96 hole motherboards, pipette 4 μ L compound solutions to other one piece of 96 orifice plate, add 96 μ L damping fluids, be considered as middle 96 orifice plates; Shake 10 minutes, mixing, from middle 96 orifice plate transferase 12 .5 μ L to 384 orifice plates;
(3) mTOR kinase reaction
1. 4 times of kinase solution are prepared: the mTOR solution (final concentration of mTOR is 2.5nM) adopting 1 times of buffer, 4 times of final concentrations, get each hole (adding 1 times of damping fluid of 2.5 μ L without enzyme control wells) of 2.5 μ L to 384 orifice plates, concussion mixing;
2. prepare 2 times of substrate solutions: the substrate solution (final concentration of ULight-4E-BP1 peptide and ATP is 50nM, 10.8 μMs) adopting 1 times of buffer, 2 times of final concentrations, get each hole of 5 μ L to 384 orifice plates, concussion mixing;
3. kinase reaction: incubated at room 1 hour;
(4) kinase assay:
1. preparation detects solution: adopt Lance detection buffer to detect solution (final concentration of EDTA and Eu-anti-phospho-4E-BP1 antibody is respectively 8mM, 2nM) containing 2 times of final concentrations of EDTA and Eu-anti-phospho-4E-BP1 antibody; Getting 10 μ L detects in each hole of solution to 384 orifice plate;
2. of short duration centrifugal mixing, incubated at room 60 minutes;
(4) plate is read
2.PI3K α zymetology is evaluated
(1) 1 times of damping fluid is prepared: comprise 50mM HEPES (pH 7.5), 3mM MgCl
2, 1mM EGTA, 100mM NaCl, 0.03%CHAPS, 2mM DTT;
(2) compound gradient dilution: 100 times of compounds of the highest final concentration of preparation, if the highest final concentration is 10 μMs, needs preparation containing the compound of 1mM;
4 times of dilutions: the above-mentioned solution getting 20 μ L, add the 100%DMSO of 60 μ L, dilute successively, totally 10 concentration, then in two blank well, add the 100%DMSO of 100 μ L respectively, as a control group (without compound with without enzyme contrast), this 96 orifice plate is labeled as motherboard; From above 96 hole motherboards, pipette 4 μ L compound solutions to other one piece of 96 orifice plate, add 96 μ L damping fluids, be considered as middle 96 orifice plates; Shake 10 minutes, mixing; From middle 96 orifice plate transferase 12 .5 μ L to 384 orifice plates;
(3) PI3K alpha kinase reaction
1. prepare 4 times of kinase solution: the PI3K α solution (final concentration of PI3K α is 1.65nM) adopting 1 times of buffer, 4 times of final concentrations, get each hole (except control wells) of 2.5 μ L to 384 orifice plates, concussion mixing;
2. prepare 2 times of substrate solutions: the substrate solution (final concentration of PIP2 and ATP is 50 μMs, 25 μMs) adopting 1 times of buffer, 2 times of final concentrations, get each hole of 5 μ L to 384 orifice plates, concussion mixing;
3. kinase reaction: incubated at room 1 hour;
(4) kinase assay: add termination reaction in 10 μ L Kinase-Glo reagent (under being positioned over room temperature environment in advance) to each hole of 384 orifice plates; Of short duration centrifugal mixing, incubated at room 15 minutes;
(5) plate is read
Data processing
MTOR zymetology is evaluated and the reaction of PI3K alpha kinase: adopt Graphpad 5.0 to carry out curve fitting, draw IC50.
Calculate inhibiting rate=(sample Lance signal-minimum value)/(maximum value-minimum value) * 100
The IC of each compound is calculated according to inhibiting rate
50value.
Experimental result and conclusion:
The restraining effect of table 2 pair mTOR, PI3K α enzymic activity
From table 2, the compounds of this invention 1 pair of mTOR enzyme, PI3K α enzyme have good inhibit activities.
Embodiment
The embodiment of form by the following examples, is described in further detail foregoing of the present invention.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following examples.All technology realized based on foregoing of the present invention all belong to scope of the present invention.
Embodiment one N-hydroxyl-7-(5-(9-oxo-10-(3-trifluoromethyl)-9,10-dihydro pyrido [3,2-c] [1,5] naphthyridines-2-base) pyrimidine-2-oxygen base) preparation of heptamide (compound 1)
(1) preparation of 7-(5-bromo pyrimi piperidine-2-oxygen base) oil of cognac
Bromo-for 5-2-hydroxy pyrimidine (0.875g, 5.0mmol) and 7-bromine oil of cognac (1.3g, 5.5mmol) are dissolved in N, dinethylformamide (12mL), adds cesium carbonate (3.26g, 10.0mmol), reaction is stirred and is spent the night at 80 DEG C, cooling, with ethyl acetate (80mL) dilution, uses water, saturated common salt water washing successively, organic phase anhydrous sodium sulfate drying, concentrated, obtain faint yellow solid 1.4g, yield 84.6%.
(2) preparation of 7-(5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyrimidine-2-oxygen base) oil of cognac
1; 7-(5-bromo pyrimi piperidine-2-oxygen base) oil of cognac (331mg is added successively in 4-dioxane (20mL); 1.0mmol), duplex tetramethyl ethylene ketone boric acid ester (381mg; 1.5mmol), Potassium ethanoate (295mg; 3.0mmol) with [1; 1 '-bis-(diphenylphosphine) ferrocene] palladium chloride dichloromethane complex (20mg); reaction is stirred 12 hours in 90 DEG C under nitrogen protection, not treatedly after cooling is directly used in next step.
(3) preparation of 7-(5-(9-oxo-10-(3-trifluoromethyl)-9,10-dihydro pyridos [3,2-c] [1,5] naphthyridines-2-base) pyrimidine-2-oxygen base) oil of cognac
In the upper step reaction solution of cooling, i.e. 7-(5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan alkane-2-base) pyrimidine-2-oxygen base) oil of cognac (about 1.0mmol), add the chloro-10-of 2-(3-trifluoromethyl) pyrido [3,2-c] [1,5] naphthyridines-9 (10H)-one (301mg, 0.80mmol), four (triphenyl phosphorus) palladium (15mg), 2N sodium carbonate solution (2.4mL).System is under nitrogen protection in 90 DEG C of reaction 16h; cool to room temperature; filter; be dissolved in after organic layer concentrating under reduced pressure in methylene dichloride, washing successively, saturated common salt washing, anhydrous sodium sulfate drying; concentrated; silica gel column chromatography (100% ethyl acetate), obtains product 219mg, yield 46.2%.
(4) preparation of 7-(5-(9-oxo-10-(3-trifluoromethyl)-9,10-dihydro pyridos [3,2-c] [1,5] naphthyridines-2-base) pyrimidine-2-oxygen base) enanthic acid
By 7-(5-(9-oxo-10-(3-trifluoromethyl)-9,10-dihydro pyrido [3,2-c] [1,5] naphthyridines-2-base) pyrimidine-2-oxygen base) oil of cognac (219mg, 0.37mmol) be dissolved in tetrahydrofuran (THF) (10mL), the aqueous solution that 10mL is dissolved with a hydronium(ion) Lithium Oxide 98min (47mg, 1.1mmol) is added under ice bath.Room temperature reaction 3h, monitors reaction through TLC and completes.Add water in system, dilute hydrochloric acid regulates pH ≈ 3-4, separates out solid, filters, dry, obtains white solid 191mg, yield 91.6%.
(5) preparation of N-hydroxyl-7-(5-(9-oxo-10-(3-trifluoromethyl)-9,10-dihydro pyridos [3,2-c] [1,5] naphthyridines-2-base) pyrimidine-2-oxygen base) heptamide
By 7-(5-(9-oxo-10-(3-trifluoromethyl)-9,10-dihydro pyrido [3,2-c] [1,5] naphthyridines-2-base) pyrimidine-2-oxygen base) enanthic acid (191mg, 0.339mmol) with triethylamine (0.15mL, 1.1mmol) be dissolved in methylene dichloride (20mL), isopropyl chlorocarbonate (42mg is dripped under ice bath, 0.34mmol), drip and finish, react three hours under proceeding to room temperature, not treated, be directly used in next step.
By oxammonium hydrochloride (47mg, 0.676mmol) be dissolved in methylene dichloride (10mL) with triethylamine (0.1mL, 0.72mmol), room temperature lower magnetic force stirs half an hour, then reaction solution is joined in the reaction soln of upper step, continue stirred at ambient temperature 24 hours, use water, saturated common salt water washing after adding 50mL dchloromethane successively, organic phase anhydrous sodium sulfate drying, concentrated, anti-phase preparation, obtains white solid 90mg, yield 45.9%.
Molecular formula: C
29h
25f
3n
6o
4molecular weight: 578.19 mass spectrums (M+H): 479.2
1H-NMR(CDCl
3，400MHz)δ：9.08(1H，s)，8.48(1H，d)，8.22(2H，s)，8.06(1H，d)，7.93(1H，d)，7.86(1H，d)，7.77(1H，t)，7.58(1H，d)，7.49(1H，s)，7.04(1H，d)，4.43(2H，t)，2.22(2H，t)，1.86(2H，quintet)，1.75(2H，quintet)，1.55-1.40(6H，m).
Claims (4)
1. logical compound shown in formula I, its pharmacy acceptable salt or its steric isomer:
Wherein
X is O;
R
1for by 1-3 R
9the phenyl replaced;
A is pyridyl, pyrimidyl;
R
2, R
3, R
4be respectively hydrogen;
R
5, R
6independently be hydrogen;
R
9for the C replaced by 1-3 fluorine
1-4alkyl;
Y is-O;
W is C
5-7alkylidene group;
R
7and R
8be respectively hydrogen atom.
2. compound, its pharmacy acceptable salt or its steric isomer as claimed in claim 1, described compound is selected from:
3. comprise the pharmaceutical composition of the compound described in any one of claim 1 ~ 2, its pharmacy acceptable salt or its steric isomer and one or more pharmaceutical carriers, it is characterized in that described pharmaceutical composition is for clinically or pharmaceutically acceptable arbitrary formulation.
4. the compound described in any one of claim 1 ~ 2, its pharmacy acceptable salt or its steric isomer are for the preparation of the purposes treated and/or prevented in the medicine of tumour.
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