CN103373997A - 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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- CN103373997A CN103373997A CN2012101204399A CN201210120439A CN103373997A CN 103373997 A CN103373997 A CN 103373997A CN 2012101204399 A CN2012101204399 A CN 2012101204399A CN 201210120439 A CN201210120439 A CN 201210120439A CN 103373997 A CN103373997 A CN 103373997A
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- GKJIZAIQNBLCQF-UHFFFAOYSA-N CCOC(CCCCCCOc1ncc(B2OC(C)(C)C(C)(C)O2)cn1)=O Chemical compound CCOC(CCCCCCOc1ncc(B2OC(C)(C)C(C)(C)O2)cn1)=O GKJIZAIQNBLCQF-UHFFFAOYSA-N 0.000 description 1
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, R1, R2, R3, R4, R5, R6, R7 and R8 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 technical field, be specifically related to the pyrido naphthyridines analog derivative as HDAC and mTOR inhibitors, its pharmacy acceptable salt and isomer thereof, the preparation method of these compounds, the pharmaceutical preparation and the pharmaceutical composition that contain these compounds, and these compounds, its pharmacy acceptable salt or its isomer treat and/or prevent application in the medicine with the active relevant disease of HDAC and mTOR in preparation.
Background technology
The PI3K/AKT path is the most normal place of morphing among the human cancer cell, can cause cell proliferation, activation, amplifying signal.
Somatomedin finally produces crucial cell cycle and growth control regulatory factor mTOR to the mitogenetic activation of PI3K/AKT signal pathway, 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, the blood supply of control tumour.MTOR inhibitors can make cancer cells hungry, and by the effect that suppresses mTOR gross tumor volume is dwindled.
Hdac inhibitor is a kind of molecular targeted epigenetic regulation agent; by regulating histone and nonhistones acetylize state; inducing apoptosis of tumour cell, cell cycle arrest, inhibition vasculogenesis and tumour cell shift, and can be used for the treatment of multiple blood tumor and solid tumor.The hdac inhibitor of listing has Vorinostat (Vorinostat, SAHA, Zolinza) and Romidepsin (FK-228, Istodax) at present.The research of Curis company finds that hdac inhibitor and the coupling of PI3K inhibitor have synergistic function.Based on this principle, many target spots of the unit molecule HDAC/PI3K/MTOR inhibitor C U-906 that Curis company has researched and developed, preclinical study shows that it all has good anti-tumor activity in vivo and in vitro, compares with the PI3K/MTOR inhibitor, has improved drug effect, has overcome chemical sproof generation.
The present invention has simultaneously good antitumor action and reduces medicine that resistance produces as target take exploitation, 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 that a kind of HDAC/MTOR inhibitor of pyrido naphthyridines analog derivative is provided.
Technical scheme of the present invention is as follows:
Compound shown in the general formula (I), its pharmacy acceptable salt, and isomer:
Wherein
X is O or S;
R
1Be hydrogen, or be not substituted or by 1-3 R
9The C that replaces
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 is not for existing, or is not 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 respectively, halogen, cyano group, amino, hydroxyl, alkylsulfonyl ,-SO
2C
1-6Alkyl, or be not substituted or be selected from by 1-3 the C of halogen atom, hydroxyl, carboxyl substituted
1-6Alkyl, C
1-6Alkoxyl group;
R
4Be hydrogen, cyano group, amino, alkylsulfonyl ,-SO
2C
1-6Alkyl, or be not substituted or be selected from the C that halogen atom, hydroxyl, carboxyl substituent replace by 1-3
1-6Alkyl, C
1-6Alkoxyl group;
R
5, R
6Independently be hydrogen respectively, hydroxyl, halogen, amino, or be not substituted or by 1-3 C that is selected from halogen atom, hydroxyl, carboxyl substituent replacement
1-6Alkyl, C
1-6Alkoxyl group;
R
9And R
9' independently be respectively
(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 the C that hydroxyl, halogen, cyano group, trifluoromethyl replace by 1-3
1-6 alkaneBase, C
1-6Alkoxyl group,
(2) be not substituted or be selected from the C that cyano group, halogen, hydroxyl replace by 1-3
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 that replaces, 6-14 unit aryl, 3-14 unit heterocyclic radical;
R
aAnd R
bBe hydrogen independently respectively, or be not substituted or by 1-3 C that is selected from hydroxyl, halogen, cyano group replacement
1-6Alkyl;
R
c' for not being substituted or being selected from the C that hydroxyl, halogen, cyano group replace by 1-3
1-6Alkyl, C
1-6Alkoxyl group, 3-8 unit saturated mono cycloalkyl, the single heterocyclic radical of 3-8 unit;
M is 0,1 or 2;
N is 0～4;
Y is not for existing-O-,-S-,-SO-,-SO
2-,-NH-,-CONH-or-SO
2NH-;
W is not for being 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) the aryl C of 6-14 unit
1-8Alkylidene group, the aryl C of 6-14 unit
2-8Alkenylene, the aryl C of 6-14 unit
2-8Alkynyl,
(4) the heterocyclic radical C of 3-14 unit
1-8Alkylidene group, the heterocyclic radical C of 3-14 unit
2-8Alkenylene, the heterocyclic radical C of 3-14 unit
2-8Alkynyl,
(5) the cycloalkyl C of 3-8 unit
1-8Alkylidene group, the cycloalkyl C of 3-8 unit
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
1-8The aryl C of alkylidene group 6-14 unit
1-8Alkylidene group, C
1-8The aryl C of alkylidene group 6-14 unit
2-8Alkenylene, C
1-8The aryl C of alkylidene group 6-14 unit
2-8Alkynyl,
(10) C
2-8The aryl C of alkenylene 6-14 unit
1-8Alkylidene group, C
2-8The aryl C of alkenylene 6-14 unit
2-8Alkenylene, C
2-8The aryl C of alkenylene 6-14 unit
2-8Alkynyl,
(11) C
2-8The aryl C of alkynyl 6-14 unit
1-8Alkylidene group, C
2-8The aryl C of alkynyl 6-14 unit
2-8Alkenylene, C
2-8The aryl C of alkynyl 6-14 unit
2-8Alkynyl,
(12) C
1-8The heterocyclic radical C of alkylidene group 3-14 unit
1-8Alkylidene group, C
1-8The heterocyclic radical C of alkylidene group 3-14 unit
2-8Alkenylene, C
1-8The heterocyclic radical C of alkylidene group 3-14 unit
2-8Alkynyl,
(13) C
2-8The heterocyclic radical C of alkenylene 3-14 unit
1-8Alkylidene group, C
2-8The heterocyclic radical C of alkenylene 3-14 unit
2-8Alkenylene, C
2-8The heterocyclic radical C of alkenylene 3-14 unit
2-8Alkynyl,
(14) C
2-8The heterocyclic radical C of alkynyl 3-14 unit
1-8Alkylidene group, C
2-8The heterocyclic radical C of alkynyl 3-14 unit
2-8Alkenylene, C
2-8The heterocyclic radical C of alkynyl 3-14 unit
2-8Alkynyl,
(15) C
1-8The cycloalkyl C of alkylidene group 3-8 unit
1-8Alkylidene group, C
1-8The cycloalkyl C of alkylidene group 3-8 unit
2-8Alkenylene, C
1-8The cycloalkyl C of alkylidene group 3-8 unit
2-8Alkynyl,
(16) C
2-8The cycloalkyl C of alkenylene 3-8 unit
1-8Alkylidene group, C
2-8The cycloalkyl C of alkenylene 3-8 unit
2-8Alkenylene, C
2-8The cycloalkyl C of alkenylene 3-8 unit
2-8Alkynyl,
(17) C
2-8The cycloalkyl C of alkynyl 3-8 unit
1-8Alkylidene group, C
2-8The cycloalkyl C of alkynyl 3-8 unit
2-8Alkenylene, C
2-8The cycloalkyl C of alkynyl 3-8 unit
2-8Alkynyl,
(18) 3-14 unit heterocyclic radical-aryl C of 6-14 unit
1-8Alkylidene group, the 6-14 unit aryl-heterocyclic radical C of 3-14 unit
1-8Alkylidene group, the 3-14 unit heterocyclic radical-heterocyclic radical C of 3-14 unit
1-8Alkylidene group,
And described C
1-8Alkylidene group, C
2-8Alkenylene, C
2-8Carbon atom in the alkynyl can be by O, S, S (O), SO
2, NR
eOr CO replaces;
R
dBe 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
eBe hydrogen atom, the C that is not substituted or is replaced by 1 Q at least
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
1-6The alkyl amine group formyl radical, two (C
1-6Alkyl) amido formacyl, amino-sulfonyl, C
1-6The alkyl 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 the general formula (I), its pharmacy acceptable salt, and the optimal technical scheme of isomer is:
Wherein
X is O;
R
1For not being substituted or by 1-3 R
9The 3-14 unit cycloalkyl that replaces, 6-14 unit aryl, 3-14 unit heterocyclic radical, 7-12 unit volution base, 7-12 unit bridged ring base;
A is not for being substituted or by 1-3 R
9' the 6-14 unit aryl, the 3-14 unit heterocyclic radical that replace;
R
2, R
3Independently be hydrogen respectively, halogen, cyano group, amino, hydroxyl, trifluoromethyl, or trifluoromethoxy;
R
4Be hydrogen, cyano group, or amino;
R
5, R
6Independently be hydrogen respectively, hydroxyl, halogen, amino, or C
1-6Alkyl;
R
9And R
9' independently be respectively
(1) hydroxyl, halogen, amino, cyano group, or-(CH
2)
nC (O) R
c, R
cFor not being substituted or being selected from the C that hydroxyl, halogen, cyano group, trifluoromethyl replace by 1-3
1-6Alkyl, C
1-6Alkoxyl group,
(2) be not substituted or be selected from the C that cyano group, halogen, hydroxyl replace by 1-3
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 that replaces, 6-14 unit aryl, the single heterocyclic radical of 3-8 unit;
R
aAnd R
bBe hydrogen independently respectively, or be not substituted or by 1-3 C that is selected from hydroxyl, halogen, cyano group replacement
1-6Alkyl;
R
c' for not being substituted or being selected from the C that hydroxyl, halogen, cyano group replace by 1-3
1-6Alkyl, C
1-6Alkoxyl group;
M is 1 or 2;
N is 0～4;
Y is not for existing-O-,-S-,-SO
2-,-CONH-or-SO
2NH-;
W is not for being substituted or by R
dReplace
(1) C
1-8Alkylidene group, C
2-8Alkenylene,
(2) 6-10 unit aryl, 3-8 unit heterocyclic radical,
(3) the aryl C of 6-10 unit
1-8Alkylidene group, the aryl C of 6-10 unit
2-8Alkenylene,
(4) the heterocyclic radical C of 3-8 unit
1-8Alkylidene group, the heterocyclic radical C of 3-8 unit
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
1-8The aryl C of alkylidene group 6-10 unit
1-8Alkylidene group, C
1-8The aryl C of alkylidene group 6-10 unit
2-8Alkenylene,
(8) C
2-8The aryl C of alkenylene 6-10 unit
1-8Alkylidene group, C
2-8The aryl C of alkenylene 6-10 unit
2-8Alkenylene,
(9) C
1-8The heterocyclic radical C of alkylidene group 3-8 unit
1-8Alkylidene group, C
1-8The heterocyclic radical C of alkylidene group 3-8 unit
2-8Alkenylene,
(10) C
2-8The heterocyclic radical C of alkenylene 3-8 unit
1-8Alkylidene group, C
2-8The heterocyclic radical C of alkenylene 3-8 unit
2-8Alkenylene,
(11) 3-8 unit heterocyclic radical-aryl C of 6-10 unit
1-8Alkylidene group, the 6-10 unit aryl-heterocyclic radical C of 3-8 unit
1-8Alkylidene group, the 3-8 unit heterocyclic radical-heterocyclic radical C of 3-8 unit
1-8Alkylidene group,
And described C
1-8Alkylidene group, C
2-8Carbon atom in the alkenylene can be by O, S, NR
eOr CO replaces;
R
dBe 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
eBe hydrogen atom, the C that is not substituted or is replaced by 1 Q at least
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
1-4The alkyl amine group formyl radical, two (C
1-4Alkyl) amido formacyl, amino-sulfonyl, C
1-4The alkyl amine group alkylsulfonyl, two (C
1-4Alkyl) amido alkylsulfonyl, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4The alkyl-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 the general formula (I), its pharmacy acceptable salt, and the optimal technical scheme of isomer is:
Wherein
X is O;
R
1For not being substituted or by 1-3 R
9The 6-14 unit aryl that replaces, the single heterocyclic radical of 3-8 unit;
A is not for being substituted or by 1-3 R
9' the 6-14 unit aryl, the 5-10 unit heterocyclic radical that replace;
R
2, R
3, R
4Be respectively hydrogen;
R
5, R
6Independently be hydrogen respectively, 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 the C that hydroxyl, halogen, cyano group replace by 1-3
1-4Alkyl, C
1-4Alkoxyl group,
(2) be not substituted or be selected from the C that cyano group, halogen, hydroxyl replace by 1-3
1-4Alkyl, C
1-4Alkoxyl group,
(3) be not substituted or by 1-3 be selected from cyano group, trifluoromethyl, halogen ,-(CH
2)
nC (O) R
c' ,-(CH
2)
nC (O) (CH
2)
nNR
aR
b,-(CH
2)
nS (O)
mR
c' the 5-8 unit saturated mono heterocyclic radical that replaces;
R
aAnd R
bBe hydrogen independently respectively, or be not substituted or by 1-3 C that is selected from hydroxyl, halogen replacement
1-4Alkyl;
R
c' for not being substituted or being selected from the C that hydroxyl, halogen replace by 1-3
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 the C that hydroxyl, halogen, cyano group, trifluoromethyl replace by 1-3
1-4Alkyl, C
1-4Alkoxyl group,
(2) be not substituted or be selected from the C that cyano group, halogen, hydroxyl replace by 1-3
1-4Alkyl, C
1-4Alkoxyl group;
M is 1 or 2;
N is 0～4;
Y is not for existing ,-O-,-S-,-CONH-or-SO
2NH-;
W is not for being substituted or by R
dReplace
(1) C
4-8Alkylidene group,
(2) phenyl, 5-6 unit heterocyclic radical,
(3) phenyl C
1-6Alkylidene group,
(4) the heterocyclic radical C of 5-6 unit
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
2-6The heterocyclic radical C of alkenylene 5-6 unit
1-6Alkylidene group,
(8) 5-6 unit heterocyclic radical-heterocyclic radical C of 5-6 unit
1-6Alkylidene group,
And described C
4-8Alkylidene group, C
1-6Alkylidene group, C
2-6Carbon atom in the alkenylene can be by O, S, NR
eOr CO replaces;
R
dBe hydrogen atom, halogen, hydroxyl, amino, carboxyl, cyano group, C
1-4Alkyl, C
1-4Alkoxyl group or 3-6 unit cycloalkyl;
R
eBe hydrogen atom, the C that is not substituted or is replaced by 1 Q at least
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 the general formula (I), its pharmacy acceptable salt, and the optimal technical scheme of isomer is:
Wherein
X is O;
R
1For not being substituted or by 1-3 R
9The 6-10 unit aryl that replaces, 3-8 unit saturated mono heterocyclic radical, the unsaturated single heterocyclic radical of 3-8 unit;
A is not for being substituted or by 1-3 R
9' phenyl, naphthyl, the unsaturated single heterocyclic radical of 5-6 unit, the unsaturated fused heterocycle base of 9-10 unit that replace;
R
2, R
3, R
4Be respectively hydrogen;
R
5, R
6Independently be hydrogen respectively, 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 the C that hydroxyl, halogen, cyano group replace by 1-3
1-4Alkyl, C
1-4Alkoxyl group,
(2) be not substituted or be selected from the C that cyano group, halogen, hydroxyl replace by 1-3
1-4Alkyl, C
1-4Alkoxyl group,
(3) be not substituted or by 1-3 be selected from cyano group, trifluoromethyl, halogen ,-C (O) R
c' ,-C (O) (CH
2)
nNR
aR
b,-S (O)
2R
c' the 5-6 unit saturated mono heterocyclic radical that replaces;
R
aAnd R
bBe hydrogen independently respectively, or be not substituted or by 1-3 C that is selected from hydroxyl, halogen replacement
1-4Alkyl;
R
c' for not being substituted or being selected from the C that hydroxyl, halogen replace by 1-3
1-4Alkyl, C
1-4Alkoxyl group;
R
9' be
(1) hydroxyl, halogen, cyano group, amino,
(2) be not substituted or be selected from the C that cyano group, halogen, hydroxyl replace by 1-3
1-4Alkyl, C
1-4Alkoxyl group;
N is 0～4;
Y is not for existing ,-O-,-S-or-CONH-;
W is not for being 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 the alkylidene group can be by O, S, NR
eOr CO replaces;
R
dBe hydrogen atom, halogen, hydroxyl, amino, carboxyl, cyano group, C
1-4Alkyl or C
1-4Alkoxyl group;
R
eBe hydrogen atom or C
1-4Alkyl;
R
7And R
8Be respectively hydrogen atom, methyl, ethyl or ethanoyl.
Compound shown in the general formula (I), its pharmacy acceptable salt, and the optimal technical scheme of isomer is:
Wherein
X is O;
R
1For not being substituted or by 1-3 R
9The phenyl that replaces, naphthyl, 5-8 unit saturated mono heterocyclic radical;
A is not for being 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 respectively, or methyl;
R
9For
(1) amino, or-C (O) R
c, R
cBe the C that is not substituted or is replaced by 1-3 hydroxyl
1-4Alkyl,
(2) be not substituted or be selected from the C that cyano group, fluorine replace by 1-3
1-4Alkyl,
(3) be not substituted or by 1-3 be selected from cyano group, trifluoromethyl ,-C (O) R
c' ,-C (O) (CH
2)
nNR
aR
b,-S (O)
2R
c' piperazinyl, the piperidyl that replace;
R
aAnd R
bIndependently be hydrogen respectively, or C
1-4Alkyl;
R
c' be C
1-4Alkyl;
R
9' be
(1) hydroxyl, halogen, amino,
(2) be not substituted or be selected from the C that fluorine, hydroxyl replace by 1-3
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 the general formula (I), its pharmacy acceptable salt, and the optimal technical scheme of isomer is:
Wherein
X is O;
R
1For not being substituted or by 1-2 R
9The phenyl, piperidyl, the piperazinyl that replace;
A is not for being 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 respectively, or methyl;
R
9For
(1) amino, or-C (O) R
c, R
cBe the C that is not substituted or is replaced by 1-2 hydroxyl
1-4Alkyl,
(2) be not substituted or be selected from the C that cyano group, fluorine replace by 1-2
1-4Alkyl,
(3) be not substituted or be selected from the piperazinyl that cyano group, trifluoromethyl replace by 1-2;
R
9' be
(1) halogen, amino, C
1-4Alkyl,
(2) be not substituted or be selected from the C that fluorine, hydroxyl replace by 1-2
1-4Alkyl, C
1-4Alkoxyl group;
Y is-O-or-CONH-;
W is hexylidene;
R
7And R
8Be respectively hydrogen atom.
Compound shown in the general formula (I), its pharmacy acceptable salt, and the optimal technical scheme of isomer is:
Wherein
X is O;
R
1For not being substituted or by 1-2 R
9The phenyl, the piperidyl that replace,
A is not for being 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 respectively, or methyl;
R
9Be methyl, trifluoromethyl, piperazinyl, the C that cyano group replaces
1-4Alkyl, or-C (O) R
c, R
cC for the hydroxyl replacement
1-4Alkyl;
R
9' be amino, methyl or methoxy;
Y is-O-or-CONH-;
W is hexylidene;
R
7And R
8Be respectively hydrogen atom.
Present invention is described to give a definition in utilization, and the specific definition mode includes but not limited to following description.
" halogen " of the present invention comprises fluorine atom, chlorine atom, bromine atoms, iodine atom.
" C of the present invention
1-8Alkyl " alkane that refers to contain 1-8 carbon atom removes the alkyl of the straight or branched that a hydrogen atom derives; and specific examples includes but not limited to: methyl; ethyl; n-propyl; sec.-propyl; normal-butyl, the 2-methyl-propyl, the 1-methyl-propyl, 1, the 1-dimethyl ethyl, n-pentyl, the 3-methyl butyl, the 2-methyl butyl, the 1-methyl butyl, the 1-ethyl propyl, n-hexyl, the 4-methyl amyl, the 3-methyl amyl, the 2-methyl amyl, the 1-methyl amyl, 3, the 3-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2,3-dimethylbutyl, the 2-ethyl-butyl, 1-methyl-2-methyl-propyl, n-heptyl, n-octyl etc." C of the present invention
1-6Alkyl " refer to the specific examples that contains 1-6 carbon atom in the above-mentioned example." C of the present invention
1-4Alkyl " refer to the specific examples that contains 1-4 carbon atom in the above-mentioned example.
" C of the present invention
2-8Thiazolinyl " carbonatoms that refers to contain two keys is the thiazolinyl of the straight or branched of 2-8; and specific examples includes but not limited to: vinyl; the 1-propenyl; the 2-propenyl; the 3-propenyl; the 1-methyl ethylene, the 1-butylene base, crotyl, the 3-butenyl, 1-methyl-1-propylene base, 2-methyl-1-propylene base, 1-methyl-2-propenyl, 2-methyl-2-propenyl, the 1-pentenyl, pentenyl, the 3-pentenyl, the 4-pentenyl, 1-methyl isophthalic acid-butenyl, the 2-methyl-1-butene thiazolinyl, the 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, the 1-hexenyl, the 2-hexenyl, the 3-hexenyl, the 4-hexenyl, the 5-hexenyl, 1-methyl-1-pentene thiazolinyl, 2-methyl-1-pentene thiazolinyl, 3-methyl-1-pentene thiazolinyl, the 4-methyl-1-pentene base, 1-methyl-pentenyl, 2-methyl-pentenyl, 3-methyl-pentenyl, 4-methyl-pentenyl, the 1-methyl-3-pentenyl, the 2-methyl-3-pentenyl, the 3-methyl-3-pentenyl, the 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, 1,4-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, the 3-butadienyl, 1, the 4-pentadienyl, 1, the 4-hexadienyl, 1,3,5-hexatriene base, heptenyl, octenyl etc." C of the present invention
2-6Thiazolinyl " refer to the specific examples that contains 2-6 carbon atom in the above-mentioned example.
" C of the present invention
2-8Alkynyl " carbonatoms that refers to contain three key is the alkynyl of the straight or branched of 2-8; and specific examples includes but not limited to: ethynyl; 1-proyl; 2-propynyl; the ethyl acetylene base; the 2-butyne base, the 3-butynyl, 1-methyl-2-propynyl, the 1-pentynyl, the valerylene base, the 3-pentynyl, the 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, the heptyne base, octyne base etc." C of the present invention
2-6Alkynyl " refer to the specific examples that contains 2-6 carbon atom in the above-mentioned example.
" C of the present invention
1-6Alkoxyl group " refer to " C
1-6Alkyl " group that is connected with other structures by Sauerstoffatom, such 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 to the specific examples that contains 1-4 carbon atom in the above-mentioned example.
" SO of the present invention
2C
1-6Alkyl " refer to C
1-6Alkyl is by alkylsulfonyl (SO
2-) group that is connected and derives with other parts, i.e. (C
1-6Alkyl) S (O)
2-, described " C
1-6Alkyl " as mentioned before." SO of the present invention
2C
1-4Alkyl " refer to the specific examples that contains 1-4 carbon atom in the above-mentioned example.
" halo C of the present invention
1-6Alkyl " refer to that one or more " halogen " atom replaces " C
1-6Alkyl " group of deriving, described " halogen " and " C
1-6Alkyl " define such as preamble.
" C of the present invention
2-6Alkynyl " carbonatoms that refers to contain three key is the alkynyl of the straight or branched of 2-6; and specific examples includes but not limited to: ethynyl; 1-proyl; 2-propynyl; the ethyl acetylene base; the 2-butyne base, the 3-butynyl, 1-methyl-2-propynyl, the 1-pentynyl, the valerylene base, the 3-pentynyl, the 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, such 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
1-6The group that hydrogen atom is derived, i.e. a C in the alkyl-substituted amino
1-6Alkyl-NH-, described " C
1-6Alkyl " as mentioned before." C of the present invention
1-4Alkyl amine group " refer to the specific examples that contains 1-4 carbon atom in the above-mentioned example." C of the present invention
1-4Alkyl amine group " refer to the specific examples that contains 1-4 carbon atom in the above-mentioned example.
" two (C of the present invention
1-6Alkyl) amido " refer to two C
1-6Alkyl is two groups that hydrogen atom is derived, i.e. (C in the substituted-amino respectively
1-6Alkyl)
2-N-, described " C
1-6Alkyl " as mentioned before." two (C of the present invention
1-4Alkyl) amido " refer to the specific examples that contains 1-4 carbon atom in the above-mentioned example.
" C of the present invention
1-6Alkyl-carbonyl " refer to C
1-6Alkyl is by the group of carbonyl-C (O)-be connected and derive with other parts, i.e. C
1-6Alkyl-C (O)-, described " C
1-6Alkyl " as mentioned before." C of the present invention
1-4Alkyl-carbonyl " refer to the specific examples that contains 1-4 carbon atom in the above-mentioned example.
" C of the present invention
1-6Alkyl carbonyl oxy " refer to C
1-6The group that alkyl is connected and derives with other parts by carboxyl-C (O) O-, i.e. (C
1-6Alkyl) C (O) O-, described " C
1-6Alkyl " as mentioned before." C of the present invention
1-4Alkyl carbonyl oxy " refer to the specific examples that contains 1-4 carbon atom in the above-mentioned example.
" C of the present invention
1-6Alkylamidoalkyl " refer to C
1-6The group that alkyl is connected and derives with other parts by amide group-C (O) NH-, i.e. (C
1-6Alkyl) C (O) NH-, described " C
1-6Alkyl " as mentioned before." C of the present invention
1-4Alkylamidoalkyl " refer to the specific examples that contains 1-4 carbon atom in the above-mentioned example.
" C of the present invention
1-6Alkyl sulphonyl " refer to C
1-6Alkyl is by alkylsulfonyl (SO
2-) group that is connected and derives with other parts, i.e. (C
1-6Alkyl) S (O)
2-, described " C
1-6Alkyl " as mentioned before." C of the present invention
1-4Alkyl sulphonyl " refer to the specific examples that contains 1-4 carbon atom in the above-mentioned example.
" C of the present invention
1-6Alkyl sulphinyl " refer to C
1-6Alkyl is by alkylsulfonyl (group that SO-) is connected and derives with other parts, i.e. (C
1-6Alkyl) S (O)-, described " C
1-6Alkyl " as mentioned before." C of the present invention
1-4Alkyl sulphinyl " refer to the specific examples that contains 1-4 carbon atom in the above-mentioned example.
" C of the present invention
1-6Alkylsulfonamido " refer to a C
1-6The group that hydrogen atom is derived, i.e. (a C in the alkyl sulphonyl substituted-amino
1-6Alkyl) S (O)
2NH-, described " C
1-6Alkyl sulphonyl " as mentioned before." C of the present invention
1-4Alkylsulfonamido " refer to the specific examples that contains 1-4 carbon atom in the above-mentioned example.
" halo C of the present invention
1-6Alkoxyl group " refer to that one or more " halogen " atom replaces " C
1-6Alkoxyl group " group of deriving, described " halogen " and " C
1-6Alkoxyl group " define such as preamble." halo C of the present invention
1-4Alkoxyl group " refer to the specific examples that contains 1-4 carbon atom in the above-mentioned example.
" C of the present invention
1-6The alkyl amine group formyl radical " refer to C
1-6Alkyl amine group is by the group of carbonyl-C (O)-be connected and derive with other parts, i.e. (C
1-6Alkyl) NHC (O)-, described " C
1-6Alkyl " as mentioned before." C of the present invention
1-4The alkyl amine group formyl radical " refer to the specific examples that contains 1-4 carbon atom in the above-mentioned example.
" two (C of the present invention
1-6Alkyl) amido formacyl " refer to two (C
1-6Alkyl) amido is by the group of carbonyl-C (O)-be connected and derive with other parts, i.e. (C
1-6Alkyl)
2NC (O)-, described " two (C
1-6Alkyl) amido " as mentioned before." two (C of the present invention
1-4Alkyl) amido formacyl " refer to the specific examples that contains 1-4 carbon atom in the above-mentioned example.
" C of the present invention
1-6The alkyl amine group alkylsulfonyl " refer to " C
1-6Alkyl-NHSO
2-" mode connects the group of deriving, i.e. (C
1-6Alkyl) NHS (O)
2-, described " C
1-6Alkyl amine group " as mentioned before." C of the present invention
1-4The alkyl amine group alkylsulfonyl " refer to the specific examples that contains 1-4 carbon atom in the above-mentioned example.
" two (C of the present invention
1-6Alkyl) amido alkylsulfonyl " refer to two (C
1-6Alkyl) amido is by alkylsulfonyl-SO
2-the group that is connected and derives with other parts, 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 to the specific examples that contains 1-4 carbon atom in the above-mentioned example.
" C of the present invention
1-6Carbalkoxy " refer to C
1-6Alkoxyl group is by the group of-C (O)-be connected and derive with other parts, i.e. (C
1-6Alkyl) OC (O)-, described " C
1-6Alkoxyl group " as mentioned before." C of the present invention
1-4Carbalkoxy " refer to the specific examples that contains 1-4 carbon atom in the above-mentioned example.
" C of the present invention
1-8Alkylidene group " alkane that refers to contain 1-8 carbon atom removes the group of the straight or branched of deriving behind two hydrogen atoms simultaneously, and specific examples includes but not limited to: methylene radical, ethylidene, propylidene, butylidene, pentylidene, hexylidene, inferior heptyl, octylene etc." C of the present invention
4-8Alkylidene group " refer to the specific examples that contains 4-8 carbon atom in the above-mentioned example." C of the present invention
5-7Alkylidene group " refer to the specific examples that contains 5-7 carbon atom in the above-mentioned example." C of the present invention
6Alkylidene group " refer to the specific examples that contains 6 carbon atoms in the above-mentioned example.
" C of the present invention
2-8Alkenylene " carbonatoms that refers to contain two keys is the group that the alkene of the straight or branched of 2-8 removes the straight or branched of deriving behind two hydrogen atoms simultaneously, specific examples includes but not limited to: vinylidene, propenylidene, crotonylidene, inferior pentenyl, inferior hexenyl, inferior heptenyl, inferior octenyl etc.
" C of the present invention
2-8Alkynyl " carbonatoms that refers to contain three key is the group that the alkynes of the straight or branched of 2-8 removes the straight or branched of deriving behind two hydrogen atoms simultaneously, 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 the cyclic group of carbon atom all, 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 contain in " 3-14 unit cycloalkyl " specific examples of 3-6 annular atoms." 3-6 unit cycloalkyl " of the present invention refers to contain in " 3-14 unit cycloalkyl " specific examples of 3-6 annular atoms; 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 contain the saturated cyclic alkyl of 3-8 carbon atom, specific examples includes but not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, 1-methyl cyclopropyl, 1-amyl group cyclopropyl, 1,2-diethyl cyclobutyl, 1-methyl cyclobutyl, 1-butyl cyclobutyl, 1,3-dimethylcyclobutyl, 1-methylcyclopentyl, 1-butyl cyclopentyl, 1-methylcyclohexyl, 1-ethyl cyclopentyl etc.
The 3-8 unit monocycle alkyl of fractional saturation refers to that carbonatoms is 3-8 ring-type thiazolinyl, and its double bond position is in ring, and specific examples includes but not limited to:
Saturated 8-14 unit condensed ring cycloalkyl, refer to contain 8-14 annular atoms by two or more ring texturees each other shared two adjacent atoms couple together the saturated condensed ring structure that forms, specific examples includes but not limited to:
The 8-14 of fractional saturation unit monocycle alkyl refers to that 8-14 annular atoms shares each other two adjacent atoms by two or more ring texturees and couple together the condensed ring thiazolinyl that forms, and its double bond position is in encircling, and specific examples includes but not limited to:
" 6-14 unit aryl " of the present invention refers to that annular atoms all is the ring-type aromatic group 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 that contains 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.
It is formed that 8-14 unit fused ring aryl refers to share each other two adjacent carbon atoms by two or more ring texturees, condensed ring group for 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 contain 5-14 annular atoms (wherein containing at least a heteroatoms) cyclic group, saturated fused heterocycle base, the fused heterocycle base of 6-14 unit fractional saturation, the single heteroaryl of 5-8 unit, the thick heteroaryl of 6-14 unit of single heterocyclic radical, 6-14 unit that comprises the saturated single heterocyclic radical of 3-8 unit, 3-8 unit fractional saturation, described heteroatoms has nitrogen, oxygen and sulphur etc., comprises that simultaneously carbon atom, nitrogen-atoms and sulphur atom can be by oxos." 5-10 unit heterocyclic radical " of the present invention refers to the specific examples that contains 5-10 annular atoms in " 3-14 unit heterocyclic radical "." 5-6 unit heterocyclic radical " of the present invention refers to the specific examples that contains 5-6 annular atoms in " 3-14 unit heterocyclic radical "." 3-8 unit heterocyclic radical " of the present invention refers to the specific examples that contains 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; 3-8 unit heterocyclic radical " of the present invention, namely contain 3-8 the annular atoms saturated cyclic group of (wherein containing at least a heteroatoms), described heteroatoms has nitrogen, oxygen and sulphur etc., comprise simultaneously carbon atom, nitrogen-atoms and sulphur atom can be by oxos, specific examples includes but are not limited to ethylenimine, diazacyclo propane, azetidine, 1, the 2-diazetidine, tetramethyleneimine, imidazolidine, pyrazolidine, piperidines, piperazine, oxyethane, dioxirane, thiirane, trimethylene oxide, 1, the 2-dioxetane, Thietane, tetrahydrofuran (THF), tetramethylene sulfide, 1, the 3-dioxolane, 1, the 3-dithiolane, tetrahydropyrans, 1, the 4-dioxane, 1, the 3-dioxane, 1,3-oxathiane, oxaza propane Si Qing oxazole, tetrahydrochysene isoxazole, thiazolidine, morpholine etc." 5-8 unit saturated mono heterocyclic radical " of the present invention refers to the specific examples that contains 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 contain 3-8 the annular atoms ring-type thiazolinyl of (wherein containing at least a heteroatoms), its double bond position is in ring, described heteroatoms has nitrogen, oxygen and sulphur etc., comprise simultaneously carbon atom, nitrogen-atoms and sulphur atom can be by oxos, specific examples includes but are not limited to the 2H-ethylenimine, 3H-diazacyclo propylene, azete, 1, the 2-diazetine, pyrrolin, 4, the 5-glyoxalidine, 4, the 5-pyrazoline, 1,2, the 3-triazole, 1,2,4-triazole, the 2-pyridone, the 4-pyridone, 1,2-diazacyclo heptantriene, 1,3-diazacyclo heptantriene, 1,4-diazacyclo heptantriene, Isosorbide-5-Nitrae-dihydro-Isosorbide-5-Nitrae-diazacyclo sarohornene, 1,2-dithia cyclobutene, 2, the 5-dihydro-thiophene, 1,2-dithiole, 1,3-dithiole, the 2H-pyrans, the 2H-pyran-2-one, 3,4-dihydro-2H-pyrans, the 4H-pyrans, 4H-pyrans-4-ketone, 4, the 5-dihydro-oxazole, 4,5-dihydro-isoxazole, 2,3-dihydro-isoxazole, 4, the 5-thiazoline, 2H-1, the 2-oxazine, 4H-1, the 2-oxazine, 6H-1, the 2-oxazine, 2H-1, the 3-oxazine, 4H-1, the 3-oxazine, 6H-1, the 3-oxazine, 2H-1, the 4-oxazine, 4H-1, the 4-oxazine, 5,6-dihydro-4H-1, the 3-oxazine, 2H-1, the 3-thiazine, 4H-1, the 3-thiazine, 6H-1, the 3-thiazine, 2H-1, the 4-thiazine, 4H-1, the 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 containing at least a heteroatoms) by two or more ring texturees each other shared two adjacent atoms couple together the saturated condensed ring structure that forms, described heteroatoms has nitrogen, oxygen and sulphur etc., comprise that simultaneously carbon atom, nitrogen-atoms and sulphur atom can be by oxos, 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 containing at least a heteroatoms) by two or more ring texturees each other shared two adjacent atoms couple together the condensed ring thiazolinyl that forms, its double bond position is in ring, described heteroatoms has nitrogen, oxygen and sulphur etc., comprise simultaneously carbon atom, nitrogen-atoms and sulphur atom can be by oxos, specific examples includes but are not limited to six hydrogen Thienoimidazoles, hexahydro furyl and imidazoles, 4H-1, the 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.
What the single heteroaryl of 5-8 unit referred to 5-8 annular atoms has a heteroatomic cyclic group of containing of aromaticity, and specific examples includes but are not limited to furyl, thienyl, pyrryl, thiazolyl, isothiazolyl, thiadiazolyl group oxazolyl isoxazolyl oxadiazolyl, imidazolyl, pyrazolyl, 1,2, the 3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2, the 4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidyl, Isosorbide-5-Nitrae-Dioxin base, 2H-1, the 2-oxazinyl, 4H-1, the 2-oxazinyl, 6H-1, the 2-oxazinyl, 4H-1, the 3-oxazinyl, 6H-1, the 3-oxazinyl, 4H-1, the 4-oxazinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,2, the 4-triazinyl, the 1,3,5-triazines base, 1,3, the 4-triazinyl, 1,2,4,5-tetrazine base, the 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 that contains 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 that contains 3-8 annular atoms in " the single heteroaryl of 5-8 unit ".
The thick heteroaryl of 6-14 unit refer to contain 6-14 annular atoms (wherein containing at least a heteroatoms) by two or more ring texturees each other shared two adjacent atoms couple together the undersaturated condensed ring structure with aromaticity that forms, specific examples includes but not limited to: benzofuryl, the benzisoxa furyl, benzothienyl, indyl benzoxazolyl, benzimidazolyl-, indazolyl, the benzotriazole base, quinolyl, isoquinolyl, acridyl, phenanthridinyl, the 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 that contains 9-10 annular atoms in " the thick heteroaryl of 6-14 unit ".
" the aryl C of 6-14 unit of the present invention
1-8Alkylidene group " refer to one to a plurality of 6-14 aryl replacement C of unit
1-8The group that alkylidene group is derived, described " 6-14 unit aryl ", " C
1-8Alkylidene group " define such as preamble." the aryl C of 6-10 unit of the present invention
1-8Alkylidene group " refer to contain in " 6-14 unit aryl " specific examples of 6-10 annular atoms." 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.
" the aryl C of 6-14 unit of the present invention
2-8Alkenylene " refer to one to a plurality of 6-14 aryl replacement C of unit
2-8The group that alkenylene is derived, described " 6-14 unit aryl ", " C
2-8Alkenylene " define such as preamble." the aryl C of 6-10 unit of the present invention
2-8Alkenylene " refer to contain in " 6-14 unit aryl " specific examples of 6-10 annular atoms.
" the aryl C of 6-14 unit of the present invention
2-8Alkynyl " refer to one to a plurality of 6-14 aryl replacement C of unit
2-8The group that alkynyl is derived, described " 6-14 unit aryl ", " C
2-8Alkynyl " define such as preamble.
" the heterocyclic radical C of 3-14 unit of the present invention
1-8Alkylidene group " refer to one to a plurality of 3-14 heterocyclic radical replacement C of unit
1-8The group that alkylidene group is derived, described " 3-14 unit heterocyclic radical ", " C
1-8Alkylidene group " define such as preamble." the heterocyclic radical C of 3-8 unit of the present invention
1-8Alkylidene group " refer to contain in " 3-14 unit heterocyclic radical " specific examples of 3-8 annular atoms." the heterocyclic radical C of 5-6 unit 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.
" the heterocyclic radical C of 3-14 unit of the present invention
2-8Alkenylene " refer to one to a plurality of 3-14 heterocyclic radical replacement C of unit
2-8The group that alkenylene is derived, described " 3-14 unit heterocyclic radical ", " C
2-8Alkenylene " define such as preamble." the heterocyclic radical C of 3-8 unit of the present invention
2-8Alkenylene " refer to contain in " 3-8 unit heterocyclic radical " specific examples of 3-8 annular atoms.
" the heterocyclic radical C of 3-14 unit of the present invention
2-8Alkynyl " refer to one to a plurality of 3-14 heterocyclic radical replacement C of unit
2-8The group that alkynyl is derived, described " 3-14 unit heterocyclic radical ", " C
2-8Alkynyl " define such as preamble.
" the cycloalkyl C of 3-8 unit of the present invention
1-8Alkylidene group " refer to one to a plurality of 3-8 cycloalkyl substituted C of unit
1-8The group that alkylidene group is derived, described " 3-8 unit cycloalkyl ", " C
1-8Alkylidene group " define such as preamble.
" the cycloalkyl C of 3-8 unit of the present invention
2-8Alkenylene " refer to one to a plurality of 3-8 cycloalkyl substituted C of unit
2-8The group that alkenylene is derived, described " 3-8 unit cycloalkyl ", " C
2-8Alkenylene " define such as preamble.
" the cycloalkyl C of 3-8 unit of the present invention
2-8Alkynyl " refer to one to a plurality of 3-8 cycloalkyl substituted C of unit
2-8The group that alkynyl is derived, described " 3-8 unit cycloalkyl ", " C
2-8Alkynyl " define such as preamble.
" C of the present invention
1-8Alkyl 6-14 unit aryl " refer to one to a plurality of C
1-8After alkyl replaced 6-14 unit aryl, this 6-14 unit aryl removed the group that a hydrogen atom is derived, described " C simultaneously
1-8Alkyl ", " 6-14 unit aryl " define such as preamble." C of the present invention
1-8Alkyl 6-10 unit aryl " refer to contain in " 6-14 unit aryl " specific examples of 6-10 annular atoms.
" C of the present invention
1-8Alkyl 3-14 unit heterocyclic radical " refer to one to a plurality of C
1-8After alkyl replaced 3-14 unit heterocyclic radical, this 3-14 unit heterocyclic radical removed the group that a hydrogen atom is derived, described " C simultaneously
1-8Alkyl ", " 3-14 unit heterocyclic radical " define such as preamble." C of the present invention
1-8Alkyl 3-8 unit heterocyclic radical " refer to contain in " 3-14 unit heterocyclic radical " specific examples of 3-8 annular atoms.
" C of the present invention
1-8Alkyl 3-8 unit cycloalkyl " refer to one to a plurality of C
1-8After alkyl replaced 3-8 unit cycloalkyl, this 3-8 unit cycloalkyl was removed the group that a hydrogen atom is derived, described " C simultaneously
1-8Alkyl ", " 3-8 unit cycloalkyl " define such as preamble.
" C of the present invention
2-8Thiazolinyl 6-14 unit aryl " refer to one to a plurality of C
2-8Behind the alkenyl substituted 6-14 unit aryl, this 6-14 unit aryl removes the group that a hydrogen atom is derived, described " C simultaneously
2-8Thiazolinyl ", " 6-14 unit aryl " define such as preamble." C of the present invention
2-8Thiazolinyl 6-10 unit aryl " refer to contain in " 6-14 unit aryl " specific examples of 6-10 annular atoms." C of the present invention
2-6The thiazolinyl 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 one to a plurality of C
2-8Behind the alkenyl substituted 3-14 unit heterocyclic radical, this 3-14 unit heterocyclic radical removes the group that a hydrogen atom is derived, described " C simultaneously
2-8Thiazolinyl ", " 3-14 unit heterocyclic radical " define such as preamble." C of the present invention
2-8Thiazolinyl 3-8 unit heterocyclic radical " refer to contain in " 3-14 unit heterocyclic radical " specific examples of 3-8 annular atoms." 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 one to a plurality of C
2-8After the alkenyl substituted 3-8 unit cycloalkyl, this 3-8 unit cycloalkyl is removed the group that a hydrogen atom is derived, described " C simultaneously
2-8Thiazolinyl ", " 3-8 unit cycloalkyl " define such as preamble.
" C of the present invention
2-8Alkynyl 6-14 unit aryl " refer to one to a plurality of C
2-8Behind the alkynyl substituted 6-14 unit aryl, this 6-14 unit aryl removes the group that a hydrogen atom is derived, described " C simultaneously
2-8Alkynyl ", " 6-14 unit aryl " define such as preamble.
" C of the present invention
2-8Alkynyl 3-14 unit heterocyclic radical " refer to one to a plurality of C
2-8After the alkynyl base replaced 3-14 unit heterocyclic radical, this 3-14 unit heterocyclic radical removed the group that a hydrogen atom is derived, described " C simultaneously
2-8Alkynyl ", " 3-14 unit heterocyclic radical " define such as preamble.
" C of the present invention
2-8Alkynyl 3-8 unit cycloalkyl " refer to one to a plurality of C
2-8After the alkynyl substituted 3-8 unit cycloalkyl, this 3-8 unit cycloalkyl is removed the group that a hydrogen atom is derived, described " C simultaneously
2-8Alkynyl ", " 3-8 unit cycloalkyl " define such as preamble.
" C of the present invention
1-8The aryl C of alkylidene group 6-14 unit
1-8Alkylidene group " refer to C
1-8Alkylidene group connects 6-14 unit aryl and connects C
1-8The group that alkylidene group is derived, i.e. C
1-8Alkylidene group-aryl-the C of 6-14 unit
1-8Alkylidene group, described " C
1-8Alkylidene group ", " 6-14 unit aryl ", " C
1-8Alkylidene group " define such as preamble." C of the present invention
1-8The aryl C of alkylidene group 6-10 unit
1-8Alkylidene group " refer to contain in " 6-14 unit aryl " specific examples of 6-10 annular atoms.
" C of the present invention
1-8The aryl C of alkylidene group 6-14 unit
2-8Alkenylene " refer to C
1-8Alkylidene group connects 6-14 unit aryl and connects C
2-8The group that alkenylene is derived, i.e. C
1-8Alkylidene group-aryl-the C of 6-14 unit
2-8Alkenylene, described " C
1-8Alkylidene group ", " 6-14 unit aryl ", " C
2-8Alkenylene " define such as preamble." C of the present invention
1-8The aryl C of alkylidene group 6-10 unit
2-8Alkenylene " refer to contain in " 6-14 unit aryl " specific examples of 6-10 annular atoms.
" C of the present invention
1-8The aryl C of alkylidene group 6-14 unit
2-8Alkynyl " refer to C
1-8Alkylidene group connects 6-14 unit aryl and connects C
2-8The group that alkynyl is derived, i.e. C
1-8Alkylidene group-aryl-the C of 6-14 unit
2-8Alkynyl, described " C
1-8Alkylidene group ", " 6-14 unit aryl ", " C
2-8Alkynyl " define such as preamble.
" C of the present invention
2-8The aryl C of alkenylene 6-14 unit
1-8Alkylidene group " refer to C
2-8Alkenylene connects 6-14 unit aryl and connects C
1-8The group that alkylidene group is derived, i.e. C
2-8Alkenylene-aryl-the C of 6-14 unit
1-8Alkylidene group, described " C
2-8Alkenylene ", " 6-14 unit aryl ", " C
1-8Alkylidene group " define such as preamble." C2 of the present invention
-8The aryl C of alkenylene 6-10 unit
1-8Alkylidene group " refer to contain in " 6-14 unit aryl " specific examples of 6-10 annular atoms." 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
2-8The aryl C of alkenylene 6-14 unit
2-8Alkenylene " refer to C
2-8Alkenylene connects 6-14 unit aryl and connects C
2-8The group that alkenylene is derived, i.e. C
2-8Alkenylene-aryl-the C of 6-14 unit
2-8Alkenylene, described " C
2-8Alkenylene ", " 6-14 unit aryl ", " C
2-8Alkenylene " define such as preamble." C of the present invention
2-8The aryl C of alkenylene 6-10 unit
2-8Alkenylene " refer to contain in " 6-14 unit aryl " specific examples of 6-10 annular atoms.
" C of the present invention
2-8The aryl C of alkenylene 6-14 unit
2-8Alkynyl " refer to C
2-8Alkenylene connects 6-14 unit aryl and connects C
2-8The group that alkynyl is derived, i.e. C
2-8Alkenylene-aryl-the C of 6-14 unit
2-8Alkynyl, described " C
2-8Alkenylene ", " 6-14 unit aryl ", " C
2-8Alkynyl " define such as preamble.
" C of the present invention
2-8The aryl C of alkynyl 6-14 unit
1-8Alkylidene group " refer to " refer to C
2-8Alkynyl connects 6-14 unit aryl and connects C
1-8The group that alkylidene group is derived, i.e. C
2-8Alkynyl-aryl-the C of 6-14 unit
1-8Alkylidene group, described " C
2-8The alkynyl base ", " 6-14 unit aryl ", " C
1-8Alkylidene group " define such as preamble.
" C of the present invention
2-8The aryl C of alkynyl 6-14 unit
2-8Alkenylene " refer to C
2-8Alkynyl connects 6-14 unit aryl and connects C
2-8The group that alkenylene is derived, i.e. C
2-8Alkynyl-aryl-the C of 6-14 unit
2-8Alkenylene, described " C
2-8Alkynyl ", " 6-14 unit aryl ", " C
2-8Alkenylene " define such as preamble.
" C of the present invention
2-8The aryl C of alkynyl 6-14 unit
2-8Alkynyl " refer to C
2-8Alkynyl connects 6-14 unit aryl and connects C
2-8The group that alkynyl is derived, i.e. C
2-8Alkynyl-aryl-the C of 6-14 unit
2-8Alkynyl, described " C
2-8Alkynyl ", " 6-14 unit aryl " define such as preamble.
" C of the present invention
1-8The heterocyclic radical C of alkylidene group 3-14 unit
1-8Alkylidene group " refer to C
1-8Alkylidene group connects 3-14 unit heterocyclic radical and connects C
1-8The group that alkylidene group is derived, i.e. C
1-8Alkylidene group-heterocyclic radical-the C of 3-14 unit
1-8Alkylidene group, described " 3-14 unit heterocyclic radical ", " C
1-8Alkylidene group " define such as preamble." C of the present invention
1-8The heterocyclic radical C of alkylidene group 3-8 unit
1-8Alkylidene group " refer to contain in " 3-14 unit heterocyclic radical " specific examples of 3-8 annular atoms.
" C of the present invention
1-8The heterocyclic radical C of alkylidene group 3-14 unit
2-8Alkenylene " refer to C
1-8Alkylidene group connects 3-14 unit heterocyclic radical and connects C
2-8The group that alkenylene is derived, i.e. C
1-8Alkylidene group-heterocyclic radical-the C of 3-14 unit
2-8Alkenylene, described " C
1-8Alkylidene group ", " 3-14 unit heterocyclic radical ", " C
2-8Alkenylene " define such as preamble." C of the present invention
1-8The heterocyclic radical C of alkylidene group 3-8 unit
2-8Alkenylene " refer to contain in " 3-14 unit heterocyclic radical " specific examples of 3-8 annular atoms.
" C of the present invention
1-8The heterocyclic radical C of alkylidene group 3-14 unit
2-8Alkynyl " refer to C
1-8Alkylidene group connects 3-14 unit heterocyclic radical and connects C
2-8The group that alkynyl is derived, i.e. C
1-8Alkylidene group-heterocyclic radical-the C of 3-14 unit
2-8Alkynyl, described " C
1-8Alkylidene group ", " 3-14 unit heterocyclic radical ", " C
2-8Alkynyl " define such as preamble.
" C of the present invention
2-8The heterocyclic radical C of alkenylene 3-14 unit
1-8Alkylidene group " refer to C
2-8Alkenylene connects 3-14 unit heterocyclic radical and connects C
1-8The group that alkylidene group is derived, i.e. C
2-8Alkenylene-heterocyclic radical-the C of 3-14 unit
1-8Alkylidene group, described " C
2-8Alkenylene ", " 3-14 unit heterocyclic radical ", " C
1-8Alkylidene group " define such as preamble." C of the present invention
2-8The heterocyclic radical C of alkenylene 3-8 unit
1-8Alkylidene group " refer to contain in " 3-14 unit heterocyclic radical " specific examples of 3-8 annular atoms." C of the present invention
2-6The heterocyclic radical C of alkenylene 5-6 unit
1-6Alkylidene group " refer to " C
2-8Alkenylene ", " 3-14 unit heterocyclic radical ", " C
1-8Alkylidene group " in contain respectively the specific examples of 2-6 atom, a 5-6 annular atoms, a 1-6 atom
" C of the present invention
2-8The heterocyclic radical C of alkenylene 3-14 unit
2-8Alkenylene " refer to C
2-8Alkenylene connects 3-14 unit heterocyclic radical and connects C
2-8The group that alkenylene is derived, i.e. C
2-8Alkenylene-heterocyclic radical-the C of 3-14 unit
2-8Alkenylene, described " C
2-8Alkenylene ", " 3-14 unit heterocyclic radical ", " C
2-8Alkenylene " define such as preamble." C of the present invention
2-8The heterocyclic radical C of alkenylene 3-8 unit
2-8Alkenylene " refer to contain in " 3-14 unit heterocyclic radical " specific examples of 3-8 annular atoms.
" C of the present invention
2-8The heterocyclic radical C of alkenylene 3-14 unit
2-8Alkynyl " refer to C
2-8Alkenylene connects 3-14 unit heterocyclic radical and connects C
2-8The group that alkynyl is derived, i.e. C
2-8Alkenylene-heterocyclic radical-the C of 3-14 unit
2-8Alkynyl, described " C
2-8Alkenylene ", " 3-14 unit heterocyclic radical ", " C
2-8Alkynyl " define such as preamble.
" C of the present invention
2-8The heterocyclic radical C of alkynyl 3-14 unit
1-8Alkylidene group " refer to one to a plurality of C
2-8Replace C behind the alkynyl substituted 3-14 unit heterocyclic radical
1-8The group that alkylidene group is derived, described " C
2-8Alkynyl ", " 3-14 unit heterocyclic radical ", " C
1-8Alkylidene group " define such as preamble.
" C of the present invention
2-8The heterocyclic radical C of alkynyl 3-14 unit
2-8Alkenylene " refer to one to a plurality of C
2-8Replace C behind the alkynyl substituted 3-14 unit heterocyclic radical
2-8The group that alkenylene is derived, described " C
2-8Alkynyl ", " 3-14 unit heterocyclic radical ", " C
2-8Alkenylene " define such as preamble.
" C of the present invention
2-8The heterocyclic radical C of alkynyl 3-14 unit
2-8Alkynyl " refer to C
2-8Alkynyl connects 3-14 unit heterocyclic radical and connects C
2-8The group that alkynyl is derived, i.e. C
2-8Alkynyl-heterocyclic radical-the C of 3-14 unit
2-8Alkynyl, described " C
2-8Alkynyl ", " 3-14 unit heterocyclic radical " define such as preamble.
" C of the present invention
1-8The cycloalkyl C of alkylidene group 3-8 unit
1-8Alkylidene group " refer to C
1-8Alkylidene group connects 3-8 unit cycloalkyl and connects C
1-8The group that alkylidene group is derived, i.e. C
1-8Alkylidene group-cycloalkyl-the C of 3-8 unit
1-8Alkylidene group, described " 3-8 unit cycloalkyl ", " C
1-8Alkylidene group " define such as preamble.
" C of the present invention
1-8The cycloalkyl C of alkylidene group 3-8 unit
2-8Alkenylene " refer to C
1-8Alkylidene group connects 3-8 unit cycloalkyl and connects C
2-8The group that alkenylene is derived, i.e. C
1-8Alkylidene group-cycloalkyl-the C of 3-8 unit
2-8Alkenylene, described " C
1-8Alkylidene group ", " 3-8 unit cycloalkyl ", " C
2-8Alkenylene " define such as preamble.
" C of the present invention
1-8The cycloalkyl C of alkylidene group 3-8 unit
2-8Alkynyl " refer to C
1-8Alkylidene group connects 3-8 unit cycloalkyl and connects C
2-8The group that alkynyl is derived, i.e. C
1-8Alkylidene group-cycloalkyl-the C of 3-8 unit
2-8Alkynyl, described " C
1-8Alkylidene group ", " 3-8 unit cycloalkyl ", " C
2-8Alkynyl " define such as preamble.
" C of the present invention
2-8The cycloalkyl C of alkenylene 3-8 unit
1-8Alkylidene group " refer to C
2-8Alkenylene connects 3-8 unit cycloalkyl and connects C
2-8The group that alkynyl is derived, i.e. C
2-8Alkenylene-cycloalkyl-the C of 3-8 unit
2-8Alkynyl, described " C
2-8Alkenylene ", " 3-8 unit cycloalkyl ", " C
1-8Alkylidene group " define such as preamble.
" C of the present invention
2-8The cycloalkyl C of alkenylene 3-8 unit
2-8Alkenylene " be C
2-8Alkenylene connects 3-8 unit cycloalkyl and connects C
2-8The group that alkenylene is derived, i.e. C
2-8Alkenylene-cycloalkyl-the C of 3-8 unit
2-8Alkenylene, described " C
2-8Alkenylene ", " 3-8 unit cycloalkyl ", " C
2-8Alkenylene " define such as preamble.
" C of the present invention
2-8The cycloalkyl C of alkenylene 3-8 unit
2-8Alkynyl " refer to C
2-8Alkenylene connects 3-8 unit cycloalkyl and connects C
2-8The group that alkynyl is derived, i.e. C
2-8Alkenylene-cycloalkyl-the C of 3-8 unit
2-8Alkynyl, described " C
2-8Alkenylene ", " 3-8 unit cycloalkyl ", " C
2-8Alkynyl " define such as preamble.
" C of the present invention
2-8The cycloalkyl C of alkynyl 3-8 unit
1-8Alkylidene group " refer to C
2-8Alkynyl connects 3-8 unit cycloalkyl and connects C
1-8The group that alkylidene group is derived, i.e. C
2-8Alkynyl-cycloalkyl-the C of 3-8 unit
1-8Alkylidene group, described " C
2-8Alkynyl ", " 3-8 unit cycloalkyl ", " C
1-8Alkylidene group " define such as preamble.
" C of the present invention
2-8The cycloalkyl C of alkynyl 3-8 unit
2-8Alkenylene " refer to C
2-8Alkynyl connects 3-8 unit cycloalkyl and connects C
2-8The group that alkenylene is derived, i.e. C
2-8Alkynyl-cycloalkyl-the C of 3-8 unit
2-8Alkenylene, described " C
2-8Alkynyl ", " 3-8 unit cycloalkyl ", " C
2-8Alkenylene " define such as preamble.
" C of the present invention
2-8The cycloalkyl C of alkynyl 3-8 unit
2-8Alkynyl " refer to C
2-8Alkynyl connects 3-8 unit cycloalkyl and connects C
2-8The group that alkenylene is derived, i.e. C
2-8Alkynyl-cycloalkyl-the C of 3-8 unit
2-8Alkynyl, described " C
2-8Alkynyl ", " 3-8 unit cycloalkyl " define such as preamble.
" the 3-14 unit heterocyclic radical-aryl C of 6-14 unit of the present invention
1-8Alkylidene group " refer to that one replaces C to the first aryl of a plurality of 3-14 heterocyclic radical replacement 6-14 of unit
1-8The group that alkylidene group is derived, described " 3-14 unit heterocyclic radical ", " 6-14 unit aryl ", " C
1-8Alkylidene group " define such as preamble." the 3-8 unit heterocyclic radical-aryl C of 6-10 unit of the present invention
1-8Alkylidene group " refer to contain respectively in " 3-14 unit heterocyclic radical ", " the 6-14 unit aryl " specific examples of 3-8 annular atoms, a 6-10 annular atoms.
" the 6-14 unit aryl-heterocyclic radical C of 3-14 unit of the present invention
1-8Alkylidene group " refer to that one replaces C to the first heterocyclic radical of a plurality of 6-14 aryl replacement 3-14 of unit
1-8The group that alkylidene group is derived, described " 6-14 unit aryl ", " 3-14 unit heterocyclic radical ", " C
1-8Alkylidene group " define such as preamble." the 6-10 unit aryl-heterocyclic radical C of 3-8 unit of the present invention
1-8Alkylidene group " refer to contain respectively in " 6-14 unit aryl ", " the 3-14 unit heterocyclic radical " specific examples of 6-10 annular atoms, a 3-8 annular atoms.
" the 3-14 unit heterocyclic radical-heterocyclic radical C of 3-14 unit of the present invention
1-8Alkylidene group " refer to that one replaces C to the first heterocyclic radical of a plurality of 3-14 heterocyclic radical replacement 3-14 of unit
1-8The group that alkylidene group is derived, described " 3-14 unit heterocyclic radical ", " C
1-8Alkylidene group " define such as preamble." the 3-8 unit heterocyclic radical-heterocyclic radical C of 3-8 unit of the present invention
1-8Alkylidene group " refer to contain in " 3-14 unit heterocyclic radical " specific examples of 3-8 annular atoms." the 5-6 unit heterocyclic radical-heterocyclic radical C of 5-6 unit of the present invention
1-6Alkylidene group " refer to " 3-14 unit heterocyclic radical ", " C
1-8Alkylidene group " in contain respectively the specific examples of 5-6 annular atoms, a 1-6 atom.
" 7-12 unit bridged ring base " of the present invention refers to that any two rings share that two atoms that directly do not link to each other form contains 7-12 carbon atom or heteroatomic structure, and 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, is preferably the saturated bridged ring of 7-9 unit, and specific examples includes but not limited to:
7-12 unit fractional saturation bridged ring refers to have in this bridged ring that to have a ring at least be undersaturated cyclic group, is preferably 7-8 unit fractional saturation bridged ring, and specific examples includes but not limited to:
" 7-12 unit volution " of the present invention refers to that a class has that two rings share that atoms form at least contains 7-12 carbon atom or heteroatomic structure, and 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 refers to that all rings in this volution are saturated cyclic group, and specific examples includes but are not limited to:
7-12 unit fractional saturation volution refers to that having a ring in this volution at least is undersaturated cyclic group, and specific examples includes but are not limited to:
" treatment " of the present invention refers to alleviate, improvement, elimination or minimizing sign and the symptom relevant with disease or illness.
" prevention " of the present invention refers to prevent or postpones generation or the development of disease or illness or prevent or postpone therewith disease or relevant sign or the symptom of illness.
" composition " of the present invention, refer in pharmaceutical composition, be intended to comprise the inertia complexing or the polymerization that contain activeconstituents and consist of carrier, perhaps from the decomposition of one or more compositions, perhaps from the reaction of other type of one or more compositions or any product that interacts and produce, therefore, pharmaceutical composition of the present invention comprises any composition for preparing by compound and one or more pharmaceutically acceptable mixed with excipients with formula (I).
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, unless and specialize, be intended to comprise E geometrical isomer and Z geometrical isomer.Can there be different hydrogen tie points in the compound that some the present invention describe, is called as tautomer.This example can for ketone and enol form thereof, be called the keto-enol tautomerism body.The compound of formula (I) comprises single tautomer and composition thereof.The invention is intended to comprise all these type of isomeric form of compound of formula (I).Described isomer can be by standard isolation technique and the abundant purity isomer of the synthetic acquisition of zinc bromide.
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention comprises an alkali metal salt, such as sodium salt, sylvite, lithium salts etc.; Alkaline earth salt is such as calcium salt, magnesium salts etc.; Other metal-salts are such as aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt etc.; Inorganic base salts is such as ammonium salt; Organic alkali salt, such as uncle's octyl group amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycocoll alkyl ester salt, ethylenediamine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, guanidinesalt, diethyl amine 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) amido methane salt; When compound of the present invention is alkalescence, can prepare salt by the pharmaceutically acceptable non-toxic acid that comprises mineral acid and organic acid, this type of acid comprises: halogen acid salt, such as hydrofluoride, hydrochloride, hydrobromate, hydriodate etc.; Inorganic acid salt is such as nitrate, perchlorate, vitriol, phosphoric acid salt etc.; Lower alkyl sulfonate is such as mesylate, fluoroform sulphonate, esilate etc.; Arylsulphonate is such as benzene sulfonate, P-TOLUENE SULFO ACID 99's salt etc.; Organic acid salt is such as acetate, malate, fumarate, succinate, Citrate trianion, tartrate, oxalate, maleate etc.; Amino acid salts is such as glycinate, Trimethyl glycine salt, arginic acid salt, ornithine salt, glutaminate, aspartate etc.For fear of query, one, two or three salt-forming cations may be arranged, but this depends on quantity and the described cationic valence mumber of carboxyl functional group.It is evident that for those skilled in the art the pharmacy acceptable salt of the compounds of this invention can in the formation such as free carboxy place of this compound, can make by ordinary method.
" pharmaceutical composition " of the present invention refers to the compound shown in the general formula (I) and the pharmaceutical composition of pharmaceutically acceptable carrier.Its pharmacy acceptable salt and isomer thereof and one or more pharmaceutical carriers are made pharmaceutically acceptable pharmaceutical preparation, are applied to the patient who needs this treatment in modes such as oral, parenterals.During oral administration, can make conventional solid preparation with the weighting agent of routine, tackiness agent, disintegrating agent, lubricant, thinner etc., such as tablet, capsule, pill, granule etc.; When being used for administered parenterally, can be made into injection, comprise injection liquid, injectable sterile powder and concentrated solution for injection.When making injection, can adopt the ordinary method production in the existing pharmacy field, during the preparation injection, can not add additives, also can add suitable additives according to the character of medicine.
The practical methods for preparing this type of formulation is known, perhaps is apparent for those skilled in the art: referring to, Remington ' s Pharmaceutical Sciences for example, Mack Publishing Co., Eaton, PA, 16
Th, Ed, 1980.
The present invention also provides compound, its pharmacy acceptable salt and the isomer thereof shown in the general formula (I) to treat and/or prevent purposes in the medicine of tumour in preparation.
The present invention also comprises the pharmaceutical composition of the compound that contains formula (I) and utilizes the compounds for treating of formula (I) or the method for prophylaxis of tumours disease.
The delivery system administration that the form that these medical compositions of the present invention can also continue to disengage or use continue to disengage.
Part of compounds of the present invention:
General formula of the present invention (I) compound can adopt method and/or other technology known to persons of ordinary skill in the art of describing in the following flow process to synthesize, but is not limited only to following methods.
General formula (I) compound preparation technology:
(1) preparation of intermediate 1:
In dioxane, add raw material 1 (1 equivalent); raw material 2 (1.2 equivalent); add the aqueous solution of alkali (such as yellow soda ash; salt of wormwood etc.); (perhaps other palladium catalysts are such as 1 to add at last four (triphenyl phosphorus) palladium of catalytic amount; 1 '-two (diphenylphosphine) ferrocene] palladium chloride methylene dichloride complex compound); fully replace nitrogen; system backflow stoichiometric number hour under nitrogen protection; cool to room temperature; filter; be dissolved in the organic solvent behind the organic layer concentrating under reduced pressure, successively washing; the saturated common salt washing, anhydrous sodium sulfate drying; concentrated, column chromatography obtains intermediate 1.
(2) preparation of intermediate 2:
Intermediate 1 (1 equivalent) is dissolved in the tetrahydrofuran (THF) (or other polar solvents), adds the aqueous solution of lithium hydroxide (3-4 equivalent) under the ice bath, or other basic solutions (such as sodium hydroxide).Room temperature reaction is finished through the TLC monitoring reaction.Add water in system, it is slightly acidic that dilute hydrochloric acid is regulated pH, separates out solid, filters, and drying obtains intermediate 2.
(3) preparation of formula I compound:
Intermediate 2 (1 equivalent) and triethylamine or other tertiary amine (3 equivalent) are dissolved in methylene dichloride, drip isopropyl chlorocarbonate (1 equivalent) under the ice bath, drip and finish, changed under the room temperature reaction over to three hours, not treated, be directly used in next step.Also can adopt other to generate the method (for example adding diacetyl oxide) of activation acid anhydrides
Raw material 3 (2 equivalent) and triethylamine (perhaps other tertiary amines) are dissolved in methylene dichloride, stir half an hour, then reaction solution is joined in the reaction soln in upper step, continuing to continue to be stirred to reaction under the room temperature finishes, successively water, saturated common salt water washing behind the adding organic solvent diluting, the organic phase anhydrous sodium sulfate drying, concentrated, anti-phase preparation obtains target compound.
A in the above-mentioned reaction equation, X, Y, W, R
1, R
2, R
3, R
4, R
5, R
6, R
7And R
8Define such as preamble;
Below further set forth the beneficial effect of pyrido naphthyridines analog derivative of the present invention by the anti tumor activity in vitro determination experiment, but this should be interpreted as that pyrido naphthyridines analog derivative of the present invention only has following beneficial effect.
Experimental example 1 the compounds of this invention to externalHDAC1, HDAC6
It is active that zymetology suppresses
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 all are purchased from public institution.
Experimental technique:
(1) 1 times of damping fluid of preparation: comprise 50mM HEPES, pH 7.4,100mM KCl, 0.001%Tween-20,0.05%BSA, 20 μ M TCEP;
(2) compound gradient dilution: preparation contains the compound of 0.15mM concentration, gets the compound (10mM) of 15 μ L, adds the 100%DMSO of 985 μ L;
4 times of dilutions: get the mentioned solution of 20 μ L, add the 100%DMSO of 60 μ L, then totally 10 concentration add respectively the 100%DMSO of 100 μ L in two blank well, as maximum value and minimum value contrast, this 96 orifice plate is labeled as motherboard; Pipette 6 μ L compound solutions to other 96 orifice plates from 96 hole motherboards, add 94 μ L damping fluids, this moment, the concentration of compound was 3 times of final concentration; Shook mixing 10 minutes;
(3) preparation enzyme solution
Adopt 1 times of damping fluid, prepare 860 μ L enzyme solution, HDAC1 wherein, 6 enzyme concn is respectively 6.25nM, 22.7nM;
(4) preparation substrate solution
Add trypsinase and Boc-lys (AC)-AMC to 1 times damping fluid, the preparation substrate solution; For HDAC1, the concentration of trypsinase and Boc-lys (AC)-AMC is 20 μ M, and for HDAC6, the concentration of trypsinase and Boc-lys (AC)-AMC is respectively 20 μ M, 8 μ M;
(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 that contains compound), the damping fluid of transferase 45 μ L is to control wells simultaneously, incubated at room 10 minutes starts reaction in substrate solution to 384 orifice plate of transferase 45 μ L; Mixing 60 seconds gently under the room temperature, HDAC1, incubated at room is after 20 minutes, and Synergy MX (excites with emission wavelength and is respectively 355,460nm) read plate 30 minutes; HDAC6, incubated at room is after 5 minutes, and Synergy MX (excites with emission wavelength and is respectively 355,460nm) read 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
Calculate the IC of each compound according to inhibiting rate
50Value.
Experimental result and conclusion:
The restraining effect of table 1 couple HDAC1, HDAC6 enzymic activity
By as seen from Table 1,1 pair of HDAC1 enzyme of the compounds of this invention, HDAC6 enzyme have and suppress preferably active, especially the restraining effect of HDAC1 significantly are better than contrast medicine SAHA.
Experimental example 2 the compounds of this invention to externalMTOR enzyme, PI3K α
It is active that zymetology suppresses
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 all are purchased from public institution.
Experimental technique:
1.mTOR zymetology evaluation
(1) 1 times of damping fluid of preparation: comprise 50mM HEPES (pH 7.5), 10mM MgCl
2, 1mM EGTA, 3mMMnCl
2, 0.01%Tween-20,2mM DTT;
(2) compound gradient dilution: preparation is 100 times of compounds of high final concentration, if the highest final concentration is 10 μ M, need preparation to contain the compound of 1mM;
4 times of dilutions: get the mentioned solution of 20 μ L, add the 100%DMSO of 60 μ L, successively dilution, totally 10 concentration, then the 100%DMSO that in two blank well, adds respectively 100 μ L, group (without compound with without the enzyme contrast) is labeled as motherboard with this 96 orifice plate in contrast; From 96 hole motherboards, pipette 4 μ L compound solutions to other 96 orifice plates, add 96 μ L damping fluids, 96 orifice plates in the middle of being considered as; Shook 10 minutes, mixing is from middle 96 orifice plate transferase 12 .5 μ L to 384 orifice plates;
(3) mTOR kinase reaction
1. prepare 4 times of kinase solution: adopt the mTOR solution (final concentration of mTOR is 2.5nM) of 4 times of final concentrations of 1 times of damping fluid preparation, each hole (the 1 times of damping fluid that adds 2.5 μ L without the enzyme control wells) of getting 2.5 μ L to 384 orifice plates, concussion mixing;
2. prepare 2 times of substrate solutions: adopt the substrate solution (final concentration of ULight-4E-BP1 peptide and ATP is 50nM, 10.8 μ M) of 2 times of final concentrations of 1 times of damping fluid preparation, each hole of getting 5 μ L to 384 orifice plates, concussion mixing;
3. kinase reaction: incubated at room 1 hour;
(4) kinase assay:
1. preparation detects solution: 2 times of final concentrations that adopt the preparation of Lance detection damping fluid to contain EDTA and Eu-anti-phospho-4E-BP1 antibody detect solution (final concentration of EDTA and Eu-anti-phospho-4E-BP1 antibody is respectively 8mM, 2nM); 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) read plate
2.PI3K the α zymetology is estimated
(1) 1 times of damping fluid of preparation: comprise 50mM HEPES (pH 7.5), 3mM MgCl
2, 1mM EGTA, 100mM NaCl, 0.03%CHAPS, 2mM DTT;
(2) compound gradient dilution: preparation is 100 times of compounds of high final concentration, if the highest final concentration is 10 μ M, need preparation to contain the compound of 1mM;
4 times of dilutions: get the mentioned solution of 20 μ L, add the 100%DMSO of 60 μ L, successively dilution, totally 10 concentration, then the 100%DMSO that in two blank well, adds respectively 100 μ L, group (without compound with without the enzyme contrast) is labeled as motherboard with this 96 orifice plate in contrast; From above 96 hole motherboards, pipette 4 μ L compound solutions to other 96 orifice plates, add 96 μ L damping fluids, 96 orifice plates in the middle of being considered as; Shook mixing 10 minutes; 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: adopt the PI3K α solution (final concentration of PI3K α is 1.65nM) of 4 times of final concentrations of 1 times of damping fluid preparation, each hole (except the control wells) of getting 2.5 μ L to 384 orifice plates, concussion mixing;
2. prepare 2 times of substrate solutions: adopt the substrate solution (final concentration of PIP2 and ATP is 50 μ M, 25 μ M) of 2 times of final concentrations of 1 times of damping fluid preparation, each hole of getting 5 μ L to 384 orifice plates, concussion mixing;
3. kinase reaction: incubated at room 1 hour;
(4) kinase assay: add 10 μ L Kinase-Glo reagent (being positioned under the room temperature environment in advance) termination reaction to each hole of 384 orifice plates; Of short duration centrifugal mixing, incubated at room 15 minutes;
(5) read plate
Data processing
The mTOR zymetology is estimated 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
Calculate the IC of each compound according to inhibiting rate
50Value.
Experimental result and conclusion:
The restraining effect of table 2 couple mTOR, PI3K α enzymic activity
By as seen from Table 2,1 pair of mTOR enzyme of the compounds of this invention, PI3K α enzyme have and suppress preferably active.
Embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The preparation of embodiment one N-hydroxyl-7-(5-(9-oxo-10-(3-trifluoromethyl)-9,10-dihydro pyrido [3,2-c] [1,5] naphthyridines-2-yl) pyrimidine-2-oxygen base) heptamide (compound 1)
(1) preparation of 7-(5-bromo pyrimi piperidine-2-oxygen base) oil of cognac
5-bromo-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 spent the night 80 ℃ of lower stirrings, cooling is with ethyl acetate (80mL) dilution, successively water, saturated common salt water washing, the 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-dioxa boron heterocycle pentane-2-yl) pyrimidine-2-oxygen base) oil of cognac
1; add successively 7-(5-bromo pyrimi piperidine-2-oxygen base) oil of cognac (331mg in the 4-dioxane (20mL); 1.0mmol), duplex tetramethyl ethylene ketone boric acid ester (381mg; 1.5mmol), Potassium ethanoate (295mg; 3.0mmol) and [1; 1 '-two (diphenylphosphine) ferrocene] palladium chloride methylene dichloride complex compound (20mg), reaction was stirred 12 hours in 90 ℃ under nitrogen protection, not treatedly after the cooling was directly used in next step.
(3) preparation of 7-(5-(9-oxo-10-(3-trifluoromethyl)-9,10-dihydro pyrido [3,2-c] [1,5] naphthyridines-2-yl) pyrimidine-2-oxygen base) oil of cognac
In the reaction solution of upper step of cooling, be that (5-(4 for 7-, 4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) pyrimidine-2-oxygen base) oil of cognac (about 1.0mmol) adds 2-chloro-10-(3-trifluoromethyl) pyrido [3,2-c] [1,5] naphthyridines-9 (10H)-ketone (301mg, 0.80mmol), four (triphenyl phosphorus) palladium (15mg), 2N sodium carbonate solution (2.4mL).In 90 ℃ of reaction 16h, cool to room temperature filters system, is dissolved in the methylene dichloride behind the organic layer concentrating under reduced pressure under nitrogen protection; successively washing, 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 pyrido [3,2-c] [1,5] naphthyridines-2-yl) pyrimidine-2-oxygen base) enanthic acid
With 7-(5-(9-oxo-10-(3-trifluoromethyl)-9,10-dihydro pyrido [3,2-c] [1,5] naphthyridines-2-yl) pyrimidine-2-oxygen base) oil of cognac (219mg, 0.37mmol) be dissolved in the tetrahydrofuran (THF) (10mL), add the aqueous solution that 10mL is dissolved with a hydronium(ion) oxidation lithium (47mg, 1.1mmol) under the ice bath.Room temperature reaction 3h finishes through the TLC monitoring reaction.Add water in system, dilute hydrochloric acid is regulated pH ≈ 3-4, separates out solid, filters, and drying obtains white solid 191mg, yield 91.6%.
(5) preparation of N-hydroxyl-7-(5-(9-oxo-10-(3-trifluoromethyl)-9,10-dihydro pyrido [3,2-c] [1,5] naphthyridines-2-yl) pyrimidine-2-oxygen base) heptamide
With 7-(5-(9-oxo-10-(3-trifluoromethyl)-9,10-dihydro pyrido [3,2-c] [1,5] naphthyridines-2-yl) pyrimidine-2-oxygen base) enanthic acid (191mg, 0.339mmol) and triethylamine (0.15mL, 1.1mmol) be dissolved in methylene dichloride (20mL), drip isopropyl chlorocarbonate (42mg, 0.34mmol) under the ice bath, drip and finish, change under the room temperature and reacted three hours, not treated, be directly used in next step.
With oxammonium hydrochloride (47mg, 0.676mmol) and triethylamine (0.1mL, 0.72mmol) be dissolved in methylene dichloride (10mL), the room temperature lower magnetic force stirs half an hour, then reaction solution is joined in the reaction soln in upper step, continue to stir 24 hours under the room temperature successively water, saturated common salt water washing after the dilution of adding 50mL methylene dichloride, 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 (10)
1. the compound shown in the general formula (I), its pharmacy acceptable salt or its steric isomer:
Wherein
X is O or S;
R
1Be hydrogen, or be not substituted or by 1-3 R
9The C that replaces
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 is not for existing, or is not 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 respectively, halogen, cyano group, amino, hydroxyl, alkylsulfonyl ,-SO
2C
1-6Alkyl, or be not substituted or be selected from by 1-3 the C of halogen atom, hydroxyl, carboxyl substituted
1-6Alkyl, C
1-6Alkoxyl group;
R
4Be hydrogen, cyano group, amino, alkylsulfonyl ,-SO
2C
1-6Alkyl, or be not substituted or be selected from the C that halogen atom, hydroxyl, carboxyl substituent replace by 1-3
1-6Alkyl, C
1-6Alkoxyl group;
R
5, R
6Independently be hydrogen respectively, hydroxyl, halogen, amino, or be not substituted or by 1-3 C that is selected from halogen atom, hydroxyl, carboxyl substituent replacement
1-6Alkyl, C
1-6Alkoxyl group;
R
9And R
9' independently be respectively
(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 the C that hydroxyl, halogen, cyano group, trifluoromethyl replace by 1-3
1-6Alkyl, C
1-6Alkoxyl group,
(2) be not substituted or be selected from the C that cyano group, halogen, hydroxyl replace by 1-3
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 that replaces, 6-14 unit aryl, 3-14 unit heterocyclic radical;
R
aAnd R
bBe hydrogen independently respectively, or be not substituted or by 1-3 C that is selected from hydroxyl, halogen, cyano group replacement
1-6Alkyl;
R
c' for not being substituted or being selected from the C that hydroxyl, halogen, cyano group replace by 1-3
1-6Alkyl, C
1-6Alkoxyl group, 3-8 unit saturated mono cycloalkyl, the single heterocyclic radical of 3-8 unit;
M is 0,1 or 2;
N is 0～4;
Y is not for existing-O-,-S-,-SO-,-SO
2-,-NH-,-CONH-or-SO
2NH-;
W is not for being 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) the aryl C of 6-14 unit
1-8Alkylidene group, the aryl C of 6-14 unit
2-8Alkenylene, the aryl C of 6-14 unit
2-8Alkynyl,
(4) the heterocyclic radical C of 3-14 unit
1-8Alkylidene group, the heterocyclic radical C of 3-14 unit
2-8Alkenylene, the heterocyclic radical C of 3-14 unit
2-8Alkynyl,
(5) the cycloalkyl C of 3-8 unit
1-8Alkylidene group, the cycloalkyl C of 3-8 unit
2-8Alkenylene, the cycloalkyl C of 3-8 unit
2-8Alkynyl,
(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
1-8The aryl C of alkylidene group 6-14 unit
1-8Alkylidene group, C
1-8The aryl C of alkylidene group 6-14 unit
2-8Alkenylene, C
1-8The aryl C of alkylidene group 6-14 unit
2-8Alkynyl,
(10) C
2-8The aryl C of alkenylene 6-14 unit
1-8Alkylidene group, C
2-8The aryl C of alkenylene 6-14 unit
2-8Alkenylene, C
2-8The aryl C of alkenylene 6-14 unit
2-8Alkynyl,
(11) C
2-8The aryl C of alkynyl 6-14 unit
1-8Alkylidene group, C
2-8The aryl C of alkynyl 6-14 unit
2-8Alkenylene, C
2-8The aryl C of alkynyl 6-14 unit
2-8Alkynyl,
(12) C
1-8The heterocyclic radical C of alkylidene group 3-14 unit
1-8Alkylidene group, C
1-8The heterocyclic radical C of alkylidene group 3-14 unit
2-8Alkenylene, C
1-8The heterocyclic radical C of alkylidene group 3-14 unit
2-8Alkynyl,
(13) C
2-8The heterocyclic radical C of alkenylene 3-14 unit
1-8Alkylidene group, C
2-8The heterocyclic radical C of alkenylene 3-14 unit
2-8Alkenylene, C
2-8The heterocyclic radical C of alkenylene 3-14 unit
2-8Alkynyl,
(14) C
2-8The heterocyclic radical C of alkynyl 3-14 unit
1-8Alkylidene group, C
2-8The heterocyclic radical C of alkynyl 3-14 unit
2-8Alkenylene, C
2-8The heterocyclic radical C of alkynyl 3-14 unit
2-8Alkynyl,
(15) C
1-8The cycloalkyl C of alkylidene group 3-8 unit
1-8Alkylidene group, C
1-8The cycloalkyl C of alkylidene group 3-8 unit
2-8Alkenylene, C
1-8The cycloalkyl C of alkylidene group 3-8 unit
2-8Alkynyl,
(16) C
2-8The cycloalkyl C of alkenylene 3-8 unit
1-8Alkylidene group, C
2-8The cycloalkyl C of alkenylene 3-8 unit
2-8Alkenylene, C
2-8The cycloalkyl C of alkenylene 3-8 unit
2-8Alkynyl,
(17) C
2-8The cycloalkyl C of alkynyl 3-8 unit
1-8Alkylidene group, C
2-8The cycloalkyl C of alkynyl 3-8 unit
2-8Alkenylene, C
2-8The cycloalkyl C of alkynyl 3-8 unit
2-8Alkynyl,
(18) 3-14 unit heterocyclic radical-aryl C of 6-14 unit
1-8Alkylidene group, the 6-14 unit aryl-heterocyclic radical C of 3-14 unit
1-8Alkylidene group, the 3-14 unit heterocyclic radical-heterocyclic radical C of 3-14 unit
1-8Alkylidene group,
And described C
1-8Alkylidene group, C
2-8Alkenylene, C
2-8Carbon atom in the alkynyl can be by O, S, S (O), SO
2, NR
eOr CO replaces;
R
dBe 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
eBe hydrogen atom, the C that is not substituted or is replaced by 1 Q at least
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
1-6The alkyl amine group formyl radical, two (C
1-6Alkyl) amido formacyl, amino-sulfonyl, C
1-6The alkyl 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.
2. compound as claimed in claim 1, its pharmacy acceptable salt or its steric isomer:
Wherein
X is O;
R
1For not being substituted or by 1-3 R
9The 3-14 unit cycloalkyl that replaces, 6-14 unit aryl, 3-14 unit heterocyclic radical, 7-12 unit volution base, 7-12 unit bridged ring base;
A is not for being substituted or by 1-3 R
9' the 6-14 unit aryl, the 3-14 unit heterocyclic radical that replace;
R
2, R
3Independently be hydrogen respectively, halogen, cyano group, amino, hydroxyl, trifluoromethyl, or trifluoromethoxy;
R
4Be hydrogen, cyano group, or amino;
R
5, R
6Independently be hydrogen respectively, hydroxyl, halogen, amino, or C
1-6Alkyl;
R
9And R
9' independently be respectively
(1) hydroxyl, halogen, amino, cyano group, or-(CH
2)
nC (O) R
c, R
cFor not being substituted or being selected from the C that hydroxyl, halogen, cyano group, trifluoromethyl replace by 1-3
1-6Alkyl, C
1-6Alkoxyl group,
(2) be not substituted or be selected from the C that cyano group, halogen, hydroxyl replace by 1-3
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 that replaces, 6-14 unit aryl, the single heterocyclic radical of 3-8 unit;
R
aAnd R
bBe hydrogen independently respectively, or be not substituted or by 1-3 C that is selected from hydroxyl, halogen, cyano group replacement
1-6Alkyl;
R
c' for not being substituted or being selected from the C that hydroxyl, halogen, cyano group replace by 1-3
1-6Alkyl, C
1-6Alkoxyl group;
M is 1 or 2;
N is 0～4;
Y is not for existing-O-,-S-,-SO
2-,-CONH-or-SO
2NH-;
W is not for being substituted or by R
dReplace
(1) C
1-8Alkylidene group, C
2-8Alkenylene,
(2) 6-10 unit aryl, 3-8 unit heterocyclic radical,
(3) the aryl C of 6-10 unit
1-8Alkylidene group, the aryl C of 6-10 unit
2-8Alkenylene,
(4) the heterocyclic radical C of 3-8 unit
1-8Alkylidene group, the heterocyclic radical C of 3-8 unit
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
1-8The aryl C of alkylidene group 6-10 unit
1-8Alkylidene group, C
1-8The aryl C of alkylidene group 6-10 unit
2-8Alkenylene,
(8) C
2-8The aryl C of alkenylene 6-10 unit
1-8Alkylidene group, C
2-8The aryl C of alkenylene 6-10 unit
2-8Alkenylene,
(9) C
1-8The heterocyclic radical C of alkylidene group 3-8 unit
1-8Alkylidene group, C
1-8The heterocyclic radical C of alkylidene group 3-8 unit
2-8Alkenylene,
(10) C
2-8The heterocyclic radical C of alkenylene 3-8 unit
1-8Alkylidene group, C
2-8The heterocyclic radical C of alkenylene 3-8 unit
2-8Alkenylene,
(11) 3-8 unit heterocyclic radical-aryl C of 6-10 unit
1-8Alkylidene group, the 6-10 unit aryl-heterocyclic radical C of 3-8 unit
1-8Alkylidene group, the 3-8 unit heterocyclic radical-heterocyclic radical C of 3-8 unit
1-8Alkylidene group,
And described C
1-8Alkylidene group, C
2-8Carbon atom in the alkenylene can be by O, S, NR
eOr CO replaces;
R
dBe 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
eBe hydrogen atom, the C that is not substituted or is replaced by 1 Q at least
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
1-4The alkyl amine group formyl radical, two (C
1-4Alkyl) amido formacyl, amino-sulfonyl, C
1-4The alkyl amine group alkylsulfonyl, two (C
1-4Alkyl) amido alkylsulfonyl, C
1-4Alkylsulfonamido, C
1-4Alkyl sulphonyl, C
1-4The alkyl-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.
3. compound as claimed in claim 2, its pharmacy acceptable salt or its steric isomer:
Wherein
X is O;
R
1For not being substituted or by 1-3 R
9The 6-14 unit aryl that replaces, the single heterocyclic radical of 3-8 unit;
A is not for being substituted or by 1-3 R
9' the 6-14 unit aryl, the 5-10 unit heterocyclic radical that replace;
R
2, R
3, R
4Be respectively hydrogen;
R
5, R
6Independently be hydrogen respectively, 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 the C that hydroxyl, halogen, cyano group replace by 1-3
1-4Alkyl, C
1-4Alkoxyl group,
(2) be not substituted or be selected from the C that cyano group, halogen, hydroxyl replace by 1-3
1-4Alkyl, C
1-4Alkoxyl group,
(3) be not substituted or by 1-3 be selected from cyano group, trifluoromethyl, halogen ,-(CH
2)
nC (O) R
c' ,-(CH
2)
nC (O) (CH
2)
nNR
aR
b,-(CH
2)
nS (O)
mR
c' the 5-8 unit saturated mono heterocyclic radical that replaces;
R
aAnd R
bBe hydrogen independently respectively, or be not substituted or by 1-3 C that is selected from hydroxyl, halogen replacement
1-4Alkyl;
R
c' for not being substituted or being selected from the C that hydroxyl, halogen replace by 1-3
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 the C that hydroxyl, halogen, cyano group, trifluoromethyl replace by 1-3
1-4Alkyl, C
1-4Alkoxyl group,
(2) be not substituted or be selected from the C that cyano group, halogen, hydroxyl replace by 1-3
1-4Alkyl, C
1-4Alkoxyl group;
M is 1 or 2;
N is 0～4;
Y is not for existing ,-O-,-S-,-CONH-or-SO
2NH-;
W is not for being substituted or by R
dReplace
(1) C
4-8Alkylidene group,
(2) phenyl, 5-6 unit heterocyclic radical,
(3) phenyl C
1-6Alkylidene group,
(4) the heterocyclic radical C of 5-6 unit
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
2-6The heterocyclic radical C of alkenylene 5-6 unit
1-6Alkylidene group,
(8) 5-6 unit heterocyclic radical-heterocyclic radical C of 5-6 unit
1-6Alkylidene group,
And described C
4-8Alkylidene group, C
1-6Alkylidene group, C
2-6Carbon atom in the alkenylene can be by O, S, NR
eOr CO replaces;
R
dBe hydrogen atom, halogen, hydroxyl, amino, carboxyl, cyano group, C
1-4Alkyl, C
1-4Alkoxyl group or 3-6 unit cycloalkyl;
R
eBe hydrogen atom, the C that is not substituted or is replaced by 1 Q at least
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.
4. compound as claimed in claim 3, its pharmacy acceptable salt or its steric isomer:
Wherein
X is O;
R
1For not being substituted or by 1-3 R
9The 6-10 unit aryl that replaces, 3-8 unit saturated mono heterocyclic radical, the unsaturated single heterocyclic radical of 3-8 unit;
A is not for being substituted or by 1-3 R
9' phenyl, naphthyl, the unsaturated single heterocyclic radical of 5-6 unit, the unsaturated fused heterocycle base of 9-10 unit that replace;
R
2, R
3, R
4Be respectively hydrogen;
R
5, R
6Independently be hydrogen respectively, 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 the C that hydroxyl, halogen, cyano group replace by 1-3
1-4Alkyl, C
1-4Alkoxyl group,
(2) be not substituted or be selected from the C that cyano group, halogen, hydroxyl replace by 1-3
1-4Alkyl, C
1-4Alkoxyl group,
(3) be not substituted or by 1-3 be selected from cyano group, trifluoromethyl, halogen ,-C (O) R
c' ,-C (O) (CH
2)
nNR
aR
b,-S (O)
2R
c' the 5-6 unit saturated mono heterocyclic radical that replaces;
R
aAnd R
bBe hydrogen independently respectively, or be not substituted or by 1-3 C that is selected from hydroxyl, halogen replacement
1-4Alkyl;
R
c' for not being substituted or being selected from the C that hydroxyl, halogen replace by 1-3
1-4Alkyl, C
1-4Alkoxyl group;
R
9' be
(1) hydroxyl, halogen, cyano group, amino,
(2) be not substituted or be selected from the C that cyano group, halogen, hydroxyl replace by 1-3
1-4Alkyl, C
1-4Alkoxyl group;
N is 0～4;
Y is not for existing ,-O-,-S-or-CONH-;
W is not for being 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 the alkylidene group can be by O, S, NR
eOr CO replaces;
R
dBe hydrogen atom, halogen, hydroxyl, amino, carboxyl, cyano group, C
1-4Alkyl or C
1-4Alkoxyl group;
R
eBe hydrogen atom or C
1-4Alkyl;
R
7And R
8Be respectively hydrogen atom, methyl, ethyl or ethanoyl.
5. compound as claimed in claim 4, its pharmacy acceptable salt or its steric isomer:
Wherein
X is O;
R
1For not being substituted or by 1-3 R
9The phenyl that replaces, naphthyl, 5-8 unit saturated mono heterocyclic radical;
A is not for being 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 respectively, or methyl;
R
9For
(1) amino, or-C (O) R
c, R
cBe the C that is not substituted or is replaced by 1-3 hydroxyl
1-4Alkyl,
(2) be not substituted or be selected from the C that cyano group, fluorine replace by 1-3
1-4Alkyl,
(3) be not substituted or by 1-3 be selected from cyano group, trifluoromethyl ,-C (O) R
c' ,-C (O) (CH
2)
nNR
aR
b,-S (O)
2R
c' piperazinyl, the piperidyl that replace;
R
aAnd R
bIndependently be hydrogen respectively, or C
1-4Alkyl;
R
c' be C
1-4Alkyl;
R
9' be
(1) hydroxyl, halogen, amino,
(2) be not substituted or be selected from the C that fluorine, hydroxyl replace by 1-3
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.
6. compound as claimed in claim 5, its pharmacy acceptable salt or its steric isomer:
Wherein
X is O;
R
1For not being substituted or by 1-2 R
9The phenyl, piperidyl, the piperazinyl that replace;
A is not for being 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 respectively, or methyl;
R
9For
(1) amino, or-C (O) R
c, R
cBe the C that is not substituted or is replaced by 1-2 hydroxyl
1-4Alkyl,
(2) be not substituted or be selected from the C that cyano group, fluorine replace by 1-2
1-4Alkyl,
(3) be not substituted or be selected from the piperazinyl that cyano group, trifluoromethyl replace by 1-2;
R
9' be
(1) halogen, amino, C
1-4Alkyl,
(2) be not substituted or be selected from the C that fluorine, hydroxyl replace by 1-2
1-4Alkyl, C
1-4Alkoxyl group;
Y is-O-or-CONH-;
W is hexylidene;
R
7And R
8Be respectively hydrogen atom.
7. compound as claimed in claim 6, its pharmacy acceptable salt or its steric isomer:
Wherein
X is O;
R
1For not being substituted or by 1-2 R
9The phenyl, the piperidyl that replace,
A is not for being 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 respectively, or methyl;
R
9Be methyl, trifluoromethyl, piperazinyl, the C that cyano group replaces
1-4Alkyl, or-C (O) R
c, R
cC for the hydroxyl replacement
1-4Alkyl;
R
9' be amino, methyl or methoxy;
Y is-O-or-CONH-;
W is hexylidene;
R
7And R
8Be respectively hydrogen atom.
8. compound as claimed in claim 7, its pharmacy acceptable salt or its steric isomer, described compound is selected from:
9. the pharmaceutical composition that comprises each described compound of claim 1～8, its pharmacy acceptable salt or its steric isomer and one or more pharmaceutical carriers is characterized in that described pharmaceutical composition is for clinically or pharmaceutically acceptable arbitrary formulation.
10. each described compound of claim 1～8, its pharmacy acceptable salt or its steric isomer are for the preparation of the purposes in the medicine that treats and/or prevents tumour.
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| CN201210120439.9A CN103373997B (en) | 2012-04-21 | 2012-04-21 | Zinc binding group containing pyridonaphthyridine inhibitor for HDAC (Histone Deacetylase) and mTOR (Mammalian Target of Rapamycin) |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2719697A1 (en) * | 2011-06-04 | 2014-04-16 | Xuanzhu Pharma Co., Ltd. | Pyridonaphthyridine pi3k/mtor dual inhibitors and preparation and use thereof |
| US9745253B2 (en) | 2015-03-13 | 2017-08-29 | Forma Therapeutics, Inc. | Alpha-cinnamide compounds and compositions as HDAC8 inhibitors |
| US10988472B2 (en) | 2016-10-13 | 2021-04-27 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Compounds and method for blocking transmission of malarial parasite |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1747953A (en) * | 2002-12-20 | 2006-03-15 | 3M创新有限公司 | Aryl / hetaryl substituted imidazoquinolines. |
| WO2009125809A1 (en) * | 2008-04-11 | 2009-10-15 | 第一三共株式会社 | Piperidine derivatives |
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2012
- 2012-04-21 CN CN201210120439.9A patent/CN103373997B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1747953A (en) * | 2002-12-20 | 2006-03-15 | 3M创新有限公司 | Aryl / hetaryl substituted imidazoquinolines. |
| WO2009125809A1 (en) * | 2008-04-11 | 2009-10-15 | 第一三共株式会社 | Piperidine derivatives |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2719697A1 (en) * | 2011-06-04 | 2014-04-16 | Xuanzhu Pharma Co., Ltd. | Pyridonaphthyridine pi3k/mtor dual inhibitors and preparation and use thereof |
| JP2014518887A (en) * | 2011-06-04 | 2014-08-07 | シュアンジュ・ファーマ・カンパニー・リミテッド | Pyridonaphthyridine-type PI3K and mTOR dual inhibitors and their preparation and use |
| EP2719697A4 (en) * | 2011-06-04 | 2014-10-29 | Xuanzhu Pharma Co Ltd | Pyridonaphthyridine pi3k/mtor dual inhibitors and preparation and use thereof |
| US9475812B2 (en) | 2011-06-04 | 2016-10-25 | Xuanzhu Pharma Co., Ltd. | Pyridonaphthyridine type dual PI3K and mTOR inhibitor and its preparation and use |
| US9745253B2 (en) | 2015-03-13 | 2017-08-29 | Forma Therapeutics, Inc. | Alpha-cinnamide compounds and compositions as HDAC8 inhibitors |
| US10266487B2 (en) | 2015-03-13 | 2019-04-23 | Forma Therapeutics, Inc. | Alpha-cinnamide compounds and compositions as HDAC8 inhibitors |
| US10508077B2 (en) | 2015-03-13 | 2019-12-17 | Forma Therapeutics, Inc. | Alpha-cinnamide compounds and compositions as HDAC8 inhibitors |
| US10988441B2 (en) | 2015-03-13 | 2021-04-27 | Valo Early Discovery, Inc. | Alpha-cinnamide compounds and compositions as HDAC8 inhibitors |
| US11919839B2 (en) | 2015-03-13 | 2024-03-05 | Valo Health, Inc. | Alpha-cinnamide compounds and compositions as HDAC8 inhibitors |
| US10988472B2 (en) | 2016-10-13 | 2021-04-27 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Compounds and method for blocking transmission of malarial parasite |
| US11753408B2 (en) | 2016-10-13 | 2023-09-12 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Compounds and method for blocking transmission of malarial parasite |
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| Publication number | Publication date |
|---|---|
| CN103373997B (en) | 2015-07-15 |
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